Sowunmi Akintunde, Fatunmbi Bayo, Akano Kazeem, Wewe Olubunmi A, Agomo Chimere, Finomo Finomo, Ebenebe Joy, Jiya Nma, Ambe Jose, Wammanda Robinson, Ntadom Godwin, Mokuolu Olugbenga, Emechebe George, Ezeigwe Nnenna, Ayede Adejumoke I, Adewoye Elsie O, Gbotosho Grace O, Folarin Onikepe A, Happi Christian T, Oguche Stephen, Oyibo Wellington A, Useh Francis
Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria.
Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria.
BMC Infect Dis. 2017 Dec 19;17(1):781. doi: 10.1186/s12879-017-2876-9.
Artemisinin-based combination therapies (ACTs) have remained efficacious treatments of acute falciparum malaria in many endemic areas but there is little evaluation of factors contributing to the anaemia of acute falciparum malaria following long term adoption of ACTs as first-line antimalarials in African children.
Malarious <5 year-olds randomized to artemether-lumefantrine, artesunate-amodiaquine or dihydroartemisinin-piperaquine treatments were followed up clinically for 6 weeks. Anaemia was defined as haematocrit <30%; Malaria-attributable fall in haematocrit (MAFH) as the difference between haematocrit 28-42 days post- and pre-treatment; Total MAFH (TMAFH) as the difference between days 28-42 haematocrit and the lowest haematocrit recorded in the first week post-treatment initiation; Drug-attributable fall in haematocrit (DAFH) as the difference between MAFH and TMAFH; Early appearing anaemia (EAA) as haematocrit <30% occurring within 1 week in children with normal haematocrit pre-treatment. Predictors of anaemia pre-treatment, EAA, MAFH or DAFH >4% were evaluated by stepwise multiple logistic regression models. Survival analysis and kinetics of DAFH were evaluated by Kaplan-Meier estimator and non-compartment model, respectively.
Pre-treatment, 355 of 959 children were anaemic. Duration of illness >2 days and parasitaemia ≤10,000 μL were independent predictors of anaemia pre-treatment. EAA occurred in 301 of 604 children. Predictors of EAA were age ≤ 15 months, history of fever pre-treatment and enrolment haematocrit ≤35%. The probabilities of progression from normal haematocrit to EAA were similar for all treatments. MAFH >4% occurred in 446 of 694 children; its predictors were anaemia pre-treatment, enrolment parasitaemia ≤50,000 μL, parasitaemia one day post-treatment initiation and gametocytaemia. DAFH >4% occurred in 334 of 719 children; its predictors were history of fever pre-and fever 1 day post-treatment initiation, haematocrit ≥37%, and parasitaemia >100,000 μL. In 432 children, declines in DAFH deficits were monoexponential with overall estimated half-time of 2.2d (95% CI 1.9-2.6). Area under curve of deficits in DAFH versus time and estimated half-time were significantly higher in non-anaemic children indicating greater loss of haematocrit in these children.
After ten years of adoption of ACTs, anaemia is common pre-and early post-treatment, falls in haematocrit attributable to a single infection is high, and DAFH >4% is common and significantly lower in anaemic compared to non-anaemic Nigerian children.
Pan African Clinical Trial Registry (PACTR) [ PACTR201709002064150, 1 March 2017 ].
在许多疟疾流行地区，以青蒿素为基础的联合疗法（ACTs）仍然是治疗急性恶性疟的有效方法，但在非洲儿童中长期将ACTs用作一线抗疟药后，对于导致急性恶性疟贫血的因素评估较少。
将年龄小于5岁的疟疾患儿随机分为接受蒿甲醚-本芴醇、青蒿琥酯-阿莫地喹或双氢青蒿素-哌喹治疗，临床随访6周。贫血定义为血细胞比容<30%；疟疾导致的血细胞比容下降（MAFH）为治疗后28 - 42天与治疗前血细胞比容的差值；总MAFH（TMAFH）为治疗开始后第28 - 42天的血细胞比容与治疗开始后第一周记录的最低血细胞比容的差值；药物导致的血细胞比容下降（DAFH）为MAFH与TMAFH的差值；早期出现的贫血（EAA）为治疗前血细胞比容正常的儿童在1周内血细胞比容<30%。通过逐步多元逻辑回归模型评估贫血治疗前、EAA、MAFH或DAFH>4%的预测因素。分别采用Kaplan-Meier估计器和非房室模型评估生存分析和DAFH的动力学。
治疗前，959名儿童中有355名贫血。病程>2天和寄生虫血症≤10,000 μL是贫血治疗前的独立预测因素。604名儿童中有301名出现EAA。EAA的预测因素为年龄≤15个月、治疗前发热史和入组时血细胞比容≤35%。所有治疗从正常血细胞比容进展为EAA的概率相似。694名儿童中有446名MAFH>4%；其预测因素为治疗前贫血、入组时寄生虫血症≤50,000 μL、治疗开始后1天的寄生虫血症和配子体血症。719名儿童中有334名DAFH>4%；其预测因素为治疗前发热史和治疗开始后1天发热、血细胞比容≥37%以及寄生虫血症>100,000 μL。在432名儿童中，DAFH不足的下降呈单指数形式，总体估计半衰期为2.2天（95%可信区间1.9 - 2.6）。非贫血儿童中DAFH不足与时间的曲线下面积和估计半衰期显著更高，表明这些儿童血细胞比容损失更大。
采用ACTs十年后，治疗前和治疗后早期贫血常见，单次感染导致的血细胞比容下降幅度大，DAFH>4%常见，且与非贫血的尼日利亚儿童相比，贫血儿童中DAFH>情形显著更低。
泛非临床试验注册中心（PACTR）[PACTR201709002064150，2017年3月1日]
