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

Background: The 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 findings: We 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. Conclusions: We 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.

We conducted this study in the sparsely populated, southeastern Tanganyika Province of the Democratic Republic of the Congo (DRC), where malaria is endemic [14] and the frequency of formal care-seeking within public sector facilities is low [15]. The International Rescue Committee, in joint collaboration with the Ministry of Public Health, has been implementing the Rapid Access Expansion Program (RAcE) (funded by Global Affairs Canada, administered by WHO) to train and deploy CHWs to deliver iCCM in 11 health zones in Tanganyika Province. CHWs in this setting are not paid a salary, but receive a bicycle from the iCCM program to assist with travel to and from their linked health center. Services provided by CHWs are free of charge to community members. Two RaCE-participating health zones (Kalemie and Nyemba, total CHW catchment area population ~168,000) were selected as the geographic area for our study (Fig 1). Intervention, conditional follow-up; control, universal follow-up. Further details of our cluster-randomized non-inferiority trial have been published elsewhere [16]. Briefly, each of the 28 health areas (14 in each zone) consisted of a health center and a team of 1 to 18 associated CHWs: literate, locally resident volunteers who received 5 days of training on the iCCM algorithm and other core competencies (e.g., communication and recording) as per DRC Ministry of Public Health guidelines. We aimed to determine if the risk of clinical deterioration (“failure”) among children aged 2–59 months presenting to these CHWs with non-severe unclassified fever was similar between (1) those advised to follow up with the CHW on day 3 regardless of the child’s condition (universal follow-up) and (2) those advised to follow-up on day 3 only if illness did not resolve (conditional follow-up). Failure was assessed on day 8, and was defined as the child having caregiver-reported fever, 1 of the 3 CHW-treatable illnesses (i.e., malaria, diarrhea, or pneumonia), a referable danger sign, hospitalization, or death. We hypothesized that 5% of children would meet this definition under current guidelines (universal follow-up) and that the true rate of failure among children receiving the updated follow-up advice (conditional follow-up) would be 6%. Our a priori–defined non-inferiority margin for the conditional follow-up approach was 4 percentage points; specifically, conditional follow-up would be considered non-inferior if the upper bound of a 1-sided 95% confidence interval around the absolute difference in outcome rate (conditional follow-up minus universal follow-up) did not exceed 4%. We used restricted randomization balanced on zone and health area estimates of (1) population size, (2) prior 6-month likelihood of mRDT-negative febrile children (number of children mRDT negative/under-5 population), and (3) geographic distance from CHW to zonal health center to allocate the 28 health areas (and all the CHWs and the children they enrolled within these areas) to either universal or conditional follow-up advice (also see sample size section below) [16]. During the enrollment period for this study, any febrile child with neither danger signs nor a CHW-treatable illness (malaria, pneumonia, or diarrhea) was eligible; at initial presentation (day 1) all caregivers were advised to seek follow-up care with the CHW if signs worsened. The CHW then provided the cluster-specific advice about when to return for a follow-up visit. Specifically, CHWs in the universal follow-up group advised all caregivers to come back with the child on day 3, while those in the conditional follow-up group advised a return visit on day 3 only if signs remained the same or worsened. CHWs verbally requested permission to subsequently (i.e., on day 8) visit the child and caregiver at home, at which point they would explain the study and obtain consent to participate; for those agreeing to this initial recruitment, the CHW notified his/her health area data collector of the eligible child. On the scheduled day 8 visit, the CHW and data collector jointly visited the home, obtained oral informed consent, enrolled the child, and conducted a standard assessment to record outcome and covariate data. The data collector recorded axillary temperature, respiratory rate, and mid-upper arm circumference (MUAC), then the CHW assessed the child using the standard iCCM algorithm. At this visit, any child with reported fever, or who was treated by the CHW for malaria, diarrhea, or pneumonia, or who had a referable danger sign was visited again 2 weeks (and, if necessary, again 4 weeks) later; procedures on repeat visits were identical to those on day 8. Final vital status (alive/died) of all enrolled children was recorded on day 31, regardless of the number of follow-up visits conducted. An additional structured questionnaire was administered (typically on day 8) to elicit information on household demographic and socioeconomic variables, and care-seeking before and after the initial visit to the CHW. All data were collected on paper forms, and identified with a unique 6-digit code, allowing linkage of data for each individual child while maintaining anonymity of child and caregiver identity. CHWs were fully trained on study procedures, including eligibility determination and delivery of the cluster-appropriate follow-up advice. Each week, supervising data collectors checked the iCCM registers maintained by CHWs to ensure that all eligible children were identified; these measures were supplemented by periodic spot checks of registers by senior field research staff, who also conducted periodic direct observation of data collector field work. Paper forms were checked for accuracy and completeness by a data officer, then entered twice into a secure online database (REDCap) [17] using customized data entry screens with built-in validation checks. Additional details have been previously published [16]. We estimated that the true cluster-specific failure rates would vary between 1.5% and 8.5%, implying a coefficient of variation of approximately 0.35. Based on programmatic data from January to June 2015, we anticipated that of approximately 493 mRDT-negative fever cases per month across the 28 clusters, 70% would be eligible (i.e., after excluding children with danger signs or treatable conditions), leading to an annualized average cluster size of 148 eligible children, of which 90%, or 133, would be enrolled. We estimated that 12 health areas per group would be required to detect non-inferiority (i.e., 1-sided 5% significance) with 80% power [18,19], but elected to include all 28 available health areas (14 per group), thus increasing our a priori–estimated power to 86.8%. Soon after initiating enrollment, our estimate of total per cluster yield was revised to 152 (further increasing our estimated power), and leading to a final anticipated enrollment of 4,270, or 2,135 children per group. We first assessed randomization balance by comparing the distribution of child, maternal, household, socioeconomic, and CHW characteristics between the two groups, and noted any that appeared unbalanced. We next examined the proportion of children in each group whose caregivers reported receiving follow-up advice congruent with the allocation of their corresponding CHW, and the proportion of day 8 follow-up visits (i.e., outcome assessments) that occurred within ±24 hours of the scheduled date (i.e., between day 7 and 9, inclusive). The subset of children meeting both these criteria defined the group for conducting per-protocol analysis, which was our primary analytic approach, given the non-inferiority design. The primary outcome, failure at day 8, was defined as at least 1 of the following: (1) caregiver reports that the child currently has fever, (2) CHW classification of diarrhea, pneumonia, or malaria, (3) presence of a danger sign, (4) hospitalization, or (5) death. We estimated the difference in the proportion meeting this definition across the study arms (conditional minus universal) along with a 1-sided 95% confidence interval using a binomial regression model with an identity link function, and conducted robust standard error estimation to account for the clustered design. To increase the specificity of our outcomes, we additionally examined 3 alternate definitions of failure, whereby the first component (caregiver report of fever) in the above composite definition was modified. The progressively specific modifications were as follows: definition 2 required that caregiver-reported fever had been present for ≥3 days, definition 3 used measured axillary temperature ≥ 38.0°C in place of the caregivers’ report (objective clinical failure), and definition 4 eliminated fever from the composite definition of failure. These 3 additional definitions were constructed and analyzed in a manner identical to the first definition. Among all 4 definitions, the first 3 were prespecified analyses. During a post-study analytic workshop in conjunction with discussions with the data and safety monitoring board, the fourth definition (requiring that at least 1 of death, hospitalization, referral for danger signs, or a CHW-treated illness was present) was added, in an effort to further increase specificity given the higher than expected rates of caregiver-reported fever. The estimation of the difference in failure rate between the 2 groups was repeated for each definition, adjusting for (i.e., including as fixed effects) variables appearing imbalanced. An intent-to-treat analysis, whereby the above-mentioned per-protocol requirements were removed, was also conducted. Finally, given the relatively small number of clusters, we also conducted a cluster-level analysis of the primary outcome definitions, using a t test to estimate the difference in the mean cluster-level proportions. Secondary outcome analysis was descriptive; we describe the clinical presentation at enrollment, care-seeking patterns before and after enrollment, and longer-term outcomes 2 and 4 weeks later (at day 15 and day 29) of children that were classified as “failed” at day 8. All analyses were conducted using R (https://cran.r-project.org/) and Stata 14.2 (StataCorp, College Station, TX). The study protocol was approved by the Johns Hopkins Bloomberg School of Public Health’s Institutional Review Board (No. 6608), and the Ethical Committee of the Ministry of Public Health in Kinshasa, DRC (No. 001/CNES/CNES/SR/03/2015). US Centers for Disease Control and Prevention investigators participated under a non-engaged determination from their agency’s Office for Human Research Protections.

• mullany, luke c.
• van boetzelaer, elburg
• gutman, julie
• steinhardt, laura c.
• ngoy, pascal
• barbera lainez, yolanda
• wittcoff, alison
• harvey, steven a.
• ho, lara s.