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1.
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.

2.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-330688

ABSTRACT

Unlike other respiratory viruses, SARS-CoV-2 disproportionately causes severe disease in older adults and only rarely in children. To investigate whether differences in the upper airway immune response could contribute to this disparity, we compared nasopharyngeal gene expression in 83 children (<19-years-old;38 with SARS-CoV-2, 11 with other respiratory viruses, 34 with no virus) and 154 adults (>40-years-old;45 with SARS-CoV-2, 28 with other respiratory viruses, 81 with no virus). Expression of interferon-stimulated genes (ISGs) was robustly activated in both children and adults with SARS-CoV-2 compared to the respective non-viral groups, with only relatively subtle distinctions. Children, however, demonstrated markedly greater upregulation of pathways related to B cell and T cell activation and proinflammatory cytokine signaling, including TNF, IFNgamma, IL-2 and IL-4 production. Cell type deconvolution confirmed greater recruitment of B cells, and to a lesser degree macrophages, to the upper airway of children. Only children exhibited a decrease in proportions of ciliated cells, the primary target of SARS-CoV-2, upon infection with the virus. These findings demonstrate that children elicit a more robust innate and adaptive immune response to SARS-CoV-2 infection in the upper airway that likely contributes to their protection from severe disease in the lower airway.

3.
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.

4.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-296900

ABSTRACT

Background: Sequencing of the SARS-CoV-2 viral genome from patient samples is an important epidemiological tool for monitoring and responding to the pandemic, including the emergence of new mutations in specific communities. Methods: SARS-CoV-2 genomic sequences were generated from positive samples collected, along with epidemiological metadata, at a walk-up, rapid testing site in the Mission District of San Francisco, California during November 22-December 2, 2020 and January 10-29, 2021. Secondary household attack rates and mean sample viral load were estimated and compared across observed variants. Results: A total of 12,124 tests were performed yielding 1,099 positives. From these, 811 high quality genomes were generated. Certain viral lineages bearing spike mutations, defined in part by L452R, S13I, and W152C, comprised 54.9% of the total sequences from January, compared to 15.7% in November. Household contacts exposed to "West Coast" variants were at higher risk of infection compared to household contacts exposed to lineages lacking these variants (0.357 vs 0.294, RR=1.29;95% CI:1.01-1.64). The reproductive number was estimated to be modestly higher than other lineages spreading in California during the second half of 2020. Viral loads were similar among persons infected with West Coast versus non-West Coast strains, as was the proportion of individuals with symptoms (60.9% vs 64.1%). Conclusions: The increase in prevalence, relative household attack rates, and reproductive number are consistent with a modest transmissibility increase of the West Coast variants;however, additional laboratory and epidemiological studies are required to better understand differences between these variants. Summary: We observed a growing prevalence and elevated attack rate for "West Coast" SARS-CoV-2 variants in a community testing setting in San Francisco during January 2021, suggesting its modestly higher transmissibility.

5.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-290599

ABSTRACT

Unlike other respiratory viruses, SARS-CoV-2 disproportionately causes severe disease in older adults and only rarely in children. To investigate whether differences in the upper airway immune response could contribute to this disparity, we compared nasopharyngeal gene expression in 83 children (<19-years-old;38 with SARS-CoV-2, 11 with other respiratory viruses, 34 with no virus) and 154 adults (>40-years-old;45 with SARS-CoV-2, 28 with other respiratory viruses, 81 with no virus). Expression of interferon-stimulated genes (ISGs) was robustly activated in both children and adults with SARS-CoV-2 compared to the respective non-viral groups, with only relatively subtle distinctions. Children, however, demonstrated markedly greater upregulation of pathways related to B cell and T cell activation and proinflammatory cytokine signaling, including TNF, IFNgamma, IL-2 and IL-4 production. Cell type deconvolution confirmed greater recruitment of B cells, and to a lesser degree macrophages, to the upper airway of children. Only children exhibited a decrease in proportions of ciliated cells, the primary target of SARS-CoV-2, upon infection with the virus. These findings demonstrate that children elicit a more robust innate and adaptive immune response to SARS-CoV-2 infection in the upper airway that likely contributes to their protection from severe disease in the lower airway.

6.
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.

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