Leprosy Leprosy

Hansen’s diseaseHansen’s disease

Introduction Introduction

Leprosy is a chronic granulomatous infection of Leprosy is a chronic granulomatous infection of the skin and the peripheral nerves, with an the skin and the peripheral nerves, with an intracellular bacterium Mycobacterium Lepra.intracellular bacterium Mycobacterium Lepra.

Leprosy was recognized in the ancient Leprosy was recognized in the ancient civilization of China, Egypt, and India. The first civilization of China, Egypt, and India. The first known written mention of leprosy is dated known written mention of leprosy is dated 600BC.600BC.

IntroductionIntroduction Leprosy shows a wide range of clinical Leprosy shows a wide range of clinical

presentation from:presentation from:

Tuberculoid leprosy (TT) Tuberculoid leprosy (TT)

Borderline leprosy: borderline tuberculoid (BT), Borderline leprosy: borderline tuberculoid (BT), midborderline (BB), borderline lepromatous (BL).midborderline (BB), borderline lepromatous (BL).

Lepromatous leprosy (LL).Lepromatous leprosy (LL).

(Classified by Ridley & Jopling 1966)(Classified by Ridley & Jopling 1966)

A simpler field classifications depending on the A simpler field classifications depending on the number of skin lesions:number of skin lesions:

• Single skin lesion (one patch).Single skin lesion (one patch).

• Paucibacillary ( 2-5 patchs).Paucibacillary ( 2-5 patchs).

• Multibacillary more than 5 patchs)Multibacillary more than 5 patchs)

Etiologic agentEtiologic agent Mycobacterium Leprae, Mycobacterium Leprae,

discovered in 1873 by discovered in 1873 by G.A. Hansen.G.A. Hansen.

Intracellular parasite with Intracellular parasite with tropism for macrophages tropism for macrophages and Schwann cells.and Schwann cells.

Viable bacilli stained with Viable bacilli stained with carbol-fuchsin appear as carbol-fuchsin appear as solid rods with rounded solid rods with rounded ends, while those is ends, while those is irregular stain are dead.irregular stain are dead.

Etiologic agent Etiologic agent M. leprae is an acid & M. leprae is an acid &

alcohol fast alcohol fast (Ziehl-Neelsen)(Ziehl-Neelsen), , gram positive bacilli.gram positive bacilli.

Prefer to grow in cooler Prefer to grow in cooler regions of the body < regions of the body < 37ºc.37ºc.

It has never been It has never been cultivated extracellularly, cultivated extracellularly, but organism can but organism can replicate in mouse replicate in mouse footpad & 9-banded footpad & 9-banded armadilloarmadillo

Etiologic agentEtiologic agent Genome include 1605 genes encoding proteins Genome include 1605 genes encoding proteins

& 50 genes for stable RNA molecule.& 50 genes for stable RNA molecule.

More than half of the functional genes are More than half of the functional genes are replaced by inactive or pseudogenes, retaining replaced by inactive or pseudogenes, retaining the genes essential for Mycobacterial cell wall the genes essential for Mycobacterial cell wall formation.formation.

Thus M. leprae depend on host metabolic Thus M. leprae depend on host metabolic products, and this explain it’s slow rate of products, and this explain it’s slow rate of replication and inability to grow in culture.replication and inability to grow in culture.

(Shin Y,et al. 2000)(Shin Y,et al. 2000)

Etiologic agentEtiologic agent Mycobacterial cell wall contain several Mycobacterial cell wall contain several

targets for host immune response:targets for host immune response:

Phenolic glycolipid I (PGL-I).Phenolic glycolipid I (PGL-I).

Lipoarabinomannan.Lipoarabinomannan.

Other cell wall proteins purified from Other cell wall proteins purified from glycolipid component of cell wall.glycolipid component of cell wall.

Phenolic glycolipid I (PGL-I).Phenolic glycolipid I (PGL-I).

Prominent surface lipid specific for M. leprae.Prominent surface lipid specific for M. leprae.

Best characterized virulent factor:Best characterized virulent factor: Binds to C3,»»» phagocytosis of the bacterium by Binds to C3,»»» phagocytosis of the bacterium by

mononuclear phagocytes. mononuclear phagocytes. Protect against oxidative killing by hydroxyl radicals and Protect against oxidative killing by hydroxyl radicals and

superoxide anions. superoxide anions.

Phenolic glycolipid I (PGL-I).Phenolic glycolipid I (PGL-I).

• Specific tropism for Schwann cells:Specific tropism for Schwann cells: Trisaccharide terminal of PGL-I »»» G domain of Trisaccharide terminal of PGL-I »»» G domain of αα 2 2

chain of laminin 2, a basal component of lamina of chain of laminin 2, a basal component of lamina of Schwann cells restricted to peripheral nerves.Schwann cells restricted to peripheral nerves.

• Stimulates host immune response:Stimulates host immune response: Potent IgM antibody response, that is proportional to Potent IgM antibody response, that is proportional to

bacterial load and fall with therapy.bacterial load and fall with therapy.(Sridharan, et al. 2005)(Sridharan, et al. 2005)

Lipoarabinomannan:Lipoarabinomannan:

Modulates macrophages phagocytic activity, & proteins Modulates macrophages phagocytic activity, & proteins involved in cell wall synthesis.involved in cell wall synthesis.

Other cell wall proteins purified from glycolipid Other cell wall proteins purified from glycolipid component of cell wall:component of cell wall:

Act as potent T-cell antigens, stimulate protective Act as potent T-cell antigens, stimulate protective immunity in murine M. leprae infection.immunity in murine M. leprae infection.

(Britton & Lockwood, 2004)(Britton & Lockwood, 2004)

EpidemiologyEpidemiologyPrevalence:Prevalence: In the past 20 years more than 14 million In the past 20 years more than 14 million

patients have been cured.patients have been cured.

In 1985 In 1985 »»»»»» 12/10 000, dropped in 2000 »» > 12/10 000, dropped in 2000 »» > 1/10 000, with a 20% annual decrease in new 1/10 000, with a 20% annual decrease in new cases detected globally since 2001.cases detected globally since 2001.

Leprosy is eliminated from 113 countries of 122 Leprosy is eliminated from 113 countries of 122 where leprosy was considered a public health where leprosy was considered a public health problem in 1985.problem in 1985.

EpidemiologyEpidemiology In 9 countries in Africa, Asia & Latin America »»» more In 9 countries in Africa, Asia & Latin America »»» more

than 1/10 000than 1/10 000 Eighty three % of cases are present in 6 countries: India, Eighty three % of cases are present in 6 countries: India,

Brazil, Burma, Indonesia, Madagascar & Nepal.Brazil, Burma, Indonesia, Madagascar & Nepal. India account for 64% of cases world wide.India account for 64% of cases world wide.

(WHO, 2005)(WHO, 2005)

WHO African region leprosy elimination program WHO African region leprosy elimination program meeting in 2003meeting in 2003

EpidemiologyEpidemiology Primary host is human. Naturally occurring Primary host is human. Naturally occurring

infection is also reported armadillos in America & infection is also reported armadillos in America & African chimpanzee.African chimpanzee.

Sex: Male more affected than females (M/F ratio Sex: Male more affected than females (M/F ratio 1.5-2 to 1) except in some areas of Africa.1.5-2 to 1) except in some areas of Africa.

Age: All ages, about 20% of cases occur in Age: All ages, about 20% of cases occur in children below 10 years, but it is extremely rare children below 10 years, but it is extremely rare in infants.in infants.

Transmission Transmission Aerosol spread of nasal secretion, & uptake Aerosol spread of nasal secretion, & uptake

through nasal or respiratory mucosa.through nasal or respiratory mucosa.

M. Leprae in nasal secretion can survive up to M. Leprae in nasal secretion can survive up to 36 hours, or as much as nine days in tropical 36 hours, or as much as nine days in tropical areas.areas.

Proximity is an important determinant of Proximity is an important determinant of transmission, & incidence among houses hold transmission, & incidence among houses hold contacts:contacts:

8-10 for lepromatous leprosy.8-10 for lepromatous leprosy.2-4 for tuberculoid leprosy2-4 for tuberculoid leprosy

(Sridharan, et al. 2005)(Sridharan, et al. 2005)

Incubation PeriodIncubation Period

Varies widely from months to 30 yearsVaries widely from months to 30 years

With a mean of 4 years for TT and 10 years for LL.With a mean of 4 years for TT and 10 years for LL.

Subclinical infection is reported in areas of high Subclinical infection is reported in areas of high prevalence, as M. leprae DNA was detected in 5% of prevalence, as M. leprae DNA was detected in 5% of nasal swabs from normal individuals.nasal swabs from normal individuals.

(Britton & Lockwood, 2004)(Britton & Lockwood, 2004)

Host susceptibility Host susceptibility

Genetic factors can affect both the development Genetic factors can affect both the development and the pattern of the disease:and the pattern of the disease:

susceptibility loci on chromosomes 10 & 6 »» Indian susceptibility loci on chromosomes 10 & 6 »» Indian patients.patients.

Polymorphism TNF- promoter genes »» multibacillary Polymorphism TNF- promoter genes »» multibacillary leprosy in Brazilian patients.leprosy in Brazilian patients.

HLA DR2 & DR3 »» »» tuberculoid diseases, while HLA HLA DR2 & DR3 »» »» tuberculoid diseases, while HLA DQ1with lepromatous formDQ1with lepromatous form

Mutation in toll-like receptor-2 gene »» »» lepromatous Mutation in toll-like receptor-2 gene »» »» lepromatous leprosy in Koreans. leprosy in Koreans.

(Britton & Lockwood, 2004)(Britton & Lockwood, 2004)

Pathogenesis Pathogenesis Clinical forms of the diseases depend on the ability to Clinical forms of the diseases depend on the ability to

mount a cell mediated immune response.mount a cell mediated immune response. One pole (TT) »»vigorous CMI »» lesions infiltrated with One pole (TT) »»vigorous CMI »» lesions infiltrated with

Th1-like Tcell » » IFN Th1-like Tcell » » IFN , TNF , TNF αα, IL-2 and IL-15 »»well , IL-2 and IL-15 »»well demarcated granulomas with few mycobacteria found in demarcated granulomas with few mycobacteria found in the lesions.the lesions.

Diseases is limited to few well defined skin patchs or Diseases is limited to few well defined skin patchs or nerve trunks.nerve trunks.

Other pole (LL):Other pole (LL):

Absent specific cellular immunity,»» uncontrolled Absent specific cellular immunity,»» uncontrolled proliferation of bacilli with many lesions and extensive proliferation of bacilli with many lesions and extensive infiltration of the skin and nerves.infiltration of the skin and nerves.

There is no organized granuloma, foamy macrophages, There is no organized granuloma, foamy macrophages, and high antibody titer to PGL-I.and high antibody titer to PGL-I.

Deviation of CD4+ve T cells, with Th2 like cytokines IL-4 Deviation of CD4+ve T cells, with Th2 like cytokines IL-4 and IL-10, deletion of T cells, or suppressor T cells and IL-10, deletion of T cells, or suppressor T cells

PathogenesisPathogenesis Most of the patients have the intermediate form (BT,BB, Most of the patients have the intermediate form (BT,BB,

and BL).and BL). They are unstable and either progress:They are unstable and either progress:

Slowly toward lepromatous pole, orSlowly toward lepromatous pole, or

Type 1 leprosy reaction (reversal reaction)Type 1 leprosy reaction (reversal reaction)Spontaneous increased T cell reactivity & in cytokines IFN Spontaneous increased T cell reactivity & in cytokines IFN , TNF , TNF αα

Type 2 reaction (erythema nodosum leprosum)Type 2 reaction (erythema nodosum leprosum)Systemic inflammatory immune response»» extravascular immune Systemic inflammatory immune response»» extravascular immune complexes »» neutrophil infiltration, complement activation and high complexes »» neutrophil infiltration, complement activation and high

concentration of TNF concentration of TNF αα

Clinical features Clinical features Skin involvement:Skin involvement:Commonly macules or plaques rarely papules or nodules Commonly macules or plaques rarely papules or nodules

are seen.are seen.

In tuberculoid and BT, lesions are few, hypopigmented with In tuberculoid and BT, lesions are few, hypopigmented with raised edges, and with reduced sensationraised edges, and with reduced sensation

Clinical featuresClinical features

Lepromatous form, many skin lesion, Lepromatous form, many skin lesion, symmetrical, confluent in some cases, and many symmetrical, confluent in some cases, and many of them are not hypoaesthetic.of them are not hypoaesthetic.

Clinical featuresClinical features

Clinical featuresClinical features Nerve damage:Nerve damage: Peripheral nerve trunk Peripheral nerve trunk

damage:damage:Posterior tibial, ulnar, median, Posterior tibial, ulnar, median,

lateral popliteal and facial.lateral popliteal and facial.Involved nerves are enlarged, and Involved nerves are enlarged, and

with regional sensory and with regional sensory and motor loss.motor loss.

Small dermal sensory & Small dermal sensory & autonomic nerves:autonomic nerves:

Hypoaesthesia »» TT and BT.Hypoaesthesia »» TT and BT.Glove & stocking »» lepromatous Glove & stocking »» lepromatous

form. form. Pure neuritic leprosy:Pure neuritic leprosy:

Clinical featuresClinical features

Eye involvement:Eye involvement:

Blindness »»» nerve damage & Blindness »»» nerve damage & direct invasiondirect invasion

Lagophthalmus »»» orbicularis Lagophthalmus »»» orbicularis oculi »»» zygomatic & temporal oculi »»» zygomatic & temporal branches of facial nerve.branches of facial nerve.

Corneal ulceration »»» Corneal ulceration »»» anaesthesia »»» ophthalmic branch anaesthesia »»» ophthalmic branch of trigeminal nerve.of trigeminal nerve.

Clinical featuresClinical features

Systemic features:Systemic features: Nasal mucosa »»» Nasal mucosa »»»

cartilage »»» saddle cartilage »»» saddle shape.shape.

Bone destruction »»» Bone destruction »»» osteomylitis.osteomylitis.

Testicular atrophy »»» Testicular atrophy »»» loss of testosterone .loss of testosterone .

Renal involvement and Renal involvement and amyloidosis amyloidosis

DiagnosisDiagnosis

Lepromin test:Lepromin test:

Intradermal inoculation of killed Intradermal inoculation of killed M lepraeM leprae.. Early reactions (48 h, Fernandez) Early reactions (48 h, Fernandez) Late reactions (3-4 wk, Mitsuda) Late reactions (3-4 wk, Mitsuda) strongly positive responses (>5 mm) in TT or BT, while strongly positive responses (>5 mm) in TT or BT, while

patients with LL do not respond. patients with LL do not respond.

DiagnosisDiagnosis

Slit smear technique:Slit smear technique:

Skin incision in 6 sites ( ear lobes, elbow, knee and a Skin incision in 6 sites ( ear lobes, elbow, knee and a lesion)lesion)

Slit is smeared on a slide and stained with Ziehl-Slit is smeared on a slide and stained with Ziehl-Neelsen.Neelsen.

Microscopic score (1+ to 6+), reflect number of bacilli by Microscopic score (1+ to 6+), reflect number of bacilli by HPF HPF

Useful to quantitate bacterial loadUseful to quantitate bacterial load High specificity but low sensitivity 70% High specificity but low sensitivity 70%

DiagnosisDiagnosis

Serology:Serology: ELISA: to detect antibodies against carbohydrate portion ELISA: to detect antibodies against carbohydrate portion

of the PGL-I.of the PGL-I. Postive in lepromatous but not the tuberculoid form.Postive in lepromatous but not the tuberculoid form. Antibody titer decreases with effective therapy.Antibody titer decreases with effective therapy.

Polymarase chain reaction (PCR):Polymarase chain reaction (PCR): Amplify the DNA of Amplify the DNA of M lepraeM leprae Low bacterial loads (<10 bacilli) can be detected. Low bacterial loads (<10 bacilli) can be detected. 60-75% of smear -ve patients with TT leprosy have 60-75% of smear -ve patients with TT leprosy have

positive results on PCR. positive results on PCR.

DiagnosisDiagnosis

Histologic diagnosis:Histologic diagnosis: In TT: Noncaseating In TT: Noncaseating

granuloma, bacilli are few granuloma, bacilli are few or absent, dermal nerve or absent, dermal nerve involvement, with normal involvement, with normal skin organs.skin organs.

In LL: Diffuse In LL: Diffuse granulomatous reaction, granulomatous reaction, foamy macrophages, foamy macrophages, more common around more common around blood vessels and nervesblood vessels and nerves

Treatment Treatment Chemotherapy:Chemotherapy:All patient should receive multi-drug therapy (MDT).All patient should receive multi-drug therapy (MDT).

First line drugs: Rifampicin, Clofazimine, and Dapsone.First line drugs: Rifampicin, Clofazimine, and Dapsone.

TreatmentTreatment

Second line therapy: Minocycline, clarithromycin, and Second line therapy: Minocycline, clarithromycin, and ofloxacin, are highly effective against M. leprae.ofloxacin, are highly effective against M. leprae.

Reversal reaction:Reversal reaction:Peak time: during the first 2 month of therapy, even up 12 Peak time: during the first 2 month of therapy, even up 12

months, and after (MDT) is completed.months, and after (MDT) is completed.

Corticosteroids 40-60mg daily, taper 5 mg every 2-4 weeks, Corticosteroids 40-60mg daily, taper 5 mg every 2-4 weeks, duration of therapy 3-4 months.duration of therapy 3-4 months.

Recovery rate for nerve function 60-70%, less with pre-Recovery rate for nerve function 60-70%, less with pre-existing nerve damage or recurrent reaction.existing nerve damage or recurrent reaction.

TreatmentTreatmentType 2 reaction (ENL):Type 2 reaction (ENL):

Develop during 1Develop during 1stst or 2 or 2ndnd year of MDT, and can relapse year of MDT, and can relapse over several years.over several years.

Anti- inflammatory: Clofazimine 300mg daily. OrAnti- inflammatory: Clofazimine 300mg daily. Or

Drug that target overproduction of TNF-Drug that target overproduction of TNF-αα,Thalidomide ,Thalidomide 400mg daily, or pentoxifylline. Or 400mg daily, or pentoxifylline. Or

Neutralization of TNF-Neutralization of TNF-αα with monoclonal antibodies, or with monoclonal antibodies, or soluble inhibitors.soluble inhibitors.

Prophylaxis Prophylaxis Immunoprophylaxis:Immunoprophylaxis: BCG offer variable protection against leprosy (34-80%) in different BCG offer variable protection against leprosy (34-80%) in different

countries, adding heat –killed M. leprae increases the protective countries, adding heat –killed M. leprae increases the protective effect to 64%.effect to 64%.

Endemicity of leprosy, background saprophytic mycobacterial flora, Endemicity of leprosy, background saprophytic mycobacterial flora, and the age at vaccine may affect the response to vaccination.and the age at vaccine may affect the response to vaccination.

Vaccination may precipitate TT leprosy in apparently healthy Vaccination may precipitate TT leprosy in apparently healthy contacts, thus immunoprophylaxis is best carried out at an early contacts, thus immunoprophylaxis is best carried out at an early age. age.

Chemoprophylaxis:Chemoprophylaxis: Rifampicin, to close contact of a case, and can be give to children Rifampicin, to close contact of a case, and can be give to children

under the age 12 years (15mg/kg monthly for 6 months)under the age 12 years (15mg/kg monthly for 6 months)

Pregnancy & leprosyPregnancy & leprosy Little evidence that pregnancy can cause new diseases Little evidence that pregnancy can cause new diseases

or relapse.or relapse.

However, pregnant BL patients may experience type 1 However, pregnant BL patients may experience type 1 reaction in the post partum period.reaction in the post partum period.

Also lepromatous leprosy patients can experience ENL Also lepromatous leprosy patients can experience ENL during pregnancy and lactation, with early loss of nerve during pregnancy and lactation, with early loss of nerve function than non-pregnant patients.function than non-pregnant patients.

MDT (Rifampicin, Clofazimine, and Dapsone) is safe.MDT (Rifampicin, Clofazimine, and Dapsone) is safe.

HIV infection & leprosyHIV infection & leprosy

Unlike tuberculosis, leprosy is not significantly Unlike tuberculosis, leprosy is not significantly associated with HIV infection. associated with HIV infection.

HIV-associated neuropathy might be confused with HIV-associated neuropathy might be confused with leprosy neuritis, also neuropathy due to antiretroviral leprosy neuritis, also neuropathy due to antiretroviral chemotherapy might be confused with leprosy. chemotherapy might be confused with leprosy.

There is difference in treatment strategy for patients with There is difference in treatment strategy for patients with leprosy and HIV, icluding treatment of reactions.leprosy and HIV, icluding treatment of reactions.

Thank youThank you