The impact of weekly fever-screening and treatment and monthly RDT testing and treatment on the infectious reservoir of malaria in Burkina Faso: results from a cluster-randomised trial

The majority of malaria infections in endemic countries are asymptomatic and a source of onward transmission to mosquitoes. Malaria transmission and disease burden could be reduced by improving early detection and treatment of these infections with active screening approaches. In an 18-month cluster-randomized study in Sapone, Burkina Faso, households were enrolled and randomised to 1 of 3 arms: arm 1 - control; arm 2 - active weekly screening for febrile individuals and treatment if rapid diagnostic test (RDT) positive; or arm 3 – active weekly fever-screening (as arm 2) plus monthly RDT-testing regardless of symptoms. The primary outcome was parasite prevalence by qPCR in the end-of-study cross-sectional survey. Secondary outcomes included parasite and gametocyte prevalence and density in all three end-of-season cross-sectional surveys, incidence of infection, and the transmissibility of infections to mosquitoes. A total of 906 individuals were enrolled during 2 phases. In Phase 1, 412 individuals were enrolled between August 9 and 17, 2018, and in Phase 2, 494 individuals were enrolled between January 10 and 31, 2019. In the end-of-study cross-sectional survey, malaria parasite prevalence by qPCR was statistically significantly lower in arm 3 (29·26% 79/270), but not in arm 2 (45·66% 121/265), when compared to arm 1 (48·72% 133/273) (RR = 0·65, 95%CI = 0·52 to 0·81, P=0·0001). Total parasite and gametocyte prevalence and density were also significantly lower in arm 3 in all surveys. The largest differences were seen at the end of the dry season, with gametocyte prevalence 78·38 % and transmission potential 98·20% lower in arm 3 vs arm 1. Active monthly RDT testing and treatment can reduce parasite carriage and the infectious reservoir of malaria to <2% when used during the dry season. This insight may inform approaches for malaria control and elimination.

Methods
Participants were permanent residents in the  Sapone Marche and Pissy LHF catchment areas and were enrolled in a total of 181 households. Households were randomized into 3 study arms that received different levels of care.

Standard of care with Passive case detection (PCD) (performed in arms 1, 2 & 3): All participants received unique identification cards for use when attending two designated local health facilities. Clinical malaria episodes were passively monitored, with axillary temperature and medical history recorded, and malaria diagnosed by conventional Rapid Diagnostic Test (RDT; First Response Malaria Ag. pLDH/HRP2, specific for P. falciparum and/or other Plasmodium species). 

Weekly fever screening, testing, and treatment (arms 2 & 3): All participants in arms 2 and 3 were visited weekly by a community health worker to screen for fever. Participants with a current fever (≥ 37.5°C) or a history of fever in the last 24 hours were referred to a health facility and an RDT was performed.

Monthly Mass Testing and Treatment (MTAT; arm 3): In arm 3, one weekly fever screening visit per month was replaced by MTAT,  where participants presented at a central meeting point for testing by conventional RDT. RDT-positive participants were referred to a health facility for treatment.

At the start and end of each transmission season, a cross-sectional survey was conducted on all study participants (4 surveys in total). Finger-prick blood samples were taken for molecular assessment of parasite and gametocyte prevalence and density, and axillary temperature was measured. Participants with a current fever (≥37·5°C) or a history of fever in the last 24 hours were referred to an LHF for malaria diagnosis by RDT and treatment.

流行区的绝大多数疟疾感染为无症状感染，且可成为蚊虫续传播的源头。通过主动筛查手段及早发现并治疗此类感染，可降低疟疾传播风险与疾病负担。本研究在布基纳法索萨波内开展了一项为期18个月的整群随机试验（cluster-randomized study），将纳入的住户随机分配至3个研究组：第1组为对照组；第2组为针对发热个体开展每周主动筛查，快速诊断试验（Rapid Diagnostic Test, RDT）阳性者予以治疗；第3组在第2组方案基础上，增加无论有无症状均每月开展RDT检测。本研究的主要结局为研究结束时横断面调查中通过定量聚合酶链反应（quantitative polymerase chain reaction, qPCR）检测的寄生虫阳性率。次要结局包括三次季末横断面调查中的寄生虫与配子体阳性率及载量、感染发生率，以及感染向蚊虫的传播能力。研究分两个阶段共纳入906名受试者：第一阶段于2018年8月9日至17日纳入412名受试者，第二阶段于2019年1月10日至31日纳入494名受试者。与第1组（48.72%，133/273）相比，第3组研究结束时qPCR检测的疟疾寄生虫阳性率显著降低（29.26%，79/270），而第2组（45.66%，121/265）无显著统计学差异（相对危险度RR=0.65，95%置信区间CI：0.52~0.81，P=0.0001）。所有调查中，第3组的总寄生虫与配子体阳性率及载量均显著降低，其中旱季末的差异最为显著：与第1组相比，第3组的配子体阳性率降低78.38%，传播潜力降低98.20%。在旱季开展每月RDT检测与治疗，可将寄生虫携带率与疟疾感染储存宿主降至2%以下。该研究结果可为疟疾防控与消除策略提供参考。

方法
受试者为萨波内马尔什与皮西基层卫生设施（Pissy LHF）服务覆盖区域的常住居民，共纳入181户住户。住户被随机分配至3个接受不同干预强度的研究组。
所有研究组均采用被动病例检测（Passive Case Detection, PCD）作为标准诊疗流程（第1、2、3组均实施）：所有受试者将获得专属识别卡，用于前往两家指定本地医疗机构就诊。临床疟疾发作采用被动监测方式，记录腋温与病史，通过常规快速诊断试验（First Response Malaria Ag. pLDH/HRP2，针对恶性疟原虫（Plasmodium falciparum）及其他疟原虫物种）进行疟疾诊断。
第2、3组实施每周发热筛查、检测与治疗：第2、3组的所有受试者每周接受社区卫生工作者上门发热筛查。当前体温≥37.5℃或近24小时有发热史的受试者将被转诊至医疗机构，并进行RDT检测。
第3组实施每月大规模检测与治疗（Mass Testing and Treatment, MTAT）：第3组每月将1次每周发热筛查替换为MTAT，受试者前往集中采样点接受常规RDT检测。RDT阳性受试者将被转诊至医疗机构接受治疗。
在每个传播季的开始与结束，共开展4次横断面调查，对所有研究受试者进行采样。采集指尖血样本用于寄生虫与配子体阳性率及载量的分子检测评估，并测量腋温。当前体温≥37.5℃或近24小时有发热史的受试者将被转诊至基层卫生设施，通过RDT进行疟疾诊断并接受治疗。