Am. J. Trop. Med. Hyg., 86(2), 2012, pp. 246–253 doi:10.4269/ajtmh.2012.11-0409 Copyright # 2012 by The American Society of Tropical Medicine and Hygiene Infectious Etiologies of Acute Febrile Illness among Patients Seeking Health Care in South-Central Cambodia Matthew R. Kasper,* Patrick J. Blair, Sok Touch, Buth Sokhal, Chadwick Y. Yasuda, Maya Williams, Allen L. Richards, Timothy H. Burgess, Thomas F. Wierzba, and Shannon D. Putnam United States Naval Medical Research Unit 2, Jakarta, Indonesia; Control of Communicable Disease Department, Ministry of Health, Phnom Penh, Cambodia; National Institute of Public Health, Ministry of Health, Phnom Penh, Cambodia; United States Naval Medical Research Unit No. 2, Phnom Penh, Cambodia; Naval Medical Research Center, Silver Spring, Maryland Abstract. The agents of human febrile illness can vary by region and country suggesting that diagnosis, treatment, and control programs need to be based on a methodical evaluation of area-specific etiologies. From December 2006 to December 2009, 9,997 individuals presenting with acute febrile illness at nine health care clinics in south-central Cambodia were enrolled in a study to elucidate the etiologies. Upon enrollment, respiratory specimens, whole blood, and serum were collected. Testing was performed for viral, bacterial, and parasitic pathogens. Etiologies were identified in 38.0% of patients. Influenza was the most frequent pathogen, followed by dengue, malaria, and bacterial pathogens isolated from blood culture. In addition, 3.5% of enrolled patients were infected with more than one pathogen. Our data provide the first systematic assessment of the etiologies of acute febrile illness in south-central Cambodia. Data from syndromic- based surveillance studies can help guide public health responses in developing nations. INTRODUCTION Limited resources and the great diversity of acute febrile illness (AFI) etiologies in tropical regions challenge diagno- sis, treatment, and public health responses to endemic and epidemic diseases. Further confounding this is the fact that a majority of the patients present with non-descript symptoms (e.g., low-grade fever, general malaise, headache, and muscle ache) and usually no focal point of infection. Health care pro- viders lacking proper diagnostic tools are usually unable to determine specific etiologies, often diagnosing patients pre- sumptively based on clinical features and assumptions regard- ing circulating pathogens. Syndromic-based disease surveillance provides a useful methodology to systematically identify and document causes of acute fever. This approach has been used by TropNetEurop a¨1,2 to diagnose fevers of unknown origin in Turkey,3 China,4 and India and a project designed by the U.S. Centers for Disease Control and Prevention (CDC, Atlanta, GA) for the same purpose along the United States-Mexico border. In Southeast (SE) Asia, a prospective study of Thai patients presenting with acute undifferentiated febrile illness deter- mined the etiologies of over 40% of cases, with the most prev- alent being influenza, dengue, and rickettsial infections.5 In Latin America, surveillance identified the etiology of acute undifferentiated febrile illness in Ecuador in 40% of enrolled patients, identifying a number of pathogens that have not pre- viously been isolated in the country.6 Emerging and re-emerging diseases are a concern in SE Asia during a dynamic time of population growth, urbanization, and global migration. Infections from dengue virus, malaria parasites, influenza viruses, hepatitis viruses, rickettsiae, and Leptospira have previously been shown to impact popula- tions across SE Asia. However, among the SE Asian nations, limited data exists on the etiologies of AFI in the Kingdom of Cambodia. Earlier studies reported illnesses among Cambodian refugee populations that had either immigrated *Address correspondence to Matthew R. Kasper, Department of Bacteriology, U.S. Naval Medical Research Unit 6, Lima, Peru, Unit 3230, DPO, AA 34031. E-mail: matthew.kasper@med.navy.mil 246 to the United States or occupied refugee camps in Thailand.7,8 These works documented infections by agents such as malaria, hepatitis, cryptosporidium, and tuberculosis that presented in an often stressed and undernourished patient cohort. More recent studies conducted in Cambodia used both prospective and/or syndromic approaches. Infectious etiologies of enceph- alitic syndromes among patients admitted to a provincial hos- pital near Phnom Penh9 were identified in 35 of 88 (40%) human immunodeficiency virus (HIV)-seronegative patients; 11 bacterial, 1 fungal, and 23 viral infections (Japanese enceph- alitis virus [JEV] the principal causative agent of disease). A hospital-based study among children in Phnom Penh was con- ducted to diagnose hemorrhagic fever, encephalitis, or hepatitis in children,10 reporting that hepatitis A and JEV contributed greatly to the burden of disease in this population. In 2006, we initiated clinic-based surveillance to ascertain the etiologies of AFI among patients seeking treatment at peri-urban and rural health care clinics and hospital outpatient departments in Cambodia. Herein, we describe the demographics, symptoms, and identified etiologies of the patients seeking health care for AFI from December 2006 to December 2009. MATERIALS AND METHODS Ethical considerations. Eligible subjects voluntarily enrolled in accordance with an Institutional Review Board proto- col approved by U.S. Naval Medical Research Unit Two (NAMRU2) in compliance with all applicable Federal regu- lations governing the protection of human subjects and the National Ethics Committee of the Royal Kingdom of Cambodia, Ministry of Health. Written consent was obtained from patients 18 years of age and older. For patients younger than 18 years of age, written consent was obtained from a parent or legal guardian. Additionally, written assent was obtained from patients between 8 and 17 years of age. For all individuals, the informed consent was verbally explained and questions solicited. Site selection and study enrollment. Clinic-based acute fever surveillance was initiated in December 2006. Patients were initially recruited from outpatient clinics of two referral hospitals, but during the course of the study, additional clinics