Non-malarial Febrile Illness in Children in Areas of Perennial Malaria Transmission
Condition: Malaria; Non-malarial Febrile Illness
MeSH terms: Malaria; Hyperthermia; Fever
Study type: Interventional

Summary: 
      To evaluate the causes of non-malarial febrile illness in children living in an area of
      perennial malaria transmission and to determine if these children who test negative for
      malaria by rapid diagnostic test receive any benefit from antimalarial therapy.
    

Detailed description: 
      Until recently, national and global malaria control authorities recommended clinical
      diagnosis-based solely on the presence or history of fever-for most malaria treatment
      settings in sub-Saharan Africa where malaria transmission is sustained and intense. To some
      extent this recommendation was based on the fact that conventional antimalarial treatments
      like chloroquine or sulfadoxine-pyrimethamine (SP) were relatively affordable and safe and
      that microscopic diagnosis was complex and difficult to maintain in remote rural settings. It
      was economically advantageous and logistically more feasible to treat all potential cases as
      malaria than to extend microscopic diagnosis to every level of the health system. This
      approach has resulted in extensive over-treatment, particularly among older children and
      adults, and may have contributed to the rapid development of antimalarial drug resistance.

      Although much has been written recently on the cost-effectiveness of expanding malaria
      diagnosis, available information is scarce on a number of other important reasons why
      clinical diagnosis has been recommended for so long, especially among children living in high
      transmission settings. First, uncomplicated malaria can progress to severe or fatal illness
      within 24 to 48 hours of onset. Numerous care-seeking studies have demonstrated that
      caretakers seldom arrive at formal health facilities within 24 or 48 hours after the onset of
      uncomplicated febrile illness. If a diagnostic test imposes additional barriers-such as cost,
      time delay, or referral-requiring a positive parasitological diagnosis could put children
      whose cause of fever is malaria infection at greater risk of progressing to severe or fatal
      illness. Second, although the current approach based on clinical diagnosis appears to result
      in substantial over-treatment, it is still possible to demonstrate that children living in
      malaria transmission areas benefit from additional scheduled doses of antimalarial treatment,
      even when they are not ill. For example, a meta-analysis of six trials of
      sulfadoxine-pyrimethamine (SP) given to children at routine immunization visits demonstrated
      an average decrease of 30% in episodes of clinical malaria, 15% in anemia, and 24% in
      all-cause hospital admissions among children receiving SP compared to children who did not
      receive the drug at these visits. Finally, providers and clients may be inclined to disregard
      a negative blood slide or RDT, especially in situations where they have not identified an
      additional treatable cause of illness. Withholding antimalarial treatments from such children
      might adversely affect provider and client satisfaction and poor client satisfaction may
      reduce subsequent health facility utilization. It might also encourage disappointed clients
      to seek treatment in the private sector where a broad range of antimalarial drugs-most of
      them single drug treatments that contribute to the development of resistance and which are
      not recommended in the national treatment policy-can be obtained without diagnostic
      confirmation.

      We propose a longitudinal cohort study to evaluate the identifiable causes of treatable fever
      among 1000 malaria-negative children presenting to outpatient health clinics in Miono,
      Bagamoyo District, Tanzania using a variety of clinical, microbiological and serologic
      methods. In addition we intend to follow these 1000 malaria-negative children for up to 91
      days or until their next malaria infection to assess their clinical progress and need for
      further malaria treatment. To compare the relative benefit of providing antimalarial
      treatment even to malaria-negative children, half of the participants will be randomized to
      receive first-line treatment for malaria as currently recommended; the other half will
      receive treatment only for other identified illnesses.

      Alternative Hypothesis: Febrile, parasite-negative children treated for malaria have better
      clinical and longitudinal outcomes (as measured by prevalence of anemia at the end of the
      follow up period, reticulocyte count repeat visits to the health facility, hospitalization,
      and time to next infection with malaria parasites) than febrile, parasite-negative children
      not treated for malaria in areas of high transmission.
    

Intervention name(s): Artemether-Lumefantrine
Intervention type(s): Drug
Intervention description(s): Artemether-lumefantrine (Coartem; Novartis) administered twice daily for three days as tablets containing 20 mg of artemether plus 120 mg of lumefantrine at a dosage of:
1 tablet (for patients weighing 5-14 kg)
2 tablets (for patients weighing 15-24 kg)
Other intervention name(s): CoArtem, Novartis
Intervention MeSH terms: Lumefantrine; Artemether; Artemether, Lumefantrine Drug Combination
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: malaria; presumptive treatment; Integrated Management of Childhood Illness; fever