coronavirus disease 2019 (COVID-19) causes severe illness including cytokine storms, but mortality among countries differs largely. In the present study, we investigated the association between human ...leukocyte antigen (HLA) class I, which plays a major role in susceptibility to viral infections, and the mortality of COVID-19.
data of allele frequencies of HLA-A, -B and -C and COVID-19 mortality were obtained for 74 countries from the Allele Frequency Net Database and worldometer.info. Association between allele frequency of each HLA and mortality was assessed by linear regression followed by multivariable regression. Subsequently, association of HLA-C*05 to its receptor
, expressed on natural killer (NK) cells, and differential mortality to historic pandemics were analyzed.
HLA-A*01, -B*07, -B*08, -B*44 and -C*05 were significantly associated with the risk of deaths (adjusted
= 0.040, 0.00081, 0.047, 0.0022, 0.00032, respectively), but only HLA-C*05 remained statistically significant (
= 0.000027) after multivariable regression. A 1% increase in the allele frequency of HLA-C*05 was associated with an increase of 44 deaths/million. Countries with different mortality could be categorized by the distribution of HLA-C*05 and its receptor
, which in combination cause NK cell-induced hyperactive immune response. Countries with similar ethnic and/or geographic background responded in a similar pattern to each pandemic.
we demonstrated that allele frequency of HLA-C*05 and the distribution pattern with its receptor
strongly correlated with COVID-19 mortality. Host genetic variance of innate immunity may contribute to the difference in mortality among various countries and further investigation using patient samples is warranted.
Solid organ transplant (SOT) recipients are at greater risk of coronavirus disease 2019 (COVID-19) and have attenuated response to vaccinations. In the present meta-analysis, we aimed to evaluate the ...serologic response to the COVID-19 vaccine in SOT recipients. A search of electronic databases was conducted to identify SOT studies that reported the serologic response to COVID-19 vaccination. We analyzed 44 observational studies including 6158 SOT recipients. Most studies were on mRNA vaccination (mRNA-1273 or BNT162b2). After a single and two doses of vaccine, serologic response rates were 8.6% (95% CI 6.8-11.0) and 34.2% (95% CI 30.1-38.7), respectively. Compared to controls, response rates were lower after a single and two doses of vaccine (OR 0.0049 95% CI 0.0021-0.012 and 0.0057 95% CI 0.0030-0.011, respectively). A third dose improved the rate to 65.6% (95% CI 60.4-70.2), but in a subset of patients who had not achieved a response after two doses, it remained low at 35.7% (95% CI 21.2-53.3). In summary, only a small proportion of SOT recipients achieved serologic response to the COVID-19 mRNA vaccine, and that even the third dose had an insufficient response. Alternative strategies for prophylaxis in SOT patients need to be developed.
In this meta-analysis that included 6158 solid organ transplant recipients, the serologic response to the COVID-19 vaccine was extremely low after one (8.6%) and two doses (34.2%). The third dose of the vaccine improved the rate only to 66%, and in the subset of patients who had not achieved a response after two doses, it remained low at 36%. The results of our study suggest that a significant proportion of solid organ transplant recipients are unable to achieve a sufficient serologic response after completing not only the two series of vaccination but also the third booster dose. There is an urgent need to develop strategies for prophylaxis including modified vaccine schedules or the use of monoclonal antibodies in this vulnerable patient population.
Proton pump inhibitor (PPI) use has been associated with reduced diversity of the gut microbiome and may lead to worse clinical outcomes in inflammatory bowel disease (IBD). We aimed to evaluate ...whether PPI use affects clinical outcomes in a real-world setting.
Healthcare claims data of adult IBD patients were obtained from the IBM MarketScan Database. Multivariable analysis and propensity score-matched analysis were performed to assess associations between PPI use and new biologic start, and IBD-related hospitalizations and surgeries.
A total of 46,234 IBD patients were identified (6,488 (14%) and 39,746 (86%) patients with and without PPI, respectively). Patients on PPI were more likely to be older, female, and smokers and less likely to be on immunomodulators. Multivariable analyses demonstrated that PPI use was associated with new biologic start (odds ratio (OR) 1.11, 95% confidence interval (CI) 1.04-1.18), and IBD-related admissions (OR 1.95, 95% CI 1.74-2.19) and surgeries (OR 1.46, 95% CI 1.26-1.71). Following propensity score matching, patients on PPI remained more likely to start a new biologic (23% vs 21%, p = 0.011), and have IBD-related admissions (8% vs 4%, p < 0.001) and surgeries (4% vs 2%, p < 0.001). Subgroup analyses stratified by age, smoking, and glucocorticoid use showed similar results. There was a dose-response relationship between the number of PPI prescriptions and the risk of new biologic use (p < 0.001) and IBD-related admissions (p < 0.001).
PPI use was associated with worse clinical outcomes in patients with IBD in the real-world setting. Further studies are warranted to validate these findings, but caution may be needed when prescribing a PPI to IBD patients.
Study highlights WHAT IS KNOWN
Proton pump inhibitors (PPIs) are one of the most prescribed therapies in the United States (US).
Reduction of gastric acid secretion by PPI use increases the risk of imbalance in gut microbiota composition and may increase the risk of enteric infections.
Recent studies have reported that the use of PPI was associated with development of inflammatory bowel disease (IBD) and reduced rates of remission in patients on infliximab therapy, which may be due to alterations of intestinal microbiota.
WHAT IS NEW HERE
In a large real-world US healthcare database study, IBD patients with PPI use were more likely to have a new biologic medication started, have an IBD-related surgery, and have an IBD-related hospitalization, which remained significant after adjusting for confounders by multivariable analysis, propensity-score matched analysis, and subgroup analysis.
Appropriate clinical review of PPI necessity may need to be performed in patients with IBD when considering prescribing a PPI or who are already on PPI therapy.
Patients with cancer have an increased risk of coronavirus disease 2019 (COVID-19) and an attenuated responses to various vaccines. This meta-analysis aims to assess the serologic response to ...COVID-19 vaccination in patients with cancer.
Electronic databases were systematically searched on August 1, 2021 for studies that reported the serologic response to COVID-19 vaccine in cancer patients. Random effects models were used to achieve pooled serologic response rates and odds ratios (ORs).
We analyzed 16 observational studies with a total of 1453 patients with cancer. A majority of studies used mRNA vaccines (BNT162b2 or mRNA-1273). The proportion of patients achieving a serologic response after a single and two doses of COVID-19 vaccine were 54.2% (95% confidence interval CI 41.0-66.9) and 87.7% (95% CI 82.5-91.5), respectively. Patients with hematologic cancers had a lower response rate after the second dose of vaccine compared to those with solid organ cancers (63.7% vs. 94.9%), which was attributable to the low response rates associated with certain conditions (chronic lymphocytic leukemia, lymphoma) and therapies (anti-CD20, kinase inhibitors). A lower proportion of patients with cancer achieved a serologic response compared to control patients after one and two doses of vaccine (OR0.073 95% CI 0.026-0.20 and 0.10 95% CI 0.039-0.26, respectively).
Patients with cancer, especially those with hematologic B-cell malignancies, have a lower serologic response to COVID-19 vaccines. The results suggest that cancer patients should continue to follow safety measures including mask-wearing after vaccination and suggest the need for additional strategies for prophylaxis.
Several lifestyle-related factors, such as obesity and diabetes, have been identified as risk factors for Coronavirus disease 2019 (COVID-19) mortality. The objective of this study was to examine the ...global association between lifestyle-related factors and COVID-19 mortality using data from each individual country.
The association between prevalence of seven lifestyle-related factors (overweight, insufficient physical activity, smoking, type-2 diabetes, hypertension, hyperlipidaemia, and age over 65) and COVID-19 mortality was assessed by linear and multivariable regression among 186 countries. The cumulative effect of lifestyle-related factors on COVID-19 mortality was assessed by dividing countries into four categories according to the number of lifestyle-related factors in the upper half range and comparing the mean mortality between groups.
In linear regression, COVID-19 mortality was significantly associated with overweight, insufficient physical activity, hyperlipidaemia, and age ≥65. In multivariable regression, overweight and age ≥65 demonstrated significant association with COVID-19 mortality (p = .0039, .0094). Countries with more risk factors demonstrated greater COVID-19 mortality (P for trend <.001).
Lifestyle-related factors, especially overweight and elderly population, were associated with increased COVID-19 mortality on a global scale. Global effort to reduce burden of lifestyle-related factors along with protection and vaccination of these susceptible groups may help reduce COVID-19 mortality.
Microscopic colitis has been increasingly recognized as a cause of chronic diarrhoea. We aimed to characterize the role of disease-related factors and treatments on the clinical outcomes of ...microscopic colitis.BACKGROUND AND AIMSMicroscopic colitis has been increasingly recognized as a cause of chronic diarrhoea. We aimed to characterize the role of disease-related factors and treatments on the clinical outcomes of microscopic colitis.We retrospectively reviewed the medical records of patients with microscopic colitis who were treated at the University of Chicago and Oregon Health & Science University between August 2010 and May 2016. Patient characteristics and treatments were evaluated as predictors of clinical outcomes using univariate and multivariate analyses. Clinical remission was defined as no symptoms associated with microscopic colitis based on physician assessment and histologic remission was defined as no evidence of histological inflammation of microscopic colitis.METHODSWe retrospectively reviewed the medical records of patients with microscopic colitis who were treated at the University of Chicago and Oregon Health & Science University between August 2010 and May 2016. Patient characteristics and treatments were evaluated as predictors of clinical outcomes using univariate and multivariate analyses. Clinical remission was defined as no symptoms associated with microscopic colitis based on physician assessment and histologic remission was defined as no evidence of histological inflammation of microscopic colitis.Seventy-two patients with microscopic colitis were included in the study (28 with lymphocytic colitis and 44 with collagenous colitis). Non-steroidal anti-inflammatory drugs, proton pump inhibitors and selective serotonin reuptake inhibitors were used in 23 (31.9%), 14 (19.4%) and 15 (20.8%), respectively, at the time of diagnosis. Among 46 patients with adequate follow-up data, 25 (54.3%) patients achieved clinical remission. Response to budesonide (p = .0002) and achieving histologic remission (p = .0008) were associated with clinical remission on univariate analysis. On multivariate analysis, budesonide response (p = .0052) was associated with clinical remission (odds ratio 25.00, 95% confidence interval 2.63-238.10). Among 22 patients who underwent a follow-up colonoscopy, five patients (22.7%) achieved histologic remission. All patients with histologic remission maintained clinical remission without medication, whereas only two patients (11.8%) were able to discontinue medical therapy when histologic inflammation was present (p = .0002).RESULTSSeventy-two patients with microscopic colitis were included in the study (28 with lymphocytic colitis and 44 with collagenous colitis). Non-steroidal anti-inflammatory drugs, proton pump inhibitors and selective serotonin reuptake inhibitors were used in 23 (31.9%), 14 (19.4%) and 15 (20.8%), respectively, at the time of diagnosis. Among 46 patients with adequate follow-up data, 25 (54.3%) patients achieved clinical remission. Response to budesonide (p = .0002) and achieving histologic remission (p = .0008) were associated with clinical remission on univariate analysis. On multivariate analysis, budesonide response (p = .0052) was associated with clinical remission (odds ratio 25.00, 95% confidence interval 2.63-238.10). Among 22 patients who underwent a follow-up colonoscopy, five patients (22.7%) achieved histologic remission. All patients with histologic remission maintained clinical remission without medication, whereas only two patients (11.8%) were able to discontinue medical therapy when histologic inflammation was present (p = .0002).In the present cohort of patients with microscopic colitis, a favourable response to budesonide was significantly associated with long-term clinical remission, and all patients achieving histological remission were able to maintain clinical remission without further medical therapy. Larger studies are required to confirm these findings.CONCLUSIONSIn the present cohort of patients with microscopic colitis, a favourable response to budesonide was significantly associated with long-term clinical remission, and all patients achieving histological remission were able to maintain clinical remission without further medical therapy. Larger studies are required to confirm these findings.
Background:
Approximately 25% of patients with ulcerative colitis UC experience a severe flare requiring steroid therapy to avoid colectomy. We performed a systematic review and meta-analysis to ...assess the efficacy of tacrolimus as a rescue therapy for active UC.
Methods:
Electronic databases were searched for relevant studies assessing the efficacy of tacrolimus for active UC. Outcomes included short- and long-term clinical response, colectomy free rates, and rate of adverse events in randomised controlled trials RCTs and observational studies.
Results:
Two RCTs comparing high trough concentration 10–15ng/ml versus placebo n = 103 and 23 observational studies n = 831 were identified. Clinical response at 2 weeks was significantly higher with tacrolimus compared with placebo (risk ratio RR = 4.61, 95% confidence interval CI = 2.09–10.17, p = 0.15 x 10-3 among RCTs. Rates of clinical response at 1 and 3 months were 0.73 95% CI = 0.64–0.81 and 0.76 95% CI = 0.59–0.87, and colectomy-free rates remained high at 1, 3, 6, and 12 months 0.86, 0.84, 0.78, and 0.69, respectively among observational studies. Among RCTs, adverse events were more frequent compared with placebo RR = 2.01, 95% CI = 1.20–3.37, p = 0.83 x 10-2, but there was no difference in severe adverse events RR = 3.15, 95% CI = 0.14–72.9, p = 0.47. Severe adverse events were rare among observational studies 0.11, 95% CI = 0.06–0.20.
Conclusions:
In the present meta-analysis, tacrolimus was associated with high clinical response and colectomy-free rates without increased risk of severe adverse events for active UC.
Interleukin (IL)-17 and T helper 17 (TH17) cells, a distinct subset of CD4+ T cells which promotes the expression of IL-17, mediate host defensive mechanisms to various infections and are involved in ...the pathogenesis of autoimmune diseases including inflammatory bowel disease (IBD), psoriasis, and rheumatic diseases. IL-17 inhibitors have shown to be effective in psoriasis, but failed to demonstrate response in IBD. Further, clinical trials of IL-17 inhibitors reported some cases of new onset IBD. We aim to discuss the roles of IL-17 and TH17 cells among autoimmune diseases and the possible immunological mechanisms of new onset IBD in patients undergoing IL-17 inhibitors.
A non-systematic literature review using PubMed/Medline.
IL-17 inhibitors, which either target IL-17 A (secukinumab and ixekizumab) or the IL-17 receptor (brodalumab), have demonstrated clinical benefits in plaque psoriasis, psoriatic arthritis, or axial spondyloarthritis. However, secukinumab and brodalumab have shown no clinical benefit in Crohn's disease and led to frequent serious adverse events including worsening of Crohn's disease. Further, some cases of new onset IBD were reported in clinical trials of IL-17 inhibitors. Consistently, an animal model of colitis has demonstrated that IL-17 can directly inhibit the development of T helper 1 (TH1) cells and TH1 cells can induce aggressive colitis in the absence of IL-17 signaling.
IL-17 and TH17 cells might have protective rather than pro-inflammatory roles in the intestine. IL-17 inhibition may induce inflammation in the intestine by favoring TH1 pathways, which explain the lack of response to IL-17 inhibitors in IBD.
•IL-17 and TH17 cells play important roles in the pathologies of autoimmune diseases.•Monoclonal antibodies targeting IL-17 have demonstrated clinical benefits.•Clinical trials of IL-17 inhibitors reported new onset inflammatory bowel disease.•IL-17 can directly inhibit the development of TH1 cells.•TH1 cells may induce aggressive colitis in the absence of IL-17 signaling.
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