Leprosy: a case series and review.

Abstract: Hansen disease, historically known as leprosy, is caused by Mycobacterium leprae. The disease is rare in the United States but remains endemic among certain immigrant populations, and may manifest years after infection. The US military has a number of active duty troops originally from endemic countries. Recently, three US soldiers with Hansen disease were evaluated at Walter Reed Army Medical Center. The mean time to diagnosis was 8 months (range, 2 to 18 months). All three patients were initially misdiagnosed and treated for other skin infections or contact dermatitis. These cases illustrate the importance of prompt recognition and treatment of Hansen disease to prevent permanent disability and disfigurement. The clinical presentation, diagnosis, classification, and currently recommended therapeutic regimens for Hansen disease are discussed.

Key Words: Hansen disease, immigrant, leprosy, military

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Hansen disease is rare in the United States, with a declining incidence since the 1980s and only 102 new cases reported in 1998. (1) Although a small number of endemic cases come from Hawaii, Texas, and Louisiana, the majority of cases (85%) are reported among immigrant or refugee populations. (1)

Physicians can encounter leprosy in any situation, but certain practice settings favor its appearance. The first results from the Compact of Free Association with the United States, which permits indigenous people from the Western Pacific Islands to join the US military. Because of the long incubation period (3 months to 40 years, with an average incubation period of 2 to 4 years), infection with Mycobacterium leprae may not be evident at the time of enlistment. (1) Similarly, immigrants can be a source of imported cases from endemic countries. The expanding role for the United States in managing refugee populations is likely to increase contact with persons infected with M leprae as well.

During a recent 1-month period, three patients were evaluated at Walter Reed Army Medical Center (WRAMC) for leprosy. All three patients were initially misdiagnosed and had been treated for some other condition (ie, contact dermatitis or Tinea corpora). The ability to recognize the diagnosis and provide prompt therapy is essential to prevent the long-term morbidity and disfigurement associated with leprosy. The three cases are presented, followed by a discussion regarding the diagnosis, classification, and currently recommended treatment regimens for Hansen disease.

Case Reports

Patient 1

Patient 1 was a 26-year-old male soldier originally from Pohnpei, Micronesia, who initially presented to his Troop Medical Clinic (TMC) at Fort Gordon, Georgia, complaining of a rash on his abdomen. He described the rash as a "red ring" with central clearing, which spread over his trunk and became pruritic. Both Lyme disease and allergic reaction were considered; initial empiric therapy consisting of a topical steroid, and hydroxyzine was prescribed. The lesions persisted and the patient developed paresthesias on the dorsa of his feet, calves, hands, and face, as well as bilateral lower extremity edema. Biopsy tissue showed superficial and deep granulomatous inflammation in a perineural and perivascular distribution consistent with borderline tuberculoid leprosy (Fig. 1), for which 300 mg rifampin orally once per day and 100 mg dapsone orally once per day were initiated. One month into treatment, the lesions were still present and increasingly dysesthetic. The patient was transferred to WRAMC for evaluation and management of a presumed drug-resistant M leprae infection.

At arrival at WRAMC, the patient's physical examination was notable for numerous erythematous, scaly, annular, dysesthetic, and anesthetic plaques on his face, trunk, and extremities (Fig. 2). He also had edematous hands with telescoping of the fingers. His neurologic examination was significant for diminished sensation to fine touch on the right cheek, lateral aspect of the left arm, and both legs below the knees. Vibratory sensation was also decreased at the first left metatarsal phalangeal joint and the ankles bilaterally. The patient had pain-limited range of motion in both hands and feet. This patient's presentation was consistent with a type I reversal reaction, and he was started on 100 mg prednisone and 500 mg naproxen orally per day, 15 mg methotrexate once per week, and 300 mg gabapentin at night. His rifampin dose was increased to 600 mg orally per day. The patient gradually responded to therapy. He was medically discharged from the Army and returned to Micronesia with follow-up there.

Patient 2

Patient 2 was a 21-year-old male soldier from the Marshall Islands who immigrated to the United States in 2000 to join the Army. In February 2002, while training in Louisiana, he noted a "flesh-colored," dysesthetic lesion on his left upper extremity. In the ensuing week, similar lesions appeared on his right upper extremity, chest, back, and both lower extremities, prompting the patient to present to the TMC for evaluation. He was prescribed a topical antifungal for presumed T corpora, but the lesions persisted. Subsequent biopsied tissue showed superficial and deep inflammation with granulomas and numerous acid-fast bacilli evident by Fite stain. (2) The histology was consistent with borderline lepromatous-type leprosy. Therapy was initiated with dapsone and rifampin, and the patient was transferred to WRAMC for further treatment.

At WRAMC, physical examination was notable for diffuse hypopigmented macules and plaques on the back and all extremities, as well as an anesthetic scaly patch with delineated margins over the left gastrocnemius (Fig. 3). The distal legs were paresthetic on palpation, but grossly enlarged nerves and foot drop were absent. Clofazimine was added to the therapeutic regimen with good response, and the patient eventually returned to his unit without lasting sequelae.

Patient 3

Patient 3 was a 26-year-old male soldier from Kosrae, Micronesia. In February 2002, he developed several sharply demarcated erythematous and anesthetic papules on his left arm. These lesions spread, eventually involving his face, back, and all four extremities. Empiric therapy with a topical antifungal failed, and in July 2002 the diagnosis of leprosy was made by tissue biopsy. Therapy with 100 mg dapsone orally per day and 600 mg rifampin orally per day was initiated, and the patient was transferred to WRAMC for further treatment.

The patient's physical examination was significant for multiple anesthetic hypopigmented macules and plaques on his chest and extremities and a small nodule (2 X 2 cm) on his left mandible. Repeat biopsy showed superficial and deep perivascular and periadnexal lymphohistiocytic infiltrate with sparing of the epidermis. The biopsy results and the nodule's appearance were consistent with borderline lepromatous leprosy, and clofazimine was added to the patient's regimen. He tolerated therapy and eventually returned to his unit.

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Discussion

Although references to leprosy can be found as early as the biblical period, the disease was misunderstood until 1873, when Norwegian physician Gerhard Henrik Armauer Hansen, after whom the disease was renamed, first identified M leprae as the causative organism. (3) Despite subsequent advances in diagnosis and treatment, leprosy remains problematic in countries such as Brazil and India, where the incidence is highest, as well as several other countries to which US soldiers are deployed. (4) Moreover, the Compact of Free Association, which permits Western Pacific Islanders to join the US military, provides a small influx of imported cases from Micronesia and the Marshall Islands. Neither of these territories met the World Health Organization's goal of leprosy elimination in 2002. (5)

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The three cases described in this report illustrate the presentation of the disease among soldiers emigrating from endemic countries. Given the prolonged incubation period of M leprae, infection in a person originating from one of these countries or other countries where leprosy is endemic may not be clinically evident for some time. (1) Moreover, modes of transmission are poorly defined, with only one third of cases having known long-term exposure to an infected person. (6) Aerosol or direct skin contact through a compromised skin barrier are suspect routes, but there is no definitive proof. (7) The presence of phenolic glycolipid-I antigen (a chemical unique to M Leprae) in the soil has led some researchers to believe that soil is a potential source. (6,8) Unfortunately, without better evidence, providers are unable to predict who is at increased risk or even who has been exposed.

The presentation of Hansen disease can be variable, as illustrated by the three cases reported above, and the disease should be considered in any patient from an endemic country presenting with a nonhealing skin lesion. Lesions characteristically develop on the elbows, knees, or ears, where bacilli tend to live. (4) Anesthetic lesions or enlarged nerves should heighten the suspicion for the diagnosis.

The nature of the lesion is dictated by the patient's immune response to the M leprae bacillus. Traditionally, leprosy patients are classified according to the Ridley-Jopling scale. Indeterminate leprosy, not represented in our case presentations, occurs in patients who have an effective cell-mediated immune response. Typically, there is a single hypopigmented or erythematous anesthetic lesion, which spontaneously resolves. (4,9) Tuberculoid leprosy also reflects a sufficient cell-mediated immune response, but these patients have one or two hypopigmented, erythematous, and anesthetic macules with a raised margin. Lepromatous leprosy, which may occur in the setting of immune dysfunction, presents with diffuse erythematous lesions ranging from macules to nodules which may have indistinct borders. The borderline types of leprosy are less clearly defined and may have features of several variants.

The Ridley-Jopling scale is cumbersome and has been replaced by the more facile World Health Organization system, which categorizes disease as either paucibacillary or multibacillary. (1) Paucibacillary leprosy is defined as five or fewer skin lesions with the absence of bacilli in skin smears. Conversely, multibacillary leprosy is characterized by the presence of six or more lesions and may be skin smear-positive. When comparing the two systems, indeterminate and borderline tuberculoid disease are analogous to paucibacillary leprosy, whereas borderline, lepromatous, and multibacillary disease are comparable. (4)

Neurologic findings are common in patients with Hansen disease. Sensory and/or motor deficits typically course along nerves in patients with tuberculoid leprosy, but have more diffuse distribution in patients with borderline or lepromatous disease. (4) The most commonly affected nerves are the ulnar (claw hand), median (ape hand), common peroneal (foot drop), facial, and great auricular nerves. (4) Neurologic deficits vary and may include paralysis, anesthesia, and anhydrosis. (3,4)

An uncommon complication that may occur among both treated and untreated patients is the reactional episode, of which there are two types: type 1 or reversal reaction and type 2 reaction, also known as erythema nodosum leprosum. (1) These syndromes most commonly emerge within the first year of treatment but can occur at any time during the course of disease. (4) The type 1 reaction is called an "upgrading," or reversal reaction, and represents cell-mediated, delayed type hypersensitivity to disintegrating mycobacteria. (1) It occurs most commonly in borderline lepromatous patients but can occur in borderline tuberculoid and mid-borderline as well. (1) Patients can have new skin lesions or increased inflammation of preexisting lesions and, potentially, neuritis.

Patient 1 in our series, whose facial lesions and extensive skin involvement increased his risk of complication, illustrates the type 1 reversal reaction. (1) His reaction occurred during therapy and was manifested by increasingly dysesthetic lesions and diminished peripheral sensation. Treatment, which consists of anti-inflammatory agents (eg, prednisone and methotrexate) and analgesics (eg, gabapentin and naproxen), was initiated early with good response. Although our patient responded to medical therapy, some require surgical decompression of swollen nerves to prevent irreversible neurologic injury. (1)

The second type of reaction, erythema nodosum leprosum, typically occurs in pregnant females and patients younger than 40 years of age with borderline lepromatous or lepromatous leprosy. (1) It is thought to reflect an inflammatory response to M leprae resulting in immune complex deposition. (4, 10) Both tumor necrosis factor-[alpha] and interferon-[gamma] are elevated in patients undergoing erythema nodosum leprosum reactions and are probably produced in response to antigens shed by disintegrating mycobacteria. (10,11) Patients typically present with new, small, tender erythematous nodules, and they may have fever, arthralgias, neuritis, vasculitis, and adenopathy. (4) Thalidomide is the agent of choice, generally effecting good response within 24 to 48 hours. (1,4) In addition, steroids may be used to manage neuritis.

The diagnosis of Hansen disease is initially made by history and physical examination, and then confirmed by skin smear or lesion biopsy, which helps to guide therapy. Staining by the Fite method is optimal for the detection of acid-fast bacilli. (1,2) Newer diagnostic methods include assaying for antibodies to phenolic glycolipid-1 (PGL-1) and polymerase chain reaction amplification of M leprae genomic sequences. (1,3) Yet, serology is limited by insensitivity in patients with paucibacillary disease, and polymerase chain reaction amplification is generally useful only when bacilli are evident by Fite stain. (1,12,13) Even with the best diagnostics, however, leprosy will not be recognized in the absence of clinical suspicion. As evidenced by our three case presentations, early misdiagnosis can occur in low prevalence areas. The average time to diagnosis in the United States is approximately 2 years from presentation, which can lead to unnecessary complications of the disease. (14)

As with other mycobacterial diseases, the treatment for M leprae infection consists of a multidrug regimen. The six currently used anti-infectives include rifampin, dapsone, clofazimine, minocycline, ofloxacin, and clarithromycin. The last three agents are infrequently used and will not be discussed. Dapsone is a bacteriostatic drug that competitively inhibits para-aminobenzoic acid (PABA), disrupting folate metabolism. (1) It was used as monotherapy until the 1980s, when the emergence of dapsone-resistant M leprae prompted the World Health Organization to recommend multidrug regimens. (1,15) Rifampin and clofazimine are now used in addition to dapsone to minimize resistance and increase treatment success.

Rifampin acts by inhibiting the Mycobacterium RNA polymerase B-subunit. A single dose typically reduces 99.9% of the burden of viable organisms, and patients with lepromatous leprosy are noninfectious within 2 days of initiating treatment. (1) Dapsone and clofazimine are less bactericidal, but when used in combination will similarly reduce the number of viable bacilli within 3 months. (4) The mechanism of action of clofazimine is unknown.

The current recommendations for paucibacillary disease in the United States are dapsone (100 mg orally per day) and rifampin (600 mg orally per day) for 1 year. For multibacillary disease, dapsone (100 mg orally), rifampin (600 mg orally), and clofazimine (50 mg orally) for 2 years are recommended. (16) Relapse rates after these regimens are low (0.1% for paucibacillary and 0.06% for multibacillary) but can occur; (3) and patients should be evaluated roughly every 3 months for relapse or reaction. In the event of relapse, mouse foot-pad sensitivity testing should be performed with a multibacillary regimen to ensure drug sensitivity. The patient should then be treated for 2 years, followed by daily dapsone or clofazimine for life. (1,16)

Rifampin is generally well tolerated, but patients should be warned that the drug discolors secreted body fluids (urine, tears, and sweat). Uncommon adverse effects include hepatitis, renal failure, thrombocytopenia, and hemolytic anemia. (1,3) Dapsone can cause hemolytic anemia in individuals with glucose-6-phosphate deficiency, and patients should be tested for this before initiating treatment. Dapsone has also been infrequently implicated in allergic reactions and agranulocytosis. (1,4) Clofazamine may cause gastrointestinal upset and skin pigmentation.

Conclusion

Although the prevalence of leprosy is low in the United States, imported cases occur, as shown by the three patients presented in this report. Moreover, the current tempo of overseas operations increases the likelihood that the military clinician will encounter the diagnosis among an endemic population. Similarly, civilian clinicians may confront leprosy when treating immigrants, treating patients living in states where the disease occurs naturally (Texas, Louisiana, and Hawaii), or when treating patients during humanitarian missions. Familiarity with the disease is essential so as to initiate appropriate therapy and avert lasting sequelae.

Accepted August 11, 2004.

References

1. Ooi WW, Moschella SL. Update on leprosy in immigrants in the United States: Status in the year 2000. Clin Infect Dis 2001;32:930-937.

2. Ridley DS, Job CK, in Hastings RC (ed): Leprosy. New York, Churchill Livingstone, 1985, p 129.

3. Ishii N. Recent advances in the treatment of leprosy. Dermatology Online J 2003;9:5.

4. Jacobson RR, Krahenbuhl JL. Leprosy. Lancet 1999;353:655.

5. Leprosy Elimination Unit. Leprosy in the WHO Western Pacific Region 2000. http://stoptb.wpro.who.int/StopTB_docs/leprosy_review_2000.pdf. WHO Regional Office for the Western Pacific, Manila, Philippines, 2002.

6. Chakrabarty AN, Dastidar SG. Is soil an alternative source of leprosy infection? Acta Lepr 2001-2002;12:79-84.

7. Abraham S, Mozhi NM, Joseph GA, et al. Epidemiological significance of first skin lesion in leprosy. Int J Lepr 1998;66:131-139.

8. Blake LA, West BC, Lary CH, Todd JR IV. Environmental nonhuman sources of leprosy. Rev Infect Dis. 1987;9:562-577.

9. Modlin RL, Rea TH. Immunopathology of leprosy, in Hastings RC (ed): Leprosy. 2nd edition. Edinburgh, Churchill Livingstone, 1994 pp 225-234.

10. Khanolkar-Young S, Rayment N, Brickell PM, et al. Tumor necrosis factor alpha (TNF-alpha) synthesis is associated with the skin and peripheral nerve pathology of leprosy reversal reactions. Clin Exp Immunol 1995;99:196-202.

11. Barnes PF, Chatterjee D, Brennan PJ, et al. Tumor necrosis factor production in patients with leprosy. Infect Immunol 1992;60:1441-1446.

12. Parkash O, Chaturvedi V, Girdhar BK, et al. A study on performance of two serological assays for the diagnosis of leprosy patients. Lepr Rev 1995;66:26-30.

13. Scollard DM, Gillis TP, Williams DL. Polymerase chain reaction assay for the detection and identification of Mycobacterium leprae in patients in the United States. Am J Clin Pathol 1998;109:642-646.

14. Meyers WM. Leprosy, in Guerrant RL, Walker DH, Weller PF (eds): Tropical Infectious Disease: Principles and Practice. Philadelphia, Churchill Livingstone, 1999, p 480.

15. World Health Organization Study Group on Leprosy. Chemotherapy of leprosy control programs (WHO technical report series 675). Geneva, World Health Organization, 1982.

16. Yoder LJ, Guerra IE. Hansen disease: A guide to management in the United States. Carville, LA, National Hansen's Disease Programs, 1996.

RELATED ARTICLE: Key Points

* Despite the low incidence of leprosy in the United States, certain populations, including immigrants, remain at risk for the disease.

* The average time to diagnosis in the United States is approximately 2 years from presentation, which can lead to unnecessary complications.

* Leprosy should be considered in any patient with a nonhealing skin lesion, especially if they have neurologic deficits or have lived in an endemic area.

* Classification of leprosy into paucibacillary and multibacillary disease is not only academic but directs appropriate therapy.

* Reversal reaction and erythema nodosum leprosum are two reactional episodes that can occur in leprosy patients at any time during the disease.

CPT Joshua D. Hartzell, MD, MC, USA, LTC Michael Zapor, MD, PHD, MC, USA, CPT Suzette Peng, MD, MC, USA, and MAJ Timothy Straight, MD, MC, USA

From the Department of Internal Medicine and the Department of Infectious Disease, Walter Reed Army Medical Center, Washington, DC.

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Department of the Army, the US Department of Defense, or Walter Reed Army Medical Center.

Reprint requests to Cpt. Joshua Hartzell, MD, Department of Internal Medicine, Walter Reed Army Medical Center, 6900 Georgia Avenue, NW, Washington, DC 20307. E-mail: [e-mail]