Prevalence and prognostic value of elevated troponins in patients hospitalised for coronavirus disease 2019: a systematic review and meta-analysis

Background The clinical significance of cardiac troponin measurement in patients hospitalised for coronavirus disease 2019 (covid-19) is uncertain. We investigated the prevalence of elevated troponins in these patients and its prognostic value for predicting mortality. Methods Studies were identified by searching electronic databases and preprint servers. We included studies of hospitalised covid-19 patients that reported the frequency of troponin elevations above the upper reference limit and/or the association between troponins and mortality. Meta-analyses were performed using random-effects models. Results Fifty-one studies were included. Elevated troponins were found in 20.8% (95% confidence interval [CI] 16.8–25.0 %) of patients who received troponin test on hospital admission. Elevated troponins on admission were associated with a higher risk of subsequent death (risk ratio 2.68, 95% CI 2.08–3.46) after adjusting for confounders in multivariable analysis. The pooled sensitivity of elevated admission troponins for predicting death was 0.60 (95% CI 0.54–0.65), and the specificity was 0.83 (0.77–0.88). The post-test probability of death was about 42% for patients with elevated admission troponins and was about 9% for those with non-elevated troponins on admission. There was significant heterogeneity in the analyses, and many included studies were at risk of bias due to the lack of systematic troponin measurement and inadequate follow-up. Conclusion Elevated troponins were relatively common in patients hospitalised for covid-19. Troponin measurement on admission might help in risk stratification, especially in identifying patients at high risk of death when troponin levels are elevated. High-quality prospective studies are needed to validate these findings. Systematic review registration PROSPERO CRD42020176747 Supplementary Information The online version contains supplementary material available at 10.1186/s40560-020-00508-6.


Introduction
Coronavirus disease 2019 (covid-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) remains a pandemic, with considerable mortality and morbidity exerting pressure on global health-care systems. Patients with covid-19 experience a wide range of disease severity. Prognostic tools that efficiently stratify individual's risk of experiencing adverse outcomes may facilitate patients and clinicians in the informed decision-making process [1].
Despite being primarily a respiratory infection, covid-19 has important impacts on many vital organs, including the heart [2,3]. A growing number of reports have documented myocardial injury reflected by elevated circulating cardiac troponin concentrations among infected patients [4][5][6][7][8]. However, elevated troponins frequently occur in patients with conditions other than acute coronary syndromes, and the mechanisms are complex. For this reason, the American College of Cardiology recommended that troponin is ordered for covid-19 patients only when the diagnosis of acute myocardial infraction is being considered on clinical grounds [9]. On the other hand, the UK National Institute for Health and Care Excellence supported troponin testing for wider indications, including patients with non-specific symptoms of possible myocardial injury such as shortness of breath and severe fatigue [10]. Besides, some opinion papers advocated for systematic troponin testing in all covid-19 patients requiring hospital admission for prognostication purpose [11,12]. These conflicting recommendations regarding the use of troponins in evaluating covid-19 patients reflect major gaps in our understanding of the clinical significance of elevated troponins in this context.
Several recent studies have reported on the relevance of elevated troponins to severity of covid-19 and risk of death, including large retrospective studies from major epicentres such as Wuhan, New York City and some European countries as well as studies with prospective designs [13][14][15][16]. We undertook a systematic review and meta-analysis to evaluate the prevalence of elevated troponins in hospitalised covid-19 patients, the performance of elevated troponins in predicting mortality and the quality of currently available evidence.

Methods
This study was conducted following the modified CHAR MS (CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies) for reviews of prognostic factors (CHARMS-PF) guidelines [17] and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (checklist in Table S1) [18]. The study protocol was registered prospectively in PROSPERO (CRD42020176747).

Literature search and eligibility criteria
We searched English and Chinese databases (PubMed, Embase, Chinese National Knowledge Infrastructure and Chinese Biomedical Database) and preprint servers (medRxiv, bioRxiv, ChinaXiv, Research Square and SSRN) for research articles on covid-19 published after 1 December 2019, with no restrictions on language or peer review status. Details of the search strategy are listed in Table S2. The last update of literature search was performed on 15 October 2020. Studies were considered eligible if they were observational or interventional studies that (1) enrolled patients that required hospitalisation for covid-19 pneumonia, (2) measured cardiac-specific troponin T or I concentrations on hospital admission or during hospital stay and (3) reported the prevalence of elevated troponins among patients who received troponin measurement or the association between troponin concentrations and mortality during the follow-up. Elevated troponins were defined as troponin concentrations higher than the upper reference limit value predetermined by the local laboratory. We excluded (1) studies that specifically enrolled patients admitted for cardiovascular reasons, organ transplant recipients or deceased patients; (2) studies that reported myocardial injury but the diagnosis was not based solely on troponin measurements or the upper reference limit of troponin test was not used as the diagnostic criteria; and (3) case reports or case series involving fewer than 10 patients. When more than one study from the same institutions with overlapping time period of recruitment were identified, we chose the one with the largest sample size for inclusion, except when our outcomes of interest were reported only in smaller studies.

Study selection, data extraction and quality assessment
Two researchers (BCZ and WFL) independently screened the identified records, first based on the title and abstract and subsequently based on the full manuscript. The reference lists of relevant manuscripts were searched to identify additional eligible studies. Using predefined forms, both researchers independently extracted data on study design, time of recruitment and follow-up, characteristics of patients and troponin tests, frequency of troponin elevation and, if available, the number of survivors and nonsurvivors among patients with and without elevated troponins. For studies that performed multivariable analysis to assess the association between elevated troponins and mortality, we extracted the adjusted effect estimates with confidence intervals (CI) and the variables in multivariable models. Risk of bias assessment for studies reporting on the prevalence of elevated troponins was conducted using a tool developed for prevalence studies [19]. Key study features assessed were sample selection and measurement quality. The Quality in Prognosis Studies (QUIPS) tool was used to assess the risk of bias of studies on the prognostic performance of troponins [20]. The tool includes the evaluation of 6 domains: study participation, study attrition, prognostic factor measurement, outcome assessment, study confounding, and statistical analysis and reporting. Disagreements between researchers were resolved by consensus, and a third researcher was involved when necessary.

Statistical analysis
Statistical analyses were performed using Stata® version 12.0 (StataCorp, College Station, TX, USA). All metaanalyses were based on random-effects models due to the anticipated high degree of heterogeneity among studies. To estimate the prevalence of elevated troponins in patients admitted for covid-19, we pooled the proportion of patients with elevated troponins among those who received at least one troponin measurement. The Freeman-Tukey double arcsine transformation method was used to account for studies reporting very low prevalence estimates.
To assess the predictive value of troponins for mortality, we pooled the multivariable-adjusted associations between elevated troponins and mortality. For this analysis, studies that did not measure troponins on hospital admission were not included, because troponins are expected to rise in late deterioration of the illness and have less predictive utility at that time. We also excluded studies that modelled troponin as a continuous predictor or did not use the upper reference limit of the troponin test, because the association between troponin concentrations and mortality risk may not be linear and because the use of study-specific optimal cut-off thresholds in meta-analysis may result in overestimation of the prognostic value of a biomarker [21]. We converted adjusted odds ratios reported by included studies to risk ratios (RR) using a published formula [22] and assumed that hazard ratios reasonably approximated RRs. For studies where more than one effect estimates were given for different levels of troponin elevation versus reference, a study-unique effect estimate was generated using a fixed-effects model before being included in the random-effects meta-analysis. We calculated the summary RR with 95% CI using the generic inverse variance method. Considering that dozens of commercial troponin assays with different epitope targets and analytical characteristics are used in clinical practice, we calculated 95% prediction intervals (PI) to inform the distribution of prognostic effects of elevated troponins across different measurement methods in future studies [23].
We evaluated publication bias using the funnel plot and Egger's test. When significant publication bias was found, we used trim-and-fill method to adjust our results. The magnitude of heterogeneity was assessed by the Higgins I 2 statistic. Subgroup analyses in case of substantial heterogeneity (I 2 > 50%) were conducted based on the characteristics of troponin assays (troponin T or I, high-sensitivity or contemporary assays) and the geographical location, sample size, risk of bias and peer review status of included studies.
The predictive ability of troponin was further assessed by constructing a hierarchical summary receiver operating characteristic curve using the bivariate model [24]. Based on the model, we determined the overall sensitivity, specificity and positive and negative likelihood ratios of elevated troponins on hospital admission for predicting death. These measures of predictive accuracy reflect the intrinsic performance of troponins and are independent of the mortality of underlying study populations. For practical purposes, we estimated the post-test risk of death using the Fagan nomogram, considering a pre-test probability as the pooled risk of death among the included patients.

Prevalence of elevated troponins
In total, 49 studies reported or allowed calculation of prevalence estimates for elevated troponins above the upper reference limit in patients hospitalised for covid-19. The risks of bias of these studies in estimating prevalence are summarised in Table S3. The studies differed in patient population (patients admitted to hospital or patients admitted in ICU) and timing of troponin measurement (on admission or during hospital stay). We decided to conduct separate analyses for studies using different methodologies because these may have significant influence on the observed prevalence of elevated troponins.

Elevated troponins and mortality
In 28 studies [13-15, 25-27, 31, 32, 34, 37, 38, 41, 43-46, 48, 49, 51, 52, 55, 57, 61, 65, 67, 68, 70, 71], data on the relationship between troponins (on admission or during hospital stay) and mortality of patients with covid-19 could be extracted. The risks of bias of these studies in assessing the prognostic value of troponins are summarised in Table S4. Many of the studies were at high risk of selection bias due to the lack of systematic troponin measurement and incomplete in-hospital follow-up. Besides, 10 studies did not adjust for relevant confounders (e.g. age, cardiovascular comorbidities). The results of studies that conducted multivariable analysis and the confounders adjusted for were listed in Table  S5. In the following analyses, we focused only on studies that measured troponins on hospital admission, because troponin tests at this point of time might be useful for early risk stratification, whereas tests ordered during hospitalisation may have been a response to patients' deteriorating conditions and thus would have more diagnostic but less predictive values.
We conducted a meta-analysis of 11 studies (13,889 patients) that reported multivariable-adjusted associations between admission troponins above the upper reference limit and mortality [13-15, 26, 27, 32, 37, 45, 46, 55, 67]. Elevated troponins on admission were associated with an increased risk of death (RR 2.68, 95% CI 2.08-3.46). There was substantial heterogeneity (I 2 = 76.2%); the 95% prediction interval was wide (1.12-5.94) but did not include 1 (Fig. 2). Possible publication bias was found by the funnel plot ( Figure  S5a) but not confirmed by the Egger's test (P = 0.203). We conducted a sensitivity analysis using the trim-and-fill method, which confirmed the stability of the association (RR 2.59, 95% CI 2.01-3.35) ( Figure S5b). When we excluded 5 studies judged as having high risk of bias from meta-analysis, elevated troponins on admission remained a significant risk   factor for subsequent death (RR 2.08, 95% CI 1.81-2.40), and the heterogeneity was eliminated (I 2 = 0%). The results of subgroup analyses were shown in Table S6.

Discussion
The findings of this systematic review and meta-analysis demonstrated that elevated troponins are relatively common in patients hospitalised for covid-19 and appear to be independently associated with death. Elevated troponins had a pooled prevalence of 20.8% in patients with covid-19 on hospital admission. The estimate appeared higher when the troponin concentrations during hospital stay was considered and in patients admitted to ICU. Our findings are consistent with those of previous studies showing that myocardial injury occurs frequently in patients with severe respiratory infections caused by other viruses or bacteria [72][73][74]. Common mechanisms of myocardial injury in these conditions may include oxygen supply-demand mismatch, systemic hyperinflammation, and microvascular dysfunction and thrombosis. Besides, recent pathological and imaging studies indicated that acute atherosclerotic plaque rupture, stress cardiomyopathy, direct cardiomyocytes damage by the SARS-CoV-2 virus and myocarditis may also be the causes of troponin elevation in some patients with covid-19 [75][76][77][78]. We observed significant heterogeneity in the prevalence of elevated troponins across individual studies, which is likely attributable to several factors. The demographics and burden of comorbidities of patient populations from different countries may be different. Besides, there are no universal criteria for hospital admission for covid-19 patients; the criteria may vary across different places and different phases of the disease spread. These resulted in considerable heterogeneity among study cohorts in baseline characteristics such as age, cardiovascular diseases and the severity of respiratory infection, which would produce widely varying frequencies of elevated troponins. Moreover, multiple troponin assays with different analytical sensitivities were used for assessing myocardial injury. Studies that used high-sensitivity assays may find higher prevalence of elevated troponins than those using less sensitive earlier-generation troponin assays. Despite the heterogeneity, our pooled estimate with a relatively narrow confidence interval represents a substantial minority of patients with elevated troponins on hospital admission, indicating an important involvement of the heart in severe forms of covid-19.
Similar to findings in patients with other severe respiratory illnesses, elevated troponins appeared to have prognostic implications for patients admitted for covid-19. Some recent systematic reviews and meta-analyses have reported on the associations between elevated troponins and adverse outcomes of covid-19 [5-8, 79, 80]. However, there are several limitations to these analyses, including not accounting for the time point of troponin measurements and the cut-off threshold for troponin elevation, the variability in outcome definitions, the lack of adjustment for confounders and the inclusion of overlapping cohorts in analysis. In this study, we addressed the predictive value of troponin by focusing on troponin measured on hospital admission and on the hard outcome of death. We found that admission troponin concentrations higher than the upper reference limit were associated with a more than twofold risk of death in multivariable analyses. The stability of this association was supported by various sensitivity and subgroup analyses. Thus, troponin testing may provide prognostic information independent of other routinely assessed demographic and clinical factors for covid-19 patients early on patient admission, so that it might help clinicians in triage decision-making. Our results suggested that measurement of troponin levels at the time of hospital admission for covid-19 might be included in the diagnostic workup to identify patients at increased risk of worse outcome and those who may require higher level of surveillance and more intensive treatment.
In addition, our bivariate analysis suggested that troponin may be especially helpful to identify patients at high mortality risk when it is elevated. However, the prognosis of patients with normal troponin levels was still worrisome (mortality of~9%). This is not surprising because injuries in other organ systems during the course of disease are also important factors of death [81]. Thus, the detection of a normal troponin level at hospital admission may not be considered as a sign of very low mortality risk or criteria for early discharge. The combination of troponin with other clinical information might achieve more accurate prognostication than either alone [45].
While higher mortality rates of patients with elevated troponins were consistently reported by the included studies, only two studies ascertained the mechanisms of death of patients [14,15]. Interestingly, there was no significant difference in causes of death between patients with or without elevated troponin who deceased. It might be hypothesised that elevated troponins reflect the severity of involvement of different organs and tissues in covid-19 patients and may predict higher mortality of both cardiovascular and non-cardiovascular causes.
We acknowledge several limitations to our metaanalysis. There is significant heterogeneity in the prevalence of elevated troponins on admission and the strength of their association with mortality, presumably reflecting differing patient background, troponin assays and therapeutic practices among study centres. In addition, many of the included studies did not measure troponin systematically for all patients on their admission, and the indications for troponin measurement were poorly reported. Selective troponin sampling may have resulted in a systematic overestimation of the prevalence of elevated troponins in these studies. However, our pooled analysis of 19 studies at low risk of bias (studies that measured troponin concentrations on admission in > 90% of patients) yielded similar prevalence estimate. On the other hand, patients that did not received troponin measurement tended to have milder illness, lower prevalence of myocardial injury and lower risks of subsequent death [49]. Thus, their exclusion might have biassed the observed strength of association between elevated troponins and death toward a smaller magnitude. Overall, while we cannot be certain about the accuracy of estimates for the prevalence of elevated troponins and the associated risk of death, we believe that important inferences can still be made. Across a heterogeneous group of patients hospitalised for covid-19, myocardial injury reflected by troponin concentrations above the upper reference limit was relatively common and did consistently correlate with excess risk of death.
In this study, despite that we evaluated the association between elevated troponins and death based on multivariable analyses, our result may still be subject to residual confounding. Baseline comorbidities such as cardiovascular and kidney diseases are both strongly associated with higher troponin concentrations and are independent risk factors for mortality of covid-19 [82,83], but they were not fully adjusted for in some of the included studies. However, dissecting the relative contributions of entwined conditions of pre-existing chronic myocardial injury, new-onset acute myocardial injury and reduced troponin clearance caused by renal impairment may be impossible, even if individual patient data from original studies were available. Thus, we could not address the question whether covid-19 infection-related myocardial injury directly influences the survival of patients. However, this limitation should not detract from the potential value of elevated troponins as a marker for early identification of covid-19 patients at high risk of death.
Other limitations of this study included the fact that we could not evaluate the utility of serial troponin testing during the first few days after admission in the identification of and risk assessment for patients with myocardial injury, because single troponin measurements on admission were reported in most studies. In addition, we were not able to evaluate the long-term impact of elevated troponins on admission or during hospital stay on the cardiovascular health of covid-19 survivors. Given the limitations of available evidence, the justification of measuring troponin as a prognostic tool for patients hospitalised for covid-19 warrants further investigation. Ongoing registries that systematically collect cardiovascular data in covid-19 patients, such as the CAPACITY-COVID [84], will hopefully contribute to a better understanding of the implications of troponin measurements in patients with covid-19.

Conclusion
The present meta-analysis suggests that among patients hospitalised for covid-19, admission troponin concentrations above the upper reference limit are common and are predictive for subsequent death. Clinically, the presence of elevated troponins on admission may facilitate risk stratification by enabling early identification of patients at high mortality risk. Large prospective studies with systematic troponin sampling and adequate followup are needed to validate the prognostic implications of elevated troponins for patients admitted for covid-19.
Additional file 1: Table S1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Table S2. Literature search strategy (PubMed as example). Table S3. Risk of bias assessment for studies on the prevalence of elevated troponin in patients hospitalised for covid-19. Table S4. Quality in Prognostic Studies (QUIPS) risk of bias assessment for studies on the association between elevated troponin and mortality. Table S5. Multivariable-adjusted association between elevated troponin and mortality in patients hospitalised for covid-19. Table  S6. Subgroup analyses on the prognostic value of elevated troponins on admission for predicting death. Table S7. Covid-19 severity of illness classification. Figure S1. Pooled prevalence of elevated troponins on hospital admission. Figure S2. Funnel plot for assessing publication bias in the prevalence of elevated troponins on hospital admission. Figure  S3. Pooled prevalence of elevated troponins during hospital stay. Figure  S4. Pooled prevalence of elevated troponins in patients admitted to intensive care unit. Figure S5. (a) Funnel plot for assessing publication bias in the association between elevated admission troponins and mortality risk. (b) Funnel plot after applying the trim-and-fill method.

Abbreviations
Covid-19: Coronavirus disease 2019; SARS-CoV2: Severe acute respiratory syndrome coronavirus-2; CHARMS: CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies; PRIS MA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; CI: Confidence interval; QUIPS: Quality in Prognosis Studies; RR: Risk ratio; PI: Prediction interval