• Clinical science

Leprosy (Hansen disease)

Abstract

Leprosy (Hansen disease) is a chronic infectious disease caused by prolonged exposure to Mycobacterium leprae, an acid-fast, slow-growing, fastidious bacillus. Leprosy primarily occurs in tropical and/or developing countries and is rarely observed in the US. There are various forms whose descriptions differ among two different classification systems, but the three cardinal clinical manifestations of leprosy are hypopigmented skin lesions, nerve thickening, and peripheral nerve palsies. Long-standing cases of leprosy classically develop deformities as a result of contractures following motor nerve palsies and/or repeated injury due to sensory loss. Other chronic complications include uveitis, orchitis, and nasal septal perforation. Patients with leprosy may also present with acute lepra reactions that are characterized by painful skin lesions and neuritis. The diagnosis is usually confirmed with the help of a biopsy. Lepromin tests aid in the classification of various forms of leprosy. Treatment consists of prolonged MDT (multi-drug therapy) with dapsone and rifampin. Clofazimine is added to the therapeutic regimen in patients with multibacillary leprosy.

Epidemiology

  • US statistics
    • Incidence: 100–200 new cases annually
    • Prevalence: ∼ 4,000 cases in total
  • Sex: >
  • Peak incidence: 10–20 years
  • Endemic to tropical regions: India, Brazil, Indonesia, Nepal, Myanmar, Nigeria

Epidemiological data refers to the US, unless otherwise specified.

Etiology

  • Pathogen: Mycobacterium leprae is an obligate, intracellular, acid-fast bacilli that cannot be cultured.
  • Route of transmission
    • Respiratory droplet transmission
    • Close contact with fomites, infected soil, and/or infected individuals
    • Transmission usually requires prolonged exposure, and some individuals seem more predisposed than others
  • Infectious type: multibacillary leprosy (see “Pathophysiology” below)
  • Reservoirs: infected humans; , nine-banded armadillos , mangabey monkeys, sphagnum moss

Pathophysiology

Ridley-Jopling classification Lepromatous leprosy (LL) Borderline leprosy Tuberculoid leprosy (TT)
Borderline lepromatous leprosy (BL) Mid-borderline leprosy (BB) Borderline tuberculoid leprosy (BT)
WHO classification Multibacillary (MB) leprosy Paucibacillary (PB) leprosy
Characteristics
  • Th2 response
    • IL-4, IL-5, IL-10
    • Reciprocal inhibition of Th1 response →inadequate cell-mediated immune response → many lepra bacilli
    • Antibody production (hypergammaglobulinemia);
  • Nerve lesions are the result of M. leprae invasion.
  • M. leprae grows best at cool sites in the body (skin, mucous membranes, peripheral nerves, anterior chamber of the eye, upper respiratory tract, testes).
  • The disease is not stable in this state and shifts to TT or LL.
  • ↑ Th1 response
    • IL-2, IFN-γ, IL-12
    • Strong cell-mediated immune responsegranuloma with epitheloid cells and lymphocytes but few or no lepra bacilli
  • Nerve demyelination is the result of a T-cell mediated response.
  • Lesions may resolve spontaneously in a few years or shift to borderline type or, in rare cases, to LL.

Leprosy is a slowly progressive, chronic infection with a spectrum of clinical manifestations depending on the degree of cell immunity.

Clinical features

  • Incubation period: 3–5 years
  • The clinical manifestations vary depending on the type of leprosy (LL, TT, or intermediate forms collectively known as Borderline leprosy, which is explained in further detail in extra information)
Ridley-Jopling classification Lepromatous leprosy (LL) Borderline leprosy Tuberculoid leprosy (TT)
Borderline lepromatous leprosy (BL) Mid-borderline leprosy (BB) Borderline tuberculoid leprosy (BT)
WHO classification Multibacillary (MB) leprosy (> 5 skin lesions) Paucibacillary leprosy (≤ 5 skin lesions)
Cutaneous manifestations
  • Multiple symmetrical macules, plaques, and/or nodules
    • Nodules in the face may coalesce → leonine facies
    • Nodules may ulcerate
  • Hypesthesia of the skin lesion is less common and occurs only in late stages of the disease
  • Supraciliary and ciliary madarosis
  • Diffuse lepromatosis : no visible skin lesions but diffuse infiltration and thickening of the dermis
  • Morphology is similar to LL
  • Punched-out lesions or lesions with an inverted saucer shape are also common.
  • Lesions have the morphology of both TT and LL types in equal number.
  • Plaques and nodules are typically not seen.
  • Morphology is similar to TT except that lesions are smaller and more numerous (usually 3–10 lesions) than in TT.
  • Smaller satellite lesions next to the main lesion are classically seen.
  • Few (usually 1–3 lesions), localized, hypopigmented macules, plaques, and/or papules with well-defined, erythematous, and/or raised margins
  • Lesions are dry, scaly, anhidrotic
  • Hair loss
  • Hypesthesia of the skin lesion is common and occurs early.
Nerve involvement*
  • Occurs late but is more extensive
  • Acral, distal, symmetrical anesthesia
  • Usually begins as a “glove and stocking” neuropathy that spreads proximally
  • Similar to LL
  • Acute neuritis may occur as a result of type 1 or type 2 lepra reactions.
  • Features of both LL and TT
  • Acute neuritis may occur as a result of type 1 or type 2 lepra reactions.
  • Similar to LL
  • Nerve abscesses are quite common.
  • Acute neuritis may occur as a result of type 1 lepra reactions.
  • Occurs early but is localized
  • Asymmetric enlargement of one or many peripheral nerves
  • Acute neuritis does not occur.
Systemic manifestations
  • Similar to LL
  • Features of both LL and TT
  • Similar to LL
  • Not involved
  • *Nerve involvement leads to nerve enlargement and peripheral nerve palsies which present with sensory, motor, and/or autonomic deficits.

The three cardinal clinical manifestations of leprosy are hypopigmented skin lesions, nerve thickening, and peripheral nerve palsies!

All peripheral nerves can become affected in leprosy, but the most commonly affected are the ulnar and the peroneal nerves.

Diagnostics

Ridley-Jopling classification Lepromatous leprosy (LL) Borderline leprosy Tuberculoid leprosy (TT)
Borderline lepromatous leprosy (BL) Mid-borderline leprosy (BB) Borderline tuberculoid leprosy (BT)
WHO classification Multibacillary (MB) leprosy Paucibacillary leprosy
Skin scraping or slit-skin smear findings*
  • Smears are positive for AFB at any one location
  • Smears are negative for AFB at all locations
Biopsy findings**
  • Granulomas formed by epithelioid cells and Langerhans giant cells
  • Many lymphocytes with a a CD4::CD8 ratio of 1.2:1
  • Narrow clear subepidermal zone
  • Scanty lepra bacilli
  • No clear subepidermal zone
  • No lepra bacilli
Lepromin test*** - - - or + + or ++ +++
Lymphocyte transformation test
  • Usually negative
  • Usually positive
Antibodies to PGL-1 antigens
  • Occur in 95% of cases
  • Occur in 85% of cases
  • Occur in 60% of cases
  • *Modified Ziehl-Neelsen staining of scrapings from skin lesions, nasal swabs, and/or slit skin smears from ear lobes are used to screen for leprosy.
      • BI is primarily used to classify leprosy
  • **Punch biopsy followed by histopathological examination with modified Ziehl-Neelsen staining is used to confirm the diagnosis.
  • ***Lepromin test:
    • Antigen is injected intradermally on the ventral forearm
    • The test is positive if induration is > 5 mm
    • Measures the ability of a patient to mount a T cell response. Does not diagnose leprosy.
      • Can be positive in patients with no exposure or infection to leprosy
      • Can distinguish between lepromatous leprosy (negative result due to inadequate cell-mediated response) and tuberculoid leprosy (positive result due to strong cell-mediated immune response).
    • 0.1 mL of an antigen solution is injected intradermally on the ventral forearm and the reactions are observed.
      1. Early (Fernandez) reaction
        • Positive if induration is > 10 mm at the end of 48 hours
        • Can result in false positive results due to cross reaction with other mycobacteria
      2. Late (Mitsuda) reaction
        • Positive if a nodule > 5 mm at the end of 21 days
        • A better indicator of cell-mediated immunity to M. leprae

Diffuse hypergammaglobulinemia associated with lepromatous leprosy can cause false positive VDRL, RF, and/or ANA tests and thus result in diagnostic confusion!

Treatment

  • Definitive therapy: Multidrug therapy [1]
WHO classification Multibacillary leprosy Paucibacillary leprosy
Lepromatous leprosy (LL) Tuberculoid leprosy (TT)
Treatment duration 12 months 6 months
Dapsone 100 mg daily
Rifampin 600 mg monthly
Clofazimine 50 mg daily and 300 mg monthly x
Follow-up after treatment
  • At least annually for 5 years
At least annually for two years
  • Supportive therapy
    • Treatment of lepra reactions (see “Complications” below)
    • Rehabilitation
      • Physiotherapy to prevent contractures
      • Surgery to correct deformities (e.g., tendon transfer surgery for ulnar nerve palsy)
    • Wound care

Complications

  • Secondary deformities
    • Bone destruction → shortened digits, autoamputation
    • Neuropathic ulcers on the dorsum of the foot
    • Charcot joints
  • Nose: saddle nose deformity, anosmia, septal perforation
  • Eye
    • Lagophthalmos and corneal insensitivity → corneal ulcers
    • Invasion of the anterior chamber → chronic uveitis → blindness
  • Orchitis → testicular atrophyhypergonadotropic hypogonadism
  • Reactive amyloidosis
  • Lepra reactions (see extra information for more details)
Type of lepra reaction Type 1 (Reversal reaction) Type 2 (Erythema nodosum leprosum, ENL) Lucio phenomenon
Mechanism
  • Immune-complex reaction
  • Cutaneous vasculitis probably due to immune-complex reaction
Type of leprosy
  • Occurs in both PB and MB but only with borderline types (BT, BB, BL)
  • Occurs only in multibacillary leprosy (BL and LL)
  • Diffuse lepromatosis form of LL
Cutaneous lesions
  • Pre-existing lepromatous lesions become red, warm, swollen, and painful
  • New, red, painful, subcutaneous nodules (1–2 cm) appear symmetrically on the face, arms, and/or legs in crops and disappear within a few days without treatment (evanescent nodules)
  • Pre-existing lepromatous lesions remain unchanged.
  • Large, sharply marginated, ulcerative lesions that appear in crops over the lower limbs and may recur episodically
Neuritis
  • Common and severe
  • Less common and mild
  • Not common
Systemic manifestations
  • Not common
  • Secondary infection of the ulcers and bacterial sepsis
Treatment
  • Supportive therapy (e.g., wound care)
  • Severe Lucio phenomenon: exchange transfusion

Patients may attribute lepra reactions to side effects of medications and stop them. Therefore, they should be warned about possible lepra reactions and told to seek treatment as soon as they occur. Treatment of leprosy should not be stopped when lepra reactions occur.

The presence of tender nerves in a patient with leprosy indicates a lepra reaction!

We list the most important complications. The selection is not exhaustive.

Prevention

  • The BCG vaccine offers variable degree of protection.
  • Chemoprophylaxis is not recommended for contacts.
last updated 09/06/2018
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