SARS Unique Domain (SUD) of Severe Acute Respiratory Syndrome Coronavirus Induces NLRP3 Inflammasome-Dependent CXCL10-Mediated Pulmonary Inflammation.

Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) initiates the cytokine/chemokine storm-mediated lung injury. The SARS-CoV unique domain (SUD) with three macrodomains (N, M, and C), showing the G-quadruplex binding activity, was examined the possible role in SARS pathogenesis in this study. The chemokine profile analysis indicated that SARS-CoV SUD significantly up-regulated the expression of CXCL10, CCL5 and interleukin (IL)-1ß in human lung epithelial cells and in the lung tissues of the mice intratracheally instilled with the recombinant plasmids. Among the SUD subdomains, SUD-MC substantially activated AP-1-mediated CXCL10 expression in vitro. In the wild type mice, SARS-CoV SUD-MC triggered the pulmonary infiltration of macrophages and monocytes, inducing CXCL10-mediated inflammatory responses and severe diffuse alveolar damage symptoms. Moreover, SUD-MC actuated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome-dependent pulmonary inflammation, as confirmed by the NLRP3 inflammasome inhibitor and the NLRP3-/- mouse model. This study demonstrated that SARS-CoV SUD modulated NLRP3 inflammasome-dependent CXCL10-mediated pulmonary inflammation, providing the potential therapeutic targets for developing the antiviral agents.

No evidence of SARS-CoV-2 in hospitalized patients with severe acute respiratory syndrome in five Italian hospitals from 1st November 2019 to 29th February 2020.

BACKGROUND: On 9th January 2020, China CDC reported a novel coronavirus (later named SARS-CoV-2) as the causative agent of the coronavirus disease 2019 (COVID-19). Identifying the first appearance of virus is of epidemiological importance to tracking and mapping the spread of SARS-CoV-2 in a country. We therefore conducted a retrospective observational study to detect SARS-CoV-2 in oropharyngeal samples collected from hospitalized patients with a Severe Acute Respiratory Infection (SARI) enrolled in the DRIVE (Development of Robust and Innovative Vaccine Effectiveness) study in five Italian hospitals (CIRI-IT BIVE hospitals network) (1st November 2019 - 29th February 2020). OBJECTIVES: To acquire new information on the real trend in SARS-CoV-2 infection during pandemic phase I and to determine the possible early appearance of the virus in Italy. MATERIALS AND METHODS: Samples were tested for influenza [RT-PCR assay (A/H1N1, A/H3N2, B/Yam, B/Vic)] in accordance with the DRIVE study protocol. Subsequently, swabs underwent molecular testing for SARS-COV-2. [one-step real-time multiplex retro-transcription (RT) PCR]. RESULTS: In the 1683 samples collected, no evidence of SARS-CoV-2 was found. Moreover, 28.3% (477/1683) of swabs were positive for influenza viruses, the majority being type A (358 vs 119 type B). A/H3N2 was predominant among influenza A viruses (55%); among influenza B viruses, B/Victoria was prevalent. The highest influenza incidence rate was reported in patients aged 0-17 years (40.3%) followed by those aged 18-64 years (24.4%) and ≥65 years (14.8%). CONCLUSIONS: In Italy, some studies have shown the early circulation of SARS-CoV-2 in northern regions, those most severely affected during phase I of the pandemic. In central and southern regions, by contrast no early circulation of the virus was registered. These results are in line with ours. These findings highlight the need to continue to carry out retrospective studies, in order to understand the epidemiology of the novel coronavirus, to better identify the clinical characteristics of COVID-19 in comparison with other acute respiratory illnesses (ARI), and to evaluate the real burden of COVID-19 on the healthcare system.

Quantitative evaluation of aerosol generation during manual facemask ventilation.

Manual facemask ventilation, a core component of elective and emergency airway management, is classified as an aerosol-generating procedure. This designation is based on one epidemiological study suggesting an association between facemask ventilation and transmission during the SARS-CoV-1 outbreak in 2003. There is no direct evidence to indicate whether facemask ventilation is a high-risk procedure for aerosol generation. We conducted aerosol monitoring during routine facemask ventilation and facemask ventilation with an intentionally generated leak in anaesthetised patients. Recordings were made in ultraclean operating theatres and compared against the aerosol generated by tidal breathing and cough manoeuvres. Respiratory aerosol from tidal breathing in 11 patients was reliably detected above the very low background particle concentrations with median [IQR (range)] particle counts of 191 (77-486 [4-1313]) and 2 (1-5 [0-13]) particles.l-1 , respectively, p = 0.002. The median (IQR [range]) aerosol concentration detected during facemask ventilation without a leak (3 (0-9 [0-43]) particles.l-1 ) and with an intentional leak (11 (7-26 [1-62]) particles.l-1 ) was 64-fold (p = 0.001) and 17-fold (p = 0.002) lower than that of tidal breathing, respectively. Median (IQR [range]) peak particle concentration during facemask ventilation both without a leak (60 (0-60 [0-120]) particles.l-1 ) and with a leak (120 (60-180 [60-480]) particles.l-1 ) were 20-fold (p = 0.002) and 10-fold (0.001) lower than a cough (1260 (800-3242 [100-3682]) particles.l-1 ), respectively. This study demonstrates that facemask ventilation, even when performed with an intentional leak, does not generate high levels of bioaerosol. On the basis of this evidence, we argue facemask ventilation should not be considered an aerosol-generating procedure.

Host and viral determinants for efficient SARS-CoV-2 infection of the human lung.

Understanding the factors that contribute to efficient SARS-CoV-2 infection of human cells may provide insights on SARS-CoV-2 transmissibility and pathogenesis, and reveal targets of intervention. Here, we analyze host and viral determinants essential for efficient SARS-CoV-2 infection in both human lung epithelial cells and ex vivo human lung tissues. We identify heparan sulfate as an important attachment factor for SARS-CoV-2 infection. Next, we show that sialic acids present on ACE2 prevent efficient spike/ACE2-interaction. While SARS-CoV infection is substantially limited by the sialic acid-mediated restriction in both human lung epithelial cells and ex vivo human lung tissues, infection by SARS-CoV-2 is limited to a lesser extent. We further demonstrate that the furin-like cleavage site in SARS-CoV-2 spike is required for efficient virus replication in human lung but not intestinal tissues. These findings provide insights on the efficient SARS-CoV-2 infection of human lungs.

Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease.

The emergence of SARS-CoV-2 has created an international health crisis, and small animal models mirroring SARS-CoV-2 human disease are essential for medical countermeasure (MCM) development. Mice are refractory to SARS-CoV-2 infection owing to low-affinity binding to the murine angiotensin-converting enzyme 2 (ACE2) protein. Here, we evaluated the pathogenesis of SARS-CoV-2 in male and female mice expressing the human ACE2 gene under the control of the keratin 18 promoter (K18). In contrast to nontransgenic mice, intranasal exposure of K18-hACE2 animals to 2 different doses of SARS-CoV-2 resulted in acute disease, including weight loss, lung injury, brain infection, and lethality. Vasculitis was the most prominent finding in the lungs of infected mice. Transcriptomic analysis from lungs of infected animals showed increases in transcripts involved in lung injury and inflammatory cytokines. In the low-dose challenge groups, there was a survival advantage in the female mice, with 60% surviving infection, whereas all male mice succumbed to disease. Male mice that succumbed to disease had higher levels of inflammatory transcripts compared with female mice. To our knowledge, this is the first highly lethal murine infection model for SARS-CoV-2 and should be valuable for the study of SARS-CoV-2 pathogenesis and for the assessment of MCMs.

The lethal internal face of the coronaviruses: Kidney tropism of the SARS, MERS, and COVID19 viruses.

The kidney is one of the main targets attacked by viruses in patients with a coronavirus infection. Until now, SARS-CoV-2 has been identified as the seventh member of the coronavirus family capable of infecting humans. In the past two decades, humankind has experienced outbreaks triggered by two other extremely infective members of the coronavirus family; the MERS-CoV and the SARS-CoV. According to several investigations, SARS-CoV causes proteinuria and renal impairment or failure. The SARS-CoV was identified in the distal convoluted tubules of the kidney of infected patients. Also, renal dysfunction was observed in numerous cases of MERS-CoV infection. And recently, during the 2019-nCoV pandemic, it was found that the novel coronavirus not only induces acute respiratory distress syndrome (ARDS) but also can induce damages in various organs including the liver, heart, and kidney. The kidney tissue and its cells are targeted massively by the coronaviruses due to the abundant presence of ACE2 and Dpp4 receptors on kidney cells. These receptors are characterized as the main route of coronavirus entry to the victim cells. Renal failure due to massive viral invasion can lead to undesirable complications and enhanced mortality rate, thus more attention should be paid to the pathology of coronaviruses in the kidney. Here, we have provided the most recent knowledge on the coronaviruses (SARS, MERS, and COVID19) pathology and the mechanisms of their impact on the kidney tissue and functions.

Emerging Human Coronavirus Infections (SARS, MERS, and COVID-19): Where They Are Leading Us.

Coronavirus infections are responsible for mild, moderate, and severe infections in birds and mammals. These were first isolated in humans as causal microorganisms responsible for common cold. The 2002-2003 SARS epidemic caused by SARS-CoV and 2012 MERS epidemic (64 countries affected) caused by MERS-CoV showed their acute and fatal side. These two CoV infections killed thousands of patients infected worldwide. However, WHO has still reported the MERS case in December 2019 in middle-eastern country (Saudi Arabia), indicating the MERS epidemic has not ended completely yet. Although we have not yet understood completely these two CoV epidemics, a third most dangerous and severe CoV infection has been originated in the Wuhan city, Hubei district of China in December 2019. This CoV infection called COVID-19 or SARS-CoV2 infection has now spread to 210 countries and territories around the world. COVID-19 has now been declared a pandemic by the World Health Organization (WHO). It has infected more than 16.69 million people with more than 663,540 deaths across the world. Thus the current manuscript aims to describe all three (SARS, MERS, and COVID-19) in terms of their causal organisms (SARS-CoV, MERS-CoV, and SARS-CoV2), similarities and differences in their clinical symptoms, outcomes, immunology, and immunopathogenesis, and possible future therapeutic approaches.

Patient hematology during hospitalization for viral pneumonia caused by SARS-CoV-2 and non-SARS-CoV-2 agents: a retrospective study.

BACKGROUND: Hematological comparison of coronavirus disease (COVID-19) and other viral pneumonias can provide insights into COVID-19 treatment. METHODS: In this retrospective case-control single-center study, we compared the data of 126 patients with viral pneumonia during different outbreaks [severe acute respiratory syndrome (SARS) in 2003, influenza A (H1N1) in 2009, human adenovirus type 7 in 2018, and COVID-19 in 2020]. RESULTS: One of the COVID-19 characteristics was a continuous decline in the hemoglobin level. The neutrophil count was related to the aggravation of COVID-19 and SARS. Thrombocytopenia occurred in patients with SARS and severe COVID-19 even at the recovery stage. Lymphocytes were related to the entire course of adenovirus infection, recovery of COVID-19, and disease development of SARS. CONCLUSIONS: Dynamic changes in hematological counts could provide a reference for the pathogenesis and prognosis of pneumonia caused by respiratory viruses in clinics.

Immunological map in COVID-19.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2, a newly discovered coronavirus that exhibits many similarities with the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses (SARS-CoV and MERS-CoV, respectively). The definite pathogenesis and immunological influences of SARS-CoV-2 have not been fully elucidated. Therefore, we constructed a brief summary comparison of SARS-CoV-2, SARS-CoV, and MERS-CoV infections regarding their immunological changes. In addition, we further investigated the immunological differences between severe and nonsevere COVID-19 cases, and we searched for possible immunological predictors of the patient outcome by reviewing case series studies to date. Possible immunological predictors of a poor outcome are leukocytosis, neutrophilia, lymphopenia (both CD4 and CD8 T cells), an increased neutrophil-to-lymphocyte ratio (NLR), and increased levels of pro-inflammatory cytokines (IL-6 and TNF-α), Th1 cytokines (IL-2 and IFN-γ), regulatory T cell cytokines (IL-10) and Th17 cytokines (IL-17). A more precise immunological map needs to be established, which may assist in diagnosing this disease and facilitate immunological precision medicine treatment.

The emerging SARS-CoV-2 papain-like protease: Its relationship with recent coronavirus epidemics.

The papain-like protease (PLpro ) is an important enzyme for coronavirus polyprotein processing, as well as for virus-host immune suppression. Previous studies reveal that a molecular analysis of PLpro indicates the catalytic activity of viral PLpro and its interactions with ubiquitin. By using sequence comparisons, molecular models, and protein-protein interaction maps, PLpro was compared in the three recorded fatal CoV epidemics, which involved severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome CoV (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV). The pairwise sequence comparison of SARS-CoV-2 PLpro indicated similarity percentages of 82.59% and 30.06% with SARS-CoV PLpro and MERS-CoV PLpro , respectively. In comparison with SARS-CoV PLpro , in SARS-CoV-2, the PLpro had a conserved catalytic triad of C111, H278, and D293, with a slightly lower number of polar interface residues and of hydrogen bonds, a higher number of buried interface sizes, and a lower number of residues that interact with ubiquitin and PLpro . These features might contribute to a similar or slightly lower level of deubiquitinating activity in SARS-CoV-2 PLpro. It was, however, a much higher level compared to MERS-CoV, which contained amino acid mutations and a low number of polar interfaces. SARS-CoV-2 PLpro and SARS-CoV PLpro showed almost the same catalytic site profiles, interface area compositions and polarities, suggesting a general similarity in deubiquitination activity. Compared with MERS-CoV, SARS-CoV-2 had a higher potential for binding interactions with ubiquitin. These estimated parameters contribute to the knowledge gap in understanding how the new virus interacts with the immune system.

Recent Findings on Cell-Based Therapies for COVID19-Related Pulmonary Fibrosis.

COVID-19 has spread worldwide, including the United States, United Kingdom, and Italy, along with its site of origin in China, since 2020. The virus was first found in the Wuhan seafood market at the end of 2019, with a controversial source. The clinical symptoms of COVID-19 include fever, cough, and respiratory tract inflammation, with some severe patients developing an acute and chronic lung injury, such as acute respiratory distress syndrome (ARDS) and pulmonary fibrosis (PF). It has already claimed approximately 300 thousand human lives and the number is still on the rise; the only way to prevent the infection is to be safe till vaccines and reliable treatments develop. In previous studies, the use of mesenchymal stem cells (MSCs) in clinical trials had been proven to be effective in immune modulation and tissue repair promotion; however, their efficacy in treating COVID-19 remains underestimated. Here, we report the findings from past experiences of SARS and MSCs, and how SARS could also induce PF. Such studies may help to understand the rationale for the recent cell-based therapies for COVID-19.

Surviving the Rookie Virus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2): The Immunopathology of a SARS-CoV2 Infection.

Until July 29th, the number of confirmed coronavirus (COVID-19) cases worldwide has risen to over 16 million, within which 655 k deaths. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) emerges as the 11th global pandemic disease, showing the highest infectivity and lowest infection fatality rate. In this review, we compare the immunopathology among SARS-CoV, Middle East respiratory syndrome coronavirus, and SARS-CoV2. SARS-CoV2 is similar to SARS-CoV; it can cause lymphocytopenia and a rising granulocyte count. Here we point out the human body and concentrated society make for an excellent incubator for virus evolution. Most research energies put into developing the SARS-CoV2 vaccine are trying to block virus infection. Sixty-five percent of severe patients die with multiple organ failure, inflammation, and cytokine storm, which indicates that the patient's immune system maintains functionality. Finding a way to trigger the specific T cell subset and plasmablast in our body is the best shot to get away with SARS-CoV2.

Autopsy Tool in Unknown Diseases: The Experience with Coronaviruses (SARS-CoV, MERS-CoV, SARS-CoV-2).

In the last two decades, three unknown pathogens have caused outbreaks, generating severe global health concerns. In 2003, after nucleic acid genotyping, a new virus was named severe acute respiratory syndrome coronavirus (SARS-CoV). After nine years, another coronavirus emerged in the middle east and was named MERS-CoV (Middle East Respiratory Syndrome-Coronavirus). Finally, in December 2019, a new unknown coronavirus was isolated from a cluster of patients and was named SARS-CoV-2 (COVID-19, coronavirus disease 2019). This review aims to propose a complete overview of autopsy in the three coronaviruses over the past two decades, showing its pivotal role in the management of unknown diseases. A total of 116 studies fulfilled the inclusion criteria: 14 studies were collected concerning SARS-CoV (87 autopsy reports, from Asian and American countries), 2 studies for MERS-CoV (2 autopsy reports, from Middle-East Asian countries), and 100 studies on SARS-CoV-2 (930 autopsy reports). Analyzing the data obtained on COVID-19, based on the country criterion, a large number of post-mortem investigation were performed in European countries (580 reports), followed by American countries (251 reports). It is interesting to note that no data were found from the Oceanic countries, maybe because of the minor involvement of the outbreak. In all cases, autopsy provided much information about each unknown coronavirus. Despite advanced technologies in the diagnostic fields, to date, autopsy remains the gold standard method to understand the biological features and the pathogenesis of unknown infections, especially when awareness of a pathogen is restricted and the impact on the healthcare system is substantial. The knowledge gained through this technique may positively influence therapeutic strategies, ultimately reducing mortality.

Evidences for lipid involvement in SARS-CoV-2 cytopathogenesis.

The pathogenesis of SARS-CoV-2 remains to be completely understood, and detailed SARS-CoV-2 cellular cytopathic effects requires definition. We performed a comparative ultrastructural study of SARS-CoV-1 and SARS-CoV-2 infection in Vero E6 cells and in lungs from deceased COVID-19 patients. SARS-CoV-2 induces rapid death associated with profound ultrastructural changes in Vero cells. Type II pneumocytes in lung tissue showed prominent altered features with numerous vacuoles and swollen mitochondria with presence of abundant lipid droplets. The accumulation of lipids was the most striking finding we observed in SARS-CoV-2 infected cells, both in vitro and in the lungs of patients, suggesting that lipids can be involved in SARS-CoV-2 pathogenesis. Considering that in most cases, COVID-19 patients show alteration of blood cholesterol and lipoprotein homeostasis, our findings highlight a peculiar important topic that can suggest new approaches for pharmacological treatment to contrast the pathogenicity of SARS-CoV-2.

Molecular mechanisms of Na,K-ATPase dysregulation driving alveolar epithelial barrier failure in severe COVID-19.

A significant number of patients with coronavirus disease 2019 (COVID-19) develop acute respiratory distress syndrome (ARDS) that is associated with a poor outcome. The molecular mechanisms driving failure of the alveolar barrier upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain incompletely understood. The Na,K-ATPase is an adhesion molecule and a plasma membrane transporter that is critically required for proper alveolar epithelial function by both promoting barrier integrity and resolution of excess alveolar fluid, thus enabling appropriate gas exchange. However, numerous SARS-CoV-2-mediated and COVID-19-related signals directly or indirectly impair the function of the Na,K-ATPase, thereby potentially contributing to disease progression. In this Perspective, we highlight some of the putative mechanisms of SARS-CoV-2-driven dysfunction of the Na,K-ATPase, focusing on expression, maturation, and trafficking of the transporter. A therapeutic mean to selectively inhibit the maladaptive signals that impair the Na,K-ATPase upon SARS-CoV-2 infection might be effective in reestablishing the alveolar epithelial barrier and promoting alveolar fluid clearance and thus advantageous in patients with COVID-19-associated ARDS.

Zoonotic coronavirus epidemics: Severe acute respiratory syndrome, Middle East respiratory syndrome, and coronavirus disease 2019.

OBJECTIVE: To review the virology, immunology, epidemiology, clinical manifestations, and treatment of the following 3 major zoonotic coronavirus epidemics: severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19). DATA SOURCES: Published literature obtained through PubMed database searches and reports from national and international public health agencies. STUDY SELECTIONS: Studies relevant to the basic science, epidemiology, clinical characteristics, and treatment of SARS, MERS, and COVID-19, with a focus on patients with asthma, allergy, and primary immunodeficiency. RESULTS: Although SARS and MERS each caused less than a thousand deaths, COVID-19 has caused a worldwide pandemic with nearly 1 million deaths. Diagnosing COVID-19 relies on nucleic acid amplification tests, and infection has broad clinical manifestations that can affect almost every organ system. Asthma and atopy do not seem to predispose patients to COVID-19 infection, but their effects on COVID-19 clinical outcomes remain mixed and inconclusive. It is recommended that effective therapies, including inhaled corticosteroids and biologic therapy, be continued to maintain disease control. There are no reports of COVID-19 among patients with primary innate and T-cell deficiencies. The presentation of COVID-19 among patients with primary antibody deficiencies is variable, with some experiencing mild clinical courses, whereas others experiencing a fatal disease. The landscape of treatment for COVID-19 is rapidly evolving, with both antivirals and immunomodulators demonstrating efficacy. CONCLUSION: Further data are needed to better understand the role of asthma, allergy, and primary immunodeficiency on COVID-19 infection and outcomes.

Autopsies in pandemics - a perspective on barriers and benefits. Is it time for a revival?

Influenza virus and coronavirus pandemics regularly sweep the globe, at great cost of health and economy. Our aim was to conduct a PubMed search for autopsy studies on influenza and coronavirus to investigate the contribution of autopsies during pandemics, focussing on autopsy methods and procedures and the role of autopsy findings in pandemics. The retrieved autopsy studies generally relied on microscopy, polymerase chain reaction (PCR), immunostaining and electron microscopy. Most were small and reported on lung effects, including diffuse alveolar damage (DAD), pneumonia and tracheobronchitis. Antibiotic therapy has diminished a role for bacterial pneumonia, whereas obesity is an emerging risk factor. Autopsy studies have provided new insights into coronavirus disease 2019 (COVID-19) treatments like anti-coagulative therapy. Unfortunately, autopsies during pandemics are hampered by lack of guidelines, facilities and expertise for handling potentially infectious corpses and by widely varying recommendations for personal protective equipment and procedures. The Department of Forensic Pathology, at the Forensic Institute, at the University of Copenhagen in Denmark has, in collaboration with the Department of Pathology, Rigshospitalet, Copenhagen, initiated a prospective observational study on COVID-19-related deaths encompassing postmortem imaging, standardized autopsy procedures/reporting and extensive tissue sampling for histological, chemical, microbiological and genetic analysis. The study involves a diverse array of research groups at the University of Copenhagen, and the clinical field.

A double edged-sword - The Complement System during SARS-CoV-2 infection.

In the past 20 years, infections caused by coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 have posed a threat to public health since they may cause severe acute respiratory syndrome (SARS) in humans. The Complement System is activated during viral infection, being a central protagonist of innate and acquired immunity. Here, we report some interactions between these three coronaviruses and the Complement System, highlighting the central role of C3 with the severity of these infections. Although it can be protective, its role during coronavirus infections seems to be contradictory. For example, during SARS-CoV-2 infection, Complement System can control the viral infection in asymptomatic or mild cases; however, it can also intensify local and systemic damage in some of severe COVID-19 patients, due to its potent proinflammatory effect. In this last condition, the activation of the Complement System also amplifies the cytokine storm and the pathogenicity of coronavirus infection. Experimental treatment with Complement inhibitors has been an enthusiastic field of intense investigation in search of a promising additional therapy in severe COVID-19 patients.

Histopathology and genetic susceptibility in COVID-19 pneumonia.

BACKGROUND: The clinical features of COVID-19 pneumonia range from a mild illness to patients with a very severe illness with acute hypoxemic respiratory failure requiring ventilation and Intensive Care Unit admission. AIMS: To provide a brief overview of the existing evidence for such differences in host response and outcome, and generate hypotheses for divergent patterns and avenues for future research, by highlighting similarities and differences in histopathological appearance between COVID-19 and influenza as well as previous coronavirus outbreaks, and by discussing predisposition through genetics and underlying disease. MATERIALS AND METHOD: We assessed the available early literature for histopathological patterns of COVID-19 pneumonia and underlying risk factors. RESULT: The histopathological spectrum of COVID-19 pneumonia includes variable patterns of epithelial damage, vascular complications, fibrosis and inflammation. Risk factors for a fatal disease include older age, respiratory disease, diabetes mellitus, obesity and hypertension. DISCUSSION: While some risk factors and their potential role in COVID-19 pneumonia are increasingly recognized, little is known about the mechanisms behind episodes of sudden deterioration or the infrequent idiosyncratic clinical demise in otherwise healthy and young subjects. CONCLUSION: The answer to many of the remaining questions regarding COVID-19 pneumonia pathogenesis may in time be provided by genotyping as well careful clinical, serological, radiological and histopathological phenotyping.