Universal versus conditional day 3 follow-up for children with non-severe unclassified fever at the community level in the Democratic Republic of the Congo: A cluster-randomized, community-based non-inferiority trial

Abstract

BackgroundThe World Health Organization’s integrated community case management (iCCM) guidelines recommend that all children presenting with uncomplicated fever and no danger signs return for follow-up on day 3 following the initial consultation on day 1. Such fevers often resolve rapidly, however, and previous studies suggest that expectant home care for uncomplicated fever can be safely recommended. We aimed to determine if a conditional follow-up visit was non-inferior to a universal follow-up visit for these children.Methods and findingsWe conducted a cluster-randomized, community-based non-inferiority trial among children 2–59 months old presenting to community health workers (CHWs) with non-severe unclassified fever in Tanganyika Province, Democratic Republic of the Congo. Clusters (n = 28) of CHWs were randomized to advise caregivers to either (1) return for a follow-up visit on day 3 following the initial consultation on day 1, regardless of illness resolution (as per current WHO guidelines; universal follow-up group) or (2) return for a follow-up visit on day 3 only if illness continued (conditional follow-up group). Children in both arms were assessed again at day 8, and classified as a clinical failure if fever (caregiver-reported), malaria, diarrhea, pneumonia, or decline of health status (development of danger signs, hospitalization, or death) was noted (failure definition 1). Alternative failure definitions were examined, whereby caregiver-reported fever was first restricted to caregiver-reported fever of at least 3 days (failure definition 2) and then replaced with fever measured via axillary temperature (failure definition 3). Study participants, providers, and investigators were not masked. Among 4,434 enrolled children, 4,141 (93.4%) met the per-protocol definition of receipt of the arm-specific advice from the CHW and a timely day 8 assessment (universal follow-up group: 2,210; conditional follow-up group: 1,931). Failure was similar (difference: –0.7%) in the conditional follow-up group (n = 188, 9.7%) compared to the universal follow-up group (n = 230, 10.4%); however, the upper bound of a 1-sided 95% confidence interval around this difference (−∞, 5.1%) exceeded the prespecified non-inferiority margin of 4.0% (non-inferiority p = 0.089). When caregiver-reported fever was restricted to fevers lasting ≥3 days, failure in the conditional follow-up group (n = 159, 8.2%) was similar to that in the universal follow-up group (n = 200, 9.1%) (difference: −0.8%; 95% CI: −∞, 4.1%; p = 0.053). If caregiver-reported fever was replaced by axillary temperature measurement in the definition of failure, failure in the conditional follow-up group (n = 113, 5.9%) was non-inferior to that in the universal follow-up group (n = 160, 7.2%) (difference: −1.4%; 95% CI: −∞, 2.5%; p = 0.012). In post hoc analysis, when the definition of failure was limited to malaria, diarrhea, pneumonia, development of danger signs, hospitalization, or death, failure in the conditional follow-up group (n = 108, 5.6%) was similar to ...

Universal versus conditional day 3 follow-up for children with non-severe unclassified fever at the community level in Ethiopia: A cluster-randomised non-inferiority trial

“…Several studies from sub-Saharan Africa provide convincing evidence that mRDT-negative febrile children can be safely managed without antimalarial treatment [ 12 , 30 – 33 ]. While the overall treatment failure rate in our study (2.7%) is similar to the low rate observed in a study of malaria-negative febrile children in 2 sites in Tanzania (3%) [ 12 ], it was significantly lower than the rate observed in Zambia (9.3%) [ 25 ] or in our sister study in DRC (10.1%) [ 24 ]. One explanation may be that the relatively lower malaria endemicity in Ethiopia leads to lower numbers of false-negative cases; parasite prevalence in children under 5 years in Ethiopia is 0.6% [ 34 ] versus 10%–75% in children aged 2–9 years in Zambia [ 35 ] and 22.6% in children under 5 years in DRC [ 36 ].…”

“…While iCCM guidelines recommend universal follow-up for all children, regardless of symptom resolution, IMNCI guidelines recommend less intense conditional follow-up after 2 or 3 days (depending on malaria endemicity). To our knowledge, this study and a sister study in DRC [ 24 ] are the first to provide evidence that conditional follow-up is no less safe or marginally less safe than universal follow-up in children aged 2–59 months seen by CHWs.…”

“…The primary outcome was treatment failure rate on day 8, defined as the proportion of children whose illness was not resolved (child had any of the following: reported fever, danger sign(s), hospital admission, death, malaria, pneumonia, or diarrhoea). Three progressively stricter, and more objective, definitions of treatment failure were added in post hoc analysis to be consistent with a concurrent sister study in the Democratic Republic of the Congo (DRC) [ 24 ]: (1) reported fever ≥3 days, danger sign, hospital admission, death, malaria, pneumonia, or diarrhoea; (2) measured axillary temperature ≥ 37.5°C, danger sign, hospital admission, death, malaria, pneumonia, or diarrhoea; and (3) danger sign, hospital admission, death, malaria, pneumonia, or diarrhoea.…”