Plasma NEDD9 is increased following SARS-CoV-2 infection and associates with indices of pulmonary vascular dysfunction.

Compared to healthy volunteers, participants with post-acute sequelae of SARS-CoV-2 infection (PASC) demonstrated increased plasma levels of the prothrombotic protein NEDD9, which associated inversely with indices of pulmonary vascular function. This suggests persistent pulmonary vascular dysfunction may play a role in the pathobiology of PASC.

A human model of asthma exacerbation reveals transcriptional programs and cell circuits specific to allergic asthma.

Asthma is a chronic disease most commonly associated with allergy and type 2 inflammation. However, the mechanisms that link airway inflammation to the structural changes that define asthma are incompletely understood. Using a human model of allergen-induced asthma exacerbation, we compared the lower airway mucosa in allergic asthmatics and allergic non-asthmatic controls using single-cell RNA sequencing. In response to allergen, the asthmatic airway epithelium was highly dynamic and up-regulated genes involved in matrix degradation, mucus metaplasia, and glycolysis while failing to induce injury-repair and antioxidant pathways observed in controls. IL9-expressing pathogenic TH2 cells were specific to asthmatic airways and were only observed after allergen challenge. Additionally, conventional type 2 dendritic cells (DC2 that express CD1C) and CCR2-expressing monocyte-derived cells (MCs) were uniquely enriched in asthmatics after allergen, with up-regulation of genes that sustain type 2 inflammation and promote pathologic airway remodeling. In contrast, allergic controls were enriched for macrophage-like MCs that up-regulated tissue repair programs after allergen challenge, suggesting that these populations may protect against asthmatic airway remodeling. Cellular interaction analyses revealed a TH2-mononuclear phagocyte-basal cell interactome unique to asthmatics. These pathogenic cellular circuits were characterized by type 2 programming of immune and structural cells and additional pathways that may sustain and amplify type 2 signals, including TNF family signaling, altered cellular metabolism, failure to engage antioxidant responses, and loss of growth factor signaling. Our findings therefore suggest that pathogenic effector circuits and the absence of proresolution programs drive structural airway disease in response to type 2 inflammation.

Soluble Suppression of Tumorigenicity-2 Associates With Ventilator Dependence in Coronavirus Disease 2019 Respiratory Failure.

OBJECTIVES: We hypothesize that elevated soluble suppression of tumorigenicity-2 concentrations, a marker of pulmonary epithelial injury, reflect ongoing lung injury in acute hypoxemic respiratory failure due to coronavirus disease 2019 and associate with continued ventilator dependence. DESIGN: We associated serial plasma soluble suppression of tumorigenicity-2 levels and markers of systemic inflammation including d-dimer, C-reactive protein, and erythrocyte sedimentation rate with 30-day mortality and ventilator dependence. SETTING: Adult medical ICUs and general medicine wards at an academic teaching hospital in Boston, MA. PATIENTS: Adult patients with severe acute respiratory syndrome coronavirus 2 infection and acute hypoxemic respiratory failure admitted to the ICU (n = 72) and non-ICU patients managed with supplemental oxygen (n = 77). INTERVENTIONS: Observational study from April 25 to June 25, 2020. MEASUREMENTS AND MAIN RESULTS: ICU patients had a higher baseline body mass index and median soluble suppression of tumorigenicity-2, d-dimer, and C-reactive protein concentrations compared with non-ICU patients. Among ICU patients, elevated baseline modified Sequential Organ Failure Assessment score and log (soluble suppression of tumorigenicity-2) were associated with 30-day mortality, whereas initial Pao2/Fio2 and markers of systemic inflammation were similar between groups. Only log (soluble suppression of tumorigenicity-2) associated with ventilator dependence over time, with the last measured log (soluble suppression of tumorigenicity-2) concentration obtained on ICU day 11.5 (interquartile range [7-17]) higher in patients who required reintubation or tracheostomy placement compared with patients who were successfully extubated (2.10 [1.89-2.26] vs 1.87 ng/mL [1.72-2.13 ng/mL]; p = 0.03). Last measured systemic inflammatory markers, modified Sequential Organ Failure Assessment score, and Pao2/Fio2 were not different between patients who were successfully extubated compared with those with continued ventilator dependence. CONCLUSIONS: Plasma soluble suppression of tumorigenicity-2 is a biomarker readily measured in blood that can provide dynamic information about the degree of a patient's lung injury and real-time assessment of the likelihood of extubation success. Measures of systemic inflammation, illness severity, and oxygenation did not associate with ventilator outcomes.