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The recent report of 2 critically ill emergency physicians infected by the novel coronavirus disease 2019 (COVID-19) is a sobering reminder of the vulnerability of the nation’s health care workforce.1 While all members of the health care workforce are vital as the health care system faces perhaps its greatest challenge in memory, physicians and nurses are the caregivers who typically have the most direct contact with patients, whether through advising, triaging, or treating those who require hospitalization.
Across the nation, people, and particularly those older than 60 years, are being asked to stay at home and practice social distancing to slow the spread of infection and help avoid overwhelming hospitals that are expected to encounter shortages of needed equipment and personnel. Recent estimates from the Centers for Disease Control and Prevention indicate that the rates of hospitalizations, intensive care unit admissions, and mortality among reported COVID-19 cases in the United States are substantially higher among patients older than 45 years compared with younger patients, with case-fatality rates exceeding 1.4% among patients aged 55 to 64 years and exceeding 2.7% among those aged 65 to 74 years.2
There are large numbers of older nurses and physicians, who, if they were not in the health care workforce, would be staying at home to minimize their risk of exposure. Instead, many older clinicians are reporting for work every day. These clinicians have decades of experience, knowledge, and decision-making skills that are crucially important to guide the wise use of scarce resources when treating patients, protecting coworkers, and ensuring the capabilities of health care delivery organizations. In this Viewpoint, to better understand the prevalence of older clinicians in the workforce, we briefly summarize the age distribution of physicians and nurses by employment setting and for the largest metropolitan areas in the United States, including areas particularly affected by COVID-19, including Seattle, Washington, and New York City.
A substantial portion of hospital-based registered nurses, non–hospital-based registered nurses, and physicians are 55 years of age or older (Figure). Among the nation’s nearly 2 million registered nurses employed in hospitals, an estimated 370 000 (19%) are aged 55 to 64 years, and an estimated 55 000 (3%) are aged 65 years or older and thus, at even greater risk of complications and mortality from COVID-19. Of the approximately 1.2 million registered nurses employed outside of hospital settings, who could be called in to assist as hospital needs increase, even higher percentages are aged 55 to 64 years (24%) or aged 65 years or older (5%). The physician workforce is older still; of the approximately 1.2 million physicians in the United States, an estimated 230 000 (20%) are aged 55 to 64 years and an estimated 106 000 (9%) are aged 65 years or older.
Authors’ analysis of data is sourced from the US Census Bureau American Community Survey 2014-2018, which reports pooled data representing a combined 5-in-100 national random sample of the US population (1% of the US population in each year).3 The sample includes all individuals who reported working with an occupation of physician or surgeon (N = 48 538) or registered nurse (including nurse anesthetists and nurse practitioners [N = 168 801]). All estimates were weighted by sampling weights provided by the American Community Survey and represent full-time equivalent clinicians.
As the effects of COVID-19 are currently strongly regional, it is also important to consider how the ages of the nursing and physician workforces vary across the United States. There are considerable differences, and some of the areas with the most registered nurses and physicians aged 55 and older are among the most severely affected by the virus. The 25 largest US metropolitan areas, ranked by the percentage of the registered nurses and physicians in the workforce aged 55 years and older, is shown in the eTable in the Supplement.
Among registered nurses, the 25 areas range from nearly one-third (31.7%) aged 55 years and older in Boston, Massachusetts, to less than 1 in 5 (19.3%) in Miami, Florida. The top 3 ranked areas, in terms of having an older registered nurse workforce (including Camden, New Jersey, and East Long Island, New York), have had or are near sites of considerable COVID-19 infection (as of March 23, 2020). Regarding the physician workforce, there is even more variation between the area with the oldest physicians (Camden, New Jersey [38.9%]) and the youngest (Houston, Texas [19.4%]). Although areas with relatively older registered nurses do not necessarily have relatively older physicians, Camden, New Jersey, Fort Lauderdale, Florida, and Orange County, California, are among the top 5 areas with the oldest registered nurse and physician workforces.
It is reassuring that large numbers of older nurses and physicians are caring for patients today. These clinicians have decades worth of knowledge, experience, and relationships with coworkers that will be needed now more than ever when large numbers of patients are hospitalized with COVID-19. These clinician leaders are an essential and vitally important component of many organizations, especially because many of these older clinicians have experience with disasters, triaging, decision making, and managing staff and resources under times of great stress. Conversely, should these older nurses and physicians become infected and required to stay home, or if they become patients, the ramifications could be significant, not only in terms of the loss of their clinical expertise and presence when it is needed the most, but the loss of leadership, judgement, and maintaining morale.
Hospitals and other care delivery organizations, including state and local health departments, should carefully consider how best to protect and preserve their workforce, with careful consideration involving older physicians and nurses. Older clinicians are likely to have an even larger role in the months ahead as more regions address workforce shortages by requesting that retired physicians and nurses consider returning to the workforce during the COVID-19 outbreak, as has recently occurred in New York City, the state of Illinois, and Great Britain.4-6 While hospitals and other organizations ramp up their preparations, this is the time to determine whether there may be different roles for older clinicians that will ensure they are able to contribute over the long-term course of the pandemic. This is not to suggest that these older nurses and physicians should necessarily be precluded from providing clinical care or should be isolated, but rather to consider if their direct clinician duties can be shifted to emphasize roles with less risk of exposure. These roles may include various activities, such as consulting with younger staff, advising on the use of resources, being readily available for clinical and organizational problem solving, helping clinicians and managers make tough decisions, talking with families of patients, advising managers and executives, being public spokespersons, and liaising with public and community health organizations. In addition, hospitals will want to prepare for the effect that a severe illness or death of a colleague will have on their staff in terms of morale.
As the public, government, and the health care workforce prepare for what could be extraordinarily challenging weeks and months ahead, thought should be given on how to wisely use all health care resources, including the nation’s nurse and physician workforce—from students to the most seasoned.
The novel coronavirus disease 2019 (COVID-19) pandemic is challenging health care systems worldwide and raising important ethical issues, especially regarding the potential need for rationing health care in the context of scarce resources and crisis capacity. Even if capacity to provide care is sufficient, one priority should be addressing goals of care in the setting of acute life-threatening illness, especially for patients with chronic, life-limiting disease.
Clinicians should ensure patients receive the care they want, aligning the care that is delivered with patients’ values and goals. The importance of goal-concordant care is not new or even substantially different in the context of this pandemic, but the importance of providing goal-concordant care is now heightened in several ways. Patients most likely to develop severe illness will be older and have greater burden of chronic illness—exactly those who may wish to forgo prolonged life support and who may find their quality of life unacceptable after prolonged life support.1 In addition, recent reports suggest that survival may be substantially lower when acute respiratory distress syndrome is associated with COVID-19 vs when it is associated with other etiologies.2,3
In this context, advance care planning prior to serious acute illness and discussions about goals of care at the onset of serious acute illness should be a high priority for 3 reasons. First, clinicians should always strive to avoid intensive life-sustaining treatments when unwanted by patients. Second, avoiding nonbeneficial or unwanted high-intensity care becomes especially important in times of stress on health care capacity. Third, provision of nonbeneficial or unwanted high-intensity care may put other patients, family members, and health care workers at higher risk of transmission of severe acute respiratory syndrome coronavirus 2. Now is the time to implement advance care planning to ensure patients do not receive care they would not want if they become too severely ill to make their own decisions. As eloquently pointed out by an intensivist, “If you do not talk with [your family] about this now, you may have to have a much more difficult conversation with me later.”4 Several online resources can guide these advance care planning discussions.5-7
For patients in a community setting or living in a nursing home, clinicians should engage in discussions about goals of care now, especially with older patients with chronic disease. During this pandemic when nonessential medical visits are currently limited, these conversations may need to occur via telemedicine (either as a stand-alone appointment or in combination with an appointment designated or scheduled for another purpose). This process should include primary care and specialty clinicians (eg, cardiologists, pulmonologists, nephrologists, oncologists, and geriatricians), and patients might appreciate this opportunity to discuss advance care planning. Depending on state regulations, patients with chronic life-limiting illness should be offered the option to complete a physician order for life-sustaining treatments form, especially if they would not want to receive cardiopulmonary resuscitation (CPR) or mechanical ventilation.
For hospitalized patients, one focal point for goal-concordant care is related to discussions of code status or the use of CPR and advanced cardiac life support (ACLS). Many hospital-based clinicians overemphasize code status as the first step of a goals-of-care discussion, but asking patients about CPR before assessing values and goals leads to ineffective code status discussions. During this pandemic, it is equally important to understand a patient’s values and goals prior to discussing code status; however, the importance of avoiding inappropriate CPR has increased for 2 reasons. One reason is that although unwanted or nonbeneficial CPR under any circumstance may risk increasing psychological distress for patients’ family members,8 inappropriate CPR during the pandemic is especially stressful and potentially dangerous for health care workers. Another reason is that nonbeneficial or unwanted ACLS will strain available resources for personal protective equipment because multiple health care workers are needed for effective ACLS. Therefore, the COVID-19 pandemic heightens the importance of implementing do-not-resuscitate (DNR) orders for appropriate hospitalized patients.
The implementation of DNR orders can occur in 3 situations. First, patients or their surrogate decision makers may clearly understand and communicate that the patient would not want CPR if the heart were to stop and may even have a physician’s order for life-sustaining treatments form that specifies such. Second, patients or their surrogate decision makers may follow the recommendation of a clinician to forgo CPR; this may occur through informed consent or, occasionally, informed assent (as discussed below).9 Third, in extreme situations in which CPR cannot possibly be effective, clinicians in some health care settings may unilaterally decide to write a DNR order.10 This latter approach is not uniformly accepted and, prior to COVID-19, it rarely had a role. During this pandemic, however, in extreme situations such as a patient with severe underlying chronic illness and acute cardiopulmonary failure who is getting worse despite maximal therapy, there may be a role for a unilateral DNR to reduce the risk of medically futile CPR to patients, families, and health care workers.10
Informed assent may be a more acceptable approach to code status discussions than medical futility and may be useful for patients in whom CPR is exceedingly unlikely to allow a successful return to a quality of life they would find acceptable.9 The Figure provides a proposed guide for an approach to having an informed assent discussion with a patient or family member of a patient for whom the clinician believes CPR is not indicated. The advantage of informed assent over a more traditional informed consent approach is that the clinician does not ask the patient or designated family member to take responsibility for the decision but rather asks the patient or family member to allow the clinician to assume responsibility. Some family members may be willing to permit clinicians to make this decision while simultaneously being unable to accept responsibility themselves, even if they agree, because of the psychological burden it places on them. In this setting, informed assent may provide family members a way to agree with the clinician’s determination without assuming responsibility. Importantly, this approach places great responsibility on clinicians to enact careful prognostication and thoughtful, respectful, open communication with family members. This same responsibility is also present for informed consent.
The COVID-19 pandemic is placing tremendous stress on health care systems. There are many important components of an appropriate response to this pandemic, including public health measures to reduce rapidity and extent of spread. Another important element of the best possible response is to ensure that clinicians have high-quality discussions both about advance care planning for individuals in the community, especially those of older age and with chronic illness, and about goals of care with patients or their families when patients have illness that requires hospitalization.
Role of the Funder/Sponsor: None of the funders had a role in the preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: The authors would like to thank Anthony L. Back, MD; Ruth A. Engelberg, PhD; James Fausto, MD, eMHA; Dee Ford, MC, MSCR; and Christine Ritchie MD, MSPH, for their contributions to the practical steps for informed assent.
Coronavirus disease 2019 (COVID-19) is a newly recognized infectious disease that has spread rapidly throughout Wuhan, Hubei, China, to other provinces in China and several countries around the world. The number of fatalities owing to COVID-19 is escalating. Previous studies have described the general clinical characteristics and epidemiological findings of patients with COVID-19, and some of the clinical observations have shown that the condition of some patients with COVID-19 deteriorates rapidly.1-4
With the increasing number of confirmed cases and the accumulating clinical data, in addition to the common clinical presentation of respiratory failure caused by COVID-19, the cardiovascular manifestations induced by this viral infection has generated considerable concern. Huang et al5 reported that 12% of patients with COVID-19 were diagnosed as having acute myocardial injury, manifested mainly by elevated levels of high-sensitive troponin I. From other recent data, among 138 hospitalized patients with COVID-19, 16.7% had arrhythmias and 7.2% had acute myocardial injury.6 However, at present, specific information characterizing whether patients with COVID-19 with underlying cardiovascular disease (CVD) who develop myocardial injury during hospitalization face greater risk and have worse in-hospital outcomes remains unknown. The present study investigated the association of underlying CVD and myocardial injury with fatal outcomes of patients with COVID-19.
This single-center, retrospective, observational study was performed at the Seventh Hospital of Wuhan City, China, which is a designated hospital to treat patients with COVID-19 and supervised by the Zhongnan Hospital of Wuhan University in Wuhan, China. We retrospectively analyzed patients with COVID-19 who were diagnosed according to the interim guidance of the World Health Organization7 from January 23, 2020, to February 23, 2020, and who were either treated and discharged or died during hospitalization. Clinical information was collected on admission and during hospitalization by attending physicians.
This study complied with the edicts of the 1975 Declaration of Helsinki8 and was approved by the institutional ethics board of Zhongnan Hospital of Wuhan University and the Seventh Hospital of Wuhan City (no. 2020026). Consent was obtained from patients or patients’ next of kin.
The electronic medical records of the patients were reviewed by a trained team of physicians who worked in Seventh Hospital of Wuhan City during the epidemic period. Patient data including demographics, medical history, laboratory examinations, comorbidities, complication, treatment measures (antiviral, antibiotic, corticosteroid therapies, immune glucocorticoid therapy, and respiratory support), and outcomes were collected and analyzed.
The end point was incidence of COVID-19–associated death. Successful treatment toward hospital discharge comprised relieved clinical symptoms, normal body temperature, significant resolution of inflammation as shown by chest radiography, and at least 2 consecutive negative results shown by real-time reverse transcription–polymerase chain reaction assay6 for COVID-19.
Acute respiratory distress syndrome was defined according to the Berlin Definition.9 Malignant arrhythmia was defined as rapid ventricular tachycardia lasting more than 30 seconds, inducing hemodynamic instability and/or ventricular fibrillation. Patients were considered to have acute myocardial injury if serum levels of troponin T (TnT) were above the 99th percentile upper reference limit.5
Data were collected in consecutive patients hospitalized with COVID-19, including 211 patients who were successfully treated and discharged and 45 patients who died. We excluded 67 discharged patients and 2 patients who died because of incomplete data, leaving 144 discharged individuals and 43 individuals who died included for final analysis. Of 187 patients, 66 (35.3%) had underlying CVD including hypertension, coronary heart disease, and cardiomyopathy, and 52 (27.8%) exhibited myocardial injury as indicated by elevated TnT levels.
On admission, none showed evidence of acute myocardial infarction, chronic liver disease, thromboembolic diseases, or rheumatism. In patients with elevated plasma TnT levels who eventually were discharged or died, the median (IQR) duration from illness onset to discharge or death was 28 (22-33) and 23.5 (18.25-34.5) days, respectively. Mortality was markedly higher in patients with elevated plasma TnT levels than in patients with normal TnT levels (31 [59.6%] vs 12 [8.9%]) (Table 1).
Compared with patients with normal TnT levels (Table 1), those with elevated TnT levels were older (mean [SD] age, 71.40 [9.43] vs 53.53 [13.22]) and had a higher proportion of men (34 [65.4%] vs 57 [42.2%]). Patients with elevated TnT levels had significantly higher rates of comorbidities including hypertension (33 [63.5%] vs 28 [20.7%]), coronary heart disease (17 [32.7%] vs 4 [3.0%]), cardiomyopathy (8 [15.4%] vs 0), diabetes (16 [30.8%] vs 12 [8.9%]), chronic obstructive pulmonary disease (4 [7.7%] vs 0), and chronic kidney disease (1 [0.7%] vs 5 [9.6%]). Rates of smoking and malignant neoplasms did not differ between those with normal (11 [8.1%] vs 7 [13.5%]) and elevated TnT levels (7 [5.2%] vs 6 [11.5%]).
Patients with underlying CVD were more likely to exhibit elevation of TnT levels (36 [54.5%]) compared with patients without CVD (16 [13.2%]). During hospitalization, patients with elevated TnT levels developed more frequent complications (Table 1), including acute respiratory distress syndrome (30 [57.7%] vs 16 [11.9%]), malignant arrhythmias (6 [11.5%] vs 7 [5.2%]) including ventricular tachycardia/ventricular fibrillation, acute coagulopathy (25 [65.8%] vs 17 [20.0%]), and acute kidney injury (14 [36.8%] vs 4 [4.7%]), compared with those with normal TnT levels. However, there was no significant differences in incidence of acute liver injury between the 2 groups. Antiviral (oseltamivir, 75 mg twice a day; ribavirin, 0.5 g twice a day; umifenovir, 0.2 g 3 times a day), antibacterial (moxifloxacin, 0.4 g every day), glucocorticoid (methylprednisolone, 40-80 mg every day), and respiratory support were the main treatment approaches for the hospitalized patients (Table 1). During hospitalization, the majority of patients underwent antiviral and antibacterial therapy, with no significant difference in such therapies between patients with normal and elevated TnT levels. However, the rates of glucocorticoid therapy and mechanical ventilation were much higher in patients with elevated TnT levels compared with those with normal TnT levels.
Long-term outpatient medications prior to admission, such as antihypertensive drugs and hypoglycemic drugs, were not discontinued. Notably, the use of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) was higher in patients with elevated TnT levels (11 [21.1%] vs 8 [5.9%]; Table 1), reflecting the higher rates of CVD. The mortality rates of patients with and without use of ACEIs/ARBs was 36.8% (7 of 19) and 25.6% (43 of 168).
Among 187 patients, 7.62% (8 of 105) with normal TnT levels without underlying CVD, 13.33% (4 of 30) with normal TnT levels with underlying CVD, 37.50% (6 of 16) with elevated TnT levels without underlying CVD, and 69.44% (25 of 36) with elevated TnT levels with underlying CVD died during hospitalization (Figure 2).
Figure 3 shows the dynamic escalation of TnT and NT-proBNP levels for patients who died and those who were successfully treated and discharged. Both TnT and NT-proBNP levels increased significantly during the course of hospitalization in those who ultimately died, but no such dynamic changes of TnT or NT-proBNP levels were evident in survivors.
This report provides detailed cardiovascular information of the association between underlying CVD, myocardial injury, and fatal outcomes of patients with COVID-19. The Chinese Center for Disease Control and Prevention recently published the largest case series to date of COVID-19 in mainland China; the overall case fatality rate was 2.3% (1023 deaths among 44 672 confirmed cases), but the mortality reached 10.5% in patients with underlying CVD.10
In the current study, among 187 patients with COVID-19, 52 (27.8%) exhibited myocardial injury as demonstrated by elevation of TnT levels, and the mortality was markedly higher in patients with elevated TnT levels than in patients with normal TnT levels (59.6% vs 8.9%). The median (IQR) duration from illness onset to death was 23.23 (8-41) days in the group with elevated TnT levels. Patients with underlying CVD and escalation of TnT levels had the highest mortality (69.44%) and the shortest survival term. However, patients with underlying CVD but with normal TnT levels during the course of disease experienced a more favorable prognosis, compared with patients with elevated TnT levels but without underlying CVD (mortality, 13.3% vs 37.5%). The dynamic escalation of NT-proBNP and increased incidence of malignant arrhythmias during the course of disease in patients with elevated TnT levels is evidence that myocardial injury played a greater role in the fatal outcome of COVID-19 than the presence of underlying CVD itself.
NT-proBNP elevation and malignant arrhythmias were significantly more common in patients with elevated TnT levels, and NT-proBNP was significantly correlated with TnT levels (Figure 1). This suggests that those with myocardial injury were more likely to experience impairment in cardiac function.
The current study demonstrates that patients with underlying CVD and other comorbid conditions are more prone to experience myocardial injury during the course of COVID-19. For patients with underlying CVD, including hypertension, coronary heart disease, and cardiomyopathy, viral illness can further damage myocardial cells through several mechanisms including direct damage by the virus, systemic inflammatory responses, destabilized coronary plaque, and aggravated hypoxia. Therefore, patients with CVD are more likely to experience myocardial injury after COVID-19 infection and higher risk of death. However, it is also notable that the 16% of patients with underlying CVD but with normal TnT levels had a relatively favorable outcome in this study. These data suggest that myocardial biomarkers should be evaluated in patients with CVD who develop COVID-19 for risk stratification and possible early and more aggressive intervention.
Although the exact pathophysiological mechanism underlying myocardial injury caused by COVID-19 is not fully understood, a previous report showed that in 35% of the patients with severe acute respiratory syndrome coronavirus (SARS-CoV) infection, the SARS-CoV genome was positively detected in the heart. This raises the possibility of direct damage of cardiomyocytes by the virus.11 SARS-CoV-2 may share the same mechanism with SARS-COV because the 2 viruses are highly homologous in genome.12,13 In the current study, plasma TnT levels were significantly positively linear correlated with plasma high-sensitivity C-reactive protein levels (Figure 2), indicating that myocardial injury may be closely associated with inflammatory pathogenesis during the progress of disease. Viral particles spread through respiratory mucosa and simultaneously infect other cells, which could precipitate a cytokine storm and a series of immune responses. Huang et al5 highlighted that in patients with COVID-19, the imbalance of T helper 1 and T helper 2 responses resulted in a cytokine storm, which may contribute to myocardial injury. The release of inflammatory cytokines after infection may cause reduction in coronary blood flow, decreases in oxygen supply, destabilization of coronary plaque, and microthrombogenesis.
Unfortunately, until now, no specific antiviral drugs or vaccines have been recommended for COVID-19 except for symptomatic supportive treatment and intervention. As patients with underlying CVD are more likely to develop more severe adverse outcomes when myocardial injury occurs after COVID-19 infection and face higher risk of death, it may be reasonable to triage patients with COVID-19 according to the presence of underlying CVD and evidence of myocardial injury for prioritized treatment and even more aggressive treatment strategies. Other cardiac biomarkers such as NT-proBNP and electrocardiograms should be closely monitored for early warning and intervention.
There remains controversy concerning the use of ACEI/ARB for COVID-19. In this study, with a limited number of patients, the mortality of those treated with or without use of ACEI/ARB did not show a significant difference in outcome. Concerns about ACEI/ARB have been raised since angiotensin-converting enzyme 2 (ACE2) is a potential target for COVID-19 infection, and the increased ACE2 expression induced by ACEI or ARB would aggravate lung injury of patients with COVID-19. However, a previous study14 showed a beneficial effect of ACEI/ARB in patients admitted with viral pneumonia, as it significantly reduced the pulmonary inflammatory response and cytokine release caused by virus infection. The beneficial effect of ACEI/ARB may be related to a compensatory increase in ACE2.15 However, the evidence regarding the use of ACEI/ARB in patients with COVID-19 infection is still emerging, and larger clinical studies are required. At present, for patients with COVID-19 who previously used ACEI/ARB, the use of these drugs may not need to be discontinued based on current data.
Our study has several limitations. First, only 187 patients with confirmed COVID-19 were included, and a larger cohort study is needed to verify our conclusions. Second, as a retrospective study, some other specific information regarding cardiovascular complications and inflammation such as echocardiography and interleukin 6 were not presented in the study because the data were incomplete owing to the limited conditions in the isolation ward and the urgency of containing the COVID-19 epidemic. Third, the data in this study permit a preliminary assessment of the clinical course and outcomes of patients with COVID-19. The causes of death may involve multiple organ dysfunction in most cases, and it is difficult to differentiate the myocardial injury as the main and direct cause in an individual case. Long-term observation and prospective study design on the effectiveness of treatments specific for the myocardial injury are needed.
Myocardial injury has a significant association with fatal outcomes of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury appears relatively favorable. Myocardial injury is associated with impairment of cardiac function and ventricular tachyarrhythmias. Inflammation may be associated with myocardial injury. Aggressive treatment may be considered for the patients with myocardial injury.
Accepted for Publication: March 9, 2020.
Additional Information: We acknowledge all health care workers involved in the diagnosis and treatment of patients at Seventh Hospital of Wuhan City; we appreciate Lei Liu, MD (Shenzhen Rosso Pharmaceutical Co Ltd Medical Center, Shenzhen, China), for the consultation for statistical analysis. Compensation was not received.
The first cases of coronavirus disease 2019 (COVID-19) were reported in December 2019, originating in Wuhan, China,1 with rapid spread worldwide, and COVID-19 became a public health emergency of international concern.2 The pathogen has been identified as a novel enveloped RNA beta-coronavirus and has been named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).3 The clinical course of SARS-CoV-2 infection is mostly characterized by respiratory tract symptoms, including fever, cough, pharyngodynia, fatigue, and complications related to pneumonia and acute respiratory distress syndrome.4
Data regarding cardiovascular involvement due to SARS-CoV-2 infection are less described. Previous severe acute respiratory syndrome (SARS) beta-coronavirus infections could be associated with tachyarrhythmias and signs and symptoms of heart failure.5 The present report describes a case of cardiac involvement in a patient affected by COVID-19. The patient provided written informed consent, and the diagnostic procedures were conducted in accordance with institutional guidelines about the protection of human subjects.
An otherwise healthy 53-year-old white woman without previous history of cardiovascular disease presented to the emergency department with severe fatigue for 2 previous days. She denied chest pain, dyspnea, and further symptoms. She reported having fever and cough the week before.
On arrival to the emergency department, physical examination revealed blood pressure of 90/50 mm Hg, heart rate of 100 beats per minute, oxygen saturation of 98% while breathing ambient air, and body temperature of 36.6 °C. (She remained afebrile during the subsequent clinical course.) Arterial gas analysis showed a pH of 7.46, oxygen partial pressure of 82 mm Hg, carbon dioxide partial pressure of 32 mm Hg, and lactate level of 17.1 mg/dL (to convert to millimoles per liter, multiply by 0.111). A 12-lead electrocardiogram (ECG) showed low voltage in the limb leads, minimal diffuse ST-segment elevation (more prominent in the inferior and lateral leads), and an ST-segment depression with T-wave inversion in lead V1 and aVR (Figure 1A).
Findings on chest radiography were unremarkable (Figure 1B). Blood tests revealed elevated levels of markers of myocyte necrosis (high-sensitivity troponin T level of 0.24 ng/mL [to convert to micrograms per liter, multiply by 1] and creatine kinase–MB level of 20.3 ng/mL [to convert to micrograms per liter, multiply by 1]), elevated N-terminal pro–brain natriuretic peptide (NT-proBNP) levels (5647 pg/mL [to convert to nanograms per liter, multiply by 1]), slight increase in C-reactive protein levels (1.3 mg/dL [to convert to milligrams per liter, multiply by 10), and normal blood cell counts (Table). Blood sample tests also revealed hyperkalemia, hyponatremia, and hypochloremia. These abnormalities were treated with kayexalate, glucose and insulin solution, and sodium bicarbonate. Given the echocardiography changes, regional wall motion abnormalities, and elevated markers of myocardial necrosis, urgent coronary angiography was performed, which showed no evidence of obstructive coronary disease.
The patient was admitted to the intensive care unit with a diagnosis of suspected myopericarditis. Based on the clinical history and the COVID-19 outbreak, COVID-19 was deemed as likely. A nasopharyngeal swab was performed with a positive result for SARS-CoV-2 on real-time reverse transcriptase–polymerase chain reaction assay. Search for common cardiotropic infectious agents yielded negative results.
Transthoracic echocardiography revealed normal left ventricular (LV) dimensions with an increased wall thickness (interventricular septum, 14 mm, posterior wall, 14 mm) and a diffuse echo-bright appearance of the myocardium. There was diffuse hypokinesis, with an estimated LV ejection fraction (LVEF) of 40%. There was no evidence of heart valve disease. Left ventricular diastolic function was mildly impaired with mitral inflow patterns, with an E/A ratio of 0.7 and an average E/e′ ratio of 12. There was a circumferential pericardial effusion that was most notable around the right cardiac chambers (maximum, 11 mm) without signs of tamponade. Cardiac magnetic resonance imaging (MRI) confirmed the increased wall thickness with diffuse biventricular hypokinesis, especially in the apical segments, and severe LV dysfunction (LVEF of 35%) (Video 1 and Video 2). Short tau inversion recovery and T2-mapping sequences showed marked biventricular myocardial interstitial edema. Phase-sensitive inversion recovery sequences showed diffuse late gadolinium enhancement extended to the entire biventricular wall (Figure 2). The myocardial edema and pattern of late gadolinium enhancement fulfilled all the Lake Louise criteria for the diagnosis of acute myocarditis.6 The circumferential pericardial effusion was confirmed, especially around the right cardiac chambers (maximum, 12 mm).
During the first days of her hospitalization, the patient remained hypotensive (systolic blood pressure less than 90 mm Hg) and required inotropic support (dobutamine) in the first 48 hours, during which there was a further increase in levels of NT-proBNP (8465 pg/mL), high-sensitivity troponin T (0.59 ng/mL), and creatine kinase–MB (39.9 ng/mL), with a progressive stabilization and reduction during the following days (Table). Blood pressure progressively stabilized, although systolic pressure remained less than 100 mm Hg, and dobutamine treatment was weaned on day 4. Heart failure–directed medical treatment was started with daily doses of 50 mg of kanrenone, 25 to 50 mg of furosemide, and 2.5 mg of bisoprolol, then reduced and finally withdrawn on day 5 owing to sinus bradycardia. The patient was treated on admission with intravenous aspirin (500 mg twice daily), and given the cardiac MRI findings, hydroxychloroquine (200 mg twice daily), lopinavir/ritonavir (2 tablets of 200/50 mg twice daily), and intravenous methylprednisolone (1 mg/kg daily for 3 days)7,8 were administrated. Chest radiography was repeated on day 4 and showed no thoracic abnormalities. Transthoracic echocardiography, performed on day 6, revealed a significant reduction of LV wall thickness (interventricular septum, 11 mm; posterior wall, 10 mm), an improvement of LVEF to 44%, and a slight decrease of pericardial effusion (maximum, 8-9 mm). At the time of submission, the patient was hospitalized with progressive clinical and hemodynamic improvement.
Herein, we describe a patient without a history of cardiovascular disease admitted to the hospital with COVID-19 and severe LV dysfunction and acute myopericarditis. Our main findings are that cardiac involvement may occur with COVID-19 even without respiratory tract signs and symptoms of infection.
After the first cases describing pneumonia cases of unknown origin in Wuhan, China, SARS-CoV-2 rapidly spread worldwide with critical challenges for the public health and medical communities.1,2 The World Health Organization has declared SARS-CoV-2 a public health emergency of international concern, with a global estimate of 98 192 laboratory-confirmed cases and 3380 deaths as of March 6, 2020.
A 2020 report by the China Medical Treatment Expert Group for COVID-199 showed the spectrum of clinical and diagnostic features associated with SARS-CoV-2 infection among Chinese patients. The most common symptoms were fever (in up to 88.7% of patients during hospitalization) and cough (in 67.8% of patients), followed by dry cough, headache, fatigue, or shortness of breath. Complications were mostly related to physician-diagnosed pneumonia (91.1%) and acute respiratory distress syndrome.3,4 While the spectrum of clinical manifestation is highly related to the inflammation process of the respiratory tract, this case provides evidence of cardiac involvement as a possible late phenomenon of the viral respiratory infection. This process can be subclinical with few interstitial inflammatory cells, as reported by an autopsy study,10 or can present with overt manifestations even without respiratory symptoms, as in the present case.
Virus infection has been widely described as one of the most common infectious causes of myocarditis, especially associated with influenza and parvovirus B-19 infection.11 However, less is known about the cardiac involvement as a complication of SARS-CoV-2 infection.
Myocarditis results in focal or global myocardial inflammation, necrosis, and eventually ventricular dysfunction. Focal myocarditis is often suspected in patients presenting with chest pain after an influenzalike syndrome, with clinical evidence suggesting an acute coronary syndrome on electrocardiography or laboratory testing or with evidence of wall motion abnormalities without evidence of obstructive coronary artery disease on coronary angiography.12
The pathogenesis of cardiac involvement associated with SARS-CoV-2 may reflect a process of replication and dissemination of the virus through the blood or the lymphatic system from the respiratory tract. However, to our knowledge, there are no reports of influenza virus or coronavirus RNA in the heart, to date. Alternatively, SARS-CoV-2 could trigger an exaggerated inflammatory response that can cause myocardial injury, and this could justify the use of corticosteroids to attenuate inflammation, as in the present case. Evidence of a significant inflammatory cell infiltration has been reported in the alveoli of patients with acute respiratory distress syndrome associated with SARS-CoV-2 infection,10 and this could explain the use of corticosteroids in patients with COVID-19 (up to 58% in a series of critically ill patients13). Although ultrastructural mechanisms are not certain, a potential binding to a viral receptor of the myocyte can favor the internalization and subsequent replication of the capsid proteins and the viral genome.14,15 In this patient, increases of cardiac troponin levels as a sensitive marker of myocardial injury, the cardiac MRI findings showing diffuse edema, and the slow gadolinium washout are in line with an acute myocarditis. In addition, the onset of symptoms several days after the influenzalike syndrome may reflect these proposed mechanisms with a potential myocyte dissemination of the virus, the activation of the immune system, and, ultimately, the clinical onset of heart failure.
As endomyocardial biopsy was not performed, limitations of this report are the lack of the histological demonstration of myocarditis and the absence of viral genome search in the heart. Except for the first 48 hours during which she required inotropic support, the patient was mainly treated with heart failure–directed medical treatment. However, as described in the literature, viral myocarditis has a wide spectrum of clinical presentations, ranging from life-threating arrhythmias to advanced heart failure requiring invasive support.10
We believe that recognition by the scientific community of acute myocarditis as a possible complication associated with COVID-19 may be helpful for strict monitoring of affected patients and also for furthering knowledge of such complications for public health officials. This report highlights the importance of clinical surveillance and laboratory testing, including troponin levels, in individuals with recent symptoms of an acute illness to guarantee appropriate identification and prompt isolation of patients at risk of COVID-19 and eventually to reduce further transmission. Further evidence is needed to determine whether corticosteroids are useful in reducing the myocardial inflammatory response. We cannot exclude that a spontaneous resolution occurred or that antiviral drugs or chloroquine contributed to the improvement of this patient. Finally, awareness of atypical presentations such as this one is important to prompt patient isolation and prevent interhuman transmission.
Accepted for Publication: March 13, 2020.
Additional Contributions: We thank the patient for granting permission to publish this information.
Coronavirus disease 2019 (COVID-19) has emerged as a pandemic and a public health crisis of global proportions. As a medical community, we are actively engaged in a real-time data gathering mode to facilitate active learning and an expedited study of best practices of care. Although we are becoming more aware of the natural history of COVID-19, we have had scant information as of yet that addresses any unique risks of COVID-19 for those with underlying cardiovascular disease. Such information is of paramount importance as we now must begin to consider the potential for direct and indirect adverse effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the heart and especially so in those with already established heart disease.
The statistics to date are staggering and relentlessly mounting. As of March 25, 2020, there have been more than 430 000 individuals in more than 170 countries with confirmed COVID-19, of whom more than 19 000 have died. In the US, there have been more than 49 000 confirmed cases of COVID-19 in all 50 states and Washington, DC. It is clear that the number of infections in the US, the number needing critical care interventions, and especially the numbers of deaths will continue to escalate.
The available data from China and Italy as well as the early experience in the US indicate that COVID-19 is a relatively mild condition in most affected individuals, but in others, it can be very severe and deadly. What we now know is that individuals at greatest risk of serious illness sufficient to require intensive care and those at greatest risk of mortality are older individuals, particularly older individuals with underlying comorbid disease, including cardiovascular disease.1-5 However, severe disease requiring hospitalization and even deaths have been reported in younger adults.
Patients with long-term coronary artery disease and those with risk factors for atherosclerotic cardiovascular disease have a heightened risk of developing an acute coronary syndrome during acute infections, which has been shown previously in epidemiologic and clinical studies of influenza6-8 and other acute inflammatory conditions.9 Such acute coronary events could result from the severe increase in myocardial demand triggered by infections that precipitate myocardial injury or infarction, akin to type 2 myocardial infarction. Alternatively, circulating cytokines released during a severe systemic inflammatory stress could lead to atherosclerotic plaque instability and rupture. Similarly, patients with heart failure are also prone to hemodynamic decompensation during the stress of severe infectious illnesses. Thus, it is anticipated that patients with underlying cardiovascular diseases, which are more prevalent in older adults, would be susceptible to higher risks of adverse outcomes and death during the severe and aggressive inflammatory responses to COVID-19 than individuals who are younger and healthier. In addition, acute/fulminant myocarditis as well as heart failure have been reported with Middle East respiratory syndrome coronavirus and could be expected to occur with SARS-CoV-2, given the similar pathogenicity.
Similar observations were reported by Guo et al11 in 187 patients hospitalized with laboratory-confirmed COVID-19, of whom 52 (27.8%) had myocardial injury as determined by elevated levels of troponin T (TnT). In-hospital mortality was 59.6% (31 of 52) in those with elevated TnT levels compared with 8.9% (12 of 135) in those with normal TnT levels. Of note, the highest mortality rates were observed in those with elevated TnT levels who had underlying cardiovascular disease (25 of 36 [69.4%]), but mortality rates were also considerable in those with elevated TnT levels without prior cardiovascular disease (6 of 16 [37.5%]). In contrast, patients with known cardiovascular disease without elevation of TnT levels had a relatively favorable but still worrisome prognosis (mortality of 13.3% [4 of 30]). Guo et al11 provide additional novel insights that TnT levels are significantly associated with levels of C-reactive protein and N-terminal pro-B-type natriuretic peptide (NT-proBNP), thus linking myocardial injury to severity of inflammation and ventricular dysfunction. Their data also show progressive serial increases in both TnT and NT-proBNP levels during hospitalization in patients who follow a deteriorating clinical course toward death, whereas those with a more favorable outcome with less severe illness, successful treatment, and hospital discharge show stable low levels of these biomarkers.
Shi et al10 and Guo et al11 report remarkably similar characteristics of patients who develop myocardial injury (as assessed by elevated levels of TnI or TnT) associated with COVID-19. Patients at risk of myocardial injury are older and have a higher prevalence of hypertension, coronary artery disease, heart failure, and diabetes than those with normal levels of TnI or TnT. Patients with myocardial injury also have evidence of more severe systemic inflammation, including greater leukocyte counts and higher levels of C-reactive protein and procalcitonin as well as high levels of other biomarkers of myocardial injury and stress, such as elevated creatine kinase, myoglobin, and NT-proBNP. Further, patients who develop myocardial injury with COVID-19 have clinical evidence of higher acuity, with a higher incidence of acute respiratory distress syndrome and more frequent need for assisted ventilation than those without myocardial injury. Thus, a consistent picture emerges from these 2 reports that older patients with preexisting cardiovascular comorbidities and diabetes are prone to develop a higher acuity of illness after contracting SARS-CoV-2 associated with higher risk of myocardial injury and a markedly higher short-term mortality rate.10,11
These lines of evidence are followed by Yang and Zin12 in their Viewpoint that discusses the collision between the acute COVID-19 epidemic that has arisen in the past 3 months and the underlying cardiovascular epidemic that has been under way in China for decades. They acknowledge the many recent observations1-5 that patients with preexisting cardiovascular disease are susceptible to the most adverse complications of COVID-19, including death. Importantly, they also appropriately emphasize that there has thus far been insufficient attention to understanding the mechanisms responsible for these outcomes beyond the obvious recognition that severe infections can destabilize patients with coronary artery disease or heart failure. The current observations of Shi et al10 and Guo et al11 regarding the important association of myocardial injury with adverse outcomes begin to provide insights into other possible mechanisms, including demand ischemia that devolves into myocardial injury or plaque disruption stimulated by intense systemic inflammatory stimuli. As with other coronaviruses, SARS-CoV-2 can elicit the intense release of multiple cytokines and chemokines1,12 that can lead not only to vascular inflammation and plaque instability but also to myocardial inflammation. Direct viral infection of the myocardium is another possible causal pathway of myocardial damage and one that requires further investigation. It is noteworthy that the articles from China by Shi et al,10 Guo et al,11 and Yang and Zin12 address the unique marked affinity of SARS-CoV-2 for the host angiotensin-converting enzyme 2 receptor, which has been shown previously for other coronaviruses,13 raising the possibility of direct viral infection of vascular endothelium and myocardium. It is thus possible that in some patients with or without preexisting cardiovascular disease, COVID-19–associated myocardial injury could represent myocarditis.14 The well-documented case of acute myocarditis following a COVID-19–associated respiratory infection in a 53-year-old Italian woman with no previous heart disease, also reported in this issue by Inciardi et al,15 supports this hypothesis.
The association of myocardial injury with outcomes of COVID-19 in the 2 Chinese cohorts10,11 represent early data from patients hospitalized at the outset of the epidemic in Wuhan, during which a rapidly escalating number of patients with previously unknown serious respiratory illnesses was beginning to stretch and overwhelm local health care systems. Given the severity of illness and the primary focus on urgently managing infection and respiratory failure, it is understandable that not all patients have complete cardiac data, such as electrocardiography, and that information from more sophisticated cardiac testing, such as echocardiography, coronary angiography, and magnetic resonance imaging, are not available. That we have the current data available to study is in itself a triumph and an acknowledgment of the intent of dedicated physicians to use bedside observations to inform others.
Whether the data linking myocardial injury and high mortality risk in patients with COVID-19 from the 2 Chinese cohorts10,11 are generalizable to other countries, including the US, is yet to be determined. But the wake-up call has been delivered. We have a similar profile of elderly patients with cardiovascular disease in the US and other Western countries in which the toll of COVID-19 could be daunting. While remarkable efforts to unravel the mechanisms of myocardial injury are ongoing and candidate therapies are already entering clinical trials, as discussed in the comprehensive and scholarly review by Madjid et al,16 one message resonates with us: prevention. Until we know more, the populations described in these primary data reports should be most observant of strict hand hygiene, social distancing, and, where available, COVID-19 testing.