Lung Fluid Biomarkers for Acute Respiratory Distress Syndrome

A Systematic Review and Meta-analysis

Yishan Wang; Huijuan Wang; Chunfang Zhang; Chao Zhang; Huqin Yang; Ruiyue Gao; Zhaohui Tong


Crit Care. 2019;23(43) 

In This Article


Data Source and Study Selection

We manually searched PubMed, Embase, Wed of Science, and the Cochrane Library for studies on biomarkers for ARDS in lung fluid samples published prior to January 11, 2018. Details of the search strategy are listed in Additional file 1. We also searched the references of included studies. Two researchers screened and evaluated the eligibility of all studies independently, and a third reviewer intervened whenever there was a disagreement. The inclusion criteria were (1) original research report of adult with or at-risk of ARDS, (2) report of exact values of biomarker concentration in lung fluid related to a clinical outcome (diagnosis of ARDS in at-risk patients and/or mortality of ARDS), (3) description of demographic variables, and (4) written in English. The exclusion criteria were (1) written in languages other than English, (2) not related to ARDS/ALI, (3) not an original research, (4) in vivo/in vitro studies, (5) pediatric studies, (6) biomarker not measured in lung fluid, (7) biomarker used for treatment monitoring, and (8) only one article available for a specific biomarker for no mergeable effect size and low reliability.

Data Extraction and Quality Assessment

We built Excel spreadsheets (Microsoft Corp., Redmond, WA) to extract data from the included studies, and the two researchers finished data extraction independently. The ARDS etiology and the mean or median level and standard deviation (SD) of the biomarker in the lung fluid were obtained. When a biomarker was measured sequentially, only the day 1 measurement was extracted. We extracted lung fluid biomarker levels from different subgroups as follows: patients with ARDS versus critically ill non-ARDS controls and survivors versus non-survivors in patients with ARDS. The mean value of a biomarker's concentration was equal to the median level in this study, and standard error (SE) was converted to SD using an Excel formula. In addition, demographic variables (age, sex, and number of participants for each subgroup), diagnostic criteria for ARDS, ARDS mortality, the moment the lung fluid sample was retrieved, the sample type (BALF/other than BALF), sample retrieval location, and volume of BALF irrigation solution used were recorded. The recovery rate of BALF was also recorded, if provided.

All studies were assessed for quality according to the Quality Assessment of Diagnostic Accuracy Studies Score-2 (QUADAS-2), and the content was tailored according to the guideline of QUADAS-2.[6] Details of the tailored QUADAS-2 are listed in Additional file 2. Risk of bias and an applicability concerns graph/summary was conducted using Review Manager version 5.3 (Cochrane Collaboration, Oxford, UK).

Data Synthesis and Data Analysis

Meta-analysis was performed with Stata 13.1 (StataCorp LLC, College Station, TX). The ratio of means (RoM) was employed to assess the effect size.[7–9] RoM is the mean value of a biomarker in the ARDS group divided by the mean value in the at-risk group (meanARDS/meanat-risk) or the mean value of a biomarker in the non-survivors group divided by the mean value in the survivors group (meannon-survivor/meansurvivor). RoM of each study was log transformed and pooled using the inverse-variance method to gain a pooled, transformed RoM, which was then back-transformed to determine the pooled RoM and 95% confidence interval, using the fixed effect model of the Stata software. The significance level for this meta-analysis model was set at p < .05. Forest plots were provided for biomarkers of which four or more studies were included in this meta-analysis. Biomarkers were ranked according to pooled RoM and statistical significance. We used the Qstatistic to test the existence of heterogeneity; a p value of less than 0.10 was considered significant for heterogeneity. I2 was employed to assess the proportion of total variability due to heterogeneity. An I2 value of approximately 25% was regarded as low heterogeneity, 50% as medium, and 75% as high heterogeneity. Publication bias was assessed with Egger's regression test,[10] where a p value of less than 0.10 was considered significant for publication bias. Duval and Tweedie's trim and fill was then conducted.[11]

For the biomarkers with a significant RoM and existence of heterogeneity, we performed a subgroup meta-analysis on study type (case-control study versus another study type) or sample type (BALF versus other lung fluid), when three or more studies were included.