key: cord-0942644-x20rc6hk
authors: Wibowo, Arief; Pranata, Raymond; Akbar, Mohammad Rizki; Purnomowati, Augustine; Martha, Januar Wibawa
title: The Prognostic Performance of Troponin in COVID-19: A Diagnostic Meta-analysis and Meta-regression
date: 2021-03-02
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.02.113
sha: 7c5881d31cb91d2abd06e2210659c9cd2ea2e30a
doc_id: 942644
cord_uid: x20rc6hk

Background Cardiac injury is frequently encountered in patients with COVID-19 and is associated with an increased risk of mortality. Elevated troponin may signify myocardial damage and predicts mortality. We aimed to assess the prognostic value of elevated troponin above the 99th percentile upper reference limit (URL) on mortality and factors affecting their relationship. Methods We performed a comprehensive literature search using PubMed (MEDLINE), Scopus, and Embase from inception of the search databases until 16th December 2020. The key exposure was elevated serum troponin, defined as troponin (of any type) elevation > 99th percentile URL. The outcome was mortality due to any causes. Results There were a total of 12,262 patients from 13 studies in this systematic review and meta-analysis. Mortality was present in 23% (20-26%) of the patients. Elevated troponin was present in 31% (23-38%) of the patients. Elevated troponin was associated with increased mortality (OR 4.75 [4.07, 5.53], p < 0.001; I2: 19.9%). Meta-regression shows that the association did not vary with age (p = 0.218), male gender (p = 0.707), hypertension (p = 0.182), diabetes (p = 0.906), and coronary artery disease (p = 0864). Elevated troponin was associated with sensitivity of 0.55 [0.44, 0.66], specificity of 0.80 [0.71, 0.86], PLR 2.7 of [2.2, 3.3], NLR of 0.56 [0.49, 0.65], DOR of 5 [4, 5], and AUC of 0.73 [0.69, 0.77]. Elevated troponin resulted in a 45% probability for mortality and non-elevated troponin resulted in a 14% probability for mortality. Conclusion Elevated troponin was associated with increased mortality with a 55% sensitivity and 80% specificity.

Coronavirus disease 2019 has affected more than 105 million people globally and causes death in at least 2.3 million people.(World Health Organization, 2021) Although most COVID-19 patients have mild symptoms or even asymptomatic, there a significant proportion of patients that will experience multiple complications resulting in death. Biomarkers are crucial in a decision making process in order to facilitate an efficient resource allocation. Cardiac injury is frequently encountered in patients with COVID-19 and is associated with an increased risk of mortality. (Nishiga et al., 2020; Shi et al., 2020) Elevated troponin may signify myocardial damage and predicts mortality. However, this biomarker's prognostic performance and whether their value is affected by various comorbidities that might be present in the patients are inconclusive. Herein, we aimed to assess the progno stic value of elevated troponin above the 99 th percentile upper reference limit (URL) on mortality and factors affecting their relationship.

This study is a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) compliant meta-analysis.

We included both prospective and retrospective observational studies containing primary data on 1) patients with confirmed COVID-19, 2) troponin with cut-off points of more than 99 th percentile URL, and 3) mortality rate based on the troponin cut-off points. We excluded preprints, abstract-only publication, letters without primary data, case reports, editorial, commentaries, and non-English language articles. J o u r n a l P r e -p r o o f

We performed a comprehensive literature search using PubMed (MEDLINE), Scopus, and Embase using the keywords "covid-19" OR "sars-cov-2" OR "2019-ncov" AND "troponin" AND "mortality" OR "death" OR "non-survivor" from inception of the search databases until 16 th December 2020. After the initial search was completed, we excluded the duplicates.

Then the title/abstracts of the articles were screened for eligibility by two independent authors. The full-texts of the potentially eligible studies were assessed based on the inclusion and exclusion criteria.

Two authors extracted data independently by using a form. Data of interest include the first author, year of publication, sample size, study design, type of troponin, the cut-off point for elevated troponin, age, sex, hypertension, diabetes, coronary artery disease, and mortality rate.

The key exposure in this study was elevated serum troponin, defined as troponin (of any type) elevation of more than 99th percentile URL. The outcome was mortality, defined as clinically validated death/non-survivor due to any causes.

The association between key exposure and outcome will be reported in odds ratio (OR) and its 95% confidence interval. To assess the prognostic value of the elevated troponin, we calculate the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative LR (NLR), diagnostic odds ratio (DOR), and area under curve (AUC).

To assess the risk of bias of the included studies, two independent authors use the Newcastle-Ottawa Scale (NOS) and discrepancies that aroused were resolved by discussion.

We used STATA 16 (Stata Corp) to perform meta-analysis. Meta-analysis of proportion was performed to pool the prevalence of elevated troponin and mortality. The OR and 95% CI of the main outcome was calculated using the DerSimonian & Laird random-effects model. A p-value below 0.05 was considered significant. Heterogeneity among the studies was assessed using the I-squared (I 2 ) and Cochran Q test; in which a value of below 50% or pvalue below 0.10, respectively, indicates statistically significant heterogeneity. Metaregression analysis was performed with age, gender, hypertension, diabetes, and coronary artery disease as moderator. To assess the risk of publication bias and small-study effects, we performed funnel-plot analysis, Egger's test, and Deek's asymmetry test. Trim-and-fill analysis was performed to "normalize" the asymmetrical funnel-plot. Pooled sensitivity, specificity, summary receiver operating characteristic (SROC) curve, Fagan's nomogram, and

Deek's asymmetry plot were generated.

There were a total of 12,262 patients from 13 studies in this systematic review and metaanalysis [ Figure 1 ]. (AL Abbasi et al., 2020; Arcari et al., 2020; Connor-Schuler et al., 2020; Du et al., 2020; Harmouch et al., 2021; Heron and Chiu, 2020; Li et al., 2020; Lombardi et al., 2020; Maeda et al., 2020; Majure et al., 2021; Metkus et al., 2020; Raad et al., 2020; Mortality was present in 23% (20-26%) of the patients. Elevated troponin was present in 31% (23-38%) of the patients. The baseline characteristics of the included studies was displayed in Table 1 . The risk of bias assessment using the NOS indicate s a lowmoderate risk of bias.

J o u r n a l P r e -p r o o f 8 Elevated troponin was associated with increased mortality (OR 4.75 [4.07, 5 .53], p<0.001; I 2 :

19.9%, p=0.242) [ Figure 2 ]. Meta-regression shows that the association did not vary with age (p=0.218), male gender (p=0.707), hypertension (p=0.182), diabetes (p=0.906), and coronary artery disease (p=0.864). Egger's test showed no indication of small-study effects (p=0.536). Funnel-plot was asymmetrical [ Figure 2B ]. Trim-and-fill analysis by imputation of two studies resulted in OR of 4.52 [3.82, 5.36] [ Figure 2C ]. Figure 4 ]. Fagan's nomogram indicates that an elevated troponin resulted in a 45% post-test probability for mortality and a non-elevated troponin resulted in a 14% post-test probability for mortality [ Figure 5 ]. Deek's funnel plot indicates symmetry with respect to the regression line and quantitative plot asymmetry te st was not significant (p=0.86) [ Figure 6 ]. Univariable meta-regression and subgroup analyses indicate that age, male (gender), hypertension, and diabetes did not significantly affect the pooled sensitivity and specificity [ Figure 7 ].

Elevated troponin was associated with an almost fivefold increase in mortality compared to patients without elevated troponin with a 55% sensitivity and 80% specificity.

Meta-regression indicates that the association between elevated troponin and mortality did not vary with age, male gender, hypertension, diabetes, and coronary artery disease;

indicating that even though some of the abovementioned factors are associated with J o u r n a l P r e -p r o o f mortality, myocardial damage/dysfunction (Cavender et al., 2017; Lombardi et al., 2020; Mcevoy et al., 2015; Pattanshetty et al., 2012; Segre et al., 2015; Whelton et al., 2017; Zethelius et al., 2006) , and mortality in COVID-19 patients Raymond Pranata et al., 2020c , 2020d ; these factors did not modify the troponinmortality relationship. However, other crucial variables such as chronic kidney disease and chronic obstructive pulmonary diseases cannot be assessed because most of the studies did not report them. (Raymond Pranata et al., 2020e, 2020f) Elevated troponin was associated with 80% specificity and is associated with a 45% chance of mortality in a 23% pre-test probability for mortality. However, it has a low sensitivity of 50%, thus elevated troponin is best used for ruling in the risk mortality rather than ruling out. Funnel-plot was slightly asymmetric, indicating possible cause of publication bias, we performed a trim-and-fill analysis which slightly reduces the effect estimate. Thus, it is improbable that the publication bias will alter the positive association. Furthermore, Egger's test and Deek's asymmetry test did not detect possible publication bias. The pooled effect estimate has a low heterogeneity, indicating consistency despite different type s of troponins and populations. The low heterogeneity is likely due to the inclusion of >99 th percentile cut-off point instead of a specific cut-off point, thus the result was less likely altered by the laboratory reference values and calibrations.

Cardiac injury is frequently encountered in COVID-19 patients. Although the mechanism is only vaguely understood, the S protein and Angiotensin-Converting Enzyme 2 (ACE2) interaction are likely to be essential. (Nishiga et al., 2020; Shi et al., 2020) In addition to cardiac injury, COVID-19 may also cause arrhythmia, myocardial ischemia, and thromboembolism. (Raymond Pranata et al., 2020b) Other cardiac biomarkers such as J o u r n a l P r e -p r o o f natriuretic peptide are often elevated in COVID-19 and signify poor prognosis. (Raymond Pranata et al., 2020a) Additionally, echocardiographic parameters such as global longitudinal strain, right ventricular strain, and tricuspid annular plane systolic excursion have been shown to be a valuable tool in patients with COVID-19. Wibowo et al., 2021) These parameters may signify cardiac injury and may also be a parameter of right ventricular performance, which may be affected by ongoing lung pathologies in COVID-19.

This meta-analysis indicates that elevated troponin above 99 th percentile increases mortality by fivefold with a 55% sensitivity and 80% specificity. It has PLR of 2.7, NLR of 0.56, and AUC of 0.73. While it is quite specific for increased mortality, it has a low sensitivity. To better enhance the performance, echocardiographic and laboratory parameters such as natriuretic peptides need to be integrated in the prognostic model. This may result in a greater sensitivity and specificity, which may potentially increase its clinical usefulness.

The limitation of this study is that most of the studies were retrospective in design.

Additionally, a significant portion of the studies did not report crucial variables such as chronic kidney disease, chronic obstructive pulmonary diseases, and heart failure; thus , these variables cannot be integrated into meta-regression. Nevertheless, the low heterogeneity means that despite variations in these comorbidities, the association between elevated troponin and mortality was consistent.

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