Leprosy

Overview

Definition

Leprosy (also known as Hansen’s disease) is an infectious disease affecting skin and peripheral nerves.

Epidemiology

• Prevalence: < 1 in 10,000 since 2002
• Highest incidence in India, Brazil, Indonesia, Bangladesh, and Nigeria
• In 2015, there were 178 new cases of leprosy in the United States. 
• Immigrants account for 75% of new cases in the United States.

Etiology

Leprosy is caused by Mycobacterium leprae complex bacteria:

• Includes M. leprae and M. lepromatosis
• Acid-fast bacilli 
• Aerobic, obligate intracellular rod-shaped bacteria

Risk factors for acquisition:

• Close contact with leprosy patients
• Exposure to armadillos (natural reservoir of M. leprae)
• Older age
• Genetic factors
• Immunosuppression

Pathophysiology

• Bacteria are inhaled or transmitted through direct skin contact and are taken up by alveolar macrophages and disseminated in the blood. 
• M. leprae spreads to nerves and skin, where it proliferates (especially in Schwann cells).
• Leprosy can manifest in different forms that reflect a spectrum of the host immune response.
• Ridley–Jopling classification of leprosy:
  • Tuberculoid (TT)
  • Borderline tuberculoid (BT)
  • Mid-borderline (BB)
  • Borderline lepromatous (BL)
  • Lepromatous (LL)
  • Indeterminate (I)
• Tuberculoid and lepromatous forms are at the 2 ends of the spectrum:
  • Tuberculoid leprosy:
    • Good cellular immune response (type 1 T helper (TH1) cell response)
    • Delayed-type hypersensitivity with interferon-γ and macrophage activation
    • Involves the skin (localized) and peripheral nerves
  • Lepromatous leprosy:
    • Minimal cellular immune response
    • Humoral (antibody) response (activated by type 2 T helper (TH2) cells)
    • Extensive skin involvement
    • Nerve involvement tends to be symmetric.

Clinical Presentation

Skin lesions:

• Well demarcated in tuberculoid leprosy:
  • Usually 1 or 2 lesions
  • Central hypopigmentation or erythematous
  • Hypoesthesia
• Poorly demarcated in lepromatous leprosy:
  • Can be macular, raised, or nodular
  • Numerous; appear all over body

Other manifestations:

• Neuropathy, paresthesias
• Enlarged and tender peripheral nerves (tuberculoid leprosy)
• Painless extremity wounds
• Facial or ear lumps
• Ophthalmic injury:
  • Lagophthalmos (inability to close eyelids completely)
  • Corneal abrasions/ulcerations

Late findings may include:

• Facial paralysis
• Collapsed nose
• Clawed fingers
• Foot drop
• Lack of eyelashes/eyebrows

Possible immunologic reactions:

• Systemic inflammatory complications
• May occur before, during, or after treatment
• Two types:
  • Type 1: reversal reaction
  • Type 2: erythema nodosum leprosum
• Can be difficult to distinguish clinically
• Symptoms include:
  • Fatigue, fever, malaise
  • Neuritis, arthritis, iritis, nasopharyngeal symptoms

Lucio’s phenomenon:

• Very rare complication of lepromatous leprosy
• Necrotizing vasculopathy

Diagnosis

World Health Organization (WHO) diagnostic criteria

The WHO defines leprosy as appearing in an individual who has not completed a course of treatment and has one or more of the following:

• Painless hypopigmented or reddish skin lesions
• Peripheral nerve thickening and associated loss of sensation
• Skin smear positive for acid-fast bacilli

The WHO bases diagnosis on the above clinical presentation combined with a confirmatory laboratory test.

Laboratory studies

• Skin biopsy:
  • Full-thickness sample taken from most active margin of most active lesion
  • The Ziehl–Neelsen or Fite stain can show the presence of acid-fast bacilli, confirming the diagnosis of leprosy.
  • Slit-skin smear can help in diagnosing those with lepromatous disease.
  • M. leprae cannot be cultured in artificial media.
  • Mycobacterial culture may need to be performed to rule out other pathogens (M. tuberculosis).
• Serologic assays:
  • Detect phenolic-glycolipid-1 and lipoarabinomannan
  • 95% sensitivity for lepromatous leprosy 
  • 30% sensitivity for tuberculoid leprosy
• Molecular probes:
  • Detect 40%–50% of cases missed on histologic evaluation
  • Can fail to identify tuberculoid leprosy
• PCR:
  • Gene probes with M. leprae–specific sequences
  • Can be used to identify mycobacterium in biopsy samples, skin, nasal smears, blood, and tissue sections
• Lymphocyte migration inhibition test:
  • Tests for cell-mediated immunity to M. leprae
  • Absent in patients with lepromatous leprosy
  • Present in those with tuberculoid leprosy
• Lepromin test:
  • Not available in the United States
  • Test is done by injecting antigen intradermally.
  • Check the injection site for induration, similar to what is done for the tuberculin skin test.
  • Not reliable: detects ability to develop granulomas when exposed to antigen but not the actual exposure

Management

Management

• Multidrug therapy (MDT) regimen: 
  • Necessary to prevent drug resistance
  • Dapsone + rifampin for 12 months for tuberculoid leprosy 
  • Dapsone + rifampin + clofazimine for 24 months for lepromatous leprosy
  • Alternative medications:
    • Minocycline
    • Ofloxacin
    • Levofloxacin
    • Clarithromycin
    • Moxifloxacin
• Immunologic reactions:
  • Can be managed supportively if mild and no neuritis is present
  • Neuritis must be managed aggressively to prevent permanent nerve damage.
  • Steroids and immunosuppressants

Prevention

• No drug prophylaxis in nonendemic areas
• BCG vaccine is partly protective.
• Close contacts of affected individuals should be monitored annually for at least 5 years.
• In endemic areas, single-dose rifampin can be given for prophylaxis.

Complications

• Paralysis and crippling of hands and feet
• Autoamputation of toes and fingers
• Chronic nonhealing ulcers on bottoms of feet
• Blindness
• Loss of eyebrows
• Nose disfigurement
• Testicular atrophy

Differential Diagnosis

• Neurofibromatosis type 1: a genetic neural disorder of benign tumors that arise from the neural crest cells in the peripheral nerve sheath: Neurofibromatosis type 1 presents in the teen years as soft, painless skin nodules. Genetic testing can confirm the diagnosis after the physical exam and biopsy. Management includes surgical resection and antitumor drugs. 
• Dermatofibroma (DF): a common, benign, fibrohistiocytic proliferation reaction, usually in reaction to trauma, a viral infection, or an insect bite: Dermatofibroma presents on the anterior surfaces of the lower legs as a firm, indurated, mobile nodule that retracts beneath the skin during an attempt to compress and elevate it. Diagnosis is by biopsy. Management includes surgical resection. 
• Systemic lupus erythematosus: a systemic autoimmune disorder most commonly affecting women: Patients can present with involvement of multiple organs. Cutaneous manifestations of lupus include facial “butterfly rash” or generalized erythematous macular–papular eruption involving sun-exposed areas. Diagnosis is based on clinical suspicion and the presence of certain antibodies. Management involves steroids, immunosuppressants, and biologic agents.
• Scleroderma: an autoimmune condition characterized by diffuse collagen deposition and fibrosis: The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Diagnosis is established by a combination of physical findings and serology. There is no curative treatment. Management options are limited but include immunosuppressive medications and symptomatic treatment.