The new coronavirus SARS-CoV-2, first identified in Wuhan, China in December, 2019, can cause Severe Acute Respiratory Syndrome (SARS) with massive alveolar damage and progressive respiratory failure. We present the relevant autopsy findings of the first patient known to have died from COVID19 pneumonia in Spain, carried out on the 14th of February, 2020, in our hospital (Hospital Arnau de Vilanova-Lliria, Valencia). Histological examination revealed typical changes of diffuse alveolar damage (DAD) in both the exudative and proliferative phase of acute lung injury. Intra-alveolar multinucleated giant cells, smudge cells and vascular thrombosis were present. The diagnosis was confirmed by reverse real-time PCR assay on a throat swab sample taken during the patient's admission. The positive result was reported fifteen days subsequent to autopsy.

Autopsy findings from the first known death from Severe Acute Respiratory Syndrome SARS-CoV-2 in Spain

Infection by the new corona virus strain SARS-CoV-2 and its related syndrome COVID-19 has caused several hundreds of thousands of deaths worldwide. Patients of higher age and with preexisting chronic health conditions are at an increased risk of fatal disease outcome. However, detailed information on causes of death and the contribution of comorbidities to death yet is missing. Here, we report autopsy findings on causes of death and comorbidities of 26 decedents that had clinically presented with severe COVID-19. We found that septic shock and multi organ failure was the most common immediate cause of death, often due to suppurative pulmonary infection. Respiratory failure due to diffuse alveolar damage presented as the most immediate cause of death in fewer cases. Several comorbidities, such as hypertension, ischemic heart disease, and obesity were present in the vast majority of patients. Our findings reveal that causes of death were directly related to COVID-19 in the majority of decedents, while they appear not to be an immediate result of preexisting health conditions and comorbidities. We therefore suggest that the majority of patients had died of COVID-19 with only contributory implications of preexisting health conditions to the mechanism of death.

Causes of Death and Comorbidities in Patients with COVID-19

The mortality rate of coronavirus disease-19 (COVID-19) has been reported as 1-6% in most studies. The cause of most deaths has been acute pneumonia. Nevertheless, it has been noted that cardiovascular failure can also lead to death. Three COVID-19 patients were diagnosed based on reverse transcriptase-polymerase chain reaction of a nasopharyngeal swab test and radiological examinations in our hospital. The patients received medications at the discretion of the treating physician. In this case series, chest computed tomography scans and electrocardiograms, along with other diagnostic tests were used to evaluate these individuals. Sudden cardiac death in COVID-19 patients is not common, but it is a major concern. So, it is recommended to monitor cardiac condition in selected patients with COVID-19.

Sudden cardiac death in COVID-19 patients, a report of three cases

The mortality rate of coronavirus disease-19 (COVID-19) has been reported as 1–6% in most studies. The cause of most deaths has been acute pneumonia. Nevertheless, it has been noted that cardiovascular failure can also lead to death. Three COVID-19 patients were diagnosed based on reverse transcriptase-polymerase chain reaction of a nasopharyngeal swab test and radiological examinations in our hospital. The patients received medications at the discretion of the treating physician. In this case series, chest computed tomography scans and electrocardiograms, along with other diagnostic tests were used to evaluate these individuals. Sudden cardiac death in COVID-19 patients is not common, but it is a major concern. So, it is recommended to monitor cardiac condition in selected patients with COVID-19.

As of April 2020, the coronavirus 2019 (COVID-19) pandemic has resulted in more than 210,000 deaths globally. The most common cause of death from COVID-19 is acute respiratory failure. We report the case of a 78-year-old female with a history of hypertension, cerebrovascular accident (CVA), type 2 diabetes mellitus, and sarcoidosis, who presented to the emergency department with one day of dyspnea. The patient experienced a rapid decline in respiratory function and was intubated in the intensive care unit (ICU), meeting the Berlin criteria for severe acute respiratory distress syndrome (ARDS). Chest radiography revealed diffuse bilateral coalescent opacities, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA swab test was positive for COVID-19. The patient experienced acute kidney injury with uptrending creatinine levels and remained lethargic and unresponsive throughout her ICU stay, suggestive of potential hypoxic brain injury. In light of the patient’s poor clinical status, age, and significant comorbidities, prognosis was conveyed about medical futility and patient’s family agreed to terminal extubation and the patient expired peacefully, exactly one week from hospital admission. This case report highlights the speed at which severe ARDS can present and contribute to end-organ dysfunction in COVID-19 patients.

A Case Report of Rapidly Lethal Acute Respiratory Distress Syndrome Secondary to Coronavirus Disease 2019 Viral Pneumonia

A recently developed pneumonia caused by SARS-CoV-2 bursting in Wuhan, China, has quickly spread across the world. We report the clinical characteristics of 82 cases of death from COVID-19 in a single center. Clinical data on 82 death cases laboratory-confirmed as SARS-CoV-2 infection were obtained from a Wuhan local hospital's electronic medical records according to previously designed standardized data collection forms. All patients were local residents of Wuhan, and a large proportion of them were diagnosed with severe illness when admitted. Due to the overwhelming of our system, a total of 14 patients (17.1%) were treated in the ICU, 83% of deaths never received Critical Care Support, only 40% had mechanical ventilation support despite 100% needing oxygen and the leading cause of death being pulmonary. Most of the patients who died were male (65.9%). More than half of the patients who died were older than 60 years (80.5%), and the median age was 72.5 years. The bulk of the patients who died had comorbidities (76.8%), including hypertension (56.1%), heart disease (20.7%), diabetes (18.3%), cerebrovascular disease (12.2%), and cancer (7.3%). Respiratory failure remained the leading cause of death (69.5%), followed by sepsis/MOF (28.0%), cardiac failure (14.6%), hemorrhage (6.1%), and renal failure (3.7%). Furthermore, respiratory, cardiac, hemorrhagic, hepatic, and renal damage were found in 100%, 89%, 80.5%, 78.0%, and 31.7% of patients, respectively. On admission, lymphopenia (89.2%), neutrophilia (74.3%), and thrombocytopenia (24.3%) were usually observed. Most patients had a high neutrophil-to-lymphocyte ratio of >5 (94.5%), high systemic immune-inflammation index of >500 (89.2%), and increased C-reactive protein (100%), lactate dehydrogenase (93.2%), and D-dimer (97.1%) levels. A high level of IL-6 (>10 pg/ml) was observed in all detected patients. The median time from initial symptoms to death was 15 days (IQR 11-20), and a significant association between aspartate aminotransferase (p = 0.002), alanine aminotransferase (p = 0.037) and time from initial symptoms to death was remarkably observed. Older males with comorbidities are more likely to develop severe disease and even die from SARS-CoV-2 infection. Respiratory failure is the main cause of COVID-19, but the virus itself and cytokine release syndrome-mediated damage to other organs, including cardiac, renal, hepatic, and hemorrhagic damage, should be taken seriously as well.

Clinical characteristics of 82 cases of death from COVID-19.

COVID-19 is an acute respiratory tract infection caused by a coronavirus known as SARS-CoV-2. The common signs of infection include respiratory symptoms such as shortness of breath, breathing difficulties, dry cough, fever, and in some patients, severe acute respiratory syndrome, kidney failure, and death. 312,009 deaths from COVID-19 has been reported as of today. While respiratory symptoms are commonly caused by the infection, the use of mechanical ventilation is required for some patients. The following is intended to review the development and testing of a 3D printed and open-source mechanical ventilation device that is capable of adjusting breathing rate, volume, and pressure simultaneously and was designed according to the latest clinical observations of the current pandemic. The intuitive design of this device along with the use of primarily 3D printed or readily available components allow the rapid manufacturing and transportation of this ventilation device to the impacted regions.

Open source 3D printed Ventilation Device

Background: COVID-19 was the leading cause of death in the United States over the three-month period March through May 2020. Another perspective is COVID-19s toll in terms of years of life lost. We calculated years of life lost for COVID-19 and other leading causes of death over those three months in the US. We also predicted years of life lost for COVID-19 and ischemic heart diseases (which includes heart attacks) for March through August 2020. Methods: Years of life lost are the sum of differences between life expectancy at age of death and age at death. Average years of life lost, years of life lost divided by the number of deaths, were also calculated. We used the COVID-19 Projections Using Machine Learning model to predict years of life lost from COVID-19 through the end of August 2020. Results: COVID-19 caused 12,035 more deaths than ischemic heart diseases during March through May 2020 but ischemic heart diseases years of life lost were 1.5% greater than those for COVID-19. Average years of life lost were 10.8 and 12.4 for COVID-19 and ischemic heart diseases, respectively. At the end of August, COVID-19 may overtake ischemic heart diseases as the leading cause of deaths and years of life lost in the US. Conclusion: Each COVID-19 death causes more than a decade of lost life in the US. We are reminded of a Danish Proverb that states "Prediction is difficult, especially when dealing with the future." We suggest that while dying is bad, losing life is even worse.

COVID-19: Dying is Bad--Losing Life is Worse

Risk factors for death from COVID-19

In the last few weeks Italy first, and then several other countries across the world, have been swept up by the deadly wave of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the illness named COVID-19, from the acronym CO (corona) VI (virus) D (disease) and 19 (year of the virus identification). The medical community is working day and night to assist affected people and experts in communicable diseases are striving in multiple ways to understand the progression of events leading to the lethal respiratory syndrome.

COVID‐19: what if the brain had a role in causing the deaths?

Abstract Background. Today humanity is facing another infectious threat: a newly emerging virus SARS-CoV-2 causing COVID-19. It was already described that COVID-19 mortality among elderly people and people with such underlying conditions as obesity, cardiovascular diseases, cancer, chronic respiratory diseases, and diabetes s increased. Dysregulation of the immune responses vital for antiviral defense, which are typical for chronic inflammation, led us to a hypothesis that chronic inflammation is the main risk factor for increased susceptibility and mortality from COVID-19. Method. Based on the available information for 126 countries, statistical analysis to find out whether the difference in incidence and mortality within countries can be explained by the existing chronic inflammation among the countries population, was conducted. Results. A positive correlation between the percentage of people dying from chronic noncommunicable diseases and COVID-19 incidence (p<0.001) and mortality (p<0.001) within countries. Conclusion. The problem of COVID-19-caused high mortality rate may be a consequence of the high number of people having chronic low-grade inflammation as a precondition, and thus, one of the potential ways to reduce risk of morbidity and mortality is to focus on this widespread health problem, mainly occurring in developed countries and to take corresponding diagnostic, preventative, and treatment measures.

COVID-19 Pandemic: Is Chronic Inflammation a Major Cause of Death?

In this case report, a 50-year-old man who had no medical history, presented with multiple cardiac arrests following a week with progressing symptoms of pneumonia. After achieving return of spontaneous circulation he presented with respiratory failure with severe hypoxia, septic shock, and multiple organ failure. A chest X-ray showed signs of acute respiratory distress syndrome. Despite aggressive intensive care management, the patient died 7.5 hours after admission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was later confirmed, and the presumed cause of death was SARS-CoV-2 pneumonia. In conclusion: coronavirus disease 2019 (COVID-19) can lead to a fatal outcome in younger healthy residents, who are not treated timely in case of severe symptoms like dyspnoea.

[Fatal outcome of coronavirus disease 2019 in a previously healthy 50-year-old man].

Clinical characteristics of 82 cases of death from COVID-19

The spread of pandemic COVID-19 has created unprecedented need for information. The pandemic is the cause of significant mortality and with this the need for rapidly disseminated information for palliative care professionals regarding the prevalence of symptoms, their intensity, their resistance or susceptibility to symptom control and the mode of death for patients. METHODS: We undertook a systematic review of published evidence for symptoms in patients with COVID-19 (with a specific emphasis on symptoms at end of life) and on modes of death. Inclusion: prospective or retrospective studies detailing symptom presence and/or cause or mode of death from COVID-19. RESULTS: 12 papers met the inclusion criteria and gave details of symptom burden: four of these specifically in the dying and two detailed the cause or mode of death. Cough, breathlessness, fatigue and myalgia are significant symptoms in people hospitalised with COVID-19. Dyspnoea is the most significant symptom in the dying. The mode of death was described in two papers and is predominantly through respiratory or heart failure. CONCLUSIONS: There remains a dearth of information regarding symptom burden and mode of death to inform decisions regarding end-of-life care in patients dying with COVID-19. Rapid data gathering on the mode of death and the profile of symptoms in the dying and their prevalence and severity in areas where COVID-19 is prevalent will provide important intelligence for clinicians. This should be done urgently, within ethical norms and the practicalities of a public health, clinical and logistical emergency.

Symptom burden and clinical profile of COVID-19 deaths: a rapid systematic review and evidence summary

COVID-19 is not deadly early in life, but mortality increases exponentially with age, which is the strongest predictor of mortality. Mortality is higher in men than in women, because men age faster, and it is especially high in patients with age-related diseases, such as diabetes and hypertension, because these diseases are manifestations of aging and a measure of biological age. At its deepest level, aging (a program-like continuation of developmental growth) is driven by inappropriately high cellular functioning. The hyperfunction theory of quasi-programmed aging explains why COVID-19 vulnerability (lethality) is an age-dependent syndrome, linking it to other age-related diseases. It also explains inflammaging and immunosenescence, hyperinflammation, hyperthrombosis, and cytokine storms, all of which are associated with COVID-19 vulnerability. Anti-aging interventions, such as rapamycin, may slow aging and age-related diseases, potentially decreasing COVID-19 vulnerability.

From causes of aging to death from COVID-19

Abstract Purpose: Currently, COVID-19 is causing a large number of deaths globally. However, few researches focused on the clinical features of death patients. This study conducted a retrospective analysis of clinical characteristics and mortal causes in Chinese COVID-19 death patients. Patients and methods: The clinical characteristics of death patients were collected from publicized by local health authorities in China. Expressions of virus targets in human organs were obtained from GTEx database. Results: 159 patients from 24 provinces in China were recruited in our study, including 26 young patients under 60 and 133 aged 60 or older. The median age was 71 years, which indicated that most death patients were elderly. More male patients died of COVID-19 than females (1.65 fold). Hypertension was the most common coexisting disorder and respiratory failure was the most common direct cause of death. Fever (71.19%) and cough (55.08%) were the predominant presenting symptoms. There was one asymptomatic patient. In addition, by comparing young and old patients, heart disease was identified as an important risk factor for death in the aged patients. ACE2 and TMPRSS2 were the targets of SARS-CoV-2, we analyzed their expression in different organs. TMPRSS2 and ACE2 had a high expression in the organs which had corresponding clinical features in death patients. Conclusion: Male, age and heart disease were the main risk factors of death. Beside, asymptomatic patients with serious coexisting disorders may also die of SARS-CoV-2. Thus, more attention should be paid to the old patients with heart disease and asymptomatic patients in the treatment . Keywords: COVID-19, SARS-Cov-2, death, coexisting disorder, cause of death

The clinical characteristics and mortal causes analysis of COVID-19 death patients

The spread of pandemic COVID-19 has created unprecedented need for information. The pandemic is the cause of significant mortality and with this the need for rapidly disseminated information for palliative care professionals regarding the prevalence of symptoms, their intensity, their resistance or susceptibility to symptom control and the mode of death for patients. METHODS We undertook a systematic review of published evidence for symptoms in patients with COVID-19 (with a specific emphasis on symptoms at end of life) and on modes of death. Inclusion: prospective or retrospective studies detailing symptom presence and/or cause or mode of death from COVID-19. RESULTS 12 papers met the inclusion criteria and gave details of symptom burden: four of these specifically in the dying and two detailed the cause or mode of death. Cough, breathlessness, fatigue and myalgia are significant symptoms in people hospitalised with COVID-19. Dyspnoea is the most significant symptom in the dying. The mode of death was described in two papers and is predominantly through respiratory or heart failure. CONCLUSIONS There remains a dearth of information regarding symptom burden and mode of death to inform decisions regarding end-of-life care in patients dying with COVID-19. Rapid data gathering on the mode of death and the profile of symptoms in the dying and their prevalence and severity in areas where COVID-19 is prevalent will provide important intelligence for clinicians. This should be done urgently, within ethical norms and the practicalities of a public health, clinical and logistical emergency.

Symptom burden and clinical profile of COVID-19 deaths: a rapid systematic review and evidence summary.

The evolution of pulmonary pathology in fatal COVID-19 disease: an autopsy study with clinical correlation

Here, we report the pathological findings of nine complete autopsies of individuals who died in community settings in the UK, three of which were positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), three tested negative for SARS-CoV-2 but are likely false negatives, and three died of other respiratory infections. Autopsy revealed firm, consolidated lungs or lobar pneumonia. Histology of the lungs showed changes of diffuse alveolar damage with fibrin membrane formation, thickened alveolar walls and interstitium with lymphocytic infiltrate, and type 2 pneumocyte hyperplasia with shedding into the alveolar space. This series is the first in the world to describe autopsy findings in individuals dying suddenly in the community, not previously known to have COVID-19 infection, and the first autopsy series in the UK. During a time when testing in the UK is currently primarily offered to patients in hospital or symptomatic key workers, with limited testing available in community settings, it highlights the importance of testing for COVID-19 at autopsy. Two deaths occurred in care homes where a diagnosis of COVID-19 allowed the health protection team to provide support in that 'closed setting' to reduce the risks of onward transmission. This work highlights the need for frequent COVID-19 testing in the management of patients in community settings. Comprehensive virology and microbiology assessment is pivotal to correctly identify the cause of death, including those due to COVID-19 infection, and to derive accurate death statistics.

COVID-19 autopsy in people who died in community settings: the first series.

Covid-19 death has a different relationship with age than is the case for other severe respiratory pathogens. The Covid-19 death rate increases exponentially with age, and the main risk factors are age itself, as well as having underlying conditions such as hypertension, diabetes, cardiovascular disease, severe chronic respiratory disease and cancer. Furthermore, the almost complete lack of deaths in children suggests that infection alone is not sufficient to cause death; rather, one must have gone through a number of changes, either as a result of undefined aspects of aging, or as a result of chronic disease. These characteristics of Covid-19 death are consistent with the multistep model of disease, a model which has primarily been used for cancer, and more recently for amyotrophic lateral sclerosis (ALS). We applied the multi-step model to data on Covid-19 case fatality rates (CFRs) from China, South Korea, Italy, Spain and Japan. In all countries we found that a plot of ln (CFR) against ln (age) was approximately linear with a slope of about 5. As a comparison, we also conducted similar analyses for selected other respiratory diseases. SARS showed a similar log-log age-pattern to that of Covid-19, albeit with a lower slope, whereas seasonal and pandemic influenza showed quite different age-patterns. Thus, death from Covid-19 and SARS appears to follow a distinct age-pattern, consistent with a multistep model of disease that in the case of Covid-19 is probably defined by comorbidities and age producing immune-related susceptibility. Identification of these steps would be potentially important for prevention and therapy for SARS-COV-2 infection.

Is death from Covid-19 a multistep process?

Excess out-of-hospital deaths during COVID-19 outbreak: evidence of pulmonary embolism as a main determinant

BACKGROUND: COVID-19 can cause a fatal outcome in elderly patients, as this case report illustrates. CASE PRESENTATION: An active male in his nineties with a high level of function, despite several severe chronic diseases, was admitted to Oslo University Hospital after two days of fatigue, fever, dyspnoea and dry cough. He scored qSOFA 1 of 3 points due to high respiratory rate, and SIRS 2 of 4 points due to high respiratory rate and fever of 39.4º C. PCR for influenza virus was negative and he received benzylpenicillin for pneumonia. The chest X-ray taken initially showed no lung affection. On day 5 after symptom debut he was tested for COVID-19 which was positive. He had not been travelling to high-risk areas or been exposed to any known confirmed COVID-19 patients. On the same day, a chest CT scan was performed that showed ground-glass opacities. In subsequent days the patient's health rapidly deteriorated. He developed irreversible respiratory failure with hypoxia without hypercapnia despite substantial oxygen support. Chest X-ray taken on disease day 7 showed progression of consolidations. The patient died 9 days after symptom debut. INTERPRETATION: This case illustrates a severe course of COVID-19 with fatal outcome. The patient was also one of the earliest admitted with COVID-19 in a Norwegian hospital and marked a new phase of the epidemic, as he had not been travelling to high-risk areas or been exposed to any confirmed COVID-19 patients.

En mann i 90-årene med feber og tørrhoste./ En mann i 90-årene med feber og tørrhoste./ A man in his nineties with fever and dry cough

“Severe acute respiratory syndrome” (SARS) due to coronavirus (SARS-CoV-2) infection is a well-known cause of death. Sometimes, demise can occur unexpectedly in apparently previous healthy individual after a brief period of trivial flu-like symptoms. In these doubtful cases, the forensic pathologist could be requested to define the cause of death occurred outside the hospital. In this report, the authors describe two autopsied cases of SARS-CoV-2-related deaths which occurred suddenly at home and were not preceded by hospitalization, highlighting associated histopathologic patterns and correlating them to pathophysiology of viral infection.

SARS-CoV-2-related deaths in routine forensic autopsy practice: histopathological patterns

COVID-19 autopsy in people who died in community settings: the first series

Abstract Objectives This study aims to summarize the clinical characteristics of death cases with COVID-19 and to identify critically ill patients of COVID-19 early and reduce their mortality. Methods The clinical records, laboratory findings and radiological assessments included chest X-ray or computed tomography were extracted from electronic medical records of 25 died patients with COVID-19 in Renmin Hospital of Wuhan University from Jan 14 to Feb 13, 2020. Two experienced clinicians reviewed and abstracted the data. Results The age and underlying diseases (hypertension, diabetes, etc.) were the most important risk factors for death of COVID-19 pneumonia. Bacterial infections may play an important role in promoting the death of patients. Malnutrition was common to severe patients. Multiple organ dysfunction can be observed, the most common organ damage was lung, followed by heart, kidney and liver. The rising of neutrophils, SAA, PCT, CRP, cTnI, D-dimer, LDH and lactate levels can be used as indicators of disease progression, as well as the decline of lymphocytes counts. Conclusions The clinical characteristics of 25 death cases with COVID-19 we summarized, which would be helpful to identify critically ill patients of COVID-19 early and reduce their mortality.

Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China

Background. Coronavirus disease 2019 (COVID-19) triggered by infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been widely pandemic all over the world. The aim of this study was to analyze the influence factors of death risk among 200 COVID-19 patients. Methods. Two hundred patients with confirmed SARS-CoV-2 infection were recruited. Demographic data and clinical characteristics were collected from electronic medical records. Biochemical indexes on admission were measured and patient's prognosis was tracked. The association of demographic data, clinical characteristics and biochemical indexes with death risk was analyzed. Results. Of 200 COVID-19 patients, 163 (81.5%) had at least one of comorbidities, including diabetes, hypertension, hepatic disease, cardiac disease, chronic pulmonary disease and others. Among all patients, critical cases, defined as oxygenation index lower than 200, accounted for 26.2%. Severe cases, oxygenation index from 200 to 300, were 29.7%. Besides, common cases, oxygenation index higher than 300, accounted for 44.1%. At the end of follow-up, 34 (17%) were died on mean 10.9 day after hospitalization. Stratified analysis revealed that older ages, lower oxygenation index and comorbidities elevated death risk of COVID-19 patients. On admission, 85.5% COVID-19 patients were with at least one of extrapulmonary organ injuries. Univariable logistic regression showed that ALT and TBIL, two indexes of hepatic injury, AST, myoglobin and LDH, AST/ALT ratio, several markers of myocardial injury, creatinine, urea nitrogen and uric acid, three indexes of renal injury, were positively associated with death risk of COVID-19 patients. Multivariable logistic regression revealed that AST/ALT ratio, urea nitrogen, TBIL and LDH on admission were positively correlated with death risk of COVID-19 patients. Conclusion. Older age, lower oxygenation index and comorbidities on admission elevate death risk of COVID-19 patients. AST/ALT ratio, urea nitrogen, TBIL and LDH on admission may be potential prognostic indicators. Early hospitalization is of great significance to prevent multiple organ damage and improve the survival of COVID-19 patients.

Influence factors of death risk among COVID-19 patients in Wuhan, China: a hospital-based case-cohort study

In December 2019 a novel disease [coronavirus disease 19 (COVID-19) emerged in the Wuhan province of the People's Republic of China. COVID-19 is caused by a novel coronavirus (SARS-CoV-2) thought to have jumped species, from another mammal to humans. A pandemic caused by this virus is running rampant throughout the world. Thousands of cases of COVID-19 are reported in England and over 10,000 patients have died. Whilst there has been progress in managing this disease, it is not clear which factors, besides age, affect the severity and mortality of COVID-19. A recent analysis of COVID-19 in Italy identified links between air pollution and death rates. Here, we explored the correlation between three major air pollutants linked to fossil fuels and SARS-CoV-2 lethality in England. We compare up-to-date, real-time SARS-CoV-2 cases and death measurements from public databases to air pollution data monitored across over 120 sites in different regions. We found that the levels of some markers of poor air quality, nitrogen oxides and ozone, are associated with COVID-19 lethality in different English regions. We conclude that the levels of some air pollutants are linked to COVID-19 cases and morbidity. We suggest that our study provides a useful framework to guide health policy in countries affected by this pandemic.

Links between air pollution and COVID-19 in England

Coronavirus disease 2019 (COVID-19) is an infectious disease that primarily affects the respiratory system, but it may cause cardiovascular complications such as thromboembolism. Rarely, pulmonary embolism may be encountered in patients with severe COVID-19 infection, especially in intensive care units. An asymptomatic young case of COVID-19 presenting with sudden death due to acute massive pulmonary embolism has not been previously described. We report a 41-year-old woman presented to emergency department with sudden death during physical activity. She had only history of diabetes mellitus and she was asymptomatic until sudden death. CT pulmonary angiography and chest CT scans revealed acute massive embolism and typical imaging findings of COVID-19 pneumonia, respectively. Interestingly, the patient had no symptoms or signs of infection and also had no risk factors for thromboembolism. COVID-19 infection appears to induce venous thromboembolism, especially pulmonary embolism. The case is remarkable in terms of showing how insidious and life-threatening COVID-19 infection can be.

Sudden death due to acute pulmonary embolism in a young woman with COVID-19

The COVID-19 virus has infected millions of people and resulted in hundreds of thousands of deaths worldwide. By using the logistic regression model, we identified novel critical factors associated with COVID19 cases, death, and case fatality rates in 154 countries and in the 50 U.S. states. Among numerous factors associated with COVID-19 risk, we found that the unitary state system was counter-intuitively positively associated with increased COVID-19 cases and deaths. Blood type B was a protective factor for COVID-19 risk, while blood type A was a risk factor. The prevalence of HIV, influenza and pneumonia, and chronic lower respiratory diseases was associated with reduced COVID-19 risk. Obesity and the condition of unimproved water sources were associated with increased COVID-19 risk. Other factors included temperature, humidity, social distancing, smoking, and vitamin D intake. Our comprehensive identification of the factors affecting COVID-19 transmission and fatality may provide new insights into the COVID-19 pandemic and advise effective strategies for preventing and migrating COVID-19 spread.

Identifying novel factors associated with COVID-19 transmission and fatality using the machine learning approach

A novel coronavirus, SARS-CoV-2, emerged in December 2019, leading within a few months to a global pandemic. COVID-19, the disease caused by this highly contagious virus, can have serious health consequences, though risks of complications are highly age-dependent. Rates of hospitalization and death are less than 0.1% in children, but increase to 10% or more in older people. Moreover, at all ages, men are more likely than women to suffer serious consequences from COVID-19. These patterns are familiar to the geroscience community. The effects of age and sex on mortality rates from COVID-19 mirror the effects of aging on almost all major causes of mortality. These similarities are explored here, and underscore the need to consider the role of basic biological mechanisms of aging on potential treatment and outcomes of COVID-19.

A geroscience perspective on COVID-19 mortality

"Severe acute respiratory syndrome" (SARS) due to coronavirus (SARS-CoV-2) infection is a well-known cause of death. Sometimes, demise can occur unexpectedly in apparently previous healthy individual after a brief period of trivial flu-like symptoms. In these doubtful cases, the forensic pathologist could be requested to define the cause of death occurred outside the hospital. In this report, the authors describe two autopsied cases of SARS-CoV-2-related deaths which occurred suddenly at home and were not preceded by hospitalization, highlighting associated histopathologic patterns and correlating them to pathophysiology of viral infection.

The spreading of Coronavirus (SARS-CoV-2) pandemic, known as COVID-19, has caused a great number of fatalities all around the World. Up to date (2020 May 6) in Italy we had more than 28,000 deaths, while there were more than 205.000 infected. The majority of patients affected by COVID-19 complained only slight symptoms: fatigue, myalgia or cough, but more than 15% of Chinese patients progressed into severe complications, with acute respiratory distress syndrome (ARDS), needing intensive treatment. We tried to summarize data reported in the last months from several Countries, highlighting that COVID-19 was characterized by cytokine storm (CS) and endothelial dysfunction in severely ill patients, where the progression of the disease was fast and fatal. Endothelial dysfunction was the fundamental mechanism triggering a pro-coagulant state, finally evolving into intravascular disseminated coagulation, causing embolization of several organs and consequent multiorgan failure (MOF). The Italian Society of Clinical Hemorheology and Microcirculation was aimed to highlight the role of microcirculatory dysfunction in the pathogenetic mechanisms of COVID-19 during the spreading of the biggest challenges to the World Health.

COVID-19 Sepsis and Microcirculation Dysfunction

Covid-19: risk factors for severe disease and death.

Summary Background The pneumonia caused by the 2019 novel coronavirus (SARS-CoV-2) is a highly infectious disease, which was occurred in Wuhan, Hubei Province, China in December 2019. As of February 13, 2020, a total of 59883 cases of COVID-19 in China have been confirmed and 1368 patients have died from the disease. However, the clinical characteristics of the dyed patients were still not clearly clarified. This study aims to summarize the clinical characteristics of death cases with COVID-19 and to identify critically ill patients of COVID-19 early and reduce their mortality. Methods The clinical records, laboratory findings and radiologic assessments included chest X-ray or computed tomography were extracted from electronic medical records of 25 died patients with COVID-19 in Renmin Hospital of Wuhan University from Jan 14 to Feb 13, 2020. Two experienced clinicians reviewed and abstracted the data. Findings The mean age of the dead was 71.48 years, the average course of the disease was 10.56 days, all patients eventually died of respiratory failure. All of those who died had underlying diseases, the most common of which was hypertension (16/25, 64%), followed by diabetes (10/25, 40%), heart diseases (8/25, 32%), kidney diseases (5/25, 20%), cerebral infarction (4/25, 16%), chronic obstructive pulmonary disease (COPD, 2/25, 8%), malignant tumors (2/25, 8%) and acute pancreatitis (1/25, 4%). The most common organ damage outside the lungs was the heart, followed by kidney and liver. In the patients' last examination before death, white blood cell and neutrophil counts were elevated in 17 patients (17/25, 68%) and 18 patients (18/25, 72%), lymphocyte counts were decreased in 22 patients (22/25, 88%). Most patients' PCT, CRP and SAA levels were elevated, the percentages were 90.5% (19/21), 85% (19/20) and 100% (21/21) respectively. The levels of the last test of neutrophils (15/16, 93.8%), PCT (11/11, 100%), CRP (11/13, 84.6%), cTnI (8/9, 88.9%), D-Dimer (11/12, 91.6%) and LDH (9/9, 100%) were increased as compared to the first test, while the levels of lymphocytes were decreased (14/16, 87.5%). Interpretation The age and underlying diseases (hypertension, diabetes, etc.) were the most important risk factors for death of COVID-19 pneumonia. Bacterial infections may play an important role in promoting the death of patients. Malnutrition was common to severe patients. Multiple organ dysfunction can be observed, the most common organ damage was lung, followed by heart, kidney and liver. The rising of neutrophils, SAA, PCT, CRP, cTnI, D-Dimer and LDH levels can be used as indicators of disease progression, as well as the decline of lymphocytes counts.

Clinical characteristics of 25 death cases infected with COVID-19 pneumonia: a retrospective review of medical records in a single medical center, Wuhan, China

COVID-19: what if the brain had a role in causing the deaths?

OBJECTIVES: This study aims to summarize the clinical characteristics of death cases with COVID-19 and to identify critically ill patients of COVID-19 early and reduce their mortality. METHODS: The clinical records, laboratory findings and radiological assessments included chest X-ray or computed tomography were extracted from electronic medical records of 25 died patients with COVID-19 in Renmin Hospital of Wuhan University from Jan 14 to Feb 13, 2020. Two experienced clinicians reviewed and abstracted the data. RESULTS: The age and underlying diseases (hypertension, diabetes, etc.) were the most important risk factors for death of COVID-19 pneumonia. Bacterial infections may play an important role in promoting the death of patients. Malnutrition was common to severe patients. Multiple organ dysfunction can be observed, the most common organ damage was lung, followed by heart, kidney and liver. The rising of neutrophils, SAA, PCT, CRP, cTnI, D-dimer, LDH and lactate levels can be used as indicators of disease progression, as well as the decline of lymphocytes counts. CONCLUSIONS: The clinical characteristics of 25 death cases with COVID-19 we summarized, which would be helpful to identify critically ill patients of COVID-19 early and reduce their mortality.

Clinical characteristics of 25 death cases with COVID-19: A retrospective review of medical records in a single medical center, Wuhan, China

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 ≥65â years (OR 3.765, 95% CI 1.146â17.394; p=0.023), pre-existing concurrent cardiovascular or cerebrovascular diseases (OR 2.464, 95% CI 0.755â8.044; p=0.007), CD3+CD8+ T-cells ≤75â cells·µL-1 (OR 3.982, 95% CI 1.132â14.006; p<0.001) and cardiac troponin I ≥0.05â ng·mL-1 (OR 4.077, 95% CI 1.166â14.253; p<0.001) were associated with an increase in risk of mortality from COVID-19 pneumonia. In a sex-, age- and comorbid illness-matched case-control study, CD3+CD8+ T-cells ≤75â cells·µL-1 and cardiac troponin I ≥0.05â ng·mL-1 remained as predictors for high mortality from COVID-19 pneumonia.We identified four risk factors: age ≥65â years, pre-existing concurrent cardiovascular or cerebrovascular diseases, CD3+CD8+ T-cells ≤75â cells·µL-1 and cardiac troponin I ≥0.05â ng·mL-1 The latter two factors, especially, were predictors for mortality of COVID-19 pneumonia patients.

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

Coronavirus Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has infected more than 3.0 million people worldwide and killed more than 200,000 as of April 27, 2020, making it the most lethal pandemic since the Spanish flu of 1918.1, 2 COVID-19 may preferentially infect individuals with cardiovascular conditions, is more severe in subjects with cardiovascular comorbidities, may directly or indirectly affect the heart and may interact with cardiovascular medications.3 In addition, the widespread effects of the pandemic on the global healthcare system affects the routine and emergency cardiac care for patients who are, may be, or are not infected with COVID-19.

Current perspectives on Coronavirus 2019 (COVID-19) and cardiovascular disease: A white paper by the JAHA editors.

COVID-19 is an ongoing pandemic caused by the SARS-CoV-2 coronavirus that poses one of the greatest challenges to public health in recent years. SARS-CoV-2 is highly contagious and often leads to severe viral pneumonia with respiratory failure and death in the elderly and subjects with pre-existing conditions, but the reason for this age dependence is unclear. Here, we found that the case fatality rate for COVID-19 grows exponentially with age in Italy, Spain, South Korea, and China, with the doubling time approaching that of all-cause human mortality. In addition, men and those with multiple age-related diseases are characterized by increased mortality. Moreover, similar mortality patterns were found for all-cause pneumonia. We further report that the gene expression of ACE2, the SARS-CoV-2 receptor, grows in the lung with age, except for subjects on a ventilator. Together, our findings establish COVID-19 as an emergent disease of aging, and age and age-related diseases as its major risk factors. In turn, this suggests that COVID-19, and deadly respiratory diseases in general, may be targeted, in addition to therapeutic approaches that affect specific pathways, by approaches that target the aging process.

COVID-19 is an emergent disease of aging

This study described the epidemiologic and clinical characteristics of patients who died from SARS-CoV-2 infection, and pointed out the potential risk factors associated with fatal outcomes. Retrospective data from 42 death cases due to SARS-CoV-2 infection at Tongji Hospital Affiliated to Huazhong University of Science and Technology, Wuhan, China was analyzed. Demographics, clinical detection, laboratory findings, and treatments of the deceased were collected and analyzed. The average time between onset of symptoms and admission to the hospitals was 11 ± 5 days of hospitalization. Among the deceased, 60% were with co-morbidities. All of them were having fever and bilateral pneumonia on computed tomography, abnormal infection-related biomarkers, and renal impairment. Abnormal blood coagulation parameters that appeared in more than half of them, were consistent with disseminated intravascular coagulation. All of the patients were treated in the ICU. Based on the fact that SARS-CoV-2 infection carries a risk of mortality, we may infer a few older male patients with underlying comorbidities are likely to have the increased risk. Impaired consciousness level, markers of renal impairment and coagulation abnormalities may be poor prognostic factors.

Epidemiologic and clinical characteristics of 42 deaths caused by SARS-CoV-2 infection in Wuhan, China: A retrospective study

Objective To provide Covid-19 fatality rate, correlations with comorbidities and sensitivity of nasopharingeal swab. Design Prospective cohort study performed between February 21th and March 19rd, 2020 Setting Hospital-based study Participants Of 2,217 admitted, 766 consecutive individuals either reporting or presenting with fever, cough or dyspnea, and suspected to carry Covid-19 infection were examined. Intervention All individuals underwent body temperature and pulse oximetry recording, hematological screening, chest X-ray and/or computed tomography (CT) and SARS-COV-2 assay on nasopharyngeal swab. Onset symptoms, course, comorbidities, number of drugs, use of angiotensin converting enzyme inhibitors and angiotensin-II-receptor antagonists, and follow-up swab, clinical, hematological, and radiological exams, treatments, non-invasive respiratory support, ICU admission, and deaths were recorded. Main outcome measures Primary outcomes were non-invasive respiratory support, intensive care unit (ICU) admission, and death. Results Median age of 411 Covid-19 patients was 70.5 years (range 1-99; 66.6% males). CT was positive in 74% and negative in 3.2%. Six patients died within 72 hours; another 66 during hospitalization. Fatality rate was 17.5% (74% males). No death occurred below 60 years. Mortality was 6.6% in 60-69 decade, 21.1% in 70-79, 38.8% in 80-89, and 83.3% above 90 years. Non-invasive respiratory support rate was 27.2%; ICU admission 6.8%. Older age, cough and dyspnea at onset, hypertension, cardiovascular diseases, diabetes, renal insufficiency, >7 drugs intake and positive X-ray at admission were significantly associated with death. Low lymphocyte count, high C-reactive protein, aspartate aminotransferase and lactate dehydrogenase, and low PO2 partial pressure with high lactate at arterial blood gas analysis at admission were also significantly associated with death. Of 32 swab negative patients, 40.6% turned positive at follow-up. Using CT as reference, nasopharyngeal swab had 80% sensitivity. Comorbidity network analysis revealed homogenous distribution of deceased and 60-80 aged patients across diseases. Conclusions Covid-19 caused high mortality among patients older than 70 years and correlated by pre-existing multiorgan impairment irrespective of the age.

SARS-COV-2 comorbidity network and outcome in hospitalized patients in Crema, Italy

The current outbreak of COVID-19 severe respiratory disease, which started in Wuhan, China, is an ongoing challenge, and a major threat to public health that requires surveillance, prompt diagnosis, and research efforts to understand this emergent pathogen and to develop an effective response. Due to the scientific community's efforts, there is an increasing body of published studies describing the virus' biology, its transmission and diagnosis, its clinical features, its radiological findings, and the development of candidate therapeutics and vaccines. Despite the decline in postmortem examination rate, autopsy remains the gold standard to determine why and how death happens. Defining the pathophysiology of death is not only limited to forensic considerations; it may also provide useful clinical and epidemiologic insights. Selective approaches to postmortem diagnosis, such as limited postmortem sampling over full autopsy, can also be useful in the control of disease outbreaks and provide valuable knowledge for managing appropriate control measures. In this scenario, we strongly recommend performing full autopsies on patients who died with suspected or confirmed COVID-19 infection, particularly in the presence of several comorbidities. Only by working with a complete set of histological samples obtained through autopsy can one ascertain the exact cause(s) of death, optimize clinical management, and assist clinicians in pointing out a timely and effective treatment to reduce mortality. Death can teach us not only about the disease, it might also help with its prevention and, above all, treatment.

COVID-19 Deaths: Are We Sure It Is Pneumonia? Please, Autopsy, Autopsy, Autopsy!

In this case report, a 50-year-old man who had no medical history, presented with multiple cardiac arrests following a week with progressing symptoms of pneumonia After achieving return of spontaneous circulation he presented with respiratory failure with severe hypoxia, septic shock, and multiple organ failure A chest X-ray showed signs of acute respiratory distress syndrome Despite aggressive intensive care management, the patient died 7 5 hours after admission Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was later confirmed, and the presumed cause of death was SARS-CoV-2 pneumonia In conclusion: coronavirus disease 2019 (COVID-19) can lead to a fatal outcome in younger healthy residents, who are not treated timely in case of severe symptoms like dyspnoea

[Fatal outcome of coronavirus disease 2019 in a previously healthy 50-year-old man]

As of early June, 2020, approximately 7 million COVID-19 cases and 400,000 deaths have been reported. This paper examines four demographic and clinical factors (age, time to hospital, presence of chronic disease, and sex) and utilizes Shapley values from coalitional game theory and machine learning to evaluate their relative importance in predicting COVID-19 mortality. The analyses suggest that out of the 4 factors studied, age is the most important in predicting COVID-19 mortality, followed by time to hospital. Sex and presence of chronic disease were both found to be relatively unimportant, and the two global interpretation techniques differed in ranking them. Additionally, this paper creates partial dependence plots to determine and visualize the marginal effect of each factor on COVID-19 mortality and demonstrates how local interpretation of COVID-19 mortality prediction can be applicable in a clinical setting. Lastly, this paper derives clinically applicable decision rules about mortality probabilities through a parsimonious 3-split surrogate tree, demonstrating that high-accuracy COVID-19 mortality prediction can be achieved with simple, interpretable models.

Who dies from COVID-19? Post-hoc explanations of mortality prediction models using coalitional game theory, surrogate trees, and partial dependence plots

Assessing nitrogen dioxide (NO2) levels as a contributing factor to coronavirus (COVID-19) fatality

Forensic investigations generally contain extensive morphological examinations to accurately diagnose the cause of death. Thus, the appearance of a new disease often creates emerging challenges in morphological examinations due to the lack of available data from autopsy- or biopsy-based research. Since late December 2019, an outbreak of a novel seventh coronavirus disease has been reported in China caused by "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). On March 11, 2020, the new clinical condition COVID-19 (Corona-Virus-Disease-19) was declared a pandemic by the World Health Organization (WHO). Patients with COVID-19 mainly have a mild disease course, but severe disease onset might result in death due to proceeded lung injury with massive alveolar damage and progressive respiratory failure. However, the detailed mechanisms that cause organ injury still remain unclear. We investigated the morphological findings of a COVID-19 patient who died during self-isolation. Pathologic examination revealed massive bilateral alveolar damage, indicating early-phase "acute respiratory distress syndrome" (ARDS). This case emphasizes the possibility of a rapid severe disease onset in previously mild clinical condition and highlights the necessity of a complete autopsy to gain a better understanding of the pathophysiological changes in SARS-CoV-2 infections.

Gross and histopathological pulmonary findings in a COVID-19 associated death during self-isolation

Covid-19: Known risk factors fail to explain the increased risk of death among people from ethnic minorities.

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China: Wu C, Chen X, Cai Y, et al. JAMA Intern Med. doi:10.1001/jamainternmed.2020.0994.

BACKGROUND: Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. METHODS: In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. FINDINGS: 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. INTERPRETATION: The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. FUNDING: Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Mortality and survival of COVID-19

BACKGROUND: Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. METHODS: In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. FINDINGS: 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61-12·23; p<0·0001), and d-dimer greater than 1 µg/mL (18·42, 2·64-128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. INTERPRETATION: The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 µg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. FUNDING: Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

The current outbreak of COVID-19 severe respiratory disease, which started in Wuhan, China, is an ongoing challenge, and a major threat to public health that requires surveillance, prompt diagnosis, and research efforts to understand this emergent pathogen and to develop an effective response. Due to the scientific community’s efforts, there is an increasing body of published studies describing the virus’ biology, its transmission and diagnosis, its clinical features, its radiological findings, and the development of candidate therapeutics and vaccines. Despite the decline in postmortem examination rate, autopsy remains the gold standard to determine why and how death happens. Defining the pathophysiology of death is not only limited to forensic considerations; it may also provide useful clinical and epidemiologic insights. Selective approaches to postmortem diagnosis, such as limited postmortem sampling over full autopsy, can also be useful in the control of disease outbreaks and provide valuable knowledge for managing appropriate control measures. In this scenario, we strongly recommend performing full autopsies on patients who died with suspected or confirmed COVID-19 infection, particularly in the presence of several comorbidities. Only by working with a complete set of histological samples obtained through autopsy can one ascertain the exact cause(s) of death, optimize clinical management, and assist clinicians in pointing out a timely and effective treatment to reduce mortality. Death can teach us not only about the disease, it might also help with its prevention and, above all, treatment.

Spain is one of the countries that has suffered the most from the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the strain that causes coronavirus disease 2019 (COVID-19). However, there is a lack of information on the characteristics of this disease in the Spanish population. The objective of this study has been to characterize our patients from an epidemiological point of view and to identify the risk factors associated with mortality in our geographical area. We performed a prospective, longitudinal study on 188 hospitalized cases of SARS-Cov-2 infection in Hospital Universitari de Sant Joan, in Reus, Spain, admitted between 15th March 2020 and 30th April 2020. We recorded demographic data, signs and symptoms and comorbidities. We also calculated the Charlson and McCabe indices. A total of 43 deaths occurred during the study period. Deceased patients were older than the survivors (77.7 ± 13.1 vs. 62.8 ± 18.4 years; p < 0.001). Logistic regression analyses showed that fever, pneumonia, acute respiratory distress syndrome, diabetes mellitus and cancer were the variables that showed independent and statistically significant associations with mortality. The Charlson index was more efficient than the McCabe index in discriminating between deceased and survivors. This is one of the first studies to describe the factors associated with mortality in patients infected with SARS-CoV-2 in Spain, and one of the few in the Mediterranean area. We identified the main factors independently associated with mortality in our population. Further studies in are needed to complete and confirm our findings.

Risk factors associated with mortality in hospitalized patients with SARS-CoV-2 infection. A prospective, longitudinal, unicenter study in Reus, Spain

BACKGROUND COVID-19 can cause a fatal outcome in elderly patients, as this case report illustrates. CASE PRESENTATION An active male in his nineties with a high level of function, despite several severe chronic diseases, was admitted to Oslo University Hospital after two days of fatigue, fever, dyspnoea and dry cough. He scored qSOFA 1 of 3 points due to high respiratory rate, and SIRS 2 of 4 points due to high respiratory rate and fever of 39.4º C. PCR for influenza virus was negative and he received benzylpenicillin for pneumonia. The chest X-ray taken initially showed no lung affection. On day 5 after symptom debut he was tested for COVID-19 which was positive. He had not been travelling to high-risk areas or been exposed to any known confirmed COVID-19 patients. On the same day, a chest CT scan was performed that showed ground-glass opacities. In subsequent days the patient's health rapidly deteriorated. He developed irreversible respiratory failure with hypoxia without hypercapnia despite substantial oxygen support. Chest X-ray taken on disease day 7 showed progression of consolidations. The patient died 9 days after symptom debut. INTERPRETATION This case illustrates a severe course of COVID-19 with fatal outcome. The patient was also one of the earliest admitted with COVID-19 in a Norwegian hospital and marked a new phase of the epidemic, as he had not been travelling to high-risk areas or been exposed to any confirmed COVID-19 patients.

A man in his nineties with fever and dry cough.

In the setting of the coronavirus disease 2019 (COVID-19) pandemic, only few data regarding lung pathology induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is available, especially without medical intervention interfering with the natural evolution of the disease. We present here the first case of forensic autopsy of a COVID-19 fatality occurring in a young woman, in the community. Diagnosis was made at necropsy and lung histology showed diffuse alveolar damage, edema, and interstitial pneumonia with a geographically heterogeneous pattern, mostly affecting the central part of the lungs. This death related to COVID-19 pathology highlights the heterogeneity and severity of central lung lesions after natural evolution of the disease.

Inside the lungs of COVID-19 disease

Covid-19: Known risk factors fail to explain the increased risk of death among people from ethnic minorities

Abstract Nitrogen dioxide (NO2) is an ambient trace-gas result of both natural and anthropogenic processes. Long-term exposure to NO2 may cause a wide spectrum of severe health problems such as hypertension, diabetes, heart and cardiovascular diseases and even death. The objective of this study is to examine the relationship between long-term exposure to NO2 and coronavirus fatality. The Sentinel-5P is used for mapping the tropospheric NO2 distribution and the NCEP/NCAR reanalysis for evaluating the atmospheric capability to disperse the pollution. The spatial analysis has been conducted on a regional scale and combined with the number of death cases taken from 66 administrative regions in Italy, Spain, France and Germany. Results show that out of the 4443 fatality cases, 3487 (78%) were in five regions located in north Italy and central Spain. Additionally, the same five regions show the highest NO2 concentrations combined with downwards airflow which prevent an efficient dispersion of air pollution. These results indicate that the long-term exposure to this pollutant may be one of the most important contributors to fatality caused by the COVID-19 virus in these regions and maybe across the whole world.

Why are more BAME people dying from COVID-19?

Forensic investigations generally contain extensive morphological examinations to accurately diagnose the cause of death. Thus, the appearance of a new disease often creates emerging challenges in morphological examinations due to the lack of available data from autopsy- or biopsy-based research. Since late December 2019, an outbreak of a novel seventh coronavirus disease has been reported in China caused by “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2). On March 11, 2020, the new clinical condition COVID-19 (Corona-Virus-Disease-19) was declared a pandemic by the World Health Organization (WHO). Patients with COVID-19 mainly have a mild disease course, but severe disease onset might result in death due to proceeded lung injury with massive alveolar damage and progressive respiratory failure. However, the detailed mechanisms that cause organ injury still remain unclear. We investigated the morphological findings of a COVID-19 patient who died during self-isolation. Pathologic examination revealed massive bilateral alveolar damage, indicating early-phase “acute respiratory distress syndrome” (ARDS). This case emphasizes the possibility of a rapid severe disease onset in previously mild clinical condition and highlights the necessity of a complete autopsy to gain a better understanding of the pathophysiological changes in SARS-CoV-2 infections.

The pandemia of coronavirus disease 2019 (COVID-19) has caused more than 355,000 confirmed deaths worldwide. However, publications on postmortem findings are scarce. We present the pulmonary findings in four cases of fatal COVID-19 with a spectrum of lung pathology reflecting disease course and duration, invasive therapies, and laboratory features. Early disease is characterized by neutrophilic, exudative capillaritis with microthrombosis and high levels of IL-1beta and IL-6. Later stages are associated with diffuse alveolar damage and ongoing intravascular thrombosis in small to medium-sized pulmonary vessels, occasionally with areas of infarction equivalents, accompanied by laboratory features of disseminated intravascular coagulation. In late stages, organizing pneumonia with extensive intra-alveolar proliferation of fibroblasts and marked metaplasia of alveolar epithelium can be observed. Viral RNA is encountered in the lung, with virus particles in endothelial cells and pneumocytes. In many patients, multi-organ failure with severe liver damage sets in finally, possibly as consequence of an early-onset pro-inflammatory cytokine storm and/or thrombotic microangiopathy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00428-020-02881-x) contains supplementary material, which is available to authorized users.

The evolution of pulmonary pathology in fatal COVID-19 disease: an autopsy study with clinical correlation

Background A recently developing pneumonia caused by SARS-CoV-2 was originated in Wuhan, China, and has quickly spread across the world. We reported the clinical characteristics of 82 death cases with COVID-19 in a single center. Methods Clinical data on 82 death cases laboratory-confirmed as SARS-CoV-2 infection were obtained from a Wuhan local hospital′s electronic medical records according to previously designed standardized data collection forms. Findings All patients were local residents of Wuhan, and the great proportion of them were diagnosed as severe illness when admitted. Most of the death cases were male (65.9%). More than half of dead patients were older than 60 years (80.5%) and the median age was 72.5 years. The bulk of death cases had comorbidity (76.8%), including hypertension (56.1%), heart disease (20.7%), diabetes (18.3%), cerebrovascular disease (12.2%), and cancer (7.3%). Respiratory failure remained the leading cause of death (69.5%), following by sepsis syndrome/MOF (28.0%), cardiac failure (14.6%), hemorrhage (6.1%), and renal failure (3.7%). Furthermore, respiratory, cardiac, hemorrhage, hepatic, and renal damage were found in 100%, 89%, 80.5%, 78.0%, and 31.7% of patients, respectively. On the admission, lymphopenia (89.2%), neutrophilia (74.3%), and thrombocytopenia (24.3%) were usually observed. Most patients had a high neutrophil-to-lymphocyte ratio of >5 (94.5%), high systemic immune-inflammation index of >500 (89.2%), increased C-reactive protein level (100%), lactate dehydrogenase (93.2%), and D-dimer (97.1%). A high level of IL-6 (>10 pg/ml) was observed in all detected patients. Median time from initial symptom to death was 15 days (IQR 11-20), and a significant association between aspartate aminotransferase (p=0.002), alanine aminotransferase (p=0.037) and time from initial symptom to death were interestingly observed. Conclusion Older males with comorbidities are more likely to develop severe disease, even die from SARS-CoV-2 infection. Respiratory failure is the main cause of COVID-19, but either virus itself or cytokine release storm mediated damage to other organ including cardiac, renal, hepatic, and hemorrhage should be taken seriously as well.

Clinical characteristics of 82 death cases with COVID-19

Excess Deaths From COVID-19 and Other Causes, March-April 2020.

Rationale: The global death toll from coronavirus disease (COVID-19) virus as of May 12, 2020, exceeds 286,000. The risk factors for death were attributed to advanced age and comorbidities but have not been accurately defined.Objectives: To report the clinical features of 85 fatal cases of COVID-19 in two hospitals in Wuhan.Methods: Medical records were collected of 85 fatal cases of COVID-19 between January 9, 2020, and February 15, 2020. Information recorded included medical history, exposure history, comorbidities, symptoms, signs, laboratory findings, computed tomographic scans, and clinical management.Measurements and Main Results: The median age of the patients was 65.8 years, and 72.9% were male. Common symptoms were fever (78 [91.8%]), shortness of breath (50 [58.8%]), fatigue (50 [58.8%]), and dyspnea (60 [70.6%]). Hypertension, diabetes, and coronary heart disease were the most common comorbidities. Notably, 81.2% of patients had very low eosinophil counts on admission. Complications included respiratory failure (80 [94.1%]), shock (69 [81.2%]), acute respiratory distress syndrome (63 [74.1%]), and arrhythmia (51 [60%]), among others. Most patients received antibiotic (77 [90.6%]), antiviral (78 [91.8%]), and glucocorticoid (65 [76.5%]) treatments. A total of 38 (44.7%) and 33 (38.8%) patients received intravenous immunoglobulin and IFN-α2b, respectively.Conclusions: In this depictive study of 85 fatal cases of COVID-19, most cases were males aged over 50 years with noncommunicable chronic diseases. The majority of the patients died of multiple organ failure. Early onset of shortness of breath may be used as an observational symptom for COVID-19 exacerbations. Eosinophilopenia may indicate a poor prognosis. A combination of antimicrobial drugs did not offer considerable benefit to the outcome of this group of patients.

Clinical Features of 85 Fatal Cases of COVID-19 from Wuhan. A Retrospective Observational Study

SARS-CoV-2 has rapidly spread across the United States, causing extensive morbidity and mortality, though the histopathologic basis of severe disease cases has yet to be studied in detail. Over the past century, autopsy has contributed significantly to our understanding of numerous disease processes, but for several reasons, autopsy reports following deaths related to SARS-CoV-2 have thus far been limited across the globe. We report on the relevant cardiopulmonary findings in the first series of autopsies in the United States, with the cause of death being due to SARS-CoV-2 infection. These cases identify key pathologic states potentially contributing to severe disease and decompensation in these patients.

Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans

OBJECTIVE: This retrospective study aimed to analysis the clinical characteristics and complications in death cases with novel coronavirus disease-19 (COVID-19). METHOD: We collected the medical records of 92 patients with COVID-19 in Renmin Hospital of Wuhan University who died during January 6th to February 25th, 2020, summarized the clinical characteristics of complications. RESULTS: There were 91 death cases who developed different complications including acute respiratory distress syndrome (ARDS) (73/91), myocardial injury (31/91), liver injury (15/91), renal insufficiency (14/91), multiple organ dysfunction syndrome (MODS) (14/91) and pneumothorax (1/91). Among these patients, 83 patients had at least one complication. While 1 patient who died of recurrent gastrointestinal bleeding was not directly linked to COVID-19. CONCLUSION: The main complications of deceased patients with COVID-19 were ARDS, myocardial injury, liver injury, renal insufficiency and MODS. This article is protected by copyright. All rights reserved.

Analysis of 92 deceased patients with COVID-19

Findings from CCC19 and TERAVOLT suggest that patients with cancer may be more likely to die from COVID-19 than people in the general population. Additional mortality risk factors may include age, performance status, treatment with chemotherapy, and exposure to hydroxychloroquine plus azithromycin.

Registries Offer Insights on COVID-19-Cancer Connection.

COVID-19, the illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the deadliest pandemic to occur in this century. Common symptoms of COVID-19 include cough, myalgia, fever, chest pain, and headache. However, its clinical presentation ranges from completely asymptomatic to acute respiratory distress syndrome.[1] Pregnant women are susceptible to community spread of COVID-19 because they cannot postpone interactions with healthcare professionals and other women receiving obstetric care.

Maternal mortality from COVID-19 in Mexico.

The ongoing outbreak of COVID-19 has been expanding worldwide. As of 17 April 2020, the death toll stands at a sobering 147,027 and over two million cases, this has been straining the health care systems all over. Respiratory failure has been cited as the major cause of death but here we present a case about a patient who instead succumbed to severe metabolic acidosis with multiple organ failure.

A fatal case of COVID-19 due to metabolic acidosis following dysregulate inflammatory response (cytokine storm)

By 27 February 2020, the outbreak of coronavirus disease 2019 (COVID-19) caused 82 623 confirmed cases and 2858 deaths globally, more than severe acute respiratory syndrome (SARS) (8273 cases, 775 deaths) and Middle East respiratory syndrome (MERS) (1139 cases, 431 deaths) caused in 2003 and 2013, respectively. COVID-19 has spread to 46 countries internationally. Total fatality rate of COVID-19 is estimated at 3.46% by far based on published data from the Chinese Center for Disease Control and Prevention (China CDC). Average incubation period of COVID-19 is around 6.4 days, ranges from 0 to 24 days. The basic reproductive number (R0 ) of COVID-19 ranges from 2 to 3.5 at the early phase regardless of different prediction models, which is higher than SARS and MERS. A study from China CDC showed majority of patients (80.9%) were considered asymptomatic or mild pneumonia but released large amounts of viruses at the early phase of infection, which posed enormous challenges for containing the spread of COVID-19. Nosocomial transmission was another severe problem. A total of 3019 health workers were infected by 12 February 2020, which accounted for 3.83% of total number of infections, and extremely burdened the health system, especially in Wuhan. Limited epidemiological and clinical data suggest that the disease spectrum of COVID-19 may differ from SARS or MERS. We summarize latest literatures on genetic, epidemiological, and clinical features of COVID-19 in comparison to SARS and MERS and emphasize special measures on diagnosis and potential interventions. This review will improve our understanding of the unique features of COVID-19 and enhance our control measures in the future.

Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures

COVID-19 is a respiratory disease A recent report in Lancet examined, retrospectively, 137 patients with COVD-19 Patients that died had elevated IL-6 levels and acute respiratory distress syndrome These data have obvious implications for how to control mortality in COVID-19

COVID-19: is fibrosis the killer?

Covid-19: risk factors for severe disease and death

COVID-19 and the liver-related deaths to come

Neglected major causes of death much deadlier than COVID-19

Rationale: The current outbreak of coronavirus disease (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, spreads across national and international borders. The overall death rate of COVID-19 pneumonia in the Chinese population was 4%.Objectives: To describe the process of hospitalization and critical care of patients who died of COVID-19 pneumonia.Methods: This was a multicenter observational study of 109 decedents with COVID-19 pneumonia from three hospitals in Wuhan. Demographic, clinical, laboratory, and treatment data were collected and analyzed, and the final date of follow-up was February 24, 2020.Results: The mean age of 109 decedents with COVID-19 pneumonia was 70.7 years, 35 patients (32.1%) were female, and 85 patients (78.0%) suffered from one or more underlying comorbidities. Multiple organ failure, especially respiratory failure and heart failure, appeared in all patients even at the early stage of disease. Overall, the mean time from onset of symptoms to death was 22.3 days. All 109 hospitalized patients needed admission to an intensive care unit (ICU); however, because of limited availability, only 51 (46.8%) could be admitted. The period from hospitalization to death in the ICU group and non-ICU group was 15.9 days (standard deviation = 8.8 d) and 12.5 days (8.6 d, P = 0.044), respectively.Conclusions: Mortality due to COVID-19 pneumonia was concentrated in patients above the age of 65 years, especially those with major comorbidities. Patients who were admitted to the ICU lived longer than those who were not. Our findings should aid in the recognition and clinical management of such infections, especially with regard to ICU resource allocation.

Hospitalization and Critical Care of 109 Decedents with COVID-19 Pneumonia in Wuhan, China

Rationale: The current outbreak of coronavirus disease (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, spreads across national and international borders. The overall death rate of COVID-19 pneumonia in the Chinese population was 4%. Objectives: To describe the process of hospitalization and critical care of patients who died of COVID-19 pneumonia. Methods: This was a multicenter observational study of 109 decedents with COVID-19 pneumonia from three hospitals in Wuhan. Demographic, clinical, laboratory, and treatment data were collected and analyzed, and the final date of follow-up was February 24, 2020. Results: The mean age of 109 decedents with COVID-19 pneumonia was 70.7 years, 35 patients (32.1%) were female, and 85 patients (78.0%) suffered from one or more underlying comorbidities. Multiple organ failure, especially respiratory failure and heart failure, appeared in all patients even at the early stage of disease. Overall, the mean time from onset of symptoms to death was 22.3 days. All 109 hospitalized patients needed admission to an intensive care unit (ICU); however, because of limited availability, only 51 (46.8%) could be admitted. The period from hospitalization to death in the ICU group and non-ICU group was 15.9 days (standard deviation = 8.8 d) and 12.5 days (8.6 d, P = 0.044), respectively. Conclusions: Mortality due to COVID-19 pneumonia was concentrated in patients above the age of 65 years, especially those with major comorbidities. Patients who were admitted to the ICU lived longer than those who were not. Our findings should aid in the recognition and clinical management of such infections, especially with regard to ICU resource allocation.

Are COVID-19 Patients Dying of or with Cardiac Injury?

Rationale: The global death toll from coronavirus disease (COVID-19) virus as of May 12, 2020, exceeds 286,000. The risk factors for death were attributed to advanced age and comorbidities but have not been accurately defined. Objectives: To report the clinical features of 85 fatal cases of COVID-19 in two hospitals in Wuhan. Methods: Medical records were collected of 85 fatal cases of COVID-19 between January 9, 2020, and February 15, 2020. Information recorded included medical history, exposure history, comorbidities, symptoms, signs, laboratory findings, computed tomographic scans, and clinical management. Measurements and Main Results: The median age of the patients was 65.8 years, and 72.9% were male. Common symptoms were fever (78 [91.8%]), shortness of breath (50 [58.8%]), fatigue (50 [58.8%]), and dyspnea (60 [70.6%]). Hypertension, diabetes, and coronary heart disease were the most common comorbidities. Notably, 81.2% of patients had very low eosinophil counts on admission. Complications included respiratory failure (80 [94.1%]), shock (69 [81.2%]), acute respiratory distress syndrome (63 [74.1%]), and arrhythmia (51 [60%]), among others. Most patients received antibiotic (77 [90.6%]), antiviral (78 [91.8%]), and glucocorticoid (65 [76.5%]) treatments. A total of 38 (44.7%) and 33 (38.8%) patients received intravenous immunoglobulin and IFN-α2b, respectively. Conclusions: In this depictive study of 85 fatal cases of COVID-19, most cases were males aged over 50 years with noncommunicable chronic diseases. The majority of the patients died of multiple organ failure. Early onset of shortness of breath may be used as an observational symptom for COVID-19 exacerbations. Eosinophilopenia may indicate a poor prognosis. A combination of antimicrobial drugs did not offer considerable benefit to the outcome of this group of patients.

The Covid-19 pandemic has claimed many lives in the UK and globally. The objective of this paper is to study whether the number of deaths not registered as Covid-19-related has increased compared to what would have been expected in the absence of the pandemic. Reasons behind this might include Covid-19 underreporting, avoiding visits to hospitals or GPs, and the effects of the lockdown. I used weekly ONS data on the number of deaths in England and Wales that did not officially involve Covid-19 over the period 2015-2020. Simply observing trends is not sufficient as spikes in deaths may occasionally occur. I thus followed a difference-in-differences econometric approach to study whether there was a relative increase in deaths not registered as Covid-19-related during the pandemic, compared to a control. Results suggest that there were an additional 968 weekly deaths that officially did not involve Covid-19, compared to what would have otherwise been expected. It is possible that some people are dying from Covid-19 without being diagnosed, and/or that there are excess deaths due to other causes as a result of the pandemic. Analysing the cause of death for any excess non-covid-19 deaths will shed light upon the reasons for the increase in such deaths and will help design appropriate policy responses to save lives.

Excess mortality during the Covid-19 pandemic: Early evidence from England and Wales.

Asthma is increasingly recognized as an underlying risk factor for severe respiratory disease in patients with coronavirus disease 2019 (COVID-19), particularly in the United States. Here, we report the postmortem lung findings from a 37-year-old man with asthma, who met the clinical criteria for severe acute respiratory distress syndrome and died of COVID-19 less than 2 weeks after presentation to the hospital. His lungs showed mucus plugging and other histologic changes attributable to asthma, as well as early diffuse alveolar damage and a fibrinous pneumonia. The presence of diffuse alveolar damage is similar to descriptions of autopsy lung findings from patients with severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus, and the absence of a neutrophil-rich acute bronchopneumonia differs from the histologic changes typical of influenza. The relative contribution of mucus plugging to his hypoxemia is unknown.

Postmortem Lung Findings in an Asthmatic Patient With Coronavirus Disease 2019

As Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spreads around the World, many questions about the disease are being answered; however, many more remain poorly understood. Although the situation is rapidly evolving, with datasets being continually corrected or updated, it is crucial to understand what factors may be driving transmission through different populations. While studies are beginning to highlight specific parameters that may be playing a role, few have attempted to thoroughly estimate the relative importance of these disparate variables that likely include: climate, population demographics, and imposed state interventions. In this report, we compiled a database of more than 28 potentially explanatory variables for each of the 50 U.S. states through early May 2020. Using a combination of traditional statistical and modern machine learning approaches, we identified those variables that were the most statistically significant, and, those that were the most important. These variables were chosen to be fiduciaries of a range of possible drivers for COVID-19 deaths in the USA. We found that population-weighted density (PWD), some "stay at home" metrics, monthly temperature and precipitation, race/ethnicity, and chronic low respiratory death rate, were all statistically significant. Of these, PWD and mobility metrics dominated. This suggests that the biggest impact on COVID-19 deaths was, at least initially, a function of where you lived, and not what you did. However, clearly, increasing social distancing has the net effect of (at least temporarily) reducing the effective PWD. Our results strongly support the idea that the loosening of "lock-down" orders should be tailored to the local PWD. In contrast to these variables, while still statistically significant, race/ethnicity, health, and climate effects could only account for a few percent of the variability in deaths. Where associations were anticipated but were not found, we discuss how limitations in the parameters chosen may mask a contribution that might otherwise be present.

COVID-19 Deaths: Which Explanatory Variables Matter the Most?

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become pandemic, with substantial mortality. OBJECTIVE: To evaluate the pathologic changes of organ systems and the clinicopathologic basis for severe and fatal outcomes. DESIGN: Prospective autopsy study. SETTING: Single pathology department. PARTICIPANTS: 11 deceased patients with COVID-19 (10 of whom were selected at random for autopsy). MEASUREMENTS: Systematic macroscopic, histopathologic, and viral analysis (SARS-CoV-2 on real-time polymerase chain reaction assay), with correlation of pathologic and clinical features, including comorbidities, comedication, and laboratory values. RESULTS: Patients' age ranged from 66 to 91 years (mean, 80.5 years; 8 men, 3 women). Ten of the 11 patients received prophylactic anticoagulant therapy; venous thromboembolism was not clinically suspected antemortem in any of the patients. Both lungs showed various stages of diffuse alveolar damage (DAD), including edema, hyaline membranes, and proliferation of pneumocytes and fibroblasts. Thrombosis of small and mid-sized pulmonary arteries was found in various degrees in all 11 patients and was associated with infarction in 8 patients and bronchopneumonia in 6 patients. Kupffer cell proliferation was seen in all patients, and chronic hepatic congestion in 8 patients. Other changes in the liver included hepatic steatosis, portal fibrosis, lymphocytic infiltrates and ductular proliferation, lobular cholestasis, and acute liver cell necrosis, together with central vein thrombosis. Additional frequent findings included renal proximal tubular injury, focal pancreatitis, adrenocortical hyperplasia, and lymphocyte depletion of spleen and lymph nodes. Viral RNA was detectable in pharyngeal, bronchial, and colonic mucosa but not bile. LIMITATION: The sample was small. CONCLUSION: COVID-19 predominantly involves the lungs, causing DAD and leading to acute respiratory insufficiency. Death may be caused by the thrombosis observed in segmental and subsegmental pulmonary arterial vessels despite the use of prophylactic anticoagulation. Studies are needed to further understand the thrombotic complications of COVID-19, together with the roles for strict thrombosis prophylaxis, laboratory, and imaging studies and early anticoagulant therapy for suspected pulmonary arterial thrombosis or thromboembolism. PRIMARY FUNDING SOURCE: None.

Pulmonary Arterial Thrombosis in COVID-19 With Fatal Outcome: Results From a Prospective, Single-Center, Clinicopathologic Case Series

Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10–15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils—the ability to form neutrophil extracellular traps (NETs)—may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.

Targeting potential drivers of COVID-19: Neutrophil extracellular traps

SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), was first identified in December 2019 in Wuhan, China, and has since spread worldwide. On March 11, 2020, the World Health Organization declared COVID-19 a pandemic (1). That same day, the first confirmed COVID-19-associated fatality occurred in New York City (NYC). To identify confirmed COVID-19-associated deaths, defined as those occurring in persons with laboratory-confirmed SARS-CoV-2 infection, on March 13, 2020, the New York City Department of Health and Mental Hygiene (DOHMH) initiated a daily match between all deaths reported to the DOHMH electronic vital registry system (eVital) (2) and laboratory-confirmed cases of COVID-19. Deaths for which COVID-19, SARS-CoV-2, or an equivalent term is listed on the death certificate as an immediate, underlying, or contributing cause of death, but that do not have laboratory-confirmation of COVID-19 are classified as probable COVID-19-associated deaths. As of May 2, a total of 13,831 laboratory-confirmed COVID-19-associated deaths, and 5,048 probable COVID-19-associated deaths were recorded in NYC (3). Counting only confirmed or probable COVID-19-associated deaths, however, likely underestimates the number of deaths attributable to the pandemic. The counting of confirmed and probable COVID-19-associated deaths might not include deaths among persons with SARS-CoV-2 infection who did not access diagnostic testing, tested falsely negative, or became infected after testing negative, died outside of a health care setting, or for whom COVID-19 was not suspected by a health care provider as a cause of death. The counting of confirmed and probable COVID-19-associated deaths also does not include deaths that are not directly associated with SARS-CoV-2 infection. The objective of this report is to provide an estimate of all-cause excess deaths that have occurred in NYC in the setting of widespread community transmission of SARS-CoV-2. Excess deaths refer to the number of deaths above expected seasonal baseline levels, regardless of the reported cause of death. Estimation of all-cause excess deaths is used as a nonspecific measure of the severity or impact of pandemics (4) and public health emergencies (5). Reporting of excess deaths might provide a more accurate measure of the impact of the pandemic.

Preliminary Estimate of Excess Mortality During the COVID-19 Outbreak - New York City, March 11-May 2, 2020.

AIMS: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly evolved into a sweeping pandemic. Its major manifestation is in the respiratory tract, and the general extent of organ involvement and the microscopic changes in the lungs remain insufficiently characterised. Autopsies are essential to elucidate COVID-19-associated organ alterations. METHODS AND RESULTS: This article reports the autopsy findings of 21 COVID-19 patients hospitalised at the University Hospital Basel and at the Cantonal Hospital Baselland, Switzerland. An in-corpore technique was performed to ensure optimal staff safety. The primary cause of death was respiratory failure with exudative diffuse alveolar damage and massive capillary congestion, often accompanied by microthrombi despite anticoagulation. Ten cases showed superimposed bronchopneumonia. Further findings included pulmonary embolism (n = 4), alveolar haemorrhage (n = 3), and vasculitis (n = 1). Pathologies in other organ systems were predominantly attributable to shock; three patients showed signs of generalised and five of pulmonary thrombotic microangiopathy. Six patients were diagnosed with senile cardiac amyloidosis upon autopsy. Most patients suffered from one or more comorbidities (hypertension, obesity, cardiovascular diseases, and diabetes mellitus). Additionally, there was an overall predominance of males and individuals with blood group A (81% and 65%, respectively). All relevant histological slides are linked as open-source scans in supplementary files. CONCLUSIONS: This study provides an overview of postmortem findings in COVID-19 cases, implying that hypertensive, elderly, obese, male individuals with severe cardiovascular comorbidities as well as those with blood group A may have a lower threshold of tolerance for COVID-19. This provides a pathophysiological explanation for higher mortality rates among these patients.

Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction

INTRODUCTION: In the current study, we evaluated factors that increase the coronavirus disease (COVID-19) patient death rate by analyzing the data from two cohort hospitals. In addition, we studied whether underlying neurological diseases are risk factors for death. METHODS: In this retrospective cohort study, we included 103 adult inpatients (aged ≥ 18 years). We evaluated differences in demographic data between surviving and non-surviving COVID-19 patients. RESULTS: In a multivariate logistic analysis, age and the presence of chronic lung disease and Alzheimer’s dementia (AD) were the only significant parameters for predicting COVID-19 non-survival (p < 0.05). However, hypertension, coronary vascular disease, dyslipidemia, chronic kidney disease, diabetes, and history of taking angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors, as well as nonsteroidal anti-inflammatory drugs (NSAIDs), were not significantly associated with the death of COVID-19 patients. The optimal cutoff value obtained from the maximum Youden index was 70 (sensitivity, 80.77%; specificity, 61.04%), and the odds ratio of non-survival increased 1.055 fold for every year of age. CONCLUSIONS: Clinicians should closely monitor and manage the symptoms of COVID-19 patients who are over the age of 70 years or have chronic lung disease or AD.

Neurological diseases as mortality predictive factors for patients with COVID-19: a retrospective cohort study

Autopsies of deceased with a confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can provide important insights into the novel disease and its course. Furthermore, autopsies are essential for the correct statistical recording of the coronavirus disease 2019 (COVID-19) deaths. In the northern German Federal State of Hamburg, all deaths of Hamburg citizens with ante- or postmortem PCR-confirmed SARS-CoV-2 infection have been autopsied since the outbreak of the pandemic in Germany. Our evaluation provides a systematic overview of the first 80 consecutive full autopsies. A proposal for the categorisation of deaths with SARS-CoV-2 infection is presented (category 1: definite COVID-19 death; category 2: probable COVID-19 death; category 3: possible COVID-19 death with an equal alternative cause of death; category 4: SARS-CoV-2 detection with cause of death not associated to COVID-19). In six cases, SARS-CoV-2 infection was diagnosed postmortem by a positive PCR test in a nasopharyngeal or lung tissue swab. In the other 74 cases, SARS-CoV-2 infection had already been known antemortem. The deceased were aged between 52 and 96 years (average 79.2 years, median 82.4 years). In the study cohort, 34 deceased were female (38%) and 46 male (62%). Overall, 38% of the deceased were overweight or obese. All deceased, except for two women, in whom no significant pre-existing conditions were found autoptically, had relevant comorbidities (in descending order of frequency): (1) diseases of the cardiovascular system, (2) lung diseases, (3) central nervous system diseases, (4) kidney diseases, and (5) diabetes mellitus. A total of 76 cases (95%) were classified as COVID-19 deaths, corresponding to categories 1–3. Four deaths (5%) were defined as non-COVID-19 deaths with virus-independent causes of death. In eight cases, pneumonia was combined with a fulminant pulmonary artery embolism. Peripheral pulmonary artery embolisms were found in nine other cases. Overall, deep vein thrombosis has been found in 40% of the cases. This study provides the largest overview of autopsies of SARS-CoV-2-infected patients presented so far.

Dying with SARS-CoV-2 infection—an autopsy study of the first consecutive 80 cases in Hamburg, Germany

Notions of psychological frailty have been at the forefront of debates around the public response to the COVID-19 pandemic. In particular, there is the argument that collective selfishness, thoughtless behaviour, and over-reaction would make the effects of COVID-19 much worse. The same kinds of claims have been made in relation to other kinds of emergencies, such as fires, earthquakes, and sinking ships. We argue that in these cases as well as in the case of the COVID-19 pandemic, other factors are better explanations for fatalities - namely under-reaction to threat, systemic or structural factors, and mismanagement. Psychologizing disasters serves to distract from the real causes and thus from who might be held responsible. Far from being the problem, collective behaviour in emergencies - including the solidarity and cooperation so commonly witnessed among survivors - is the solution, one that should be harnessed more effectively in policy and practice.

COVID-19 in context: Why do people die in emergencies? It's probably not because of collective psychology

Preliminary Estimate of Excess Mortality During the COVID-19 Outbreak - New York City, March 11-May 2, 2020

OBJECTIVE: The COVID-19 pandemic has caused much morbidity and mortality to patients but also health care providers. We tabulated the cases of physician deaths from COVID-19 associated with front-line work in hopes of mitigating future events. METHOD: On April 5, 2020, Google internet search was performed using the keywords doctor, physician, death, COVID, COVID-19, and coronavirus in English and Farsi, and in Chinese using the Baidu search engine. RESULTS: We found 198 physician deaths from COVID-19, but complete details were missing for 49 individuals. The average age of the physicians that died was 63.4 years (range 28 to 90 years) and the median age was 66 years of age. Ninety percent of the deceased physicians were male (175/194). General practitioners and emergency room doctors (78/192), respirologists (5/192), internal medicine specialists (11/192) and anesthesiologists (6/192) comprised 52% of those dying. Two percent of the deceased were epidemiologists (4/192), 2% were infectious disease specialists (4/192), 5% were dentists (9/192), 4% were ENT (8/192), and 4% were ophthalmologists (7/192). The countries with the most reported physician deaths were Italy (79/198), Iran (43/198), China (16/198), Philippines (14/198), United States (9/192) and Indonesia (7/192). CONCLUSION: Physicians from all specialties may die from COVID, and these deaths will likely increase as the pandemic progresses. Lack of personal protective equipment was cited as a common cause of death. Consideration should be made to exclude older physicians from front-line work.

Physician Deaths from Corona Virus Disease (COVID-19)

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

Autopsies of deceased with a confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can provide important insights into the novel disease and its course. Furthermore, autopsies are essential for the correct statistical recording of the coronavirus disease 2019 (COVID-19) deaths. In the northern German Federal State of Hamburg, all deaths of Hamburg citizens with ante- or postmortem PCR-confirmed SARS-CoV-2 infection have been autopsied since the outbreak of the pandemic in Germany. Our evaluation provides a systematic overview of the first 80 consecutive full autopsies. A proposal for the categorisation of deaths with SARS-CoV-2 infection is presented (category 1: definite COVID-19 death; category 2: probable COVID-19 death; category 3: possible COVID-19 death with an equal alternative cause of death; category 4: SARS-CoV-2 detection with cause of death not associated to COVID-19). In six cases, SARS-CoV-2 infection was diagnosed postmortem by a positive PCR test in a nasopharyngeal or lung tissue swab. In the other 74 cases, SARS-CoV-2 infection had already been known antemortem. The deceased were aged between 52 and 96 years (average 79.2 years, median 82.4 years). In the study cohort, 34 deceased were female (38%) and 46 male (62%). Overall, 38% of the deceased were overweight or obese. All deceased, except for two women, in whom no significant pre-existing conditions were found autoptically, had relevant comorbidities (in descending order of frequency): (1) diseases of the cardiovascular system, (2) lung diseases, (3) central nervous system diseases, (4) kidney diseases, and (5) diabetes mellitus. A total of 76 cases (95%) were classified as COVID-19 deaths, corresponding to categories 1-3. Four deaths (5%) were defined as non-COVID-19 deaths with virus-independent causes of death. In eight cases, pneumonia was combined with a fulminant pulmonary artery embolism. Peripheral pulmonary artery embolisms were found in nine other cases. Overall, deep vein thrombosis has been found in 40% of the cases. This study provides the largest overview of autopsies of SARS-CoV-2-infected patients presented so far.

Dying with SARS-CoV-2 infection-an autopsy study of the first consecutive 80 cases in Hamburg, Germany

Excess mortality during the Covid-19 pandemic: Early evidence from England and Wales

Background: The current outbreak of COVID-19 infection, which started in Wuhan, Hubei province, China, in December 2019, is an ongoing challenge and a significant threat to public health requiring surveillance, prompt diagnosis, and research efforts to understand a new, emergent, and unknown pathogen and to develop effective therapies. Despite the increasing number of published studies on COVID-19, in all the examined studies the lack of a well-defined pathophysiology of death among patients who died following COVID-19 infection is evident. Autopsy should be considered mandatory to define the exact cause of death, thus providing useful clinical and epidemiologic information as well as pathophysiological insights to further provide therapeutic tools. Methods: A literature review was performed on PubMed database, using the key terms: “COVID-19”, “nCov 19”, and “Sars Cov 2”. 9709 articles were retrieved; by excluding all duplicated articles, additional criteria were then applied: articles or abstracts in English and articles containing one of the following words: “death”, “died”, “comorbidity”, “cause of death”, “biopsy”, “autopsy”, or “pathological”. Results: A total of 50 articles met the inclusion criteria. However, only 7 of these studies reported autopsy-based data. Discussion: The analysis of the main data from the selected studies concerns the complete analysis of 12,954 patients, of whom 2269 died (with a mortality rate of 17.52%). Laboratory confirmation of COVID-19 infection was obtained in all cases and comorbidities were fully reported in 46 studies. The most common comorbidities were: cardiovascular diseases (hypertension and coronary artery disease), metabolic disorders (diabetes, overweight, or obesity), respiratory disorders (chronic obstructive pulmonary disease), and cancer. The most common reported complications were: acute respiratory distress syndrome (ARDS), acute kidney injury, cardiac injury, liver insufficiency, and septic shock. Only 7 papers reported histological investigations. Nevertheless, only two complete autopsies are described and the cause of death was listed as COVID-19 in only one of them. The lack of postmortem investigation did not allow a definition of the exact cause of death to determine the pathways of this infection. Based on the few histopathological findings reported in the analyzed studies, it seems to be a clear alteration of the coagulation system: frequently prothrombotic activity with consequent thromboembolism was described in COVID-19 patients. As a scientific community, we are called on to face this global threat, and to defeat it with all the available tools necessary. Despite the improvement and reinforcement of any method of study in every field of medicine and science, encouraging the autopsy practice as a tool of investigation could also therefore, help physicians to define an effective treatment to reduce mortality.

No Autopsies on COVID-19 Deaths: A Missed Opportunity and the Lockdown of Science

BACKGROUND: From December 2019 to February 2020, 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a serious outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China. Related clinical features are needed. METHODS: We reviewed 69 patients who were hospitalized in Union hospital in Wuhan between January 16 to January 29, 2020. All patients were confirmed to be infected with SARS-CoV-2 and the final date of follow-up was February 4, 2020. RESULTS: The median age of 69 enrolled patients was 42.0 years (IQR 35.0-62.0), and 32 patients (46%) were men. The most common symptoms were fever (60[87%]), cough (38[55%]), and fatigue (29[42%]). Most patients received antiviral therapy (66 [98.5%] of 67 patients) and antibiotic therapy (66 [98.5%] of 67 patients). As of February 4, 2020, 18 (26.9%) of 67 patients had been discharged, and five patients had died, with a mortality rate of 7.5%. According to the lowest SpO2 during admission, cases were divided into the SpO2≥90% group (n=55) and the SpO2<90% group (n=14). All 5 deaths occurred in the SpO2<90% group. Compared with SpO2≥90% group, patients of the SpO2<90% group were older, and showed more comorbidities and higher plasma levels of IL6, IL10, lactate dehydrogenase, and c reactive protein. Arbidol treatment showed tendency to improve the discharging rate and decrease the mortality rate. CONCLUSIONS: COVID-19 appears to show frequent fever, dry cough, and increase of inflammatory cytokines, and induced a mortality rate of 7.5%. Older patients or those with underlying comorbidities are at higher risk of death.

Clinical Features of 69 Cases with Coronavirus Disease 2019 in Wuhan, China

Cytokine Storm: is it the only major death factor in COVID-19 patients? Coagulation role

Cytokine Storm: Is it the only major death factor in COVID-19 patients? Coagulation role

COVID-19 pandemic is an emergent cardiovascular risk factor and a major cause of mortality worldwide. Thromboembolism is highly suspected as a leading cause of death in these patients through vascular inflammation caused by SARS COV2. Until now there is no real treatment of COVID-19 and many proposed drugs are under clinical trials. Considering the high incidence of thromboembolic events in critically ill patients with COVID-19, prevention of this disorder should be essential in order to reduce mortality in these patients.

COVID-19 pandemic: do we need systematic screening of patients with cardiovascular risk factors in Low and Middle-Income Countries (LMICs) for preventing death?

INTRODUCTION: In the current study, we evaluated factors that increase the coronavirus disease (COVID-19) patient death rate by analyzing the data from two cohort hospitals. In addition, we studied whether underlying neurological diseases are risk factors for death. METHODS: In this retrospective cohort study, we included 103 adult inpatients (aged ≥ 18 years). We evaluated differences in demographic data between surviving and non-surviving COVID-19 patients. RESULTS: In a multivariate logistic analysis, age and the presence of chronic lung disease and Alzheimer's dementia (AD) were the only significant parameters for predicting COVID-19 non-survival (p < 0.05). However, hypertension, coronary vascular disease, dyslipidemia, chronic kidney disease, diabetes, and history of taking angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors, as well as nonsteroidal anti-inflammatory drugs (NSAIDs), were not significantly associated with the death of COVID-19 patients. The optimal cutoff value obtained from the maximum Youden index was 70 (sensitivity, 80.77%; specificity, 61.04%), and the odds ratio of non-survival increased 1.055 fold for every year of age. CONCLUSIONS: Clinicians should closely monitor and manage the symptoms of COVID-19 patients who are over the age of 70 years or have chronic lung disease or AD.

A large percentage of the deaths from COVID-19 occur among residents of long-term care facilities. There are two possible reasons for this phenomenon. First, the structural features of such settings may lead to death. Alternatively, it is possible that individuals in these facilities are in poorer health than those living elsewhere, and that these individuals would have died even if they had not been in these facilities. Our findings show that, controlling for the population density and the percentage of older adults in the population, there is a significant positive association between the number of long-term care beds per capita and COVID-19 mortality rates. This finding provides support for the claim that long-term care living arrangements (of older people) are a significant risk factor for dying from COVID-19.

Long-Term Care Facilities as a Risk Factor for Death Due to COVID-19

Could the decrease in the endothelial nitric oxide (NO) production and NO bioavailability be the crucial cause of COVID-19 related deaths?