Humoral antibody response following mRNA vaccines against SARS-CoV-2 in solid organ transplant recipients; a status after a fifth and bivalent vaccine dose.

Background: In solid organ transplant (SOT) recipients, the humoral response following COVID-19 vaccination is reduced, as a result of their immunosuppressed treatment. In this study, we investigated antibody concentrations after booster vaccinations until the fifth dose, the latter by monovalent or bivalent BA1 or BA4/5 vaccines. In addition, we evaluated the efficacy of vaccination by recording breakthrough infections, hospitalizations, and deaths. Method: This prospective cohort study included 438 SOT recipients (>18 years) vaccinated with mRNA vaccines against COVID-19 from January 2021 until March 2023. Blood samples were drawn before and after each vaccination and tested for SARS-CoV-2 spike RBD IgG antibodies with the lowest and highest cut-off at 7.1 and 5,680 BAU/mL, respectively. Vaccine information, breakthrough infections, and hospitalizations were collected from the medical records. Results: Most participants received BNT162b2 and 61.4% received five vaccine doses. The response proportion in SOT recipients increased from 86.7% after the fourth dose to 93.0% following the fifth dose. Antibody concentration decreased with 142.7 BAU/mL between the third and fourth dose (median 132 days, Quartile 1: 123, Quartile 3: 148) and 234.3 BAU/mL between the fourth and fifth (median 250 days, Quartile 1: 241, Quartile 3: 262) dose among those without breakthrough infection (p=0.34). When comparing the Omicron BA.1 or Omicron BA.4/BA.5 adapted vaccines, no significant differences in antibody concentration were found, but 20.0% of SOT recipients receiving a monovalent fifth vaccine dose had a breakthrough infection compared to 4.0% and 7.9% among those who received BA.1 and BA.4/BA.5 adapted vaccines, respectively (p=0.04). Since January 2021, 240 (54.8%) participants had a breakthrough infection, and 22 were hospitalized, but no deaths were observed. Conclusions: The fifth COVID-19 vaccine dose raised antibody response to 93.0% of the study population. Additional booster doses, as well as bivalent vaccines, led to higher levels of antibody concentration in SOT recipients. We found a lower incidence of breakthrough infections among SOT recipients after receiving a bivalent vaccine as a fifth dose compared to those receiving a monovalent dose. Antibody concentrations did not wane when the time between doses was prolonged from four to eight months.

Alcohol use and hepatocellular carcinoma risk in patients with alcohol-related cirrhosis.

OBJECTIVES: Insights into risk factors for hepatocellular carcinoma (HCC) among patients with alcohol-related cirrhosis (ALD cirrhosis) are important for decisions about HCC surveillance. We studied the effects of continued hazardous alcohol use in ALD cirrhosis on HCC risk. METHODS: Within a nationwide registry-based cohort of patients with ALD cirrhosis, we compared HCC risk between patients with a continued hazardous alcohol use and matched comparators. We used Fine-Gray regression to compare the risk of HCC and Cox regression to compare all-cause mortality. We also included patients with ALD cirrhosis in a clinical case-control study. Cases had HCC, and controls did not. Alcohol use was quantified using the AUDIT-C-questionnaire. Logistic regression was used to analyze the association between hazardous alcohol use and HCC risk. RESULTS: In the registry-based study, we included 8,616 patients with continued hazardous alcohol use and 8,616 matched comparators. Patients with a continued hazardous alcohol use had a lower HCC risk (subdistribution hazard ratio: 0.64, 95% confidence interval [CI]: 0.57 - 0.72) and higher mortality (hazard ratio: 1.62, 95% CI: 1.56 - 1.67). In the clinical study, we included 146 patients with ALD cirrhosis of whom 53 had newly diagnosed HCC. Hazardous alcohol use was insignificantly associated with a lower HCC risk (odds ratio: 0.61, 95% CI: 0.25 - 1.46). CONCLUSIONS: Hazardous alcohol use in patients with ALD cirrhosis is associated with higher mortality and, consequently, a lower HCC risk. Even if alcohol is carcinogenic, HCC surveillance will therefore likely be more effective in patients with ALD cirrhosis without a hazardous alcohol use.

Humoral immune response following a third SARS-CoV-2 mRNA vaccine dose in solid organ transplant recipients compared with matched controls.

Background: Solid organ transplant (SOT) recipients have shown suboptimal antibody response following COVID-19 vaccination. Several risk factors for the diminished response have been identified including immunosuppression and older age, but the influence of different comorbidities is not fully elucidated. Method: This case-control study consisted of 420 Danish adult SOT recipients and 840 sex- and age-matched controls, all vaccinated with a third homologous dose of either BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine. The primary outcome was differences in humoral immune response. The secondary outcome was breakthrough infections. Additionally, we looked for factors that could predict possible differences between the two groups. Results: Response rate increased from 186/382 (49%) to 275/358 (77%) in SOT recipients and remained on 781/790 (99%) to 601/609 (99%) in controls following a third vaccine dose. SOT recipients had significantly lower median antibody concentrations after third dose compared to controls (332.6 BAU/ml vs 46,470.0 BAU/ml, p <0.001). Lowest median antibody concentrations were seen in SOT recipients with liver disease (10.3 BAU/ml, IQR 7.1-319) and diabetes (275.3 BAU/ml, IQR 7.3-957.4). Breakthrough infections occurred similarly frequent, 150 (40%) among cases and 301 (39%) among controls (p = 0.80). Conclusion: A third COVID-19 vaccine dose resulted in a significant increase in humoral immunogenicity in SOT recipients and maintained high response rate in controls. Furthermore, SOT recipients were less likely to produce antibodies with overall lower antibody concentrations and humoral immunity was highly influenced by the presence of liver disease and diabetes. The prevalence of breakthrough infections was similar in the two groups.

Determinants of Antibody Response to a Third SARS-CoV-2 mRNA Vaccine Dose in Solid Organ Transplant Recipients: Results from the Prospective Cohort Study COVAC-Tx.

BACKGROUND: We studied factors related to humoral response in solid organ transplant (SOT) recipients following a three-dose regimen of an mRNA-based SARS-CoV-2 vaccine. METHOD: This was a prospective study of SOT recipients who received a third homologous dose of the BNT162b2 (Pfizer-BioNTech) vaccine. The anti-spike S1 IgG response was measured using the SARS-CoV-2 IgG II Quant assay (Abbott Laboratories) with a cut-off of 7.1 BAU/mL. Multiple logistic regression was used to determine the factors associated with humoral response. RESULTS: In total, 395 SOT recipients were included. Anti-spike IgG was detected in 195/395 (49.4%) patients after the second dose and 261/335 (77.9%) patients after the third dose. The overall mean increase in antibody concentration after the third dose was 831.0 BAU/mL (95% confidence interval (CI) 687.4-974.5) and 159 (47.5%) participants had at least a 10-fold increase in antibody concentration after the third dose. The increase in antibody concentration was significantly higher among patients with detectable antibodies after the second dose than those without. Cumulative time from transplantation and liver recipients was positively associated with an antibody response, whereas older age, administration of prednisolone, and proliferation inhibitors were associated with diminished antibody response. CONCLUSION: Although the third dose of the BNT162b2 vaccine improved humoral responses among SOT non-responders following the second dose, the overall response remained low, and 22.1% did not develop any response. Patients at risk of a diminished vaccine response require repeated booster doses and alternative treatment approaches.

Immunogenicity of SARS-CoV-2 mRNA vaccine in solid organ transplant recipients.

BACKGROUND: It is currently not well described if a two-dose regimen of a Covid-19 vaccine is sufficient to elicit an immune response in solid organ transplant (SOT) recipients. RESULTS: A total of 80 SOT recipients completed a two-dose regimen with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA vaccine. Only 35.0% (n = 28) were able to mount a positive IgG immune response 6 weeks after the second dose of vaccine. CONCLUSION: This emphasizes that SOT recipients need continued use of personal protective measures. Future studies need to closely examine the cellular immune response in patients with compromised antibody response to Covid-19 vaccination.

The Danish comorbidity in liver transplant recipients study (DACOLT): a non-interventional prospective observational cohort study.

BACKGROUND: Liver transplantation is the only curative treatment for patients with end-stage liver disease. Short-term survival has improved due to improved surgical techniques and greater efficacy of immunosuppressive drugs. However, long-term survival has not improved to the same extent as the short-term survival, and the 10-year survival after liver transplantation is 60%. In addition to liver- and transplant-related causes, comorbidities such as cardiovascular, pulmonary, renal, and metabolic diseases have emerged as leading causes of morbidity and mortality in liver transplant recipients. The objective of this study is to assess the burden of comorbidities and identify both liver- and transplant-related risk factors as well as traditional risk factors that contribute to the pathogenesis of comorbidity in liver transplant recipients. METHODS/DESIGN: The Danish Comorbidity in Liver Transplant Recipients (DACOLT) study is an observational, longitudinal study. We aim to include all adult liver transplant recipients in Denmark (n = approx. 600). Participants will be matched by sex and age to controls from the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS). Physical and biological measures including blood pressure, ankle-brachial index, spirometry, exhaled nitric oxide, electrocardiogram, transthoracic echocardiography, computed tomography (CT) angiography of the heart, unenhanced CT of chest and abdomen and blood samples will be collected using uniform protocols in participants in DACOLT, CGPS, and CCHS. Blood samples will be collected and stored in a research biobank. Follow-up examinations at regular intervals up to 10 years of follow-up are planned. DISCUSSION: There is no international consensus standard for optimal clinical care or monitoring of liver transplant recipients. This study will determine prevalence, incidence and risk factors for comorbidity in liver transplant recipients and may be used to provide evidence for guidelines on management, treatment and screening and thereby contribute to improvement of the long-term survival. Trial registration ClinicalTrials.gov: NCT04777032; date of registration: March 02, 2021.

International prospective observational study of upper gastrointestinal haemorrhage: Does weekend admission affect outcome?

INTRODUCTION: Out of hours admissions have higher mortality for many conditions but upper gastrointestinal haemorrhage studies have produced variable outcomes. METHODS: Prospective study of 12 months consecutive admissions of upper gastrointestinal haemorrhage from four international high volume centres. Admission period (weekdays, weeknights or weekends), demographics, haemodynamic parameters, laboratory results, endoscopy findings, further procedures and 30-day mortality were recorded. Five upper gastrointestinal haemorrhage risk scores were calculated. RESULTS: 2118 patients, 60% male, median age 66 years were studied. Compared with patients presenting on weekdays, patients presenting at weekends had no significant differences in comorbidity, pulse, systolic BP, risk scores, frequency of peptic ulcers or varices. Those presenting on weekdays had lower haemoglobin (p = 0.007) and were more likely to have a normal endoscopy (p < 0.01). Time to endoscopy was less for weeknight presentation (p = 0.001). Sixty-seven per cent of those presenting on weekdays, 75% on weeknights and 60% at weekends had endoscopy within 24 h. Transfusion requirements, need for endoscopic therapy or surgery/embolization, rebleeding rates (6.1%) and mortality (7.2%) did not differ with presentation time. CONCLUSION: This multi-centre international study in large centres found no difference in demographics, comorbidity or haemodynamic stability and no increase in mortality for patients presenting with upper gastrointestinal haemorrhage out of hours.

Non-selective beta-blockers may reduce risk of hepatocellular carcinoma: a meta-analysis of randomized trials.

BACKGROUND & AIMS: Non-selective beta-blockers (NSBB) are used in patients with cirrhosis and oesophageal varices. Experimental data suggest that NSBB inhibit angiogenesis and reduce bacterial translocation, which may prevent hepatocellular carcinoma (HCC). We therefore assessed the effect of NSBB on HCC by performing a systematic review with meta-analyses of randomized trials. METHODS: Electronic and manual searches were combined. Authors were contacted for unpublished data. Included trials assessed NSBB for patients with cirrhosis; the control group could receive any other intervention than NSBB. Fixed and random effects meta-analyses were performed with I(2) as a measure of heterogeneity. Subgroup, sensitivity, regression and sequential analyses were performed to evaluate heterogeneity, bias and the robustness of the results after adjusting for multiple testing. RESULTS: Twenty-three randomized trials on 2618 patients with cirrhosis were included, of which 12 reported HCC incidence and 23 reported HCC mortality. The mean duration of follow-up was 26 months (range 8-82). In total, 47 of 694 patients randomized to NSBB developed HCC vs 65 of 697 controls (risk difference -0.026; 95% CI-0.052 to -0.001; number needed to treat 38 patients). There was no heterogeneity (I(2) = 7%) or evidence of small study effects (Eggers P = 0.402). The result was not confirmed in sequential analysis, which suggested that 3719 patients were needed to achieve the required information size. NSBB did not reduce HCC-related mortality (RD -0.011; 95% CI -0.040 to 0.017). CONCLUSIONS: Non-selective beta-blockers may prevent HCC in patients with cirrhosis.