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American Journal of Respiratory and Critical Care Medicine ; 205(1), 2022.
Article in English | EMBASE | ID: covidwho-1927874


RATIONALE: Some biomarkers of host response to viral infection are associated with COVID-19 outcomes, but these biomarkers do not directly measure viral burden. 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 viral antigen concentration and proximal clinical deterioration in hospitalized patients. METHODS: SARS-CoV-2 nucleocapsid antigen concentrations were measured using a validated microbead immunoassay (Quanterix, NIH/NIAID laboratory) in plasma collected at enrollment from 256 subjects in a prospective observational cohort of hospitalized patients with COVID-19 from 3 hospitals, admitted between March 2020 and August 2021. Relationships between viral antigen concentration and clinical status at 1 week as measured by the World Health Organization (WHO) ordinal scale as well as ICU admission were assessed. Models were adjusted for age and sex, baseline comorbidities including immunosuppression, endogenous neutralizing antibodies, baseline COVID-19 severity, smoking status, remdesivir therapy, steroid therapy, and vaccine status. Missing covariate data were imputed using multiple imputation by chained equations. RESULTS: The median viral antigen concentration for the 35 subjects who deteriorated by 1 week was 4507 (IQR 1225-9665) pg/mL compared to 494 (IQR 18-3882) pg/mL in the 212 subjects who did not (p = 0.0004 Figure a). Using ordinal regression, each doubling in viral antigen concentration was significantly associated with a worse WHO ordinal scale at 1 week (unadjusted OR 1.07, 95% CI 1.02-1.13;adjusted OR 1.10, 95% CI 1.02-1.18). Among 168 patients not in the ICU at baseline, the median viral antigen concentration for the 40 patients who progressed to the ICU was 4697 (IQR 482- 10410) pg/mL vs. 459 (IQR 15-3062) pg/mL in the 128 patients who did not progress to require ICU care (p = 0.0001 Figure b). Using logistic regression, each doubling in viral antigen concentration was significantly associated with ICU admission (unadjusted OR 1.18, 95% CI 1.06-1.32, adjusted OR 1.40, 95% CI 1.11-1.76). CONCLUSIONS: Higher plasma viral antigen concentration at hospital admission is independently associated with a significantly worse clinical status at 1 week and a higher odds of ICU admission among hospitalized patients with COVID-19. This novel finding indicates that plasma viral antigen concentration may identify hospitalized COVID-19 patients at highest risk of short-term clinical deterioration in both clinical practice and research. Results of plasma antigen tests are available within 2-3 hours and could be integrated for identifying hospitalized COVID-19 patients who might benefit from early intervention.

PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-297038


Secondary bacterial infections, including ventilator-associated pneumonia (VAP), lead to worse clinical outcomes and increased mortality following viral respiratory infections. Critically ill patients with coronavirus disease 2019 (COVID-19) face an elevated risk of VAP, although susceptibility varies widely. Because mechanisms underlying VAP predisposition remained unknown, we assessed lower respiratory tract host immune responses and microbiome dynamics in 36 patients, including 28 COVID-19 patients, 15 of whom developed VAP, and eight critically ill controls. We employed a combination of tracheal aspirate bulk and single cell RNA sequencing (scRNA-seq). Two days before VAP onset, a lower respiratory transcriptional signature of bacterial infection was observed, characterized by increased expression of neutrophil degranulation, toll-like receptor and cytokine signaling pathways. When assessed at an earlier time point following endotracheal intubation, more than two weeks prior to VAP onset, we observed a striking early impairment in antibacterial innate and adaptive immune signaling that markedly differed from COVID-19 patients who did not develop VAP. scRNA-seq further demonstrated suppressed immune signaling across monocytes/macrophages, neutrophils and T cells. While viral load did not differ at an early post-intubation timepoint, impaired SARS-CoV-2 clearance and persistent interferon signaling characterized the patients who later developed VAP. Longitudinal metatranscriptomic analysis revealed disruption of lung microbiome community composition in patients who developed VAP, providing a connection between dysregulated immune signaling and outgrowth of opportunistic pathogens. Together, these findings demonstrate that COVID-19 patients who develop VAP have impaired antibacterial immune defense weeks before secondary infection onset. One sentence summary: COVID-19 patients with secondary bacterial pneumonia have impaired immune signaling and lung microbiome changes weeks before onset.

American Journal of Respiratory and Critical Care Medicine ; 203(9), 2021.
Article in English | EMBASE | ID: covidwho-1277339


Background: The coronavirus disease 2019 (COVID-19) pandemic has led to a rapid increase in the incidence of acute respiratory distress syndrome (ARDS). The distinct features of pulmonary biology in COVID-19 ARDS compared to other causes of ARDS, including other lower respiratory tract infections (LRTIs), are not well understood. Methods: Tracheal aspirates (TA) and plasma were collected within five days of intubation from mechanically ventilated adults admitted to one of two academic medical centers. ARDS and LRTI diagnoses and were verified by study physicians. Subjects were excluded if they received immunosuppression. TA from subjects with COVID-ARDS was compared to gene expression in TA from subjects with other causes of ARDS (OtherARDS) or mechanically ventilated control subjects without evidence of pulmonary pathology (NoARDS). Plasma concentrations of IL-6, IL-8, and protein C also were compared between these groups. Upstream regulator and pathway analysis was performed on significantly differentially expressed genes with Ingenuity Pathway Analysis (IPA). Subgroup analyses were performed to compare gene expression in COVID to ARDS associated with other viral LRTIs and bacterial LRTIs. The association of interferon-stimulated gene expression with SARS-CoV2 viral load was compared to the same association in nasopharyngeal swabs in a cohort of subjects with mild SARS-CoV2. Results: TA sequencing was available from 15 subjects with COVID, 32 subjects with other causes of ARDS (OtherARDS), and 5 mechanically ventilated subjects without evidence of pulmonary pathology (NoARDS). 696 genes were differentially expressed between COVID and OtherARDS (Figure 1A). IL-6, IL-8, B-cell receptor, and hypoxia inducible factor-1a signaling were attenuated in COVID compared to OtherARDS. Peroxisome proliferator-activated receptor (PPAR) and PTEN signaling were higher in COVID compared to OtherARDS (Figure 1B). Plasma levels of IL-6, IL-8, and protein C were not significantly different between COVID and OtherARDS. In subgroup analyses, IL-8 signaling was higher in COVID compared to viral LRTI, but lower than bacterial LRTI. Type I/III interferon was higher in COVID compared to bacterial ARDS, but lower compared to viral ARDS (Figure 1C). Compared to nasopharyngeal swabs from subjects with mild COVID-19, expression of several interferon stimulated genes was less strongly correlated with SARS-CoV2 viral load in TA (Figure 1D). IPA identified several candidate medications to treat COVID-19, including dexamethasone, G-CSF, and etanercept. Conclusions: TA sequencing identifies unique features of the host response in COVID-19. These differentially expressed pathways may represent potential therapeutic targets. An impaired interferon response in the lung may increase susceptibility to severe SARS-COV2.