Unusual Cluster In Time and Space Of Dengue-Associated Hemophagocytic Lymphohistiocytosis In Puerto Rico

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal hematologic syndrome characterized by hyperinflammation due to uncontrolled proliferation of activated lymphocytes, resulting in prolonged fever, pancytopenia, jaundice, and hepatosplenomegaly. While infection with Epstein Barr virus (EBV) is the most common recognized cause of infection-triggered HLH, there have been cases associated with other viral infections including dengue. Dengue is an acute febrile illness that is caused by any of four related but serologically distinct, mosquito-borne dengue viruses (DENV-1–4) that are endemic throughout the tropics and subtropics including Puerto Rico, a territory of the United States. Dengue can lead to a wide range of clinical outcomes, ranging from no symptoms or mild fever to potentially fatal severe dengue. In Puerto Rico, dengue most commonly affects adolescents 10–19 years old. Dengue-associated HLH (dengue-HLH) has been described in 26 case reports since 1966, but has not been previously recognized in Puerto Rico.During the start of a dengue epidemic in December 2012, the Centers for Disease Control and Prevention Dengue Branch were notified of several dengue-HLH cases at four hospitals in Puerto Rico. An investigation was conducted to: 1) determine the incidence of HLH in children since 2008; and 2) determine the infecting agent(s) associated with HLH cases. Medical records were queried to identify patients with findings compatible with HLH. To date, 681 records have been reviewed and 38 patients identified that met accepted criteria for HLH. The majority (25 patients) of the HLH cases had diagnostic evidence of DENV infection by anti-dengue IgM Enzyme Linked Immunosorbent Assay (36%) and/or DENV Polymerase Chain Reaction (68%): DENV types -1 and -4 were detected. Other causes of HLH identified were EBV and Cytomegalovirus co-infections (2), Herpes Simplex Virus (2), EBV (1), and systemic onset juvenile arthritis (2). There was one fatal dengue-HLH case (case-fatality rate [CFR]: 4.0%). Dengue-HLH cases ranged in age from 0.1–16 years, 48% were infants, and all resided in northern Puerto Rico. Among children aged 0–16 years, the average annual incidence of dengue-HLH cases in Puerto Rico from 2008 through 2011 was 0.1 cases per 100, 000 versus 2.2 cases per 100,000 in the last 12 months from June 1, 2012 to May 31, 2013, which demonstrates the dramatic increase in recent cases. The number of HLH cases may have been higher since in 14 additional cases with suspected HLH who only fullfilled 4 of the required 5/8 diagnostic criteria, laboratory investigations were incomplete.This is an unusual cluster of dengue-HLH cases in time and space afflicting mostly infants and cannot be explained by heredity. Currently there is no explanation for this outbreak of dengue-HLH. Some cases of dengue-HLH may have been overlooked in the past if severe dengue cases were not investigated for the presence of HLH criteria. We are presently conducting a case-control study to identify risk factors for developing dengue-HLH and determine why in contrast to previous experience infants were predominantly affected. Physicians in dengue endemic areas should be made aware that infection with dengue virus may lead to the hyperinflammatory syndrome HLH. Disclosures:No relevant conflicts of interest to declare.