title: Incidence and Risk Factors for Developing Dengue-Associated Hemophagocytic Lymphohistiocytosis in Puerto Rico, 2008 - 2013.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Centers for Disease Control and Prevention, Dengue Branch, San Juan, Puerto Rico.|Centers for Disease Control and Prevention, Division of Scientific Education and Professional Development, Atlanta, Georgia, United States of America.
authors.forename: Esther M
authors.initials: EM
authors.lastname: Ellis
authors.affiliation: Centers for Disease Control and Prevention, Dengue Branch, San Juan, Puerto Rico.
authors.forename: Tyler M
authors.identifier: 0000-0002-7131-8257
authors.initials: TM
authors.lastname: Sharp
authors.affiliation: Centers for Disease Control and Prevention, Dengue Branch, San Juan, Puerto Rico.
authors.forename: Janice
authors.initials: J
authors.lastname: Pérez-Padilla
authors.affiliation: Ponce Health Sciences University, Ponce, Puerto Rico.
authors.forename: Liza
authors.initials: L
authors.lastname: González
authors.affiliation: Centers for Disease Control and Prevention, Dengue Branch, San Juan, Puerto Rico.
authors.forename: B Katherine
authors.initials: BK
authors.lastname: Poole-Smith
authors.affiliation: Centers for Disease Control and Prevention, Division of Scientific Education and Professional Development, Atlanta, Georgia, United States of America.
authors.forename: Emmaculate
authors.initials: E
authors.lastname: Lebo
authors.affiliation: Centers for Disease Control and Prevention, Division of Scientific Education and Professional Development, Atlanta, Georgia, United States of America.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Baker
authors.affiliation: Centers for Disease Control and Prevention, Division of Vector-borne Diseases, Fort Collins, Colorado, United States of America.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Delorey
authors.affiliation: Centers for Disease Control and Prevention, Dengue Branch, San Juan, Puerto Rico.
authors.forename: Brenda
authors.initials: B
authors.lastname: Torres-Velasquez
authors.affiliation: Puerto Rico Children's Hospital, Bayamon, Puerto Rico.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ochoa
authors.affiliation: Puerto Rico Department of Health, San Juan, Puerto Rico.
authors.forename: Brenda
authors.initials: B
authors.lastname: Rivera-Garcia
authors.affiliation: Puerto Rico Children's Hospital, Bayamon, Puerto Rico.
authors.forename: Hector
authors.initials: H
authors.lastname: Díaz-Pinto
authors.affiliation: San Jorge Children's Hospital, San Juan, Puerto Rico.
authors.forename: Luis
authors.initials: L
authors.lastname: Clavell
authors.affiliation: University of Puerto Rico, School of Medicine, San Juan, Puerto Rico.
authors.forename: Anabel
authors.initials: A
authors.lastname: Puig-Ramos
authors.affiliation: University Medical Center, Hamburg, Germany.
authors.forename: Gritta E
authors.initials: GE
authors.lastname: Janka
authors.affiliation: Centers for Disease Control and Prevention, Dengue Branch, San Juan, Puerto Rico.
authors.forename: Kay M
authors.initials: KM
authors.lastname: Tomashek
mesh_terms: D000293:Adolescent; D000740:Anemia / Q000150:complications / Q000821:virology; D002648:Child; D002675:Child, Preschool; D003715:Dengue / Q000150:complications* / Q000175:diagnosis / Q000453:epidemiology / Q000821:virology; D003716:Dengue Virus / Q000302:isolation & purification; D058872:Epidemics; D005260:Female; D005334:Fever; D006529:Hepatomegaly / Q000209:etiology; D006801:Humans; D015994:Incidence; D007223:Infant; D008099:Liver / Q000201:enzymology / Q000503:physiopathology / Q000821:virology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000453:epidemiology* / Q000821:virology*; D008297:Male; D011647:Puerto Rico / Q000453:epidemiology; D012307:Risk Factors; D013163:Splenomegaly / Q000209:etiology; D000637:Transaminases / Q000378:metabolism
chemical_list: D000637:Transaminases