Vascular Endothelial Damage in the Pathogenesis of Organ Injury in Severe COVID-19.

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Causes of death and comorbidities in hospitalized patients with COVID-19.

Infection by the new corona virus strain SARS-CoV-2 and its related syndrome COVID-19 has been associated with more than two million 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 pre-existing health conditions to death yet is missing, which can be reliably established by autopsy only. We performed full body autopsies on 26 patients that had died after SARS-CoV-2 infection and COVID-19 at the Charité University Hospital Berlin, Germany, or at associated teaching hospitals. We systematically evaluated causes of death and pre-existing health conditions. Additionally, clinical records and death certificates were evaluated. We report 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 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.

Molecular Testing of SARS-CoV-2 Infection from Blood Samples in Disseminated Intravascular Coagulation (DIC) and Elevated D-Dimer Levels.

BACKGROUND: In 2020, the SARS-CoV-2 virus spread worldwide and infected more that 10 million people, causing more than 500,000 deaths worldwide. The infection has systemic effects on the respiratory and cardiovascular systems; thus, patients can present a variety of symptoms from asymptomatic to rapid deaths. In this paper, we present the first case of post-mortem SARS-CoV-2 molecular testing in Western part of Romania in a deceased with disseminated intravascular coagulation (DIC) and elevated D-dimer levels. METHODS: During the autopsy which took place at the Institute of Forensic Medicine from Timisoara, Romania, blood sample was collected in a vacutainer with EDTA and sent to the Laboratory of Forensic Genetics from Victor Babes University of Medicine and Pharmacy, Timisoara, Romania. Viral RNA extraction was performed automated on the Maxwell 48 RSC Extraction System (Promega, USA) using the Maxwell RSC Viral Total Nucleic Acid Purification kit (Promega, USA). After RNA extraction, the samples were amplified on a 7500 real-time PCR (Applied Biosystems, USA) using the genesig® Real-Time PCR Assay (Primer Design, UK). RESULTS: The molecular testing showed a cycle threshold value of 23.4 (1.2 x 106 copies/mL), indicating increased viral loads, which correlated with the laboratory analysis results, especially with D-dimer levels. CONCLUSIONS: In cases of coagulopathy of SARS-CoV-2, patients in hospitals should be monitored closely for thrombosis development. Thus D-dimer can be used as prognostic marker in monitoring the evolution of SARS-CoV-2 infected patients.

Interplay of COVID-19 and physiological dysfunctions.

The outbreak of the global coronavirus disease 2019 (COVID-19) pandemic continues to impact the socioeconomic fabric and the general well-being of numerous populations and communities around the world. As cases continue to rise exponentially, gaining a better understanding of the pathophysiology and the associated clinical implications of SARS-CoV-2, the causative agent of COVID-19, becomes increasingly necessary. In this article, we delineate the role of COVID-19 in physiological and immunological dysfunction. Specifically, we highlight the various possible mechanisms and effects of SARS-CoV-2 infections on major organ systems as well as their contribution toward multiorgan system failure. By analyzing studies and statistics regarding various comorbidities in COVID-19 patients, we make inferences on the linkage between COVID-19, immune injury, multiorgan system damage, and disease progression.

Severe Acute Respiratory Syndrome Coronavirus 2 Placental Infection and Inflammation Leading to Fetal Distress and Neonatal Multi-Organ Failure in an Asymptomatic Woman.

BACKGROUND: In general, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy is not considered to be an increased risk for severe maternal outcomes but has been associated with an increased risk for fetal distress. Maternal-fetal transmission of SARS-CoV-2 was initially deemed uncertain; however, recently a few cases of vertical transmission have been reported. The intrauterine mechanisms, besides direct vertical transmission, leading to the perinatal adverse outcomes are not well understood. METHODS: Multiple maternal, placental, and neonatal swabs were collected for the detection of SARS-CoV-2 using real-time quantitative polymerase chain reaction (RT-qPCR). Serology of immunoglobulins against SARS-CoV-2 was tested in maternal, umbilical cord, and neonatal blood. Placental examination included immunohistochemical investigation against SARS-CoV-2 antigen expression, with SARS-CoV-2 ribonucleic acid (RNA) in situ hybridization and transmission electron microscopy. RESULTS: RT-qPCRs of the oropharynx, maternal blood, vagina, placenta, and urine were all positive over a period of 6 days, while breast milk, feces, and all neonatal samples tested negative. Placental findings showed the presence of SARS-CoV-2 particles with generalized inflammation characterized by histiocytic intervillositis with diffuse perivillous fibrin depositions with damage to the syncytiotrophoblasts. CONCLUSIONS: Placental infection by SARS-CoV-2 leads to fibrin depositions hampering fetal-maternal gas exchange with resulting fetal distress necessitating a premature emergency cesarean section. Postpartum, the neonate showed a fetal or pediatric inflammatory multisystem-like syndrome with coronary artery ectasia temporarily associated with SARS-CoV-2 for which admittance and care on the neonatal intensive care unit (NICU) were required, despite being negative for SARS-CoV-2. This highlights the need for awareness of adverse fetal and neonatal outcomes during the current coronavirus disease 2019 pandemic, especially considering that the majority of pregnant women appear asymptomatic.

Clinical characteristics and outcomes of critically ill patients with COVID-19 admitted to an intensive care unit in London: A prospective observational cohort study.

BACKGROUND: Cohorts of severely ill patients with COVID-19 have been described in several countries around the globe, but to date there have been few published reports from the United Kingdom (UK). Understanding the characteristics of the affected population admitted to intensive care units (ICUs) in the UK is crucial to inform clinical decision making, research and planning for future waves of infection. METHODS: We conducted a prospective observational cohort study of all patients with COVID-19 admitted to a large UK ICU from March to May 2020 with follow-up to June 2020. Data were collected from health records using a standardised template. We used multivariable logistic regression to analyse the factors associated with ICU survival. RESULTS: Of the 156 patients included, 112 (72%) were male, 89 (57%) were overweight or obese, 68 (44%) were from ethnic minorities, and 89 (57%) were aged over 60 years of age. 136 (87%) received mechanical ventilation, 77 (57% of those intubated) were placed in the prone position and 95 (70% of those intubated) received neuromuscular blockade. 154 (99%) patients required cardiovascular support and 44 (28%) required renal replacement therapy. Of the 130 patients with completed ICU episodes, 38 (29%) died and 92 (71%) were discharged alive from ICU. In multivariable models, age (OR 1.13 [95% CI 1.07-1.21]), obesity (OR 3.06 [95% CI 1.16-8.74]), lowest P/F ratio on the first day of admission (OR 0.82 [95% CI 0.67-0.98]) and PaCO2 (OR 1.52 [95% CI 1.01-2.39]) were independently associated with ICU death. CONCLUSIONS: Age, obesity and severity of respiratory failure were key determinants of survival in this cohort. Multiorgan failure was prevalent. These findings are important for guiding future research and should be taken into consideration during future healthcare planning in the UK.

A Case Study of Dual Infection of Dengue and COVID-19: Presenting as Multiorgan Dysfunction in an Infant.

Dengue is a major health concern in South Asian countries transmitted by bite of day breeder mosquitoes Aedes aegypti and Aedes albopictus. Severity of plasma leak, shock, bleeding tendency and other organ dysfunction can be more pronounced in infants. The management becomes further complicated in the presence of a co-existing COVID-19 infection. Although COVID-19 infection is usually asymptomatic or has mild manifestations in children, however in presence of serious co-infection like dengue it can modify the course of the illness and lead to drastic consequences. Here, we present one such case of a 9-month-old female child who tested positive for dengue as well as COVID-19 during the ongoing corona pandemic and went on to develop shock, encephalopathy with deranged liver enzymes but managed to overcome all odds and recover from the disease by day 14 of illness.

Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), influenza, and COVID-19, beyond the lungs: a review article.

BACKGROUND: In the past 20 years four major viral infectious diseases outbreaks caused hundreds of thousands of deaths worldwide: SARS, Influenza H1N1, MERS, and COVID-19. They all present clinically initially as upper and lower respiratory tract infections and may progress to multi-organ failure. METHODS: This study was a systematic review of literature conducted in September 2020 to study extra-pulmonary complications of SARS, FLU, MERS, and current COVID-19. We carried out a systematic search using the keywords in online databases of PubMed, EMBASE, and Google Scholar until June 2020. OBJECTIVE: This article aims to review the most common extra-pulmonary manifestations of SARS, Influenza, MERS, and COVID-19. DISCUSSION: Several studies have reported extra-pulmonary conditions in patients diagnosed with SARS, Influenza, MERS, and COVID-19, either by direct viral injury or from the systemic response to the initial infection. CONCLUSION: SARS, Influenza, MERS, and COVID-19 have all been associated with dysfunction of kidneys, endocrine system, neuromuscular symptoms, perinatal complications, and myocardial injury. Progression from pulmonary disease to a systemic condition has a poor outcome and can result in multi-organ failure.

Tissue-Specific Immunopathology in Fatal COVID-19.

Rationale: In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown.Objectives: To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury.Methods: Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using multiplex immunofluorescence.Measurements and Main Results: Multiple aberrant immune responses in fatal COVID-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein between or within tissues. An arteritis was identified in the lung, which was further characterized as a monocyte/myeloid-rich vasculitis, and occurred together with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticuloendothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues.Conclusions: Tissue-specific immunopathology occurs in COVID-19, implicating a significant component of the immune-mediated, virus-independent immunopathologic process as a primary mechanism in severe disease. Our data highlight novel immunopathologic mechanisms and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma-cell responses as well as promote pathogen tolerance in COVID-19.

Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications.

The widespread occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a pandemic of coronavirus disease 2019 (COVID-19). The S spike protein of SARS-CoV-2 binds with angiotensin-converting enzyme 2 (ACE2) as a functional "receptor" and then enters into host cells to replicate and damage host cells and organs. ACE2 plays a pivotal role in the inflammation, and its downregulation may aggravate COVID-19 via the renin-angiotensin system, including by promoting pathological changes in lung injury and involving inflammatory responses. Severe patients of COVID-19 often develop acute respiratory distress syndrome and multiple organ dysfunction/failure with high mortality that may be closely related to the hyper-proinflammatory status called the "cytokine storm." Massive cytokines including interleukin-6, nuclear factor kappa B (NFκB), and tumor necrosis factor alpha (TNFα) released from SARS-CoV-2-infected macrophages and monocytes lead inflammation-derived injurious cascades causing multi-organ injury/failure. This review summarizes the current evidence and understanding of the underlying mechanisms of SARS-CoV-2, ACE2 and inflammation co-mediated multi-organ injury or failure in COVID-19 patients.

COVID-19 and multiorgan failure: A narrative review on potential mechanisms.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) in December 2019 form Wuhan, China leads to coronavirus disease 2019 (COVID-19) pandemic. While the common cold symptoms are observed in mild cases, COVID-19 is accompanied by multiorgan failure in severe patients. The involvement of different organs in severe patients results in lengthening the hospitalization duration and increasing the mortality rate. In this review, we aimed to investigate the involvement of different organs in COVID-19 patients, particularly in severe cases. Also, we tried to define the potential underlying mechanisms of SARS-CoV2 induced multiorgan failure. The multi-organ dysfunction is characterized by acute lung failure, acute liver failure, acute kidney injury, cardiovascular disease, and as well as a wide spectrum of hematological abnormalities and neurological disorders. The most important mechanisms are related to the direct and indirect pathogenic features of SARS-CoV2. Although the presence of angiotensin-converting enzyme 2, a receptor of SARS-CoV2 in the lung, heart, kidney, testis, liver, lymphocytes, and nervous system was confirmed, there are controversial findings to about the observation of SARS-CoV2 RNA in these organs. Moreover, the organ failure may be induced by the cytokine storm, a result of increased levels of inflammatory mediators, endothelial dysfunction, coagulation abnormalities, and infiltration of inflammatory cells into the organs. Therefore, further investigations are needed to detect the exact mechanisms of pathogenesis. Since the involvement of several organs in COVID-19 patients is important for clinicians, increasing their knowledge may help to improve the outcomes and decrease the rate of mortality and morbidity.

Clinical and Epidemiological Features of 46 Children <1 Year Old With Coronavirus Disease 2019 in Wuhan, China: A Descriptive Study.

The number of coronavirus disease 2019 (COVID-19) cases has exceeded 10 million. However, little is known about the epidemiology and clinical characteristics of COVID-19 infants. We collected medical information of 46 confirmed patients (<1 year old) and retrospectively analyzed epidemiological history, clinical symptoms, and laboratory test results. The median age was 5 (interquartile range, 2-7) months. Sixteen cases had fever and 27 cases had cough. Moderate disease was present in 40 cases and cardiac injury occurred in 38 cases, following by liver dysfunction in 20 cases and lymphocytosis in no cases. Of all infant patients, 2 received invasive mechanical ventilation and 1 died with multiple organ dysfunction syndrome.

Risk factors for mortality among patients with SARS-CoV-2 infection: A longitudinal observational study.

Recent literature suggests that approximately 5%-18% of patients diagnosed with severe acute respiratory syndrome coronavirus 2 may progress rapidly to a severe form of the illness and subsequent death. We examined the relationship between sociodemographic, clinical, and laboratory findings with mortality among patients. In this study, 112 patients were evaluated from February to May 2020 and 80 patients met the inclusion criteria. Tocilizumab was administered, followed by methylprednisolone to patients with pneumonia severity index score ≤130 and computerized tomography scan changes. Demographic data and clinical outcomes were collected. Laboratory biomarkers were monitored during hospitalization. Statistical analyses were performed with significance p ≤ .05. A total of 80 patients: 45 males (56.25%) and 35 females (43.75%) met the study inclusion criteria. A total of 7 patients (8.75%) were deceased. An increase in mortality outcome was statistically significantly associated with higher average levels of interleukin-6 (IL-6) with p value (.050), and d-dimer with p value (.024). Bivariate logistics regression demonstrated a significant increased odds for mortality for patients with bacterial lung infections (odds ratio [OR]: 10.83; 95% confidence interval [CI]: 2.05-57.40; p = .005) and multiorgan damage (OR: 103.50; 95% CI: 9.92-1079.55; p = .001). Multivariate logistics regression showed a statistically significant association for multiorgan damage (adjusted odds ratio [AOR]: 94.17; 95% CI: 7.39-1200.78; p = .001). We identified three main predictors for high mortality. These include IL-6, d-dimer, and multiorgan damage. The latter was the highest potential risk for in-hospital deaths. This warrants aggressive health measures for early recognition of the problem and initiation of treatment to reverse injuries.

Multiple organ injury on admission predicts in-hospital mortality in patients with COVID-19.

Multiorgan injury has been implicated in patients with coronavirus disease 2019 (COVID-19). We aim to assess the impact of organ injury (OI) on prognosis according to the number of affected organs at admission. This is a retrospective cohort study of patients with confirmed COVID-19 in Wuhan Third Hospital & Tongren Hospital of Wuhan University from February 17 to March 22, 2020. We classified the patients according to the presence and number of damaged organs (heart, liver, and kidney). The percentage of patients with no, one, two, or three organs affected was 59.75%, 30.46%, 8.07%, and 1.72%, respectively. With the increasing number of OI, there is a tendency of gradual increase regarding the white blood cell counts, neutrophil counts, levels of C-reactive protein (CRP), lactate dehydrogenase, D-dimer, and fibrinogen as well as the incidence of most complications. In a Cox regression model, individuals with OI, old age, and an abnormal level of CRP were at a higher risk of death compared with those without. Patients with three organ injuries had the highest mortality rate (57.9%; hazard ratio [HR] with 95% confidence interval [CI] vs. patients without OI: 22.31 [10.42-47.77], those with two [23.6%; HR = 8.68, 95% CI = 4.58-16.48], one [8.6%; HR = 3.1, 95% CI = 1.7-5.7], or no OI [2.6%]; p < .001). The increasing number of OI was associated with a high risk of mortality in COVID-19 infection.

Clinical retrospective study on the efficacy of Qingfei Paidu decoction combined with Western medicine for COVID-19 treatment.

BACKGROUND: Coronavirus disease 2019 (COVID-19)2 has emerged as a global pandemic. However, as effective treatments for this disease are still unclear, safe and efficient therapies are urgently needed. Qingfei Paidu decoction (QPD)3 is strongly recommended in the Chinese Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Provisional 6th Edition). However, clinical research data on the effects of QPD on COVID-19 are scarce. Our study aimed to explore the effects of combined treatment with QPD and Western medicine on COVID-19. METHODS: In this study, 63 patients with confirmed COVID-19 were analyzed. During the first 14 days of hospitalization, patients with deteriorating symptoms were administered QPD along with Western medicine therapy (the antiviral medicine selected from interferon, lopinavir, or arbidol). The clinical characteristics and blood laboratory indices (blood routine, inflammatory factors, and multi-organ biochemical indices) were examined, and the total lung severity scores were evaluated in each patient by reviewing chest computed tomography before treatment and at the end of treatment. RESULTS: Before QPD treatment, the combined treatment group showed higher blood C-reactive protein levels and more severe pulmonary inflammation and clinical symptoms than the Western medicine treatment group. Both groups met the discharge criteria after a similar length of hospitalization. At the end of treatment, circulating white blood cells, total lymphocyte count, and glutamic-oxaloacetic transaminase levels improved dramatically in both groups (P <  0.05). In contrast, C-reactive protein, creatine kinase, creatine kinase-myocardial band, lactate dehydrogenase, and blood urea nitrogen levels were improved only in the combined treatment group (P <  0.05), and C-reactive protein and creatine kinase were the most pronounced (P <  0.01). Compared with baseline, at the end of treatment, the proportion of patients with normal values of C-reactive protein, total lymphocyte count, and lactate dehydrogenase were increased in the combined treatment group (P < 0.05), whereas no significant difference was observed in the Western medicine treatment group (P >  0.05). CONCLUSION: The combination of QPD with Western medicine demonstrated significant anti-inflammatory effects compared with those of only Western medicine in patients with mild and moderate COVID-19; however, neither mortality nor length of hospitalization was affected. Moreover, the combined treatment tended to mitigate the extent of multi-organ impairment. Long-term randomized controlled trials with follow-up evaluations are required to confirm the results presented here.

The cytokine storm of COVID-19: a spotlight on prevention and protection.

INTRODUCTION: The cytokine release syndrome (CRS) of COVID-19 is associated with the development of critical illness requiring multi-organ support. Further research is required to halt progression of multi-organ injury induced by hyper-inflammation. AREAS COVERED: PubMed/MEDLINETM databases were accessed between May 9th-June 9th, 2020, to review the latest perspectives on the treatment and pathogenesis of CRS. EXPERT OPINION: Over-activity of chemotaxis triggers a macrophage activation syndrome (MAS) resulting in the release of pro-inflammatory cytokines. IL-6 and TNF- α are at the forefront of hyper-inflammation. The inflammatory cascade induces endothelial activation and capillary leak, leading to circulatory collapse and shock. As endothelial dysfunction persists, there is activation of the clotting cascade and microvascular obstruction. Continued endothelial activation results in multi-organ failure, regardless of pulmonary tissue damage. We propose that targeting the endothelium may interrupt this cycle. Immuno-modulating therapies have been suggested, however, further data is necessary to confirm that they do not jeopardize adaptive immunity. Inhibition of IL-6 and the Janus Kinase, signal transducer and activator of transcription proteins pathway (JAK/STAT), are favorable targets. Remote ischemic conditioning (RIC) reduces the inflammation of sepsis in animal models and should be considered as a low risk intervention, in combination with cardiovascular protection.