Pathogenesis Of Severe COVID-19 Research Articles

Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19

Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-19 patients, we show that markedly increased plasma von Willebrand factor (VWF) levels were accompanied by a partial reduction in the VWF regulatory protease ADAMTS13. In all patients we find this VWF/ADAMTS13 imbalance to be associated with persistence of ultra-high-molecular-weight (UHMW) VWF multimers that are highly thrombogenic in some disease settings. Incubation of plasma samples from patients with severe COVID-19 with recombinant ADAMTS13 (rADAMTS13) substantially reduced the abnormally high VWF activity, reduced overall multimer size and depleted UHMW VWF multimers in a time and concentration dependent manner. Our data implicate disruption of normal VWF/ADAMTS13 homeostasis in the pathogenesis of severe COVID-19 and indicate that this can be reversed ex vivo by correction of low plasma ADAMTS13 levels. These findings suggest a potential therapeutic role for rADAMTS13 in helping restore haemostatic balance in COVID-19 patients.

Diabetes predicts severity of COVID-19 infection in a retrospective cohort: A mediatory role of the inflammatory biomarker C-reactive protein.

Diabetes is a risk factor for developing severe COVID‐19, but the pathogenesis remains unclear. We investigated if the association of diabetes and COVID‐19 severity may be mediated by inflammation. We also hypothesized that this increased risk may extend to prediabetes. Hospitalized patients in Singapore with COVID‐19 were subdivided into three groups in a retrospective cohort: normoglycemia (HbA1c: ≤5.6%), prediabetes (HbA1c: 5.7%–6.4%) and diabetes (HbA1c: ≥6.5%). The primary outcome of severe COVID‐19 was defined by respiratory rate ≥30, SpO2 ≤93% or intensive care unit admission. The association between clinical factors on severe COVID‐19 outcome was analyzed by cox regression. Adjusted mediation analysis of C‐reactive protein (CRP) on the relationship between diabetes and severe COVID‐19 was performed. Of 1042 hospitalized patients, mean age 39 ± 11 years, 13% had diabetes, 9% prediabetes and 78% normoglycemia. Severe COVID‐19 occurred in 4.9% of subjects. Compared to normoglycemia, diabetes was significantly associated with severe COVID‐19 on both univariate (hazard ratio [HR]: 9.94; 95% confidence interval [CI]: 5.54–17.84; p < .001) and multivariate analysis (HR: 3.99; 95% CI: 1.92–8.31; p < .001), while prediabetes was not a risk factor (HR: 0.94; 95% CI: 0.22–4.03; p = .929). CRP, a biomarker of inflammation, mediated 32.7% of the total association between diabetes and severe COVID‐19 outcome. In conclusion, CRP is a partial mediator of the association between diabetes and severe COVID‐19 infection, confirming that inflammation is important in the pathogenesis of severe COVID‐19 in diabetes.

Vitamin D: A Boon to Respiratory Health in COVID-19

COVID-19 has errupted not only as a pandemic but as challenge to mankind. Life has come to a stand still. All spheres of life are affected not only in terms of jobs and economy but importantly health and well being. In Indian scenario this is of particular significance as autumn coincides with festivities, wedding season and mass gatherings. Outbreaks of respiratory viral infections, such as those caused by influenza A and Respiratory Synctial Virus have long been associated with changing season reaching a peak in winter season and nadir in summer months. Various factors could be attributed to this pattern like increased virus survival at low temperature, tendency of close gatherings in winter months and cold dry air reducing mucus in nasal passages. Clinically Vitamin D deficiency has been shown to associate with increased risk of diverse acute respiratory tract infections. It has been proposed that vitamin D, diminishes production of respiratory cytokines, which appear to play a central part in pathogenesis of severe COVID-19.

SARS-CoV-2 receptor is co-expressed with elements of the kinin\u2013kallikrein, renin\u2013angiotensin and coagulation systems in alveolar cells

SARS-CoV-2, the pathogenic agent of COVID-19, employs angiotensin converting enzyme-2 (ACE2) as its cell entry receptor. Clinical data reveal that in severe COVID-19, SARS-CoV-2 infects the lung, leading to a frequently lethal triad of respiratory insufficiency, acute cardiovascular failure, and coagulopathy. Physiologically, ACE2 plays a role in the regulation of three systems that could potentially be involved in the pathogenesis of severe COVID-19: the kinin–kallikrein system, resulting in acute lung inflammatory edema; the renin–angiotensin system, promoting cardiovascular instability; and the coagulation system, leading to thromboembolism. Here we assembled a healthy human lung cell atlas meta-analysis with ~ 130,000 public single-cell transcriptomes and show that key elements of the bradykinin, angiotensin and coagulation systems are co-expressed with ACE2 in alveolar cells and associated with their differentiation dynamics, which could explain how changes in ACE2 promoted by SARS-CoV-2 cell entry result in the development of the three most severe clinical components of COVID-19.

The immunology of COVID-19: is immune modulation an option for treatment?

SummaryIn December, 2019, an outbreak of COVID-19 emerged in Wuhan, China and quickly spread globally. As of May 7, 2020, there were 3 672 238 confirmed infections and 254 045 deaths attributed to COVID-19. Evidence has shown that there are asymptomatic carriers of COVID-19 who can transmit the disease to others. The virus incubation time shows a wide range (0–24 days) and the virus displays a high infectivity. It is therefore urgent to develop an effective therapy to treat patients with COVID-19 and to control the spread of the causative agent, severe respiratory syndrome coronavirus 2. Repurposing of approved drugs is widely adopted to fight newly emerged diseases such as COVID-19, as these drugs have known pharmacokinetic and safety profiles. As pathological examination has confirmed the involvement of immune hyperactivation and acute respiratory distress syndrome in fatal cases of COVID-19, several disease-modifying anti-rheumatic drugs (DMARDS), such as hydroxychloroquine and tocilizumab, have been proposed as potential therapies for the treatment of COVID-19. In this Review, we discuss the immunological aspects of COVID-19 and the potential implication of DMARDs in treating this disease.