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An outburst of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a grave threat to global health and the economy. As of May 13, 2020, a total of 42,81,838 cases have been confirmed, with over 2,92,376 deaths worldwide. In India, 75,048 cases have been reported to date with 2,440 deaths. Management of this new coronavirus (COVID19) has mainly focused on infection prevention, case detection, monitoring, and supportive care. As there is no vaccine or specific antiviral treatment for human SARS-CoV-2, therefore identifying the drug treatment options as soon as possible is critical for the response to the COVID19 outbreak. Pro-inflammatory cascade and cytokine storm play a key role in the pathogenesis of new coronavirus. A large number of therapeutic interventions such as antiviral, antimalarial, convalescent plasma therapy, BCG vaccine, mTOR inhibi-tors, Tissue Plasminogen Activator, Human monoclonal antibodies, Anti-parasitic agents, Immunoen-hancers, Nutritional interventions, JAK-STAT signaling inhibitors, ACE2 receptor modulators, and An-giotensin II receptor blockers have been either tried or suggested for effective treatment of patients with SARS-CoV-2 disease. Hence, we recommend that all the above potential interventions must be imple-mented in terms of their safety and efficacy through proper clinical experiments to control the emerging SARS-CoV-2 disease.Copyright © 2021 Bentham Science Publishers.
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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: Mycophenolate mofetil (MMF) use is associated with decreased antibody response to the SARS-CoV-2 mRNA vaccine series in heart and lung transplant recipients (HLTRs). Higher MMF doses have been associated with poor immunogenicity in kidney transplant recipients, but limited data exist on HLTRs. We evaluated the relationship between daily MMF dose and vaccine-induced antibody response in HLTRs. Method(s): HLTRs (n= 212) from an observational cohort were categorized by daily MMF doses (None, Low: <1000mg, Moderate: 1000-2000mg, High: >=2000mg). Semi-quantitative antibody testing was performed at 1, 3, and 6-months post-dose 2 (D2) using the Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay (EIA), testing for antibodies to SARSCoV2 spike protein receptor binding domain, and the EUROIMMUN EIA, testing for S1 domain of SARS-CoV-2 spike protein. Multivariable Poisson regression was used to estimate the risk of a negative antibody response with increasing MMF dose. Result(s): At the time of vaccination, 94 (44.3%) HLTRs reported receiving no MMF, 33 (15.6%) reported a low dose, 54 (25.7%) reported a moderate dose, and 31 (14.8%) reported a high dose regimen. There were statistically significant differences in the number of participants on mTOR inhibitors and Triple immunosuppression among the groups but the participants in all 4 dose categories were otherwise comparable (Table 1) The risk ratio of a negative post-D2 titer with low, moderate and high dose regimens compared to no MMF was 0.65 1.15 2.05 (p=0.63), 1.34 2.043.10 (p=0.001) and 1.83 2.77 4.21 (p<0.001) after adjusting for age, sex, vaccine type, time since transplant, and corticosteroid use. Conclusion(s): HLTRs taking MMF >1000mg/day are at higher risk of remaining seronegative after mRNA vaccination, with evidence of a dose-nonresponse effect. The findings support the exploration of whether targeted MMF reduction strategies in HLTRs increase SARS-CoV-2 vaccine immunogenicity. (Table Presented).
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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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Purpose: The diverse factors affecting the vaccine induced neutralizing antibody response in solid organ transplant recipients and their immunity against CoV2 variants are needed to be well characterize to understand how we improve the vaccine efficacy. Method(s): Anti-CoV2 receptor binding domain (RBD) plasma antibody response and their neutralization potency in 29 kidney and 22 heart transplant patients was determined with recombinant RBD protein binding ELISA and by calculating the 50% virus neutralization titer of the plasma antibody with ACE2-Hu-HeLa cell based pseudo virus neutralization assay against CoV2 wild type and delta variant. Result(s): We detected strong binding and protective neutralizing plasma antibody response in SOTR who were infected with CoV-2 either prior to or after the first dose of vaccine (n=8), who showed high median IC50 value > 10,000 against both the CoV2 wild type strain and the more transmissible delta variant. In contrast to this, the CoV2 uninfected and vaccinated SOTR ( naive vaccinees, n=43) had considerably lower anti-RBD plasma antibody binding titers, and only 19% of this population possessed minimally protective neutralizing antibody titer (IC50 >50) against the wild type CoV2 strain, which further decreased to 10% against the delta variant. While IgG and IgA were dominant isotypes of anti-RBD antibody induced by the CoV2 vaccines and correlated significantly (r=0.84, p=<0.001) with the CoV2 neutralization. The COV2 uninfected SOTR vaccinees who were within 1.5 years from transplantation or African American ethnicity were less likely to have detectable vaccine induced neutralizing antibody responses than the other populations. In the naive vaccinees, administration of corticosteroids in combination with calcineurin or mTOR inhibitors and antimetabolites also negatively affected the CoV2 antibody responses, while female and younger organ transplant recipients tended towards higher IgM and IgA titers. Kidney transplant recipients showed better IgG responses vs heart transplant recipients and elevated serum creatinine levels correlated with poorer antibody response to the vaccines in both kidney and heart transplant groups. Conclusion(s): These results suggest that in the absence of immunity due to CoV2 infection, vaccination in SOTRs induces much lower protective antibody levels than in healthy controls and identifies African-American ethnicity, less than 1.5 years post transplantation as additional risk factors that further exacerbate these effects. Poor kidney function negatively affected the vaccine induced antibody response.
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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: Nivolumab is a PD-1 checkpoint inhibitor that restores the pre-existing antitumor immune response by selectively blocking the interaction between PD-1 receptors on T-cells and PD-1 ligands, PD-L1 and PD-L2, on tumor cells and antigen presenting cells. Nivolumab prolongs survival in patients with metastatic kidney cancer with a good safety profile as demonstrated in the CheckMate 025 clinical trial. Material And Methods: This retrospective data involved prospectively monitored patients (named patient programm) treated with second-line nivolumab for mRCC at the University Hospital Centre Zagreb from 2016 to 2018 and the treatment continued to be funded by the Croatian Health Insurance. Patients with metastatic kidney cancer (mRCC) received tyrosine kinase inhibitors (TKI), (29/30), one patient received mTOR inhibitor as first line therapy, and subsequently they initially received nivolumab 3 mg kg NPP every 2 weeks. Later we applied a monthly dose 480 mg. Nivolumab treatment was continued in patients who did not have disease progression or grade 3 and 4 toxicity. Patients were monitored every three momths with CT of the chest, abdomen and pelvis and laboratory tests (hemathology, biochemistry, T4, TSH). We also respected patients' preference in regard to cycle dynamic by stopping nivolumab therapy or introducing SBRT during nivolumab therapy. Results: We treated a total of 30 patients (22 men and 8 women) with mRCC, who initially received TKI or mTOR therapy with median age 60.2 ± 9.79 years at diagnosis of kidney cancer. Most patients belonged to intermediate-risk groups. Majority of patients (23/30) were treated with sunitinib as the first line treatment after nephrectomy. Six patients had CR (20%) but two of them died in 2021, one of COVID- 19 and one of haed and neck cancer. Currently, 6 (20%) are alive, ECOG=0, 4 (13.3%) have CR without therapy, expressed in months-23, 33, 35 and 53 (treatment-free survival). Median OS first line with TKI therapy was 34 months while median OS second line with nivolumab was 17 months. Patients with sarcomatoid component in pathohistology report have longer survival. Patients with bone metastases have shorter survival to patients with other metastases. Conclusion: Nivolumab demonstrated clinical efficacy in the CheckMate 025 clinical trial and in clinical practice as second line treatment after patients had previously received TKI. Our results show that six years after first cycle of nivolumab as second line therapy 6 out of 30 patient (20%) are alive, ECOG=0. Further research should show which sequence therapy would be the best for each patient. Research about potential immunotherapy biomarkers which would indicate who responds to the therapy and who does not is ongoing.
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Background. Studies of solid organ transplant recipients (SOTr) hospitalized for Covid-19 have focused on short-term outcomes with approximately 30 days of follow-up time. Intermediate-term mortality and associated risk factors for intermediate-term death have not previously been reported. Methods. Using data from a multi-center registry, we assessed mortality by 90 days among SOTr hospitalized for Covid-19 between 3/1/2020 and 12/31/2020. Multivariable Cox-proportional hazard models were used to compare risk factors for mortality by 28 and 90 days. Covariates were selected a priori based on known predictors of death in SOTr hospitalized for Covid-19. All patients were followed for 90 days or were censored at the time of death or last clinical contact, if this occurred prior to day 90 after diagnosis. Results. Among SOTr hospitalized for Covid-19, 198/979 (20%) died within 90 days of diagnosis and 37/198 (19%) of deaths occurred between days 29 and 90. Risk factors for mortality by day 90 days included age >65 years (1.8, 95% CI 1.3-2.4, P< 0.001), lung transplant (compared to non-lung) (1.6, 95% CI 1.1-2.4, P=0.02), chronic lung disease (2.2, 95% CI 1.5-3.4, P=0.002) and heart failure (1.9, 95% CI 1.2-2.9), which were similar to risk factors reported for 28-day mortality (Table 1). Diagnosis during the second half of 2020 (6/20-12/31/20) was associated with lower mortality by 28 days (aHR 0.7, 95% CI 0.5-1.0, P=0.03) compared to diagnosis during the early half of 2020 (3/1-6/19/20);however, mortality by 90 days was similar in the late and early time periods (aHR 0.9, 95% CI 0.7-1.2, P=0.54). Obesity and mTOR inhibitor use were also associated with death by 28 but not 90 days. Kaplan-Meier survival curves by time period of diagnosis are shown in Figure 1. Vertical tick marks represent censored cases. Early 2020 refers to cases diagnosed between March 1 and June 19, 2020 and late 2020 refers to cases diagnosed between June 20 and December 31, 2020. Conclusion. Approximately 20% of deaths among SOTr hospitalized for Covid-19 occurred between days 29 and 90. Future investigations are required to discern the mechanism(s) for the improvement in early, but not late, mortality among SOTr with Covid-19 during the course of the pandemic.
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Background Liver transplant (LT) recipients frequently show no or low response after two SARS-CoV-2 vaccinations. However, the relevance of different clinical risk factors (RF) for a suboptimal response is still unanswered. Methods Anti-SARS-CoV-2 antibody titers of 141 LT patients determined after the second vaccination assigned them to low ( < 100 BAU/ml) or high response. The relevance of previously identified clinical RF for low response (diabetes, chronic kidney injury, hypertension or age > 65y) and antiproliferative immunosuppression were now analyzed in detail. Results The full clinical data set was available in 101 patients (55 low, 46 high responders). In total, 82 % of low and 52 % of high responders had one or more clinical RF. The risk of low response for patients having at least one, two or three clinical RF increased from 31 % (N = 10 of 32) to 65 % (N = 45 of 69), 86 % (N = 32 of 37) and 93 % (N = 13 of 14), respectively. If all four RF were present, the risk of low response increased to 100 % (N = 6 of 6). Also, a more frequent use of MMF or mTOR-inhibitors was detected in low responders (74 %) compared to high responders (37 %). Of the 26 % (N = 12) of low responders not receiving antiproliferative immunosuppression the majority had one (25 %) or more (50 %) clinical RF. Conclusion If clinical RF are present, the risk of low SARS-CoV-2 vaccination response increases 1.6-fold and with the number of RF. These data can help to identify patients under immunosuppression with the highest risk of suboptimal response to further SARS-CoV-2 vaccinations.