Clinical and Health Affairs
Lepromatous Leprosy Masquerading as Acute Sarcoidosis
A Case Report and Literature Review
By Mrinal M. Patnaik, M.D., Dale Hammerschmidt, M.D., Jo-Anne H. van Burik, M.D., Jose Jessurun, M.D., and Peter Smyth, M.D.
Abstract
Leprosy is uncommon in North America. Because it has a prolonged incubation period and can masquerade with a variety of manifestations, many patients with leprosy experience a significant delay in diagnosis and treatment. Lepra reactions are of 2 types: reversal (type 1) and erythema nodosum leprosum (ENL) (type 2). Type 1 or reversal reactions represent an increase in cell-mediated immunity, whereas type 2 or ENL is caused by antigen-antibody complex formation and deposition after antigen release from dying lepra bacilli. This article describes the diagnostic challenges presented by a Minnesota patient eventually found to have lepromatous leprosy. That challenge was compounded by the fact that the clinical scenario closely mimicked connective tissue/ immune complex disease and by the fact that the patient presented in a location where the incidence and prevalence of leprosy is extremely low.
Leprosy or Hansen’s disease is a chronic granulomatous disease with far-reaching socioeconomic consequences that is most commonly seen in the developing world. More than 80% of cases occur in South Asia, Brazil, and parts of Africa.1 In the United States, the prevalence of leprosy has been approximated at around 4,000 cases, with 100 to 200 new cases being reported annually. Most of these cases are diagnosed in California, Texas, New York, and Hawaii, and most often they are seen in immigrants from Mexico, the Caribbean islands, and Southeast Asia.2
There are 2 broad subcategories of lepra reactions. Type 1 lepra reactions are a delayed hypersensitivity reaction. They are typically seen in patients with borderline leprosy caused by their inherent immunological instability.3,4 Type 1 lepra reactions are termed reversal reactions if there is an associated rapid increase in specific cell-mediated immunity, as occurs during initiation of therapy. On the other hand, if borderline leprosy patients remain untreated, the natural tendency of the disease is to downgrade slowly toward the lepromatous pole, a phenomenon called a downgrading type 1 reaction.3-6 Type 2 reactions, commonly referred to as erythema nodosum leprosum (ENL), are immune-mediated and present with systemic features such as fever, arthritis, myalgias, neuritis, synovitis, dactylitis, scleritis, episcleritis, uveitis, and classical crops of tender, erythematous papules, plaques, or nodules.7,8 The ENL reaction develops as an immune complex response to fresh exposure to antigens from Mycobacterium leprae, which is generally seen after the initiation of multibacillary therapy. The reaction tends to wax and wane depending on the degree and extent of antigen release.9,10 More than 50% of lepromatous leprosy patients and 25% of patients with borderline lepromatous leprosy experience a type 2 lepra reaction.8 These reactions often develop during the first year of therapy.11 Most take place when the patient is well into treatment.12
Case Report
A 32-year-old man presented to the clinic complaining of high-grade intermittent fevers, night sweats, severe joint pain, and an erythematous maculopapular rash that had persisted for 1 month. His primary care physician obtained a skin biopsy that was suggestive of erythema nodosum and referred him to the University of Minnesota Medical Center for further assessment for a possible immune complex disorder. The physician had seen the patient a month earlier at the onset of his illness and prescribed a 7-day course of levofloxacin for a presumed upper respiratory infection. The patient was originally from Matamoras, Mexico, but had lived in McLeod County, Minnesota, for the past 10 years. He had not returned to Mexico during that time.
On examination, the man was febrile with a temperature of 103.4 degrees F. He demonstrated alopecia areata on his scalp and supercilliary madarosis. Nearly 300 intensely erythematous macules and papules were distributed over his body, mostly on his chest, back, thighs, and the volar surfaces of his forearms. Surprisingly, few lesions were found on the shins, a site classically involved with lesions of erythema nodosum. The lesions were painful, tender, and nonpruritic. The patient stated that the lesions would come in crops and subside within a few days, followed by residual pigmentation and lichenification. The small joints of his hand were swollen and tender, and he demonstrated a restricted range of motion bilaterally. He had synovial thickening and swelling in the right elbow and in both knees. A tender left axillary lymph node, along with a right inguinal node, could be palpated. There was no ocular involvement. The superficial nerves were not thickened; however, the patient complained of paraesthesias and dysesthesias in both forearms, with no evident neurological deficit. His lungs were clear to auscultation. His heart sounds were without rubs, murmurs, or gallops. The spleen felt firm but was enlarged and tender. Apart from the widely distributed erythema nodosum, there were no other cutaneous rashes, petechiae, ecchymosis, palpable purpura, bullous myringitis, or erythema multiforme.
A clinical diagnosis of erythema nodosum was made, and this was thought to be secondary to an immune complex disorder such as sarcoidosis. The investigation continued with diagnostic studies (Table).
Figure 1
Biopsy of Patient's Left Axillary Node, Hematoxylin and Eosin Stain
Foamy histiocytes with vacuolated cytoplasm, also known as Virchow cells, reveal marked histiocytosis.
Greater magnification reveals partial replacement of the lymph node parenchyma with pale to clear histiocytes.
Figure 2
Biopsy of Patient's Left Axillary Node, Fite Stain
Numerous acid-fast bacilli (red areas) are seen within the histiocytes, which is consistent with lepromatous leprosy.
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The presumptive initial diagnosis of acute sarcoidosis could not be supported, as there was no hilar lymphadenopathy, interstitial lung involvement, ocular manifestations, enhanced uveo-parotid uptake on PET scan, or cranial nerve palsies. The patient was treated with intravenous steroids followed by oral steroids for a flare up of his symptoms. Within days of discontinuing the steroids, his symptoms reappeared, and he presented again with severe erythema nodosum and palpable axillary lymph nodes. An
in toto biopsy of a left axillary node demonstrated marked sinus histiocytosis at histopathological evaluation. The interfollicular areas and lymphoid sinuses were replaced by vacuolated macrophages, also called as Virchow cells (Figure 1). A Fite stain revealed the presence of numerous beaded acid-fast bacilli consistent with lepromatous leprosy (Figure 2). Based on these findings, an initial diagnosis of ENL was made. The patient was started on 600 mg of rifampin and 300 mg of clofazimine once a month, along with 100 mg of dapsone, 50 mg of clofazimine, and 200 mg of thalidomide once daily.
Erythema nodosum leprosum as a de novo manifestation of leprosy is uncommon. Our initial thought was that the use of quinolones in this patient could have precipitated mycobaterial antigen release and caused the ENL. In order to confirm our hypothesis, we obtained the initial skin biopsy slides that had been read in McLeod County. Interestingly, these slides were intensely positive for acid-fast bacilli and showed a significant increase in dermal macrophages without clear evidence of panniculitis or vasculitis. This patient had presented with severe lepromatous leprosy. Based on these observations, the thalidomide was discontinued and the patient went on to complete his treatment course with good response.
Discussion
We report this case because of the diagnostic dilemma posed in correctly identifying the cause of this patient’s myriad symptoms. In a country where leprosy is rare, unless there is a high clinical index of suspicion, a large number of cases will be initially misdiagnosed resulting in progression of the disease, spread of the disease to proximal contacts, and the use of inappropriate therapies such as corticosteroids, which can potentially worsen the disease.
Erythema nodosum leprosum is an intense immune complex disease produced by the release of mycobacterial antigens, which subsequently induce the formation and deposition of immune complexes along with complement protein, affecting multiple organ systems and producing a plethora of manifestations.10,12,13 Typically, ENL is seen in patients with the borderline lepromatous and lepromatous forms of leprosy because of the high bacillary load of these patients and their poor cell-mediated immunity for M. leprae.14 Defective T-cell and mononuclear cell function are thought to lead to poor recognition of bacillary antigens when they are replicating within the monocytes and macrophages. Initiation of therapy, especially with bactericidal drugs, leads to a release of mycobacterial antigens and results in an enhanced and exaggerated humoral response. The antigen antibody complexes formed cause a massive immune complex disease.15
Studies have shown that ENL typically presents within the first few months of therapy.10,16 However, during this period, reversal reactions are far more common.17 Episodes of ENL subsequently occur at a higher frequency during the second and third year following the start of multidrug therapy.10,17-20 There have been a fair number of reports of untreated lepromatous leprosy presenting de novo as ENL.17,21-23 In a study from Brazil, Nery et al. followed a cohort of 162 newly diagnosed multibacillary patients and observed them for reactional episodes.24 At the point of diagnosis, 11% of the patients presented de novo with lepra reactions, of which 5% had reversal reactions and 6% had ENL.24 In their retrospective study on 386 leprosy patients in Nepal, Van Brakel et al. observed that the prevalence of ENL upon initial examination was 5.7%, as compared with 28% for reversal reactions.21
The exact precipitants that trigger the release of antigens and initiate the subsequent antigen-antibody complex are still not clearly defined. Numerous triggers have been identified including surgical procedures, pregnancy, parturition, trauma, intercurrent illnesses, vaccinations, and physical and mental stress.8,25 Numerous drugs, including iodides, bromides, dapsone, sulfonamides, and fluroquinolones, are thought to trigger this reaction, acting as weak bacterial agents. In a case report, Dave et al. reported that ofloxacin was capable of precipitating a rare variant of ENL characterized by the presence of pustular and necrotic skin lesion.26 A single dose of ofloxacin, a combination therapy consisting of rifampin, ofloxacin, and minocycline (ROM), is now commonly used in developing countries for treatment of single skin lesions.27-29 One may speculate that the frequent use and abuse of quinolones, especially in developing countries, could be a possible factor in precipitating these reactions.
Our patient presented with a clinical picture suggestive of an acute variant of sarcoidosis called Lofgren’s syndrome.30 This disorder is characterized by high-grade fevers, severe systemic symptoms, arthritis, erythema nodosum, and bilateral hilar lymph nodes.31 Our case patient did not have hilar lymphadenopathy. But subsequent diagnostic studies to confirm the suspected diagnosis of sarcoidosis were negative. Subtle clinical features consistent with the later diagnosis of leprosy included supercilliary madarosis and the presence of paraesthesias suggesting a peripheral neuritis, although the patient did not have clinically palpable superficial nerves.
The incubation period of leprosy is usually between 2 years and 7 years, and can be even longer.32 Our patient had last been to Mexico nearly 10 years prior to manifestation of his disease. Mexico, however, has a low prevalence rate for leprosy, with figures in 2004 showing a prevalence rate of less than 1 case per 10,000 people.33 This combination of factors, along with the de novo presentation as suspected erythema nodosum, resulted in the initial misdiagnosis and numerous unnecessary tests.
A diagnosis was eventually made with a lymph node biopsy showing features suggestive of lepromatous leprosy. We initially treated the patient as having lepromatous leprosy with ENL. However, once the original skin biopsies were obtained and reanalyzed, we were able to correctly identify that the patient in fact had severe lepromatous leprosy.
Conclusion
With the growing number of refugees and immigrants arriving in Minnesota, practicing physicians need to be well-aware of chronic granulomatous diseases, which are known to present with myriad features that make them hard to diagnose. Leprosy in particular is a challenge because of its long and variable incubation period. Immigrants who have lived in the United States for many years, especially those who haven’t returned to their home countries at all, are often considered to be at low risk for tropical diseases. Unfortunately, it is in this group of patients that chronic diseases such as tuberculosis and leprosy often go unrecognized, resulting in a large number of fatalities. MM
Mrinal Patnaik is with the department of internal medicine, Dale Hammerschmidt is with the department of internal medicine’s division of hematology-oncology, Jo-Anne van Burik is with the department of internal medicine’s division of infectious diseases, and Jose Jessurun is with the department of laboratory medicine and pathology at the University of Minnesota. Peter Smyth is with Glencoe Medical Center in Glencoe, Minnesota.
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