Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
International Rescue Committee, Kalemie, Democratic Republic of the Congo.
PLoS Med. 2018 Apr 17;15(4):e1002552. doi: 10.1371/journal.pmed.1002552. eCollection 2018 Apr.
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.
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.
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.
ClinicalTrials.gov NCT02595827.
世界卫生组织的综合社区病例管理（iCCM）指南建议，所有出现无并发症发热且无危险体征的儿童，在第 1 天初次就诊后的第 3 天应进行随访。然而，此类发热通常迅速消退，并且之前的研究表明，对无并发症发热的期待性家庭护理可以安全推荐。我们的目的是确定对这些儿童进行有条件随访是否不劣于常规随访。
我们在坦桑尼亚联合共和国和刚果民主共和国开展了一项以社区为基础的非劣效性、集群随机对照试验，纳入了在社区卫生工作者（CHW）处就诊的年龄在 2-59 个月的无严重非分类发热的儿童。将（n=28）个 CHW 集群随机分配，以建议照护者（1）无论疾病是否缓解（按照现行世卫组织指南；常规随访组），都在第 1 天初次就诊后的第 3 天进行随访，或（2）仅在疾病持续存在时进行随访（有条件随访组）。在第 8 天，两组儿童均再次进行评估，如果出现发热（照护者报告）、疟疾、腹泻、肺炎或健康状况恶化（出现危险体征、住院或死亡），则被归类为临床失败（失败定义 1）。我们还检验了其他替代的失败定义，即首先将照护者报告的发热限定为至少持续 3 天的发热（失败定义 2），然后用腋温测量代替（失败定义 3）。研究参与者、提供者和研究人员均未设盲。在纳入的 4434 名儿童中，有 4141 名（93.4%）符合接受 CHW 提供的特定手臂建议和及时进行第 8 天评估的方案定义（常规随访组：2210 名；有条件随访组：1931 名）。在有条件随访组（n=188，9.7%）和常规随访组（n=230，10.4%）中，失败率相似（差异：-0.7%）；然而，该差异的单侧 95%置信区间上限（-∞，5.1%）超过了预设的非劣效性边界（4.0%）（非劣效性 p=0.089）。当将照护者报告的发热限定为持续≥3 天的发热时，有条件随访组（n=159，8.2%）的失败率与常规随访组（n=200，9.1%）相似（差异：-0.8%；95%CI：-∞，4.1%；p=0.053）。如果在失败定义中用腋温测量代替照护者报告的发热，有条件随访组（n=113，5.9%）的失败率与常规随访组（n=160，7.2%）相比不劣效（差异：-1.4%；95%CI：-∞，2.5%；p=0.012）。在事后分析中，当失败定义限于疟疾、腹泻、肺炎、出现危险体征、住院或死亡时，有条件随访组（n=108，5.6%）的失败率与常规随访组（n=147，6.7%）相似，且在非劣效性边界内（95%CI：-∞，2.9%；p=0.017）。局限性包括最初低估临床失败的比例以及簇特异性失败率的差异较大，这降低了我们估计的准确性。此外，安全问题加剧，导致研究的最后几个月招募速度放缓。
我们发现，建议照护者仅在第 3 天儿童病情恶化或仍未好转时返回，与建议所有照护者在第 3 天返回相比，在第 8 天导致了相似的照护者报告的发热和其他临床结局发生率。决策者可以考虑修订 iCCM 框架内管理无并发症发热的指南。
ClinicalTrials.gov NCT02595827。
