Exposure to ambient air pollutants and acute respiratory distress syndrome risk in sepsis.

PURPOSE: Exposures to ambient air pollutants may prime the lung enhancing risk of acute respiratory distress syndrome (ARDS) in sepsis. Our objective was to determine the association of short-, medium-, and long-term pollutant exposures and ARDS risk in critically ill sepsis patients. METHODS: We analyzed a prospective cohort of 1858 critically ill patients with sepsis, and estimated short- (3 days), medium- (6 weeks), and long- (5 years) term exposures to ozone, nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO), particulate matter < 2.5 µm (PM2.5), and PM < 10 µm (PM10) using weighted averages of daily levels from monitors within 50 km of subjects' residences. Subjects were followed for 6 days for ARDS by the Berlin Criteria. The association between each pollutant and ARDS was determined using multivariable logistic regression adjusting for preselected confounders. In 764 subjects, we measured plasma concentrations of inflammatory proteins at presentation and tested for an association between pollutant exposure and protein concentration via linear regression. RESULTS: ARDS developed in 754 (41%) subjects. Short- and long-term exposures to SO2, NO2, and PM2.5 were associated with ARDS risk (SO2: odds ratio (OR) for the comparison of the 75-25th long-term exposure percentile 1.43 (95% confidence interval (CI) 1.16, 1.77); p < 0.01; NO2: 1.36 (1.06, 1.74); p = 0.04, PM2.5: 1.21 (1.04, 1.41); p = 0.03). Long-term exposures to these three pollutants were also associated with plasma interleukin-1 receptor antagonist and soluble tumor necrosis factor receptor-1 concentrations. CONCLUSION: Short and long-term exposures to ambient SO2, PM2.5, and NO2 are associated with increased ARDS risk in sepsis, representing potentially modifiable environmental risk factors for sepsis-associated ARDS.

Validating a Proteomic Signature of Severe COVID-19.

COVID-19 is a heterogenous disease. Biomarker-based approaches may identify patients at risk for severe disease, who may be more likely to benefit from specific therapies. Our objective was to identify and validate a plasma protein signature for severe COVID-19. DESIGN: Prospective observational cohort study. SETTING: Two hospitals in the United States. PATIENTS: One hundred sixty-seven hospitalized adults with COVID-19. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We measured 713 plasma proteins in 167 hospitalized patients with COVID-19 using a high-throughput platform. We classified patients as nonsevere versus severe COVID-19, defined as the need for high-flow nasal cannula, mechanical ventilation, extracorporeal membrane oxygenation, or death, at study entry and in 7-day intervals thereafter. We compared proteins measured at baseline between these two groups by logistic regression adjusting for age, sex, symptom duration, and comorbidities. We used lead proteins from dysregulated pathways as inputs for elastic net logistic regression to identify a parsimonious signature of severe disease and validated this signature in an external COVID-19 dataset. We tested whether the association between corticosteroid use and mortality varied by protein signature. One hundred ninety-four proteins were associated with severe COVID-19 at the time of hospital admission. Pathway analysis identified multiple pathways associated with inflammatory response and tissue repair programs. Elastic net logistic regression yielded a 14-protein signature that discriminated 90-day mortality in an external cohort with an area under the receiver-operator characteristic curve of 0.92 (95% CI, 0.88-0.95). Classifying patients based on the predicted risk from the signature identified a heterogeneous response to treatment with corticosteroids (p = 0.006). CONCLUSIONS: Inpatients with COVID-19 express heterogeneous patterns of plasma proteins. We propose a 14-protein signature of disease severity that may have value in developing precision medicine approaches for COVID-19 pneumonia.

Association of vancomycin plus piperacillin-tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study.

PURPOSE: Although dozens of studies have associated vancomycin + piperacillin-tazobactam with increased acute kidney injury (AKI) risk, it is unclear whether the association represents true injury or a pseudotoxicity characterized by isolated effects on creatinine secretion. We tested this hypothesis by contrasting changes in creatinine concentration after antibiotic initiation with changes in cystatin C concentration, a kidney biomarker unaffected by tubular secretion. METHODS: We included patients enrolled in the Molecular Epidemiology of SepsiS in the ICU (MESSI) prospective cohort who were treated for ≥ 48 h with vancomycin + piperacillin-tazobactam or vancomycin + cefepime. Kidney function biomarkers [creatinine, cystatin C, and blood urea nitrogen (BUN)] were measured before antibiotic treatment and at day two after initiation. Creatinine-defined AKI and dialysis were examined through day-14, and mortality through day-30. Inverse probability of treatment weighting was used to adjust for confounding. Multiple imputation was used to impute missing baseline covariates. RESULTS: The study included 739 patients (vancomycin + piperacillin-tazobactam n = 297, vancomycin + cefepime n = 442), of whom 192 had cystatin C measurements. Vancomycin + piperacillin-tazobactam was associated with a higher percentage increase of creatinine at day-two 8.04% (95% CI 1.21, 15.34) and higher incidence of creatinine-defined AKI: rate ratio (RR) 1.34 (95% CI 1.01, 1.78). In contrast, vancomycin + piperacillin-tazobactam was not associated with change in alternative biomarkers: cystatin C: - 5.63% (95% CI - 18.19, 8.86); BUN: - 4.51% (95% CI - 12.83, 4.59); or clinical outcomes: dialysis: RR 0.63 (95% CI 0.31, 1.29); mortality: RR 1.05 (95%CI 0.79, 1.41). CONCLUSIONS: Vancomycin + piperacillin-tazobactam was associated with creatinine-defined AKI, but not changes in alternative kidney biomarkers, dialysis, or mortality, supporting the hypothesis that vancomycin + piperacillin-tazobactam effects on creatinine represent pseudotoxicity.

Early Plasma Nuclear DNA, Mitochondrial DNA, and Nucleosome Concentrations Are Associated With Acute Kidney Injury in Critically Ill Trauma Patients.

Circulating nucleic acids, alone and in complex with histones as nucleosomes, have been proposed to link systemic inflammation and coagulation after trauma to acute kidney injury (AKI). We sought to determine the association of circulating nucleic acids measured at multiple time points after trauma with AKI risk. DESIGN: We conducted a prospective cohort study of trauma patients, collecting plasma on presentation and at 6, 12, 24, and 48 hours, defining AKI over the first 6 days by Kidney Disease Improving Global Outcomes serum creatinine and dialysis criteria. We determined kinetics of plasma mitochondrial DNA (mtDNA), nuclear DNA (nDNA), and nucleosome levels across time points and associations with AKI using multivariable linear mixed-effects models, adjusted for injury characteristics and blood transfusions. We evaluated the association of presentation nucleic acid damage-associated molecular patterns (DAMP) concentrations with subsequent AKI, adjusting for injury severity using multivariable logistic regression. SETTING: Academic level I trauma center. PATIENTS: Trauma patients (n = 55) requiring intensive care for greater than or equal to 24 hours after presentation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: AKI developed in 17 patients (31%), a median of 12.0 hours (interquartile range, 6.2-24.1 hr) after presentation. mtDNA demonstrated a time-varying association with AKI (p = 0.022, interaction with time point), with differences by AKI status not emerging until 24 hours (ß = 0.97 [95% CI, 0.03-1.90] log copies/uL; p = 0.043). Patients who developed AKI had higher nDNA across all time points (overall ß = 1.41 log copies/uL [0.86-1.95 log copies/uL]; p < 0.001), and presentation levels were significantly associated with subsequent AKI (odds ratio [OR], 2.55 [1.36-4.78] per log copy/uL; p = 0.003). Patients with AKI had higher nucleosome levels at presentation (ß = 0.32 [0.00-0.63] arbitrary unit; p = 0.048), a difference that was more pronounced at 24 hours (ß = 0.41 [0.06-0.76]; p = 0.021) and 48 hours (ß = 0.71 [0.35-1.08]; p < 0.001) (p = 0.075, interaction with time point). CONCLUSIONS: Plasma nucleic acid DAMPs have distinct kinetics and associations with AKI in critically ill trauma patients. nDNA at presentation predicts subsequent AKI and may be amenable to targeted therapies in this population.

New-onset IgG autoantibodies in hospitalized patients with COVID-19.

COVID-19 is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. Here we develop three protein arrays to measure IgG autoantibodies associated with connective tissue diseases, anti-cytokine antibodies, and anti-viral antibody responses in serum from 147 hospitalized COVID-19 patients. Autoantibodies are identified in approximately 50% of patients but in less than 15% of healthy controls. When present, autoantibodies largely target autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes. A subset of autoantibodies targeting traditional autoantigens or cytokines develop de novo following SARS-CoV-2 infection. Autoantibodies track with longitudinal development of IgG antibodies recognizing SARS-CoV-2 structural proteins and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins.

New-Onset IgG Autoantibodies in Hospitalized Patients with COVID-19.

Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. We developed three different protein arrays to measure hallmark IgG autoantibodies associated with Connective Tissue Diseases (CTDs), Anti-Cytokine Antibodies (ACA), and anti-viral antibody responses in 147 hospitalized COVID-19 patients in three different centers. Autoantibodies were identified in approximately 50% of patients, but in <15% of healthy controls. When present, autoantibodies largely targeted autoantigens associated with rare disorders such as myositis, systemic sclerosis and CTD overlap syndromes. Anti-nuclear antibodies (ANA) were observed in ∼25% of patients. Patients with autoantibodies tended to demonstrate one or a few specificities whereas ACA were even more prevalent, and patients often had antibodies to multiple cytokines. Rare patients were identified with IgG antibodies against angiotensin converting enzyme-2 (ACE-2). A subset of autoantibodies and ACA developed de novo following SARS-CoV-2 infection while others were transient. Autoantibodies tracked with longitudinal development of IgG antibodies that recognized SARS-CoV-2 structural proteins such as S1, S2, M, N and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. COVID-19 patients with one or more autoantibodies tended to have higher levels of antibodies against SARS-CoV-2 Nonstructural Protein 1 (NSP1) and Methyltransferase (ME). We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins.

Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread within the human population. Although SARS-CoV-2 is a novel coronavirus, most humans had been previously exposed to other antigenically distinct common seasonal human coronaviruses (hCoVs) before the coronavirus disease 2019 (COVID-19) pandemic. Here, we quantified levels of SARS-CoV-2-reactive antibodies and hCoV-reactive antibodies in serum samples collected from 431 humans before the COVID-19 pandemic. We then quantified pre-pandemic antibody levels in serum from a separate cohort of 251 individuals who became PCR-confirmed infected with SARS-CoV-2. Finally, we longitudinally measured hCoV and SARS-CoV-2 antibodies in the serum of hospitalized COVID-19 patients. Our studies indicate that most individuals possessed hCoV-reactive antibodies before the COVID-19 pandemic. We determined that ∼20% of these individuals possessed non-neutralizing antibodies that cross-reacted with SARS-CoV-2 spike and nucleocapsid proteins. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but they were boosted upon SARS-CoV-2 infection.

Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread within the human population. Although SARS-CoV-2 is a novel coronavirus, most humans had been previously exposed to other antigenically distinct common seasonal human coronaviruses (hCoVs) before the COVID-19 pandemic. Here, we quantified levels of SARS-CoV-2-reactive antibodies and hCoV-reactive antibodies in serum samples collected from 204 humans before the COVID-19 pandemic. We then quantified pre-pandemic antibody levels in serum from a separate cohort of 252 individuals who became PCR-confirmed infected with SARS-CoV-2. Finally, we longitudinally measured hCoV and SARS-CoV-2 antibodies in the serum of hospitalized COVID-19 patients. Our studies indicate that most individuals possessed hCoV-reactive antibodies before the COVID-19 pandemic. We determined that ~23% of these individuals possessed non-neutralizing antibodies that cross-reacted with SARS-CoV-2 spike and nucleocapsid proteins. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but paradoxically these hCoV cross-reactive antibodies were boosted upon SARS-CoV-2 infection.