Incidence and Risk Factors for Developing Dengue-Associated Hemophagocytic Lymphohistiocytosis in Puerto Rico, 2008 - 2013

Abstract

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal disorder characterized by fever, pancytopenia, hepatosplenomegaly, and increased serum ferritin. HLH is being increasingly reported as a complication of dengue, a common tropical acute febrile illness.Methodology/Principal FindingsAfter a cluster of pediatric dengue-associated HLH patients was identified during the 2012–2013 dengue epidemic in Puerto Rico, active surveillance and a case-control investigation was conducted at four referral hospitals to determine the incidence of HLH in children and identify risk factors for HLH following dengue. Patients with dengue-associated HLH (cases) were matched by month of illness onset and admission hospital to dengue patients that did not develop HLH (controls). During 2008–2013, a total of 33 HLH patients were identified, of which 22 (67%) were associated with dengue and 1 died (dengue-associated HLH case-fatality rate: 4.5%). Two patients with dengue-associated HLH had illness onset in 2009, none had illness onset during the 2010 dengue epidemic, and 20 had illness onset during the 2012–2013 epidemic. Frequency of infection with either dengue virus (DENV)-1 or DENV-4 did not differ between cases and controls. Cases were younger than controls (median age: 1 vs. 13 years, p < 0.01), were hospitalized longer (18 vs. 5 days, p < 0.01), and were admitted more frequently to pediatric intensive care units (100% vs. 16%, p < 0.01). Cases had co-infection (18.2% vs. 4.5%, p = 0.04), recent influenza-like illness (54.5% vs. 25.0%, p = 0.01), and longer duration of fever (7 vs. 5 days; p < 0.01). Cases were more likely to have lymphadenopathy, hepatomegaly, splenomegaly, anemia, and elevated liver transaminases (p ≤ 0.02).Conclusions/SignificanceDuring this cluster of dengue-associated HLH cases that was temporally associated with the 2012–2013 epidemic, most patients with dengue-associated HLH were infants and had higher morbidity than dengue inpatients. Physicians throughout the tropics should be aware of HLH as a potential complication of dengue, particularly in patients with anemia and severe liver injury.

Dengue hemophagocytic syndrome: A systematic review and meta‐analysis on epidemiology, clinical signs, outcomes, and risk factors

“…In India, 77.8% of the reported cases were confirmed during 2011 to 2012, the DENV‐1 was dominant followed by DENV‐3 during 2008 to 2012 . In Puerto Rico, 87.0% of the reported cases were identified during 2012 to 2013, the DENV‐1 was dominant in that period . These findings suggest that the dominance of dengue virus serotypes in India and Puerto Rico may be associated with the clear difference of the reported cases between DENV‐1 and DENV‐2 identified in this systematic review and meta‐analysis.…”

“…There was only one study on risk factors for developing dengue‐associated HLH . Case and control groups in that study were dengue‐associated HLH and dengue only.…”

“…Patients with the dengue‐associated hemophagocytic syndrome have been defined as “ Cases, ” on the other hand, among the dengue patients those who did not develop hemophagocytic syndrome were defined as “ Controls ” in the study …”

“…Hence, we suggest that both LDH levels and serum ferritin level should be examined to reduce delayed diagnosis of the hemophagocytic syndrome. In addition to the LDH and an elevated serum ferritin levels, another study demonstrated that younger age, longer duration of fever, anemia, hepatomegaly, and increased AST/ALT are significantly associated with hemophagocytic syndrome among the dengue‐infected patients.…”

“…EBV is a well‐known cause of secondary HLH and the main trigger of primary HLH . EBV and other members of the Herpesviridae family have been the most consistently reported virus associated HLH . In typical DF, in an endemic area of both dengue and vivax malaria, a high prevalence of co‐infection was found, from 5.3% to 23.2% .…”