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Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2 + TMPRSS2 + cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

Background Patients with severe Coronavirus Disease 2019 (COVID-19) have respiratory failure with hypoxemia and acute bilateral pulmonary infiltrates, consistent with acute respiratory distress syndrome (ARDS). It has been suggested that respiratory failure in COVID-19 represents a novel pathologic entity. Research Question How does the lung histopathology described in COVID-19 compare to the lung histopathology described in SARS and H1N1 influenza? Study Design and Methods: We conducted a systematic review to characterize the lung histopathologic features of COVID-19 and compare them against findings of other recent viral pandemics, H1N1 influenza and SARS. We systematically searched MEDLINE and PubMed for studies published up to June 24, 2020 using search terms for COVID-19, H1N1 influenza and SARS with keywords for pathology, biopsy, and autopsy. Using PRISMA-IPD guidelines, our systematic review analysis included 26 articles representing 171 COVID-19 patients; 20 articles representing 287 H1N1 patients; and eight articles representing 64 SARS patients. Results In COVID-19, acute phase diffuse alveolar damage (DAD) was reported in 88% of patients, which was similar to the proportion of cases with DAD in both H1N1 (90%) and SARS (98%). Pulmonary microthrombi were reported in 57% of COVID-19 and 58% of SARS patients, as compared to 24% of H1N1 influenza patients. Interpretation DAD, the histologic correlate of ARDS, is the predominant histopathologic pattern identified in lung pathology from patients with COVID-19, H1N1 influenza and SARS. Microthrombi were reported more frequently in both patients with COVID-19 and SARS as compared to H1N1 influenza. Future work is needed to validate this histopathologic finding and, if confirmed, elucidate the mechanistic underpinnings and characterize any associations with clinically important outcomes.

Objective Recent cohort studies have identified obesity as a risk factor for poor outcomes in coronavirus disease 2019 (COVID‐19). To further explore the relationship between obesity and critical illness in COVID‐19, the association of BMI with baseline demographic and intensive care unit (ICU) parameters, laboratory values, and outcomes in a critically ill patient cohort was examined. Methods In this retrospective study, the first 277 consecutive patients admitted to Massachusetts General Hospital ICUs with laboratory‐confirmed COVID‐19 were examined. BMI class, initial ICU laboratory values, physiologic characteristics including gas exchange and ventilatory mechanics, and ICU interventions as clinically available were measured. Mortality, length of ICU admission, and duration of mechanical ventilation were also measured. Results There was no difference found in respiratory system compliance or oxygenation between patients with and without obesity. Patients without obesity had higher initial ferritin and D‐dimer levels than patients with obesity. Standard acute respiratory distress syndrome management, including prone ventilation, was equally distributed between BMI groups. There was no difference found in outcomes between BMI groups, including 30‐ and 60‐day mortality and duration of mechanical ventilation. Conclusions In this cohort of critically ill patients with COVID‐19, obesity was not associated with meaningful differences in respiratory physiology, inflammatory profile, or clinical outcomes.

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Influenza and other respiratory viruses present a significant threat to public health, national security, and the world economy, and can lead to the emergence of global pandemics such as from COVID-19. A barrier to the development of effective therapeutics is the absence of a robust and predictive preclinical model, with most studies relying on a combination of in vitro screening with immortalized cell lines and low-throughput animal models. Here, we integrate human primary airway epithelial cells into a custom-engineered 96-device platform (PREDICT96-ALI) in which tissues are cultured in an array of microchannel-based culture chambers at an air–liquid interface, in a configuration compatible with high resolution in-situ imaging and real-time sensing. We apply this platform to influenza A virus and coronavirus infections, evaluating viral infection kinetics and antiviral agent dosing across multiple strains and donor populations of human primary cells. Human coronaviruses HCoV-NL63 and SARS-CoV-2 enter host cells via ACE2 and utilize the protease TMPRSS2 for spike protein priming, and we confirm their expression, demonstrate infection across a range of multiplicities of infection, and evaluate the efficacy of camostat mesylate, a known inhibitor of HCoV-NL63 infection. This new capability can be used to address a major gap in the rapid assessment of therapeutic efficacy of small molecules and antiviral agents against influenza and other respiratory viruses including coronaviruses.

Objective Soluble ST2 (sST2) and IL-6 concentrations have been associated with the inflammatory cascade of acute respiratory distress syndrome (ARDS). We determined whether sST2 and IL-6 levels can be used as prognostic biomarkers to guide weaning from mechanical ventilation and predict the need for reintubation. Design, Setting, and Patients We assayed plasma sST2 (N=826) concentrations and IL-6 (N=755) concentrations in the Fluid and Catheter Treatment Trial (FACTT), a multi-center randomized controlled trial of conservative fluid management in ARDS. We tested whether sST2 and IL-6 levels were associated with duration of mechanical ventilation, the probability of passing a weaning assessment, and the need for reintubation. Measurements and Main Results In models adjusted for APACHE score and other relevant variables, patients with higher day 0 and day 3 median sST2 and IL-6 concentrations had decreased probability of extubation over time (day 0 sST2 HR 0.85, 95% CI 0.72–1.00, P=.05; day 0 IL-6 HR 0.64, 95% CI 0.54–0.75, P<.0001; day 3 sST2 HR 0.64, 95% CI 0.54–0.75; P<.0001; day 3 IL-6 HR 0.73, 95% CI 0.62–0.85, P=.0001). Higher biomarker concentrations were also predictive of decreased odds of passing day 3 weaning assessments (sST2 OR 0.62, 95% CI 0.44–0.87, P=.006; IL-6 OR 0.61, 95% CI 0.43–0.85, P=.004) and decreased odds of passing a spontaneous breathing trial (sST2 OR 0.45, 95% CI 0.28–0.71, P=.0007; IL-6 univariate analysis only OR 0.55, 95% CI 0.36–0.83, P=.005). Finally, higher biomarker levels were significant predictors of need for reintubation with OR 3.23, 95% CI 1.04–10.07, P=.04 for sST2 and OR 2.58, 95% CI 1.14–5.84, P=.02 for IL-6. Conclusions Higher sST2 and IL-6 concentrations are each associated with worse outcomes during weaning of mechanical ventilation and increased need for reintubation in patients with ARDS. Biomarker-directed ventilator management may lead to improved outcomes in weaning of mechanical ventilation in patients with ARDS.

BackgroundSubspecialty fellows can serve as a tremendous educational resource to residents; however, there are multiple barriers to an effective resident-fellow teaching interaction in the setting of inpatient consultation. We designed and evaluated a resident-directed intervention to enhance communication and teaching during consultation on the general medicine wards.MethodsFive medical teams were randomized to receive the intervention over a 3 month period (3 control, 2 intervention teams). The intervention was evaluated with pre and post-intervention surveys.ResultsFifty-nine of 112 interns completed the pre-intervention survey, and 58 completed the post-intervention survey (53 % response rate). At baseline, 83 % of the interns noted that they had in-person interactions with fellows less than 50 % of the time. 81 % responded that they received teaching from fellows in less than 50 % of consultations. Following the intervention, the percentage of interns who had an in-person interaction with fellows greater than 50 % of the time increased in the intervention group (9 % control versus 30 % intervention, p = 0.05). Additionally, interns in the intervention group reported receiving teaching in more than 50 % of their interactions more frequently (19 % control versus 42 % intervention, p = 0.05). There were no differences in other measures of teaching and communication.ConclusionsWe demonstrate that a time-efficient intervention increased perceptions of in-person communication and the number of teaching interactions between interns and fellows. Further studies are warranted to determine whether such an approach can impact resident learning and improve patient care.Electronic supplementary materialThe online version of this article (doi:10.1186/s12909-016-0796-9) contains supplementary material, which is available to authorized users.