Cardiac troponin in hospitalized COVID-19 patients Incidence, predictors, and outcomes.pdf

Research Article Annals of Clinical Biochemistry 2023, Vol. 0(0) 1–10 © The Author(s) 2023 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/00045632231216599 journals.sagepub.com/home/acb Cardiac troponin in hospitalized COVID-19 patients: Incidence, predictors, and outcomes Praveen Gupta1 , Anunay Gupta1, Sandeep Bansal1 and Ira Balakrishnan2 Abstract Background: The incidence, predictors, and association of cardiac troponin with mortality in hospitalized COVID-19 were not adequately studied in the past and were also not reported from an Indian hospital. Methods: In this retrospective cohort study, the cardiac troponin of 240 hospitalized COVID-19 patients was measured. The incidence, predictors, and association of elevated cardiac troponin with in-hospital mortality were determined among hospitalized COVID-19 patients. Results: The cardiac troponin was elevated in 12.9% (31/240) of the patients. The troponin was elevated in the patients in the older age group (64 years vs. 55 years, p = .002), severe COVID-19 illness (SpO2 < 90%) (93.5% vs. 60.8%, p < .001), low arterial oxygen saturation (SpO2) (80% vs. 88%, p = .001), and low PaO2/FiO2 ratio (p < .0001). The patients with elevated cardiac troponin had elevated total leukocyte counts (TLC) (p = .001), liver enzyme (p = .025), serum creatinine (p = .011), N-terminalPro Brain natriuretic peptide (p < .0001), and d-dimer (p < .0001). The majority of the patients with elevated cardiac troponin were admitted to the intensive care unit (90.3% vs. 51.2%; p < .0001), were on a ventilator (61.3% vs. 21.5%; p < .0001), and had higher mortality (64.5% vs. 19.6%; p < .0001). The Kaplan–Meir survival analysis showed that the patients with elevated troponin had worse survival (p log-rank<.0001). Age, NT-ProBNP, d-dimer, and ventilator were the predictors of elevated troponin in multivariate logistic regression analysis. The Cox-regression analysis showed a signiﬁcant association between elevated cardiac troponin and in-hospital mortality (adjusted hazard ratio 2.13; 95% conﬁdence interval [CI] 1.145–3.97; p = .017). Two-thirds (65%) of patients with elevated cardiac troponin died during their hospital stay. Conclusions: COVID-19 patients with elevated cardiac troponin had severe COVID illness, were more commonly admitted to an intensive care unit, were on a ventilator, and had high in-hospital mortality. Keywords COVID-19, Troponin, N-terminal Pro-BNP, severe acute respiratory syndrome-coronavirus-2, electrocardiogram Accepted: 2nd November 2023 Introduction Various studies in the past demonstrated elevated troponin (cTn) or myocardial injury among COVID-19 patients. The incidence of elevated cTn in previous studies ranged from 19.7% to 62.3%.1–7 The presence of elevated cTn or myocardial injury was signiﬁcantly associated with inhospital mortality, ranging between 37% and 60% in these studies.1–7 Patients with elevated cTn were found to have low oxygen saturation, sepsis, electrolyte imbalance, 1 Department of Cardiology, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India 2 Department of Anesthesia and Critical Care, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India Corresponding author: Praveen Gupta, Department of Cardiology Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi 110029, India. Email: [email protected] 2 high blood sugar level, acute kidney and liver injury, hypoproteinemia, coagulation abnormality, multiorgan involvement, being admitted to an intensive care unit, being on a ventilator, and the worst in-hospital survival.1–8 However, the majority of studies suffered from selection bias and reported cardiac troponin in severely ill COVID-19 patients.1–8 Different studies from our region reported conﬂicting results regarding the association between elevated cardiac troponin and in-hospital mortality. A few studies reported an association and a few studies observed no association between elevated troponin and in-hospital mortality.9–12 The majority of the Indian studies about cardiac troponin were small in sample size, reported multiple biomarkers, had a selection bias, were not comprehensive, and did not report the ECG and echocardiography data of the study population.9–12 Although Vyas et al. reported increased mortality among COVID-19 patients with elevated cardiac troponin in a large study from India. However, there was no data available regarding the severity of COVID-19 illness, oxygen saturation, PaO2/FiO2 ratio of the study population (the risk factors for in-hospital mortality and elevated troponin), and the underlying reasons and details regarding the parameters included in the multivariate analysis. Additionally, Vyas et al. have included the maximum value of cardiac troponin in hospitalized COVID-19 patients, a confounding bias, as the physicians might have repeated the troponin in the severely ill patients and in the patients with initially elevated cardiac troponin in that study.9 Methods Study objectives The study was conducted to determine the incidence and association of elevated cardiac troponin with mortality in hospital-admitted COVID-19 patients. The study’s other objective was to determine the predictors of elevated cardiac troponin among hospital-admitted COVID-19 patients. Study design and setting It was a single-center, retrospective, non-blinded, investigator-initiated study conducted at a large public sector, tertiary care, and teaching hospital. The Institutional Ethics Committee’s approval was taken, and the study was conducted according to the 1975 Declaration of Helsinki. The written informed consent was waived off because of the retrospective nature of the study. Participants and follow-up This study population included real-time polymerase chain reaction (RT-PCR)-positive COVID-19 patients who were admitted to the hospital. The study included consecutively Annals of Clinical Biochemistry 0(0) admitted COVID-19 patients between the periods of January 2021 and April 2021. The exclusion criteria for the study were patients of age less than 12 years and patients for whom the cardiac troponin was not measured during the hospital stay. The hospital’s electronic medical record system was used for the collection of patient data regarding demographic details, blood investigations, chest X-rays, and in-hospital courses (the use of a ventilator, death, or discharge). The diagnosis of COVID-19 was conﬁrmed by using an RT-PCR test (Supplemental ﬁle). All the COVID19 patients admitted to the hospital were treated according to a standard AIIMS COVID-19 treatment protocol. Echocardiograms (Philips IE33) for the study population were done by echocardiographers doing more than 300 echocardiograms per month. The left ventricular ejection fraction (LVEF) was determined by using a visual estimation method. The electrocardiograms (ECGs) were done by using a BLT electrocardiography machine (Guangdong Biolight Meditech Co. Ltd., Zhuhai, China) and were reported by cardiologists who interpret more than 20,000 ECGs per year and were blinded to the study protocol. In this study, a mild-to-moderate COVID19 illness was deﬁned when a patient had systemic arterial oxygen saturation (SpO2) ≥90%, and a severe COVID-19 illness was deﬁned when a patient had SpO2 < 90% at admission. Analytical methodology. The cardiac troponin was deﬁned as elevated when the measured cardiac troponin was >99% of the Upper Range Limit (URL) (>0.1 µg/L at our institution). The cardiac troponin was measured as soon as possible after hospital admission among the study patients. Cardiac troponin I (cTnI) was measured using a cTnI fast test kit (AGAPPE, Ernakulam, Kerala, India). It was an immunoﬂuorescence-based assay that was a lateral ﬂow test. The reference range of the above mentioned test to measure cTnI was 0.1–50.0 µg/L, with a lower detection limit of ≤0.1 µg/L. The within-run precision of the test was 10%, and the between-run precision was 15%. The cardiac troponin I was measured quantitatively in the whole blood sample, plasma, or serum by the ﬂuorescence immunochromatography technique in this test. A 3 mL of a patient’s blood sample was collected in a heparinized test tube after taking precautions to avoid any hemolysis at the time of collection. The sample was tested immediately or stored at a 2–8° temperature for processing within 7 days. The frozen sample was brought to room temperature before testing. We applied the whole blood or serum sample to a test strip. This test strip contained a ﬂuorescence latex labeled anti-human cTnI monoclonal antibody and another test line coated with an anti-human cTnI monoclonal antibody. The cTnI present in the blood sample is bound to the ﬂuorescence latex-labeled anti-human cTnI monoclonal antibody after applying the blood to the test strip. This complex moved to the detection zone of the test card by Gupta et al. capillary action. Another antigen–antibody cTnI monoclonal antibody present on the test line detected this marked antigen– antibody complex. The ﬂuorescence intensity of the test line depends on the concentration of cTnI in the blood sample. We inserted the test card into the MISPA REVO immunoﬂuorescence quantitative analyzer. The analyzer measured the concentration of troponin I in the blood sample and displayed it on the analyzer screen. A printed value of cTnI was then downloaded from the analyzer. Statistics We used mean, median, standard deviation, and interquartile range (IQR) to depict quantitative variables and proportions for qualitative variables. A comparison between normally distributed quantitative data and qualitative data was performed using the T-test and the Chi-square/Fischer’s exact test, respectively. To determine the predictors for elevated cardiac troponin, multivariable logistic regression analysis was used. The multivariable Cox regression analysis was used to identify the association between elevated cardiac troponin and in-hospital mortality. Kaplan– Meier survival analysis was used to plot the survival curve. The receiver operating characteristic (ROC) curve was plotted to determine the area under curve (AUC) and the speciﬁcity of cardiac troponin. Data were entered into EpiData 3.1 and analyzed with SPSS V.21 and R software. Results A total of 305 consecutively admitted patients between the periods of January 2021 and April 2021 were analyzed for the study. However, troponin was measured in only 240 patients during their hospital stay and was included in the study. The median age of the study population was 56.5 (20–87) years, with 65.4% (157/240) being male. Thirteen percent (31/240) of the study population had elevated cTnI levels (>99% of the URL) (Table 1). The median age of the patients with elevated cTnI was 64 years, compared to 55 years in patients with normal cTnI (p = .002) (Figure 1, graphical abstract) (Table 1). The patients with elevated cTnI had severe COVID-19 illness (SpO2<90% at admission) (93.5% vs. 60.8%, p < .001), low systemic arterial oxygen saturation (SpO2) (80% vs. 88%; p = .001), and a signiﬁcantly low PaO2/FiO2 ratio (94 vs. 153; p < .0001). However, there was no difference between the patients with elevated cTnI and normal cTnI for obesity (35.3% vs. 38.2%; p = 1.00), diabetes mellitus (DM) (42% vs. 36.4%; p = .556), hypertension (HTN) (48.4% vs. 37.3%; p = .243), a history of coronary artery disease (CAD) (9.7% vs. 10.5%; p = 1.00), chronic kidney disease (CKD) (12.9% vs. 6.7%; p = .245), chronic obstructive disease (COPD) (3.2% vs. 3.3%; p = 1.00), and left ventricular dysfunction (LVEF < 40%) (3.2% vs. 2.4%; p = .568) (Table 1). 3 The total leukocyte count (TLC) (p = .001), liver enzyme (p = .025), and serum creatinine (p = .011) were considerably high in the patients with elevated cTnI. The levels of markers of inﬂammation (serum ferritin [p = .664] and interleukin-6 [IL-6] [p = .701]) were similar between the two groups. Although the d-dimer level was high in the patients with elevated cTnI (p < .0001). The level of N-terminal-Pro Brain natriuretic peptide (NT-ProBNP) was high in the patients with elevated cTnI (P < .0001) (Table 1). The patients with elevated cTnI had more atrial arrhythmias (22.5% vs. 6.2%; p = .023) and prolonged corrected QT interval (QTc) (433 msec vs. 419; p = .043) than patients with normal cTnI. The patients with elevated cTnI were more commonly admitted to the intensive care unit (ICU) (90.3% vs. 51.2%; p < .0001), were on a ventilator (61.3% vs. 21.5%; p < .0001), and had signiﬁcantly high in-hospital mortality (64.5% vs 19.6%; p < .0001). The length of hospital stay was signiﬁcantly shorter in patients with elevated cTnI than in patients with normal cTnI (7 days vs 12 days; p = .0009) (Table 1). The ECG in patients with elevated cTnI showed a signiﬁcantly higher incidence of sinus tachycardia (p < .0001), ST-segment elevation (p < .0001), and ST-segment depression (p = .0006) (Tables 1 and 2, Supplemental Figure 1). The echocardiography data showed regional wall motion abnormalities more commonly in the patients with elevated cTnI (p = .008). However, no signiﬁcant difference was observed between the two groups for LVEF<40% (p = .226), chamber dilatation, or valvular regurgitation (p > .05) (Table 1). To determine the predictors of elevated cTnI, the multivariate logistic regression analysis (by backward elimination) was done after including variables with p < .05 in the univariate analysis (age, TLC, deranged liver function test, serum creatinine (mg/dl), SpO2 at admission, PaO2/ FiO2 ratio, NT-ProBNP [ng/L], d-dimer [µg/L], atrial arrhythmias, ventilator, and admission to ICU). It showed a signiﬁcant association of age, NT-ProBNP, d-dimer, and ventilator with elevated cTnI (Table 3). We did the multivariate Cox regression analysis (by backward elimination) for the association between mortality and cTnI. In the multivariate Cox regression analysis model, we included age, total leukocyte count (mm3), deranged liver function test, serum creatinine (mg/dl), elevated NT-ProBNP, PaO2/FiO2 ratio, presence of arrhythmias, mechanical ventilation, and QTc (msec) (variable with p < .05 between the two groups). The multivariate analysis showed a signiﬁcant association between elevated cTnI and in-hospital mortality among hospital-admitted COVID-19 patients. The patients with elevated cTnI had two times higher in-hospital mortality than the patients with normal cTnI (adjusted hazard ratio 2.13; 95% conﬁdence interval [CI] 1.145–3.97; p = .017) (Table 3). The Kaplan–Meier survival analysis shows that the mortality in the patients with elevated cTnI was signiﬁcantly higher than 4 Annals of Clinical Biochemistry 0(0) Table 1. It showed the baseline characteristics, laboratory parameter, and in-hospital outcome of patients with normal and elevated cardiac troponin I.25 Variable Normal troponin (N: 209) Age (years) – IQR 55.0 (42–65) Sex (male) 66.0 (%138/209) Severe coronavirus at admission (SpO2<90%) 60.8% (127/209) Obesity 38.2% (39/102) Hypertension 37.3% (78/209) Diabetes mellitus 36.4% (76/209) Coronary artery disease 10.5% (22/209) Chronic kidney disease 6.7% (14/209) LVEF<40% 2.4% (5/209) Chronic obstructive pulmonary disease (COPD) 3.3% (7/209) Fever 67.9% (142/209) Dyspnoea 81.3% (170/209) Heart rate (/min) 96 (86–110) Systolic BP (mmHg) – IQR 124 (112–140) Diastolic BP (mmHg) – IQR 80 (70–87) SpO2 (%)– IQR 88 (80–93) Respiratory rate (/min) – IQR 22 (19–26) TLC (109/L) 9.350 (6.70–12.875) HbA1C – IQR 8 (7–10) Deranged LFT (>2 times of the URL) 30.6% (63/206) Serum creatinine (µmol/L) – IQR 61.9 (53.0–88.42`) Acute kidney injury 13.6% (28/206) PaO2/FiO2 – IQR 153 (100–273) Elevated NT-ProBNP 57.7% (120/208) NT-ProBNP (ng/L) – IQR 425 (103–1658) Troponin I (µg/L) 0.1 (0.1–0.1) Elevated D-dimer 97% (191/197) d-dimer (µg/L) – IQR 1570 (1203–2217) Elevated serum ferritin 53.6% (104/194) Serum ferritin-(µg/L) – IQR 384.6 (213–637) Elevated Interleukin-6 (IL-6) 99.5% (193/194) IL-6 (pg/ml) – IQR 190.8 (124–231) QTc interval (msec) – IQR 419 (392–438) ARDS 76.5% (137/179) Atrial arrhythmias 6.2% (13/209) Oxygen required 83.3% (174/209) Ventilator 21.5% (45/209) Non-invasive Ventilator 17.7% (37/209) Invasive Ventilator 11.0% (23/209) ICU admission 51.2% (107/209) Death 19.6% (41/209) Length of stay (days) – IQR 9 (5–12) Low-molecular weight heparin 86.1% (180/209) Remdesivir 52.9% (110/208) Steroid 85.6% (179/209) ECG parameters of COVID-19 patients with and without elevated cardiac troponin Sinus tachycardia 19.2% (40/208) T-wave inversion 7.3% (15/205) ST-segment depression 2.9% (6/205) ST-segment elevation 1.5% (3/205) Elevated troponin (N: 31) p-Value 64 61.3% 93.5% 35.3 48.4% 41.9% 9.7% 12.9% 3.2% 3.2% 77.4% 87.1% 100 128 80 80 25 12.150 9 51.6% 88.42 19.4% 94 96.8% 7583 0.77 100% 2217 64.3% 454.6 100% 193.7 433 93.1% 22.5% 96.8% 61.3% 35.5% 45.2% 90.3% 64.5% 5 93.5% 64.5% 96.8% (55–75) (19/31) (29/31) (6/17) (15/31) (13/31) (3/31) (4/31) (1/31) (1/31) (24/31) (27/31) (90–121) (110–140) (74–90) (70–88) (22–29) (10.025–20.775) (9–11) (16/31) (61.9–114.95) (6/31) (68–177) (30/31) (3031–20975) (0.19–4.57) (29/29) (1864–2617) (18/28) (213–643) (28/28) (115–221) (410–450) (27/29) (6/31) (30/31)`` (19/31) (11/31) (14/31) (28/31) (20/31) (3–9) (29/31) (20/31) (30/31) .002 .68 <.001 1.00 .243 .556 1.00 .264 .568 1.00 .404 .616 .151 .984 .420 .001 .003 .001 .268 .025 .011 .411 <.0001 <.0001 <.0001 <.0001 1.000 <.0001 .316 .664 1.000 .701 .043 .049 .023 .058 <.0001 .024 <.0001 <.0001 <.0001 .009 .389 .251 .145 (16/30) (3/29) (5/29) (6/29) <.0001 .474 .006 <.0001 53.3% 10.3% 17.2% 20.7% (continued) Gupta et al. 5 Table 1. (continued) Variable Normal troponin (N: 209) Elevated troponin (N: 31) Diffuse ST segment elevation 1.5% (3/205) 0% (0/29) S1Q2T3 0.5% (1/205) 3.6% (1/28) Echocardiography details of COVID-19 patients with and without elevated cardiac troponin Echocardiography done 12.9% (27/209) 48.4% (15/31) Left atrial enlargement 11.1% (3/27) 13.3% (2/15) Left ventricle enlargement 7.4% (2/27) 6.7% (1/15) Right atrial enlargement 0% (0/27) 13.3% (2/15) Right ventricle enlargement 0% (0/27) 13.3% (2/15) Regional wall motion abnormality 11.1% (3/27) 53.3% (8/15) Left anterior descending artery 3.7% (1/27) 33.3% (5/15) Right coronary artery 0% (0/27) 13.3% (2/15) Left circumﬂex artery 7.4% (2/2) 6.7% (1/15) LVEF<40% 11.1% (3/27) 33.3% (5/15) Tricuspid regurgitation 0% (0/27) 26.7% (4/15) Mitral regurgitation 11.1% (3/27) 13.3% (2/15) Diastolic dysfunction 22.2% (6/27) 13.3% (2/15) Pericardial effusion 3.7% (1/27) 0% (0/15) p-Value 1.000 .226 <.0001 1.0000 1.000 .122 .122 .008 .226 .012 1.000 .190 1.000 We used proportion (%) for dichotomous variables and the median with interquartile range (IQR) for continuous variables. For calculating the p-value, the Chi-square test for dichotomous variables and the Mann–Whitney U test for continuous variables, given non-parametric distribution, were used. Elevated troponin was deﬁned as troponin more than 0.1 µg/L. Elevated NT-ProBNP was deﬁned as NT-ProBNP level more than 300 ng/L. Elevated d-dimer was deﬁned as level more than 250 µg/L. Serum ferritin level more than 350 µg/L deﬁned the elevated levels. Deranged liver function test (LFT) was deﬁned as SGOP/SGPT> 2 times of the upper range of normal limit. Reference for SI unit [25]: Alldredge BK, Corelli RL, Ernst ME, et al. Koda-kimble and Young’s applied therapeutics: the clinical use of drugs. Wolters Kluwer/Lippincott Williams & Wilkins; 2013. Abbreviations: BP: Blood pressure; LVEF: Left ventricular ejection fraction; SpO2: Saturation at admission; ICU: Intensive care unit; IL-6 Interleukin-6; NTProBNP: N-terminal pro-brain-type natriuretic peptide; TLC: Total leukocyte count; ARDS: Acute respiratory distress syndrome; QTc: Corrected QT interval; URL: Upper Range Limit; HbA1C: Glycosylated haemoglobin; ECG: Electrocardiogram. the mortality in patients with normal cTnI (p log-rank < .0001) (Figure 2). We divided the patients with elevated cTnI and SpO2 < 90% (29/31) into four equal quartiles in ascending order of serum cTnI levels after excluding two COVID-19 patients with SpO2 > 90% (one patient with hypertrophic obstructive cardiomyopathy with atrial arrhythmia and another with inferior wall myocardial infarction). It showed the patients in the 4th quartile of serum cTnI had the highest mortality with no signiﬁcant difference (Figure 3; Panels A & B). The presence of elevated cTnI (>0.1 µg/L) had a speciﬁcity of 95% (95% CI: 91.23–97.48) and a sensitivity of 32.79% (95% CI: 21.31–46.00) for in-hospital mortality in our study. The ROC curve analysis showed that the cTnI (cutoff of 0.17 µg/L) has the highest speciﬁcity (96%) with very low sensitivity (28%) for predicting mortality among COVID-19 patients. The AUC for the elevated cTnI in the ROC curve was 63.3% (95% CI: 0.546–0.721; P = .002) (Supplemental Figure 2). Discussion In our study, (1) 13% (31/240) of the COVID-19 patients had elevated cTnI levels during their hospital stay; (2) the patients with elevated cTnI were more commonly admitted in the ICU, were on a ventilator, had more arrhythmias, and had a shorter hospital stay; (3) 2/3 (64.5%) of the patients with elevated cTnI died during their hospital stay; (4) patients with elevated cTnI had the worst survival compared to patients with normal cTnI; and (5) elevated cTnI troponin had a very high speciﬁcity for mortality among hospitaladmitted COVID-19 patients although with low sensitivity. In our study, elevated cTnI was observed in 13% of the study population. Contrary to this, previous research reported a signiﬁcantly high incidence of elevated troponin among hospital-admitted COVID-19 patients. For example, the incidence of elevated troponin was 34.5% in Vyas et al., 19.7% in Shi et al., 45.3% in Lombardi et al., 27.6% in Abass et al., and 62.3 in Weber et al. studies.1–4,9 In the majority of the previous studies, troponin was measured in severely ill COVID-19 patients, leading to selection bias.1–10 However, in our study, troponin was measured in COVID-19 patients irrespective of illness severity. A signiﬁcantly high number of mild/moderate COVID-19 illness patients (SpO2 ≥ 90%) (35% [84/240]) had troponin measurement in our study, which can explain the low incidence of elevated troponin in our study. The presence of advanced age with elevated cardiac troponin in our study was similar to that reported in the 6 Annals of Clinical Biochemistry 0(0) Figure 1. Box-plot (graphical abstract). The box plot is showing that the COVID-19 patients with an elevated cardiac troponin I (cTnI) had advanced age, high serum NT-ProBNP and cTnI levels, had low SpO2 and PaO2/FiO2 ratio, and a shorter hospital stay (p < .05). Table 2. Characteristics of patients with elevated cTnI and ST-segment elevation in the ECG. Severity of COVID STE at Age admission Patients (years) Sex illness STE (leads) Suspected ICU Ventilator diagnosis 1* 2 80 72 F M Severe Severe No Yes V1–V4 V1–V5 Yes Yes No No 3 38 M Mild Yes II,III,Avf No No IWMI 4 75 F Severe No V1–V5 AWMI Yes No Myocarditis AWMI CMRI Coronary angiography No No No Infarct in the LAD territory No RCA 90% stenosis, single stent deployed No No Died/ discharged Died Discharged Discharged Discharged STE: ST-segment elevation; ICU: Intensive care unit; M: Male; F: Female; CMRI: Cardiac magnetic resonance imaging; LAD: Left anterior descending artery; RCA: Right coronary artery; IWMI: Inferior wall myocardial infarction; AWMI: Anterior wall myocardial infarction. * The ECG of patient 1 is provided as supplemental Figure 1. past.1–4 Furthermore, the age of our study population and the patients with and without elevated cardiac troponin were similar to those reported from India.9,11,12 Contrary to this, we had a much younger population of patients with elevated cardiac troponin than studies from other regions of the world.1–8 The younger demographic proﬁle of the population; the presence of comorbidities like DM, HTN, CAD, CKD, and cerebrovascular accident (CVA) in a younger age group in our population that predisposes patients to COVID-19 pneumonia and its complications; and the selection bias in the previous studies regarding the measurement of cardiac troponin can explain the younger age of COVID-19 patients with elevated troponin in our study.13–20 In contrast to our study, previous studies observed HTN, DM, CAD, heart failure, and atrial ﬁbrillation as predominant comorbidities in COVID-19 patients with elevated troponin.1–9 The measurement of troponin, irrespective of the illness severity and comorbidities, in our study could be the reason for the above observation. Gupta et al. 7 Table 3. Multivariate regression analysis for the factors associated with in-hospital mortality and elevated cardiac troponin. Multivariate Cox-regression analysis for the factors associated with in-hospital mortality Variables Hazard ratio 95% conﬁdence interval p-Value Age (years) Total leukocyte count (mm3) Deranged LFT (>2 times of URL) Serum creatinine (mg/dl) PaO2/FiO2 Elevated NT-ProBNP Elevated troponin I QTc (msec) Atrial arrhythmias Ventilator (invasive & non-invasive) 1.015 1.00 1.781 1.143 0.996 0.702 2.134 1.013 2.597 3.566 0.993––1.038 1.000––1.000 0.961––3.302 1.034––1.263 0.992––1.001 0.302––1.629 1.145––3.977 1.005–1.020 1.105––6.104 1.799––7.072 .182 .098 .067 .009 .085 .410 .017 .001 .029 <.0001 Multivariate binary logistic regression analysis for the factors associated with elevated cTnI in COVID-19 patients Variables Odds ratio 95% Conﬁdence interval p-Value Age NT-ProBNP (pmol/L) Ventilator D-dimer (pg/ml) 1.049 1.000 6.427 1.001 1.007––1.093 1.000––1.000 2.037––20.28 1.000––1.0001 .022 <.0001 .002 .015 Abbreviation: NT-ProBNP: N-terminal pro-brain-type natriuretic peptide; QTc: Corrected QT interval; URL: Upper Range of normal limit. Deranged liver function test (LFT) was deﬁned as SGOP/SGPT> 2 times of the upper range of normal limit. Figure 2. Survival analysis. The Kaplan–Meir survival analysis showed the worst survival for the COVID-19 patients with an elevated cardiac troponin I (cTnI) compared to the patients with normal cTnI. 8 Annals of Clinical Biochemistry 0(0) Figure 3. Bar graph. The bar graph shows high mortality in patients with the 3rd quartile of cTnI among patients with elevated cardiac troponin (Panel A). However, after excluding two patients with SpO2 ≥ 90%, the bar graph shows the highest mortality in patients with the 4th quartile of cTnI (Panel B). The presence of severe COVID-19 illness, low SpO2 at admission, and evidence of multiorgan dysfunction like higher TLC, elevated liver enzyme, and higher serum creatinine in COVID-19 patients with elevated cTnI in our study indicates severe illness and a worse prognosis in these patients, as observed previously.1,2,5 The multiorgan involvement in patients with elevated troponin could be due to severe hypoxia, an inﬂammatory cytokine storm, direct inﬁltration of tissue by the virus, oxidative stress, disseminated intravascular coagulation, and angiotensinconverting enzyme II (ACE II) receptor-mediated liver, kidney, and gastrointestinal injury, and it suggests a high risk of mortality in these patients.21,22 The high incidence of admission to the ICU, use of a ventilator, in-hospital mortality, and shorter hospital stays in our study were consistent with the previously reported studies.1–9 In our study, the higher in-hospital mortality in patients with elevated cardiac troponin, leading to shorter hospital stay, indicates severe illness in these patients at admission, which in turn corroborates low systemic oxygen saturation and multiorgan dysfunction at admission in these patients. Previous studies have suggested inﬂammation, myocarditis, cytokine storm, type II myocardial injury, and global stress as the mechanisms for myocardial injury and, hence, troponin elevation.1–10 We have only one patient with a suspected diagnosis of myocarditis. Also, no signiﬁcant difference was observed for the LVEF between patients with and without elevated troponin in our study. It suggests that the direct viral-induced myocardial injury, or myocarditis, was not the reason for troponin elevation in our study. The independent association of NT-ProBNP, d-dimer, and ventilator with cTnI in our study suggests that myocardial stress, myocardial injury, systemic inﬂammation, microvascular thrombi, and severe hypoxia-induced myocardial injury in ventilator patients (type II myocardial injury) were the etiologies for cTnI elevation in our study. The independent association of elevated troponin with age in our study could be because of an age-associated increase in serum cardiac troponin as observed in the past. It suggests a need for a different cutoff of elevated troponin in COVID-19 patients with advanced age instead of using a similar cutoff of cardiac troponin for the entire cohort.23,24 Gupta et al. The independent association of elevated troponin with mortality and its occurrence in patients admitted to the ICU, on a ventilator, and with a shorter hospital stay in our study and various other studies also suggest that troponin elevation and hence myocardial injury indicates severe hypoxia and the terminal stage of the COVID-19 illness.1–10 cTnI was found to have high speciﬁcity for mortality among COVID-19 patients in our study. Hence, we think the assessment of cardiac troponin can help in the early triage and prognostication of COVID-19 patients. 9 Anita), Yash Kumar, Uday Kumar, Nikhil, and Himani Arora in conducting this study. Declaration of conﬂicting interests The author(s) declared no potential conﬂicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) received no ﬁnancial support for the research, authorship, and/or publication of this article. Study’s limitations Ethical approval The signiﬁcant limitation of our study was that although we measured cTnI as soon as possible after admission, but it was not possible in all the patients. Hence, the cTnI was measured at different points in time. Also, no serial assessment of cTnI was done in our study population during the hospital stay. The lack of detailed echocardiography data for the study population, cardiac MRI, and a coronary angiogram for the patients with elevated cardiac troponin were other major limitations of our study. However, as the study was conducted at a single center, all the blood investigations and troponin essays were done by a single standardized method in our study. Vardhman Mahvir Medical College & Safdarjung Hospital, New Delhi (India) (IEC/VMMC/SJH/Project/2020-12/CC-92). Conclusion In this study, elevated cTnI in hospitalized COVID-19 patients was observed in the severely ill patients who were admitted to the ICU, were on a ventilator and had high in-hospital mortality. The elevated cTnI in COVID-19 patients indicates severe hypoxia and the terminal stage of the illness. The cTnI was independently associated with mortality in COVID-19 patients. Guarantor PG. Contributorship Praveen Gupta: Study conceptualization, visualization, methodology, design, data collection, data interpretation, data analysis, writing original draft, and writing-review and editing; Anunay Gupta: Data collection, writing original draft, writing-review, and editing; Sandeep Bansal: Writing original draft, and writing-review and editing; Ira Balakrishnan: Data collection and data interpretation. ORCID iD Praveen Gupta  https://orcid.org/0000-0003-4954-0967 Supplemental material Supplemental material for this article is available online. References Acknowledgements We acknowledge the role of Kapil Gupta (Consultant and associate professor, Department of Anesthesia and Critical Care), Dr Nitin Tyagi (Senior Resident, Department of Biochemistry), Dr Sumita Saluja, Dr. Monica Sharma (Consultant, Department of Hematology), Siya Gupta, Dr Khushboo Srivastav (Department of Ophthalmology, Shubh Netram, Nirman Vihar, New Delhi, India), Ram Niwas, Sonali (lab technicians, Department of Hematology), all the consultants, junior residents, and senior residents from the Department of Anesthesia and Critical Care (Dr. Usha Ganpathy, Dr. Anjali, Dr. Shruti, Dr. Pramod, Dr. Amandeep, Dr. Aditi Narang, & Dr. Yasna), the Department of Medicine, the Department of Cardiology (Dr. Sourab Agstam, Dr. Preeti Gupta, Dr. HS Isser, Dr. Ansari, Dr. Dinkar Bhasin, Dr. Arvind, Dr. Gaurav Arora, Dr. Rahul, Dr. Tushar, & Dr. GauravKumar Divani), Dr. Navnita Kisku (Department of Cardiothoracic and Vascular Surgery), the Department of Community Medicine (Dr. Namita Srivastava & Dr. 1. 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