Research Article: 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

Date Published: April 17, 2018

Publisher: Public Library of Science

Author(s): Luke C. Mullany, Elburg W. van Boetzelaer, Julie R. Gutman, Laura C. Steinhardt, Pascal Ngoy, Yolanda Barbera Lainez, Alison Wittcoff, Steven A. Harvey, Lara S. Ho, Lars Åke Persson

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 that in the universal follow-up group (n = 147, 6.7%), and within the non-inferiority margin (95% CI: −∞, 2.9%; p = 0.017). Limitations include initial underestimation of the proportion of clinical failures as well as substantial variance in cluster-specific failure rates, reducing the precision of our estimates. In addition, heightened security concerns slowed recruitment in the final months of the study.ConclusionsWe found that advising caregivers to return only if children worsened or remained ill on day 3 resulted in similar rates of caregiver-reported fever and other clinical outcomes on day 8, compared to advising all caregivers to return on day 3. Policy-makers could consider revising guidelines for management of uncomplicated fever within the iCCM framework.Trial registrationClinicalTrials.gov NCT02595827

Partial Text: Continued progress in reducing deaths in children under 5 years old in the context of weak health systems depends partially on the extent to which community health workers (CHWs) can rapidly identify and manage sick children in outpatient settings within their community [1–3]. The World Health Organization (WHO) provides guidelines for CHW cadres in low-resource settings to care for sick children aged 2–59 months through implementation of integrated community case management (iCCM) of common childhood illnesses [4,5], an extension of the integrated management of childhood illness (IMCI) approach to the community level. These guidelines prescribe that CHWs assess children through a combination of caregiver-directed questions and examination. For children with malaria, pneumonia, or diarrhea, CHWs provide direct treatment; for children with danger signs (such as inability to drink or breastfeed, vomiting everything, convulsions, or lethargy/loss of consciousness), CHWs refer immediately to a health center. Caregivers of children who present with fever but are neither diagnosed with malaria, pneumonia, or diarrhea nor have danger signs (non-severe unclassified fever) are advised to return with the child for reassessment on day 3 [4,5].

In these rural communities of southeastern DRC, caregivers depend heavily on government-supported CHWs to respond to childhood illnesses, most commonly febrile illnesses. Caregivers and CHWs alike are best served if frameworks such as iCCM containing guidelines for fever management are based on the best available evidence, and promote efficiency in use of scarce resources, including CHW and caregiver time. In this study, we found that advising caregivers of children under 5 years old presenting with uncomplicated fever to return on day 3 only if signs continued or worsened resulted in similar rates of clinical failure in the week after presentation when compared with current guidance of universal follow-up visits on day 3. Compared to caregiver-reported fever, the statistical strength of the evidence for non-inferiority was greater for measured fever, danger signs requiring referral, or other clinical outcomes (CHW-treatable diagnoses, hospitalization, or death). We also observed consistency of parameter estimates (i.e., little difference in failure rates) across all definitions, when considering individual components of the clinical failure definitions, and when taking an intent-to-treat versus per-protocol analytic approach. This study was planned in conjunction with a similar sister study in Southern Nations, Nationalities, and Peoples’ Region, Ethiopia (ClinicalTrials.gov identifier NCT02926625), where the prevalence of malaria is much lower. The results were similar, with an absolute difference of –3.81% (95% CI: −∞, 0.65%) between the conditional and universal follow-up groups for the primary outcome [20], indicating that the conditional approach was minimally inferior or non-inferior to universal follow-up across at least 2 different settings of malaria epidemiology and health systems.

Source:

http://doi.org/10.1371/journal.pmed.1002552

 

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