key: cord-0861263-8l35bkpk
authors: Chaudhary, Rahul; Garg, Jalaj; Houghton, Damon E.; Murad, M. Hassan; Kondur, Ashok; Chaudhary, Rohit; Wysokinski, Waldemar E.; McBane, Robert D.
title: Thrombo-inflammatory Biomarkers in COVID-19: Systematic Review and Meta-analysis of 17,052 patients
date: 2021-02-08
journal: Mayo Clin Proc Innov Qual Outcomes
DOI: 10.1016/j.mayocpiqo.2021.01.009
sha: 6afec9646ae6ee176e08bdd8a894f4566bd21e26
doc_id: 861263
cord_uid: 8l35bkpk

Objective To evaluate differences in thrombo-inflammatory biomarkers between patients with severe COVID-19 infection/death and mild infection. Patients and Methods Medline, Cochrane Central Register of Controlled Trials, Embase, EBSCO, Web of Science, and CINAHL databases were searched for studies comparing thrombo-inflammatory biomarkers in COVID-19 among severe/non-survivors and non-severe/survivors from January 1, 2020 through July 11, 2020. Inclusion criteria: (1) hospitalized patients ≥18 years comparing severe/non-survivors vs. non-severe/survivors; (2) biomarkers of inflammation and/or thrombosis. A random-effects model was used to estimate the weighted mean difference (WMD) between the two groups of COVID-19 severity. Results Seventy-five studies were included (17,052 patients). Patients with severe COVID-19/non-survivors were older, a greater proportion were men, had a higher prevalence of hypertension, diabetes, cardiac or cerebrovascular disease, chronic kidney disease, malignancy, and COPD. The thrombo-inflammatory biomarkers were significantly higher in patients with severe disease including D-dimer (WMD 0.60, 0.49-0.71, I2=83.85%), fibrinogen (WMD 0.42, 0.18-0.67, I2=61.88%, p<0.001), CRP (WMD 35.74, 30.16-41.31, I2=85.27%), high sensitivity-CRP (WMD 62.68, 45.27-80.09, I2=0%), Interleukin-6 (WMD 22.81, 17.90-27.72, I2=90.42%) and, ferritin (WMD 506.15, 356.24-656.06, I2=52.02%). Moderate to significant heterogeneity was observed for all parameters. Sub-analysis based on disease severity, mortality, and geographic region of studies demonstrated similar inferences. Conclusions Thrombo-inflammatory biomarkers (D-dimer, Fibrinogen, CRP, hs-CRP, ferritin, and IL-6) and marker of end-organ damage (hs-Troponin I) are associated with increased severity and mortality in COVID-19 infection.

As coronavirus disease 2019 continues to spread across the world, there is accumulating evidence supporting the relative contribution of specific comorbidities and laboratory patterns among severely affected patients necessitating intensive care admission or resulting in mortality . The US Food and Drug Administration recently approved remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in hospitalized patients with severe disease [defined as patients with oxygen saturation ≤ 94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO) 57 ]. A 10-day course has been approved for COVID-19 infected patients who require invasive mechanical ventilation and/or ECMO and a 5-day course for patients not requiring mechanical ventilation and/or ECMO 56 . With the availability of potential treatment, the identification of clinical and laboratory predictors of severe disease is urgently needed to further risk stratify patients and optimize the allocation of medications to improve clinical outcomes. Earlier meta-analyses have evaluated such predictors; however, at the time of their publication, limited data were available, reducing the confidence in their conclusions. Moreover, the data available at the time of prior meta-analyses were exclusively from China, where the COVID-19 infection initially spread. These analyses combined data from multiple studies with overlapping populations and could not account for any racial/ethnic differences in the thromboinflammatory milieu [76] [77] [78] . We hypothesized differences in thrombo-inflammatory milieu according to disease severity and race/ethnicity. The aim of the current systematic review and meta-analysis was to 1) compare the differences in comorbidities and thrombo-inflammatory biomarkers between patients with severe COVID-19 infection/death due to COVID-19 infection and mild COVID-19 infection, and 2) assess the relative contribution of race/ethnicity in the J o u r n a l P r e -p r o o f

This systematic review was performed according to Cochrane Collaboration guidance and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement 79 . The study was exempt from institutional review or ethical board review due to no access to patient-level data.

We searched PubMed, The Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases from January 1, 2020 through July 11, 2020. We included prospective or retrospective studies that compared severe or fatal COVID-19 infection with mild COVID-19 infection or COVID-19 survivors. The search strategy is included in the supplementary appendix 1. All references of the retrieved articles were reviewed for further identification of potentially relevant studies. The identified studies were systematically assessed using the inclusion and exclusion criteria described below.

Two reviewers (RC and JG) independently selected the studies and abstracted data on study characteristics, design, reported comorbidities, laboratory parameters, and reported clinical outcomes. Discrepancies between the two reviewers were resolved by discussion and consensus.

The final results were reviewed by the senior investigators (WEW and RDM) (Figure 1) . The eligibility criteria were (1) hospitalized patients ≥18 years comparing severe/non-survivor COVID-19 positive patients vs. non-severe/survivor COVID-19 patients; (2) reported biomarkers of inflammation and/or thrombosis. Studies of pregnant women (due to inherent J o u r n a l P r e -p r o o f changes in markers of thrombo-inflammation during pregnancy) and reports with incomplete reporting of biomarkers were excluded. Abstracts, case reports, conference presentations, editorials, reviews, expert opinions, and literature published, not available in English, were excluded.

Severe COVID-19 was designated when the patients had one of the following criteria: groups, e.g., critical vs. mild illness, were chosen for analysis. The acute cardiac injury was determined if serum levels of cardiac biomarkers (e.g., troponin I) were above the 99th percentile upper reference limit, or new abnormalities were shown in electrocardiography and/or echocardiography.

Assessment of risk of bias for each study was performed using the Newcastle-Ottawa scale for cohort studies 80 . This tool addresses the domains of patient selection, comparability of groups, and outcome assessment.

We used the random-effects model to pool results across studies and estimate the weighted mean difference (WMD) and odds ratio (OR). We evaluated heterogeneity of effects using the Higgins I-squared (I 2 ) statistic with heterogeneity defined as I 2 <25% as non-significant heterogeneity, between 25%-50% as mild heterogeneity, between 50%-75% as moderate heterogeneity and >75% as high heterogeneity. We evaluated the assumption of combining data from patients with severe disease with non-survivors and combining non-severe disease data with survivors, by doing each analysis separately. We also compared the results of studies with patients from China vs. other locations. A two-tailed p < 0.05 was considered statistically significant. Meta-analysis was performed using the Comprehensive Meta-Analysis software Table 1 and

We deemed all the studies to be at a high risk of bias due to unadjusted analyses and variability in groups with comorbidities and prognostic factors.

Among demographics, patients in the severe/non-survivor group were significantly older compared to non-severe/survivor group (64.4±7.5 years vs. 52.5±9.1 years), a greater proportion were men (64.8% vs. 53.5%), and there was a high prevalence of hypertension (44.7% vs. 22 .6%), diabetes (28.3% vs. 15.9%), cardiac or cerebrovascular disease (23.1% vs. 7.5%), chronic kidney disease (8.5% vs. 3.3%), chronic liver disease (5.1% vs. 3.5%), malignancy (9.9% vs. 6.9%) and, chronic obstructive pulmonary disease (8.5% vs. 3%) compared to nonsevere/survivor group. As expected, the severe/non-survivor group had higher mortality (32.3% vs. 

Sensitivity analysis was performed by separating disease severity from survivorship.

Thus, a separate analysis was done comparing severe vs. non-severe disease, and another analysis compared survivors to non-survivors. In general, both analyses provided similar conclusions (Table 2) . Additionally, the weighted mean differences in thrombo-inflammatory biomarkers were compared between studies conducted in China (n=60) and other countries (n=15) to address the overlap of the study population in the published studies from China ( Table   1 ). The non-Chinese population had a higher comorbidity burden, including hypertension, diabetes, cardiac or cerebrovascular disease, chronic kidney disease, and chronic obstructive pulmonary disease. Otherwise, results were similar in the two populations (supplementary appendix table 5). Also, there were significant differences between the groups in the weighted mean difference for platelet count, fibrinogen level, and hs-Troponin I. The difference in Ddimer levels between the severe/non-survivor and the non-severe/survivor groups was more pronounced in the non-Chinese population. In contrast, the difference between the two groups in Chinese patients) with only 15 studies from other countries. Among the included studies, the non-Chinese study participants had a higher prevalence of comorbidities, including hypertension, diabetes, cardiac or CVD, CKD, chronic liver disease, and COPD. Also, the difference in the Ddimer levels between the severe/non-survivor and the non-severe/survivor groups was more pronounced in the non-Chinese population. In contrast, the difference between CRP levels was more pronounced in the Chinese population (Table 3) . It can be hypothesized that a difference in the comorbidity burden and thrombo-inflammatory milieu between the East Asians, Caucasians, and African Americans could be contributory to the higher case fatality noted in Europe and the United States. However, due to the limited published literature from other countries, our J o u r n a l P r e -p r o o f confidence in these estimates is low. It remains to be determined if racial differences in thrombo-inflammatory milieu affect COVID-19 outcomes.

This study has several limitations. In our analysis, we combined the sub-groups of severe COVID-19 with non-survivors which could lead to potential confounders. We addressed the confounders by performing a sub-group analysis comparing severe vs. non-severe COVID-19 and non-survivor vs. survivors and the results were consistent with the main analysis ( Table 2) .

Additionally, the included studies had heterogenous populations with differing burden of comorbidities and not all outcomes were available in all included studies. This was reflected in the Higgins I-squared (I 2 ) statistic with 57% reflecting significant heterogeneity and 29% reflecting moderate heterogeneity in the analyzed biomarkers. Another confounder was that majority of the studies were Chinese with potential overlapping populations artificially amplifying the effect of certain comorbidities and biomarkers (multiple studies reported from the same hospital, Table 1 ). To address this limitation, WMDs among thrombo-inflammatory biomarkers were compared according to the country of origin of the study, i.e., Chinese versus non-Chinese (supplementary appendix table 5). However, due to lacking data from non-Chinese countries, definite conclusion could not be drawn about the differential weightage of comorbidities and biomarkers among racial/ethnic groups. As literature continues to increase, it would be imperative to identify the potential role of genetics in the prevalence of poor clinical outcomes among African Americans and Caucasians compared to East Asians. Another caveat in the available data was that the values of D-dimer (concerning units of measurement) were significantly varied in reporting between studies, and several papers misreported the measuring unit making the values 1000 times smaller or higher 105 . While performing the analysis, these values were adjusted to reflect appropriate differences between the two groups. Additionally, J o u r n a l P r e -p r o o f significant heterogeneity between studies coupled with the high risk of bias (due to unadjusted analyses and unbalanced groups) reduces the confidence in the interpretation of the results.

Publication bias is also highly likely in a field that primarily consists of small unregistered observational studies.

Thrombo-inflammatory biomarkers (D-dimer, Fibrinogen, CRP, hs-CRP, ferritin, and IL-6) and indicators of cardiac damage (hs-Troponin I) on admission were associated with the severity and mortality with COVID-19 infection. Comorbidities conferring higher risk coupled with thrombo-inflammatory biomarkers might assist in the development of risk prediction models for the severity and prognosis of COVID-19. Such models could potentially aid in the selection of population to receive early therapeutic strategies, e.g., remdesivir therapy and improve clinical outcomes. 

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 2 Italy -Non-survivor vs. Survivor Retrospective Burian et al. 3 Germany -ICU vs. non-ICU Retrospective Cen et al. 4 China