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1. Bacterial, viral, and parasitic infections were identified in 87%, 81%, and 11% of febrile Tanzanian outpatient children respectively, but when these laboratory data were combined with clinical criteria, the burden of disease shifted to 22%, 71%, and 11%, respectively. 

2. Malaria, radiologically confirmed pneumonia, and typhoid fever were more common among those with severe illness compared to those with mild illness (P<0.001, P=0.008, P=0.01 respectively). 

Evidence Rating Level: 4 (Below Average)          

Study Rundown: This case series endeavored to characterize the etiologic cause of febrile illness in a sample of 1010 children attending outpatient clinics in Tanzania in areas of relatively low malaria endemicity. Given the promise of Haeomphilus influenza type B and pneuomococcal conjugate vaccination in reducing the incidence of bacterial infections among children, it is important to understand the etiologic cause of febrile illness in children living in regions with relatively low malaria endemicity, or who have tested negative with point-of-care malaria testing. Overall, this study attempted to employ biologic diagnostic technologies to better understand the cause of fever in children who are often treated by way of case-management guidelines that emphasize sensitivity over specificity and may expose children to unnecessary antibiotics.

The strengths of this study include the large sample size in clinics from both urban and rural parts of Tanzania, which provide a stronger representation of the nation as a whole; however, caution is required in applying the results to areas with different baseline levels of malaria endemicity and other seasonal changes in infectious disease epidemiology. The blending of microbiologic and molecular data with pre-set clinical diagnostic guidelines allowed the authors to characterize the differences between the presumptive causes of febrile illness for lab-only data versus combined data. This emphasized the fact that interpreting an infectious cause of fever with lab data alone can be misleading. Furthermore, the results underscore the fact that in the absence of severe illness signs and once malaria has been ruled out, most febrile outpatient children in Tanzania could be treated conservatively without antibiotics. One major drawback of the study is the fact that there were no control cases of nonfebrile children that would have allowed the authors to verify the clinical significance of serologic and molecular markers of infectious pathogens.

Click to read the study, published today in NEJM

Click to read an accompanying editorial in NEJM

Relevant Reading:  Overdiagnosis of malaria in patients with severe febrile illness in Tanzania

In-Depth [case series]: This case series characterized the causes of febrile syndromes in young children in the setting of relatively low malaria endemicity. This study involved 1010 febrile children meeting study criteria of age 2 months to 10 years and axillary temperature of 38º or higher; those with severe malnutrition or WHO emergency signs were excluded. The subjects were consecutive patients at two outpatient clinics in Tanzania, one of which was urban and the other rural. Subjects underwent standardized history-taking and clinical examinations and systematic collection of blood/nasopharyngeal specimens, serologic tests, culture, and molecular tests following a set of prespecified criteria.

Overall, 25,743 biologic tests were performed and 1232 distinct clinical or microbiologic diagnoses were made. The most common diagnosis was acute respiratory infection (62.2% of children), followed by systemic infection (13.3%), nasopharyngeal viral infection (11.9%), malaria (10.5%), gastroenteritis (10.3%), urinary tract infection (5.9%), typhoid fever (3.7%), skin/mucosal infection (1.5%), and meningitis (0.2%).  The cause of fever was undiagnosed in 3.2% of the children. 22.6% of children had multiple conditions diagnosed; more than 50% of children with malaria had a secondary diagnosis, regardless of parasitic density. Malaria, radiologically confirmed pneumonia, and typhoid fever were more common among those with severe illness compared to those with mild illness (P<0.001, P=0.008, P=0.01, respectively). Bacterial, viral, and parasitic infections were identified in 87%, 81%, and 11% of patients respectively, but when these laboratory data were combined with clinical criteria to determine diagnoses, the burden of disease shifted to 22%, 71%, and 11%, respectively.

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