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1.
European psychiatry : the journal of the Association of European Psychiatrists ; 65(Suppl 1):S592-S592, 2022.
Article in English | EuropePMC | ID: covidwho-2073269

ABSTRACT

Introduction There is paucity of epidemiological studies from the Arab world and most of the focus of available international data is on the early months of the pandemic. Objectives We conducted the first cross-sectional national phone survey of adults in Qatar during the end of the first wave of the pandemic (December 2020 -January 2021) to estimate the prevalence and determinants of depression and/or anxiety. Methods We used the Physician Health Questionnaire-9 and Generalized Anxiety Disorder-7 with cut-off scores of ≥10;the revised UCLA loneliness scale;and questions related to COVID-19 status, death of family or friend, quarantine, health and changes in living arrangements. Bivariate and logistic regression models estimated associations between thirteen variables and combined depression-anxiety (score of 20 or higher). Results The two-week prevalence of depression was 6.5% (95%CI: 5.1-8.4), of anxiety 5.1% (95%CI: 3.8-6.9), but only 2.5% sought mental health professional help since the pandemic started. When including loneliness (OR=1.57, p (<0.001) in the model, the following variables were statistically significantly associated with depression-anxiety: female gender (OR=1.90, p=0.037), Qatari nationality (OR=2.37, p=0.018), Arab ethnicity (OR=3.14, p=0.007), and COVID-19 death of family or friend (OR=3.06, p=0.003). Without adjusting for loneliness, younger age (18-29 versus 40+ years of age: OR=2.9, p=0.004) and chronic health conditions (OR=2.0, p=0.029) were significantly associated with depression-anxiety. Conclusions Prevalence of depression and/or anxiety during the end of the first wave of COVID-19 pandemic in Qatar was similar to pre-pandemic estimates. Mental health service should focus on young adults, women, the bereaved, lonely and those with chronic health problems. Disclosure No significant relationships.

2.
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.

3.
American Journal of Respiratory and Critical Care Medicine ; 205(1), 2022.
Article in English | EMBASE | ID: covidwho-1927703

ABSTRACT

Introduction: Due to Covid-19 restrictions on collecting and processing sputum samples in real time in clinic, we designed a novel sputum home collection method with immediate freezing and delayed processing (“home”). A validation study was carried out to compare key sputum endpoints using the “home” vs “real time (RT)” collection and processing methods. Sputum soluble phase proteomics, mucins and RNA/DNA endpoints were measured and compared between the 2 methods to assess the validity of the “home” method. Methods: Spontaneous sputum samples were collected from N=10 healthy adult volunteers. Each sample was split evenly by weight and processed, half by the “home” method and half by the RT method. Home method samples were first aliquoted into 3 collection tubes (T) as follows: T1: 100-250mg for mucin analysis (refractive index, gel chromatography, and CsCl gradients);T2 and T3: equal weights each, T2 for proteomic analysis (MesoScale Discovery) and T3 for RNA/DNA analysis (Isohelix collection kit). Each was immediately frozen at -20 deg C (24-48hr), then at -80 deg C (2-4 weeks) without any processing. Thawed home T1 and T2 samples were processed by treating with 8M Urea (1:1) to deactivate SARS-CoV-2 if present. T1 was then stored at 2-4 deg C, and T2 was processed with 7x DPBS, centrifuged and recovered supernatants stored at -80 deg C. In contrast, the RT sputum was first treated with 8M Urea (1:1) soon after collection, and then processed for mucins and proteomics per the “home” method above. The remaining cell pellet from the RT processed sample was stored in Zymo research RNA/DNA shield (0.5ml) and, along with home T3 samples, extracted and analyzed for qualitative and quantitative yield, as well as for genes of interest. Paired T-Test analysis compared all sputum endpoints between the home and RT method. Results: There were no statistically significant differences (p<0.05) between the home and RT method for any mucin (MUC5B, MUC5AC, MUC5AC:MUC5B ratio, total mucin) or proteomic endpoint (IL-1a, IL-6, IL-8, TNFalpha, TIMP1, TIMP2, MMP-9, CRP, MPO). In addition, except for CRP and MUC5AC, correlation between sample pairings was strong (correlation coefficient R, range = 0.5-0.9) and statistically significant (p<0.05) for all sputum endpoints. RNA/DNA results are still pending. Conclusion: The sputum “home collection method with immediate freezing and delayed processing” does not result in significantly different proteomic and mucin measurements when compared to the same samples being processed in real time in an identical manner.

4.
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.

5.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-333706

ABSTRACT

RATIONALE: Asthma is associated with chronic changes in the airway epithelium, a key target of SARS-CoV-2. Many epithelial changes are driven by the type 2 cytokine IL-13, but the effects of IL-13 on SARS-CoV-2 infection are unknown. OBJECTIVES: We sought to discover how IL-13 and other cytokines affect expression of genes encoding SARS-CoV-2-associated host proteins in human bronchial epithelial cells (HBECs) and determine whether IL-13 stimulation alters susceptibility to SARS-CoV-2 infection. METHODS: We used bulk and single cell RNA-seq to identify cytokine-induced changes in SARS-CoV-2-associated gene expression in HBECs. We related these to gene expression changes in airway epithelium from individuals with mild-moderate asthma and chronic obstructive pulmonary disease (COPD). We analyzed effects of IL-13 on SARS-CoV-2 infection of HBECs. MEASUREMENTS AND MAIN RESULTS: Transcripts encoding 332 of 342 (97%) SARS-CoV-2-associated proteins were detected in HBECs (>=1 RPM in 50% samples). 41 (12%) of these mRNAs were regulated by IL-13 (>1.5-fold change, FDR < 0.05). Many IL-13-regulated SARS-CoV-2-associated genes were also altered in type 2 high asthma and COPD. IL-13 pretreatment reduced viral RNA recovered from SARS-CoV-2 infected cells and decreased dsRNA, a marker of viral replication, to below the limit of detection in our assay. Mucus also inhibited viral infection. CONCLUSIONS: IL-13 markedly reduces susceptibility of HBECs to SARS-CoV-2 infection through mechanisms that likely differ from those activated by type I interferons. Our findings may help explain reports of relatively low prevalence of asthma in patients diagnosed with COVID-19 and could lead to new strategies for reducing SARS-CoV-2 infection.

6.
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.

7.
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.

8.
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.

10.
Vaccines ; 9(5), 2021.
Article in English | CAB Abstracts | ID: covidwho-1302566

ABSTRACT

Global COVID-19 pandemic containment necessitates understanding the risk of hesitance or resistance to vaccine uptake in different populations. The Middle East and North Africa currently lack vital representative vaccine hesitancy data. We conducted the first representative national phone survey among the adult population of Qatar, between December 2020 and January 2021, to estimate the prevalence and identify potential determinants of vaccine willingness: acceptance (strongly agree), resistance (strongly disagree), and hesitance (somewhat agree, neutral, somewhat disagree). Bivariate and multinomial logistic regression models estimated associations between willingness groups and fifteen variables. In the total sample, 42.7% (95% CI: 39.5-46.1) were accepting, 45.2% (95% CI: 41.9-48.4) hesitant, and 12.1% (95% CI: 10.1-14.4) resistant. Vaccine resistant compared with hesistant and accepting groups reported no endorsement source will increase vaccine confidence (58.9% vs. 5.6% vs. 0.2%, respectively). Female gender, Arab ethnicity, migrant status/type, and vaccine side-effects concerns were associated with hesitancy and resistance. COVID-19 related bereavement, infection, and quarantine status were not significantly associated with any willingness group. Absence of or lack of concern about contracting the virus was solely associated with resistance. COVID-19 vaccine resistance, hesitance, and side-effects concerns are high in Qatar's population compared with those globally. Urgent public health engagement should focus on women, Qataris (non-migrants), and those of Arab ethnicity.

11.
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.

12.
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.

13.
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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