key: cord-1036188-ul53w55f authors: Geng, Yong-Jian; Wei, Zhi-Yao; Qian, Hai-Yan; Huang, Ji; Lodato, Robert; Castriotta, Richard J. title: Pathophysiological Characteristics and Therapeutic Approaches for Pulmonary Injury and Cardiovascular Complications of Coronavirus Disease 2019 date: 2020-04-17 journal: Cardiovasc Pathol DOI: 10.1016/j.carpath.2020.107228 sha: 0e59c4a5d15a4b7f56c45f01ecd70eaf15be6efe doc_id: 1036188 cord_uid: ul53w55f Abstract The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a major health crisis, with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) having infected over a million people around the world within a few months of its identification as a human pathogen. Initially, SARS-CoV-2 infects cells in the respiratory system and causes inflammation and cell death. Subsequently, the virus spreads out and damages other vital organs and tissues, triggering a complicated spectrum of pathophysiological changes and symptoms, including cardiovascular complications. Acting as the receptor for SARS-CoV entering mammalian cells, angiotensin converting enzyme-2 (ACE2) plays a pivotal role in the regulation of cardiovascular cell function. Diverse clinical manifestations and laboratory abnormalities occur in patients with cardiovascular injury in COVID-19, characterizing the development of this complication, as well as providing clues to diagnosis and treatment. This review provides a summary of the rapidly appearing laboratory and clinical evidence for the pathophysiology and therapeutic approaches to COVID-19 pulmonary and cardiovascular complications. The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a major health crisis, with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) having infected over a million people around the world within a few months of its identification as a human pathogen. Initially, SARS-CoV-2 infects cells in the Since December 2019, an acute severe viral infectionivolving primarily the respiratory system has emerged with rapid transmission around the world to over a million people within a few months. Named coronavirus disease 2019 by the World health organization 1 , the disease pandemic has resulted in a major health crisis. The pathogen of COVID-19 has been attributed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel beta coronavirus closely related to severe acute respiratory syndrome coronavirus (SARS-CoV) 2 has resulted in many infections and death throughout the world 3 . Unlike those seen in influenza, the morbidity and transmission modality of COVID-19 appear more severe and uncontrollable 4 . The primary pulmonary injury and subsequent cardiovascular complications constitute the key pathophysiology of this deadly disease. This review updates and summarizes the pathophysiological features, possible underlying mechanisms, and clinical characteristics of pulmonary and cardiovascular injury of COVID-19. The highly contagious virus, SARS-CoV-2, has been identified as the primary pathogen responsible for the development of COVID-19. It belongs to the Coronaviridae family 5 . Structurally and functionally similar to most members of the Betacoranavirus Subgroup B, SARS-CoV-2 ( Fig. 1 ) has thought to be descended from a bat gene pool as the seventh member of coronavirus family known to infect humans, and comprises a positive-sense single-stranded RNA with 50-200nm in size 6 . Among the other 6 coronaviruses capable of causing illnesses, only SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) reportedly cause severe disease and fatalities 7 . Infection by the other 4 coronaviruses remains asymptomatic or mildly symptomatic in normal people. According to the full-length genome sequencing, SARS-CoV-2 is 79.5% homologous with SARS-CoV. Like SARS-CoV, SARS-CoV-2 infects lung alveolar epithelial cells by receptor-mediated endocytosis in association with angiotensin converting enzyme II (ACE2) 8 . An epidemiological study enrolling 44672 confirmed cases in China has indicated that the overall case-fatality rate of SARS-CoV-2 was about 2.3% 9 , whereas it was 9.6% (774/8096) in the SARS-CoV epidemic 10 and 34.4% (858/2494) in the MERS-CoV outbreak 11 . Mortality in Italy, Spain and France may be higher and closer to that of SARS-CoV. This may be due to strain variation, yet to be determined. However, in consideration of rapidly increasing numbers of confirmed cases and evidence of human-to-human transmission 12, 13 , the SARS-CoV-2 infectivity seems to be stronger than SARS-CoV and MERS-CoV. Ultrastructural examination of SARS-CoV-2 by cryo-electron microscopy has demonstrated that the binding affinity of SARS-CoV-2 to ACE2 appears approximately 10-to 20-fold higher than SARS-CoV, structurally explaining why SARS-CoV-2 has a high contagiousness 14 . In spite of the fact that SARS-CoV-2 has infected more than a million individuals it is largely unknown how and when the virus has been evolving and interacts with other microorganisms (Table 1) in the lung and other vital organs, such as heart and brain. Shen, et al. 15 has recently reported a genomic diversity of SARS-Cov-2 in patients with COVID-19. They observed, by meta-transcriptomal sequencing for the bronchoalveolar lavage fluid samples from of COVID-19, community-acquired pneumonia, and healthy individuals. They observed a limited polymorphism and diversity in the intra-host setting, and a substantial proportion of bacteria in several COVID-19 patients, similar to other patients with non-coronaviral pneumonia. As a common complication of viral infection, especially for respiratory viruses, secondary bacterial infection often results in a significant increase in morbidity or even mortality. Indeed, in the retrospective observational study of 85 fatal cases of COVID-19, Du, et al. 16 reported that in addition to SARS-Cov-2 infection, simultaneously or secondarily, other pathogens may participate in the COVID-19 development and complications, contributing to the severity and mortality of COVID-19. Thus, co-infection of other pathogens certainly complicates the pathogenesis and management of COVID-19. As recommended by WHO, most countries, including the United States, have adapted similar diagnostic procedures for COVID-19 and harvest certain clinical and epidemiologic information for diagnosis ( Initially, testing for all other sources of respiratory infection is implemented while assessing epidemiologic factors to assist their diagnosis, including the information as to whether the person has had close contact with a patient with laboratory-confirmed COVID-19 within 14 days of symptom onset or a history of travel from affected geographic areas or epicenters within 14 days. The clinical profiles and diagnosis for COVID-19 have been well documented to date. However, new evidence is now emerging that this deadly disease is far more mystery than previously thought as many cases appeared atypical and easily misdiagnostic 17 Table 2 ). Wang et al. 18 suggest that diagnosing the confirmed case should base on suspected case with any one item of pathogenic or serological evidence as following: (1) real-time PCR test positive for SARS-CoV-2; (2) viral whole genome sequencing showing high homogeneity to the known novel coronaviruses; (3) positive for the specific IgM antibody and IgG antibody to SARS-CoV-2 in serum test; or a change of the SARS-CoV-2-specific IgG antibody from negative to positive, or titer rising ≥4 times in the recovery phase above that in the acute phase. SARS-CoV-2 mainly attacks the respiratory system, clinically characterized by the rapid development of pneumonia, and in severe cases, the acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome 19 . The death rate remains high in those admitted to the intensive care and on ventilator due to complications of respiratory and cardiac failure 16 In epidemiology, high prevalence of cardiovascular dysfunction has been recently reported in COVID-19 patients, especially those with critical medical conditions 29 . In a study of 138 COVID-19 patients, 10 patients (7.2%) were diagnosed as acute myocardial injury based on the elevation of high-sensitivity cardiac troponin I (hs-cTnI), and 8 of them admitted into the intensive care unit (ICU) 12 injury was independently associated with higher risk of in-hospital mortality 27 . Hence, early myocardial injury in COVID-19 leads to a poor prognosis in COVID-19 patients. Changes of cardiac-specific biomarkers in the peripheral blood have been reported in patients with COVID-19. As stated above, hs-cTnI acts as one of the specific biomarkers of myocardial injury 37 The binding between SARS-CoV spike protein and ACE2 on the cardiomyocyte surface also triggers the Ras-ERK-AP-1 pathway and activates the C-C motif chemokine ligand 2 (CCL2, a pro-fibrosis factor) 41 . The above theories are supported by an autopsy report of heart samples from SARS patients, in which the presence of SARS-CoV in the heart was associated with marked down-regulation of ACE2 expression as well as a significant increase in macrophage infiltration and interstitial fibrosis, verifying ACE2 inhibition is involved in SARS-CoV-driven myocardial injury 49 . The specific cellular mechanism for SARS-CoV-2 invading and damaging cardiomyocytes has not been clearly demonstrated yet, but it is probable that SARS-CoV-2 shares the similar mechanism with its relative SARS-CoV. A recent study investigated ultrastructure of full-length human ACE2 with cryo-EM 51 , indicating that SARS-CoV-2 also invaded host cells via spike protein trimers binding to an ACE2 homodimer. In addition, the interface between the receptor binding domains of spike proteins on SARS-CoV-2 is quite similar to that between the SARS-CoV and ACE2. Furthermore, the serine protease TMPRSS2 is also indispensable for the entry of SARS-CoV-2 52 . Given that the high similarity of cellular entry with that of SARS-CoV, it is reasonable to speculate that SARS-CoV-2 interferes in ACE2 expression in the same way. However, this needs to be verified in cardiomyocytes in the further study. Myocardial oxygen supply is determined by coronary blood flow and its oxygen carrying capacity while myocardial oxygen demand is determined by systolic wall tension, contractility, and heart rate 53 . This physiological mechanism may be involved in SARS-CoV-2-induced myocardial injury. As is well-known, pulmonary dysfunction is the primary insult of SARS-CoV-2, which induces hypoxemia, hypotension and, in some cases, shock 20, 39 . As a consequencet, an insufficient oxygen supply may occur in multiple organs including the heart. Concomitantly, myocardial oxygen demand is increased in virus-infection states, as high metabolic rate induces an augmented burden on the myocardium 54 55, 56 . Among so many cytokines, IL-6 serves as the core of cytokine storm, given that IL-6 not only amplifies cytokine storm by stimulating production of other pro-inflammatory cytokines, but also results in vascular leakage, interstitial edema 57 . Moreover, IL-6 has also been shown to weaken papillary muscle contraction, which causes myocardial dysfunction 58 . In addition, IFNγ is also regarded as a marker of cytokine storm, causing cell apoptosis through regulating JAK/STAT1 axis and p38-MAPK1 59 . However, anti-inflammatory cytokines such as IL-4 and IL-10 are also increased in COVID-19 patients, and their levels are also related to disease severity 55, 56 , demonstrating the close relation between pro-and anti-inflammation. Cytokine storm is a clear contributor to COVID-19-related myocardial injury, demonstrated by a study that revealed that increased levels of IL-6 were significantly associated with high hs-TnI levels 26 , a cardiac-selective biomarker of myocardial infarction and injury 37 . Further studies are needed to explore the cytokine expression in cardiomyocytes, which will promote a better understanding for SARS-CoV-2-induced inflammation in cardiac tissue. Overall, direct infection through ACE2, the imbalance between myocardial oxygen supply and demand, and the abnormal immune response constitute the most plausible explanations for myocardial injury associated with COVID-19. To be noted, however, the above speculation is mostly based on clinical observation of COVID-19. Therefore, more in-depth research is required to understand the pathophysiology of SARS-CoV-2-induced myocardial injury in order to contribute to the future development of effective treatment. The general clinical symptoms found in COVID- 19 suggesting that myocardial inflammation occurred in COVID-19 patients 30 . As the cytokine storm and consequent inflammatory response are suggested to be the mechanisms contributing to myocardial injury, low EAT density showed in chest CT scan appears to be a high-risk factor for myocardial injury. However, low EAT density is not the optimal imaging parameter of COVID-19-related myocardial injury since it is an indirect sign of inflammation and may be substantively influenced by subjective factors in clinical practice. Other imaging modalities with high sensitivity and specificity such as echocardiography and myocardial magnetic resonance imaging should be preferentially chosen if appropriate. Treatment of COVID-19 has been mostly restricted to supportive measures as there has been, to date, no specific therapy available to treat this disease. Pre-existing poor-health conditions increase the risk of cardiovascular comorbidity, with poorer Hydroxychloroquine and chloroquine are traditional anti-malarial and autoimmune disease drugs. They have been shown to control the SARS-Cov-2 infection in vitro 61, 68 . The underlying mechanism may involve the increase in the endosomal pH required for virus/cell fusion， interference with the glycosylation of ACE2 69 The structural evidence of SARS-Cov-2 invasion of cells via ACE2 has led to the hypothesis that ACEI/ARB treatment potentially induces overexpression of ACE2, which subsequently increases the susceptibility of host cells to SARS-Cov-2 invasion and the risk of infection or worsening the severity of disease 80 Other therapies with less evidence-based foundation are also worth mentioning. Plasma treatment means transfusing convalescent plasma containing anti-virus polyclonal antibodies, and were proved to be effective in treating SARS patients and COVID-19 patients in observational studies 81, 82 . Although the number of patients so treated is small, this does make scientific sense. Dilated horse anti-SARS-CoV-2 serum could cross-neutralize SARS-CoV-2 in an in vitro study 8  General discomforts, typically fever, fatigue, headache, muscle ache, diarrhea, etc.  Signs and symptoms of lung and airway abnormalities, typically cough and dyspnea.  Total white blood cell counts showing normal, decreased, or reduced lymphocyte count in the early onset stage, and increased neutrophils in more advanced cases.  Real-time PCR test positive for SARS-CoV-2.  Viral sequencing showing high homogeneity to SARS-CoV-2.  Serum test positive for SARS-CoV-2 specific IgM and IgG.  Chest radiography or CT scan showing multiple mottling and ground-glass opacities with or without consolidation in the lung periphery. . Schematic demonstration of the viral injury to the lung and heart triggering the "Lung-Heart" syndromes with a combination of the respiratory and cardiovascular adverse events and conditions. 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All the co-authors have no conflict of interest to be declared.