Comment
Despite a decrease in its prevalence through a World Health Organization (WHO)–empowered eradication program, leprosy still represents a health problem in endemic areas.1,2 It is characterized by a wide range of immune responses to Mycobacterium leprae, displaying a spectrum of clinical and histopathologic manifestations that vary from the tuberculoid or paucibacillary pole with a strong cell-mediated immune response and fewer organisms to the lepromatous or multibacillary pole with weaker cell-mediated immune response and higher loads of organisms.3 In addition to its well-known cutaneous and neurologic manifestations, leprosy can present with a variety of manifestations, including constitutional symptoms, musculoskeletal manifestations, and serologic abnormalities; thus, leprosy can mimic rheumatoid arthritis, spondyloarthritis, and vasculitis—a pitfall that may result in misdiagnosis as a rheumatologic disorder.3-7
The chronic course of leprosy can be disrupted by acute, immunologically mediated reactions known as lepra reactions, of which there are 3 types.8 Type I lepra reactions are cell mediated and occur mainly in patients with borderline disease, often representing an upgrade toward the tuberculoid pole; less often they represent a downgrade reaction. Nerves become painful and swollen with possible loss of function, and skin lesions become edematous and tender; sometimes arthritis develops.9 Type II lepra reactions, also known as erythema nodosum leprosum (ENL), occur in borderline lepromatous and lepromatous patients with a high bacillary load. They are characterized by fever, body aches, tender cutaneous/subcutaneous nodules that may ulcerate, possible bullous lesions, painful nerve swellings, swollen joints, iritis, lymphadenitis, glomerulonephritis, epididymo-orchitis, and hepatic affection. Both immune-complex and delayed hypersensitivity reactions play a role in ENL.8,10 The third reaction is a rare aggressive type known as Lucio phenomenon or Lucio leprosy, which presents with irregular-shaped, angulated, or stellar necrotizing purpuric lesions (hemorrhagic infacrtions) developing mainly on the extremities. The lesions evolve into ulcers that heal with atrophic scarring.2,11 Lucio phenomenon develops as a result of thrombotic vascular occlusion secondary to massive invasion of vascular endothelial cells by lepra bacilli.2,11-14 Involvement of the scrotal skin, such as in our patient, is rare.
Lucio phenomenon mainly is seen in Mexico and Central America, and few cases have been documented in Cuba, South America, the United States, India, Polynesia, South Africa, and Southeast Asia.15-17 It specifically occurs in patients with untreated, diffuse, nonnodular lepromatous leprosy (pure and primitive diffuse lepromatous leprosy (DLL)/diffuse leprosy of Lucio and Latapí). This type of leprosy was first described by Lucio and Alvarado18 in 1852 as a distinct form of lepromatous leprosy characterized by widespread and dense infiltration of the whole skin by lepra bacilli without the typical nodular lesions of leprosy, rendering its diagnosis challenging, especially in sporadic cases. Other manifestations of DLL include complete alopecia of the eyebrows and eyelashes, destructive rhinitis, and areas of anhidrosis and dyesthesia.2
Latapí and Chévez-Zomora19 defined Lucio phenomenon in 1948 as a form of histopathologic vasculitis restricted to patients with DLL. Histopathologically, in addition to the infiltration of the skin with acid-fast bacilli–laden foamy histiocytes, lesions of Lucio phenomenon show features of necrotizing (leukocytoclastic) vasculitis with fibrinoid necrosis20 or vascular thrombi with minimal perivascular lymphocytic infiltrate and no evidence of vasculitis.11 Medium to large vessels in the deep dermis and subcutaneous tissue show infiltration of their walls with a large number of macrophages laden with acid-fast bacilli.11 Cases with histopathologic features mimicking antiphospholipid syndrome with endothelial cell proliferation, thrombosis, and mild mononuclear cell infiltrate also may be seen.20 In all cases, ischemic epidermal necrosis is seen, as well as acid-fast bacilli, both singly and in clusters (globi) within endothelial cells and inside blood vessel lumina.
Although Lucio phenomenon initially was thought to be immune-complex mediated like ENL, it has been suggested that the main trigger is thrombotic vascular occlusion secondary to massive invasion of the vascular endothelial cells by the lepra bacilli, resulting in necrosis.14 Bacterial lipopolysaccharides promote the release of IL-1 and tumor necrosis factor α, which in turn stimulate the production of prostaglandins, IL-6, and coagulation factor III, leading to vascular thrombosis and tissue necrosis.21,22 Moreover, antiphospholipid antibodies, which have been found to be induced in response to certain infectious agents in genetically predisposed individuals,23 have been reported in patients with leprosy, mainly in association with lepromatous leprosy. The reported prevalence of anticardiolipin antibodies ranged from 37% to 98%, whereas anti-β2-glycoprotein I antibodies ranged from 3% to 19%, and antiprothrombin antibodies ranged from 6% to 45%.24,25 Antiphospholipid antibodies have been reported to play a role in the pathogenesis of Lucio phenomenon.11,13,15,26 Our case supports this hypothesis with positive anticardiolipin antibodies, anti-β2 glycoprotein antibodies, and positive lupus anticoagulant.
In accordance with Curi et al,2 who reported 5 cases of DLL with Lucio phenomenon, our patient showed a similar presentation with positive inflammatory markers in association with a negative autoimmune profile (ANA, ANCA-C&P) and negative venereal disease research laboratory test. It is important to mention that a positive autoimmune profile (ANA, ANCA-C&P) can be present in leprotic patients, causing possible diagnostic confusion with collagen diseases.27,28
An interesting finding in our case was the negative slit-skin smear results. Although the specificity of slit-skin smear is 100%, as it directly demonstrates the presence of acid-fast bacilli,29 its sensitivity is low and varies from 10% to 50%.30 The detection of acid-fast bacilli in tissue sections is reported to be a better method for confirming the diagnosis of leprosy.31
The provisional impression of hemophagocytic lymphohistiocytosis in the lymph node biopsy in our patient was excluded upon detection of acid-fast bacilli in the foamy histiocytes infiltrating the lymph node; moreover, the normal serum lipids and serum ferritin argued against this diagnosis.32 Leprosy tends to involve the lymph nodes, particularly in borderline, borderline lepromatous, and lepromatous forms.33 The incidence of lymph node involvement accompanied by skin lesions with the presence of acid-fast bacilli in the lymph nodes is 92.2%.34
Our patient showed an excellent response to antileprotic treatment, which was administered according to the WHO multidrug therapy guidelines for multibacillary leprosy,35 combined with low-dose prednisolone, acetylsalicylic acid, and anticoagulant treatment. Thalidomide and high-dose prednisolone (60 mg/d) combined with antileprotic treatment also have been reported to be successful in managing recurrent infarctions in leprosy.36 The Fournier-like gangrenous ulcer of the scrotum was managed by surgical debridement and vacuum therapy.
It is noteworthy that the WHO elimination goal for leprosy was to reduce the prevalence to less than 1 case per 10,000 population. Egypt is among the first countries in North Africa and the Middle East regions to achieve this target supervised by the National Leprosy Control Program as early as 1994; this was further reduced to 0.33 cases per 10,000 population in 2004, and reduced again in 2009; however, certain foci showed a prevalence rate more than the elimination target, particularly in the cities of Qena (1.12) and Sohag (2.47).37 Esna, where our patient is from, is an endemic area in Egypt.38
Conclusion
Leprosy is a great mimicker of many connective tissue diseases, including vasculitis. Antiphospholipid antibodies are involved in Lucio phenomenon. Recognition of Lucio phenomenon is important to initiate prompt treatment and avoid morbidity and mortality. We report a rare case of diffuse nonnodular lepromatous leprosy in Egypt in which Lucio phenomenon was the first diagnostic presentation. Scrotal involvement with Lucio phenomenon was not previously reported in any case of Lucio leprosy.