Abstract: We included 23 studies (n = 4192) assessing the accuracy of IL-6 for the diagnosis of sepsis in critically ill adults. Twenty studies that were available as conference proceedings only are awaiting classification. The included participants were heterogeneous in terms of their distribution of age, gender, main diagnosis, setting, country, positivity threshold, sepsis criteria, year of publication, and origin of infection, among other factors. Prevalence of sepsis greatly varied across studies, ranging from 12% to 78%. We considered all studies to be at high risk of bias due to issues related to the index test domain in QUADAS-2. The SROC curve showed a great dispersion in individual studies accuracy estimates (21 studies, 3650 adult patients), therefore the considerable heterogeneity in the collected data prevented us from calculating formal accuracy estimates. Using a fixed prevalence of sepsis of 50% and a fixed specificity of 74%, we found a sensitivity of 66% (95% confidence interval 60 to 72). If we test a cohort 1000 adult patients under suspicion of sepsis with IL-6, we will find that 330 patients would receive appropriate and timely antibiotic therapy, while 130 patients would be wrongly considered to have sepsis. In addition, 370 out of 1000 patients would avoid unnecessary antibiotic therapy, and 170 patients would have been undiagnosed of sepsis. This numerical approach should be interpreted with caution due to the limitations described above. Our evidence assessment of plasma interleukin-6 concentrations for the diagnosis of sepsis in critically ill adults reveals several limitations. High heterogeneity of collected evidence regarding the main diagnosis, setting, country, positivity threshold, sepsis criteria, year of publication, and the origin of infection, among other factors, along with the potential number of misclassifications, remain significant constraints for its implementation. The 20 conference proceedings assessed as studies awaiting classification may alter the conclusions of the review once they are fully published and evaluated. Further studies about the accuracy of interleukin-6 for the diagnosis of sepsis in adults that apply rigorous methodology for conducting diagnostic test accuracy studies are needed. The conclusions of the review will likely change once the 20 studies pending publication are fully published and included.

Plain-language summary: We performed a thorough literature search for studies reporting the use of IL-6 levels for detection of sepsis up to January 2019. We found 23 studies enrolling 4192 severely ill adults. Our assessment of the evidence reveals the complexity of the research topic, represented in the high variability of information reported by the studies. We found the characteristics of assessed patients to vary considerably between studies in terms of age, gender, setting, initial diagnosis, indicative value for sepsis, and source of infection, among other factors. This variability in the collected data prevented a formal numerical synthesis of the findings. Using the available data to perform an approximated estimation of the consequences, we found that 700 out of 1000 patients under suspicion of sepsis might be correctly classified, but 130 out of 1000 patients would be wrongly considered as having sepsis, while 170 out of 1000 patients might be incorrectly considered as not having sepsis. These errors would result in a serious increase in the risk of further morbidity and death due to delays of adequate treatment. This information should be interpreted with caution due to limitations in the collected data. We judged the included studies to have important limitations in their validity, hence they are at high risk of providing distorted results (i.e. to be at high risk of bias).