Enhanced Humoral Immune Response After COVID-19 Vaccination in Elderly Kidney Transplant Recipients on Everolimus Versus Mycophenolate Mofetil-containing Immunosuppressive Regimens.

BACKGROUND: Elderly kidney transplant recipients (KTRs) represent almost one third of the total kidney transplant population. These patients have a very high coronavirus disease 2019 (COVID-19)-related mortality, whereas their response to COVID-19 vaccination is impaired. Finding ways to improve the COVID-19 vaccination response in this vulnerable population is of uttermost importance. METHODS: In the OPTIMIZE trial, we randomly assign elderly KTRs to an immunosuppressive regimen with standard-exposure calcineurin inhibitor (CNI), mycophenolate mofetil, and prednisolone or an adapted regimen with low dose CNI, everolimus, and prednisolone. In this substudy, we measured the humoral response after 2 (N = 32) and 3 (N = 22) COVID-19 mRNA vaccinations and the cellular response (N = 15) after 2 vaccinations. RESULTS: . The seroconversion rates of elderly KTRs on a standard immunosuppressive regimen were only 13% and 38% after 2 and 3 vaccinations, respectively, whereas the response rates of KTRs on the everolimus regimen were significantly higher at 56% ( P = 0.009) and 100% ( P = 0.006). Levels of severe acute respiratory syndrome coronaVirus 2 IgG antibodies were significantly higher at both time points in the everolimus group ( P = 0.004 and P < 0.001). There were no differences in cellular response after vaccination. CONCLUSIONS: An immunosuppressive regimen without mycophenolate mofetil, a lower CNI dose, and usage of everolimus is associated with a higher humoral response rate after COVID-19 vaccination in elderly KTRs after transplantation. This encouraging finding should be investigated in larger cohorts, including transplant recipients of all ages.

Impact of COVID-19 social distancing measures on lung transplant recipients: decline in overall respiratory virus infections is associated with stabilisation of lung function.

BACKGROUND: Coronavirus disease 2019 (COVID-19) social distancing measures led to a dramatic decline in non-COVID-19 respiratory virus infections, providing a unique opportunity to study their impact on annual forced expiratory volume in 1 s (FEV1) decline, episodes of temporary drop in lung function (TDLF) suggestive of infection and chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTRs). METHODS: All FEV1 values of LTRs transplanted between 2009 and April 2020 at the University Medical Center Groningen (Groningen, The Netherlands) were included. Annual FEV1 change was estimated with separate estimates for pre-social distancing (2009-2020) and the year with social distancing measures (2020-2021). Patients were grouped by individual TDLF frequency (frequent/infrequent). Respiratory virus circulation was derived from weekly hospital-wide respiratory virus infection rates. Effect modification by TDLF frequency and respiratory virus circulation was assessed. CLAD and TDLF rates were analysed over time. RESULTS: 479 LTRs (12 775 FEV1 values) were included. Pre-social distancing annual change in FEV1 was -114 (95% CI -133- -94) mL, while during social distancing FEV1 did not decline: 5 (95% CI -38-48) mL (difference pre-social distancing versus during social distancing: p<0.001). The frequent TDLF subgroup showed faster annual FEV1 decline compared with the infrequent TDLF subgroup (-150 (95% CI -181- -120) versus -90 (95% CI -115- -65) mL; p=0.003). During social distancing, we found significantly lower odds for any TDLF (OR 0.53, 95% CI 0.33-0.85; p=0.008) and severe TDLF (OR 0.34, 0.16-0.71; p=0.005) as well as lower CLAD incidence (OR 0.53, 95% CI 0.27-1.02; p=0.060). Effect modification by respiratory virus circulation indicated a significant association between TDLF/CLAD and respiratory viruses. CONCLUSIONS: During COVID-19 social distancing the strong reduction in respiratory virus circulation coincided with markedly less FEV1 decline, fewer episodes of TDLF and possibly less CLAD. Effect modification by respiratory virus circulation suggests an important role for respiratory viruses in lung function decline in LTRs.

Use of Tumor Necrosis Factor-α Antagonists Is Associated With Attenuated IgG Antibody Response Against SARS-CoV-2 in Vaccinated Patients With Inflammatory Bowel Disease.

Introduction: Patients with Inflammatory Bowel Disease (IBD) frequently receive immunomodulating treatment, which may render them at increased risk of an attenuated immune response upon vaccination. In this study, we assessed the effects of different types of commonly prescribed immunosuppressive medications on the serological response after vaccination against SARS-CoV-2 in patients with IBD. Methods: In this prospective observational cohort study, IgG antibody titers against SARS-CoV-2 were measured 2-10 weeks after completion of standard vaccination regimens in patients with IBD. Clinical characteristics, previous history of SARS-CoV-2 infection, type of vaccine (mRNA- or vector-based) and medication use were recorded at the time of sampling. Subsequently, a chemiluminescent microparticle immunoassay was used for the quantitative determination of IgG antibodies against the receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2. Results: Three hundred and twelve (312) patients with IBD were included (172 Crohn's disease [CD] and 140 ulcerative colitis [UC]). Seroconversion (defined as titer of >50 AU/ml) was achieved in 98.3% of patients. Antibody concentrations were significantly lower in patients treated with TNF-α-antagonists vs. non-users of TNF-α-antagonists (geometric mean [95% confidence interval]: 2204 [1655-2935] vs. 5002 [4089-6116] AU/ml, P<0.001). In multivariable models, use of TNF-α-antagonists (P<0.001), vector vaccines (P<0.001), age (>50 years) (P<0.01) and CD (P<0.05) were independently associated with lower anti-SARS-CoV-2 antibody titers. In patients who received mRNA vaccines, users of thiopurines (either prescribed as monotherapy or in combination with biologicals) demonstrated significantly lower antibody titers compared to thiopurine non-users (P<0.05). Conclusion: Despite reassuring findings that most patients with IBD have detectable antibodies after anti-SARS-CoV-2 vaccination, TNF-α-antagonists were found to be strongly associated with an attenuated IgG antibody response after vaccination against SARS-CoV-2, independent of vaccine type, the time elapsed after vaccination and blood sampling, prior SARS-CoV-2 infection and patient age. Patients treated with thiopurines and receiving mRNA-based vaccines demonstrated lower anti-SARS-CoV-2 antibody titers compared with non-users.

Impact of COVID-19 social distancing measures on lung transplant recipients: decline in overall respiratory virus infections is associated with stabilisation of lung function

Background COVID-19 social distancing measures led to a dramatic decline in non-COVID respiratory virus (RV) infections, providing a unique opportunity to study their impact on annual FEV1 decline, episodes of temporary drop in lung function (TDLF) suggestive of infection and chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTR). Methods All FEV1 values of LTR transplanted between 2009-April 2020 were included. Annual FEV1 change was estimated with separate estimates for pre- social distancing (2009/2020) and the year with social distancing measures (2020/2021). Patients were grouped by individual TDLF frequency (frequent/infrequent). RV circulation was derived from weekly hospital-wide RV infection rates. Effect modification by TDLF frequency and RV circulation was assessed. CLAD and TDLF rates were analyzed over time. Results 479 LTR (12 775 FEV1 values) were included. Pre- social distancing annual change in FEV1 was −114 mL [95%CI;−133;−94], while during social distancing FEV1 did not decline: +5 mL [−38;48] (difference pre- versus during social distancing: p<0.001). The frequent TDLF subgroup showed faster annual FEV1 decline compared to infrequent TDLF (−150 mL [−181;−120] versus −90 mL [−115;−65] p=0.003). During social distancing, we found significantly lower odds for any TDLF (OR 0.53 [0.33;0.85], p=0.008) and severe TDLF (OR 0.34 [0.16;0.71] p=0.005) as well as lower CLAD incidence (OR 0.53 [0.27;1.02] p=0.060). Effect modification by RV circulation indicated a significant association between TDLF/CLAD and RVs. Conclusion During social distancing the strong reduction in RV circulation coincided with markedly less FEV1 decline, fewer TDLFs and possibly less CLAD. Effect modification by RV circulation suggests an important role for RVs in lung function decline in LTR.

Use of Tumor Necrosis Factor-α Antagonists Is Associated With Attenuated IgG Antibody Response Against SARS-CoV-2 in Vaccinated Patients With Inflammatory Bowel Disease

Introduction Patients with Inflammatory Bowel Disease (IBD) frequently receive immunomodulating treatment, which may render them at increased risk of an attenuated immune response upon vaccination. In this study, we assessed the effects of different types of commonly prescribed immunosuppressive medications on the serological response after vaccination against SARS-CoV-2 in patients with IBD. Methods In this prospective observational cohort study, IgG antibody titers against SARS-CoV-2 were measured 2-10 weeks after completion of standard vaccination regimens in patients with IBD. Clinical characteristics, previous history of SARS-CoV-2 infection, type of vaccine (mRNA- or vector-based) and medication use were recorded at the time of sampling. Subsequently, a chemiluminescent microparticle immunoassay was used for the quantitative determination of IgG antibodies against the receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2. Results Three hundred and twelve (312) patients with IBD were included (172 Crohn’s disease [CD] and 140 ulcerative colitis [UC]). Seroconversion (defined as titer of >50 AU/ml) was achieved in 98.3% of patients. Antibody concentrations were significantly lower in patients treated with TNF-α-antagonists vs. non-users of TNF-α-antagonists (geometric mean [95% confidence interval]: 2204 [1655-2935] vs. 5002 [4089-6116] AU/ml, P<0.001). In multivariable models, use of TNF-α-antagonists (P<0.001), vector vaccines (P<0.001), age (>50 years) (P<0.01) and CD (P<0.05) were independently associated with lower anti-SARS-CoV-2 antibody titers. In patients who received mRNA vaccines, users of thiopurines (either prescribed as monotherapy or in combination with biologicals) demonstrated significantly lower antibody titers compared to thiopurine non-users (P<0.05). Conclusion Despite reassuring findings that most patients with IBD have detectable antibodies after anti-SARS-CoV-2 vaccination, TNF-α-antagonists were found to be strongly associated with an attenuated IgG antibody response after vaccination against SARS-CoV-2, independent of vaccine type, the time elapsed after vaccination and blood sampling, prior SARS-CoV-2 infection and patient age. Patients treated with thiopurines and receiving mRNA-based vaccines demonstrated lower anti-SARS-CoV-2 antibody titers compared with non-users.

The effect of COVID-19 on transplant function and development of CLAD in lung transplant patients: A multicenter experience.

BACKGROUND: Concerns have been raised on the impact of coronavirus disease (COVID-19) on lung transplant (LTx) patients. The aim of this study was to evaluate the transplant function pre- and post-COVID-19 in LTx patients. METHODS: Data were retrospectively collected from LTx patients with confirmed COVID-19 from all 3 Dutch transplant centers, between February 2020 and September 2021. Spirometry results were collected pre-COVID-19, 3- and 6-months post infection. RESULTS: Seventy-four LTx patients were included. Forty-two (57%) patients were admitted, 19 (26%) to the intensive care unit (ICU). The in-hospital mortality was 20%. Twelve out of 19 ICU patients died (63%), a further 3 died on general wards. Patients with available spirometry (78% at 3 months, 65% at 6 months) showed a significant decline in mean forced expiratory volume in 1 second (FEV1) (ΔFEV1 138 ± 39 ml, p = 0.001), and forced vital capacity (FVC) (ΔFVC 233 ±74 ml, p = 0.000) 3 months post infection. Lung function improved slightly from 3 to 6 months after COVID-19 (ΔFEV1 24 ± 38 ml; ΔFVC 100 ± 46 ml), but remained significantly lower than pre-COVID-19 values (ΔFEV1 86 ml ± 36 ml, p = 0.021; ΔFVC 117 ± 35 ml, p = 0.012). FEV1/FVC was > 0.70. CONCLUSIONS: In LTx patients COVID-19 results in high mortality in hospitalized patients. Lung function declined 3 months after infection and gradually improved at 6 months, but remained significantly lower compared to pre-COVID-19 values. The more significant decline in FVC than in FEV1 and FEV1/FVC > 70%, suggested a more restrictive pattern.

Treatment of severe acute ulcerative colitis in SARS-CoV-2 infected patients: report of three cases and discussion of treatment options.

In the wake of the coronavirus disease 2019 (COVID-19) pandemic, it is unclear how asymptomatic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected patients who present with acute severe ulcerative colitis (UC) can be treated effectively and safely. Standard treatment regimens consist of steroids, immunomodulatory drugs, and biological therapies, but therapeutic decision-making becomes challenging as there are uncertainties about how to deal with these drugs in patients with COVID-19 and active UC. Importantly, guidelines for this particular group of patients with UC are still lacking. To inform therapeutic decision-making, we describe three consecutive cases of patients with active UC and COVID-19 and discuss their treatments based on theoretical knowledge, currently available evidence and clinical observations. Three patients were identified through our national inflammatory bowel disease network [Initiative on Crohn's and Colitis (ICC)] for whom diagnosis of SARS-CoV-2-infection was established by reverse transcription-polymerase chain reaction (RT-PCR) testing in nasopharynx, stools, and/or biopsies. Acute severe UC was diagnosed by clinical parameters, endoscopy, and histopathology. Clinical guidelines for SARS-CoV-2-negative patients advocate the use of steroids, calcineurin inhibitors, or tumor necrosis factor alpha (TNF-α)-antagonists as induction therapy, and experiences from the current three cases show that steroids and TNF-α-antagonists could also be used in patients with COVID-19. This could potentially be followed by TNF-α-antagonists, vedolizumab, or ustekinumab as maintenance therapy in these patients. Future research is warranted to investigate if, and which, immunomodulatory drugs should be used for COVID-19 patients that present with active UC. To answer this question, it is of utmost importance that future cases of patients with UC and COVID-19 are documented carefully in international registries, such as the SECURE-IBD registry.