Hemophagocytic lymphohistiocytosis (HLH) and erythema nodosum leprosum (ENL) result from a complex agent–host interaction and form a continuum of the same spectrum. The macrophages laden with lepra bacilli present antigens to Th1 cells leading to increased production of chemokines, pro-inflammatory cytokines (tumour necrosis factor-alpha and interferon-gamma), activation of T-cells, neutrophils and macrophages and production of immune complexes which cause further amplification of immune response leading to ENL and tissue damage. The persistence and proliferation of lepra antigens can cause uncontrolled cytokine storm and activation of macrophages leading to a defective T-cell and NK-cell function, thus causing HLH. Despite similar pathophysiology, the prevalence of HLH in ENL is very rare, and to the best of our knowledge, there are only three case reports to date in this regard. We present here a case of a 30-year-old female with ENL who progressed to HLH. Informed consent of the patient was duly taken.
A 30-year-old multi-gravida was diagnosed with borderline lepromatous leprosy (BL) with ENL at 28 weeks of pregnancy and started on multi-drug therapy multi-bacillary (MDT-MB) and tapering dose of oral steroids. She responded well to chemotherapy; however, she discontinued treatment on her own and presented again at 36 weeks of gestation with fever and fresh crops of erythematous raised lesions over the face, and upper and lower limbs suggestive of ENL [Figure 1]. Skin biopsy showed leucocytoclastic vasculitis and perineural infiltration by acid-fast bacilli laden foamy cells [Figure 2]. The Bacteriological Index of the patient was 5. She was restarted on MDT and oral steroids; however, her condition worsened and hence early induction of labour was done at 35 weeks. The patient had an uneventful normal vaginal delivery and thalidomide was added post-partum. However, the patient developed high-grade fever, anorexia, jaundice, periorbital puffiness and pedal oedema. Her laboratory investigations are summarized in Table 1. Contrast-enhanced computerized tomography chest and abdomen revealed gross ascites, bilateral pleural effusion and splenomegaly. The patient was suspected to develop dapsone hypersensitivity syndrome (DHS), hence dapsone was stopped. She was administered broad-spectrum antibiotics and supportive therapy. However, the patient continued to be febrile with worsening hyperbilirubinemia (serum bilirubin – 3.8 → 7.6 → 16.4 → 25.6 mg/dL). In view of pancytopenia, splenomegaly, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia and hemophagocytosis on bone marrow aspirate (as shown in Figure 2), the patient was diagnosed with HLH. She was started on intravenous immunoglobulin (2 g/kg) over 5 days along with intravenous dexamethasone, and rifampicin and thalidomide were stopped. There was gradual improvement in her condition over one month, including the normalization of hematological and biochemical parameters. She was restarted on oral prednisolone and placed on second-line MDT (ofloxacin 400 mg OD, clarithromycin 500 mg OD and clofazimine 100 mg A/D) as there was an earlier clinical suspicion of DHS along with HLH. The patient is currently tolerating the treatment well without any recurrence of ENL.
ENL is a type II lepra reaction seen in approximately 60% of lepromatous leprosy and 10% of borderline lepromatous leprosy patients. Pregnancy and lactation are major precipitating factors; however, few studies have found stress, puberty, intercurrent infections, vaccination, anti-tubercular therapy, HIV and malaria as potential triggers. Our patient presented initially at 28 weeks of pregnancy when she was diagnosed as BL with ENL; however, despite her initial response, she reported back with fresh crops after discontinuation of therapy on her own. She developed high-grade fever, periorbital puffiness, pedal oedema, splenomegaly, progressive hyperbilirubinemia, gross ascites and bilateral pleural effusion after restarting MDT in post-partum period raising suspicion of DHS. DHS is a multi-system potentially fatal disorder characterized by a triad of fever, skin rashes and internal organ involvement, more commonly hepato-pulmonary, seen several weeks to six months after starting dapsone in 0.5–3.6% of patients. However, our patient had pancytopenia, hypofibrinogenemia, hyperferritinemia and hypertriglyceridemia in addition to splenomegaly. Hence HLH was a more plausible diagnosis and bone marrow aspirate subsequently confirmed the diagnosis. The H-score of our patient was 234, which suggested a 98–99% probability of HLH syndrome.
ENL and HLH are progressive ramifications of agent–host interaction seen in leprosy. While ENL is an immune-mediated type III hypersensitivity reaction, HLH is triggered by defective NK-cell and cytotoxic T-cell response leading to persistence and proliferation of the lepra bacilli, uncontrolled cytokine storm and activation of macrophages. The HLH 2004 criteria required five of eight criteria for secondary HLH, which included (i) fever >38.5°C for a minimum of seven days, (ii) splenomegaly, (iii) cytopenia of two or more lineages (hemoglobin <10 g/dL, absolute neutrophil count <1000/mL, platelets <100000/mL), (iv) hypertriglyceridemia (>265 mg/dL) or hypofibrinogenemia (<150 g/L), (v) serum ferritin >500 ng/mL, (vi) elevated soluble CD25/IL2R levels >2400 IU/mL, (vii) decreased or absent NK-cell activity and (viii) hemophagocytosis in bone marrow, spleen or lymph node. The supportive criteria include neurological manifestations, hyperbilirubinemia, elevated liver transaminases, hyponatremia, coagulopathy and raised lactate dehydrogenase levels. The revised proposed HLH 2009 criteria required (i) the presence of three of four features, fever, splenomegaly, bicytopenia and hepatitis, and at least one of four which include (i) hemophagocytosis, (ii) hyperferritinemia, (iii) decreased or absence of NK-cell activity and (iv) elevated soluble CD25/IL2R levels. The paucity of routine availability of assays for NK-cell function and soluble CD25 levels in equivocal situations can be overcome by using an online calculator-based H-score. Our patient fulfilled HLH 2004, HLH 2009 and H score criteria for HLH.
This case depicts a rare and potentially fatal complication of ENL seen in leprosy, which is a common tropical infection. A vigil for HLH syndrome is vital for promptly halting the unabated cytokine storm that can lead to catastrophic sequelae.
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