key: cord-0834648-oetpdxov
authors: Metkus, Thomas S.; Sokoll, Lori J.; Barth, Andreas S.; Czarny, Matthew J.; Hays, Allison G.; Lowenstein, Charles J.; Michos, Erin D.; Nolley, Eric P.; Post, Wendy S.; Resar, Jon R.; Thiemann, David R.; Trost, Jeffrey C.; Hasan, Rani K.
title: Myocardial Injury in Severe COVID-19 Compared With Non–COVID-19 Acute Respiratory Distress Syndrome
date: 2020-11-13
journal: Circulation
DOI: 10.1161/circulationaha.120.050543
sha: b868628d1790882b06b9e6fb36e8fd2afdd49f2f
doc_id: 834648
cord_uid: oetpdxov

BACKGROUND: Knowledge gaps remain in the epidemiology and clinical implications of myocardial injury in coronavirus disease 2019 (COVID-19). We aimed to determine the prevalence and outcomes of myocardial injury in severe COVID-19 compared with acute respiratory distress syndrome (ARDS) unrelated to COVID-19. METHODS: We included intubated patients with COVID-19 from 5 hospitals between March 15 and June 11, 2020, with troponin levels assessed. We compared them with patients from a cohort study of myocardial injury in ARDS and performed survival analysis with primary outcome of in-hospital death associated with myocardial injury. In addition, we performed linear regression to identify clinical factors associated with myocardial injury in COVID-19. RESULTS: Of 243 intubated patients with COVID-19, 51% had troponin levels above the upper limit of normal. Chronic kidney disease, lactate, ferritin, and fibrinogen were associated with myocardial injury. Mortality was 22.7% among patients with COVID-19 with troponin under the upper limit of normal and 61.5% for those with troponin levels >10 times the upper limit of normal (P<0.001). The association of myocardial injury with mortality was not statistically significant after adjusting for age, sex, and multisystem organ dysfunction. Compared with patients with ARDS without COVID-19, patients with COVID-19 were older and had higher creatinine levels and less favorable vital signs. After adjustment, COVID-19–related ARDS was associated with lower odds of myocardial injury compared with non–COVID-19–related ARDS (odds ratio, 0.55 [95% CI, 0.36–0.84]; P=0.005). CONCLUSIONS: Myocardial injury in severe COVID-19 is a function of baseline comorbidities, advanced age, and multisystem organ dysfunction, similar to traditional ARDS. The adverse prognosis of myocardial injury in COVID-19 relates largely to multisystem organ involvement and critical illness.

M yocardial injury manifested by elevations in cardiac troponin is common in patients with coronavirus disease 2019 (COVID-19). [1] [2] [3] Myocardial injury has also been proposed as a prognostic factor. 4, 5 The pathogenesis of myocardial injury in COVID-19 is not established but is likely multifactorial, involving patient-, disease-, and treatment-specific factors. 6 Important knowledge gaps remain in understanding the epidemiology and clinical implications of myocardial injury in COVID- 19. First, although crude mortality rates are higher in patients with COVID-19 with myocardial injury compared with those without, variable covariate adjustment has been performed in studies to date. 2, 4, [7] [8] [9] [10] [11] [12] The dictum that a single marker of myocardial injury is independently prognostic in severe COVID-19 should be investigated with comparative studies. Second, the determinants of myocardial injury in COVID-19 are not well-established. A conceptual model of COVID-19 myocardial injury includes systemic inflammation, hypoxemia, vasopressor requirement, and thrombophilia, which remain to be clarified. 6 Third, it is not clear whether the incidence of myocardial injury in hospitalized patients with CO-VID-19 is truly higher than that observed in traditional acute respiratory distress syndrome (ARDS). ARDS is one of the most common causes of hypoxemic respiratory failure 13 and manifests as acute hypoxemia within a week of a known pulmonary insult with bilateral pulmonary infiltrates not referable to alternate causes such as atelectasis or left heart failure. 14 Up to 38% of patients with ARDS have been shown to have troponin levels above the 99th percentile cut point. 15 Understanding whether the prevalence and pattern of myocardial injury in COVID-19 differ from ARDS unrelated to COVID-19 is important in defining the CO-VID-19 clinical phenotype, particularly given the ongoing debate as to whether COVID-19-related respiratory failure represents typical ARDS or not. 16 We performed a retrospective cohort study of clinical factors and outcomes associated with myocardial injury in hospitalized patients critically ill with COVID-19 and a comparative study of myocardial injury within a COVID-19 cohort to myocardial injury within a cohort of patients with ARDS unrelated to COVID-19. We hypothesized that myocardial injury would be present in a significant number of patients with COVID-19 and that after adjusting for degree of critical illness, the association of myocardial injury with mortality in CO-VID-19 would be mitigated. We also hypothesized that the prevalence and prognostic value of troponin in CO-VID-19 would be similar to that of general ARDS after covariate adjustment.

Data for patients with COVID-19 who required intubation were obtained from JH-CROWN (the Johns Hopkins Health System COVID-19 Precision Medicine Analytic Platform Registry). This registry aggregates electronic health data for all patients with COVID-19 across the 5 hospitals in the Johns Hopkins Healthcare System. We included all patients with confirmed COVID-19 who were intubated within our health system between March 15 and June 11, 2020, and who had troponin levels assessed within 24 hours of intubation. We focused our analysis only on intubated patients because of a priori scientific interest, because of high patient risk, and to facilitate a comparison of myocardial injury and outcomes with a previous cohort of intubated patients with ARDS.

For comparison with patients with ARDS without COVID-19, we used a subset of patients from a previous cohort study to assess myocardial injury in ARDS 15, 17 (MI-ARDS [Myocardial Injury in Acute Respiratory Distress Syndrome Study]). This cohort consists of patients with ARDS who were enrolled in clinical trials by the ARDS Network. The initial MI-ARDS consisted of patients with ARDS attributable to diverse causes including sepsis, trauma, transfusions, and pneumonia. To enable a comparison of diseases with similar pathophysiology, we chose to use only patients with ARDS who had ARDS attributable to pneumonia. We previously measured troponin using plasma taken within 24 hours of intubation in all patients. 15, 17 Clinical and demographic data and outcomes were collected as part of trial protocols. 18, 19 For this comparison, we used 506 patients with ARDS attributable to primary pneumonia. We chose to use primary pneumonia ARDS as the comparison group because of the inherent heterogeneity of the ARDS syndrome 16, 20 and because patients with COVID-19 manifest primary hypoxemic respiratory failure as an indication for intubation. 21 The inclusion criteria and ARDS definition for patients in the MI-ARDS study included a ratio of partial pressure of oxygen (Pao 2 ) to fraction of inspired

What Is New?

• Half of intubated patients with coronavirus disease 2019 (COVID-19) manifest myocardial injury, but mortality risk associated with myocardial injury is attenuated after adjustment for degree of critical illness. • Myocardial injury is less common in COVID-19 compared with conventional acute respiratory distress syndrome after adjusting for confounders of age, renal dysfunction, and degree of critical illness.

What Are the Clinical Implications?

• Myocardial injury in COVID-19 is reflective of baseline risk and comorbidities and underlying multisystem organ dysfunction. • Most myocardial injury in COVID-19 is related to critical illness, but given isolated reports of frank myocarditis and other severe direct cardiac manifestations, it is important to identify these rare and distinct manifestations. 

All included patients in both cohorts had troponin levels assessed within 24 hours before or after intubation to ensure uniform temporality of the exposure variable. The 5 hospitals contributing data to the JH-CROWN registry use either clinical troponin T or troponin I assays. For patients with multiple troponin measurements within the 24 hours surrounding intubation, we used the highest value. To enable pooling of the cohort for analysis, we classified troponin as a categorical variable. Troponin was classified as less than upper limit of normal (ULN) for each assay, between 1 and 5 times ULN, between 5 and 10 times ULN, and >10 times ULN. The ULN for each assay is displayed in Table I in the Data Supplement. The distribution of patients within each clinical category was similar among the patients with troponin T and troponin I and similar when troponin was considered in quartiles. This categorization is analogous to the predetermined classification scheme in MI-ARDS. For troponin measurements in the ARDS population, a highly sensitive troponin I assay was used (Abbott ARCHITECT), which allows for detection of circulating troponin to a limit of detection of 2 ng/dL; the assays used in the patients with COVID-19 were clinical assays that were not highly sensitive ( Table I in the Data Supplement). To enable comparison with the clinical troponin assays used in the patients with COVID-19, we categorized troponin I as <26 ng/L (corresponding to 99th percentile of a healthy reference population), between 26 and 130 ng/L, between 130 and 260 ng/L, and >260 ng/L. We also considered troponin as a binary variable in both cohorts as positive versus negative, with negative being below ULN for the patients with COVID-19 and <26 ng/L for the ARDS cohort. Troponin I and troponin T were considered as log-transformed continuous variables in separate linear regression models in the COVID-19 group to determine clinical characteristics associated with myocardial injury. For patients with troponin below ULN, we set values to halfway between 0 and ULN.

The primary outcome for both groups was in-hospital mortality. Follow-up was complete for all patients. Covariates of interest included demographic and clinical information, laboratory values, inflammatory biomarkers, and ventilator parameters. The registry includes Elixhauser comorbidities 22 generated using International Classification of Diseases-10 codes to identify previous medical history and chronic medical problems. Laboratory data were set to the worst value within the 24 hours before or after intubation. Ventilator data were set to the worst value within 24 hours after intubation. A secondary outcome of ventilator-free days was calculated as the number of days free of mechanical ventilation within the first 28 days after intubation, by convention. 15 

Because data in the JH-CROWN registry were drawn from the electronic medical record, data were not complete for all covariates, as shown in Table II in the Data Supplement. Data were complete for the exposure of troponin assessment, the outcome of in-hospital death, demographics, and comorbidities. To address missing data, we performed multiple imputation to obtain unbiased estimates of the association between myocardial injury and outcome. Multiple imputation was performed using chained equations and 50 imputations. 23 The variables that were complete were used as auxiliary variables. We used the "mi estimate" command in Stata, which combines the multiply imputed data sets using the Rubin formula. 24 The results with and without multiple imputation were similar; therefore, we report the results using multiple imputed datasets. Interleukin-6 and fibrinogen had high levels of missingness and so were not imputed. Analyses incorporating those biomarkers were by complete-case analysis only. For descriptive analysis, comparisons were made using linear regression for continuous variables and logistic regression for categorical variables across the independent variable of interest (category of troponin, death, and COVID-19 status).

We categorized the exposure variable of troponin into clinical categories as described: below ULN, <5 times ULN, between 5 and 10 times ULN, and >10 times ULN. We also classified troponin as a dichotomous variable: positive or negative. In the COVID-19 population, we performed Cox proportional hazard models and Kaplan-Meier survival analysis to determine the association of myocardial injury with in-hospital mortality. We performed univariable analyses followed by progressive adjustment for age and sex and then age, sex, and multiorgan dysfunction (represented by creatinine, bilirubin, Pao 2 /FIo 2 ratio, vasopressor use, and lactate levels). We chose these covariates on the basis of factors used to calculate the Sequential Organ Failure score. 25 The Sequential Organ Failure score itself was not used because not all components were directly captured in the JH-CROWN database. The proportional hazard assumption was assessed by inspection of Schoenfeld residuals and time dependence of covariates. The assumption of proportionality was met. We also compared the association of myocardial injury with death in patients with COVID-19 and patients with ARDS without COVID-19. We assessed the interaction of COVID-19 status and myocardial injury with death with Cox proportional hazard models.

To identify determinants of troponin T and troponin I in COVID-19, we performed linear regression with log-transformed troponin levels as the dependent variable and clinical and demographic factors as the independent variable in univariable models. Factors with P<0.1 in univariable models were then assessed in adjusted models. The adjusted models included the factor of interest and covariates known 

to be associated with myocardial injury: age, sex, and creatinine level.

To determine the degree of association of COVID-19 with myocardial injury as compared with traditional ARDS, we performed logistic regression with positive troponin as the dependent variable (corresponding to 26 ng/L for patients with ARDS without COVID-19 and troponin above the ULN for this COVID-19 cohort) and COVID-19 status compared with ARDS as the independent variable in univariable and multivariable models adjusting for age, sex, and multiorgan dysfunction. Analyses were performed using STATA 15. P value <0.05 was considered statistically significant.

Of 328 intubated patients in our health system with COVID-19, 243 had troponin assessed within 24 hours of intubation and were included in the study. There were no major differences in age, sex, ethnicity, comorbidities, or death rates among patients who did versus did not have troponin checked (Table III in 

Overall mortality rate was 36.2%. Mortality was 22.7% among intubated patients with COVID-19 with troponin under the ULN and was greater with higher troponin levels, up to 61.5% among those with the highest troponin levels (P<0.001; Figure 1 ). The distribution of myocardial injury was also different comparing survivors with nonsurvivors: among survivors, 59% had troponin below the ULN and <10% troponin >10 times the ULN; among nonsurvivors, 31% had troponin below the ULN and 27% troponin >10 times ULN (P<0.001; Figure 1 ). Troponin I and Troponin T were also higher in nonsurvivors when considered as continuous variables (Table 2) .

Other factors associated with mortality in descriptive analyses included older age, chronic kidney disease and higher creatinine, lactate levels, lower fibrinogen, and higher ferritin levels ( Figures 2 and 3 . The association of myocardial injury with mortality attenuated with progressive covariate adjustment and was no longer statistically significant after adjusting for age, sex, creatinine, bilirubin, Pao 2 /FIo 2 ratio, vasopressor use, and lactate levels ( Figure 3 ). 

Myocardial injury detected with cardiac biomarkers has garnered attention as a high-risk marker in In this study of myocardial injury in COVID-19 compared with traditional ARDS, we report several findings. First, half of intubated patients with COVID-19 manifest myocardial injury assessed by clinical troponin assays, which is associated with a graded increase in overall mortality. However, the magnitude of mortality risk is attenuated after adjustment for degree of critical illness, suggesting that myocardial injury is reflective of baseline risk and comorbidities and underlying multisystem organ dysfunction. Age, comorbidities, ferritin, and fibrinogen are associated with myocardial injury in COVID-19. Myocardial injury is actually less common in COVID-19 compared with conventional ARDS after adjusting for confounders of age, renal dysfunction, and degree of critical illness. Our findings place myocardial injury in COVID-19 in context of that observed in general ARDS, add to the evidence base for the usefulness 

Of intubated patients with COVID-19, we report approximately half with myocardial injury, which is consistent 

with other reports of up to 44% rates of myocardial injury. 2, 3, 8 Our study included only the most severely affected patients with COVID-19, who were intubated, explaining the high percentage of myocardial injury observed. High rates of myocardial injury are also observed in non-CO-VID-19-related critical illnesses including ARDS 15,17 and sepsis, 26 and we demonstrate that the unadjusted profile of myocardial injury is similar between patients with CO-VID-19 and a group of patients with ARDS secondary to pneumonia. However, the clinical profile of patients with COVID-19 compared with patients with conventional ARDS was higher risk, including more advanced age, more renal failure, and more severe lung disease. Given worse critical illness, more myocardial injury would be expected. After adjusting for severity of disease, therefore, the odds of myocardial injury in COVID-19 were lower than in conventional ARDS. The COVID-19 pandemic has resulted in a large number of critically ill patients presenting for care simultaneously, and it is debated which features of COVID-19 are unique to the virus versus facets of general critical illness. 16, 27 Our results suggest that myocardial injury in severe COVID-19 is not substantially different in magnitude from that in general ARDS and in fact may be of lesser magnitude adjusting for age and comorbidities, acknowledging that we are performing comparisons across disparate assays.

There are many potential mechanisms of elevated troponin in COVID-19, including thrombotic and plaque rupture ORIGINAL RESEARCH ARTICLE events, supply-demand mismatch, and direct cardiac viral toxicity. 28, 29 We found that older age, acute and chronic renal dysfunction, and serum lactate levels were strongly associated with myocardial injury, consistent with studies in patients without COVID-19. 15 The inflammatory and prothrombotic milieu of COVID-19 is hypothesized to also contribute to myocardial injury. 30, 31 Higher ferritin and lower fibrinogen were associated with troponin levels in our study. Higher ferritin levels may simply reflect more active systemic inflammation, although ferritin levels have also been associated with myocardial infarction in case-control studies. 32 Ferritin has also been proposed to participate in the myocyte response to ischemia. 33 The lower fibrinogen may reflect consumption, microvascular thrombosis, and endothelial dysfunction contributing to myocardial injury. 34, 35 Therefore, our work reinforces inflammation as a factor associated with myocardial injury and suggests that pathways involving coagulation and iron metabolism may be fruitful mechanistic areas of inquiry.

A growing evidence base supports that myocardial injury is associated with poor prognosis in COVID-19, 8, 29 and our findings support prior findings; in our critically ill patient population, myocardial injury was associated with >2-fold hazard for death. Yet the association of myocardial injury with mortality attenuated greatly after adjustment for age, sex, and multisystem organ dysfunction. We observed a similar pattern in the general ARDS population. 15 These findings suggest that the association of myocardial injury with outcome in COV-ID-19 is a function of underlying critical illness and multisystem organ dysfunction, particularly concomitant renal dysfunction. The implication naturally follows that principles of critical care to optimize organ dysfunction would mitigate some of this risk and improve outcomes in patients with COVID-19 with myocardial injury. This premise is further supported by the fact that autopsy studies have not shown widespread direct myocarditis from COVID-19. 36 MRI reports suggest abnormal myocardial signal in many patients with COVID-19, 37-40 but patients with myocardial injury attributable to sepsis also manifest significant and common abnormalities on cardiac MRI. 41 In our study, patients with COVID-19 with myocardial injury had worse prognosis than patients with pneumonia ARDS with myocardial injury; whether this incremental adverse prognosis is related to baseline comorbidities or to differing pathogenesis 

of myocardial injury such as thrombotic complications 36 needs to be clarified. The fact that the interaction of myocardial injury with COVID-19 status lessened after covariate adjustment supports the fact that much of the difference relates to degree of critical illness.

It is debated whether COVID-19-related lung disease represents a form of traditional ARDS or has a distinct pathophysiology, with advocates of both viewpoints. 42, 43 We report crude rates of myocardial injury as similar to traditional ARDS, although after adjusting for clinical differences, the severely affected COVID-19 population had lower odds of myocardial injury. This could represent survivor bias, with individuals most severely affected experiencing cardiac arrest [44] [45] [46] and death before surviving to assessment. Similar factors are associated with myocardial injury in both COVID-19 and traditional ARDS, 15 including age, creatinine, and multisystem organ failure. This paradigm is supported by autopsy series suggesting virus involvement of pulmonary tissue with diffuse alveolar damage but rare microthrombi and endotheliitis; lymphocytic myocarditis was seen rarely but most patients had no evidence of direct cardiac involvement. 36, 47 Whether the hypercoagulable state and increased system inflammation observed in COVID-19 are unique features causing myocardial injury should be further investigated. Considering myocardial injury broadly, most cases seem related to critical illness, but there are isolated reports of frank myocarditis and other severe direct cardiac manifestations, 1, 48 and it is important to identify these rare and distinct manifestations.

Limitations of our study include its observational nature; thus, hypotheses can be inferred but causal inference is not established. Our data are drawn from a single academic health system in a single state; in the context of a very heterogenous pandemic, reports from other health care systems are needed and anticipated. We chose a priori to focus only on intubated patients because of scientific interest and to enable our direct comparison to ARDS. Because our dataset is drawn from clinical care, there are missing data requiring imputation techniques, but results are similar in considering imputed and nonimputed data. In considering the comparison between ARDS and COVID-19, the MI-ARDS study was a cross-sectional study with troponin checked in all patients; in COVID-19, the decision to check troponin was made clinically. Thus, patients without troponin assessed were not included in the COVID-19 group, which could introduce bias. However, baseline characteristics and outcomes of patients with COVID-19 who did and did not have troponin checked were similar. An additional limitation relates to the fact that different assays were used within the hospitals admitting patients with COVID-19 and in the ARDS cohort, which provides challenges for direct comparisons. Outcomes of COVID-19 are variable across centers, which could reflect local epidemiology of the pandemic, patient risk profile, and local resources, among other factors. Echocardiography and other detailed cardiac imaging is not available in our data set, and formal cardiac imaging is often deferred in COVID-19 in lieu of informal pointof-care ultrasound. Thus, an assessment of ventricular function and wall motion abnormalities in patients with COVID-19 is not available in this study. This is an important area for future research. 

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Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19)

Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China

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Comparison of two fluid-management strategies in acute lung injury

ARDS subphenotypes: understanding a heterogeneous syndrome

Respiratory pathophysiology of mechanically ventilated patients with COVID-19: a cohort study

Comorbidity measures for use with administrative data

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Link between coagulation abnormalities and microcirculatory dysfunction in critically ill patients

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COVID-19: myocardial injury in survivors

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Nonischemic myocardial changes detected by cardiac magnetic resonance in critical care patients with sepsis

CO-VID-19 does not lead to a "typical" acute respiratory distress syndrome

Respiratory mechanics of COVID-19-versus non-COVID-19-associated acute respiratory distress syndrome

Characteristics associated with out-of-hospital cardiac arrests and resuscitations during the novel coronavirus disease 2019 pandemic in

Out-of-hospital cardiac arrest and acute coronary syndrome hospitalizations during the COVID-19 surge

Out-ofhospital cardiac arrest during the COVID-19 pandemic in the province of Padua

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Case 24-2020: a 44-year-old woman with chest pain, dyspnea, and shock

The data used for this publication were part of JH-CROWN (the Johns Hopkins Health System COVID-19 Precision Medicine Analytic Platform Registry), which is based on the contribution of many patients and clinicians.

Data Supplement Tables I-V