Tuberculosis

1. ABSTRACT

Tuberculosis (TB) is a fatal disease that is transmitted through air and is caused by
Mycobacterium tuberculosis that generally affects the pulmonary portion of the human body
and leading to severe coughing, fever and chest pain. Although the ongoing research on
tuberculosis from few past years has provided valuable information about tuberculosis
transmission, detection and treatment. Tuberculosis puts stress on public health because of
its high mortality rates after HIV/AIDS. WHO (World Health Organization) is working
closely with countries, partners and civil societies in scaling up the TB response. This
review article will focus on the epidemiology, diagnosis, symptoms, treatment of TB and
provide a knowledge on the current epidemiology, pathogenesis and immune response,
proper treatment and control of TB. Interferon-gamma release assay are whole blood tests in
diagnosing TB but unable to distinguish tuberculosis infection from tuberculosis disease.
Thus, Tuberculin skin test are used around all over the world for tuberculosis diagnosis. To
fight against this fatal disease that has no boundaries, it is necessary to clear and understand
all the mechanisms of TB overall with giving better information about its treatment.

Keywords: Mycobacterium tuberculosis, WHO, Epidemiology, Tuberculin Skin Test.

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2. INTRODUCTION

Tuberculosis (TB), also known colloquially as the "white death", or historically as

consumption, is an infectious disease usually caused by Mycobacterium tuberculosis
(MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of
the body. Most infections show no symptoms, in which case it is known as latent
tuberculosis. Around 10% of latent infections progress to active disease which, if left
untreated, kill about half of those affected. Typical symptoms of active TB are chronic
cough with blood-containing mucus, fever, night sweats, and weight loss. Infection of other
organs can cause a wide range of symptoms.

Tuberculosis is spread from one person to the next through the air when people who have
active TB in their lungs cough, spit, speak, or sneeze. People with latent TB do not pread the
disease. Active infection occurs more often in people with HIV/AIDS and in those who
smoke. Diagnosis of active TB is based on chest X-rays, as well as microscopic examination
and culture of body fluids. Diagnosis of latent TB relieson the tuberculin skin test (TST) or
blood tests.

Prevention of TB involves screening those at high risk, early detection and treatment of
cases, and vaccination with the bacillus Calmette - Guérin (BCG) vaccine. Those at high
risk include household, workplace, and social contacts of people with active TB.

Treatment requires the use of multiple antibiotics over a long period of time. Antibiotic
resistance is a growing problem, with increasing rates of multiple drug-resistant tuberculosis
(MDR- TB).

In 2018, one quarter of the world's population was thought to have a latent infection of TB.
New infections occur in about 1% of the population each year. In 2022, an estimated10.6
million people developed active TB, resulting in 1.3 million deaths, making it the second
leading cause of death from an infectious disease after COVID-19. As of 2018.

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3. REVIEW OF LITERATURE ON TUBERCULOSIS

Leitch A.G. et al., 1995 stated that disease due to Mycobacterium tuberculosis is less
common than expected in HIV-positive patients. He experienced that tuberculosis is
reported to complicate HIV infection in those dually infected with Mycobacterium
tuberculosis and HIV at the rate of approximately 10% per annum. Therefore, this study
determines the outcome in HIV-positive patients known to have been tuberculin skin test
positive. On the basis of similar historical skin test data appropriate to the age groups of the
HIV-positive patients, to predict the total number of cases of tuberculosis expectedyearly.

Collazos J. et al., 1995 discussed the chemotherapy of tuberculosis from ancient to recent.
His article provides an overview of the past, present, and future aspects of chemotherapy for
TB. The reported efficacy of rifampin was a major breakthrough becausethe regimens which
included rifampin were able to treat TB in all patients.

Mouroux J. et al., 1996 reported about Surgical Management of Pleuropulmonary

Tuberculosis and analysed the result of procedures. He concluded that the morbidity and
mortality rates in his group of patients were 31.25% and 12.5%, respectively. The surgery
had both therapeutic and diagnosticindications for the management of pleuropulmonary
tuberculosis.

Keith P.W.J. et al., 1997 stated that Bacille Calmette-Guerin (BCG) is the most widely used
vaccine worldwide. However, its efficacy varies from 80% to zero among studies. A meta-
analysis of all the published prospective trials and case-control studies indicates
approximately 50% efficacy against all forms of tuberculosis, but it is even more effective
against the invasive forms of the disease, meningitis and miliary tuberculosis. Geographic
latitude accounts for 41% of the variance between studies. The variability between different
BCG preparations and the role of environmental nontuberculous mycobacteria are discussed
as major factors in the inconsistent results of BCG vaccinetrials.

Wilcke J.T.R. et al., 1998 concluded that if the diagnosis of pulmonary TB missed the risk
may be high if patients present with an X-ray unusual for TB, but this is fortunately seen
only in approximately 8% of cases of pulmonary tuberculosis. Unusual X-ray is
morecommonly found in patients with the related disease, such as diabetes and cancer. If the
chest X-ray shows cavities, but the smear is negative for Mycobacterium, TB is unlikely and

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further diagnostic procedures should be performed without waiting for culture results.

Lounis N. et al., 1999 studied and stated the impact of iron loading and iron chelation on
murine tuberculosis. Iron loading in mice enhanced the multiplication of M. tuberculosis in
the spleens but not in the lungs. Deferoxamine exhibited significant activity against M.
tuberculosis in iron-loaded mice and isoniazid therapy was strongly bactericidal in both
iron-loaded and non-iron-loaded mice.

Sierra C. et al., 2000 reported that extra laryngeal head and neck tuberculosis has a slow
duration of action but it is difficult to diagnose due to no involvement of lung.

John J.T. et al., 2001 described the risk factor involved during post-transplant tuberculosis
sand stated in his article that diabetes mellitus and chronic liver disease are risk factors for
post-transplant TB. He also concluded that any type of infection, liver problem and hyper
glycaemia can be fatal in the case of transplantation tuberculosis.

Nguyen V.H.,2002 illustrated that intestinal obstruction due to tuberculosis is un common in

comparison to other causes of mechanical bowel obstruction, but it is common in the course
of intestinal tuberculosis, with or without treatment. The aims of the study were to determine
some clinical and pathological features and to evaluate the role of surgery and also to suggest the
best procedure for the management of this disease.

Rizzo P.B. et al., 2003 stated that laryngeal tuberculosis almost disappeared after 1950 but,
related to the increase in pulmonary forms, may still be found and, being uncommon, is
often misdiagnosed.

Esteban J. et al., 2004 confined in his studies about Drug resistance among Mycobacterium
tuberculosis strains in immigrants, he determined the impact of drug resistance in
tuberculosis among immigrant patients in Madrid Spain During the time.

Abal A.T. et al., 2005 described the effect of cigarette smoking on sputum smear conversion
in adults with active pulmonary tuberculosis. In conclusion, he stated that smoking did not
influence sputum smear conversion in tuberculosis. However, as expatriate smokers and
smokers with advanced disease showed a delay in smear conversion, smoking should be
discouraged in patients with pulmonary tuberculosis.

Saltini C., 2006 concluded that rifampicin, isoniazid, and pyrazinamide as the first line

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drugs for short course in his article chemotherapy and diagnosis of tuberculosis.

Arnold C., 2007 stated that different genetic markers indicate that the species M.
tuberculosis have different strained families, each with a single ancestor. An analysis of
genetic marker deviation from the common ancestor of each of these families will improve
understanding of the individual marker evolution rates and the degree.

Bukhary Z.A. et al., 2008 illustrated in his review article that relation between TB and
diabetes mellitus, there is a need to alert all physicians about the potential impact of diabetes
mellitus on the control of tuberculosis and its treatment. It is important to check fasting
blood sugar in new patients with tuberculosis and to screen all patients with diabetes
mellitus for latent Mycobacterium tuberculosis infection. Patients with combined diabetes
mellitus and tuberculosis require close monitoring for the control of both diseases.

Gopinath K. et al., 2009 narrated that specific PCR and culture examination of spot urine
samples from suspected pulmonary TB patients significantly improved the detection rate of
Pulmonary TB and should be encouraged in resource-limited settings and where multiple
pulmonary specimens are not feasible.

Schirmer P. et al., 2010 stated in his article that between 50% and 75% of patients with
osteoarticular TB and approximately 33-50% of patients with spinal TB have an associated
primary lung focus or have a reported history of pulmonary TB. In one study of spinal TB,
MTB was found elsewhere in the body in approximately 40% of cases, and 50% of those
cases had pulmonary involvement. Most reports suggest that spinal TB results from a
primary focus outside of the spine, and spread is postulated to be via hematogenous or
lymphatic dissemination.

Chen T.C. et al., 2011 described in his article Fluoroquinolones are associated with delayed
treatment and resistance in tuberculosis: a systematic review and meta-analysis that
Empirical fluoroquinolone prescriptions for pneumonia are associated with longer delays in
diagnosis and treatment of pulmonary TB and a higher risk of developing fluoroquinolone
resistant in M. tuberculosis.

Sneh S. et al., 2012 stated that primary hepatic TB is fatal if remained undiagnosed and its
result from tubercular bacilli gaining access to the portal vein from a microscopic tubercular

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focus in the bowel with subsequent healing taking place at the site of entry leaving no trace
of it.

Naha K. et al., 2013 described that in developing countries with a high prevalence of TB in
the general population, the possibility of incidental TB in a patient with HIV should always
be considerd.

Sugarman J. et al., 2014 estimated that 2,16,500 (95% uncertainty range) active
tuberculosis cases existed in pregnant women globally in 2011. The greatest burdens were in
the WHO African region with 89,400 cases and the WHO South East.

Aziza R. et al., 2015 ascertained that it raised the harmful impact of smoking on the clinical
and radiological presentation of tuberculosis, and late bacteriological negativity, therefore
we need to integrate smoking control into the national TB control program to completely
obsolete TB.

Mehraj J. et al., 2016 confirmed that there is a need to focus on extrapulmonary TB among
female populations to document the epidemiology in South Asia, and examine the risk
factors, diagnostic modalities, treatment strategies, and outcomes to carry out preventive and
controls.

Cataldi A.A. et al., 2017 illustrated that there is a number of drugs that can cure TB but his
article focuses on azole compounds and All azole compounds tested in his study showed
inhibitory activity against MDR M. tuberculosis clinical isolates bacteria.

Wakamatsu K. et al., 2018 concluded in his article that Prognostic factors in patients with
miliary tuberculosis that in patients with miliary tuberculosis, old age, ARDS (Acute
Respiratory Distress Syndrome) and consciousness disturbance were factors associated with
poor prognosis.

Singh A. et al., 2019 stated about the abdominal TB in Indians that although the burden of
the disease remains the same, the availability of newer investigations has aided in its early
diagnosis and availability of good drugs has reduced the mortality and morbidity.

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4. HISTORY

Figure 3.1

Egyptian mummy in the British Museum – tubercular decay has been found in the spine.

Tuberculosis has existed since antiquity. The oldest unambiguously detected M.

tuberculosis gives evidence of the disease in the remains of bison in Wyoming dated to
around 17,000 years ago. However, whether tuberculosis originated in bovines, then
transferred to humans, or whether both bovine and human tuberculosis diverged from a
common ancestor, remains unclear. A comparison of the genes of M. tuberculosis
complex (MTBC) in humans to MTBC in animals suggests humans did not acquire
MTBC from animals during animal domestication, as researchers previously believed.
Both strains of the tuberculosis bacteria share a common ancestor, which could have
infected humans even before the Neolithic Revolution. Skeletal remains show some
prehistoric humans (4000 BC) had TB, and researchers have found tubercular decay in
the spines of Egypti anmummies dating from 3000 to 2400 BC. Genetic studies suggest
the presence of TB in the Americas from about AD 100.

Before the Industrial Revolution, folklore often associated tuberculosis with vampires.
When one member of a family died from the disease, the other infected members would
lose their health slowly. People believed this was caused by the original person with TB
draining the life from the other family members.

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 Development of treatments

In Europe, rates of tuberculosis began to rise in the early 1600s to a peak level in the
1800s, when it caused nearly 25% of all deaths. In the 18th and 19th century, tuberculosis
had become epidemic in Europe, showing a seasonal pattern. Tuberculosis caused
widespreadpublic concern in the 19th and early 20th centuries as the disease became
common among the urban poor. In 1815, one in four deaths in England was due to
"consumption". By 1918, TB still caused one in six deaths in France. After TB was
determined to be contagious, in the 1880s, it was put on a notifiable-disease list in Britain;
campaigns started to stop people from spitting in public places, and the infected poor
were "encouraged" to enter sanatoria that resembled prisons (the sanatoria for the middle
and upper classes offered excellent care and constant medical attention). Whatever the
benefits of the "fresh air" and labor in the sanatoria, even under the best conditions, 50%
of those who entered died within five years (c. 1916).

Robert Koch did not believe the cattle and human tuberculosis diseases were similar,
which delayed the recognition of infected milk as a source of infection. During the first
half of the1900s, the risk of transmission from this source was dramatically reduced after
the application of the pasteurization process. Koch announced a glycerin extract of the
tubercle bacilli as a "remedy" for tuberculosis in 1890, calling it "tuberculin".

Although it was not effective, it was later successfully adapted as a screening test for the
presence of presymptomatic tuberculosis. World Tuberculosis Day is marked on 24
March each year, the anniversary of Koch's original scientific announcement. When the
Medical Research Council formed in Britain in 1913, it initially focused on tuberculosis
research. Albert Calmette and Camille Guérin achieved the first genuine success in
immunization against tuberculosis in 1906, using attenuated bovine-strain tuberculosis. It
was called bacille Calmette–Guérin (BCG). The BCG vaccine was first used on humans
in 1921InFrance, but achieved widespread acceptance in the US, Great Britain, and
Germany only after World War II.

By the 1950s mortality in Europe had decreased about 90%. Improvements in sanitation,
vaccination, and other public-health measures began significantly reducing rates of
tuberculosis seven before the arrival of streptomycin and other antibiotics, although

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 Current Reemergence

Because of the emergence of multidrug-resistant tuberculosis (MDR-TB), surgery has been re-
introduced for certain cases of TB infections. It involves the removal of infected chest cavities
("bullae") in the lungs to reduce the number of bacteria and to increase exposure of the remaining
bacteria to antibiotics in the bloodstream. Hopes of eliminating TB ended with the rise of drug-
resistant strains in the 1980s. The subsequent resurgence of tuberculosis resulted in the
declaration of a global health emergency by the World Health Organization (WHO) in 1993.

Signs and symptoms

Figure 3.2

The main symptoms of variants and stages of tuberculosis are given, with many symptoms
overlapping with other variants, while others are more (but not entirely) specific for certain
variants. Multiple variants may be present simultaneously.

Tuberculosis may infect any part of the body, but most commonly occurs in the lungs (known as
pulmonary tuberculosis). Extrapulmonary TB occurs when tuberculosis develops outside of the
lungs, although extrapulmonary TB may coexist with pulmonary TB.

General signs and symptoms include fever, chills, night sweats, loss of appetite, weight loss, and

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fatigue. Significant nail clubbing may also occur.

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 Pulmonary

If a tuberculosis infection does become active, it most commonly involves the lungs (in
about 90% of cases). Symptoms may include chest pain and a prolonged cough producing
sputum. About 25% of people may not have any symptoms (i.e., they remain
asymptomatic). Occasionally, people may cough up blood in small amounts, and in very
rare cases, the infection may erode into the pulmonary artery or a Rasmussen's aneurysm,
resulting in massive bleeding. Tuberculosis may become a chronic illness and cause
extensive scarring in the upper lobes of the lungs. The upper lung lobes are more
frequently affected by tuberculosis than the lower ones. The reason for this difference is
not clear. It may be due to either better air flow, or poor lymph drainage within the upper
lungs.

 Extrapulmonary

Main article: Extrapulmonary tuberculosis. In 15–20% of active cases, the infection spreads
outside the lungs, causing other kinds of TB. These are collectively denoted as extrapulmonary
tuberculosis. Extrapulmonary TB occurs more commonly in people with a weakened immune
system and young children. In those with HIV, this occurs in more than 50% of cases. Notable
extrapulmonary infection sites include the pleura (in tuberculous pleurisy), the central nervous
system (in tuberculous meningitis), the lymphatic system (in scrofula of the neck), the
genitourinary system (in urogenital tuberculosis), and the bones and joints (in Pott disease of the
spine),among others. A potentially more serious, widespread form of TB is called "disseminated
tuberculosis"; it is also known as miliary tuberculosis. Miliary TB currently makes up about 10%
of extrapulmonary cases.

 Mycobacteria

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Figure 3.3

Scanning electron micrograph of M. tuberculosis. The main cause of TB is

Mycobacterium tuberculosis (MTB), a small, aerobic, nonmotile bacillus. The high lipid
content of this pathogen accounts for many of its unique clinical characteristics. It divides
every 16 to 20 hours, which is an extremely slow rate compared with other bacteria,
which usually divide in less than an hour. Mycobacteria have an outer membrane lipid
bilayer. If a Gram stain is performed, MTB either stains very weakly "Gram-positive" or
does not retain dye as a result of the high lipid and my colicacid content of its cell wall.
MTB can withstand weak disinfectants and survive in a drystate for weeks. In nature, the
bacterium can grow only within the cells of a host organism, but M. tuberculosis can be
cultured in the laboratory.

Using histological stains on expectorated samples from phlegm (also called sputum),
scientists can identify MTB under a microscope. Since MTB retains certain stains even
after being treated with acidic solution, it is classified as an acid-fast bacillus. The most
common acid-fast staining techniques are the Ziehl–Neelsen stain. and the Kinyoun stain,
which dye acid-fast bacilli a bright red that stands out against a blue background.

Auramine-rhodamine staining and fluorescence microscopy are also used. The M.

tuberculosis complex (MTBC) includes four other TB-causing mycobacteria: M. bovis
,M. africanum, M. canettii, and M. microti. M. africanum is not widespread, but it is a
significant cause of tuberculosis in parts of Africa.

M. bovis was once a common cause of tuberculosis, but the introduction of

pasteurizedmilk has almost eliminated this as a public health problem in developed
countries.

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Figure 3.4 Public health campaigns in the 1920s tried to halt the spread of TB.

Fig. 3.5 Image explaining the transmission of TB

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Figure. 3.6 Image shows general symptoms of TB

5. TRANSMISSION

When people with active pulmonary TB cough, sneeze, speak, sing, or spit, they expel
infectious aerosol droplets 0.5 to 5.0 µm in diameter. A single sneeze can release up to
40,000 droplets Each one of these droplets may transmit the disease, since the infectious
dose of tuberculosis is very small (the inhalation of fewer than 10 bacteria may cause an
infection).

 Risk of transmission

People with prolonged, frequent, or close contact with people with TB are at particularly
high risk of becoming infected, with an estimated 22% infection rate.

A person with active but untreated tuberculosis may infect 10–15 (or more) other people
per year.

Transmission should occur from only people with active TB – those with latent infection
are not thought to be contagious. The probability of transmission from one person to

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another depends upon several factors, including the number of infectious droplet sex
pelled by the carrier, the effectiveness of ventilation, the duration of exposure, the
virulence of the M. tuberculosis strain, the level of immunity in the uninfected person,
and others. The cascade of person-to-person spread can be circumvented by segregating
those with active ("overt") TB and putting them on anti-TB drug regimens. After about
two weeks of effective treatment, subjects with nonresistant active infections generally do
not remain contagious to others.

If someone does become infected, it typically takes three to four weeks before the newly
infected person becomes infectious enough to transmit the disease to others.

 Risk factors

This is a particular problem in sub-Saharan Africa, where HIV infection rates are high.

Of those without HIV infection who are infected with tuberculosis, about 5–10% develop
active disease during their lifetimes; in contrast, 30% of those co-infected with HIV
develop the active disease.

Use of certain medications, such as corticosteroids and infliximab (an anti-αTNF

monoclonal antibody), is another important risk factor, especially in the developed world.
Other risk factors include: alcoholism, diabetes mellitus (3-fold increased risk),silicosis
(30-fold increased risk), tobacco smoking (2-fold increased risk),indoor air pollution,
malnutrition, young age, recently acquired TB infection, recreational drug use, severe
kidney disease, low body weight, organ transplant, head and neck cancer, and genetic
susceptibility(the overall importance of genetic risk factors remains undefined).

 Infection susceptibility

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Figure 5.1

Tobacco smoking increases the risk of infections (in addition to increasing the risk of
active disease and death). Additional factors increasing infection susceptibility include
young age. Pathogenesis Robert Carswell's illustration of tubercle About 90% of those
infected with M. tuberculosis have asymptomatic, latent TB infections (sometimes called
LTBI),with only a 10% lifetime chance that the latent infection will progress to overt,
active tuberculous disease. In those with HIV, the risk of developing active TB increases
to nearly 10% a year. If effective treatment is not given, the death rate for active TB cases
is up to 66%.

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Figure 5.2 Microscopy of tuberculous epididymitis. H&E stain

TB infection begins when the mycobacteria reach the alveolar air sacs of the lungs, where
they invade and replicate within endosomes of alveolar macrophages.

Macrophages identify the bacterium as foreign and attempt to eliminate it by

phagocytosis. During this process, the bacterium is enveloped by the macrophage and
stored temporarily in a membrane-bound vesicle called a phagosome. The phagosome
then combines with a lysosome to create a phagolysosome. In the phagolysosome, the cell
attempts to use reactive oxygen species and acid to kill the bacterium. However, M.
tuberculosis has a thick, waxy mycolic acid capsule that protects it from these toxic
substances. M. tuberculosis is able to reproduce inside the macrophage and will
eventually kill the immune cell.

The primary site of infection in the lungs, known as the Ghon focus, is generally located
in either the upper part of the lower lobe, or the lower part of the upper lobe. Tuberculosis
of the lungs may also occur via infection from the blood stream. This is known as a
Simonfocus and is typically found in the top of the lung.

This hematogenous transmission can also spread infection to more distant sites, such as
peripheral lymph nodes, the kidneys, the brain, and the bones.

All parts of the body can be affected by the disease, though for unknown reasons it rarely
affects the heart, skeletal muscles , pancreas, or thyroid.

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Tuberculosis is classified as one of the granulomatous inflammatory diseases.

Macrophages, epithelioid cells, T lymphocytes, B lymphocytes, and fibroblasts aggregate
to form granulomas, with lymphocytes surrounding the infected macrophages. When
other macrophages attack the infected macrophage, they fuse together to form a giant
multinucleated cell in the alveolar lumen. The granuloma may prevent dissemination of
the mycobacteria and provide a local environment for interaction of cells of the immune
system.
However, more recent evidence suggests that the bacteria use the granulomas to avoid
destruction by the host's immune system. Macrophages and dendritic cells in the
granulomas are unable to present antigen to lymphocytes; thus the immune response is
suppressed.
Bacteria inside the granuloma can become dormant, resulting in latent infection Another
feature of the granulomas is the development of abnormal cell death (necrosis) in the
center of tubercles. To the naked eye, this has the texture of soft, white cheese and is
termed caseous necrosis.

If TB bacteria gain entry to the blood stream from an area of damaged tissue, they
canspread throughout the body and set up many foci of infection, all appearing as tiny,
white tubercles in the tissues.

This severe form of TB disease, most common in young children and those with HIV, is
called miliary tuberculosis. People with this disseminated TB have a high fatality rate
even with treatment(about 30%).In many people, the infection waxes and wanes. Tissue
destruction and necrosis are of ten balanced by healing and fibrosis.

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6. DIAGNOSIS

Tuberculosis diagnosis

Figure 6.1 M. tuberculosis (stained red) in sputum

 Active tuberculosis

Diagnosing active tuberculosis based only on signs and symptoms is difficult, as is diagnosing the
disease in those who have a weakened immune system. A diagnosis of TB should, however, be
considered in those with signs of lung disease or constitutional symptoms lasting longer than two
weeks.

A chest X-ray and multiple sputum cultures for acid-fast bacilli are typically part of the initial
evaluation . Interferon-γ release assays (IGRA) and tuberculin skin tests are of little use in most
of the developing world . IGRA have similar limitations in those with HIV.

A definitive diagnosis of TB is made by identifying M. tuberculosis in a clinical sample (e.g.,

sputum, pus, or a tissue biopsy). However, the difficult culture process for this slow-growing
organism can take two to six weeks for blood or sputum culture. Thus, treatment is often begun
before cultures are confirmed.

Nucleic acid amplification tests and adenosine deaminase testing may allow rapid diagnosis of
TB. Blood tests to detect antibodies are not specific or sensitive, so they are not recommended.

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 Latent tuberculosis

Figure 6.2 Mantoux tuberculin skin test

The Mantoux tuberculin skin test is often used to screen people at high risk for TB.
Those who have been previously immunized with the Bacilli Calmette-Guerin vaccine may have
a false-positive test result.
The test may be falsely negative in those with sarcoidosis, Hodgkin 'slymphoma, malnutrition,
and most notably, active tuberculosis. Interferon gamma release assays, on a blood sample, are
recommended in those who are positive to the Mantoux test.
These are not affected by immunization or most environmental mycobacteria, so they generate
fewer false-positive results.
However, they are affected by M. szulgai, M. marinum, and M. kansasii. IGRAs may increase
sensitivity when used in addition to the skin test, but may be less sensitive than the skin test when
used alone.
The US Preventive Services Task Force (USPSTF) has recommended screening people who are at
high risk for latent tuberculosis with either tuberculin skin tests or interferon-gamma release
assays.
While some have recommend testing health care workers, evidence of benefit for this is poor as of
2019.
The Centers for Disease Control and Prevention (CDC) stopped recommending yearly testing of
health care workers without known exposure in 2019.
Prevention

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Figure 6.3 Tuberculosis public health campaign in Ireland, c. 1905

Tuberculosis prevention and control efforts rely primarily on the vaccination of infants and the
detection and appropriate treatment of active cases. The World Health Organization (WHO)
has achieved some success with improved treatment regimens, and a small decrease in case
numbers. Some countries have legislation to involuntarily detain or examine those suspected to
have tuberculosis, or involuntarily treat them if infected.

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7. VACCINES

The only available vaccine as of 2021 is bacillus Calmette-Guérin (BCG).

In children it decreases the risk of getting the infection by 20% and the risk of infection turning
into active disease by nearly 60%.
It is the most widely used vaccine worldwide, with more than 90% of all children being vaccinated.
The immunity it induces decreases after about ten years. As tuberculosis is uncommon in most of
Canada, Western Europe, and the United States, BCG is administered to only those people at high
risk.

Part of the reasoning against the use of the vaccine is that it makes the tuberculin skin test falsely
positive, reducing the test's usefulness as a screening tool.

Several vaccines are being developed.

Intradermal MVA85A vaccine in addition to BCG injection is not effective in preventing
tuberculosis.

 Public health
Public health campaigns which have focused on overcrowding, public spitting and regular
sanitation (including hand washing) during the 1800s helped to either interrupt or slow spread
which when combined with contact tracing, isolation and treatment helped to dramatically curb the
transmission of both tuberculosis and other airborne diseases which led to the elimination of
tuberculosis as a major public health issue in most developed economies.

Other risk factors which worsened TB spread such as malnutrition were also ameliorated, but since
the emergence of HIV a new population of immunocompromised individuals was available for TB
to infect.

The World Health Organization (WHO) declared TB a "global health emergency" in 1993, and in
2006, the Stop TB Partnership developed a Global Plan to Stop Tuberculosis that aimed to save
14 million lives between its launch and2015.

A number of targets they set were not achieved by 2015, mostly due to the increase in HIV-
associated tuberculosis sand the emergence of +multiple drug-resistant Tuberculosis. A
tuberculosis classification system developed by the American Thoracic Society is used primarily in
public health programs.

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In 2015, it launched the End TB Strategy to reduce deaths by 95% and incidence by 90% before
2035. The goal of tuberculosis elimination is hampered by the lack of rapid testing, of short and
effective treatment courses, and of completely effective vaccines.
The benefits and risks of giving anti-tubercular drugs in those exposed to MDR-TB is unclear.

Making HAART therapy available to HIV-positive individuals significantly reduces the risk of
progression to an active TB infection by up to 90% and can mitigate the spread through this
population

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8. TREATMENT

Treatment of TB uses antibiotics to kill the bacteria. Effective TB treatment is difficult, due to the
unusual structure and chemical composition of the mycobacterial cell wall, which hinders the
entry of drugs and makes many antibiotics ineffective.
Active TB is best treated with combinations of several antibiotics to reduce the risk of the bacteria
developing antibiotic resistance. The routine use of rifabutin instead of rifampicin in HIV-positive
people with tuberculosis is of unclear benefit as of 2007.
Acetylsalicylic acid (aspirin) at a dose of 100 mg per day has been shown to improve clinical
signs and symptoms, reduce cavitary lesions, lower inflammatory markers, and increase the rate
of sputum-negative conversion in patients with pulmonary tuberculosis.
 Latent TB
Latent TB is treated with either isoniazid or rifampin alone, or a combination of isoniazid with
either rifampicin or rifapentine.
The treatment takes three to nine months depending on the medications used. People with latent
infections are treated to prevent them from progressing to active TB disease later in life.
Education or counselling may improve the latent tuberculosis treatment completion rates.
 New onset
The recommended treatment of new-onset pulmonary tuberculosis, as of 2010, is six months of a
combination of antibiotics containing rifampicin, isoniazid, pyrazinamide, and ethambutol for
the first two months, and only rifampicin and isoniazid for the last four months. Where resistance
to isoniazid is high, ethambutol may be added for the last four months as an alternative. Treatment
with anti-TB drugs for at least 6 months results in higher success rates when compared with
treatment less than 6 months, even though the difference is small. Shorter treatment regimen may
be recommended for those with compliance issues.
There is also no evidence to support shorter anti-tuberculosis treatment regimens when compared
to a 6-month treatment regimen.
However recently, results from an international, randomized, controlled clinical trial indicate that
a four-month daily treatment regimen containing high-dose, or "optimized", rifapentine with
moxifloxacin (2PHZM/2PHM) is as safe and effective as the existing standard six-month daily
regimen at curing drug-susceptible tuberculosis (TB) disease.

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 Recurrent disease
If tuberculosis recurs, testing to determine which antibiotics it is sensitive to is important before
determining treatment. If multiple drug-resistant TB (MDR-TB) is detected, treatment with at
least four effective antibiotics for 18 to 24 months is recommended.
 Medication administration
Directly observed therapy, i.e., having a health care provider watch the person take their
medications, is recommended by the World Health Organization (WHO) in an effort to reduce the
number of people not appropriately taking antibiotics.
The evidence to support this practice over people simply taking their medications independently is
of poor quality.
There is no strong evidence indicating that directly observed therapy improves the number of
people who were cured or the number of people who complete their medicine.
Moderate quality evidence suggests that there is also no difference if people are observed at home
versus at a clinic, or by a family member versus a health care worker.
Methods to remind people of the importance of treatment and appointments may result in a small
but important improvement.
There is also not enough evidence to support intermittent rifampicin-containing therapy given two
to three times a week has equal effectiveness as daily dose regimen on improving cure rates and
reducing relapsing rates.
There is also not enough evidence on effectiveness of giving intermittent twice or thrice weekly
short course regimen compared to daily dosing regimen in treating children with tuberculosis.
Medication resistance
Primary resistance occurs when a person becomes infected with a resistant strain of TB. A person
with fully susceptible MTB may develop secondary (acquired) resistance during therapy
because of inadequate treatment, not taking the prescribed regimen appropriately (lack of
compliance), or using low-quality medication.
Drug-resistant TB is a serious public health issue in many developing countries, as its treatment is
longer and requires more expensive drugs. MDR-TB is defined as resistance to the two most
effective first-line TB drugs: rifampicin and isoniazid. Extensively drug- resistant TB is also
resistant to three or more of the six classes of second-line drugs. It was first observed in 2003 in
Italy, but not widely reported until 2012, and has also been found in Iran and India. There is some
efficacy for linezolid to treat those with XDR-TB but side effects and discontinuation of
medications were common. Bed aquiline is tentatively supported for use in multiple drug-

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resistant.
XDR-TB is a term sometimes used to define extensively resistant TB, and constitutes one in ten
cases of MDR-TB. Cases of XDR TB have been identified in more than 90% of countries
For those with known rifampicin or MDR-TB, molecular tests such as the Genotype MTBD Rs l
Assay (performed on culture isolates or smear positive specimens) may be useful to detect
second-line anti-tubercular drug resistance.

Figure 8.1

Age-standardized disability-adjusted life years caused by tuberculosis per 100,000

inhabitants in2004.

Progression from TB infection to overt TB disease occurs when the bacilli overcome the immune
system defenses and begin to multiply. In primary TB disease (some 1–5% of cases), this occurs
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soon after the initial infection. However, in the majority of cases, a latent infection occurs with
no obvious symptoms. These dormant bacilli produce active tuberculosis in 5–10% of these
latent cases, often many years after infection.

The risk of reactivation increases with immunosuppression, such as that caused by infection with
HIV. In people coinfected with M. tuberculosis and HIV, the risk of reactivation increases to
10% per year. Studies using DNA fingerprinting of M. tuberculosis strains have shown
reinfection contributes more substantially to recurrent TB than previously thought, with
estimates that it might account for more than 50% of reactivated cases in areas where TB is
common. The chance of death from a case of tuberculosis is about 4% as of 2008, down from 8%
in 1995.
In people with smear-positive pulmonary TB (without HIV co-infection), after 5 years without
treatment, 50-60% die while 20-25% achieve spontaneous resolution (cure). TB is almost always
fatal in those with untreated HIV co-infection and death rates are increased even with
antiretroviral treatment of HIV.

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9. EPIDEMIOLOGY

Roughly one-quarter of the world's population has been infected with M. tuberculosis, with new
infections occurring in about 1% of the population each year. However, most infections with M.
tuberculosis do not cause disease, and 90–95% of infections remain asymptomatic. In 2012, an
estimated 8.6 million chronic cases were active. In 2010, 8.8 million new cases of
tuberculosis were diagnosed, and 1.20–1.45 million deaths occurred (most of these occurring in
developing countries). Of these, about 0.35 million occur in those also infected with HIV. In 2018,
tuberculosis was the leading cause of death worldwide from a single infectious agent. The total
number of tuberculosis cases has been decreasing since 2005, while new cases have decreased
since 2002.
Tuberculosis incidence is seasonal, with peaks occurring every spring and summer. The reasons for
this are unclear, but may be related to vitamin D deficiency during the winter. There are also
studies linking tuberculosis to different weather conditions like low temperature, low humidity and
low rainfall. It has been suggested that tuberculosis incidence rates may be connected to climate
change.
 At-risk groups
Tuberculosis is closely linked to both overcrowding and malnutrition, making it one of the
principal diseases of poverty. Those at high risk thus include: people who injectillicit drugs,
inhabitants and employees of locales where vulnerable people gather (e.g., prisons and homeless
shelters), medically underprivileged and resource-poor communities, high- risk ethnic minorities,
children in close contact with high-risk category patients, and health- care providers serving these
patients.
The rate of tuberculosis varies with age. In Africa, it primarily affects adolescents and young
adults. However, in countries where incidence rates have declined dramatically (such as the
United States), tuberculosis is mainly a disease of the elderly and
immunocompromised (risk factors are listed above).Worldwide, 22 "high-burden" states or
countries together experience 80% of cases as well as 83% of deaths.
In Canada and Australia, tuberculosis is many times more common among the Indigenous peoples,
especially in remote areas. Factors contributing to this include higher prevalence of predisposing
health conditions and behaviors, and overcrowding and poverty. In some Canadian Indigenous
groups, genetic susceptibility may play a role.
Socioeconomic status (SES) strongly affects TB risk. People of low SES are both more likely to

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contract TB and to be more severely affected by the disease. Those with low SES are more likely to
be affected by risk factors for developing TB (e.g., malnutrition, indoor air pollution, HIV co-
infection, etc.), and are additionally more likely to be exposed to crowded and poorly ventilated
spaces. Inadequate healthcare also means that people with active disease who facilitate spread are
not diagnosed and treated promptly; sick people thus remain in the infectious state and (continue
to) spread the infection.
 Geographical epidemiology
The distribution of tuberculosis is not uniform across the globe; about 80% of the population in
many African, Caribbean, South Asian, and eastern European countries test positive in tuberculin
tests, while only 5–10% of the U.S. population test positive. Hopes of totally controlling the
disease have been dramatically dampened because of many factors, including the difficulty of
developing an effective vaccine, the expensive and time- consuming diagnostic process, the
necessity of many months of treatment, the increase in HIV-associated tuberculosis, and the
emergence of drug-resistant cases in the 1980s.
In developed countries, tuberculosis is less common and is found mainly in urban areas. In Europe,
deaths from TB fell from 500 out of 100,000 in 1850 to 50 out of 100,000 by 1950. Improvements
in public health were reducing tuberculosis even before the arrival of antibiotics, although the
disease remained a significant threat to public health, such that when the Medical Research Council
was formed in Britain in 1913 its initial focus was tuberculosis research.
In 2010, rates per 100,000 people in different areas of the world were: globally 178, Africa 332, the
Americas 36, Eastern Mediterranean 173, Europe 63, Southeast Asia 278, and Western Pacific
139.
 Russia
Russia has achieved particularly dramatic progress with a decline in its TB mortality rate from 61.9
per 100,000 in 1965 to 2.7 per 100,000 in 1993;however, mortality rate increased
to 24 per 100,000 in 2005 and then recoiled to 11 per 100,000 by 2015.
 China
China has achieved particularly dramatic progress, with about an 80% reduction in its TB mortality
rate between 1990 and 201 The number of new cases has declined by 17% between 2004 and 2014.
 Africa
In 2007, the country with the highest estimated incidence rate of TB was Eswatini, with 1,200
cases per 100,000 people. In 2017, the country with the highest estimated incidence rate as a % of
the population was Lesotho, with 665 cases per 100,000 people. In South Africa, 54 200 people

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died in 2022 from TB. The incidence rate was 468 per 100 000 people; in 2015, this was 988 per
100 000. The total incidence was 280 000 in 2022; in 2015, this was 552 000.
 India
As of 2017, India had the largest total incidence, with an estimated 2,740,000 cases.
According to the World Health Organization (WHO), in 2000–2015, India's estimated mortality
rate dropped from 55 to 36 per 100,000 population per year with estimated 480 thousand people
died of TB in 2015. In India a major proportion of tuberculosis patients are being treated by private
partners and private hospitals. Evidence indicates that the tuberculosis national survey does not
represent the number of cases that are diagnosed and recorded by private clinics and hospitals in
India.
 North America
In the United States, Native Americans have a fivefold greater mortality from TB, and racial and
ethnic minorities accounted for 84% of all reported TB cases. The overall tuberculosis case rate in
the United States was 3 per 100,000 persons in 2017.In Canada, tuberculosis was endemic in some
rural areas as of 1998.
 Western Europe
In 2017, in the United Kingdom, the national average was 9 per 100,000 and the highest incidence
rates in Western Europe were 20 per 100,000 in Portugal.

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Figure 9.1 Number of new cases of tuberculosis per 100,000 people in 2016

Figure 9.2 Tuberculosis deaths per million persons in 2012

Figure 9.3 Tuberculosis deaths by region, 1990 to 2017

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 Names
Tuberculosis has been known by many names from the technical to the familiar.
Phthisis (Φθισις) is a Greek word for consumption, an old term for pulmonary tuberculosis;
around 460 BCE, Hippocrates described phthisis as a disease of dry seasons.
The abbreviation TB is short for tubercle bacillus. Consumption was the most common
nineteenth century English word for the disease, and was also in use well into the twentieth
century. The Latin root con meaning 'completely' is linked to summer meaning 'to take up from
under'.

Figure 9.4

In The Life and Death of Mr. Badman by John Bunyan, the author calls consumption "the captain
[193]
of all these men of death." "Great white plague" has also been used.

 Art and literature

Painting The Sick Child by Edvard Munch, 1885–1886, depicts the illness of his sister Sophie, who
died of tuberculosis when Edvard was 14; his mother also died of the disease.
Tuberculosis was for centuries associated with poetic and artistic qualities among those infected,
and was also known as "the romantic disease". Major artistic figures such as the poets John Keats,
Percy Bysshe Shelley, and Edgar Allan Poe, the composer Frédéric Chopin, the playwright

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Anton Chekhov, the novelists Franz Kafka, Katherine Mansfield, Charlotte Brontë, Fyodor
Dostoev sky, Thomas Mann, W. Somerset Maugham, George Orwell, and Robert Louis
Stevenson, and the artists Alice Neel, Jean-Antoine Watteau, Elizabeth Siddal, Marie Bashkirt
seff, Edvard Munch, Aubrey Beardsley and Amedeo Modigliani either had the disease or were
surrounded by people who did. A widespread belief was that tuberculosis assisted artistic talent.
Physical mechanisms proposed for this effect included the slight fever and toxaemia that it
caused, allegedly helping them to see life more clearly and to act decisively. Tuberculosis formed
an often-reused theme in literature, as in Thomas Mann's The Magic Mountain, set in a
sanatorium; in music, as in Van Morrison's song "T.B. Sheets" in opera, as in Puccini's Labohème
and Verdi's La Traviatain art, as in Munch's painting of his ill sister; and in film, such as the 1945
The Bells of St. Mary's starring Ingrid Bergman as a nun with tuberculosis.
 Public health efforts
Further information: Tuberculosis elimination
In 2014, the WHO adopted the "End TB" strategy which aims to reduce TB incidence by 80%
and TB deaths by 90% by 2030 The strategy contains a milestone to reduce TB incidence by
20% and TB deaths by 35% by 2020 However, by 2020 only a 9% reduction in incidence per
population was achieved globally, with the European region achieving 19% and the African
region achieving 16% reductions Similarly, the number of deaths only fell by 14%, missing the
2020 milestone of a 35% reduction, with some regions making better progress (31% reduction in
Europe and 19% in Africa) Correspondingly, also treatment, prevention and funding milestones
were missed in 2020, for example only 6.3 million people were started on TB prevention short of
the target of 30 million World Health Organization (WHO), the Bill and Melinda Gates
Foundation, and the U.S. government are subsidizing a fast-acting diagnostic tuberculosis test for
use in low- and middle-income countries as of 2012 In addition to being fast-acting, the test can
determine if there is resistance to the antibiotic rifampicin which may indicate multi-drug
resistant tuberculosis and is accurate in those who are also infected with HIV. Many resource-
poor places as of 2011 have access to only sputum micros copy
India had the highest total number of TB cases worldwide in 2010, in part due to poor disease
management within the private and public health care sector. n Programs such as the Revised
National Tuberculosis Control Program are working to reduce TB levels among people
receiving public healthcare.
A 2014 EIU-healthcare report finds there is a need to address apathy and urges for increased
funding. The report cites among others Lucica Ditui "[TB] is like an orphan. It has been neglected

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even in countries with a high burden and often forgotten by donors and those investing in health
interventions." Slow progress has led to frustration, expressed by the executive director of the
Global Fund to Fight AIDS, Tuberculosis and Malaria – Mark Dybul: "we have the tools to end
TB as a pandemic and public health threat on the planet, but we are not doing it." Several
international organizations are pushing for more transparency in treatment, and more countries
are implementing mandatory reporting of cases to the government as of 2014, although adherence
is often variable. Commercial treatment providers may at times overprescribe second-line drugs
as well as supplementary treatment, promoting demands for further regulations. The government
of Brazil provides universal TB care, which reduces this problem. Conversely, falling rates of TB
infection may not relate to the number of programs directed at reducing infection rates but may be
tied to an increased level of education, income, and health of the population. Costs of the disease,
as calculated by the World Bank in 2009 may exceed US$150 billion per year in "high burden"
countries. Lack of progress eradicating the disease may also be due to lack of patient follow-up
– as among the 250 million rural migrants in China There is insufficient data to show that active
contact tracing helps to improve case detection rates for tuberculosis Interventions such as house-
to-house visits, educational leaflets, mass media strategies, educational sessions may increase
tuberculosis detection rates in short- term. There is no study that compares new methods of
contact tracing such as social network analysis with existing contact tracing methods
 Stigma
Slow progress in preventing the disease may in part be due to stigma associated with TB. Stigma
may be due to the fear of transmission from affected individuals. This stigma may additionally
arise due to links between TB and poverty, and in Africa, AIDS Such stigmatization may be both
real and perceived; for example, in Ghana, individuals with TB are banned from attending public
gatherings. Stigma towards TB may result in delays in seeking treatment lower treatment
compliance, and family members keeping cause of death secret – allowing the disease to spread
further. In contrast, in Russia stigma was associated with increased treatment compliance. TB
stigma also affects socially marginalized individuals to a greater degree and varies between
regions.
One way to decrease stigma may be through the promotion of "TB clubs", where those infected
may share experiences and offer support, or through counseling Some studies have shown TB
education programs to be effective in decreasing stigma, and may thus be effective in increasing
treatment adherence. Despite this, studies on the relationship between reduced stigma and
mortality are lacking as of 2010, and similar efforts to decrease stigma surrounding AIDS have

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been minimally effective. Some have claimed the stigma to be worse than the disease, and
healthcare providers may unintentionally reinforce stigma, as those with TB are often perceived
as difficult or otherwise undesirable. A greater understanding of the social and cultural
dimensions of tuberculosis may also help with stigma reduction.
10. CONCLUSION
Tuberculosis remains a deadly disease throughout the world. Many efforts to remove TB have
been hampered due to poverty, lack of health care access, drug resistance, immunosuppressed
populations (e.g. HIV infected persons, Diabetes patient or any other infection) and global
migration. Effective management is carried out by using a combination of clinical, radiographic,
microbiological, histopathologic methods and initiation of appropriate multidrug therapy. In
addition to the effective treatment of patients with active TB, public health management strategies
include diagnosis, contact investigation, and testing of persons who came into close contact with
patients with active TB. The increasing population, poverty, improper treatment is the main
reason behind the growth of TB. Short course chemotherapy has been considered to be very
effective and fruitful in the treatment of TB. Some mandatory steps might be taken to minimising
the resistance problem in antitubercular drugs and to provide better efficacy and potent
therapeutic effect.
The conclusion of a tuberculosis review article typically summarizes the key findings, discusses
implications for further research or clinical practice, and may suggest potential interventions or
areas for improvement in tuberculosis prevention, diagnosis, and treatment. It may also highlight
any limitations of the study or gaps in current understanding that need to be addressed in future
research.
"In conclusion, this review has highlighted the significant burden of tuberculosis globally,
particularly in low- and middle-income countries. Despite advances in diagnosis and treatment,
challenges remain in controlling the spread of the disease, including drug resistance, limited
access to healthcare services, and social determinants of health. Moving forward, it is imperative
to prioritize efforts in research and public health interventions to address these challenges. This
may involve developing new diagnostic tools, improving access to affordable and effective
treatments, implementing targeted prevention strategies, and addressing social and economic
factors that contribute to the persistence of tuberculosis. Collaboration between governments,
healthcare providers, researchers, and communities will be essential in achieving the goal of
ending the tuberculosis epidemic by 2030, as outlined by the Sustainable Development Goals."
Our analysis has illuminated several key themes and areas for future exploration. Firstly, the

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emergence of drug-resistant strains poses a formidable threat to tuberculosis control efforts,

necessitating continued surveillance, research, and the development of novel therapeutics.
Additionally, the persistent socio-economic determinants of tuberculosis, including poverty,
overcrowded living conditions, and limited access to healthcare, highlight the importance of
addressing broader social inequalities in combating the disease.
Furthermore, the advent of new technologies, such as molecular diagnostics and whole-genome
sequencing, presents promising avenues for improving early detection and treatment monitoring,
particularly in resource-limited settings. However, the translation of these innovations into
accessible and affordable tools for frontline healthcare providers remains a critical challenge.
Moreover, the intersectionality of tuberculosis with other infectious diseases, such as HIV/AIDS
and COVID-19, underscores the importance of integrated healthcare approaches and strengthened
health systems to ensure comprehensive and effective care for affected individuals.
Looking ahead, concerted efforts are needed to advance the global tuberculosis agenda. This
includes sustained investment in research and development, enhanced international collaboration,
and the implementation of evidence-based policies and interventions tailored to local contexts.
Additionally, prioritizing community engagement, stigma reduction, and patient-centered care
approaches are essential for fostering trust, improving treatment adherence, and promoting health
equity.
In conclusion, while the road ahead may be challenging, the fight against tuberculosis is far from
insurmountable. By harnessing the collective expertise and resources of governments, healthcare
providers, researchers, and communities, we can strive towards the ambitious goal of ending the
tuberculosis epidemic and ensuring a healthier, more equitable future for all."

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