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

<div><p>Background</p><p>Hemophagocytic 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.</p><p>Methodology/Principal Findings</p><p>After 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).</p><p>Conclusions/Significance</p><p>During 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.</p></div

Municipality of residence of dengue and dengue-associated hemophagocytic lymphohistiocytosis patients identified at four referral hospitals in, Puerto Rico, January 2008–June 2013.

<p>Municipality of residence of dengue and dengue-associated hemophagocytic lymphohistiocytosis patients identified at four referral hospitals in, Puerto Rico, January 2008–June 2013.</p

Laboratory-positive dengue (n = 3,475) and dengue-associated hemophagocytic lymphohistiocytosis (HLH) (n = 22) patients identified at four referral hospitals in Puerto Rico during January 2008 through June 2013.

<p>Laboratory-positive dengue (n = 3,475) and dengue-associated hemophagocytic lymphohistiocytosis (HLH) (n = 22) patients identified at four referral hospitals in Puerto Rico during January 2008 through June 2013.</p

Demographic characteristics and clinical and laboratory features of 22 patients with dengue-associated hemophagocytic lymphohistiocytosis that were identified at four referral hospitals in Puerto Rico during January 2008 through June 2013.

<p>Demographic characteristics and clinical and laboratory features of 22 patients with dengue-associated hemophagocytic lymphohistiocytosis that were identified at four referral hospitals in Puerto Rico during January 2008 through June 2013.</p

Demographic, clinical, and laboratory characteristics of patients with dengue-associated hemophagocytic lymphohistiocytosis (cases) or dengue only (controls) identified in four referral hospitals in Puerto Rico during January 2008 through June 2013.

<p>Demographic, clinical, and laboratory characteristics of patients with dengue-associated hemophagocytic lymphohistiocytosis (cases) or dengue only (controls) identified in four referral hospitals in Puerto Rico during January 2008 through June 2013.</p

Measuring the water and soil environments

<p>Characteristics of all fatal laboratory-positive dengue case-patients detected by the Enhanced Fatal AFI Surveillance System, Puerto Rico, 2010–2012.</p

Demographic characteristics, symptoms and medical outcomes reported by 1,500 residents of Tudor, Mombasa, participating in serologic survey for dengue virus infection (DENV), April through May 2013.

<p>* Bleeding manifestations included nose bleeding, bleeding from gums, blood in vomitus, blood in urine, blood in stool, or heavy vaginal bleeding.</p><p>Demographic characteristics, symptoms and medical outcomes reported by 1,500 residents of Tudor, Mombasa, participating in serologic survey for dengue virus infection (DENV), April through May 2013.</p

Epidemiological curve of 267 suspected dengue cases detected at hospitals from January–May, 2013, of which 155 (58%) were confirmed to have a current DENV infection and included a single fatal case.

<p>Epidemiological curve of 267 suspected dengue cases detected at hospitals from January–May, 2013, of which 155 (58%) were confirmed to have a current DENV infection and included a single fatal case.</p

Map of 210 dengue virus (DENV) infected participants in Tudor, Mombasa, Kenya.

<p>Participants with evidence of current or recent DENV infection were distributed throughout the Tudor district, and there was no statistically significant clustering by area. Solid black circles represent IgM anti-DENV positive participants, white circles represent RT-PCR positive participants.</p

Enhanced Surveillance for Fatal Dengue-Like Acute Febrile Illness in Puerto Rico, 2010-2012

<div><p>Background</p><p>Dengue is a leading cause of morbidity throughout the tropics; however, accurate population-based estimates of mortality rates are not available.</p><p>Methods/Principal Findings</p><p>We established the Enhanced Fatal Acute Febrile Illness Surveillance System (EFASS) to estimate dengue mortality rates in Puerto Rico. Healthcare professionals submitted serum and tissue specimens from patients who died from a dengue-like acute febrile illness, and death certificates were reviewed to identify additional cases. Specimens were tested for markers of dengue virus (DENV) infection by molecular, immunologic, and immunohistochemical methods, and were also tested for West Nile virus, <i>Leptospira spp</i>., and other pathogens based on histopathologic findings. Medical records were reviewed and clinical data abstracted. A total of 311 deaths were identified, of which 58 (19%) were DENV laboratory-positive. Dengue mortality rates were 1.05 per 100,000 population in 2010, 0.16 in 2011 and 0.36 in 2012. Dengue mortality was highest among adults 19–64 years and seniors ≥65 years (1.17 and 1.66 deaths per 100,000, respectively). Other pathogens identified included 34 <i>Leptospira spp</i>. cases and one case of <i>Burkholderia pseudomallei</i> and <i>Neisseria meningitidis</i>.</p><p>Conclusions/Significance</p><p>EFASS showed that dengue mortality rates among adults were higher than reported for influenza, and identified a leptospirosis outbreak and index cases of melioidosis and meningitis.</p></div