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1.
Gastroenterology ; 162(7):S-278, 2022.
Article in English | EMBASE | ID: covidwho-1967264

ABSTRACT

Introduction: More adverse clinical outcomes following SARS-CoV-2 infection are reported in patients treated with infliximab/thiopurines (IFX/THIO), compared with biological monotherapy with anti-TNF or vedolizumab (VDZ). VDZ has been associated with a heightened and more durable serological response after infection and vaccination, compared to IFX. However, whether IBD patients on VDZ have a fully intact systemic response to SARS- CoV2 remains unknown. We explored the serological and functional neutralizing response after SARS-CoV-2 infection in IBD patients treated with VDZ, IFX or IFX/THIO compared to true healthy controls to guide treatment decisions and vaccination strategies. Methods: Serum from 640 IBD patients attending routine infusions in Oxford and London (May to December 2020) was screened by the Abbott assay for SARS-CoV-2 nucleocapsid (N) antibodies. Serum from seropositive patients was compared to seropositive health care workers (Table 1). Antibody reactivity to the SARS-CoV-2 wild type (WT) strain receptor-binding domain (RBD), full-length spike, and N was assayed by IgG/IgA ELISA over time as well as by IgG MSD V-PLEX ELISA at the time of seropositivity. A pseudotyped SARS-CoV-2 virus microneutralization assay was used to detect neutralizing antibodies to the WT, and an ELISA-based inhibition assay to compare differential inhibition of the WT vs. delta variant (DV) SARS-CoV-2 RBD-ACE2 interaction. Results: All IBD patients showed significantly reduced IgG antibody responses compared to healthy controls to all SARS-CoV-2 antigens, using MSD V-PLEX (Figure 1A-C). The greatest reduction in IgG response by ELISA was observed in patients treated with IFX/THIO (p=0.00019), whereas IgG response over time declined significantly faster in the IFX treated group (p=0.019). IgA responses were significantly reduced in the IFX/THIO group compared to healthy controls (p=0.009), but not in the IFX or VDZ group. The rate of decline in these monotherapy groups was not significantly different to healthy controls. Compared to healthy controls, functional SARS-CoV-2 neutralization was reduced in each treatment group (Figure 1D), with the greatest effect in patients receiving IFX/THIO (p=0.00000091). Neutralizing capacity to the DV was significantly reduced in 68.1% of IBD patients (30/44, p=0.0005). Conclusion: Both IFX and VDZ are associated with significantly reduced IgG responses to multiple SARS-CoV-2 antigens, and with impaired functional SARS-CoV-2 neutralizing antibody capacity, compared to healthy individuals. However, whilst IgG and neutralization responses are reduced in IBD patients on biological monotherapy, these findings were most pronounced in the combination treatment group. As neutralizing antibody responses are associated with protection, these observations may impact on decision-making regarding treatment and vaccination strategies.(Table Presented)(Figure Presented)

2.
PubMed; 2020.
Preprint in English | PubMed | ID: ppcovidwho-333615

ABSTRACT

BACKGROUND AND AIMS: The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn's disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course. METHODS: We examined the expression of colon ACE2 using RNA-seq and quantitative (q) RT-PCR from 69 adult CD and 14 NIBD control patients. In a subset of this cohort we validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients. RESULTS: Colonic ACE2 expression was significantly higher in a subset of adult CD patients (ACE2-high CD). IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of diagnosis, with a Cox regression analysis finding that high ACE2 levels is an independent risk factor (OR 2.18;95%CI, 1.05-4.55;p=0.037). CONCLUSION: Increased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that may impact CD disease-related outcomes.

3.
Radiotherapy and Oncology ; 163:S27, 2021.
Article in English | EMBASE | ID: covidwho-1747440

ABSTRACT

Purpose: Adjuvant radiation plays a significant role in reducing loco-regional recurrences in uterine cancers. Standard treatment consists of daily radiation for five weeks which can be challenging for patients and the healthcare system, especially during the COVID-19 pandemic. Hypofractionated radiotherapy has been evaluated and established in other pelvic malignancies. This study aims to evaluate the acute urinary and bowel toxicities, and patient reported outcomes following stereotactic hypofractionated adjuvant radiation for endometrial cancer. Materials and Methods: This is a prospective phase I/II trial in which patients with endometrial cancer planned for adjuvant radiation received 30Gy in 5 fractions, every other day or once weekly. Treatment was delivered at two centres with volumetric arc radiation therapy with a body-vacuum immobilization, bowel enema and 3D image-guidance. Toxicity assessment, outcomes and patient reported quality of life (QOL, EORTC core QLQ-C30 and endometrial EN24) were collected at baseline, fractions (F) 3 and 5, and at regular follow-up intervals. Higher scores represent better global QOL/health status or worse symptoms (scale 0 -100). Changes in QOL over time were investigated with linear mixed-effects models. A p-value threshold of 0.05 was used for statistical significance. A change in QOL score of > 10 points was considered clinically significant. Results: The median age of the 41 enrolled patients is 66 (range: 51 - 88). Histologies included 29 endometrioid adenocarcinoma, eight serous/clear cell, one carcinosarcoma, and three dedifferentiated. Thirty patients had Stage I disease while three had Stage 2 and eight Stage 3. Seven patients received sequential chemotherapy and 3 had additional vault brachytherapy. Median follow-up is nine months, with worst toxicity (GI or GU) of Grade 1 and 2 in 63% and 24% respectively. No patients have experienced a Grade 3 or higher toxicity. Patient-reported diarrhea and gastrointestinal domain scores were statistically significantly worse than baseline at F5 (mean paired difference = 27.2;8.7, p<.005) and six weeks (mean paired difference = 7.9;5.1, p<0.05), and returned to baseline levels at 12 weeks. The only clinically significant change (>10) from baseline was in diarrhea at F5. There were no significant changes in urinary domain, overall health and quality of life scores. No loco-regional recurrences have been found;three patients recurred distantly, of which two died of metastatic disease. Conclusions: Stereotactic hypofractionated radiation is feasible and well-tolerated with short-term follow-up. Longer follow-up and future randomized studies are needed to further evaluate this treatment.

4.
Journal of Crohn's and Colitis ; 16:i069-i070, 2022.
Article in English | EMBASE | ID: covidwho-1722298

ABSTRACT

Background: Recent data have highlighted adverse clinical outcomes in IBD patients treated with infliximab/thiopurines (IFX/ THIO) upon infection with SARS-CoV-2, as well as attenuated serological responses after infection and vaccination in patients treated with IFX. To provide mechanistic insight, we explored the serological and functional anti-viral response after infection in IBD patients treated with VDZ, IFX or IFX/THIO compared to healthy controls to guide clinical decision-making regarding treatment and vaccination strategies. Methods: Serum from 640 IBD patients attending routine infusions in Oxford and London in May to December 2020 was screened for anti-SARS-CoV-2 antibody responses by the Abbott assay. Serum from seropositive patients was compared to seropositive health care workers (Table 1). Antibody reactivity to the SARS-CoV-2 wild type strain receptor-binding domain (RBD), full-length spike, and nucleocapsid was assayed by IgG/IgA ELISA over time as well as by IgG high-throughput MSD V-PLEX ELISA at the time of seropositivity. A pseudotyped SARS-CoV-2 virus microneutralization assay was used to detect neutralising antibodies to the wild type, and an ELISA-based inhibition assay to compare differential inhibition of the wild type vs. delta variant SARS-CoV-2 RBD-ACE2 interaction. Results: All IBD patients showed significantly reduced IgG antibody responses compared to healthy controls for all SARS-CoV-2 antigens, using MSD V-PLEX ELISA (Figure 1). The greatest reduction in IgG response by ELISA was observed in individuals treated with IFX/THIO (p=0.00019), whereas IgG response over time declined significantly faster in the IFX treated group (p=0.019). IgA responses were significantly reduced in the IFX/THIO group compared to healthy controls (p=0.009), but not in the IFX or VDZ monotherapy group. The rate of decline in these monotherapy groups was also not significantly different to healthy controls. Functional SARS-CoV-2 neutralisation was significantly lower in all IBD patients compared to healthy controls, with the greatest reduction in patients receiving IFX/THIO (Figure 2A;p=0.00000091). The delta variant inhibition capacity was significantly reduced in 68.1% of IBD patients (30/44, Figure 2B;p=0.0005). Conclusion: IFX/THIO is associated with significantly lower IgA and IgG responses, and with impaired functional SARS-CoV-2 neutralising antibody capacity, compared to healthy individuals. Whilst IgG and neutralisation responses are reduced in each group of IBD patients, these findings were most pronounced in the combination treatment group. As neutralising antibody responses are associated with protection, this observation may impact on decision-making regarding treatment and vaccination/antiviral strategies.

5.
MEDLINE;
Preprint in English | MEDLINE | ID: ppcovidwho-326575

ABSTRACT

COVID-19 is an ongoing global crisis in which the development of effective vaccines and therapeutics will depend critically on understanding the natural immunity to the virus, including the role of SARS-CoV-2-specific T cells. We have conducted a study of 42 patients following recovery from COVID-19, including 28 mild and 14 severe cases, comparing their T cell responses to those of 16 control donors. We assessed the immune memory of T cell responses using IFNgamma based assays with overlapping peptides spanning SARS-CoV-2 apart from ORF1. We found the breadth, magnitude and frequency of memory T cell responses from COVID-19 were significantly higher in severe compared to mild COVID-19 cases, and this effect was most marked in response to spike, membrane, and ORF3a proteins. Total and spike-specific T cell responses correlated with the anti-Spike, anti-Receptor Binding Domain (RBD) as well as anti-Nucleoprotein (NP) endpoint antibody titre (p<0.001, <0.001 and =0.002). We identified 39 separate peptides containing CD4 + and/or CD8 + epitopes, which strikingly included six immunodominant epitope clusters targeted by T cells in many donors, including 3 clusters in spike (recognised by 29%, 24%, 18% donors), two in the membrane protein (M, 32%, 47%) and one in the nucleoprotein (Np, 35%). CD8+ responses were further defined for their HLA restriction, including B*4001-restricted T cells showing central memory and effector memory phenotype. In mild cases, higher frequencies of multi-cytokine producing M- and NP-specific CD8 + T cells than spike-specific CD8 + T cells were observed. They furthermore showed a higher ratio of SARS-CoV-2-specific CD8 + to CD4 + T cell responses. Immunodominant epitope clusters and peptides containing T cell epitopes identified in this study will provide critical tools to study the role of virus-specific T cells in control and resolution of SARS-CoV-2 infections. The identification of T cell specificity and functionality associated with milder disease, highlights the potential importance of including non-spike proteins within future COVID-19 vaccine design.

7.
Hepatology ; 74(SUPPL 1):318A-319A, 2021.
Article in English | EMBASE | ID: covidwho-1508736

ABSTRACT

Background: The COVID-19 pandemic has provided a unique opportunity to evaluate global intensive care unit (ICU) admission practices. Patients with chronic liver disease (CLD) and cirrhosis may have limited or variable access to ICU. We aimed to describe international ICU admission rates and outcomes in critically-ill patients with CLD and COVID-19. Methods: Data were combined from two international registries (SECURE-Liver and COVID-Hep) for patients with CLD and lab-confirmed COVID-19 deemed sick enough to require ICU admission by the reporting clinician. Rates of ICU admission or decline, and respective outcomes were compared by country. We performed a secondary analysis comparing ICU admissions/declines and outcomes from the United States (US) and United Kingdom (UK), the two greatest contributing countries. Results: Between 25 March 2020 and 3 February 2021, 319 patients with CLD and COVID-19 from 27 countries were deemed to require ICU care. There was considerable country-level variability in ICU decline rates (Figure 1A), although mortality following ICU admission was similar by country (Figure 1B). Rates of ICU admission differed significantly between the US (75/79, 95%) and UK (22/77, 29%) (p<0.001). However, there were no differences in the US and UK in mortality after ICU admission (42/75 [56%] vs. 10/22 [45%];p=0.468;Figure 1B) or mortality after invasive ventilation (29/59 [49%] vs. 9/17 [53%];p=1.000). Both in those requiring ICU admission and admitted to the ICU, there were no differences in age, sex, Charlson Comorbidity Index or Child Pugh Score. Only four US patients were declined ICU admission of whom 2 (50%) died compared to 55 UK patients declined ICU admission of whom 51 (93%) died. Baseline factors associated with being declined ICU admission in the UK were older age, alcohol-related liver disease, and Child B/C cirrhosis. In both US and UK cohorts, the reason for not admitting patients to ICU was due to this being deemed inappropriate (futile) by the responsible clinician, except for one case in both countries in which no ICU bed was available. Information relating to patient goals of care, longterm outcomes in survivors, and granular detail regarding organ support requirements were not available. Conclusion: Patients with CLD and critical COVID-19 were over 3-times more likely to be admitted to ICU in the US than the UK despite having similar baseline characteristics. However, the rates of mortality following ICU admission were comparable between the two countries. ICU bed availability was not a key factor in decline rates. The differing thresholds for escalation to ICU with similar post admission outcomes warrants further discussion.

8.
Hepatology ; 74(SUPPL 1):318A, 2021.
Article in English | EMBASE | ID: covidwho-1508693

ABSTRACT

Background: Despite recent advances, the management of COVID19 is complicated by vaccine availability, the modest efficacy of existing treatments, and the potential for viral resistance. Therefore, there is a pressing need for new prophylactic and therapeutic agents. Modifying the expression of the SARS-CoV-2 entry receptor ACE2 could prevent viral infection and limit disease progression. Here, we identify that ACE2 expression is controlled by the transcription factor farnesoid X receptor (FXR) and demonstrate that ACE2 downregulation through FXR antagonism, using approved drugs, such as ursodeoxycholic acid (UDCA), could represent a novel therapeutic strategy to complement current approaches. Methods: Primary cholangiocyte, pulmonary and intestinal organoids were propagated using established protocols. Marker expression was assessed using singlecell RNA sequencing, QPCR, immunofluorescence and flow cytometry. FXR binding on DNA was assessed with chromatin immunoprecipitation. SARS-CoV-2 was isolated from bronchoalveolar lavage of a COVID19 patient. Viral load was measured via QPCR. Human livers not used for transplantation were perfused ex-situ using the metra (OrganOx) normothermic perfusion device. Serum ACE2 activity was measured with commercial kits. Patient data from the COVID-Hep and SECURE-Liver registries were compared using propensity score matching. Results: FXR activation directly upregulated ACE2 transcription in organoids from COVID19 affected tissues, including the biliary, gastrointestinal and respiratory systems. Conversely, FXR antagonism with z-guggulsterone or UDCA, had the opposite effect. Importantly, both drugs reduced susceptibility to SARS-CoV-2 infection in lung, cholangiocyte and gut organoids. Furthermore, systemic administration of UDCA in human organs perfused ex-situ downregulated ACE2 and reduced SARS-CoV-2 infection ex-vivo. Oral UDCA rapidly reduced serum ACE2 in vivo. Registry data showed a correlation between UDCA administration and better clinical outcomes in COVID19 patients, including hospitalisation, ICU admission, mechanical ventilation and death. Conclusion: We discovered FXR as a novel therapeutic target against SARS-CoV-2 and we identified approved FXR inhibitors which could be repurposed to potentially treat COVID19, paving the road for future clinical trials to validate these results.

9.
Hepatology ; 74(SUPPL 1):327A-328A, 2021.
Article in English | EMBASE | ID: covidwho-1508685

ABSTRACT

Background: A number of factors can inform ICU escalation decisions, including the likelihood of survival and patient co-morbidities. This study examined prior liver transplant (LT) recipients and patients with chronic liver disease (CLD) diagnosed with SARS-CoV-2, and compared the rate of ICU admission and decline amongst those who were sick enough to require ICU care. Methods: Patient data from 12 March 2020 to 6 May 2021 was extracted using two international reporting registries (SECURE-Liver and COVID-Hep). Patients had a history of LT or CLD, laboratory-confirmed SARS-CoV-2, and were deemed ill enough to require ICU care. Patients were either admitted to the ICU, or declined admission due to inadequate capacity or because ICU escalation was deemed inappropriate. We compared patient characteristics by ICU decline, and compared ICU decline rates by LT and CLD categories with unadjusted and multivariable logistic regression. Results: 173 LT recipients were admitted to the hospital with SARS-CoV-2 (transplant year 1986-2020, median age 63, 74% male), and 66 (38.2%) were deemed unwell enough to require ICU care. Among those sick enough to require ICU care, 55 (83.3%) were admitted to the ICU and 11 (16.7%) were declined admission. Compared to those admitted to the ICU, patients declined ICU admission were significantly older (median 69 yrs vs 62 yrs, p=0.01) but otherwise similar in other characteristics. ICU decline rates in prior LT recipients (16.7%) were similar to patients with non-cirrhotic CLD (16.1%, p=0.96), but substantially lower than patients with Child A cirrhosis (31.8%, p=0.03), Child B cirrhosis (37.1%, p=0.006) and Child C cirrhosis (38.7%, p=0.004). Differences in ICU decline between LT recipients and Child B or C cirrhosis remained statistically significant after adjustment for age, sex and major co-morbidities. Among patients admitted to the ICU, mortality was higher in LT recipients compared to non-cirrhotic CLD (OR 0.31, 95% CI 0.14-0.71) but lower in LT recipients compared to Child C cirrhosis (OR 3.85, 95% CI 1.47-10.11) after adjustment for age, sex and co-morbidities (see Figure 1). Conclusion: ICU decline was less likely in LT recipients compared to patients with decompensated cirrhosis. LT recipients may be seen as gaining more benefit from ICU care, given the higher mortality amongst patients with decompensated cirrhosis. This is in line with prior data showing decompensated cirrhosis is a predictor of higher mortality in patients with SARS-CoV-2. Moreover, large investment of resources in LT recipients may make them more likely to be admitted to the ICU.

10.
Gut ; 70(SUPPL 3):A4, 2021.
Article in English | EMBASE | ID: covidwho-1467707

ABSTRACT

Introduction The management of COVID19 is complicated by vaccine availability, the modest efficacy of existing treatments, and the potential for viral resistance. Therefore, there is a pressing need for new prophylactic and therapeutic agents. The viral receptor ACE2 is an ideal target as it is required for SARS-CoV-2 entry in host cells. Modifying ACE2 expression could prevent infection and/or limit disease progression. Nevertheless, the mechanisms controlling ACE2 expression remain elusive. Aims To identify pathways controlling the transcriptional regulation of ACE2, and exploit them to reduce SARS-CoV-2 infection. Methods Organoids from primary biliary, intestinal and pulmonary epithelia were derived and cultured as previously described. Single-cell RNA sequencing, QPCR, immunofluorescence and flow cytometry were used to assess marker expression. Chromatin immunoprecipitation was used to assess FXR binding on DNA. Bronchoalveolar lavage SARS-CoV-2 patient isolates were used for infection experiments. Human livers not used for transplantation were connected to the metra (OrganOx) normothermic perfusion device and perfused ex-situ using therapeutic doses of UDCA for 12 hours. ACE2 activity was measured following manufacturer's instructions. Patient data from the COVID-Hep and SECURE-Liver registries were compared using propensity score matching for sex, age and Child-Turcotte-Pugh score. Results We first demonstrated that cholangiocytes are susceptible to SARS-CoV-2 infection in vivo and in organoid culture. We then used cholangiocyte organoids to identify FXR as a transcriptional regulator of ACE2. We validated our results in pulmonary and intestinal organoids, showing that ACE2 regulation by FXR represents a broad mechanism present in multiple COVID19-affected tissues. We then demonstrated that approved FXR inhibitors, such as ursodeoxycholic acid (UDCA) and z-guggulsterone (ZGG), decrease ACE2 levels and reduce viral infection in vitro in primary biliary, intestinal and pulmonary organoids. We interrogated the impact of systemic UDCA administration in human livers perfused ex-situ, demonstrating reduced ACE2 levels and SARS-CoV-2 infection. Furthermore, we showed that commencing UDCA treatment lowers ACE2 levels in primary biliary cholangitis (PBC) patients. Finally, we identified a correlation between UDCA treatment and better clinical outcome in COVID-19 patients, including hospitalisation, ICU admission, mechanical ventilation and death, using registry data. Conclusion We identified FXR as a novel master regulator of ACE2 expression. Using a bench-to-bedside approach we combined in vitro, ex-vivo and patient data to demonstrate the efficacy of ACE2 downregulation against SARS-CoV-2 infection and identified approved and inexpensive drugs (UDCA, ZGG) which could be repurposed as prophylactic and therapeutic agents against SARS-CoV-2 infection, paving the road for future clinical trials.

11.
International Journal of Radiation Oncology, Biology, Physics ; 111(3):S18-S19, 2021.
Article in English | Academic Search Complete | ID: covidwho-1428032

ABSTRACT

Adjuvant radiation plays a significant role in reducing locoregional recurrences in uterine cancers. Standard treatment consists of daily radiation for 5 weeks which can be challenging for patients and the healthcare system, especially during the COVID pandemic. Hypofractionated radiotherapy has been evaluated and established in other pelvic malignancies. This study aims to evaluate the acute urinary and bowel toxicities, and patient reported outcomes following stereotactic hypofractionated adjuvant radiation for endometrial cancer. This is a prospective phase I/II trial in which patients with endometrial cancer planned for adjuvant radiation received 30 Gy in 5 fractions, every other day or once weekly. Treatment was delivered at two centers with volumetric arc radiation therapy with a body-vacuum immobilization, bowel enema and 3D image-guidance. Toxicity assessment, outcomes and patient reported quality of life (QOL, EORTC core QLQ-C30 and endometrial EN24) were collected at baseline, fractions (F) 3 and 5, and at regular follow-up intervals. Higher scores represent better global QOL/health status or worse symptoms (scale 0 – 100). Changes in QOL over time were investigated with linear mixed-effects models. A P -value threshold of 0.05 was used for statistical significance. A change in QOL score of ≥ 10 points was considered clinically significant. The median age of the 41 enrolled patients is 66 (range: 51 – 88). Histologies included 29 endometrioid adenocarcinoma, 8 serous/clear cell, 1 carcinosarcoma, and 3 dedifferentiated. Thirty patients had stage 1 disease while 3 had stage 2 and 8 stage 3. Seven patients received sequential chemotherapy and 3 had additional vault brachytherapy. Median follow-up is 9 months, with worst toxicity (GI or GU) of grade 1 and 2 in 63% and 24% respectively. No patients have experienced a grade 3 or higher toxicity. Patient-reported diarrhea and gastrointestinal domain scores were statistically significantly worse than baseline at F5 (mean paired difference = 27.2;8.7, P <.005) and 6 weeks (mean paired difference = 7.9;5.1, P < 0.05), and returned to baseline levels at 12 weeks (Table 1). The only clinically significant change (≥ 10) from baseline was in diarrhea at F5. There were no significant changes in urinary domain, overall health and quality of life scores. No locoregional recurrences have been found;3 patients recurred distantly, of which 2 died of metastatic disease. Stereotactic hypofractionated radiation for uterine cancers is feasible and well-tolerated with short-term follow-up. Longer follow-up and future randomized studies are needed to further evaluate this treatment. [ABSTRACT FROM AUTHOR] Copyright of International Journal of Radiation Oncology, Biology, Physics is the property of Pergamon Press - An Imprint of Elsevier Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

16.
American Journal of Respiratory and Critical Care Medicine ; 203(9), 2021.
Article in English | EMBASE | ID: covidwho-1277075

ABSTRACT

RATIONALE: Several studies have identified host immune signatures that are associated with COVID-19. However, it is unclear whether these immune signatures are specific to COVID-19 or are merely reflective of illness severity. In vitro studies have demonstrated that human T-cell responses to SARS-CoV-2-specific antigens are mediated through interferon-gamma (IFN-γ). Methods: We prospectively enrolled a multi-site cohort of patients admitted to the ICU under suspicion for COVID-19 who were then determined to be SARS-CoV-2-positive (n = 82) or-negative (n = 97) by RT-PCR. We measured multiple molecular and cellular immune profiles from blood and endotracheal aspirates (ETAs) collected on ICU admission. Our primary analysis tested for associations between IFN-γ and interferon-inducible mediators (CXCL10 and soluble PD-L1 (sPD-L1)) in blood or ETAs and SARS-CoV-2 status. We then stratified our cohort into SARS-CoV-2-negative and-positive groups and tested for associations between interferon-inducible mediators and clinical outcomes and SARS-CoV-2-copy-number. We used cytometry time-of-flight (CyTOF) to simultaneously measure 39 cell surface and intracellular markers on peripheral blood mononuclear cells collected from a subset of patients with ARDS. We then compared immune cell signatures in subjects with vs. without SARS-CoV-2. Results: The mean APACHE III score was higher in SARS-CoV-2-negative vs.-positive subjects (80±30 vs. 69±29), but the groups were otherwise well-matched. SARS-CoV-2-positive subjects had higher plasma concentrations of IFN-γ, CXCL10, and sPD-L1 relative to SARSCoV-2-negative patients adjusting for age, sex, and severity of illness (all p ≤ 0.01). The levels of IL-6, TNF-α, IL-8, MCP-1, and IL-17A were not significantly different between the two groups. SARS-CoV-2-positive subjects also had higher CXCL10 concentrations in ETAs than SARS-CoV-2-negative subjects. Higher plasma concentrations of CXCL10 and sPD-L1 were associated with higher mortality (Table 1) and more severe respiratory disease (ventilator-free days (VFDs), ARDS) in SARS-CoV-2-positive, but not-negative, patients. In contrast, higher IL-6 was associated with a lower number of VFDs and ARDS in both groups. IFN-γ and CXCL10 (but not IL-6) were associated with SARS-CoV-2-copy-number. Using CyTOF, we found SARS-CoV-2-positive subjects had a lower proportion of CXCR3+ (CXCL10 receptor) T-cells, a higher proportion of PD-L1+ monocytes, and less T-cell and monocyte intracellular cytokine staining vs. SARS-CoV-2-negative patients. Conclusion: Our findings suggest interferon-inducible mediator responses and immune cell hypofunction are characteristic of critically ill subjects with SARS-CoV-2 compared with similar patients without SARS-CoV-2. Our identification of immune signatures that are associated with SARS-CoV-2 infection but are distinct from other forms of critical illness clarifies COVID-19 pathophysiology.

17.
American Journal of Respiratory and Critical Care Medicine ; 203(9), 2021.
Article in English | EMBASE | ID: covidwho-1277037

ABSTRACT

Rationale: Analyses of blood biomarkers involved in the host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection can reveal distinct biological pathways and inform development and testing of therapeutics for COVID-19. Objective: To evaluate host endothelial, epithelial and inflammatory biomarkers in COVID-19Methods: We prospectively enrolled 169 ICU patients with suspicion of COVID-19 infection, including 78 (46%) patients positive and 91 (54%) negative for SARS-CoV-2 infection from April to September, 2020. We compared 22 plasma biomarkers in blood collected within 24 hours and 3 days after ICU admission. Measurement and Main Results: ICU patients with and without COVID-19 had similar rates of severe acute kidney injury, shock, thromboembolism and in-hospital mortality. Rates of ARDS were higher in COVID-19 (aRR = 5.9, 95% CI: 3.2-11.0). While concentrations of interleukin 6 and 8 were not different between groups, markers of epithelial cell injury (soluble receptor for advanced glycation end products, sRAGE) and acute phase proteins (serum amyloid A, SAA) were significantly higher in COVID-19 compared to non-COVID-19, adjusting for demographics and APACHE III scores (Figure 1). In contrast, angiopoietin 2:1 (Ang-2:1 ratio) and soluble tumor necrosis factor receptor 1 (sTNFR-1), markers of endothelial dysfunction and inflammation, were significantly lower in COVID-19 (Bonferroni corrected p<0.002). Ang-2:1 ratio and SAA were associated with mortality only in non-COVID-19 patients.Conclusions: These studies demonstrate that, unlike other well-studied causes of critical illness, endothelial dysfunction is not characteristic of severe COVID-19 early after ICU admission. Pathways resulting in elaboration of acute phase proteins and inducing epithelial cell injury may be promising targets for therapeutics. 2 (Table Presented).

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