Mycobacterium leprae

OVERVIEW: What every practitioner needs to know

Are you sure your patient has leprosy? What should you expect to find?

Leprosy (Hansen’s disease) is caused by the acid fast bacterium Mycobacteria leprae and can present with varied clinical symptoms that primarily involve skin and peripheral nerves, along a continuum of severity.
Understanding the classifications of leprosy is helpful, as these correlate to the underlying organism-host immune system interaction and the resultant clinical manifestations.
By the Ridley-Jopling classification, based on a combination of clinical and biopsy findings:

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Tuberculoid (TT) has a strong immune response with few organisms visible in a biopsy of the dermis, and relatively limited clinical disease. These patients usually present with one to three well demarcated skin lesions with decreased sensation and hypopigmentation.
Borderline tuberculoid (BT) is along the spectrum closer to TT
Mid-borderline (BB) is midway between TT and lepromatous (LL)
Borderline lepromatous (BL) is along the spectrum closer to LL
Lepromatous leprosy (LL) has a relatively weak immune response, with sheets of macrophages and many organisms present in biopsy of the dermis, it is associated with more severe clinical disease. These patients present with numerous, widely dispersed, heterogeneous appearing skin lesions, including nodules and plaques.
Indeterminate (I) is when the biopsy sample is consistent with leprosy but it is too early in the course to know where the patient will fall in the Ridley–Jopling spectrum.

Most patients fall into the middle categories (BT, BB, BL), rather than the extremes of TT or LL.
In areas where biopsy is not available, the World Health Organization (WHO) has made broad clinical categories of paucibacillary leprosy (PB), which is defined as five or fewer skin lesions and multibacillary (MB), in which there are six or more lesions
Peripheral neuropathy is another hallmark of leprosy, in addition to the skin symptoms. This usually presents as decreased sensation, paresthesias, and, eventually motor loss, rather than pain in the nerve distribution. The early skin lesions themselves often demonstrate decreased sensation; in TT, this is usually limited to areas around the skin lesions, whereas, in LL, there can be more generalized involvement.
Examples of nerve involvement and the resultant clinical symptoms are facial nerve leading to lagophthalmos; great auricular nerve leading to facial edema; or a swollen, tender common peroneal nerve leading to foot drop.
Physical findings may be minimal in early disease and in some patients with TT disease.
The skin findings may range from a solitary macule to heaped, nodular and widely distributed lesions.
There is usually decreased sensation to light touch or pin prick.
Tender or enlarged peripheral nerves may be seen, including the great auricular nerve, the radial nerve, the ulnar nerve, and the common peroneal nerve.
Because of decreased sensation, patients may also present with burns, cuts or other wounds on hands or feet.
In late disease, especially with LL, there can be disfiguring collapse of the nasal septum, loss of eyebrows or eyelashes, foot drop, claw hand, and lagophthalmos. Because the organism favors the cooler areas of the body, the trunk is relatively spared compared to the extremities, ear lobes, and nose.
Involvement of the nasal mucosa can lead to edema, rhinorrhea and epistaxis.
In addition to lagophthalmos, eye findings can include conjunctival and corneal dryness, corneal abrasions, and decreased corneal sensation.

How did the patient develop leprosy? What was the primary source from which the infection spread?

The mechanisms of transmission are not completely understood but may involve human-to-human spread via nasal secretions in the majority of cases.
In the United States and Latin America, leprosy has been shown a zoonotic infection, via the nine-banded armadillo. People who have killed or eaten these animals have become infected.

Which individuals are at greater risk of developing leprosy?

Older individuals are at increased risk
Those with exposure to the nine-banded armadillo, which is endemic in the Southern United States, are at risk if they handle, kill or eat the animal.
Immunosuppressed individuals (organ transplantation, bone marrow disorders, human immunodeficiency virus) are at increased risk.
Individuals with certain variations of genes involved in innate immunity have increased susceptibility to infection.
Variations in cell-mediated immunity can affect the severity of clinical manifestations once infection has occurred and determine the classification along the spectrum from tuberculoid to lepromatous leprosy.

Beware: there are other diseases that can mimic leprosy:

Leprosy can be mistaken for cutaneous leishmaniasis, lupus vulgaris, sarcoidosis, syphilis, yaws, psoriasis, atypical mycobacterial infections, and cutaneous lymphoma.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Routine blood tests are not helpful in making the diagnosis.

Results that confirm the diagnosis

The diagnosis is generally made in the setting of chronic skin lesions, sensory changes, or enlarged and tender peripheral nerves; a biopsy of a cutaneous nerve shows acids fast bacilli.

What imaging studies will be helpful in making or excluding the diagnosis of leprosy?

Imaging studies are not generally useful in making or excluding the diagnosis of leprosy.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

Infectious Diseases should be consulted.

If you decide the patient has leprosy, what therapies should you initiate immediately?

Multiple drug therapy is required for the effective treatment of leprosy. Monotherapy is not appropriate.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

In endemic regions, therapy can be initiated based on a classic clinical presentation, even in the absence of acid fast bacilli on a biopsy. The regimens outlined in Table I should be used if possible.

2. Other key therapeutic modalities.

Alternative treatments for leprosy include minocycline, clarithromycin, levofloxacin, moxifloxacin, or ofloxacin.
All have been shown to have bactericidal activity against M. leprae but should only be used with expert consultation in select cases when first-line agents (e.g., dapsone, rifampin, clofazamine) cannot be used.
Patients with neuritis due to leprosy should be treated with corticosteroids at relatively high doses for prolonged periods (e.g., Prednisone 60mg po qd for 5-6 months). Again, this should be done in close consultation with a local infectious diseases clinician or, in the United States, the National Hansen’s Disease Program (800-642-2477).
Even with corticosteroid treatment, 30% of patients with neuritis may not have their symptoms resolve.

What complications could arise as a consequence of leprosy?

What should you tell the family about the patient's prognosis?

Patients can have multiple complications as a result of leprosy.
Neuritis may include loss of sensation, parenthesis, or painful neuropathies; a primary goal of early diagnosis and treatment of leprosy is to avoid development of neuritis. However, once this occurs, nerve function may remain impaired in up to 30% of patients, particularly those with recurrent or prolonged neuritis, or other underlying nerve disease.
Immunologic reactions are systemic inflammatory syndromes that can occur before, during, or after treatment.

These are categorized into two types:

Type 1 reaction (T1R), also known as reversal reaction (RR), is usually associated with BT, BB, or BL disease on the Ridley-Jopling classification of leprosy.

Type 2 reaction (T2R), also known as erythema nodosum leprosum (ENL), is usually associated with BL or LL disease.

Both types can present along a spectrum of severity that can be life-threatening and include severe nerve damage and inflammatory reactions that mimic shock. Generally, symptoms are less severe and include worsening of existing cutaneous lesions, or development of new ones, malaise, fever, neuritis, and arthritis.

In T2R, biopsies of new cutaneous lesions typically reveal large numbers of polymorphonuclear cells (PMNs), which are characteristic of T2R.

The causes of T1R and T2R are not well understood.

Both T1R and T2R are managed by continuing antimicrobial therapy against M. leprae, with the addition of prednisone or other anti-inflammatory medications, such as cyclosporine or thalidomide. Expert consultation should be sought prior to treatment.
Another possible rare complication of leprosy is the Lucio phenomenon. This complication presents acutely as severe lesions due to vascular compromise in patients with untreated LL. Patients from Mexico are at higher risk.

What-if scenarios:

If the peripheral nerves innervating or surrounding the eye are affected in leprosy, it is important to assess whether the eyelid can close to protect the cornea from drying or becoming abraded. Management with ophthalmology is necessary.

How do you contract leprosy and how frequent is this disease?

Leprosy is most commonly found in developing countries. The countries with the highest numbers of new cases annually include Nigeria, Brazil, Indonesia, and India.

Transmission has not been fully elucidated, but likely occurs person-to-person via respiratory secretions.

Risk factors for transmission of leprosy include close contact with an index case, older susceptible individuals, a higher burden of microorganisms in the index case, and immunosuppression in the susceptible individual.

The nine-banded armadillo is the only species other than humans that is known to be a reservoir for M. leprae. There have been human cases of leprosy in people who have handled or eaten armadillos.

What pathogens are responsible for this disease?

Mycobacterium leprae.

How do these pathogens cause leprosy?

M. leprae has a very small genome, indicating that it depends on host mechanisms for growth and replication. It is an obligate intracellular organism and expresses phenolic glycolipid 1 (PG1) on its outer capsule, which may decrease free radical formation and, therefore, help the organism survive host defenses. Other glycoproteins decrease the function of lymphocytes and macrophages.

What other clinical manifestations may help me to diagnose and manage leprosy?

The World Health Organization (WHO) has made broad clinical categories of paucibacillary leprosy (PB), which is defined as five or fewer skin lesions and multibacillary (MB) in which there are six or more lesions.
Peripheral neuropathy is another hallmark of leprosy, in addition to the skin symptoms. This usually presents as decreased sensation, parasthesias, and, eventually, motor loss, rather than pain in the nerve distribution. The early skin lesions themselves often demonstrate decreased sensation; in TT, this is usually limited to areas around the skin lesions, whereas, in LL, there can be more generalized involvement.
Examples of nerve involvement and the resultant clinical symptoms are facial nerve leading to lagophthalmos; great auricular nerve leading to facial edema; or a swollen, tender, common peroneal nerve leading to foot drop.

Physical findings may be minimal in early disease and in some patients with TT disease.
The skin findings may range from a solitary macule to heaped, nodular, and widely distributed lesions.
There is usually decreased sensation to light touch or pin prick.
Tender or enlarged peripheral nerves may be seen, including the great auricular nerve, the radial nerve, the ulnar nerve, and the common peroneal nerve.
Because of decreased sensation, patients may also present with burns, cuts, or other wounds on hands or feet.
In late disease, especially with LL, there can be disfiguring collapse of the nasal septum, loss of eyebrows or eyelashes, foot drop, claw hand, and lagophthalmos. Because the organism favors the cooler areas of the body, the trunk is relatively spared compared to the extremities, ear lobes, and nose.
Involvement of the nasal mucosa can lead to edema, rhinorrhea, and epistaxis.
In addition to lagophthalmos, eye findings can include conjunctival and corneal dryness, corneal abrasions, and decreased corneal sensation.

How can leprosy be prevented?

Prophylactic drug treatment to contacts of cases is not warranted.
There is no vaccine for leprosy; however, Bacillus Calmette-Guerin (BCG) vaccine given for tuberculosis has some cross-protective effect against M. leprae.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Duthie, MS, Gillis, TP, Reed, SG. “Advances and hurdles on the way toward a leprosy vaccine”. Hum Vaccin. vol. 7. 2011. pp. 1172-83. (This source reviews the prospects of a M. leprae vaccine.)

Legendre, DP, Muzny, CA, Swiatlo, E. “Hansen's disease (Leprosy): current and future pharmacotherapy and treatment of disease-related immunologic reactions”. Pharmacother. vol. 32. 2012. pp. 27-37. (This is a thorough review of current treatment options and possible future directions.)

Spencer, JS, Brennan, PJ. “The role of phenolic glycolipid I (PGL-I) in serodiagnosis and in the pathogenesis of leprosy”. Lepr Rev. vol. 82. 2011. pp. 344-57. (This is a good overview of pathogenesis and mechanism of a PGL-I as a virulence factor.)

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