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The immunological features that distinguish COVID-19-associated acute respiratory distress syndrome (ARDS) from other causes of ARDS are incompletely understood. Here, we report the results of comparative lower respiratory tract transcriptional profiling of tracheal aspirate from 52 critically ill patients with ARDS from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a “cytokine storm,” we observe reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS is characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity. In silico analysis of gene expression identifies several candidate drugs that may modulate gene expression in COVID-19 ARDS, including dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 is characterized by impaired interferon-stimulated gene (ISG) expression. The relationship between SARS-CoV-2 viral load and expression of ISGs is decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients reveals distinct immunological features of COVID-19 ARDS.

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Life-threatening ‘breakthrough’ cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.

Background Studies quantifying SARS-CoV-2 have focused on upper respiratory tract or plasma viral RNA with inconsistent association with clinical outcomes. The association between plasma viral antigen levels and clinical outcomes has not been previously studied. Our aim was to investigate the relationship between plasma SARS-CoV-2 nucleocapsid antigen (N-antigen) concentration and both markers of host response and clinical outcomes. Methods SARS-CoV-2 N-antigen concentrations were measured in the first study plasma sample (D0), collected within 72 h of hospital admission, from 256 subjects admitted between March 2020 and August 2021 in a prospective observational cohort of hospitalized patients with COVID-19. The rank correlations between plasma N-antigen and plasma biomarkers of tissue damage, coagulation, and inflammation were assessed. Multiple ordinal regression was used to test the association between enrollment N-antigen plasma concentration and the primary outcome of clinical deterioration at one week as measured by a modified World Health Organization (WHO) ordinal scale. Multiple logistic regression was used to test the association between enrollment plasma N-antigen concentration and the secondary outcomes of ICU admission, mechanical ventilation at 28 days, and death at 28 days. The prognostic discrimination of an externally derived “high antigen” cutoff of N-antigen ≥ 1000 pg/mL was also tested. Results N-antigen on D0 was detectable in 84% of study participants. Plasma N-antigen levels significantly correlated with RAGE (r = 0.61), IL-10 (r = 0.59), and IP-10 (r = 0.59, adjusted p = 0.01 for all correlations). For the primary outcome of clinical status at one week, each 500 pg/mL increase in plasma N-antigen level was associated with an adjusted OR of 1.05 (95% CI 1.03–1.08) for worse WHO ordinal status. D0 plasma N-antigen ≥ 1000 pg/mL was 77% sensitive and 59% specific (AUROC 0.68) with a positive predictive value of 23% and a negative predictive value of 93% for a worse WHO ordinal scale at day 7 compared to baseline. D0 N-antigen concentration was independently associated with ICU admission and 28-day mechanical ventilation, but not with death at 28 days. Conclusions Plasma N-antigen levels are readily measured and provide important insight into the pathogenesis and prognosis of COVID-19. The measurement of N-antigen levels early in-hospital course may improve risk stratification, especially for identifying patients who are unlikely to progress to severe disease.

ImportanceAdvance care planning (ACP) prepares patients and caregivers for medical decision-making, yet it is underused in the perioperative surgical setting, particularly among older adults undergoing high-risk procedures who are at risk for postoperative complications. It is unknown what patient factors are associated with perioperative ACP documentation among older surgical patients.ObjectiveTo assess ACP documentation among high-risk patients 65 years and older undergoing elective surgery.Design, Setting, and ParticipantsIn this observational cohort study including 3671 patients 65 years and older undergoing elective surgery at a tertiary academic center in California, electronic health record data were linked to the National Surgical Quality Improvement Project outcomes data and the California statewide death registry. The study was conducted from January 1 to December 31, 2019. Data were analyzed from January to May 2022.ExposuresElective surgery requiring an inpatient admission.Main Outcomes and MeasuresACP documentation, defined as a discussion regarding goals of care documented in an ACP note, an advance directive, or a physician order for life-sustaining treatment (POLST) form, within 90 days before elective surgery requiring inpatient admission. Multivariate regression was performed to identify factors associated with missing ACP.ResultsAmong 3671 patients (median [IQR] age 72 [65-94] years; 1784 [48.6%] female; 401 [10.9%] Asian, 155 [4.2%] Black, 284 [7.7%] Latino/Latina, 2647 [72.1%] White, and 184 [5.0%] of other races or ethnicities, including American Indian or Alaska Native, Native Hawaiian or Pacific Islander, multiple races or ethnicities, other, and unknown or declined to respond, combined owing to small numbers), 539 (14.7%) had ACP documentation in the 90-day presurgery window. Of these 539, 448 (83.1%) had advance directives, and 60 (11.1%) had POLST forms. The 30-day and 1-year mortality were 0.7% (n = 27) and 6.6% (n = 244), respectively. Missing ACP was significantly associated with male sex (adjusted odds ratio [aOR], 1.39; 95% CI, 1.14-1.69) and having a non-English preferred language (aOR, 1.78; 95% CI, 1.18-2.79). Medicare insurance was significantly associated with having ACP (aOR for missing ACP, 0.63; 95% CI, 0.40-0.95).Conclusions and RelevanceIn this study, perioperative ACP was uncommon, particularly in men, individuals with a non-English preferred language, and those without Medicare insurance coverage. The perioperative setting may represent a missed opportunity for ACP for older surgical patients. When addressing ACP for surgical patients, particular attention should be paid to overcoming language-related disparities.

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