无 HIV 感染的非洲和亚洲儿童需住院治疗的严重肺炎的病因：PERCH 多国家病例对照研究。

BACKGROUND: Pneumonia is the leading cause of death among children younger than 5 years. In this study, we estimated causes of pneumonia in young African and Asian children, using novel analytical methods applied to clinical and microbiological findings. METHODS: We did a multi-site, international case-control study in nine study sites in seven countries: Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia. All sites enrolled in the study for 24 months. Cases were children aged 1-59 months admitted to hospital with severe pneumonia. Controls were age-group-matched children randomly selected from communities surrounding study sites. Nasopharyngeal and oropharyngeal (NP-OP), urine, blood, induced sputum, lung aspirate, pleural fluid, and gastric aspirates were tested with cultures, multiplex PCR, or both. Primary analyses were restricted to cases without HIV infection and with abnormal chest x-rays and to controls without HIV infection. We applied a Bayesian, partial latent class analysis to estimate probabilities of aetiological agents at the individual and population level, incorporating case and control data. FINDINGS: Between Aug 15, 2011, and Jan 30, 2014, we enrolled 4232 cases and 5119 community controls. The primary analysis group was comprised of 1769 (41·8% of 4232) cases without HIV infection and with positive chest x-rays and 5102 (99·7% of 5119) community controls without HIV infection. Wheezing was present in 555 (31·7%) of 1752 cases (range by site 10·6-97·3%). 30-day case-fatality ratio was 6·4% (114 of 1769 cases). Blood cultures were positive in 56 (3·2%) of 1749 cases, and Streptococcus pneumoniae was the most common bacteria isolated (19 [33·9%] of 56). Almost all cases (98·9%) and controls (98·0%) had at least one pathogen detected by PCR in the NP-OP specimen. The detection of respiratory syncytial virus (RSV), parainfluenza virus, human metapneumovirus, influenza virus, S pneumoniae, Haemophilus influenzae type b (Hib), H influenzae non-type b, and Pneumocystis jirovecii in NP-OP specimens was associated with case status. The aetiology analysis estimated that viruses accounted for 61·4% (95% credible interval [CrI] 57·3-65·6) of causes, whereas bacteria accounted for 27·3% (23·3-31·6) and Mycobacterium tuberculosis for 5·9% (3·9-8·3). Viruses were less common (54·5%, 95% CrI 47·4-61·5 vs 68·0%, 62·7-72·7) and bacteria more common (33·7%, 27·2-40·8 vs 22·8%, 18·3-27·6) in very severe pneumonia cases than in severe cases. RSV had the greatest aetiological fraction (31·1%, 95% CrI 28·4-34·2) of all pathogens. Human rhinovirus, human metapneumovirus A or B, human parainfluenza virus, S pneumoniae, M tuberculosis, and H influenzae each accounted for 5% or more of the aetiological distribution. We observed differences in aetiological fraction by age for Bordetella pertussis, parainfluenza types 1 and 3, parechovirus-enterovirus, P jirovecii, RSV, rhinovirus, Staphylococcus aureus, and S pneumoniae, and differences by severity for RSV, S aureus, S pneumoniae, and parainfluenza type 3. The leading ten pathogens of each site accounted for 79% or more of the site's aetiological fraction. INTERPRETATION: In our study, a small set of pathogens accounted for most cases of pneumonia requiring hospital admission. Preventing and treating a subset of pathogens could substantially affect childhood pneumonia outcomes. FUNDING: Bill & Melinda Gates Foundation.

背景：肺炎是导致 5 岁以下儿童死亡的主要原因。在这项研究中，我们使用新的分析方法对临床和微生物学发现进行了分析，以估计非洲和亚洲年轻儿童肺炎的病因。

方法：我们在七个国家的九个研究地点进行了一项多地点、国际病例对照研究：孟加拉国、冈比亚、肯尼亚、马里、南非、泰国和赞比亚。所有研究地点都进行了 24 个月的研究。病例为因严重肺炎住院的 1-59 个月龄儿童。对照组为随机从研究地点周围社区选择的年龄匹配的儿童。对鼻咽部和口咽部（NP-OP）、尿液、血液、诱导痰、肺抽吸物、胸腔积液和胃抽吸物进行培养、多重 PCR 或两者检测。主要分析限于无 HIV 感染且 X 线胸片异常的病例和无 HIV 感染的对照。我们应用贝叶斯、部分潜在类别分析来估计个体和人群水平的病因因素的概率，纳入病例和对照数据。

结果：2011 年 8 月 15 日至 2014 年 1 月 30 日，我们纳入了 4232 例病例和 5119 例社区对照。主要分析组由 1769 例（4232 例的 41.8%）无 HIV 感染且 X 线胸片阳性和 5102 例（5119 例的 99.7%）无 HIV 感染的社区对照组成。1752 例病例中，555 例（31.7%）有喘息（各研究地点范围为 10.6-97.3%）。30 天病例死亡率为 6.4%（1769 例中的 114 例）。血培养阳性 56 例（1749 例的 3.2%），分离出的最常见细菌为肺炎链球菌（19 例[33.9%]）。几乎所有病例（98.9%）和对照（98.0%）在 NP-OP 标本中至少有一种病原体通过 PCR 检测到。在 NP-OP 标本中检测到呼吸道合胞病毒（RSV）、副流感病毒、人偏肺病毒、流感病毒、肺炎链球菌、b 型流感嗜血杆菌（Hib）、非 b 型流感嗜血杆菌和卡氏肺孢子虫与病例状态相关。病因分析估计病毒占病因的 61.4%（95%可信区间[CrI]为 57.3-65.6%），细菌占 27.3%（23.3-31.6%），结核分枝杆菌占 5.9%（3.9-8.3%）。与严重病例相比，非常严重肺炎病例中病毒较少（54.5%，95% CrI 为 47.4-61.5% vs 68.0%，62.7-72.7%），细菌较多（33.7%，27.2-40.8% vs 22.8%，18.3-27.6%）。RSV 是所有病原体中病因比例最大的（31.1%，95% CrI 为 28.4-34.2%）。人鼻病毒、人偏肺病毒 A 或 B、人副流感病毒、肺炎链球菌、结核分枝杆菌和流感嗜血杆菌各占病因分布的 5%或以上。我们观察到百日咳博德特菌、副流感 1 型和 3 型、parechovirus-enterovirus、卡氏肺孢子虫、RSV、鼻病毒、金黄色葡萄球菌和肺炎链球菌的病因比例因年龄而异，以及 RSV、金黄色葡萄球菌、肺炎链球菌和副流感 3 型的严重程度而异。每个地点的前 10 种病原体占该地点病因比例的 79%或以上。

解释：在我们的研究中，一小部分病原体导致了大多数需要住院治疗的肺炎病例。预防和治疗一组病原体可能会显著影响儿童肺炎的结局。

资助：比尔及梅琳达·盖茨基金会。