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1.
Critical Care (London, England) ; 26(1):278, 2022.
Article in English | MEDLINE | ID: covidwho-2029727

ABSTRACT

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.

2.
American Journal of Respiratory and Critical Care Medicine ; 205(1), 2022.
Article in English | EMBASE | ID: covidwho-1927902

ABSTRACT

Introduction: Dexamethasone decreases mortality in patients with severe COVID-19. The effects of dexamethasone on inflammation and repair in patients with severe COVID-19 are not well understood. We integrated tracheal aspirate (TA) and peripheral blood bulk/single-cell RNA sequencing to study the effect of dexamethasone on patients with COVID-19 ARDS. Methods: We studied selected patients from a cohort of adults with COVID-19 admitted to three hospitals in San Francisco, California from April 2020 to February 2021. Immunosuppression was not used to treat COVID-19 ARDS at these hospitals prior to July 2020, but was routinely used in these patients after this date. For this analysis, we included patients who were mechanically ventilated for COVID-19 ARDS for whom sequencing samples were available within four days of intubation. We excluded patients who received steroids prior to July 2020, subjects who received immunosuppression other than dexamethasone (e.g., tocilizumab) prior to sample collection, and chronically immunosuppressed subjects. We compared bulk RNASeq from TA and single cell RNASeq from TA and whole blood from subjects who received dexamethasone to subjects who did not receive dexamethasone. In addition, we studied the effect of dexamethasone on peripheral blood cytokine concentrations to confirm the effects of observed changes in gene expression. Results: TA bulk RNASeq was available from 20 subjects (six dexamethasone, 14 non-dexamethasone). There was no significant difference in age, sex, smoking, or BMI between groups. After correcting for multiple comparisons, 947 genes were differentially expressed in TA from subjects who received dexamethasone. Ingenuity Pathway Analysis predicted decreased activation of interferon, JAK/STAT, and NLRP12 signaling in subjects who received dexamethasone (Figure 1A). TA scRNASeq samples were available from ten dexamethasone-treated subjects and nine non-dexamethasone subjects. Whole blood scRNAseq samples were available for seven dexamethasone and eight non-dexamethasone subjects (Figure 1B). Eight subjects (three treated with dexamethasone) had both TA and whole blood scRNAseq samples available for analysis. Dexamethasone had distinct effects on the proportions of immune cells in tracheal aspirates and whole blood (Figure 1C). In 36 dexamethasone vs 42 non-dexamethasone subjects, treatment with dexamethasone was associated with significantly increased concentrations of IL-10 and decreased concentrations of IL-6 (Figure 1D). Conclusions: Dexamethasone decreases pro-inflammatory gene expression in the respiratory tract and peripheral blood of patients with COVID-19 ARDS. The effect of dexamethasone on specific cell populations may be distinct in the respiratory tract and peripheral blood.

3.
American Journal of Respiratory and Critical Care Medicine ; 205(1), 2022.
Article in English | EMBASE | ID: covidwho-1927886

ABSTRACT

Introduction: In COVID-19-related acute respiratory distress syndrome (ARDS), two distinct subphenotypes have been identified with differential outcomes and responses to corticosteroid therapy. We aimed to evaluate (1) whether clinical data can identify subgroups in a broader group of patients with SARS-CoV-2 pneumonia and (2) the extent to which corticosteroids demonstrate heterogeneity of treatment effect across such subgroups. Methods: We retrospectively studied all SARS-CoV-2 patients hospitalized for >24 hours and requiring oxygen support across 11 BJC HealthCare hospitals from June-December 2020. We excluded the initial surge (March-May 2020), as clinical care was heterogeneous and corticosteroid use low during this period. Using prespecified routinely-collected vital sign and laboratory indicator variables, we sought distinct clinical subphenotypes of SARS-CoV-2 pneumonia through latent class analysis (LCA). Across LCA subphenotypes, we evaluated the relationship between corticosteroid treatment and patient outcomes. We used multivariable logistic regression (dependent variable = composite of death/hospice) to explore treatment interaction between corticosteroid exposure and LCA subphenotype, adjusting for age and maximal SOFA score within 24 hours of admission as surrogates for indication. Results: The 3-class LCA model best fit the 1845-patient cohort (p=0.007). Class-1 (n=1456) had mean standardized values of all indicator variables near zero;Class-2 (n=235) manifested profound isolated hypoxemia;and Class-3 (n=154) displayed multiorgan failure, shock, and neutrophilia (Figure-1A). Despite representing <25% of the cohort, Classes 2 (n=109, 46%) and 3 (n=70, 46%) comprised >50% of the primary outcome (vs Class-1: n=151, 10%;p<0.001). Corticosteroids were more frequently administered in Class-2 (n=215, 91%) than in Class-1 (n=1071, 74%) or Class-3 (n=110, 71%, p<0.001;Figure-1B). Adjusted analyses demonstrated interaction between LCA class and corticosteroid treatment for the primary outcome (Class-1, p=0.003;Class-3, p=0.002). Corticosteroids were associated with increased adjusted odds for the primary outcome in Class-1 (aOR 2.11, 95% CI 1.33-3.50, p=0.002) and decreased adjusted odds for the primary outcome in Class-3 (aOR 0.44, 95% CI 0.19-0.98, p=0.048). Class-2 showed no outcome differences between the corticosteroid and noncorticosteroid groups (aOR 1.03, 95% CI 0.38-2.81, p=0.95). Conclusions: Three distinct subphenotypes of SARS-CoV-2 pneumonia demonstrate different clinical outcomes and corticosteroid response. No clear effect was seen among patients with isolated hypoxemia, whereas those with multiorgan failure appeared to benefit. Our findings suggest that among hospitalised patients in our healthcare system, corticosteroid therapy was associated with increased risk of harm. Prospective studies are needed to evaluate the efficacy of corticosteroids in SARS-CoV-2 pneumonia in predictively-enriched trials.

4.
American Journal of Respiratory and Critical Care Medicine ; 205(1), 2022.
Article in English | EMBASE | ID: covidwho-1927874

ABSTRACT

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.

5.
American Journal of Respiratory and Critical Care Medicine ; 205(1), 2022.
Article in English | EMBASE | ID: covidwho-1927857

ABSTRACT

Background: Latent class analyses in patients with acute respiratory distress syndrome (ARDS) have identified “hyper-inflammatory” and “hypo-inflammatory” phenotypes with divergent clinical outcomes and treatment responses. ARDS phenotypes are defined using plasma biomarkers and clinical variables. It is currently unknown if these phenotypes have distinct pulmonary biology and if pre-clinical models of disease replicate the biology of either phenotype. Methods: 45 subjects with ARDS (Berlin Definition) and 5 mechanically ventilated controls were selected from cohorts of mechanically ventilated patients at UCSF and ZSFG. Patients with COVID-19 were excluded from this analysis. A 3-variable classifier model (plasma IL-8, protein C, and bicarbonate;Sinha 2020) was used to assign ARDS phenotypes. Tracheal aspirate (TA) RNA was analyzed using established bulk and single-cell sequencing pipelines (Langelier 2018, Sarma 2021). Differentially expressed (DE) genes were analyzed using Ingenuity Pathway Analysis (IPA). Microbial community composition was analyzed with vegan. Fgsea was used to test for enrichment of gene sets from experimental ARDS models in genes that were differentially expressed between each phenotype and mechanically ventilated controls. Results: Bulk RNA sequencing (RNAseq) was available from 29 subjects with hypoinflammatory ARDS and 10 subjects with hyperinflammatory ARDS. 2,777 genes were differentially expressed between ARDS phenotypes. IPA identified several candidate upstream regulators of gene expression in hyperinflammatory ARDS including IL6, TNF, IL17C, and interferons (Figure 1A). 2,953 genes were differentially expressed between hyperinflammatory ARDS and 5 ventilated controls;in contrast, only 243 genes were differentially expressed between hypoinflammatory ARDS and controls, suggesting gene expression in the hypoinflammatory phenotype was more heterogeneous. Gene sets from experimental models of acute lung injury were enriched in hyperinflammatory ARDS but not in hypoinflammatory ARDS (Figure 1B). Single cell RNA sequencing (scRNAseq) was available from 6 additional subjects with ARDS, of whom 3 had hyperinflammatory ARDS. 14,843 cells passed quality control filters. Hyperinflammatory ARDS subjects had a markedly higher burden of neutrophils (Figure 1C), including a cluster of stressed neutrophils expressing heat shock protein RNA that was not present in hypoinflammatory ARDS. Expression of a Th1 signature was higher in T cells from hyperinflammatory ARDS. Differential expression analysis in macrophages identified increased expression of genes associated with mortality in a previous study of ARDS patients (Morell 2019). Conclusions: The respiratory tract biology of ARDS phenotypes is distinct. Hyperinflammatory ARDS is characterized by neutrophilic inflammation with distinct immune cell polarization. Transcriptomic profiling identifies candidate preclinical disease models that replicate gene expression observed in hyperinflammatory ARDS.

6.
American Journal of Respiratory and Critical Care Medicine ; 205(1), 2022.
Article in English | EMBASE | ID: covidwho-1927743

ABSTRACT

Rationale: The ROSE trial was a multicenter unblinded randomized clinical trial comparing early neuromuscular blockade (NMB) to usual care in patients with moderate to severe ARDS (NEJM 2019). This trial (n=1006) was stopped early for futility yet a subgroup analysis found that among Hispanic/Latino participants the NMB intervention group had a significantly lower mortality (32%) compared to those in the control group (53.7% p=0.02 for interaction). To evaluate potential contributors to these differences we compared baseline clinical and biological characteristics among Hispanic/Latino participants in the intervention vs control group. Methods: We compared demographics primary ARDS risk factor illness severity ventilatory parameters comorbidities and plasma biomarkers at baseline between the NMB intervention and control group for all 118 Hispanic/Latino patients recruited to the ROSE trial (11.6% of the trial population). We used multiple logistic regression to examine whether the mortality difference by treatment group would persist after controlling for the factors that differed significantly between groups. Results: At baseline Hispanic/Latino participants randomized to the control group had greater disease severity scores (APACHE III SOFA;p<0.05 for both) and a higher prevalence of shock (p=0.01) compared to those randomized to the intervention. There were no significant differences between groups in causes of lung injury or baseline ventilatory parameters. In an unadjusted logistic regression model the NMB intervention was significantly associated with mortality (OR 0.42;95%CI 0.20-0.89 p=0.02). The NMB intervention was no longer significantly associated with mortality when adjusting for severity of by illness by either SOFA score (OR 0.53;95%CI 0.24-1.20 p=0.13), APACHE III (OR 0.51, 95%CI 0.20- 1.30 p=0.16) or shock as defined by the need for vasopressors (OR 0.48, 95%CI 0.22-1.03, p=0.06). Hispanic/Latino participants in the control group had significantly higher interleukin-8 (p=0.02) and lower bicarbonate (p=0.045) than those in the intervention group. Conclusion: Together these clinical and biomarker data support the conclusion that the lower mortality associated with NMB in the Hispanic/Latino subgroup may have been partially due to baseline imbalances in systemic severity of illness. This finding underscores the need to cautiously interpret apparent treatment benefits within small subgroups. The COVID-19 pandemic has highlighted ethnic and racial disparities in ARDS. Future trials will benefit from increased representation of populations that are disproportionately affected to minimize the impact of spurious findings related to small sample sizes while creating more statistical power to prospectively address disparities.

8.
PubMed; 2022.
Preprint in English | PubMed | ID: ppcovidwho-337234

ABSTRACT

In the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic1, considerable focus has been placed on a model of viral entry into host epithelial populations, with a separate focus upon the responding immune system dysfunction that exacerbates or causes disease. We developed a precision-cut lung slice model2,3 to investigate very early host-viral pathogenesis and found that SARS-CoV-2 had a rapid and specific tropism for myeloid populations in the human lung. Infection of alveolar macrophages was partially dependent upon their expression of ACE2, and the infections were productive for amplifying virus, both findings which were in contrast with their neutralization of another pandemic virus, Influenza A virus (IAV). Compared to IAV, SARS-CoV-2 was extremely poor at inducing interferon-stimulated genes in infected myeloid cells, providing a window of opportunity for modest titers to amplify within these cells. Endotracheal aspirate samples from humans with the acute respiratory distress syndrome (ARDS) from COVID-19 confirmed the lung slice findings, revealing a persistent myeloid depot. In the early phase of SARS-CoV-2 infection, myeloid cells may provide a safe harbor for the virus with minimal immune stimulatory cues being generated, resulting in effective viral colonization and quenching of the immune system.

9.
PubMed; 2020.
Preprint in English | PubMed | ID: ppcovidwho-333583

ABSTRACT

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense. ONE SENTENCE SUMMARY: In severe COVID-19 patients, the immune system fails to generate cells that define mild disease;antibodies in their serum actively prevents the successful production of those cells.

10.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-330704

ABSTRACT

Secondary bacterial infections, including ventilator-associated pneumonia (VAP), lead to worse clinical outcomes and increased mortality following viral respiratory infections including in patients with coronavirus disease 2019 (COVID-19). Using a combination of tracheal aspirate bulk and single-cell RNA sequencing (scRNA-seq) we assessed lower respiratory tract immune responses and microbiome dynamics in 28 COVID-19 patients, 15 of whom developed VAP, and eight critically ill uninfected controls. Two days before VAP onset we observed a transcriptional signature of bacterial infection. Two weeks prior to VAP onset, following intubation, we observed a striking impairment in immune signaling in COVID-19 patients who developed VAP. Longitudinal metatranscriptomic analysis revealed disruption of lung microbiome community composition in patients with VAP, providing a connection between dysregulated immune signaling and outgrowth of opportunistic pathogens. These findings suggest that COVID-19 patients who develop VAP have impaired antibacterial immune defense detectable weeks before secondary infection onset.

11.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-297038

ABSTRACT

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.

13.
American Journal of Respiratory and Critical Care Medicine ; 203(9), 2021.
Article in English | EMBASE | ID: covidwho-1277339

ABSTRACT

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.

14.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-8864

ABSTRACT

Secondary bacterial infections, including ventilator-associated pneumonia (VAP), lead to worse clinical outcomes and increased mortality following viral respiratory infections including in patients with coronavirus disease 2019 (COVID-19). Using a combination of tracheal aspirate bulk and single-cell RNA sequencing (scRNA-seq) we assessed lower respiratory tract immune responses and microbiome dynamics in 28 COVID-19 patients, 15 of whom developed VAP, and eight critically ill uninfected controls. Two days before VAP onset we observed a transcriptional signature of bacterial infection. Two weeks prior to VAP onset, following intubation, we observed a striking impairment in immune signaling in COVID-19 patients who developed VAP. Longitudinal metatranscriptomic analysis revealed disruption of lung microbiome community composition in patients with VAP, providing a connection between dysregulated immune signaling and outgrowth of opportunistic pathogens. These findings suggest that COVID-19 patients who develop VAP have impaired antibacterial immune defense detectable weeks before secondary infection onset.

15.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-6307

ABSTRACT

We performed comparative lower respiratory tract transcriptional profiling of 52 critically ill patients with the acute respiratory distress syndrome (ARDS) from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a cytokine storm, we observed reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS was characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity that were predicted to be modulated by dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 was characterized by impaired interferon-stimulated gene expression (ISG). We found that the relationship between SARS-CoV-2 viral load and expression of ISGs was 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 with COVID-19 ARDS did not demonstrate cytokine storm but instead revealed a unique and dysregulated host response predicted to be modified by dexamethasone.

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