TUBERCULOSIS

IN INFANCY
AND CHILDHOOD
4th edition
2016

Philippine Pediatric Society, Inc.

Committee on Handbook on
Childhood Tuberculosis
 DISCLAIMER
The recommendations contained in the document of the PHILIPPINE
PEDIATRIC SOCIETY, INC. COMMITTEE ON TB HANDBOOK IN CHIL-
DREN are intended to GUIDE practitioners in detection and management of
pediatric patients with tuberculosis. In no way should the recommendations
be regarded as absolute rules, since nuances and peculiarities in individual
cases or particular communities may entail differences in the specific ap-
proach. In the end, the recommendations should supplement, and NOT re-
place, sound clinical judgment made on a case-to-case basis.

ii
PHILIPPINE PEDIATRIC SOCIETY, INC.

TUBERCULOSIS
IN INFANCY
AND CHILDHOOD
4th edition 2016

COMMITTEE ON HANDBOOK
ON CHILDHOOD TUBERCULOSIS

iii
 MESSAGE FROM THE PRESIDENT OF THE
PHILIPPINE PEDIATRIC SOCIETY

I would like to congratulate the contributors and editors of the Handbook on Tu-
berculosis in Infancy and Childhood, ably led by Dr. Cleotilde How, Chair of the
PPS Committee on TB Handbook. After almost two years of painstaking and
diligent work, the 4th edition of Tuberculosis in Infancy and Childhood has come
to fruition. This edition continues a line of excellent TB handbooks designed to
equip pediatricians and health practitioners dedicated to the study and manage-
ment of childhood and infant tuberculosis with up to date clinical information and
current approaches to prevention, detection, diagnosis, and treatment.

Tuberculosis remains to be an important multidimensional problem across all

ages. While as pediatricians we seek to apply the best possible medical solu-
tions, we also can exert a positive influence on the other aspects of TB detec-
tion and control. This handbook is a very useful information resource; it is imper-
ative that we translate this knowledge into action.

iv
 MESSAGE FROM THE PAST PRESIDENT OF THE
PHILIPPINE PEDIATRIC SOCIETY

The 4th edition of the TB Handbook is an exceptional source of information on

Tuberculosis in Children for the practicing Pediatricians, Pediatric residents-in-
training and students of Pediatric Medicine. It is the collaborative work of the
members of the PPS Committee on TB Handbook with the Pediatric Infectious
Diseases Society of the Philippines [PIDSP] and the Philippine Academy of Pe-
diatric Pulmonologists, Inc. [PAPP].

The Committee on the TB Handbook on the recent and current evidence-based

information, advice from the experts in infectious diseases and in pediatric pul-
monary medicine, the WHO Guidelines on TB in Children and other relevant
sources of clinical information on TB.

The chapters of the TB Handbook will walk us through the Epidemiology local
and international data, the clinical presentations of the disease, its diagnosis
and the treatment the TB disease.

Most important to the success of this 4th edition is the dedication and hard work
of the committee members and the team leader Dr Telly How, whose commit-
ment to excellence is unparalleled; your committee members got the right mix of
dedication and enthusiasm.

The Philippine Pediatric Society congratulates the committee and indeed grate-
ful to you all for a job well done!

Mabuhay!

Milagros S. Bautista, MD
Immediate Past President
Philippine Pediatric Society, Inc.

v
 FOREWORD
The 4th edition of Tuberculosis in Infancy and Childhood has a history that dates back
to its first publication in 1993, to serve as a supplement of the already established PPS
Handbook on Infectious Diseases, marking its 25th year then. The idea for that maiden
issue came about during the First National Consensus in Tuberculosis in 1989 by the
Tri-Chest organizations. That 1st edition was preceded in 1975 by the Manual on Tuber-
culosis in Filipino Children by Dr Mita Pardo de Tavera, whose work in AKAP (Alay
Kapwa Kilusang Pangkalusugan) exemplified what community-based TB control can
do.

Numerous contributors to succeeding editions worked to provide the essential tools of

the time for management of TB. The 2nd edition in 2003 incorporated the 1997 National
Consensus on Childhood Tuberculosis while the 3rd edition in 2010 incorporated State-
ments from the Evidence-based Clinical Practice Guidelines Childhood Tuberculosis
published in 2008. Although bearing the same name, this piece has doubled in size and
content from the first ―handbook‖.

Several key publications coming out in 2014 provided the impetus for this new edition
of TBIC and to consult local guidelines for agreement in best practices. Among these
are the WHO Guidance for national tuberculosis programmes on the management of
tuberculosis in children (Second edition) , the International Standards for Tuberculosis
Care (ISTC, 3rd edition), the Department of Health National Tuberculosis Control Pro-
gram (DOH-NTP) Manual of Procedures (MOP, 5th edition) and an earlier WHO Rapid
advice: treatment of tuberculosis in children in 2010/2011. The Universal Health Care
policy of the government and the new TB Law present a challenge for the multidiscipli-
nary health sector that leads the effort for TB prevention and control.

The issue over what age range constitutes a ―child‖ or an ―adolescent‖ needs mention
here as it follows operational lines in TB control. Although the WHO definition of a
―child‖ general falls under the age of 19 years, in the WHO Guidance a ―child‖ refers to
the 0-10 age group. A child over 10 years is expected to expectorate for sputum smear
and culture. Further, the approach to management of TB in adolescents has followed
the standards set in the care of adults. The Manual of Procedures sets the age of 15 as
the cut-off in application of diagnostic criteria. The early teens falls somewhere in the
middle of the overlap. In computing for dose requirements of anti-TB drugs, it is not the
age but the weight of 25 kg that arbitrarily divides the child from the adult.

Changes from Previous Edition and the Way Forward

All chapters underwent revisions in form and content with new information and guide-
lines. Noteworthy in the milestones are the signing of the new TB Law, reproduced in
the Appendix section. A recent development in the field of TB microbiology is the char-
acterization of M. tuberculosis diversity that has spurred molecular epidemiology. A
new approach to diagnosis in children is presented in a revised algorithm in the DOH/
NTP Manual of Operations. With more data on the Xpert MDR/RIF, bacteriologic confir-
mation particularly in children in both pulmonary and extrapumonary TB is now aided
vi
with the wider application and use of this landmark test, referred to as a ―game-
changer‖. More specific antigens have also presented more sensitive and more spe-
cific tests in the crop of new TB diagnostics. However there seems to be a lag in their
development and utilization at point-of-care, even of the Xpert MDR/RIF, as strongly
expressed in the 2016 Pipeline Report. This poses a challenge to practitioners and
health administrators. Conversely, the lag similarly challenges clinicians and health-
workers to adopt the refined symptom screening instead, to supplement the current
gap in diagnostics.

At the doorstep are some marketed molecular/NAAT tests like FluoroType MTB, the
GeneChip, LiPA Z (line probe assay for PZA resistance), many more LPAs,
PureLamp (manual NAAT), MBio Array System (measures 57 MTN ag-ab reactions)
and CAD 4TB (digital CXR for TB screening). While new data are still forthcoming,
WHO still does not recommend LPAs on smear-negative samples. Candidate bi-
omarkers like LAM (lipoarabinomannan), CRP (C-reactive proteins), TAM-TB (T-cell
activation marker-tuberculosis), RNA and gene expression signatures are being ex-
plored to detect active TB and be able to differentiate active TB from latent infection.
Quality of tests and affordability still have to come hand-in-hand, particularly in high-
burden low-resource countries.

A long time coming is the development and arrival of the new fixed-dose-
combinations (HRZ, HR ) as child-friendly dispersible tablets; a single dispersible
ethambutol as fourth drug in the intensive phase and a single dispersible isoniazid for
IPT. Ongoing Phase 3 clinical trials in children for second-line drugs (bedaquiline and
delamanid) are expected to be completed to join the race to combat MDR-TB. Not
only is there a push for early clinical trials in children (and pregnant/lactating women),
there is equally a surge for repurposed drugs (eg, clofazimine, PAS) to supplement
the dearth of anti-TB drugs.

A new chapter on Adjunctive Therapy includes the role of corticosteroids, surgery and
nutrition. The search for new vaccines has not yielded a likely candidate. The direc-
tion of vaccine research is not the search for a replacement for BCG, given the short-
fall in vaccine trials. There is a change in perspective, taking a closer look at the
mechanism of immunity, which has traditionally centered on cell-mediated immunity,
but looking elsewhere for new targets to measure the effects of new candidate vac-
cines. An abbreviated International Classification of Diseases (ICD-10): Tuberculosis
is reproduced on Appendix 3 to supplement use of this system in hospital audits.

The chapter on prevention and control reemphasizes the value of contact investiga-
tion, active case-finding and isoniazid preventive therapy (IPT). Transmission reduc-
tion (eg, cough etiquette) and simple hygiene are not as technology-bound but essen-
tial for the business of infection control. Success relies more on implementation, re-
cording and reporting, quite a culture shock for the busy private practitioner. To deal
with TB, even he/she has to transform into a public health practitioner and join the
team. Integration is key at all levels: search-and-control TB operations means going
to both pediatric and adult clinics, in Maternal and Child Health units, in IMCI and EPI

vii
clinics, Well-Child/Sick-Child units, that is, everywhere you find children and adults who
are at risk for TB. TB and HIV, TB and diabetes, TB and smoking, other co-morbidities
that matter. Integration also involves partnerships with common advocacies – in com-
munication, education, livelihood, nutrition, shelter, cleanwater.

Acknowledgments
The Board of Trustees led by Dr Mila S Bautista wholeheartedly supported this project
from the time it was conceived in late 2014 until the change of hands under the leader-
ship of Dr Alexander O Tuazon, when the manuscript was launched in the 2016 annual
convention.

The members of the panel of editors (How CH, Paje-Villar EB, Carlos JC, Ong-Lim AL)
have worked hard in deliberating on the manuscripts with the able assistance of Dr Sa-
rah Makalinaw. Dr Paje-Villar, who was editor of the first edition, has kept her constant
presence and scrutiny up to this latest work. The set of contributors per chapter have
similarly met the challenge of bringing the data and information up to par, with constant
revisions and verification of sources. The group is extremely grateful to Ms Thess Victo-
ria and staff from PPS and PIDSP for arranging meetings and venues, keeping track of
members, providing materials needed and coordination work.

Our respective families, for the chunks of time spent away from them; they will be re-
lieved, until the next work comes along. We thank them in the words of Francis Fukuya-
ma ―simply by being there‖.

For The Editorial Panel and Committee Members/Contributors:

Cleotilde Hidalgo How, MD, FPPS, FPSECP

Chair, PPS Committee on TB Handbook

viii
 PHILIPPINE PEDIATRIC SOCIETY, INC.
BOARD OF TRUSTEES 2014-2016 BOARD OF TRUSTEES 2016-2018

Officers Officers
MILAGROS S BAUTISTA, MD ALEXANDER O TUAZON, MD
President President

ALEXANDER O TUAZON, MD SALVACION R GATCHALIAN, MD

Vice President Vice President

SALVACION R GATCHALIAN, MD JOSELYN A EUSEBIO, MD

Secretary Secretary

EDWIN V RODRIGUEZ, MD ANNA LISA T ONG-LIM, MD

Assistant Secretary Assistant Secretary

JOSELYN A EUSEBIO, MD FLORENTINA U TY, MD

Treasurer Treasurer

JOSE B SALAZAR, MD JOSEFINO A. REGALADO, MD

Assistant Treasurer Assistant Treasurer

MELINDA M ATIENZA, MD MILAGROS S BAUTISTA, MD

Immediate Past President Immediate Past President

Members Members
CYNTHIA P DANIEL, MD FRANCIS XAVIER M DIMALANTA,
RHODORA D DIAZ, MD MD
BENJAMIN T LIM, MD BENJAMIN T LIM, MD
RENIE M MAGUINSAY, MD CESAR M ONG, MD
MAY B MONTELLANO, MD WINSTON FELIX J. QUEBEC, MD
CESAR M ONG, MD WILFREDO R SANTOS, MD
FLORENTINA U TY, MD NELLY S SIMON, MD ALFREDO A.
YAP, MD

ix
COMMITTEE ON TB HANDBOOK IN CHILDREN

Chair Cleotilde H How, MD

Co-Chair Clara R Rivera, MD

Members: Josephine Aldaba, MD

Ma. Cecilia G Ama, MD
Myra R Asuncion-Son, MD
Ma. Lorela S Averilla, MD
Maria Anna P Bañez, MD
Gyneth Lourdes G Bibera, MD
Mary Ann C Bunyi, MD
Cristan Q Cabanilla, MD
Maria Rosario Z Capeding, MD
Josefina C Carlos, MD
Luis T Chan, Jr MD
Michelle C Cuvin, MD
Anjanette De Leon, MD
Maria Nerissa T De Leon, MD
Cynthia Cecilia J De Ocampo, MD
Carmina A Delos Reyes, MD
Eva L Dizon, MD
Ana Liza H Duran, MD
Arlene Dy-Co, MD
Heidilita Espinoza, MD
Fatima I Gimenez, MD
Grace Devota G Go, MD
Ma. Liza Antoinette M Gonzales, MD
Gracia Perpetua M Lagarejos, MD
Lily L Lao, MD
Anna Lisa O Lim, MD
Imelda A Luna, MD
Mary Antonette C Madrid, MD
Cecilia Nelia C Maramba-Lazarte, MD
Mary Antonette C Madrid, MD
Maricar Paguia, MD
Estrella B Paje Villar, MD
Ma. Theresa T Policarpio, MD
Jaime A Santos, MD
Belen Amparo M Velasco, MD

x
 LIST OF EDITORS AND CONTRIBUTORS

EDITORS
CLEOTILDE H HOW, MD, FPPS, FPSECP
Retired Professor of Pharmacology and Clinical Pediatrics, UP College of Medicine

ESTRELLA B PAJE-VILLAR, MD, DTM&H, FPPS, FPIDSP, FPSECP

Retired Professor, Department of Pediatrics, Faculty of Medicine and Surgery
Consultant, Pediatric Infectious Diseases, University of Sto. Tomas Hospital and Philippine Chil-
dren‘s Medical Center

JOSEFINA C CARLOS, MD, DTM&H, FPPS, FPIDSP, FPSMID

Professor of Pediatrics, College of Medicine, University of the East–Ramon Magsaysay Memori-
al Medical Center, Inc.
Consultant, Pediatric Infectious Diseases: University of the East – Ramon Magsaysay Memorial
Medical Center, Inc., Rizal Medical Center, Our Lady of Lourdes Hospital, Philippine Heart
Center

ANNA LISA T ONG-LIM, MD, FPPS, FPIDSP

Associate Professor, Department of Pediatrics, College of Medicine - Philippine General Hospi-
tal, University of the Philippines Manila
Section Chief, Section of Infectious and Tropical Disease, Department of Pediatrics, College of
Medicine - Philippine General Hospital, University of the Philippines Manila

xi
CONTRIBUTORS
MYRA R ASUNCION-SON, MD, DPPS, DPAPP
Consultant, St. Luke's Medical Center Global City, Parañaque Doctors Hospital

MARIA ANNA P BAŇEZ, MD, FPPS, FPIDSP

Assistant Professor A, FEU-NRMF Institute of Medicine
Medical Specialist III, Philippine Children‘s Medical Center and Jose R. Reyes Memorial Medical
Center
Consultant, Quezon City General Hospital

GYNETH LOURDES D BIBERA, MD, FPPS, FPIDSP

Consultant, University of the East-Ramon Magsaysay Memorial Medical Center

MARY ANN C BUNYI, MD, FPPS, FPIDSP

Faculty, Department of Microbiology and Parasitology, College of Medicine, Pamantasan ng
Lungsod ng Maynila
Head, Office of Professional Education and Training, Philippine Children‘s Medical Center
Secretary, Pediatric Infectious Disease Society of the Philippines
Consultant, Philippine Children‘s Medical Center

CRISTAN Q CABANILLA, MD, FPPS, FPAPP

Consultant, Section of Pulmonology, Philippine Children's Medical Center

MARIA ROSARIO Z CAPEDING, MD

Head, Department of Microbiology, Research Institute for Tropical Medicine
Member, Asian Expert Bureau on Pediatric Vaccines and Asian Advisory Board on Vaccines

JOSEFINA C CARLOS, MD, DTM&H, FPPS, FPIDSP, FPSMID

Professor of Pediatrics, College of Medicine, University of the East–Ramon Magsaysay Memori-
al Medical Center, Inc.
Consultant, Pediatric Infectious Diseases: University of the East – Ramon Magsaysay Memorial
Medical Center, Inc., Rizal Medical Center, Our Lady of Lourdes Hospital, Philippine Heart
Center

LUIS T CHAN, JR, MD, FPPS

Associate Member, Pediatric Infectious Disease Society of the Philippines
Consultant, Fe del Mundo Medical Center and De Los Santos Medical Center

MICHELLE C CUVIN, MD, DPPS, DPIDSP

Consultant, East Avenue Medical Center, Ospital ng Makati, St. Frances Cabrini Medical Center,
Victor R Potenciano Memorial Medical Center

ANJANETTE DE LEON, MD, FPPS, FPAPP, FPSCCM, MBA-H

Medical Specialist IV, Lung Center of the Philippines
Training Officer, Mandaluyong City Medical Center
Consultant, Our Lady of Lourdes Hospital, Victor R. Potenciano Memorial Medical Center, Anti-
polo Doctors Hospital, Philippine Heart Center

MARIA NERISSA A DE LEON, MD, MM, FPPS, FPAPP, FPSCCM, FPCCP

Consultant: East Avenue Medical Center, Philippine Heart Center, Dr. Jesus Delgado Memorial
xii
 Hospital

CYNTHIA CECILIA J DE OCAMPO, MD, DPPS, DPIDSP

Consultant, De Los Santos Medical Center, Our Lady of Lourdes Hospital, Philippine Chil-
dren‘s Medical Center
CARMINA A DELOS REYES, MD, FPPS, FPIDSP
Clinical Associate Professor of Pediatrics, University of the Philippines– College of Medicine
Training Officer, Section of Infectious and Tropical Diseases in Pediatrics (INTROP), Philip-
pine General Hospital

ANA LIZA H DURAN, MD, FPPS, Ll.B., MMHoA

Consultant, East Avenue Medical Center
Pediatric National TB Program Coordinator, East Avenue Medical Center

HEIDILITA ESPINOZA, MD, FPPS, FPAPP

Assistant Chair, Jesus Delgado Memorial Hospital
Consultant, Marikina Valley Medical Center, Cornell Medical Center, Capitol Medical Center

FATIMA I GIMENEZ, MD, FPPS, FPIDSP

Adjunct Faculty, Ateneo de Manila School of Medicine and Public Health
Consultant, Philippine Children‘s Medical Center, Victor R. Potenciano Medical Center

GRACE DEVOTA G GO, MD, FPPS, FPIDSP

Chairman, Department of Pediatrics, Mary Chiles General Hospital
Consultant, De Los Santos Medical Center, Sta Ana Hospital

MARIA LIZA ANTOINETTE M GONZALES, MD, MSc CE, FPPS, FPIDSP

President, Pediatric Infectious Disease Society of the Philippines
Associate Professor of Pediatrics, University of the Philippines– College of Medicine
Assistant Chair for Research, Department of Pediatrics, Philippine General Hospital

CLEOTILDE H HOW, MD, FPPS, FPSECP

Retired Professor of Pharmacology and Clinical Pediatrics, UP College of Medicine

MARY ANTONETTE C MADRID, MD, FPPS, FPIDSP

Assistant Professor, Department of Microbiology and Parasitology, College of Medicine, Pa-
mantasan ng Lungsod ng Maynila
Consultant, Philippine Children‘s Medical Center

ANNA LISA T ONG-LIM, MD, FPPS, FPIDSP

Associate Professor, University of the Philippines– College of Medicine
Section Chief, Section of Infectious and Tropical Diseases in Pediatrics
(INTROP), Department of Pediatrics, Philippine General Hospital

MARICAR PAGUIA, MD, FPCR

Active Consultant, St. Luke‘s Medical Center
Secretary, Residency Training council, Philippine College of Radiology

ESTRELLA B PAJE-VILLAR, MD, DTM&H, FPPS, FPIDSP, FPSECP

Retired Professor, Department of Pediatrics, Faculty of Medicine and Surgery
Consultant, Pediatric Infectious Diseases, University of Sto. Tomas Hospital and Philippine

xiii
 Children‘s Medical Center

MARIA THERESA T POLICARPIO, MD, FPPS, FPAPP, FPSCCM

Masters in Management Major in Hospital Administration
Head, Pediatric Bronchoscopy Section, Lung Center of the Philippines
Member, Institutional Ethics Review Board, Lung Center of the Philippines
Professor, FEU-NRMF
Chair, Research Committee, Department of Pediatrics, East Avenue Medical Center
Chair, Customer Satisfaction, Quality Management System, East Avenue Medical Center

CLARA R RIVERA, MD, FPPS, FPAPP

Professor, UST Faculty of Medicine and Surgery
Chair, UST Hospital Department of Pediatrics
Past President, Philippine Academy of Pediatric Pulmonologists, Inc.

JAIME A SANTOS, MD, FPPS, FPIDSP

Head, Section of Pediatric Infectious Disease, Philippine Children‘s Medical Center
Professor and Chair of Microbiology, Our Lady of Fatima University College of Medicine

xiv
 GLOSSARY: DEFINITIONS
Acquired Resistance – refers to the bacterial resistance in patients with some record of previ-
ous treatment

Asymptomatic or Latent tuberculosis infection – infection associated with tuberculin hyper-

sensitivity and a positive tuberculin test with no striking clinical or roentgenographic manifesta-
tions

BCG – stands for Bacillus Calmette-Guerin, is an attenuated vaccine strain of M. bovis used to
immunize against tuberculosis

Directly observed therapy (DOT) – an intervention by which medication is administered direct-

ly to the patient by a health care professional or trained third party (not a relative or a friend),
who observes and documents that the patient ingests each dose of medication

Drug-resistant Tuberculosis – tuberculosis, usually pulmonary, excreting bacilli resistant to

one or more antituberculosis drugs

Exposed person – a person who has had recent contact with another person with suspected or
confirmed contagious pulmonary tuberculosis disease and who has a negative tuberculin (or
IGRA) reaction, normal physical examination findings, and chest radiographic findings that are
not compatible with tuberculosis

Extensively drug-resistant tuberculosis (XDR-TB) – a subset of MDR-TB with a strain of My-

cobacterium tuberculosis complex that is resistant to isoniazid and rifampicin, any quinolone,
and at least one of three second-line injectable drugs: kanamycin, capreomycin, or amikacin

Ghon focus – the initial lung lesion of primary TB

Incubation period – time interval from exposure to the mycobacterium to the development of
delayed type hypersensitivity reaction as manifested by a positive TST (or IGRA)

Latent Tuberculosis Infection (LTBI) – Mycobacterium tuberculosis complex infection in a per-

son who has a positive TST (or IGRA) result, with no physical findings of disease and chest radi-
ograph findings that are normal

Mantoux test – a skin test for tuberculosis infection, using tuberculin PPD (purified protein de-
rivative) administered intradermally/intracutaneously at a specified tamount and positive result
read as induration between 48 to 72 hours of injection

Miliary TB – a form of generalized hematogenous TB due to a massive invasion of the blood-

stream by the tubercle bacilli seeding in various sites

Monoresistance – resistance to one antituberculous drug

Multidrug-resistance (MDR) – resistance to at least isoniazid and rifampicin

Mycobacterium tuberculosis – the bacterium that causes tuberculosis

Poly-resistance – resistance to more than one antituberculosis drug, other than isoniazid and

xv
rifampicin

Pott’s disease – TB of the spine

Primary complex – composed of the primary focus, lymphangitis, localized pleural effusion and
regional lymphadenitis, demonstrable by radiographic study

Primary resistance – bacterial resistance present in patients who have not received prior treat-
ment with antituberculosis drugs

Subcentimeter – size less than one centimeter in greatest diameter

Scrofuloderma – TB of the skin overlying a caseous lymph node that has ruptured to the out-
side, leaving an ulcer or a sinus

Source case – the person, usually with pulmonary TB, who has transmitted infection with Myco-
bacterium tuberculosis

Tuberculin – a protein extracted from Mycobacterium tuberculosis that is used in a skin test to
determine if a person has been exposed to tuberculosis and infected with the tuberculoprotein
from the organism

Tuberculin Skin Testing (TST) – a diagnostic test to determine the presence of delayed-type
hypersensitivity reaction to tuberculoproteins, either from natural infection with the organism or
in reaction to the mycobacterium antigen in BCG. A positive reaction will manifest as an indura-
tion; cut-off size determined by conditions set

Tuberculosis – a highly contagious infection and disease caused by exposure to the virulent
bacterium Mycobacterium tuberculosis, progressing from infection to disease, when signs and
symptoms become manifest, either from pulmonary or extrapulmonary involvement

xvi
 GLOSSARY: ABBREVIATIONS
AFB acid-fast bacilli FM fluorescence microscopy

ART anti-retroviral therapy GI growth index

ARTI annual risk of TB infection H, INH isoniazid

AST aminotransferase HBHA heparin-binding hemagglutinin

ATS American Thoracic Society HIV human immunodeficiency virus

BCG Bacillus Calmette-Guerin HLA histocompatibility leukocyte

antigen
CO2 carbon dioxide
IL-6 interleukin-6
CDC Centers for Disease Control
and Prevention IL-12 interleukin-12

CDR case detection rate IFN-γ interferon gamma

CMI cell-mediated immunity IGRA interferon gamma release as

say
CT computerized tomography
IUATLD International Union Against
DOH-NTP Department of Health-National Tuberculosis and Lung Dis
Tuberculosis Program ease

DOT directly observed therapy/ LAM Lipoarabinomannan

treatment
LGUs Local Government Units
DOTS directly observed therapy short
-course LJ Lowenstein-Jensen (medium)

DOTCh directly observed therapy in LTBI Latent Tuberculosis Infection

children
MDG Millennium Development Goal
DR drug-resistant
MDR Multidrug-Resistance (resistant
DRS drug resistance and suscepti to at least HR)
bility
MRI magnetic resonance imaging
DTH delayed-type hypersensitivity
MGIT Mycobacteria Growth Indicator
E ethambutol Tube

ELISA enzyme-linked immunosorbent MMR Measles-Mumps-Rubella

assay
MOTT Mycobacteria other than TB
ELISPOT enzyme-linked immunospot
assay MTB Mycobacterium tuberculosis

xvii
 GLOSSARY: ABBREVIATIONS
MTBC Mycobacterium tuberculosis PTB pulmonary tuberculosis
complex
R rifampicin
MPT multiple puncture test
RFLP Restriction fragment length
NAAT nucleic acid amplification test polymorphism

NK natural killer S streptomycin

NO nitric oxide TB tuberculosis

NGO non-government organization TGF-β transforming growth factor –

beta
NPV negative predictive value
TNF-α tumor necrosis factor – alpha
Nramp natural resistance associated
macrophage protein TST tuberculin skin test

NTP/NTBP National Tuberculosis Pro TU tuberculin units

gram
WHO World Health Organization
NTM non-tuberculous mycobacteria
XDR extensively drug-resistant
NTPS Nationwide Tuberculosis Prev
alence Survey Z, PZA pyrazinamide

OPV oral polio vaccine ZN Ziehl-Neelsen

PAS para-aminosalicylic acid

PCR polymerase chain reaction

PhilCAT Philippine Coalition Against

Tuberculosis

PIDSP Pediatric Infectious Disease

Society of the Philippines

PPD Purified Protein Derivative

PPM Public-Private Mix

PPS Philippine Pediatric Society

PPV Positive Predictive Value

PSMID Philippine Society of Microbiol

ogy and Infectious Diseases

xviii
 TABLE OF CONTENTS
Message 1 iv

Message 2 v

Foreword vi

Incoming and Outgoing PPS BOT ix

Committee on TB Handbook in Children x

List of Editors and Contributors xi

Glossary xv

Abbreviations xvii

Table of Contents

Chapter 1 Highlights 1
Estrella Paje-Villar, MD, Josefina Carlos, MD,
Ana Liza Duran, MD

Chapter 2 Epidemiology 9
Luis Chan Jr., MD, Ana Liza Duran, MD

Chapter 3 Microbiology 19
Jaime Santos,MD, Mary Antonette Madrid,MD

Chapter 4 Immune Responses 30

Jaime Santos,MD, Mary Antonette Madrid,MD

Chapter 5 Pathogenesis 39
Maria Anna Banez, MD, Cynthia De Ocampo,MD

Chapter 6 Clinical Forms 48

Gyneth Lourdes Bibera, MD, Mary Ann Bunyi,MD,
Michelle Cuvin, MD, Fatima Gimenez, MD

Chapter 7 Diagnosis 69
Cleotilde How,MD

xix
Chapter 8 Tuberculin Skin Test 83
Luis Chan Jr.,MD, Cleotilde How,MD

Chapter 9 Radiologic Findings 97

Myra Asuncion-Son, MD, Maricar Paguia,MD,

Chapter 10 Diagnostic Tests / Laboratory Findings 114

Ma. Liza Antoinette Gonzales,MD,
Maria Rosario Capeding,MD, Carmina Delos Reyes,MD

Chapter 11 Management 137

Anna Lisa Ong-Lim, MD

Chapter 12 Drug-Resistant Tuberculosis 153

Anjanette de Leon, MD, Heidilita Espinoza, MD

Chapter 13 Tuberculosis in Special Situations 164

Clara Rivera MD, Maria Theresa Policarpio, MD,
Grace Devota Go, MD

Chapter 14 Adjunctive Management 205

Cleotilde How MD, Cristan Cabanilla, MD,
Maria Nerissa de Leon, MD, Anna Lisa Ong-Lim, MD

Chapter 15 Prevention and Control 216

Josefina C Carlos MD, Luis Chan Jr.,MD
Ana Liza Duran, MD

Appendix 1A Diagnostic Algorithm 237

Appendix 1B Screening of Pediatric Drug-Susceptible Household 238

Contacts of TB

Appendix 2 BCG 239

Appendix 3 International Classification of Disease 242

Appendix 4 RA 10767 244

xx
I

1
Highlights
Estrella B Paje-Villar, MD
Josefina C Carlos, MD
Ana Liza H Duran, MD
1910 Founding of the Philippine Islands Anti-Tuberculosis Society now known
as the Philippine Tuberculosis Society Inc (PTSI), a private agency with
government subsidy

TB Mortality rate was 487/100,000 population

1930 Creation of the Tuberculosis Commission by virtue of Republic Act (RA)

3743 under the Philippine Health Service (Ministry of Health), now De-
partment of Health (DOH)

1933 Transfer of the TB Commission‘s powers and functions to the Ministry of

Health

Establishment of Philippine Charity Sweepstakes Office (PCSO) to fund

the PTSI through the Philippine Charity Sweepstakes Law (RA 4130)

1949 A ―miracle drug‖, streptomycin (S), was first used for TB treatment

1950 Creation of the Division of Tuberculosis under the Secretary of

Health

Establishment of TB Center at DOH compound in collaboration with San

Lazaro Hospital TB Ward

Addition of para - aminosalicylic acid (PAS) to the TB regimen with

S

1951 Introduction of BCG vaccination program with assistance from

UNICEF

1954 Enactment of Tuberculosis Law (RA 1136)

Use of triple anti-TB therapy consisting of isoniazid (H), PAS & S

1958 Establishment of the Bureau of Disease Control which included the Divi-
sion of TB by virtue of Executive Order no. 288

1964 Conduct of the Minglanilla Prevalence Survey, the first TB prevalence

survey carried out in the province of Cebu, which showed the prevalence
of smear positive at 4/1,000 population

1968 Implementation of the TB Control Program in all rural health units

(RHUs) under RA 1086

Use of sputum microscopy as a diagnostic tool for TB

2
1973 Launching of the Domiciliary Care Program

Formation of the Philippine College of Chest Physicians (PCCP) as an

accredited non-government organization (NGO) society of the Philippine
Medical Association (PMA)

1974 Offering of the Anti – TB treatment using H, S and Ethambutol (E) for 18
months

1975 Publication of Tuberculosis in Filipino Children by Dr. Mita Pardo de

Tavera

1976 Establishment of the National Institute of Tuberculosis (NIT) in coopera-

tion with the WHO and UNICEF

Rifampicin (R) became available in the Philippines

Implementation of the compulsory BCG vaccination in the Philippines

1978 Nation-wide implementation of the National TB Control Program

(NTBP)

1980 Publication of the First National TB Program Manual of Procedures,

which highlighted the use of sputum microscopy as the primary diagnos
tic tool for TB and the introduction of the standard drug regimen for TB
treatment.

1981-1983 Conduct of the First National TB Prevalence Survey by the National In-
stitute for Tuberculosis (NIT)

Establishment of the Lung Center of the Philippines (LCP)

1984 Tuberculosis all forms as the 3rd leading cause of mortality 52.6/100,000
population (Philippine Health Statistics)

1986 Creation of the TB Control Service with EO no. 119, under the Office of
Public Health Services (Ministry of Health which became the Department
of Health)

Launching of Short-Course Chemotherapy (SCC) which highlighted the

use of rifampicin for sputum-positive and cavitary cases by chest x-ray

S or E was used in the intensive regimen at Quezon Institute (QI)

1987 Nationwide implementation of strengthened NTBP as one of the impact

programs of DOH with allocation of drugs and supplies

3
1988 Publication of the National TB Program Manual of Procedures (2nd
edition), which marked the adoption of the Short Course Chemotherapy
(SCC) for the management of TB cases under the National TB Preva-
lence; presented the results of the 1981- 1983 First National TB Preva-
lence Survey (NPS); introduced the itinerant team approach to selected
regions/ provinces and intensified the training, monitoring/supervision in
low performing areas.

First reference to the Public-Private Mix (PPM) for TB Control in the Phil-
ippine NTBP manual

1989 Issuance of the first consensus statement by the Tri-Chest organization,

led by the Philippine College of Chest Physicians (PCCP)

1990 Financial and technical support to the NTBP from the Italian government
and World Bank for improving TB control in Regions V, VIII, X and in
other cities and provinces

1991 Local Government Units (LGUs) became the implementer of TB program

under the Local Government Code

1993 Conduct of a WHO-assisted external evaluation on NTBP in Regions IV,

VI, VII, VIII

First NTBP SEAMIC Conference with other Asian Countries

Formation of the National TB Advisory Council

Publication of Tuberculosis in Infancy & Childhood (1st edition) by

the Philippine Pediatric Society (PPS)

1994 Field testing of new NTBP policies and guidelines and establishment of
First TB Reference Laboratory in Cebu under the DOH-JICA Project

1994 Launching of hospital-based NTBP

Founding of the Philippine Coalition Against Tuberculosis (PhilCAT)

Tuberculosis in all forms as the 5th leading cause of mortality

39.8/100,000 population (Philippine Health Statistics)

1995 Establishment of the TB Reference Laboratory in Regions I, IX, XI

Formulation of the revised policies and guidelines on TB management

per Administrative Order No. 1-A

Launching of Target: Stop TB (slogan: Sigaw ng Bayan, TB ay La

4
 banan)

Offering of the Directly Observed Therapy Short Course (DOTS) by the

University of Santo Tomas Hospital TB Clinic

1996 The 3rd Annual Convention of PhilCAT, in collaboration with the PPS and
the Pediatric Infectious Disease Society of the Philippines (PIDSP) with
the theme: Childhood Tuberculosis, a Concern for All

Declaration of August 19 as National TB Day by virtue of Procla

mation No. 840

Observance of the first World TB Day on March 24 spearheaded by

PhilCAT

Launching of Target: StopTB Part II (slogan: TB ay Labanan, Gamutan

ay Tutukan)

WHO supported CRUSH TB project in new NTBP policies and guide-

lines and DOTS Strategy (Tutok Gamutan)

1997 Conduct of the Second National Tuberculosis Prevalence Survey in the

Philippines

Joint publication of National Consensus on Childhood Tuberculosis

(NCCT) by the PPS, PIDSP and PhilCAT

Development of Technical Guidelines of the New TB Control Program by

the Department of Health (DOH), in collaboration with DOH-JICA (Japan
International Cooperation Agency), Public Health Development Project
and the WHO Western Pacific Regional Office (WPRO), in accordance
with the recommendations from the external evaluation conducted by
WHO in 1993

1998 Expansion of CRUSH TB using DOTS in seven provinces

Development of Technical Guidelines of the New TB Control Program,

with emphasis on DOTS or ―Tutok Gamutan‖

Establishment of the Center for Tuberculosis in Children, Philippines

(CTCP) by Dr. Fe del Mundo

Issuance of Memorandum Circular No 98-155 pronouncing the NTBP as

the No. 1 priority health program of the LGUs and the prescribing of
DOTS

Launching of Strategy Project Lusog Baga (―Healthy Lungs‖)

5
 Creation of the Task Force on Childhood Tuberculosis through De-
partment Order No 248-H s. 1998 (amended in 2001): a DOH initiative in
cooperation with PPS and other agencies.

1999 Development of the first Clinical Practice Guidelines on the Diagnosis,

Treatment and Control of TB was developed and spearheaded by the
Philippine Society of Microbiology and Infectious Diseases (PSMID) with
the PCCP and the DOH

Health Sector Reform Agenda of DOH put NTBP on top priority

Formal initiation by the WHO of PPM for TB control during the first global
assessment of PPM in TB control

2000 Expansion of DOTS Program

2001 Publication of the National TB Program Manual of Procedures (3rd

edition), which served as reference in the orientation/training of the pri-
vate sector and other government agencies in their implementation of
NTP-DOTS.

Establishment of National TB Reference Laboratory (NTRL)

Strengthening advocacy strategies: TB Health Promotion Plan (NCHP),

with slogan: Huwag Mahiya, TB Ipagamot Na)

2002 Formulation of the Comprehensive and Integrated Policy for TB Control

Creation of TB Diagnostic Committees to review sputum smear-nega

tives

Achievement of a nationwide coverage for DOTS strategy in the public

health sector (from 2002 to 2003)

2003 Development of the Comprehensive and Unified Policy (CUP) to control

TB by the DOH and PhilCAT under EO No. 187

Adoption of the Public-Private Mix DOTS (PPMD)

Shifting of single dose formulation to fixed dose combination (FDC)

drugs for adults

First National Drug Resistance Survey supported by WHO and JICA be-
came the basis for the policy to address multi – drug resistant (MDR) TB

Publication of Tuberculosis in Infancy and Childhood (2nd edition) by

6
 PPS

2004 Issuance of Hospital-based NTBP-DOTS policies

Lung Center of the Philippines became the government‘s counterpart

support to the DOTS-plus initiative

Formulation of Operational Guidelines on PPMD developed by NTBP in

cooperation with PhilCAT, WHO and the Global Fund to Fight AIDS, Tu-
berculosis and Malaria (GFATM)

Institutionalization of DOTS certification and Philhealth TB OPD Benefit

Package

Tuberculosis all forms as the 6th leading cause of mortality 31/100,000

population (Philippine Health Statistics)

Publication of the Guidelines for Implementing Tuberculosis Control Pro-

gram in Children

2005 Publication of the National TB Program Manual of Procedures (4th

edition) which included the use of fixed dose combination anti-TB drugs,
external quality assessment, adoption of the Public-Private Mix DOTS,
strengthening of the TB Diagnostic Committees, DOTS facility certifica-
tion and accreditation, and development of the health promotion plan
specific to TB.

Issuance of Guidelines for the Implementation of Policy and Program on

TB Prevention and Control in the Workplace

2006 Scaling up of PPMD continued; it expanded to address the urban poor in

Metro Manila

Formulation by PPS of the Evidence - based Clinical Practice Guide-

lines on Childhood Tuberculosis 1st edition (published 2008)

Publication of global guidelines by the WHO and launching of the Inter-

national Standards for Tuberculosis

Creation of the National TB/HIV Collaborating Committee

2006 – 2010 Inclusion of the PPMD component in the National Strategic Plan to stop
TB in the Philippines

2007 Conduct of the Third National Tuberculosis Prevalence Survey

TB - respiratory as the 6th leading cause of morbidity in the Philippines

7
 136/100,000 population; TB - all forms with morbidity rate at
152/100,000 population (Philippine Health Statistics National Epidemiol-
ogy Center, DOH)

2007 – 2008 Establishment of 220 PPMD units nationwide covering 40% of the popu-
lation and contributing 90% in the national case detection

2008 Publication of the revised Guidelines for Implementing Tuberculosis

Control Program in Children

2009 Publication of the Principles and Practices of PPM for Tuberculosis

Care and Control by the DOH & PhilCAT

2010 initiation of the 2010-2016 Philippine Plan of Action to Control TB

(PhilPACT) under the leadership of the DOH through the National TB
Control Program (NTP)

2012 PPS co-sponsored the 2012 World TB Day (24 March 2012) at the V.
Luna General Hospital Gymnasium, as well as the 16th PhilCAT Annual
Convention at the Crowne Plaza (17-17 August 2012)

2013 WHO organized external NTP review – Joint Program Review (JPR) of
the PhilPACT

2014 Reassessment and revision of PhilPACT, led by the National Tuberculo-

sis Control Program, through its midterm evaluation. The updated Phil-
PACT guides the country in its intensified effort to control TB in 2014-
2016. (Updated 2010-2016 PhilPACT)

WHO Guidance on the National Tuberculosis Programmes on the Man-

agement of Tuberculosis in Children, 2nd edition.

Institution of PhilHealth Package for TB

International Standards for Tuberculosis Care, 3rd edition

2016 Republic Act No. 10767 ―Comprehensive Tuberculosis Elimination Plan Act‖
was signed into law on April 26, 2016.

23rd PhilCAT Annual Convention sponsored by the Pediatric Infectious

Disease Society of the Philippines (PIDSP) on 18-19 August 2016 at the
Crowne Plaza

8
 2
Epidemiology
Luis T Chan, Jr, MD
Ana Liza H Duran, MD

OUTLINE
1 Overview

2 Tuberculosis key facts

3 Global and Regional Burden of TB

4 TB in Children

5 Drug-Resistant TB

6 TB and HIV Coinfection

7 Mode of Transmission of TB

8 Risk Factors for TB

9
OVERVIEW
Tuberculosis (TB) ranks along HIV as a leading cause of death from an infectious dis-
ease1. Mycobacterium tuberculosis (MTB) causes this infectious disease and primarily
affects the lungs and other sites as well. TB is seen in different parts of the world, and
death from the disease is still high.
TUBERCULOSIS KEY FACTS1,2:
 In 2013, the treatment success rate continued to be high at 86% among All New TB
cases.
 Between 2000 and 2014, TB treatment alone saved an estimated 35 million lives
among HIV- people.
 In 2014, 9.6 million people are estimated to have fallen ill with TB: 5.4 million men,
3.2 million women and 1.0 million children.
 6 million TB cases were reported to WHO. Of these, 5.7 million were newly di-
agnosed and another 0.4 million were already on treatment.
 Among pulmonary TB cases, 58% were bacteriologically confirmed.
 There were an estimated 700,000 TB deaths among HIV- men and 340,000
among HIV- women
 TB killed 1.5 million people: 1.1 million HIV negative and 0.4 million are HIV
positive.
 The death toll comprised 890,000 men, 480,000 women and 140,000 children.

GLOBAL AND REGIONAL BURDEN OF TB1

In 2014, there were an estimated 9.6 million incident cases of TB globally, equivalent to
126 cases per 100,000 population. The absolute number of incident cases is falling
slowly at an average rate of 1.5% per year from 2000-2012 and 0.6% between 2012
and 2013. Of the estimated 9.6 million people who developed TB in 2014, more than
half (58%) occurred in Asia and the African Region (28%). Smaller proportion of cases
occurred in the Eastern Mediterranean, European and American Regions.
The 9.6 million incident cases in 2014 included 1.1 million to 1.3 million (11-13%)
among people living with HIV (PLHIV) with the best estimate of 1.2 million (12%). The
proportion of TB cases co-infected with HIV was highest in countries in the African re-
gion. Overall, 32% of TB cases were estimated to be co-infected with HIV in this region,
which accounted for 74% of TB cases among people living with HIV worldwide. In parts
of Southern Africa, more than 50% of TB cases were co-infected with HIV.
Globally, 123,000 cases of MDRTB or RR-TB who are eligible for treatment with
MDRTB regimens were notified to WHO in 2014. India, the Russian Federation and
South Africa accounted for almost half of the total. These 123,000 cases represented
41% of the estimated 300,000 MDRTB cases among pulmonary TB patients that were
notified in 2014, and 26% of the estimated 480,000 (range 360,000-610,000) incident
MDRTB cases worldwide in 2014.

10
The number of incident TB cases relative to population size (the incidence rate) varies
widely among countries. The lowest rates are found predominantly in high-income
countries, including most countries in Western Europe, Canada, United States of Amer-
ica, Japan, Australia, and New Zealand. In these countries, the incidence rate is less
than 10 cases/100,000 population.
Globally, the incidence rate was relatively stable form 1990 up until around 2000, and
then started to fall, achieving the MDG target ahead of the 2015 deadline. Between
2000 and 2013, the average rate of decline per year was 1.5%.
There were an estimated 13 million prevalent cases (range, 11 million to 14 million) of
TB in 2014, equivalent to 174 cases/100,000 population. By the end of 2015, it is esti-
mated that the prevalence rate will have fallen 42% globally since 1990, missing the
target. However, two regions met the target before 2015 (the Region of the Americas
and the Western Pacific Region) and the Southeast Asia Region reached the target
(according to the best estimate) in 2015. TB prevalence is falling in all of the other three
regions.
The number of TB deaths per 100,000 population averaged 16 globally in 2014, and 21
when TB deaths among HIV positive people are included. There is considerable varia-
tion among countries, ranging from under 1 TB death per 100,000 population (Western
Europe, Canada, USA, Australia and New Zealand) to more than 40 deaths per
100,000 population in much of the African Region as well as 3 High Burden Countries
(HBCs) in Asia (Bangladesh, Cambodia and Myanmar), and the 2 HBCs in the 2 East-
ern Mediterranean Region (Afghanistan and Pakistan).
Globally, the TB mortality rate (excluding deaths among HIV+ people) fell by 47% be-
tween 1990 and 2015, narrowly missing the target of a 50% reduction.
Western Pacific Region1,2,3
The Western Pacific Region, where the Philippines belongs, has an estimated popula-
tion of about 2 billion. The incidence of TB, including HIV positive patients, is 85 per
100,000 population. Mortality rate, excluding HIV+TB, is presently at 4.8 per 100,000
population while that of HIV+TB patients is 0.27/100,000 population. The prevalence
rate is 116 per 100,000 population in 2014. The estimated number of notified new and
relapse cases is close to 1.4 million, while the Case Detection Rate, all forms, is 85%.
(Table 2.1)

11
Table 2.1. Estimates of TB Burden 2014
NUMBER (Thousands) RATE (per 100,000
population)
Mortality (excludes 88 (81-95) 4.8 (4.4-5.1)
HIV+TB)
Mortality (HIV+TB only) 5 (4-6) 0.27 (0.23-0.31)
Prevalence (includes 2,100 (1,900-2,400) 116 (102-128)
HIV+TB)
Incidence (includes 1600 (1500-1600) 85 (80-89)
HIV+TB)
Incidence (HIV+TB only) 31 (28-35) 1.7 (1.5-1.9)
Case detection, all forms 85 (81-90)
(%)
National Profile1,2,3
Tuberculosis is the sixth leading cause of morbidity and mortality in the Philippines;
the country is ninth out of the 22 highest TB-burden countries in the world and has one
of the highest burdens of multi-drug resistant TB3. In 2014, the estimated incidence of
TB including HIV positive TB patients is 290,000 and TB deaths totaled 10,000 exclud-
ing HIV with TB. The WHO data of 2014 showed the Philippine TB incidence rate at
288/100,000 population, while the prevalence rate is at 417/100,000 population. The
percentage of the incidence of TB cases that are HIV positive was at 2.6/100,000 pop-
ulation in 2014. (Table 2.2).
Table 2.2. Estimates of TB Burden 2014
NUMBER RATE
(thousands) (per 100,000 population)
Mortality (excludes 10 (9-11) 10 (9.1-11)
HIV+TB)
Mortality (HIV+TB only) 0.08 (0.055-0.11) 0.08 (0.06-0.11)
Prevalence (includes 410 (360-470) 417 (367-471)
HIV+TB)
Incidence (includes 290 (250-320) 288 (254-324)
HIV+TB)
Incidence (HIV+TB only) 2.5 (2-3.2) 2.6 (2-3.3)
Case detection, all forms 85 (76-97)
(%)

TB IN CHILDREN
At least half a million children become ill with TB each year. Seventy to eighty percent

12
of children with TB, have the disease in their lungs (Pulmonary TB). The rest are af-
fected by TB disease in other parts of the body (Extrapulmonary TB). In 2014, children
aged <15 years of age accounted for 6.5% of notified cases. An estimated 550,000
children became ill with TB and 80,000 children who were HIV negative died from TB
in 2013. There were an additional 81,000 (range: 69,000-93,000) TB deaths among
HIV- children, equivalent to 27% of total HIV- TB deaths. In 2014, 359,000 new and
relapse cases among children were reported, an increase of about 30% compared with
2013. The largest increases were in India (about 30,000) and the Philippines (about
10,000).1

DRUG RESISTANT TB1,2,3

Resistance to drugs poses a grave threat to the prevention, treatment and control of
TB. Drug-resistant TB is extremely difficult and costly to treat. Persons with drug-
resistant TB are more likely to die of TB than those who have drug-susceptible TB.
The problem of drug resistance is man-made, which arises from noncompliance and
improper use of anti-tuberculous drugs particularly in areas with poor TB control pro-
grams. Locally, there is limited data on drug resistance of MTB in children. Most of the
culture and sensitivity studies on MTB are done on adult patients.
Globally, there is an estimated 3.3% of new TB cases and 20% of previously treated
cases have MDR-TB. The number of cases detected (123,000) worldwide represented
41% of the global estimate. Detection gaps were worst in the Western Pacific Region
where the number of cases detected was only 19% of the number of notified cases es-
timated to have MDR-TB.
In the Philippines, MDRTB among all new TB cases was 2%, with 21% for retreatment
cases. (Table 2.3). The estimate total of MDR-TB cases among notified pulmonary TB
cases, both new and retreatment, is at 11,100 in 2014. There was also a noted in-
crease in the total cases of Rifampicin Resistant/Multidrug Resistant Tuberculosis (RR/
MDRTB) from 17,241 cases in 2013 to 27,287 cases in 2014. There were 3,000 labor-
atory-confirmed RR-/MDR-TB cases and 2680 patients who were started on MDR-TB
treatment in 2014 (Table 2.4).
Table 2.3. Estimates of MDR-TB burden 2014
NEW RETREATMENT
% of TB cases with MDR-TB 2 (1.4-2.7) 21 (16-29)
MDR-TB cases among noti- 4,600 (3,300-6,300) 6,500 (4,700-8,700)
fied pulmonary TB cases

13
Table No. 2.4. Reported cases of RR-/MDR-TB 2014
NEW RETREATMENT TOTAL
Cases tested for RR-/MDR-TB 4,415 (5%) 20,196 (67%) 27,287
Laboratory-confirmed RR-/MDR 3,000
-TB cases
Patients started on MDR-TB 2,680
treatment

TB AND HIV CO-INFECTION1,2

HIV/AIDS with TB is a fatal combination. HIV infection contributes substantially to the
increase in the number of TB cases. With its ability to destroy the immune system, HIV
is the most significant risk factor for the progression of dormant TB infection to clinical
disease. HIV positive individuals are 20 to 30 times more likely to develop TB than
those who do not have HIV. TB is the leading cause of death in adults with HIV; one in
every four people with HIV dying from TB.
Globally, 51% of notified TB patients have a documented HIV result in 2014. An esti-
mated 12% of the 9.6 million people who developed TB in 2014 were HIV positive, the
figure highest in the African region at 79%.1 Of the 1.5 million people killed, 0.4 million
are HIV positive with an estimated 190,000 TB deaths among HIV+ men, and 140,000
among HIV+ women. There were an additional 55,000 (range: 50,000-60,000) TB
deaths among HIV+ children, equivalent to 14% of the total number of HIV+ deaths. TB
treatment supported by ART saved an additional 8.4 million lives among HIV+ people.1
In the Philippines, out of the 290,000 total TB cases in 2014, an estimate of 53,354
(20%), are TB patients with known HIV status, thus increasing the estimate to almost
10 times (5,034) in 20131 (Table 5.1).
Table No. 2.5. TB/HIV 2014
NUMBER (%)
TB patients with known HIV status 53,354 (20)
HIV-positive TB patients 108 (<1)
HIV-positive TB patients on co-trimoxazole preventive thera- 20 (19)
py (CPT)
HIV-positive TB patients on anti-retroviral therapy (ART) 53 (49)
HIV-positive people screened for TB 5,995
HIV-positive people provided with IPT

MODE OF TRANSMISSION OF TB4

14
M. tuberculosis is transmitted through the air (not by surface contact). It is carried in
airborne particles in droplet nuclei form measuring 1- 5 micra in diameter. Infectious
droplet nuclei are generated when persons who have pulmonary or laryngeal TB dis-
ease cough, sneeze, shout, sing or spit. Depending on the environment, these tiny par-
ticles can remain suspended in the air for several hours. Transmission occurs when a
person inhales the droplet nuclei containing MTB, and the droplet nuclei traverse the
mouth or nasal passages, upper respiratory tract, and bronchi to reach the alveoli of the
lungs.
The other modes of transmission are through ingestion of contaminated, unpasteurized
dairy products from infected cattle resulting in bovine TB (caused by the Mycobacte-
rium bovis); skin inoculation from contamination of an abrasion, which usually occurs
among pathologists and laboratory personnel (prosector's wart).5 Fomites are not im-
portant in its transmission, thus special handling of utensils and bed linens are not nec-
essary.6

INFECTIOUSNESS OF TB PATIENTS4
The infectiousness of a person with TB disease is directly related to the number of tu-
bercle bacilli expelled into the air. A person is considered more infectious when more
tubercle bacilli are expelled. Infectiousness of TB patients also depends on a variety of
factors: susceptibility (immune status) of the exposed individual, environmental factors
that affect the concentration of M. tuberculosis organisms and the proximity, frequency,
and duration of exposure to an infectious source. In general patients who have suspect-
ed or confirmed TB disease should be considered infectious if:
1. They are coughing, undergoing cough-inducing procedures, or have positive
sputum smear results for acid-fast bacilli (AFB), presence of pulmonary cav-
ity;
and
2. They are not receiving adequate anti-tuberculosis therapy, have just started
therapy, or have a poor clinical or bacteriologic response to therapy.
The risk of TB infection among child contacts is associated with the proximity
and duration of contact and the degree of lung involvement and/or sputum smear posi-
tivity of the index case, which is usually from an infectious adolescent or adult.7-10 Child-
hood TB arises most often as a result of the inhalation of droplet nuclei approximately 1
to 5 micra in size containing M. tuberculosis bacilli expectorated by a sputum smear-
positive individual with pulmonary TB. TB infected infants and postpubertal adolescents
are at increased risk for progression to TB disease, and children aged less than five
years are at increased risk for disseminated disease.11

RISK FACTORS FOR TB12

15
TB disease may develop within weeks in some individuals infected with TB and who
have weak immune systems. Other TB infected individuals may develop TB disease
years after exposure once their immune system is compromised. Overall, about 5 to
10% of infected persons who do not receive treatment for LTBI will develop TB disease
at some time in their lives. For persons whose immune systems are weak, especially
those with HIV infection and AIDS, the risk of developing TB disease is significantly
higher than for persons with normal immune systems.
Risk of Exposure and Infection
The risk of exposure and of acquiring infection is dependent on significant contact:
closeness of contact and extent of disease or infectiousness of the source who is usu-
ally an older family or household member with partially treated or unrecognized and
untreated pulmonary TB. Family and community conditions such as overcrowding are
important extrinsic factors. A similar risk holds for institutionalized children and workers
in hospitals, orphanages, prisons, homes for the elderly and shelters for street children.
Risk of Progression from Infection to Active Disease
The risk of progression of the infection to active disease is determined by age, time af-
ter exposure and initial infection, nutritional status, intercurrent disease, immunosup-
pression and other intrinsic host factors. Generally three to four percent of infected indi-
viduals progress to active TB during the first year after infection (tuberculin conversion);
it occurs in 5-15%, thereafter.
Persons at high risk for developing TB disease fall into two main categories – those
who have been recently infected with TB bacteria and those who have medical condi-
tions that weaken the immune system.
Persons who have been recently infected with TB bacteria
 Close contacts of a person with infectious TB disease
 Persons who have migrated from areas of the world with high rates of TB
 Children less than 5 years of age who have a positive Tuberculin Skin Test (TST)
 Groups with high rates of TB transmission, such as homeless persons, injection
drug users, and persons with HIV infection
 Persons who work or reside with people who are at high risk for TB in facilities or
institutions such as hospitals, homeless shelters, correctional facilities, nursing
homes, and residential homes for those with HIV

Persons with medical conditions that weaken the immune system

 Babies and young children often have weak immune systems. Other people can
have weak immune systems, too, especially people with any of these conditions:
 HIV/AIDS infection
 Substance abuse
 Silicosis
 Diabetes mellitus
 Severe kidney disease
 Undernutrition
 Organ transplants
16
 Malignancies
 Immunosuppression, e.g. by corticosteroids, anti-neoplastics, etc.

Influence of chemotherapy on transmission and spread of disease

Strict compliance with the recommended standard chemotherapy for various forms and
categories of TB contributes greatly to the dynamics of disease prevention and its gen-
eral impact on control. For most patients, infectiousness appears to decline rapidly
within 2 weeks after adequate and appropriate treatment is started; however, the rate of
decline varies from patient to patient. Some patients with unrecognized or inadequately
treated drug-resistant TB disease may remain infectious for weeks or even months. Pa-
tients with drug-resistant TB disease may not respond to the initial drug regimen and
may remain infectious until they receive adequate treatment.

17
REFERENCES:
1. World Health Organization. Global Tuberculosis Report 2015
2. http://www.who.int/tb/publication/2015/factsheet_tb_2015 update November
2015.pdf
3. World Health Organization_HQ_Reports TB Country Profile
4. Centers for Disease Control and Prevention, National Center for HIV, STD and TB
Prevention Division of Tuberculosis Elimination. Core Curriculum on Tuberculosis,
What the Clinician Should Know. 6th ed. 2013
5. Frampton MW. An outbreak of tuberculosis among hospital personnel caring for a
patient with a skin ulcer. Ann Intern Med. 1992;117:312.
6. Haas DW. Mycobacterial diseases. Philadelphia, Churchill Livingstone. 2000. p.
2576-2607. (GL Mandell, Douglas, JE Bennett, editors. Principles and Practice of
Infectious Diseases. 5th ed.).
7. Grzybowski S, Barnett GD, Styblo K. Contacts of cases of active pulmonary tuber-
culosis. Bull Int Union Tuberc. 1975;50:90–106.
8. Marks SM, Taylor Z, Qualls NL, et al. Outcomes of contact investigations of infec-
tious tuberculosis patients. Am J Respir Crit Care Med. 2000;162:2033–8.
9. Kenyon TA, Creek T, Laserson K, et al. Risk factors for transmission of Mycobacte-
rium tuberculosis from HIV-infected tuberculosis patients, Botswana. Int J Tuberc
Lung Dis. 2002;6:843–50.
10. Lienhardt C, Sillah J, Fielding K, et al. Risk factors for tuberculosis infection in chil-
dren in contact with infectious tuberculosis cases in The Gambia, West Africa. Pedi-
atrics. 2003;111:e608–14.
11. American Academy of Pediatrics, Committee on Infectious Diseases. Tuberculosis.
Elk Grove Village, IL: American Academy of Pediatrics. 2003. p. 642–60.
(Pickering LK, editor. 2003 Redbook: report of the Committee on Infectious Diseas-
es. 26th ed.).
12. National Tuberculosis Controllers Association, Center for Disease Control. Guide-
lines for the Investigation of Contacts of Persons with Infectious Tuberculosis.
MMWR Weekly. 2005 December 16;54:RR-15.

18
 3
Microbiology
Jaime A Santos, M.D
Mary Antonette C Madrid, M.D

OUTLINE
1 Overview

2 Morphology and taxonomy

3 Physiology and growth character-

istics

4 Antigenic structure and determi-

nants of virulence

5 Laboratory Diagnosis

6 M. tuberculosis genome sequence

19
OVERVIEW
Mycobacterium tuberculosis, classified under the M. tuberculosis complex, is the agent
that causes tuberculosis in humans. Tuberculosis continues to be a subject of interest
in the medical field as there are still a lot to be investigated on the disease agent‘s viru-
lence and new information derived from the M. tb genome can contribute to the devel-
opment of therapeutic and preventive strategies. The availability of Xpert MTB/Rif as-
say, a real time-DNA based test, has revolutionized TB case detection by providing
early results. This chapter discusses the morphology, taxonomy, growth characteristics,
virulence factors, laboratory diagnosis, and the M. tb genome sequence.

MORPHOLOGY AND TAXONOMY

Mycobacteria are aerobic, nonmotile, and slightly curved or straight bacilli.
They retain carbolfuchsin dye when decolorized with acid-ethanol by the Ziehl-
Neelsen method (acid-fastness). The organisms contain high-molecular-weight
(60 to 90 carbons) mycolic acids in their cell walls.1 They are classified into: (a)
M. tuberculosis complex; and (b) nontuberculous mycobacteria [previously
referred to as atypical mycobacteria or mycobacteria other than tuberculosis
(TB) or MOTT], which includes M. avium-intracellulare, M. kansasii and all other
species.2
Mycobacterium tuberculosis complex (MTBC) includes species that cause tu-
berculosis in humans and other mammals. Though member species are very
closely related genetically, not all have been given species status. The following
are the named species of this complex: Mycobacterium tuberculosis (M. tuber-
culosis), M. bovis, M. caprae, M. africanum, M. microti, M. canetti, and M. pinni-
pedii 1,3,4
Bacille Calmette-Guerin (BCG), which is used for vaccination, is presumed to
be derived from M. bovis. BCG however, is now seen to have features that dif-
ferentiate it from other strains of M. bovis.3 M. bovis causes disease in cattle,
humans and other mammals, while M. tuberculosis causes disease only in hu-
mans. In addition to M. tuberculosis, humans are also the principal host of M.
africanum and canetti. Goats, voles, and seals are the principal hosts of M.
caprae, M. microti and M. piniipedii, respectively.4
The primary mode of transmission of M. bovis is ingestion of contaminated milk and
meat. While M. bovis requires oxygen for growth, it is inhibited by the higher tension
required by M. tuberculosis. It is also intrinsically resistant to pyrazinamide. Over time,
pasteurization, tuberculin testing of cattle, and killing of infected animals, has consider-
ably decreased the incidence of M. bovis. 5,6
The Runyon classification scheme groups nontuberculous mycobacteria (NTM)

20
based on growth rate and pigmentation. This scheme is becoming less important due to
increasing availability of new methods of rapid detection of mycobacteria. A rapidly
growing or pigmented isolate of Mycobacteria is not to be mistaken as M. tuberculosis 7
Among the important members of NTM are (1) M. avium complex (MAC), M. kansasii
and M. xenopi that can cause pulmonary disease; (2) M. avium and M. scrofulaceum
can cause lymphadenitis particularly in children, and, (3) MAC and M. kansasii are
causes of disseminated disease among HIV patients.8
Unlike members of the MTBC, NTMs have a wide range of pathogenicity and are not
transmissible from one human to another. The NTMs are also more difficult to treat be-
cause they are relatively drug resistant compared to M. tuberculosis.8
The phylogeographically relevant clonal distribution of the M. tuberculosis complex can
be accessed in the SpolDB4database.9,10
A more recent characterization of M. tb diversity and molecular epidemiology utilizing
the mycobacterial interspersed repetitive units–variable number of DNA tandem re-
peats (MIRU–VNTRs) method described another international database, the SITVIT-
WEB. This database has genotyping information on more than 62,582 isolates from
153 countries compared to only spoligotyping information on 39,295 isolates from 122
countries contained in the previous version of the SpolDB4 database.11,12

PHYSIOLOGY AND GROWTH CHARACTERISTICS

Mycobacteria are obligate aerobes; generally, they have simple growth requirements.
Many strains have surface growths and clumping characteristics in liquid, synthetic me-
dia. Tweens (nonionic detergents) are added to promote dispersed growth. The growth
rate of mycobacteria is slow but is enhanced by 6% to 8% carbon dioxide. Optimal tem-
perature for the growth of M. tuberculosis is 35oC to 40oC.

ANTIGENIC STRUCTURE AND DETERMINANTS OF VIRULENCE

The specific structures, antigens, and mechanisms responsible for the virulence of M.
tuberculosis are not known with certainty; but, trehalose dimycolate (cord factor) and
sulfatides have been associated with the ability of virulent strains to produce disease.
In vitro, cord factor is responsible for the morphologic appearance of M. tuberculosis
cells – serpentine cords of bacilli in close, parallel arrangements. However, its role in
human TB remains unknown. Studies in mice demonstrated it to be strong inducers of
cytokine secretion as well as neutrophil recruitment.13 Sulfatides are peripherally locat-
ed glycolipids that inhibit fusion of secondary lysosomes with bacilli-containing phago-
somes within a macrophage, possibly promoting intracellular survival of the organisms. 1
Lipoarabinomannan (LAM), an important molecule in the mycobacterial cell wall, is a
dominant mycobacterial antigen.4 The Man-LAM (mannan-capped LAM) variant pre-
21
sent in MTBC has been shown to be responsible for enhanced bacilli survival and entry
into macrophages.14

LABORATORY DIAGNOSIS
TB bacilli have a slow doubling time of 18 to 24 hours.2 Although the newly developed
techniques like PCR give earlier results, demonstration of the organism by culture is
still considered the gold standard for the diagnosis of TB.3

Specimen
Specimens include pulmonary secretions, urine, genital discharge, CSF, blood, pleural
fluid, and other biologic fluids. Demonstration of the bacilli in children is limited by the
fact that childhood TB (primary tuberculosis) is often paucibacillary and that very young
children cannot raise any sputum. For these reasons, a gastric aspirate specimen as-
sumes greater importance for children compared to adults. (For collection and handling
of specimens see chapter 8 on diagnostic tests)
The quality of specimens submitted for microbial investigation affects the performance
of the laboratory test. Specimens should reflect the site of infection and preferably col-
lected aseptically15

Microscopy
Acid-fast staining techniques:
a. The ZN technique (or the hot method) uses carbol fuchsin, which is taken up
by the cell even after treatment with acid alcohol. Mycobacteria will appear
as red rods against a blue background. Heat is applied in this method.
b. Kinyoun or cold stain is a modification of the ZN method and does not in-
volve application of heat. It uses a higher concentration of phenol with carbol
fuchsin. Mycobacteria appear as above.
c. Auramine-O stain makes use of auramine instead of carbol fuchsin. TB bacil-
li are seen fluorescing under the fluorescence microscope. The use of fluo-
rescent stain increases sensitivity of microscopy.15
Culture
Non-sterile specimens contaminated with commensal organisms undergo decontami-
nation prior to inoculation onto culture media. This is achieved thru the use of either
NaOH method or Nalc-NaOH method. 15

Culture Media15
The following are the suggested media for cultivation of Mycobacteria from clinical
specimens:
1. Solid Media is either egg-based or agar-based. Among the egg-based media, LJ is
the most popular
 Agar-based: Middlebrook 7H10, Middlebrook 7H11, Mitchison's selective 7H11
 Egg-based: Wallenstein, Lowenstein-Jensen (LJ) with RNA, LJ with pyruvic ac-

22
 id; Ogawa16
2. Liquid Media15
 Middlebrook 7H9 broth
 Dubos Tween Albumin broth
 Commercial liquid-based mycobacterial culture systems:
 Bactec 460 TB
 Bactec Mycobacterial Growth Indicator Tube (MGIT) 960 system
 VersaTREK (ESP II) culture system
 MB/BacT system

Of these culture media, the currently available ones in some local laboratories are Low-
enstein-Jensen, Middlebrook, Ogawa and Bactec.

Culture Method
1. Conventional
Conventional culture of mycobacteria involves inoculation on solid media. If this is the
only method used, inoculation of both the egg-based and agar-based media is recom-
mended. For specimens such as sputum that are contaminated with normal bacterial
flora, a selective medium containing antimicrobial agents, such as Mitchison's selective
7H11 agar, should also be inoculated.1
Conventional culture media should be examined for growth twice a week, for the first
four weeks, starting from day 3 to 5 postinoculation, and thereafter, once a week until
the eighth week. Positive cultures should be identified to the level of species using ei-
ther biochemical or molecular methods.16
The major advantage of conventional culture is that it allows visualization of colony
morphology and pigmentation. Disadvantages of conventional solid media are pro-
longed time of growth of mycobacteria (3 to 4weeks) and low sensitivity. 1,6,17,18 This is
because the doubling time (every 12-24 hours) of M. tuberculosis is extremely slow
compared to most bacteria.16
While solid media are still being used by most centers, the use of liquid media such as
Middlebrook 7H9 and Dubos Tween broths offers the advantage of more rapid growth
of mycobacteria as well as a higher isolation rate, than on solid media.15
2. BACTEC TB System and other commercial liquid-based culture systems
The most widely used system is the semi-automated BACTEC TB system which utilizes
broth media (one for blood and another for all other specimen types) that contain 14-C-
labeled palmitic acid substrate. Each specimen (5.0 ml of blood or 0.5 ml of all other
specimen types) is inoculated into one vial and an antibiotic mixture is added to speci-
mens other than blood. Bacilli multiply in the broth and utilize the 14-C-labeled sub-
strate, releasing CO2 into the head space above the broth. The amount of CO2 is
measured by the BACTEC 460, which calculates the growth index (GI). A GI greater
than ten suggests that mycobacteria are present. Vials containing mycobacteria are

23
sub-cultured to a solid medium, and direct tests for identification are done. 1 Bactec 460
(Beckton Dickinson) was the first commercial liquid-based mycobacterial culture system
used. It has been considered a standard against which most other systems were com-
pared15
There are advantages to the BACTEC TB system: rapid detection of growth (5 to 12
days); increased sensitivity compared with solid media; the ability to distinguish MTBC
from other mycobacterial species; and rapid susceptibility testing of isolates of M. tuber-
culosis. The major disadvantage of the BACTEC system is its radioactivity; the dispos-
al of which is expensive and may be problematic for some institutions1, 6, 17 However,
there are now non-radiometric BACTEC systems which provide a viable alternative to
the original radiometric BACTEC.18
Other available commercial liquid-based mycobacterial culture systems include Bactec
MGIT 960 culture system, Versa TREK culture system, and MB/BacT system. Bactec
MGIT is a system that uses a modified 7H11 broth containing an indicator that fluo-
resces under UV light. As oxygen in the medium is consumed, the indicator will fluo-
resce. Fluorescence is detected either manually using a Wood‘s lamp, or automatically
and continuously if Bactect 960 instrument is available. MB/BacT uses a colorimetric
sensor that changes color as increased amounts of C02 produced by the growing or-
ganism is detected. VersaTREK system monitors gas-related pressure changes that
occurs during bacterial multiplication. This was previously marketed as ESP II culture
system. 15
DNA Fingerprinting
Analysis of the M. tuberculosis genome is made through DNA fingerprinting, which
uses the restriction fragment-length polymorphism (RFLP) method. DNA fingerprinting
differentiates M. tuberculosis from other members of the MTBC and other atypical iso-
lates; it also permits the identification of patterns of spread of a particular M. tuberculo-
sis strain among individuals, which makes it possible to obtain the source of infection,
track down changes in antimicrobial susceptibility and allows for differentiation between
human and bovine isolates.6, 18, 19, 20 This technique utilizes restriction enzymes or en-
donucleases that cut DNA at specific "recognition" sites and which in turn results in
short segments or restriction fragments of DNA with lengths that vary according to the
particular enzyme used. The DNA fingerprints with unequal lengths and specific nucle-
otide sequences can be compared, in a map-like fashion, with the DNA patterns of M.
tuberculosis organisms from other individuals. If the patterns are the same, they sug-
gest a common source of exposure.6, 19
Nucleic acid amplification test (NAAT)
Using a nucleic acid probe, M. tuberculosis-specific nucleic acid sequences located on
regions of differences between mycobacterial DNA are amplified, allowing direct detec-
tion of organisms in clinical specimens. NAATs can also distinguish among MTBC or-
ganisms, can identify NTM, and has a role in rapid detection of drug resistance. It is
regarded as a complementary tool to the conventional laboratory approach to TB diag-
nosis, giving accurate and rapid results. Limitations to its use include diminished sensi-
tivity in smear-negative and non-respiratory samples, and cost.21 A commonly used
NAAT is PCR.
24
Xpert MTB/RIF assay
This is a new rapid diagnostic tool that simultaneously detects the presence of M. tu-
berculosis complex and rifampicin resistance, giving results in as early as 2 hours from
test run. It is a nucleic acid amplification test using the GeneXpert platform (developed
by Cepheid, Sunnyvale CA, U.S.). Sample purification, nucleic acid amplification and
detection of target sequence are combined in a single Xpert MTB/RIF cartridge. A rea-
gent that comes with the assay is added to the collected sample, then mixed and incu-
bated, before it is placed in the cartridge and loaded in the instrument. Following sam-
ple loading, all succeeding steps are fully automated. There is thus very minimal opera-
tor training needed. In addition to this, safety concerns on handling biohazardous mate-
rials are minimized because the assay‘s reagent is tuberocidal. These characteristics
make the test suitable for use outside a central or reference laboratory. The instrument,
however, will need an uninterrupted, stable electrical supply, temperature control and
yearly calibration.22, 23
Rifampicin resistance can been used to represent multidrug resistance since rifampicin
monoresistance is uncommon,24 and most isolates that are resistant to rifampicin are
also resistant to INH. The use of molecular methods for rapid detection of rifampicin is
feasible since >95% of resistance is associated with mutations in a limited region of the
M. tuberculosis rpoB gene (the gene that encodes the beta subunit of RNA polymerase
to which rifampicin binds under wild-type conditions), while INH resistance involves at
least four different genes and would be more difficult to detect. 21 Xpert MTB/Rif makes
use of molecular beacon technology to identify rifampicin resistance. 23 Molecular bea-
cons are nucleic acid hybridization probes that bind to target DNA sequences in regions
(such as the rpoB gene) where there are resistance mutations. The probes will fluo-
resce when bound to a target. Presence of mutation will prevent fluorescence. 21
XPERT MTB/RIF assay amplifies MTBC-specific sequence of the rpoB gene, then mu-
tations are searched for in the rifampicin resistance determining region (RRDR) using 5
molecular beacon probes (Probes A to E). 25
The test will determine if MTBC was detected or not detected in the sample. An
―invalid‖ result is also possible for which the test should be repeated. If MTBC was de-
tected, it will also indicate the following: 1) Rifampicin resistance detected, 2) Rifampic-
in resistance not detected, or, 3) Rifampicin resistance indeterminate. 22 Detailed steps
involved in the test are discussed in number of web sources.23, 25, 26
Based on WHO‘s Current Policies and Guidance, Xpert MTB/RIF is being recommend-
ed as an initial diagnostic test in suspected cases of MDR-TB or HIV-associated TB, as
well as a follow-on test for smear-negative specimens. WHO‘s recommendation on the
use of XpertMTB/Rif apply to the following specimens: processed or unprocessed spu-
tum, gastric lavage or aspirate, CSF, lymph node and other tissues. There are still inad-
equate data on the utility of the test for stool, blood and urine specimens.23
Conventional culture methods for TB detection take around 2-6 weeks before growth is
detected and an additional 3 weeks waiting time is needed for drug resistance results to
become available. The availability of XpertMTB/Rif assay sets an important milestone
in TB diagnosis and control as it offers rapid means of detecting MTBC and drug re-
sistance. Unnecessary regimens are avoided, appropriate drugs are provided, and in-
25
fection control is timely implemented.
For more information on the use of this test for TB diagnosis, please refer to
chapter 10.

M. TUBERCULOSIS GENOME SEQUENCE

Two strains of M. tuberculosis have been fully sequenced to date: the CDC-1551 (the
so-called "Oshkosh" strain) isolated from a male working in a children's clothing facto-
ry, which is highly virulent in mice but has not caused widespread epidemics in man; 27
and H37Rv, first isolated in 1905 but which has retained its virulence over the years in
animal models, is drug-susceptible, and can be genetically manipulated.28 The genome
is a circular chromosome with 4.4 million base pairs (surpassed in size only by E. coli
among the bacterial genomes completed to date), 4000 genes, and a high G + C con-
tent (65%). A large part of its coding capacity is devoted to enzymes involved in lipo-
genesis and lipolysis (explaining the large amount of lipids in the mycobacterial cell
wall) and to two new families of glycine-rich proteins.
Updated gene-based information on the H37RV strain is presented in TubecuList, a
relational database which can be accessed at http://tuberculist.epfl.ch/ . In their 2013
release, over 700 protein coding sequences have been updated.29, 30
Comparing isolates from clinical specimens shows remarkable genome sequence con-
servation but these novel proteins may be a significant source of antigenic variation
among strains. There are four copies of the previously known mce gene which encodes
a macrophage-colonizing factor. New mobile genetic elements (insertion sequences)
have also been found. Sequencing of whole genomes of the other members of the M.
tuberculosis complex, including that for M. avium subspecies paratuberculosis31 M.
smegmatis and M. bovis, has been described. The members of the M. tuberculosis
complex has increased the numbers of insertion sequence elements, which might ex-
plain higher intra-species variability in M. tuberculosis compared to other species of
mycobacteria.32 Although aerobic, M. tuberculosis also has pathways associated with
anaerobic metabolism which may be responsible for long-term persistence in tissues.33
Knowledge gained from the M. tuberculosis genome completion will elucidate pathways
of cell wall synthesis and bacterial metabolism—these can become potential drug tar-
gets in the future. It can also add to our understanding of how drug resistance occurs
and can contribute to both future vaccine design and investigational attempts at im-
munomodulation.

26
REFERENCES:
1. Woods, Gail. Mycobacteria. In: Henry‘s clinical diagnosis and management
by laboratory methods. 22nd ed. / [edited by] Richard A. McPherson, Mat-
thew R. Pincus. Saunders Elsevier Ltd. PA. 2011, p. 1145.
2. Baron S. Mycobacteria and Nocardia. In Medical Microbiology. 4 th ed. UTMC;
1996.
3. Grange JM, Yates MD, de Kantor IN. Guidelines for specification within the
Mycobacterium tuberculosis complex. WHO/EMC/ZOO/96.4.
4. Grange, GM. The genus Mycobacterium and Mycobacterium tuberculosis
complex. In: Tuberculosis A Comprehensive Clinical Reference. Zumla A.I.
and Schaaf H.S. eds. Saunders Elsevier Ltd., Oxford, UK, 2009, pp. 44-59.
5. Grange JM. Pathogenesis of tuberculosis: pathway to apical localization. Tu-
bercle and Lung Disease. 1995;76:276-277.
6. Baron EJ, et. al. Tuberculosis. In: Bailey and Scott‘s Diagnostic Microbiology.
9th ed. p. 590-633.
7. Mycobacterium. In: Medical Microbiology 7th ed. Murray PR, Rosenthal KS,
Pfaller MA. eds. Saunders, Elsevier Inc. Philadelphia, PA. 2013, pp. 235-247
8. Daley CL, Heifets L. Other mycobacteria causing human disease. In: Tuber-
culosis A Comprehensive Clinical Reference. Zumla A.I. and Schaaf H.S.
eds. Saunders Elsevier Ltd., Oxford, UK, 2009, pp.60-74.
9. SpolDB4database web link: http://www.pasteur-guadeloupe.fr/tb/
bd_myco.html or http://www.pasteur-guadeloupe.fr:8081/SITVITDemo
10. Brudley et al. Mycobacterium tuberculosis complex genetic diversity: mining
the fourth international spoligotyping database (SpolDB4) for classification,
population genetics and epidemiology. BMC Microbiol 2006 Mar 6;6 (1) : 23.
11. Demay et al. A publicly available international multimarker database for stud-
ying Mycobacterium tuberculosis genetic diversity and molecular epidemiolo-
gy. Infect Genet Evol. vol 12, issue 4, 2012 June.
12. http://www.pasteur-guadeloupe.fr:8081/SITVIT_ONLINE
13. Geisel RE, Sakamoto K, Russell DG, et al. In vivo activity of released cell
wall lipids of Mycobacterium bovis bacillus Calmette-Gue ́rin is due principal-
ly to trehalose mycolates. J Immunol 2005;174:5007–5015.

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14. Kang PB, Azad AK, Torrelles JB, et al. The human macrophage mannose
receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated
phagosome biogenesis. J Exptl Med 2005;202:987–999.
15. Whitelaw AC and Sturm WA. Microbiological testing for Mycobacterium tu-
berculosis. In: Tuberculosis A Comprehensive Clinical Reference. Zumla A.I.
and Schaaf H.S. eds. Saunders Elsevier Ltd., Oxford, UK, 2009, pp. 169-
178.
16. Palomino JC, Leão SC, Ritacco V. Tuberculosis 2007: From basic science
to patient care. 1st ed. Available from: www.TuberculosisTextbook.com
17. Luquin M, et. al. Comparison of a biphasic non-radiometric system with Low-
enstein-Jensen and Bactec-460 system for recovery of mycobacteria from
clinical specimens. Tubercle and Lung Disease. 1996;77:449-453.
18. Behr H, Small PM. Molecular fingerprinting of Mycobacterium tuberculosis:
How can it help the clinician? Clinical Infectious Diseases. 1997;25:806-810.
19. Nogueira JM, et. al. Correspondence: Molecular approach to identifying
route of M. tuberculosis transmission in a village. The Int. Journal of Tuber-
culosis and Lung Diseases. 2000;4(1):91-93.
20. Rigouts L, et. al., Use of DNA restriction fragment typing in the differentiation
of M. tuberculosis complex isolates from animals and humans in Burundi.
Tubercle and Lung Diseases. 1996;77:264-268.
21. Daniel Brodie and Neil W Schluger. Nucleic acid amplification for detection
of Mycobacterium tuberculosis. In: Tuberculosis A Comprehensive Clinical
Reference. Schaaf and Zumla (Eds). pp 197-204
22. CDC. A new diagnostic tool to diagnose TB. The Xpert MTB/RIF Assay.
Downloaded from: http://www.cdc.gov/tb/publications/factsheets/pdf/
xpertmtb-rifassayfactsheet_final.pdf
23. World Health Organization. Automated real-time nucleic acid amplification
technology for rapid and simultaneous detection of tuberculosis and rifampic-
in resistance: Xpert MTB/RIF assay for the diagnosis
of pulmonary and ex-
trapulmonary TB
in adults and children. Policy update.

24. Cruz AT, Starke J. Tuberculosis. In: Feign and Cherry’s Textbook of Pediat-
ric Infectious Diseases. Feign RD, Cherry JD, Demmler-Harrison GJ and
Kaplan SL (eds). Philadephia USA Saunders Elsevier, 7th ed, 2014, 1335-
1380

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25. Xpert MTB/RIF package insert. Cephaid, Sunnyvale CA, USA. Revised Feb-
ruary 2015. Downloaded from: http://www.cepheid.com/administrator/
components/com_productcatalog/library-
files/2cc115cd6ba267207c04661a3d0fcfc8-Xpert-MTB-RIF-ENGLISH-
Package-Insert-301-1404-Rev-B-February-2015.pdf
26. http://www.finddiagnostics.org/programs/tb/find_activities/
automated_naat.html
27. Genome sequence and analysis. The Institute for Genomic Research. Avail-
able from: www.tigr.com
28. Cole ST, Brosch R, et. al. Deciphering the biology of Mycobacterium tuber-
culosis from the complete genome sequence. Nature. 1998;393;537-544.
29. Lew, JM, Kapopoulou A, Jones LM, Cole ST. TubercuList—10 years after.
Tuberculosis (Edinb). 2011 Jan;91(1):1-7.
30. TubercuList - Mycobacterium tuberculosis Database: tuberculist.epfl.ch/
31. Li L, Bannantine JP, Zhang Q, et. al. The complete genome sequence of My-
cobacterium avium subspecies paratuberculosis. Proc Natl Acad Sci (USA).
2005;102:12344-9.
32. Maari PR, Bannantine JP, Golding GB. Comparative genomics of metabolic
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33. Young DB. Blueprint for the white plague. Nature. 1998;393:515-516.

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 4
Immune Responses
Jaime A Santos, M.D
Mary Antonette C Madrid, M.D

OUTLINE
1 Overview

2 The role of Macrophages

3 The role of T-lymphocytes

4 Role of genetic determinants

5 Immune response and course of

TB infection

30
OVERVIEW
The healthy tuberculin reactor and a patient with severe miliary tuberculosis (TB) repre-
sent the two ends of the spectrum of TB infection and disease—extremely effective and
poor immune responses to M. tuberculosis. A relatively good immune response is seen
in a patient with TB pleuritis (as evidenced by few bacilli in pleural fluid, resolution of
disease without treatment and preserved tuberculin skin test responses), while a rela-
tively poor immune response leads to advanced, progressive pulmonary disease. While
immune responses do not entirely account for the clinical spectrum of TB infection as it
does in leprosy, an enhanced understanding of the immunology of TB coupled with the
knowledge gained from the sequencing of the M. tuberculosis genome could signifi-
cantly lead to breakthroughs in vaccine development and TB immunotherapy.1, 2,3
Although there are differences between murine models of TBs and human TB disease,
there is extensive agreement and experimental support for the following: macrophages
and T lymphocytes are the primary defenses against TB; antibodies and B lympho-
cytes have little role, if any, in protecting one against TB; and. the role of neutrophils
and natural killer (NK) cells is unclear.

THE ROLE OF MACROPHAGES4,5

Phagocytosis and killing
The initial encounter of TB bacilli with macrophages in the lungs may be the most im-
portant contributor to subsequent events. While intracellular killing follows phagocyto-
sis, M. tuberculosis can evade such killing mechanisms. Among their survival strategies
are: (1) prevention of acidification of phagosomes (where TB bacilli are found within
macrophages); (2) neutralization of the effects of reactive oxygen intermediates by my-
cobacterial cell wall components; (3) inhibition of plasma membrane repair;6 and (4)
probable inhibition of phagosome-lysosomal fusion through secretion of SapM (acid
phosphatase)7, PknG,8 and glycosylated phosphotadyl-inositol (mannose-capped
lipoarabinomannan [Man-LAM]).9 Man-LAM is a cell wall component of M. tuberculosis
that can serve as a mimic of mammalian phosphatidylinositols and can block the host
phosphatidylinositol 3-kinase and its enzymatic product PI3-P required for the matura-
tion of phagosomes into phagolysosomes.9,10 It is also likely, but not proven, that TB
bacilli can escape into the cytoplasm from the phagosome. Among the killing mecha-
nisms of macrophages, the role of nitric oxide is very likely.
Antigen presentation and cytokine production
TB bacilli can also induce macrophages to produce a variety of cytokines; these in-
clude transforming growth factor beta (TGF-b), interleukin-6 (IL-6), which can suppress
T cell responses, and interleukin-12 (IL-12), which can enhance T-helper responses.11
A major function of macrophages is to present antigens to a variety of T cell popula-
tions. These T cells produce IFN gamma, which activates macrophages to instigate the
intracellular killing of mycobacteria through reactive nitrogen and reactive oxygen medi-
ated mechanisms.12,13,14 Hougardy and colleagues demonstrated that regulatory T cells

31
suppress IFN-gamma responses to protective antigens, such as HBHA; this suggests
another escape mechanism of M. tuberculosis.13
Mycobacterial Antigens
In mice, protective immunity against TB can be induced by live, but not dead, mycobac-
teria while delayed-type hypersensitivity (DTH) can be induced by either dead or live
organisms or by cell wall components. This phenomenon suggests that protection and
tuberculin reaction are dissociable; that secreted antigens are important relative to cell-
bound or structural antigens, and that the way the antigen is presented to the immune
system is crucial for immunity. Among the prime candidates of protective antigens are
ESAT-6,15 and the 30 kDa a or 85 B antigen.3 Another protective antigen that has come
to prominence is heparin-binding hemagglutinin (HBHA), a mycobacterial antigen that
can induce mycobacterial aggregation. Presence of antibodies against HBHA (anti-
HBHA antibodies) inhibits hemagglutination, mycobacterial aggregation, as well as at-
tachment to epithelial cells.16 HBHA has also been shown to stimulate secretion of high
levels of IFN-γ by peripheral blood lymphocytes among subjects with latent TB infec-
tion.17,18

THE ROLE OF T LYMPHOCYTES

T Cell-Derived Cytokines11
In animal studies, CD4 T cell (T-helper cell) depletion resulted in severe TB, while
CD4 T cell transfer resulted in the protection of recipients. In humans, HIV infection with
CD4 depletion resulted in severe TB and higher levels of mycobacteremia. These data
point to the key role of CD4 T cells in antimycobacterial immunity.
CD4 T cells show varied cytokine production with a subset (termed Th1) producing in-
terferon-gamma (IFN-g), tumor necrosis factor-alpha (TNF-a), and IL-2; these are pro-
inflammatory cytokines. IFN-g is known to enhance macrophage intracellular killing for
many intracellular pathogens. Its role in macrophage intracellular killing of M. tuberculo-
sis has been demonstrated in mice. At the other extreme, a subset of CD4 T cells—
called Th2, produce cytokines important in humoral immunity. Th1 responses appear to
have a protective role in TB. Diminished Th1 responses have been seen in peripheral
blood mononuclear cells in pulmonary TB patients with no enhancement of Th2 re-
sponses.19 Also, high levels of Th1 cytokines have been demonstrated in human pleu-
ral effusions.20
The balance between Th1 and Th2 responses appears to be important in TB disease.
Numerous studies have implicated the Th1 cytokines as protective although no clear in-
vitro demonstration of macrophage activation with recombinant IFN-g to achieve M. tu-
berculosis intracellular killing has been noted to date. The relative contributions of other
cell types to the total pattern of cytokine production in TB are also not known. It is likely
that it is the overall pattern of cytokine effects which is important in-vivo and that agents
(viral infections e.g. measles, immunosuppressants and others) which alter this balance
could significantly affect protection against M. tuberculosis or could even alter clinical
presentation.

32
Cells mediating the tuberculin skin test (delayed-type hypersensitivity) are CD4-
positive, producing mostly Th1 cytokines. DTH response is associated with, but not
identical to, cell-mediated immunity. The reasons may be: (1) DTH responses are a
function of CD4 T cells, whereas protective immunity involves CD8 T cells (cytotoxic
T lymphocytes) and unconventional T-cell subsets as well; (2) PPD does not contain
all the antigens derived from M. tuberculosis; and (3) in TB patients who have granulo-
ma formation but have negative tuberculin test, T cells may be trapped in granulomas
reflecting their accumulation at the site of defense.21
A recognized subset of T-helper cells, called Th17 cells, were found to be an important
modulator of inflammation and CD4+ T-cell recall or memory response. Th17 cells se-
crete IL-17, can recruit neutrophils, monocytes and CD4+ T-cells producing IFN-
gamma, and stimulate chemokine expression.22
Anergy, indicated by a negative tuberculin test, reflects suppression of DTH from pro-
cesses which interfere with Th1 response i.e. malnutrition, HIV infection, steroid thera-
py and severe tuberculosis itself (as a result of production of inhibitory cytokines like
TGF-b). Anergy is often transient and reverts to normal when underlying causes are
resolved.23
The possibility of modifying deleterious immune responses or shunting the immune
response to a direction favorable to the patient is among the driving forces behind re-
search on cytokines and tuberculosis.
Cytolytic or Cytotoxic T Lymphocytes
Cytolytic or cytotoxic T cells kill cells harboring intracellular pathogens including M. tu-
berculosis. These cells either exhibit granzyme/perforin-mediated killing of target cells
(in which the cell membrane is destroyed as an initial step) or induce apoptosis (in
which destruction of target cell DNA occurs followed by lysis of the cell). Although CD8
T cells are known as cytotoxic T cells, they are also capable of lysing monocytic cells
infected with M. tuberculosis, mostly through apoptosis.2, 15 CD8 T cells have likewise
been shown to be cytotoxic against M. bovis-infected macrophages in-vitro.24 The rela-
tive contribution of cytolytic T cells to the total protective immune response to TB is un-
known but is expected to be significant.

ROLE OF GENETIC DETERMINANTS

A BCG resistance gene (BCGr) linked with the molecule Nramp (natural resistance as-
sociated macrophage protein) has been characterized in mice associated with protec-
tion against S. typhimurium and L. donovani. However, evidence that it protects mice
against virulent M. tuberculosis is equivocal at best.25 Likewise, a human homologue to
Nramp has been found on chromosome 2. There is evidence that variant alleles in the
Nramp1 gene are associated with increased replication of mycobacterial rather than
susceptibility to TB.26
Epidemiologic data from twin studies, however, indicate that susceptibility has genetic

33
determinants and may be related to the largely unexplored relationship between histo-
compatibility leukocyte antigen (HLA) complex and TB. Studies on the completed hu-
man genome sequence could give leads in predicting human susceptibility genes.3,27

IMMUNE RESPONSE AND COURSE OF TB INFECTION3

If not removed by mucociliary defenses, TB bacilli enter the alveoli where they encoun-
ter alveolar macrophages; there may be unknown genetic determinants making the
macrophages more permissive to the growth of these bacilli. TB bacilli can also evade
intracellular killing mechanisms and get carried to lymph nodes and other organs.
In the lungs, macrophages may introduce antigen to T cells resulting in its expansion,
including the development of memory T cells (of which DTH cells may be a subset).
The result may be tuberculin-positive persistence and/or long-term protection. The in-
flammatory Th1 responses elicited may result to local pulmonary infiltrates and hilar
adenopathy–the picture of primary complex—resulting in containment. Other children
may get on such a response but sometimes fail to contain the bacilli, thus resulting to a
progressive disease: this could be a consequence of the imbalance between proinflam-
matory and immunosuppressive effects. Still, other children may fail to mount an effec-
tive Th1 response, intrinsically or through immunosuppression (even a heavy bacterial
load may cause immunosuppressive cytokines to predominate), and develop miliary
TB, which is characterized by poor inflammatory and DTH responses and which often
occurs among the very young who may have inadequate immune responses.
The development of progressive disease occurs in about 10% of affected individuals.
Even after adequate treatment, some bacilli persist in a dormant state, which is known
as latent TB infection—a state where the individual is clinically asymptomatic. Reactiva-
tion of dormant bacilli leads to active disease.28 Factors that promote development and
maintenance of latency include: low concentrations of oxygen and nurtrient in chronic
granulomas; and local production of TNF alpha and nitric oxide (NO).29-32 Animal stud-
ies show TNF alfa, interferon gamma, and NO significantly maintain infection in the la-
tent state.31,32
In cases where infection is contained, depression of cell-mediated immunity (e.g. with
HIV infection, malnutrition, disease or drugs) may lead to reactivation. Reactivation in
15% of cases occurs at extrapulmonary sites without apparent lung lesions. 33,34
Immune response in the very young:
There is relative immaturity of the immune system of young children. Those under age
1 year are particularly susceptible to develop tuberculosis, and are at increased risk of
developing disseminated disease, particularly TBM. Innate and adaptive responses of
young children are comparatively weaker allowing for more serious, advanced disease
states. In animal models, there is suboptimal macrophage functionality to explain im-
paired innate responses. Dendritic cells, which play an important role in the regulation
of immune responses following infection with the tubercle bacilli, have been shown to
be less functional in children and young animals. Studies on children with congenital

34
infection identified possible reasons for the development of disease and these include:
1) impaired antigen-specific CD4þ T-lymphocyte responses, 2) decreased capacity of
neonatal T-lymphocytes to secrete IFN gamma and TNF alpha, 3) cytokine production
leans towards a Th2 response, and 4)suboptimal response of CD8þ T-
lymphocytes.35,36.37

See Chapter 5 (Pathogenesis) Sxn III for more on immunopathogenesis.

35
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of Infectious Diseases 1989; 11 (supplement 2): S366-8.

2. Barnes PF : Immunology of Tuberculosis. Seminars in Pediatric Infectious Diseases 1993;

vol 4 (no 4): 232-40.

3. Ellner JJ: The Immune Response in Human Tuberculosis – Implications for Tuberculosis
Control. The Journal of Infectious Diseases 1997; 176:1351-9.

4. Riley LW: Phagocytosis of M. tuberculosis in Rom WN, Garay S (ed): Tuberculosis, Boston,
New York, Little, Brown and Company, 1996; 281-9.

5. Schlesinger LS. Entry of M. tuberculosis into mononuclear phagocytes in Shinnick TM (ed.)

Tuberculosis: Current Topics in Microbiology and Immunology, Berlin, Heidelberg, Springer-
Verlag, 1996; 71-96.

6. Divangahi M. M. tuberculosis evades macrophage defenses by inhibiting plasma membrane

repaif. Nature Immunol. Doi:10.10381ni.1758.

7. Vergne I, Chua J, Lee HH, Lucas M, Belisle J et al.Mechanism of phagolysosome biogene-

sis block by viable Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA 2005; 102: 4033
–8.

8. Walburger A, Koul A, Ferrari G, Nguyen L, Prescianotto-Baschong C et al. Protein kinase G

from pathogenic mycobacteria promotes survival within macrophages. Science 2004; 304:
1800–4.

9. Fratti RA, Chua J, Vergne I, Deretic V. Mycobacterium tuberculosis glycosylated phosphati-

dylinositol causes phagosome maturation arrest. Proc. Natl. Acad. Sci. USA 2003; 100:
5437–42.

10. Vergne I, Singh S, Roberts E, Kyei G, Master S et al. Autophagy in immune defense against
Mycobacterium tuberculosis. Autophagy 2006; 2: 175–8

11. Barnes PF and Rom WN. Cytokine Production in Tuberculosis in Rom WN and Garay S
(ed.): Tuberculosis, Boston, New York, Little Brown and Company, 1996; 291-303.

12. Ribeiro-Rodrigues R, Resende Co T, Rojas R, Toossi Z, Dietze R et al. A role for

CD4+CD25+ T cells in regulation of the immune response during human tuberculosis. Clin.
Exp. Immunol. 2006; 144: 25–34.

13. Hougardy JM, Place S, Hildebrand M, Drowart A, Debrie AS et al. Regulatory T cells de-
press immune responses to protective antigens in active tuberculosis. Am. J. Respir. Crit.
Care Med. 2007; 176: 409–16.

14. Rook GA. Th2 cytokines in susceptibility to tuberculosis. Curr.Mol. Med. 2007; 7: 327–37.]

15. Kumararatne DS and Dockrell HM. Mechanisms of Antimycobacterial immunity. Bailliere‘s

Clinical Infectious Diseases, 1997, 4(2): 131-56.

16. Menozzi FD, Rouse JH, Alavi M, Laude-Sharp M, Müller J, et al. (1996) Identification of a

36
 heparin-binding hemagglutinin present in mycobacteria. J Exp Med 184: 993–1001.

17. Masungi C, Temmerman S, Van Vooren JP, Drowart A, Pethe K, et al. (2002) Differential T
and B cell responses against Mycobacterium tuberculosis heparin-binding hemagglutinin
adhesin in infected healthy individuals and patients with tuberculosis. J Infect Dis 185: 513–
520.

18. Temmerman S, Pethe K, Parra M, Alonso S, Rouanet C, et al. (2004) Methylation-

dependent T cell immunity to Mycobacterium tuberculosis heparin-binding hemagglutinin.
Nat Med 10: 935–941.

19. Zhang M, Lin Y, Iyer DV et al. T-cell cytokine responses in human infection with Mycobacte-
rium tuberculosis, Infection and Immunity, 1995, 63: 3231-34.

20. Barnes PF, Fong SJ, Brennan PJ et al. Local production of TNF and IFN- in tuberculous
pleuritis, Journal of Immunology, 1990, 145: 149-154.

21. Kauffmann SHE. Immunity to Extracellular Bacteria in. Paul WE (ed.) Fundamental Immu-
nology, Philadelphia, Lippincott-Raven, 1999; 1335-72.

22. Khader SA, Bell GK, Pearl JE, Fountain JJ, Rangel-Moreno J et al. IL-23 and IL-17 in the
establishment of protective pulmonary CD4+ T cell responses after vaccination and during
Mycobacterium tuberculosis challenge. Nat. Immunol. 2007; 8: 369–77

23. Karim M and Ellmer JJ. Mechanisms of Anergy in Rom WN and Garay S (ed.): Tuberculo-
sis, Boston, New York, Little Brown and Company, 1996; 343-51.

24. Turner J and Dockrell HM, Stimulation of Human peripheral blood mononuclear cells with
live Mycobacterium bovis BCG activates cytolytic CD84 T cells in vitro, Immunology, 1996;
87: 339-42.

25. Medina E, North RJ, Evidence inconsistent with a role for the BCG gene (Nramp1) in re-
sistance of mice to infection with virulent Mycobacterium tuberculosis., Journal of Experi-
mental Medicine, 1996; 183: 1045-51.

26. Soborg C, Andersen AB, Madsen HO, Kok-Jensen A, Skinhoj P, Garred P. Natural-
Resistance-Associated Macrophage Protein 1 Polymorphisms are Associated with Micros-
copy-Positive Tuberculosis. The Journal of Infectious Disease. 2002;186:577-21

27. Initial sequencing and analysis of the human genome. The genome international sequenc-
ing consortium. Nature, 2001; 409: 860-921

28. Palomino JC, Leão SC, Ritacco V. Tuberculosis 2007 From basic science to pa-
tient care TuberculosisTextbook.com First Edition
29. Parrish NM, Dick JD, Bishai WR. Mechanism of latency in Mycobacterium tubercu-
losis. Trends Microbiol 1998; 6: 107-12.
30. Voskuil, M. I., Schnappinger, D., Harrell, M. I., Visconti, K. C., Dolganov, G. M.,
Sherman, D. R. & Schoolnik, G. K. (2002). Inhibition of respiration by nitric oxide
induces a Mycobacterium tuberculosis persistence program. J Exp Med 198, 705–
713.

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31. Arriaga AK, Orozco EH, Aguilar LD, Rook, GAW, Hernandez-Pando R. Immunologi-
cal and pathological comparative analysis between experimental latent tuberculosis
infection and progressive pulmonary tuberculosis. Clin Exp Immunol 2002; 128: 229
-37.
32. Flynn JL, Scanga CA, Tanaka KE, Chan J. Effects of aminoguanidine on latent mu-
rine tuberculosis. J Immunol 1998; 160: 1796-806.
33. Farel LS, Lowell AM, Meador MP. Extrapulmonary tuberculosis in the United
States. Am J Epidemiol 1979; 109: 205-17.
34. Hopewell PC. Overview of clinical tuberculosis. In: Bloom BR. Ed. Tuberculosis:
pathogenesis, protection, and control. Washington DCASM Press 1994; pp. 25-46.
35. Eley BS and Beatty DW. The basic immunology of tuberculosis. In: Tuberculosis: A
Comprehensive clinical reference. Schaaf HS and Zumla AI (eds). Saunders Else-
vier 2009, 75-86.
36. Lewinsohn DA, Gennaro ML, Scholvinck L, et al. Tuberculosis immunology in chil-
dren: diagnostic and therapeutic challenges and opportunities. Int J Tuberc Lung
Dis 2004;8:658–674.
37. Smith S, Jacobs RF, Wilson CB. Immunobiology of childhood tuberculosis: a win-
dow on the ontogeny of cellular immunity. J Pediatr 1997;131:16–26

38
 5
Pathogenesis
Maria Anna Pablo-Baňez, MD
Cynthia Cecilia J de Ocampo, MD

OUTLINE
1 Overview

2 Source of Infection

3 Risk Factors for Acquiring Infec-

tion

4 Transmission and Portal of Entry

5 Incubation Period

6 Pathogenesis and pathophysiolo-

gy of tuberculosis

7 Timetable of Tuberculosis

39
OVERVIEW
A series of events occurs from exposure to M. tuberculosis, its transmission and the
development of infection and disease. A good grasp of the natural history enables one
to understand the broad spectrum of disease and the approach to management.

SOURCE
Children are usually infected by a tuberculous adult or adolescent in the immediate
household, but exposure can occur in a school, day care, or other closed settings. The
risk of infection is greatest with a household exposure to a sputum smear-positive
source.1,7 Contributory environmental factors, which increase the probability of trans-
mission, include overcrowding and poor ventilation.2 ,7

RISK FACTORS FOR ACQUIRING INFECTION

Acquiring tuberculosis (TB) involves a close interaction between the host and the or-
ganism. Risk factors for infection to occur are present in the host and the organism. A
major host factor is an immunocompromised state, whether primary or ac-
quired.3Although genetic susceptibility to infection has been proposed as a risk factor,
there appears to be no solid data to implicate a single genetic trait.4 Specific for M. tu-
berculosis is the identification of several virulence factors through genomic sequencing.
5

According to the World Health Organization (WHO), the following are the key risk fac-
tors for TB:1

 Household contact with a newly diagnosed smear (+) case

TB infection in children depends on the infectivity, proximity and duration of con-
tact with the source case. After a prolonged household exposure with a sputum
smear positive source, 60-80% of children become infected. When the source
case is smear-negative, 30-40% of children become infected. TB morbidity among
children with a history of family exposure is 2.5 times that in children without
known exposure.6,7

 Age less than 5 years

Age is the most important factor that determines the risk of progression to disease
following primary infection among immune-competent children. Infants are at
greatest risk. The risk decreases but remains significant in the second year of life
and is lowest in children 5-10 years old.7

 Immunocompromised state (e.g. severe malnutrition, HIV)

Host immunity is also considered a major determinant for disease development.
Immunocompromised children such as those with severe malnutrition, HIV, or oth-
er forms of immunosuppression are at high risk.7
40
There are additional groups who are also considered at high risk for exposure and in-
fection, which include the following8:
 Residents and employees of closed settings (e.g. correctional institutions, nursing
homes, homeless shelters, hospitals serving high-risk populations, drug treatment
centers)
 Medically underserved, low-income populations
 High-risk racial or ethnic minority populations
 Injection drug users
 Children exposed to adults with certain medical conditions (e.g. diabetes mellitus,
silicosis, cancer, end-stage renal disease, gastrectomy)

TRANSMISSION AND PORTAL OF ENTRY

Tuberculosis being an airborne disease, tubercle bacilli are transmitted through inhala-
tion of droplet nuclei from a contagious source. The infective nuclei, measuring 5 micra,
are small enough to avoid being swept away by the mucociliary system of the respirato-
ry tract. Such nuclei are eventually deposited in the alveoli. Although, theoretically, a
single organism may cause disease, it is generally accepted that about 5 to 200 inhaled
bacilli are necessary for a successful infection.2
Perinatal transmission of M. tuberculosis from the mother to her offspring has been re-
ported. This can occur transplacentally through the umbilical vein from a mother with
primary hematogenous TB during pregnancy, aspiration/ingestion of infected amniotic
fluid in utero or during delivery, or inhalation of TB bacilli at or soon after delivery, which
is the most common route of perinatal transmission.8

INCUBATION PERIOD
Incubation period or the time between entry of the tubercle bacilli into the body and the
development of tissue hypersensitivity manifested as a reactive tuberculin test, ranges
from 3 to12 weeks8,10. It may be shorter when the inoculum is large.8,9

PATHOGENESIS AND PATHOPHYSIOLOGY

Primary Tuberculosis
Much of our knowledge about the early pathogenesis of primary TB infection comes
from animal model studies.11,13
Primary infection occurs in persons without previous exposure to tubercle bacilli. Fol-
lowing inhalation of the organism, scavenging non-activated, alveolar macrophages
ingest the tubercle bacilli. Once inside, the bacilli may get destroyed or inhibited, de-
pending upon the virulence of the organism and the innate microbicidal ability of the
macrophages. If the macrophages fail to destroy the bacilli, such bacilli undergo unre-

41
strained replication. Some macrophages carry the bacilli from the lung to regional (hilar
and mediastinal) lymph nodes, from which they may be disseminated via lymphatics or
bloodstream to other sites, including kidneys, meninges, epiphyseal plates of long
bones, vertebrae and apical segments of the upper lobes of the lungs.
Eventually, the logarithmic increase in the number of bacilli is inhibited by the develop-
ment of both cell-mediated immunity (CMI) and delayed-type hypersensitivity (DTH).
Infected macrophages present tuberculous antigens to T lymphocytes.
T lymphocytes get sensitized, to produce a progeny of similarly reactive cells that se-
crete lymphokines (IFN gamma and TNF) and activate macrophages, thereby increas-
ing their concentration of lytic enzymes and greatly enhancing their capacity to kill the
bacilli. These lytic enzymes in the activated macrophages, which include epitheliod
macrophages and Langhans giant cells, however, may also cause tissue necrosis if
released into surrounding tissue.
The development of a population of activated lymphocytes responsive to M. tuberculo-
sis antigen constitutes the delayed-type hypersensitivity response (DTH) to the organ-
ism. The related development of activated macrophages with increased capacity to in-
gest and destroy the bacilli comprises the cell-mediated immunity (CMI).These re-
sponses work together to contain the infection.
The classic lesion in the lung of primary tuberculosis is a caseous granuloma called the
Ghon focus. It is characteristically located peripherally in any part of the lungs, close to
the pleura. A granuloma has a soft, semi-soild core surrounded by epithelioid macro-
phages, Langhans giant cells and lymphocytes.
Dissemination of the bacilli from the primary granuloma in the lungs to the hilar nodes
causes a granulomatous lymphadenitis. The combination of granulomatous hilar lym-
phadenitis and Ghon focus forms the Ghon complex.
In most instances, the primary infection is controlled with a reactive tuberculin skin test
as the only evidence of infection. In both the lungs and lymph nodes,the lesions of the
Ghon complex heal by fibrosis,but subsequent calcification may occur. While most of
the bacilli die, a few may remain viable and reactivate later, if immune mechanisms
wane or fail.11,12,13,14

Progressive Primary Tuberculosis

A less common alternative course is progressive primary tuberculosis that frequently
results to a disseminated disease. This occurs when the immune system is weakened
and fails to control the multiplication of TB bacilli. This may be brought about by any
state of immunosuppression and observed more commonly among children under 2
years of age.
The primary focus enlarges steadily into a large caseous center, then liquefies to form a
primary cavity allowing TB bacilli to multiply extensively. The enlarging focus leads to
erosion of infected debris into a bronchus, causing further intrapulmonary spread. Like-
wise, the enlarging hilar and mediastinal nodes may also compress the bronchi to
42
cause collapse of the distal lung, as in the ―middle lobe syndrome.‖ If the obstruction is
partial, this may cause air-trapping and overdistention of a lobe or segment.
While an occult lymphohematogenous spread frequently occurs early in primary TB be-
fore the development of hypersensitivity to tuberculous antigens, one form of dissemi-
nated TB is miliary disease, which is analogous to bacterial sepsis. This occurs when
progressive caseous necrosis,usually in the hilar lymph node, erodes into a blood ves-
sel such as a pulmonary vein, allowing the bacilli to spread most commonly into the
lungs, liver, spleen, bone marrow, and meninges. Pathologically and radiographically,
miliary TB consists of numerous small, yellow-white nodules, less than 2 mm (millet
seed-like) in all affected organs.8,12 14 However,the term miliary TB is now used to de-
note all forms of progressive, widely disseminated hematogenous TB, even if the clas-
sical pathologic or radiologic findings are absent15

Secondary (Adult-type) TB
This occurs following re-infection with M.tuberculosis or reactivation of dormant bacilli in
the Ghon focus or complex. Reactivation is usually brought about by immunosuppres-
sion from whatever cause. The lungs, particularly in the apices, are most often affected
due to higher oxygen tension and poor lymphatic drainage, but infection may be widely
disseminated.
In secondary TB, tissue destruction is brought about by progressive, frequently exten-
sive caseous necrosis due to inability to contain the bacteria. The course is variable.
The localized inflammation may undergo organization and healing into a fibrocalcified
nodule, progress into caseating granulomas with cavitation, or disseminate to other or-
gans via rupture into a bronchus, pulmonary artery, pulmonary veins or lymphat-
ics.8,12,14

TIMETABLE OF TUBERCULOSIS
Wallgren‘s timetable of TB previously described the early course and its progression
over time (see figure 5.1)8,19. Complications of tuberculosis occur during the first five
years after the initial infection. An arrested or silent lesion may reactivate, heralding the
complications.

43
Figure 5.1 Wallgren’s Timetable of Tuberculosis8,19

The end of the initial asymptomatic incubation period, around 3-12 weeks after the pri-
mary infection is characterized by hypersensitivity reactions such as fever, erythema
nodosum, positive TST response, and primary complex on chest x-ray. Hypersensitivi-
ty to tuberculoprotein antigens once developed after infection is expected to remain re-
active for life.
It is estimated that an immunocompetent adult without treatment has a 5-10% risk to
develop the disease during their lifetime.8,10,16 On the other hand, serious, life-
threatening forms of the disease will develop within 1 to 2 years in as many as 40 per-
cent of immunocompetent infants with untreated tuberculosis infection.8,10
One to three months after the primary infection, following the occult hematogenous
spread during the incubation, is the highest risk for TB meningitis and disseminated
(miliary) TB. However, TB meningitis and military tuberculosis may also occur after any
time interval.
Around 3 to 7 months after the primary infection is the period of secondary airway in-
volvement due to infected lymph nodes in children younger than 5 years of age. Large
reactive pleural effusions can also occur during this time but more often among children
older than 5 years of age.
44
Approximately 1 to 3 years after the primary infection is the period of osteoarticular TB
in children under 5 years of age, and adult type of disease among adolescents. The risk
of TB progression following primary infection is much less by the time calcification ap-
pears. In adolescents, adult type disease may have a delayed clinical onset after calcifi-
cation, ranging from as early as 3 months to as late as 20 years.
More than 3 years after the primary infection, when the calcification is completed, the
highest risk period is said to have passed. However, some of the very late manifesta-
tions of TB, including primary pulmonary reactivation may occur. Renal involvement
appears much later, which is usually 5 to 25 years after the initial infection.7
With regards to TB-related mortality, infants have the highest risk following primary in-
fection at 5 to 10% as they are more likely to develop more severe forms of TB. The
risk decreases to 1% between 1 to 4 years old and with the lowest risk at < 0.5% at 5 to
14 years old. The risk again increases to more than 2% after 15 years of age. 7 In a re-
port by Schaaf et al17 it was estimated that 13% of children under 3 months with TB
died. Among children below 10 years old, majority of mortality occurred within the 1 st
year following the primary infection, but for older children who developed adult type
cavitary disease, mortality declined more slowly.7 TB-related mortality resulting from a
sputum smear-positive household source case is almost twice as high compared to an
infection from an unknown source case. Mortality rate is three times increased among
TST-positive reactors than those who are TST-negative reactors.18

45
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Saunders Elsevier Ltd., Oxford, UK; 2009:129-132
17. Schaaf HS, Gie RP, et al.Tuberculosis in infants less than 3 months of age.Arch Dis
Child .1993;69:371-374
18. Marais BJ, Gie RP, Schaaf HS, et al. The Clinical Epidemiology of Childhood Pul-
monary tuberculosis: a critical review of literature from the pre-chemotherapy era.
Int J Tuberc Lung Dse. 2004; 8:278-285
19. Wallgren, A. Primary pulmonary tuberculosis in children. Am J Dis
Child.1935;49:1105-1136

47
 6
Clinical Forms
Gyneth Lourdes G Bibera, MD,
Mary Ann C Bunyi, MD,
Michelle C Cuvin, MD,
Fatima I Gimenez, MD

OUTLINE
1 Overview

2 Definition of Terms

3 Pulmonary TB

4 Extrapulmonary TB

48
OVERVIEW
Mycobacterium tuberculosis can produce infection and disease in almost every tissue
and organ in the body. The disease is usually the result of dissemination from an initial
primary focus. Since infection usually takes place by way of the respiratory tract, the
lung is the first organ involved and it is here that the initial major manifestations of dis-
ease occur.
Distinction must be made between infection and disease. With primary infection, pa-
tients are asymptomatic. When disease is present, early manifestations are mild with
nonspecific systemic symptoms of low grade fever, lassitude, easy fatigability, anorexia,
weight loss, malaise, and night sweats which are common to many illnesses in child-
hood. With progression and chronicity, symptoms may be respiratory or other mean
depending on the main site.

DEFINITION OF TERMS
TB Exposure – a condition in which a child is in close contact with an active adult TB
cases, but without any signs and symptoms of TB, with negative TST reaction, and no
radiologic and laboratory findings suggestive of TB.1
TB Infection or Latent TB infection (LTBI) – a condition in which a child has no signs
and symptoms presumptive of TB nor radiologic or laboratory evidence, but has a posi-
tive TST reaction1
TB disease – a presumptive TB who after clinical and diagnostic evaluation (TST and/
or radiology) is confirmed to have TB. Classification is either based on the bacteriologi-
cal status or on the anatomical site.1

 Bacteriological status1
 Bacteriologically confirmed – biological specimen is positive by smear mi-
croscopy, culture or rapid diagnostic tests (such as Xpert MTB/RIF)
 Clinically diagnosed – does not fulfil the criteria for bacteriological confirma-
tion but has been diagnosed with active TB by a clinicial or other medical
practitioner who has decided to give the patient a full course of TB treat-
ment. Cases diagnosed on the bases of Xray abnormalities or suggestive
histology, and extrapulmonary cases without laboratory confirmation are also
included.

 Anatomical Site2
 Pulmonary TB (PTB) – refers to a case of tuberculosis involving the lung pa-
renchyma. A patient with both pulmonary and extrapulmonary TB should be
classified as a case of pulmonary TB
 Extrapulmonary TB (EPTB) – refers to a case of tuberculosis involving or-
gans other than the lungs (eg. Larynx, pleura, lymph nodes, abdomen, geni-
tourinary tract, skin, joints and bones, meninges). Histologically diagnosed
EPTB through biopsy of appropriate sites will be considered clinically diag-

49
 nosed TB. Laryngeal TB, through likely sputum smear-positive, is consid-
ered an extrapulmonary case in the absence of lung infiltrates on chest x-
ray.

PULMONARY TB (PTB)
Primary Disease
This is the initial of children who inhale the Mycobacterium tuberculosis. it contains 3
elements namely: the Ghon focus, lymphadenitis, and lymphangitis. In 95% of cases,
it heals by fibrosis and/or calcification.
Primary TB in children is asymptomatic in up to 65% of patients.2 There are no striking
clinical manifestations. Signs and symptoms can vary substantially in the population
although infants and young children are likely to have more signs and symptoms than
school-aged children. Occasionally, the initiation of the infections is marked by several
days of low grade fever and mild cough.3 Fever alone or sometimes with pleuritic or ret-
rostenal pain of gradual onset can also be seen. Fever can be low grade in character
which can last for an average of 14 to 21 days.4
Progressive Primary Tuberculosis
This is a condition which develops when initial infection fails to heal and continues to
progress over a period of months or years, causing further pulmonary and even distant
organ involvement
Secondary (Reactivation) Tuberculosis2
A condition which represents reactivation of an old, possibly subclinical infection. This
occurs in less than 10% of the cases of primary infection. This tends to produce more
damage to the lungs than does primary tuberculosis
This is more common in adolescents than in younger children. Clinical manifestations
include chronic or persistent cough, prolonged fever, chest pain, hemoptysis, and su-
praclavicular adenitis. Most of these features may however improve within several
weeks after starting effective treatment, but the cough may persist for several months.
Miliary Tuberculosis
This refers to clinical disease resulting from the hematogenous dissemination of Myco-
bacterium tuberculosis. It can arise as a result of progressive primary infection or via
reactivation of latent form with subsequent spread. It is considered to be the most com-
mon clinically significant form of disseminated tuberculosis which occurs when massive
numbers of tubercle bacilli are released into the bloodstream causing disease in two or
more organs.2 Originally a pathologic and then a radiographic description, the term mili-
tary tb is now used to denote all forms of progressive, widely disseminated hematog-
enous tuberculosis.4
The clinical presentation of military TB is protean and non-specific, depending on the
load of organisms and where they lodge.3 Manifestations can be acute and explosive
and the patient may become gravely ill in several days3 but are more likely to be sub-
50
acute or chronic. This can also present with relatively acute onset and rapid clinical
course such as multiorgan failure, septic shock and acute respiratory distress syn-
drome (ARDS). The subacute or chronic presentations of military TB include failure to
thrive, fever of unknown origin and dysfunction of one or more organ systems including
the brain.5,6 The most common extrapulmonary sites of disease include the lymphatic
system, bones and joints and the liver. In children with military tuberculosis, clinical
presentation is similar to that in adults. Chills, night sweats, hemoptysis, and produc-
tive cough have been reported less frequently in the pediatric population while periph-
eral lymphadenopathy and hepatomegaly are more common in children compared with
adults. Signs or symptoms or peritonitis are found in 20 to 40% of patients with ad-
vanced disease.3

EXTRAPULMONARY TB
Endobronchial tuberculosis
This condition can be a complication of primary tuberculosis which results to enlarge-
ment of peribronchial lymph nodes with subsequent compression or intrabronchial,
which is the nodal extension into the bronchus. Such obstruction can result to sudden
death due to asphyxia, obstructive emphysema (partial obstruction with hyperaeration
of a lobar segment), or atelectasis of a distal segment (complete obstruction of the lu-
men). The right middle lobe is more vulnerable by its anatomical feature and drainage.
Signs and symptoms of progression include moderately high fever, anorexia, night
sweats, loss of weight and paroxysmal cough ending in cyanosis. Crepitant rales and
expiratory wheezes are likewise noted, often mistaken for pertussis or bronchial asth-
ma.
Cervical Lymph Nodes (Scrofula), adenitis
Tuberculous lymphadenitis is the most common form of extrapulmonary TB and proba-
bly the most common cause of chronic lymhadenitis in children. TB lymphadenitis in
the cervical region is known as scrofula.7,8 Narang et al reported the prevalence of this
disease in children up to 14 years of age is approximately 4.4 per 1000 cases in India. 9
In the Philippines, a study by Santos reported that TB of the lymph nodes accounts for
6.1% of extrapulmonary tuberculosis with mean age of 5.8 years.10 The disease is pre-
sent at all ages but more frequently at ages 10 to 18 years (39.1%). The most common
location was the anterior cervical space in children (49.4%), followed by the axillary
and supraclavicular areas.11,12
TB lymphadenitis may occur during primary tuberculous infection or as a result of reac-
tivation of dormant foci or direct extension from a contiguous focus. The infection may
spread from primary focus to regional lymph nodes and continue to spread via the lym-
phatic system to other nodes or may pass through the nodes to reach blood stream,
from where it can spread to virtually all organ of the body.13
The most common presentation is unilateral single or multiple slowly growing non-
tender lymphadenopathy which can be present for up to 12 months before diagnosis.

51
Early in the course, the nodal enlargement is usually firm, painless, rubbery, discrete or
matted noted fixed to surrounding structures; the overlying skin may be indurated. The
patient may have low-grade fever and sometimes acute respiratory infections precipi-
tate or aggravate superficial tuberculous lymphadenitis.7,12 Other systemic clinical signs
such as weight loss and tiredness may be present. Concomitant primary pulmonary
tuberculosis is also reported in several studies.2,11
Fistula formation is seen in nearly 10% of tuberculous cervical lymphadenitis. Lymph
node abscess may burst infrequently leading to a chronic non-healing sinus and ulcer
formation. Direct extension of the tuberculosis into the skin from the underlying struc-
tures or by contact exposure to tuberculosis can also be seen as scrofuloderma.13
Cervical lymph nodes may be palpable in normal young children. Enlargement can be
caused be infections other than TB, such as carious teeth, infected tonsils, acute upper
respiratory tract infection and Hodgkin‘s disease. Hence, diagnosis of TB as a cause of
lymphadenitis should include a careful history of exposure to infectious tuberculosis,
tuberculin skin test and chest radiography.
The use of fine-needle aspiration, combined with new, rapid molecular diagnostic tests,
can improve the diagnosis of tuberculous lymphadenopathy and provide valuable infor-
mation for appropriate treatment.12,15,16
Central Nervous System
Various forms of CNS tuberculosis include tuberculous meningitis, serous meningitis,
tuberculoma or TB brain abscess or spinal tuberculous leptomeningitis.
Tuberculous meningitis
Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis
and causes substantial morbidity and mortality in children and adults. 17,18 A local study
by Santos noted meninges are the most common organ involved in extrapulmonary tu-
berculosis with mean age of 6.2 years.19 However, deaths due to tuberculous meningi-
tis worldwide each year are unknown due to difficulties in diagnosis and under reporting
in children, especially when infection causes early death.14 This disease has been esti-
mated to develop in one of every 300 untreated primary infections, most frequently in
children younger than 6 years but uncommon in infants younger than 4 months. TBM
usually appears within 2 to 6 months after initial infection, and accompanies miliary tu-
berculosis in approximately 50 percent of cases.14,20
Tubercle bacilli are distributed during the lymphohematogenous spread into all parts of
the body including the central nervous system. However, they do not multiply as well in
nervous system, as in other areas as the lungs. Thus, CNS tuberculosis, although an
early manifestation of infection, usually does not appear simultaneously with miliary
spread. Caseous foci in the brain and meninges may remain dormant for many years
and may discharge tubercle bacilli into the subarachnoid space. A thick gelatinous exu-
date develops around the basal cisterns, Sylvian fissure and the brainstem causing ob-
struction leading to hydrocephalus and papilledema. Vasculitis can result to thrombosis
and subsequent infarction.14,21

52
1. Clinical Manifestations and Diagnosis
TB meningitis is typically subacute with broad and may be nonspecific clinical course
making early diagnosis difficult.17,21,22 Also, the low yield of microbiological confirmation
complicates diagnosis. A high index of suspicion is needed to make an early diagnosis
and the key factors to diagnose TBM is the persistence of symptoms, detection of pul-
monary or other forms of tuberculosis and identification of a recent close contact with
infectious tuberculosis (within the past 12 months). 3,11,12,13
Onset of tuberculous meningitis is usually gradual occurring over a period of approxi-
mately 3 weeks. The clinical course is divided into three stages: The first stage is char-
acterized by personality changes, irritability, anorexia, listlessness, and some fever.
After 1 or 2 weeks, the second stage begins with signs of increased intracranial pres-
sure and cerebral damage appear: drowsiness, stiff neck, cranial nerve palsies, ine-
quality of the pupils, vomiting, tache cérébrale, absence of the abdominal reflexes, and
convulsions that may be tonic or clonic, focal or generalized. The third stage is charac-
terized by coma, irregular pulse and respirations, and rising fever.20
A history of contact with an adult who has infectious tuberculosis aids in establishing
the diagnosis. However, the family history of tuberculosis may be negative and the con-
tagious adult may not be identified.20
The evidence of TB infection or disease outside the CNS can significantly increase the
probability or possibility that a child with cerebral signs and symptoms has TBM. How-
ever, a great number of patients, especially when HIV negative and the very young,
may present with normal chest radiography.18,28,29 Chest radiograph findings may re-
veal typical of primary TB or it may have a miliary pattern21, but in many cases, by the
time the meningitis develops, the original focus in the lungs may no longer be demon-
strable by plain radiographic studies.30
The tuberculin skin test (TST) is of limited value and with variable sensitivities. It is
very useful if positive; if negative, it does not rule out TBM. An HIV infection in patients
with TBM reduces the likelihood of positive TST results.18
The diagnosis of TBM is difficult and may be based only on clinical and preliminary cer-
ebrospinal fluid (CSF) findings. Lumbar puncture should be done and characteristics
CSF findings noted. CSF may be clear but with increased opening pressure. It is usual-
ly opalescent and contain 50 to 500 white blood cells/mm3, with polymorphonuclear leu-
kocytes predominant very early in the disease and lymphocytes predominant later.
CSF glucose level may be at the lower limits of normal early in the second stage and is
very low by the third stage. The protein content may be normal initially but rises to a
very high concentration, at which pellicle forms on standing.6,14,16 CSF sample should
be sent for acid fast smear but a single sample has low sensitivity, 20-40%. CSF cul-
ture also has low sensitivity (~ 40-80%) and can take several weeks for the result.23
Neuroimaging can also contribute in the diagnosis of TB meningitis. The most com-
mon brain computed tomography (CT) or magnetic resonance (MR) features in children
with TBM are hydrocephalus in 80% and basal meningeal enhancement in 75% of
young children.28,32 Hypodensities due to cerebral infarcts, cerebral edema and nodular

53
enhancing lesions may also be seen.23
A variety of newer diagnostic methods such as polymerase chain reaction (PCR), ELI-
SA, latex agglutination have been recently developed and used to search for mycobac-
terial antigens in the spinal fluid. These tests are valuable aids in the rapid diagnosis of
TBM, particularly in the pediatric age group.33,34
Empirical antituberculosis therapy should be started promptly in all patients suspected
with TB meningitis because treatment delay is strongly associated with death. 35 Adjunc-
tive treatment with corticosteroids improves survival but does not prevent severe disa-
bility.36
The most important determinant of outcome is the stage of illness at which the diagno-
sis is made and appropriate treatment is given.37 Despite treatment, childhood tubercu-
lous menigitis has very poor outcome particularly with stage 3 TB meningitis.25,38
2. Other Forms (Tuberculoma, Brain Abscess, Spinal leptomeningitis )
Other forms of central nervous system tuberculosis include tuberculoma, TB brain ab-
scess and spinal TB leptomeningitis.
Tuberculomas are enlarged granulomatous foci within the brain parenchyma and TB
brain abscess lacks the giant cell and granulomatous reaction associated with tubercu-
loma. Both are manifested clinically as space occupying lesion. Tuberculomas occur
most often in children younger than 10 years old and often located infratentorial or at
the base of the brain around the cerebellum. In contrast, tuberculomas in adults are
supratentorial.20,39,40 Clinical manifestations include headaches, seizures, papilledema
and focal deficits may all occur. The presentation of brain abscess is more subacute (1
week to 3 months after infection), but much slower than pyogenic brain abscesses. Tu-
berculomas may present months to years after infection.22
Careful evaluation, knowledge of exposure to tuberculosis, a tuberculin skin test, chest
radiography, and computed tomography help recognized the disease in time to begin
appropriate chemotherapy before neurosurgical intervention is needed.
Tuberculous spinal meningitis may manifest as an acute, subacute, or chronic form
which is often characterized by myelopathy, with progressive ascending paralysis. Pa-
tients may develop acute paraplegia with sensory deficits and urinary retention which
often mimics transverse myelitis or Guillain-Barré syndrome. The subacute form is of-
ten dominated by myeloradiculopathy, with radicular pain and progressive paraplegia or
tetraplegia. A less virulent chronic form might mimic a very slowly progressive spinal
cord compression or a non-specific arachnoiditis. The dorsal cord is affected most com-
monly, followed by the lumbar and the cervical regions.
Bones and Joints
Bones and joints tuberculosis accounts for approximately 10-15% of the extrapulmo-
nary tuberculosis and only 2% of all cases of tuberculosis.40,41,42 A local study by San-
tos noted 6.1% of cases with extrapulmonary tuberculosis have bone involvement with
mean age of 6.2 years.10 It can be seen in 1 to 5 percent of children with untreated pri-

54
mary infection and becomes symptomatic one to three years after initial pulmonary in-
fection. Tubercle bacilli are disseminated to skeletal structures during lymphohematog-
enous spread during the initial infection or may be develop as a direct extension from a
caseous regional lymph node or by extension from a neighboring infected bone. Very
young children are more vulnerable to suffer from this form than older children because
of increased blood flow through the growing bones. The lesion usually starts as an area
of endarteritis in the metaphysis of the long bone, where the blood supply is more
abundant.20,44
Skeletal tuberculosis should be considered immediately in any child who is known to
have been infected with tubercle bacilli and in whom a bone or joint lesion develops
and in any child with a persistent, not otherwise explained bone or joint lesion.
TB of the Spine (Pott’s Disease)
The spine (especially the vertebrae) is the most common skeletal site affected by tu-
berculosis, followed by the hip and knee.43,45 Vertebral tuberculosis or tuberculous
spondylytis constitutes about 50% of all cases.43,46 Often, a history of trauma is present
and contributes either in activation of an underlying lesion or simply to draw attention to
the process.20
In spinal tuberculosis, there is destruction of the intervertebral disk space and adjacent
vertebral bodies, collapse of the spinal elements, and anterior wedging leading to the
characteristic angulation and gibbus (palpable deformity because of involvement of
multiple vertebrae) formation. The upper lumbar, lower thoracic and lumbosacral spine
are most frequently involved sites. Multiple vertebrae are typically affected more fre-
quently the vertebral body. Distortion of spinal column leads to severe kyphosis (Pott‘s
disease).43,20,45,46
Back pain is the most frequent symptom of spinal tuberculosis and progression is slow
and insidious.48 Duration of illness varies with average duration ranging from 4 to 11
months. Usually, patients seek advice only when there is severe pain, marked deformi-
ty, or neurological symptoms.43 Signs and symptoms include ―night cries‖ and restless
sleep, daily low-grade fever, and peculiar position (such as torticollis with cervical le-
sions) or gait. Sensory disturbance and bowel and bladder dysfunction are also com-
mon in children.46 Physical examination findings include marked ―guarding‖ because of
dorsal muscle spasm, local pain and tenderness, gibbus deformity or reflex changes
including clonus.14,45
Serious complications such as paravertebral abscess (Pott‘s abscess), retropharyngeal
abscess, psoas abscess and neurologic lesions are seen in 10-30% of the TB of the
spine. Neurologic involvement such as paraplegia and even paresis range from 25-
39% in foreign literature and 17-44% in the Philippines. These result from inflammation
of the spinal cord secondary to an adjacent cold abscess, granuloma in the extradural
space, or spinal vessel thrombosis. 14,30
TB of the Joints
Tuberculosis of the hip is second to spine as the common site of skeletal tuberculosis.
Other weight bearing joints such as knee, shoulders and elbows are also frequently in-

55
volved.44 Insidious onset of pain, stiffness and limp on walking or refusal to walk were
the main clinical features in children. The outcome of tuberculosis of the hip in children
depends on the extent of the disease. Tuberculosis of the femoral head and neck may
lead to various deformities.49,50
Tuberculous arthritis is rare in children and monoarticular in 90% of cases. Weight
bearing joints and only exceptionally the joints of the upper extremities are primarily
involved.20 TB arthritis result from direct invasion of tubercle bacilli into a joint space or
as a consequence of an aseptic reactive polyarthritis (Poncet's disease).51
Gastrointestinal/Abdominal Tract
Gastrointestinal tuberculosis or abdominal tuberculosis includes infection of the perito-
neum, hollow or solid abdominal organs (intestinal tract, liver, spleen, pancreas, mes-
entery) and abdominal lymph nodes.52,2,53,54 Although uncommon in children, there
have been reports that it is second in frequency after pulmonary disease and a signifi-
cant rise has also been observed to occur in association with HIV infection. 53,55 In India
and Tunisia, the most common forms of abdominal TB are nodal involvement, peritoni-
tis and intestinal disease53,55 while liver (6.1%), ileum (1.5%), perineum (1.5%), and
spleen (1.5%) are the abdominal organs involved in a local study done over a 4-year
period in a tertiary government hospital.10
The clinical presentation is both varied and non-specific (Table 6.1). Common present-
ing symptoms are abdominal enlargement, abdominal pain and weight loss.2 Malnutri-
tion is a common feature. Abdominal pain is described in various ways but is most of-
ten cramping in nature and can be diffuse or localized in either the right upper or lower
quadrant.30 Most children often appear systemically ill and anemic with low grade fever.
Distended abdomen, ascites, abdominal mass typically located in the right lower quad-
rant and hepatomegaly are the most common signs.
The reported prevalence of pulmonary TB in children with abdominal TB ranges from
20%-60%. Most commonly, the onset of abdominal tuberculosis is insidious although
some children may present with acute symptoms.2
The diagnosis is oftentimes delayed and is usually made through a combination of radi-
ologic, endoscopic, microbiologic, histologic, and molecular techniques. The absence of
radiologic or clinical signs of pulmonary disease does not exclude the diagnosis. Ab-
dominal TB should be considered in the differential diagnosis of children presenting
with acute abdomen, particularly in areas with high TB incidence. Prognosis is poor in
the presence of severe malnutrition, disseminated TB disease and presence of co-
morbidities.2

56
Table 6.1 of Clinical Presentations of abdominal tuberculosis in children*2,53,54 (in
percentage)
Signs Tinsa, Shah, Saczek, Talwar, Veeragan- John- Da-
and et.al et.al et.al. et.al dham son vies
Symp- (2010) (2010) (2001) (2000) (1996) (1987) (198
toms N= 13 N= 32 N = 45 N = 125 N = 26 N = 59 2)
Ab- 77 53 51 100 71 44 60
dominal
pain
Ab- 62 - 64 38 35 92 42
dominal
disten-
tion
Growth - 47 56 58 69 78 30
failure,
weight
loss
Fever 31 75 47 74 50 - 34

Loss of - 41 - 54 15 - 24
appetite
Ascites - 20 44 35 44 7
Ab- 15 - 47 12 23 56 -
dominal
mass
Extra- - - 49 n/a 19.2 47 18
ab- (extraintestin
dominal al TB)
lymph
node en-
largemen
t

*Table Modified from Schaaf – TUBERCULOSIS: A comprehensive Clinical Reference, 2009

TB enteritis (Intestinal TB)

Ingestion of sputum infected with the tubercle bacilli is the most important suggested
cause of the disease. Lymphohematogenous spread may also occur. Direct spread
from an adjacent organ is a rare source.2 Primary TB of the intestinal tract is uncommon
in the Philippines because Filipinos are not fresh milk drinkers and because of pasteuri-
zation of milk. Occasionally, tuberculous enteritis accompanies extensive pulmonary
cavitation especially in older children. Involvement of the intestinal tract, commonly the
ileocecal area, with extension to the mesenteric lymph nodes and peritoneum results
from ingestion of bronchial secretions contacting tubercle bacilli form a caseous pulmo-
nary focus. The bacilli are taken up by the lymphoid tissue, giving rise to local ulcers
followed by mesenteric adenitis and sometimes peritonitis. Additional symptoms and

57
signs to look out for, include vague abdominal pain, intussusceptions, blood in the stool
and sinus formation after an uncomplicated appendectomy.56 Although rectal bleeding
and hematemesis are rare in children, intestinal TB should be considered in the differ-
ential diagnosis of children with an intestinal bleed, particularly in high TB incidence
countries.2 Enlarged caseous and calcified mesenteric lymph glands (―tabes mesenter-
ica‖) are often accidentally discovered on roentgenogram of the abdomen as ―shadows
of increased density‖ which incites local inflammatory reaction. These mesenteric
nodes become matted and result in adhesions interfering with intestinal motility, thus
producing intestinal obstruction or compression of the portal vein, giving rise to ascites
and dilatation of the superficial abdominal veins.
TB peritonitis
Tuberculous peritonitis is commonly due to rupture of a caseous abdominal lymph node
and less frequently from a focus in the intestine or fallopian tube. Clinically, it is classi-
fied into ―plastic‖ and serous types: the former being less common and characterized by
tender abdominal masses and a doughy abdomen and the latter by ascites and signs of
peritonitis. Symptoms of fever, abdominal pain, weight loss, anorexia and clinical evi-
dence of ascites are common.60
In a clinical study in Mexico involving autopsied cases of children dying from tuberculo-
sis (TB), 95.2% (20/21) of children with evidence of peritoneal tuberculosis at autopsy
had evidence of disease arising from a site other than the peritoneum. The sites were
either secondary to a pulmonary lesion or as an extension to the peritoneum from pri-
mary or secondary intestinal lesions. This would suggest that primary peritoneal tuber-
culosis is not common. The presence of ascites is a constant indicator of peritoneal dis-
ease, and the cases referred to in literature as ―dry‖ or ―sclerotic‖ peritoneal tuberculo-
sis are very seldom seen in children.55
The presence of ascites usually warrants aspiration and analysis of ascetic fluid. Analy-
sis of ascitic fluid often shows exudative features with lymphocytic predominance and
serum ascitic fluid albumin gradient less than 1.1 g/dL57. The protein content is usually
elevated (> 25g/L).2 The ascitic fluid-blood glucose ratio may be helpful in differentiating
tuberculous peritonitis from other causes of ascites. In the study by Wilkins, the ratio
was less than 0.96, and in patients with non-tuberculous ascites the ratio was greater
than 0.96, the difference being statistically significant.56,58
Hepatobiliary TB
A subset of patients with extrapulmonary TB have the infection confined solely and pre-
dominantly in the liver or biliary tract. Majority of patients present with non-specific
symptoms such as fever, malaise, fatigue, night sweats, anorexia and weight loss.
Those who have prominent hepatic complaints may manifest with jaundice, abdominal
pain, hepatosplenomegaly and ascites. This form of infection is referred to as ―Primary
Miliary TB of the Liver‖ by some authors.
Khan, et al described three forms of hepatic tuberculosis. The most common form seen
in 50% to 80% of patients dying of pulmonary tuberculosis is diffuse hepatic involve-
ment with pulmonary or miliary tuberculosis. The second form is diffuse hepatic infiltra-
tion without recognizable pulmonary involvement. The third very rare form presents as

58
focal or local tuberculoma or abscess. Isolated liver tuberculosis (ILT) is the rarest form
of local hepatic TB. The reported overall incidence for ILT is 0.3%. Hepatic tuberculo-
sis lesions that appear as masses larger than 2mm in diameter are referred to as mac-
ronodular and pseudotumoral tuberculosis. These lesions are indistinguishable from
other focal lesions in the liver such as hepatocellular carcinoma and Hodgkin‘s disease
by imaging techniques. Most of the time, histopathologic diagnosis is necessary.59
TB of the pancreas
This is a rare condition and occurs secondarily to generalized TB and occasionally in
far advanced cases. There is scarcity of literature on pancreatic tuberculosis with most
published material being case reports.
Cutaneous Tuberculosis
Cutaneous tuberculosis is a chronic granulomatous disease caused by Mycobacterium
tuberculosis and rarely by Mycobacterium bovis. Most published studies in childhood
skin tuberculosis are from developing countries where Southeast Asia contributing
much of the epidemiological data. In India, the reported prevalence of childhood skin
tuberculosis varies from 18% to 54%. Pakistan has recorded the highest prevalence of
childhood skin tuberculosis, with 82% of all skin tuberculosis being reported in chil-
dren.65
Cutaneous tuberculosis manifests in several clinical forms:
1. lesions by inoculation from an exogenous source or after inoculation with BCG vac-
cine;
2. lesions resulting from hematogenous dissemination;
3. lesions arising from an exogenous source; and
4. erythema nodosum52
A simple classification of cutaneous tuberculosis includes true primary and secondary
skin lesions and tuberculids (see Table 6.2). Scrofuloderma is the most common form
of childhood cutaneous TB. Scrofuloderma indicates TB of the skin overlying a caseous
lymph node that has ruptured to the outside, leaving an ulcer or a sinus. Frequently, the
lesions are in the cervical area but may also involve the inguinal, submandibular and
axillary groups.56,65
Table 6.2 Classification of Skin Tuberculosis in Children
PRIMARY SECONDARY TUBERCULIDS

Tuberculous chancre Lupus vulgaris Micropapular lichen

Miliary tuberculosis Scrofuloderma Scrofuloderma
Tuberculous verrucosa cutis Papular-papulonecrotic tuber-
Tuberculous gumma culid
(metastatic abscess) Nodular-nodular tuberculid
Orificial tuberculosis (erythema induratum)

59
Ocular Tuberculosis
Ocular TB is reported occasionally in tertiary hospitals that admit the more serious or
complicated forms of TB. In literature, it frequently involves the conjunctiva and the cor-
nea in the form of conjunctivitis and phylctenular keratoconjunctivitis.56 Ocular TB may
occur at any age – during primary infection or reactivation of latent disease and may be
seen in 14-60% of patients with systemic TB. Patients may be immunocompetent or
may have varying degrees of immunosuppression. The rise in HIV/AIDS cases has also
led to an increase in ocular TB.2 In 2007, Gupta,et.al. updated the clinical spectrum,
laboratory investigation, and diagnostic criteria that would serve as guide in the diagno-
sis of presumed or confirmed intraocular TB so that anti-tuberculous therapy (ATT) can
be initiated on a rational basis.66

The conjunctiva can serve as the portal of entry for the bacilli, especially after trauma. A
local reaction is induced in the form of unilateral lacrimation and reddening, with subse-
quent formation of yellowish-gray nodules on the palpebral conjunctivae. Enlargement
of the preauricular, submandibular and cervical lymph nodes are commonly noted. In
patients with pulmonary and systemic TB, choroiditis is the most common ocular mani-
festation.

Phlyctenular keratoconjunctivitis is considered a hypersensitivity reaction to tuberculin.

The typical patient is likely to be a malnourished child with single to multiply 1-3mm,
grey to yellow colored, jelly-like nodules usually clustered on the limbus and surround-
ed by dilated conjunctival vessels. Pain, redness, lacrimation and photophobia are ob-
served and the lesions may recur for weeks, affecting one or both eyes. Tuberculous
involvement of the ciliary body, iris, uvea, and TB presenting as orbital mass are rare
clinical entities.

Tubercles of the choroid, frequently multiple, often have been found in 70% of patients
with miliary TB and in children with uncomplicated TB. These heal slowly with deposi-
tion of retinal segment.56

In a local study done in a tertiary government hospital involving 108 patients with tuber-
culosis, 6.8% had signs of ocular inflammation. There was unilateral presentation of all
patients labelled as presumed ocular TB (POTB), concurring with the reports of some
authors that ocular TB is usually unilateral. Posterior segment lesions were the predom-
inant finding in this series which is logical since choroidal tubercles and retinal vasculitis
hematogenous seeding of bacilli. Another common ocular lesion found in the study was
non-granulomatous anterior uveitis with posterior synechiae.66

A tuberculin skin test (TST) and biopsy with culture can be performed to confirm the
diagnosis. The specificity of the TST for Mycobacterium tuberculosis increases with
larger skin reaction and with a history of exposure to an active case of TB.

60
Genitourinary Tract Tuberculosis
Renal TB is an uncommon complication of primary TB occurring very late, up to 15 to
20 years after primary infection. In a local study done on extrapulmonary TB, genitouri-
nary TB constituted 3%. Genitourinary involvement were mostly seen in children older
than 7 years of age.10 However, TB bacilli can be recovered from the urine of patients
with miliary TB and in some cases with pulmonary TB. Hematogenous spread can give
rise to tubercles in the glomeruli, with resultant caseating sloughing lesions which dis-
charge TB bacilli into the tubules. Infection can be unilateral or bilateral and can spread
caudad to involve the bladder. The disease can be insidious in onset and has strikingly
few specific symptoms. In 75% of patients, however, they would present with symptoms
related to urinary tract inflammation such as dysuria, hematuria, sterile pyuria, and flank
pain. Renal tuberculosis should be suspected in the presence of destructive pulmonary
TB with persistent, painless, sterile pyuria associated albuminuria and hematuria. Re-
peated cultures of the urine are advisable and for those with persistent pyuria, a com-
plete urologic investigation is mandatory. Children whose urine reveal presence of tu-
bercle bacilli are considered to be highly infectious and should be isolated until their
urine is sterile.56

Genital tuberculosis is uncommon in both sexes before puberty. It may arise either as a
metastatic lesion during lymphohematogenous spread or by direct extension from an
adjacent lesion of the bone, gut or the urinary tract. Frequently, other forms of TB ac-
counts with initial infection, such as pleural effusion, are also present. In females, the
fallopian tubes are the most frequently involved (90 to 100% of cases), followed by the
endometrium (50%), ovaries (20 to 30%), and cervix (2 to 4%). Signs and symptoms
include lower abdominal pain, amenorrhea, a lower abdominal mass and free peritone-
al fluid. These are to be considered in mothers when managing newborns suspected of
infection (e.g., congenital TB) in the perinatal period. TB of the external genitalia has
been seen as a manifestation of child abuse. Males may develop primary TB of the pe-
nis after circumcision manifesting as massive inguinal lymphadenopathy. Epididymitis
or epididymo-orchitis can likewise occur characterized by gradual onset of nodular,
painless swelling of the scrotum with a dragging pain in the groin.56

TB of the Middle Ear/ Mastoiditis

Involvement of the middle ear is rare and classically seen in children more than adults.2
Diagnosis should be highly suspected in the presence of painless otorrhea unrespon-
sive to conventional treatment in a patient with tuberculosis.

Proposed routes of spread mentioned in literature are: hematogenous, usually from dis-
tant sites; direct extension from adjacent structures; external, from perforation of the
tympanic membrane; passage through an infected genital canal; and via the placenta
in congenital infection.60,61

61
Characteristic features include painless otorrhea, preauricular lymphadenopathy, oto-
scopic findings of tympanic membrane perforation, granulomatous tissue and bone ne-
crosis. However, in the review by Sens et al., the more common clinical findings were
of significant otalgia, serous otitis media which could become purulent from secondary
bacterial infection and profound hearing loss. Complications arise from delay in diagno-
sis. Facial paralysis is one reported complication that is seen more frequently in chil-
dren than adults.61

Tuberculous mastoiditis is usually a complication of unrecognized and therefor untreat-

ed TB otitis media.2 Pain with or without swelling of the postauriular area can be clinical
features of patients with affected mastoids.

Perinatal/Postnatal Tuberculosis
Congenital TB left unrecognized and untreated may result in significant morbidity and
mortality. Often mentioned as a rare occurrence, published figures may be an underes-
timate particularly in endemic areas where diagnosis may have been missed or under
reported.

For infection to occur, possible routes include: hematogeneous spread from the umbili-
cal vein, ingestion in utero or intrapartum of infected amniotic fluid, or postpartum inha-
lation from a source case which is usually the mother. Ingestion via breastmilk is not a
known mode of transmission.62

Distinguishing true congenital TB from postnatal transmission is difficult. Some authors

prefer to use the term perinatal tuberculosis as timing of infection in most cases is not
ascertained. To delineate, Cantwell and colleagues have defined congenital TB as any
infant with a TB lesion and one or more of the following criteria:

1. present within the first week of life;

2. a primary hepatic complex or caseating hepatic granuloma
3. TB infection of the placenta or endometrial TB in the mother; or (iv)exclusion of the
possibility of postnatal transmission by excluding TB in other contacts.62
In the absence of the aforementioned criteria and the non-specific clinical features, a
clinician relies on having a high index of suspicion and a detailed history and physical
examination. A maternal history of unresolving pneumonia, possible contact with a
member of the household with tuberculosis, a history of treatment for TB or infection
with HIV should be sought. Other vital information include infertility, poor reproductive
performance, recurrent abortions, stillbirth, premature rupture of membranes and pre-
term labor which are all established effects of tuberculosis in pregnancy.62 It is notewor-
thy to keep in mind that a certain percentage of mothers may also be asymptomatic.63
In neonates, it remains to be a leading differential diagnosis. It may present like sepsis
or a congenital infection. A few important clues to the possibility of congenital tuberculo-
sis include: unresponsive or worsening pneumonia, an infant born to a mother diag-
62
nosed with TB, an infant with high lymphocyte counts in the CSF without an identified
bacterial pathogen or fever and hepatosplenomegaly.63 In a review of 38 case reports
by Schaaf and colleagues, the most common signs and symptoms were respiratory dis-
tress, hepatomegaly and splenomegaly, failure to thrive, prematurity, and low birth
weight. 64
In the same paper, of culture confirmed cases of congenital TB versus that of postnatal
TB in children less than three months of age, miliary TB, lobar segmental opacification
and bronchopneumonia were the more common radiologic features found.64

63
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Med Bull. 2015 Feb 18. Pii:idv003. (Epub ahead of print)
26. Yaramis,A1,et.al. Central nervous system tuberculosis in children: a review of 214
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27. Principi,N.,susanna Esposito. Diagnosis and therapy of tuberculous meningitis in
children. Tuberculosis 92 (2012) 377e383.
28. Solomons RS, et.al. Chest radiograph findings in children with tuberculous menin-
gitis. Int J tuberc Dis. 2015 Feb; 19 (2): 2004-4. Doi: 10-5588/ijtld.14.0634.
29. PPS Inc. Tuberculosis in Infancy and Childhood. 3rd ed. 2010
30. Donald, Peter R., Johan F. Schoeman. Perspective: Tuberculous Meningitis. N
Eng J Med 351; 17. www.NEJM. ORG. Oct. 2004
31. Etlik, Omer, et.al. Radiologic and clinical findings in tuberculous meningitis. Eur J
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32. Sagarika, Haldar, et.al. Efficient diagnosis of tuberculous meningitis by detection of
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of Medical Microbiology (2009), 58, 616-624.
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33. Rafi, A. Naghily B. Efficiency of polymerase chain reaction for the diagnosis of tu-
berculous meningitis. Southeast Asigan J Trop Med Public Health 2003 Jun; 34(2):
357-60.
34. Thwaites G,et.al. British Infection Society guidelines for the Diagnosis and treat-
ment of tuberculosis of the central nervous system in adults and children. J Infect
2009 Sept; 59(3): 167 – 87. Doi: 10. 1016/j.inf.2009.06.011. Epub 2009 Jul 4.
35. Guy E. Thwaites,et.al. Dexamethasone for the Treatment of Tuberculous meningi-
tis in adolescents and adults. N Engl J Med 2004; 351: 1741 – 51.
36. Lee,LV. Neurotuberculosis among Filipino children: an 11 years experience at the
Philippine Children‘s Medical Center. Brain Dev. 2000 Dec; 22(8):
37. Buonsenso D, et.al. Management of central nervous system tuberculosis in chil-
dren: light and shade. Eur Rev Med Pharmacol Sci. 2010 Oct; 14 (10): 845-5.
38. Bathla,G.et.al. Manifestations of cerebral tuberculosis. Singapore Med J 2011; 52
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39. Ning, Guo,et.al. Infratentotiral Tuberculoma Mimics tumor in immunocompetent
adults: an analysis of 11 patients. Open Journal of Modern Neurosurgery. 2013, 3,
36-40 http://dx.doi.org/10.4236/0jmn.2013.33008 P
40. Gautam, MP,et.al. Pott‘s spine and paraplegia. JNMA J Nepal Med Assoc 2005 Jul
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41. Hosalkar, HS, et.al. Skeletal tuberculosis in children in the Western world: 18 new
cases with a review of literature. J Child Orthop (2009) 3: 319-324. DOI 10. 1007/s
11832-009-0184 – 7
42. Kumar R. Spinal tuberculosis: with reference to the children of Northern India.
Child‘s Nerv Syst 2005 Jan; 21 (1): 19 – 26. Epub 2004 spt 30
43. Haider Abdul-Lateef Moussa. Bones and Joints Tuberculosis. Bahrain Medical
Bulletin., Vol 29, No.1, March 2007.
44. Ravindra Kumar Garg, Dilip singh Somvanshi. Spinal tuberculosis: a review. The
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2: 1 doc: 10.4103/2152-7806.75459.
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49. MAF Mohideen, MN Rasool. Tuberculosis of the hip joint region in children. SA
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2010 May; 64(5) 204-9
53. Tinsa, F.et.al. Abdominal tuberculosis in children. J Pediatr Gastroenterol Nutr.
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56. Dinler,G. et.al. Tuberculous peritonitis in children: Reports of nine patients and re-
view of the literature. World J Gastroenterol vol. 14 (47); 2008 Dec 21.
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68
 7
Diagnosis
Cleotilde H How, MD

OUTLINE
1 Overview

2 Approach to Diagnosis

3 Unique Features of Tuberculosis

in Children

4 The Spectrum of Exposure, infec-

tion and Disease

5 Classification

6 Criteria for Diagnosis

7 Two Entry Points for Recognition

and Case Finding

69
OVERVIEW

The epidemiology of tuberculosis (TB) in children continues to be described in esti-

mates. To be able to recognize a child with TB and achieve a count close to the actual
number, skillful use of basic clinical tools for diagnosis is needed – a careful history-
taking and physical examination with the appropriate laboratory tests. These are found
in the 2014 WHO Guidance for national tuberculosis programmes on the management
of tuberculosis in children1, the International Standards of TB Care (ISTC)2 the DOH/
NTP Manual of Procedures (MOP)3 and the Fundamentals of Pediatrics.4 Many of the
definitions and discussions are directly taken from these sources which also derive from
the WHO definitions and reporting framework for tuberculosis.5

APPROACH TO DIAGNOSIS
Marais BJ, et al6 suggest a rational framework integrating old and new concepts to meet
these diagnostic challenges through the use of accurate case definitions (e.g., differenti-
ating primary infection from active disease); risk stratification (age less than 2 years
having the greatest risk of progression to disease); and accurate disease classification.
An earlier review by Daniel7 approaches the diagnosis of mycobacterial disease based
on recognition of either the infecting agent or the host‘s response to the agent.
For those tests based on recognition of the agent, there are direct methods that do not
employ prior amplification, such as direct sputum (AFB, acid-fast bacilli) smear, rapid
culture (BACTEC) and tuberculostearic acid detection. Those that employ amplification
include sputum smear after short-term culture, ultraviolet microscopy with fluorescence
stains, short-term culture with antigen detection by immunoassay, and polymerase
chain reaction such as the nucleic acid amplification tests (NAATs) exemplified by the
Xpert MTB/RIF.
Marais and Pai8 outline the traditional and new approaches to the diagnosis of mycobac-
terial disease. They cite important WHO landmark developments that focus on essential
tools to aid in reaching an accurate diagnosis, particularly in resource-limited TB-
endemic settings. The authors included symptom-based screening9, along with tubercu-
lin skin test (TST), chest radiography and tuberculosis (TB) culture. Of these, it is the
identification of the tubercle bacilli that offers positive confirmation of TB disease.
When the presenting symptom is nonspecific, it may not be of value in recognizing ac-
tive disease. With more clearly-defined clinical features in the refined symptom-based
screening10 there is greater basis for making a diagnosis and early treatment. A symp-
tom screen is also necessary for assessment of an asymptomatic child considered vul-
nerable in a high-risk environment. A child below 3 to 5 years of age who is asympto-
matic but exposed to a documented case of pulmonary tuberculosis calls for prompt
preventive chemotherapy. See Chapter 15 (Prevention and Control)
Recognition of host response is best illustrated in the TST, chest radiology and serolo-
gy. The introduction of enzyme-linked immunosorbent assay (ELISA) and the develop-

70
ment of more specific antigens (recognized by monoclonal antibody) have tremendous-
ly improved serodiagnosis. Those new modalities for detection of the organism and its
products include pathogen-based and immune-based assays.8
Cuevas et al11 reviewed the TB diagnostics for children in high-burden countries, noting
the lack of sufficient number of research studies and a dearth of evidence of test perfor-
mance in children. Novel markers for T-cell activation with proof of concept12 have
emerged to develop more advanced assays for the diagnosis of active TB in children,
prospectively ushering in tests that can differentiate active disease from infection men-
tioned in the 2016 WHO Pipeline Report.13
These diagnostic tests are further discussed in Chapters 8 (Tuberculin Skin
Test), 9 (Radiologic Findings) and 10 (Diagnostic Tests/Laboratory Findings).

UNIQUE FEATURES OF TUBERCULOSIS (TB) IN CHILDREN

The diagnosis of childhood TB is especially difficult compared to that of an adult in the
absence of a gold standard in many cases. The factor of age, stage of development
and the vulnerability of the young are considered important. These also offer the way to
approach management in this age group.
There are common barriers to early recognition and the needed intervention or preven-
tive treatment. A common misconception that presents a barrier is that children rarely
develop life-threatening TB. Accurate rates of mortality and morbidity, disease preva-
lence and incidence, are hampered by low resources particularly in high-burden coun-
tries.14 The lag time from exposure to infection and disease is difficult to assess.15
TB in Children Compared to Adult TB
Child TB has been referred to as ―the missing diagnosis‖ mainly because of the occur-
rence of asymptomatic infection (i.e. latent TB infection or LTBI) and in early disease.
Children present with protean manifestations (fever, cough, weight loss, weakness etc.)
difficult to distinguish from other childhood diseases. Adults present more frequently
with localized disease, often with pulmonary symptoms like cough, with less constitu-
tional manifestations than children. Children are at greater risk for dissemination, seri-
ous complications and death, than adults. See Chapter 6 (Clinical Forms and Fea-
tures)
Moreover, definitive diagnosis by sputum smear and culture of Mycobacterium tubercu-
losis is even more difficult because of the poor bacteriologic yield brought on by the
paucibacillary character of majority of TB in the young and the difficulty of collecting
specimen in them. Demonstration of acid-fast bacilli on microscopy and/or histologic
changes on biopsy can only provide presumptive diagnosis in the absence of a positive
culture. Radiologic examination is often equivocal; that requires consensus among radi-
ologists for a clear-cut set of criteria. The TST has logistic limitations on top of high
false-negative finding even under ideal settings, discussed below.

71
Vulnerability of the Young
Young children are most vulnerable among household members who are exposed to
an adult index case or source case, who remains untreated or even with treatment, fails
to complete therapy. These children are at greatest risk to develop infection, disease
and its complications, with progression, dissemination or even death. More operational
research is needed to address the need for more data in low-income countries.16 See
Chapter 2 (Epidemiology), Chapter 3 (Microbiology) and Chapter 4 (Immune Re-
sponses)
Approach to Management
In a child to be assessed for TB, the resources for diagnosis are often limited, not just
in confirmatory tests but even in the basic clinical skills to recognize TB. The clinician in
such a situation has to optimize skills to process the clinical picture presented and aim
for a clinical diagnosis, or ideally, a bacteriologic diagnosis.
Use of a symptom-based screening tool9 and a ―refined symptom-based approach‖10
referred to earlier are designed to improve the diagnosis of pulmonary TB in children.
The recommended approach to diagnosis is summarized from the guidelines adopted
for this edition.1,2,3,4

 Careful history, including history of TB contact and symptoms consistent with TB;
 Clinical examination, including growth assessment;
 Tuberculin skin test
 Bacteriological confirmation whenever possible
 HIV testing
 Investigations relevant for suspected pulmonary or extrapulmonary TB

THE SPECTRUM OF TB: DIFFERENTIATING EXPOSURE, INFECTION AND

DISEASE
The spectrum of TB from exposure to infection and disease is defined in Chapter 6 for
the proper perspective in tracking the natural course of the disease and the application
of the appropriate clinical assessment, diagnostic test and intervention. This is summa-
rized in Table 7.1, with the differentiating points in the criteria used.tabulated in the
2008 DOH/NTP Manual17

72
Table 7.1. Spectrum of TB exposure, infection and (pulmonary) disease. (modifiedfrom
DOH/NTP Table17)
TB Exposure TB Infection TB Disease
Exposure positive positive positive
Signs & symptoms negative negative positive
Tuberculin skin test negative positivea positivea
Chest X-ray negative negative (may be positive)b
Direct sputum smear negative negative (may be positive)c
microscopy (DSSM)
Other diagnostics negative (may be positive)d (may be positive)d

a
may be false negative in many children
b
may be positive, showing hilar adenopathy and the Ghon complex
c
may be negative due to paucibacillary nature in children and difficulty of specimen collection
d
may be positive in immunology-based tests like IGRA

CLASSIFICATION OF TB DISEASE1-5
Classification of TB disease is based on bacteriological status, anatomical site, history
of previous treatment, HIV status and drug susceptibility testing of clinical isolates.
Treatment outcome definitions make a distinction according to whether a patient has
been treated for drug-susceptible or drug-resistant TB; discussed in Chapter 11
(Management of TB).
Classification Based on Bacteriological Status
Bacteriologically-confirmed TB case is one from whom a biological specimen is posi-
tive by smear microscopy, culture or WHO-approved rapid diagnostic tests (such as
Xpert MTB/RIF).
Clinically-diagnosed TB case is one who does not fulfill the criteria for bacteriological
confirmation but has been diagnosed with active TB by a clinician or a medical practi-
tioner who has decided to give the patient a full course of TB treatment. This definition
includes cases diagnosed on the basis of X-ray abnormalities (i.e., not solely) or sug-
gestive histology, and extrapulmonary cases without laboratory confirmation.
Classification Based on Anatomical Site
Pulmonary TB (PTB) refers to bacteriologically-diagnosed or clinically-diagnosed
case of TB involving the lung parenchyma or the tracheobronchial tree. A patient with
both pulmonary and extrapulmonary TB should be classified as a case of pulmonary
TB.
PTB is characterized by the formation of lesions mainly in the lungs. To establish a di-
agnosis of PTB, a DSSM is of great value when a child can expectorate and the DSSM
is performed. Therefore, a child over ten years or those below who are able to expec-
torate sputum, can be categorized into PTB, sputum smear-positive, or, PTB, spu-

73
tum smear-negative. Culture studies should be done when indicated, particularly
when drug resistance is confirmed or suspected.
The course varies according to whether or not there is progression of the disease. In
the Chapter on TB in the local competency-based textbook of pediatrics4, there are two
forms of TB classified as:

 Primary tuberculosis; and,

 Progressive-primary tuberculosis, with local spread to contiguous structures within
the lungs and thorax; or with lymphohematogenous spread to distant sites.
With reinfection or reactivation of the disease at some period of time after the primary
TB may present as:
 ―Secondary TB‖ or ―Adult-type TB‖.

Extrapulmonary TB (EPTB) refers to a case of TB involving organs other than the

lungs (e.g., larynx, pleura, lymph nodes, abdomen, genitourinary tract, skin, joints and
bones, meninges). Histologically-diagnosed EPTB through biopsy of appropriate sites
will be considered clinically-diagnosed TB. Laryngeal TB, though likely sputum smear-
positive, is considered an EPTB case in the absence of lung infiltrates on CXR.
Signs and symptoms of EPTB are referable to the site of lesion. Mild EPTB seen with
cervical adenitis is brought to attention due to an anterior neck mass that may or may
not be accompanied by symptoms. Other forms of EPTB may be serious or complicat-
ed, with greater risk of mortality particularly in the younger age- group.8,15

Classification Based on History of Previous Treatment

New case - A patient who has never had treatment for TB or who has taken anti-TB
drugs for less than one (<1) month. Isoniazid preventive therapy (IPT) or other preven-
tive regimens are not considered as previous TB treatment.
Retreatment case - A patient who has been previously treated with anti-TB drugs for at
least one (1) month in the past.
Classification based on HIV status
HIV-negative patient refers to any bacteriologically-confirmed or clinically-diagnosed
case of TB who has a negative result from HIV testing at the time of TB diagnosis.
HIV-positive patient refers to any bacteriologically-confirmed or clinically-diagnosed
case of TB who has a positive result from HIV testing at the time of TB diagnosis. See
Chapter 13 (TB in Special Situations) for discussion on TB in HIV and immuno-
compromised children.

Classification based on Drug Susceptibility Testing

MonoresistantTB - resistance to one first-line anti-TB drug only
Polydrug-resistant TB - resistance to more than one first-line anti-TB drug (other than
74
both isoniazid and rifampicin)
Multidrug-resistant TB (MDR-TB) - resistance to at least both isoniazid and rifampicin
Extensively drug-resistant TB (XDR-TB) - resistance to any fluoroquinolone and to at
least one of three second-line injectable drugs (capreomycin, kanamycin and amika-
cin), in addition to multidrug-resistance
Rifampicin-resistant TB (RR-TB) - resistance to rifampicin detected using phenotypic
or genotypic methods, with or without resistance to other anti-TB drugs. It includes any
resistance to rifampicin, whether monoresistance,multidrug resistance, polydrug re-
sistance or extensive drug resistance.

Classification according to Treatment Outcome3

This classification is discussed in Chapter 11(Management of TB)

Other Classifications
The International Classification of Diseases (ICD)-1018 provides a more detailed system
of classification that is site-specific, as well as, descriptive of the level of diagnostic
work-up done.

CRITERIA FOR DIAGNOSIS OF TB

A positive culture with or without a positive smear for M. tuberculosis is the gold stand-
ard for the diagnosis of TB and must be sought for whenever possible. 1,2,3 In the ab-
sence of bacteriologic evidence, however, a child is presumed to have active TB if
three or more of the following criteria are present as seen in the 1997 PPS National
Consensus on Childhood Tuberculosis19 and reflected in future guidelines.1-4,17

 exposure to an adult/ adolescent with active TB disease (EPIDEMIOLOGIC)

 signs and symptoms suggestive of TB (CLINICAL)
 positive tuberculin skin test (IMMUNOLOGIC)
 abnormal chest radiograph suggestive of TB (RADIOLOGIC)
 laboratory findings suggestive of TB (histological, cytological, biochemical, immuno-
logical and/or molecular) (LABORATORY)

Presumptive TB refers to any person whether adult or child with signs and/or symp-
toms suggestive of TB whether pulmonary or extra-pulmonary, or those with CXR find-
ings suggestive of active TB.5 Clinical signs and symptoms are sought to arrive at a
presumptive diagnosis in children below 15 years and in those 15 years and above.

Epidemiologic Considerations
Every effort must be made to establish a history of exposure to TB. In a great majority
75
of childhood TB, the source of infection is the parent, grandparent or caregiver. Howev-
er, because the Filipino family is characterized as an extended one, inquiry must be
made on all possible case contacts to include all relatives and close friends who were
in contact with the patient.
For young children, the more probable source of infection is in the home—among close
household contacts. Many older children are infected by outside sources such as
teachers, group leaders or young adults. Widespread infection may develop from a sin-
gle active case at school or a day-care center as basis for the clinical question on ex-
posure or history of contact.
The PPS Evidence-based Clinical Practice Guidelines20 made recommendations on
the diagnosis, treatment and prevention of TB in children. New information in the last
decade have added more evidence to strengthen established procedures or modify the
approach to management.

Clinical Manifestation
Many children with primary TB are asymptomatic in the early stage of the disease or
may present with minor constitutional manifestations such as low grade fever, lassi-
tude, easy fatigability, anorexia, weight loss, malaise and night sweats, which are all
protean and common to many illnesses.
The DOH/NTP Manual of Procedures3 outlines the criteria for initiating investigation
among children below 15 years and those 15 years and above, to launch more tests
that will help confirm the diagnosis of TB. These are reproduced below, formatted with
highlights.

Box 7.1 Identification of Presumptive TB

1. Note the patient‘s general information on the individual treatment record or pa-
tient‘s chart.
2. Ask or check for clinical signs and symptoms to identify a presumptive TB.
a. For patients 15 years old and above, a presumptive TB has any of the following:
i. Cough of at least 2 weeks duration with or without the following symptoms:
 Significant and unintentional weight loss;
 Fever;
 Bloody sputum (hemoptysis);
 Chest/back pains not referable to any musculoskeletal disorders;
 Easy fatigability or malaise;
 Night sweats; and,
 Shortness of breath or difficulty of breathing.

76
ii.. Unexplained cough of any duration in:
 a close contact of a known active TB case;
 high-risk clinical groups (e.g., HIV/AIDS, diabetes, end-stage renal disease, can-
cer connective tissue diseases, autoimmune diseases, silicosis, patients who un-
derwent gastrectomy or solid organ transplantation and patients on prolonged
systemic steroids); and,
 high risk populations (e.g., elderly, urban poor, inmates and other congregate set-
tings).

b. For patients below 15 years old, a presumptive PTB has any of the following:
i. At least three (3) of the following clinical criteria:
 coughing/wheezing of 2 weeks or more, especially if unexplained;
 unexplained fever of 2 weeks or more after common causes such as malaria or
pneumonia have been excluded;
 loss of weight/failure to gain weight/weight faltering/loss of appetite;
 failure to respond to 2 weeks of appropriate antibiotic therapy for lower respiratory
tract infection;
 failure to regain previous state of health 2 weeks after a viral infection or exanthe-
ma (e.g., measles); and,
 fatigue, reduced playfulness, or lethargy (e.g., child has lost his/her normal ener-
gy).

ii. Any one (1) of the above signs and symptoms (e.g., clinical criteria) in a child
who is a close contact of a known active TB case.
c. CXR findings suggestive of PTB, with or without symptoms, regardless of
age.
d. Presumptive extra-pulmonary TB may have any of the following:
 gibbus, especially of recent onset (resulting from vertebral TB);
 non-painful enlarged cervical lymphadenopathy with or without fistula formation;
 neck stiffness (or nuchal rigidity) and/or drowsiness suggestive of meningitis that
is not responding to antibiotic treatment, with a sub-acute onset or raised intracra-
nial pressure;
 pleural effusion;
 pericardial effusion;
 distended abdomen (i.e., big liver and spleen) with ascites;
 non-painful enlarged joint; and
 signs of tuberculin hypersensitivity (e.g., phlyctenular conjunctivitis, erythema
nodosum).

77
 3. Ask and verify the following:
a. History of previous anti-TB treatment and its details
b. Exposure to active TB cases or presumptive TB (including MDR-TB, if applicable)
within the workplace, family or household
c. Presence of clinical or other high-risk factors (e.g., HIV/AIDS, diabetes, end-stage
renal disease, cancer, connective tissue diseases, autoimmune diseases, silicosis,
patients who underwent gastrectomy or solid organ transplantation and patients on
prolonged systemic steroids)
4. Once identified as a presumptive TB, record the patient in Form 1. Presumptive TB
Masterlist.

Physical findings are also nonspecific and localizing symptoms may be absent even in
the presence of extensive disease. There are, however, clinical findings compatible
with TB such as relatively painless lymphadenitis, meningitis with insidious onset, gib-
bus, skin granuloma, erythema nodosum, and phlyctenular conjunctivitis. The presence
of such findings suggests TB disease and warrant work-up to confirm the diagnosis.
The next step in the investigation is to decide to treat as active TB if the child has any
three (3) of the following criteria, (1997 PPS Consensus).19
i. Positive exposure to an adult/adolescent with active TB disease;
ii. Positive tuberculin test (a positive TST confirms TB infection after exposure);
iii. Positive signs and symptoms suggestive of TB;
iv. Abnormal chest radiograph suggestive of TB;
v. Laboratory findings suggestive or indicative of TB.
In a low-resource country, early detection of active TB can prevent delays in interven-
tion and control of TB infection and disease. Application of a systematic screening par-
ticularly in high-risk groups avoids more delays in treatment and control.21,22 A simple
but ―refined symptom-based approach‖ to diagnose pulmonary TB in children found a
high degree of accuracy by risk-stratification with the combined presence of three well-
defined symptoms of cough, weight loss and fatigue.10 Emphasis on careful history and
clinical exam including growth assessment are paramount.1
See Chapter 6 (Clinical Forms and Features)
Immunologic Evidence of Infection
According to Dr Mita Pardo de Tavera,23 ―the tuberculin test is the most important diag-
nostic tool in tuberculosis, be it recent or remote, active or inactive. In the time-table of
tuberculosis it is this biochemical alteration in the tissues of the host that precedes, by a
comfortable margin of time ranging from several months to even years, the clinical, the
bacteriologic and radiologic evidence of the disease.‖
The only means of making a diagnosis of TB infection without disease (i.e., in latent

78
tuberculosis infection or LTBI) is through a TST and IGRA test. The TST is based on
the fact that infection with M. tuberculosis produces sensitivity to certain components of
this organism (antigens or specifically, tuberculins). The reaction to intracutaneously
injected tuberculin is that of a delayed cellular hypersensitivity.
A significant reaction means that hypersensitivity to mycobacterial protein has devel-
oped, but does not necessarily signify the presence of disease. Clinically, a delayed
hypersensitivity reaction to tuberculin is nearly always a manifestation of previous infec-
tion with either M. tuberculosis, a variety of nontuberculous mycobacteria, or a previous
BCG vaccination; it can antedate isolation of M. tuberculosis from sputum or other
specimens.
Characteristic features of a delayed hypersensitivity reaction include: a delayed
course, reaching its peak 48 up to 72 hours after the administration of tuberculin; an
indurated character largely because of its cellular infiltration; and occasionally, occur-
rence of vesiculation and necrosis. Interpretation of TST reaction is dictated by the pur-
pose for which the test was given and on the consequences of false classification. A
variety of factors—host, antigen used, method of administration, reading and record-
ing—can cause decreased ability to respond to tuberculin or can yield a false negative
test.
Mantoux Test1,2
The current standard for TST is the Mantoux test which is the intradermal administra-
tion of 0.1 ml of solution containing 0.1 ug of 5 tuberculin units (TU) of purified protein
derivative (PPD)-S or 2 TU of PPD-RT 23 with Tween 80.
The Tine (multipuncture) Test, the Two-Step Test and the BCG Test (accelerated BCG
reaction) were discussed in the previous editions of TBIC. These tests are no longer
part of current practice.
Immunologic-based Testing2
Immunologic-based testing with interferon-gamma release assay (IGRA) such as
QuantiFERON-TB Gold, Gold In-Tube and T-Spot are fairly specific to M. tuberculosis
complex thus it is not affected by previous BCG vaccination. Like TST, however, it can-
not distinguish between latent infection and disease.
The sensitivity, specificity, positive and negative predictive values of the tuberculin skin
test, its rationale, procedure and interpretation - and its comparison with immunologic-
based testing like IGRAs - are discussed more thoroughly in Chapter 8 (Tuberculin Skin
Test).
Radiologic Findings
There are no pathognomonic radiographic findings in childhood TB. Neither the pres-
ence nor absence of the primary disease can be determined conclusively from the
chest film alone. Perhaps the only radiographic finding that may be highly suggestive of
TB in infants and children is the uniform stippling of both lungs found in miliary TB.

79
To appreciate the primary complex on chest radiograph, a lateral projection is neces-
sary. With frontal projections alone, the different components of the primary complex
may be obscured by the heart and other structures. Partially calcified mediastinal nodes
sometimes lie in the midsagittal thoracic plane and may be visible only on lateral films.
A variety of diseases and conditions may be mistaken for TB. Sarcoidosis and mycotic
infections produce shadows in the lung that may resemble TB. Tuberculous lobar and
lobular consolidations may be indistinguishable from that due to pneumoccal or strepto-
coccal disease.
See Chapter 9 (Radiologic Findings).

Laboratory Examinations
Bacteriologic studies are discussed in Chapter 3 (Microbiology of Mycobacterium tuber-
culosis). Laboratory findings suggestive of TB by other diagnostic tests and histological,
cytological, biochemical, and immunological and/or molecular tests are discussed sepa-
rately in Chapter 10 (Diagnostic Tests).

TWO ENTRY POINTS FOR THE RECOGNITION/CASE-FINDING OF TUBER-

CULOSIS IN CHILDREN17
The DOH/NTP Guideline points to two ways to identify children who might have TB ex-
posure, infection or disease.
Symptomatology
The first entry point is when there is a symptomatic child consulting for signs and symp-
toms suggestive of tuberculosis, one of the five criteria discussed under the 1997 PPS
Consensus Statement (clinical manifestations) and under the DOH/NTP MOP as a
―presumptive TB‖ case requiring further studies to confirm the diagnosis..
Contact Screening
The second entry point is contact screening of children who belong to the household or
close environment of a registered TB case.
These entry points are incorporated in the MOP2014 algorithms3 reproduced in Appen-
dix 1, including conditions where there are no resources for TST and chest X-ray.
MOP 2014 ALGORITHM
An Algorithm in Appendix 1 reproduced from the Manual of Operations of the DOH/NTP
gives a step-by-step visual guide for the MD to reach a clinical or bacteriological diag-
nosis starting from the first step of presumptive TB to initiate further tests and lead to
satisfying at least 3 of the 5 criteria in children less than 15 years.

80
REFERENCES
1. Guidance for national tuberculosis programmes on the management of tuberculosis
in children. Geneva, World Health Organization, 2014. (WHO/HTM/TB/2014.03)
2. TB Care I. International Standards for Tuberculosis Care, Edition 3, TB CARE I,
The Hague, 2014.
3. Manual of Procedures of the National Tuberculosis Control Program, 2014.
4. Villar EP, Santos JA, Madrid MAC. Chapter 28 Tuberculosis pp679—737.
In:.Fundamentals of Pediatrics: competency-based (Eds Navarro XR, Bauzon AF,
Aguilar JS, Malanyaon OQ). C & E Publishing, Quezon City, 2014.
5. Definitions and reporting framework for tuberculosis – 2013 revisions. World Health
Organization, 2013 (WHO/HTM/TB/2013.2).
6. Marais BJ, Gie RP, Schaaf HS et al. Childhood pulmonary tuberculosis. Old wis-
dom and new challenges. Am J Respir Crit Care Med. 2006;173:1078-1090.
7. Daniel TM. The rapid diagnosis of tuberculosis: A selective review. J Lab Clin
Med.1990;1:277-282.
8. Marais BJ, Pai M. Recent advances in the diagnosis of childhood tuberculosis. Arch
Dis Child. 2007;92:446-452.
9. Marais BJ, Hesseling AC, Gie RP et al.. The burden of childhood tuberculosis and
the accuracy of routine surveillance data in a high-burden setting. Int J Tuberc
Lung Dis, 2006; 10: 259-63.
10. Marais BJ, Gie RP, Hesseling CH et al. A Refined Symptom-based Approach to
Diagnose Tuberculosis in Children, Pediatrics, 2006: 1350-59.
11. Cuevas LE, Petrucci R, Swaminathan S. Tuberculosis diagnostics for children in
high-burden countries: what is available and what is needed. Paediatrics and Child
Health 2012, 32: S2-30-37. DOI 10.1179/2046904712Z.00000000076.
12. Portevin D, Moukambi F, Clowes P, Bauer A, Chachage M, Ntinginya NE, et al As-
sessment of the novel T-cell activation marker-tuberculosis assay for diagnosis of
active tuberculosis in children: a prospective proof-of-concept study.
www.thelancet.com/infection.PublishedonlineSeptember1,2014. http://
dx.doi.org/10.1016/S1473-3099(14)70884-9.
13. Clayden P, Collins S, Frick M, Harrington M, Horn T, Jefferys R, Lessem E, McKen-
na L. 2016 Pipeline Report. HIV and TB. Drugs, Diagnostics, Vaccines, Preventive
Technologies, Research Toward a Cure, and Immune-Based and Gene Therapies
in Development. TAG i-base, www.pipelinereport.org.
14. Enarson PM, Enarson DA, Gie R. Management of tuberculosis in children in low

81
 income countries. Int J Tuberc Lung Dis. 2005;9:1299-1304.
15. Marais BJ, Schaaf HS, Donald PR. Management of Tuberculosis in Children and
New Treatment Options. Infectious Disorders – Drug Targets, 2011; 11:144-156.
16. Zachariah R, Harries AD, Ishikawa N, Rieder HL, Bissell K, Laserson K, Massaquoi
M, Van Herp M, Reid T. Operational research in low-income countries: what, why
and how? Lancet Infect Dis. 2009;9:711-17.
17. Training Modules for TB in Children, 2008. Department of Health/National TB Pro-
gram.
18. World Health Organization International Classification of Diseases (ICD) 10.
www.who.int/classifications/icd/en.
19. National Consensus on Childhood Tuberculosis. Philippine Pediatric Society. 1997.
20. Evidence-Based Clinical Practice Guidelines. Childhood Tuberculosis. Philippine
Pediatric Society,. 2008.
21. Lonnroth K, Corbett E, Golub J, Godfrey-Faussett, Uplekar M, Weil D, Raviglione
M. Int J Tuberc Lung Dis, 2013; 17: 289-298. http://dx.doi.org/10.5588/ijtld.12.0797.
22. World Health Organization. WHO Systematic screening for active tuberculosis:
Principles and recommendation. (WHO/HTM/TB/2013.04). http://www.who.int/tb/
tbscreening
23. de Tavera, P. M. Tuberculosis in Filipino Children.1975.

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 8
Tuberculin Skin Test
Cleotilde H How, MD
Luis T Chan, Jr, MD

OUTLINE
1 Overview

2 The Procedure

3 Interpretation

4 Special Considerations

5 Interferon gamma release assays

versus tuberculin skin tests

83
OVERVIEW
Since Koch‘s discovery of the tuberculin in the year 1890, the Mantoux tuberculin skin
test (TST) has been used as the standard method in demonstrating Mycobacterium
tuberculosis (MTB) infection. In 2001 the US-FDA initially approved and recognized the
interferon-y gamma release assay blood test (IGRA) as an alternative diagnostic tool to
the TST for M. tuberculosis infection.1 The TST and IGRAs are indirect tests that meas-
ure immunologic responses that suggest past or present exposure to the TB bacilli.
While both tests are designed to detect tuberculosis (TB) exposure and latent TB infec-
tion (LTBI); it may also be used as a presumptive test for TB disease2,3 in conjunction
with other criteria4,5,6 or with bacteriologic confirmation7. See Chapter 7(Diagnosis)
A diagnosis of LTBI requires that active TB be excluded by history and physical exami-
nation to check for suggestive signs and symptoms, chest X-ray, and or bacteriologic
evidence - before treatment is initiated. The goal of testing for LTBI is to identify individ-
uals who are at increased risk for the development of active tuberculosis (TB) and
therefore benefit from treatment of latent TB infection.8
In the absence of bacteriologic evidence, a positive TST is one of the five (5) criteria
set by the Philippine Pediatric Society in making a presumptive diagnosis of TB dis-
ease in children9. The TST is also an important tool in TB control and prevention. The
recognition of latent TB infection or LTBI (i.e. TB infection without disease) helps in the
decision-making for preventive chemotherapy; especially in the under-fives, who are at
increased risk of infection progressing to TB disease. LTBI in the young is also consid-
ered a sentinel event, reflecting recent transmission. Thus the TST is important as an
epidemiological tool for tuberculin surveys in assessing the annual risk of TB infection
(ARTI).10
Tuberculin reactivity provides a general measure of a person‘s cellular immune respon-
siveness.. It is based on a delayed (cellular) hypersensitivity to certain antigens of the
TB organism contained in extracts of culture filtrates known as ―tuberculin‖11,12. The de-
layed (cellular) hypersensitivity reaction is manifested clinically as a type IV immune
response mediated by sensitized T lymphocytes and is characterized by an indurated
response to the intradermal injection of protein from the cell wall of the tubercle bacil-
lus.
A prior infection with the Mycobacterium tuberculosis (M. tuberculosis) or tuberculopro-
teins from BCG vaccine results in T-cell sensitization that releases lymphokines at the
site of injection. These lymphokines then induce local vasodilation, edema, fibrin depo-
sition, and recruitment of other inflammatory cells to the area resulting in induration.
Features of the reaction include:12 (1) its delayed course, reaching a peak in 48 – 72
hours after injection of the antigen; (2) its indurated character; and (3) its occasional
vesiculation and necrosis. Reaction to the tuberculin starts five to six hours after injec-
tion, in which maximal induration is noted within 48 to 72 hours post-injection and sub-
sides over a period of days.
In most children the delayed-type hypersensitivity response to tuberculin, which is the
estimated interval between TB exposure and detectable skin test reactivity (referred to

84
as the window period) ranges from two to twelve weeks.13,14 Analysis of data collected
from studies indicates that eight weeks is the outer limit of this window period. A nega-
tive test result obtained less than eight weeks after exposure is therefore considered
unreliable for excluding TB infection. The Centers for Disease Control and Prevention
(CDC) recommends a TST in individuals with history of contact with an infectious
source, between eight to ten weeks after the most recent TB exposure and if initial TST
result is negative among individuals with history of contact with an infectious
source.13,15 The Department of Health - National TB Program (DOH – NTP) recom-
mends a repeat TST at three months after a negative TST in a TB symptomatic child or
three months after a negative TST in children four years of age and below.16

THE PROCEDURE4
The Mantoux test is the standard and recommended method of giving the tuberculins
for TB screening. It employs an introduction of a small amount of tuberculoprotein
(purified protein derivative or PPD) into the intradermal tissues with a small-gauge nee-
dle.
Infants, children, pregnant women, HIV – infected individuals or persons vaccinated
with BCG vaccine can have a TST. It is contraindicated for persons who have had a
severe reaction (e.g., necrosis, blistering, anaphylactic shock or ulcerations) to a previ-
ous TST.13
Preparations of PPD for Mantoux Tuberculin Skin Testing
Purified protein derivative (PPD) or tuberculin, which is used for most skin testing, is
isolated from culture filtrate by protein precipitation. Tuberculin units are defined on a
weight basis: one tuberculin unit (1 TU) equals 0.02 microgram (ug) in 0.1 mL of tuber-
culin PPD-RT 23 SSI. The standard test dose of a commercial PPD preparation is de-
fined as the dose of the product that is biologically equivalent to that contained in five
tuberculin units (5 TU) of PPD-S (i.e. it elicits reactions of equivalent size + 20%)17,18,19.
PPD–RT 23
The World Health Organization (WHO) and the International Union Against Tuberculo-
sis and Lung Disease (IUATLD) recommend the 2 tuberculin units (2 TU) PPD-RT 23,
as the standardized dose for Mantoux TST surveys14. The PPD–RT 23 is the most
widely used TST in the world10,16. This is equivalent to two-fifths the concentration of
antigen determined to be bioequivalent to 5 TU of PPD-S, the standard tuberculin prep-
aration.12,17,20 Therefore, a dose of 0.1 ml of 2 TU PPD-RT 23 is biologically equivalent
to 0.1 mL of 5 TU PPD-S.
PPD–S
The American Thoracic Society and the Centers for Disease Control and Prevention
(CDC) in the US endorse the 5 TU of PPD-S as the standard dose for TST in North
America. Newly manufactured batches of tuberculin are bioassayed, and the 5 TU
standard is the amount of material which produces results equal to those produced by 5
TU PPD-S = 0.1 microgram of PPD-S.18,19

85
Using 10 mm as the positive cut-off point for tuberculin reactivity, a simultaneous study
involving 202 health workers comparing the PPD reactivity between 2 TU PPD-RT 23
and 5 TU PPD-S was found to be comparable13. The skin test reaction sizes with the
two antigens (i.e. 2 TU PPD-RT 23 and 5 TU PPD-S) did not differ statistically, based
on age, sex or prior BCG vaccination. As a rule of thumb, 0.1 ml of the 2 TU of RT 23
will have a tuberculin reactivity similar to 0.1 mL of the 5 TU of PPD-S11,12.
Administration, Reading, and Recording of the Mantoux TST11,12,20
A valid TST entails standardization of procedures, training and supervision of person-
nel, and practice. Only trained health care providers/workers are advised to administer
and read the Mantoux TST.
Administration of the Test
Locate the site of injection, about 2 inches below the elbow joint in the volar aspect of
the forearm. Clean the preferred site with alcohol swab and air dry. For one time test,
use a disposable tuberculin syringe with gauge 25 to 27 short bevel needle (i.e. ¼- to ½
-inch). Aspirate 0.1 mL of either the 2 TU of PPD-RT 23 or the 5 TU of PPD-S and in-
ject the needle bevel up intradermally. A pale wheal of six to ten mm in diameter should
be evident after injection; otherwise, repeat the test on an area at least two inches
away from the original site.
Untoward reactions to tuberculin are uncommon. Some delicately sensitive individuals
may have vesicular or ulcerating local reactions to skin testing. Much less encountered
are regional adenopathy and fever. Advise subjects not to scratch or apply any oint-
ments or cream on the injected site.
Reading and Recording of the Test
The TST should be read between 48 to 72 hours after administration. Positive TST re-
actions can be measured accurately for up to seven days, while negative TST reactions
can be read accurately up to 72 hours only21.
Under good light, visually inspect the injected area for any reaction to tuberculin which
is the induration (palpable, raised hardened area) and not the erythema. The diameter
of the indurated area should be measured across the forearm (perpendicular to the
long axis). Using the fingertips, palpate and locate for the widest diameter of induration
and mark both edges of the widest induration across the forearm using a ball pen. With
a standard ruler and using the mm part, place the ―0‖ ruler line inside left dot edge and
read ruler line inside the right dot edge.
The size of induration should be recorded in millimeters. If no induration is found, ―0
mm‖ should be recorded. Do not record as ―positive‖ or ―negative‖.

INTERPRETATION
The interpretation of a PPD reaction should be based on the purpose for which the test
is given, the prevalence of TB infection in the population being tested, and the conse-
quences of false classification. An accurate interpretation of the TST requires
86
knowledge of the antigen used (tuberculin), the proper technique in the administration
and reading of the test, results of epidemiological and clinical experience with the test,
and conditions that can bring about the false positive and false negative interpretations
of the tests.
Factors that May Affect the TST Reaction
False-positive reactions21
Certain individuals may have a positive reaction to the TST even though they are not
infected with M. tuberculosis. The causes of these false-positive reactions may include,
but are not limited to the following:
 Infection with nontuberculous mycobacteria
 Previous BCG vaccination
 Incorrect method of TST administration
 Incorrect measurement and interpretation of reaction
 Incorrect strength of antigen used
A history of BCG vaccine is not a contraindication for tuberculin skin testing. Post-BCG
tuberculin reactions develop six to 12 weeks after vaccination22,23. BCG immunization
and other nontuberculous mycobacteria (NTM) can bring about tuberculin reactivity.
Reaction sizes caused by nontuberculous mycobacteria are usually £ 10 mm of indura-
tion.21
However, the tuberculin reaction believed to be affected by BCG wanes after five years
from immunization. About 80% to 90% of children who received BCG in their infancy
have non-reactive6 TST at five years of age.22,23,24 Studies have shown that infants, chil-
dren, and adults from countries with intermediate and high TB rates have the same
prevalence of significant tuberculin reactions, regardless of BCG status.25,26,27
A positive PPD reaction in individuals residing in areas highly endemic for TB, e.g.
>100/100,000 population, is most likely due to exposure from natural infection caused
by M. tuberculosis, rather than those caused by non-tuberculous mycobacteria (NTM)
or BCG immunization, since most patients who receive BCG vaccination during infancy/
childhood lose their cutaneous hypersensitivity reaction to tuberculin within five
years.11,12,18 Therefore, a significant reaction more likely represents true exposure to TB
especially in the setting of a recent exposure.

False-negative reactions
Some individuals may have a negative reaction to the TST even if they are infected
with the M. tuberculosis. Factors that may cause false negative reactions to the Man-
toux test are enumerated in Table 8.1.

87
Table 8.1 Factors that may cause false negative reactions to the Mantoux test
Factors related to the person being tested
 infections: viral - measles, mumps, chickenpox; bacterial - typhoid fever, brucel-
losis, typhus, leprosy, pertussis tuberculous, pleurisy; fungal - South American
blastomycosis
 live attenuated virus vaccinations against measles, mumps, polio, chicken pox
 metabolic derangements - e.g. chronic renal failure
 nutritional factors - e.g. severe protein depletion
 diseases affecting lymphoid organs such as Hodgkin‘s disease, lymphoma,
chronic lymphocytic leukemia and sarcoidosis
 corticosteroids and other immunosuppressive agents
 age: newborns and elderly patients with ―waned‖ sensitivity
 incubating or recent, far advanced or overwhelming infection with M. tuberculo-
sis
 stresses such as surgery, burns, mental illness, and graft versus host reactions
 complete anergy, giving negative skin test response to PPD as well or other skin
test antigens
Factors related to the tuberculin used
 improper storage - exposure to light and heat
 improper dilution
 chemical denaturation
 contamination
 adsorption into the syringe - partially controlled by adding Tween 80
Factors related to the method of administration
 injection of too little antigen
 delayed administration after drawing into syringe
 too deep injection
Factors related to error in reading and recording of results
 inexperienced reader
 conscious or unconscious bias
 error in recording

Source: The American Thoracic Society11

Live-virus vaccines, such as OPV, Varicella, MMR, Rotavirus or oral typhoid (TY21a)
may cause suppression of the tuberculin reaction28. For this reason, the TST should be
postponed at least four-to-six weeks from a live-vaccine administration. The TST how-
ever may be administered at the same time with a live-vaccine provided that they are
injected on different anatomical sites29.
The Department of Health – National TB program (DOH – NTP) recommends that the
TST be delayed for two months after a bout of measles, mumps, chicken pox or whoop-
ing cough; in cases of generalized skin lesions (e.g. scabies, impetigo, atopic dermati-
tis, allergies), the TST should be delayed until lesions have completely healed.16
88
Tween 80 is incorporated with the diluent for PPD to reduce adsorption, since PPD is
adsorbed in varying amounts by glass and plastics once diluted14. To minimize loss of
potency due to adsorption, the tuberculin should not be transferred from one container
to another. Contamination should always be avoided by observing aseptic technique
when aspirating from the vial; the PPD must be administered at once when test syringe
dose is filled.
The tuberculin solution should be stored in a refrigerator with temperature between +2
to +8 degrees Celsius (not frozen). During transport, a suitable environment and tem-
perature must be maintained by properly monitoring the temperature with a thermome-
ter inside the cold chest. Exposure to strong light should be avoided.
Using 5TU PPD-S or 2TU RT23 the Mantoux test should be read between 48 and 72
hours after administration.
Recommendations for the Positive Cut–Off Size of the Mantoux TST
The likelihood that a person with a positive PPD is actually infected with M. tuberculosis
is dependent upon the prevalence of TB within the population group in which the per-
son belongs to and the risk factors for progression to TB disease. These form the ba-
ses for the different cut-offs used to classify a skin test as positive. The sensitivity and
specificity of the TST would depend on the prevalence of TB and non-tuberculous my-
cobacteria (NTM) in the area, BCG status and the cut-off point used for defining posi-
tive tuberculin reactivity.16,17,18 Listed are the recommendations of some of the medical
institutions/organizations and research studies:
There is agreement in the cut-off value by the Philippine Pediatrics Society (PPS)6,9
with the DOH – NTP5 and the World Health Organization (WHO)4 American Academy
of Pediatrics, Centers for Disease Control and Prevention, American Thoracic Socie-
ty13,14,15 are in consonance with the lower cut-off in the size of induration for a positive
reading, in a high-risk environment.
The PPS, DOH–NTP and WHO define a positive tuberculin test as an area of skin indu-
ration measuring 10 mm or more regardless of BCG status. An induration of 5 mm or
more is considered positive in the following conditions: (1) Severely malnourished chil-
dren (with clinical evidence of marasmus or kwashiorkor); and (2) Those who are im-
munocompromised (with congenital immune deficiencies, HIV- AIDS or with a history of
prolonged intake of immunosuppressants).
The results of the TST are interpreted in the context of the patient‘s risk for M tubercu-
losis infection, i.e. exposure to TB disease or risk of progression to TB disease. The
three cut-off points when defined according to risk factor will improve the sensitivity and
specificity of the TST.
An induration of >5mm is considered positive for populations with the highest risk of
having TB infection and disease; these are: 1) HIV-infected persons; 2) those who had
close contact with an infectious TB source; 3) persons with chest radiographs con-
sistent with prior untreated TB; 4) organ transplant recipients; and 5) other immunosup-
pressed patients (e.g., those taking the equivalent of >15 mg/d of prednisone for 1

89
month or those taking TNF-α antagonists).
The >10mm cut-off point is recommended for populations with high risks of having TB
infection and disease and for persons living in areas were TB is highly prevalent and
>15mm for populations with no risk factors.
National TB Prevalence Surveys
The national TB prevalence surveys done in 1981-1983 and in 1997 (using the 1TU-
PPD RT-23 and the 2-TU–PPD-RT-23 respectively) both showed the positive cut-off
point for tuberculin reactivity at 8mm induration30. In the 2007 nationwide TB preva-
lence survey, the positive cut–off was lowered from 8mm to 7mm due to the possibility
of under reading of the tuberculin reactions.
Rationale for Choosing the Positive Cut-off Value of the TST
Deliberations in the choice for the most appropriate definition of a positive cut point for
tuberculin reactivity should be weighed judiciously between over-diagnosis and under-
diagnosis of TB infection and disease. The positive cut-off value in tuberculin reactivity
should best discriminate TB infection and disease from normal subjects based on the
sensitivity, specificity, and positive predictive value of the test with clinical and epidemi-
ological considerations.
Sensitivity, Specificity and Positive Predictive Value (PPV)
The sensitivity of the diagnostic test refers to the probability that the test result will be
positive, while specificity refers to the probability that the test will be negative. 30 The
PPV, on the other hand, refers to the probability that a person with a positive result ac-
tually has the disease; it also serves as a crude measure of relative cost-efficiency, i.e.
it reflects the ratio of the screening program yield, i.e. number of true positives, to the
cost of misdiagnoses, i.e. no. of false positives and false negatives for a given number
of screens.30,31
Local studies using the 10mm induration size as the positive cut–off value for the TST
showed a sensitivity ranging from 64.7% to 99.7% and a specificity of 54% to 97.7%
26,27,,
False-positive tuberculin tests can occur in persons who have been infected with
nontuberculous mycobacteria and in persons who have received BCG vaccine. These
false-positive reactions result in lower specificity, low PPV and low probability of LTBI.
Epidemiologic and Clinical Considerations
The Mantoux PPD TST is the best screening test for patients with asymptomatic TB. In
places where the prevalence for TB infection is high, the specificity and PPV of the
PPD TST are remarkably increased, resulting to a superior tool for screening purpos-
es11. As the prevalence of the disease increases, it becomes more likely that the person
being tested actually has the disease with less false positive results. Hence, the more
prevalent the disease, the more sensitive the test must be.
A lower positive cut-off point e.g., from >10mm to >8mm or from >10mm to >5mm indu-
ration — results to less false negative cases, thus increasing the probability of diagnos-
ing more children with TB infection and disease. This is the rationale for a lower posi-
tive cut-off value (i.e. from 10 mm to 5 mm) in individuals with history of close contact

90
with a known or suspected infectious case of TB, in persons with clinical findings sug-
gestive of TB and in persons with chest x-ray readings suggestive of TB.
Since tuberculin reactivity provides a general measure of a person‘s cellular immune
responsiveness, a lower positive cut-off point, e.g. from 10mm to 5mm induration, is
recommended for immunocompromised individuals (e.g. HIV infection, and severely
malnourished children - those with clinical evidence of marasmus or kwashiorkor) who
may be unable to mount an immune response to the TST and thus have false negative
TST results7 or for persons taking immunosuppressive drugs that could decrease the
person‘s cellular immune responsiveness to the tuberculin.
Tuberculin skin test reactions using the Mantoux method should be interpreted in the
same manner for persons who have received BCG and for those who did not11,15. Ap-
proximately 10% of children with culture-proven TB are Mantoux test negative.38,39 Like-
wise, a negative reaction to the TST does not necessarily rule out TB.
Individuals with positive TST results is likely to have a positive reaction to the TST for
life; hence, an individual with a previous positive TST is not required to undergo subse-
quent testing11,14,39 The PPD tuberculin test reaction should always be correlated with
the recipient‘s history of exposure to an infectious TB source, presence of clinical signs
and symptoms suggestive of TB or with chest radiograph findings (if done), in order to
judiciously diagnose TB infection and disease and immediately manage such cases
appropriately.

SPECIAL CONSIDERATIONS FOR TUBERCULIN TESTING

Anergy15,39
Anergy is the inability to react to a TST because of a weakened immune system. The
absence of a reaction to the TST does not rule out the diagnosis of TB infection. Aner-
gy may be caused by many factors, such as HIV infection, severe febrile illness, mea-
sles or other viral infections, Hodgkin‘s disease, sarcoidosis, live-virus vaccination, the
administration of corticosteroids or immunosuppressive drugs, and the underdeveloped
immune system in young infants. The use of anergy testing in conjunction with tubercu-
lin skin testing is not routinely recommended.
Skin Test Conversion15
Skin test conversion refers to a change from a negative to a positive result. It is indica-
tive of recent infection with M. tuberculosis, regardless of age. An increase in reaction
size of >10mm induration within a period of two years for persons with previous nega-
tive TST reactions, is classified as conversion to positive.

INTERFERON GAMMA RELEASE ASSAYS (IGRAS) VERSUS TUBERCULIN

SKIN TEST (TST)
Interferon-gamma release assays (IGRAs) are diagnostic tools for latent tuberculosis

91
infection (LTBI). They are surrogate markers of Mycobacterium tuberculosis infection
and indicate a cellular immune response to M. tuberculosis Blood assays for tuberculo-
sis, commonly referred to as interferon gamma release assays (IGRAs), are based on
the principle of interferon-gamma being critical to regulation of the cell-mediated im-
mune response to Mycobacterium tuberculosis (MTB) infection1.
The currently available and FDA-approved IGRA assays for MTB include QuantiFER-
ON-TB Gold in-Tube test (QFT-GIT) and the T-SPOT.TB. Both assays measure the
interferon-gamma response to MTB proteins, including early secretory antigenic target-
6 (ESAT-6) and culture filtrate protein-10 (CFP-10).1 Because these assays quantitate
a biologic response, testing of a fresh blood specimen having adequate viable white
blood cells is crucial to obtaining accurate results.3
Key Facts: TSTs and IGRAs testing for TB infection and TB disease1,2,3
 TST and IGRA generally should not be tested on persons with low risk of TB infec-
tion and TB disease.
 Neither IGRA nor TST can distinguish active TB from latent tuberculosis infection
 IGRA can distinguish LTBI from previous BCG administration
 Routine testing with both TST and an IGRA is not generally recommended. Excep-
tions include suspected active TB in immune compromised patients, or indetermi-
nate results from either test.
 An IGRA is the test of choice in two instances; for people who have received BCG,
either as a vaccine or as chemotherapy and under circumstances where the tested
person is unlikely to return to have the TST read.
 TST is preferred over IGRA for children less than 5 years of age.

Live vaccines may affect both TSTs and IGRA results. IGRA testing should be done
either on the same day of live vaccine administration or be postponed at least four-to-
six weeks from a live-vaccine administration
Advantages, Limitations and Disadvantages of IGRAs over TST1,2,3
IGRAs can be used as a diagnostic tool for TB infection similar to TST e.g. in contact
investigations, test during pregnancy, screening for health workers and for others un-
dergoing serial evaluation for M. tuberculosis infection. However its use is not recom-
mended in high-burden low-resource countries.4,7
IGRAs blood tests require only a single visit to a health care provider to draw the blood
and the results can be available in 24 hours. Results are not affected by prior BCG ad-
ministration through vaccination or chemotherapy. It also does not boost responses by
subsequent tests.
Apart from its availability and a much higher cost of the IGRA tests over the TST, some
disadvantages include immediate processing of blood samples within 8 – 30 hours after
collection while white blood cells are still viable, errors in collecting/transporting blood
specimens or in running and assay interpretation. False positive results also may occur
due to infection with other mycobacterial organisms, including M. kansasii, M. szulgai,
and M. marinum, due to their production of ESAT-6 and CFP-10

92
The Mantoux TST is preferred over IGRA for children less than 5 years of age. Blood
extraction for IGRA testing can pose as a challenge in young children requiring at least
1 – 2 mL. as blood test specimen. Limited studies show a reduced sensitivity in the
IGRA test over TST in young children and HIV-infected children.

93
REFERENCES:
1. National Institute for Health and Clinical Excellence. Clinical Diagnosis and Man-
agement of Tuberculosis, and Measures for its Prevention and Control. March
2011
2. World Health Organization. Tuberculosis IGRA TB Tests Policy Statement 2011
3. Centers for Disease Control and Prevention. Updated Guidelines for Using Interfer-
on Gamma Release Assays to Detect Mycobacterium tuberculosis Infection, United
States. MMWR 2010; 59 (No.RR-5)
4. Guidance for national tuberculosis programmes on the management of tuberculo-
sis in children. Geneva, World Health Organization, 2014. (WHO/HTM/TB/2014.03)
5. Manual of Procedures of the National Tuberculosis Control Program, 2014.
6. Philippine Pediatric Society. Evidence-based clinical practice guidelines for child-
hood tuberculosis. 2008.
7. TB Care I. International Standards for Tuberculosis Care, Edition 3, TB CARE I,
The Hague, 2014.
8. WHO Guidance on the Management of Latent TB Infection (LTBI), 2015
9. Consensus Statements on Child TB. Philippine Pediatric Society 1997
10. Menzies D. EDITORIALS: Tuberculin surveys - why?. Int J Tuberc Lung Dis.
1998;2 (4):263-264.
11. American Thoracic Society. Diagnostic Standards and Classification Tuberculosis
in Adults and Children. Am J Respir Crit Care Med. 2000;161:1387.
12. Huebner RE, Schein W, Bass, Jr JB. The tuberculin skin test. Clin Infect Dis.
1990;17:968-975.
13. Centers for Disease Control and Prevention. Targeted tuberculin testing and inter-
preting tuberculin skin test results -Fact sheet. 2009. Available from: http://
www.cdc.gov/tb/publications/factsheets/testing/skintestresults.htm.
14. Pediatric Tuberculosis Collaborative Group. Targeted Tuberculin Skin Testing and
Treatment of Latent Tuberculosis Infection in Children and Adolescents. PEDIAT-
RICS. 2004 Oct;114(4):1175-1201.

15. National Tuberculosis Controllers Association; CDC. Guidelines for the Investiga-
tion of Contacts of Persons with Infectious Tuberculosis. MMWR; 16 December
2005;54(RR15):1-37.

16. Philippine Department of Health. Training modules for TB in children. 2008.

94
17. Haslov K., Head, Analysis and Control Department, Comparability of the Tuberculin
unit (T.U.) of Tuberculin PPD RT23 to the international standard for purified protein
derivative of mammalian Tuberculin PPD-S (or PPD-M) Statens Serum Institut, Di-
vision of Vaccine, Sept. 4, 1996
18. Bass JB. The tuberculin test. Marcel Dekker: New York; 1993. (Reichman LB,
Hershfield ES, editors. Tuberculosis: A Comprehensive International Approach.).
19. Furcolow ML, Howell B, Nelson WE, Palmer CEE. Quantitative studies of the tuber-
culin reaction I. Titration of tuberculin sensitivity and its relation to tuberculous infec-
tion. Public Health Reports. 1941;56:1082.
20. American Thoracic Society Medical Section of American Lung Association. Diag-
nostic Standards and Classification of Tuberculosis. American Review of Respirato-
ry Disease. 1990 Sept;142(3):725-735.
21. Centers for Disease Control and Prevention. Targeted tuberculin testing and treat-
ment of latent tuberculosis infection. 2005. Available from: http://www.cdc.gov/tb/
publications/slidesets/LTBI/default.htm.
22. Lifschitz M. The value of the tuberculin skin test as a screening test for tuberculosis
among BCG-vaccinated children. Pediatrics. 1965;36:624-7.
23. Landi S, Ashley MJ, Grzybowski S. Tuberculin sensitivity following the intradermal
and puncture methods of BCG vaccination. Can Med Assoc J. 1967;97:222-5.
24. Joncas JH, Robitaille R, Gauthier T. Interpretation of the PPD skin test in BCG-
vaccinated children. Can Med Assoc J. 1975;113:127-8.
25. Fox AS, Lepow ML. Tuberculin skin testing in Vietnamese refugees with a history of
BCG vaccination. Am J Dis Child. 1983;137:1093-1094.
26. Chan LT Jr, Marcelo M, Tan M, Chiong J. A Proposed Scoring System for Child-
hood Pulmonary Tuberculosis. Philippine Journal of Pediatrics. 1995 Jan-Mar;45(1).
27. Chan LT Jr, Tan M, Chiong J, Estabillo–Tavu T. The validation of the Chan scoring
system for childhood pulmonary tuberculosis. The Philippine Journal of Pediatrics.
1997 Oct-Dec;46(4).
28. Centers for Disease Control and Prevention. Guide to vaccine contraindications and
precautions. Available from: http://www.cdc.gov/vaccines/recs/vac-admin/
downloads/contraindications-guide-508.pdf.
29. Advisory Committee on Immunization Practices (ACIP). General recommendations
on immunization. MMWR. 1994;43:15.
30. Tupasi T. The 1997 National Tuberculosis Prevalence Survey: Final Report.
31. Tupasi T. The 2007 National Tuberculosis Prevalence Survey: Final Report.

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32. Sackett DL, Haynes RB, Tugwll P. Clinical Epidemiology: A Basic Science for Clini-
cal Medicine. Boston: Little Brown and Company; 1985.
33. Fletcher RH, Fletcher SW ,Wagner EH. Clinical Epidemiology- The Essentials. Bal-
timore: Williams & Wilkins; 1987.
34. Alon MJC, Gatchalian S, Tabora C. PPD tuberculin Test reactivity of Filipino infants
aged 6 months and 1 year vaccinated with BCG at birth. The Philippine Journal of
Pediatrics. 2001;50:32-35.
35. De la Cruz JM, Garcia I, PahatiL, de Leon MNA. PPD reactivity among high risk Fili-
pino children with or without BCG vaccination. The Philippine Journal of Pediatrics.
1999;48:70-74.
36. Johnson H, Lee B, Kelly E, McDonnell T. Tuberculin sensitivity and the BCG scar in
tuberculosis contacts. Tuber Lung Dis. 1995;35:113-7.
37. Smith MHD, Starke JR, Marquis JR. Tuberculosis and opportunistic mycobacterial
infections. Philadelphia: W.B. Saunders Co; 1992. p.1321-1362. (Feigin RD, Cherry
JD, editors. Textbook of Pediatric Infectious Diseases, 2 vols, 3rd ed.).
38. Steiner P, Rao M, Victoria MS, et al. Persistently negative tuberculin reactions. Am
J Dis Child. 1980;134:747-750.
39. Core Curriculum on Tuberculosis. What the Clinician Should Know: Centers for
40. Disease Control and Prevention National Center for HIV, STD, and TB Prevention
41. Division of Tuberculosis Elimination; http://www.cdc.gov/tb/education/corecurr/
index.htm 2010.

96
 9
Radiologic Findings
Maricar Paguia, MD
Myra R Asuncion-Son, MD

OUTLINE
1 Overview of Chest Radiography in
Children and Other Ancillary Tests

2 Radiologic Manifestations of Pul-

monary Tuberculosis

97
OVERVIEW OF CHEST RADIOGRAPHY IN CHILDREN AND OTHER ANCIL-
LARY TESTS
The chest x-ray is the most basic and widely used radiological investigation used for
pulmonary tuberculosis.
Chest radiography is helpful in localizing the site of tuberculosis (TB) lesions. Although
not specific for the diagnosis of pulmonary TB, it becomes important when diagnosing
in places where TB is highly prevalent and where facilities for bacteriologic examination
are not easily available.1 Tuberculin skin test reaction lags behind radiological findings2.
Sputum almost always is unavailable for testing, and gastric washings are only positive
in 30-40% of cases.3 Because of all these limiting factors, Mycobacterium tuberculosis
is isolated in less than 50% of pediatric cases. Hence, the diagnosis of tuberculosis
(especially during the early stages), often relies on imaging findings. A study done by
Gwee et al showed that chest x-ray was able to demonstrate tuberculosis in a small but
noteworthy number of children in the absence of clinical symptoms.
Chest radiographic evidence parallel that of the pathologic changes of tuberculous in-
fection. These are divided into: 1) initial exposure or primary TB; and 2) post primary or
primary progressive TB. Reactivation of previous infection or progression of an initial
infection exemplifies the latter.
The primary complex is composed of the primary focus, lymphangitis, localized
pleural effusion and regional lymphadenitis. The hallmark of the initial disease is the
relatively large size of the adenitis compared with the relatively insignificant size of
the initial focus in the lungs.31
In radiological studies, it is important that we consider the following points in the inter-
pretation of chest film in children, particularly in those suspected with TB:

 Clinical history, i.e. exposure, signs and symptoms

 Tuberculin test
 Information that should be provided to the radiologist, such as:
 Is the patient a diagnosed case of TB?
 Is the patient on therapy or has completed a full course of TB regimen?
The proper equipment and technique are necessary to obtain an adequate chest x-ray;
and these should conform to the following:

 Recommended guidelines for standardization available at the Department of Health

 Regular calibration of equipment to ensure good quality of films
 Reiterate proper exposure, parameters (300 to 500ma), positioning and degree of
inspiration
 Pertinent, old films should be made available
 Standard views, frontal (PA/AP) and lateral, are recommended on every pediatric
patient for a complete and accurate identification and interpretation of the primary
complex15

98
Lateral view of chest radiograph increases the sensitivity/yield of diagnosis in detecting
hilar adenopathy,16 but the use of high kilovolt (kv) view does not significantly improve
the accuracy of diagnosis.17 Partially calcified mediastinal nodes may be visible only in
lateral projections.
The common chest radiologic finding in primary TB is lymphadenopathy. Should an en-
larged lymph node be noted on chest x-ray, it should be interpreted as nonspecific
lymph node enlargement. Radiologists should refrain from using ―primary complex‖ un-
less the lymph node enlargement is associated with parenchymal disease and that per-
tinent clinical information strongly suggests such diagnosis. Providing a list of differen-
tial diagnosis is encouraged by clinicians. Lymphadenopathy can also be seen in viral
and bacterial infections. A radiological follow-up allows excluding of sequela or a preex-
isting pulmonary abnormality such as TB; however, follow-up x-rays are to be delayed
two to three weeks after the clinical recovery due to the late radiological recovery after
treatment.26 If lymphadenopathy persists, mycobacterial etiology can be considered 15.
The most common cause of calcification in children is TB. However, other diseases,
such as Histoplasmosis, Coccidioidomycosis and Aspergillosis, may also produce in-
trathoracic calcifications which a radiograph cannot differentiate from those due to TB.
Calcifications can also be demonstrated in the nodes regional to inoculations with BCG
vaccine; these, however, tend to disappear more quickly than those associated with
natural infections.
There are no pathognomonic radiographic findings. Perhaps the only finding that may
be highly suggestive of TB in infants and children is the uniform stippling of both lungs
found in miliary TB.
Historically, bronchography was useful in the definition of bronchial stenosis or bronchi-
ectasis. At present, special imaging techniques, such as computed tomography and
magnetic resonance imaging, may be of particular value in defining nodules, cavities
cysts, calcifications, contours of large bronchi and vascular details in lung parenchy-
ma.6
A cross-sectional study among Filipino children six months to 18 years old with a posi-
tive chest x-ray, positive tuberculin test and positive history of TB contact with symp-
toms suggestive of TB disease like cough, fever, weight loss, hemoptysis, anorexia,
dyspnea, weakness was done at the Philippine Heart Center. The over-all positive pre-
dictive value for diagnosing TB disease among these children using chest x-ray was
only 59% compared to chest computed tomography CT scan which was 98%. In Filipi-
no children, the specific lesions seen in chest CT scans are subcentimeter (lymph
nodes which are enlarged in the peri-hilar region of the lungs, but these are less than
one centimeter in greatest diameter), calcified nodes, peribronchial, axillary, bilateral
hilar nodes, pericardiac nodes with ring enhancement, and granuloma.18 This is similar
to the characteristic CT findings of childhood TB in other countries of low attenuation
with rim enhancement or calcification of mediastinal and hilar lymph nodes.19
In another local study done among diagnosed patients four months to 18 years old
(n=83), review of radiographs revealed the following findings: lymphadenopathies, in-

99
cluding lymph node enlargement as a solitary finding and as part of Ghon focus (64%),
parenchymal infiltrates (78%), air-space opacities (63%), cavitary lesions (21%), mili-
tary pattern (10%), bronchial and tracheal compressions (12%), and atelectasis (22%).
Only 7% of the subjects had normal radiographs.
Pleural effusion was present in one-fourth of the primary cases. Five had massive effu-
sion, one of which was proven to be empyema. Two patients presented with cardiac
shadow enlargement. One had pericardial effusion, while the other had constrictive per-
icarditis. Paraspinal masses associated with osseous destruction were appreciated in
10%; Pott‘s disease was observed in the old age bracket while a significantly higher
proportion of lymphadenopathy was noted among the younger group. Miliary TB was
linked with younger age bracket, positive culture results, and high mortality.40.
In the evaluation of children with known or suspected pulmonary TB, CT scans cannot
be routinely recommended because of its high cost, the need for IV sedation and the
risk involved in administering a contrast medium. However, when chest radiographs are
normal or when the presence of mediastinal lymphadenopathy cannot be seen by chest
x-ray but TB disease is clinically suspected, CT scan may be used in the diagnosis of
TB disease in pediatric age groups, especially when there is difficulty in establishing
definite diagnosis. 18,19,27,28

RADIOLOGIC MANIFESTATIONS OF PULMONARY TUBERCULOSIS

Pulmonary Tuberculosis
Primary Tuberculosis
In the same way that clinical manifestations of the initial tuberculous infection are mea-
ger or absent, there are instances when there are no abnormal radiologic signs in the
thorax. The sole evidence of TB infection is a positive tuberculin test. The initial radio-
graphic picture, whether in a child or adult, is usually parenchymal infiltration accompa-
nied by ipsilateral lymph node enlargement. Changes in the lymph node tend to persist
longer than the parenchymal shadows.4
In primary tuberculous infection, the radiologic patterns reflect the development of the
pathologic complex seen with initial exposure to the tubercle bacilli. The infection,
which is primarily spread through inhaled droplet, is seen mostly in the lung. In its com-
plete form, the primary complex is composed of the following characteristics; however,
not all features are necessary to make the diagnosis13

 size and shape in the radiolucent lung;

 enlarged regional nodes;
 lymphangitis that produces linear shadows of increased density connecting the pul-
monary focus and the regional nodes; and
 localized pleural effusion that appears as a shadow of increased density in the pleu-
ral space contiguous to the primary focus.

100
The most common chest radiograph findings in childhood TB are lymphadenopathy and
parenchymal abnormalities, which occurs in 83% to 92% in the first case19,20 and in
60.8% in the second case.20,21
As a rule, pleural exudates and lymphangitis are not clearly seen. Common radiological
findings are enlarged retrocardiac lymphadenopathy in 70% of the cases, hilar ade-
nopathy with pulmonary infiltrates in 20% and pleural effusion in 6-11%.5,20 Chest radio-
graphs may be normal in up to 10% of patients who have proven primary TB.8
Hilar adenopathy has a specificity of 36%. Because of its low specificity, this radiologi-
cal finding should not be used as a sole basis in initiating treatment, especially when
there are no other manifestations suggesting TB.5 The lymphatic drainage of the lungs
occurs predominantly from left to right, and therefore, the nodes in the right upper para-
tracheal area appear to be the ones most often affected.
Mediastinal lymphadenopathy, on the other hand, has been found to be a more likely
characteristic in children with both tuberculous meningitis and military TB than those
with miliary TB or TB meningitis alone.
Many primary lesions are subpleural and the lymphatic drainage of the apical pleura is
in the cervical nodes. The primary focus can look like any pneumonia and be situated
anywhere. All areas of the lung may be involved.
The principal components of the primary complex and their fate are discussed further
below.
1. Parenchymal Involvement
The parenchymal reaction is typically that of acinar consolidation, which is usually ho-
mogenous in density and with ill-defined margins, except where it abuts against a fis-
sure. It predominantly involves the upper lobes with preferential location between ante-
rior or posterior segments and between right and left. Quite frequently, it also involves
the apex of a lower lobe.
Atelectasis is important in the production of massive shadows. It frequently affects the
anterior segments of the upper and middle lobes of the right lung due to bronchial com-
pression by enlarged lymph nodes. There is surprisingly little shift in the heart and other
mediastinal structures; instead, the healthy lung on the same side expands and fills in
the space previously occupied by the collapsed segment. Lobar involvement is most
probably a combination of parenchymal consolidation and parenchymal atelectasis. An
entire lobe, often the right middle lobe, may be affected.
Large primary foci and their perifocal reactions may occupy all or most of a lobe and
obscure the lymphangitis and pleural exudate. Perifocal shadows may represent pneu-
monic consolidation, atelectasis or pleural exudate, singly or in combination. With the
gradual clearing of the perifocal shadows, the pulmonary lesion (primary focus) may
remain obscured or may become visible later. In other cases, large calcifying pulmo-
nary foci may dwarf the remainder of the tuberculous complex. Cavitation of the primary
focus with a perifocal exudate may occasionally be seen but is considered a rare mani-

101
festation of pulmonary TB in infants and children.
2. Lymph Node Involvement
Hilar or paratracheal lymph node enlargement is the radiologic finding that clearly differ-
entiates primary from postprimary TB. The lymph node enlargement is usually unilat-
eral. Highly suggestive of primary TB is the large size of the adenitis relative to the in-
significant size of the primary lung focus.
Progression from Ghon focus and lymph node disease tend to occur more frequently
among the younger age group (less than 5 years of age) and adolescents (>10
years).40
3. Airway Involvement
Tracheobronchial involvement is a common occurrence; it is usually the result of bron-
chi compression due to enlarged lymph nodes. It may also result from a long-standing
or untreated infection. Bronchial obstruction due to tuberculous lymph nodes may pre-
sent radiographically as:

 Hyperaeration: It may occur in a lobar segment, a lobe, or even an entire lung.

Roentgenograms, best taken on expiration show hyperaeration, usually without me-
diastinal displacement, probably because of fixation of the tuberculous mediastinal
nodes.

 Segmental atelectasis: Described as fan-shaped, homogenous density, which most

commonly occurs on the middle lobe.

 Collapse-consolidation lesions: A roentgenographic finding in which there is only

conspicuous atelectasis and consolidation as the salient pathologic process. The
volume of the segment is undiminished or seems increased.
As mentioned, radiographic manifestations in TB with tracheobronchial involvement are
nonspecific. A normal chest x-ray does not exclude tracheobronchial pathology. In a
study done in pediatric patients with primary TB who underwent CT studies, bronchial
involvement was noted in up to 37% of the subjects19. For cases in which airway in-
volvement is suspected, direct visualization thru fiberoptic tracheobronchoscopy (FOT)
remains the definitive study; however, this is invasive. A local study was done compar-
ing FOT and computed tomography (CT) scan findings in pediatric patients with primary
progressive tuberculosis and tracheobronchial involvement. CT studies showed high
correlation with the FOT findings. FOT remains to play a major role in the diagnosis of
tracheobronchial TB; however, the lumen distal to the obstructed airways cannot be
evaluated.37 38 CT studies, on the other hand, was able to evaluate the airways distal to
the obstructed airways.40
4. Pleural Involvement
Pleurisy is so common in primary TB that it should be considered as a component of
the complex rather than a complication. It may appear as a localized pleural effusion
contiguous to the primary foci, which will become evident many months after the ap-
pearance of TB in the lung, or will manifest as a localized pleural thickening late in the

102
disease. The pleural effusion may also be generalized, unilateral, or bilateral as seen
more commonly in progressive type of pulmonary TB. It may obscure the underlying
pulmonary changes, especially when it is large. The pleuritis may be small, localized
and asymptomatic or it may occur in the form of generalized effusion usually three to
six months after the infection occurs. Differentiating effusion from extensive pneumonic
lesion is difficult; thus, lateral decubitus radiographic views are helpful in confirming the
presence of pleural fluid.31
5. Resolution of Radiologic Changes
Regression of radiographic abnormalities in pulmonary TB is a slow process. In the first
three months of treatment, worsening of radiographic findings, which consists of exten-
sion of parenchymal involvement and enlargement of nodes, may be observed in al-
most one third of pediatric patients receiving appropriate therapy.20 Due to the great
variation in the velocity of healing in the different components of each complex, healing
may present a wide variety of findings in different cases. Resorption may begin in the
different stages of healing: during fibrosis, hyalinization, or calcification in different parts
of the complex.
In the small proportion of children with radiological evidence of the disease, clearing
usually occurs within six months to two years after institution of therapy. 9 In other re-
ports, the enlarged lymph node and parenchymal disease can persist for two to three
years or even longer.20 Chest x-ray findings should always be correlated with the clini-
cal manifestations.
Complete resolution, but without apparent residual, is seen in the majority of cases. In
some cases, atelectasis remains due to residual lymph node enlargement. A significant
percentage of children who have had atelectasis during the active stage of the disease
showed residual bronchiectasis in the affected areas.
In interpreting calcification on chest x-ray, calcification may be due to healed, healing,
or quiescent infection; thus, it should be correlated with the history of treatment.
Duration of follow up for patients with primary TB depends on the patient‘s clinical sta-
tus after therapy. Radiologists can recommend follow up study for as early as three to
six months or sooner if the patient is not responding to treatment. If patient has good
clinical response, a follow up x-ray would be to the clinician‘s discretion.15

Postprimary Tuberculosis

1. Chronic Pulmonary Tuberculosis / Reactivation

In chronic pulmonary TB, the disease tends to localize in the apical and posterior seg-
ments of the upper lobes and involves the right lung more than the left. Lymph node
enlargement is not a feature. The radiological pattern may be highly suggestive, but it is
not diagnostic, and is simulated by several infections of different etiologies—mycotic,
bacterial, viral and parasitic.

103
The following are radiologic features seen in chronic pulmonary tuberculosis:

 Local exudative TB: The most common radiographic manifestation of reactivation

pulmonary TB is focal or patchy heterogeneous consolidation involving the apical
and posterior segments of the upper lobes and the superior segments of the lower
lobes.

 Local fibroproductive TB: The relatively poor definition of the exudative lesion is re-
placed by shadow, which is more sharply circumscribed, homogenous, and usually
of somewhat irregular and angular contour. Cavitation may be seen. Healing occurs
by fibrosis and the resultant cicatrisation may result in loss of volume. If there is sig-
nificant volume loss, compensatory signs may become evident such as elevation of
the ipsilateral hilum, over inflation of the rest of the affected lung, and in some cas-
es, formation into bullae. This pattern is more commonly seen in chronic pulmonary
TB.

 Cavitation: Cavities are the radiological hallmark of reactivation TB; they are evident
radiographically in 20% to 45% of patients.27 The wall of an untreated tuberculous
cavity is moderately thick, and its inner surface is fairly smooth. An air-fluid level is
seldom seen. With adequate therapy, a cavity may disappear or regress into a pa-
per-thin, air-filled cystic space. Cavitation is seen both in progressive and chronic
types of pulmonary TB.
Caseous material in a tuberculous focus may simulate cavitation because of its high
lipid content that produces a shadow slightly less dense than the wall. An aid to dif-
ferentiation is the contrast between the inner wall and the central radiolucency. Air
in apposition to a wall tends to show a sharper definition than when the interface is
liquid against solid.

 Tuberculoma: In approximately five percent of patients with reactivation TB, the

main manifestation is a tuberculoma, which is defined as a sharply marginated,
round or oval lesion, measuring 0.5 to 4.0 cm in diameter, and situated most com-
monly in an upper lobe, the right more than the left ranging from 0.5 to 4 cm or
more in diameter.28 Typically, they are smooth and sharply circumscribed while up
to a fourth may be smooth and lobulated. Small discrete shadows in the immediate
vicinity of the main lesion (satellite lesions) may be identified. There may be irregu-
lar thickening of the wall of the draining bronchus and in some, of the actual bron-
chostenosis.
The majority of these lesions remains stable and may calcify. The larger the lesion,
the more active it is, and those exceeding three cm in diameter should be resected.

 Acute Tuberculous Pneumonia: Characteristically, bronchogenic spread leads to

the formation of multiple small acinar shadows. Extension of the disease may be
indistinguishable from those caused by other bacteria. An open cavity or discrete
acinar shadows in parts of the lung remote from the massive consolidation suggest
that the cause is tuberculous in origin.

104
2. Miliary Tuberculosis
In the event of an explosive and massive spread into the bloodstream, both lungs are
evenly seeded with innumerable foci of approximately the same sizes. At first, these
lesions are too small to be visualized. The pattern may not become apparent until sev-
eral weeks after the patient is seen .The lesions require at least 2 ½ weeks to become
perceptible and would first appear as a indistinguishable nodule of a uniform size of 2
mm.10
As the foci become larger and older, multiple small shadows appear which stipple both
lungs more or less uniformly (―millet-seed‖ densities). This stippling of the lungs is the
most diagnostic radiological change in pulmonary TB during infancy and childhood. Lat-
er, stippling in the lungs coalesce thus, producing a richly stippled pattern (―snowstorm
effect‖).
A local study was done correlating the different radiographic patterns of primary TB with
clinical presentation, microbiologic, as well as polymerase chain reaction (PCR) find-
ings. Results of said study showed that the yield of PCR was highest among the group
with disseminated military pattern compared to those who have lymph node disease,
progression from Ghon focus, and pleural effusion.
With adequate treatment, clearing is quite rapid and without residual. Considerable im-
provement may be observed within five weeks after initiating treatment, while clearing
is complete in seven to 22 months, with a mean of 16 weeks.
This miliary pattern may also be seen in sarcoidosis, pneumoconiosis, disseminated
carcinomatosis, and fungal and viral infections. Miliary calcification is extremely rare in
miliary TB. Other causes are to be considered such as histoplasmosis, coccidioidomy-
cosis, schistosomiasis and paragonimiasis.

3. Airway Tuberculosis
 Tuberculous bronchiectasis: In endobronchial TB, the bronchi are affected in sever-
al different ways: a) exogenous lymph node compression; b) intrinsic granuloma
formation; and c) bronchiectasis.
Bronchographic evidence of distortion and dilatation of the bronchial tree
(bronchiectasis) may develop when the bronchial wall is infected. Healing by fibro-
sis and cicatrization leads to irreversible dilatation. Obstruction of a segmental bron-
chus from compression by enlarged lymph nodes or by bronchostenosis can lead to
destructive pneumonitis and subsequent bronchiectasis.
Bronchiectasis is twice more frequent in patients with hemoptysis. This may be
asymptomatic and suggested only by non-resolving radiographic shadows despite
adequate treatment. A definitive diagnosis of bronchiectasis is made through bron-
chography, CT scan, and bronchoscopy.

 Tuberculous bronchostenosis: Tuberculous bronchitis may occur in the absence of

a demonstrable x-ray abnormality. If left untreated, cicatricial bronchostenosis is

105
 almost inevitable with its resultant obstructive atelectasis, pneumonitis, and bronchi-
ectasis. Persistent respiratory wheeze may suggest the diagnosis. The principal CT
scan findings in airway TB are circumferential wall thickening and luminal narrow-
ing, which involves a long segment of the bronchi. In active diseases, the airways
are narrowed irregularly in their lumen and have thick walls whereas, in fibrotic dis-
ease, the airways are narrowed smoothly and have thin walls. The left main bron-
chus is involved more frequently in fibrotic disease; whereas, both main bronchi are
equally involved in active disease.30

Extrapulmonary Tuberculosis
Diagnosis of extra-pulmonary TB is often difficult. Although positive chest radiographic
findings or a positive tuberculin skin test supports the diagnosis, negative results do not
exclude extra-pulmonary TB.4
Musculoskeletal Tuberculosis

1. TB Spondylitis/Spinal TB (Pott‘s Disease)

Most often, the disease process begins in the anterior part of the vertebral body, adja-
cent to the end plate, which affects the lower thoracic and upper lumbar spine. In the
process, more than one vertebra is affected, and commonly, the vertebral body is more
involved than the posterior segment.22 The collapse of a vertebral body, particularly the
anterior segment, may result in tuberculous kyphosis and characteristic gibbus for-
mation. Paraspinal infection may involve the psoas muscle, resulting in psoas abscess,
which can extend into the groin and thigh. Occasionally, a large, paraspinal cold ab-
scess with no osseous lesion is identified at radiography. In such cases, CT scan is of
great value in demonstrating a small focus of vertebral involvement.22 Calcification with-
in the abscess is virtually pathognomonic of TB.9,12
The most important differential diagnosis is pyogenic vertebral osteomyelitis. Many oth-
er disease processes including metastatic disease, primary vertebral neoplasm and
rare spinal infections (low grade pyogenic infections),22 such as brucellosis, fungal in-
fections and sarcoidosis, have imaging findings similar to those of spinal TB . However,
the diagnosis of TB is favored if there is a presence of a large, calcified, and paraverte-
bral mass and an absence of sclerosis or new bone formation. Conversely, interverte-
bral disk destruction is more characteristic of a pyogenic infection.12
2. Extraspinal Tuberculous Osteomyelitis
Tuberculous osteomyelitis is usually hematogenous in origin and is commonly seen in
bones of the extremities, including the small bones of the hands and feet. In long, tubu-
lar bones, TB often involves the epiphyses. In children, metaphyseal foci can involve
the growth plate; this feature differentiates TB from pyogenic infection. 22 Cystic TB is a
type of tuberculous osteomyelitis that affects children more often than adults. The le-
sions consist of well-defined, metaphyseal areas of hyperlucency with variable amounts
of sclerosis. Tuberculous dactylitis involves the short tubular bones of the hands and
feet in children. At radiography, these lesions demonstrate soft-tissue swelling and peri-
ostitis, followed by gradual bone destruction and sequestrum formation. Expansion of
the bone with cystic changes is known as ―spina ventosa‖. The radiological differential
106
diagnosis includes pyogenic or fungal infections, syphilitic dactylitis, sarcoidosis, hemo-
globinopathies, hyperparathyroidism, and leukemia.23
3. TB Arthritis
TB of the joints is characteristically a monoarticular disease primarily involving the
large, weight-bearing joints such as the hip and knee.23 The triad of juxtaarticular osteo-
porosis, peripherally located osseous erosions, and gradual narrowing of the interosse-
ous space is termed the PHEMISTER triad and is characteristic of TB arthritis. Relative
preservation of the joint space is highly suggestive of TB arthritis, while early loss of
articular space is more typical of rheumatoid arthritis.

Central Nervous System Tuberculosis

Central Nervous System (CNS) TB may take a variety of forms, including meningitis,
tuberculoma, abscess, cerebritis and part of disseminated TB.22
1. TB Meningitis
In an unpublished, retrospective study of cranial CT scans of 100 patients (<17 years
old) done in 2008 at St. Luke‘s Medical Center and presented in the 8th Annual Scien-
tific Meeting of the Asia Oceanic Society of Pediatric Radiology (AOSPR) in Cambodia,
result showed that in a non-contrast and enhanced CT, the most specific finding in the
diagnosis of CNS TB is basal cistern hyperdensity.21 Abnormal meningeal enhance-
ment that is typically most pronounced in the basal cisterns may be well seen with both
CT and MR imaging. This enhancement of the basal cisterns corresponds to the gelati-
nous exudates. Communicating hydrocephalus is the most common complication of TB
meningitis. Also, ischemic infarcts are commonly seen as a complication of cranial TB
meningitis. The majority of the infarct is seen in the basal ganglia and internal capsule
and can result from vascular compression and occlusion of small perforating vessels.4
Long term sequelae of these infarcts include focal areas of atrophy. 22 Cranial nerve in-
volvement occurs in 17% to 70% of cases, commonly affecting the second, third, fourth,
and seventh cranial nerves.23
The differential diagnosis for TB meningitis includes other infectious agents (non-
tuberculous bacteria, viruses, fungi, parasites), non-infectious inflammatory disease
affecting the leptomeninges (rheumatoid disease, sarcoidosis), and primary or second-
ary neoplastic involvement of meningeal surfaces (meningiomatosis, neoplastic menin-
gitis from a peripheral tumor source, cerebrospinal fluid seeding from a primary tumor
of the CNS).22
2. Tuberculoma
Parenchymal disease can occur with or without meningitis and usually manifests as
tuberculomas. The initial pathogenesis of CNS tuberculoma is identical to that of tuber-
culous meningitis. Instead of rupturing into subarachnoid space, however, tubercles
continue to grow, walled off from brain parenchyma and meninges by a dense fibrous
capsule. Grossly, the lesions are well-circumscribed masses varying in sizes from less
than a centimeter up to several centimeters. A patient can have one or several tubercu-
lomas localized to any brain region. Tuberculomas occasionally develop during or after
treatment for TB meningitis. These may be solitary but are more commonly multiple.

107
The frontal and parietal lobes are commonly the most affected regions. At CT, tubercu-
lomas appear as rounded or ovulated masses with low or high attenuation and with var-
ying degree of edema. Calcification is uncommon. They demonstrate homogenous or
ring enhancement and have irregular walls of varying thickness.4 If the caseous core of
a tuberculoma liquefies, a TB abscess results. These patients with TB abscess tend to
be clinically worse overall than those with correspondingly sized tuberculoma. Clinical
sequelae of CNS tuberculomas and abscesses primarily include seizures and corre-
lates of increased intracranial pressure. Tuberculous abscess is a rare complication of
CNS TB in the general population, which is seen in four percent to eight percent of pa-
tients with CNS TB but without HIV infection. In a study done by Whiteman et al in
1995, the incidence of CNS TB increases in patients infected with HIV, reaching up to
20%. In contrast to the solid caseation observed in tuberculoma with few tubercle bacil-
li, the center of the abscess is semiliquid pus teeming with tubercle bacilli. The wall of a
tuberculous abscess lacks the giant cell epithelioid reaction of a TB granuloma. Further
distinguishing characteristics of abscesses include size and multiplicity; they tend to be
larger than tuberculomas and have a more accelerated clinical course. Tuberculomas
are often multiple, while abscesses are usually solitary.31
3. Spinal Tuberculous Meningitis
The MR imaging features of spinal TB meningitis consist of CSF loculation and oblitera-
tion of the spinal subarachnoid space, with loss of outline of the spinal cord in the cervi-
cothoracic spine, and matting of the nerve roots in the lumbar region. Contrast-
enhanced imaging reveals nodular, thick, linear, intradural enhancement, which can
completely fill the subarachnoid space.23 This could sometimes give a normal appear-
ance on an enhanced, non-contrast MR image; it emphasizes the importance of utiliz-
ing contrast when there is a clinical question of possible spinal infection.23
Head and Neck Tuberculosis
Tuberculosis in the head and neck represents about 15% of cases of extra-pulmonary
TB. The most common location is within neck nodes, often manifesting as bilateral,
painless cervical lymphadenitis, also known as scrofula. The nodes involved are initially
homogeneous but later undergo central necrosis. These nodes may be difficult to differ-
entiate from the necrotic nodes seen in metastatic head and neck squamous cell carci-
nomas. Nodal calcification often develops late in TB, which helps differentiate TB nodes
from malignancy.23
Tuberculous otomastoiditis can result from hematogenous spread or from direct exten-
sion from the upper respiratory tract. CT demonstrates soft-tissue attenuation in the
tympanic cavity in the early stages and destruction of middle ear structures in the later
stages. Associated retroauricular or epidural abscess may also be seen. Ocular TB re-
sults from hematogenous spread and can involve any part of the eye. Chorioretinitis
and uveitis are the most common manifestations.22
Abdominal Tuberculosis
Lymphadenopathy is the most common radiographic manifestation of abdominal TB,
which is seen in 55% to 66% of patients.23 Mesenteric, omental, and peripancreatic

108
lymph nodes are the most commonly involved. The nodes are usually large and multi-
ple and demonstrate peripheral enhancement with central areas of low attenuation at
contrast-enhanced CT.22
Peritonitis is the most common clinical manifestation of abdominal TB, affecting one-
third of all patients. The condition is subdivided into three main types: wet, fibrotic, and
dry. The wet type, which is characterized by a large amount of free or loculated viscous
fluid—which at CT is usually slightly hyperattenuating relative to water due to its high
protein and cellular content—is seen in most patients. The fibrotic-fixed type and the
dry or plastic type are less common. Fibrotic type is characterized by large omental and
mesenteric cake-like masses with matting of bowel loops. At CT, it manifests as mott-
led, low-attenuation masses with nodular soft-tissue thickening. Omental thickening and
caking can also be seen at ultrasound. Dry type peritonitis is seen in ten percent of cas-
es and is characterized by mesenteric thickening, fibrous adhesions, and caseous nod-
ules. Its imaging manifestations are highly suggestive of, but not specific for, TB. 23
Ileocecal involvement is seen in 80% to 90% of patients with abdominal
TB.1.Thickening of the valve lips or wide gaping of the valve with narrowing of the termi-
nal ileum (Fleischner sign) has been described as a characteristic of TB. At CT, one
half of patients with gastrointestinal TB shows circumferential thickening of the cecum
and terminal ileum, enlargement of the ileocecal valve and mesenteric lymphadenopa-
thy.4 The differential diagnosis for ileocecal TB includes amebiasis, Crohn‘s disease,
and primary cecal malignancy. Involvement of the esophagus, stomach, and proximal
small bowel is rare. Esophageal TB is usually due to extrinsic compression at the level
of the carina from lymphadenopathies.23
Hepatosplenic TB generally manifests in a micronodular (miliary) or macronodular
(tuberculoma) form. On CT scans, numerable tiny, low attenuation foci may be seen.
The macronodular form is rare. The spleen is probably always seeded during the initial
lymphohematogenous spread. Only rarely are the tubercles which are numerous
enough and large enough to undergo cassation and calcify.5
Adrenal involvement in TB is rare. It may manifest as unilateral or bilateral adrenal
masses with central areas of necrosis. Enlarged adrenal glands are also seen in pa-
tients with recent or concurrent renal tuberculous infection. Adrenal atrophy with calcifi-
cation may be seen in patients with healed, prior TB, and these patients may present
with Addison disease.22
Tuberculosis affecting the pancreas is rare. Its occurrence may pose a diagnostic prob-
lem when differentiating it from carcinoma of the pancreas. Most patients have constitu-
tional symptoms and vague abdominal pain. Fine needle aspiration should be consid-
ered in young patients presenting with a cystic pancreatic mass, especially, in those
with constitutional symptoms living in endemic regions.32
Renal Tuberculosis
Tuberculosis may involve the genitourinary tract as a secondary site following hematog-
enous dissemination from the lungs.22 The earliest radiographic abnormality is a ―moth-

109
eaten‖ calyx due to erosion. This finding is followed by papillary necrosis. Poor renal
function, dilatation of the pelvocalyceal system due to a stricture of the ureteopelvic
junction, or destructive dilatation or localized hydrocalycosis related to an infundibular
stricture may be seen. Cavitations within the renal parenchyma may be detected as
irregular pool of contrast material.4 Ureteral involvement is seen in 50% of patients with
genitourinary TB. CT may demonstrate thickening of the ureteral wall and inflammatory
changes of the periureteral. As the disease progresses, urography demonstrates short-
or long-segment ulceration of the ureter. Chronic fibrotic strictures result in a beaded or
corkscrew appearance. Chronic thickening of the ureteral wall may also cause fore-
shortening (pipe-stem ureter). The most common finding in TB cystitis is reduced ca-
pacity of the bladder.22
Genital Tuberculosis
Genital TB involves, almost always, the fallopian tubes in women (94% of cases), usu-
ally causing bilateral salpingitis. Findings at hysterosalpingography are always abnor-
mal, with obstruction and multiple constrictions of the fallopian tubes and endometrial
adhesions or deformity of the cavity. Male involvement is confined to the seminal vesi-
cles or prostate gland, with occasional calcification (10% of cases). Contrast-enhanced
CT shows hypoattenuating prostatic lesions, which likely represent foci of caseous ne-
crosis and inflammation. Nontuberculous pyogenic prostatic abscesses have a similar
CT appearance; its spread is hematogenous and self-limiting. The testes and epididym-
ides are rarely involved. US shows focal or diffuse areas of decreased echogenicity;
however, these findings are very nonspecific.22,23
Cardiac Tuberculosis
Tuberculosis involving the heart is rare, accounting for only 0.5% of cases of extrap-
ulmonary TB. The main presenting finding is pericardial involvement, particularly in im-
munocompromised patients. Myocardial involvement is seen less often. The primary
sign of tuberculous pericarditis is pericardial thickening of more than 3 mm as seen on
CT. CT demonstrates a thickened, irregular pericardium, frequently, with associated
mediastinal lymphadenopathy. Most patients have distention of the inferior vena cava
to a diameter greater than 3 cm; pleural effusions, typically bilateral; and deformities of
the intraventricular septum. Less than 20% have pericardial effusions or develop local-
ized pericardial calcifications.23 A historical cohort study (2000 to 2009) of 179 patients
(0 to 19 years old) with an initial presentation of either pleural effusion or pericardial
effusion was done at the Philippine Heart Center. Ninety-one patients (51%) presented
initially with pleural effusion while 88 patients (49%), with pericardial effusion. Those
patients who initially presented with pericardial effusion are highly associated with ac-
quired heart disease (74%) then TB (45%).30

110
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29. Krysl J, Korzeniewska-Kosela M, Muller NL, FitzGerald JM. Radiologic features of
pulmonary tuberculosis: an assessment of 188 cases. Can Assoc Radiol J.
1994;45:101–107.
30. Yeon JJ, Kyung SL. Pulmonary Tuberculosis: Up-to- Date Imaging and Manage-
ment. AJR. 12008 September; 91.
31. Behrman RE, Kliegman RM, Arvin AM. Textbook of Pediatrics. 18th ed. Philadelph-
ia: Saunders; 2007.
32.
33. Damian MS (MD), De leon NA (MD), Bautista MS (MD), De Guia TS (MD), Ayuyao
FG (MD). Risk Factors of Pleuro-pericardial Effusion among Pediatric Patients
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 initially Presenting with Pleural effusion and Pericardial Effusion alone at
Philippine Heart Center. 2009. (Presented at the Asia Pacific Society of Respirology
Convention, Seoul, South Korea, November 2009)
34. Whiteman M, Espinoza L, Post MJ , Bell MD, and Falcone S. Central nervous sys-
tem tuberculosis in HIV-infected patients: clinical and radiographic findings. AJNR
Am. J. Neuroradiol. 1995 Jun;16:1319-1327.
35. Lo SF, Ahchong AK, Tang And CN, Yip AWC. Pancreatic tuberculosis: case reports
and review of the literature. J.R.Coll. Surg. Edinb. 1998 February;43:65-69.
36. Gwee A, Pantazidou A, Ritz N, et al. To x-ray or not to x-ray? Screening asympto-
matic children for pulmonary TB: a retrospective audit. Arch Dis Child 2013; 98:401
37. van den Bos F, Terken M, Ypma et al. Tuberculous meningitis and military tubercu-
losis in young children. Trop Med Intl Health 2004; 9:309
38. Ip MS, So SY, Lam WK, Mok CK. Endobronchial tuberculosis revisited. Chest 1986;
89: 727-730
39. Smith LS, Schillaci RF, Sarlin RF. Endobronchial tuberculosis: Serial fiberoptic
bronchoscopy and natural history. Chest 1987; 91: 649-647.
40. Laya BF, Concepcion NDP, dela Eva RC, Mendoza AR, Sanchez MO, Goco NB,
Buenaflor MTS. Computed tomography with Multiplanar Reformation and 3D-
Volume Rendering Technique in Correlation with Fiberoptic Tracheobronchoscopy
for Thoracic Evaluation of Children with Primary Progressive Tuberculosis and Tra-
cheobronchial Involvement. St. Luke‘s J Med 2011; 07: 17-19.
41. Sanchez MO, Mendoza AR, Laya BF. Primary Progressive Tuberculosis in Chil-
dren: Radiographic Patterns in Correlation with Clinical Presentation and Microbio-
logic Studies. St. Luke‘s J Med 2011; 07: 59-65

113
 10
Diagnostic Tests/
Laboratory Findings
Ma. Liza Antoinette M Gonzales, MD
Maria Rosario Z Capeding, MD
Carmina A Delos Reyes, MD

OUTLINE
1 Diagnostic Mycobacteriology

2 Procedures for Collection and

Transport of Various Specimen
Types for TB Diagnosis

3 Histologic Examination

4 Serological Tests

5 Molecular Diagnostic Tests

6 T-Cell-Based Assays (Interferon-

Gamma Release Assays)

114
DIAGNOSTIC MYCOBACTERIOLOGY
Detection of acid fast bacilli (AFB) in microscopically examined stained smears is the
first bacteriologic evidence of the presence of mycobacteria in clinical specimens using
either Ziehl-Neelsen or Kinyoun carbol fuchsin stains. AFB smear microscopy is the
easiest, least expensive and most rapid procedure where the results can be obtained
within an hour from obtaining preliminary information. While it provides the physician
with a presumptive diagnosis of active tuberculosis (TB), it also gives a quantitative es-
timation of the number of bacilli on the smear and implies the degree of infectiousness
of the patient.1,2 A positive AFB smear may represent either M. tuberculosis (MTB) or
some non-tuberculous mycobacterium; therefore, it is not sufficient evidence for bacte-
riologic diagnosis.
The overall sensitivity of AFB smear is variable, ranging from 20 to 80%; however, its
specificity is high (≥97%).3 Sensitivity of smear microscopy is generally higher in older
children (more than 5 years of age) and adolescents, and in children of all ages with
severe disease4, however, is significantly reduced in patients with extrapulmonary TB
and in HIV-infected TB patients. Several factors can influence the sensitivity of AFB
smear: specimen type, number of obtained specimens, and staining method. It is esti-
mated that the lowest concentration of organisms that can be detected by microscopic
examination is 104 AFB per ml of sputum.2,3
Fluorescence microscopy (FM), in which auramine-based staining causes the acid-fast
bacilli to fluoresce against a dark background, are increasingly used in many parts of
the country. A comprehensive systematic review of 45 studies using culture as the gold
standard indicates that FM is 10% more sensitive than conventional microscopy and
examination of fluorochrome-stained smears takes less time.5 It allows a much larger
area of the smear to be seen resulting to a more rapid examination of the specimen up
to four times faster and easier counting of the bacilli. Its specificity is comparable to
conventional microscopy.6
Fluorescent light-emitting diode (LED) microscopy for diagnosis of tuberculosis provide
a relatively inexpensive light source for fluorescence microscopy. Evidence show that
the diagnostic accuracy of LED microscopy is comparable to that of conventional fluo-
rescence microscopy and it surpasses that of conventional Ziehl-Neelsen microscopy
by an average of 10%. It showed 84% sensitivity and 98% specificity against culture as
the reference standard. This is recommended for use in high-volume laboratories.7

Mycobacterial Culture and Drug Susceptibility

Culture of TB bacilli is of great importance not only for bacteriological confirmation of
active TB and confirmation of the diagnosis but also to test for drug susceptibility. TB
culture should be done on all specimens, regardless of AFB smear results. Although
there are newer techniques that give rapid results, demonstration of the TB bacilli by
solid culture is still regarded as the gold standard for diagnosis. 8,9 MTB can be cultured
in specific solid or liquid broth media.

115
Mycobacterial culture has a low sensitivity in children, where only about 10 to 50% of
tuberculous cases are culture-proven10,11 owing to the paucibacillary nature of the dis-
ease and difficulty of specimen collection.12 Fortunately, for most children with pulmo-
nary TB, culture confirmation is not necessary if the epidemiologic, tuberculin skin test
and roentgenographic information are compatible with the disease.13 However, cultures
should be obtained from the child if the source case is unknown or has a drug-resistant
organism, or if the child is immunocompromised or has extrapulmonaryTB.
Traditional culture methods utilize solid culture media that include the egg-potato-based
media (e.g. Lowenstein-Jensen, Ogawa) and the agar-based media (e.g. Middlebrook
7H10, Middlebrook 7H11 and Mitchison‘s selective 7H11). Incubation of inoculated me-
dia in 5% to 10% carbon dioxide atmosphere enhances the number of positive isolates
and the number of culturable colonies. It is limited by suboptimal sensitivity, slow turna-
round time and the low bacteriologic yields in children with active TB. The isolation of
organisms often require four-to-six weeks and another two-to-four weeks for suscepti-
bility testing.1,2,3,4,14
Mycobacterial culture with the use of commercial broth-based liquid culture media are
more rapid and sensitive than solid culture techniques in detecting TB bacilli. It has re-
duced the average detection time of broth smear-positive and smear-negative samples
by nearly 50%. Liquid culture systems provide results in 7-14 days (up to 42 days for a
negative result) significantly faster than solid culture techniques. 15 Liquid systems are
more prone to contamination and its manipulation of large volumes of infectious materi-
al mandates appropriate biosafety measures. Both culture systems have specificities of
nearly 100% but have lower sensitivity.1,2,3,11,13,15
The growth of mycobacteria in liquid media, regardless of its type, requires 5% to 10%
carbon dioxide (CO2), which is already provided in the culture vials or is added accord-
ing to manufacturer‘s instructions. The most commonly used are Septi-Check AFB and
Mycobacteria Growth Indicator Tube (MGIT). The liquid culture system, such as BacT/
Alert, also has a feature that monitors the continuous growth of mycobacteria. In this
system, growth is detected by CO2 production through the use of colorimetric CO2 sen-
sor in each bottle and through BACTEC 9000 MB by monitoring O2consumption with
the use of a fluorescent sensor. Both manual and automated systems are availa-
ble.1,2,3,4,13,16,17
Drug-susceptibility testing (DST) is performed in two methods: phenotypic and genotyp-
ic. Phenotypic methods involve culturing M. tuberculosis in the presence of anti-TB
agents to detect growth (indicates resistance) or inhibition of growth (indicates suscepti-
bility). Phenotypic DST methods are performed as direct or indirect in solid or liquid me-
dia. Liquid culture systems for DST reduce the turn-around time to as short as 10 days,
compared with the 28-42 days needed for conventional solid media. Genotypic meth-
ods target specific molecular mutations associated with resistance against anti-TB
agents.18

116
Collection and Transport of Specimens for Demonstration of Tubercle
Bacilli
Mycobacterial infections occur in almost any site in the body; therefore, a variety of clin-
ical samples are appropriate specimens for laboratory analysis. In children, specimens
include gastric aspirate, sputum, cerebrospinal fluid, pleural fluid, bronchial washings,
urine, pus, bone marrow, and biopsy or resected tissue. Proper collection of specimens
is essential for the diagnosis in children because of the fewer tubercle bacilli present.
Specimens must be collected in sterile, leak proof, disposable and appropriately la-
belled containers and must be stored under conditions that inhibit the growth of con-
taminants, since most specimens will contain bacteria other than mycobacteria. Certain
specimen collection procedures are optimal for MTB. All specimens from non-sterile
sites must be decontaminated before culture.1,2,3,4

PROCEDURES FOR COLLECTION AND TRANSPORT OF VARIOUS SPECI-

MEN TYPES FOR TB DIAGNOSIS
Gastric aspirate or lavage
This procedure is recommended for infants and children who are unable to produce
sputum even with aerosol inhalation. Specimens should be collected in the morning
before the patients eat and while they are still in bed. Gastric aspiration is best per-
formed in hospitalized patients. About 5mL to 10mL of gastric content should be aspi-
rated. For gastric lavage, 25mL to 50 mL of sterile distilled water is injected through the
stomach tube. Gastric fluid is recovered through aspiration and placed in a leak-proof,
sterile container such as a 50mL conical tube. The maximum volume of gastric fluid
that must be collected is 15mL. The specimen should be transported to the laboratory
as soon as possible at room temperature. This procedure is repeated once daily for
three consecutive days. If transport is delayed for more than one hour, the specimen
must be neutralized with 100mg sodium carbonate within one hour of collection and
stored at room temperature. Further, the specimen must be processed promptly, since
mycobacteria die rapidly in gastric washings. MTB can be isolated from only 30-45% of
children and 70% of infants with pulmonary TB (PTB).
Sputum
For older children who are able to expectorate, a series of two sputum specimens
should be collected in two different days before start of therapy. The patient should be
instructed to follow these steps to obtain a good specimen: (1) clean and thorough rinse
the mouth with water; (2) breathe deeply three times; (3) after the third breath, cough
hard and try to bring up sputum from deep in the lungs; and (4) expectorate the sputum
into a sterile container collecting at least one teaspoonful. The minimum desired vol-
ume of the sputum specimen is 3mL. The sputum specimen must be transported to the
laboratory as soon as possible; if delayed for more than one hour, the specimen must
be stored and refrigerated. Sputum specimens must not be pooled.
Respiratory (bronchial wash, lavage, brushings; endotracheal aspirate,
transtracheal aspirate, nasopharyngeal aspirate)
Collect respiratory washing or aspirates in a sputum trap and place the brush in a ster-
117
ile, leak-proof container with up to 5mL of sterile saline. The minimum desired volume
of respiratory specimens or aspirates is 3mL. The specimen should be transported as
soon as possible to the laboratory at room temperature and must be stored and refrig-
erated if transport is delayed for more than one hour.
Cerebrospinal Fluid (CSF)
CSF of about 1-2mL must be collected aseptically into a sterile, leak-proof container
such as a 50mL conical tube. A separate CSF sample must be collected for chemistry
and hematology and must be transported to the laboratory as soon as possible if stored
at room temperature. CSF specimen must not be refrigerated or frozen except when
PCR test is considered.

Tissue/Lymph Node

Tissue or lymph node specimen can be collected aseptically during surgery or biopsy and
placed in a sterile, leak-proof container such as a 50mL conical tube. Two to 3mL of sterile sa-
line must be added to the tissue for transport. The tissue specimen must be transported as soon
as possible at room temperature. If transport is delayed for more than one hour, the tissue must
be stored and refrigerated. Always submit as much tissue as possible.

Abscess, Cellulitis, Eye exudate, Skin lesion

Surface exudate may be removed by wiping off with sterile saline or 70% alcohol. Fluid
abscess material should be collected with a syringe or its tissue removed aseptically.
For open lesions or abscesses, the exudates or abscess fluid can be aspirated from
under the margin of the lesion or abscess. Exudates and abscess fluid should be col-
lected in a sterile, leak-proof container, such as 50mL conical tube and must be trans-
ported as soon as possible if at room temperature. If transport is delayed for more than
one hour, the exudates or abscess fluid must be stored and refrigerated. The specimen
must not be transported in a commercial swab transport device or in a transport medi-
um. The exudate or abscess fluid must not be frozen and tissue should not be pre-
served. Tissue (at least 1g, if possible) or fluid is preferred. A swab is strongly discour-
aged unless it is the only specimen available. Submit swabs in 2-3mL sterile saline or
preferably in 7H9 broth.
Blood
Ten milliliter of whole blood must be collected aseptically in a 10mL, yellow-top collec-
tor tube containing sodium polyanetholsulfonate (SPS), or green-top collector tube con-
taining heparin; a red-top tube, EDTA (purple-top), or ACD (yellow-top) cannot be used
to collect blood. Minimum volume required is 1mL. The blood specimen should not be
refrigerated or frozen and must be transported as soon as possible at room tempera-
ture.
Body Fluids
Fluid of about 10-15mL must be aseptically collected into a sterile, leak-proof container,
such as a sterile 50mL conical tube or a sterile urine collection container. A swab
dipped in fluid cannot be submitted. The specimen must be transported as soon as
possible at room temperature or stored and refrigerated but cannot be allowed to
freeze.
118
Bone Marrow aspirate
To aspirate bone marrow, the puncture site must be prepared just like for surgical inci-
sion. A blood collector tube may be used to collect the bone marrow specimen. The
collected bone marrow is transferred into a 10mL, yellow-top collector tube containing
SPS or submitted in a sterile, leak-proof container, such as a 50mL conical tube. The
specimen must be transported as soon as possible and stored at room temperature but
must not be refrigerated or frozen.
Urine, including collections from a catheter
About 40mL of urine (midstream is never advised) or other specimens collected from a
catheter must be collected in a sterile, leak-proof container such as a sterile 50ml coni-
cal tube. Minimum volume required is 10-15mL. It is preferable to collect the first morn-
ing specimen daily for three consecutive days in 8-24 hour intervals (24 hours when
possible). The specimen must be transported as soon as possible at room temperature;
if transport is delayed for more than one hour, the urine specimen must be refrigerated.
Pooling or urine specimens or addition of preservatives to the urine should not be done.
Twenty-four hour urine specimens are undesirable because of excessive dilution, high-
er contamination, and difficulty in concentrating.
Stool
Culture from feces for mycobacteria is not encouraged except for patients with Human
Immunodeficiency Virus (HIV) who may have a high concentration of mycobacteria in
their lower intestinal tract.

HISTOLOGIC EXAMINATION
Biopsy of a node, skin lesion, bone or pleura may permit a quick presumptive diagno-
sis, as well as yield specimens for bacteriologic examination. The classic pathologic
lesion in TB consists of caseating granulomas, which may demonstrate AFB. The path-
ologic events in the initial tuberculous infection will depend upon the balance among
the mycobacterial antigen load, cell-mediated immunity which enhances intracellular
killing and tissue hypersensitivity which promotes extracellular killing. 3,19 When the anti-
gen load is small and the degree of tissue sensitivity is high, granuloma formation re-
sults from the organization of lymphocytes, macrophages, Langerhans giant cells, and
fibroblasts. When both antigen load and the degree of hypersensitivity are high, granu-
loma formation is less organized.

SEROLOGICAL TESTS
Immunodiagnostic methods based on the detection of antigen or antibodies to TB bacilli
have not come into widespread clinical use unlike with other infectious diseases. De-
spite hundreds of studies published, serology has found little place in the routine diag-
nosis of TB in adults and children because both sensitivity and specificity of the various
tests were highly variable.20,21 Results have shown that for all commercial serological
tests, sensitivity ranged from 0-100% for diagnosing both pulmonary and extrapulmo-
119
nary TB while specificity ranged from 31-100% for PTB and from 59-100% for extrap-
ulmonary TB.20 None of these studies were conducted in children. Due to the incon-
sistent and imprecise findings for currently available serological tests, WHO strongly
recommends that commercial serodiagnostic or serological tests should not be used for
the diagnosis of pulmonary and extrapulmonary TB.21

MOLECULAR DIAGNOSTIC TESTS

Nucleic Acid Amplification Tests (NAATs)
Nucleic acid amplification tests (NAATs) utilize techniques to amplify nucleic acid re-
gions specific to the MTB complex. In theory, NAATs can detect a single bacillus in a
specimen such as sputum, gastric aspirate, pleural fluid, cerebrospinal fluid, or blood. A
variety of amplification methods have been developed to detect specific sequences of
MTB and other mycobacteria. Targets include insertion and repetitive elements, various
protein encoding genes, deoxyribonucleic acid (DNA), ribosomal ribonucleic acid
(rRNA), and others. The most common target is the IS6110 followed by the 65-kDa an-
tigen. These polymerase chain reaction (PCR) assays target either DNA or rRNA and
the assays could be based on conventional DNA-based PCR, nested PCR and reverse
transcriptase (RT)-PCR.22-27 NAATs are available as ―in-house‖ assays or as commer-
cial kits. In-house assays are PCR assays developed in noncommercial laboratories
that vary widely in protocol and laboratory methods for every institution. Performance of
in-house NAATS has been highly variable in studies probably because of variability in
patient populations, DNA extraction and amplification protocols, and operator experi-
ence. As a result, in-house assays have not gained widespread acceptance.28
Commercial NAATs use various methods for amplification that are standardized and
produce more consistent results compared to in-house assays. The Amplicor PCR test,
the Amplified MTB test, and the BD ProbeTec ET Direct TB assay are currently US-
FDA approved and can be used on platforms capable of sample batch processing for
confirmation of culture-positive samples or sputum specimens and for confirmation of
smear-negative samples.29 The earlier NAATs required manual sample preparation and
lysis of cells, involving both cen-trifugation and heating prior to amplification. Overall,
the sensitivity of these assays range from 72% to 94% with specificities reported to be
96% to 100%.30,31 Higher sensitivity (86% to 96%) with similar specificity (≥ 98%) is
reported with the Roche COBAS® TaqMan® MTB test, an automated extraction plat-
form that enables automated extraction, reaction preparation and manual transfer to
their amplification platforms.32,33 This assay has received regulatory approval in Canada
and Japan. Another automated platform is the Abbott m2000 RealTime MTB assay,
currently only available as a research tool.29
In the Philippines, many of these tests are available with the Amplicor MTB test and
Cobas Amplicor being the most commonly used commercial NAATs. Loop-mediated
isothermal amplification (LAMP) is also available but it is used mainly as a research
tool. In-house PCRs are also in various stages of development in different institutions.
These tests are being used mainly for research purposes only due to the costs of the
reagents and the machines required to run them.
120
NAATs are useful because of the rapid and early detection of causative mycobacteria
in clinical samples that could be important in the following: when diagnosis is urgently
needed due to the severity of disease; when diagnosis is difficult, particularly in smear-
negative cases, and; in paucibacillary disease such as TB in children, extrapulmonary
TB, TB in immunocompromised patients, and disseminated TB.34
These potential advantages must be weighed against the disadvantages of these rapid
diagnostic tests, some of which are common to all molecular assays and others specific
to particular assays. Among the most important limitations of current molecular assays
in resource-limited countries are the cost, the need for laboratory infrastructure that can
accommodate molecular testing, stable uninterrupted electricity supply, and require-
ment for highly trained staff.34 Since none of the methods are capable of detecting re-
sistance to all the antituberculosis drugs, these rapid molecular methods cannot re-
place culture and conventional antimicrobial susceptibility testing to detect multidrug-
resistant (MDRTB) and extensively drug resistant TB (XDRTB).34
Nucleic Acid Amplification Tests in Pediatric Tuberculosis
Studies evaluating the performance of commercial NAATs in children using various
specimens (gastric aspirate, bronchoalveolar lavage, CSF, urine, lymph node biopsy,
pleural fluid) compared to predefined criteria based on a combination of clinical fea-
tures, epidemiological history, radiological findings and results of tuberculin test to diag-
nose active TB in children have reported low and variable sensitivities ranging from 4-
90% with generally higher specificities, ranging from 75-97%.35-44 Problems with NAATs
include false positive results attributed to carry-over of amplicons from previous reac-
tions or to cross-contamination with MTB DNA from positive clinical samples during the
processing procedure and inability to distinguish tuberculous infection from disease in
children.35,38,45 Therefore, a negative NAAT result never eliminates TB as a diagnostic
possibility, and a positive result does not confirm it.34 Results of the NAATs should al-
ways be interpreted in conjunction with microscopy and culture results, clinical manifes-
tations, epidemiological data, imaging and other laboratory tests. The high cost of the
test, labor-intensive procedure and problems in specificity preclude its use as part of
the routine initial evaluation of pediatric patients suspected to have TB.
Nucleic Acid Amplification Tests in Pulmonary and Extrapulmonary Tuberculosis
Several recent meta-analyses and reviews have synthesized the evidence on accuracy
of NAATs for respiratory46-50 and non-respiratory specimens.51-53 The studies were con-
ducted in both adults and children and showed that the NAATs are useful in confirming
the diagnosis of pulmonary or extrapulmonary TB due to their high specificity and posi-
tive predictive values—characteristics that confer value in terms of their ability to rule in
TB. Rarely, false positive results may occur due to contamination of the sample with
environmental mycobacteria causing non-specific binding to the probe.15 However,
NAATs reported only modest and highly variable sensitivity, varying from 50-80%, with
lower sensitivities noted in smear-negative and extrapulmonary TB.6,15,54 Sensitivity is
variable due to the presence of PCR inhibitors in clinical specimens, low organisms and
loss of nucleic acids during processing of clinical specimens.4
Due to these limitations, NAATs should be used in conjunction with conventional and
other tests, as well as clinical and epidemiological data in order to absolutely rule out
121
disease.15 More evaluation on these technologies and assays are required to ensure
that performance is acceptable or optimal to justify the investment required for their im-
plementation. Furthermore, the high cost and level of technical support needed pre-
vented widespread adoption in TB endemic countries. None of these assays or their
successors have been endorsed by WHO.29
Line Probe Assays
This technology involves a series of steps including extraction of DNA from mycobacte-
rial isolates or directly from clinical specimens, PCR amplification of specific fragments
of the MTB genome followed by hybridization of labeled PCR products to DNA oligonu-
cleotide probes bound to a solid membrane or strip. Colorimetric detection allows visu-
alization of the bands or lines where hybridization has occurred, corresponding to the
presence of TB and a sensitive or resistant genotype (hence, the term ‗‗line-probe‘‘ as-
say).55-58 Line probe assays currently available on the market for rapid detection of MTB
complex and resistance are the INNO-LiPA RIF TB (Innogenetics, Zwijndrecht, Bel-
gium), GenoType MTBDR/MTBDRplus and Geno-Type MTBDRsl (both HainLifesci-
ence, GmbH, Nehren, Germany).54 In the Philippines, the INNO-LiPA RIF TB is availa-
ble in national reference centers.
These line probe assays are sensitive tests that can be used for a variety of purposes,
including diagnosis of MTB complex, speciation of other nontuberculous mycobacteria,
and genotyping common drug resistance alleles for rifampicin and other antituberculo-
sis drugs within a 24-hour period.56,59-60 Data from systematic reviews and meta-
analyses to evaluate assay performance results against conventional drug susceptibility
test methods on isolates of MTB and on smear-positive sputum specimens showed that
line probe assays are highly sensitive (≥97%) and specific (≥99%) for the detection of
rifampicin resistance.61 Line probe assays have not been specifically assessed in pedi-
atric populations; however, because the majority of pediatric samples are smear-
negative, their role would be primarily for detection of resistance in positive culture
samples.62
Line probe assays are recommended by the WHO for use only on smear-positive spu-
tum specimens and isolates of MTB.18 These assays are not recommended as a com-
plete replacement for conventional culture and drug susceptibility testing, which is still
necessary to confirm resistance to drugs other than isoniazid and rifampicin. 6 Perfor-
mance of line probe assays is restricted to central or national reference centers due to
the requirements for appropriate equipment (a thermocycler is required to generate la-
beled amplicons), trained personnel to avoid error in reading the strips, and a dedicated
site within the laboratory to reduce the potential for contami-nation.54
GeneXpert MTB/RIF assay
The GeneXpert MTB/RIF assay (Xpert® MTB/RIF Cepheid, Sunnyvale, California,
USA), is the first fully automated, cartridge-based NAAT for TB that represents a major
advancement in TB diagnostics because it simplifies molecular testing by fully integrat-
ing and automating three processes (sample preparation, amplification and detection).
This real time-PCR-based molecular test can simultaneously detect TB bacteria and
rifampicin resistance in clinical specimens outside conventional laboratory settings in
less than 2 hours and can be used by operators with minimal technical expertise even
122
in peripheral laboratories in developing countries.63-65 This test makes it possible for
patients to be treated promptly and to identify those who need second-line drug treat-
ment.6,63,64 Target detection and characterization is performed in real time using nucleic
acid hybridization probes (molecular beacons), each labeled with a colored fluorophore
responding to a specific target sequence within the rpoB gene of M. tuberculosis. 59
Studies have shown that the GeneXpert MTB/RIF test is more sensitive and specific
than smear microscopy for detecting MTB but is less sensitive or similar to that of broth
or liquid culture.18,54,66,67
Recently, the Gene Xpert MTB/RIF test has become available for use not only in na-
tional reference centers in the Philippines but in various hospitals and rural health units
all over the country, largely through support from global funding agencies.
Gene Xpert MTB/RIF test for Pulmonary Tuberculosis
Studies in children have shown improved yield and sensitivity of the Xpert MTB/RIF on
various specimens. A systematic review and meta-analysis on the accuracy of Xpert
MTB/RIF to diagnose pulmonary TB in children using a variety of respiratory speci-
mens, showed that sensitivity varied from 55-90% for samples of expectorated sputum,
40-100% for induced sputum sensitivity and 40-100% for gastric lavage or aspirate.68
Confidence intervals overlap for each specimen type, suggesting that no specimen type
is superior. Specificities for all studies and specimen types ranged from 93-100%.
When results of the studies were combined, the pooled sensitivity of Xpert MTB/RIF
compared against culture was 66% (95% CI 52-77%) for expectorated or induced spu-
tum and 66% (95% CI 51-81%) for gastric lavage or aspirate, with higher sensitivity on
smear positive samples (96%) than for smear-negative samples (55%) regardless of
HIV status. For the diagnosis of RIF resistance, the sensitivity and specificity of Xpert
were 83.3% and 99.1%, respectively.68 Results are similar to a more recent meta-
analysis which showed that compared with culture, the pooled sensitivities and specific-
ities of Xpert for tuberculosis detection were 62% (95% CI 51–73%) and 98% (95% CI
97–99%), respectively, with use of expectorated or induced sputum samples and 66%
(95% CI 51–81%) and 98% (95% CI 96–99%), respectively, with use of samples from
gastric lavage.69 Xpert's pooled sensitivity and specificity to detect rifampicin resistance
was 86% (95% credible interval 53–98) and 98% (94–100), respectively.69
Based on results of clinical evaluation, laboratory validation and demonstration studies
in a variety of settings and systematic reviews, WHO endorsed the Xpert® MTB/RIF
assay for use in pulmonary TB. 68,70 WHO recommended that the Xpert MTB/RIF assay
should be used as a replacement for conventional microscopy, culture and drug sus-
ceptibility testing as the initial diagnostic test in both adults and children with PTB and
suspected at risk for drug-resistant TB or have HIV-associated TB.70,71 In the update,
acknowledging resource implications particularly in low income countries, WHO also
recommends that Xpert MTB/RIF assay may be used rather than conventional micros-
copy and culture as the initial diagnostic test in all other individuals suspected of having
TB, if resources are available.4,6,68,72
Studies on collection of 2 or more specimens in children have shown conflicting results,
with some studies showing increased sensitivity of the Xpert MTB/RIF from collection of
a second specimen73,74 but not in other studies.75,76 Due to the added resources needed
123
for testing multiple specimens with no clear advantages, WHO recommends use of a
single specimen for diagnostic testing. 72
Gene Xpert MTB/RIF test for Extrapulmonary Tuberculosis
Despite limited studies in patients with TB meningitis, WHO recommends that the Xpert
MTB/RIF be used as the preferred test rather than conventional microscopy and culture
as the initial diagnostic test for cerebrospinal fluid specimens due to the urgency of rap-
id diagnosis.6,68,77 Thus in situations where sample volume is low or additional speci-
mens cannot be obtained, Xpert MTB/RIF should be given preference over culture. For
other cases of extrapulmonary TB, Xpert MTB/RIF may be used for testing lymph
nodes and other tissues instead of conventional microscopy, culture, or histopathology.
In a systematic review, the pooled sensitivity of the Xpert MTB/RIF to detect peripheral
lymph node TB in children was 86% (95% CI, 65-96%) and the pooled specificity was
81% (95% CI, 54-93%).68 These recommendations do not apply to stool, urine or
blood, given the lack of data on the utility of Xpert MTB/RIF on these specimens.6,68
Overall, results of studies in children show that sensitivity of Xpert MTB/RIF is still lower
than culture confirmation or clinical diagnosis for extrapulmonary TB. Further larger pro-
spective studies of patients with suspected TB at the most common extrapulmonary
anatomic sites, including children and those with pleural TB and TB meningitis, are
needed to assess the role of Xpert MTB/RIF in the diagnosis of EPTB in specific popu-
lations.6 Hence, the Xpert MTB/RIF assay should not be used as the sole test for evalu-
ation. A child suspected to have pulmonary or extrapulmonary TB, particularly if it is
severe or progressing rapidly should undergo further diagnostic testing and should be
treated even if the Xpert MTB/RIF result is negative on one specimen or if the test is
not available.4,68 Use of the Xpert MTB/RIF test does not eliminate the need for conven-
tional microscopy, culture, and drug susceptibility testing that are required to monitor
treatment and to detect resistance to drugs other than rifampicin. 6

T CELL BASED ASSAYS (INTERFERON GAMMA RELEASE ASSAYS)

Interferon-Gamma Release Assays (IGRAs) are whole-blood tests developed to aid in
TB diagnosis. They work by measuring a person‘s immune reactivity to MTB. Fresh
blood samples are mixed with antigens specific for MTB complex strains and absent
from the BCG vaccine strain. White blood cells from infected persons (T lymphocytes)
release IFN-g as a marker of infection or active TB.78,79 A positive test result suggests
that MTB infection is likely while a negative test result suggests that infection is unlikely.
Commercially available, FDA-approved indirect and adjunct tests for TB infection are
the QuantiFERON TB Gold (QFT-G, Cellestis, Australia based on PPD) and the newer
generation QuantiFERON TB Gold In-Tube (QFT-GIT, Cellestis, Australia based on
ESAT-6 and CFP-10).80 They are whole-blood based enzyme-linked immunosorbent
assays (ELISAs) which measure the amount of interferon-gamma produced in re-
sponse to specific MTB antigens (QFT-G:ESAT-6 and CFP 10; QFT-GIT:ESAT-6, CFP
10, TB7.7 . An enzyme-linked immunospot (ELISPOT)-based T-SPOT.TB (Oxford-
Immunotec, UK) measures the number of peripheral mononuclear cells that produce
124
interferon-gamma after stimulation with ESAT-6 and CFP-10. 15, 80-84
The Quantiferon TB Gold is able to discriminate between MTB and M. avium intracellu-
lare complex infection .85 It responds to multiple antigens spontaneously and does not
boost anamnestic immune responses.86 Key disadvantages are the false-positive re-
sults in BCG-vaccinated people and the inability to discriminate between most of the
atypical mycobacteria and MTB. 86
The Quantiferon TB Gold-In Tube that are based on RD1-specific antigens ESAT-6 and
CFP-10, can overcome some of the above disadvantages. In vivo and in vitro experi-
ments have shown that the combination of ESAT-6 and CFP-10 has a higher sensitivity
and specificity than PPD in the diagnosis of TB infection.87, 88
Systematic reviews have been done and have shown that IGRAs perform differently in
high versus low TB and HIV incidence settings.15 WHO recommends that either IGRA
or TST can be used to test for latent TB infection (LTBI) in high-income and upper mid-
dle-income countries which have a low burden of TB disease (estimated TB incidence
<100 per 100,000 population).89 However, there are no current guidelines for their use
in low and middle-income countries where TB and/or HIV burdens are high.89 Lower
sensitivity in high-burden settings were documented. This shows that mere extrapola-
tion of data on IGRAs from high-income countries to low and middle-income settings
with high TB infection rates is inappropriate.
To address this gap in knowledge, the WHO commissioned systematic reviews on the
use of IGRAs in low and middle-income countries. In particular, the studies looked into
the performance of IGRAs in the diagnosis of active TB, its use in children, its use in
HIV-infected individuals, its use as a screening tool for healthcare workers, and its use
in contact screening and outbreak investigations.89 The diagnostic accuracy of the
IGRAs in the diagnosis of latent TB infection and active TB in different populations and
clinical settings is summarized in the following section.
Use of IGRAS for Diagnosis of Latent TB Infection
IGRAs and the tuberculin skin test (TST) are surrogate markers of MTB infection. Both
tests indicate a cellular immune response to recent or remote sensitization with MTB.
There is no currently available gold standard for the detection of MTB infection and nei-
ther of these tests can distinguish TB infection from active disease.89 IGRAs just like
the TST should be used in conjunction with the risk of acquiring TB, radiography, and
other clinical and diagnostic evaluations. IGRAs differ however from the TST in that it
requires sophisticated laboratory infrastructure and technical expertise.
IGRAs may have the following advantages: the test requires a single patient visit, the
result can be available in 24 hours due to automated testing (which eliminates reader
bias), a booster phenomenon does not occur (which proves to be of value in screening
people repeatedly exposed to TB), and it is not affected by previous BCG vaccina-
tion.15,87
The test has disadvantages and limitations as well. There is a need to perform a blood
test and the blood sample needs to be processed immediately, within 8-30 hours after

125
collection while white blood cells are still viable. The test is expensive, and there is pau-
city of data on the use of IGRAs particularly in children younger than 5 years, persons
with recent exposure to MTB, and immunocompromised patients. 88-90
One systematic review showed that IGRAs based on RD1-specific antigens, ESAT-6 or
CFP-10, correlate better with intensity of exposure and are more likely to detect LTBI
accurately compared with TST/PPD-based assays. IGRAs are also more likely to be
independent from BCG vaccination and HIV status.15 In recent years, IGRAs have been
widely endorsed in high-income countries for diagnosing LTBI.78
However, due to the lower sensitivity of IGRAs in low and middle-income countries,
there are no current guidelines for their use in these high-burden settings to screen in-
dividuals with repeated TB exposure such as healthcare workers and contacts of active
TB cases and for identifying individuals at risk of developing active TB. 89
Use of IGRAs in health care worker (HCW) screening
In the systematic review conducted by WHO, evidence for use of IGRAs for LTBI
screening of HCW in low and middle-income countries was limited and based on low
quality data from two cross-sectional studies. Results showed that positivity of both
IGRA and TST were high at 40-66%, although IGRA positivity was slightly lower than
the TST. Data are lacking on serial IGRA testing and on the predictive value of IGRAs
in HCWs for high-burden TB and/or HIV settings. 89
Use of IGRAs in contact screening and outbreak investigations
IGRAs have not shown additional benefit over the TST in screening for LTBI in adult
and pediatric contacts, or in outbreak investigations. In the systematic review, 16 low
quality studies evaluated IGRAs in contact screening and outbreak investigations, 75 %
of contact studies included children. Majority of studies were cross-sectional and the
heterogeneity in study designs and outcomes assessed made it impossible to pool the
data. Despite the limitations, majority of the studies showed comparable LTBI preva-
lence by TST or IGRAs in contacts. The most commonly observed discordance was of
the TST-positive/IGRA negative type. Both IGRAs and TST showed positive associa-
tions with higher levels of exposure in cross-sectional studies but the strength of asso-
ciation varied across studies. Concordance between TST and IGRAs was variable.
Predictive value of IGRAs
Neither IGRAs nor the TST should be used for the identification of individuals at risk of
developing active TB. Results are based on three very low quality studies that provided
the incidence rate ratios (IRR) of TB stratified by IGRA as well as TST status at base-
line. Association with subsequent incident TB in those who tested positive compared to
test negatives appeared higher for IGRA than for TST but this was not statistically sig-
nificant. Both the TST and IGRA show positive associations between exposure gradient
and test results but there was variability in the strength of the associations across popu-
lations, irrespective of BCG vaccination. There was no statistically significant increase
in the incidence of TB in IGRA-positives compared to IGRA-negatives and majority of
individuals (95%) with a positive IGRA result did not progress to active TB on follow-up.
Both IGRAs and the TST appeared to have a modest predictive value and did not help
identify those who are highest risk of progression to TB disease.

126
Use of IGRAS for Diagnosis of Active TB
IGRAs were developed to replace the TST in the diagnosis of latent TB infection. It was
not intended for detecting cases of active TB. IGRAs, just like the TST, cannot distin-
guish LTBI from active TB. Because of this, they are expected to have poor specificity
for active TB in high-burden settings due to a high background prevalence of LTBI. The
low performance of IGRAs in these settings was partly attributed to anergy due to ad-
vanced disease, malnutrition, and HIV-associated immune suppression. Laboratory
procedures and infrastructure may have also contributed to the low performance of
IGRAs.
The systematic review89 showed that for T-SPOT, the pooled sensitivity was 83% (95%
CI 70%-91%) and the pooled specificity was 58% (95% CI 42%-73%). For QFT-GIT
the pooled sensitivity was 73% (95% CI 61%-82%) and pooled specificity was 49%
(95% CI 40%-58%). On the average about 25% of patients with culture-confirmed ac-
tive TB could be expected to be IGRA negative in low and middle-income countries,
and this could lead to serious patient consequences. However, it is important to note
that the quality of evidence for the use of IGRAs in the diagnosis of active TB was low.
There was no evidence to show that IGRAs were more sensitive than the TST for diag-
nosing active TB, and IGRAs have no added value beyond conventional microbiologic
tests for the diagnosis of active TB.
Use of IGRAs in children
Results from two small studies with low methodological quality showed that there was
no difference in the performance of TST and IGRAs for diagnosing LTBI and for deter-
mining incidence of active TB in children. 89
Use of IGRAs in HIV-infected individuals
Studies on use of IGRAs in HIV-infected individuals had small sample size and were of
very low quality, hence results should be interpreted cautiously. In persons with active
TB (used as a surrogate reference for LTBI), pooled sensitivity estimates were higher
for T-SPOT (72%, 95% CI 62%-81%) than for QFT-GIT (61%, 95% CI 41%-75%). Oth-
er studies showed that IGRAs have a poor positive predictive value but a high negative
predictive value for active TB, implying that that no HIV-infected person with a negative
IGRA result developed culture positive TB. Generally, the sensitivity of IGRAs was low-
er at 60-70% among HIV-positive individuals, suggesting that nearly 33% of HIV-
positive patients with active TB would be IGRA-negative. The IGRA was no more con-
sistently sensitive that the TST and the impact of advanced immunosuppression on
IGRA validity remains unclear.
Overall, the studies show that there is insufficient data and low-quality evidence on the
performance of IGRAs in low and middle-income countries, typically those with a high
TB and/or HIV burden. 89 Both the IGRAs and the TST cannot accurately diagnose
active TB nor can they predict the risk of infected individuals developing active TB.
Moreover, IGRAs are more costly and technically complex to do than the TST and the
increased cost of the former given the comparable performance of the TST, does not
justify the replacement of the TST by IGRAs as a public health intervention in resource-
limited settings.

127
Based on existing evidence, the WHO issued policy statements in 2011 that IGRAs
should not be used for the diagnosis of pulmonary or extra-pulmonary TB in low and
middle-income countries, nor for the diagnostic work-up of adults and children suspect-
ed of active TB, irrespective of HIV status. 89 IGRAs should not replace the TST for the
diagnosis of latent TB infection in children and should not be used for the screening of
latent TB infection in adult and pediatric contacts (including HIV positive individuals),
nor in outbreak investigations. IGRAs should not be used in HCW screening programs.
Neither IGRAs nor the TST should be used for the identification of individuals at risk of
developing active TB. In children, there may be additional harm associated with blood
collection and issues such as acceptability and cost have not been adequately ad-
dressed in previous studies.

128
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doi:10.1183/09031936.00176311
78. Centers for Disease Control and Prevention. Updated Guidelines for Using Interfer-
on Gamma Release Assays to Detect Mycobacterium tuberculosis Infection, United
States. MMWR 2010; 59.
79. Somoskovi, A, Song Q, Mester J, Tanner C, Hale YM, Parsons LM, Salfinger M.
Use of molecular methods to identify the Mycobacterium tuberculosis complex
(MTBC) and other mycobacterial species and to detect rifampicin resistance in
MTBC isolates following growth detection with the BACTEC MGIT 960 system. J
Clin Microbiol. 2003 Jul;41(7):2822-2826.
80. Cellestis. Clinicians Guide to Quantiferon-TB Gold. Available from: http://
www.cellestis.com/IRM/contentAU/gold/clinicians guide.pdf. 2004.
81. Forbes BA, Sahm DF, Weisfeild AS. Bailey & Scott‘s Diagnostic Microbiology. 12th
Ed. Mosby Elsevier; 2007.
82. Pottumarthy S, Morris AJ, Harrison AC, Wells VC. Evaluation of the tuberculin gam-
ma interferon assay: potential to replace the Mantoux skin test. J Clin Microbiol.
1999; 37:3299-32.
83. Fietta A, Meloni F, Cascina A, Morosini M, Marena C, Troupioti P, et al. Compari-
son of a whole-blood interferon-gamma assay and tuberculin skin testing in patients
with active tuberculosis and individuals at high or low risk of Mycobacterium tuber-
culosis infection. Am J Infect Control. 2003; 31:347-353.
84. Oxford Immunotech Limited. T Spot TB. Available from: http://www/
oxfordimmunotec.com/products.htm.2004. Mabtech AB. EliSpot-assay procedure.
URL:http:///.mabtech.com/elispot.asp.2004.
85. Streeton JA, Desem N, Jones SL. Sensitivity and specificity of a gamma interferon
blood test for tuberculosis infection. Int J Tuberc Lung Dis. 1998;2:443-450.
86. Mazurek GH, LoBue PA, Daley CL, Bernardo J, Lardizabal AA, Bishai WR et al.
Comparison of a whole-blood interferon gamma assay with tuberculin skin testing
for detecting latent Mycobacterium tuberculosis infection. Centers for Disease Con-
trol and Prevention. MMWR Recomm Rep. 2003; 52 (RR-w): 15-18..
87. Chapman AL, Munkata M, Wilkinson KA, Pathan AA, Ewer K, Ayles H et al. Rapid
detection of active and latent tuberculosis infection in HIV-positive individuals by
enumeration of Mycobacterium tuberculosis-specific T cells. AIDS 2002; 16:2285-
2293.
88. Barnes PF. Diagnosing latent tuberculosis infection: the 100 year upgrade. Am J
Resp Crit Care Med 2001; 163:807-8.
89. World Health Organization. Use of tuberculosis interferon-gamma release assays

135
 (IGRAs) in low and middle-income countries: policy statement. WHO 2011
90. Morris K. WHO recommends against inaccurate tuberculosis tests. Lancet 2011;
377:113-114

136
 11
Management
Anna Lisa T Ong-Lim, MD

OUTLINE
1 Aims and Basic Principles of Ther-
apy

2 Anti-Tuberculosis Drugs

3 Recommended Regimens

4 Preventive Therapy

137
AIMS AND BASIC PRINCIPLES OF THERAPY
The drug therapy of tuberculosis aims to achieve several objectives. These include
cure of the patient by rapid elimination of most of the metabolically active and rapidly
replicating bacilli; prevention of death from active TB or its late effects; prevention of
relapse by eliminating slowly and intermittently multiplying bacilli; prevention of drug
resistance by using a combination of drugs; and finally, decrease of TB transmission to
others.1
A thorough knowledge of the microbiology of tuberculosis is necessary to understand
the basis for the treatment strategies currently being utilized. The need for multiple
drugs and the prolonged duration of therapy is explained by the following characteris-
tics of the causative organism 2:
1. bacilli live in several sites within the host, and each site (ex. open cavities, closed
lesions, macrophages) contains organisms with different population sizes, metabol-
ic activities and replication rates;
2. mycobacteria replicate slowly, can remain dormant for prolonged periods, and can
be eradicated only during replication;
3. naturally occurring drug resistant mutants are present within large bacterial popula-
tions even before chemotherapy is started.
In addition, it is thought that within each patient, there are TB populations consisting of
four groups, defined by drug efficacy 3:
1. actively growing bacilli found in open cavities, which are killed by bactericidal drugs;
2. slowly multiplying or non-replicating TB bacilli (located in caseous lesions) that un-
dergo spurts of metabolism and are killed by sterilizing drugs;
3. intracellular bacilli present in the acidic compartments of macrophages or in acidic
lung lesions, for which sterilizing drugs are also effective;
4. TB persisters found in hypoxic microenvironments, which are non-responsive to
most anti-TB drugs.
Controlled clinical trials have thus demonstrated the principles on which treatment rec-
ommendations are based: treatment of disease must contain multiple drugs to which
the organisms are susceptible; drugs must be taken regularly, and drug therapy must
continue for a sufficient length of time.4
Although the therapeutic principles stated above are valid regardless of the age of the
patient, several pharmacologic considerations unique to children need to be considered
in their treatment 5:
1. the pharmacokinetics and pharmacodynamics of various anti-tuberculosis drugs are
different in children;
2. children generally have fewer mycobacterial organisms and are thus less likely to
develop secondary drug resistance (see Chapter 12 Treatment of Drug-Resistant
Tuberculosis);
3. extrapulmonary disease is more common in children; medications used must there-

138
 fore penetrate specific body sites and tissues;
4. children tolerate higher doses of anti-tuberculous medications per kilogram of body
weight with fewer side effects;
5. there may be a need to modify medications to a form that children can tolerate,
which can cause problems with stability, bioavailability and compliance.
Present treatment regimens consist of multiple drugs given simultaneously. Since mu-
tant organisms naturally resistant to multiple drugs are extremely rare, this strategy de-
creases the likelihood of selecting out drug-resistant organisms and prevents the emer-
gence of resistance. An initial intensive phase (consisting of three or four drugs to
which the TB bacilli are susceptible) promotes efficient killing of actively dividing organ-
isms and leads to the rapid reduction of large bacillary populations; this provides relief
of symptoms, terminates transmission and prevents the emergence of drug resistance.
A longer continuation phase (using fewer drugs) then follows, which kills slowly or inter-
mittently dividing bacilli, sterilizes lesions and prevents relapse.
In both adults and children, numerous trials have proven the efficacy of short-course, 6-
month chemotherapy for drug-sensitive pulmonary tuberculosis. Efforts to shorten the
duration of therapy to even fewer than 6 months, however, have been associated with
significant relapse rates.6
Because of the need for prolonged treatment, adherence to therapy is still the major
issue determining its effectiveness. Several strategies have thus been explored to de-
crease treatment costs and promote patient compliance. The World Health Organiza-
tion endorses directly observed treatment (DOT), which involves direct observation of
medication intake. This ensures that medication is taken in the right combination and
appropriate dosage, maximizes the likelihood of completion of therapy, and prevents
the development of drug resistance.
The optimal dosing frequency for new patients with pulmonary TB is once daily
throughout the course of therapy, however adherence to such regimens remains a
challenge. There are differing recommendations on the use of intermittent regimens to
treat TB in children; a recent systematic review comparing intermittent twice-weekly
versus daily treatment among children 15 years and below concluded that ―trials con-
ducted to date are insufficient to support or refute the use of intermittent twice- or thrice
-weekly, short-course treatment regimens‖. 7
The WHO does not recommend twice-weekly regimens, since any missed dose leads
to a significant reduction of the total quantity of drugs received by the patient and can
lead to treatment failure.8 In addition, the 2009 WHO Treatment of Tuberculosis states
that the rates of acquired drug resistance are higher among patients receiving intermit-
tent dosing throughout therapy; in patients with pre-treatment isoniazid resistance,
three times weekly dosing during the intensive phase was associated with significantly
higher risks of failure and acquired drug resistance.9 Thus, the WHO‘s Rapid Advice
2010 specifies that thrice-weekly regimens may be considered only during the continu-
ation phase of treatment, for children known to be HIV-uninfected and living in settings
with well-established DOT.

139
Contact tracing remains a key step for effective tuberculosis therapy and control. The
treatment of tuberculosis ―can only be successful within the framework of overall medi-
cal and social management of patients and their contacts. The ultimate elimination of
tuberculosis requires an organized and smoothly functioning network of primary and
referral services based on cooperation between the private and public sectors of medi-
cal care.‖ 4

ANTI- TUBERCULOSIS DRUGS

Anti-tuberculosis drugs possess three main properties: bactericidal activity, sterilizing
activity and the ability to prevent resistance. The bactericidal activity of an agent is de-
fined as the killing of bacilli in log-phase growth, while a drug is considered to have a
sterilizing effect when it is able to kill slowly growing or non-replicating bacilli. The steri-
lizing activity of a drug also reflects its ability to shorten duration of therapy. 10
The most effective bactericidal drugs are isoniazid and rifampicin, which are active
against all populations of TB bacilli. In addition to its bactericidal effect, rifampicin is al-
so the most potent sterilizing drug available. Pyrazinamide and streptomycin are like-
wise bactericidal against some populations of TB bacilli. Pyrazinamide is only active in
the acidic intracellular environment of macrophages and in areas of acute inflammation,
while streptomycin is bactericidal against rapidly multiplying TB bacilli. Ethambutol is
used together with other drugs to prevent emergence of resistant bacilli. 8
Anti-tuberculosis drugs have traditionally been classified as first-line drugs, with superi-
or efficacy and acceptable toxicity; and second-line drugs, having either less efficacy,
greater toxicity or both. Isoniazid, rifampicin, pyrazinamide, and ethambutol are all clas-
sified as first-line drugs.
All other drugs used for the treatment of tuberculosis are generally referred to as se-
cond-line or ―reserve‖ drugs. These agents are used as alternatives when there is ei-
ther resistance or adverse reactions, e.g hypersensitivity to first-line medications. The
second-line drugs include (1) injectables such as aminoglycosides (streptomycin, kana-
mycin, amikacin) and capreomycin; (2) fluoroquinolones, including levofloxacin, moxi-
floxacin and ofloxacin; (3) analogs of rifampicin (e.g. rifabutin, rifapentine); and (4) oral
bacteriostatic agents like para–aminosalicylic acid, cycloserine, terizidone, thionamide
and protionamide.
Streptomycin, formerly a first-line drug, is now classified as a second-line drug because
increasing resistance has reduced its usefulness. However in selected cases
(meningitis, established liver disease), it may still be used as part of initial treatment. 11
A last group of medications (group 5 drugs) are agents with an unclear role in the treat-
ment of drug-resistant TB, and thus are not recommended by the World Health Organi-
zation for MDR-TB treatment. These include clofazimine, linezolid, amoxicillin-
clavulanic acid, thiocetazone, imipenem/cilastatin, high dose isoniazid and clarithromy-
cin.
Two new drugs have recently been approved for the management of MDR-TB among
patients ≥ 18 years of age. Bedaquiline has proven to be effective in reducing time to

140
culture conversion in adults with pulmonary MDR-TB. Likewise delamanid has been
shown to be effective in increasing the proportion of patients achieving sputum culture
conversion after 8 weeks of treatment. 12
Table 11.1 lists the first-line anti-tuberculosis drugs, including details on the dosing,
mechanisms of action and adverse effects associated with these agents. The recom-
mended pediatric drug doses are based on the World Health Organization‘s 2010 Rap-
id Advice: Treatment of TB in Children. The Department of Health‘s 2014 Manual of
Procedures has adopted these recommended doses for the country‘s National Tuber-
culosis Control Program, with the exception of pyrazinamide; the local recommendation
for this drug specifies a slightly lower dose and is used in the table below.
Since adolescents show greater similarity to adults than to young children with respect
to dosage requirements, risk of MDR-TB, and adverse drug reactions, it is recommend-
ed that older children and adolescents be treated at adult dosages once they reach a
body weight of 25 kg. 1
Table 11.1. First-line anti-tuberculosis drugs (continued on next page)
Drug Drug Dose per Kg Mechanism Adverse Reac- Comments
Body Weight of Action tions / Interac-
Children Adults tions
Pyra- 30 (20- 25 (20- Disruption of Nausea, vomit- Discontinue
zinamide 40) mg/ 30) mg/ membrane ing; most com- if AST >3-5x
(Z) kg/day kg/day energy me- mon cause of normal val-
(max 2 g/ (max 2 g/ tabolism hepatotoxicity uesa
day) day) in regimens
also containing Requires
H and R; dose modifi-
hypersensitivity cation in
reactions and renal failure
polyarthralgia
Ethambutol 20 (15- 15 (15- Inhibits Peripheral neu- Previously
(E) 25) mg/ 20) mg/ transferase ropathy and omitted from
kg/day kg/day enzymes retrobulbar op- regimens for
(max 1.2 (max 1.2 involved in tic neuritis children be-
g/day) g/day) cell wall (impairment of cause of
synthesis visual acuity difficulty of
and red-green monitoring
color vision) optic neuri-
tis; new evi-
dence
shows safe-
ty in children
at recom-
mended
doses in the
absence of
renal impair-
ment

141
Isoniazid (H) 10 (10-15) 5 (4-6) mg/ Bactericidal Hepatitis, periph- Plasma half-
mg/kg/day kg/day against ac- eral neuropathy, life of H var-
(max 300 (max 300 tively growing allergic skin re- ies from < 1
mg/day) mg/day) M. tuberculo- actions; possible hour in fast
sis; bacterio- hemolysis acetylators to
static against among G6PD- > 3 hours in
non- deficient patients slow acetyla-
replicating tors
organisms; Inhibits drug-
inhibits my- metabolizing For H and R,
colic acid enzymes (DME), discontinue if
synthesis; leading to in- AST >3-5x
also likely creased risk of normal val-
inhibits the phenytoin, uesa
catalase- ethosuximide
peroxidase and carbamaze- For H and R,
enzyme pine toxicity no dose ad-
justment for
renal dys-
Rifampicin 15 (10-20) 10 (8-12) Inhibits DNA- Hepatitis, hyper- function.
(R) mg/kg/day mg/kg/day dependent sensitivity reac-
(max 600 (max 600 RNA poly- tions (including a
mg/day) mg/day) merase systemic flulike H and R are
syndrome + best ab-
thrombocytope- sorbed on an
nia in patients empty stom-
given intermittent ach
high-dose thera-
py), orange dis- When co-
coloration of administering
body fluids anti-TB and
antiretroviral
Induces DME, drugs, seek
resulting in de- guidance
creased plasma from clini-
levels of some cians familiar
drugs such as with potential
AEDs (including interactions
phenytoin), anti -
infectives (ex.
clarithromycin,
erythromycin,
chlorampheni-
col), hormonal
therapy agents
(ethinylestradiol,
norethindrone,
tamoxifen, levo-
thyroxine), corti-
costeroids, etc.

142
a
Drug-induced liver injury is defined as AST level ≥ 3 times the upper limit of normal in the pres-
ence of symptoms, or 5 times more than the upper limit in the absence of any symptoms

References:
1. American Thoracic Society.CDC,MMWR. Treatment of tuberculosis infection in
adults and children. 20 June 2003;52(RR-11).
2. CDC. TB Guideline. Accessed from: http://www.CDC.gov/tb/pubs/PDA
3. CDC. Core Curriculum on Tuberculosis. What the Clinician Should Know. 6th ed.
2013. Accessed from: https://www.cdc.gov/tb/education/corecurr/pdf/corecurr_all.pdf
4. Curry InternationalTuberculosis Center and California Department of Public Health,
2012: Tuberculosis Drug Information Guide, 2nd edition. Accessed at http://
www.currytbcenter.ucsf.edu/tbdruginfo
5. Davis PDO,(ed).Clinical Tuberculosis.London:Chapman and Hall;1994:151-152.
6. Diagnosis, Treatment, Prevention and Control of Tuberculosis in Adult Filipinos: Up-
date.2006
7. Stop TB Partnership Childhood TB Subgroup. Chapter 2: Anti-tuberculosis treatment
in children [Official Statement. Guidance for National Tuberculosis Programmes on the
management of tuberculosis in children. Chapter 2 in the series]. The International
Journal of Tuberculosis and Lung Disease.Nov 2006. 10(11);1205-1211(7).

The World Health Organization has developed a symptom-based approach to manag-

ing side effects of anti-tuberculosis drugs. Symptoms are classified as either major or
minor; major side effects require discontinuation of the implicated drugs while for minor
symptoms, drugs can be continued. Management recommendations are listed in the
table below.
Table 11.2. Symptom-based approach to management of major side effects
MAJOR SIDE EFFECTS DRUG(S) IMPLICATED MANAGEMENT
Skin rash with or without Isoniazid, rifampicin, Stop implicated drug
itching pyrazinamide, streptomycin (s)
Deafness Streptomycin
Vertigo and nystagmus Streptomycin
Jaundice, hepatitis Isoniazid, rifampicin, pyra-
zinamide
Confusion Most anti-TB drugs
Visual impairment Ethambutol
Shock, purpura, acute Rifampicin
renal failure
Decreased urine output Streptomycin

Modified from World Health Organization (2010). Treatment of Tuberculosis: Guide-

lines. 4th ed. 2010

143
Table 11.3 Symptom-based approach to management of minor side effects
MINOR SIDE EFFECTS DRUG(S) IMPLI- MANAGEMENT
CATED
Anorexia, nausea, ab- INH Give drugs with small meals or sched-
dominal pain Rifampicin ule before bedtime; advise to swallow
PZA medications slowly with small sips of
water
If symptoms persist or worsen, or
there is prolonged vomiting or any
signs of bleeding, consider as MAJOR
side effect (stop TB drugs and refer)
Joint pains PZA Aspirin, NSAID or paracetamol
Burning, numbness or tin- INH Add pyridoxine (5-10 mg/day) to treat-
gling sensation in hands / ment regimen for exclusively-
feet breastfed infants, infants of breast-
feeding mothers on isoniazid, pa-
tients on meat- and milk-deficient di-
ets, pregnant adolescents, patients
with conditions predisposing to neu-
ropathy (including diabetes, uremia,
malnutrition, and HIV infection).

Drowsiness INH Reassurance; give drugs at bedtime

Orange/ red urine Rifampicin Reassurance; patient should be told
that this is an expected effect of rifam-
picin treatment
Flu syndrome (fever, Intermittent rifampic- Change from intermittent to daily ri-
chills, malaise, headache, in dosing fampicin dosing
bone pain)

Modified from World Health Organization (2010). Treatment of Tuberculosis: Guide-

lines. 4th ed. 2010

Since it is often difficult to determine which of the multiple drugs being taken is the rea-
son for an adverse reaction, the following table may provide guidance as to the likeliest
cause.

144
Table 11.4 Likeliest causes of adverse drug reactions
Most likely à least likely cause
Hepatitis- ALT/ Pyrazinamide Isoniazid Rifampicin Ethambutol
AST predomi- (very rare)
nant
Cholestatic Rifampicin
jaundice
Upper GIT Rifampicin Pyrazinamide Isoniazid Ethambutol
symptoms
Arthralgia Pyrazinamide Rifampicin (flu- Isoniazid (drug- Ethambutol
like syndrome) induced lupus)
Hypersensitivity Isoniazid Rifampicin Pyrazinamide Ethambutol
(fever, rash,
other symp-
toms)

Modified from: Queensland Australia Department of Health. (2015). Treatment of Tu-

berculosis in Adults and Children. Version2.1.
A special concern for the pediatric age group is the stability of liquid formulations used
for therapy, which can have a significant impact on patient response. It must be noted
that co-administration of isoniazid and rifampicin with vitamin C appears to inactivate
suspensions.13 In addition, liquid forms of anti-tuberculosis drugs that contain sucrose
are heat- and light-unstable; those containing sorbitol are less unstable but can induce
gastrointestinal tract symptoms such as diarrhea and abdominal cramps.
Some experts have thus abandoned the use of syrups and instead advocate the addi-
tion of sweetened vehicles (e.g. applesauce, fruit juice) to crushed tablets or capsule
contents. Furthermore, the WHO now recommends the use of fixed-dose combination
(FDC) tablets because of several advantages:
1. Prescription errors are less likely to occur, because dosage recommendations and
weight adjustments are less complicated;
2. There are less tablets to ingest, which may improve patient adherence;
3. If treatment is not observed, the patient cannot be selective about which drugs to
take, therefore decreasing the chances of monotherapy.
As of December 2015, the WHO and its partners have announced the availability of
FDCs with the following formulations:
1. Rifampicin 75 mg + Isoniazid 50 mg + Pyrazinamide 150 mg, for the intensive
phase, and
2. Rifampicin 75 mg + Isoniazid 50 mg, for the continuation phase
These formulations are expected to be available by 2016. Treatment can then be ad-
ministered more efficiently, with fewer pills to be used over less weight bands:14

145
Table 11.5 Dosing table for FDCs

Number of tablets Number of tablets

Weight Band Intensive phase: Continuation phase
RHZ 75/50/150* RH 75/50
4-7 kg 1 1
8-11 kg 2 2
12-15 kg 3 3
16-24 kg 4 4
25+ kg Adult dosages recommended

*Ethambutol (15-25 mg/kg) should be added in the intensive phase for children with
extensive disease or living in settings where the prevalence of HIV or of isoniazid re-
sistance is high
Though these FDCs will provide isoniazid at a dose below 10-15 mg/kg/day in some
weight bands, the WHO has noted that an isoniazid dosage of 7 mg/kg will provide ade-
quate levels in almost all children; thus the isoniazid dosing range may be extended to
7-15 mg/kg, with the mid-range placed at 10 mg/kg. 1

RECOMMENDED REGIMENS
Drug therapy regimens employed in tuberculosis are designed to achieve varying
goals. For the patient exposed to Mycobacterium tuberculosis without evidence of in-
fection or active disease, the objective is to prevent the onset of infection (―primary
prophylaxis‖). For the patient with latent TB infection, the drug regimen aims at prevent-
ing progression of infection to active disease (―secondary prophylaxis‖). Finally, for the
patient classified as having disease, the goals include not only cure for the individual
patient, but also decrease in transmission to the community.
There is a standard code for anti-TB treatment regimens, which uses an abbreviation
for each anti-TB drug, e.g. isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambu-
tol (E). A regimen consists of two phases: the initial and continuation phases. The num-
ber at the front of each phase represents the duration of that phase in months. A sub-
script number (e.g. 3) following a drug abbreviation is the number of doses per week of
that drug. If there is no subscript number following a drug abbreviation, treatment with
that drug is daily. An alternative drug (or drugs) appears as an abbreviation (or abbrevi-
ations) in parentheses.
Example: 2HRZE/4HR
The initial phase is 2HRZE. Duration of this phase is 2 months. Drug treatment is daily
(no subscript numbers after the abbreviations) with isoniazid, rifampicin, pyrazinamide
and ethambutol. The continuation phase is 4HR. Duration of this phase is 4 months,

146
with isoniazid and rifampicin once daily on empty stomach (one hour before, or two
hours after, a meal) 15.
Treatment regimens are assigned based on the anatomical site of involvement, bacteri-
ologic confirmation status as well as history of previous treatment. The World Health
Organization‘s most recent guideline (Guidelines for Treatment of Tuberculosis, 4th edi-
tion, 2010) as well as the 2nd edition of the Guidance for National Tuberculosis Pro-
grammes on the Management of Tuberculosis in Children (2014) outline a treatment
strategy that has become the basis of the Department of Health‘s recommendations,
listed below.
The following table describes the different registration groups based on treatment histo-
ry.
Table 11.6 TB disease registration groups
Registration Group Definition of Terms
New A patient who has never had treatment for
TB* or who has taken anti-TB drugs for <1
month
Relapse A patient previously treated for TB who has
been declared cured, or completed treatment
in their most recent treatment episode, and is
presently diagnosed with bacteriologically-
confirmed or clinically-diagnosed TB.
Treatment after failure A patient who has been previously treated
for TB and whose treatment failed at the end
of their most recent course. This includes:
A patient whose sputum smear or culture
Re-treatment

is positive at 5 months or later during

treatment.
A clinically diagnosed patient (e.g child
or extra-pulmonary TB) for whom
sputum examination cannot be done
and who does not show clinical im-
provement anytime during treatment.
Treatment after lost to follow up A patient who was previously treated for TB
(TALF) but was lost to follow-up for ≥ 2 months in
their most recent course of treatment, and is
currently diagnosed with either bacteriologi-
cally- confirmed or clinically-diagnosed TB
Previous treatment, outcome un- Patients who have been previously treated
known (PTOU) for TB but whose outcomes after their most
recent course of treatment are unknown or
undocumented
Other Patients who do not fit into any of the catego-
ries listed above
*Prophylaxis and treatment for latent TB infection (LTBI) are not counted as anti-TB
treatment
147
(Reproduced from: Department of Health. (2014). Manual of Procedures of the Tuber-
culosis Control Program. 5th edition.)
Once a patient has been classified into a registration group, the treatment regimen can
be assigned. The regimens currently recommended for drug-sensitive tuberculosis by
the National Tuberculosis Control Program of the Department of Health are listed be-
low.
Table 11.7 Recommended treatment regimens for adults and children
Category of Treat- Classification and Registration Group Treatment Regi-
ment men
Category I Pulmonary TB, new (whether bacteriologi- 2HRZE / 4HR
cally- confirmed or clinically-diagnosed)

Extra-pulmonary TB, new (whether bacterio-

logically-confirmed or clinically-diagnosed)
except CNS/ bones or joints
Category Ia Extra-pulmonary TB, new (CNS/bones or 2HRZE / 10HR
joints)
Category II Pulmonary or extra-pulmonary, previously 2HRZES / 1HRZE /
treated drug-susceptible TB (whether bacte- 5HRE
riologically-confirmed or clinically-diagnosed)
Relapse
Treatment after failure
Treatment after Lost to Follow-up
(TALF)
Previous treatment outcome unknown

Categry IIa Extra-pulmonary, previously treated drug- 2 HRZES / 1HRZE /

susceptible TB (whether bacteriologically 9 HRE
confirmed or clinically-diagnosed- CNS /
bones or joints)

(Reproduced from: Department of Health. (2014). Manual of Procedures of the National

Tuberculosis Control Program. 5th edition.)
The recommendation to start treatment with four drugs for new cases is based on con-
cerns regarding the high prevalence of isoniazid resistance, since the global weighted
mean of any isoniazid resistance (excluding MDR) is already at 7.4% among new pa-
tients.9 In a June 2012 report published by USAID, the Philippines is stated as having
one of the highest rates of INH resistance among new TB patients (14%) worldwide.16
The four-drug initial phase also reflects the need for more intensive treatment in areas
of high HIV prevalence, as this regimen will reduce the risk for development and trans-
mission of MDR-TB. Since the change was implemented in adult treatment regimens,
this also required similar revisions to be considered for children.1

148
The issues of drug resistance and HIV prevalence were also taken into consideration in
the 2003 joint recommendation for TB treatment issued by the American Thoracic Soci-
ety, CDC and the Infectious Disease Society of America; this recommendation states
that a four-drug intensive phase including ethambutol can be safely used in children
when warranted by epidemiologic circumstances.17

PREVENTIVE THERAPY
Prophylaxis aims to prevent the following conditions:
1. Development of infection among contacts exposed to active disease: primary
prophylaxis
2. Progression of latent TB infection to disease: secondary prophylaxis
Prophylaxis is recommended for children under 5 years or among those with other risk
factors for rapid development of disease, particularly immunosuppressed individuals.
This is because disease may set in even before conversion of the tuberculin skin test.
Several well-controlled studies have demonstrated the favorable effect of isoniazid on
reduction of complications due to lymphohematogenous and pulmonary spread after
infection. The protective effect of isoniazid in the latter situation has been shown to last
from 19 to 30 years.18
One approach to prophylaxis is proposed by the Department of Health in its National
Tuberculosis Control Program. Once TB disease has been excluded, isoniazid preven-
tive therapy (IPT) is recommended for (1) all HIV-positive individuals, (2) children less
than 5 years old who are household contacts of a bacteriologically confirmed TB case,
regardless of the TST results or (3) children less than 5 years old who are household
contacts of a clinically diagnosed TB case, if the TST result is positive. The regimen
consists of a 6-month course of isoniazid, given at a dose of 10mg/kg once daily. 19
The following algorithm illustrates a more comprehensive approach to prophylaxis. This
was proposed in the National Consensus on Childhood Tuberculosis 1997 and contin-
ues to be recommended by the Philippine Pediatric Society:

149
 TB Exposure

< 5 years
Yes
Start INH for 3
old months

No

Radiologic
Repeat findings
Positive and / or, Yes TB Disease
Mantoux
test af- signs /
symptoms Multiple Drug Ther-
ter 3
suggestive apy
months
of TB

Negative
No

Discontinue H LTBI
If no BCG scar, Continue > 6H
give BCG

Reproduced from Philippine Pediatric Society, Pediatric Infectious Disease Society of

the Philippines, Philippine Coalition Against Tuberculosis. National Consensus on
Childhood Tuberculosis, 1997.

150
REFERENCES
1. World Health Organization. Guidance for national tuberculosis programmes on the
management of tuberculosis in children. 2nd ed. 2014.
2. American Academy of Pediatrics Committee on Infectious Diseases. Chemotherapy
for tuberculosis in infants and children. Pediatrics 1992; 89(1): 161-165.
3. Evangelopolous D et al. Understanding anti-tuberculosis drug efficacy: rethinking
bacterial populations and how we model them. International Journal of Infectious
Diseases 32 (2015) 76–80.
4. American Thoracic Society and the Centers for Disease Control. Treatment of tu-
berculosis and tuberculosis infection in adults and children. Am J Respir Critic Care
Med 1994 May; 149 (5): 1359-74.
5. Rom WN and Stuart Garay, eds. Tuberculosis. 1996. Boston: Little, Brown and Co.
p 683.
6. Rom WN and Stuart Garay, eds. Tuberculosis. 1996. Boston: Little, Brown and Co.
p 758.
7. Bose A, Kalita S, Rose W, Tharyan P. Intermittent versus daily therapy for treating
tuberculosis in children. Cochrane Database Syst Rev. 2014 Jan 28;1:CD007953.
8. World Health Organization. Treatment of tuberculosis: guidelines for national pro-
grams, 3rd edition. 2003.
9. World Health Organization. Treatment of tuberculosis: guidelines. Fourth edition,
2010.
10. Gumbo T et al. Pharmacokinetics-pharmacodynamics of pyrazinamide in a novel in
vitro model of tuberculosis for sterilizing effect: a paradigm for faster assessment of
new antituberculosis drugs. Antimicrob. Agents Chemother. August 2009; 53(8):
3197-3204).
11. CDC. Core Curriculum on Tuberculosis. What the Clinician Should Know. 6th ed.
2013. Accessed from: https://www.cdc.gov/tb/education/corecurr/pdf/
corecurr_all.pdf.
12. NHS England. Clinical Commissioning Policy: Bedaquiline and Delamanid for de-
fined patients with MDR-XDR-TB. Accessed from https://
www.engage.england.nhs.uk/consultation/specialised-services-consultation/
user_uploads/bedaquiline-delamanid-policy-upd.pdf.
13. Wallace Jr. RJ et al. 2015. Chap 38. Antimycobacterial agents. In Bennett JE et al.
eds. Mandell, Douglas, and Bennett‘s Principles and Practice of Infectious Diseas-
es, 8th ed. Phladelphia, Elsevier Saunders.
14. World Health Organization. Factsheet: New fixed-dose combinations for the treat-
151
 ment of TB in children. Accessed from: http://www.who.int/tb/FDC_Factsheet.pdf?
ua=1.
15. World Health Organization. Guidance for national tuberculosis programmes on the
management of tuberculosis in children. 1st ed. 2006.
16. USAID/Philippines: External Evaluation of the Tuberculosis Portfolio (2006–2011).
Accessed from http://pdf.usaid.gov/pdf_docs/pdact786.pdf.
17. Centers for Disease Control and Prevention. Treatment of Tuberculosis, American
Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR
2003;52(No. RR-11):1-77.
18. Starke JR and Margaret HD Smith. 1998. Tuberculosis. In Feigin RD and JD Cher-
ry, eds. Textbook of Pediatric Infectious Diseases 4th ed. Philadelphia: WB Saun-
ders Co. p 1225.
19. Department of Health. (2014). Manual of Procedures of the National Tuberculosis
Control Program. 5th edition.

152
 12
Drug-Resistant TB
Anjanette de Leon,MD
Heidilita Espinoza,MD

OUTLINE
1 Overview

2 Definitions

3 Pathophysiology

4 Diagnosis

5 Risk Factors

6 Treatment

7 Prevention

153
OVERVIEW
The management of drug-resistant tuberculosis remains to be a challenge among
health care professionals. Thus, it is vital to identify such patients with the help of ex-
pertise in this area. The WHO has a revised definition of cases of drug-resistant tuber-
culosis based on drug susceptibility testing (DST) of clinical isolates confirmed to be M.
tuberculosis (MTB) namely: monoresistance, multidrug-resistance, polydrug re-
sistance, extensive drug resistance and rifampicin resistance.1 Establishing a diagnosis
is quite difficult so a detailed and careful history should be obtained. Likewise, radiolog-
ic findings are comparable with that of drug-susceptible tuberculosis thus making the
diagnosis more difficult. Other diagnostic procedures include baseline sputum culture
and sensitivity prior to treatment and nucleic acid tests such as GeneXpert MTB/RIF,
MTBDRplus and MTBDRs which are all helpful but expensive. The approach to man-
agement can be medical and surgical. With medical treatment, this is based on three
strategies which includes standardized, empirical and individualized. Surgery is an op-
tion in cases where patient remains to be smear positive, with resistance to a large
number of drugs and has localized pulmonary disease.

DEFINITIONS
Uniform definitions among health care professionals are vital to have standardized pa-
tient registration, correct assignment to treatment regimens and in comparing research
outcomes. Drug-Resistant Tuberculosis (DRTB) is confirmed through laboratory tests
that show that the infecting isolates of MTB grow in vitro in the presence of one or more
anti-tuberculosis drugs.

 Drug-resistant tuberculosis refers to a case of tuberculosis (TB), usually pulmo-

nary, excreting bacilli-resistant to one or more anti-tuberculosis drugs.1

 Primary resistance refers to the bacterial resistance present in patients who have
not received prior treatment with anti-tuberculosis drugs.

 Acquired resistance refers to the bacterial resistance in patients with some record
of previous treatment.1
The World Health Organization defines five categories:2
 Monoresistance: resistance to one anti-tuberculosis drug
 Multidrug-resistance (MDR): resistance to at least both isoniazid and rifampicin
 Polydrug-resistance: resistance to more than one first line anti-tuberculosis drug,
other than both isoniazid and rifampicin
 Extensive drug-resistance: resistance to isoniazid and rifampicin, any flouroquin-
olone, and at least one of three second line injectable drugs: kanamycin, capreomy-
cin, or amikacin.
 Rifampicin resistance: resistance to rifampicin detected using phenotypic or geno-
typic methods, with or without resistance to other anti-TB drugs. It includes any re-
sistance to rifampicin, whether mono-resistance, multidrug resistance, polydrug re-
sistance or extensive drug resistance.28

154
The National Consensus on Childhood Tuberculosis proposed the following criteria for
defining DRTB:5,24,28
Confirmed MDR-TB disease is defined as clinical evidence of TB disease together
with the detection of MTB (either by culture or molecular probe) from a specimen col-
lected from the subject with genotypic (e.g., GeneXpert) or phenotypic resistance to at
least Rifampicin.3,5,6,7,8,9
Clinical evidence of TB (TB Disease) would mean the presence of at least one
of the following signs or symptoms: persistent cough, weight loss, failure to
thrive, persistent unexplained fever, persistent unexplained lethargy or reduced
playfulness, or the presence of any of the following in the neonate like pneumo
nia, unexplained hepatosplenomegaly, or sepsis-like illness
Probable MDR-TB disease is defined as the clinical evidence of TB disease AND pres-
ence of one of the following: (a) positive clinical response to MDR-TB treatment, or (b)
immunological evidence of TB infection (i.e., a positive TST or IGRA test result at
screening), AND documented exposure to a source case of MDR-TB based on a stand-
ardized questionnaire or an adult who died of TB.
Clinical evidence of TB (TB Disease) would mean the presence of at least one
of the following signs or symptoms
(1) Lack of clinical improvement despite adequate therapy for at least 2
months. This would mean any of the following: persistent fever with no
apparent cause; worsening of radiologic findings; new complications
arise; and poor weight gain(less than 10%) and well-being;
(2) Previous inadequate treatment and the presence of other risk factors like
cavitary lesions and HIV/AIDS infection.

PATHOPHYSIOLOGY
Drug resistance can be attributed to two pathways: primary drug resistance and sec-
ondary/acquired drug resistance.
Primary drug resistance would mean that the patient was exposed to a drug resistant
TB strain and would have the same way of transmission as that of regular TB. On the
other hand, secondary drug resistance is a result of inadequate, inappropriate and in-
complete treatment resulting to development of resistant strains.
Treatment Outcome Definition
 Cured Treatment completed as recommended by the national policy without
evidence of failure AND three or more consecutive cultures taken at
least 30 days apart are negative after the intensive phase

 Treatment completed Treatment completed as recommended by the national

policy without evidence of failure BUT no record that
155
 three or more consecutive cultures taken at least 30 days apart
are negative after the intensive phase

DIAGNOSIS
In pediatric cases, diagnosis of DRTB can be a problem. For all cases of childhood TB,
whether suspected to be of a drug-resistant strain or not, the adult source case should
be sought, and if resources are available, the drug susceptibility of the MTB isolate of
either adult source case or child be determined. Risk factors for resistance should al-
ways be elicited. For most children, drug susceptibility information come from the MTB
isolate that is obtained from the adult who transmitted the infection 3 since no isolate is
usually obtained from the child. Thus, studies have shown that patterns of drug re-
sistance in children tend to mirror those found in adult patients.4 In most communities, a
good clinical response to treatment may be a reasonable basis to assume that the or-
ganism is susceptible. If the clinical response is slow or when new complications arise,
the possibility of DRTB should be considered,5 thus requiring revision of treatment regi-
men.
In May 2013, WHO convened an Expert Group to evaluate the data and formulate rec-
ommendations on the use of Xpert MTB/RIF in children. This was later approved upon
by the WHO Guideline Review Committee in October 2013.
This would mean that using the Xpert MTB/RIF can: (i) help in the diagnosis of pulmo-
nary TB and rifampicin resistance in children; and (ii) Xpert MTB/RIF for the diagnosis
of extrapulmonary TB in children. The technology is recommended, especially in se-
verely ill children where rapid diagnosis is important although this does not negate or
exclude TB if a negative Xpert MTB/RIF result would come out, needing for a clinical
decision on these cases be made. 26

RISK FACTORS
The following are important risk factors for the development of drug resistance:12

 Failure to adhere to the appropriate treatment regimen;

 Previous inappropriate treatment for TB especially if prolonged;
 Contact with another patient known to have drug-resistant disease;
 Immigration from an area with a high incidence of DRTB;
 HIV seropositivity (does not in itself increase the chance of drug resistance but
does accelerate infection developing into MDR).

TREATMENT
The treatment regimens for MDR-TB is highly complicated. Most of the time, treatment
is empiric on initial intensive phase of treatment until drug susceptibility testing is avail-
able on the MTB isolate to address the treatment to be given, the patient‘s previous

156
treatment history for TB, information on drug resistance patterns of known MDR-TB pa-
tients with whom a given patient has been in close contact, and available information
on HIV status.
Common treatment strategies for DRTB are as follows:

 STANDARDIZED, where drug resistance and susceptibility (DRS) data from repre-
sentative patient populations are used to base regimen design in the absence of
individual DST, and all patients in a defined group or category receive the same
regimen.

 EMPIRICAL, where each regimen is individually designed based on the patient‘s

previous history of anti-tuberculosis treatment and with consideration of DRS data
from the representative patient population; and

 INDIVIDUALIZED, where each regimen is designed based on the patient‘s previous

history of anti-tuberculosis treatment and individual DST results.
A combination of these treatment strategies is often used.
Basic Principles in the Treatment of MDRTB
Children with MDR-TB are managed in much the same way as adults, although with
some differences. Confirmed MDR-TB may be difficult to affirm and clues like expo-
sure to a recent close contact with an adult MDR-TB case or failing to respond to ad-
herent first-line treatment should be empirically treated as an MDR-TB case.
Treatment is divided into an intensive phase, which focuses on sputum culture conver-
sion (SCC) from positive growth of MTB to a negative culture. Continuation phase of
treatment is focused on ensuring sterilization. For the intensive phase, at least 4drugs
which are known or suspected to have efficacy for a given patient‘s MTB isolate are
used; however, whenever possible, 5 drugs should be used to ensure a higher re-
sponse to treatment. The patient‘s treatment regimen are selected in a step-wise man-
ner, as recommended by the WHO Programmatic Guidelines for the Management of
Drug-resistant Tuberculosis. Whenever possible, it should have any first line drugs to
which the strain is susceptible; it should include an injectable drug; it should also have
a quinolone and must consider drug resistance data of an individual or area and the
patient‘s treatment history when designing a regimen.25 The injectable agent is usually
continued for 8months. The continuation phase is continued and a full treatment course
can last for 20 to 24 months; although some patients are treated for less than 18
months after culture conversion.
Treatment of MDR-TB involves the use of a regimen designed based on the history of
drugs taken by the patient. In addition, drugs commonly used in the country and preva-
lence of resistance to first- and second-line drugs should be considered when design-
ing a regimen. Referral to a center with a Programmatic Management of Drug Re-
sistant TB Program is most ideal in order to have access to appropriate laboratory facil-
ities, to ensure a steady supply of medications, as well as, to provide expert supervi-
sion. There are specialized MDR-TB treatment centers distributed across Metro Manila

157
(i.e. Dr. Jose N. Rodriguez Memorial Hospital in Tala Caloocan, Lung Center of the
Philippines and KASAKA DOTS Treatment Center, Quezon Institute both in Quezon
City, and PTSI in Tayuman, Manila) and provinces as well.
Drug dosages are determined by body weight. When adverse effects are noted, they
should be treated immediately and adequately in order to minimize the risk of treatment
interruptions and prevent increased morbidity and mortality due to serious adverse ef-
fects. Most importantly, each dose is given as directly observed therapy (DOT)
throughout the treatment and a treatment card is marked for each observed dose.13,14
The table below summarizes the drugs used in the treatment of MDRTB.
Table 12.1. Drugs used in the treatment of MDRTB
Grouping Drugs
Group 1 Isoniazid, Rifampicin, Ethambutol, Pyra-
First-line oral agents zinamide
Group 2 Injectable agents Kanamycin, Amikacin, Capreomycin,
Streptomycin
Group 3 Fluoroquinolones Moxifloxacin, Levofloxacin, Ofloxacin
Group 4 Oral bacteriostatic Ethionamide, Prothionamide, Cyclo-
second-line agents serine, Terizidone, p-aminosalicylic acid
(PAS)
Group 5 Clofazimine, Linezolid, Amoxicillin-
Agents with unclear efficacy clavulanic acid, thioacetazone,
(not recommended by WHO Imipenem/cilastatin, clarithromycin, high
for routine use in MDR-TB -dose isoniazid (16-20 mkd)
patients)

Adjuvant therapies in DRTB treatment

A number of other modalities are used to lessen adverse effects and morbidity as well
as improve DRTB treatment outcomes. They include nutritional support and use of cor-
ticosteroids, especially in those with severe respiratory insufficiency, central nervous
system, and pericardial involvement.
Treatment of Extensively Drug-Resistant Tuberculosis (XDR-TB)
The latest expert consensus on how to manage XDR-TB is summarized below:
1. Use any Group 1 agents that may be effective.
2. Use an injectable agent to which the strain is susceptible and consider an extended
duration of use (12 months or possibly the whole treatment). If resistant to all inject-
able agents, it is recommended to use an agent the patient has never used before.
3. Use a later-generation fluoroquinolone such as moxifloxacin.
4. Use all Group 4 agents that have not been used extensively in a previous regimen
or any of those likely to be effective.

158
5. Use two or more agents from Group 5.
6. Consider high-dose isoniazid treatment if low-level resistance is documented.
7. Consider adjuvant surgery if there is localized disease.
8. Ensure strong infection control measures.
9. Treat HIV.
10. Provide comprehensive monitoring and full adherence support.

159
Table 12.2 Different Characteristics of Second-line Anti-tuberculosis Agents15,16
Daily
Mecha-
dose Max daily Adverse ef- Other com-
Grouping Drugs nism of
in mg/ dose fects ments
Action
kg,
Kanamy- 15-30 1g Nephrotoxici- Avoid in
cin ty pregnancy
Group 2 inhibits 15- Ototoxicity
Injectable Amikacin protein 22.5
agents synthesis Neuromuscu- Dose adjust-
Capreo- 15-30 lar blockade ment in renal
mycin insufficiency
15-20 800 mg Gastric irrita- avoid in
Ofloxacin div q tion. pregnancy
12 h
Group 3
Inhibits 7.5-10 750 mg
Fluoro- Levofloxa- DNA gy- Not approved dose adjust-
quinolon cin rase for children ment in renal
es
7.5-10 400 mg due to con- insufficiency
Moxifloxa-
cern with
cin
arthopathy
Ethiona- 15-20 1g vomiting, gas- teratogenic;
mide Inhibits tric irritation, contraindi-
mycolic hypothyroid- cated in
acid syn- ism, malab- pregnancy
Prothiona- thesis sorption
mide

10-20 psychiatric, dose adjust-

neurological; ment in renal
pyridoxine insufficiency;
Group 4
used for pre- avoid in
Oral bac- inhibits vention pregnancy
teriostati pepti-
c second- Cyclo- doglycan teratogenic
line serine synthesis in animals;
agents avoid in
pregnancy;
adjust dose
in renal dis-
ease
inhibits 150 12 g vomiting, gas-
Para- tric irritation;
Aminosali folic acid
and iron hepatotoxic,
cylic acid hypersensitiv-
metabo-
lism ity

160
PREVENTION OF MDR-TB
Many new cases of MDR-TB are created each year by a combination of physician error
(prescribing inadequate regimens), genetic predisposition and poor patient compliance
with treatment, which turn fully susceptible organisms, or those with less complex re-
sistance pattern develop to MDR-TB.
Programmatic failures may result in an insufficient or erratic supply of antituberculosis
drugs or poor drug quality which may affect bioavailability and lead to a reduction in
drug efficacy. Poor case management, such as permitting patients to self-administer or
tailor their own regimens may also induce drug resistance.17
MDR-TB can be controlled by the universal implementation of the WHO TB control
strategy (DOTS), which emphasizes use of standardized treatment regimens, an unin-
terrupted supply of high-quality drugs, and directly-observed treatment. Given the high
morbidity and mortality, as well as, the high cost of treating MDR-TB patients, it is es-
sential that TB control programs employ these measures to prevent MDR TB.18

161
REFERENCES:
1. Crofton J, Chaulet P, Maher D. Guidelines for the management of drug-resistant
tuberculosis. Geneva: World Health Organization; 1997.
2. Rich M, et al. Guidelines for the programmatic management of drug-resistant tuber-
culosis, Emergency update. Geneva: World Health Organization; 2008.
3. Swanson D, Starke J. Drug Resistant Tuberculosis in Pediatrics. Pediatric Clinics of
North America. 1995;42:553-575.
4. Steiner P, Rao M, Mitchell M, et al. Primary drug-resistant tuberculosis in children.
Correlation of drug-susceptibility patterns of matched patient and source case
strains of Mycobacterium tuberculosis. Am J Dis Child. 1985;139:780-782.
5. Jacobs R, Starke J. Tuberculosis in Children. Medical Clinics of North America.
1993;77:1335-1405.
6. Starke J. Modern approach to the diagnosis of tuberculosis in children. Pediatric
Clinics of North America. 1988; 35:441-459.
7. Davidson P. Drug Resistance and Selection of Therapy for Tuberculosis. Am. Rev.
Respiratory Diseases. 1987;136:255-256.
8. Jacobs, Richard F.M.D. Multiple Drug Resistance Tuberculosis. Clinical Infectious
Diseases. 1994;19:1-10.
9. Neville K, et.al. The Third Epidemic MultiDrug Resistant tuberculosis. Chest.
1994;105:45-47.
10. Global tuberculosis control: epidemiology, strategy, financing: WHO report 2009.
11. Tuberculosis in the Philippines. Philippine Tuberculosis Society, Inc. 2009.
12. Data on the Tuberculosis Epidemic. TB: A Crossroads. WHO Report on the Global
Tuberculosis Epidemic; 1998:42-51.
13. Guidance for the national tuberculosis programme on the management of tubercu-
losis in children. Geneva. World Health Organization. 2006 (WHO/HTM/
TB/2006.371).
14. Centers for Disease Control and Prevention. Treatment of Tuberculosis. American
Thoracic Society, CDC, and Infectious Disease Society of America. MMWR.
2003;52 (No. RR-11).
15. Zhang Y. The Magic Bullets and Tuberculosis Drug Targets. Annu Rev Pharmacol
Toxicol. 2005;45:529-64.
16. Brunton L, editor. Goodman & Gilman‘s the pharmacologic basis of therapeutics.
11th edition. The McGraw-Hill Companies. 2006.
162
17. Ormerod L. Multidrug-resistant tuberculosis (MDR-TB): epidemiology, prevention
and treatment. British Medical Bulletin. 2005;73-74(1):17-24.
18. Spradling P. Prevention of Multidrug-Resistant Tuberculosis. Division of TB Elimi-
nation, NCHSTP, Centers for Disease Control and Prevention, Atlanta, GA.
19. Mendoza MT, Ang CF, Lazo S, Isaac C. In vitro susceptibility of multi-drug resistant
Mycobacterium tuberculosis isolated from Filipino patients. Phil J Microbiol Infect
Dis 2004; 33(3):95-97.
20. The Global MDR-TB & XDR-TB Response Plan 2007-2008.
21. www.stoptb.org/wg/mdrtb.
22. The use of delamanid in the treatment of multidrug-resistant tuberculosis Interim
policy guidance. WHO 2014.
23. Robert Roos .European Group Offers Treatment for MDRTB, XDRTB. CIDRAP
News | Mar 24, 2014
24. Companion handbook to the WHO guidelines for the programmatic management of
drug-resistant tuberculosis. WHO 2014.
25. Management of MDR-TB: A field guide A companion document to Guidelines for
the programmatic management of drug-resistant tuberculosis. WHO 2009.
26. Guidance for national tuberculosis programmes on the management of tuberculosis
in children Second edition. WHO 2014.
27. 2013 Manual of Procedures of the National TB Control Program, 5th edition. De-
partment of Health, Philippines 2013.
28. Definitions and reporting framework for tuberculosis – 2013 revision (updated De-
cember 2014) . WHO 2013.
29. Seddon JA, Perez-Velez CM, Schaaf HS, et al. Consensus Statement on Research
Definitions for DrugResistant Tuberculosis in Children. J Pediatric Infect Dis Soc.
2013; 2(2):100-109.

163
 13
TB in Special Situations
Clara R Rivera, MD
Maria Theresa T Policarpio, MD
Grace Devota G Go, MD

OUTLINE
1 Overview

2 Tuberculosis in Pregnancy and Lac-

tation

3 Newborns of Tuberculous Mothers

4 Tuberculosis in Children with Liver

Impairment

5 Tuberculosis In Patients With Renal

Failure

6 Tuberculosis in Immunocompro-
mised Children

7 Most Common Adverse Drug Effects

164
OVERVIEW
This chapter presents the treatment of tuberculosis (TB) in special situations like preg-
nant and breastfeeding mothers with TB, the newborns of tuberculous mothers in differ-
ent circumstances like latent tuberculosis infection (LTBI) and active TB. Treatment
difficulties in the management of TB in children with drug-induced liver disease, liver
and renal impairment and specific dosing guidelines for patients with renal insufficiency
and end-stage renal disease are provided.
Immunodeficiency, especially in people living with Human Immunodeficiency Virus
(PLHIV) and Human Immunodeficiency Virus (HIV) infected children, and other special
situations where patients are immunosuppressed have increased susceptibility to tu-
berculosis infection and disease are discussed.
Combination chemotherapy for tuberculosis is associated with a predictable incidence
of adverse effects, some mild, some serious. Mild adverse effects can generally be
managed with symptomatic therapy, whereas with more severe effects, the offending
drug or drugs must be discontinued. Although it is important to be attuned to the poten-
tial for adverse effects, it is at least equally important that first-line drugs not be stopped
without adequate justification. A summary of the approaches that should be taken in
managing the common adverse effects of tuberculosis treatment will be discussed but
proper management of more serious adverse reactions often requires expert consulta-
tion.1

TUBERCULOSIS IN PREGNANCY AND LACTATION

Tuberculosis (TB) in pregnancy should be treated without delay. Untreated TB will
cause more harm than adverse events associated with treatment of pregnant women
and babies.1,7 Infants born to women with untreated TB have higher risks of having fe-
tal growth retardation, small for gestational age, low APGAR scores, low birth weight
and rarely congenital TB.2 lsoniazid (H), rifampicin (R), ethambutol (E) and pyra-
zinamide (Z) constitute the standard treatment for pregnant women in the intensive
phase1,3 The World Health Organization (WHO) recommends the use of this drug for
two months. Pyridoxine (Vitamin B6) at 25mg/day is recommended for all pregnant
women taking isoniazid.12
Breastfeeding is encouraged because only minimal amounts of the drug are excreted
in breast milk. At most, 3% of the maternal dose is excreted in breastmilk.11 Drug levels
in breast milk are not sufficient for treatment or prophylaxis of TB in the infant. 1,2,5,6
Mothers receiving treatment for TB can safely breastfeed but should be given pyridox-
ine supplements. However, it would be better to advise the mother to feed the baby be-
fore taking the daily dose of anti-TB drugs.12

165
Management of pregnant mothers with latent TB infection (LTBI)
Pregnant women diagnosed with LTBI are at high risk of developing active TB, espe-
cially if they are HIV-positive, have had contact with active TB cases, or reveal new tu-
berculin skin test (TST) positivity within the past 2 years.13
Asymptomatic pregnant women with positive TST results, normal chest radiographic
findings, and recent contact with a contagious person should be considered for isonia-
zid preventive therapy (IPT). The recommended duration is 9 months. Therapy in these
circumstances should begin after the first trimester. However, under WHO/DOH-NTP,
the mother should be given isoniazid for at least 6 months immediately without delay
with pyridoxine supplementation to diminish the risk of peripheral neuropathy.14
Management of pregnant mothers with TB disease
Most anti-tuberculosis drugs are safe for pregnant women. Streptomycin (S) and other
aminoglycosides should be avoided because of their ototoxicity. The use of capreomy-
cin. ethionamide, fluoroquinolones or cyloserine is not recommended.1,4 Women who
become pregnant while on treatment should continue therapy, except for streptomycin
and fluoroquinolone. Treatment includes 2HRZE4HR.1,2,3,4 Advise pregnant women that
successful treatment of TB with the recommended standardized treatment regimen (i.e.
2HRZE/4HR) is important for a successful outcome of pregnancy. Pregnant women
taking isoniazid should be given pyridoxine at 25mg/day.12

NEWBORNS OF TUBERCULOUS MOTHERS

Treatment recommendations in newborns of tuberculous mothers depend on different
circumstances. 1,2,3,4,6,7,12
Management of a newborn whose mother has LTBI
After birth, the infant should not be separated from the asymptomatic TST-positive
mother with a negative chest X-ray but should be given BCG. Tuberculin-positive moth-
er without active TB does not pose any risk to the newborn.
Management of a newborn whose mother has TB disease
The mother who has current TB disease but has undergone treatment for two weeks or
more is presumed to be no longer contagious at the time of delivery. However, the pos-
sibility of congenital TB should be ruled out. (Note: see section on congenital TB.) If
the newborn is well (absence of any signs or symptoms presumptive of TB), do not give
BCG first. Instead give IPT for three months. After 3 months, perform TST. If TST is
negative, stop IPT and give BCG. If TST is positive and baby remains well, continue
IPT for another 3 months. After 6 months of IPT and if the baby remains well, give
BCG. If TST is not available and the newborn is well, the newborn should receive 6
months of IPT followed by BCG immunization.
Separation is recommended for a mother who has current TB disease but has not re-
ceived treatment. The infant upon delivery should receive isoniazid. If the maternal TB
isolate is isoniazid-resistant, rifampicin should instead be given. The placenta should be
sent for AFB stain and TB culture and sensitivity and should be histologically examined

166
for granulomata. The baby should be evaluated for congenital TB. Once the infant has
received isoniazid or rifampicin and the mother has undergone appropriate therapy,
separation is no longer required. If initial TST turns out negative, the test should be re-
peated after three months. If TST turns out positive but chest X-ray is negative, isonia-
zid or rifampicin should be continued to complete six months. If the TST and chest X-
ray of the mother are negative and she has completed her treatment, BCG should be
administered to the infant while isoniazid or rifampicin should be discontinued.
If the mother has extrapulmonary disease, such as tuberculous meningitis, miliary,
bone or joint TB, the infant must be monitored closely for possible congenital tuberculo-
sis. If a newborn infant is suspected of having congenital tuberculosis, a TST, chest
radiography, lumbar puncture, and appropriate cultures and radiography should be per-
formed promptly. The TST result is usually negative in newborn infants with congenital
or perinatally acquired infection. Hence, regardless of the TST results, treatment of the
infant should be initiated promptly with isoniazid, rifampicin, pyrazinamide and an ami-
noglycoside (eg. streptomycin).14
Currently, the accepted mode of treatment is isoniazid, rifampicin, pyrazinamide and
either ethambutol or streptomycin for first 2 months followed by isoniazid and rifampicin
for 4 to 10 months.15,16 Depending on the disease category, recovery has been ob-
tained by the combination of isoniazid, rifampicin, streptomycin and pyrazinamide for
initial 2 months. If congenital TB is ruled out, preventive therapy should be given similar
to cases of newborns whose mother has TB disease.

TUBERCULOSIS IN CHILDREN WITH LIVER IMPAIRMENT

Tuberculosis in Children with Liver Disease
Difficulties arise in the treatment of patients with liver disease because certain anti-TB
drugs (HRZ) are potentially hepatotoxic and can aggravate liver injury. In such cases,
regimens should include less hepatotoxic agents.
In patients with liver disease, liver function tests should be carried out before initiating
anti-tuberculous therapy for baseline levels.21 It is also important to perform a sustained
monitoring of alanine transaminase (ALT) 2x a week during the first 2 weeks, then on a
weekly basis until the end of the second month, and on a monthly basis thereafter till
the end of treatment.19
Isoniazid and rifampicin are potentially hepatotoxic but their combination is more toxic
than either drug alone. Total dose of isoniazid should not exceed 10mg/kg/day when
combined with rifampicin.
Two hepatotoxic drugs may be used in moderately severe disease in the treatment reg-
imen without pyrazinamide (PZA). If PZA cannot be included in the initial phase of treat-
ment, then it should consist of at least isoniazid, rifampicin, and ethambutol given daily
for 2 months followed by isoniazid and rifampicin for 7 months in the continuation
phase.19 In another treatment regimen without pyrazinamide, pyrazinamide is generally

167
substituted with a fluoroquinolone or an aminoglycoside as per the clinician‘s prefer-
ence. The proposed regimen is a combination of rifampicin, isoniazid, fluoroquinolone/
aminoglycoside and ethambutol for 2 months followed by 4 months of rifampicin and
isoniazid.18
Hepatotoxic drugs are completely avoided in decompensated liver cirrhosis. The vari-
ous drugs which can be used in a combination regimen are ethambutol, aminoglyco-
sides, fluoroquinolones, cycloserine and other newer non-hepatotoxic drugs with at
least 3 anti-TB drugs to be used in any combination regimen for around 18 to 24
months. One such possible regimen is the combination of streptomycin, ethambutol
and a fluoroquinolone for 18 to 24 months.20 However, there are no clinical trials to
prove the efficacy of such combinations.
Tuberculosis in Children with Drug-Induced Hepatitis
Hepatotoxicity may occur anytime during treatment but usually manifest in the first 2-4
weeks of therapy. Other causes of hepatitis must be ruled out. Children have a low risk
of developing drug-induced hepatitis. It has been noted that there is an increasing risk
of hepatitis with increasing age. The main principle is to reduce the number of hepato-
toxic drugs from the treatment regimen beyond 20 years of age and to increase the du-
ration of treatment.
Increases in transaminase values are frequently encountered during the first two
months of treatment. Elevation of serum liver enzymes up to two to four times occurs
rarely in children. In children less than 5 years old with elevated transaminases less
than 5 times normal and who are asymptomatic, stopping of drugs is not warranted.
However, if gastrointestinal symptoms such as nausea, vomiting and abdominal pain or
jaundice is noted, hepatotoxic first-line drugs should be discontinued or modified de-
pending on the level of serum liver enzyme aspartate aminotransferase (AST). Drug-
induced liver injury is defined as AST level three or more times than the upper limit of
normal in the presence of symptoms or five times more than the upper limit in the ab-
sence of any symptoms. AST of less than five times more than normal is mild toxicity;
AST of five to ten times more than normal is moderate; and a level of ten times more
than normal is severe.1,2,4,8
Restarting of the anti-TB drugs should be done slowly. The suspect anti-TB medica-
tions should be reintroduced one at a time after the AST level returns to less than two
times more than the upper limit of the normal. Rifampicin should be restarted first be-
cause it is less likely to cause hepatotoxicity compared to isoniazid and pyrazinamide.
There is no risk for hepatitis using rifampicin alone. However, risk increases when isoni-
azid and rifampicin are given together.2 If there is no increase in AST after one week,
isoniazid may be restarted. PZA will be restarted after INH if AST is not increasing. If
symptoms recur or AST increases, the last drug added must be stopped.
If hepatitis is severe, PZA must be discontinued and replaced by ethambutol or INH
and rifampicin be continued for nine months. Among the first-line anti-TB drugs the inci-
dence of pyrazinamide-induced hepatotoxicity during treatment is the highest and may
be severe and prolonged.1,3

168
TUBERCULOSIS IN CHILDREN WITH RENAL IMPAIRMENT
The diagnosis of TB in patients with renal failure is often delayed and may be masked
by either the underlying disease or by the symptoms of renal failure. Extrapulmonary
presentations are common. 51.6% incidence of extrapulmonary TB, with the peritoneal
and pleural involvement being the most common sites.57 Tuberculosis should be sus-
pected in end-stage renal failure patients with fever of unknown origin (T > 38.3C on
several occasions) and unexplained weight loss, especially when attempts to obtain a
clinical diagnosis fail despite an extensive laboratory and diagnostic work-up. All lymph
node groups should be carefully palpated as axillary and inguinal adenopathy may be
overlooked. Cardiovascular examination should identify clinical signs of pericardial effu-
sion. Respiratory examination may identify the presence of pleural effusion. The pres-
ence of ascites should be noted and the macroscopic appearance of peritoneal dialy-
sate should be checked for a cloudy appearance. Abdominal adenopathy and renal en-
largement associated with obstructive uropathy as well as bladder enlargement related
to urinary obstruction should be identified.
Sputum examination and chest radiography are needed. Radiography of the chest pat-
tern may be atypical (lower zone disease, miliary involvement, adenopathy and/or pleu-
ral effusion). An enlarged cardiac shadow may indicate the presence of pericardial effu-
sion. Hypercalcemia has been described as a feature of TB in patients with end-stage
renal failure .Ultrasound examination of the abdomen is useful for confirming abdominal
sites of TB including the presence of ascites, adenopathy, and splenic and renal TB.
Biopsy and culture of needle aspirates from extrapulmonary and pulmonary sites of pa-
thology are often required: the pleura (preferably biopsy), bronchial lavage and trans-
bronchial biopsies, peritoneal aspirates, lymph nodes (aspirate or biopsy), liver (biopsy)
and joints (aspirate or biopsy). Dialysate from peritoneal lavage should always be sent
for culture as acid-fast bacilli (AFB) staining alone on lavage fluid has a low diagnostic
yield.
Management
The recommended initial TB treatment regimen for patients with renal failure or severe
renal insufficiency is 2 months of isoniazid, rifampicin, pyrazinamide and ethambutol,
followed by 4 months of isoniazid and rifampicin. Although the first-line drugs, isoniazid,
rifampicin and pyrazinamide, are eliminated by the liver, management of patients with
renal insufficiency could be complicated. There are some alterations in dosages and
dosing interval of the anti-TB drugs in order to maintain peak plasma concentration.
Isoniazid and rifampicin are eliminated almost entirely by liver metabolism and biliary
excretion; these drugs could be given at the same doses in case of renal impairment.
Although pyrazinamide is metabolized in the liver, its metabolites may accumulate in
patients with renal disease. Ethambutol is 80% cleared by the kidney; hence it may also
accumulate in patients with renal disease. A longer dosing interval and the administra-
tion of PZA and EMB three times a week is recommended. Because of an increased
risk of nephrotoxicity and ototoxicity, streptomycin should be avoided in patients with
renal failure. If streptomycin must be used, the dosage is 15 mg/kg, two or three times
per week to a maximum of 1 gram per dose, and serum levels of the drug should be
monitored.

169
A thorough drug chart review should be performed prior to prescribing TB medication to
identify potential drug interactions especially in transplant patients. The selection and
doses of anti-TB drugs should preferably be decided in consultation with a nephrologist.
Anti-TB drugs that are significantly dependent on renal clearance are ethambutol,
levofloxacin, cycloserine, streptomycin, kanamycin, capreomycin, and amikacin.
Drug absorption may be unpredictable in patients with renal failure due to nausea and
vomiting resulting from uremia, and patients should be questioned regularly about the-
se symptoms.
Creatinine clearance should be measured in all patients with renal disease prior to
treatment. The timing of drug administration is important. Drugs should generally be
administered after hemodialysis to prevent loss of drug during dialysis. This is especial-
ly relevant for PZA, which is efficiently removed by hemodialysis. The injectable agents
– streptomycin, kanamycin, capreomycin and amikacin – are also partially removed and
should be given after hemodialysis. Of the standard TB drugs, rifampicin is not re-
moved by hemodialysis due to its wide volume of distribution and high degree of protein
binding. Isoniazid and ethambutol are removed by hemodialysis but to a lesser extent
than PZA.
End-stage renal failure (ESRF) patients with TB may pose an infective risk to immuno-
compromised renal transplant cases and other patients in dialysis units. Infection con-
trol measures and contact tracing should be applied. In patients with ESRF on TB treat-
ment, the same general principles for management of patients with renal failure apply.
A thorough drug chart review should be performed prior to prescribing TB medication to
identify potential drug interactions especially in transplant patients on cyclosporine and
mycophenolate mofetil. The selection and doses of TB drugs should preferably be de-
cided in consultation with a nephrologist.
Box 13.1 Anti-tuberculous drugs that significantly dependent on renal clearance
Ethambutol
Levofloxacin
Cycloserine
Kanamycin
Capreomycin
Amikacin
(Metabolites of pyrazinamide may accumulate.)

The recommended initial TB treatment regimen for patients with renal failure or severe
renal insufficiency is 2 months of isoniazid, rifampicin, pyrazinamide and ethambutol,
followed by 4 months of isoniazid and rifampicin.13 Although the first-line drugs, isonia-
zid, rifampicin and pyrazinamide, are eliminated by the liver, management of patients
with renal insufficiency could be complicated. There are some alterations in dosages
and dosing interval of the anti-TB drugs in order to maintain peak plasma concentration
Isoniazid and rifampicin are eliminated almost entirely by liver metabolism and biliary
excretion; these drugs could be given at the same doses in case of renal impairment.
Although pyrazinamide is metabolized in the liver, its metabolites may accumulate in
170
patients with renal disease. Ethambutol is 80% cleared by the kidney; hence it may also
accumulate in patients with renal disease. A longer dosing interval and the administra-
tion of PZA and EMB three times a week is recommended. Because of an increased
risk of nephrotoxicity and ototoxicity, streptomycin should be avoided in patients with
renal failure. If streptomycin must be used, the dosage is 15 mg/kg, two or three times
per week to a maximum of 1 gram per dose, and serum levels of the drug should be
monitored.
In severe renal impairment with creatinine clearance less than 10 mL/min, reduction of
isoniazid dose to 200mg is recommended.1,6,10 Serum concentration of streptomycin is
allowed at 5 μg/mL and should be given eight hours before dialysis. Ethambutol should
be given eight hours before dialysis and at 25 mg/kg, three time a week when creati-
nine level is between 50 to 100 mL/min; and two times a week when creatinine level is
between 30 to 50 mL/min. Pyrazinamide is recommended at the low end of 15 to 20
mg/kg and requires supplemental dosing if given before dialysis. Generally, anti-
tuberculous drugs should be given after hemodialysis to avoid filtration of the drugs dur-
ing the procedure.2,4 Directly-observed therapy (DOT) should be facilitated in patients
undergoing hemodialysis for better outcome.1,2

TUBERCULOSIS IMMUNOCOMPROMISED CHILDREN

Children with Human Immune Deficiency/ Acquired Immunodeficiency Syndrome (HIV/
AIDS), hematologic and malignant neoplasms, and with prolonged use of systemic ster-
oids of more than 15 mg prednisone for two to three weeks (patients taking the equiva-
lent or ≥ 15 mg/day of prednisone for 1 month or more or those taking Tumor Necrosis
Factor-alpha (TNF-α) antagonists are predisposed to the development of TB disease.
In immunocompromised patients, cell-mediated immunity, macrophage function and
cytokine production are compromised.7,48
Tuberculosis in HIV Immunocompromised Children
Most children living with HIV are infected by mother-to-child transmission. The peak
age prevalence for HIV is therefore in infants and young children (<5 years), who also
make up the age group in which it is most difficult to confirm the cause of acute or
chronic lung disease, including TB. Children with HIV have an increased incidence of
tuberculous disease.23
As in adults, TB is a leading cause of death in HIV-infected children. Children living in
HIV-affected households are at increased risk of TB exposure and infection irrespective
of their own HIV status, with those who are HIV-infected being at increased risk of de-
veloping TB disease progression.24,25
The clinical manifestations and radiographic appearances tend to be similar with immu-
nocompetent children but manifestations in these children can be more severe and un-
usual and can involve extrapulmonary involvement of multiple organs such as lymph
nodes and pleura or disseminated (miliary) disease; less commonly the pericardium,
meninges/brain, or abdomen is also involved.26 Overall, the clinical presentation of TB

171
in HIV-infected children, may depend on degree of immunocompromise, with severe,
disseminated forms more frequently found in patients with advanced HIV infection.
Approach to TB Diagnosis in Pediatric HIV
The clinical approach to TB diagnosis is similar to adults with sputum smear-negative
disease, taking into account the likelihood of TB exposure, proof of Mycobacterium tu-
berculosis (MTB) infection (tuberculin skin test induration of ≥5 mm, or a positive MTB
interferon-gamma-release assay), clinical features, and chest X-ray signs suggestive of
TB, as well as appropriate microbiological evaluation.27,28
The cornerstone of diagnostic methods for LTBI is the TST, administered by Mantoux
test. Because children with HIV infection are at high risk for TB, annual skin testing is
recommended to diagnose LTBI.
TST is less sensitive in children living with HIV than in HIV-negative children; induration
of > 5 mm is considered positive if the child is living with HIV.
Interferon-gamma release assays (IGRAs) should not replace the TSTin low- and mid-
dle-income countries for the diagnosis of latent TB infection in children or for the diag-
nostic work-up of children (irrespective of HIV status) suspected of TB disease in these
settings.29
The WHO has endorsed Xpert MTB/RIF as a primary TB diagnostic test in symptomatic
people living with HIV.30,31 However, Xpert MTB/RIF cannot be used to rule out TB, and
MTB culture remains a necessary diagnostic tool.

Prevention of TB in children living with HIV infection

All children living with HIV infection in a TB endemic setting should therefore be regu-
larly screened for TB by clinical assessment at each visit to a health facility or contact
with a health worker. Evaluation should aim to identify those patients who are likely to
have TB disease, requiring anti-TB treatment, and those who should start IPT.
1. Primary prophylaxis
Recommendations have also been made for IPT for infants and children living with HIV
who are considered unlikely to have TB and have no known exposure to TB; this is also
known as primary prophylaxis 32,33,34,35
Children living with HIV who are more than 12 months of age and who are unlikely to
have TB disease on symptom-based screening and have no contact with a TB case:
- should be offered 6 months of IPT (10 mg/kg per day, range 7–15 mg/ kg, maximum
dose 300 mg/day) as part of a comprehensive package of HIV prevention and care ser-
vices if living in settings with a high TB prevalence (Strong recommendation, low quali-
ty of evidence)
- might be offered 6 months of IPT (10 mg/kg per day, range 7–15 mg/kg, maximum
dose 300 mg/day) as part of a comprehensive package of HIV prevention and care ser-

172
vices if living in settings with a medium or low TB prevalence ((Conditional recommen-
dation acknowledging resource implications, low quality of evidence)
The WHO recommended that children over 12 months of age and living with HIV
should be screened and be given IPT for tuberculosis.36 Although not a requirement for
starting IPT, TST may be done as part of eligibility screening in some settings.
If a child presents with any of the following symptoms below, an investigation for tuber-
culosis in accordance with existing national guidelines and other diseases should be
done. 36
1. poor weight gain defined as reported weight loss, very low weight ( weight-for-age
less than -3 z-score), underweight (weight-for-age less than -2 z-score), confirmed
weight loss (>5%) since last visit, or growth curve flattening;
2. fever;
3. current cough; and
4. contact history with a TB case
If the case is not TB or there are other diagnoses, follow up patient and give appropri-
ate treatment respectively and consider giving IPT to both cases. If the diagnosis is
consistent with tuberculosis, treat patient accordingly.
If the child does not manifest any of the symptoms, the child may receive IPT if there
are no contraindications like active hepatitis (acute or chronic), and symptoms of pe-
ripheral neuropathy. Past history of TB should not be a contraindication for starting IPT.
All children and infants less than one year old should be provided with IPT if they have
household contact history with an infectious TB case.
2. BCG vaccination in HIV infected children
In children who are known to be HIV-infected, BCG vaccine should not be given be-
cause of the risk of disseminated BCG disease.37 (Recommendation strength and evi-
dence quality have not been graded)
In infants whose HIV status is unknown, are born to HIV-positive mothers, and lack
symptoms suggestive of HIV, BCG vaccine should be given after considering local fac-
tors.37

Contact Screening and Case-Finding

Clinical evaluation of household and close contacts for active TB should be done on
the basis of their risk for having or developing active TB or for the potential conse-
quences of the disease if it develops. Priority should be given to contacts who are: 38
1. children with symptoms suggestive of TB;
2. children <5 years of age;
3. children with known or suspected immunocompromising conditions (especially
those living with HIV); and
4. child contacts of index cases with multidrug-resistant or extensively drug-resistant
173
 TB (proven or suspected)
(Strong recommendation, very low quality of evidence)
1. Suspected HIV infection of source case and contact
In settings of high HIV prevalence, all household and close contacts of people with TB
should be counselled and tested for HIV.38 (Strong recommendation, very low quality of
evidence)
In settings of low HIV prevalence, all household members and close contacts of people
with TB who have symptoms compatible with TB disease may be offered counseling
and testing for HIV as part of their clinical evaluation.38 (Conditional recommendation,
very low quality of evidence)
All household contacts of an index case who is a person living with HIV should be
counselled and tested for HIV.38 (Strong recommendation, very low quality of evidence)

Treatment of TB in Children living with HIV

1. Anti-TB Therapy
Children living in settings where the prevalence of HIV is high should be treated with a
four-drug regimen (HRZE) for 2 months followed by a two-drug regimen (HR) for 4
months.
Children with suspected or confirmed pulmonary TB or tuberculous peripheral lymphad-
enitis living in settings with a high HIV prevalence (or with confirmed HIV infection)
should not be treated with intermittent regimens (i.e. twice-weekly or thrice-weekly dos-
es).39 (Strong recommendation, low to moderate quality evidence against the use of
intermittent treatment in children)
Each child should be assessed 2 weeks after the start of TB treatment then reviewed
monthly with clinical monitoring, which should include symptom assessment, weight
measurement, assessment of adherence to treatment and enquiry about any adverse
events.
Possible reasons for treatment failure are non-compliance with therapy, drug-resistant
TB or alternative diagnoses (incorrect diagnosis of TB).
All children living with HIV who have successfully completed treatment for TB disease
should receive isoniazid for an additional 6 months.40
When compared with HIV-negative children, responses to TB treatment and outcome
are poorer for children living with HIV. Before the availability of ART, many deaths in
children with TB/HIV occurred in the first 2 months following the start of TB treatment.
Medical risk factors for poor treatment response and mortality include severe malnutri-
tion, co- infections, severe immunosuppression and high viral load.
Additional therapy recommended for HIV-infected children with TB, which may help to
improve TB treatment outcomes, includes co-trimoxazole preventive therapy, the early

174
start of ART and pyridoxine supplementation along with nutritional support.
2. Co-trimoxazole Preventive Therapy
Co-trimoxazole (CTX) is a broad-spectrum antimicrobial agent that prevents a range of
secondary bacterial and parasitic infections in eligible adults and children living with
HIV. Daily prophylaxis co-trimoxazole preventive therapy (CPT) prolongs survival in
children living with HIV and reduces the incidence of co-morbidities. It also reduces the
risk of co-infections such as pneumocystis pneumonia in HIV-exposed infants. CPT is
therefore recommended for all HIV-exposed infants and children living with HIV, includ-
ing those with TB41 and should be implemented as an integral component of a package
of HIV- related services.42
CTX prophylaxis is indicated in all HIV exposed infants starting at 4-6 weeks and all
infants with presumptive clinical diagnosis of severe symptomatic HIV until no longer
breastfeeding and HIV has been excluded.43 This strategy may be considered in set-
tings such as TB programs with a high prevalence of HIV and with limited health infra-
structure.
The following confirmed HIV-infected infants and children should receive CTX prophy-
laxis:43

 For less than 1 year of age regardless of CD4% or clinical status

 For children aged 1-5 years diagnosed with WHO stages 2,3, and 4 regardless of
CD4% OR any WHO stage and CD4<25% (in resource –limited settings, CTX may
be started when the CD4 count has dropped to <25% at age <5 years or is <350
cells/mm3 at <6 years.)
The aim is to reduce the morbidity and mortality associated with malaria, bacte
rial diarrheal diseases and pneumonia, in addition to the prevention of PCP and
toxoplasmosis. In other settings where the use of CTX is limited to preventing
PCP, CTX may be started when the CD4 count has dropped to <20% at age 5
or is <200 cell/mm3 at >6 years.

 For less than 6 years diagnosed with any WHO clinical stage and CD4<350 (same
as in re source-limited settings as above) or with WHO stage 3 or 4 and any CD4
level (asymptomatic children in WHO clinical stage 1 do not require CTX prophylax-
is. However, it is strongly recommended to measure the CD4 count as asymptomat-
ic children may also have laboratory signs of immunodeficiency)
The indications for initiating, discontinuing and monitoring CPT are included in
the 2006 WHO guidelines on co-trimoxazole prophylaxis for HIV-related infec-
tions among children, adolescents and adults: recommendations for a public
health approach.44 The recommended dose of CTX is 150 mg TMP/m2 SMX 750
mg/m2 .45
3. Antiretroviral Therapy
Antiretroviral therapy (ART) in children living with HIV aims to improve the length and
quality of life, reduce HIV-related morbidity and mortality by reducing the incidence of
175
opportunistic infections (including TB), reduce the viral load, restore and preserve im-
mune function, and restore and preserve normal growth and development. ART im-
proves TB treatment outcomes for children living with HIV.
WHO 46 recommends that ART be provided to all people with a confirmed HIV diagno-
sis and a CD4 count of 500 cells/mm3 or less, giving priority to those with severe/
advanced HIV disease or a CD4 count of 350 cells/mm3 or less.
WHO also recommends that ART be initiated in people with active TB and HBV co-
infection with severe liver disease, all pregnant and breastfeeding women with HIV, all
children younger than 5 years living with HIV and all individuals with HIV in serodiscord-
ant relationships, regardless of CD4 cell count.
TB treatment should be started first, followed by ART within 8 weeks of the start of TB
treatment. For those with a CD4 count below 50 cells/mm3, ART should be provided
within 2 weeks of the start of TB treatment.46
For first-line ART, use of simplified and less toxic regimens – as fixed-dose combina-
tions whenever possible – is recommended as the most effective and convenient ap-
proach. Regimens comprising of a non-thymidine nucleoside reverse-transcriptase in-
hibitor (NRTI) backbone (tenofovir disoproxil fumarate (TDF) or abacavir (ABC) + lamiv-
udine (3TC)) and one non-nucleoside reverse-transcriptase inhibitor (NNRTI) efavirenz
(EFV) are maintained as the preferred choices in adolescents and children older than 3
years. For children younger than 3 years, a protease inhibitor (PI)-based regimen is the
preferred approach in combination with ABC or zidovudine (AZT).46
The following is the summary of recommendations on when to start ART in children.46
1. For all infants less than 1 year regardless of CD4 count
2. For one to less than 5 years ( priority are children ≤ 2 years, or with WHO stage 3
or 4, or CD4 count ≤750 cells/mm3 OR <25% )
3. For 5 years and above diagnosed with WHO stage 3 or 4 or CD4≤500 cells/mm3
(priority case if CD4≤350 cells/mm3)
Selecting ARV regimens that are compatible with TB therapy is essential. Interactions
between rifampicin (rifabutin preferred because of less enzyme induction property) and
lopinavir/ritonavir (LPV/r) or nevirapine (NVP) mean that co-treatment in children under
three years is challenging, but a recent large randomized controlled trial of ART in chil-
dren has generated preliminary evidence on the efficacy of triple nucleoside therapy
which, despite limited data in the context of TB co-treatment, offers a suitable option for
children who require TB treatment while already receiving ART. 46, 47
WHO also recommends ART for all patients with HIV and drug-resistant TB requiring
second-line anti-TB drugs, irrespective of CD4 count, as early as possible (within the
first 8 weeks) following the start of anti-TB treatment.46
The recommended regimen for children and infants starting ART while on TB treatment
is as follows:46

176
1. For younger than 3 years, start 2 NRTIs NVP ensuring that dose is 200mg/m2 OR
Triple NRTI (AZT + 3TC + ABC)a
2. For 3 years and above, start 2 NRTIs + EFV OR Triple NRTI (AZT + 3TC + ABC)a
The following is the recommended regimen for children and infants starting TB treat-
ment while on ART.46
1. For children on standard NNRTI-based regimen (2 NRTIs +EFV or NVP) younger
than 3 years, continue NVP ensuring that dose is 200 mg/mm3 or Triple NRTI
(AZT+3TC +ABC)a
2. For children on standard NNRTI-based regimen (2 NRTIs +EFV or NVP) 3 years
and older, may continue regimen if on EFV or If on NVP, change to EFV or Triple
NRTI (AZT+3TC+ABC)a
3. For children on standard PI-based regimen(2 NRTIs +LPV/r) younger than 3 years,
may receive Triple AZT (AZT+3TC+ABC)a or change to NVP ensuring that dose is
200mg/m2 or continue LPV/r and consider adding RTV to achieve full therapeutic
dose (increase RTV until same dose as LPV in mg, in a ratio of 1:1)
4. For children on standard PI-based regimen (2 NRTIs +LPV/r) 3 years and above
and with no history of NNRTI- based regimen failure, change to EFV (as the pre-
ferred option and could be maintained after termination of TB treatment to allow
simplification and harmonization with ARVs regimen in older children) or Triple
NRTI (AZT+3TC+ABC)a or continue LPV/r consider adding RTV to achieve full ther-
apeutic dose (RTV;LPV/r in 1:1 ratio in mg)
5. For children on standard PI-based regimen (2 NRTIs +LPV/r) 3 years and above
and with history of NNRTI- based regimen failure, start on Triple NRTI
(AZT+3TC+ABC)a or continue LPV/r and consider adding RTV to achieve full thera-
peutic dose (RTV:LPV/r in 1:1 ratio in mg). Consultation with experts for construc-
tion of second-line regimen should be considered.
Notes:
 Abbreviations used: ABC abacavir; AZT zidovudine; EFV efavirenz; LPV/r lop-
inavir/ritonavir; NNRT non-nucleoside reverse-transcriptase inhibitor; RTV ritonavir;
3TC lamivudine
a
 Triple NRTI is recommended only for the duration of TB treatment; an age –
appropriate PI-or NNRTI-based regimen should be restarted at termination of rifam-
picin-based therapy. This regimen should be considered as the preferred option for
children less than 3 years on LPV/r-based regimen when starting TB treatment and
also as the preferred regimen for children older than 3 years with history of NNRTI
failure.
4. Immune Reconstitution Inflammatory Syndrome (IRIS)36
Sometimes known as a paradoxical reaction, immune reconstitution inflammatory syn-
drome (IRIS) is a temporary clinical deterioration that may occur within 3 months of
177
starting ART and most commonly within the first month. It is the result of reconstitution
of cell-mediated immunity in response to mycobacterial antigens and can give rise to
diagnostic and management challenges. Immune reconstitution can also occur with im-
proved nutritional status during anti-TB treatment. It can simulate worsening of TB dis-
ease, with fever and increased size of lymph nodes or tuberculomas. Risk factors for
IRIS include low baseline CD4 count, extensive TB, early initiation of ART, and rapid
immunological and virological responses to ART. Though a cause of significant morbid-
ity, TB-IRIS and BCG-IRIS are not associated with an increased mortality risk.
With respect to TB, there are two main presentations: exacerbation of known TB dis-
ease in a child living with HIV who started anti-TB treatment and ART; or development
of TB disease in a child starting ART.
In all cases, anti-TB treatment should be continued; the addition of corticosteroids may
sometimes be useful. If there is any doubt, the child should be referred to the next level
of care.
Tuberculosis in non-HIV immunosuppressed patients
Patients who are immunosuppressed have increased susceptibility to tuberculosis in-
fection and disease. The risk associated with each cause of immunosuppression var-
ies, but is most profound with drug-induced immunosuppression in the management of
malignancy and organ transplantation, and is milder in diabetes mellitus. In some dis-
eases, the risk represents the dual effects of susceptibility conferred by the disease
state and its treatment. The risk, presentation, investigation and approach to manage-
ment varies according to the cause.
Diabetes Mellitus
The increased risk of developing TB in diabetes mellitus (DM) varies according to the
background prevalence and various host factors, including patient's age and sex, body
mass, duration of diabetes and most importantly, adequacy of glycemic control. TB may
result in impaired glucose tolerance that improves/resolves after successful treatment.
In pediatrics, this host factor of concern is the a) duration of diabetic disease; b) male
sex considered to be greater risk of TB than females; c) glycemic control; and d) body
mass. Most important determinant of developing TB is the level of diabetic control that
patients maintain. Increased risk of smear-positive disease has been demonstrated at
HbA1c levels of 9% or more. Low body mass in younger ones has been demonstrated
to be an independent risk factor for TB. Active TB may also be associated with impaired
glucose tolerance that improves/resolves after successful TB chemotherapy.50 This im-
pairment maybe transient; thus, patients diagnosed with diabetes while on TB treat-
ment should be reviewed once treatment has been completed.
1. Clinical Features of TB in Diabetes Patients
Clinical features and presentations are similar to those without diabetes. Unusual
presentation is the higher incidence of extra-pulmonary disease (i.e. laryngeal TB).
Some of the symptoms of TB are similar to poorly controlled diabetes and its co-
morbidities, hence the diagnosis of TB maybe overlooked or delayed.

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BOX 13.2. Comprehensive history and evaluation of the tuberculosis-diabetes
mellitus patient49
Diabetes History
Type and onset of diabetes.
Diabetic treatment history and drug administration and supply.
Level of prior diabetes education.
Dietary history and eating plan.
Monitoring and Glycemic control.
Episodes and symptoms of hypoglycemia
Evidence of target organ damage.
Micro vascular: renal, ocular, neuropathy.
Macro vascular: cardiac, arterial disease, stroke.
Other: gastroparesis, impotence

Tuberculosis history
Duration and symptoms.
Presence of Extra pulmonary disease
Presence of complication of the disease
Smoking and prior lung disease

Focus of examination should be directed towards detecting complications of diabetes,

complications of pulmonary TB (pleural, laryngeal) and evidence of extra-pulmonary
and disseminated disease (meningitis, lymphadenopathy, organomegaly, peritoneal
and joint disease). Monitoring of visual acuity alongside color perception should be car-
ried out.
2. Investigations
Sputum smear positivity is seen frequently as the pretreatment pulmonary bacillary load
maybe high as well as cavitation disease is higher than in non- diabetics51.
In chest radiography, the pattern is typical in majority but atypical presentations have
been described. A preponderance of cavitary and lower zone distribution was found in
the study of Pérez-Guzmán et al. There was a decreased frequency of upper lung field
lesions and cavitations more often in the lower lung fields.52 With increasing patient
age, basal distribution of disease and other atypical presentations may increase.
3. Management
Since the development of tuberculous disease may be accompanied by loss of diabetic
control, a temporary increase in treatment, on occasions involving a switch to insulin
injections in those on oral anti-diabetic drugs, may be indicated. The need to increase
the doses of oral hypoglycaemic agents is their increased metabolism resulting from
the induction of the cytochrome P-450 enzyme system by rifamycins.53 Guler et al re-
ported a higher rate of persistence of sputum smear and culture positivity after 2
months of treatment, independent of the extent of pulmonary disease,54 and Restrepo
et al noted that patients with TB and diabetes were more likely to be smear-positive at
diagnosis, and remain positive at the end of 1 and 2 months of treatment.55This finding
may be attributed to the greater tendency of cavitary disease in diabetics. In contrast to

179
these reports, others have described better patient compliance and treatment success
rates in diabetics.13 However, relapse rates might also be higher.56

Tuberculosis in patients with neoplasia

An increased incidence of TB has been associated with many malignancies, but the
assessment of relative risk with different forms of malignancy is confounded by the
functional state of patients (weight loss, cachexia and extent of spread) and the level of
immunosuppression caused by different modalities of treatment, particularly chemo-
therapy. In general, however, the risk is greater in hematologic malignancy than with
solid tumors, and greater with chemotherapy regimens that result in bone marrow and
immune suppression. In one review of TB in patients with malignancy, in 30% of cases
TB was observed at the time of diagnosis of the malignancy, and in half TB developed
during 18 months of therapy. Other surveys have reported that patients with active pul-
monary TB are at increased risk of dying of cancer.58 However, from a diagnostic per-
spective, cancer and TB are often confused, and both must be considered in patients
with unusual presentations of either.
Patients with hematological malignancies such as Hodgkin‘s disease, adult T-cell leu-
kemia and other lymphoproliferative disease receiving high doses of corticosteroids and
fludarabine or who are hematopoietic stem cell recipients have been considered to be
at a three-fold higher risk than those with other hematological malignancies of develop-
ing TB. In their series, Silva et al reported a prevalence of 2.6% of TB in patients with
hematological malignancies, with the highest rates (6.9%) in patients with chronic lym-
phocytic leukemia (CLL).59
1. Clinical presentation and diagnosis of tuberculosis in patients with malignan-
cies
The diagnosis of TB in patients with malignancies is often delayed for several reasons.
Symptoms in hematological malignancies are often attributed to tumor progression,
general loss of functional status and nutrition or anemia and other side effects of ag-
gressive chemotherapy. Diagnostic confusion and the risk of delayed diagnosis is
greatest in patients with bronchial malignancy where these conditions may coexist.
However, this delay is probably even greater in TB control programs that rely solely on
sputum examination for management decisions, since these require treatment failure
(either bacteriological or clinical) before chest radiographs are reviewed, and the major-
ity of cases of malignancy diagnosed in this way are in an advanced stage. Treatment
algorithms should therefore include signs and symptoms that prompt review for the
presence of bronchial malignancy.

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BOX 13.3. History and clinical signs suggesting bronchial malignancy in patients
with tuberculosis49
A history of smoking and previous bronchial or upper respiratory tract malignancy.
Failure to gain weight on therapy especially in patients with drug- susceptible M.
tuberculosis on initial cultures.
The presence of persistent chest pain.
Ongoing or new hemoptysis while on TB treatment.
Hoarseness of new onset.
Persistence of radiological infiltrates or appearance of new ones.

In patients with TB and suspected malignancy, repeated sputum cytology has been
shown to improve the diagnostic yield but this is not feasible when hemoptysis is pre-
sent and or when patients are unable to expectorate.60 The latter can be overcome in
some by use of sputum-inducing methods, but fine needle aspiration under radiograph-
ic guidance (preferably using a CT scan) or bronchoscopy has the highest success rate
in confirming the diagnosis.
2. Treatment and Prognosis
Tuberculosis occurring in malignancy is treated along standard lines, but attention must
be paid to potential drug interactions and side effects in patients who are debilitated by
cancer or on aggressive chemotherapy or radiotherapy. Where surgery for cancer is
planned, it is advisable to delay this for at least some weeks until TB chemotherapy has
been started. Where possible, a longer delay and even completion of TB treatment is
advised in patients scheduled to receive chemotherapy and bone marrow transplanta-
tion. However, this must be weighed against the impact of such delays upon prognosis
of the malignancy.
3. Complications
Clinicians prescribing TB medication and following up patients with co-morbid disease
should be attentive to potential drug interactions between TB drugs and multiple
chemotherapeutic agents; the effects of nausea and vomiting on drug absorption; the
effects of general debility and impaired mobility on drug collection and treatment com-
pliance; the risk of transmission of TB from these to other susceptible patients in clinic
and hospital facilities serving patients with cancer and hematological diseases; and the
development of other cancer and treatment-related lung disease including: opportunis-
tic lung infections such as fungal pneumonia, drug-induced lung disease, radiation lung
injury, and pulmonary thromboembolic disease.

Corticosteroid use and risk of tuberculosis

Corticosteroids may serve both as a treatment and as a risk factor in TB. On one hand,
their use may increase the risk of infection, progression to disease and dissemination.
On the other hand, their therapeutic use rests on the anti-inflammatory activity in some
TB settings such as systemic lupus erythematosus (SLE), glandular involvement in chil-
dren obstructing airways, pleurisy, pericarditis, peritonitis, meningitis and ocular in-

181
volvement.61-65 Corticosteroids can also be used for treating the paradoxical response
and IRIS associated with TB treatment, especially in patients on antiretroviral therapy.66
SLE and collagen vascular diseases comprise a major category of disease in which
corticosteroids are used – either as a long-term remittive agent or for the treatment of
flare-ups of acute arthritis in rheumatoid arthritis and SLE. The risk of TB appears to
vary by disease, indication and dosing schedule. It is greater in patients with lupus than
those with rheumatoid arthritis,67 and is more common in patients with organic brain
syndrome, vasculitis and nephritis, and in patients who receive intravenous ‗pulse‘
methylprednisolone or high cumulative doses of prednisolone.68 The use of prophylactic
isoniazid (INH) does not appear to effectively prevent recurrence of TB in lupus patients
in highly endemic areas, and may be associated with an increased risk of lupus flare.
In asthma and chronic obstructive pulmonary disease (COPD), inhaled corticosteroids
are used in patients and severe COPD. In addition, short courses of systemic cortico-
steroids are used for exacerbations of both diseases. Inhaled corticosteroids are also
considered to be safe in children and adults with asthma who are tuberculin-positive
and there is no evidence of increased risk of tuberculous infection or disease.69
In diffuse parenchymal lung disease, systemic corticosteroids are the most widely used
treatment like sarcoidosis, idiopathic pulmonary fibrosis, lymphocytic interstitial pneu-
monitis, cryptogenic organizing pneumonia and non-specific interstitial pneumonia.
Studies of the potential risk associated with their use in these diseases are confounded
by several factors. Firstly, studies from places with both high and low prevalence of TB
have confirmed an increased incidence of TB in patients with diffuse parenchymal lung
disease unrelated to treatment.70 Secondly, the presence of diffuse radiographic chang-
es and frequent follow-up provided to these patients have an impact, both positive and
negative upon the detection and diagnosis of intercurrent TB. Thirdly, for sarcoidosis,
there is a long-standing debate concerning a possible etiological role for MTB, which, if
accepted, would alter the interpretation of TB as a complication of treatment.71,72 How-
ever, cases of TB developing in patients with sarcoidosis receiving corticosteroids have
been reported.73,74
1. Clinical features and Investigations
Tuberculosis associated with corticosteroid treatment frequently presents in unusual
forms, or as extra-pulmonary or disseminated disease. A high index of suspicion is re-
quired, particularly in high-prevalence countries, and the general approach and selec-
tion of investigations is similar to that for other immunocompromised patients. In those
with interstitial disease, detection of new pulmonary lesions, particularly if these are
nodular or miliary, is a particular problem. Computed Tomography (CT) scanning is of
value, not only for defining new lesions but also for seeking patterns of specific diag-
nostic value. These include cavitation and new pleural involvement as features of TB,
aspergillomas in pre-formed cavities and sequestra suggesting locally invasive asper-
gillosis.
2. Treatment and Prognosis
The treatment and outcome of TB patients occurring in association with corticosteroid
use is similar to those without such treatment. However, in those with pre-existing lung

182
disease, the combined effects with TB may result in significant long-term loss of pulmo-
nary reserve and/or development of bronchiectasis and susceptibility to infections. Sup-
portive care and even domiciliary oxygen might be necessary.
3. Prevention
Recommendations concerning INH prophylaxis in patients on systemic corticosteroids
vary and are tentative because of lack of firm evidence on the doses of corticosteroids
at which the risk increases, and a similar absence of cost/benefit analyses of chemo-
prophylaxis in this setting. Any benefits of treatment must be weighed against the risk
of side effects, especially hepatotoxicity. The American Thoracic Society Statement
notes these facts and suggests that chemoprophylaxis is unnecessary for patients re-
ceiving moderate doses of oral prednisolone up to 10 mg per day, as the risk of devel-
oping TB is uncertain, even in high-prevalence communities.70,75 According to these
guidelines, chemoprophylaxis should be considered for patients receiving doses higher
than this. Chemoprophylaxis is not necessary for patients receiving inhaled corticoster-
oids.

Tuberculosis in organ transplant patients

As for other high-risk patients, the incidence of TB following solid organ transplantation
reflects the local prevalence of TB, and may be as high as 15% in areas of high TB en-
demicity. In low-incidence areas the risk of TB in transplant patients has been estimat-
ed to be between 36 and 74 times higher than that in the general population. 76 Singh et
al identified 511 cases of TB in 109 reports and the incidence of TB among heart, liver
and lung recipients varied from 1% to 1.4%, 0.9% to 2.3% and 2% to 6.5%, respective-
ly, in these three categories of patients.
1. Clinical presentation in organ transplant patients
Two patterns of TB are observed in organ transplant patients: 1) localized pulmonary
disease and/or 2) disseminated disease. The risk of disseminated disease is higher
with regimens containing anti-T-cell antibodies or anti-CD3 monoclonal antibody
(OKT3). Presenting symptoms are similar to that of TB developing in other clinical set-
tings and include fever, night sweats, unexplained weight loss and loss of appetite. In
patients with disseminated disease, additional symptoms include those referable to the
systems/organs.
2. Diagnostics
A wide range of chest radiographic patterns varying from focal infiltrates to miliary and
diffuse nodular patterns have been observed. Comparison should be made with pre-
transplant radiographs, with particular attention to abnormalities that might suggest pre-
vious TB.
For patients with radiological infiltrates the first approach is sputum examination and
culture, but in those with high fever and in periods of profound immunosuppression, the
yield from blood cultures is also significant and these should be performed. Fiberoptic
bronchoscopy under local anesthesia is often necessary, especially in those with dif-
fuse disease. A combined approach of segmental small-volume lavage, brushing of

183
several affected segments of lung and collection of a post-bronchoscopy sputum sam-
ple provides the highest yield. Transbronchial and/or endobronchial biopsies are also
advised, especially if alternative diagnoses are being considered, but these increase
the risk of hemoptysis, pneumothorax and other complications of the procedure.
A less invasive option, suitable for patients with accessible discrete lesions that can be
accurately located on CT scanning, is transthoracic fine needle aspiration. Transbron-
chial needle aspiration is also useful where hilar or mediastinal nodes are observed. In
view of the risks of bleeding, particularly in renal transplant recipients, measurement of
blood counts including hemoglobin, platelet count and international normalized ratio
(INR) as well as bleeding time are necessary.
Biopsies and needle aspiration should not be attempted on patients with abnormal INR,
low platelet count or prolonged bleeding times, and if other attempts to make the diag-
nosis fail and, upon review of risks and benefits, these procedures are still considered
essential, the abnormality should be corrected using standard measures before they
are attempted.77
Depending on the suspected organ involvement of TB, other tests might be required.
These include liver function tests, ultrasound examination of the heart, and CT scans of
abdomen and chest. Examination of urine for sterile pyuria, a feature in renal TB, ex-
amination of cerebrospinal fluid for suspected meningitis and biopsies of liver, skin le-
sion, lymph node and less obvious sites like the synovium and vertebra may be re-
quired. An aggressive approach is often necessary since the differential diagnoses in-
clude other opportunistic infections such as disseminated aspergillosis that requires
specific therapy, and malignancies (lymphomas, Kaposi‘s sarcoma and both solid or-
gan and hemopoeitic malignancies) as these are more common in transplant recipients.
3. Isoniazid prophylaxis in solid organ transplantation
All transplant patients should receive a tuberculin skin test prior to transplantation. Ap-
proximately 70% have negative reactions but those that are positive are at greater risk.
The recommendations for INH chemoprophylaxis in renal and heart transplant recipi-
ents are described below. These recommendations are based on the fact that these
patients do not appear to be at a higher risk of developing isoniazid hepatotoxicity than
the general population, that the case fatality rate for transplant recipients is almost
30%, and that in a further similar proportion the allograft is rejected. These dire conse-
quences of untreated dormant disease argue for chemoprophylaxis, at least in low-
prevalence areas.

184
BOX 13.4. Indications of isoniazid prophylaxis for solid organ transplant recipi-
ents49
1. Tuberculin reactivity > 5mm before transplantation.
2. Patients with the following characteristics regardless of reactivity:
 Radiographic evidence of old TB and no prior prophylaxis;
 History of inadequately treated TB;
 Close contact with an infectious patient; and
 Recipient of an allograft from a donor with a history of untreated TB
or tuberculin reactivity without adequate prophylaxis.
3. Newly infected persons (recent conversion of tuberculin test to positive).

Tuberculosis following gastrectomy

After gastrectomy bypass surgery, there is a loss of protective effects of acid gastric
secretions on ingested mycobacteria, and development of malnutrition resulting from
malabsorption associated with intestinal bypass surgery. However, malabsorption may
also play a role after gastrectomy as symptoms of severe dumping have been reported
to be more common in patients who developed TB and most such patients had low
BMI.78,79 The incidence of TB following gastrectomy varied (1.7% to 12.3%) in 12 re-
ported studies during 1948 to 1977, but in the three largest series the incidence was
only 1.7-2.5%.80 In Japan a high incidence of gastrectomy was performed for treat-
ment of gastric carcinoma, 9.1% of cases of TB reported over a 3-year period had a
history of gastric resection.79
1. Management
In view of the potential postoperative risk of TB it is advisable, although not based on
the results of prospective trials, to obtain a full history of previous TB and Bacillus
Calmette-Guerin (BCG) vaccination, and to perform a chest radiograph. INH chemo-
prophylaxis should be considered for untreated patients with radio- graphic evidence of
previous TB and those with a strongly positive TST but surgery need not be delayed
unless TB is confirmed. The presence of a low BMI or poor nutritional status strength-
ens the indication for chemoprophylaxis.
After gastrectomy, patients require regular follow-up with attention to the presence of
complications associated with risk of TB – dumping syndrome, malnutrition, fistula for-
mation and recurrence of tumour within the gastric remnant. Symptoms such as sweat-
ing and weight loss may be attributed to dumping, but alertness should be maintained,
as these could also be due to TB. A further consideration in patients with malabsorp-
tion is whether, when treated for TB, therapeutic drug monitoring is necessary to en-
sure that adequate levels of mycobactericidal drugs are achieved.

Tuberculosis following jejunoileal bypass surgery

Jejunoileal bypass surgery has been used to effect weight loss in patients refractory to
non-surgical methods. There are numerous case reports of patients undergoing this
form of surgery developing TB postoperatively, and it is estimated that between 0.3%

185
and 0.4% of patients who have undergone this form of surgery (with most of whom re-
siding in countries with a low incidence of TB) develop TB. Tuberculosis following jeju-
noileostomy is usually extrapulmonary: 82% in one series.81 In a small case series of
seven cases, the mean interval between surgery and the diagnosis of TB was 16
months.82 Initial symptoms included fever and rapid weight loss. Weight loss is often
observed as a second period of decline after stabilization of the initial phase of weight
loss resulting from the bypass surgery.81
1. Management
Chest radiography and TST should be performed on all patients being considered for
bypass surgery.82 Tuberculous chemoprophylaxis is advised for patients with a positive
TST response measuring 10 mm or more prior to surgery, which should be delayed for
at least 6 months. As for patients with TB following gastrectomy, therapeutic drug moni-
toring should be performed because drug absorption in patients following jejunoileal
bypass surgery is often unpredictable.
Tumor necrosis factor-a (TNF-A)49 is a pro-inflammatory cytokine that exists in trans-
membrane and soluble forms and acts as a ligand that stimulates apoptosis. Through
its receptor binding, particularly to receptor TNFR1, it is involved in host defenses
against intracellular organisms like MTB, by enhancing intracellular killing and stimulat-
ing granuloma formation, thereby limiting dissemination. However, excessive produc-
tion of TNF-a can have detrimental effects, including the development of caseous ne-
crosis and excessive wasting in patients with TB. The most extensively studied anti-
TNF-a agents are infliximab, etanercept and adalimumab.
Infliximab is a humanized murine chimeric monoclonal antibody with high bind
ing affinity and specificity for TNF-a that forms stable complexes with monomer
ic and trimeric forms of TNF-a, crosslinking between molecules. It also binds to
transmembrane TNF-a. Infliximab is administered as an intravenous infusion at
weeks 0 and 2 of therapy followed by an infusion every 8 weeks. Its half-life is
10.5 days. It can be used for treatment of rheumatoid arthritis, Crohn‘s disease,
ankylosing spondylitis and psoriatic arthritis.
Etanercept is a dimeric fusion protein that forms less stable complexes with
monomeric and membrane bound TNF, but binds well to trimeric TNF-a and
forms stable complexes with TNF-b. It is given twice weekly as a subcutaneous
injection and has a shorter half-life of approximately 3 days.
a. Epidemiology of anti-TNF therapy and tuberculosis
The association between anti-TNF treatment and increased risk of TB was first ob-
served in post-approval pharmacovigilance data from patients with rheumatoid arthritis
and other autoimmune conditions treated with these agents. This was later confirmed
by information gathered by the Spanish Society of Rheumatology. It appears that when
used in countries other than the USA, the risk is positively associated with the preva-
lence of TB in the general population. The onset of TB is earlier with infliximab than
with etanercept, and dissemination is common. Reactivation of latent TB infection
(LTBI) rather than reinfection is often the suspected cause of disease.86

186
The Food and Drug Administration has estimated that in the USA, the age-adjusted in-
cidence of TB in all patients exposed to anti-TNF-a agents is 8.2 cases per 100,000
patient years of exposure. The British Thoracic Society estimates that the risk of TB in
patients with rheumatoid arthritis treated with infliximab is increased five-fold.80 Com-
parisons of the rates of developing TB with these two agents should be interpreted with
caution as these are influenced by the medical indication for which the agent was giv-
en, duration of treatment, concurrent therapy and other risk factors for TB. However, it
appears that the risk is higher with infliximab than with etanercept given these limita-
tions of interpretation.
b. Assessment of patients being considered for Anti-TNF-a treatment
Risk assessment for TB infection should be performed in a patient eligible for anti-TNF-
a therapy comprising a history, physical examination, chest radiology and tuberculin
skin test.
Patients should be questioned on their TB history including BCG vaccination, results of
previous TST, previous treatment for TB and outcome of treatment. When anti-TNF-a
treatment is commenced, inquiry into symptoms of TB should be made at each visit,
and features of TB, including extrathoracic manifestations – nodes, organomegaly and
abdominal ascites – which occur in over 50% of cases, should be sought.
Chest radiography
The chest radiograph is part of the minimum requirement in the work-up of patients for
therapy as there is evidence that TST alone, even when steroid therapy is stopped a
week prior to skin testing, may not be sufficiently sensitive to identify latent TB in the
target group of patients (rheumatoid arthritis, spondyloarthropathies and patients with
inflammatory bowel disease).85 However, as the chest radiograph will be normal in
most patients with LTBI, it has limited usefulness as a screening test. Three outcomes
with the radiographic investigation can potentially be expected.

 Normal chest radiograph—The action in these cases needs to be determined in

conjunction with the TST. The utility of the TST in patients on immunosuppression
and previous BCG vaccination is discussed below.

 Abnormal radiograph suggesting active tuberculosis—If abnormalities suggest ac-

tive TB, the patient should be referred for treatment, and use of anti-TNF treatment
delayed until it is completed.

 Abnormal radiograph suggesting previous tuberculosis

 Previous adequate treatment: If the radiograph is consistent with previous
TB and the patient has received adequate treatment for TB as judged by a
thoracic physician, they can commence anti-TNF treatment but should be
monitored clinically every 3 months and chest radiography and sputum cul-
tures performed if respiratory symptoms develop.

 Previous inadequate or no treatment: The risk of active disease in this group

is high and patients should be appropriately investigated by a thoracic physi-
cian for possible active disease. Even if active disease is excluded, there
187
 remains a high annual risk of reactivation and the risk–benefit in this group
strongly favors tuberculous chemoprophylaxis before anti-TNF is com-
menced.
Tuberculin skin testing
Assessment for LTBI is recommended for all patients prior to commencement of anti-
TNF agents. The TST is the standard test proposed for this purpose. However, false-
positive reactions may be attributable to exposure to non-tuberculous mycobacteria or
BCG vaccination in childhood. False-negatives are also not uncommon in the diseases
for which anti-TNF is indicated. Anergy was present in 83% of patients with inflammato-
ry bowel disease receiving corticosteroids with or without other immunosuppressive
therapy.83 For this reason, some recommend that TST not be performed on patients
already on immunosuppressive therapy.84 In view of these limitations associated with
TST, the potential role of IGRA in identifying patients with LTBI is being actively investi-
gated, but firm recommendations are awaited.
c. Tuberculosis chemoprophylaxis for patients receiving anti-TNF-a therapy49
Two regimens have been proposed:
 isoniazid for 6 months (6H) (although 9 months is recommended in some guide-
lines, this is associated with an increased risk of hepatotoxicity); and

 rifampicin plus isoniazid for 3 months (3RH). This approach is thought to be associ-
ated with better adherence, but a disadvantage is the higher rate of drug-induced
hepatitis in the face of co-administration of other potentially hepatotoxic immuno-
suppressive drugs.
Liver function testing (aminotransferases) is recommended at the start of chemopro-
phylaxis and should be monitored at least every 3 months. If the regimen contains ri-
fampicin, the dose of prednisone (if in use) will need to be doubled. In patients with a
normal chest radiograph and who are not tuberculin test-assessable (because of con-
current immunosuppressive therapy), it may be started at the same time as chemopro-
phylaxis. However, a pragmatic approach is, when possible, to defer anti-TNF-a treat-
ment until chemoprophylaxis is complete.
d. Management of TB in patients on anti-TNF-a therapy
Current evidence suggests that patients who are currently receiving anti-TNF-a therapy
should also receive full standard anti-TB chemotherapy. In this situation, where a pa-
tient is already on anti-TNF-a therapy and withdrawal might place them at risk of dis-
ease deterioration, the patient may continue therapy provided that there is satisfactory
evidence of response to TB treatment.

MOST COMMON ADVERSE DRUG EFFECTS1,48 49

The World Health Organization (WHO) classifies side effects of anti-TB drugs as minor
or major. Patients experiencing minor side effects can usually continue the same treat-

188
ment; in those with major side effects the relevant drug should be stopped and usually
the patient needs hospitalization.
Factors influencing side effects of anti-TB treatment: age, HIV infection, alcohol and
substance abuse, nutritional status and diabetes. Old age is a risk factor for hepatotoxic
side effects of anti-TB treatment. The toxic effects of aminoglycosides on kidney func-
tion, balance and hearing are more frequent in old age. A serious concern in young
children is that they may be unable to communicate with caregivers regarding sensory
side effects such as reduced hearing (aminoglycosides), vision (ethambutol, isoniazid)
or peripheral neuropathy (isoniazid). Similar logic applies to a certain extent in the treat-
ment of pregnant women, since one will be unable to assess the occurrence of side
effects in the fetus. The main problem with alcoholic TB patients is ensuring treatment
compliance. Patients consuming significant quantities of alcohol may be more prone to
side effects, such as hepatitis. In the event of worsening liver function on anti-TB treat-
ment, it may be challenging to diagnose whether the liver damage is due to alcohol or a
result of anti-TB drug-induced hepatotoxicity. Malnutrition and particularly vitamin defi-
ciencies may increase the risk of side effects of anti-TB treatment. Most notably, lack of
B vitamins, such as pyridoxine, increases the risk of peripheral neuropathy, and proba-
bly also other neurological side effects. Visual impairment, renal failure and peripheral
neuropathy are common complications in patients with diabetes. Diabetic renal failure
may increase the risk of renal failure as a side effect of anti-TB therapy. Ethambutol-
induced optic neuritis may be more difficult to detect in a patient with diabetic retinopa-
thy. The consequences of even modest visual reduction due to ethambutol have great-
er significance if vision is already impaired by diabetic complications.
Symptom-based approach to managing minor and major side effects of anti-TB
drugs49
Table 13.1 Minor side effects
Symptom Drugs Management
Minor gastrointestinal up- Pyrazinamide, rifampicin Continue anti-TB drugs,
set, anorexia, nausea, check doses.
abdominal pain
Give drugs with small
meal or just before going
Joint pains Pyrazinamide Aspirin
Non-steroidal anti-
inflammatory drugs
Burning sensation in the Isoniazid Pyridoxine 100 mg daily
Orange/red urine Rifampicin Harmless
Reassurance
Inform patient at start of
treatment

189
Table 13.2 Major side effects
Symptom Drugs Management
Itching, skin rash Thioacetazone Stop anti-TB drugs
(streptomycin, isoniazid,
rifampicin, pyrazinamide)
Deafness (no earwax on Streptomycin Stop streptomycin and
otoscopy) give ethambutol instead.
Dizziness, vertigo, nystag- Drug: Streptomycin Stop streptomycin, use
mus ethambutol.
Jaundice (other causes Isoniazid, pyrazinamide, Stop anti-TB drugs
excluded), hepatitis Strep- rifampicin
tomycin
Confusion Most anti-TB drugs Stop anti-TB drugs.
Suspect acute liver failure
if jaundice is present.
Urgent liver function test
and prothrombin time
Visual impairment (other Ethambutol Stop ethambutol
causes excluded)
Shock, purpura, acute re- Rifampicin Stop rifampicin
nal failure

Dermatologic Adverse Effects

All drugs used in treating tuberculosis can cause a rash. The response to a patient with
a rash depends on its severity.
Minor rash
a) The rash may be minor, affecting a limited area or being predominantly manifested
as itching, or flushing with or without a rash. These usually involves the face and scalp;
may cause redness/watering of the eyes. It usually occurs 2-3 hours after drug inges-
tion. Causative agents are rifampicin and pyrazinamide. In which case antihistamines
diphenhydramine, chlorpheniramine, loratadine should be given for symptomatic relief,
but all antituberculosis medications can be continued.
b) Flushing and/or itching of the skin with or without a rash PLUS hot flashes, palpita-
tions, headache and/or increased blood pressure. It occurs immediately after ingestion
of tyramine-containing foods (cheese, red wine) or certain fish (tuna,skipjack). It usual-
ly resolves within 2 hours. Advise patient not to ingest foods listed above while receiv-
ing INH.48
Petechial rash
A petechial rash may suggest thrombocytopenia in patients taking RIF. The platelet
count should be checked and, if low, RIF hypersensitivity should be presumed to be
the cause. RIF should be stopped and the platelet count monitored until it returns to
baseline; RIF should not be restarted. 1

190
Generalized erythematous rash
a) If there is a generalized erythematous rash, especially if it is associated with fever
and/or mucous membrane involvement, all drugs should be stopped immediately. If the
patient has severe tuberculosis, three new drugs (e.g., an aminoglycoside and two oral
agents) should be started. When the rash is substantially improved the medications can
be restarted one by one, at intervals of 2–3 days. RIF should be restarted first (because
it is the least likely to cause rash, and it is the most important agent), followed by INH,
and then EMB or PZA. If the rash recurs the last drug added should be stopped. If no
rash appears after the first three drugs have been restarted, the fourth drug should not
be restarted unless the rash was relatively mild and the fourth drug is considered es-
sential for therapy. 1
If a reaction occurs during drug rechallenge (see rechallenge dose table under Hepati-
tis) and the causative drug cannot be discontinued, refer to specialist for drug desensiti-
zation. Drug desensitization should not be attempted with severe skin reactions or
those involving the mouth or mucous membranes (e.g. exfoliative dermatitis and Ste-
vens- JohnsonSyndrome).48

Gastrointestinal upset: nausea, vomiting, and diarrhea, hepatitis

Gastrointestinal reactions are common, particularly in the first few weeks of therapy.
Many of the anti-tuberculosis drugs can cause gastrointestinal upset.
Nausea/ Vomiting48
Table 13.3 Causative Agents: Ranked by frequency
+++++ Clofazimine, ethionamide, para-aminosalicylic acid (PAS)
++++ Rifampin
+++ rifabutin, isoniazid (twice and thrice weekly dosing)
++ ethambutol, pyrazinamide, ofloxacin, levofloxacin
+ isoniazid, rifapentine, cycloserine, aminoglycosides*, capreomycin*

*Although nausea and vomiting are uncommon adverse effects of the aminoglycosides
(streptomycin, amikacin, kanamycin) and capreomycin, it may be an indication of vestibular tox-
icity (inner-ear toxicity). If this occurs, contact a TB Control physician.

1. Rule out other causes of nausea and vomiting

The following are questions to ask: Examine how the medication is being administered:
 Is the medication being administered as a liquid? Administration of large volumes
may cause vomiting because of the limited stomach capacity in infants and chil-
dren. If this is the cause, the child usually vomits immediately after medication ad-
ministration.
 Is child gagging when medicine is administered? Children frequently ―gag‖ to avoid
taking medicine. Administration of medication through a syringe is the best method
to avoid ―gagging.‖

191
 Does the child take the medicine on an empty stomach? If so, give medications af-
ter meals (e.g. ask school nurse to administer medications after lunch).
Management
Food and drug administration
Isoniazid and rifampin should be administered 1 hour before or 2 hours after food in-
gestion for maximum drug absorption. If nausea and/or vomiting occurs, administer iso-
niazid and rifampin with food (better to give the drug with food and have some de-
creased absorption than to not have the patient ingest the drug at all because of the
side effect). All other TB medications can be administered without regard to food. Op-
tions for patients who cannot swallow tablets and capsules (some adults and infants/
children)

 Liquid preparations
 Availability: Isoniazid is the only commercially available liquid product. Ri-
fampin and pyrazinamide suspensions can be prepared from the tablets/
capsules. Ethambutol suspensions cannot be prepared because of drug
stability problems
 Limitations of liquid preparations: The volume of the liquid required for each
dose may be too large for the patient to tolerate (especially in infants and
children). Diarrhea may occur due to the lactose and sucrose content in liq-
uid preparations. Prepared suspensions have limited stability and some sus-
pension are not palatable (bitter tasting)

 Crushing capsules and tablets

 This is preferred to administration of liquid formulations because the admin-
istration of a large volume of liquid to children is avoided and drug stability is
not an issue.
 Procedure: Open and empty capsule contents into mortar, place tablets in
the mortar and crush to a fine powder with a pestle (or other suitable con-
tainer and ―crusher‖ if mortar and pestle are not available). Mix the powder
with a pleasant tasting substance to mask the taste of the pills i.e.
juice, flavored syrup (e.g. cherry), applesauce ice cream, chocolate syrup
(seems to mask bitter tastes well). Administer immediately after mixing with
a spoon, medication cup or syringe if the mixture does not taste good and is
rejected by the patient, continue to mix medications with different substanc-
es until an acceptable mixture is found (especially with children)
2. Consider measuring liver function tests to rule out drug induced hepatic dys-
function
In the presence of gastrointestinal symptoms, serum AST and bilirubin should be meas-
ured. If the AST level is less than three times the upper limit of normal, the symptoms
are assumed not to be due to hepatic toxicity. However, if the AST level is three or
more times the upper limit of normal, the symptoms should be assumed to represent
hepatic toxicity, and the patient should be evaluated as described below.

192
The initial approach to gastrointestinal intolerance, not associated with hepatic toxicity,
is to change the hour of drug administration and/or to administer the drugs with food. If
patients are taking daily DOT, the timing of the drug administration should be altered,
preferably to be closer to meal time. Alternatively, food can be taken at the time of DOT
administration. (In many programs food is offered as an incentive with DOT.) Patients
receiving self-administered therapy can take the medications at bedtime. If gastrointes-
tinal intolerance persists, it may be best for all medications to be taken with meals.1
Diarrhea
Table 13.4 Causative Agents: Ranked by frequency
+++++ Clofazimine, ethionamide, para-aminosalicylic acid (PAS)
+++ Rifampin
++ rifabutin, ofloxacin, levofloxacin
+ isoniazid, ethambutol, pyrazinamide, rifapentine, cycloserine, amino-
glycosides, capreomycin

1. Management
Withhold drugs until diarrhea resolves. Then, restart drugs one at a time every 4 days
beginning with drugs that are least likely to cause diarrhea. If the patient was receiving
a twice or thrice weekly regimen when the diarrhea began, consider switching to a 5x/
week regimen. If diarrhea recurs when one particular drug is added to the regimen,
consider discontinuing the causative agent and adding other TB drugs and/or extend-
ing the duration of treatment. If diarrhea occurs with multiple drugs, consider separat-
ing medication administration times. Different drugs in the regimen should be adminis-
tered several hours apart. Do not split doses for individual drugs (possible exceptions:
ethionamide, ofloxacin). For example: administer INH 200mg in the morning and rifam-
pin 300mg in the evening. If diarrhea continues and an alternate regimen cannot be
utilized consider the addition of an anti-motility agent (loperamide). Adsorbents (kaolin-
pectin, polycarbophil) should not be prescribed because decreased absorption of the
TB drugs may occur.
Hepatitis
Hepatitis is not a common adverse effect in children on anti-TB treatment, but is proba-
bly the most serious. Three of the first-line anti-tuberculosis drugs, INH, RIF, and PZA,
can cause drug-induced liver injury (AST level three or more times the upper limit of
normal in the presence of symptoms, or five or more times the upper limit of normal in
the absence of symptoms).
If the AST level is less than 5 times the upper limit of normal, toxicity can be considered
mild; an AST level 5--10 times normal defines moderate toxicity; and an AST level
greater than 10 times normal (i.e., greater than 500 IU) is severe. In addition to AST
elevation, occasionally there are disproportionate increases in bilirubin and alkaline
phosphatase. This pattern is more consistent with rifampin hepatotoxicity.

193
 Clinical Presentation
 Symptoms: nausea, vomiting, abdominal tenderness, discomfort near the ribs on
the right upper abdomen, jaundice (yellowing of skin and whites of the eyes)
 Signs: hepatic enlargement, increased liver function tests (LFTs)
2. Causative Agent
 INH + Rifampin > INH alone >> pyrazinamide* alone > rifampin alone > ethiona-
mide
*Early reports of pyrazinamide hepatotoxicity occurred in patients who received 40-50mg/kg/d
for prolonged periods. Hepatotoxicity has not been reported with extensive use of lower doses
(15-30mg/kg/d) in short course regimens.

3. Management
a. Asymptomatic patients with an increase in LFTs from baselines
It is important to note that an asymptomatic increase in AST concentration occurs in
nearly 20% of patients treated with the standard four drug regimen. In the absence of
symptoms therapy should not be altered because of modest asymptomatic elevations
of AST, but the frequency of clinical and laboratory monitoring should be increased. In
most patients, asymptomatic aminotransferase elevations resolve spontaneously.
However, if AST levels are more than five times the upper limit of normal (with or with-
out symptoms) or more than three times normal in the presence of symptoms, hepato-
toxic drugs should be stopped immediately and the patient evaluated carefully. Similar-
ly, a significant increase in bilirubin and/or alkaline phosphatase is cause for a prompt
evaluation. Serologic testing for hepatitis A, B, and C should be performed and the pa-
tient questioned carefully regarding symptoms suggestive of biliary tract disease and
exposures to other potential hepatotoxins, particularly alcohol and hepatotoxic medica-
tions. Drug-induced hepatitis is usually a diagnosis of exclusion but in view of the fre-
quency with which other possible causes are present in any given patient, determining
the cause may be difficult.
Because the schedule for restarting anti-tuberculosis medications is slower with hepati-
tis than for rash or drug fever it is generally prudent to give at least three non-
hepatotoxic anti-tuberculosis drugs until the specific cause of hepatotoxicity can be de-
termined and an appropriate longer term regimen begun.
The suspect anti-tuberculosis medications should be restarted one at a time after the
AST concentration returns to less than two times the upper limit of normal. (In patients
with elevated baseline AST from preexisting liver disease, drugs should be restarted
when the AST returns to near baseline levels.) Because RIF is much less likely to
cause hepatotoxicity than is INH or PZA, and is the most effective agent, it should be
restarted first. If there is no increase in AST after about 1 week, INH may be restarted.
PZA can be started 1 week after INH if AST does not increase. If symptoms recur or
AST increases, the last drug added should be stopped. If RIF and INH are tolerated,
and hepatitis was severe, PZA should be assumed to be responsible and should be
discontinued. In this last circumstance, depending on the number of doses of PZA tak-
en, severity of disease, and bacteriological status, therapy might be extended to 9
months.

194
b. Symptomatic patients
Hold all drugs and obtain Liver Function Tests (LFTs). If LFTs are within normal ranges,
refer to the Management of Nausea/Vomiting section. If LFTs are elevated, hold drugs
until symptoms resolve and the transaminases decreases to < 2x normal. Ethambutol
and pyrazinamide should be started if drug therapy cannot be held secondary to the
patient‘s clinical condition. Use streptomycin if pyrazinamide is suspected to be the
cause of hepatotoxicity.
Rechallenge the patient after resolution of signs and symptoms by adding drugs to the
regimen every 4 days: (See Drug Rechallenge Initial Drug Dose below). Start Rifampin
for 3 days, if patient remains asymptomatic, then add INH for 3 days; if patient remains
asymptomatic, then add pyrazinamide (Initial dose 15-20mg/kg/d) for 3 days.
c. Timing of reintroduction of anti-tuberculosis drugs
If blood tests for assessing the liver function are available, reintroduction of anti-TB
drugs can be started as soon as the liver tests have normalized. However, in many high
-burden settings, laboratory testing facilities are scarce and liver function testing may
not be possible. In these situations, treatment will be guided by the symptoms. Usually,
jaundice and other symptoms will subside in 1 to 2 weeks. The WHO recommends that
the regular anti-TB drugs be reintroduced 2 weeks after jaundice has disappeared.
If signs and symptoms recur with rechallenge, discontinue the responsible drug and
modify the regimen and/or duration of therapy as required.
BOX 13.5 Drug Rechallenge Protocol: Sequence of reintroduction of antitubercu-
losis drugs
Drug sequence (Initial Dose Day 1): Likelihood of drug causing the reaction
INH (50mg): +
RIF (75mg): ++
PZA (250): +++
EMB(100mg): +
SMZ(125mg): ++

Drug fever
Recurrence of fever in a patient who has been receiving therapy for several weeks
should suggest drug fever, especially if the patient is showing microbiological and radi-
ographic improvement. It should be noted, however, that fever from tuberculosis may
persist for as long as 2 months after therapy has been initiated. Fever may also be a
manifestation of a paradoxical reaction, especially in patients with HIV infection The
clinical hallmark of drug fever is that the patient looks and feels well despite having a
high fever (often greater than 39°C). There is no specific pattern to the fever. Eosino-
philia may or may not be present.
The first step in management of a possible drug fever is to ensure that there is no su-
perinfection or worsening of tuberculosis. If these potential causes are excluded all
drugs should be stopped. Drug-related fever usually will resolve within 24 hours. Pa-
tients with severe tuberculosis should be given at least three new drugs in the interim.
195
Once the fever has resolved, the same protocol as described above for restarting drugs
in the presence of a rash should be followed.
Miscellaneous Adverse Effects
1. Arthalgias (joint pain)
 Symptoms: Pain and tenderness of joints, fingers, shoulders, knees, etc. (usually
mild)
 Causative Agents: pyrazinamide>>ethambutol>isoniazid
 Management: TB medications do not require discontinuation. Low dose non-
steroidal anti-inflammatory agents (NSAIDS) can be used for pain relief as needed.
If symptoms persist, consider referral for rheumatologic evaluation.
2. Arthalgias Type 2 (Gouty Arthritis)
 Causative Agents: pyrazinamide>>ethambutol
 Symptoms: pain, tenderness and swelling of joints: fingers, shoulders, knees, etc.
(usually severe)
 Signs: elevated serum uric acid concentrations
 Management:
 TB medications usually do not require discontinuation. If acute swelling is
present, the affected joint should be aspirated and examined for urate crys-
tals to confirm the diagnosis of acute gouty arthritis.
 Low-dose non-steroidal anti-inflammatory agents (NSAIDS) can be used for
pain relief, which includes: indomethacin, ibuprofen, and naproxen. Colchi-
cine is an alternative to NSAIDS; the dose is 0.5-1.2 mg x1, then 0.5-0.6 mg
q 1-2 hours until joint pain is relieved or nausea, vomiting or diarrhea oc-
curs. Pain usually resolves after 4-8 mg cumulative dose. Maximum dose is
8mg. A steroid may be required for severe attacks. Recurrent episodes may
occur while the patient remains on pyrazinamide or ethambutol. Consider
using prophylactic colchicine at 0.6mg one to two times daily and continue
until causative agent is discontinued. Consider referral for rheumatologic
evaluation for acute gouty arthritis attacks.
3. Influenza Syndrome
 Symptoms: fever, headache, bone pain usually occurs 1-2 hours after drug admin-
istration (usually resolves within 12 hours of drug administration)
 Causative Agents: rifampin > rifabutin (intermittent regimens > daily regimens)
 Management:
 More common with high dose (>1200mg), intermittent therapy than with dai-
ly dosing. Ιt occurs in 10% of patients receiving 600mg twice weekly and
may also occur with daily therapy when administered irregularly (e.g. in
noncompliant patients).
 Switch from intermittent therapy to daily dosing. Symptomatic therapy may
be required when switching from intermittent to daily therapy to prevent the
reaction with initial doses. Usually presents after 3-6 months of inter-
mittent therapy and 1 to 2 hours after rifampin administration. Resolution of
symptom usually occurs within 12 hours

196
4. Neurotoxicity
a. Peripheral Neuropathy
 Causative Agents: INH>>>ethambutol
 Clinical Presentation:
 Prickling, tingling or burning sensation of the fingers and/or toes
 usually occurs in a glove-and-stocking distribution.
 Management
 peripheral neuropathy rarely occurs in children unless severe malnutrition is
present
 peripheral neuropathy is uncommon if the patient is receiving pyridoxine
(vitamin B6)
 if peripheral neuropathy occurs, it can be treated with pyridoxine 100-200mg
po q daily while the patient is receiving INH.
b. Nervous System Effects in Children
 Causative Agent: INH
 Clinical Presentation: Drowsiness or hyperactivity, dizziness, tonic-clonic seizure
(rare)
 Management
 Drowsiness: Make sure the dose does not exceed 10mg/kg/day and add
pyridoxine 50mg to the regimen. Administer medications around afternoon
naps or at bedtime (e.g. administer school DOT at the end of the day so the
child can take a nap after school)
 Hyperactivity: Make sure the dose does not exceed 10mg/kg/day. Switch to
twice weekly dosing as soon as possible. If the child becomes hyperactive
only on the days of medication administration, then the medication is the
cause. Add pyridoxine 50mg daily for 6 weeks, then twice weekly for the re-
mainder of therapy.
 Dizziness: Make sure the dose does not exceed 10mg/kg/d
 Tonic/clonic seizures: Hospitalize the child and administer isoniazid to docu-
ment the reaction. If a seizure occurs, discontinue isoniazid and add an al-
ternative agent to the regimen
c. Optic Neuritis
 Causative Agents: ethambutol >>INH
 Clinical Presentation
 Blurred vision (decrease in the ―sharpness‖ of objects)
 ―spots‖ present in patient‘s field of vision
 red/green color blindness
 Management: Children with complaints of vision changes should be referred to spe-
cialist for evaluation and discontinue the drug.

197
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69. Bahceciler NN, Nuhoglu Y, Nursoy MA, et al. Inhaled corticosteroid therapy is safe
in tuberculin- positive asthmatic children. Pediatr Infect Dis J 2000; 19(3):215–218.

202
70. Bateman ED. Is tuberculosis chemoprophylaxis necessary for patients receiving
corticosteroids for respiratory disease? Respir Med 1993;87(7): 485–487.
71. Fidler H, Rook GA, Johnson NM, et al. Search for mycobacterial DNA in granulom-
atous tissues from patients with sarcoidosis using the polymerase
chain reaction. Am Rev Respir Dis 1993;147(3): 777–778.
72. Wong CF, Yew WW, Wong PC, et al. A case of concomitant tuberculosis and sar-
coidosis with mycobacterial DNA present in the sarcoid lesion. Chest 1998;114
(2):626–629.
73. Knox AJ, Wardman AG, Page RL. Tuberculous pleural effusion occurring during
corticosteroid treatment of sarcoidosis. Thorax 1986;41(8):651.
74. 74. Baughman RP, Lower EE. Fungal infections as a complication of therapy for
sarcoidosis. QJM 2005; 98(6):451–456.
75. Targeted tuberculin testing and treatment of latent tuberculosis infection. American
Thoracic Society. MMWR Recomm Rep 2000;49(RR-6):1–51.
76. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ trans-
plant recipients: impact and implications for management. Clin Infect Dis 1998;27
(5):1266–1277.
77. British Thoracic Society guidelines on diagnostic flexible bronchoscopy. Thorax
2001;56(Suppl 1): i1–21.
78. Hanngren A, Hedenstedt S, Reizenstein P. Nutritional studies in patients with
dumping syndrome. I. Subjects with postcibal symptoms. Am J Dig Dis 1967;12
(1):71–80.
79. Yokoyama T, Sato R, Rikimaru T, et al. Tuberculosis associated with gastrectomy.
J Infect Chemother 2004;10(5):299–302.
80. Snider DE Jr. Tuberculosis and gastrectomy. Chest 1985;87(4):414–415.
81. Snider DE Jr. Jejunoileal bypass for obesity: a risk factor for tuberculosis. Chest
1982;81(5):531.
82. Yu VL. Onset of tuberculosis after intestinal bypass surgery for obesity. Guidelines
for evaluation, drug prophylaxis, and treatment. Arch Surg 1977;112(10): 1235–
1237.
83. Mow WS, Abreu-Martin MT, Papadakis KA, et al. High incidence of anergy in in-
flammatory bowel disease patients limits the usefulness of PPD screening before
infliximab therapy. Clin Gastroenterol Hepatol 2004;2(4):309–313.
84. Provenzano G, Ferrante MC, Simon G. TB screening and anti-TNFa treatment.
Thorax 2005;60(7):613.

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85. Sichletidis L, Settas L, Spyratos D, et al. Tuberculosis in patients receiving anti-
TNF agents despite chemoprophylaxis. Int J Tuberc Lung Dis 2006;10(10): 1127–
1132.
86. Bieber J, Kavanaugh A. Consideration of the risk and treatment of tuberculosis in
patients who have rheumatoid arthritis and receive biologic treatments. Rheum Dis
Clin North Am 2004;30(2):257–270, v.

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 14
Adjunctive Management
Cleotilde H How, MD
Cristan Q Cabanilla, MD
Maria Nerissa A de Leon, MD
Anna Lisa T Ong-Lim, MD

OUTLINE
1 Overview

2 Corticosteroids
Anna Lisa T Ong-Lim, MD

3 Surgery
Cristan Q Cabanilla, MD
Maria Nerissa A de Leon, MD

4 Nutrition
Cleotilde H How, MD

205
OVERVIEW
There are several modalities employed in the management of tuberculosis, both phar-
macologic and non-pharmacologic: corticosteroids, surgery and nutritional support.
These have been considered to be of value in promoting healing and reducing the com-
plications and residual effects of the disease.

CORTICOSTEROIDS
The benefit of corticosteroids has been evaluated in the following forms of complicated
TB:
1. TB meningitis, where it acts by reducing vasculitis, inflammation, and intracranial
pressure, which may then lead to improved circulation of chemotherapeutic drugs
through the brain.1 Corticosteroids should be routinely used in HIV-negative pa-
tients with TB meningitis, to reduce death and residual neurologic deficit.2
2. TB pericarditis, where corticosteroids are recommended as adjunctive therapy dur-
ing the first 11 weeks of anti-tuberculosis therapy.3
3. TB pleural effusion, where a recent systematic review concludes that there is insuf-
ficient data to support routine use.4 Although steroids do not appear to reduce the
development of residual pleural thickening, some studies showed a significantly
more rapid resolution of symptoms.3
4. Endobronchial TB, where enlarged mediastinal lymph nodes cause respiratory diffi-
culty or a severe collapse-consolidation lesion in the middle or lower lobes, when
bronchiectasis is likely to be a troublesome sequela.1
In HIV-negative patients, corticosteroids may be a useful adjunct to the treatment of
tuberculosis, particularly when the host inflammatory response is contributing to tissue
damage or is impairing function.
The drug most frequently used is prednisone given 2 mg/kg daily, for 4 weeks. For the
most seriously ill children the dose may be increased to 4 mg/kg daily (maximum 60
mg/day). The dose of prednisone should be gradually tapered over 1-2 weeks before
finally being discontinued.5 In TB pericarditis, the adult dose for prednisone is 60 mg/
day given for 4 weeks, followed by 30 mg/day for 4 weeks, 15 mg/day for 2 weeks, and
5 mg/day for the last week (a total of 11 weeks). The dose for children is 1mg/kg body
weight, decreasing the dose over the treatment period as described for adults.3

206
REFERENCES
1. Cruz AT and Starke JR. 2014. Tuberculosis. In Cherry JD, Harrison GJ et al, eds.
Feigin and Cherry‘s Textbook of Pediatric Infectious Diseases 7th ed. Philadelph-
ia: Elsevier Saunders. p 1375.
2. Prasad K and MB Singh. Corticosteroids for managing tuberculous meningitis.
Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD002244.
DOI: 10.1002/14651858.CD002244.pub3)
3. Centers for Disease Control and Prevention. Treatment of Tuberculosis. American
Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR
2003;52(No. RR-11).
4. Engel ME et al. Corticosteroids for tuberculous pleurisy. Cochrane Database of
Systematic Reviews 2007, Issue 4. Art. No.: CD001876. DOI: 10.1002/14651858.
CD001876.pub2
5. World Health Organization. Treatment of Tuberculosis: Guidelines for National
Programmes. Third edition, 2003.

207
SURGERY
While the use of surgery is now rarely indicated because of the effectiveness of anti-
tuberculous drugs, there are certain conditions in which it may play a vital role in estab
-lishing the diagnosis and overall treatment of tuberculosis.
Diagnostic modality
Rapid and definitive diagnosis to facilitate early and appropriate treatment in TB has
been reported in the use of two surgical interventions, namely fine needle aspiration
biopsy and laparoscopy. Fine needle aspiration biopsy, with or without CT or ultra
-sound guidance, to obtain specimen for direct microscopy, nucleic acid amplification
test and culture has been recommended for cervical or axillary lymphadenopathy1,2,
soft tissue and bone lesion3,4and mediastinalmass5,6. Laparoscopy in suspected ab-
dominal TB has been reported in adults7-9and children10. Procedure-related complica-
tions were reported to be minimal1-6.
Treatment modality
Surgical intervention is absolutely necessary as a life-saving procedure (or as an
emergency approach, for without surgery death is imminent and unavoidable) in the
following conditions: massive hemoptysis; tension pneumothorax; pericarditis with res-
piratory or blood circulation insufficiency; intrinsic or extrinsic airway obstruction, sac-
cular bronchiectasis3,11 postmeningitic hydrocephalus12,13, tuberculoma in the lung pa-
renchyma resulting into compression3,11 or brain as a space-occupying lesion3, spinal
involvement with neurologic deficit,paravertebral abscess or instability due to kyphotic
deformity14,15,intestinal obstruction with or without perforation16,17 and hydronephro-
sis19=18. Masoud et al3 have included these other indications for surgery in TB:
Urgent approach for irreversible TB progression, despite adequate anti-TB chemo-
therapy and for recurrent haemoptysis that cannot be stopped by other treatment
methods.
Elective approach for (a) localised forms of cavitary TB with continuous Mycobacte-
rium tuberculosis excretion confirmed by bacteriological examination and DSST after 4
–6 months of supervised anti-TB chemotherapy; (b) MDR/XDR-TB characterised by
failure of anti-TB chemotherapy; (c) complications and sequelae of the TB process
(including MDR/XDR-TB) like spontaneous pneumothorax and pyopneu-mothorax;
pleural empyema with or without bronchopleural fistula; Aspergilloma; nodular–
bronchial fistula; broncholith; pachypleuritis or pericarditis with respiratory and blood
circulation insufficiency; post-TB stenosis of trachea and large bronchi; symptomatic
and chronic post-TB bronchiectasis.
For patients with drug-resistant TB, resection of the lung (as an adjuvant therapy) is
indicated for those with treatment failure.3
Marrone et al19 in a systematic review of 24 studies from 1975 to 2012 concluded that
treatment success rate was higher among patients undergoing surgery compared with
those treated with anti-TB drugs alone (OR 2.24, 95% CI1.68 – 2.97). All-cause mor-
tality is decreased by 24%. The positive effect of surgery on treatment success almost

208
doubled in the subgroup of XDR-TB patients (>400 cases, OR 4.55) compared with
MDR-TB patients (OR 2.27).
Surgery plays a limited role in the management of drug-sensitive tuberculosis and is
reserved for management of late complications, such as hydrocephalus, obstructive
uropathy, constrictive pericarditis and neurological involvement from Pott‘s disease 13.
Among patients with drug-resistant tuberculosis, surgery is most effective for patients
with localized pulmonary disease that can be completely resected. This includes pa-
tients whose sputum cultures remain positive for longer than three months despite ap-
propriate therapy, or those with isolates resistant to all of the first-line oral agents. Re-
section alone should not be considered curative; patients with multidrug-resistant TB
should continue anti-tuberculous therapy for 18 months following surgery20

209
REFERENCES
1. Coetzee L(1), Nicol MP, Jacobson R, Schubert PT, van Helden PD, Warren RM,
Wright CA.: Rapid diagnosis of pediatric mycobacterial lymphadenitis using fine
needle aspiration biopsy. Pediatr Infect Dis J. 2014;3):893-6.
2. Wright CA, Warren RM, Marais BJ. Fine needle aspiration biopsy: an undervalued
diagnostic modality in paediatric Mycobacterial disease. Int J Tuberc Lung Dis.
2009 13:1467-75
3. Masoud Dara, G Sotgiu, R Zaleskis and GB Migliori.Untreatable tuberculosis: is
surgery the answer? Eur Respir J 2015;45:577–582 DOI:
10.1183/09031936.00229514
4. Gupta S, Takhtani D, Gulati M, Khandelwal N, Gupta D, Rajwanshi A, Gupta S,Suri
S Sonographically guided fine-needle aspiration biopsy of lytic lesions of the
spine: technique and indications. J Clin Ultrasound. 1999;27:123-9.
5. Gulati M, Venkataramu NK, Gupta S, Sood BP, Sheena DM, Gupta SK, Suri S. Ul-
trasound guided fine needle aspiration biopsy in mediastinal tuberculosis. Int J Tu-
berc Lung Dis. 2000;4):1164-8.
6. Khan J), Akhtar M, von Sinner WN, Bouchama A, Bazarbashi M. CT-guided fine
needle aspiration biopsy in the diagnosis of mediastinal tuberculosis Chest.
1994;106):1329-32.
7. Guirat A), Affes N, RejabH,Trigui H, Ben Amar M, Mzali R:.[Role of laparoscopy in
the diagnosis of peritoneal tuberculosis in endemic areas Med Sante Trop. 2015
5:87-91
8. Krishnan P, Vayoth SO, Dhar P, Surendran S, Ponnambathayil S:.Laparoscopy in
suspected abdominal tuberculosis is useful as an early diagnostic method. ANZ J
Surg. 2008;78:987-9
9. Safarpor F, Aghajanzade M, Kohsari MR, Hoda S, Sarshad A, Safarpor D.: Role of
laparoscopy in the diagnosis of abdominal tuberculosis. Saudi J Gastroenterol
2007;13:133-5
10. Dinler G), Sensoy G, Helek D, Kalayci AG.: Tuberculous peritonitis in children: re-
port of nine patients and review of the literature. World J Gastroenterol.2008;14
(47):7235-9
11. Madansein R, Parida S, Padayatchi N, Singh N, Master I, Naidu K, Zumla A,
Maeurer M.: Surgical treatment of complicationsofpulmonary tuberculosis, including
drug resistant tuberculosis Int J Infect Dis. 2015 Mar;32:61-7.
12. Bajpai M, Nambhirajan L, Dave S, Gupta AK: Surgeryin tuberculosis Indian J Pedi-
atr 2000;67(2 Suppl):S53-7

210
13. Rajshekhar V: Surgery for brain tuberculosis: a review 2015 ActaNeurochir (Wien).
2015;14
14. Rasouli MR, Mirkoohi M, Vaccaro AR:Spinal Tuberculosis: Diagnosis and Manage-
mentAsian Spine J 2012;6:294~308
15. Moon MS, Kim SS, Moon YW, Moon H, Kim SS: Surgery-related complications and
sequelaein managementof tuberculosis of spine Asian Spine J. 2014;8:435-45.
16. Mukhopadhyay A, Dey R, Bhattacharya U. Abdominal tuberculosis with an acute
abdomen:our clinical experience. J ClinDiagnRes. 2014;8):NC07-9.
17. Awasthi S, Saxena M, Ahmad F, Kumar A, Dutta S.: Abdominal Tuberculosis: A Di-
agnostic Dilemma J ClinDiagn Res. 2015;9(5):EC01-3
18. Krishnamoorthy S, Gopalakrishnan G.: Surgical management of renal tuberculo-
sis.Indian J Urol. 2008;24:369-75
19. Marrone MT, V Venkataramanan, M Goodman, AC Hill, JA Jereb and SR Mase.
Surgical interventions for drug-resistant tuberculosis: a systematic review and meta
-analysis. Int J Tuberc Lung Dis 2013; 17(1):6-16
20. Schluger NW. Diagnosis, treatment, and prevention of drug-resistant tuberculosis.
In: UpToDate, C Fordham von Reyn (Ed), UpToDate, Waltham, MA. (Accessed on
27 Feb 2016).

211
NUTRITION
Overview
The interaction of nutrition and tuberculosis is important in the assessment and man-
agement of patients with tuberculosis.1,2 As a general measure in patient care, all as-
pects of therapy includes good nutritional support for patients with TB to improve out-
come of treatment and quality of life when the body is allowed to recover and normal
function restored. Children especially the young are more vulnerable than adults to TB
infection and nutritional neglect; extra care can make a difference in outcome.
Comorbidity
Undernutrition and TB are co-morbid conditions and this synergy is considered to mu-
tually impact each other adversely.1,2 Undernutrition increases the risk of TB and in turn
TB can lead to undernutrition with the underlying pathology affecting host defense. This
renders a child at risk for progression from TB infection to active disease, with in-
creased risk of poor treatment outcome, TB relapse and death.3
Nutrition
The WHO guideline1 aims to help improve health outcomes for people with TB, through
improved nutritional care and support. It provides guidance on nutritional assessment,
advice and treatment, and its integration into clinical care for people with TB. The guid-
ing principles and recommendations focus on nutrition assessment, counselling and
management to improve the clinical care of people with TB. Considered an essential
part of services for people with TB they can be adapted according to disease burden,
health-care infrastructure, including human resources.
Resource gap
Access of communities to adequate food supply and medical services and goods (e.g.
anti-TB drugs) has to be assured particularly in high- burden low-resource areas as
part of their regular TB care package. With the intensive global effort to improve TB di-
agnosis, treatment and control, TB prevalence and death rates have been reduced in
many countries where national TB programmes had been vigorous in their campaigns.
Still, in many other countries the incidence of TB is declining at a slow pace4 and TB
remains a major public health threat where resources are limited and the attendant
poverty and disease are aggravating factors.3
Barriers
There are barriers to the diagnosis of tuberculosis5 in common with undernutrition that
includes ignorance, fear, mistrust, shame. One of the six symptoms that should arouse
suspicion of TB in a young child with unexplained cough and fever is weight loss or fail-
ure to gain weight. It should trigger further clinical assessment of possible TB and se-
verity of nutritional deficiency for prompt intervention.6,7
Weight loss
Weight loss is a red flag that draws attention towards case-finding. Among children at
risk for TB faltering weight can be from poor intake of adequate amounts of food that
will provide the essential macronutrients and micronutrients. This can be due to loss of
appetite and metabolic changes attendant to the disease process. The resultant low

212
body mass index (BMI) (<18.5 kg/m2) and poor weight gain/weight loss is an important
parameter not only for diagnosis but for assessment of severity and for monitoring re-
sponse to treatment and for prognostication. A low value is associated with an in-
creased risk of death.8
Monitoring growth
The CDC recommends that the WHO growth charts be used to monitor the growth of
infants and children ages 0 to 2 years (in the US) and the CDC growth charts to monitor
growth for children age 2 years and older (in the US)9. The WHO BMI-for-age-and-sex
Z-score is used in children and adolescents aged 5–19 years. Weight-for-length or
weight-for-height Z-score is the recommended indicator for children who are less than 5
years of age, with midupper arm circumference being used to identify cases in need of
life-saving nutrition management.10 The PPS Preventive Pediatric Health Care Hand-
book (2016) has the BMI for age of boys and girls 2 to 5 years, and 5 to 19 years, to
provide a handy tool for monitoring growth. It also gives the weight for age, height for
age, and weight for length/height.11-14
Evidence for supplementation
The available literature cited in the WHO publication1 show that the evidence on the
clinical benefits for supplementation in patients with TB is insufficient. The standard of
care in the field – prescribing or providing nutritional support - is still the accepted norm.
The required dietary energy from macronutrients (e.g. protein, carbohydrate and fat), ,
is similar for people with active TB and for those without TB. It generally follows a rec-
ommended distribution that all people consume approximately 15–30% of energy as
protein,25–35% as fat and 45–65% as carbohydrate.15
Coping in disasters
In countries often visited by disasters, victims - particularly the children- are at risk for
catastrophic illnesses that come with food deprivation, interrupted health services
(including immunizations, nutrition programs, DOTS services) and the harsh physical
conditions with displacement from home and shelters, brought on by floods, typhoons
and earthquakes. In the section on TB during disasters the DOH Manual of Proce-
dures16 provides instructions following disaster situations ―to re-establish TB services to
reduce mortality and morbidity due to interrupted treatment arising from lack of follow-
up, drugs, facilities, and human resource‖. There are strategies to achieve this objective
and the algorithm to ensure that all existing TB patients can resume treatment after the
acute relief operations.
Integration
Patients with TB should be assessed regularly and receive advice and support ensuring
adequate nutrition particularly for children with a chronic debilitating illness like TB is
necessary for a holistic approach17,18. Children with TB and severe undernutrition will
be an extreme challenge requiring skills in a multidisciplinary and comprehensive ap-
proach, as provided in guidelines for child TB6,7. TB care can be integrated with other
services like maternal and child health services, nutrition and immunization programs.
There are still many aspects in the nutritional support of patients with TB that can im-
prove the outcome of treatment.19-22

213
REFERENCES
1. Guideline: Nutritional care and support for patients with tuberculosis. Geneva:
World Health Organization; 2013.
2. Scoping meeting for the development of guidelines on nutritional/food support to
prevent TB and improve health status among TB patients. Meeting report, Geneva,
2–4 November 2009. Geneva: World Health Organization; 2010 (http://
www.who.int/nutrition/publications/nutandtb_meeting_report/en/index.html, ac-
cessed 10 August 2016).
3. Hood MLH. A narrative review of recent progress in understanding the relationship
between tuberculosis and protein energy malnutrition. Eur J Clin Nutr.
2013;67:1122-1128; doi:10.1038/ejcn.2013.1432.
4. WHO Global tuberculosis report 2015 (WHO/HTM/TB/2015.22) (https://www.health
-e.org. accessed 10 August2016)
5. Chiang SS, Roche S, Contreras C, Alarcὀn V, del Castillo H, Becerra MC. Barriers
to the diagnosis of childhood tuberculosis: a qualitative study. Intl J TB Lung Dis.
2015;1144-52.
6. Guidance for national tuberculosis programmes on the management of tuberculosis
in children. Geneva, World Health Organization, 2014. (WHO/HTM/TB/2014.03).
7. Tuberculosis in Infancy and Childhood. Philippine Pediatric Society, 2016.
8. Zachariah R, Spielmann MP, Harries AD, Salaniponi FM. Moderate to severe mal-
nutrition in patients with tuberculosis is a risk factor associated with early death.
Trans. R. Soc. Trop. Med. Hyg. 2002;96:291–4. www.ncbi.nlm.gov/
pubmed/12174782.
9. CDC growth charts for the United States: methods and development.ISBN 0-8406-
0575-7 www.cdc.gov/growthcharts/cdc_charts.htm, accessed 10 August2016
10. World Health Organization. Growth reference data for 5–19 years (http://
www.who.int/growthref/en/, accessed 10 August2016).
11. PPS Preventive Pediatric Health Care Handbook. Philippine Pediatric Society,
2016.
12. World Health Organization, United Nations Children‘s Fund. WHO child growth
standards and the identification of severe acute malnutrition in infants and children.
A joint statement by the World Health Organization and the United Nations Chil-
dren‘s Fund. Geneva: World Health Organization and United Nations Children‘s
Fund; 2009 (http://www.who.int/nutrition/publications/
severemalnutrition/9789241598163_eng.pdf, accessed 10 August 2016).
13. World Health Organization. The WHO child growth standards (http://www.who.int/

214
 childgrowth/en/, accessed 10 August 2016).
14. Physical status: the use and interpretation of anthropometry. Report of a WHO Ex-
pert Committee. Geneva: World Health Organization; 1995 (WHO Technical Report
Series 854) (http://www.who.int/childgrowth/publications/physical_status/en/, ac-
cessed 10 August 2013).
15. Institute of Medicine. Dietary reference intakes for energy, carbohydrate, fiber, fat,
fatty acids, cholesterol, protein, and amino acids. Washington, DC: National Acade-
mies Press; 2005. (In: Guideline: Nutritional care and support for patients with tu-
berculosis. Geneva: World Health Organization; 2013).
16. Manual of Procedures of the National Tuberculosis Program (5th edition). Depart-
ment of Health, 2014.
17. Guideline: Updates on the management of severe acute malnutrition in infants and
children. Geneva: World Health Organization; 2013.
18. Management of severe malnutrition: a manual for physicians and other senior
health workers. Geneva: World Health Organization; 1999 (http://www.who.int/
nutrition/publications/severemalnutrition/9241545119/en, accessed 10 August2016)
19. Papathakis P, Piwoz E. Nutrition and tuberculosis: a review of the literature and
considerations for TB control programs. USAID/Africa‘s Health for 2010. Washing-
ton DC: Agency for International Development; 2008 (http://pdf.usaid.gov/pdf_docs/
PNADL992.pdf.
20. Dodor E. Evaluation of nutritional status of new tuberculosis patients at the Effia-
Nkwanta regional hospital. Ghana Med. J. 2008;42(1): 22–8 (http://
www.ncbi.nlm.nih.gov/pmc/articles/PMC2423338..
21. Ramakrishnan CV, Rajendran K, Jacob PG, Fox W, Radhakrishna S. The role of
diet in the treatment of pulmonary tuberculosis. An evaluation in a controlled chem-
otherapy study in home and sanatorium patients in South India. Bull. World Health
Organ. 1961;25:39–59 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2555577/pdf/
bullwho00319-0062.pdf, 60.
22. Paton NI, Chua YK, Earnest A, Chee CB. Randomized controlled trial of nutritional
supplementation in patients with newly diagnosed tuberculosis and wasting. Am. J.
Clin. Nutr. 2004;80:460–5.

215
 15
Prevention and Control
Josefina C Carlos, MD
Luis T Chan, Jr, MD
Ana Liza H Duran, MD

OUTLINE
1 Overview

2 Surveillance

3 Containment

4 TB Infection Control Measures

216
OVERVIEW
Control of TB is based on the principles of surveillance and containment. Surveillance
is mainly concerned with case finding of TB and monitoring of cases, while contain-
ment involves treatment and prevention.1 TB control is a continuing process of collect-
ing, analyzing, interpreting and disseminating information about trends in disease and
infection with the ultimate goal of significantly reducing the burden of TB in the com-
munity.
The three basic strategies critical to the prevention and control of TB, in order of prior-
ity2:
1. Case finding with appropriate therapy
2. Contact tracing of exposed individuals for presence of infection or disease
3. Testing of groups with high risk for TB infection to identify those requiring treat-
ment for latent infection.
TB infection control program has become a crucial component of TB control due to
the increasing co-morbidity of TB and HIV cases and the emergence of multidru-
gresistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). Effective TB
control policies require a sustained political, institutional and financial commitment
from both public and private sectors of the society.

SURVEILLANCE
Case Finding of TB Disease3
Case finding is the identification and diagnosis of TB cases among individuals with
presumptive signs and symptoms for tuberculosis. The three types of TB disease
case finding used by the National TB Program (NTP) are defined as follows:

 Passive case finding - involves screening of symptomatic patients for TB disease

upon consultation at the health facility.

 Active case finding - involves the lead effort of a health worker to find TB cases in
the community or among those who do not consult with personnel in a DOTS fa-
cility

 Intensified case finding – involves active case finding among individuals belonging
to special or defined populations (e.g., high-risk groups including those who con-
sult or find themselves at the facility for other purposes).
The NTP advocates detection of acid – fast TB bacilli using direct sputum smear mi-
croscopy (DSSM) for adults and children who can expectorate. DSSM is the easiest,
least expensive, readily accessible and the most rapid procedure to diagnose infec-
tious TB cases. It is also used to: a) monitor progress of patients with TB while they
are on anti–TB treatment; and b) confirm cure at the end of treatment.

217
TB bacilli isolation in young children is difficult to obtain due to their inability to expec-
torate sputum effectively. Consequently young children are also considered less infec-
tious than adults due to: 1) the inability of most young children to expectorate sputum
efficiently and 2) the few numbers of TB bacilli in their sputum i.e. paucibacillary.
Diagnosis of childhood TB is mainly achieved through a symptom based screening ap-
proach, history of contact to an infectious TB source and with tuberculin skin testing
(TST) and chest radiographs as diagnostic aids. The DOH/NTP recommends its two
entry points guideline for the recognition/case finding TB in children. See Chapter 11:
Diagnosis of TB in children.
The other tests endorsed by TB programs for diagnosing TB are TB culture and drug
susceptibility test, tuberculin skin test and rapid diagnostic test (e.g., Xpert MTB/RIF)
which shall be used for TB diagnosis among presumptive drug resistant TB, people liv-
ing with HIV (PLHIV) with signs and symptoms of TB, smear-negative adults with chest
x-ray findings suggestive of TB, smear-negative children and extra-pulmonary TB.
The screening and treatment of children with TB disease and TB infection forms an im-
portant component in the strategy and assessment of TB control programs since;

 Tuberculous children reflect ongoing transmission of TB cases in the surrounding

community; they are the most likely victims of an infectious TB adult source, with
those < five years old, having the greatest propensity for developing the more se-
vere forms of TB such as extrapulmonary TB (miliary TB, TB meningitis and Pott‘s
disease);
 Children infected with TB represent a significant number in the next generation of
TB cases. They are important reservoirs in terms of numbers, from which future TB
cases may arise later in adulthood/adolescence ;
 The trend in annual risk of TB infection, that is based on age-specific (children be-
tween five and nine years old) prevalence of tuberculin reactions, complements the
reported incidence of active TB, from which the effectiveness of TB control
measures can be gauged.4
Contact Investigation2,5
Contact Investigation is intended to identify persons with previously undiagnosed or
undetected cases of TB among the contacts of an index case and persons who are
candidates for treatment of latent tuberculosis infection. The determination of priorities
for contact investigation is based on the likelihood that a contact: 1) has undiagnosed
tuberculosis; 2) is at high risk of developing tuberculosis if infected; 3) is at risk of hav-
ing severe tuberculosis if the disease develops; and 4) is at high risk of having been
infected by the index case.
Index case is the initially-identified TB case of any age in a specific household or other
comparable setting in which others may have been exposed. The index case may or
may not be the source case.

218
Figure 15.1 Concentric Circle Approach (Adapted from Iyanna Dary. TB Contact Investigation
Module 15. Health Resources and Services Administration [HRSA])

The Concentric Circle Approach is used to identify contacts who are high, medium, or
low risk.12 A close contact is a person who shared an enclosed space such as the
household, a social gathering place, workplace or facility, for extended periods within a
day with the index case during the three (3) months before commencement of the cur-
rent treatment episode11
A child with TB reflects ongoing transmission of TB cases and warrants prompt and
systematic contact investigation for an undiagnosed adult/adolescent source case. The
purpose of the investigation is to find the following: (1) contacts (and treat those) who
have TB disease in order to break the cycle of transmission; (2) those with latent TB
infection (LTBI); and (3) those at high risk of developing TB disease, who requires treat-
ment until LTBI can be excluded.6
Clinical evaluation of household and close contacts for active TB should be done on
the basis of their risk for having or developing active TB or for the potential conse-
quences of the disease if it develops. Priority should be given to contacts who are7:

 persons with symptoms suggestive of tuberculosis;

 children aged <5 years;
 contacts with known or suspected immunocompromised states, particularly HIV in-
fection; and
 contacts of patients with MDR/XDR tuberculosis.

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Targeted Tuberculin Skin Testing (TST) for LTBI
Routine TST for TB screening is not recommended. Targeted Tuberculin skin testing
for LTBI is a strategic component of TB control that identifies persons who are at high
risk for developing TB disease and who would benefit from treatment of LTBI when de-
tected.8 The preferred method of screening for TB infection is the Mantoux TST. Tuber-
culin skin-testing programs should be conducted only among populations with high-risk
for progression of infection to disease and discouraged among persons with low risk.
In conducting tuberculin skin testing among targeted populations, cases warranting
treatment must be initiated and completed, with facilities for follow-up of cases diag-
nosed.
Interferon-gamma release assays (IGRAs) should not replace the tuberculin skin test
(TST) in low- and middle-income countries for the diagnosis of latent TB infection in
children or for the diagnostic work-up of children (irrespective of HIV status) suspected
of TB disease in these settings.8
World Health Organization (WHO) Recommendations for TST Screening3
Every household contacts identified to be a presumptive TB should be evaluated based
on the NTP case finding procedures.
All asymptomatic household contacts less than 5 years old of a bacteriologically con-
firmed index case shall undergo TST. If TST is negative, these contacts should be giv-
en IPT. If TST is positive, rule out TB disease with CXR before starting IPT. However, if
TST and CXR are not available, the child contact of a bacteriologically confirmed index
case can be given IPT based on the physician‘s clinical assessment.
All asymptomatic household contacts less than 5 years old of a clinically diagnosed in-
dex case shall undergo TST. If TST is negative, do not give IPT and advise to seek/
consult immediately if signs and symptoms of TB develop. If TST is positive, give IPT.
All asymptomatic household contacts 5 years old and above (with normal CXR findings,
if done) are advised to seek/consult immediately if signs and symptoms of TB develop.
Young children living in close contact with a source case of smear-positive pulmonary
TB are at particular risk of TB infection and disease. The risk of infection is greatest if
the contact is close and prolonged such as the contact of an infant or toddler with a
mother or other caregivers in the household. The risk of developing disease after infec-
tion is much greater for infants and young children under five years of age than it is for
children over five years old.
The best way to detect LTBI is through the TST. These tests should be used where
they are available to screen exposed contacts. If the TST and CXR are not readily
available, this should not preclude contact screening and management, as this
can be conducted on the basis of simple clinical assessment.

220
CONTAINMENT
Containment of TB concerns the stopping of spread of the infection and disease
through chemotherapy of patients with TB disease and treatment of LTBI. Preventive
therapy refers to the use of a simple regimen such as isoniazid to prevent the develop-
ment of active TB disease in persons known to have or likely to be infected with M. tu-
berculosis. However, it is not expected to result in true prevention (i.e., prevention of
infection in persons exposed to persons with infectious TB).8
Prevention
There are three essential measures embodied within the National TB Programs for
the prevention of TB in children. These preventive measures include:
1. Detection of sources of infection and the appropriate treatment of TB excretors
who are usually adolescents and adults;
2. BCG vaccination of newborns in countries where the transmission of TB is high;
and
3. Chemoprophylaxis for the prevention of infection among those at risk by expo-
sure to an infectious TB case or the prevention of overt disease among those al-
ready infected
(1997 National Consensus on Childhood TB)

Detection of sources of infection is discussed above in case-finding under surveillance;

these TB excretors need appropriate treatment to ensure removal of bacillary load from
existing pockets of reservoir.10,11 For successful therapy, continuous monitoring is nec-
essary to ensure compliance. Directly-observed therapy short-course (DOTS) is one
approach.
Directly Observed Therapy Short-Course (DOTS)3
DOTS is an effective way to monitor adherence to anti-TB therapy, in which a health
partner directly watches the patient swallow the correct dose of medication daily to en-
sure treatment compliance. The daily treatment regimen rather than the intermittent one
is the preferred regimen under the National TB Program. The five key elements of the
DOTS Strategy are: (1) sustained political commitment; (2) access to quality-assured
TB sputum microscopy; (3) standardized short-course chemotherapy with direct obser-
vation of drug intake; (4) a regular, uninterrupted supply of all essential anti-TB drugs;
and (5) a standardized recording and reporting system.
DOTS can be done in any accessible and convenient place for the patient as long as
the treatment partner can effectively ensure the patient‘s intake of the prescribed drugs
and monitor his/ her reactions to the drugs. During weekends and holidays or in special
and exceptional cases, trained family members may be assigned to administer oral
medications. These special cases refer to treatment of children, when DOT schedule is
in conflict with the patient‘s work or school schedule and unable to access other DOTS

221
facilities, poor access to DOTS facility due to geographical barriers, in debilitated or
bedridden patients and in indigenous peoples where cultural beliefs limit the choice of a
treatment partner. 3
Under the National TB Program, TB control services are provided mainly through public
primary health care facilities operated by local government units in a devolved set-up.
There are additional DOTS facilities within the NTP‘s network of service providers that
either refer diagnosed TB patients for treatment or directly provide TB treatment ser-
vices using DOTS strategy. These include private outpatient clinics; public and private
primary, secondary and tertiary care hospitals; workplaces; clinics under faith-based
organizations and community based nongovernmental organizations (NGOs); and pub-
lic institutions such as military facilities, jails and prisons.13 As of December 2015, there
are 1,739 Philhealth accredited DOTS facilities nationwide.14 The TB DOTS Referral
System is an effective two way referral system where a receiving facility provides feed-
back to a referring facility. Major reasons for referral are for TB diagnosis, registration
and initiation of treatment, continuation of treatment as when a patient initially diag-
nosed in one facility is referred to another facility near his/her residence, management
of serious side effects and complications, screening of MDR-TB and screeining of TB
among PLHIV.3
The TB registry contains a list of treatment for TB patients and their progress monitor-
ing towards cure. The TB recording and reporting system consists of a laboratory reg-
istry with a list of all patients with smear tests, treatment cards with details on intake of
medications, and follow-up of sputum examinations. These reporting forms are submit-
ted from the districts to the national level.
Since adopting the Directly Observed Treatment Short Course Strategy in all public fa-
cilities in 2003, the country has made significant progress in the battle against TB. 15 As
of 2014, national indicators for TB Case Detection Rate (CDR) and Treatment Success
Rate (TSR) are at 85% and 90%, respectively. These improved values show that the
country is on its way on achieving its targets.
Bacillus Calmette-Guerin (BCG) and Vaccine Development
Bacille Calmette Guerin (BCG) is a vaccine derived from a live attenuated strain of My-
cobacterium bovis. It is the only known vaccine in use against TB. BCG vaccination in-
duces artificial primary immunity to TB for prevention of subsequent illness caused by
virulent bacilli.16
At least 4 billion people were immunized with BCG since its discovery; making it the
most widely used vaccine worldwide.17 The use of BCG vaccine has shown varied dif-
ferences in protective efficacy results in different studies. The variation in protective ef-
fect from different trials ranged from 0% to 80%.This has been attributed to several fac-
tors: differences in BCG strains, differences in prevalence of infections with environ-
mental mycobacteria, genetic and physiological differences between the populations
and different immunological mechanisms against forms of disease with varying patho-
genesis.18
A meta-analysis on the efficacy of BCG vaccination in newborns and infants by Colditz,

222
et. al in 1995 concluded that BCG vaccination of newborns and infants reduces the risk
of TB by 50% on the average.19,20 Another meta-analysis of 10 randomized clinical tri-
als and eight case control studies analyzed the protective effect and confidence inter-
vals for pulmonary and meningeal/miliary disease. There was considerable variation in
the protective effect of BCG against pulmonary TB. The summary protective effect
against meningeal and miliary TB was 86% (95% CI:65,95) and in case control studies
75% (95%CI:64,84). According to the study, a more likely explanation is that immuno-
logical mechanisms operate against different forms of disease, with BCG being more
effective in preventing the hematogenous spread of tuberculous bacteria as in meningi-
tis and miliary forms.18 A recent finding shows that in a high burden country for TB,
BCG confers protection against incident TB disease among those with household expo-
sure in those younger than 10 years (RR, 0.35, 95% CI‘s, 0.19-0.66).22
The recommendation to give BCG at birth is supported by the theory that exposure to
certain varieties of mycobacteria can give rise to a cell-mediated response which op-
poses the protective effect of subsequent BCG vaccination. Therefore, the recommen-
dation is to give BCG at birth or soon thereafter before any exposure to environmental
mycobacteria.23
BCG is not recommended in countries where TB rates are low, since it would increase
tuberculin reactivity, thereby making the tuberculin test less accurate. Being a live at-
tenuated vaccine, BCG is not recommended to be given to immunocompromised indi-
viduals. Likewise the BCG accelerated test should not be used for TB screening.
According to WHO, those persons who have received BCG vaccination are not recom-
mended to be vaccinated again, since available evidence does not support such prac-
tice. Multiple vaccinations are not recommended for anyone.24
The best strategy to eliminate TB is through a new and more effective TB vaccine. 25
The ideal vaccine should be safe even when administered to immunocompromised per-
sons (e.g., persons with HIV infection) and not hypersensitive to PPD that will cross-
react with TST and thereby limiting its specificity. The vaccine should protect against
diseases resulting from subsequent infection (i.e. pre-exposure), as well as, endoge-
nous reactivation of an earlier infection (i.e. post-infection). Considering the limitations
of preventive therapy, an effective post-infection vaccine could be the most important
new tool to help eliminate TB.
In high-incidence countries, a post-infection vaccine could be administered even among
adults in high-risk groups (e.g. health-care workers), and its wide application could
have a major global impact. Until this ideal TB vaccine is available, the early detection
and completion of appropriate treatment (through DOTS) of LTBI and TB disease would
remain as the best strategy to effectively control TB.26
In recent years, there has been a dramatic increase in the number of candidate TB vac-
cines evaluated in research laboratories. Better understanding of the immunological
deficits of BCG and impressive progress in knowledge of mycobacterial genomics have
paved the way for promising new products. The main vaccine targets are prevention of
infection in naïve individuals, prevention of reactivation of latent infection, and thera-

223
peutic vaccines to prevent relapse in TB patients. Successful prevention-of-recurrence
trials may lead to the development of therapeutic vaccines that will either shorten the
duration of treatment or enhance response to therapy. Currently, the most favored re-
search strategies include recombinant modified BCG vaccines, attenuated strains of M.
tuberculosis, subunit vaccines, and DNA vaccines. 27, 44
Several hypotheses have been forwarded regarding the variable effectiveness of BCG
against PTB and these are, namely: differences between BCG daughter strains, inade-
quate dosage of BCG in some trials, interference by environmental mycobacteria, ge-
netic differences in human populations and geographic differences in clinical isolates of
Mycobacterium tuberculosis. The decrease in effectiveness of BCG against PTB has
been hypothesized to be a consequence of increased immune suppression by BCG
antioxidants. As BCG evolved through different passages, and genomic duplications/
mutations occurred in the process, BCG production of antioxidants is increased thereby
suppressing the host‘s oxidant dependent immune response.28 So a new model of BCG
evolution is hoped to be one that reduces BCG antioxidants, thereby enhancing its im-
munogenicity against PTB. Another finding that may explain the decreased effective-
ness of BCG against PTB is the loss of BCG strain T-cell epitopes as the BCG strain
underwent repeated human manipulation over the years. So the restoration of lost BCG
strain epitopes may be a useful future vaccine developmental strategy.29
Isoniazid Preventive Therapy (IPT)
The risk to develop active TB following infection is high, based on the age as well as
the immune status of the child. The younger the patient is, the higher is the chance to
develop active tuberculosis, 30-40% in <1, 10-20% in 1-2 years, and 5% in 2-5 years of
age. The progress to active TB usually occurs within 12 months of primary infection.30
WHO, recognizing the identification and treatment of LTBI as a tool of global TB con-
trol, recommends isoniazid preventive therapy for 6 months (10 mg/kg/day, range 7-15
mg/kg/day, maximum dose: 300 mg/day) in children <5 years of age, who are house-
hold or close contacts of people with TB and who, after an appropriate clinical evalua-
tion, are found not to have active TB (strong recommendation, high quality of evidence
based on WHO GRADE System).31
Likewise, IPT for 6 months is recommemded to children living with HIV who are >12
months of age and who are unlikely to have TB disease on symptom based screening
and have no contact with a TB case.31
The 2010 Cochrane Review on INH for preventing TB in non-HIV infected persons in-
volving 11 RCT‘s with N=73,373 patients, the authors found the difference in 6 months
IPT vs. 12 months IPT not statistically significant.32
For high income or upper middle income countries with low incidence TB (IR
<100/100,000), the 2014 WHO Guidelines on the Management of Latent Tuberculosis
Infection( a Cochrane Review involving 53 RCT‘s), reports 6H is preferred over 9H
based on resource requirements, feasibility and acceptability by patients. The same
Cochrane Review reported that 6 months of INH is equivalent to 9 months of INH, as
well as INH and rifapentine weekly for 3 months, or 3-4 months of INH and rifampicin,

224
or 3-4 months of rifampicin ( 6H~9H~INH + RPT weekly x 3 months~ 3-4 mos HR ~ 3-4
mos R) as other regimens for LTBI.33
Patients on IPT should be properly documented and registered, based on the NTP-
DOTS Program. Register the child using Form 4 (TB Treatment/IPT Register) and Form
9 (IPT register). Monitor and assess the child at least every 2 months (weigh monthly
and adjust dosage according to weight; clinical manifestations). If the child develops
any sign or symptom, evaluate accordingly, and if found to have TB disease, stop IPT
and start on treatment for TB disease and declare IPT outcome as failed. The out-
comes of IPT are, namely: (1) completed; (2) lost to follow-up (a child who interrupted
IPT for two months or more); (3) died (a child who dies for any reason during the
course of IPT); (4) failed ( a child who develops TB disease during the IPT), and (5) not
evaluated ( a child who has been transferred to another health facility with referral for
continuation of IPT and whose treatment outcome is not known).3
Structures for TB Control
An effective national TB program should have a high cure rate, a low level of acquired
drug resistance, with a high case detection rate.34 TB control programs should have
ready access in providing health care with the necessary personnel, infrastructure, fa-
cilities, services and goods. Every health promoter and caregiver has to understand the
problem and be familiar with its network to optimize use of all resources available ac-
cording to set targets.
World Health Organization (WHO) Global Tuberculosis Programme
The WHO Global TB Programme provides global leadership on matters critical to TB,
develops evidenced-based policies, strategies, and standards for TB prevention, care
and control, and monitors their implementation. Together with Member States, it pro-
vides technical support and builds sustainable capacity. It monitors the global TB situa-
tion and measures progress in TB care and control. It is also responsible for the gener-
ation, translation and dissemination of valuable knowledge on TB. It likewise facilitates
and engages in partnerships for TB action.35
The World Health Organization Global TB Programme and the European Respiratory
Society have jointly led consultation among broad cross section of stakeholders to
match TB needs with digital health solutions. In September 2015, WHO developed the
Digital Health for the End TB strategy: an agenda for action.The said agenda aims to
scale up TB response through information and communication technology and outlines
the strategic directions to promote the integration of digital health concepts into TB pre-
vention and care activities. 36
WHO‘s new End TB Strategy has three pillars namely: Pillar 1- Integrated patient cen-
tered TB care and prevention; Pillar 2- Bold policies and supportive systems and Pillar
3- Intensified research and innovation.
Among the initiatives are the use of video treatment support for TB patient via mobiles,
eHealth portal to improve TB care, use of electronic medication monitors for TB pa-
tients, digital dashboards for TB indicators, epidemiological trends and digital notifica-
tion of TB cases and web based training for health professionals.36

225
National Tuberculosis Control Program3
The National Tuberculosis Control Program (NTP) is one of the public health programs
being managed and coordinated by the Infectious Diseases for Prevention and Control
Division (IDPCD) of the Disease Prevention and Control Bureau (DPCB) of the DOH.
The NTP has the mandate to develop TB control policies, standards and guidelines,
formulate the national strategic plan, manage program logistics, provide leadership and
technical assistance to the lower health offices/ units, manage data and monitor and
evaluate the program. The program‘s TB diagnostic and treatment protocols and strate-
gies are in accordance with the global strategy of STOP TB Partnership and the poli-
cies of World Healh Organization (WHO) and the International Standards for TB Care
(ISTC)3.
The NTP works with various offices of the DOH and coordinates with the Philippine
Health Insurance Corporation( Philhealth) for TB –DOTS accreditation and utilization of
the TB- DOTS outpatient benefit package. 3
The various regional, provincial and city NTP teams of the DOH are responsible for the
management and control of tuberculosis in these areas. DOTS facilities which could
either be public health facilities or NTP engaged private facilities provide TB diagnostic
and treatment services that are in accordance with NTP protocol.
NTP closely works with the 17 government offices and five private organization in com-
pliance with the Comprehensive and Unified Policy(CUP) issued by the office of the
President in 2003.37 Under the framework of public-private collaboration in TB DOTS,
NTP collaborates with non-governmental organizations such as the Philippine Coalition
against TB(PhilCAT), a consortium of 60 groups , and the 100 year old Philippine TB
Society, Inc.(PTSI) and many other organizations. Various developmental partners and
their projects provide technical and financial support to NTP such as the WHO, United
States Agency for International Development (USAID) , Global Fund AIDS, TB and
Malaria (Global Fund) , Research Institute of TB/ Japan Anti TB Associations (RIT/
JATA), Korean Foundation for International Health (KOFIH) and Korean International
Cooperation Agency (KOICA).3
The NTP in cooperation with Knowledge Management and Information Technology
Service (KMITS) developed the Integrated Tuberculosis Information System (ITIS) in
September 2014. ITIS is the official electronic TB information system and is designed to
collect, consolidate and report TB data on time from all health facilities managing TB. 38
Local Government Units are also assisted by the NTP in organizing the TB Diagnostic
Committees (TBDC) to reduce over and underdiagnosis of TB and ensure that active
TB cases are placed on treatment. TBDC is composed of experts in the hospitals and
specialists with training in TB together with the PPMD unit head or City TB Coordinator
who meet once a week or twice a month to improve the quality of diagnosis of sputum
smear negative chest radiography suggestive of pulmonary TB (sn-PTB). Treatment
dilemma of certain TB cases are also referred and discussed during the meetings.
Case records are presented individually, the history is obtained from the TBDC referral
form and discussed by the TB Coordinator and consensus is reached by the TBDC
members on the appropriate management of the case. TBDC recommendations range

226
from treatment initiation to surveillance of a patient not categorized as an active case of
TB. These TBDC activities contribute to TB control in the country by ensuring the judi-
cious use of resources.39
1. Vision , goals , objectives and strategies of the NTP3
Based on the updated 2010 -2016 Philipine Plan of Action to Control TB (PhilPACT),the
NTP‘s vision, goals, targets and objectives are as follows:
VISION: TB free Philippines
Goal: By 2016, the following should have been achieved :
Incidence rate : 246/ 100,000
Prevalence rate: 414/100,000
Mortality rate: 23/100,000
Targets by 2016:
Case Detection Rate, all forms 90%
Treatment Success Rate, all forms 90%
Notification Rate of MDRTB 62%
0f estimated MDR among notified TB cases
Treatment Success rate of MDR-TB cases 75%
Table 15.1 Objectives and Strategies: 3
OBJECTIVE STRATEGY
1. Reduce local variation in 1. Localize implementation of TB control.
TB control performance 2. Monitor health system performance.
(Governance and health information).
2. Scale up and sustain coverage of 3. Engage both public and private health
DOTS implementation (Health service care providers.
delivery and human resource). 4. Promote and strengthen positive be-
haviour of communities.
5. Address MDR-TB, TB/HIV, and needs
of vulnerable population.
3. Ensure provision of quality TB ser- 6. Regulate and make available quality
vices (Regulation) TB diagnostic tests and drugs.
7. Certify and accredit TB care provid-
ers.
4. Reduce out-of-pocket expenses relat- 8. Secure adequate funding and improve
ed to TB care (Financing) allocation and efficiency of fund utiliza-
tion.

The Philippines has achieved its Millennium Development Goals in TB at the end of
2015.The Sustainable Development Goals (SDG) replaced the MDGs which expired at
the end of 2015. Under Goal 3 of SDGs, health is strongly reflected which aims to
―Ensure healthy lives and promote well-being for all at all ages.‖ The target on TB is
included under this which states that ―by 2030 end the epidemics of AIDS, tuberculosis,

227
malaria and neglected tropical diseases and combat hepatitis, water borne diseases,
and other communicable diseases.‖ The indicators for this SDG is TB incidence per
1000 person years which is the estimated number of new and relapse tuberculosis cas-
es arising in a given year, expressed as the rate per 100,000 population (WHO). All
forms of TB are included including cases in people living with HIV. Another indicator is
the number of TB deaths which is the number of deaths attributable to TB in a given
year excluding HIV positive TB deaths (WHO). Household surveys and health facility
data given during the annual reporting per country contribute much to the global data-
base.

2. Current Key initiatives to respond to the TB problem3

The overarching strategy of the NTP is the DOTS or directly observed treatment short
course. This was expanded under the WHO-endorsed STOP TB strategy that the coun-
try adopted from 2006-2010. In 2010, DOH issued the 2010 – 2016 Philippine Plan of
Action to Control TB ( PhilPACT) as the roadmap for controlling TB.
The NTP has eight key initiatives namely: a) public-private mix DOTS(PPMD) , where
the private sector was engaged to adopt and practice NTP policies and guidelines and
PPMD staff were trained on TB DOTS; b) enhanced hospital TB DOTS, where internal
and external referral systems were strengthened and hospitals acted either as referring
or DOTS providing hospitals; c) Programmatic Management of Drug Resistant TB,
where treatment centers and sites provided diagnostic and treatment services to drug
resistant TB; d) TB HIV collaborative studies; where provision of medical services to
patients with TB and HIV co –infection were done through close coordination between
NTP and National AIDS/ STI Prevention and Control Program (NASPCP); e) TB in jails
and prisons, where TB diagnosis and treatment were extended to inmates of jails and
prisons through close coordination of the Department of Justice through the Bureau of
Corrections and DILG through the Bureau of Jail Management and Penology (BJMP);
f)TB DOTS certification and accreditation, where DOTS facilities are certified by DOH
through the Regional Offices based on ten DOTS standards and facilities were also ac-
credited by Philhealth; g) expansion of TB laboratory services , where TB microscopy
centers were established in different hospitals and in the private sector with a total of 18
culture centers at present and plans of increasing the number to 29 centers by 2016;
As of October 2015, there are 108 public and private centers giving free GeneXpert h)
Community TB care, where community participation as well as patient support groups
are encouraged to improve TB diagnosis and management.
3. The Manual of Procedures for the NTP
The Manual of Procedures (MOP) for the National TB Control Program is the basis for
the implementation of the tuberculosis program in all DOTS facilities in the Philippines.
The first MOP was developed in 1980 although earlier versions where conceived as
early as the 1960‘s. Later revisions started in 1988, 2001, 2004 and the 5th was pub-
lished in 2013 and rolled out in 2014.

228
a. Networking: The Role of Private Practitioners, NGOs and Volunteers
Notification of TB cases
Notifying the appropriate sectors of all TB cases seen and initiating treatment are key
factors for effective TB control. Reported TB cases to the national health authorities
each year account for less than half the estimated number of TB cases worldwide, and
private practitioners in countries with high burden of TB in general do not report TB cas-
es to their relevant national health authority. In the Philippines, public-private partner-
ships accounted for 9% of all notifications in 2007.3
Involvement of Private Practitioners in TB Control Programs and TB Education of
the Community
In the 2007 National TB Prevalence Survey, the following are the health seeking behav-
ior among TB symptomatic individuals; self medicated (43.4%); no action taken
(25.1%); and those who sought medical consult (34.6%). More than half (54.3%) who
sought consult went to public health care givers; with an almost equal number went to
the DOTS centers (26.7%) and public hospitals/clinics (26.4%).40
Although majority of TB symptomatic individuals now seek consult in government hos-
pitals and DOTS centers, the latest National TB Prevalence Survey showed private
practitioners still manage a substantial number of TB symptomatic cases, i.e. in private
clinics (21.7%) and private hospitals (16%).40 The active participation of private physi-
cians in advocating the current strategies for TB control of the National TB program and
the notification of TB cases seen should be encouraged and strictly implemented.
TB management practices of private practitioners may deviate greatly from the best
practice methods being advocated. Private practitioners rely mostly on chest x-ray in
diagnosing TB cases, with varied drug regimens used in treating TB infection and dis-
ease. Every physician, therefore, has to be updated on the prevailing TB status and its
implications, current trends in diagnosis and treatment, management of MDR-TB, HIV
and TB with the latest practices advocated for TB prevention, control and elimination.
As lead health care providers, physicians play a vital part in the social awareness of
TB, through adequate education of the public. The public should be informed on the
magnitude of the TB problem, its mode of transmission, clinical course, preventive
measures, availability of cure, importance of early recognition and detection of TB
through cost-effective tools with emphasis on the immediate institution and completion
of adequate anti-TB therapy.
Public-Private Mix41,42
The WHO initiated the Public-Private Mix (PPM) in 1995 as a strategy that would link all
health care entities within the private and public sectors including health providers in
other government ministries to national TB programs for expansion of DOTS activities.
The WHO advocates the NTPs to work with the private sector to initiate and sustain
productive collaboration. In 2008, case notifications increased by 18% in areas where
Public-Private Mix DOTS (PPMD) was implemented. Treatment success rates among

229
patients managed in PPMD units have been in the range 85–90%.
PPM initiatives have been implemented in 40% of the Philippines and account for 9% of
national notifications.3 PPM in the Philippines is known as PPMD (Public-Private Mix for
DOTS) and was adopted as a national strategy to increase case detection and improve
access to DOTS services in poor urban areas in 2003. Since then, a close collaboration
between the NTP and the Philippines Coalition Against Tuberculosis (PhilCAT) has pro-
duced impressive results. As Sub-Recipient (SR) of the Global Fund TB Project (July 1,
2012 to March 31, 2014), PhilCAT scales up Hospital DOTS, engaging 212 public and
174 private hospitals as partners for finding the ―missingTB cases‖, instilling a
―partnership in the referral system‖, contributing a total of 12,330 cases or about 5.6%
of the Philippines‘ total estimated cases (all forms).43
PPM helps increase TB case detection and reduces diagnostic delays by involving all
health care providers in timely referral and diagnosis, ensuring proper notification of all
diagnosed cases, and enrollment on appropriate treatment under program guidelines.
The engagement of private providers entails adequate training of these providers to
ensure that the quality of their services is aligned with the International Standards for
TB care. In addition, evidence shows that private providers are often the first point of
contact for health services. These providers (with adequate training) could play an im-
portant role in case detection and referral of patients to the public sector cutting down
significantly on diagnostic delays.
All health care providers have critical roles in TB control including: helping identify peo-
ple with TB; prescribing treatment; acting as treatment supervisors; tracing treatment
defaulters; providing information and spreading awareness, training and supervision of
health care staff; and management of drug supplies and equipment.
TB in the Community: Role of Private Practitioners in TB Control Program
The control of TB in the country can only be realized through collaboration. In the up-
dated 2010-2016 Philippine Plan of Action to Control Tuberculosis (2014 PhilPACT),
one of its strategies in scaling up and sustaining coverage of DOTS implementation is
to engage both public and private health care providers. The Philippine Ambulatory Pe-
diatric Association, Inc. (PAPA), whose majority membership involves pediatricians,
carries out its mission by providing holistic, innovative and socially responsible
healthcare for children in the home, school and community through one of its projects,
a Community Based Tuberculosis Control Project- ―Tb Rally‖ in collaboration with the
National Guidelines for TB in children. From 2001 to 2013, PAPA had been involved in
in 8 municipalities of the country. In doing these projects, PAPA had demonstrated that
control of childhood TB entails the collaboration and clear set-goals of all key players,
namely: the government through the local government unit (LGU) providing the logisti-
cal support, the municipal health officer and the RHU team, funding from the Non-
Government Organizations as well as the government (Office of Congress 2nd District of
Sorsogon) as well as the private pediatric practitioners from PAPA and the locality, the
latter assisting in providing the technical knowledge and expertise through training,
guidance, monitoring and community empowerment to follow-up and complete the pro-
gram. Other stakeholders like the Rotary, the church and other religious organizations

230
and the Department of Education assist in community mobilization thus localizing the
implementation of TB control.
In doing these projects, PAPA has demonstrated that the control of childhood tubercu-
losis entails more time, effort, funding, manpower and political will. A private-public
partnership and the collaboration of all the key players play a very significant role in
lessening the burden of TB, ensure success and future eradication of tuberculosis
among the Filipino children.

TB INFECTION CONTROL MEASURES 5,8,11

TB infection control is a combination of measures and strategies aimed at effectively
minimizing the risk of TB transmission within populations in a particular setting. The
foundation of such infection control is early, prompt and accurate diagnosis, and the
proper management of TB patients and people suspected to have TB.
TB infection control measures should be based on a careful assessment of risk for
transmission of TB in the facility or surroundings - e.g. health-care facility, congregate
setting and household. The goals of effective TB infection control programs are to:

 Detect TB disease accurately, early and promptly

 Isolate those who have or are suspected of having TB disease (airborne precau-
tions)
 Treat people who have or who are suspected of having TB disease

The TB infection control (TBIC) measures include three levels of hierarchy - ad-
ministrative controls, engineering controls and wearing of respiratory protective
equipment when necessary.
Administrative Controls
Administrative controls are the first line of defense; it impacts the largest number of
people and the most important level in the hierarchy of TBIC. This involves measures
that will reduce risk of TB transmission by preventing the generation of droplet
nuclei or reducing exposure to droplet nuclei; and has the greatest impact on pre-
venting the spread of TB. It is intended primarily to reduce the risk of uninfected per-
sons exposed to persons who have TB disease, with emphasis on prompt detection
and treatment of TB cases and observance of airborne precautions. Administrative con-
trol measures include:

 Promptly identifying people with TB symptoms (triage)

 Separating or isolating infectious patients
 Controlling the spread of pathogens – promoting cough etiquette
 Minimizing the time spent by patients in health care facility
 Reducing diagnostic delays
 Early initiation of treatment for TB patients
 Providing a package of prevention, treatment and care interventions for staff

231
Administrative measures involve creating guidelines in TB infection control suitable to
the needs of the population; training of staff in the prompt detection/recognition, preven-
tion and treatment of TB cases; education of patients and increasing community aware-
ness; and coordination and communication with the existing TB program.

Environmental Controls
The use of environmental control involves technologies that will significantly pre-
vent the spread by reducing the concentration or inactivation of infectious drop-
let nuclei in ambient air. It is considered as the second line of defense for preventing
the spread of TB and, in combination with appropriate administrative controls, will re-
duce the risk of infection.
Primary environmental controls manage the source of infection by using local exhaust
ventilation (hoods, tents, or booths) and dilute and remove contaminated air by using
general ventilation. Secondary environmental controls manage the airflow to prevent
contamination of air in areas adjacent to the source (airborne infection isolation [AII]
rooms formerly called negative pressure rooms) and clean the air by using high effi-
ciency particulate air (HEPA) filtration, or ultraviolet germicidal irradiation.
Cost-effective environmental control measures that could be used at the DOTS facilities
are natural ventilation and mixed mode mechanical ventilation (i.e., use of fans together
with natural ventilation).
For DOTS facilities, the following are practical and simple measures that could be
adopted:

 Open windows and doors to improve natural ventilation;

 Evaluate and document direction of airflow daily in high-risk areas within the DOTS
facility. Use smoke test (incense sticks or mosquito coil) to visualize air move-
ment;
 Place or re-arrange furniture and seating such that staff-patient interaction occur
with airflow passing from health worker to patient or between health worker and
patient, rather than from patient to health worker (i.e., airflow from ―clean to dirty‖);
 Ensure that fans are clean and working properly.

Isolation rooms should have its own ventilation source and exhaust. Air that comes
from Isolation rooms should NOT recirculate into the general air circulation. Isolation
rooms meant to function as source isolation for infectious cases should be constructed
with the recommended ventilation of 12 air exchanges per hour.

Respiratory Protective Equipment

The use of respiratory protective equipment (i.e. an air tight fitting mask such as an N-
95 mask or higher) in situations that pose a high risk of exposure to M. tuberculosis
can further reduce risk for exposure of health care workers to infectious droplet
nuclei expelled into the air from an infectious TB source. When donning masks,

232
make sure the mask would fit snuggly to the face and below the chin with the flexible
band of the mask fit to the nose bridge.
Particulate respirators are designed to protect health care workers and other individuals
from inhaling droplet nuclei and should not be worn by patients; while surgical masks
should not be worn by the health-care workers, these are designed to reduce the num-
ber of droplets being exhaled into the air by persons with infectious TB disease when
they talk, breath, cough or sneeze. Persons with suspected or confirmed infectious TB
disease should be given and encouraged to use a surgical mask to minimize the risk of
expelling droplet nuclei into the air.
The particulate respirators should meet or exceed the Centers for Disease Control and
Prevention/National Institute for Occupational Services and Health (CDC/NIOSH)-
certified N95 or CE-certified FFP2 standards (filter at least 95% of airborne particles ≥
0.3 μm in diameter).

General Infection Control Efforts: Cough Etiquette and Hand Hygiene

Promoting healthy practices in the general population, i.e. proper hand washing and
cough etiquette are vital components in the prevention of transmission of pathogens in
the immediate surroundings. To minimize the spread of droplet nuclei, any coughing
patient with a respiratory infection – in particular, patients with or suspected of having
TB – should be educated in cough etiquette and respiratory hygiene.
Hand hygiene is an essential element of good infection control practices. Although
hand hygiene does not directly decrease TB transmission (since the TB bacilli are
transmitted only through the airborne route and not by surface or direct contact), the
implementation of TB control measures should be observed as part of general infection
control intervention.
Hand washing with soap and water or disinfect hands with at least 70% strength alco-
hol based hand sanitizer gels or wipes is recommended. Hand hygiene should be ob-
served after touching blood, body fluids, secretions, excretions, contaminated items;
immediately wash hands after removing gloves; between patient contacts and after
coughing and sneezing.
The initial step in cough etiquette is to turn away from people when about to cough
or sneeze. Always cover the mouth and nose when coughing or sneezing with a
disposable tissue. If a tissue is not readily available, the sleeve near the elbow or up-
per arm may be used to cover mouth or nose. The used tissues must be disposed pref-
erably in a sealed waste container.
The use of physical barriers when coughing or sneezing can include a piece of cloth, a
tissue or a surgical mask; and such items should be properly disposed of as part of res-
piratory hygiene practice. Using bare hands as physical barrier when coughing or
sneezing is not recommended since it increases transmission of pathogens through
surface contact and direct contact with other individuals.

233
REFERENCES:

1. Philippine Pediatric Society, Committee on Handbooks on Childhood Tuberculosis.

Tuberculosis in Infancy and Childhood. 3rd ed. 2010.
2. World Health Organization. Global Tuberculosis Control, Surveillance, Planning,
Financing (Report). 2009.
3. National TB Control Program, Manual of Procedures 5th edition 2013. Published by
the Department of Health, Philippines
4. Menzies D. Tuberculin surveys- why? (Editorials). Int J Tuberc Lung Dis. 1998;2
(4):263-264.
5. TB CARE I. International Standards for Tuberculosis Care, Edition 3. TB CARE I,
The Hague, 2014
6. Centers for Disease Control and Prevention, National Center for HIV, STD and TB
Prevention Division of Tuberculosis Elimination. Core Curriculum on Tuberculosis,
What the Clinician Should Know. 4th ed. April 2000
7. Recommendations for investigating contacts of persons with infectious tuberculosis
in low- and middle-income countries. Geneva, World Health Organization, 2012
(WHO/HTM/TB/2012.9)
8. Centers for Disease Control and Prevention, National Center for HIV, STD and TB
Prevention Division of Tuberculosis Elimination. Core Curriculum on Tuberculosis,
What the Clinician Should Know. 6th ed. 2013.
9. Use of tuberculosis interferon-gamma release assays (IGRAs) in low- and middle-
income countries: policy statement. Geneva, World Health Organization, 2011
(WHO/HTM/TB/2011.18)
10. WHO policy on TB infection control in health-care facilities, congregate settings and
households. 2009 (WHO/HTM/TB/2009.419.)
11. Guidance for national tuberculosis programmes on the management of tuberculosis
in children – 2nd ed. 2014
12. Iyanna Dary. TB Contact Investigation Module 15. Health Resources and Services
Administration (HRSA). Retrieved from :slideplayer.com/slide/3898111
13. R. Vianzon et al. (May 2013) The tuberculosis profile of the Philippines, 2003-2011:
advancing DOTS and beyond. WPSAR Vol. 4, No. 2, 2013
14. Philhealth Accredited DOTS Facilities. December 2015 Retrieved from http://www.
Philhealth.gov.ph

234
15. Research monograph. PhilPACT Retrieved from http//www.doh.gov.ph/sites/default
16. Goh T, et al. A Comparative Study of Japanese and British BCG Vaccine Strains in
Newborn Infants. Asia Pacific Journal. 1989;3(1):32-40.
17. Asia-Pacific Vaccination Council. General Information on the Disease and the Vac-
cine. September 2002.
18. Rodrigues L, Diwan V. Protective Effect of BCG against TB Meningitis and Miliary
Tuberculosis: A Meta-analysis. International Journal Epidemiology. 1993;22
(6):1154-1158.
19. Colditz G, et al. The Efficacy of BCG Vaccination in Newborns and Infants in the
Prevention of Tuberculosis: Meta-Analysis of Published Literature. Pediatrics.
1995;96(1):29-35.
20. Brewer T. Preventing Tuberculosis with BCG Vaccine: A Meta-analysis of the Liter-
ature. Clinical Infectious Disease. 2000;31(Suppl)S:64-67.
21. Philippine Pediatric Society. Guide for Clinical Practice Guidelines: Childhood Tu-
berculosis. 2008:51.
22. Zelner JL, et al. Protection from BCG and IPT. Am J Respir Crit Care Med Vol 189
(7), Apr 1, 2014, pp853-859
23. Is BCG Vaccination Effective? Tubercle 62. 981;219-221.
24. World Health Organization. Weekly Epidemiological Record. Aug 1995;70(32):229-
231.
25. Advisory Council for the Elimination of Tuberculosis (ACET). June 1998; Develop-
ment of new Vaccines for Tuberculosis (Recommendations of the ACET). 21 Au-
gust 21 1998/47(RR13):1-6.
26. Weekly Epidemiological Record No. 4, 2004; 79,25-40.Available at http://
www.who.int/wer.
27. World Health Organization. Treatment of Tuberculosis: Guidelines for National
Programmes. 3rd ed. 2003
28. Kernodle DS, CID 2010: 51, (17 July), 177.
29. Wen Zhang, et al. Genomic Sequencing and Analysis of BCG Vaccine Strains.
PLOS One, Aug 2013.
30. Marais BJ, et al. The Natural History of Intra-thoracic TB. Int J Trans Lung Dis
2004; B(4):392-402.
31. WHO Guidance for NTP‘s on the Management of TB in Children, 2nd ed. 2014.

235
32. Smeija M, et al. Isoniazid for preventing TB in non-HIV infected persons. The
Cochrane Library, 2010, Issue 1.
33. WHO Guidance on the Management of Latent TB Infection (LTBI), 2015
34. World Health Organization. Treatment of Tuberculosis: Guidelines for National Pro-
grammes. 3rd edition. 2003
35. The Global TB Programme (2016, June) Retrieved from http://www.who.int/tb/
about/en/
36. Digital Health for the End TB Strategy (2015,Oct 7) Retrieved from http//
www.who.int/tb/areas-of-work/digital - health
37. Department of Health and Philippine Coalition Against Tuberculosis. Comprehen-
sive and Unified Policy for TB Control in the Philippines, Manila 2003
38. Utilization of the Integrated TB Information System (ITIS) in Quarterly National TB
Control Program (NTP) Reports. DOH Memorandum Order No. 2014-0284, Sep-
tember 2014
39. Queri et al. (2012) Tuberculosis Diagnosis Committees‘ Contribution to the National
TB Program in Manila and Quezon City. International Union Against Tuberculosis
and Lung Disease Journal Vol 2(3) pp.83-86
40. .Tropical Disease Foundation, Inc and Department of Health. Nationwide Tubercu-
losis Prevalence Survey 2007
41. World Health Organization website. Available from http:// www. Who. Int/ tb/
careproviders/ppm/en/index.html
42. Department of Health, Philippines, World Health Organization. Joint Tuberculosis
Programme Review. 2009
43. Mortera LL. Continuing the Legacy.KOALISYON 2013 pp.48 -49
44. 2016 TAG‘s Pipeline Report. Tuberculosis (TB) Edition. Progress in TB Vaccine De-
velopment, pp.19-23

236
 APPENDIX 1A. DIAGNOSTIC ALGORITHM

Reference: Manual of Procedures of the National Tuberculosis Control Program, 2014.

237
 APPENDIX 1B. SCREENING OF PEDIATRIC DRUG-
SUSCEPTIBLE HOUSEHOLD CONTACTS OF TB

Reference: Manual of Procedures of the National Tuberculosis Control Program, 2014.

238
 APPENDIX 2. BCG IMMUNIZATION
CLEOTILDE H HOW, MD
BACKGROUND/RATIONALE
Mycobacterium bovis was first isolated by Nocard in 1902 but it was Calmette and
Guerin who developed the attenuated strain by allowing 231 passages in 13 years, be-
ginning in 1908. Although the first vaccine was given orally in 1912, the other forms of
the vaccine were later introduced intradermally (1927), by multiple puncture (1939) and
by scarification (1947).
The BCG vaccines at present that are used throughout the world in more than 100
countries may differ because of genetic changes that have occurred among the various
bacterial strains. This renders efficacy of different vaccination programs or trials highly
variable as well.
The immediate objective of BCG vaccination is to activate host cell-mediated immunity
through an innocuous primary infection, but not disease, with the live-attenuated bacil-
lus. Epidemiologic (e.g. case-control) studies and meta-analyses of published clinical
trials have shown the protective efficacy of BCG (up to 80%) against serious forms of
the disease such as meningitis and military tuberculosis. Evidence is not consistent to
support its efficacy against acquiring the infection among the exposed or progression to
primary disease once infected.
See Chapter 15 (Prevention and Control)

INDICATIONS
Use of the vaccine is part of the Expanded Programme on Immunization (EPI) of the
World Health Organization (WHO) for administration at birth or immediately thereafter.
It is recommended that infants be vaccinated soon after birth, just before discharge
from the nursery or lying-in clinic or at first consultation at the local health center or pri-
vate clinic. All previously unvaccinated children who consult at the health center are
given BCG as a preventive measure under the National TB Control Program.
BCG immunization of premature infants and those born with the condition, intrauterine
growth retardation (IUGR), are covered by the same guidelines of chronological age
and dosage requirement as their full-term counterparts with appropriate weight-for-age.
Prematurity or presence of IUGR should not be the reason for delay or withholding of
BCG.
Direct BCG inoculation without prior tuberculin testing has been shown to be safe
among these infants and children. In high-risk groups, however, where exposure and
disease are already suspected even in the very young, doing a tuberculin test is done
to prevent severe local reactions with BCG. This may uncover disease when correlated
with the other criteria for diagnosis of tuberculosis. BCG should also be considered in
older individuals such as health care workers who are still tuberculin negative and who
239
may be at great risk for acquiring infection and progression to disease once infected.

PREPARATION, STORAGE, DOSE AND ADMINISTRATION

The BCG vaccine is available as a lyophilized powder which is heat- and light- sensitive
and must therefore be refrigerated, together with the solvent, between +2 and +8 C.
Once reconstituted (when the solvent has been added to the powder), the vaccine must
be kept refrigerated and used within the next 2-3 hours or according to the manufactur-
er‘s specifications.
The recommended dose is 0.05mL for newborns up to 1 month of age and 0.1mL
thereafter. A 1-mL sterile syringe with a 26-gauge 3/8 needle is used for injection. The
amount of vaccine required is injected intradermally on the superficial layer of the skin.
For newborns, the conventional site is the right deltoid region; for school entrants, the
left deltoid region is used. A wheal between 7 and 9mm in diameter will be created up-
on injection; this disappears within several minutes.

PRECAUTIONS, WARNING AND POSSIBLE ADVERSE EFFECTS

The parents are advised about what local reactions to expect to occur within a given
time. After approximately 2 weeks, a small, red, slightly tender swelling will appear at
the injection site. This will develop into a small abscess after another 2 weeks and will
then ulcerate, heal and form a scar over the next few weeks. The time course from vac-
cination to scar formation will take about 12 weeks.
Other reactions that may occur include: abscess at the injection site and/or lymph node
enlargement on the same side (e.g. axillary lymph nodes), an indolent ulcer that per-
sists for more than 12 weeks after vaccination or that extends beyond the area of injec-
tion, keloid scare among those who are prone. In most instances, reassurance of the
parents and routine bathing with care is enough; inspection of the local reaction at fol-
low-up visits should prompt the physician or caregiver if there is need for additional sur-
gical care, dressing or drainage, or further referral.
Serious complications to watch out for such as osteitis and disseminated BCG infection
are quite rare but have been reported. Fatal outcomes have occurred primarily among
the immunocompromised. It is recommended that such cases be immediately referred
to an infectious disease or TB expert for appropriate therapy, including anti-TB chemo-
therapy.

CONTRAINDICATIONS
The National Consensus on Childhood Tuberculosis (1997) and the earlier Consensus
in 1989 including the following conditions when BCG is not allowed: presence of im-
240
mune deficiency diseases or states where the immune system may be suppressed be-
cause of malignant disease or high-dose and/or prolonged therapy with corticosteroids
and other immunosuppressants; all HIV-infected children and adolescents, whether
asymptomatic or symptomatic. There is a new initiative to offer BCG even to HIV-
infected children who are asymptomatic, with normal CD4 and CD8 counts.

ADVANCES IN TB VACCINE DEVELOPMENT

The existing BCG vaccine has been in use for almost a century, still the only vaccine
with general acceptance in spite of its limitations. It does not protect against infection
with Mycobacterium tuberculosis nor does it protect against pulmonary disease, which
is responsible for widespread transmission and uncurbed TB burden. Although it is
claimed to protect against severe forms of TB, it has no apparent impact on this global
pandemic. There is a need for a more effective vaccine that will be safe even for HIV-
infected children and adults.
By 2015, the Stop TB Working Group on New Vaccines hopes to have a new TB vac-
cine ready for global distribution. This has been made possible by the decoding of the
Mycobacterium tuberculosis (MTB) genome. Several approaches are being studied:
1. Pre-exposure TB vaccines, intended for use in newborns and young infants, to re-
place or amplify BCG early in life; and to older children and adolescents who have
not yet been exposed or infected.
2. Post-exposure TB vaccines, given post-infancy and school children, adolescents
and adults who have latent TB infection, to reduce progression to disease
3. Therapeutic vaccines, to be given to individuals with active TB in conjunction with
anti-TB treatment, to shorten the duration of drug therapy or reduce relapses after
completion of treatment.
While we await these developments with great expectation, we still have this single
vaccine at our disposal, for the protective effect it can offer to the millions of children
still needing some form of intervention to battle TB in its many forms.
As a great worker on childhood TB remarked: ―There is no doubt that BCG vaccine ef-
fectively raises host resistance that every Filipino child must be given the chance to
benefit from it.‖ – M. Pardo de Tavera (1975)

REFERENCE
1. Centers for Disease Control and Prevention. The role of BCG vaccine in the pre-
vention and control of tuberculosis in the United States: a joint statement by the Ad-
visory Committee for the Elimination of Tuberculosis and the Advisory Committee
on Immunization Practices. MMWR Morb Mortal Wkly Rep. 1996; 45 (RR-4): 1-18

241
APPENDIX 3. INTERNATIONAL CLASSIFICATION OF DISEASES
(ICD)

CODE DIAGNOSIS
A15 Respiratory tuberculosis, bacteriologically and histologically confirmed
A15.0 Tuberculosis of lung, confirmed by sputum microscopy, with or without
culture
A15.1 Tuberculosis of lung, confirmed by culture only
A15.2 Tuberculosis of lung, confirmed histologically
A15.3 Tuberculosis of lung, confirmed by unspecified means
A15.4 Tuberculosis of intrathoracic lymph nodes, confirmed bacteriologically
and histologically
A15.5 Tuberculosis of larynx, trachea, and bronchus, confirmed bacteriological-
ly and histologically
A15.6 Tuberculous pleurisy, confirmed bacteriologically and histologically
A15.7 Primary respiratory tuberculosis, confirmed bacteriologically and histolog-
ically
A15.8 Other respiratory tuberculosis, confirmed bacteriologically and histologi-
cally
A15.9 Respiratory tuberculosis unspecified, confirmed bacteriologically and his-
tologically
A16 Respiratory tuberculosis, not confirmed bacteriologically and histological-
ly
A16.0 Tuberculosis of lung, bacteriologically and histologically negative
A16.1 Tuberculosis of lung, bacteriological and histological examination not
done
A16.2 Tuberculosis of lung, without mention of bacteriological or histological
confirmation
A16.3 Tuberculosis of intrathoracic lymph nodes, without mention of bacterio-
logical or histological confirmation
A16.4 Tuberculosis of larynx, trachea and bronchus, without mention of bacteri-
ological or histological confirmation
A16.5 Tuberculous pleurisy, without mention of bacteriological or histological
confirmation
A16.7 Primary respiratory tuberculosis without mention of bacteriological or his-
tological confirmation
A16.8 Other respiratory tuberculosis, without mention of bacteriological or histo-
logical confirmation
A16.9 Respiratory tuberculosis unspecified, without mention of bacteriological
or histological confirmation
A17+ Tuberculosis of nervous system
A17.0 Tuberculous meningitis (G01*)

242
 CODE DIAGNOSIS
A17.0 TB Meningitis
G01
A17.0+ Tuberculous meningitis
A17.1 Meningeal tuberculoma (G07*)
A17.1+ Meningeal tuberculoma (G07*)
A17.8 Other tuberculosis of nervous system
A17.8+ Other tuberculosis of nervous system
A17.9 Tuberculosis of nervous system, unspecified (G99.8*)
A17.9+ Tuberculosis of nervous system, unspecified (G99.8*)
A18 Tuberculosis of other organs
A18.0 Tuberculosis of bones and joints
A18.0+ Tuberculosis of bones and joints
A18.1 Tuberculosis of genitourinary system
A18.2 Tuberculous peripheral lymphadenopathy
A18.3 Tuberculosis of intestines, peritoneum and mesenteric glands
A18.4 Tuberculosis of skin and subcutaneous tissue
A18.5 Tuberculosis of eye
A18.6 Tuberculosis of ear
A18.7 Tuberculosis of adrenal glands (E35.1*)
A18.7+ Tuberculosis of adrenal glands (E35.1*)
A18.8 Tuberculosis of other specified organs
A19 Miliary tuberculosis
A19.0 Acute miliary tuberculosis of a single specified site
A19.1 Acute miliary tuberculosis of multiple sites
A19.2 Acute miliary tuberculosis, unspecified
A19.8 Other miliary tuberculosis
A19.9 Miliary tuberculosis unspecified

Reference: World Health Organization. International Classification of Diseases

(ICD) 10. www.who.int/classification/icd/en

243
 APPENDIX 4. REPUBLIC ACT NO. 10767

S. No. 2653
H. No. 5042
Republic of the Philippines
Congress of the Philippines
Metro Manila

Sixteenth Congress
Third Regular Session
Begun and held in Metro Manila, Monday, the twenty-seventh day of July, two thou-
sand fifteen.

[REPUBLIC ACT NO. 10767]

AN ACT ESTABLISHING A COMPREHENSIVE PHILIPPINE PLAN OF ACTION TO
ELIMINATE TUBERCULOSIS AS A PUBLIC HEALTH PROBLEM AND APPROPRI-
ATING FUND THEREFORE
Be it enacted by the Senate and House of Representatives of the Philippines in Con-
gress assembled:
SECTION 1. Title – This Act shall be known as the ―Comprehensive Tuberculosis Elim-
ination Plan Act‖.
SEC. 2. Declaration of Policy. – The State is mandated to adopt an integrated and
comprehensive approach to health development. Towards this end, the State shall
support and expand efforts to eliminate tuberculosis as a public health problem by in-
creasing investments for its prevention, treatment and control, and adopting a multisec-
toral approach in responding to the disease.
SEC. 3. Definition of Terms. – As used in this Act:
(a) Comprehensive Philippine Plan of Action to Eliminate Tuberculosis refers to the
program of the national government for the elimination of tuberculosis in the country;
and
(b) Tuberculosis or TB refers to an infectious but curable disease caused by bacteria
called Mycobacterium tuberculosis. It is transmitted from a TB patient to another
through coughing, sneezing and spitting and while the bacterium usually affects the
lungs, it may also affect the bone and other organs like the kidney and the liver.
SEC. 4. Comprehensive Philippine Plan of Action to Eliminate Tuberculosis. – The
Secretary of the Department of Health (DOH) shall establish a Comprehensive Philip-

244
pine Plan of Action to Eliminate Tuberculosis in consultation with appropriate public and
private entities. The Philippine Plan of Action shall consist of the following:
(a) The country‘s targets and strategies in addressing the disease;
(b) The prevention, diagnosis, treatment, care and support, and other components of
the country‘s response;
(c) The development and application of appropriate technologies to diagnose and treat
the disease;
(d) The strengthening of linkages with local and international organizations for possible
partnership in education, advocacy, research and funding assistance;
(e) The establishment of a review and monitoring system to gather data and monitor
the progress made in the elimination of tuberculosis; and
(f) The immediate mobilization of anti-TB services during and after natural and man-
made disasters through collaborative efforts of national and local governments and oth-
er entities.
SEC. 5. Strengthening of the National and Regional Coordinating Committees. – The
National Coordinating Committee (NCC) and the Regional Coordinating Committee
(RCC) of the DOH shall serve as the National TB Control Program‘s (NTP‘s) arm in
strengthening and supporting nationwide capacity for program operations and bridging
collaborative efforts between the public and private sector.
The Secretary of Health shall continue to improve the capability of the existing NCC
and RCC in ensuring efficiency in the implementation, monitoring and evaluation of the
Philippine Plan of Action and in the coordination of efforts of various sectors.
SEC. 6. Research, Demonstration Projects, Education and Training. – The Secretary of
Health shall, directly or through grants to public or nonprofit private entities, perform the
following activities:
(a) Conduct basic and clinical research based on the health agenda to be developed by
partners in the academe, health professional groups and other local health partners
with possible support from foreign organizations;
(b) Develop demonstration projects to generate evidence for responsive policies and to
develop regional capabilities for the prevention, detection, control, and elimination of
tuberculosis;
(c) Conduct nationwide public information campaign and education programs;
(d) Undertake education, training and clinical skills improvement activities for health
care providers;
(e) Provide support for model centers to sustain their initiatives under subparagraphs

245
(b), (c) and (d); and
(f) Collaborate with local and foreign organizations for partnership in various activities
and in providing technical and funding support.
SEC. 7. Strengthening of the Regional Centers for Health Development in the Provision
of Health Services to Eliminate TB. – The Secretary of Health shall strengthen the Re-
gional Centers for Health Development in the provision of health services to eliminate
TB by undertaking the following activities:
(a) Provide free laboratory services through the DOH retained hospitals;
(b) Provide reliable supply of drugs to patients for free by ensuring that local health cen-
ters, through coordination with local government units (LGUs) concerned, have suffi-
cient supply of medicines for the communities they serve;
(c) Undertake public information and education programs to train the public on basic
ways and means to prevent the spread of tuberculosis;
(d) Train and enhance the capability of health providers in both public and private hos-
pitals;
(e) Ensure the proper monitoring of tuberculosis cases in the country; and
(f) Ensure that monitoring services are extended as far as practicable, at the lowest lo-
cal level health unit.
SEC. 8. Education Programs. – The Secretary of Health, in coordination with the Com-
mission on Higher Education (CHED), shall encourage the faculty of schools of medi-
cine, nursing or medical technology and allied health institutions, to intensify infor-
mation and education programs, including the development of curricula, to significantly
increase the opportunities for students and for practicing providers to learn the princi-
ples and practices of preventing, detecting, managing, and controlling tuberculosis.
SEC. 9. Inclusion in Basic Education. – The Secretary of Health, in coordination with
the Secretary of the Department of Education (DepED), shall work for the inclusion of
modules on the principles and practices of preventing, detecting, managing and control-
ling tuberculosis in the health curriculum of every public and private elementary and
high school.
SEC. 10. Media Campaign. – The Secretary of Health, in coordination with the Philip-
pine Information Agency (PIA), shall encourage local media outlets to launch a media
campaign on tuberculosis control, treatment and management, using all forms of multi-
media and other electronic means of communication.
The media campaign shall include materials that would discourage the general public
from spitting in public places and exhibiting unhygienic behavior that tend to undermine
the overall effort of preventing the spread of the disease.

246
SEC. 11. Regulation on Sale and Use of TB Drugs. – The Food and Drug Administra-
tion (FDA) shall strengthen its implementation of the ―No prescription, No anti-TB
drugs‖ to regulate the sale and use of anti-TB drugs in the market. It shall also ensure
the quality of TB drugs distributed in the market.
SEC. 12. Notification on TB Cases. – All public and private health centers, hospitals
and facilities shall observe the national protocol on TB management arid shall notify the
DOH of all TB cases as prescribed under the Manual of Procedures of the National TB
Program and the Philippine Plan of Action on Tuberculosis Control.
SEC. 13. PhilHealth TB Package. – The Philippine Health Insurance Corporation, oth-
erwise known as the PhilHealth, shall, as far as practicable, expand its benefit package
for TB patients to include new, relapse and return-after-default cases, and extension of
treatment.
The PhilHealth shall enhance its present outpatient Directly Observed Treatment Short
Course (DOTS) package to make it more responsive to patients‘ needs. It shall likewise
increase the number of accredited DOTS facilities to widen target beneficiaries who
may avail of reimbursements.
SEC. 14. Report. – The Secretary of Health shall submit an annual report to the Com-
mittees on Health of the Senate and the House of Representatives on the activities car-
ried out to comply with the provisions of this Act.
SEC. 15. Appropriations. – The amount necessary to implement the provisions of this
Act shall be charged against the appropriations of the DOH, the DepED, the CHED and
the PIA under the General Appropriations Act.
SEC. 16. Implementing Rules and Regulations. – The DOH, in consultation with the
DepED, the CHED, the PIA, the LGUs, nongovernment organizations and other con-
cerned entities, shall issue the rules and regulations implementing the provisions of this
Act within ninety (90) days from its effectivity.
SEC. 17. Separability Clause. – If any provision or part hereof is held invalid or de-
clared unconstitutional, the other provisions which are not affected thereby shall contin-
ue to be in full force and effect.
SEC. 18. Repealing Clause. – Any law, presidential decree or issuance, executive or-
der, letter of instruction, administrative order, rule or regulation contrary to or incon-
sistent with the provisions of this Act is hereby repealed, modified or amended accord-
ingly.
SEC. 19. Effectivity. – This Act shall take effect fifteen (15) days after its publication in
the Official Gazette or in a newspaper of general circulation.
Approved,

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 (Sgd.) FELICIANO BELMONTE
(Sgd.) FRANKLIN M.
JR.
DRILON
Speaker of the House
President of the Senate
of Representatives

Senate Bill No. 2653 which was approved by the Senate on January 18, 2016 was
adopted by the House of Representatives as an amendment to House Bill No. 5042 on
January 19, 2016.

(Sgd.) MARILYN B. BARUA-

YAP (Sgd.) OSCAR G. YABES
Secretary General Secretary of the Senate
House of Representatives

Approved: APR 26 2016

(Sgd.) BENIGNO S. AQUINO III
President of the Philippines

248