Clinical and epidemiologic characteristics of dengue and other etiologic agents among patients with acute febrile illness, Puerto Rico, 2012–2015

Abstract

Identifying etiologies of acute febrile illnesses (AFI) is challenging due to non-specific presentation and limited availability of diagnostics. Prospective AFI studies provide a methodology to describe the syndrome by age and etiology, findings that can be used to develop case definitions and multiplexed diagnostics to optimize management. We conducted a 3-year prospective AFI study in Puerto Rico. Patients with fever ≤7 days were offered enrollment, and clinical data and specimens were collected at enrollment and upon discharge or follow-up. Blood and oro-nasopharyngeal specimens were tested by RT-PCR and immunodiagnostic methods for infection with dengue viruses (DENV) 1–4, chikungunya virus (CHIKV), influenza A and B viruses (FLU A/B), 12 other respiratory viruses (ORV), enterovirus, Leptospira spp., and Burkholderia pseudomallei. Clinical presentation and laboratory findings of participants infected with DENV were compared to those infected with CHIKV, FLU A/B, and ORV. Clinical predictors of laboratory-positive dengue compared to all other AFI etiologies were determined by age and day post-illness onset (DPO) at presentation. Of 8,996 participants enrolled from May 7, 2012 through May 6, 2015, more than half (54.8%, 4,930) had a pathogen detected. Pathogens most frequently detected were CHIKV (1,635, 18.2%), FLU A/B (1,074, 11.9%), DENV 1–4 (970, 10.8%), and ORV (904, 10.3%). Participants with DENV infection presented later and a higher proportion were hospitalized than those with other diagnoses (46.7% versus 27.3% with ORV, 18.8% with FLU A/B, and 11.2% with CHIKV). Predictors of dengue in participants presenting <3 DPO included leukopenia, thrombocytopenia, headache, eye pain, nausea, and dizziness, while negative predictors were irritability and rhinorrhea. Predictors of dengue in participants presenting 3–5 DPO were leukopenia, thrombocytopenia, facial/neck erythema, nausea, eye pain, signs of poor circulation, and diarrhea; presence of rhinorrhea, cough, and red conjunctiva predicted non-dengue AFI. By enrolling febrile patients at clinical presentation, we identified unbiased predictors of laboratory-positive dengue as compared to other common causes of AFI. These findings can be used to assist in early identification of dengue patients, as well as direct anticipatory guidance and timely initiation of correct clinical management.

Author summary

We conducted a prospective study of acute febrile illness (AFI) in Puerto Rico to better understand the etiology of AFI among all age groups in the tropics. Such findings could assist clinicians to identify disease-specific characteristics, which can then be used to initiate proper patient management. We enrolled 8,996 AFI patients and tested them for dengue viruses 1–4 (DENV 1–4) and 21 other pathogens. A pathogen was detected in 55% of patients, most frequently chikungunya virus (CHIKV, 18%), influenza A or B virus (FLU A/B, 12%), DENV 1–4 (11%), or another respiratory virus (ORV, 10%). Participants with dengue presented later after symptom onset and were hospitalized more often (47%) than patients with another etiology of AFI (27% with ORV, 19% with FLU A/B, and 11% with CHIKV). Predictors of patients with dengue differed by timing of presentation but included eye pain, nausea, and low white blood cell or platelet counts; negative predictors included symptoms of respiratory illness. By enrolling febrile patients at clinical presentation, we identified unbiased predictors of patients with dengue as compared to other common AFI. Findings can be used to diagnose dengue patients to provide early and appropriate clinical management.