title: Acute Uncomplicated Febrile Illness in Children Aged 2-59 months in Zanzibar - Aetiologies, Antibiotic Treatment and Outcome.
abstract: BACKGROUND
  Despite the fact that a large proportion of children with fever in Africa present at primary health care facilities, few studies have been designed to specifically study the causes of uncomplicated childhood febrile illness at this level of care, especially in areas like Zanzibar that has recently undergone a dramatic change from high to low malaria transmission.
  
  
  METHODS
  We prospectively studied the aetiology of febrile illness in 677 children aged 2-59 months with acute uncomplicated fever managed by IMCI (Integrated Management of Childhood Illness) guidelines in Zanzibar, using point-of-care tests, urine culture, blood-PCR, chest X-ray (CXR) of IMCI-pneumonia classified patients, and multiple quantitative (q)PCR investigations of nasopharyngeal (NPH) (all patients) and rectal (GE) swabs (diarrhoea patients). For comparison, we also performed NPH and GE qPCR analyses in 167 healthy community controls. Final fever diagnoses were retrospectively established based on all clinical and laboratory data. Clinical outcome was assessed during a 14-day follow-up. The utility of IMCI for identifying infections presumed to require antibiotics was evaluated.
  
  
  RESULTS
  NPH-qPCR and GE-qPCR detected ≥1 pathogen in 657/672 (98%) and 153/164 (93%) of patients and 158/166 (95%) and 144/165 (87%) of controls, respectively. Overall, 57% (387/677) had IMCI-pneumonia, but only 12% (42/342) had CXR-confirmed pneumonia. Two patients were positive for Plasmodium falciparum. Respiratory syncytial virus (24.5%), influenza A/B (22.3%), rhinovirus (10.5%) and group-A streptococci (6.4%), CXR-confirmed pneumonia (6.2%), Shigella (4.3%) were the most common viral and bacterial fever diagnoses, respectively. Blood-PCR conducted in a sub-group of patients (n = 83) without defined fever diagnosis was negative for rickettsiae, chikungunya, dengue, Rift Valley fever and West Nile viruses. Antibiotics were prescribed to 500 (74%) patients, but only 152 (22%) had an infection retrospectively considered to require antibiotics. Clinical outcome was generally good. However, two children died. Only 68 (11%) patients remained febrile on day 3 and three of them had verified fever on day 14. An additional 29 (4.5%) children had fever relapse on day 14. Regression analysis determined C-reactive Protein (CRP) as the only independent variable significantly associated with CXR-confirmed pneumonia.
  
  
  CONCLUSIONS
  This is the first study on uncomplicated febrile illness in African children that both applied a comprehensive laboratory panel and a healthy control group. A majority of patients had viral respiratory tract infection. Pathogens were frequently detected by qPCR also in asymptomatic children, demonstrating the importance of incorporating controls in fever aetiology studies. The precision of IMCI for identifying infections requiring antibiotics was low.
authors.affiliation: Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden.|Department of Paediatrics, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Elfving
authors.affiliation: Malaria Research, Department of Microbiology, Tumour and Cell biology, Karolinska Institutet, Stockholm, Sweden.|Department of Medicine, Kungälv Hospital, Kungälv, Sweden.
authors.forename: Deler
authors.initials: D
authors.lastname: Shakely
authors.affiliation: Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Andersson
authors.affiliation: Department of Family Health Care Nursing, University of California San Francisco, San Francisco, United States of America.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Baltzell
authors.affiliation: Zanzibar Malaria Elimination Programme, Ministry of Health, Zanzibar, Tanzania.
authors.forename: Abdullah S
authors.initials: AS
authors.lastname: Ali
authors.affiliation: Department of Paediatrics, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Marc
authors.initials: M
authors.lastname: Bachelard
authors.affiliation: Department of Microbiology, Tumor and Cell biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kerstin I
authors.initials: KI
authors.lastname: Falk
authors.affiliation: Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Ljung
authors.affiliation: Zanzibar Malaria Elimination Programme, Ministry of Health, Zanzibar, Tanzania.
authors.forename: Mwinyi I
authors.initials: MI
authors.lastname: Msellem
authors.affiliation: Zanzibar Malaria Elimination Programme, Ministry of Health, Zanzibar, Tanzania.
authors.forename: Rahila S
authors.initials: RS
authors.lastname: Omar
authors.affiliation: Aix Marseille University, UM63, WHO collaborative centre for rickettsioses and other arthropod borne bacterial diseases, Faculté de Médecine, Marseille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Parola
authors.affiliation: Malaria Research, Department of Microbiology, Tumour and Cell biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Weiping
authors.initials: W
authors.lastname: Xu
authors.affiliation: Akademistatistik, Centre for Applied Biostatistics, Occupational and Environmental Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Max
authors.initials: M
authors.lastname: Petzold
authors.affiliation: Department of Paediatrics, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Birger
authors.initials: B
authors.lastname: Trollfors
authors.affiliation: Malaria Research, Department of Microbiology, Tumour and Cell biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Björkman
authors.affiliation: Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Lindh
authors.affiliation: Malaria Research, Department of Microbiology, Tumour and Cell biology, Karolinska Institutet, Stockholm, Sweden.|Centre for Clinical Research Sörmland, Uppsala University, Uppsala, Sweden.|Department of Women's and Children's Health, International Maternal and Child Health Unit (IMCH), Uppsala University, Uppsala, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mårtensson
mesh_terms: D000208:Acute Disease; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D002675:Child, Preschool; D005260:Female; D005334:Fever / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007223:Infant; D007251:Influenza, Human / Q000188:drug therapy*; D008297:Male; D011446:Prospective Studies; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000453:epidemiology; D013636:Tanzania / Q000453:epidemiology; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents
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