A double blind randomized community-based trial of amoxicillin versus placebo for non-severe pneumonia in children aged 2-59 months in Pakistan

肺炎是低收入国家儿童患病和死亡的主要原因。为了减少肺炎造成的死亡，世界卫生组织和儿童基金会制定了儿童疾病综合管理算法，该算法简化了对肺炎和腹泻等常见儿童疾病的管理，将其分为不同的严重程度，以便初级保健提供者确定最适当的病例管理。许多肺炎病例被归类为非严重肺炎（定义为呼吸频率高于规定的年龄截止值的呼吸急促）。由于初级保健机构关于这类“肺炎”病因的信息不完整，世卫组织的治疗指南是根据医院肺炎病例的培养信息制定的，这些肺炎病例的严重程度和病因各不相同。目前世卫组织的指南提倡使用口服抗生素治疗非严重肺炎。然而，据推测，大多数不需要住院的非重度肺炎是病毒病因，因此不需要抗生素治疗。所有肺炎儿童的抗生素治疗费用很高;仅在南亚和撒哈拉以南非洲估计就达2亿美元。由于超过60%的肺炎被归类为非严重肺炎，这给低收入国家已经资源不足的项目带来了压力。在没有任何益处的情况下给予抗生素还会使儿童面临副作用的风险，并增加社区中抗菌药物耐药性的风险。这种不确定性构成了拟议研究的基础。我们建议在临床试验中表明，无论是否接受抗生素治疗，诊断为WHO定义的非严重肺炎的儿童的结局都是相似的。本研究将在巴基斯坦卡拉奇低收入社区的5个初级卫生保健中心进行，这些中心具有丰富的试验经验。被确定为呼吸急促但无任何危险体征的儿童将由初级卫生中心的研究医生随机接受WHO推荐的口服抗生素（阿莫西林45 mg/kg/天，每日两次）或匹配的安慰剂（一种味道和外观与阿莫西林相似但不含活性成分的药物），持续3天。将使用计算机生成的随机化列表将抗生素阿莫西林或安慰剂分配给儿童，其方式是在试验结束时，试验两组中的儿童数量相等。根据样本量的统计计算，我们需要分配521名儿童接受阿莫西林治疗，相同数量的儿童接受安慰剂治疗。所有儿童将在早上在初级卫生保健医生的监督下接受抗生素或安慰剂。晚上的剂量将由当地雇用的社区卫生工作者（CHW）提供，他们将访问儿童的家中。所有儿童将在第3天由研究医生再次评估，以查看儿童的高呼吸频率体征是否已消退。所有持续高呼吸率和/或出现表明疾病进展的新临床体征的儿童将被标记为治疗失败。两个治疗组中总会有一些治疗失败的儿童;我们假设两组中治疗失败的人数相等，即约7%。如果我们能够在这项试验的帮助下证明，给非严重肺炎儿童开抗生素没有额外的好处，我们将建立一个证据基础，以修订目前的世卫组织指南，从而减轻已经资源紧张的卫生系统的财政负担，并减少家庭的自付费用。从长远来看，这将对减少全球抗生素耐药性产生影响。

Pneumonia is a major cause of illness and death in children in low-income countries. With a view to decreasing death from pneumonia, the World Health Organization and UNICEF developed the the Integrated Management of Childhood Illness (IMCI) algorithm which simplifies management of common childhood illnesses such as pneumonia and diarrhoea into different levels of severity for determining the most appropriate case management by primary healthcare providers. Many pneumonia cases are categorized as non-severe pneumonia (defined as fast breathing above the specified age cut-off for respiratory rates). As there is incomplete information regarding the cause of this type of "pneumonia" from primary care settings, treatment guidelines by WHO are dictated by culture information from hospital pneumonia cases which are different in severity and cause. Current WHO guidelines advocate the use of oral antibiotics for non-severe pneumonia. However, it is postulated that most non severe pneumonia not requiring hospitalization is of viral aetiology, thus does not require antibiotic treatment. The cost of antibiotic treatment for all children with pneumonia is high; an estimated US$ 200 million in South Asia & sub Saharan Africa alone. Since more than 60% of pneumonia is classified as non-severe, this puts a strain on already under-sourced programmes in low-income countries. Giving antibiotics where they confer no benefit also puts the child at risk of side effects and increases the risk of antimicrobial resistance in the community. This uncertainty forms the basis of the proposed study. We propose to show in a clinical trial that the outcome of children diagnosed with WHO defined non severe pneumonia is similar regardless of whether they receive antibiotics or not. This study will be conducted in five primary health care centres located in low income communities of Karachi, Pakistan, with extensive trial experience. Children identified to have fast breathing without any danger signs will be randomized to receive either three days of the WHO recommended oral antibiotic (Amoxicillin 45mg/kg/day divided twice daily) or matching placebo (a drug that will taste and look like the amoxicillin but will not have an active ingredient) by a study physician working at the primary health centre. The assignment of the antibiotic amoxicillin or placebo to a child will be done using a computer generated randomization list in a manner that at the end of the trial, there are equal numbers of children in both arms of the trial. Based on the statistical calculations for sample size, we will need to assign 521 children to receive amoxicillin and the same number of children to receive placebo. All children will receive the antibiotic or placebo under supervision of the primary health care physician in the morning. Evening doses will be delivered by locally hired Community Health Workers (CHWs) visiting the children at their home. All children will be assessed again on day 3 by a study physician to see if the child's presenting sign of high respiratory rate has resolved or not. All children with persistently high respiratory rate and/or development of a new clinical sign indicating illness progression will be labelled a treatment failure. There will invariably be some children with treatment failure in both the treatment arms; we hypothesize that there will be equal number of treatment failures in both the groups i.e. around 7%. If we are able to show with the help of this trial that there is no added advantage of prescribing antibiotics to children with non-severe pneumonia we will develop an evidence base to revise the current WHO guidelines and thus reduce the financial burden on an already resource constrained health system and also decrease out of pocket expenses for families. In the long term this will have implications for decreasing global antimicrobial resistance to antibiotics.