BACKGROUND. Corticosteroids are widely used in patients with COVID 19, although their benefit-to-risk ratio remains controversial. METHODS. Patients with severe COVID-19–related acute respiratory distress syndrome (ARDS) were included from December 29, 2019 to March 16, 2020 in 5 tertiary Chinese hospitals. Cox proportional hazards and competing risks analyses were conducted to analyze the impact of corticosteroids on mortality and SARS–CoV-2 RNA clearance, respectively. We performed a propensity score (PS) matching analysis to control confounding factors. RESULTS. Of 774 eligible patients, 409 patients received corticosteroids, with a median time from hospitalization to starting corticosteroids of 1.0 day (IQR 0.0–3.0 days) . As compared with usual care, treatment with corticosteroids was associated with increased rate of myocardial (15.6% vs. 10.4%, P = 0.041) and liver injury (18.3% vs. 9.9%, P = 0.001), of shock (22.0% vs. 12.6%, P < 0.001), of need for mechanical ventilation (38.1% vs. 19.5%, P < 0.001), and increased rate of 28-day all-cause mortality (44.3% vs. 31.0%, P < 0.001). After PS matching, corticosteroid therapy was associated with 28-day mortality (adjusted HR 1.46, 95% CI 1.01–2.13, P = 0.045). High dose (>200 mg) and early initiation (≤3 days from hospitalization) of corticosteroid therapy were associated with a higher 28-day mortality rate. Corticosteroid use was also associated with a delay in SARS–CoV-2 coronavirus RNA clearance in the competing risk analysis (subhazard ratio 1.59, 95% CI 1.17–2.15, P = 0.003). CONCLUSION. Administration of corticosteroids in severe COVID-19–related ARDS is associated with increased 28-day mortality and delayed SARS–CoV-2 coronavirus RNA clearance after adjustment for time-varying confounders. FUNDING. None.

Since the 2019 novel coronavirus disease (COVID-19) outbreak originated from Wuhan, Hubei Province, China, at the end of 2019, it has become a clinical threat to the general population worldwide. Among people infected with the novel coronavirus (2019-nCoV), the intensive management of the critically ill patients in intensive care unit (ICU) needs substantial medical resource. In the present article, we have summarized the promising drugs, adjunctive agents, respiratory supportive strategies, as well as circulation management, multiple organ function monitoring and appropriate nutritional strategies for the treatment of COVID-19 in the ICU based on the previous experience of treating other viral infections and influenza. These treatments are referable before the vaccine and specific drugs are available for COVID-19.

Lung injury is often studied without consideration for pathologic changes in the chest wall. In order to reduce the incidence of lung injury using preemptive mechanical ventilation, it is important to recognize the influence of altered chest wall mechanics on disease pathogenesis. In this study, we hypothesize that airway pressure release ventilation (APRV) may be able to reduce the chest wall elastance associated with an extrapulmonary lung injury model as compared with low tidal volume (LVt) ventilation. Female Yorkshire pigs were anesthetized and instrumented. Fecal peritonitis was established, and the superior mesenteric artery was clamped for 30 min to induce an ischemia/reperfusion injury. Immediately following injury, pigs were randomized into (1) LVt (n = 3), positive end-expiratory pressure (PEEP) 5 cmH2O, V t 6 cc kg−1, FiO2 21 %, and guided by the ARDSnet protocol or (2) APRV (n = 3), P High 16–22 cmH2O, P Low 0 cmH2O, T High 4.5 s, T Low set to terminate the peak expiratory flow at 75 %, and FiO2 21 %. Pigs were monitored continuously for 48 h. Lung samples and bronchoalveolar lavage fluid were collected at necropsy. LVt resulted in mild acute respiratory distress syndrome (ARDS) (PaO2/FiO2 = 226.2 ± 17.1 mmHg) whereas APRV prevented ARDS (PaO2/FiO2 = 465.7 ± 66.5 mmHg; p < 0.05). LVt had a reduced surfactant protein A concentration and increased histologic injury as compared with APRV. The plateau pressure in APRV (34.3 ± 0.9 cmH2O) was significantly greater than LVt (22.2 ± 2.0 cmH2O; p < 0.05) yet transpulmonary pressure between groups was similar (p > 0.05). This was because the pleural pressure was significantly lower in LVt (7.6 ± 0.5 cmH2O) as compared with APRV (17.4 ± 3.5 cmH2O; p < 0.05). Finally, the elastance of the lung, chest wall, and respiratory system were all significantly greater in LVt as compared with APRV (all p < 0.05). APRV preserved surfactant and lung architecture and maintenance of oxygenation. Despite the greater plateau pressure and tidal volumes in the APRV group, the transpulmonary pressure was similar to that of LVt. Thus, the majority of the plateau pressure in the APRV group was distributed as pleural pressure in this extrapulmonary lung injury model. APRV maintained a normal lung elastance and an open, homogeneously ventilated lung without increasing lung stress.

Background: Observational studies have indicated a potential association between autoimmune diseases and the occurrence of sepsis, with an increased risk of mortality among affected patients. However, whether a causal relationship exists between the two remains unknown. Methods: In the Mendelian randomization (MR) study, we accessed exposure Genome-wide association study (GWAS) data from both the MRC Integrative Epidemiology Unit (MRC-IEU) and the FinnGen consortium. GWAS data for sepsis and its 28-day mortality were obtained from MRC-IEU. We employed univariable, multivariable, and reverse MR analyses to explore potential associations between autoimmune disorders and sepsis and its 28-day mortality. Additionally, a two-step mediation MR analysis was performed to investigate indirect factors possibly influencing the relationship between autoimmune disorders and sepsis. Afterward, we conducted an observational analysis to further explore the relationship between autoimmune disease and occurrence as well as 28-day mortality of sepsis using a real-world database (the MIMIC-IV database). A cohort of 2537 patients diagnosed with autoimmune disease were extracted from the database for analysis. Multivariable logistic regression models were used to confirm the association between autoimmune diseases and the occurrence of sepsis, as well as the 28-day mortality associated with sepsis. Results: In univariable MR analysis, there appeared to be causal relationships between genetically predicted type 1 diabetes (OR = 1.036, 95% CI = 1.023–1.048, p = 9.130E-09), rheumatoid arthritis (OR = 1.077, 95% CI = 1.058–1.097, p = 1.00E-15) and sepsis, while a potential causal link was observed between celiac disease and sepsis (OR = 1.013, 95% CI = 1.002–1.024, p = 0.026). In a subsequent multivariable MR analysis, only rheumatoid arthritis was found to be independently associated with the risk of sepsis (OR = 1.138, 95% CI = 1.044–1.240, p = 3.36E-03). Furthermore, there was no causal link between autoimmune disorders and 28-day mortality from sepsis. In reverse MR analysis, sepsis was suggested to potentially trigger the onset of psoriasis (OR = 1.084, 95% CI = 1.040–1.131, p = 1.488E-04). In the real-world observational study, adjusting for multiple confounders, rheumatoid arthritis (OR = 1.34, 95% CI = 1.11–1.64, p = 0.003) and multiple sclerosis (OR = 1.31, 95% CI = 1.03–1.68, p = 0.02) were associated with a higher risk of sepsis. In addition, we did not find that autoimmune diseases were associated with 28-day mortality from sepsis. Conclusion: Both in observational and MR analysis, only rheumatoid arthritis is highly correlated with occurrence of sepsis. However, autoimmune disease was not associated with an increased 28-day mortality in patient with sepsis. Sepsis may increase the risk of developing psoriasis.

Background: Advances in organoid culture technology have provided a greater understanding of disease pathogenesis, which has been rarely studied in sepsis before. We aim to establish a suitable organoids-based intestinal injury model for sepsis. Methods: Stable passaged organoids were constructed and pre-treated with lipopolysaccharide (LPS) to mimic sepsis-induced intestinal injury. The LPS-induced sepsis model was used as a reference. We used quantitative real-time polymerase chain reaction to evaluate the RNA levels of inflammatory factors and antimicrobial peptides. Enzyme-linked immunosorbent assay was used to evaluate the protein levels, hematoxylin and eosin staining was used to evaluate the pathology of the small intestine of mice, and immunohistochemistry and immunofluorescence were used to evaluate the intestinal epithelial barrier function. Perkin Elmer Operetta™ was used to obtain high-resolution images of three-dimensional organoids. Results: An LPS concentration >150 μg/mL after 24 h was identified to cause organoid growth restriction. The fluorescence intensity of zonula occludens-1 and occludins at LPS concentrations >100 μg/mL decreased significantly after 24 h. After LPS stimulation for 8 h, the RNA expression levels of interleukin (IL)-1α, tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, IL-6, and regenerating islet-derived protein 3 alpha, beta, and gamma increased. These results resembled those of intestinal epithelial layer alterations in a mouse sepsis model. For IL-10, the RNA expression level increased only when the LPS level >200 μg/mL for 24 h. Conclusions: This study provides the primary intestinal in vitro model to study the effects of LPS-induced intestinal injury resembling sepsis. This model provides a platform for immune associated mechanism exploration and effective drug screening.