In 1991, the World Health Organization and its member states resolved to reduce the global prevalence of Hansen's disease (leprosy) by at least 90%. Despite its waning prevalence, however, the disease remains endemic in parts of Africa, Asia, and Latin America. Moreover, imported cases are occasionally encountered in nonendemic areas. This fact, coupled with the current tempo of overseas deployments, makes it imperative that military physicians familiarize themselves with both the presentation and potential complications of Hansen's disease. Here, we present the case of a soldier referred to Walter Reed Army Medical Center for apparent worsening of his disease despite appropriate antibiotic therapy. On evaluation, the patient was diagnosed with reversal reaction, an immune-mediated phenomenon resembling disease exacerbation and requiring prompt intervention to avert lasting sequelae. Following the case presentation, we discuss the clinical manifestations, pathophysiology, and management of reversal reactions as well as the related entity erythema nodosum leprosum.
Although Hansen's disease (leprosy) persists in endemic regions, its global prevalence is declining, and in most countries, it is no longer considered to be a public health problem (as defined by prevalence greater than 1/10,000 in a population above one million). In the United States, the diagnosis is exceedingly uncommon. In 1996, for example, there were 112 reported cases, the majority of which were clustered within Texas, California, and Hawaii.1 Despite its waning prevalence, Hansen's disease remains problematic in parts of Africa, Asia, and Latin America. This fact, coupled with the current tempo of overseas deployments by U.S. armed forces, increases the likelihood that Medical Corps officers will eventually encounter the diagnosis. Consequently, a military physician deploying from a low prevalence area may not only miss the diagnosis but may be unfamiliar with the presentation and management of potential complications. One such complication is the reactional episode, a collective term for two immune-mediated reactions (reversal reaction [RR], erythema nodosum leprosum [ENL]) resembling disease exacerbation. The following is an illustrative case report and brief discussion about the clinical presentation and management of patients undergoing these reactions.
A 26-year-old Micronesian man, living in Germany, was diagnosed with borderline tuberculoid Hansen's disease after presenting with progressive skin lesions and paresthesia of 3 months' duration. Biopsy demonstrated acid-fast bacilli and granulomas, and therapy with dapsone and rifampin was initiated. Following an initial response to therapy, there was an abrupt flare in the intensity of the lesions and allodynia developed. The patient was subsequently transferred to our institution for further evaluation and management. Examination revealed a stocky male with numerous erythematous, scaling, annular plaques on the face, trunk, and extremities (Fig. 1). Some were hypoesthetic and others dysesthetic. The patient also had edema of the face and hands with clawing of the latter (Fig. 2). Neurological examination was notable for diminished sensation to light touch and temperature along the distribution of the maxillary and mandibular branches of the fifth cranial nerve on the right, the lateral aspect of the left upper extremity, and both lower extremities below the knees. There were no grossly enlarged nerves, but palpation along the ulnar nerves was painful. Aside from ichthyotic skin changes on the dorsum of both feet (Fig. 3), examination was otherwise unremarkable. Several lesions were biopsied, and histopathology was notable for both the presence of perivascular and perineural granulomas as well as the absence of acid-fast bacilli (Fig. 4).
Antibiotic therapy with dapsone and rifampin was continued, and the patient was treated symptomatically for his neuralgia with nonsteroidal anti-inflammatory drugs and gabapentin. The patient's clinical presentation and histopathology were suggestive of reaction, and aggressive therapy was instituted with gradual clinical improvement.
During the course of the disease, both treated and untreated patients may suffer from a reactional episode. The particular reaction corresponds to the type of disease. Generally, patients with borderline disease undergo RR, whereas those with lepromatous disease are at risk for ENL. Roughly one-half of the patients being treated for (borderline) lepromatous disease will develop ENL.2 This is a humoral-mediated phenomenon resembling an arthus reaction and probably results from the formation of complexes consisting of circulating antibodies and antigens released from disintegrating Mycobacterium leprae bacteria.3 Clinical features may include: fever, iridocyclitis, synovitis, adenopathy, hepatosplenomegaly, orchitis, neuralgia, glomerulonephritis (secondary to the deposition of immune complexes in the kidneys), and the formation of tender erythematous cutaneous and subcutaneous nodules, which are prone to ulceration and necrosis. Histology may show cutaneous, neural, and vascular infiltration by neutrophils, edema, and in severe cases, destruction of the dermis.
RRs are associated with borderline disease and, unlike ENL, represent cell-mediated delayed-type hypersensitivity to M. leprae antigens. The preceding case report is typical of RRs. Patients may abruptly develop fever and skin lesions may become swollen and erythematous. Moreover, neuritis is common and may lead to irreversible paralysis such as clawhand (as in the patient presented) or foot drop as well as sensory loss with consequent trauma deformities. In one study, the prevalence of RRs at first examination was 28%, of which one-half were complicated by neurological impairment.4 Histological features, if present, may include: decrease in mycobacterial burden, lymphocytic infiltration, giant cell formation, enlargement of granulomas, organized clusters of epithelioid cells, fibrinoid necrosis (likely due to tumor necrosis factor-[alpha] and interleukin-1), and edema.5 Because of the potential difficulty in distinguishing relapsing Hansen's disease from a RR, established criteria have been formulated to define each condition.6 Whereas relapse is characterized by an increase in the number of lesions, the presence of acid-fast bacilli in the skin and response to antibacterial therapy, RRs are manifested by an exacerbation of extant lesions, a negative skin smear, response to anti-inflammatory therapy, and typical histology.
In addition to the clinical and histological features, various components of the immune response to M. leprae infection have been investigated as potential markers for reactional episodes. These can generally be classified as cellular, humoral, and molecular responses and include: modulation of T lymphocyte subset populations;7-9 altered levels of circulating and in situ immune complexes;10 altered release of cytokines (specifically, tumor necrosis factor-[alpha],11 interleukin-1 and -2,12,13 and neopterin14); and variable expression of adhesion molecules.15
Risk factors for the development of RRs are incompletely understood. Clearly, the risk is greatest among treated patients during their first year of therapy (the patient presented commenced antibiotics several months before his reaction) with a gradual decline thereafter.4,16 Similarly, borderline patients with extensive lesions or thickened nerve trunks are at increased risk for RRs.17 However, a role for other variables such as sex, age, duration of infection, bacterial burden, vaccination status, and degree of disability are unproven.
ENL and RRs are medical emergencies requiring prompt intervention. The mainstay of therapy for both is anti-inflammatory medications, typically prednisone or prednisolone, without interruption of the antibiotic regimen. The use of anti-inflammatory drugs in patients with Hansen's disease has been shown to dampen both the expression of cytokines within skin lesions18 and the release of nitric oxide by macrophages.19 Long courses are generally required with gradual titration to the lowest dose effecting a clinical response. In addition to steroids, clofazimine, an inhibitor of mycobacterial replication with potent anti-inflammatory properties, may be used in the treatment of ENL. A role for clofazimine in the management of RRs has not been established.20 The immunomodulating drug thalidomide is also used to treat ENL reactions. Because of its teratogenic properties, however, its use is contraindicated in pregnant women and fertile women not using contraception.21 Other interventions with anecdotal benefit include cyclosporine22 (RR), plasma exchange23 (RR), and leukocyte infusions24 (ENL).
Early treatment of reactional episodes decreases the risk of permanent disability or deformity. Of course, this is contingent upon prompt recognition of the diagnosis. For the military physician, familiarity with Hansen's disease and its complications may be hindered by limited geographical distribution, low prevalence even in areas where the disease is highly endemic, and relatively low attack rates among adults. Nonetheless, cases of Hansen's disease among U.S. military personnel have been recorded as far back as the Spanish-American War. For example, during the period from 1921 to 1940, 32 veterans were admitted to the National Leprosarium (formerly, the U.S. Marine Hospital) at Carville, Louisiana. Of these, 30 patients had served in endemic areas (mostly the Philippines). Cases have similarly been reported among veterans of both World Wars as well as indigenous Vietnamese during the conflict in Southeast Asia.25 Given the current cadence of overseas operations, it is reasonable for the military physician to maintain at least some familiarity with the diagnosis and its potential complications.
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Guarantor: MAJ Michael Zapor, MC USA
Contributors: MAJ Michael Zapor, MC USA*; MAJ Keith Kaplan, MC USA[dagger]; COL Clifton Hawkes, MC USA*
* Infectious Diseases Service, Walter Reed Army Medical Center, Washington, DC 20307.
[dagger] Department of Pathology, Walter Reed Army Medical Center, Washington, DC 20307.
The opinions contained herein are those of the authors and are not necessarily those of the Department of Defense, United States Army, or Walter Reed Army Medical Center.
This manuscript was received for review in September 2002. The revised manuscript was accepted for publication in February 2003.
Copyright Association of Military Surgeons of the United States Nov 2003
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