Non-generalizability of biomarkers for mortality in SARS-CoV-2: a meta-analyses series

ABSTRACT Rationale Sophisticated prognostic scores have been proposed for SARS-CoV-2 but do not always perform consistently. We conducted these meta-analyses to uncover why and to investigate the impact of vaccination and variants. Methods We searched the PubMed database for the keywords ‘SARS-CoV-2’ with ‘biomarker’ and ‘mortality’. All studies published from 01/12/2020 to 31/03/2023 were surveyed. To aggregate the data, the meta library in R was used, and a random effects model fitted to obtain pooled AUCs and 95% confidence intervals for the European/North American, Asian, and overall datasets. Results Biomarker effectiveness varies significantly in different continents. Admission CRP levels are a good prognostic marker for mortality in Asian countries, with a pooled area under curve (AUC) of 0.83 (95%CI 0.80-0.85), but only an average predictor of mortality in Europe/North America, with a pooled AUC of 0.67 (95%CI 0.63-0.71, P< 0.0001). We observed the same pattern for D-dimer and IL-6. This variability explains why the proposed prognostic scores did not perform evenly. Notably, urea and troponin had pooled AUCs ≥0.78 regardless of location, implying that end-organ damage at presentation is a key prognostic factor. Very little data is available for vaccinated and variant cohorts but it appears that inflammatory biomarkers are performing less well. We note a significant lag from the pandemic advent to data availability and this has no doubt impacted on patient care. Conclusions Biomarker efficacies vary considerably by region. It is imperative that the infrastructure for collecting clinical data should be put in place ahead of a future pandemic. Summary box What is already known on this topic Biomarkers such as CRP, D-dimer, and interleukin-6 have been proven to have prognostic value in SARS-CoV-2. However prognostic scores using these as building blocks have performed unevenly in different locations. What this study adds Commonly used biomarkers for SARS-CoV-2 have different efficacies in different parts of the world. For example, admission CRP and interleukin-6 levels are good prognostic markers for mortality in Asian countries but only average in Europe and North America. Prognostic markers and scores cannot be ‘transplanted’ from one region to another. This has implications not just for SARS-CoV-2 but also for scores in other conditions. We note a significant lag from the pandemic advent to data availability and this has no doubt impacted on patient care. How this study might affect research, practice, or policy Biomarkers and by extension prognostic scores should be validated in their target country/population before use. The infrastructure for data collection and analysis should be put in place so that this process can happen rapidly (ideally in an automated manner), in case of another pandemic.