Leprosy (Hansen's Disease)

Definition and Causative Agent

Microbiology

• Obligate intracellular pathogen - cannot be cultured in vitro
• Acid-fast bacillus (weakly acid-fast on standard Ziehl-Neelsen; best visualized with Fite stain)
• Replicates optimally at 32-34°C (human skin temperature) - this explains why it avoids warm core organs
• Doubling time: approximately 12-14 days (extremely slow)
• Virulence factor: phenolic glycolipid-1 (PGL-1) - mediates invasion of host cells and binding to peripheral nerve basal lamina
• Inhibits mitochondrial energy metabolism to evade host immune response
• Primary target: Schwann cells of the peripheral nervous system
• Clusters characteristically in "globi" (clumps/bundles) inside macrophages (lepra cells)
• Sherris & Ryan's Medical Microbiology, 8th Ed.; Park's Textbook of Preventive & Social Medicine

Epidemiology

• Park's Textbook of Preventive & Social Medicine; Red Book 2021

Pathogenesis and Immunology

• Robbins, Cotran & Kumar; Sherris & Ryan's Medical Microbiology

Classification

1. Tuberculoid (TT)
2. Borderline Tuberculoid (BT)
3. Mid-Borderline (BB)
4. Borderline Lepromatous (BL)
5. Lepromatous (LL)

• Paucibacillary (PB): 1-5 skin lesions (usually TT/BT)
• Multibacillary (MB): >5 skin lesions (usually BB/BL/LL)
• Red Book 2021

Cardinal Clinical Features

1. Hypopigmented or erythematous skin patch(es) with loss of sensation (light touch affected first)
2. Thickened peripheral nerves
3. Acid-fast bacilli in slit-skin smears or biopsy

• Park's Textbook of Preventive & Social Medicine

Clinical Forms

Tuberculoid Leprosy

• Dry, scaly, flat-to-raised lesions - irregular shapes, hyperpigmented elevated margins, depressed pale centers (central healing)
• Asymmetric large peripheral nerve involvement
• Nerves enclosed in granulomatous reactions; small peripheral twigs destroyed
• Complications: skin anesthesia, muscle atrophy, contractures, paralysis, autoamputation, corneal ulceration (facial nerve palsy)
• Histology: well-formed granulomas resembling tuberculosis, with almost no bacilli (paucibacillary)

Lepromatous Leprosy

• Symmetric skin thickening, nodules, plaques on face/ears/wrists/elbows/knees
• Progressive nodule coalescence → leonine facies
• Madarosis (loss of eyebrows/eyelashes)
• Widespread invasion of Schwann cells and perineural macrophages
• Nasal mucosa involvement: rhinitis, septal perforation, nasal depression ("saddle nose")
• Testes destruction → sterility
• Histology: lipid-laden foamy macrophages (lepra cells) packed with "globi" of acid-fast bacilli; CD8+ T cells dominant; sparse CD4+
• In advanced disease: bacilli present in sputum and blood

Lepra Reactions (Immunologic Exacerbations)

Type 1 - Reversal Reaction (LR-1)

• Occurs in borderline forms (BT, BB, BL)
• Mechanism: sudden increase in effective CMI
• Features: acute tenderness/swelling of skin lesions and nerves, new lesion development, ulceration possible
• No fever or systemic toxicity typically
• Treatment: Prednisone (1 mg/kg/day; with methotrexate as a sparing agent for long-term use)

Type 2 - Erythema Nodosum Leprosum (ENL / LR-2)

• Occurs in borderline lepromatous and lepromatous forms
• Mechanism: systemic immune complex deposition
• Features: tender red subcutaneous papules/nodules, high fever, migratory polyarthralgia, painful lymphadenopathy, iridocyclitis, rarely nephritis
• Treatment: Thalidomide (100-400 mg/day for 4 days) under strict supervision; also prednisone
• Red Book 2021

Diagnosis

• Gold standard: Skin biopsy with histopathologic examination by experienced pathologist (Fite stain for AFB)
• Slit-skin smears: AFB visible in MB/lepromatous forms, rarely in PB/tuberculoid
• PCR (for M. leprae and M. lepromatosis) - available at specialized centers
• Molecular tests for drug resistance and strain typing
• Lepromin skin test (DTH response) - no longer routinely available
• Tuberculin/IGRA: NOT used for leprosy diagnosis
• Pre-treatment workup: G6PD deficiency screen, CBC, LFTs, rule out active TB (especially if HIV+)
• Red Book 2021

Treatment - Multidrug Therapy (MDT)

• Infectivity ceases within a few days of starting MDT
• Relapse is rare: 0.01-0.14%
• Multi-drug therapy prevents resistance (resistance to all 3 agents is documented but extremely rare)
• Rifampin renders the patient non-infectious within ~3 weeks
• MDT is provided free of charge by WHO globally
• Isolation is NOT required - standard precautions only
• Red Book 2021

Disability and Complications

• Leading cause of permanent physical disability among communicable diseases worldwide
• Unrecognized trauma due to anesthesia → ulcers, fractures, bone resorption, autoamputation
• Eye involvement: corneal scarring - all patients should have ophthalmologic evaluation
• Deformities: claw hand, foot-drop, claw toes, plantar ulcers, saddle nose, lagophthalmos

Control Measures

• Reportable disease (US: report to state health authorities, CDC, and NHDP)
• Household contacts: initial examination (no prolonged follow-up if asymptomatic)
• Chemoprophylaxis: not recommended
• BCG vaccine: 28-60% protective; used as adjunct in Brazil; may precipitate leprosy in subclinically infected individuals
• No vaccines approved in the US specifically for leprosy

• Robbins, Cotran & Kumar - Pathologic Basis of Disease
• Red Book 2021 - Report of the Committee on Infectious Diseases
• Park's Textbook of Preventive and Social Medicine
• Sherris & Ryan's Medical Microbiology, 8th Ed.

Recent evidence note: A 2024 systematic review (PMID 39308868) updates leprosy immunopathogenesis, reinforcing the Th1/Th2 dichotomy and highlighting the role of regulatory T cells in lepromatous disease - consistent with the textbook framework above.