BACKGROUND Community acquired pneumonia (CAP) is a severe and often rapidly deteriorating disease. To better understand its dynamics and potential causal relationships, we analyzed time series data of cytokines, blood and clinical parameters in hospitalized CAP patients. METHODS Time series data of 10 circulating cytokines, blood counts and clinical parameters were related to baseline characteristics of 403 CAP patients using univariate mixed models. Bivariate mixed models were applied to analyze correlations between the time series. To identify potential causal relationships, we inferred cross-lagged relationships between pairs of parameters using latent curve models with structured residuals. RESULTS IL-6 levels decreased faster over time in younger patients (Padj = 0.06). IL-8, VCAM-1, and IL-6 correlated strongly with disease severity as assessed by the sequential organ failure assessment (SOFA) score (r = 0.49, 0.48, 0.46, respectively; all Padj < 0.001). IL-6 and bilirubin correlated with respect to their mean levels and slopes over time (r = 0.36 and r = 0.46, respectively; Padj < 0.001). A number of potential causal relationships were identified, e.g., a negative effect of ICAM-1 on MCP-1, or a positive effect of the level of creatinine on the subsequent VCAM-1 concentration (P < 0.001). CONCLUSIONS These results suggest that IL-6 trajectories of CAP patients are associated with age and run parallel to bilirubin levels. The time series analysis also unraveled directed, potentially causal relationships between cytokines, blood parameters and clinical outcomes. This will facilitate the development of mechanistic models of CAP, and with it, improvements in treatment or surveillance strategies for this disease. TRIAL REGISTRATION clinicaltrials.gov NCT02782013, May 25, 2016, retrospectively registered.

中文翻译：

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社区获得性肺炎患者的细胞因子动态、免疫细胞计数和疾病严重程度——揭示潜在的因果关系

背景社区获得性肺炎(CAP)是一种严重且经常迅速恶化的疾病。为了更好地了解其动力学和潜在的因果关系，我们分析了住院 CAP 患者的细胞因子、血液和临床参数的时间序列数据。方法 10 种循环细胞因子、血细胞计数和临床参数的时间序列数据与使用单变量混合模型的 403 名 CAP 患者的基线特征相关。应用双变量混合模型来分析时间序列之间的相关性。为了识别潜在的因果关系，我们使用具有结构化残差的潜在曲线模型推断参数对之间的交叉滞后关系。结果 年轻患者的 IL-6 水平随时间下降更快（Padj = 0.06）。IL-8、VCAM-1、IL-6 与疾病严重程度密切相关，通过顺序器官衰竭评估 (SOFA) 评分（分别为 r = 0.49、0.48、0.46；所有 Padj < 0.001）。IL-6 和胆红素与它们的平均水平和随时间的斜率相关（分别为 r = 0.36 和 r = 0.46；Padj < 0.001）。确定了许多潜在的因果关系，例如 ICAM-1 对 MCP-1 的负面影响，或肌酐水平对后续 VCAM-1 浓度的积极影响（P < 0.001）。结论 这些结果表明 CAP 患者的 IL-6 轨迹与年龄相关并且与胆红素水平平行。时间序列分析还揭示了细胞因子、血液参数和临床结果之间直接的、潜在的因果关系。这将促进 CAP 机械模型的开发，并随之改进该疾病的治疗或监测策略。试验注册clinicaltrials.gov NCT02782013，2016 年5 月25 日，追溯注册。