Background

The management of childhood infections remains inadequate in resource-limited countries, resulting in high mortality and irrational use of antimicrobials. Current disease management tools, such as the Integrated Management of Childhood Illness (IMCI) algorithm, rely solely on clinical signs and have not made use of available point-of-care tests (POCTs) that can help to identify children with severe infections and children in need of antibiotic treatment. e-POCT is a novel electronic algorithm based on current evidence; it guides clinicians through the entire consultation and recommends treatment based on a few clinical signs and POCT results, some performed in all patients (malaria rapid diagnostic test, hemoglobin, oximeter) and others in selected subgroups only (C-reactive protein, procalcitonin, glucometer). The objective of this trial was to determine whether the clinical outcome of febrile children managed by the e-POCT tool was non-inferior to that of febrile children managed by a validated electronic algorithm derived from IMCI (ALMANACH), while reducing the proportion with antibiotic prescription.

Methods and findings

We performed a randomized (at patient level, blocks of 4), controlled non-inferiority study among children aged 2–59 months presenting with acute febrile illness to 9 outpatient clinics in Dar es Salaam, Tanzania. In parallel, routine care was documented in 2 health centers. The primary outcome was the proportion of clinical failures (development of severe symptoms, clinical pneumonia on/after day 3, or persistent symptoms at day 7) by day 7 of follow-up. Non-inferiority would be declared if the proportion of clinical failures with e-POCT was no worse than the proportion of clinical failures with ALMANACH, within statistical variability, by a margin of 3%. The secondary outcomes included the proportion with antibiotics prescribed on day 0, primary referrals, and severe adverse events by day 30 (secondary hospitalizations and deaths). We enrolled 3,192 patients between December 2014 and February 2016 into the randomized study; 3,169 patients (e-POCT: 1,586; control [ALMANACH]: 1,583) completed the intervention and day 7 follow-up. Using e-POCT, in the per-protocol population, the absolute proportion of clinical failures was 2.3% (37/1,586), as compared with 4.1% (65/1,583) in the ALMANACH arm (risk difference of clinical failure −1.7, 95% CI −3.0, −0.5), meeting the prespecified criterion for non-inferiority. In a non-prespecified superiority analysis, we observed a 43% reduction in the relative risk of clinical failure when using e-POCT compared to ALMANACH (risk ratio [RR] 0.57, 95% CI 0.38, 0.85, p = 0.005). The proportion of severe adverse events was 0.6% in the e-POCT arm compared with 1.5% in the ALMANACH arm (RR 0.42, 95% CI 0.20, 0.87, p = 0.02). The proportion of antibiotic prescriptions was substantially lower, 11.5% compared to 29.7% (RR 0.39, 95% CI 0.33, 0.45, p < 0.001). Using e-POCT, the most common indication for antibiotic prescription was severe disease (57%, 103/182 prescriptions), while it was non-severe respiratory infections using the control algorithm (ALMANACH) (70%, 330/470 prescriptions). The proportion of clinical failures among the 544 children in the routine care cohort was 4.6% (25/544); 94.9% (516/544) of patients received antibiotics on day 0, and 1.1% (6/544) experienced severe adverse events. e-POCT achieved a 49% reduction in the relative risk of clinical failure compared to routine care (RR 0.51, 95% CI 0.31, 0.84, p = 0.007) and lowered antibiotic prescriptions to 11.5% from 94.9% (p < 0.001). Though this safety study was an important first step to evaluate e-POCT, its true utility should be evaluated through future implementation studies since adherence to the algorithm will be an important factor in making use of e-POCT’s advantages in terms of clinical outcome and antibiotic prescription.

Conclusions

e-POCT, an innovative electronic algorithm using host biomarker POCTs, including C-reactive protein and procalcitonin, has the potential to improve the clinical outcome of children with febrile illnesses while reducing antibiotic use through improved identification of children with severe infections, and better targeting of children in need of antibiotic prescription.

Trial registration

ClinicalTrials.gov NCT02225769

中文翻译：

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一种新型电子算法，使用宿主生物标志物即时检验测试坦桑尼亚儿童的发热性疾病（e-POCT）：一项随机对照非劣效性试验

背景

在资源有限的国家，对儿童期感染的管理仍然不足，导致高死亡率和不合理使用抗菌剂。当前的疾病管理工具，例如儿童疾病综合管理（IMCI）算法，仅依赖于临床体征，还没有利用可帮助识别患有严重感染的儿童和儿童的现成的即时检验（POCT）需要抗生素治疗。e-POCT是一种基于当前证据的新颖电子算法；它指导临床医生进行整个咨询，并根据一些临床体征和POCT结果推荐治疗方法，其中一些在所有患者中进行（疟疾快速诊断测试，血红蛋白，血氧仪），而其他仅在选定的亚组中进行（C反应蛋白，降钙素，血糖仪） ）。

方法和发现

我们在坦桑尼亚达累斯萨拉姆的9所门诊进行了一项针对2至59个月大的患有急性发热疾病的儿童的随机（非病患，每组4个）对照非劣效性研究。同时，两个医疗中心也记录了常规护理。主要结局是随访的第7天临床失败的比例（严重症状，在第3天/后出现临床肺炎或在第7天出现持续症状）的比例。如果e-POCT的临床失败比例不比ALMANACH的临床失败比例差3％（在统计变异范围内），则可以宣布为非自卑。次要结局包括在第0天开具抗生素的比例，初次转诊和在第30天出现严重不良事件（二次住院和死亡）。我们报名了3，2014年12月至2016年2月之间的192名患者进入随机研究；3,169例患者（e-POCT：1,586；对照组[ALMANACH]：1,583）完成了干预并进行了第7天的随访。使用e-POCT，在每个协议的人群中，临床失败的绝对比例为2.3％（37 / 1,586），而ALMANACH组为4.1％（65 / 1,583）（临床失败的风险差异为-1.7， 95％CI -3.0，-0.5），满足非自卑的预定标准。在一项未预先指定的优势分析中，我们发现与eALPOACH相比，使用e-POCT时临床失败的相对风险降低了43％（风险比[RR] 0.57、95％CI 0.38、0.85，使用e-POCT，在每个协议的人群中，临床失败的绝对比例为2.3％（37 / 1,586），而ALMANACH组为4.1％（65 / 1,583）（临床失败的风险差异为-1.7， 95％CI -3.0，-0.5），满足非自卑的预定标准。在一项未预先指定的优势分析中，我们发现与eALPOACH相比，使用e-POCT时临床失败的相对风险降低了43％（风险比[RR] 0.57、95％CI 0.38、0.85，使用e-POCT，在每个协议的人群中，临床失败的绝对比例为2.3％（37 / 1,586），而ALMANACH组为4.1％（65 / 1,583）（临床失败的风险差异为-1.7， 95％CI -3.0，-0.5），满足非自卑的预定标准。在一项未预先指定的优势分析中，我们发现与eALPOACH相比，使用e-POCT时临床失败的相对风险降低了43％（风险比[RR] 0.57、95％CI 0.38、0.85，p = 0.005）。e-POCT组严重不良事件的比例为0.6％，而ALMANACH组为1.5％（RR 0.42，95％CI 0.20，0.87，p = 0.02）。抗生素处方的比例从29.7％大幅降低至11.5％（RR 0.39，95％CI 0.33，0.45，p <0.001）。使用e-POCT，最常见的抗生素处方适应症是严重疾病（57％，103/182处方），而使用控制算法（ALMANACH）则是非严重呼吸道感染（70％，330/470处方）。在常规护理队列中的544名儿童中，临床失败的比例为4.6％（25/544）；94.9％（516/544）的患者在第0天接受了抗生素治疗，而1.1％（6/544）的患者出现了严重的不良事件。与常规护理相比，e-POCT的临床失败相对风险降低了49％（RR 0.51，95％CI 0.31，0.84，p = 0.007），抗生素处方从94.9％降低至11.5％（p <0.001）。尽管此安全性研究是评估e-POCT的重要的第一步，但其真实效用应通过未来的实施研究进行评估，因为遵守该算法将成为利用e-POCT在临床结果和抗生素方面的优势的重要因素处方。

结论

e-POCT是一种使用宿主生物标志物POCT（包括C反应蛋白和降钙素）的创新电子算法，有望改善发热性儿童的临床结局，同时通过改善对严重感染儿童的识别和更好的靶向性来减少抗生素的使用需要抗生素处方的孩子。

试用注册

ClinicalTrials.gov NCT02225769