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1.
Gastroenterology ; 162(7):S-1280, 2022.
Article in English | EMBASE | ID: covidwho-1967446

ABSTRACT

Background & Aims: Prior studies have indicated the presence of hepatic inflammation (as signified by elevated liver function test (LFT) values), as conferring an escalated risk toward adverse outcomes in patients admitted with COVID-19. In line with this hypothesis, we study the various thresholds of LFTs and its associated prognostic risks toward COVID- 19 related hospital deaths Method: This was a single-center retrospective study involving patients admitted with COVID-19. Univariate Cox regression analysis identified the LFT variables significantly associated with our primary endpoint, in-hospital death. Subsequently, 500 iterations of thresholds were generated for each biomarker to estimate the prognostic relationship between biomarker and endpoint. Multivariate Cox regression and event-analyses were performed for each threshold to identify the minimal cutoffs at which the prognostic relationship was significant. Event curves were drawn for each significant relationship. Results: A total of 858 patients with COVID-19 were included with a median follow-up time of 5 days from admission. From the total, 90 patients passed away during admission (10.5%). The deceased cases were more likely to be older (66.2 vs 55.3y p<0.001);however, there was no difference in gender (male: 66 vs 56.2% p=0.11). Between the cases and controls (no-death), deceased cases had higher incidence of nonalcoholic fatty liver disease (7.78 vs 2.99% p=0.042), COPD (18.9 vs 7.80% p=0.001), lung cancer (4.44 vs 0.65% p= 0.009), ICU admissions (81.1 vs 26% p<0.001), and intubation events (84.4 vs 19.5% p<0.001), however there was no difference in alcohol use (21.1 vs 30.6% p=0.083) and alcoholic liver disease (5.56 vs 2.08% p=0.097). Upon univariate Cox analysis, the following LFT parameters were associated with in-hospital death: Bilirubin (p<0.001), AST (p<0.001), ALT (p<0.001). However, alkaline phosphatase (p=0.449) was not associated with the primary endpoint. The iterations of event regression analyses using 500 sequences of LFT thresholds showed the following cutoffs to be significantly associated with in-hospital death (minimally significant values): ALT (281.71 IU/L), AST (120.94 IU/L), bilirubin (2.615 mg/ dL). On the multivariate analysis, while controlling for demographics and cardiopulmonary/ medical comorbidities, the following adjusted hazard ratios were derived for each cutoff: ALT (aHR: 6.43 95%CI 1.85-22.40), AST (aHR: 3.35 95%CI 1.84-6.11), and bilirubin (aHR: 2.77 95%CI 1.15-6.65). Conclusion: The delineated cutoffs for AST, ALT, and bilirubin levels can serve as clinical benchmarks to help determine when a COVID-19 infection poses significant risk. Given this finding, the cutoffs can be used as part of a risk assessment for patients to support early preventative therapies and medical management. (Table Presented)

2.
Gastroenterology ; 162(7):S-1279-S-1280, 2022.
Article in English | EMBASE | ID: covidwho-1967445

ABSTRACT

Background and Aims: While the relationship between elevated liver enzymes and COVID- 19 related adverse events is well-established, a liver-dependent prognostic model that predicts the risk of death is helpful to accurately stratify admitted patients. In this study, we use a bootstrapping-enhanced method of regression modeling to predict COVID-19 related deaths in admitted patients. Method: This was a single-center, retrospective study. Univariate and multivariate Cox regression analyses were performed using 30-day mortality as the primary endpoint to establish associated hepatic risk factors. Regression-based prediction models were constructed using a series of modeling iterations with an escalating number of categorical terms. Model performance was evaluated using receiver operating characteristic (ROC) curves. Model accuracy was internally validated using bootstrapping-enhanced iterations. Results: 858 patients admitted to hospital with COVID-19 were included. 78 were deceased by 30 days (9.09%). Cox regression (greater than 20 variables) showed the following core variables to be significant: INR (aHR 1.26 95%CI 1.06-1.49), AST (aHR 1.00 95%CI 1.00- 1.00), age (aHR 1.05 95%CI 1.02-1.08), WBC (aHR 1.07 95%CI 1.03-1.11), lung cancer (aHR 3.38 95%CI 1.15-9.90), COPD (aHR 2.26 95%CI 1.21-4.22). Using these core variables and additional categorical terms, the following model iterations were constructed with their respective AUC;model 1 (core only): 0.82 95%CI 0.776-0.82, model 2 (core + demographics): 0.828 95%CI 0.785-0.828, model 3 (prior terms + additional biomarkers): 0.842 95%CI 0.799-0.842, model 4 (prior terms + comorbidities): 0.851 95%CI 0.809-0.851, model 5 (prior terms + life-sustaining therapies): 0.933 95%CI 0.91-0.933, model 6 (prior terms + COVID-19 medications): 0.934 95%CI 0.91-0.934. Model 1 demonstrated the following parameters at 0.91 TPR: 0.54 specificity, 0.17 PPV, 0.98 NPV. Bootstrapped iterations showed the following AUC for the respective models: model 1: 0.82 95%CI 0.765-0.882, model 2 0.828 95%CI 0.764-0.885, model 3 0.842 95%CI 0.779-0.883, model 4: 0.851 95%CI 0.808-0.914, model 5: 0.933 95%CI 0.901-0.957, model 6: 0.934 95%CI 0.901- 0.961. Conclusion: Model 1 displays high prediction performance (AUC >0.8) in both regression-based and bootstrapping-enhanced modeling iterations. Therefore, this model can be adopted for clinical use as a calculator to evaluate the risk of 30-day mortality in patients admitted with COVID-19. (Table Presented)

3.
Gastroenterology ; 162(7):S-886-S-887, 2022.
Article in English | EMBASE | ID: covidwho-1967382

ABSTRACT

Introduction: Coronavirus Disease 2019 (COVID-19) is an ongoing public health crisis that has sickened or precipitated death in millions. The etiologic agent of COVID-19, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), infects the intestinal epithelium and can persist long after the respiratory infection has cleared. We previously observed that intestinal SARS-CoV-2 infection levels varied by individual donors and did not correlate positively with ACE2, the cognate SARS-CoV-2 receptor. Therefore we aimed to delineate host factors that influence viral infection in the intestine. Methods: Published dataset GSE75214 was downloaded and expression levels of select genes were querried. Primary human ileal spheroids (enteroids), derived from healthy donors and patients with Crohn's disease (CD), were grown on 2D transwells until confluent. Cells were differentiated for 3d before infection with a modified vesicular stomatitis virus expressing the SARS-CoV-2 spike protein (VSV-SARS-CoV-2) and GFP for 1h at a multiplicity of infection of ~0.5. Cells were harvested pre-infection and 24h after infection and expression of select genes was performed by qRT-PCR. Expression data were fit to a linear regression model to predict viral RNA levels. Results: Small intestine biopsy samples from CD patients demonstrated a reduction in ACE and an increase in CTSB and CTSL expression during active inflammation compared to healthy controls. Viral RNA expression did not correlate with ACE2 expression in CD enteroids. A subset of CD enteroids exhibited enhanced protease expression (TMPRSS2, TMPRSS4, CTSL), each of which correlated with higher viral RNA levels (P=0.04, P=0.002, P=0.006, respectively). Expression of these proteases was higher in the pre-infection for the sample subset. Principle component analysis of uninfected expression data demonstrated these samples clustered separately from the others, with the difference driven by TMPRSS2, TMPRSS4, and CTSL. Modeling viral RNA levels based on gene expression revealed expression levels of these proteases are a predictive expression signature. Conclusions: Host protease expression can predict SARS-CoV-2 infection and represent potential therapeutic targets for COVID-19. This is consistent with the recent report showing that cathepsin inhibition reduces SARS-CoV-2 spike-mediated syncytia formation. High expression of these proteases in the intestine may also be a novel biomarker for the risk of intestinal complications associated with COVID-19.(Figure Presented)RNA data from dataset GSE75214 demonstrating reduced ACE2 and increased CTSB and CTSL in patients with Crohn's disease during active inflammation compared to healthy controls. (Figure Presented) Enteroids from healthy control donors and patients with Crohn's disease were grown in 2D transwells and expression of indicated genes was assessed in pre-infection (A) and after infection with VSV-SARS-CoV-2 (B)

4.
Gastroenterology ; 162(7):S-836, 2022.
Article in English | EMBASE | ID: covidwho-1967372

ABSTRACT

Background and Aims: In patients with COVID-19, obesity may increase risk of hospitalisation, use of mechanical ventilation and patient mortality. High liver fat, body mass index (BMI) and male sex are significant predictors of hospitalisation risk following COVID-19. However, BMI is a poor indicator of body fat distribution. Here, we studied ectopic fat accumulation within the liver and pancreas and body composition through multiparametric magnetic resonance (mpMR) and compared participants with and without hospitalisation for COVID-19. Method: Participants with laboratory-confirmed or clinically suspected SARSCoV- 2 infection were recruited to the COVERSCAN study (NCT04369807;median time from initial symptoms = 177 days) and underwent a multi-organ mpMR scan (CoverScan®, Perspectum Ltd). Measures of liver and pancreatic fat (PDFF), liver fibroinflammation (cT1) and body composition [visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), skeletal muscle index (SMI)] were analysed. Differences between participants hospitalised (n = 59) and not hospitalised (n = 348) for COVID-19 were assessed using Wilcoxon signedrank tests. Univariate and multivariate analyses were performed on all biomarkers to assess the hospitalisation risk. Data presented are median values. Results: Approximately 6-months after initial symptoms, participants hospitalised following COVID-19 had significantly elevated pancreatic fat (3.8 % vs 2.8 %, p < 0.01), liver fat (3.8 % vs 2.4 %, p < 0.01) and liver cT1 (735ms vs 706ms, p < 0.01) compared to those who convalesced at home. Though hospitalised participants had a significantly elevated BMI (27 kg/m2 vs 25 kg/m2, p = 0.014), it was VAT, but not SAT, that was significantly elevated (132 cm2 vs 86 cm2, p < 0.01). Univariate analysis revealed that male sex, advanced age and elevated BMI, VAT, pancreatic fat, liver fat, and liver cT1 were all significantly predictive of hospitalisation following COVID- 19. In multivariate analysis, only age remained significantly predictive of hospitalisation. In hospitalised people with obesity (³ 30 kg/m2), VAT, liver cT1 and liver fat, but not BMI nor pancreatic fat, remained significantly elevated [VAT: 220 cm2 vs 152cm2, p = 0.01 (Figure 1);liver fat: 9.9 % vs 4.2 %, p = 0.003;liver cT1: 782ms vs 742ms, p = 0.012]. Conclusion: mpMR revealed significantly elevated visceral and ectopic fat deposition within the liver and pancreas in hospitalised participants following COVID-19. In obese participants, BMI was not significantly different in hospitalised, and non-hospitalised patients, whereas visceral fat, liver fibroinflammation and liver fat were significantly elevated. Our work highlights body fat distribution an important consideration for COVID-19 risk profiling, which cannot be sufficiently evaluated based on BMI alone. (Figure Presented) Figure 1. Comparison of liver fat (left), pancreatic fat (middle) and visceral adipose tissue (right) between participants hospitalised and not hospitalised following COVID-19.

5.
Gastroenterology ; 162(7):S-611-S-612, 2022.
Article in English | EMBASE | ID: covidwho-1967352

ABSTRACT

Introduction Objective evaluation of treatment response is the gold standard in ulcerative colitis (UC). In this setting, intestinal ultrasound (IUS) is a non-invasive alternative to endoscopy. Recent studies showed change in IUS parameters after treatment initiation but studies with an endoscopic reference standard are scarce. The aim of this study was to evaluate early change of IUS parameters and determine cut-off values for endoscopic endpoints in UC patients starting anti-inflammatory treatment. Methods In this longitudinal prospective study consecutive patients with moderate-severe UC (baseline endoscopic Mayo score (EMS)≥2) starting an anti-inflammatory treatment were included. Clinical scores, biochemical parameters and IUS parameters were collected at baseline, after 2 (T1), 6 (T2) and 8-26 weeks (T3) around time of the second sigmoidoscopy/colonoscopy. Bowel wall thickness (BWT), Colour Doppler signal (CDS), haustrations, inflammatory fat and wall layer stratification were measured as previously established1. Endoscopic remission (ER) and mucosal healing (MH) were evaluated in the sigmoid and defined as EMS=0 and EMS≤1, respectively. The ultrasonographist and endoscopist were blinded for the outcomes of endoscopy and IUS, respectively. Results 51 consecutive patients were included (Table 1) of whom 31 underwent a second endoscopy. Two additional patients underwent colectomy and were considered non-responders. 18 patients did not undergo second endoscopy due to the COVID-19 pandemic (n=2), refusal (n=5), loss to follow-up (n=1) or treatment escalation because of clinical deterioration confirmed by IUS and biomarkers before second endoscopy was performed (n=10). BWT was significantly lower from T2 onwards in patients reaching MH (p=0.026) and ER (p=0.002) at T3 (Fig 1). A significant decrease in BWT was already visible at T1 in patients receiving infliximab (median DBWT T0-T1: -26% [-43% - -6%], p=0.001) or tofacitinib (median ∆BWT T0-T1: -33% [-46% - -5%], p=0.001) but not in patients treated with vedolizumab (median ∆BWT T0-T1: -14% [-43% - 5%], p=0.11). Most accurate BWT cut-off values at T3 to determine MH and ER were 3.52 mm (AUROC: 0.95, 95% CI: 0.86-1.00, p<0.0001, sens:91%, spec:91%) and 2.98 mm (AUROC: 0.94, 95% CI: 0.85-1.00, p=0.001, sens:87%, spec:100%), respectively. At T2, BWT per 1 mm increase and CDS were inversely associated with MH (BWT: OR: 0.48 (0.24-0.96, p=0.038);CDS: OR 0.16 (0.03-0.83), p=0.028) and ER (BWT: OR: 0.30 (0.11-0.76), p=0.01). Conclusion BWT and CDS 6 weeks after start of treatment could predict MH and ER. In addition, treatment response at IUS is drug-specific. Furthermore, we have provided accurate BWT cut-off values for endoscopic outcomes. In a point-of-care setting, (early) treatment evaluation with IUS could guide treatment decision in UC in order to optimize treatment response. 1. Bots et al. JCC 2021

6.
Gastroenterology ; 162(7):S-498, 2022.
Article in English | EMBASE | ID: covidwho-1967329

ABSTRACT

Background Gastrointestinal infections cause a significant burden to the Australian healthcare system each year, with acute gastroenteritis infections costing up to $359 million AUD ($258 million USD) in 2016. Viral causes of gastroenteritis, particularly Norovirus, account for the majority of these cases. Given the contagious nature of many causes of bacterial and viral gastroenteritis, it was hypothesized that widespread lockdowns and increased public health focus on regular hand hygiene would contribute to a reduction in hospital presentations with gastrointestinal infections. Melbourne, Victoria, Australia first went into lockdown in March 2020 and remained in various forms of lockdown until late 2020. Methods A retrospective study comparing rates of hospitalization for bacterial and viral gastroenteritis was performed at The Royal Melbourne Hospital between February-August in both 2019 and 2020. Rates of admission were compared between the two years, as well as the causative organism and the outcome of the presentation. Descriptive statistics were provided to summarise demographic characteristics. Outcomes between the two years were compared using paired t-tests for continuous variables and Pearson chi-square for categorical variables. All data analysis was performed using Stata 16.1 and p-values £0.05 were considered statistically significant. Results Demographic data are summarised in Table 1. 283 patients were hospitalized with gastroenteritis in 2019 pre-pandemic, compared to 147 in 2020 during the COVID-19 pandemic. There was a significant reduction in the number of patients admitted with positive fecal cultures from 2019 to 2020 (87 vs 57, p < 0.01). The number and percentage of patients presenting with Norovirus reduced by greater than 90% in 2020 compared to 2019 (Table 2) (Odds Ratio: 0.093 [Confidence Interval: 0.02-0.41], p<0.01). There was a reduction in the number of presentations with Salmonella, however, this did not reach statistical significance (p=0.50). The number of patients presenting with Clostridium difficile significantly increased in 2020 compared to 2019 (21 versus 25, p=0.01) (Table 2). Rates of antibiotic treatment and intensive care admission were greater in 2020 compared to 2019 however there was no significant difference in biomarkers, length of stay, or mortality (Table 2). Conclusion A significant decrease in the incidence of hospitalization secondary to acute gastrointestinal infections was observed during the COVID-19 pandemic. Norovirus presentations decreased by greater than 90% between 2019 and 2020. The rate of other GI infections was similar between pre-pandemic and pandemic time points. These findings suggest that public health measures, such as social distancing and hand hygiene, may be a useful adjunct to prevent Norovirus infections in the future and could result in significant healthcare savings.(Table Presented)TABLE 1: PATIENT DEMOGRAPHICS(Table Presented) TABLE 2: GASTROINTESTINAL CULTURE POSITIVE INFECTIONS 2019 VERSUS 2020

7.
Gastroenterology ; 162(7):S-383, 2022.
Article in English | EMBASE | ID: covidwho-1967304

ABSTRACT

Introduction: The SARS-CoV-2 pandemic highlighted the need for a way to predict progression to critical illness and ICU admission amongst infected patients. Previous liver disease is a known risk for progression to critical illness. Attempts to identify biomarkers for progression to critical illness suggest inflammatory markers and coagulation markers as useful. We used a machine learning approach to compare the admission liver panel and inflammatory biomarker assays in hospitalized COVID-19 patients with extant mild or severe hepatic disease who progressed to critical illness (ICU admission) versus those who were progression-free. Methods: We included data ed under IRB exemption from electronic medical records (EMR) for SARS-CoV-2 patients admitted to the hospital with chronic liver disease ICD-10-CM codes. Demographics, laboratory results and administrative data were archived and analyzed (SAS, Cary, NC). Generalized regression identified inflammatory and liver panel biomarkers assayed within 8h of hospital admission associated (p<.05) with progression to critical illness. Retained biomarkers underwent bootstrap forest analysis forming a receiver operating characteristic (ROC) that optimized area under ROC (AUROC) estimating model accuracy (precision). Continuous data summarized with median [IQR] were compared using Kruskal-Wallis Test. Discrete data summarized as counts or proportions were compared with chi-squared test. Two-tailed p<.05 was significant. Results: Out of the 4411 COVID-19 patients who were discharged between March 14, 2020 and September 30, 2021, 333 with a previous diagnosis chronic liver disease were included in this study. Demographics for this population are presented in Table 1. Statistical values for biomarkers and progression to critical illness are seen in table 1. Statistically significant markers are compared via explained variance and ROC curve in Figure 1. Although AST and D-dimer were statistically significant markers of progression to critical illness, when modelled as a predictive biomarker, they were not informative in the aggregated ensemble. Therefore, they were not included in the modeling analysis. Conclusion: Hypoalbuminemia, inflammatory markers, D-dimer, and AST were significantly associated with progression to critical illness. Indexing liver specific synthetic function (albumin) to CoV-2 evoked inflammatory markers improves explained variance for progression to critical illness. Alternative liver synthetic function biomarker (INR), ALT, and ALP were not a significant prognostic indicator for progression to severe illness. To our knowledge, this is debut of modeling hypoalbuminemia indexed with multiple routinely assayed inflammatory biomarkers for baseline risk assessment in COVID-19 patients with liver disease. (Table Presented) (Figure Presented)

8.
Gastroenterology ; 162(7):S-293, 2022.
Article in English | EMBASE | ID: covidwho-1967291

ABSTRACT

Background: One of the myriad issues COVID-19 has generated is a concern for increased capacity to generate autoimmune disease. (Saad et al, 2020, Ehrenfeld et al 2020). Recent case reports have potentially linked new onset UC associated with recent COVID infection (Aydin et al 2020), which raises concern for potential impact of COVID-19 infection rates on pediatric IBD diagnosis rates. As non-pharmaceutical interventions massively decreased the incidence of infectious illnesses in the first year of the pandemic (Sullivan et al, 2020), IBD rates would likely be expected to stay stable or decrease. We have formed a consortium of New York City pediatric institutions aimed at characterizing this change, and here report findings from the Children's Hospital of Montefiore, Maimonides Medical Center, SUNY Downstate, and New York University. Methods: New IBD diagnoses were identified between 2016-2019, as well as new diagnoses documented between 3/2020 and 3/2021. Data was examined using a direct comparison of new diagnostic rate 3/20-3/21 to mean diagnostic rate from 2013-2019. Results: an overall secular increase in IBD diagnostic rate of approximately 5% was noted, consistent with prior findings demonstrating increased incidence of IBD annually (Ye et al, 2020). Direct comparison with mean diagnostic rate over the preceding 4 years noted a substantial increase in diagnostic rate in the pandemic year relative to previous year average, with 109 new diagnoses in our consortium compared to an average of 79. Our data demonstrates this increase is driven by the institutions in the Brooklyn and the Bronx, with a 51% increase in diagnoses (78 compared to mean of 51.5, 95% CI 10.19). NYU diagnostic rate was 31 (previous mean of 27.5, 95% CI 5.29). This aligns well with published rates of COVID-19 in these regions, with the outer boroughs averaging 14,169 cases/100k and Manhattan 10,516/100k. Discussion: Our results suggest a possible increase in IBD diagnostic rate in the outer boroughs of New York City, aligning with density of COVID-19 infections, despite surveillance data from NYC DOH demonstrating almost nonexistent pediatric influenza-like-illness. There are many possible confounding factors in this initial work with substantial further evaluation needed, but this data is suggestive of a possible capacity for COVID19 to generate new onset IBD in excess of normal infections and normal rates of presentation. Next steps will include expanding data collection to additional NYC institutions, subgroup analysis by disease type, gender, age of presentation, more detailed analysis of biomarkers, and geospatial analysis given geographic variations in COVID19 infection density.

9.
Gastroenterology ; 162(7):S-279, 2022.
Article in English | EMBASE | ID: covidwho-1967268

ABSTRACT

Background and Aims: Initial reports on US COVID-19 showed different outcomes in different races. In this study, we use a diverse large cohort of hospitalized COVID-19 patients to determine predictors of mortality. Methods: We analyzed data from hospitalized COVID- 19 patients (n=5,852) from 8 hospitals. Demographics, comorbidities, symptoms and laboratory data were collected. Results: The cohort contained 3,662 (61.7%) African Americans (AA), 286 (5%) American Latinx (LAT), 1,407 (23.9%), European Americans (EA), and 93 (1.5%) American Asians (AS). Survivors and dead patients' mean ages were 58 and 68 for AA, 58 and 77 for EA, 44 and 61 for LAT, and 51 and 63 for AS. Mortality rates for AA, LAT, and EA were 14.8%, 7.3%, and 16.3%. Mortality increased among patients with the following characteristics: age, male gender, New York region, cardiac disease, COPD, diabetes mellitus, hypertension, history of cancer, immunosuppression, elevated lymphocytes, CRP, ferritin, D-Dimer, creatinine, troponin, and procalcitonin. Use of mechanical ventilation, respiratory failure, shortness of breath (SOB) (p<0.01), fatigue (p=0.04), diarrhea (p=0.02), and increased AST (p<0.01), significantly correlated with death in multivariate analysis. Male sex and EA and AA race/ethnicity had a higher frequency of death. Diarrhea was among the most common GI symptom amongst AAs (6.8%). When adjusting for comorbidities, significant variables were age (over 45 years old), male sex, EA, patients hospitalized in Indiana, Michigan, Georgia, and District of Columbia. When adjusting for disease severity, significant variables were age over 65 years old, male sex, EA as well as having SOB, elevated CRP, and D-dimer. Glucocorticoid usage was associated with an increased risk of COVID- 19 death in our cohort. Conclusion: Among this large cohort of hospitalized COVID-19 patients enriched for African Americans, predictors of mortality include male gender, diarrhea, elevated AST, comorbidities, respiratory symptoms and failure, and elevation of inflammatory- related biomarkers. These findings may reflect the extent of systemic organ involvement by SARS-CoV-2 and subsequent progression to multi-system organ failure. High mortality in AA in comparison with LAT is likely related to a high frequency of comorbidities and older age among AA.

10.
Gastroenterology ; 162(7):S-278-S-279, 2022.
Article in English | EMBASE | ID: covidwho-1967265

ABSTRACT

Background: Human-associated microbial communities have been linked to host immune response to respiratory viral infections. Prior investigations have observed shifts in the composition of the gut or respiratory microbiome in severe COVID-19. However, there has been no comprehensive metagenomic evaluation of the interaction between lower respiratory and gut microbiomes and host immune factors in COVID-19. Methods: From April 2020 to May 2021, we prospectively enrolled 153 hospitalized patients with mild (n=12), moderate (n=65), and severe (n=76) COVID-19 infection categorized using established clinical criteria. We longitudinally collected stool (n=270) for metagenomic profiling, and in a subset, we generated comprehensive host-microbiome-molecular profiles by collecting sputum metagenomes (n=87 participants with 212 samples) and blood cytokine levels (n=109 with 181 samples) weekly until hospital discharge. We performed omnibus testing of overall gut and respiratory community structure, species-level differential abundance testing using mixed effects modeling accounting for repeated sampling, hierarchical clustering of paired gut and respiratory metagenomic profiles, and multi-omic machine learning classification of disease severity. Results: Patients with severe COVID-19 tended to be older, were more frequently male, had higher rates of overweight/obesity, and a greater mean Charlson Comorbidity Index. Patients with severe COVID-19 infection had significantly decreased stool and respiratory microbiome a-diversity irrespective of antibiotic administration. COVID severity accounted for a small proportion of variance in stool (R2=2.4%, p=0.002) and sputum (R2=4.4%, p= 0.03) profiles. Hierarchical clustering of paired gut and respiratory samples from patients with severe COVID revealed the joint expansion of oral-typical taxa typically present during systemic inflammation (i.e., increases in Streptococcus and Peptostreptococus spp. in both gut and sputum). A pro-inflammatory milieu defined by a composite elevation of circulating plasma cytokines (e.g., IL-6, TNF-a, and IL-29 among others) were linked to broad microbial excursions in community structure for both stool and sputum as measured by Bray-Curtis distances. A random forest classifier incorporating either stool or sputum taxonomic features and accounting for age, sex, body mass index, and recent antibiotic use achieved excellent classification of biospecimens from patients with severe vs. non-severe COVID patients (AUROC > 0.80). Conclusions: Alterations of the gut and respiratory microbiome were associated with differences in host immune response and COVID-19 disease severity. Further studies are needed to identify the potential role of human-associated microbial communities as a biomarker for poor patient outcomes in COVID-19 who may warrant escalated levels of care.(Figure Presented) Fig. 1. (A) Using unsupervised feature selection (species abundance > 0.001) inclusive of taxa differentially abundant by non-parametric Wilcoxon rank-sum testing (nominal p-value < 0.05), (B) we performed random forest classification using a twice-repeated 5-fold crossvalidation scheme to predict COVID-19 disease severity from shotgun metagenomic stool profiles (C) yielding an AUROC of 0.91.

11.
Gastroenterology ; 162(7):S-268-S-269, 2022.
Article in English | EMBASE | ID: covidwho-1967259

ABSTRACT

Introduction The CytospongeTM test is a non-endoscopic method to collect cells from the oesophagus and test for biomarkers of early oesophageal cancer and its precancerous form, Barrett's oesophagus. The real-world implementation pilots of the Cytosponge has been accelerated in response to the COVID-19 pandemic. At the onset of the pandemic, when endoscopy services were paused, guidelines from the British Society of Gastroenterology were updated to recommend the use of alternatives including the Cytosponge. In December 2020, NICE published a Medtech Innovation Briefing for use of the Cytosponge test as a triage tool for endoscopy to identify people at risk of oesophageal cancer. Aims & methods Implementation pilots were launched within the NHS in England and Scotland, as well as the Innovate UK-funded research project, Project DELTA. The Cytosponge test was offered to two patient cohorts as an alternative to endoscopy: (1) patients already diagnosed with Barrett's Oesophagus, and so in need of routine surveillance;and (2) patients referred from primary care with reflux symptoms. Samples were received, processed and analysed at the ISO 15189:2012 accredited laboratory at Cyted. Pathology reports were issued with TFF3, p53 and atypia biomarker results and clinical recommendations. Any reports positive for p53/atypia biomarkers were double reported. Here, we evaluate the real-world laboratory metrics for the Cytosponge test in secondary care. Results Between August 2020 and November 2021, Cytosponge tests were delivered to 5373 patients at 48 hospitals across England and Scotland. For 4842 diagnostic reports issued by mid-November, 2807 patients had Barrett's Oesophagus and 2034 reflux symptoms. For Barrett's surveillance, 2629 (93.7%) of patient samples had sufficient cellular material for analysis, including sampling the gastric cardia. Of these 324 (12.3%) exhibited cellular atypia (including uncertain significance), dysplasia, or aberrant p53 expression. These patients were recommended to have an endoscopy. Patients without evidence of atypia/dysplasia/p53 were recommended surveillance by Cytosponge or endoscopy after the recommended interval by clinical guidelines. In the symptomatic reflux cohort, 1854 (91.2%) patient samples had sufficient cellular material for analysis, including sampling the gastric cardia. Of these 185 (10.0%) exhibited intestinal metaplasia corroborated by TFF3 expression and a further 44 (2.4%) exhibited atypia/ dysplasia/p53. These patients were recommended to have an endoscopy. Otherwise, patients were recommended management according to symptoms. Discussion A high-quality centralised laboratory service has enabled accelerated real-world implementation of the Cytosponge in the secondary care setting. This has enabled triage and care of patients who have not been able to access endoscopy during the COVID-19 pandemic.

12.
Sleep Medicine ; 100:S180, 2022.
Article in English | EMBASE | ID: covidwho-1967126

ABSTRACT

Introduction: The SARS-COV-2 pandemic has resulted in over than 5 millions confirmed deaths. Although vaccination is a major strategy to control this pandemic, to date, only 54% of the world population has received at least one dose of a COVID-19 vaccine. Booster inoculations are increasingly recommended. Thus, the vaccination effort may need to continue for several years before the epidemic can be considered as contained. Although antibody response is just one facet of the adaptive immune system’s response to vaccination, it is considered to be a clinically significant biomarker of protection. The role of insufficient sleep duration in individual differences in antibody responses to vaccination against influenza or hepatitis has been examined in a number of studies, with somewhat mixed results. In order to summarize and clarify these findings, we have used a meta-analytical approach to determine whether the current body of evidence suggests that optimizing sleep duration may be an easily modifiable behavior that could increase the efficacy of anti-viral vaccination. Materials and Methods: The PubMed database was searched with the combination “sleep*” and “vaccin*” keywords. Studies were selected if they met the following criteria: (1) were performed on healthy human adults;(2) assessed vaccine efficacy by antibody titers or protection status;(3) performed subjective (survey items, questionnaire, sleep diary, interview) and/or objective (actigraphy, polysomnography) measures of sleep duration;(4) were laboratory-conducted studies of manipulation of sleep duration over 1 or more nights;(5) were cohort studies;(6) were peer reviewed original research papers. Since the number of available studies was small, we have engaged in a collaborative effort with the authors of all publications to obtain the information needed to optimize the estimation of the pooled effect size (ES) and the 95% confidence intervals: log transformed data when non parametric testing was used;calculation of separate ES for men and women;analyses corrected for age and overweight/obesity status whenever appropriate;sleep data no more than one week apart from inoculation. Number of participants, mean, beta or odd ratio and their respective dispersion were collected. The ES was interpreted as small when ≤0.20, moderate when >0.50 - ≤ 0.80 or large when >0.80. Results: No relationship was observed between self-reported short sleep and vaccine efficacy (n=504;overall ES=0.16 [-0.12, 0.44]). In contrast, when studies that used objective measures of sleep were examined, a robust adverse impact of short sleep on vaccine efficacy was detected (n=282;overall ES=0.96 [0.15, 1.78]). The pooled ES for experimental studies (n=111) was 0.84 [0.20, 1.49] and 1.08 [0.10, 2.06] for prospective studies (n=171). The meta-analysis did not find significant differences in ES between women and men. Conclusions: When assessed objectively, short sleep duration was associated with a clinically relevant decrease in efficacy of anti-viral vaccination. These findings suggest that achieving adequate amount of sleep during the time window surrounding the time of inoculation may increase the efficacy of vaccines against diverse strains of viruses, possibly including strains of SARS-CoV-2. Acknowledgements: Collectively, the authors acknowledge the support of their respective institutions in these challenging times.

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Indian Journal of Forensic Medicine and Toxicology ; 16(2):326-333, 2022.
Article in English | EMBASE | ID: covidwho-1957671

ABSTRACT

Coronavirus disease 2019 discovered in December 2019, Wuhan, China. It was transmitted globally producing the present COVID-19 pandemic. Concerns have been raised about the potential impact of COVID-19 on male reproductive organs and male fertility as the number of infections in the male community has increased. The objectives of current study are studying the relationship between the plasma levels of testosterone and the markers of immune reaction with the severity and mortality in a sample of COVID-19 patients. A cross section study included NO= 103 male patients affected by SARS-CoV-2 pneumonia, diagnosed by PCR and chest CT scan, (≥ 18 years old), and recovered in the respiratory intensive care unit (RICU). Several biochemical risk factors were determined Free Testosterone, sex hormone binding globulin (SHBG) were measured by Enzyme-Linked Immunosorbent Assay(ELISA), D-dimer, Ferritin, CRP, Urea, Creatinine were measured by automated method by using Abbott Architect c4000 and Complete Blood Count(CBC). The results show that the serum free testosterone and SHBG levels a significant lower in non-survivor patients than survivor patients with COVID-19. While the other biomarkers (D-dimer, Ferritin, Urea, Creatinine) were significant higher in non-survivor patients than survivor patients. The CRP, WBC and lymphocyte showed that no significant between the both group of patients. In conclusion the study showed that lower free testosterone and SHBG levels enable significant role in increasing risk of COVID-19 mortality amongst adult male patients.

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Journal of Research in Medical Sciences ; 27(1):43, 2022.
Article in English | EMBASE | ID: covidwho-1957520

ABSTRACT

Background: Since December 2019, the world is struggling with an outbreak of coronavirus disease-2019 (COVID-19) infection mostly represented as an acute respiratory distress syndrome and has turned into the most critical health issue worldwide. Limited information is available about the association between dynamic changes in the naso/oropharyngeal viral shedding in infected patients and biomarkers, aiming to be assessed in the current study. Materials and Methods: This quasi-cohort study was conducted on 31 patients with moderate severity of COVID-19 manifestations, whose real-time polymerase chain reaction (RT-PCR) test was positive for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) RNA at baseline. RT-PCR was rechecked for patients every 3-4 days until achieving two negative ones. In parallel, biomarkers, including lymphocyte count, lactate dehydrogenase (LDH), and C-reactive protein (CRP), were assessed every other day, as well. Viral shedding also was assessed. Results: Spearman's correlation test revealed a significant direct correlation between the viral shedding from the symptom onset and the time, in which CRP (P = 0.0015, r = 0.54) and LDH (P = 0.001, r = 0.6207) return to normal levels after symptom onset, but not for lymphocyte count (P = 0.068, r = 0.34). Conclusion: Based on the current study's findings, the duration of SARS-CoV-2 RNA shedding was directly correlated with the required time for LDH and CRP return to normal levels. Therefore, these factors can be considered the determinants for patients' discharge, isolation, and return to social activities;however, further investigations are required to generalize the outcomes.

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Journal of Pediatric Infectious Diseases ; 2022.
Article in English | EMBASE | ID: covidwho-1956443

ABSTRACT

Objective: Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory syndrome associated with multiorgan damage that occurs following coronavirus disease 2019 (COVID-19). Research on clinical and laboratory findings, and imaging studies, aiming to predict the progression to severe disease state is limited. This study recruited patients with MIS-C who presented with mild or severe symptoms from a single center in Turkey and evaluated factors related to their symptoms. Methods: This retrospective study included 25 pediatric patients with mild and severe presentations of MIS-C. We explored the differences in demographic and clinical data on clinical severity to understand their possible diagnostic and prognostic values. Results: Patients with MIS-C had cardiovascular symptoms (68%), gastrointestinal symptoms (64%), dermatologic/mucocutaneous findings (64%), lung involvement (36%), and neurological symptoms (16.0%). About 45.1% of patients with MIS-C had manifestations that overlapped with Kawasaki disease. Eleven patients (44%) were admitted to the intensive care unit, and one (4%) patient died. Grouping based on clinical severity did not differ statistically in terms of gender, age, height, weight, body mass index, and duration of hospital stay. Procalcitonin and ferritin levels correlated with disease severity. The receiver operating characteristic curve for D-dimer gave the highest value of area under the curve, among other biomarkers. The cutoff value for D-dimer was determined as more than 6780. Conclusions: Although COVID-19 is usually mild in children, some can be severely affected, and clinical severity in MIS-C can differ from mild to severe multisystem involvement. This study shows that procalcitonin, ferritin, and D-dimer levels may give us information about disease severity.

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TH Open ; 6(3):E194-E212, 2022.
Article in English | EMBASE | ID: covidwho-1956435

ABSTRACT

Thrombomodulin (TM) is a type-I transmembrane protein that is mainly expressed on endothelial cells and plays important roles in many biological processes. Circulating TM of different forms are also present in biofluids, such as blood and urine. Soluble TM (sTM), comprised of several domains of TM, is the major circulating TM which is generated by either enzymatic or chemical cleavage of the intact protein under different conditions. Under normal conditions, sTM is present in low concentrations (<10 ng/mL) in the blood but is elevated in several pathological conditions associated with endothelial dysfunction such as cardiovascular, inflammatory, infection, and metabolic diseases. Therefore, sTM level has been examined for monitoring disease development, such as disseminated intravascular coagulation (DIC), sepsis and multiple organ dysfunction syndrome in patients with novel coronavirus disease 2019 (COVID-19) recently. In addition, microvesicles (MVs) that contain membrane TM (MV-TM) have been found to be released from activated cells which also contribute to levels of circulating TM in certain diseases. Several release mechanisms of sTM and MV-TM have been reported, including enzymatic, chemical, and TM mutation mechanisms. Measurements of sTM and MV-TM have been developed and explored as biomarkers in many diseases. In this review, we summarize all these advances in three categories as follows: (1) release mechanisms of circulating TM, (2) methods for measuring circulating TM in biological samples, and (3) correlation of circulating TM with diseases. Altogether, it provides a whole picture of recent advances on circulating TM in health and disease.

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American Journal of Stem Cells ; 11(3):37-55, 2022.
Article in English | EMBASE | ID: covidwho-1955743

ABSTRACT

Objective: Mesenchymal stem cells can serve as a therapeutic option for COVID-19. Their immunomodula-tory and anti-inflammatory properties can regulate the exaggerated inflammatory response and promote recovery of lung damage. Method: Phase-1, single-centre open-label, prospective clinical trial was conducted to evaluate the safety and efficacy of intravenous administration of mesenchymal stem cells derived from umbilical cord and placenta in moderate COVID-19. The study was done in 2 stages with total 20 patients. Herein, the results of stage 1 including first 10 patients receiving 100 million cells on day 1 and 4 with a follow up of 6 months have been discussed. Results: No adverse events were recorded immediately after the administration of MSCs or on follow up. There was no deterioration observed in clinical, laboratory and radiological parameters. All symptoms of the study group resolved within 10 days. Levels of inflammatory biomarkers such as NLR, CRP, IL6, ferritin and D-dimer improved in all patients after intervention along with improved oxygenation demonstrated by improvement in the SpO2/FiO2 ratio and PaO2/FiO2 ratio. None of the patients progressed to severe stage. 9 out of 10 patients were discharged within 9 days of their admission. Improvements were noted in chest x-ray and chest CT scan scores at day 7 in most patients. No post-covid fibrosis was observed on chest CT 28 days after intervention and Chest X ray after 6 months of the intervention. Conclusion: Administration of 100 million mesenchymal stem cells in combina-tion with standard treatment was found to be safe and resulted in prevention of the cytokine storm, halting of the disease progression and acceleration of recovery in moderate COVID-19. This clinical trial has been registered with the Clinical Trial Registry-India (CTRI) as CTRI/2020/08/027043. http://www.ctri.nic.in/Clinicaltrials/pmaindet2. php?trialid=43175.

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International Journal of Pharmaceutical and Clinical Research ; 14(7):246-253, 2022.
Article in English | EMBASE | ID: covidwho-1955721

ABSTRACT

Objectives: This present study was to evaluate the role of biomarkers for diagnosis and management of COVID-19 patients. Methods: Throat-swab upper respiratory specimens were obtained from 100 patients and real-time PCR (polymerase chain reaction) was used to confirm SARS-CoV-2 infection. Clinical characteristics and blood biochemical tests of COVID-19 patients were examined and recorded. Venous blood (4.5 mL) was obtained. Blood samples were dispensed into a gel tube. All tubes were allowed to stand for 30 minutes at room temperature, followed by centrifugation for 10 minutes at 3500 rpm to get the serum. Liver and kidney function test were performed to all patients. Results: In this present study, out of 100 COVID-19 patients, they had 20(20%) diabetic, 29(29%) smokers, 04(04%) cancerous and 15(15%) hypertensives. Mean age of COVID-19 patients was 42.4±13.18 years. Conclusions: Abnormalities in biochemical markers play a pivotal role in the SARS-CoV-2 pandemic, it is not only from a diagnostic point of view but also in terms of the management and prognosis of COVID-19 patients. It helps for clinical decision making in order to adjust the therapy to the biological changes experienced by the subjects. Changes in the biochemical markers indicate abnormalities in various tissues and organs, indicating the development of COVID-19. Urea, CK, and LDH show the most predictive parameters of severe COVID-19 patients. LDH as an important biomarker is associated with poor outcomes in COVID-19 patients.

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European Journal of Clinical Pharmacology ; 78, 2022.
Article in English | EMBASE | ID: covidwho-1955687

ABSTRACT

The proceedings contain 294 papers. The topics discussed include: impact of the genotype and phenotype of CYP3A and P-GP on the apixaban and rivaroxaban blood concentrations in real-world setting;direct oral anticoagulant-related bleeding in atrial fibrillation patients alters DNA methylation of NOS3 and KDR genes;impact of obesity on dexamethasone pharmacokinetic in COVID-19 hospitalized patients: an observational exploratory study;intestinal permeability in transplant patients: are systemic short-chain fatty acids an early biomarker?;immunogenicity 5-months after homologous or heterologous booster vaccination in health care workers primed with Ad26.COV2.S;geographic variation in top-10 prescribed medication and potentially inappropriate prescription in Portugal: an ecological study of 2.2 million older adults;quantitative proteomics of hepatic drug-metabolizing enzymes and transporters in patients with colorectal cancer liver metastasis;pharmacological characterization of a novel lipid-rich breast cancer patient-derived xenograft;and multiple sclerosis drugs and dental and gingival disorders: an observational retrospective study and disproportionality analysis in the world pharmacovigilance database.

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