Leprosy (Hansen Disease)

Overview

Causative Organism

• Obligate intracellular pathogen that cannot be cultured in vitro
• Grows optimally at 32-34°C (the temperature of human skin), explaining its predilection for cool peripheral tissues
• Proliferates in dermal macrophages and disseminates hematogenously
• Secretes no toxins; virulence depends on its cell wall, particularly the lipid PGL-1, which is critical for host cell invasion
• BCG vaccination confers partial cross-protection (M. leprae is genetically similar to M. tuberculosis)
• The organism inhibits mitochondrial energy metabolism to evade the immune response

Transmission

• Primarily via human respiratory secretions
• Rare zoonotic transmission from armadillos has been documented
• Overall communicability is low; most exposed individuals never develop disease

Classification

Ridley-Jopling Spectrum (Immunological Basis)

WHO Classification (Operational - for treatment)

• Paucibacillary (PB): up to 5 skin lesions, slit-skin smear negative
• Multibacillary (MB): 6 or more skin lesions, or smear-positive

Pathogenesis

• Tuberculoid leprosy: Strong Th1 response with classically activated (M1) macrophages, IL-2, IFN-γ, and a Th17 component. Microbial burden is low; granulomas form. Analogous to M. tuberculosis - IFN-γ mobilizes effective macrophage killing.
• Lepromatous leprosy: Weak Th1 response, relative Th2 and regulatory T-cell predominance. Bacteria multiply unchecked. Occasional antibody production against M. leprae antigens forms immune complexes that can cause erythema nodosum, vasculitis, and glomerulonephritis.

Clinical Features

Tuberculoid Leprosy

• Localized, flat, red lesions that enlarge with indurated, elevated, hyperpigmented margins and depressed pale centers (central healing)
• Skin lesions are anesthetic - definite loss of sensation (light touch, pain, temperature)
• Asymmetric involvement of large peripheral nerves; nerve damage can be severe
• Nerves enclosed within granulomatous reactions; small twigs are destroyed
• Complications: chronic skin ulcers, contractures, paralyses, autoamputation of digits, keratitis from facial nerve involvement

Lepromatous Leprosy

• Affects skin, peripheral nerves, anterior eye chamber, upper airways (to larynx), testes, hands, and feet
• CNS and vital organs are spared (too warm for bacterial growth)
• Macular, papular, or nodular lesions on face, ears, wrists, elbows, and knees
• Progressive coalescing nodules produce the characteristic leonine facies
• Symmetric nerve involvement (unlike tuberculoid); ulnar and peroneal nerves particularly affected
• Skin lesions are hyposthetic or anesthetic
• Nasal: persistent inflammation, bacilli-laden discharge
• Testes: destruction of seminiferous tubules → sterility
• Lymph nodes and spleen: foamy macrophage aggregates

Histopathology

• Tuberculoid: Granulomas resembling tuberculosis; bacilli almost never found (paucibacillary)
• Lepromatous: Large aggregates of lipid-laden macrophages called lepra cells, filled with masses ("globi") of acid-fast bacilli; abundant bacteria (multibacillary)

Cardinal Signs (Diagnosis)

1. Hypopigmented or erythematous skin lesion(s) with definite loss or impairment of sensation
2. Involvement of peripheral nerves demonstrated by definite thickening with sensory impairment (greater auricular, ulnar, radial, median, lateral popliteal, posterior tibial, sural, superficial peroneal nerves are the most commonly palpated)
3. Positive AFB in slit-skin smears, biopsy, or positive PCR

Diagnostic Tools

Slit-Skin Smear

• Taken from 4 sites: right earlobe, forehead, chin, left buttock (men) or left upper thigh (women)
• Stained with Ziehl-Neelsen reagent; examined by light microscope
• Bacteriological index graded on a logarithmic scale from 0 to 6

Skin Biopsy

• Confirms diagnosis, classifies disease, supports diagnosis of reactions, and determines cure post-MDT
• Macular lesions: biopsy from the middle; plaques: from the active indurated edge

PGL-1 Antibody Test (Serology)

• PGL-1 is a specific lipid on the M. leprae cell wall
• Positive in 90-95% of multibacillary cases; only 25-60% of paucibacillary cases
• ML flow test (immunochromatographic lateral-flow assay): 92-97% sensitivity in MB, 32-40% in PB
• A newer quantitative UPC-LFA test has higher specificity in paucibacillary disease

Lepromin (Mitsuda) Test

• Intradermal injection of inactivated M. leprae; induration read at 3-4 weeks
• Measures cellular immunity to M. leprae
• Negative in lepromatous (BL/LL) leprosy → indicates lack of protective cellular response

PCR

• Detects as few as 1-10 bacilli; positive in 60-75% of smear-negative cases
• Multiplex PCR (RLEP, SodA, 16S rRNA genes) useful for early diagnosis and screening household contacts

Nerve Function Assessment

• Semmes-Weinstein monofilament test is the gold standard; ballpoint pen used in the field
• Voluntary muscle testing: eye closure (facial), finger abduction (ulnar), thumb opposition (median), wrist extension (radial), ankle extension (peroneal)
• Ultrasound imaging can detect early nerve enlargement
• Nerve conduction studies: sensory parameters affected months before clinical tests become positive

Differential Diagnosis

Leprosy Reactions

Type 1 Reaction (Reversal Reaction - T1R)

• Can occur in tuberculoid, borderline tuberculoid, or borderline lepromatous patients
• Cell-mediated immune activation attacking M. leprae antigen
• Affected nerves enlarge and become tender; sudden loss of nerve function can be permanent
• May also be subacute/chronic with limited symptoms but severe underlying damage
• Histology: perivascular and perineural edema, large numbers of lymphocytes; bacilli reduced

Type 2 Reaction (Erythema Nodosum Leprosum - ENL)

• Occurs in 50% of BL or lepromatous patients, usually within a few years of starting MDT or during pregnancy
• Mechanism: immune complex-mediated vasculitis with local complex formation, elevated TNF-α, complement membrane attack complex
• Systemic symptoms: fever, myalgias, arthralgias, anorexia
• Characteristic skin lesions: erythematous, subcutaneous/dermal nodules widely distributed, NOT at existing lesion sites; favor extensor arms and medial thighs (unlike classic erythema nodosum)
• Multisystem involvement: conjunctivitis, neuritis, keratitis, iritis, synovitis, nephritis, orchitis, hepatosplenomegaly, lymphadenopathy
• Labs: elevated ESR and CRP, neutrophilia
• Histology: leukocytoclastic vasculitis

Lucio Phenomenon

• Uncommon; occurs in diffuse lepromatous leprosy ("la bonita" type), mainly in western Mexico
• Purpuric macules → bullous lesions → rapid ulceration (especially below the knees)
• Lacks neutrophilia and systemic symptoms (differs from ENL)
• Not triggered by MDT initiation; often the initial presenting event

Treatment

WHO-Recommended Multidrug Therapy (MDT)

Drug Mechanisms and Side Effects

• Rifampin: Inhibits DNA-dependent RNA polymerase; given monthly in leprosy (different from TB dosing). Risk of hepatotoxicity is low at monthly intervals; harmless urine discoloration.
• Dapsone: Blocks folic acid synthesis; weakly bactericidal; half-life ~28 hours. Risks: mild hemolysis, anemia, rarely psychosis. "DDS syndrome" (dapsone hypersensitivity syndrome) - a severe adverse event, typically 6 weeks after starting treatment.
• Clofazimine: Causes skin discoloration (the main compliance concern in paucibacillary disease).

Relapse Monitoring

• Paucibacillary: 2 years of monitoring post-treatment
• Multibacillary: at least 5 years
• Relapse can be difficult to distinguish from T1R in paucibacillary disease; a therapeutic trial of glucocorticoids (improvement within 4 weeks = T1R; no response = relapse)

Drug-Resistant Leprosy

• Rifampin resistance: treat with at least two second-line drugs (clarithromycin, minocycline, or a quinolone - ofloxacin, levofloxacin, or moxifloxacin) plus clofazimine for 6 months, then clofazimine plus one second-line drug for 18 months
• Dual rifampin + ofloxacin resistance: clarithromycin + minocycline + clofazimine for 6 months, then clarithromycin or minocycline + clofazimine for 18 months

Treatment of Reactions

• Prednisolone 1 mg/kg/day (max 60-80 mg; WHO field protocol: 40 mg/day)
• Taper by 5 mg every 2 weeks over 20 weeks (better outcomes than a 12-week taper)
• Assess every 2 weeks; include nerve function assessment
• Reaction flares often return when dose falls below 10-20 mg/day - balance prolonged use risks with benefit

• Mild first-time ENL: aspirin + pentoxifylline
• Most effective rapid-acting drug: thalidomide 100-200 mg once or twice daily (blacklisted in many countries due to teratogenicity; strict contraception required for women of childbearing age)
• Multisystem ENL (eyes, testes, kidneys, joints): longer treatment course needed
• Prednisolone is the alternative where thalidomide is unavailable

Complications and Disability

• Chronic skin ulcers from loss of protective sensation
• Contractures and fixed-joint deformities
• Bone absorption and autoamputation of digits
• Keratitis and corneal ulceration from facial nerve paralysis (lagophthalmos)
• Sterility (testicular destruction in lepromatous leprosy)
• "Silent neuritis" or "quiet nerve paralysis" - progressive nerve damage with minimal symptoms

Key Points Summary