SHORT REPORT: ASSESSMENT OF THE WORLD HEALTH ORGANIZATION SCHEME FOR CLASSIFICATION OF DENGUE SEVERITY IN NICARAGUA ANGEL BALMASEDA,† SAMANTHA NADIA HAMMOND,† MARIA ANGELES PÉREZ, RICARDO CUADRA, SORAYA SOLANO, JULIO ROCHA, WENDY IDIAQUEZ, AND EVA HARRIS* Departamento de Virología, Centro Nacional de Diagnóstico y Referencia, Ministerio de Salud, Managua, Nicaragua; Division of Infectious Diseases, School of Public Health, University of California, Berkeley, California; Infectious Diseases Unit, Hospital Infantil Manuel de Jesús Rivera, Managua, Nicaragua; Hospital Escuela Oscar Danilo Rosales Arguello, León, Nicaragua Abstract. The World Health Organization (WHO) scheme for classification of dengue severity was evaluated in a three-year study of 1,671 confirmed dengue cases in three Nicaraguan hospitals. The WHO classification of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) was compared with the presence of hemorrhagic mani- festations, signs of vascular permeability, marked thrombocytopenia, and shock in 114 infants, 1,211 children, and 346 adults. We found that strict application of the WHO criteria fails to detect a significant number of patients with severe manifestations of dengue, especially in adults. The four serotypes of the mosquito-borne dengue virus (DEN1–4) cause a spectrum of illness ranging from the self- limiting dengue fever (DF) to more severe, life-threatening forms of the disease termed dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Dengue contin- ues to spread throughout tropical and subtropical regions worldwide, affecting an estimated 50–100 million people each year. 1 DHF/DSS was first defined in 1974 2 based on studies of children in Southeast Asia in the 1960s. 3 The principal re- quirements for a DHF classification are hemorrhagic mani- festations, vascular permeability (plasma leakage), and thrombocytopenia (platelet count 100,000/mm 3 ); the addi- tional presence of hypotension or narrow pulse pressure along with clinical signs of shock designates DSS. DHF/DSS has served as a useful classification of severe dengue to aid in disease identification for treatment, epidemiologic surveil- lance, and studies of dengue pathogenesis. However, as den- gue spreads into new regions worldwide, geographic and age- related differences are being observed in the range of clinical manifestations, and variations are apparent in the capacity of sites to adhere to the strict case definition established by the World Health Organization (WHO). 4–7 In this short report, we examine the application of the WHO scheme in hospital- ized dengue patients in Nicaragua, compared with the docu- mented presence of the four key clinical manifestations asso- ciated with severe dengue. This study was conducted from January 1999 to December 2001 in three major hospitals in the two largest cities in Nica- ragua: the national pediatric reference hospital, Hospital In- fantil Manuel de Jesús Rivera, and the Hospital Roberto Cal- deron in Managua and the Hospital Escuela Oscar Danilo Rosales Arguello in León. For details of the study design, see the accompanying paper by Hammond and others. 8 The study was reviewed and approved by the Committee for the Pro- tection of Human Subjects at the University of California, Berkeley, and the Ethical Review Committee of the Centro Nacional de Diagnóstico y Referencia of the Nicaraguan Min- istry of Health. The WHO and Pan American Health Organization criteria were used to classify dengue severity. 9,10 Dengue fever and DF with hemorrhagic manifestations (DFHem) were consid- ered mild disease, and DHF and DSS were considered severe disease syndromes. Dengue hemorrhagic fever was defined as fever with hemorrhagic manifestations, thrombocytopenia (platelet count 100,000/mm 3 ), and hemoconcentration or other signs of plasma leakage; DSS was defined as DHF plus either hypotension for age (systolic pressure <80 mm of Hg for those <5 years of age and <90 mm of Hg for those 5 years of age) or narrow pulse pressure (20 mm of Hg) 10 in the presence of clinical signs of shock (e.g., slow capillary filling, cold clammy skin). Alongside the DHF/DSS classifi- cation, severe clinical manifestations of dengue were defined as internal hemorrhage, plasma leakage, shock, and/or plate- let count 50,000/mm 3 . Internal hemorrhage consisted of me- lena, hematemesis, hematuria, and/or menorrhagia. Signs of plasma leakage included the presence of pleural effusion, as- cites, and/or hemoconcentration (20% increase in hemato- crit over the value at discharge or hematocrit values 20% of the normal value for age and sex). 4 Shock was characterized by narrow pulse pressure or hypotension with or without documented clinical signs of shock. A confirmed dengue case was determined by the presence of DEN-specific IgM anti- bodies, a 4-fold increase in the titer of total antibodies to dengue virus in paired acute and convalescent sera, and/or detection of dengue virus by reverse transcription– polymerase chain reaction or virus isolation. Laboratory methods are described in the accompanying paper by Ham- mond and others. 8 Data were entered and analyzed using Epi-Info (Centers for Disease Control and Prevention, At- lanta, GA). Crude odds ratios (ORs) and their Cornfield 95% confidence intervals (CIs) were calculated using chi-square analysis for significance. Of 3,173 suspected dengue cases that came to the study hospitals, 1,671 were confirmed as positive for dengue virus infection, including 114 infants, 1,211 children, and 346 adults. One thousand eighty-five (65%) patients were seen at the hospitals in Managua and 586 (35%) patients were attended at the hospital in León. Since the DEN-2 serotype predomi- nated over the entire period studied, data from all three years were combined. To evaluate how effectively the WHO classification scheme distinguished between mild and severe disease, four key se- vere clinical manifestations associated with dengue (shock, † These two authors contributed equally to this study. * Address correspondence to Eva Harris, Division of Infectious Dis- eases, School of Public Health, 140 Warren Hall, University of Cali- fornia, Berkeley, CA 94720-7360. E-mail: eharris@berkeley.edu Am. J. Trop. Med. Hyg., 73(6), 2005, pp. 1059–1062 Copyright © 2005 by The American Society of Tropical Medicine and Hygiene 1059