key: cord-0857124-avq8iw0c
authors: Aldien, Arwa Saed; Ganesan, Gowrii S.; Wahbeh, Farah; Al-Nassr, Noor; Altarawneh, Heba; Al Theyab, Lolwa; Aldien, Summia Saed; Tomerak, Sara; Naveed, Hiba; Elshazly, Mohamed B.; Zakaria, Dalia
title: Systemic Inflammation May Induce Cardiac Injury in COVID-19 Patients Including Children and adolescents without Underlying Cardiovascular Diseases: A Systematic Review.
date: 2021-04-15
journal: Cardiovasc Revasc Med
DOI: 10.1016/j.carrev.2021.04.007
sha: 17cc0400a4895c9bc05baaa4ffa7b17384873f76
doc_id: 857124
cord_uid: avq8iw0c

Coronavirus disease 2019(COVID-19) is an ongoing global pandemic with a daily increasing number of affected individuals and a relatively high mortality rate. COVID-19 patients that develop cardiac injury are at increased risk of a worse clinical course with higher rates of mortality. Increasing amounts of evidence suggest that a system-wide inflammatory response and a cytokine storm mediated type syndrome plays a crucial role in disease progression. This systematic review investigates the possible role of hyperinflammation in inducing cardiac injury as one of the severe complications of COVID-19. A systematic literature search was performed using PubMed, Embase and Scopus databases to identify relevant clinical studies that investigatedc ardiovascular injury manifestations and reported inflammatory and cardiac biomarkers in COVID-19 patients. Only 29 studies met our inclusion criteria and the majority of these studies demonstrated significantly elevated inflammatory and cardiac blood markers. It was evident that underlying cardiovascular diseases may increase the risk of developing cardiac injury. However, many COVID-19 patients included in this review, developed different types of cardiac injury without having any underlying cardiovascular diseases. Furthermore, many of these patients were either children or adolescents. Therefore, age and comorbidities may not always be the two main risk factors that dictate the severity and outcome of COVID-19. Further investigations are required to understand the underlying mechanisms of pathogenicity as an urgent requirement to develop the appropriate treatment and prevention strategies. These strategies may specifically target hyperinflammation as a suspected driving factor forsome of the severe complications of COVID-19.

Over the past year, coronavirus diseases 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a major public health emergency. On March 11 th 2020, the World Health Organisation (WHO) declared it a worldwide pandemic 1 . As of December 7, 2020, the number of new cases continues to increase with over 4.3 million new cases and 74,824 new deaths over a one-week period, leading to a total of over 70 million cases and 1.6 million deaths globally 2 . The disease presents with a very heterogeneous clinical course of varying severity -from asymptomatic carriers to multi-organ failure and death 3 . Due to the significant mortality burden caused by COVID- 19 , there has been an increased emphasis on identifying the risk factors leading to the severe outcomes of COVID-19 as a means of potentially implementing early interventions to reduce mortality. The symptoms of COVID-19 range from mild to severe and the most common reported symptoms occurring 1-14 days after virus exposure, being fever, dry cough, difficulty breathing, anosmia and dysgeusia 1,4 . Similar to SARS-CoV, SARS-CoV-2 invades the host cells by interacting with angiotensin-converting enzyme 2 (ACE2) which is part of the Renin-Angiotensin-Aldosterone-System (RAAS). ACE2 is expressed in the lung cells as well as other organs 5,6 .

The RAAS system comprises several proteins that play multiple roles in regulating blood pressure 7 . ACE, which is expressed by different types of tissues, converts angiotensin I (ATI)

The primary reported cause of death in COVID-19 patients is respiratory failure.

However, cardiac dysfunction has been reported as the next cause of mortality 1, 4 . Acute cardiac injury, defined as troponin I elevation and electro-cardiac changes, has been reported in 7-17% of hospitalised patients, with increased incidence in more severe cases 1 . Therefore, understanding the underlying mechanisms of the COVID-19 induced cardiac injury (CI) may help to develop and optimise the treatment protocols for those patients. As such, this review was conducted to illustrate and investigate the COVID-19 induced CI and the particular role of hyperinflammation as a possible causative factor.

We conducted a systematic literature search to collect data about any cardiovascular injury related to SARS-CoV-2 infection. A comprehensive online search was performed using PubMed, Embase and Scopus databases between January and July, 2020 to identify relevant studies. Combinations of the following search terms were included: severe acute respiratory syndrome coronavirus, severe-acute-respiratory-syndrome-coronavirus-2, 2019ncov, 2019ncov, covid-19, covid19, covid2019, ncov2019, ncov-2019, hcov19, sars-cov-2, coronavirus, coronaviruses, corona-virus, corona-viruses, covid, hcov, coronavirus [MeSH Terms], heart, cardiac, cardio, coronary, CVD, myocardial, cardiovascular. The systematic review was conducted using Covidence. During the initial phase of screening, all articles in English, that were peer-reviewed and published were included regardless of study design, with no restrictions on country, age or gender of study participants. During the full-text screening, Case reports and case series reporting COVID-19 patients with CI were included only if data for the inflammatory and cardiac blood markers were provided. Similarly, cohort studies reporting the blood inflammatory and cardiac markers data of two populations of COVID-19 patients with or without CI were also included. Cohort studies that did not J o u r n a l P r e -p r o o f Journal Pre-proof separate the data of COVID-19 patients with CI from that of COVID-19 patients without CI were excluded as the results were not conclusive for the purpose of this study. Articles that did not contain original patient data, articles written in any language other than English, duplicate articles, review papers, or irrelevant to the topic were excluded from the study. All phases of screening including title and abstract and full-text screening were conducted independently by two different reviewers for each study using Covidence and disagreements were resolved by consensus. Data extraction included collecting the demographic and clinical data of patients reported in each study whenever data were available. These data included age, sex, cardiovascular conditions, presenting condition/symptoms, other comorbidities, imaging, treatment/interventions, and inflammatory and cardiac blood test results.

Categorical variables were expressed as percentages while continuous variables were expressed as mean and standard deviation or range of results. Data were extracted from each study by two different reviewers. Figure 1 shows the results of database search and screening. The flow diagram summarizes the details of our protocol. After removing the duplicates, a total of 1192 studies were retrieved, and among those 185 studies were selected for full-text screening. Only 29 studies that met the inclusion criteria were included. A total of 156 studies were excluded as 15 studies were irrelevant to the data of interest, 113 had wrong outcomes or wrong settings, six were not in English, two were duplicates and 20 studies did not have enough data.

The results from our search yielded eight cohort studies with control and 21 case series/reports and one cohort study without a control group. Most of the reported cohort studies were conducted in China (six studies), and one each from Turkey and the UK. Eight J o u r n a l P r e -p r o o f Journal Pre-proof of the case reports were from the USA, five from Italy, two from China, two from France and one each from India, Luxembourg, Spain, Poland, and Germany.

Most of the cohort studies and case reports/series identified cardiac injury by elevated troponin T or troponin I. However, the majority of case reports/series used different types of scans/tests for diagnosis in addition to measuring the troponin levels which are detailed in the following sections.

The cohort studies included 2204 COVID-19 patients in total, of which 443 developed cardiac injury (CI) during the course of infection [12] [13] [14] [15] [16] [17] [18] [19] proportions of the CI group with comorbid CVD 13, 14, [17] [18] [19] . In general, the CI groups in five studies were found to have a significantly higher proportion of patients with different underlying comorbidities including diabetes, COPD, hypertension, CKD and cerebrovascular disease (CeVD) 12, 13, [17] [18] [19] . 16 . They reported no significant difference in the level of C-reactive protein (CRP) or troponin I between those who had normal vs RV dilation and dysfunction 16 Ferritin levels ranging from 600 to 7634 ng/mL were reported 21, 22, 26, [28] [29] [30] [32] [33] [34] 36, 38 .

Supplementary table 4 includes the reference ranges for the blood markers reported in this review. Figure 2 shows that 71% of the studies reported at least one inflammation marker above the threshold that may indicate hyperinflammation/cytokine storm syndrome (CSS) in COVID-19 patients. Comparable results were observed when the studies were divided based on the age of patients as children/adolescents or adults (73% and 70% respectively).

Hyperinflammation/CSS was defined as CRP> 150 mg/L and/or ferritin> 1500 ng/mL or IL-6> 80 pg/mL. 

Increasing amounts of evidence suggest that a system-wide inflammatory response and a cytokine storm type syndrome plays a crucial role in the progression of COVID-19 and it is therefore now established to be one of the disease hallmarks [41] [42] [43] . This was attributed to the recruitment of immune cells triggered by a rapid rate of viral replication leading to the release of cytokines. This cycle is perpetuated by high levels of cellular destruction which induces recruitment of immune cells and further dysregulated release of cytokines 42 . These markers are reported to be positively correlated with COVID-19 severity, and current studies are evaluating the use of routine blood tests as a predictor of severity 44 .

In order to assess the role of hyperinflammation in developing cardiac injury, studies that enrolled two groups of COVID-19 patients who developed or did not develop CI were included. Seven out of the eight included cohort studies reported at least one inflammatory marker in a significantly higher level than the non-CI group [12] [13] [14] [15] [16] [17] [18] [19] . COVID-19 associated CSS J o u r n a l P r e -p r o o f refers to the excessive immune response which is characterised by high levels of CRP, IL-6 and ferritin, as well as other features such as lymphopenia and multi-organ failure.

Furthermore, IL-6 levels ≥80 pg/mL were reported to predict an increased risk of respiratory failure and death 45 patients as CRP and ferritin serum levels higher than 150 mg/L and 1500 ng/mL respectively 46, 47 . Interestingly, 71% of the case studies without control reported at least one inflammation marker above the threshold that may indicate hyperinflammation or CSS. This indicates that many of the COVID-19 patients enrolled in the case studies had a hyperinflammatory state which may support the involvement of systemic hyperinflammation in triggering CI. This is further supported by the observed significantly higher inflammatory markers in the CI patients compared with the non-CI patients enrolled in the cohort studies. Previous literature demonstrated that IL-6 is an essential mediator in the cytokine release cascade, as it increases permeability leading to organ dysfunction being elevated in nearly two-thirds of hospitalized patients and being nearly three times higher in ICU patients 3, 43 . Some studies have shown that IL-6 and granulocyte stimulating factor (GM-CSF) could potentially be secreted by T cells during the infectious period and decreasing levels of IL-6 have been linked to clinical improvement from COVID-19 40 . IL-6 and ferritin together have been shown to be significantly increased in patients who died compared to survivors 44 . Moreover, CRP has been found to be the most sensitive indicator of an acute inflammatory response, however, there is some controversy about if there is statistical significance in levels between different severities of COVID-19 42, 44 . This may explain the consensus in our collected data which revealed that at least one inflammation marker, CRP, PCT, IL-6 or ferritin, was significantly higher in the CI compared to the non-CI patients while some inflammation markers reached thousands of times higher than normal in the patients of the case reports/series.

Only four cohort studies with control groups reported the level of D-dimer, three of which reported significantly higher levels in the CI compared with the non-CI group [12] [13] [14] .

Autopsy studies reported that endothelial inflammation was associated with the attachment of inflammatory immune cells in different organs including the heart in addition to microvascular thrombosis, which is associated with elevated D-dimer levels 48 

Old age and underlying comorbidities were reported as the main risk factors for cardiac abnormalities in COVID-19 patients. Xu et al. collected data from 102 COVID-19 patients divided into two groups with and without cardiac abnormalities including acute cardiac injury 49 . High proportion of patients who had acute cardiac injury were aged >60 years with underlying comorbidities including hypertension and CVD. Similarly, it was observed in six out of the eight included cohort studies that higher proportions of COVID-19 patients who developed CI had underlying baseline CVD 13, 14, [17] [18] [19] . It was previously reported that pulmonary infections induced hypoxemia, respiratory failure, hypotension or shock may compromise the oxygen supply to the myocardium. In patients with comorbidities such as J o u r n a l P r e -p r o o f CVD or hypertension, the mismatch between oxygen supply and demand is amplified even further increasing the chances of CI [50] [51] [52] [53] . SARS-CoV-2 may also directly attack the cardiomyocytes by interacting with ACE2 expressed in the cardiac tissue, triggering a cascade of events that may lead to a hyperinflammatory state. Consequently, patients with underlying CVD may be more affected by the direct viral attack 50, 54 . Therefore, it is evident that comorbid CVD may increase the risk of developing CI during the course of infection. 

Out of the 443 patients who developed CI as reported by the eight included cohort studies, 341 had myocardial injury which was identified by elevated troponin T or I [17] [18] [19] .

RV dilation and dysfunction was detected in 82 patients and was identified by TTE 16 . 

Previous reports including comparing the effect of cardiotropic and non-cardiotropic viruses showed that the cardiotropic viruses may cause arrhythmia, atrioventricular block, myocardial infarction, cardiogenic shock, congestive heart failure while the non-cardiopathic viruses may cause arrhythmia, myocardial infarction, cardiogenic shock and congestive heart failure 57 . It is consequently hard to distinguish between both types of viruses by solely relying on clinical presentation. However, differences were observed in the histology where lymphocytic myocarditis was mainly caused by the non-cardiopathic viruses while lymphocytic, eosinophilic and giant-cell myocarditis and cardiac sclerosis were caused by the cardiotropic viruses 57 . Gatta and Dolan reported that the autopsy-proven myocardial localization of the virus has rarely been reported 58 Inflammatory cytokines may lead to apoptosis or necrosis of the myocardial cells.

Furthermore, systemic hyperinflammation may reduce coronary blood flow, destabilize other coronary plaque, and lead to micro-thrombogenesis, particularly in patients with comorbid CVD 13 .

RAAS inhibitors are widely used to treat hypertension and heart failure. Several studies reported that RAAS inhibitors upregulate ACE2 expression 64, 65 . This led to some arguments regarding the possible role of RAAS inhibitors in increasing the risk and/or the severity of COVID-19 and some recommended to discontinue the medications during the pandemic 66, 67 . Interestingly, Sattar et al., (2020) reported that they stopped the initial regimen of the RAAS inhibitor drug in their patient in response to these recommendations 35 .

The patient who had comorbid hypertension and diabetes died due to respiratory failure.

Several studies reported that RAAS inhibitors did not affect the outcome of COVID-19 while some described their protective role by reducing serum inflammatory and cardiac markers and reducing mortality 68, 69, 70 . SARS CoV-2 was found to downregulate ACE2 receptors in the cardiopulmonary system, leading to the accumulation of ATII which is known to have proinflammatory properties 71 . This may also play a role in the hyperinflammatory state triggered by the virus. Therefore, RAAS inhibitors may play two contradictory roles during the course of SARS-CoV-2 infection by upregulating ACE2 which may increase the risk of infection but meanwhile reduce inflammation. As RAAS inhibitors have not been reported to increase the severity of COVID-19, this may support the hypothesis of systemic inflammation being the main causative factor behind CI. If CI is caused by the direct viral attack of the cardiomyocytes, RAAS inhibitors should have been associated with worse prognosis in COVID-19 patients who used the drugs. It is worth noting that the users of RAAS inhibitors have comorbidities that may even increase the severity and mortality due to COVID-19.

While multiple lines of evidence support the involvement of hyperinflammation in the development of cardiac injury, it is still unclear why some but not all COVID-19 patients develop a severe hyperinflammatory response. In general, it was reported that SARS-CoV-2 may inhibit different antiviral defense mechanisms including the IFN-I signaling pathway through various mechanisms. IFN-I is known to create an antiviral state and to inhibit viral replication. Therefore, the impairment of the IFN-I signaling pathways may lead to uncontrolled viral replication which may cause the dysregulated inflammatory response 72, 73 . 

Due to the accumulating evidence suggesting that hyperinflammation mediates many of the complications of COVID-19, the use of potent anti-inflammatory drugs as part of the treatment protocols has been an important aspect to consider. Based on previous experience with SARS-CoV, different treatments and interventions have been implemented as an attempt to treat COVID-19. Among those treatments are the potent anti-inflammatory glucocorticoids which are used to suppress hyperinflammation. Initially, observational studies showed that glucocorticoid benefit was dependent on serum CRP level of COVID-19 patients 75 . The RECOVERY trial group however showed that treatment with 6 mg/day of dexamethasone for 10 days reduced mortality in hospitalised COVID-19 patients who required supplemental oxygen or mechanical ventilation 76 . Some studies reported other types of anti-inflammatory drugs such as IL-1 receptor antagonist 27 . Furthermore, tocilizumab, which blocks the IL-6 receptor has been reported by several studies as one of the drugs being used to treat COVID- 19 22,26,27,32,36,38 .

While it is evident that underlying CVD may increase the risk of cardiac injury, many COVID-19 patients included in this study developed different types of cardiac injury without previously having any of the reported risk factors including age and comorbidities. Overall, multiple evidences suggest that cardiac injury is triggered by the systemic hyperinflammation Number/percentage of case reports/series that reported at least one inflammation marker above the threshold that may indicate hyperinflammation/cytokine storm syndrome (CSC) in children/adolescents (a), adults (b) or children/adolescents and adults (c). Hyperinflammation/CSC was defined as CRP> 150 mg/L and/or ferritin> 1500 ng/mL or IL-6> 80 pg/mL Figure 3 . Types of cardiac injury (CI) in the COVID-19 patients included in the case reports/series. Pie chart "a" illustrates that 69% of children/adolescents developed myocarditis, 5% developed myocarditis with Kawasaki like symptoms, 3% developed Kawasaki like symptoms only and 5% developed other types of cardiac injury. Pie chart "b" shows that 55% of adults developed myocarditis, 36% developed other types of cardiac injury while 9% developed Takostubo syndrome.

Age and underlying cardiovascular comorbidities of COVID-19 patients who developed cardiac injury (CI) in the included case reports/series. Pie chart "a" illustrates that 78% of the patients with CI were children/adolescents. Pie chart "b" illustrates that none of children/adolescents who developed CI had any underlying CVD and 91% of them did not have any comorbidities. Pie chart "c" illustrates that only 50% of the adults who developed CI had comorbid HTN and/or CVD. 

SARS-CoV-2 Infection and Cardiovascular Disease: COVID-19 Heart

WHO Coronavirus Disease (COVID-19) Dashboard | WHO Coronavirus Disease (COVID-19) Dashboard. Accessed

Malakan Rad E. Cardiovascular disease in COVID-19: a systematic review and meta-analysis of 10,898 patients and proposal of a triage risk stratification tool

Cardiovascular Implications of the COVID-19 Pandemic: A Global Perspective

Structure, Function, and Evolution of Coronavirus Spike Proteins

SARS coronavirus entry into host cells through a novel clathrin-and caveolae-independent endocytic pathway

Renin-angiotensin-aldosterone (RAAS): The ubiquitous system for homeostasis and pathologies

Angiotensin II revisited: new roles in inflammation, immunology and aging

Angiotension-(1-7) and antihypertensive mechanisms

Immunologic Effects of the Renin-Angiotensin System

Impact of cardiovascular disease and cardiac injury on inhospital mortality in patients with COVID-19: a systematic review and meta-analysis

Prognostic significance of cardiac injury in COVID-19 patients with and without coronary artery disease. Coron Artery Dis

Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)

Retrospective Study of Risk Factors for Myocardial Damage in Patients With Critical Coronavirus Disease 2019 in Wuhan

SARS-CoV-2-Induced Immune Dysregulation and Myocardial Injury Risk in China

Echocardiographic Findings in Patients With COVID-19 Pneumonia

Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019

Association of Cardiac Injury With Mortality in J

Hospitalized Patients With COVID-19 in Wuhan, China

Acute myocardial injury is common in patients with COVID-19 and impairs their prognosis

Cardiac MRI in Children with Multisystem Inflammatory Syndrome Associated with COVID-19

Cases With Non-respiratory Symptoms as the First Manifestation in Children. Front Pediatr

A Recovered Case of COVID-19 Myocarditis and ARDS Treated With Corticosteroids, Tocilizumab, and Experimental AT-001

COVID-19 cardiac involvement in a 38-day old infant

Acute Inflammation and Elevated Cardiac Markers in a Two-Month-Old Infant with Severe Acute Respiratory Syndrome Coronavirus 2 Infection Presenting with Cardiac Symptoms

Myocarditis in a 16-year-old boy positive for SARS-CoV-2. The Lancet

Toxic shock-like syndrome and COVID-19: A case report of multisystem inflammatory syndrome in children (MIS-C)

Acute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children

Pharmaco-invasive Therapy for STEMI in a Patient with COVID-19: A Case Report

Case 18-2020: A 73-Year-Old Man with Hypoxemic Respiratory Failure and Cardiac Dysfunction

Cardiac dysfunction and thrombocytopeniaassociated multiple organ failure inflammation phenotype in a severe paediatric case of COVID-19

Diffuse Myocardial Inflammation in COVID-19

Multiparametric Cardiac Magnetic Resonance Imaging

Pediatric Life-Threatening Coronavirus Disease 2019 With Myocarditis

New onset severe right ventricular failure associated with COVID-19 in a young infant without previous heart disease

Multisystem Inflammatory Syndrome with Features of Atypical Kawasaki Disease during COVID-19 Pandemic

Myocardial localization of coronavirus in COVID-19 cardiogenic shock

Takotsubo cardiomyopathy triggered by SARS-CoV-2 infection in a critically ill patient

Intramural Hematoma as Unexpected Complication of COVID-19 Infection

Heart failure exacerbation as only presenting sign of COVID-19

Terra incognita: clinically suspected myocarditis in a patient with severe acute respiratory syndrome coronavirus 2 infection

First case of COVID-19 complicated with fulminant myocarditis: a case report and insights

Advancement in biosensors for inflammatory biomarkers of SARS-CoV-2 during 2019-2020

Association of inflammatory markers with the severity of COVID-19: A meta-analysis

Elevated interleukin-6 and adverse outcomes in COVID-19 patients: a meta-analysis based on adjusted effect estimates

Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis

Confronting the controversy: interleukin-6 and the COVID-19 cytokine storm syndrome

Delving beneath the surface of hyperinflammation in COVID-19

COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study

Solomon Scott D. Severe COVID-19 Is a Microvascular Disease

Clinical Characteristics and Risk Factors of Cardiac Involvement in COVID-19

COVID-19 and cardiac injury: clinical manifestations, biomarkers, mechanisms, diagnosis, treatment, and follow up

At the heart of COVID-19

Renin-Angiotensin System and Cardiovascular Functions

Acute myocarditis associated with novel Middle east respiratory syndrome coronavirus

The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association

The Epidemiology and Pathogenesis of Kawasaki Disease. Front Pediatr

Cardiac injuries in coronavirus disease 2019 J o u r n a l P r e -p r o o f (COVID-19)

Pathophysiology and Cardiac Autopsy in COVID-19 related Myocarditis

Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases

COVID-19 and the cardiovascular system

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome

COVID-19 and Multiorgan Response

Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Receptor Blockers on Cardiac Angiotensin-Converting Enzyme 2

SARS-CoV-2 receptor ACE2 gene expression and RAAS inhibitors

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

The interplay between the immune system, the renin angiotensin aldosterone system (RAAS) and RAAS inhibitors may modulate the outcome of COVID-19: A systematic review

Continued In-Hospital Angiotensin-Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker Use in Hypertensive

Patients Is Associated With Positive Clinical Outcome

The effect of RAS blockers on the clinical characteristics of COVID-19 patients with hypertension

Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19

Activation and evasion of type I interferon responses by SARS-CoV-2

The Role of Type I Interferons in the Pathogenesis and Treatment of COVID-19

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Effect of Systemic Glucocorticoids on Mortality or Mechanical Ventilation in Patients With COVID-19

Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report

J o u r n a l P r e -p r o o f