Leprosy

Leprosy, also known as Hansen’s disease, is a chronic bacterial infection caused by Mycobacterium leprae complex bacteria. Symptoms primarily affect the skin and peripheral nerves, resulting in cutaneous manifestations (e.g., hypopigmented macules) and neurologic manifestations (e.g., loss of sensation). Leprosy is known for its historical stigma and psychosocial effects on infected persons, prompting the World Health Organization (WHO) to pursue a disease elimination plan that led to significant reduction in the prevalence of leprosy. The diagnosis of leprosy is established clinically and supported with skin biopsy. It is treated with long-term multidrug antibiotic combinations. Untreated leprosy leads to disability and permanent damage to the skin, nerves, limbs, and eyes.

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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
Clinical spectrum of leprosy
TuberculoidLepromatous
PresentationImmunocompetent individualsImmunocompromised individuals
LocationSkin and nervesSkin and nerves
Symptoms
  • Early peripheral nerve damage
  • Complete sensory loss
  • Visible nerve enlargement
  • Autoamputation of the digits
  • Rash: a few hypopigmented atrophic plaques with flat centers and raised demarcated borders
  • Late diffuse nerve damage, patchy sensory loss
  • No nerve enlargement
  • Rash: many macules, papules, or nodules, with damage to nose cartilage, bone, testicles; “lion-like” facies

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

Three patients suffering from leprosy:
Note the nose disfigurement and digit amputations.

Image: “Tahitians suffering from leprosy” by Unknown author. License: Public Domain

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.

References

  1. Scollard D, Stryjewski B, Dasco M. (2020). Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis. UpToDate. Retrieved March 3, 2021, from https://www.uptodate.com/contents/leprosy-epidemiology-microbiology-clinical-manifestations-and-diagnosis
  2. Smith D. (2020). Leprosy. Emedicine. Retrieved March 2, 2021, from https://emedicine.medscape.com/article/220455-overview
  3. Moschella SL. (2004). An update on the diagnosis and treatment of leprosy. J Am Acad Dermatol 51:417.
  4. World Health Organization. (2010). Surveillance of drug resistance in leprosy. Wkly Epidemiol Rec 86:237–240.
  5. World Health Organization. (2019). Guidelines for the diagnosis, treatment, and prevention of leprosy. ARO/Department of Control of Neglected Tropical Diseases. March 2, 2021, from https://www.who.int/en/news-room/fact-sheets/detail/leprosy
  6. Centers for Disease Control and Prevention. CDC Immigration Requirements: Technical Instructions for Hansen’s Disease (Leprosy) for Panel Physicians. Retrieved March 2, 2021, from Xxxxx
  7. World Health Organization. (2016). Global leprosy update, 2015: time for action, accountability and inclusion. Source: Wkly Epidemiol Rec 91:405–420.

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