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Introduction: Lung transplant recipients (LTR) are at significant risk for severe covid-19 disease. The oral combination therapy Nirmatrelvir plus Ritonavir (Paxlovid) has been shown to reduce the risk for disease progression. Due to drug interactions with calcineurin inhibitors (CNI), significant concern exists in treating LTR with Paxlovid. We describe safety related outcomes of Paxlovid use among our LTR. Method(s): We retrospectively collected data of all LTR with a positive COVID-19 test since Paxlovid was available in Israel from January 2022 - May 2022. During this time, Paxlovid was the drug of choice, unless contraindicated. Data collection included: demographics, hospitalization for covid-19, death of any cause and drug related adverse events. Result(s): A total of 96 LTR tested positive for covid-19 during this period. View inline There was no evidence of posterior reversible encephalopathy (PRES), seizures, kidney failure or ED visits in any of the paxlovid treated patients. Conclusion(s): Despite significant drug related interactions between CNI and Paxlovid, the drug can be administrated safely in LTR. Given the high risk for severe covid-19 disease among LTR and the demonstrated safety of this study, use of paxlovid among this population should be considered.
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Introduction: Membranous nephropathy is one of the most common causes of nephrotic syndrome. Among the available treatment options, the tried and tested regimen is the modified Ponticelli regimen. Despite adequate therapy, studies have shown that close to one-quarter of patients fail to attain complete remission. However, data is limited regarding patients who are resistant to this regimen. Method(s): This was an ambispective, observational study conducted in Madras Medical College, Chennai, India between April 2021 to August 2022. All patients with biopsy-proven primary membranous nephropathy resistant to modified Ponticelli regimen were included. Complete remission was defined as proteinuria < 0.5g/day combined with a stable eGFR. Partial remission was defined as reduction of proteinuria by 50% to < 3.5g/day but >0.5g/day. Resistance to therapy was defined as the failure to attain at least partial remission, 12 months after completion of modified Ponticelli regimen. Result(s): A total of 13 patients were enrolled in the study. The median age was 41 years (IQR 38-49) with a male preponderance (n=9;69%). Serum MPLA2R antibody was positive for 9 patients. All patients were negative for ANA and serology for hepatitis B, hepatitis C and HIV were negative. The most common clinical presentation was with nephrotic syndrome, seen in nine patients (69.23%). Renal failure was seen at presentation in 4 patients (30.76%), with one patient warranting initiation of hemodialysis. At 12 months, post completion of modified Ponticelli regimen, the median quantum of proteinuria was 8.7 grams per day. Due to trend towards normalisation of serum albumin and immunological remission, 3 patients were managed with optimised RAS inhibition after modified Ponticelli regimen. Currently, they are in partial remission. Four patients were treated with a second course of modified Ponticelli regimen. Of them one patient is in partial remission, while two patients had progressed to end-stage renal disease and are currently on maintenance hemodialysis. One patient who was resistant to the second course, was managed with a trial of calcineurin inhibitors (CNI) therapy followed by 4 doses of Rituximab (500mg each) due to persistent proteinuria. However, he was lost to follow up during the COVID pandemic and presented with end stage renal disease warranting hemodialysis. A trial of CNI therapy was given to 6 patients. All patients had nephrotic-range proteinuria 12 months post CNI therapy initiation. Five patients were then given Rituximab, among whom, two patients attained complete remission, while three patients have attained immunological and clinical remission. One patient was given a second trial of modified Ponticelli regimen following CNI therapy and is currently in complete remission. Two of these patients developed thrombotic complications - one patient diagnosed with coronary artery disease and one patient with renal vein thrombosis. Conclusion(s): Rituximab is a promising option for patients with primary membranous nephropathy who do not respond to modified Ponticelli regimen. No conflict of interestCopyright © 2023
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Purpose: To evaluate the safety and generation rate of Ab anti spike rate in SOT patients at 28 and 90 days after completing the Covid 19 vaccination scheme. Method(s): Multicenter prospective study in SOT with a complete vaccination scheme who agreed to participate in the study . Demographic , vaccination: schedule;time;adverse effects and transplant variables were collected. The generation rate of antispike antibodies was evaluated by the COVIDAR-IgG method at the Universidad de Buenos Aires School of Medicine. Result(s): 113 SOT patients were included (September 6th to October 4th). Median age was 53 (IQR 42.5-63, women 36.8%). Transplant type: 72.8% renal , 13.1% cardiac, 12.3% liver, 0.9% pancreas and 0.9% lung. Deceased donors 71.1%. The median time after transplantation to vaccination was 65 months (IQR 30 120 R 2-429). Only 7% of patients developed rejection within the year prior to vaccination and no patient rejected post vaccination. 74.3% (n 84) had triple immunosuppressive maintenance regimen (steroids + calcineurin inhibitors (ICN) + antiproliferative), 24 pts (21.1%) double regimen WITHOUT steroids and 5 (4.3%) monotherapy with IC. Vaccination schedule: Sputnik 14.5%, Sputnik-Astrazeneca 4.4%, Sputnik-Moderna 28.9%, Sinopharm 3.5%, Astrazeneca 34.2%. Vaccine-related adverse events were observed in 18.4% of patients, 82% were mild. 40% of SOT responded with Antispike Ab , with a lower response rate in kidney transplantation p <0.0007 RR 0.48 (0.32-0.71) and use of triple immunosuppressive maintenance regimen p <0.00009 RR 0.419 (0.26 -0.66). Patients previously infected with Covid-19 prior to vaccine (11.45% pts), had a higher response rate p <0.0001 RR 2.58 (1.90-3.51).No patients developed COVID-19 after vaccination. Conclusion(s): In our SOT population, a lower generation rate of anti-spike Ab was observed, compared to the reported in the general population. Renal Tx and the triple IS regimen were associated with a lower response rate. Covid-19 prior to vaccination was associated with a higher antibody response to the vaccine.
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Purpose: The COVID-19 pandemic portends significant morbidity and mortality in immunocompromised individuals. Vaccination against COVID-19 among immunocompromised population is an essential step to minimize deadly complications. Numerous studies have shown an association between immune status, disease severity, and suboptimal responsiveness to vaccination. Additionally, data suggests that elevated IgG levels correlated with host viral neutralization. We herein present data indicating that induction and maintenance immunosuppression therapy affects responsiveness to vaccination among kidney transplant recipients. Method(s): The study data was retrospectively analyzed for 48 kidney transplant patients who received mRNA type COVID-19 vaccine at our institution. Majority of patients received vaccination between January and March 2021;two doses in total. The 30 days post-vaccination SARS-CoV-2 spike antigen-specific IgG levels were measured to assess immunological response to vaccine. Result(s): The included patients underwent kidney transplantation between 1983 and 2020. Among these patients, 35% showed detectable peak COVID IgG serum levels 30 days after the 2nd vaccine dose. A total of 31 patients (65%) did not show any response;majority of these non-responders (62%) were heavily immunocompromised, either on high dose Mycophenolate (at least 720 mg twice daily) in addition to standard Calcineurin inhibitor/Sirolimus+/-Prednisone), or had received high dose Thymoglobulin (6 mg/kg or more) within a year of vaccination. Among immunocompetent patients, over 95% immunological responsiveness or viral neutralization after the second vaccination dose has been reported. Conclusion(s): Anti-thymocyte globulin as induction immunosuppression and antimetabolites like Mycophenolate as maintenance immunosuppression serve as the cornerstone of transplantation management. However, their utilization impacts B cell proliferation, thereby reducing antibody production and the effectiveness of the SARS-CoV-2 vaccine in transplant patients. The ability of these immunosuppressive medications to suppress responsiveness to the SARS CoV-2 vaccine supports the need for 1) regular immunological surveillance post-vaccination among transplant patients, and 2) the need for a third or possibly fourth booster dose to achieve a sustained and effective response.
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Purpose: Compared to azathioprine (AZA), mycophenolate (MPA) is implicated in an increased risk of several viral infections. Contrariwise, mTOR inhibitors (mTORi) are protective. Therefore, the study proposal is to evaluate the Covid-19 outcomes among kidney transplants (KT) patients under different maintenance immunosuppressive regimens. Method(s): We analyzed 90-day outcomes after Covid-19 infection using nationalwide Brazilian cohort data. RT-PCR positive patients tested between Mar/20 and Apr/21 (before immunization) were included. Patients using calcineurin-inhibitors (CNI)-free regimens were excluded. Result(s): 1,833 patients from 44 centers were analyzed, divided into three groups: CNI-AZA (n=389), CNI-MPA (n=1,258), and CNI-mTORi (n=186). Except for donor source, time after KT, and diabetes, demographics were similar among groups (Table1). The main outcomes are shown in Table 1. Considering CNI-AZA as the reference group, center-adjusted multivariable Cox regression showed that the CNIMPA group was associated with higher 30-day fatality (HR 1.65, 95% CI 1.17-2.33, p=0.004), effected also demonstrated in 90-day fatality (HR 1.43, 95%CI 1.06-1.93, p=0.020). CNI-mTORi was neutral for the 30-day fatality (HR 0.75, 95%CI 0.43- 1.29, p=0.296), but protective for the 90-day (HR 0.56, 95%CI 0.34-0.94, p=0.027). Conclusion(s): This data suggests that maintenance immunosuppressive drugs impact Covid-19 outcomes in kidney transplant patients. While MPA is associated with poor prognosis, mTORi seems to be protective. (Figure Presented).
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Purpose: To characterize demographics, treatment patterns, and outcomes among 3,998 transplant patients hospitalized for COVID-19 over 16 months of the pandemic (May '20-Aug '21). Method(s): Adult patients in a transplant cohort (TC) and non-transplant cohort (NTC) hospitalized with COVID-19 (ICD-10: U07.1) were compared in the Premier Healthcare Database from May '20-Aug '21. Baseline measures in first two days, demographics, comorbidity, COVID-19 treatments and immunosuppressants were analyzed. Outcomes included mortality (discharge status expired or hospice) and hospital and ICU LOS. Result(s): 3,998 TC patients were hospitalized for COVID-19 in 587 US hospitals. Compared to NTC, TC were younger (61 vs 64 yrs;p<.0001), less likely to be white (59% vs 67%;p<.0001), obese (24% vs 33%;p<.0001) or have COPD (17% vs 24%;p<.0001). TC had higher rates hypertension (84% vs 69%;p<.0001), renal disease (80% vs 22%, p<.0001), diabetes (48% vs 29%;p<.0001) and chronic heart failure (23% vs 18%;p<.0001). During hospitalization, a lower proportion of TC needed any oxygen therapy compared to NTC (p<.05). Compared to NTC, fewer TC received remdesivir (RDV) (44% vs 48%;p<.0001), but more received corticosteroids (87% vs 78%;p<.0001), anticoagulants (44% vs 29%;p<.0001) and convalescent plasma (18% vs 16%;p=0.007). In TC, 44% received MMF, 73% calcineurin inhibitors and 5% mTOR. Use of MMF did not change over time (43% May-Jul 2020;43% Aug- Dec 2020;45% 2021). TC had higher ICU admission rates (31% vs 28%;p.001), but similar hospital LOS and ICU LOS compared to NTC. All-cause mortality in NTC (15% overall;16% May-Jul 2020;16% Aug-Dec 2020;14% 2021) was not significantly different than TC over time (16% overall;13% May-Jul 2020;16% Aug-Dec 2020;16% 2021). Conclusion(s): Very few large studies have assessed COVID-19 management in transplant patients over time. All-cause mortality was comparable in both cohorts despite TC immunosuppression. RDV use was lower in TC. Uncertainty around MMF use in COVID-19 patients did not impact reported use of MMF. Further analyses are needed to evaluate confounding factors (medication sequence, time since transplant, disease severity) and impact of external factors such as earlier testing and treatment for COVID-19, vaccination, and new variants. (Table Presented).
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Purpose: We aimed to investigate the mortality from SARS-CoV-2 in kidney transplant recipients in the Bronx, New York since the beginning of the pandemic Methods: Between March 16, 2020 and November 5, 2021, 453 patients were diagnosed with SARS-CoV-2 infection. 316 were diagnosed by RT-PCR while the remaining 137 tested positive for anti-SARS-CoV-2 nucleocapsid IgG and did not have significant symptoms and had not been previously tested by RT-PCR Results: Of the 316 patients diagnosed by RT-PCR, 214 patients were hospitalized while 102 patients were managed at home as outpatient. 194 (61.3%) were male, median age 61 years old (IQR: 48-69), predominantly Hispanic (56.2%) and African American (29.5%). 75% received a deceased-donor renal transplant, 58% received anti-thymocyte induction. Most patients were on triple immunosuppression (95% on calcineurin inhibitors, 87% on anti-metabolite, and 97% on prednisone). Hypertension was the most common comorbidity followed by diabetes mellitus, heart disease and lung disease. A total of 65 patients (20.5%) died. The mortality rate was 37 % (47/128) in patients diagnosed between March 16 and April 30, 2020. From May 1, 2020 to end of December 2020 mortality rate has significantly decreased to 11% (7/61). Since the beginning of 2021 till November 5, 2021 the mortality rate is 7.7% (10/129). Twenty-seven patients were diagnosed with COVID-19 despite being partially of fully vaccinated (25 fully vaccinated, 2 after one dose of vaccine). 13/27 (48%) were managed at home while 14/27 (52%) were hospitalized and 2 (7%) of them died. Twenty-eight patients received treatment with casirivimab and imdevimab post diagnosis of SARS-CoV-2 starting 2021 and none of those patients have died. Conclusion(s): In summary, mortality from SARS-CoV-2 infection in kidney transplant recipients was higher earlier at the pandemic and has significantly decreased over time. This could be explained by initial exposure of the patients with higher viral load due to lack of personal protection and social distancing. However, since the judicious use of monoclonal antibodies and vaccination, in addition to social distancing protocols and use of facemask, the mortality in kidney transplant recipients has decreased over time.
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Purpose: Mortality from COVID-19 among kidney transplant recipients (KTR) is unacceptably high, and their response to up to three vaccinations against SARSCoV- 2 is strongly impaired. We provide the first systematic analysis of serological response to up to five repeated vaccinations in nonresponding KTR. Method(s): We retrospectively analyzed serological response to basic immunization, as well as administration of three, four and five doses of SARS-CoV-2 vaccine in KTR from December 27, 2020 until December 31, 2021. In particular, the influence of different dose adjustment regimens for mycophenolic acid (MPA) on serological response to fourth vaccination was analyzed. Result(s): In total, 4.277 vaccinations against SARS-CoV-2 in 1.478 patients were analyzed. Serological response was 19.5% after 1.203 basic immunizations, and increased to 29.4%, 55.6%, and 57.5% after 603 third, 250 fourth and 40 fifth vaccinations, resulting in a cumulative response rate of 88.7% (figure 1A-B). Patients with belatacept immunosuppression show impaired cumulative serological response (4.4%, 12.4%, and 16.4%) in comparison to patients with calcineurin inhibitor (CNI)- based immunosuppression (19.1%, 37.6%, and 70.1%) after basic immunization, three, and four vaccinations (figure 1C-F). In patients with CNI and MPA maintenance immunosuppression, pausing MPA and adding 5 mg prednisolone equivalent before the fourth vaccination increased serological response rate to 75% in comparison to no dose adjustment (52%) or dose reduction (46%) without occurence of rejections (figure 2). Conclusion(s): Repeated SARS-CoV-2 vaccination of up to five times effectively induces serological response in kidney transplant recipients. It can be enhanced by pausing MPA at the time of vaccination. Patients with belatacept immunosuppression are unlikely to achieve sufficient serological response and require different approaches.
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Purpose: Kidney transplant recipients (KTR) are at increased risk of mortality from COVID-19. We conducted a cohort study among KTR from the French Solid Organ Transplant COVID-19 (SOT COVID) registry to investigate the association between maintenance immunosuppressive drugs and 60-day mortality in KTR with COVID-19. Method(s): Data from all KTR with COVID-19 included in SOT COVID 02/28/2020 and 12/30/2020 were retrieved. Among them, 116 were excluded because of missing data on immunosuppressive therapy. We evaluated associations between immunosuppressive drugs and death <=60 days of 1st symptoms using logistic regression, with all baseline characteristics considered to influence outcome or immunosuppressive regimen. Benjamini-Hochberg correction was used for controlling false positive rate;40 multiple imputations were performed. Adjusted p-value <0.05 was considered statistically significant. Result(s): There were 1,451 KTR included. Median age was 58 years, 963 (66.4%) were men. Most frequent comorbidities were hypertension (n=1188, 81.9%), diabetes (501, 34.5%), cardiovascular disease (428, 29.5%). Median time since transplant was 71 months. Maintenance immunosuppression regimen included calcineurin inhibitors (1295, 89.2%), antimetabolites (1205, 83%), corticosteroids (1094, 75.4%), Mammalian Target of Rapamycin inhibitors (144, 9.9%) and belatacept (58, 4.0%). Among 1,451 KTR, 201 (13.9%) died <=60 days. Older age and baseline creatininemia were associated with mortality (OR: 1.09 [1.07-1.11];1.01 [1.005- 1.009], p<0.001). Corticosteroid-free regimens were associated with a significantly lower risk of death (OR: 0.48 [0.31;0.76], p=0.011). All other variables yielded non-significant adjusted p-values. Conclusion(s): Corticosteroid-free regimens were associated with a lower risk of death in KTR with COVID-19. While a short course of high-dose corticosteroids is beneficial in severely ill COVID-19 patients, prolonged maintenance corticosteroids expose to chronic immune disorders that may predispose KTR to severe forms of COVID-19.
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SESSION TITLE: Lung Transplantation: New Issues in 2022 SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/19/2022 11:15 am - 12:15 pm PURPOSE: Immunosuppressed patients are more susceptible to severe infection due to COVID-19. Management of lung transplant recipients is especially difficult due to constant exposure of the graft to the environment, leading to increased risk of rejection and requiring higher levels of maintenance immunosuppressive regimens. Mortality rates for lung transplant recipients with COVID-19 infection have ranged from 15% to 40% in published case series. We report our centers experience in managing lung transplant recipients with COVID-19 infections in a moderate-volume lung transplant center in Grand Rapids, Michigan. METHODS: This is a single center review of all lung transplant recipients with a COVID-19 diagnosis from March 2020 to December 2021. Recipients’ demographics and baseline characteristic, as well as their management, post infectious complications, and mortality data, were reviewed. RESULTS: In 2019, our center performed 48 lung transplants. During the study period, 42 of the 219 (19%) lung transplant recipients followed at our center had COVID-19 infections diagnosed by nasal or nasopharyngeal PCR testing. Twenty-four (57%) were male, mean age of 60.5 (range 25-77). Thirty-six (86%) patients had bilateral lung transplants. The diagnosis leading to their transplantation were COPD (N=18, 43%), idiopathic pulmonary fibrosis (N=12, 29%), cystic fibrosis (N=5, 12%), other pulmonary fibrosis (N=3, 7%), alpha-1 antitrypsin deficiency (N=2, 5%), Sarcoidosis (N=1, 2%), and ARDS (N=1, 2%). Almost all patients were on standard three drug immunosuppressive regimens which included a steroid, calcineurin inhibitor, and nucleotide-blocking agent, at the time of diagnosis. Mean time from transplant to diagnosis of COVID-19 was 34.6 months (range 1 to 104 months). Fifteen (36%) of the patients were unvaccinated. Once diagnosed, patients were advised to monitor their home spirometry and vitals at least daily. They were evaluated weekly via telemedicine by a physician or advanced practice provider. They received the following treatments: monoclonal antibody (N=31, 74%), increased steroids (N=5, 12%), remdesivir (N=2, 5%), Tocilizumab (N=1, 2%). Eleven (26.2%) patients required hospitalization, 4 (10%) required ICU admission and intubation. Mean length of stay was 7.5 days (median of 3 days). Three (7%) patients required oxygen at discharge. Of the 42 infected patients, 3 (7.1%) died on day 3, 16 and 326 days from the date of infection. CONCLUSIONS: Our center reports a lower mortality rate than previously published data in lung transplant recipients infected with COVID-19. We attribute this to availability of the vaccine, early detection and treatment, as well as close monitoring of the patients. CLINICAL IMPLICATIONS: Though COVID-19 infection can have devastating complications in lung transplant recipients, vaccinations and monoclonal antibody treatment reduce morbidity and mortality in this population. DISCLOSURES: No relevant relationships by Phillip Camp research relationship with United Therapeutics Please note: 2016- ongoing by Reda Girgis, value=Grant/Research research relationship with Pfizer Please note: 2014-2020 by Reda Girgis, value=Grant/Research Speaker/Speaker's Bureau relationship with Boehringher Ingelheim Please note: 2016-ongoing by Reda Girgis, value=Honoraria Speaker/Speaker's Bureau relationship with Genentech Please note: 2016-ongoing by Reda Girgis, value=Honoraria no disclosure on file for Ryan Hadley;No relevant relationships by Sheila Krishnan No relevant relationships by Edward Murphy No relevant relationships by Gayathri Sathiyamoorthy
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Introduction: Coronavirus Disease (COVID 19) is now considered a pandemic by the WHO. Not much studies have described the pattern and outcomes of kidney disease in COVID patients. Although diffuse alveolar damage and acute respiratory failure are the main features of COVID-19, the involvement of other organs need to be explored. Kidney disease could be a factor which could have a negative outcome in patients with COVID 19. Renal transplant recipients are a special population who can be affected by the CoViD pandemic due to the immunosuppressant drugs they are on. They are also at risk because of the other co-morbidities they have. Mortality in this population is found to be 20-30% according to a few studies. So this study is aimed at assessing the clinical profile of this population in a tertiary care centre in South Indian. Methods: A Prospective study and short term follow-up of all CoViD-19 afflicted post renal transplant patients admitted in a tertiary care hospital between May 2020 to July 2021 was done. Clinical characteristics, laboratory data and outcome data were obtained. Factors affecting death and graft dysfunction were studied. Data was presented as mean with standard deviation. Multivariate regression analysis was performed to identify independent risk factors that predicted graft dysfunction and death. Results: A total of 51 cases of CoViD-19 positive renal transplant patients got admitted. The mean age of this cohort was 40 years. Males represented a higher proportion (84.3%) than females. There was 38 LRRTR and 13 DDRTR. 10 patients had history of treatment for graft rejection recently. Most common co morbidity was Diabetes (17.6%);presenting symptoms at the time of COVID-19 included fever (96.1%), cough (90.2%), and breathlessness (72.5%). Clinical severity ranged from asymptomatic (3.9%), mild (23%), and moderate (3.9%) to severe (68.6%). Strategies to modify immunosuppressant’s included discontinuation of anti metabolites without changes in calcineurin inhibitors and steroids (45%). Overall patient mortality was 33.3% (17 of 51) and 100% (17 of 17) in patients requiring invasive ventilator support. Dyspnea and altered mental status at presentation, severe CoViD and need for RRT were risk factor for death. ISD regimen change, Remdesvir and oxygen therapy had significant effect on survival. Graft dysfunction was seen in 96.1% of patients. No significant risk factors were identified for graft dysfunction. Severity of CoViD-19 was found to be an independent risk factor for mortality as per multivariate analysis. Of the 34 patients who survived, 15 had persistent graft dysfunction after 4 weeks of follow-up. Conclusions: Altered metal status at presentation, severe CoViD pneumonia and need for RRT were risk factors for mortality. ISD regimen change, Remdesvir and oxygen therapy had significant effect on survival. Severity of CoViD-19 pneumonia was found to be an independent risk factor for mortality as per multivariate analysis. Graft dysfunction was seen in 96.1% of patients.Of the 34 patients who survived, after 4 weeks of follow-up, 15 had a higher SCr than their baseline value. No conflict of interest
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BACKGROUND AND AIMS: The COVID-19 vaccination programme has been monumental in the protection against SARS-CoV-2 infection. However, recent research has shown suboptimal responses in immunosuppressed patients, such as those with solid organ transplant receiving immunosuppressive (IS) treatment. Whilst initial studies have suggested patients have improved humoral response to booster vaccines, the data are still limited [1]. We have examined the differences in SARSCoV- 2 anti-spike antibodies in renal transplant patients between second and third doses of the vaccine and aimed to determine if those that had a poor response to the initial vaccine course developed adequate immunity following booster vaccination. METHOD: A cohort study of 63 renal transplant patients receiving immunosuppression was constructed from a single centre between December 2020 and December 2021. All patients received a full course of the UK government approved SARS-CoV-2 vaccine as well as a third booster dose. Enzyme-linked immunosorbent assays for SARS-CoV-2 anti-spike antibodies were carried out and titres of ≥0.8 U/mL were considered reactive. RESULTS: Of the 63 patients included, the median age was 55 years (IQR: 44-66). All patients received three doses of the SARS-CoV-2 vaccine and anti-spike antibodies were checked 32.2 ± 17 days following the third dose. Thirty-eight patients received two doses of Oxford-AstraZeneca followed by one dose of Pfizer-BioNTech. Twentyfive patients received three doses of Pfizer-BioNTech. 46.0% (n = 29) of patients had a detectable antibody response following two doses of the vaccine and 87.3% (n = 55) had a discernible response following the booster. The average titre value rose by 201% between the second and third doses. Eight patients had undetectable antibodies following the second dose and half (n = 4) developed evidence of humoral immunity following the booster. Whilst increasing age and shorter time from transplantation was associated with poor humoral response to both second and third doses, it did not reach statistical significance;P = 0.29, P = 0.059 respectively. Ten patients had previous COVID-19 infection: 2 remained seronegative following 3 vaccines, and both were within 12 months of transplantation. Those receiving calcineurin inhibitors (CNI) and antimetabolite treatment were associated with lower antibody titres compared with those receiving CNI alone (Table 1). CONCLUSION: We have shown that despite three doses of the vaccine, some highrisk renal transplant patients remain vulnerable to COVID-19 and fail to develop an adequate humoral response to the vaccine. Time from transplantation and IS medications have a significant effect on SARS-CoV-2 anti-spike antibody production. Whilst some studies have suggested those with solid organ transplants mount a lower immune response to mRNA based vaccines [2], our cohort did not demonstrate this difference. Going forward there are still a number of unanswered questions about the significance and effectiveness of COVID antibodies, as well as the long-term protection they offer [3]. Developing ways in which we can protect those with poor humoral response despite repeated vaccination is vital. (Table Presented).
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BACKGROUND AND AIMS: COVID-19 infection in solid organ transplant recipients (SOT) is associated with increased morbidity and mortality due to comorbidities and immunosuppression state (Chaudhry ZS et al, 2020). Although vaccines represent the greatest hope to control COVID-19 pandemic, several studies showed the low immunogenicity of a two-dose mRNA COVID-19 vaccine regimen in SOT as compared with general population (Boyarsky BJ et al, 2021). Based on this evidence, on September 2021, the Italian Medicine Agency (AIFA) authorized a third vaccine administration as additional primary dose to immunocompromised patients. The aim of this study is to evaluate the seroconversion rate after the third dose of BNT162b2 (Pfizer-BioNTech) SARS-CoV-2 mRNA vaccine in kidney transplant recipients (KTRs) and to investigate the baseline factors associated with the absence of the antibody response. METHOD: we performed a prospective and observational study on a monocentric cohort of 329 consecutive Caucasian KTRs given three doses of the BNT162b2 COVID-19 vaccine. Key exclusion criteria were a previous history of COVID-19 infection and transplantation or having underwent chemotherapy treatment within the last year. Antibody response against the spike protein was tested on blood sample collected before the administration of vaccine (T0), at 15 and 90 days after the second dose (T2 and T3, respectively) and one month after the third dose (T5). The level of antibodies was assessed using the Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay (positive cut-off ≥ 0.8 U/mL). A total of 22 patients were excluded from the analysis because categorized as SARS-CoV-2-pre-immunized according to the antibodies' baseline status (T0) above the positivity cut-off. The Local Ethics Committees approved the study protocol and written informed consent was obtained before enrolment. RESULTS: The study population of 307 KTRs was 57.10 ± 13.10 years, with a predominance of male sex (64.2%). Median time from transplantation to vaccine was 10 [IQR 5-17] years. Blood analysis at baseline revealed mean eGFR assessed by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to be 56.95 ± 23.04 mL/min/1.73 m2. The standard immunosuppressive regimen consisted of glucocorticoids in all patients, calcineurin inhibitors (88.6% of patients), antimetabolites (73.3% of patients) and mTOR inhibitors (in 15.6% of patients). The first two doses were administered 21 days apart, and the third dose was administrated 172 ± 4 days after the second dose. In our cohort, 43.3% patients (133/307) responded to the vaccine at T2. The proportion of responders increased to 68.4% (186/272) at T3 (median antibody level: 5.2 [0.40-74.07]). One month after the third dose, a positive antibody titer was detected in 251 of 307 patients (81.8%) (median antibody titre: 1137.50 [9.32- 4189.75]). The response curve starting at T2 and increasing at T3 makes apparent that there is a distinctive kinetic of humoral response in immunocompromised patients compared to immunocompetent individuals (Walsh EE et al., 2020). A multivariate analysis showed that the negative response to the third primary dose was associated with antimetabolite immunosuppressants (P = .001), lower estimated glomerular filtration rate (P < .001) and female sex (P = .04) (Figure 1). No serious adverse events were reported. Neither De novo DSAs nor change in proteinuria were reported after vaccination. The limitation of this study is the absence of assays for cellular immune response. CONCLUSION: Although the exact threshold of antibody titer for protection against SARS-CoV-2 infection remains unclear, the ability of the additional mRNA COVID- 19 vaccine dose to increase both immune response (Figure 2A) and the prevalence of seroconversion rate (Figure 2B) associated with the acceptable safety profile supports its use after an initial 2-dose mRNA COVID-19 primary vaccine series in immunocompromised patients. (Table Presented).
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INTRODUCTION: In kidney transplant recipients, belatacept is usually pursued indefinitely after it has been started. In the setting of the belatacept shortage and after having evaluated the benefit-risk ratio, we established a strategy consisting of time-limited belatacept therapy/transient calcineurin inhibitor withdrawal, whose results are analyzed in that study. METHODS: We considered all the kidney transplant recipients that had been switched from conventional immunosuppressive therapy to belatacept and then for whom belatacept has been withdrawn intentionally. Furthermore, in the first 8 patients, we assessed changes in peripheral blood mononuclear cells (PBMC) transcriptome using RNAseq before and 3 months after belatacept withdrawal. RESULTS: Over the study period, 28 out of 94 patients had belatacept intentionally withdrawn including 25 (89%) switched to low-dose CNI. One rejection due to poor compliance occurred. The eGFR after 12 months remained stable from 48 ± 19 mL.1.73 m-2 to 46 ± 17 mL.1.73 m-2 (p = 0.68). However, patients that resumed belatacept/withdrew CNIs (n = 10) had a trend towards a better eGFR comparing with the others (n = 15): 54 ± 20 mL.1.73 m-2 vs. eGFR 43 ± 16 mL.1.73 m-2, respectively (p = 0.15). The only factor associated with belatacept resumption was when the withdrawal took place during the COVID-19 outbreak. Transcriptome analysis of PBMCs, did not support rebound in alloimmune response. CONCLUSIONS: These findings underpin the use of belatacept as part of a time-limited therapy, in selected kidney transplant recipients, possibly as an approach to allow efficient vaccination against SARS-CoV-2.
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Background: Both mRNA-based Covid-19 vaccines, BNT162b2 (BioNTech/Pfzer) and mRNA-1273 (Moderna), efectively decrease the risk for severe Covid-19 disease in the general population. However, vaccination success is less likely in immunocompromised individuals. Methods: To assess the rate of humoral response to a full (two-fold) primary mRNA vaccination, defned by manufacturer cut-of > = 7.1 BAU/ml (SARS-CoV-2 IgG II Quant assay, Abbott), and identify clinical and laboratory parameters associated with failed humoral response in recipients of an allogeneic hemat-opoietic stem cell transplant (HSCT), 167 HSCT recipients were evaluated in this single-center retrospective study. Variables studied included time since HSCT to vaccination, time between vaccination to titer measurement, age of recipient and donor, ongoing anti-tumor therapy, individual immunosuppressives, type of GHVD-prophylaxis, sex, donor/recipient relationship, and vaccine type, and the immunologic parameters (assessed closely to vaccination), CD4, CD8, CD19, and NK blood-cell counts, immunoglobulin levels (IgA, IgG, and IgM), both by univariate and multivariate analyses. Results: Tirty-seven HSCT recipients (22 %) developed no detectable antibody-response. Median time from HSCT to vaccination was 10.2 months (range, 2.5-88.9) in non-responders, while it was 35.3 months (3.0-215.1) in responders (p < 0.001). By multivariable analysis, a higher CD19 (B cell) count was associated with humoral vaccination response adjusted odds ratio (aOR) 3.3 per 100 B-cells/mcl (CI 95 % [1.78-6.20], p < 0.001). Concurrent immunosuppression with mycophenolate mofetil (MMF) plus/minus a calcineurin inhibitor decreased the probability of response (aOR 0.04, CI 95 % [0.01-0.24], p < 0.001). Conclusions: Our fndings may contribute to a more profound understanding of risk factors for failure of mRNA-based SARS-CoV-2 vaccination in HSCT recipients.
ABSTRACT
There is minimal information on coronavirus disease 2019 (COVID-19) in developing countries regarding renal transplant recipients (RTRs). This paper aimed to study the clinical profile, immunosuppressive regimen, treatment, and outcomes in an RTR with COVID-19. This retrospective study was conducted in the nephrology department of Sri Aurobindo Medical College & Postgraduate Institute, Indore (MP), India, from April 1, 2020 to December 15, 2020. We studied 15 patients, of which 13 were treated at our hospital and two were treated in OPD. The median age of transplant recipients was 45 (Interquartile range [IQR]: 26–62) years, the majority being males, and recipients presented at a median of 4 (IQR: 0.3–11) years after transplant. The most common comorbidities included hypertension in 14 (94%) and diabetes 3 (20%) patients. The presenting symptoms at presentation were cough (80%), headache (52%), fever (46%), and breathlessness (26%). Clinical severity as per computerized tomography (CT) severity score ranged from mild (20%), moderate (53%), and severe (27%). Strategies to modify immunosuppressants included discontinuation of antimetabolites without changes in calcineurin inhibitors and steroids (100%). Antiviral therapy (Favipiravir and Remdesivir) was associated with better outcomes and reduced hospital stay. Risk factors for mortality included ABO-incompatibility, severity of disease, high Coronavirus Disease 2019 (COVID-19) Reporting and Data System (CO-RADS) score, allograft dysfunction before COVID-19 infection, acute kidney injury, elevated inflammatory markers, and intensive care unit/ventilator requirement. Overall patient mortality was 13.2%. Risk factor for mortality in COVID-19 positive with RTR appears to be ABO-incompatible transplant, having a previous history of rejection, and patient requiring ventilatory support.
ABSTRACT
Background. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased morbidity and mortality in immunocompromised individuals, including solid organ transplant recipients (SOTR). Despite being excluded from phase 1-3 SARS-CoV-2 vaccine clinical trials, SOTR were identified as high-risk populations and prioritized for vaccination in public health guidelines. We aimed to evaluate the antibody response to two doses of the BNT162b2 (Pfizer-BioNTech) vaccine in SOTR as compared to healthy controls (HC). Methods. SOTR and HC scheduled to receive two doses of BNT162b2 vaccine and able to complete required follow-up visits were enrolled. Blood specimens were collected from participants before receiving the first and second doses and 21-42 days after the second dose. Enzyme-linked immunosorbent assay (ELISA) was used to detect immunoglobulin G (IgG) to the SARS-CoV-2 spike receptor-binding domain (RBD). Generalized estimating equations with a working independence correlation structure were used to compare anti-RBD IgG levels between SOTR and HC at each study visit and within each group over time. All models were adjusted for age, sex, and pre-vaccination seroreactivity in the ELISA. Results. A total of 54 SOTR and 26 HC were enrolled, with mean (SD) ages of 72 (3.6) and 62 (6.7) years, 61% and 35% were male, and 91% and 88% were white, respectively. The most common organ transplant types were kidney (41%) and liver (37%). All SOTR were receiving calcineurin inhibitors. The median time post-transplantation was 7 years. SOTR had markedly lower mean anti-RBD IgG levels when compared to HC with adjusted mean differences of -0.76 (95%CI: [-1.04, -0.47];p < 0.001) ELISA units (EU) and -1.35 (95%CI [-1.68, -1.01];p < 0.001) EU after the first and second doses, respectively (Figure 1). Both groups had a significant increase in anti-SARS-CoV-2 IgG levels after the second dose. However, the magnitude was lower in SOTR, 0.49 (95%CI [0.31, 0.69];p < 0.001) EU than in HCs, 1.08 (95% CI [0.91, 1.24];p < 0.001) EU. Figure 1. Anti-SARS-CoV-2 RBD IgG levels in solid organ transplant recipients and healthy controls before receiving the BNT162b2 vaccine (baseline), post-vaccine dose 1, and post-vaccine dose 2. Conclusion. Our study showed SOTR mounted weaker humoral immune responses than HC to SARS-CoV-2 vaccines. Given a lower response, SOTR should continue to practice social distancing and masking until data on vaccine efficacy are available in this vulnerable population.
ABSTRACT
Introduction: Randomized trials demonstrated ~95% efficacy of SARS-CoV-2 spike messenger RNA (mRNA) vaccines. Patients (pts) after allogeneic hematopoietic cell transplant (HCT) have a variable period of immune deficiency and the impact of diagnosis, treatment regimens, GvHD, and immunosuppression on vaccine (vacc) immunogenicity is unknown. Methods: We performed a retrospective analysis of 149 consecutive pts (Table) who received a SARS-CoV-2 vacc between 12/17/2020, and 5/21/21, and were tested for anti-SARS-CoV-2 S1/S2 antibodies. Serology testing was performed with the Liaison® SARS-CoV-2 S1/S2 IgG assay (DiaSorin) with ≥15 AU/mL defined as a positive result. Pts with prior COVID-19 infection were excluded. Pts received mRNA-1273/Moderna (n= 46), BNT162b2/Pfizer-BioNTech (n= 100) or Jannsen vacc (n= 3). Reactogenicity was not investigated. Demographic and treatment variables were tested for prediction of vaccine response using Chi-square test or Fisher's exact test for categorical variables and two-sample t test for continuous variables. Univariate and multivariable logistic regression analyses with backward selection using Akaike information criterion (AIC) were used to examine interdependence of those variables and odds ratios (OR) with 95% confidence intervals (CI). Results: Pts underwent HCT from a related HLA matched sibling (n=36), related haploidentical (n= 23), or matched/mismatched unrelated donor (n= 89). 93% received fludarabine in the HCT conditioning regimen (data not shown). All pts received a calcineurin inhibitor (CNI) and 76 pts received ATG for GvHD prophylaxis. All pts achieved at least mixed donor lymphoid engraftment (data not shown). Median time from HCT to 1st vaccination was 26 months (range, 3-258 months). Median age at time of vaccination was 61 years (range, 24-78) and 75 (50%) were female. Serology was tested at a median of 37 days (range, 6-119 days) after the second vacc dose. Serology was tested <14 days in 3 pts;all were seropositive. No pt developed COVID-19 during the period of observation. 101 pts (67%) tested positive for anti-SARS-CoV-2 S1/S2 antibodies (vacc responders). Of the responders, the median time from HCT to 1st vacc was 45.5 months (range, 3-258, SD 39.78). Among the 23 pts between 3-9 months after HCT, 26% (n=6) had a positive antibody response, but all were receiving ongoing immunosuppression at time of vaccination. 29% (n=29) vacc responders were receiving prednisone (pred) in the management of cGvHD at the time of vaccination. 48 pts did not mount an antibody response (vacc non-responders). Of the non-responders, 30 pts were receiving cGvHD treatment at the time of vacc, 31 pts were taking pred, and 20 pts were taking CNIs. In univariate analysis, we found a history of prolonged use of pred (>8 weeks) and/or CNIs, on current treatment for cGvHD at time of vacc, and receipt of rituximab in the preceding 12 months predicted for lack of response (Table). Active use of pred and treatment with pred >8 weeks in the preceding 12 months prior to vacc predicted vacc non-response [OR 0.221;95% CI (0.106 - 0.456);p<0.001] and [OR 0.408;95% CI (0.197 - 0.844);p=0.016] in univariate analysis, respectively, however, active use of pred was predictive [OR 0.07;95% CI (0.016-0.304;p<0.001] while pred treatment >8 weeks was not [OR 2.00;95% CI (0.55-7.298;p=0.293] in multivariable analysis. Other significant predictors for non-response in the multivariable analysis include pt use of ruxolitinib [OR, 0.233, 95% CI, (0.067-0.808);p=0.022], and rituximab within 1 year [OR, 0.026, 95% CI, (0.007-0.099);p<0.001]. Discussion: In this study, we found that 67% allogeneic HCT pts developed anti-SARS-CoV-2 S1/S2 antibodies after SARS-CoV-2 vaccination. Predictors of non-response after adjustment for potential confounders, were factors that are expected to suppress immune response including active use of immunosuppressive medications. Consistent with prior studies, anti-CD20 therapy likely impairs humoral response to vaccination. Ruxolitinib also appears to impair response. owever, a proportion of pts being actively treated for cGvHD responded to vaccination and these pts should still be encouraged to receive vaccination in consideration of the COVID-19 mortality risk. Many questions remain including the protective benefit of immune response, the duration of response, and the potential value of booster vaccinations in non-responders. [Formula presented] Disclosures: Rowley: ReAlta Life Sciences: Consultancy.