Immune responses and clinical outcomes after COVID-19 vaccination in patients with liver disease and liver transplant recipients.

BACKGROUND & AIMS: Comparative assessments of immunogenicity following different COVID-19 vaccines in patients with distinct liver diseases are lacking. SARS-CoV-2-specific T-cell and antibody responses were evaluated longitudinally after one to three vaccine doses, with long-term follow-up for COVID-19-related clinical outcomes. METHODS: A total of 849 participants (355 with cirrhosis, 74 with autoimmune hepatitis [AIH], 36 with vascular liver disease [VLD], 257 liver transplant recipients [LTRs] and 127 healthy controls [HCs]) were recruited from four countries. Standardised immune assays were performed pre and post three vaccine doses (V1-3). RESULTS: In the total cohort, there were incremental increases in antibody titres after each vaccine dose (p <0.0001). Factors associated with reduced antibody responses were age and LT, whereas heterologous vaccination, prior COVID-19 and mRNA platforms were associated with greater responses. Although antibody titres decreased between post-V2 and pre-V3 (p = 0.012), patients with AIH, VLD, and cirrhosis had equivalent antibody responses to HCs post-V3. LTRs had lower and more heterogenous antibody titres than other groups, including post-V3 where 9% had no detectable antibodies; this was heavily influenced by intensity of immunosuppression. Vaccination increased T-cell IFNγ responses in all groups except LTRs. Patients with liver disease had lower functional antibody responses against nine Omicron subvariants and reduced T-cell responses to Omicron BA.1-specific peptides compared to wild-type. 122 cases of breakthrough COVID-19 were reported of which 5/122 (4%) were severe. Of the severe cases, 4/5 (80%) occurred in LTRs and 2/5 (40%) had no serological response post-V2. CONCLUSION: After three COVID-19 vaccines, patients with liver disease generally develop robust antibody and T-cell responses to vaccination and have mild COVID-19. However, LTRs have sustained no/low antibody titres and appear most vulnerable to severe disease. IMPACT AND IMPLICATIONS: Standardised assessments of the immune response to different COVID-19 vaccines in patients with liver disease are lacking. We performed antibody and T-cell assays at multiple timepoints following up to three vaccine doses in a large cohort of patients with a range of liver conditions. Overall, the three most widely available vaccine platforms were immunogenic and appeared to protect against severe breakthrough COVID-19. This will provide reassurance to patients with chronic liver disease who were deemed at high risk of severe COVID-19 during the pre-vaccination era, however, liver transplant recipients had the lowest antibody titres and remained vulnerable to severe breakthrough infection. We also characterise the immune response to multiple SARS-CoV-2 variants and describe the interaction between disease type, severity, and vaccine platform. These insights may prove useful in the event of future viral infections which also require rapid vaccine development and delivery to patients with liver disease.

SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (<380 AU ml-1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies.

The Effect of Adiposity on Anti-Tumor Necrosis Factor-Alpha Levels and Loss of Response in Crohn's Disease Patients.

INTRODUCTION: A high body mass index is known to adversely affect antitumor necrosis factor-alpha trough levels and secondary loss of response (SLOR) in patients with Crohn's disease. We hypothesize that high levels of adiposity negatively affect these outcomes and aimed to determine if this relationship exists. METHODS: We performed a retrospective cross-sectional study of 69 patients with Crohn's disease from two tertiary inflammatory bowel disease centers between February 1, 2015, and June 30, 2018. Primary responders to infliximab (IFX) or adalimumab (ADA) who had a trough level performed within 6 months of CT or MRI scan and at least 12 months of clinical follow-up were eligible for inclusion. Body composition as measured on CT/MRI scans were correlated with trough concentration and time SLOR. Multivariate adjustments were made for established risk factors known to affect trough levels and SLOR. RESULTS: Of 69 included patients, 44 (63.8%) and 25 (36.2%) patients received IFX and ADA, respectively. Multivariate analysis revealed that IFX trough concentrations were inversely correlated with visceral fat area (-0.02 [-0.04, -0.003], P = 0.03), visceral fat index (-0.07 [-0.12, -0.01], P = 0.02) and visceral fat: skeletal muscle area ratio (-3.81 [-7.13, -0.50], P = 0.03), but not body mass index (-0.23 [-0.52, 0.06], P = 0.11). No predictive factors were found for ADA. Increased total adipose area was associated with an increased risk of SLOR in ADA-treated patients, but not IFX-treated patients (hazard ratio = 1.01 [1.002, 1.016], P = 0.011). DISCUSSION: Visceral adiposity is an important predictor of IFX trough levels, and high total adiposity predicts for SLOR to ADA.

Ensuring donor safety: is venesecting therapeutic donors to haemoglobin levels below Blood Service guidelines safe?

Therapeutic phlebotomy is the cornerstone of treatment for HFE haemochromatosis (HH). Current Australian Red Cross LifeBlood Service guidelines mandate measuring haemoglobin (Hb) levels prior to phlebotomy and if below 130 g/l in men or 120 g/l in women, donors are deferred from donating whole blood. Therapeutic donation below these levels may take place where both the treating doctor and a blood service medical officer approve. The aim of the current study was to determine whether adverse events are more frequent in those who undergo therapeutic phlebotomy below current Hb thresholds applied to volunteer therapeutic donors. A retrospective review of all therapeutic donations was undertaken for the financial year 2016-2017. The data were obtained through the Australian Red Cross Blood Service. Inclusion criteria were any donor between 16 and 70 years of age, weighing more than 50 kg and meeting blood service guidelines for donation. All adverse events recorded in an electronic quality system were obtained and associated with donor haemoglobin level. Statistical analyses were performed using analysis of variance or Fisher's exact test (GraphPad Prism). About 34 886 therapeutic phlebotomy donations occurred during 2016-2017, of whom the majority were referred for HH (34 089). In total, 365 of 34 886 donations (0·0105%) were complicated by an adverse event. A total of 305 (0·0087%) therapeutic donations occurred while below the lower limit of blood service Hb threshold for their respective genders. Of the donations that occurred below the blood service threshold, 3 of 305 (0·0098%) had an adverse event compared with 362 of 34 581 donations above the lower limit threshold (0·0105%, P = 0·99). The incidence of adverse events was not increased in the group which underwent therapeutic phlebotomy below the current Australian Red Cross Blood Service Hb threshold compared with those above threshold, indicating safety of treatment at Hb levels lower than currently recommended.

Otitic meningitis, superior semicircular canal dehiscence, and encephalocele: a case series.

BACKGROUND: Otitic meningitis in the postantibiotic era is still a serious condition, requiring intensive treatment and prolonged rehabilitation. In view of the significant morbidity and mortality rate, conditions that may increase the likelihood of otitic meningitis developing should be treated promptly. The incidence of meningitis after asymptomatic encephaloceles of the middle cranial fossa varies greatly, and the management differs between elective surgical repair and expectant careful observation. Superior semicircular canal dehiscences (SSCDs) are postulated to have a congenital origin and are associated with a thin or dehiscent tegmen. Several cases of simultaneous SCCD and tegmen defects have been reported, but the findings of otitic meningitis, SCCD, and encephaloceles has, to the best of our knowledge, not been previously explored in the literature. METHODS: We reviewed a series of 4 patients who all presented with a combination of otitic meningitis, encephaloceles, and SSCD. RESULTS: All the 4 patients we reviewed had meningitis secondary to otitis media with computed tomographic scans confirming the presence of SCCD with ipsilateral tegmen tympani defects and associated cephaloceles. All patients were treated with intravenous antibiotics and underwent surgery that ranged from myringotomy and ventilation tube insertions, mastoidectomy, and burr hole drainage for temporal lobe abscess. They were all associated with intensive care unit admission, significant morbidity, and prolonged hospital stays. There were no mortalities. CONCLUSION: We propose that in all SSCD patients, a careful computed tomographic examination of the cranial base should be undertaken to exclude other associated tegmen tympani defects. In cases of SSCD requiring surgery, we support the view that elective surgical repair be recommended where asymptomatic ipsilateral encephaloceles are found, to reduce the risk of otitic meningitis.