Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Alongside investigations into the virology of SARS-CoV-2, understanding the fundamental physiological and immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and rational design of effective therapies. Here, we provide an overview of the pathophysiology of SARS-CoV-2 infection. We describe the interaction of SARS-CoV-2 with the immune system and the subsequent contribution of dysfunctional immune responses to disease progression. From nascent reports describing SARS-CoV-2, we make inferences on the basis of the parallel pathophysiological and immunological features of the other human coronaviruses targeting the lower respiratory tract - severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Finally, we highlight the implications of these approaches for potential therapeutic interventions that target viral infection and/or immunoregulation.

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The trinity of COVID-19: immunity, inflammation and intervention.

Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

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Extrapulmonary manifestations of COVID-19.

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases.

Background The new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused more than 210 000 deaths worldwide However, little is known about the causes of death and the virus's pathologic features Objective To validate and compare clinical findings with data from medical autopsy, virtual autopsy, and virologic tests Design Prospective cohort study Setting Autopsies performed at a single academic medical center, as mandated by the German federal state of Hamburg for patients dying with a polymerase chain reaction-confirmed diagnosis of COVID-19 Patients The first 12 consecutive COVID-19-positive deaths Measurements Complete autopsy, including postmortem computed tomography and histopathologic and virologic analysis, was performed Clinical data and medical course were evaluated Results Median patient age was 73 years (range, 52 to 87 years), 75% of patients were male, and death occurred in the hospital (n = 10) or outpatient sector (n = 2) Coronary heart disease and asthma or chronic obstructive pulmonary disease were the most common comorbid conditions (50% and 25%, respectively) Autopsy revealed deep venous thrombosis in 7 of 12 patients (58%) in whom venous thromboembolism was not suspected before death; pulmonary embolism was the direct cause of death in 4 patients Postmortem computed tomography revealed reticular infiltration of the lungs with severe bilateral, dense consolidation, whereas histomorphologically diffuse alveolar damage was seen in 8 patients In all patients, SARS-CoV-2 RNA was detected in the lung at high concentrations; viremia in 6 of 10 and 5 of 12 patients demonstrated high viral RNA titers in the liver, kidney, or heart Limitation Limited sample size Conclusion The high incidence of thromboembolic events suggests an important role of COVID-19-induced coagulopathy Further studies are needed to investigate the molecular mechanism and overall clinical incidence of COVID-19-related death, as well as possible therapeutic interventions to reduce it Primary funding source University Medical Center Hamburg-Eppendorf

Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study.

Little is known of the pathologic changes that lead to death in patients with COVID-19. This study reports the autopsy findings of consecutive patients who died with a diagnosis of COVID-19.

Autopsy Findings and Venous Thromboembolism in Patients With COVID-19.

The aim of this study was to identify factors associated with the death of patients with COVID-19 pneumonia caused by the novel coronavirus SARS-CoV-2. All clinical and laboratory parameters were collected prospectively from a cohort of patients with COVID-19 pneumonia who were hospitalised to Wuhan Pulmonary Hospital (Wuhan City, Hubei Province, China) between 25 December 2019 and 7 February 2020. Univariate and multivariate logistic regression was performed to investigate the relationship between each variable and the risk of death of COVID-19 pneumonia patients. In total, 179 patients with COVID-19 pneumonia (97 male and 82 female) were included in the present prospective study, of whom 21 died. Univariate and multivariate logistic regression analysis revealed that age ≥65 years (OR 3.765, 95% CI 1.146‒17.394; p=0.023), pre-existing concurrent cardiovascular or cerebrovascular diseases (OR 2.464, 95% CI 0.755‒8.044; p=0.007), CD3+CD8+ T-cells ≤75 cells·μL−1 (OR 3.982, 95% CI 1.132‒14.006; p We identified four risk factors: age ≥65 years, pre-existing concurrent cardiovascular or cerebrovascular diseases, CD3+CD8+ T-cells ≤75 cells·μL−1 and cardiac troponin I ≥0.05 ng·mL−1. The latter two factors, especially, were predictors for mortality of COVID-19 pneumonia patients.

https://erj.ersjournals.com/content/erj/55/5/2000524.full.pdf

Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study.

Histopathologic Changes and SARS–CoV-2 Immunostaining in the Lung of a Patient With COVID-19 Background: Although many studies have demonstrated the epidemiologic characteristics of SARS–CoV-2 disease (COVID-19), details of pathologic changes in the lung are still lacking. Objective: To describe the histopathologic changes in the lung of a patient with COVID-19. Case Report: A 72-year-old man with a history of diabetes and hypertension presented with fever and cough. His throat and pharyngeal swabs were positive for SARS–CoV-2 by day 6 after the initial symptoms. Rapidly progressive respiratory failure required endotracheal intubation and mechanical ventilation 1 week after presentation. Lung tissue was obtained by transthoracic 14-gauge needle biopsy from the left upper anterior segment (Figure 1, A, arrow), left upper lingular segment (Figure 1, B, arrow), and left lower lobe (Figure 1, C, arrow), coinciding with groundglass opacities on chest computed tomography (CT). Two throat swab samples were collected from the tonsils and posterior pharyngeal wall. Biopsy lung sections were analyzed with hematoxylin– eosin staining, and immunostaining for SARS–CoV-2 was conducted as reported elsewhere (1). Throat swabs were assessed for SARS–CoV-2 by using real-time reverse transcriptase polymerase chain reaction assays (2). The CT scans revealed patchy bilateral ground glass–like opacifications (Figure 1A-C, arrows). Despite antiviral therapies, respiratory and hemodynamic instability continued and the patient died 3 weeks after diagnosis. Permission for postmortem transthoracic needle biopsy, but not autopsy, was obtained from the patient's family. Histopathologic examination of lung biopsy tissues revealed diffuse alveolar damage, organizing phase. Denuded alveolar lining cells (Figure 2, A-1, arrow 1), with reactive type II pneumocyte hyperplasia, were noted (Figure 2, A-1, arrow 2). Intra-alveolar fibrinous exudates were present (Figure 2, A-2, arrow 3), along with loose interstitial fibrosis and chronic inflammatory infiltrates (Figure 2, A-2, arrow 4). Intra-alveolar loose fibrous plugs of organizing pneumonia were noted (Figure 2, A-3, arrow 5), with presence of intra-alveolar organizing fibrin seen in most foci (Figure 2, A-4, arrow 6). Immunostaining of lung sections with an antibody to the Rp3 NP protein of SARS–CoV-2 revealed prominent expression on alveolar epithelial cells (Figure 2, B, top panel), including damaged, desquamated cells within the alveolar space

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Histopathologic Changes and SARS-CoV-2 Immunostaining in the Lung of a Patient With COVID-19.

Comparison of Hospitalized Patients With ARDS Caused by COVID-19 and H1N1.

Comparison of Hospitalized Patients with Acute Respiratory Distress Syndrome Caused by COVID-19 and H1N1

Author response to the correspondence regarding “Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study” https://bit.ly/31X8cal

https://erj.ersjournals.com/content/erj/56/3/2002961.full.pdf

Ming Hu

Papers

Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study.

Histopathologic Changes and SARS-CoV-2 Immunostaining in the Lung of a Patient With COVID-19.

Comparison of Hospitalized Patients With ARDS Caused by COVID-19 and H1N1.

Comparison of Hospitalized Patients with Acute Respiratory Distress Syndrome Caused by COVID-19 and H1N1

Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2.