Enteric Disease Department, Infectious Disease Directorate, Naval Medical Research Center, Silver Spring, MD, United States of America.
Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America.
PLoS One. 2018 Mar 28;13(3):e0194325. doi: 10.1371/journal.pone.0194325. eCollection 2018.
Since 1946 the controlled human infection model (CHIM) for Shigella has been used to improve understanding of disease pathogenesis, describe clinical and immunologic responses to infection and as a tool for vaccine development. As the frequency and intent for use in vaccine comparisons increases, standardization of the primary endpoint definition is necessary.
Subject-level data were obtained from previously conducted experimental Shigella CHIM studies. Signs and symptoms severity were categorized consistently across all studies. Sign and symptom correlations were estimated and univariate models were utilized to describe the association between stool output and other Shigella-attributable signs and symptoms. Multiple correspondence and hierarchical clustering analyses were performed to describe the co-occurrence of signs and symptoms. A disease score is proposed based on the co-occurrence of these events.
Data were obtained on 54 subjects receiving 800 to 2000 colony forming units (cfu) of S. flexneri. The median maximum 24 hour stool output was 514 ml (IQR: 300, 998 ml) with a median frequency of 6 (IQR: 4, 9). Subjects reported abdominal pain or cramps (81.5%), headache (66.7%) and anorexia (64.8%), 50.0% had a fever and 27.8% had gross blood in multiple loose stools. Multiple correspondence analyses highlighted co-occurrence of symptoms based on severity. A 3-parameter disease severity score predicted shigellosis endpoints and better differentiated disease spectrum.
Dichotomous endpoints for Shigella CHIM fail to fully account for disease variability. An ordinal disease score characterizing the breadth of disease severity may enable a better characterization of shigellosis and can decrease sample size requirements. Furthermore, the disease severity score may be a useful tool for portfolio management by enabling prioritization across vaccine candidates with comparable efficacy estimates using dichotomous endpoints.
自 1946 年以来，志贺氏菌的人体感染控制模型（CHIM）一直被用于增进对疾病发病机制的理解、描述对感染的临床和免疫反应，并作为疫苗开发的工具。随着在疫苗比较中使用的频率和意图增加，有必要对主要终点定义进行标准化。
从以前进行的实验性志贺氏菌 CHIM 研究中获得了受试者水平的数据。所有研究均一致地对体征和症状的严重程度进行分类。估计了体征和症状之间的相关性，并使用单变量模型来描述粪便排出量与其他志贺氏菌相关体征和症状之间的关联。进行多元对应分析和层次聚类分析，以描述体征和症状的同时出现情况。根据这些事件的同时发生情况提出了疾病评分。
共获得 54 名接受 800 至 2000 个集落形成单位（cfu）的 S. flexneri 的受试者的数据。24 小时内最大粪便排出量的中位数为 514ml（IQR：300，998ml），中位数频率为 6（IQR：4，9）。受试者报告腹痛或痉挛（81.5%）、头痛（66.7%）和食欲不振（64.8%），50.0%有发热，27.8%有大量血液在多次松散粪便中。多元对应分析强调了根据严重程度同时出现的症状。一个 3 参数疾病严重程度评分预测了志贺氏菌病终点，并更好地区分了疾病谱。
志贺氏菌 CHIM 的二分终点不能充分说明疾病的变异性。一个描述疾病严重程度广度的有序疾病评分可能使志贺氏菌病的特征描述更加完善，并减少样本量要求。此外，疾病严重程度评分可能是一种有用的工具，通过在使用二分终点具有可比疗效估计的疫苗候选物之间进行优先级排序，实现投资组合管理。
