Leprosy

Azin Ayatollahi, MD
Assistant Professor of Dermatology

Center for Research and Training in Skin Diseases and Leprosy

Tehran University of Medical Sciences
 Definition

• Leprosy (Hansen’s disease) is a chronic

infection and its sequelae caused by
Mycobacterium leprae, and affecting primarily
skin and nerves.
• In advanced stages, the bacilli can be found in
all tissues except CNS, GI and lung.
 Epidemiology

• Subclinical infection is common in endemic

areas.
• It is most common between the ages of 10-14,
35-44 years (postprimary infection) and in
males.
• The tuberculoid form is more common, and
the median age of onset is less in TL.
 Etiology

• Etiologic agent is Mycobacterium

leprae (Hansen's bacillus), the
first bacterium ever discovered
and linked to a disease in human,
by Hansen in 1873
• It is an obligate, intracellular,
acid-fast bacillus.
• Generation time 12-14 days.
• Optimal growth temperature 32-
34ºC.
Taken from the University of Iowa website
 Etiology

• Principally infects
Schwann cells and the
skin.
• Similar isolates from all
over the world.
• Cannot be cultivated on
artificial media
• The organism can be
cultivated in mouse
footpads and armadillo
 A newly discovered cause of leprosy

• Mycobacterium lepromatosis
– The genome contained 3,215,823 nucleotides
– Matched ~87% with the M. leprae genome.
– Smallest of all mycobacterial genomes known to
date.
– Diverged ~10 million years ago from their last
common ancestor
– Han, et al. Genome Announc 2015; 3(3): e00513-15.
 M. leprosmatosis
• Identified so far in
leprosy patients from:
– Mexico, Canada, Brazil,
Burma, Singapore

• Likely the dominant

cause of leprosy in
Mexico
– Vera-Cabrera, et al. J Clin
Microbiol 2011; 49:4366-8.

-Han, et al. Int J Dermatol 2012; 51: 952–9.

 Classification – Ridley & Jopling

• TT-Tuberculoid leprosy
• BT- Borderline Tuberculoid leprosy
• BB-Borderline leprosy
• BL- Borderline Lepromatous leprosy
• LL- Lepromatous Leprosy
 Classification - WHO

• Multibacillary or paucibacillary
– The paucibacillary: TT and most BT
– The multibacillary: BB, BL and LL
 Nine-banded armadillo
(Dasypus novemcinctus)

• Only natural host other than humans

• Armadillos must have acquired M. leprae from humans
in the last 300 years, because:
– No pre-Columbian existence of leprosy in Americas
– Leprosy was well established in 1750 among settlers in
vicinity of New Orleans
• New evidence suggests that zoonotic transmission of
M. leprae from armadillos in the southern United
States.
-Balamayooran, et al. Clin Dermatol 2015; 33:108–15.
-Truman, et al. N Engl J Med 2011;364:1626-33.
 Zoonotic Leprosy?
• For transmission to occur
between armadillos and
humans, direct contact
with armadillos, such as
exposure to blood and
fresh tissue while
preparing the flesh for
cooking, likely provides
the greatest risk for
exposure to large numbers
of viable leprosy bacilli.
-Balamayooran, et al. Clin Dermatol 2015; 33:108–15.
 Transmission

• Probably transmitted via the inhalation of

respiratory droplets of multibacillary patients,
but the exact mechanism remains unknown.
• Interestingly, most leprosy cases in the U.S.
occur in TX and LA, where most armadillos
reside.
 Transmission

• Transmission requires:
– Untreated multibacillary patient
– Susceptible host
– Prolonged, close contact
• Incubation time of tuberculoid leprosy is up to
5 years; lepromatous leprosy: 20 years or
longer.
 Genetics

• Both genetic and environmental factors are

important in disease susceptibility and
expression.
• Monozygotic twin 60-80% and dizygotics
15-25% concordance
• A susceptibility locus on chromosome
10p13 has been identified in India.
• MHC class II antigens influence disease
expression: DR2 and DR3 in TL, DQ1 in
LL.
Pathogenesis
 Immunology

Tuberculoid leprosy
• Cell Mediated Immunity
• CD4/CD8=2
• Th1 cytokines (IL2, IL12, IL18, g-INF, GM-CSF)
• Higher expression of Toll-like receptors 1 & 2 on
APCs
Lepromatous leprosy
• Humoral Immunity
• CD8/CD4=2
• Th2 cytokines: IL4 – IL10
 Clinical Manifestations
Indeterminate Leprosy
• A few macules with ill-defined borders and no
anesthesia or signs of sensory or motor nerve
damage or hair loss
• Scalp, axilla and groins are spared.
• Slight pandermal perineurovascular and peri-
appendageal chronic inflammation.
• Without demonstrating bacilli: Diagnosis can only
be presumptive
 Clinical Manifestations
Indeterminate Leprosy
 Clinical Manifestations
Tuberculoid (TT) leprosy

• The lesions are scanty, dry, erythematous,

hypopigmented papules or plaques with
sharply defined edges.
• Anesthesia is prominent (except on the face).
• The number of lesions ranges from 1 to 5,
and the lesions heal rapidly on
chemotherapy.
Tuberculoid (TT) leprosy
Tuberculoid (TT) leprosy
 Clinical Manifestations
Borderline Tuberculoid (BT)

• The lesions are asymmetrical and may be

scanty.
• Dry, hairless plaques with central
hypopigmentation.
• Nerve enlargement is usually found and the
lesions are usually anesthetic.
Borderline Tuberculoid (BT)
 Clinical Manifestations
Borderline Borderline (BB)
• The lesions are irregularly dispersed and
shaped erythematous plaques with punched-
out centers.
• Dermal edema is prominent in the lesions.
• Macrophages are activated to epitheloid cells
Borderline Borderline (BB)
 Clinical Manifestations
Borderline Lepromatous (BL)
• Less numerous and less symmetrical than LL
lesions.
• Often display some central dimples.
• The lymphocytes are more prominent in BL and
there is a tendency for some activation of
macrophages to form poorly to moderately defined
granulomas.
• Perineural fibroblast proliferation forming an
typical “onion skin” in cross section.
Borderline Lepromatous (BL)
 Clinical Manifestations
Lepromatous Leprosy (LL)

• The lesions usually are numerous and symmetrically

arranged, scalp and flexures are spared.
• The patients are not notably hypoesthetic.
• Disturbances of sensation and nerve paralyses
develop after large peripheral nerve involved: glove
and stocking
• Most common involved nerves: ulnar, radial and
common peroneal nerves.
Lepromatous Leprosy (LL)
Lepromatous Leprosy (LL)
Lepromatous Leprosy (LL)
 Pure Neural Leprosy

• Asymmetric thickening of peripheral nerves

without skin lesions
• All types may occur in this form.
 Why disabilities occur?
• ¼ of patients will have permanent neurologic deficit.

• Disabilities such as loss of sensation and deformities

of hands/feet/eyes occur because:
– Late diagnosis and late treatment with MDT
– Advanced disease (MB leprosy)
– Leprosy reactions which involve nerves
– Lack of information on how to protect insensitive parts
 Muscle weakness and paralytic deformity

Nerve trunk damaged Deformity

Ulnar nerve Claw fingers
Median nerve Claw thumb
Radial nerve Drop-wrist
Common peroneal nerve Drop-foot
Posterior tibial nerve Claw toes
Facial nerve Lagophthalmos
 Leprosy Reactions
Type I Type II (Erythema nodosum
leprosum)
Seen in borderline patients, Seen in LL and BL, before,
mostly BL, common in first during or after Tx
year of Tx
Type IV Delayed Type III Hypersensitivity-
Hypersensitivity Humoral antibody response
causes vasculitis
Skin lesions become swollen and Fever, arthralgia and painful
erythematous, induces increased erythematous nodules
intraneural inflammation and
edema, which is damaging.
Type I reactions
Type I reactions
Type II reactions
Type II reactions
Type II reactions
 Difference between type-1
and type-2 reactions
Type-2 Type-1
Lepromatous (BL, LL) Borderline (BT, BB, BL) Spectrum
New nodules in crops Existing lesions develop erythema Skin lesions
and edema
Not so severe Frequent and severe Nerve damage
Fever, malaise, arthralgia, and Not common Systemic symptoms
lymphadenitis are common
They are very common Iritis, orchitis, and Other organ
glomerulonephritis do NOT occur
Relapse is common Relapse is infrequent Course
Broken bacilli Not seen AFB
Urine: Albuminuria Routine: normal Investigations
Type-3 antigen antibody reaction Type-4 antigen-antibody reaction Pathogenesis
(immune complex) raised IgG, IgM, (DTH)
C2 and C3
Edema with neutrophilic infiltrate Edema with reduced bacilli and Histopathology
and vasculitis increased lymphocytes, the
granulomas are disorganized
 Difference between reversal reaction
and relapse
Relapse Reversal
After 1 year of stopping Tx Within 4 weeks to 6 months Time of onset
during treatment or within 6
months after stopping treatment
Slow, gradual Sudden may occur overnight Speed of onset
Does not occur Frequent, may be seen in nerves Pain/tenderness
New lesions are minimal Several lesions appear New lesions
Erythema and infiltration at the Shiny, erythematous and swollen Old lesions
margins ONLY
May occur in one of few Many nerves are involved with Nerve involvement
nerves, loss of nerve function pain, tenderness, and loss of
develops slowly function
- Excellent Treatment with steroids
Absent May bepresent Systemic disturbance
Positive Negative Skin smears
 Systemic associations
• The eye is at risk due to involvement of nerves
V and VII.
• Wide dissemination is the rule in LL and BL,
but except for URT, eyes and testis, clinical
manifestations are rare.
• Leprosy and HIV do not influence the course
of each other, but HIV may predispose to
neuritis and reactions.
From Bologna et al (eds.).
2012
 Sequels of leprosy

.Madarosis, saddle nose, and blindness in the left eye

From Bologna et al. (eds.) 2012
 Sequels of leprosy

Eye involvement and bluish discoloration due to

treatment with clofazimine.
From: Bologna et al. (eds.) 2012
 Diagnosis
• Presence of 2 of 3:
1. Typical skin lesions with sensory loss
2. Sensory or motor neuropathy
3. Positive skin smear

Or

4. Enlargement of nerves
5. Anesthesia of skin
6. Typical skin lesions
 Diagnosis

• Paraclinical:
1.Slit-skin smears
2.Nasal secretions smear
3.Histopathology
4.PCR
5.Lepromin skin test
6.Serology
 How to diagnose leprosy?

• Examine skin
• Check for patches
• Test for sensation
• Count the number of
patches
• Look for damage to
nerves
 How to examine for leprosy?

• Examine in a well-lit room

• Examine the whole body
• Ask since when the patch was noticed
• Ask what treatments have been tried
• Test for sensation
• Look for any visible deformities
 Leprosy patches...

…. Can be pale, reddish

or copper coloured
…. Lack sensation to
pain, touch and heat
 Leprosy patches ...

…can be flat or raised

…do not itch
Leprosy patches ….

… can appear anywhere

… do not itch
… usually do not hurt
 Check for loss of sensation

• Take a pointed soft object

(feather, cotton wick)
• Lightly touch alternately
the patch and normal skin
• Ask the person to point
where they were touched
• In case of loss of sensation the person will be able to
point to where they were touched on the normal skin
but not on the patch.
 Consider the diagnosis of leprosy if:

• Simultaneous skin lesions and peripheral nerve

abnormalities
• A peripheral neuropathy of unknown type in a patient
in or from an endemic area, (so-called pure neuritic
leprosy)
• Birth or residence in an endemic area or a family
member with leprosy
• Simultaneous palsies of cranial nerves V and VII,
considered to leprosy until proven otherwise.
 What is not leprosy
• Skin patches which
– have normal feeling
– are present from birth
– cause itching
– are white, black, dark red or silver coloured
– show scaling
– appear and disappear periodically
– spread quickly
 What is not leprosy (cont.)

• Signs of damage to hands/feet/face without

loss of sensation
– due to other reasons like injury, accidents, burns,
birth defects
– due to other diseases like arthritis
– due to other conditions causing paralysis
 Slit-Skin Smear

• Ziehl-Neelsen method: weakly acid-fast

• Modifications of the Ziehl-Neelsen method
(collectively called Fite-Farraco stains)
• Bacilli are usually found in macrophage and nerves.
• Bacillary index (BI): the numbers of bacilli per oil
immersion field (OIF): 5-6 in LL, 3-4 in BL, 2 in
• BB, 1 in BT, 0 in TT.
• Morphological index (MI): the percentage of solid-
staining (viable) bacteria
BI - MI
 Lepromin Skin Test

• Lepromin: crude preparation of heat-killed bacilli from

lepromatous nodule or infected armadillo liver
• 0.1 ml of lepromin is injected intradermally
• Fernandez reaction: at 48 hours similar to PPD, cross-
reaction with other mycobacteria
• Mitsuda reaction: induration > 7 mm at 3-4 weeks, more
specific.
• It is positive in 100% of TT, 85% of BT, negative in BB to
LL, positive in healthy controls.
• It is more valuable in classification than diagnosis.
 PCR

• Several probes have been used.

• Negative in 50% of paucibacillary so positive
result is more helpful than negative result.
 Serology

• Lipoarabinomannan (LAM)
• Phenolic glycolipid (PGL)
• Protein antigens
• Various autoantibodies
• PGL serology is positive in 90% of MB, 40-
50% of PB, and 5-10% of healthy controls.
 Treatment

• Chemotherapy
– Multidrug therapy (MDT)
– ROM

• Physiotherapy
• Reconstructive Surgery
 Multi Drug Therapy (MDT)

• Multibacillary forms of • Paucibacillary forms

Leprosy -Tuberculoid
– Borderline -Borderline-tuberculoid
– Borderline-Lepromatous • Dapsone
– Lepromatous • Rifampicin
• Dapsone
Rifampicin
Clofazimine

www.who.int/lep/
 Treatment regimens

• PB Adult
(Treatment: 6 blister packs)
– Rifampicin 600 mg once a month
– Dapsone 100 mg every day

• MB Adult
(Treatment: 12 blister packs)
– Rifampicin 600 mg once a month
– Clofazimine 300 mg once a month
– Clofazimine 50 mg and dapsone 100
mg every day
 Newer drug combinations

ROM

Rifampicin Ofloxacin Minocycline

(600mg) (400mg) (100mg)

Recommended for two categories of leprosy:-

• Single skin lesion paucibacillary leprosy with one dose of
ROM. Patients have a high tendency to heal without specific
treatment
• Multibacillary leprosy – patients who can not accept
clofazimine of MDT. Treated with 24 monthly doses of ROM
 Managing reactions (1)

• Early diagnosis and prompt treatment of reactions

– Every patient should be informed about the signs
and symptoms of reactions
– Inform them to go as soon as possible to the health
centre
– Reassure patients that:
• reactions can be treated
• they are not a side-effect to MDT
• does not mean that MDT is not working
 Managing reactions (2)

• Rest is very important:

– Help to get leave from work or school for a few
days (e.g. medical certificate)
• Control of pain and fever
– Aspirin or paracetamol
• Continue MDT regularly
 Managing reactions (3)

• Reactions which only involve the skin:

– rest and pain-killers are usually sufficient.
– If there is no improvement within few days or worsening,
then specific treatment is needed
• Reactions which involves the nerves
– start treatment with a course of corticosteroids (e.g.
prednisolone) as soon as possible
– will control all signs/symptoms of reaction
 Treatment of ENL

• Thalidomide 100-200 mg QN, may be added

prednisolone (0.5-1.0 mg/kg), tapering later over 6-
8 weeks.
• Glucocorticoid in conjunction with clofazimine at
200 mg/day may be effective.
 Prevention

• Early case detection

• MDT
• Isolation
• Contact examination
• Chemoprophylaxis
• Vaccine
WHO disability grading
 Disabilities can be prevented
• The best way to prevent disabilities is:
– early diagnosis and prompt treatment with MDT

• Inform patients (specially MB) about common

signs/symptoms of reactions
• Ask them to come to the centre ASAP
• Start treatment for reaction ASAP
• Inform them how to protect insensitive hands/feet/eyes
• Involve family members in helping patients
What is elimination?
 What does elimination as a public health
problem mean?

• Reducing the case load to less than 1 case per

10 000 inhabitants
– by detecting and curing all cases of leprosy
– leading to a reduction in the source of infection
and the disease burden in communities
– so that leprosy is likely to disappear naturally as it
already has from many countries
 Global Leprosy Situation

• “The Enhanced global strategy for further

reducing the disease burden due to leprosy
2011–2015”
– Aims to reduce the global rate of new cases with
grade-2 (i.e. visible) disabilities per 100 000
population by at least 35% by the end of 2015,
compared with the baseline at the end of 2010.
– Underlines the importance of early detection and
quality of care in an integrated service setting.
 ‫وضعيت جذام‬
‫در‬
‫ايران‬
‫وزارت بهداشت‪ ،‬درمان و آموزش‬
‫پزشكي جمهوري اسالمي ايران‬
‫مركز مديريت بيماريها‪ ،‬اداره سل و‬
 ‫• اكنون موارد جذام بسيار محدود بوده و سالهاست كه اين‬
‫بيماري در ايران به مرحله حذف رسيده است ‪ .‬شناسايي موارد‬
‫جديد نيز در كشور از سال ‪ 1364‬روندي رو به كاهش داشته‬
‫است‪.‬‬
‫• اين روند نزولي كه بويژه در مناطق اندميك بيماري يعني‬
‫آذربايجان شرقي و غربي‪ ،‬اردبيل‪ ،‬گيالن‪ ،‬گلستان‪ ،‬خراسان‪،‬‬
‫سيستان و بلوچستان‪ ،‬هرمزگان‪ ،‬بوشهر‪ ،‬خوزستان‪ ،‬لرستان‪،‬‬
‫كرمانشاه‪ ،‬كردستان‪ ،‬قزوين‪ ،‬زنجان وتهران بخوبي نمايان مي‬
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very much for
your attention!