Dear Editor,
Critical illness and sepsis are often associated with a troponin rise.1 , 2 Therefore, troponin, in daily clinical practice, is frequently used as a marker of disease severity and as a predictor of future unfavourable outcomes.1 Recently, several studies including a recent paper in this Journal by Zheng and colleagues, investigated the prognostic role of biomarkers of myocardial injury (i.e. troponins) with mortality in hospitalized patients with coronavirus disease 2019 (COVID-19).3, 4, 5 Of note, those meta-analyses included studies that reported primarily unadjusted effect estimates of increased in-hospital mortality with higher troponin levels. Compared to patients with normal troponin levels, those with elevated troponins and consequently worse outcome were older and had higher rates of comorbidities including coronary artery disease, hypertension, chronic kidney disease, and diabetes.3, 4, 5 As a consequence, the final results of those studies showed a significant heterogeneity and markedly different risk estimates of mortality (risk ratios were 43.24, 3.85, and 7.95, and I2 were 34%, 90% and 65% for the studies of Zheng et al., Li et al., and Santoso et al. respectively).3, 4, 5 Therefore, the crucial question is whether cardiac injury is an independent prognostic marker in COVID-19 or it is simply related to the burden of concomitant cardiovascular disease .
Although we clearly know that troponin levels are higher in non-survivors of COVID-19, and that a significant percentage of hospitalised patients are presented with elevated cardiac troponins, the data on its independent prognostic role beyond accompanying cardiovascular comorbidities are still missing.6
Therefore, we (MV, AVP) systematically searched Medline and Scopus (using the search terms “troponin” AND “coronavirus 2019″ OR “2019-nCoV” OR “SARS-CoV-2″ OR “COVID-19″) to identify all observational cohort studies published between Jan 1, 2020 and Apr 30, 2020, that compared outcome (in-hospital mortality) in consecutive patients hospitalized with COVID-19 with and without troponin elevation. High-sensitivity cardiac troponin I was reported in the included studies and tests were performed within 48 h after the admission. Cardiac injury was defined if the serum troponin level was above the 99th percentile upper reference limit. A meta-analysis of studies that reported adjusted effect estimates was conducted using the generic inverse variance method, and heterogeneity between studies was investigated using the Cochrane‘s Q test and I2 statistic. Publication bias was assessed graphically using a funnel plot. Analyses were conducted using statistical software MedCalc Version 19.1.5.
Overall, 36 documents were initially identified based on our search criteria, and four studies were included in the final analysis7, 8, 9, 10 including a total of 982 patients (Table 1 ). Median age of the population was 67 years (range 58 to 71 years), 51% were males (range 49% to 69%), 36% had hypertension, and 20% had cardiovascular or cerebrovascular comorbidities. Three studies were retrospective7, 8, 9 and one was prospective in nature.10
Table 1.
Characteristics of studies included in meta-analysis.
| Author, year | Country | Patients (n) | Age (years) | Male (%) | HTN (%) | DM (%) | CVD (%) | Study design | Mortality (%) | Troponin positive (%) | Adjusted effect estimate (95% CI) | Confounders |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Wang L, 2020 | China | 339 | 71 | 49 | 41 | 16 | 22 | R | 19.2 | 20.6 | HR 1.55 (0.75–3.19) | Age, acute kidney injury, arrhythmia, ARDS, heart failure, bacterial infection |
| Shi S, 2020 | China | 416 | 64 | 49 | 31 | 14 | 16 | R | 13.7 | 19.7 | HR 3.41 (1.62–7.16) | Age, hypertension, diabetes, CVD, heart failure, chronic obstructive pulmonary disease, renal failure, cancer, ARDS |
| Zhang F, 2020 | China | 48 | 71 | 69 | 67 | 21 | 50 | R | 35.4 | 27.1 | HR 10.90 (1.28–92.93) | Age, creatinine, d-dimer, oxygen saturation |
| Du RH, 2020 | China | 179 | 58 | 54 | 32 | 18 | 16 | P | 11.7 | 23.0 | OR 4.08 (1.17–14.25) | Age, CVD, CD3+CD8+ T cells |
ARDS, acute respiratory distress syndrome; CI, confidence interval; CVD, cardiovascular or cerebrovascular disease; DM, diabetes mellitus; HR, hazard ratio; HTN, hypertension; OR, odds ratio; P, prospective; R, retrospective.
A total of 160 (16%) patients died during in-hospital stay. Elevated (positive) cardiac troponin was present in 21% of patients with COVID-19, and ranged between 20% and 27%. Meta-analysis of studies that reported adjusted hazard ratios (HR, fixed effects model), showed a significant association between elevated troponin values and mortality (HR = 2.48; 95% CI 1.50–4.11) (Fig. 1 A), without significant heterogeneity between studies (I2 = 52%, Cochran Q = 4.17, p = 0.12), and no publication bias was detected (Fig. 1B).
Fig. 1.
(A) Forest plot of hazard ratios (HRs) for high-sensitivity cardiac troponin to predict in-hospital mortality in patients with coronavirus disease 2019 (COVID-19).
(B) Funnel plot of HRs showing no publication bias.
The meta-analysis was conducted using the generic inverse variance method, and pooled HR was reported with 95% confidence interval (CI). There was no significant heterogeneity observed across studies.
The predictive value of troponin in COVID-19 could be the result of several potential mechanisms: (1) myocarditis caused by the virus, (2) cytokine mediated myocardial injury (cytokine storm), (3) coronary small-vessel disease (microangiopathy) due to pro-thrombotic state and endothelial dysfunction associated with COVID-19, and (4) associated (previously silent) coronary artery disease with subsequent type 2 myocardial infarction (i.e. supply-demand mismatch), which altogether may contribute to poor prognosis.3, 4, 5
In conclusion, troponin positivity is common in hospitalised COVID-19 patients, and may serve as an additional risk stratification tool in everyday clinical setting. These results are of prognostic importance, since patients with elevated troponins have higher risk of in-hospital mortality, are more prone to deterioration during hospital stay and so deserve more focused clinical attention.
Conflict of Interest
The authors declare no competing interests.
Footnotes
The authors declare no conflict of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
References
- 1.Lippi G., Cervellin G., Sanchis-Gomar F. Predicting mortality with cardiac troponins: recent insights from meta-analyses. Diagnosis (Berl) 2019 doi: 10.1515/dx-2019-0061. pii: /j/dx.ahead-of-print/dx-2019-0061/dx-2019-0061.xml. [DOI] [PubMed] [Google Scholar]
- 2.Vrsalovic M. Prognostic effect of cardiac troponin elevation in acute aortic dissection: a meta-analysis. Int J Cardiol. 2016;214:277–278. doi: 10.1016/j.ijcard.2016.03.230. [DOI] [PubMed] [Google Scholar]
- 3.Zheng Z., Peng F., Xu B., Zhao J., Liu H., Peng J., Li Q., Jiang C., Zhou Y., Liu S., Ye C., Zhang P., Xing Y., Guo H., Tang W. Risk factors of critical & mortal COVID-19 cases: a systematic literature review and meta-analysis. J Infect. 2020 doi: 10.1016/j.jinf.2020.04.021. pii: S0163-4453(20)30234-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Santoso A., Pranata R., Wibowo A., Al-Farabi M.J., Huang I., Antariksa B. Cardiac injury is associated with mortality and critically ill pneumonia in COVID-19: a meta-analysis. Am J Emerg Med. 2020 doi: 10.1016/j.ajem.2020.04.052. pii: S0735-6757(20)30280-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Li J.W., Han T.W., Woodward M., Anderson C.S., Zhou H., Chen Y.D., Neal B. The impact of 2019 novel coronavirus on heart injury: a systemic review and Meta-analysis. Prog Cardiovasc Dis. 2020 doi: 10.1016/j.pcad.2020.04.008. pii: S0033-0620(20)30080-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Lippi G., Lavie C.J., Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): evidence from a meta-analysis. Prog Cardiovasc Dis. 2020 doi: 10.1016/j.pcad.2020.03.001. pii: S0033-0620(20)30055-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Shi S., Qin M., Shen B., Cai Y., Liu T., Yang F., Gong W., Liu X., Liang J., Zhao Q., Huang H., Yang B., Huang C. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan. China. JAMA Cardiol. 2020 doi: 10.1001/jamacardio.2020.0950. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Wang L., He W., Yu X., Hu D., Bao M., Liu H., Zhou J., Jiang H. Coronavirus disease 2019 in elderly patients: characteristics and prognostic factors based on 4-week follow-up. J Infect. 2020 doi: 10.1016/j.jinf.2020.03.019. pii: S0163-4453(20)30146-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Zhang F., Yang D., Li J. Myocardial injury is associated with in - hospital mortality of confirmed or suspected COVID - 19 in Wuhan, China: a single center retrospective cohort study. MedRxiv. 2020;17 doi: 10.1101/2020.03.21.20040121. [DOI] [Google Scholar]
- 10.Du R.H., Liang L.R., Yang C.Q., Wang W., Cao T.Z., Li M., Guo G.Y., Du J., Zheng C.L., Zhu Q., Hu M., Li X.Y., Peng P., Shi H.Z. Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-COV-2: a prospective cohort study. Eur Respir J. 2020 doi: 10.1183/13993003.00524-2020. pii: 2000524. [DOI] [PMC free article] [PubMed] [Google Scholar]