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      Etiology of Severe Non-malaria Febrile Illness in Northern Tanzania: A Prospective Cohort Study

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          Abstract

          Introduction

          The syndrome of fever is a commonly presenting complaint among persons seeking healthcare in low-resource areas, yet the public health community has not approached fever in a comprehensive manner. In many areas, malaria is over-diagnosed, and patients without malaria have poor outcomes.

          Methods and Findings

          We prospectively studied a cohort of 870 pediatric and adult febrile admissions to two hospitals in northern Tanzania over the period of one year using conventional standard diagnostic tests to establish fever etiology. Malaria was the clinical diagnosis for 528 (60.7%), but was the actual cause of fever in only 14 (1.6%). By contrast, bacterial, mycobacterial, and fungal bloodstream infections accounted for 85 (9.8%), 14 (1.6%), and 25 (2.9%) febrile admissions, respectively. Acute bacterial zoonoses were identified among 118 (26.2%) of febrile admissions; 16 (13.6%) had brucellosis, 40 (33.9%) leptospirosis, 24 (20.3%) had Q fever, 36 (30.5%) had spotted fever group rickettsioses, and 2 (1.8%) had typhus group rickettsioses. In addition, 55 (7.9%) participants had a confirmed acute arbovirus infection, all due to chikungunya. No patient had a bacterial zoonosis or an arbovirus infection included in the admission differential diagnosis.

          Conclusions

          Malaria was uncommon and over-diagnosed, whereas invasive infections were underappreciated. Bacterial zoonoses and arbovirus infections were highly prevalent yet overlooked. An integrated approach to the syndrome of fever in resource-limited areas is needed to improve patient outcomes and to rationally target disease control efforts.

          Author Summary

          The syndrome of fever is caused by a large number of infectious diseases. Malaria is thought to have been declining in the tropics since 2004. Increasing use of malaria diagnostic tests reveal a growing proportion of patients with fever who do not have malaria. While malaria diagnostic tests may be available, healthcare workers have few tools to diagnose causes of fever other than malaria. In order to identify major causes of fever other than malaria in northern Tanzania, we studied 870 patients with fever who were sufficiently ill to require admission to hospital. Malaria was uncommon and over-diagnosed, whereas invasive infections, including bloodstream infections, were underappreciated. Infections associated with animals such as brucellosis, leptospirosis, Q fever, and spotted fever group rickettsioses as well as viral infections transmitted by mosquitoes were common yet overlooked. We recommend that research on the syndrome of fever in resource-limited areas should focus on a wide range of potential causes. Animal-associated infections should be prioritized in patient management and disease control.

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          Most cited references31

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          Laboratory medicine in Africa: a barrier to effective health care.

          Providing health care in sub-Saharan Africa is a complex problem. Recent reports call for more resources to assist in the prevention and treatment of infectious diseases that affect this population, but policy makers, clinicians, and the public frequently fail to understand that diagnosis is essential to the prevention and treatment of disease. Access to reliable diagnostic testing is severely limited in this region, and misdiagnosis commonly occurs. Understandably, allocation of resources to diagnostic laboratory testing has not been a priority for resource-limited health care systems, but unreliable and inaccurate laboratory diagnostic testing leads to unnecessary expenditures in a region already plagued by resource shortages, promotes the perception that laboratory testing is unhelpful, and compromises patient care. We explore the barriers to implementing consistent testing within this region and illustrate the need for a more comprehensive approach to the diagnosis of infectious diseases, with an emphasis on making laboratory testing a higher priority.
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            Overdiagnosis of malaria in patients with severe febrile illness in Tanzania: a prospective study.

            To study the diagnosis and outcomes in people admitted to hospital with a diagnosis of severe malaria in areas with differing intensities of malaria transmission. Prospective observational study of children and adults over the course a year. 10 hospitals in north east Tanzania. 17,313 patients were admitted to hospital; of these 4474 (2851 children aged under 5 years) fulfilled criteria for severe disease. Details of the treatment given and outcome. Altitudes of residence (a proxy for transmission intensity) measured with a global positioning system. Blood film microscopy showed that 2062 (46.1%) of people treated for malaria had Plasmodium falciparum (slide positive). The proportion of slide positive cases fell with increasing age and increasing altitude of residence. Among 1086 patients aged > or = 5 years who lived above 600 metres, only 338 (31.1%) were slide positive, while in children < 5 years living in areas of intense transmission (< 600 metres) most (958/1392, 68.8%) were slide positive. Among 2375 people who were slide negative, 1571 (66.1%) were not treated with antibiotics and of those, 120 (7.6%) died. The case fatality in slide negative patients was higher (292/2412, 12.1%) than for slide positive patients (142/2062, 6.9%) (P < 0.001). Respiratory distress and altered consciousness were the strongest predictors of mortality in slide positive and slide negative patients and in adults as well as children. In Tanzania, malaria is commonly overdiagnosed in people presenting with severe febrile illness, especially in those living in areas with low to moderate transmission and in adults. This is associated with a failure to treat alternative causes of severe infection. Diagnosis needs to be improved and syndromic treatment considered. Routine hospital data may overestimate mortality from malaria by over twofold.
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              Malaria misdiagnosis: effects on the poor and vulnerable.

              Effective and affordable treatment is recommended for all cases of malaria within 24 h of the onset of illness. Most cases of "malaria" (ie, fever) are self-diagnosed and most treatments, and deaths, occur at home. The most ethical and cost-effective policy is to ensure that newer drug combinations are only used for true cases of malaria. Although it is cost effective to improve the accuracy of malaria diagnosis, simple, accurate, and inexpensive methods are not widely available, particularly in poor communities where they are most needed. In a recent study in Uganda, Karin Kallander and colleagues emphasise the difficulty in making a presumptive diagnosis of malaria, and highlight the urgent need for improved diagnostic tools that can be used at community and primary-care level, especially in poorer populations (Acta Trop 2004; 90: 211-14). WHERE NEXT? Health systems need strengthening at referral and community level, so that rapid accurate diagnosis and effective treatment is available for those who are least able to withstand the consequences of illness. Indirect evidence strongly suggests that misdiagnosis of malaria contributes to a vicious cycle of increasing ill-health and deepening poverty. Much better direct evidence is needed about why and how misdiagnosis affects the poor and vulnerable.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                1935-2727
                1935-2735
                July 2013
                18 July 2013
                : 7
                : 7
                : e2324
                Affiliations
                [1 ]Division of Infectious Diseases and International Health, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America
                [2 ]Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America
                [3 ]Duke Global Health Institute, Duke University, Durham, North Carolina, United States of America
                [4 ]Kilimanjaro Christian Medical Centre, Moshi, Tanzania
                [5 ]Kilimanjaro Christian Medical College, Tumaini University, Moshi, Tanzania
                [6 ]Centre for International Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
                [7 ]Rickettsial Zoonoses Branch, Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
                [8 ]Bacterial Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
                [9 ]Emerging Infectious Diseases Signature Research Program, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore
                [10 ]Mawenzi Regional Hospital, Moshi, Tanzania
                Institut Pasteur, France
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JAC JAB. Performed the experiments: JAC ABM WLN RFM RAS RLG EEO VPM WS GDK JAB. Analyzed the data: JAC. Contributed reagents/materials/analysis tools: WLN RFM RAS RLG EEO. Wrote the paper: JAC ABM WLN RFM RAS RLG EEO VPM WS GDK CM JAB. Managed the research program: CM. Sought and obtained funding: JAB.

                Article
                PNTD-D-13-00411
                10.1371/journal.pntd.0002324
                3715424
                23875053
                ac00dcad-c5b9-4b98-b7b2-043148e0d042
                Copyright @ 2013

                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 22 March 2013
                : 9 June 2013
                Page count
                Pages: 8
                Funding
                This research was supported by an International Studies on AIDS Associated Co-infections (ISAAC) award, a United States National Institutes of Health (NIH) funded program (U01 AI062563). Investigator support was received from NIH awards ISAAC (JAC ABM VPM GDK CM JAB); AIDS International Training and Research Program (D43 PA-03-018 to JAC VPM GDK CM JAB); the Duke Clinical Trials Unit and Clinical Research Sites (U01 AI069484 to JAC VPM GDK CM JAB); the Duke Center for AIDS Research (P30 AI 64518 to JAB); the Center for HIV/AIDS Vaccine Immunology (U01 AI067854 to JAC, JAB); and the joint NIH-NSF Ecology of Infectious Disease program and the UK Economic and Social Research Council and Biotechnology and Biological Sciences Research Council (R01TW009237 to JAC, VPM, WS, CM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine
                Infectious Diseases
                Bacterial Diseases
                Bacteremia
                Bloodstream Infections
                Leptospirosis
                Q-Fever
                Rickettsia
                Salmonellosis
                Neglected Tropical Diseases
                Brucellosis
                Leptospirosis

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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