Inhibition of p38 signaling curtails the SARS-CoV-2 induced inflammatory response but retains the IFN-dependent antiviral defense of the lung epithelial barrier.

SARS-CoV-2 is the causative agent of the immune response-driven disease COVID-19 for which new antiviral and anti-inflammatory treatments are urgently needed to reduce recovery time, risk of death and long COVID development. Here, we demonstrate that the immunoregulatory kinase p38 MAPK is activated during viral entry, mediated by the viral spike protein, and drives the harmful virus-induced inflammatory responses. Using primary human lung explants and lung epithelial organoids, we demonstrate that targeting p38 signal transduction with the selective and clinically pre-evaluated inhibitors PH-797804 and VX-702 markedly reduced the expression of the pro-inflammatory cytokines IL6, CXCL8, CXCL10 and TNF-α during infection, while viral replication and the interferon-mediated antiviral response of the lung epithelial barrier were largely maintained. Furthermore, our results reveal a high level of drug synergism of both p38 inhibitors in co-treatments with the nucleoside analogs Remdesivir and Molnupiravir to suppress viral replication of the SARS-CoV-2 variants of concern, revealing an exciting and novel mode of synergistic action of p38 inhibition. These results open new avenues for the improvement of the current treatment strategies for COVID-19.

3D Ex vivo tissue platforms to investigate the early phases of influenza a virus- and SARS-CoV-2-induced respiratory diseases.

Pandemic outbreaks of viruses such as influenza virus or SARS-CoV-2 are associated with high morbidity and mortality and thus pose a massive threat to global health and economics. Physiologically relevant models are needed to study the viral life cycle, describe the pathophysiological consequences of viral infection, and explore possible drug targets and treatment options. While simple cell culture-based models do not reflect the tissue environment and systemic responses, animal models are linked with huge direct and indirect costs and ethical questions. Ex vivo platforms based on tissue explants have been introduced as suitable platforms to bridge the gap between cell culture and animal models. We established a murine lung tissue explant platform for two respiratory viruses, influenza A virus (IAV) and SARS-CoV-2. We observed efficient viral replication, associated with the release of inflammatory cytokines and the induction of an antiviral interferon response, comparable to ex vivo infection in human lung explants. Endolysosomal entry could be confirmed as a potential host target for pharmacological intervention, and the potential repurposing potentials of fluoxetine and interferons for host-directed therapy previously seen in vitro could be recapitulated in the ex vivo model.

Sustained Impairment in Cardiopulmonary Exercise Capacity Testing in Patients after COVID-19: A Single Center Experience.

Background: Following COVID-19, patients often present with ongoing symptoms comparable to chronic fatigue and subjective deterioration of exercise capacity (EC), which has been recently described as postacute COVID-19 syndrome. Objective: To objectify the reduced EC after COVID-19 and to evaluate for pathologic limitations. Methods: Thirty patients with subjective limitation of EC performed cardiopulmonary exercise testing (CPET). If objectively limited in EC or deteriorated in oxygen pulse, we offered cardiac stress magnetic resonance imaging (MRI) and a follow-up CPET. Results: Eighteen male and 12 female patients were included. Limited relative EC was detected in 11/30 (36.7%) patients. Limitation correlated with reduced body weight-indexed peak oxygen (O2) uptake (peakV̇O2/kg) (mean 74.7 (±7.1) % vs. 103.6 (±14.9) %, p < 0.001). Reduced peakV̇O2/kg was found in 18/30 (60.0%) patients with limited EC. Patients with reduced EC widely presented an impaired maximum O2 pulse (75.7% (±5.6) vs. 106.8% (±13.9), p < 0.001). Abnormal gas exchange was absent in all limited EC patients. Moreover, no patient showed signs of reduced pulmonary perfusion. Using cardiac MRI, diminished biventricular ejection fraction was ruled out in 16 patients as a possible cause for reduced O2 pulse. Despite noncontrolled training exercises, follow-up CPET did not reveal any exercise improvements. Conclusions: Deterioration of EC was not associated with ventilatory or pulmonary vascular limitation. Exercise limitation was related to both reduced O2 pulse and peakV̇O2/kg, which, however, did not correlate with the initial severity of COVID-19. We hypothesize that impaired microcirculation or limited peripheral O2 utilization might be causative for prolonged deterioration of EC following acute COVID-19 infection.

Quality of Life in Brain Tumor Patients and Their Relatives Heavily Depends on Social Support Factors during the COVID-19 Pandemic.

The COVID-19 pandemic is associated with significant morbidity, mortality, and restrictions on everyday life worldwide. This may be especially challenging for brain tumor patients given increased vulnerability due to their pre-existing condition. Here, we aimed to investigate the quality of life (QoL) in brain tumor patients and relatives in this setting. Over twelve weeks during the first wave of the pandemic (04-07/2020), brain tumor patients and their families from two large German tertiary care centers were asked to complete weekly questionnaires for anxiety, depression, distress, and well-being. Information regarding social support and living conditions was also collected. One hundred participants (63 patients, 37 relatives) completed 729 questionnaires over the course of the study. Compared to relatives, patients showed more depressive symptoms (p < 0.001) and reduced well-being (p = 0.013). While acceptance of lockdown measures decreased over time, QoL remained stable. QoL measures between patients and their families were weakly or moderately correlated. The number of social contacts was strongly associated with QoL. Age, living conditions, ongoing therapy, employment, and physical activity were other predictors. QoL is correlated between patients and their families and heavily depends on social support factors, indicating the need to focus on the entire family and their social situation for QoL interventions during the pandemic.

Persisting SARS-CoV-2 viraemia after rituximab therapy: two cases with fatal outcome and a review of the literature.

SARS-CoV-2 infection can cause severe pneumonia (COVID-19). There is evidence that patients with comorbidities are at higher risk of a severe disease course. The role of immunosuppression in the disease course is not clear. In the present report, we first describe two cases of persisting SARS-CoV-2 viraemia with fatal outcome in patients after rituximab therapy.