What is leprosy, how is it transmitted, and what is its treatment?

Leprosy (Hansen Disease): Overview

Leprosy is a chronic bacterial infection caused by Mycobacterium leprae that primarily affects the skin, peripheral nerves, and upper respiratory mucosa, with transmission occurring through prolonged close contact via respiratory droplets, though it has low pathogenicity and low virulence despite being highly infective. 1

Causative Organism and Pathogenesis

• Causative agent: Mycobacterium leprae (and the recently discovered M. lepromatosis), an acid-fast, slow-multiplying, gram-positive bacillus that cannot be cultured in vitro due to reductive genome evolution 2, 3
• Target tissues: The bacterium has a predilection for Schwann cells in peripheral nerves, skin, mucosa of the upper respiratory tract, and eyes 4, 5
• Mechanism of nerve damage: M. leprae primarily infects Schwann cells in peripheral nerves, leading to inflammation, nerve damage, and development of disabilities including peripheral neuropathy and weakness 4, 5
• Incubation period: Long incubation period, reflecting the slow multiplication rate of the organism 6

Transmission and Contagiousness

• Primary route: Transmission occurs via aerosol droplets from respiratory secretions during prolonged close contact with untreated multibacillary patients 4
• Secondary route: Broken skin-to-skin contact may also transmit the organism 4
• Infectivity paradox: While highly infective, leprosy has low pathogenicity and low virulence, meaning most exposed individuals do not develop clinical disease 6
• Reservoir: The nine-banded armadillo serves as a natural reservoir for M. leprae 4
• Transmission uncertainty: Despite extensive research, the exact transmission routes are not completely understood 2

Clinical Spectrum and Classification

The disease manifests as a spectrum based on the host's cellular immune response to M. leprae, ranging from tuberculoid (strong cell-mediated immunity) to lepromatous (weak cell-mediated immunity) forms 1, 7:

Tuberculoid (Paucibacillary) Form

• Skin lesions: One or a few well-demarcated, hypopigmented, and anesthetic skin lesions with active spreading edges and clearing centers 1, 7
• Nerve involvement: Peripheral nerve swelling or thickening may occur 1, 7
• Bacillary load: Low bacterial burden 3
• Immune response: Strong cell-mediated immunity 7

Lepromatous (Multibacillary) Form

• Skin lesions: Multiple erythematous papules and nodules or infiltration of the face, hands, and feet with bilateral and symmetrical distribution that progresses to skin thickening 1, 7
• Contagiousness: More contagious form due to high bacillary load 6
• Systemic involvement: May affect upper respiratory mucosa leading to nasal symptoms 7
• Immune response: Weak cell-mediated immunity 7

Borderline (Dimorphous) Form

• Presentation: Skin lesions characteristic of both tuberculoid and lepromatous forms 1, 7
• Instability: Clinically unstable and may shift toward either pole of the spectrum 7

Indeterminate Form

• Early presentation: Early lesions, usually hypopigmented macules, without developed tuberculoid or lepromatous features 1, 7
• Natural history: May evolve into other forms or resolve spontaneously 6

Diagnosis

Clinical Criteria

• Cardinal signs: Diagnosis requires one or more of three cardinal signs: hypopigmented or erythematous skin patches with definite loss of sensation, thickened peripheral nerves, and acid-fast bacilli on skin smears or biopsy 5
• Neurological findings: Loss of sensation in skin lesions is pathognomonic and distinguishes leprosy from other dermatological conditions 5

Laboratory Confirmation

• Gold standard: Demonstration of acid-fast bacilli in skin or dermal nerve, obtained from full-thickness skin biopsy of a lepromatous lesion 1, 7
• Skin bacilloscopy: Slit-skin smears can detect acid-fast bacilli, particularly in multibacillary cases 6
• Histopathology: Skin biopsy with histopathological examination complements clinical diagnosis 6

Treatment

Multidrug Therapy (MDT) Regimens

For Multibacillary Leprosy (12 months duration): 8, 9

• Rifampin: 600 mg monthly (supervised dose)
• Clofazimine: 300 mg monthly (supervised) plus 50 mg daily (unsupervised)
• Dapsone: 100 mg daily

For Paucibacillary Leprosy (6 months duration): 3

• Rifampin: 600 mg monthly (supervised)
• Dapsone: 100 mg daily

Alternative single-dose regimen for paucibacillary leprosy: Rifampin, ofloxacin, and minocycline given as a single dose 6

Pre-Treatment Screening and Monitoring

• G6PD deficiency screening: Mandatory before initiating dapsone due to risk of hemolytic anemia and methemoglobinemia 8, 9
• Baseline ECG: Required before clofazimine due to QT interval prolongation risk 8, 9
• Regular monitoring: Complete blood count and liver function tests during dapsone therapy 8, 9
• QT interval monitoring: ECG at 2 weeks after starting clofazimine and after adding any QT-prolonging medications 9

Drug-Specific Considerations

Dapsone:

• Adverse effects: Hemolytic anemia, methemoglobinemia, nausea, vomiting 9
• Monitoring: Regular CBC and liver function tests 8, 9

Clofazimine:

• Dosing: 50-100 mg daily with meals or milk to maximize absorption and reduce GI effects 9
• Skin pigmentation: Pink to brownish-black discoloration occurs in 75-100% of patients within 1-4 weeks, resolving 6-12 months after stopping 9
• Other adverse effects: Ichthyosis, gastrointestinal intolerance, QT interval prolongation 9
• Formulation: Available as 50 mg and 100 mg gelcaps that cannot be split 9

Rifampin:

• Mechanism: Bactericidal against M. leprae 6
• Dosing: Fixed-dose 600 mg monthly (not weight-based) 9

Critical Treatment Principles

• Continue MDT during complications: Treatment should not be interrupted due to skin complications or wound healing 8
• Distinguish reactions from treatment failure: Leprosy reactions (Type 1 reversal reactions, Type 2 erythema nodosum leprosum) require anti-inflammatory management but continuation of MDT 8, 9
• Type 1 reversal reactions: Treat with corticosteroids while continuing MDT 8
• Duration: Recent WHO guidelines reduced multibacillary treatment from 24 to 12 months 6

Treatment Response and Follow-up

• Expected response: Lesion flattening by 4-6 weeks after treatment initiation 8, 9
• Post-treatment surveillance: Monitor for signs of relapse, though resistance is emerging despite MDT 3
• Long-term complications: Immunological sequelae (leprosy reactions) may appear during therapy or several years later and are frequently difficult to treat 2

Special Populations

• Pregnancy: Treatment should be continued during pregnancy as benefits outweigh risks, with close monitoring required 9
• Pediatrics: Clofazimine has been well-tolerated in pediatric leprosy trials at 1-2 mg/kg/day (maximum 100 mg) 9

Prevention and Public Health Considerations

• Early detection: Critical to preventing irreversible nerve damage and disabilities 4
• Contact tracing: Close contacts should receive prophylaxis and monitoring 4
• Community awareness: Education of populations at risk and health workers is essential for early diagnosis 6
• Elimination status: Global elimination (prevalence <1 per 10,000 population) was achieved in 2000, but >200,000 new cases are still reported annually, particularly in India, Brazil, and Indonesia 2, 3
• Transmission continues: High new case detection rates indicate active transmission despite MDT implementation 5

Common Pitfalls

• Delayed diagnosis: Failure to recognize early indeterminate lesions leads to progression to more severe forms with irreversible nerve damage 6
• Misdiagnosis: Loss of sensation in skin lesions is pathognomonic; failure to test for this leads to misdiagnosis as other dermatological conditions 5
• Premature treatment discontinuation: Stopping MDT due to leprosy reactions worsens outcomes; reactions require anti-inflammatory therapy while continuing MDT 8, 9
• Inadequate monitoring: Failure to screen for G6PD deficiency before dapsone or monitor QT interval with clofazimine can lead to serious adverse events 8, 9