Severe hemophagocytic lymphohistiocytosis as a complication of drug-induced hypersensitivity syndrome.

Dear Editor,

Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis is a rare but fatal condition caused by inappropriate activation of macrophages against one's blood cells and characterized by histiocyte proliferation and hemophagocytosis, resulting in fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, liver dysfunction, and coagulopathy. This condition is usually secondary to infection, autoimmune disorder, or malignancy.[1] Here, we present a rare case of severe HPS as a complication of drug-induced hypersensitivity syndrome in a previously healthy patient.

A 24-year-old African American female patient with no significant medical history presented to our hospital with complaints of lower back pain, fever, vomiting, rash, and sore throat. The presentations were preceded by an upper respiratory tract infection 2 weeks earlier. She took a single dose of amoxicillin-clavulanate after which a pruritic skin rash developed on her back, arms, and thighs. The patient had a temperature of 103.1 F, blood pressure of 119/89 mmHg, pulse of 142 beats per minute, and oxygen saturation of 98% in room air. Examination showed a left-sided non-tender non-fluctuating mass on the back, measuring approximately 4 × 4 cm, and a generalized macular rash on the left upper chest wall, lower back, both upper extremities, and thighs. Blood tests revealed a white blood cell count of 18,500/mm3 (neutrophils 74%, lymphocytes 6%, and eosinophils 9%), hemoglobin level of 12.4 gm/dl, hematocrit of 38.8%, and platelets 1,97,000/mm3. Her electrolytes and liver function tests were within normal limits. Rapid strep test was negative. During hospitalization, the patient's clinical status deteriorated with persistent fever, hypotension, and respiratory failure requiring mechanical ventilation. Computed tomography (CT) scan of the chest, abdomen, and pelvis revealed bilateral cervical lymphadenopathy measuring 2 cm, patchy perihilar consolidations, left axillary lymphadenopathy measuring 3.4 cm, bilateral pleural effusions, left inguinal lymphadenopathy measuring 2.2 cm, and mild splenomegaly. Laboratory studies showed normal white blood cell levels, but a progressive decline in hemoglobin and platelet levels, elevated liver enzymes (alanine aminotransferase 450 U/L, normal 0–37 U/L, aspartate aminotransferase 500 U/L, normal 0–40 U/L), elevated bilirubin (150 μmol/L, normal 0–22.6 μmol/L), elevated ferritin level (>75 000 μg/L, normal 16–320 μg/L), hypertriglyceridemia (2,798 U/L), hypofibrinogenemia (fibrinogen 1.0 g/L), prolonged prothrombin time and activated partial thromboplastin time, and international normalized ratio (INR). Complement levels, ANA titer, anti-dsDNA antibody, anti-SSA antibody, ribonuclear protein antibody, antiJo1, antiScl70, and rheumatoid factor were negative. Blood cultures and serology for human immunodeficiency virus; hepatitis A, B, and C; tests for tuberculosis (PPD and quantiFERON gold); Cytomegalovirus (IgM, IgG, and PCR); Human Herpes Virus-8 PCR; Human Herpes Virus-6 PCR; Parvovirus PCR; and Epstein Barr Virus (IgM, IgG, and PCR) were all negative. A gallium scan was negative. A lymph node biopsy could not be done considering severe coagulopathy (INR > 5). A bone marrow biopsy was done, and it revealed hemophagocytosis by macrophages, without any evidence of hematologic malignancy [Figure 1]. Soluble CD25 receptor was elevated at 7,867 pg/ml. Intravenous immunoglobulin (IVIG) was administered. An extensive search for an infectious, neoplastic, or autoimmune cause of the hemophagocytosis remained negative.

Figure 1

Bone marrow biopsy smear demonstrating hemophagocytosis

The patient's constellation of clinical features (fever, splenomegaly) and laboratory evaluation (hypofibrinogenemia, cytopenia in peripheral blood, hypertriglyceridemia, elevated ferritin, high soluble CD25 receptor level, and hemophagocytosis in bone marrow without any obvious evidence of malignancy) fulfilled the criteria for the diagnosis of HPS. A dose of etoposide 150 mg/m2 was started and the patient was scheduled to receive another dose on the fourth day of initiation of treatment, followed by 100 mg of cyclosporine provided daily later in the patient's course. By day 15, the patient clinically improved and was weaned from intubation. The patient was discharged on tapering doses of decadron. On outpatient follow-up two weeks later, laboratory reports were completely normal, and there was a dramatic clinical improvement.

The patient presented with characteristic drug hypersensitivity-related febrile exanthema, and subsequently, developed cytopenias that are not usually part of this syndrome. It is suggested that cell destruction by cytotoxic antibodies[2] and a reversible depression of stem cell activity[3] with myeloid maturation blockade contribute to the pathophysiology of the cytopenias. Drug hypersensitivity results in hypercytokinemia, leading to uncontrolled activation of benign scavenger macrophages and development of hemophagocytosis in the reticuloendothelial system.[4] This entity is probably underdiagnosed because both syndromes share nonspecific symptoms, bone marrow biopsies are not usually part of the diagnostic work-up in a classic drug hypersensitivity syndrome, and hemophagocytosis pathology can be missed on bone marrow aspiration.[5] This case illustrates the diagnostic and therapeutic importance of considering all possible underlying causes in a patient with HPS, including a drug-induced etiology.