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1.
Hematology, Transfusion and Cell Therapy ; 44:S362-S363, 2022.
Article in English | EMBASE | ID: covidwho-2179140

ABSTRACT

Introducao: Linfohistiocitose Hemofagocitica (LHH) e uma sindrome de ativacao do sistema imune que ocorre como desordem familiar ou condicao esporadica em associacao com uma variedade de "gatilhos". Caracteriza-se por condicao hiperinflamatoria, potencialmente fatal, causada por resposta imune altamente estimulada, mas ineficaz. Linfohistiocitose Hemofagocitica Familiar (LHF), e doenca genetica autossomica recessiva, afeta principalmente lactentes. Rapidamente fatal, mediana de sobrevida menor que dois meses apos diagnostico, se nao tratada. Pacientes que iniciam o quadro no periodo neonatal, associado a colestase e frequentemente fatal. Relato do caso: Fem, 4 dias vida, br, pais jovens nao consanguineos. Tranferida ao HMIMJ para avaliacao da Hepatologia - quadro de Colestase Neonatal com rapida evolucao. Na UTI: Corada, icterica +4/+4, hepato-esplenomegalia. Ex lab - 5 dias vida - Hb 14,4 Leuco 2.710 neutro 760 Plaq 26.000 cr 0.3 ur 34 BT 43 BD 37 BI 6 Fibrinog 106 TG 245 Colest 184 BT 43.4 BD 37.22 BI 6.25 TGO 261 TGP128 GGT 557 FA 122 DHL568 Ferritina 4.379. COVID-19 e sorologias neg. Mielograma - raros histiocitos hemofagociticos. HD - LHF em rapida evolucao, solicitado exoma. Plaq cada 12h e Ig EV - 1 g/kg em 10h - 2 dias. Dexametasona 10 mg/m2/dia - 14 dias, e apos 5 mg/m2/dia - mantida, aguardando o medicamento Emapalumabe (anticorpo anti IFN-gamma humano administrado com dexametasona). Melhora por 2 sem, piora com hipertrigliceridemia, Ferritina 54.039, hipofibrinogenemia e graves citopenias/20 dias vida - dexametasona 5 mg/m2/dia e iniciado Emapalumabe 1 mg/kg/dose - 2 x /sem, com aumento progressivo 3, 6 e 10 mg/m2/dia. A partir do 5degree dia Emapalumabe - melhora progressiva clinico-laboratorial/27 dias vida - Hb 9.5 Leuco 4.720 neutro 1650 Plaq 110.000 Coagulogr NL fibrinog 190 ur 36.6 cr 0.2 PT 6.2 Alb 3.7 BT 6.32 BD 4.56 BI 1.76 TGO 402 TGP 649 GGT 1.136 FA 284/39 dias vida - recebeu 7dose de Emapalumabe - Hb 8.2 Leuco 10.700 neutro 5.500 Plaq 111.000 Coagulogr NL Fibrinogenio 219 u 37.6 cr 0.2 PT 5.9 alb 3.3 BT 3.31 BD 2.18 BI 1.13 TGO 301 TGP 463 GGT 1.227 FA 301/42 dias vida - Hb 8.6 Leuco 9.340 neutro 4.550 Plaq 96.000 BD 1.69 BI 1.15 DHL 612 TGO 448 TGP 599 GGT 1.172 FA 370 fibrinog 201. Recebeu 9 doses de Emapalumabe. 16.03.21 - Exoma - Linfohistiocitose Hemofagocitica Familiar Tipo 3 (FHL3). Transferida ao ITACI - finalizou a medicacao e realizou TCTH. Boa evolucao ate 2 meses pos TMO, quando desenvolveu Doenca Veno-Oclusiva (VOD), evoluiu para obito. Discussao: Falencia hepatica aguda e rara em neonatos e evolui com elevadas taxas de mortalidade. A etiologia dessa condicao difere daquelas ocorrendo em criancas maiores. Diagnosticos diferenciais sao hemocromatose, LHF, infeccoes virais e alguns defeitos metabolicos. Existem alguns relatos de neonatos com LHF apresentando-se com hidropsia fetal e falencia hepatica fulminante. Conclusao: LHF e uma doenca rara cujas manifestacoes ocorrem principalmente nos dois primeiros anos de vida. A apresentacao neonatal e incomum. Na literatura, poucos casos sao relatados nas primeiras semanas de vida e com rapida evolucao para falencia hepatica aguda. A evolucao desses casos e frequentemente para obito. Entretanto, estabelecer o diagnostico tem importantes implicacoes para o aconselhamento genetico. Copyright © 2022

2.
Journal of Clinical and Diagnostic Research ; 16(8):DC53-DC57, 2022.
Article in English | EMBASE | ID: covidwho-2067196

ABSTRACT

Introduction: In the search of effective medicines against Coronavirus Disease-2019 (COVID-19) besides the conventional mode of treatment many medicines belonging to alternative therapeutics claimed to be effective in this disease. In homeopathy-a branch of alternative medicine some medicines are claimed to be effective in COVID-19 after human trials. Aim: To study whether ultradiluted preparation of Phosphorus 6CH (centesimal (C) dilutions, using Hanhemann's (H) dilution method) can protect damaging action of Delta Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) spike protein Receptor Binding Domain (RBD) in Gallus gallus embryo in relation to their gross appearances, histopathological changes and cytokine changes. Materials and Methods: An in-vivo fertilized chick embryo model experimental analysis was carried out at the Genetic Research Laboratory of Heritage Institute of Technology, Kolkata, West Bengal, India. The whole experimental study was done in a time period of November 2021 to January 2022 and the data collected were analysed using statistical software Minitab. About 14 days old Gallus gallus embryonated eggs were inoculated with the antigen along with the vehicle alcohol controls. The Phosphorus 6CH was used to see whether it can prevent or cure the damaging action of the spike protein in the embryo in different experimental sets. results: The notable finding in this experiment is the remarkable elevated expression of Interleukin (IL)-10 gene in the curative, preventive sets as well as in the medicine control sets in comparison to antigen and alcohol control sets. In case of Transforming Growth Factor, (TGF) β1 there was enhanced expression of TGF β1 gene in the alcohol 6C set and antigen set which gets ameliorated with Phosphorus 6CH. The morbid anatomy of the embryo and the histopathological picture of the liver of the embryo also reflected similar findings in these two experimental sets. After statistical analysis it was found that there was significant correlation in between Interferon (IF) γ and IL-10 in these experimental results which appears very important. conclusion: The homeopathic medicine phosphorus 6CH is capable of maintaining cytokine balance in Delta SARS-CoV-2 spike protein RBD induced pathogenecity in Gallus gallus embryo.

3.
RMD Open ; 8(2) (no pagination), 2022.
Article in English | EMBASE | ID: covidwho-2064276

ABSTRACT

Objectives Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are overlapping autoinflammatory diseases affecting people over 50 years. The diseases are treated with immunosuppressive drugs such as prednisolone, methotrexate, leflunomide and tocilizumab. In this study, we assessed the immunogenicity and safety of SARS-CoV-2 vaccinations in these diseases (based on humoral and cellular immunity). Methods Patients (n=45 GCA, n=33 PMR) visited the outpatient clinic twice: pre-vaccination and 4 weeks after the second dose (BNT162b2 or ChAdOx1 vaccine). Patients with previous SARS-CoV-2 infection were excluded. In both pre-vaccination and post-vaccination samples, anti-Spike antibody concentrations were assessed and compared with age-, sex-and vaccine-matched control groups (n=98). In addition, the frequency of SARS-CoV-2 Spike-specific T-cells was assessed by IFN-gammaELIspot assay, and side effects and disease activity were recorded. Results GCA/PMR patients did not have reduced antibody concentrations compared with controls. However, linear regression analysis revealed a significant association of methotrexate and >10 mg/day prednisolone use with lower antibody concentrations in GCA/PMR patients. Evidence of cellular immunity, as assessed by ELIspot assay, was found in 67% of GCA/PMR patients. Patients using >10 mg/day prednisolone had reduced cellular immunity. Importantly, vaccination did not lead to significant side effects or changes in disease activity. Conclusions SARS-CoV-2 vaccination was safe for GCA/PMR patients and immunogenicity was comparable to other older individuals. However, patients using methotrexate and particularly >10 mg/day prednisolone did show lower vaccine responses, which corroborates findings in other autoinflammatory patient populations. These patients may therefore be at higher risk of (potentially even severe) breakthrough SARS-CoV-2 infection. Copyright ©

4.
American Journal of Transplantation ; 22(Supplement 3):766-767, 2022.
Article in English | EMBASE | ID: covidwho-2063544

ABSTRACT

Purpose: Administration of mRNA-based SARS-CoV-2 vaccines confers protection from SARS-CoV-2 infection and reduces its severity in the general population. It has been suggested that mounting a coordinated adaptive immune response characterized by production of neutralizing antibodies and SARS-CoV-2 spike proteinspecific T-cells correlates with protection from infection. Studies in organ transplant recipients have demonstrated suboptimal responses after 2 doses of SARS-CoV-2 vaccination;however, the impact of different immunosuppressive regimens (IS) on T-cell responses is not well described. This study prospectively evaluated the impact of IS on T-cell responses in a kidney transplant (KTx) population and compared these to 26 healthy controls. Method(s): In this single-centre, prospective study, 92 KTx on follow-up at our centre were enrolled after informed consent. T-cell responses were evaluated before and after each of 2 doses of BNT162b2 SARS-CoV-2 vaccine administered 21 days apart: before each dose, 10-14 days after Dose1 and 21-24 days after Dose2. The study population included 69.6% Live-Donor and 30.4% Deceased-Donor KTx. Longitudinal assessment of the quantity of spike-specific T-cells was performed by stimulating whole blood with peptides covering the SARS-CoV-2 spike protein, followed by cytokine (IFN-gamma, IL-2) measurement (JCI, Tan et al, 2021). KTx were stratified by maintenance IS into 4 groups and T-cell responses compared between groups. Result(s): As shown (Figures 1A, 1B), in comparison to healthy controls, KTx displayed poor spike-specific T-cell responses as measured by IFN-gamma and IL-2 release. Percent responders were significantly lower for KTx vs. healthy controls: 6.5% vs. 92.3% after Dose1 (P<0.00001) and 27.2% vs. 100% after Dose2 respectively. There was a significant impact of different IS regimens (Figure 1C);percent responders after Dose2 were 19%, 43%, 40% and 71% for KTx receiving CNI-MPA-Pred, CNI-Aza-Pred, mTORi and Other regimens respectively (P=0.013). Conclusion(s): Our results highlight the critical role of IS on T-cell responses to SARS-CoV-2 vaccination. In the context of the COVID-19 pandemic, monitoring T-cell and antibody responses over time after vaccination, modulating IS and modifying vaccination strategies are clearly needed to protect this vulnerable population.

5.
American Journal of Transplantation ; 22(Supplement 3):769-770, 2022.
Article in English | EMBASE | ID: covidwho-2063536

ABSTRACT

Purpose: The SARS-CoV-2 pandemic has had a significant impact on the field of solid organ transplant(SOT). Immunization against SARS-CoV-2 is globally available since 2021. SOT recipients represent a vulnerable group with a higher risk of infection and worse outcomes from COVID-19 compared with the general population. There is a concern for the efficacy of SARS-CoV-2 vaccination amongst SOT recipients. We aimed to assess immunogenicity, safety and breakthrough infections after SARS-CoV-2 vaccination. Method(s): We conducted a systematic review and a meta-analysis using articles from 8 databases published from January 1,2020 to July 13,2021. We included studies reporting data regarding SOT and SARS-CoV-2 post vaccine antibody response or cellular response;safety of vaccination;and SARS-CoV-2 infection after at least one vaccine dose. A meta-analysis of postvaccine antibody response and death in breakthrough infections was conducted using a random-effects model. Result(s): Initially, we identified 572 potential studies. After careful review, we included 64 studies for systematic review and 46 studies for meta-analysis. We identified 6,710 SOT recipients. Pooled incidence of antibody positivity after completion of any vaccine schedule was 28.3% (95% confidence interval[CI] 22.5-34.8%). Pooled incidence of antibody positivity after messenger RNA vaccination with 2 doses and 3 doses were 29.3%(95%CI 23.58%-35.74%) and 57.4%(95%CI 48.63-65.78%), respectively. Twelve reports on interferon-gamma response to SARS-CoV-2 spike antigen peptides showed a positivity between 30.4% and 55.0% after messenger RNA vaccines. The most common side effect after vaccination was site pain. Only 5 cases developed rejection but no graft loss. The pooled incidence of death in breakthrough infections was 17.1%(95%CI 10.2%-27.2%). Conclusion(s): Our findings show that only 29% of SOT recipients could mount antibodies after 2 doses of messenger RNA vaccines, with an improved response seen after 3 doses (57%). Even with 3 doses, the immunogenicity is still suboptimal and further studies to investigate the optimal vaccination strategies in this population are needed.

6.
American Journal of Transplantation ; 22(Supplement 3):1016-1017, 2022.
Article in English | EMBASE | ID: covidwho-2063502

ABSTRACT

Purpose: COVID-19 has poor outcomes in transplant recipients with reduced antibody responses. However, the exact cellular immune response against SARS-CoV-2 remains largely unclear. We developed novel assays to analyze differential cellular immune responses in individual subjects and groups. Method(s): We assessed the T cell proliferative responses against spike, membrane, and nuclear proteins of SARS-CoV-2, or a mixture of all these peptides (mix) using 3H-thymidine incorporation and CFSE dilution assays. We have also established a SARS-CoV-2-specific multiplexed cytokine IsoLight at single-cell resolution. This is a very powerful technology that employs IsoPlexis' IsoCodechip with 12,000 micro-chambers. Each microchamber is pre-coated with a 32-plex antibody array to capture secreted cytokines. The results were evaluated using IsoSpeak software. Result(s): COVID-19 convalescent subjects (n=3) showed a very strong proliferative response to S/M/N and mix peptides of SARS-CoV-2 when compared to uninfected normal subjects who had only marginal proliferative responses. CFSE dilution assays demonstrated that spike and mix proteins markedly increased the proliferation of CD3 cells comprised of both CD4 and CD8 subsets. In the IsoLight assay, single-cell functional heterogeneity mapping 3D tSNE analysis showed a distinct combinatorial cytokine secretion pattern in stimulated cells compared to unstimulated controls (Fig.1). Polyfunctional activity topography-Principal component analysis (PAT-PCA) revealed that IFN-g, IL2, and MIP-1b drove the polyfunctional heterogeneity. When the percentage of polyfunctional cells (>=2 cytokines/cell), and polyfunctional strength index (PSI) were evaluated, CD8 cells secreted high levels of effector and chemoattractive cytokines while CD4 cells secreted effector and stimulatory cytokines. Most importantly, the depth and breadth of T cell responses, particularly the cytokine polyfunctionality correlated with the severity of the disease the patients had experienced. Conclusion(s): This novel COVID19-specific IsoLight cytokine assay is a powerful technology that can be utilized for in-depth analysis of T cell polyfunctionality at the single-cell level and for further differentiating the anti-SARS-CoV-2 immune capabilities of vulnerable individuals such as transplant patients.

7.
American Journal of Transplantation ; 22(Supplement 3):873, 2022.
Article in English | EMBASE | ID: covidwho-2063493

ABSTRACT

Purpose: Kidney transplant recipients (KTRs) are highly vulnerable to severe COVID-19, however are poorly protected by vaccination. Additional vaccine doses have achieved limited improvements in serological neutralisation or T cell response. A novel strategy to boost vaccine response is needed. Method(s): KTRs (n=80) and healthy cohabitants (HCs;n=80) were recruited from a transplant centre in South Australia to undergo a 2-dose vaccination schedule with BNT162b2 or ChAdOx1. KTRs were most commonly receiving the standard-of-care (SOC) triple therapy: tacrolimus, mycophenolate mofetil, prednisolone. Following 2 vaccine doses (median 21 days;IQR 21-24), spike-specific IgG and T cell responses (by IFNgamma ELISpot) were measured to assess vaccine immunogenicity, and live virus neutralisation and anti-receptor binding domain (RBD) IgG (Elecsys, Roche) were evaluated as correlates of protection from infection and disease. In an extended cohort comparing SOC (n=15) and sirolimus-inclusive (n=15) protocols, function and phenotype of antigen-specific T cells were further interrogated by flow cytometry. Result(s): Vaccine immunogenicity was profoundly reduced in KTRs, with a >1,000- fold lower median anti-spike IgG titre, and >10-fold lower median antiviral T cell response relative to HCs. Thresholds for protective anti-RBD IgG (100 U/mL) and serological neutralisation (50% neutralisation at a serum dilution of 1/40) were achieved by 6.7% and 10.9% of KTRs, respectively, and by 100% of cohabitants. In an extended cohort, patients on mTOR inhibitors (mTORi;sirolimus or everolimus) achieved 4-fold higher rates of serological neutralisation than those on SOC therapy (34.6% vs 7.9%). Remarkably, sirolimus use was associated with a median antiviral T cell response 55-fold greater than SOC therapy, and 5-fold greater than HCs. SARSCoV- 2-specific CD4+ and CD8+ T cells in these patients were highly polyfunctional and formed robust central memory out to 3 months post second vaccine dose. Conclusion(s): These data underscore priority vaccination of cohabitants as an effective strategy to protect KTRs, and support a randomised controlled trial of immunosuppression modification with sirolimus as a strategy to directly improve vaccine responses in KTRs.

8.
American Journal of Transplantation ; 22(Supplement 3):637-638, 2022.
Article in English | EMBASE | ID: covidwho-2063471

ABSTRACT

Purpose: Solid organ transplant recipients (SOTRs) are at increased risk for severe COVID-19 and exhibit lower antibody responses to SARS-CoV-2 vaccines. This study aimed to determine if pre-vaccination cytokine levels are associated with antibody response to SARS-CoV-2 vaccination. Method(s): A cross-sectional study was performed among 58 SOTRs before and after two-dose mRNA vaccine series, 35 additional SOTRs before and after a third vaccine dose, with comparison to 16 healthy controls (HCs). Anti-spike antibody was assessed using the IgG Euroimmun ELISA. Electrochemiluminescence detectionbased multiplexed sandwich immunoassays were used to quantify plasma cytokine and chemokine concentrations (n=20 analytes). Concentrations between SOTRs and HCs, stratified by ultimate antibody response to the vaccine, were compared using Wilcoxon-rank-sum test with false discovery rates (FDR) computed to correct for multiple comparisons. Result(s): In the study population, 100% of HCs, 59% of SOTRs after two doses and 63% of SOTRs after three doses had a detectable antibody response. Multiple baseline cytokines were elevated in SOTRs versus HCs. There was no significant difference in cytokine levels between SOTRs with high vs low-titer antibodies after two doses of vaccine. However, as compared to poor antibody responders, SOTRs who went on to develop a high-titer antibody response to a third dose of vaccine had significantly higher pre-third dose levels of several innate immune cytokines including IL-17, IL-2Ra, IL-6, IP-10, MIP-1alpha, and TNF-alpha (FDR <0.05). Conclusion(s): A specific inflammatory profile or immune state may identify which SOTRs are likely to develop stronger sero-response and possible protection after a third dose of SARS-CoV-2 vaccine.

9.
American Journal of Transplantation ; 22(Supplement 3):638, 2022.
Article in English | EMBASE | ID: covidwho-2063446

ABSTRACT

Purpose: Prior studies suggest that two doses of mRNA vaccine in SOTR may result in lower antibody and T-cell responses relative to levels seen following natural SARS-CoV-2 infection. In this study, we evaluated whether three doses of mRNA-1273 vaccine result in immune responses more comparable to, or greater than, natural infection. Method(s): Serum was collected 4-6 weeks from symptom onset in n=74 SOTR recovered from SARS-CoV-2 infection, and in n=60 SOTR receiving a third dose of mRNA-1273. Disease severity in the infection cohort ranged from mild to severe, but no deaths were reported. Vaccinated SOTR all had negative anti-nucleoprotein antibody results to confirm absence of infection. SARS-CoV-2 serology was assessed using an anti-spike (S) receptor binding domain (RBD) immunoassay (Roche). Neutralizing antibodies (nAb) were assessed using a commercial surrogate virus neutralization test (SVNT) targeting wildtype (WT), alpha, beta and delta strains (GenScript). A subset of participants underwent spike-specific T-cell testing (infection n=50, three doses n=34). PBMCs were stimulated overnight with overlapping peptides and frequencies of S-specific polyfunctional CD4+ and CD8+ T-cells (expressing IFN-gamma and IL-2) were measured by intracellular cytokine staining. Mann Whitney U, and Chi-square tests were used for statistical comparisons;significance was defined at p<0.05. Result(s): Anti-S RBD antibodies in SOTR recovered from infection were similar to levels in those receiving three doses of mRNA-1273 (median U/mL [IQR]: 73.5 [14.9-240.1] vs. 313.8 [313.8-2191.0];p=0.17). Relative to SOTR recovered from infection, the proportion of SOTR positive for nAb after three doses of vaccine was significantly lower. This was true for WT (93.2% vs. 60.0%, p<0.0001) and all variants tested - alpha: 90.5% vs. 56.7%, p<0.0001;beta: 67.6% vs. 50%, p=0.039;and delta: 85.1% vs. 55%, p=0.0001. Spike-specific polyfunctional CD4+ T-cell frequencies were similar between infection and three doses of vaccine (median cell frequency [IQR]: 241.7 [50-539.7] vs. 432.4 [50-1226];p>0.05). Spike-specific polyfunctional CD8+ T-cells were uncommonly detected following infection or vaccination. Vaccinated participants were significantly older than infected SOTR (p<0.001), and some differences in type of transplant were found between groups. However, sex and type of immunosuppressive medications were similar between infected and vaccinated SOTR cohorts (p>0.05). Conclusion(s): Three doses of mRNA vaccine may be required to optimize binding antibody, and to a lesser extent, CD4+ T-cell immunity, to levels similar to natural infection. However, nAb responses to wild-type virus and variants of concern were highest in SOTR recovered from infection when compared to vaccinated patients. These data provide further evidence of impaired SARS-CoV-2 vaccine responses in SOTR.

10.
American Journal of Transplantation ; 22(Supplement 3):768, 2022.
Article in English | EMBASE | ID: covidwho-2063440

ABSTRACT

Purpose: Short-term adaptive immune memory has been reported among immunocompetent (IC) and convalescent Solid Organ Transplant (SOT) individuals following SARS-CoV-2 infection as well as after active vaccination. However, quality and longevity of anti-viral immune memory comparisons between natural and active immunization has not been thoroughly assessed among SOT. Method(s): SARS-CoV-2-specific adaptive immune memory was assessed at different compartments (serological, memory B cells [mBC] and cytokine [Th1: IFN-gamma, IL-2, IFN-gamma/IL-2 and Th2: IL-21 and IL-5] producing T cells) by ELISA and FluoroSpotbased assays, respectively, in 41 convalescent patients with severe COVID-19 (22 SOT and 19 IC) and 39 vaccinated patients (19 SOT and 20 IC) with a mRNA-based vaccine) at different time-points post immunization (T1=21days after infection/1st dose;T2=3months after infection/2nd dose;T3=6months after infection/2nd dose). Additionally, a group of convalescent mild (19 SOT and 19 IC) and asymptomatic patients (9 SOT and 10 IC) were also evaluated at T3. Result(s): Overall, statistically significant higher immune responses in all immune compartments were observed in convalescent patients than among those after vaccination. After vaccination, low seropositivity rates (5,88%) were observed among SOT after 1st dose, whereas seroconversion was fully achieved in IC patients and SOT with severe COVID-19 (p<0.001). Similarly, while the presence of mBc after vaccination progressively increased over time, it was less pronounced and significantly delayed among SOT than convalescent patients in all time points (p<0.001 T1, T2 and T3). SARS-CoV-2-specific Th1 and Th2 frequencies were significantly higher among vaccinated IC patients than SOT, being these responses significantly lower than those observed in convalescent among SOTT and IC patients (p<0.001 T1, T2 and T3). At 6 months after vaccination, IgG titers, mBc frequencies and Th1/ Th2 T-cell responses after two-dose vaccination in SOT mimicked those observed in convalescent SOT with an asymptomatic/mild clinical COVID-19 infection. Conclusion(s): The type of immunization against SARS-CoV-2, either natural or active after vaccination, clearly differentiates the quality and length of adaptive immune memory, with a clear weaker immune response observed among SOT.

11.
American Journal of Transplantation ; 22(Supplement 3):908-909, 2022.
Article in English | EMBASE | ID: covidwho-2063435

ABSTRACT

Purpose: To determine if Apadenoson or Regadenoson has a therapeutic effect in attenuating hyper-inflammation and improving survival rate in K18-hACE2mice or Syrian hamsters infected with SARS-CoV-2. Method(s): 6-8 weeks old male K18-hACE2mice were divided into Control group that received vehicle;Test group 1 that received the drug (Apadenoson or Regadenoson) 24hrs prior to challenge with SARS-CoV-2;and Test Group 2 (Drug-delay), that received the drug with a 5 hr delay post-viral infection (n=6/grp). Viral dose was 1250 PfuHong Kong/VM20001061/2020 delivered via intranasal route. Drug was delivered subcutaneously using 1007D ALZET pumps. 6 weeks old Syrian hamsters were divided into Control group that received Vehicle and Virus (n=4) and 2 test groups (n=5/group) that received Apadenoson+Virus and Regadenoson+Virus. Drugs were delivered by 2ML2 ALZET pumps (4ug/kg/hr). Hamsters were inoculated intratracheally with 750PFU SARS-CoV-2 WA1 strain prior to treatment. Mice were weighed and clinical scores recorded daily. Bronchoalveolar lavage fluid (BALF) and serum were collected along with lungs. Plethysmography was done on days 0, 2, 4 and 7. Result(s): Apadenoson administered post-infection was efficacious in decreasing weight loss, improving clinical score, and increasing the survival rate in K18-hACE2 mice, i.e. 50% survival was observed at Day 5 and at Day 7 post-infection for drug given before or after infection respectively. Apadenoson given post-infection improved the histopathology that was observed in the vehicle control group, decreased pro-inflammatory IL-6, IFN-gamma, MCCP-1, MIP-1beta, IP-10, and Rantes in serum, increased anti-inflammatory Ang1-7 levels, and decreased monocytes in BALF. 42% of mice that received Regadenoson pre-challenge survived infection compared to 6.25% in the vehicle or Drug delay (drug given post-infection) groups. Viral titers in the lungs of Regadenoson-treated mice were found decreased. Treatment also significantly decreased CD4+, CD8+T cells, eosinophils, and neutrophils in BALF. Plethysmography, in hamsters, showed significant improvement of pulmonary function parameters, Rpef and PenH, following treatment with Apadenoson given post-infection. Apadenoson cleared the virus from BALF and maintained Ang1-7 levels. Both drugs decreased plasma IFN-gamma levels. Conclusion(s): Treatment with Apadenoson attenuated inflammation, improved pulmonary function, decreased weight loss, and enhanced survival rate following infection with SARS-CoV-2 virus. The results demonstrate the translational significance of Apadenoson in the treatment of COVID-19.

12.
American Journal of Transplantation ; 22(Supplement 3):426-427, 2022.
Article in English | EMBASE | ID: covidwho-2063400

ABSTRACT

Purpose: Due to heterogeneity observed in the kidney transplant population, it has been extremely challenging for traditional methods such as histopathology to predict graft outcomes. In this real-world evidence(RWE) study, we applied machine learning (ML) models to a multi-analyte urinary biomarker assay to predict whether a kidney allograft would experience a rejection episode. Method(s): A cohort of 550 (37.5% biopsy matched) urine samples from patients across 3 renal transplant centers were used to develop a predictive ML model (scaled 0-100) to prognosticate allograft failure. Samples were collected between 1-1539 days post-transplant from allograft recipients with ages ranging from 7-77 years. Of the 206 biopsy matched samples, acute kidney allograft rejection (AR) and no-rejection (NR) phenotypes were confirmed in 136 and 70 respectively. We also evaluated the developed ML model on two additional cohorts of 15 COVID+ transplant recipients and 30 non-transplant healthy population. The ML model incorporates clinico-demographics with 6 urinary biomarkers: Clusterin, total protein, CXCL10, Creatinine, cfDNA and methylated cfDNA. Monte Carlo confidence intervals for the model incorporated biomarker assay and sample variances. Result(s): The novel rejection score was able to discriminate AR from NR efficiently. Score below 32 classified stable allograft, score range of 32 - 55 identified progression of AR, and Score > 55 identified AR with high sensitivity: 92%, and specificity: 89%;AUC: 96% and accuracy: 91%(figure). The associated NPV and PPV of 87% and 93% respectively. In the COVID cohort with 86% clinician assessed rejection, the median score was 51(IQR:30-87). In the non-transplants the median score was 19(IQR:13-26). It was established that presence of COVID was not a confounder in the model. Conclusion(s): The accuracy of the novel rejection score emphasizes the promise of applying ML algorithms as an aid to decision-making in evaluating graft outcomes with high sensitivity and specificity. Moreover, this RWE retrospective analysis demonstrates the efficacy of the urine multi-analyte approach to accurately predict acute rejection in kidney transplant recipients. (Figure Presented).

13.
American Journal of Transplantation ; 22(Supplement 3):443, 2022.
Article in English | EMBASE | ID: covidwho-2063389

ABSTRACT

Purpose: SARS CoV-2 vaccination elicits both robust humoral and T-cell immune responses in healthy individuals. However, a comprehensive assessment of immune responses to SARS-CoV-2 vaccination in renal allograft recipients is variable and dependent primarily on Spike IgG levels. Here, we analyzed the humoral and T-cell responses in vaccinated transplant recipients. Method(s): 61Tx patients maintained either on Tacrolimus (TAC, 32) or Belatacept (BELA, 29) who were greater than one month post 2nd dose of the Pfizer BNT162b2, and 41 healthy individuals were enrolled. Fresh whole blood was incubated with SARS CoV-2 Spike peptides pool and the activated CD4+ (IL-2/TNF-alpha)+ and CD8+ (TNF-alpha/IFN-gamma)+ T cells were enumerated by flow cytometry and defined as CoV-2-specific T cells. Plasma was analyzed for Spike Receptor Binding Domain (RBD)-specific IgG by ELISA. The Spike RBD-specific IgG levels and Spikespecific CD4+/CD8+ T-cell immune responses were analyzed in TAC- and Bela- Tx patients along with healthy controls. Result(s): Our data demonstrated poor Spike IgG and T cell immune responses in Tx patients1M post-2nd dose of vaccine (21% v. 93% in positive Spike IgG and 37% v. 88% in positive T cell responses, Tx v. controls, respectively). However, 34% of Spike IgG (-) patients demonstrated positive CD4+ and/or CD8+ T-cell immune responses. No significant difference in T cell immunity was found between TAC and BELA treated patients. Conclusion(s): Immunocompromised Tx patients demonstrated significant defects in humoral and T cell immune response after vaccination. Patients maintained on TAC v. BELA demonstrated similar depressions in immune responses post-vaccination. 34% of vaccinated Tx patients, demonstrated Spike-specific T cell immunity despite being Spike IgG negative. This is suggestive of a divergent immune response with dominant cellular immunity. These observations are important since activation of T-cell immunity early after exposure to SARS-CoV2, while not preventing infection will likely modify severity of disease. (Table Presented).

14.
Chest ; 162(4):A2145, 2022.
Article in English | EMBASE | ID: covidwho-2060901

ABSTRACT

SESSION TITLE: Unique Inflammatory and Autoimmune Complications of COVID-19 Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Sarcoidosis is a disorder with multisystem involvement of unclear, and likely multifactorial, etiology. A majority of cases (up to 90%) include lung involvement, and hilar/mediastinal lymphadenopathy is frequently seen. Since the beginning of the COVID-19 pandemic, multiple complications of COVID-19 have been reported. We present a case of a female patient who developed new-onset, biopsy-proven Pulmonary Sarcoidosis after having COVID-19 pneumonia. CASE PRESENTATION: A forty-eight-year-old female with a past medical history of hypertension presented to the emergency department with a complaint of fever, shortness of breath, and cough. She was subsequently diagnosed with COVID-19 infection/pneumonia. A computed tomography angiogram of the chest was completed to evaluate an abnormal chest radiograph and to rule out pulmonary embolism and revealed pulmonary nodules throughout both lungs with mediastinal and hilar lymphadenopathy. She was referred to the pulmonary clinic for further evaluation of her abnormal computed tomography scan of the chest and presented after quarantine for her COVID-19 infection. She denied any history of Sarcoidosis and denied any mold exposure. She underwent bronchoscopy, and pathology results were consistent with non-caseating granulomas concerning for Sarcoidosis. Over the course of a few days, her symptoms improved. Repeat computed tomography scan of the chest was completed, which showed complete resolution of the previously identified pulmonary nodules with interval improvement of mediastinal adenopathy. DISCUSSION: With the increased number of COVID-19 cases worldwide, an ever-growing list of pulmonary and extrapulmonary manifestations of COVID-19 have been reported. To our knowledge based on literature review, there have only been a few case reports of COVID-19 induced Sarcoidosis. Although the pathophysiology of Sarcoidosis largely remains unknown, inflammation is mediated through the dysregulation of several different cytokines (1). Behbahani, et al. proposed noncaseating granulomas formation as a sarcoid-like immune reaction to SARS-CoV-2. Ekinci et al. reported type-I IFN and IFN-γ role in triggering granuloma formation (2). In our patient, the biopsy-proven presence of non-caseating granuloma formation and subsequent rapid improvement of radiological lesions on computed tomography scan after recovery from COVID-19 pneumonia supports the diagnosis of COVID-19 induced Sarcoidosis. CONCLUSIONS: With the COVID-19 pandemic ongoing, physicians must be aware of the pulmonary and extrapulmonary manifestations of COVID-19 infection. Further studies are required in order to manage such cases and to evaluate COVID-19 infection as an infectious antigen capable of triggering granulomatous inflammation resulting in Pulmonary Sarcoidosis. Reference #1: Capaccione KM, McGroder C, Garcia CK, Fedyna S, Saqi A, Salvatore MM. COVID-19-induced pulmonary sarcoid: A case report and review of the literature. Clin Imaging. 2022;83:152-158. doi:10.1016/j.clinimag.2021.12.021 Reference #2: Polat Ekinci A, Büyükbabani N, Meşe S, Pehlivan G, Okumuş NG, Ağaçfidan A, Özkaya E. COVID-19-triggered sarcoidal granulomas mimicking scar sarcoidosis. J Eur Acad Dermatol Venereol. 2021 Aug;35(8):e477-e480. doi: 10.1111/jdv.17286. Epub 2021 May 1. PMID: 33871106;PMCID: PMC8250646. DISCLOSURES: No relevant relationships by Zachary Anderson No relevant relationships by Sakina Batool No relevant relationships by Adnan Khan No relevant relationships by Bireera Muzaffar No relevant relationships by Ramsha Zafar

15.
Chest ; 162(4):A329, 2022.
Article in English | EMBASE | ID: covidwho-2060565

ABSTRACT

SESSION TITLE: Post-COVID-19 Infection Complications SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: The COVID-19 pandemic has been full of obstacles for the medical field. Considerable advancements have been made, yet we continue to discover new associations with this novel virus. In this case, we discuss a patient who was hospitalized for COVID-19 on 7/18/2020 in the intensive care unit. He developed a persistent cough with hemoptysis several months after discharge and was found to have active tuberculosis. The COVID-19 pandemic has continued to raise concerns regarding the repercussions of this infection, and as this case shows, includes reactivation of latent tuberculosis infections (LTBI) in affected patients. CASE PRESENTATION: A 59-year-old Latino male never-smoker with a history of diabetes (A1c 8.4%) presented 07/18/2020 for complaints of shortness of breath and cough. At that time, he tested positive for COVID-19. He was escalated to the ICU and required intubation. During his hospitalization, he received remdesivir for 5 days and dexamethasone 6 mg daily for 10 days with taper prior to his discharge. He was able to be extubated and oxygen requirement decreased to 2 liters nasal cannula. Patient was subsequently discharged on 09/14/2020. He began developing a persistent cough with noted hemoptysis in 02/2021 and was referred to pulmonology at that time. High resolution CT scan of the chest was ordered and revealed thick-walled cavitary lesions of various sizes throughout both lungs although with an upper lobe predominance and tree-in-bud nodularity as well as tracheomegaly. AFB and QuantiFERON Gold assay were positive. Patient reported he had done multiple mission trips to endemic areas before COVID pandemic but had not been during the pandemic. Patient underwent quarantine and treatment for active tuberculosis. DISCUSSION: Tuberculosis reactivation results from previous latent bacteria that becomes active either from inducible factors or spontaneously. Risk factors for reactivation include HIV/AIDS, steroid use, diabetes, kidney disease, and smoking. [1] The primary basis of these risk factors is the immunosuppression conferred to the patient. COVID-19 has the potential to cause a disruption of the immune system which could predispose a patient to reactivation of LTBI. Studies have shown that defects or interference of the IFN-γ pathway can cause susceptibility to intracellular infections, including tuberculosis.[2] There may be an acquired disruption in this pathway caused by COVID-19, although more research is required. CONCLUSIONS: The COVID-19 pandemic has raised concerns for increased risk of reactivation of latent infection as well. In this case, the patient had multiple risk factors, but certainly a diagnosis of COVID-19 could weaken the immune system allowing for the reactivation of LTBI. This association will require more research to solidify. It is important, as seen in the case discussed above, to continue to be vigilant in diagnosis and treatment of our patients. Reference #1: Riley L. UpToDate. UpToDate – Evidence-based Clinical Decision Support ;Wolters Kluwer. Published September 15, 2021. Accessed February 2, 2022. https://www.uptodate.com/contents/tuberculosis-natural-history-microbiology-and-pathogenesis?search=tuberculosis&source=search_result&selectedTitle=4~150&usage_type=default&display_rank=4 Reference #2: Kampmann B, Hemingway C, Stephens A, et al. Acquired predisposition to mycobacterial disease due to autoantibodies to IFN-gamma. J Clin Invest 115: 2480-2488, 2005. DISCLOSURES: No relevant relationships by Steven Colby No relevant relationships by Radhika Shah

16.
Journal of Pediatric Gastroenterology and Nutrition ; 75(Supplement 1):S47-S48, 2022.
Article in English | EMBASE | ID: covidwho-2058252

ABSTRACT

Background: 30-50% of pediatric acute liver failure (PALF) is of unknown cause, or indeterminate PALF (iPALF), which frequently results in transplantation. A subset of iPALF is characterized by T-cell activation. Some children with acute severe hepatitis of unknown etiology (SH-u) can evolve to iPALF. Hemophagocytic Lymphohistiocytosis (HLH) is a well-defined hyper-inflammatory condition characterized by marked T-cell activation and frequent severe liver involvement. We postulated SH-u evolving to iPALF has hyper-inflammatory immune signatures that are identifiable before fulfilling PALF criteria, and might overlap with those seen in HLH. We compared the immune dysregulation signatures of children with HLH to children with SH-u, PALF cases with known etiologies, and healthy pediatric controls (HC). Method(s): Between 2019-2021, we prospectively enrolled 14 patients hospitalized with SH-u and 7 patients with PALF of known etiologies. Age dependent standard of care diagnostic studies were performed. SH-u was defined as ALT> 500, INR < 2, and no hepatic encephalopathy. HLH enrollees fulfilled the 2004 diagnostic criteria. High dimension T-cell immunophenotyping, cytokine and chemokine profiling (71-plex) was done for SH-u, HLH (n=5), and HC (n= 16) peripheral blood samples. T cell activation was prospectively identified by co-expression of surface activation markers HLA-DR and CD38. Based on immune studies in HC, CD8 effector memory (EM) activation of >9% distinguished patients with significant T cell activation from HC. This cutoff of >9% was therefore used to identify SH-u patients with T cell activation. Normally distributed data were compared by either a two-tailed t-test or an ordinary One-Way Anova test with Turkey's multiple comparison test. Non-normally distributed data were compared by either the Mann-Whitney test or Kruskal-Wallis test with Dunn's multiple comparisons test. P Values < 0.05 were deemed significant. Result(s): Subjects ranged in age from 4 days to 19 years old. There were no age or sex differences between the groups. One SH-u patient had prior COVID infection, but no subject met MIS-c criteria. Two SH-u patients ultimately evolved to PALF criteria with INR> 2. All patients with SH-u had higher CD8 EM T-cell activation (mean +/- SEM = 43.7+/-6.3%;range 9.2 to 81.3;p<0.0001), which was significantly higher than HC (2.9+/-0.5%) and PALF of known etiology (4.0+/-0.9%) . However, the amplitude of T-cell activation was lower in the SH-u group relative to the HLH group (90.3+/-2.7%;p<0.0001), as shown in Figure 1. A similar trend in T cell activation was noted in the CD4 compartment. Overall, the activation in the CD8 compartment was much greater than in CD4. SH-u patients had a decreased CD4/CD8 ratio compared to the PALF group. Despite higher T cell activation in patients with SH-u compared to PALF, ferritin, often used to screen for hyper-inflammation, was lower in the SH-u group when compared to PALF group (1240+/-609 vs. 39517+/-32149;p<0.05) and very significantly lower than HLH (32415 +/- 14845;p =0.002). 50% of patients with SH-u etiology had ferritin < 500 mg/L. Cytopenia (hemoglobin < 9 g/dL, ANC < 1000/mL, platelets < 100,000/mL) is characteristic of patients with HLH. Despite overlapping T cell activation with HLH, the SH-u cohort had only 2 patients with this feature: one with thrombocytopenia and one with neutropenia. Supportive of this higher T cell activation, we noted chemokines driven by IFN-gamma, CXCL9 and CXCL10, to be elevated in SH-u compared to HCs and comparable to HLH patients. As a proof of concept, 1 patient with SH-u and thrombocytopenia underwent treatment with Emapalumab (an IFN-gamma blocking antibody) along with other immune modulators both with complete liver, immune, and platelet count recovery. Conclusion(s): Our cohort of SH-u was associated with significant T-cell activation. In addition, our patients with HLH and SH-u with T cell activation had similar increased IFN-gamma activity. Despite this T cell activation, ferritin values were significantly lower in SH-u compared to PALF without T cell activation. Ferritin may not be a reliable screening test to identify SH-u patients with significant T cell activation. If validated in a larger well-defined population of SH-u, the results may suggest a role for IFN-gamma blocking agents in a subgroup of SH-u prior to PALF or before bone marrow failure development.

17.
Infektsionnye Bolezni ; 20(2):23-32, 2022.
Article in Russian | EMBASE | ID: covidwho-2044283

ABSTRACT

Objective. To clarify the features of the defect in the function of NK cells, T lymphocytes, the interferon system in patients with moderate and severe COVID-19. Patients and methods. Tests of the peripheral blood of 50 COVID-19 patients aged 61(57–71) and having the moderate and severe disease were performed. The following parameters were measured: the quantity of CD3+CD19–, CD3+CD4+, CD3+CD8+ T lymphocytes, NK – (CD3–CD16+CD56+), and TNK – CD3+CD16+CD56+ with expression density considered membrane receptors (MFI) (FC 500 Beckman Coulter, USA), the levels of IFN-α, IFN-γ, IL-6, TNF-α cytokines (IFA). Results. Combined immunodeficiency associated with quantitative and functional defects in NK, T lymphocytes and their subsets was revealed in moderate and severe COVID-19. An imbalance of cytokines has been established: blockade of the production of IFN-α and IFN-γ against the background of a significant increase in IL-6 and TNF-α, which negatively affects both the number and functionality of the participants in the immune response and is associated with a severe course and poor prognosis of COVID-19. Conclusion. The data obtained demonstrate the need to develop new strategies and tactics for the treatment of COVID-19, including replacement systemic therapy with recombinant IFN-α2b in combination with antioxidants (Viferon®) in adequate therapeutic doses, aimed at restoring the normal functioning of T lymphocytes, NK and the interferon system.

18.
Swiss Medical Weekly ; 152:25S-26S, 2022.
Article in English | EMBASE | ID: covidwho-2040836

ABSTRACT

Background: The role of T cell immunity in protection against COVID-19 in immunosuppressed patients who failed to mount serological responses remains ill defined. Hypothesis: Vaccine-based intradermal skin test (IDT) serves as a surrogate marker of T cell responses in seronegative immunosuppressed patients. Methods: We compared anti-SARS-CoV-2 antibodies and cellular responses in vaccinated immunosuppressed (IS) patients (n = 58), healthy unvaccinated naive controls (NC, n = 8) and healthy vaccinated controls (VC, n = 32) by Luminex, IFN-γ ELIPSOT and IDT 3 to 6 months after vaccination. In 3 VC we performed a skin biopsy 24h after IDT and performed single-cell RNAseq of the skin-infiltrating CD45+ cells Results: Seronegative NC had no detectable T cell responses and negative IDR, whereas VC had anti-SARS-CoV-2 antibodies (100%), positive ELIPSOT (90%) and IDR (90%). Overall IS patients had significantly less antibodies up to 39 weeks after vaccination compared to VC but similar ELIPSOT responses. ELISPOT was positive in 33.3 % and 66.6 % and IDR in 62.5% and 90.5% of seronegative vs seropositive IS patients respectively. Conversely, patients with negative IDR had significantly lower T cell responses and IgG titers than those with positive IDR. Importantly, the TCR repertoire of infiltrating skin lymphocytes revealed 18/1064 clonotypes with known specificities against SARS-CoV-2. Conclusion: Our results indicate that local reaction to IDR is partially composed of SARS-CoV-2-specific T cells. IDR represents a promising tool to cost-effectively monitor SARS-CoV-2 specific T cell immunity in IS patients.

19.
HemaSphere ; 6:291-292, 2022.
Article in English | EMBASE | ID: covidwho-2032117

ABSTRACT

Background: The ongoing COVID-19 pandemic has resulted in more than 419 million cases and more than 5.9 million deaths. Preious studies hae indicated inferior responses to SARS-CoV-2 accination across different hematological diseases. Through this prospectie cohort study, we examined the deelopment and durability of anti-receptor binding domain (RBD) IgG after two doses of BNT162b2 in 179 patients with either multiple myeloma (MM) or Chronic Lymphatic B-cell Leukemia (B-CLL) six months after accination and compared to immunocompetent controls. Aims: We aimed to inestigate the durability of immune responses to COVID-19 accination in patients with MM or B-CLL compared to healthy controls, and to identify risk factors for humoral non-response, including type of diagnosis. Methods: We measured anti-receptor binding domain (RBD) IgG after two doses of BNT162b2 in 179 patients (MM: n=78, B-CLL: n=101) and 179 age and sex matched healthy controls up to six months after first accination. Anti- RBD IgG leels and neutralizing capacity of antibodies were measured at first and second dose of BNT162b2 and two and six months after first dose. Humoral response was defined as anti-RBD IgG > 225 AU/mL with a neutralizing index ≥ 25%. Humoral non-response was defined as the absence of a humoral response. T-cell responses were assessed six months after the first dose using an ELISA-based interferon-gamma release assay. A positie T-cell response was defined as IFN-γ release > 200 mIU/mL. Data on diagnoses were obtained through medical records, and data on accination status were obtained from the Danish Vaccination Register. Results: In patients with MM or B-CLL, the geometric mean concentration (GMC) of anti-RBD IgG increased from baseline 1.49 AU/mL (95% CI: 1.21-1.84) to three weeks after the first accine dose 15.10 AU/mL (95% CI: 9.39- 24.29) and after receiing the second dose 1179.60 AU/mL (95% CI: 727.78-1919.85). From two to six months after first accine there was a significant decline in the GMC of anti-RBD IgG to 252.75 AU/mL (95% CI: 159.17-403.43). The mean neutralizing capacity in patients with MM or B-CLL was lower than in controls at all time points after the first accine dose. Six months after first accine dose, 79 of 179 (44.1%) patients with MM or B-CLL had a positie humoral response, while this was the case for 170 of 179 controls (95.0%), p<0.001. Haing MM or B-CLL was significantly associated with risk of humoral non-response. This was most pronounced in B-CLL patients who had an age and sex adjusted risk ratio (RR) of 12.25 (95% CI: 6.42-23.38, p< 0.001) of humoral non-response compared to healthy controls. For MM patients the RR was 4.65 (95% CI: 2.21-9.80, p< 0.001). T-cell response was assessed in a subset of 48 patients with MM (n=28) or B-CLL (n=20) and 26 controls, six months after first accine dose. A total of 21 (43.8%) patients with MM (12/28) or B-CLL (9/20) and 14 (53.8%) controls had a positie T-cell response (p =0.56). Seen of 20 (35.0%) patients with MM or B-CLL who did not deelop a humoral response, deeloped a T-cell response (MM: 3/8, B-CLL: 4/12), while 14 of 28 (50.0%) patients with MM or B-CLL who deeloped a humoral response deeloped a T-cell response (p =0.46, MM: 9/11, B-CLL: 5/8). In healthy controls 14 of 25 (56.0%) people who deeloped a humoral response also deeloped a T-cell response. Summary/Conclusion: Humoral response to BNT162b2 was impaired in patients with MM or B-CLL compared to healthy controls. Both patients with MM and B-CLL were at higher risk of humoral non-response compared to healthy controls.

20.
HemaSphere ; 6:2786-2787, 2022.
Article in English | EMBASE | ID: covidwho-2032115

ABSTRACT

Background: In most individuals, protective humoral and cellular immunity develops after two doses of the BNT162b2 Pfizer vaccine. In patients with lymphoma, humoral response is weaker and almost universally abrogated in patients who received anti-CD20 monoclonal antibodies. Whether cellular immune response is also abrogated is unknown. Aims: To determine whether patients with lymphoma develop specific T-cell mediated cellular response to BNT162b2 Pfizer vaccine. Methods: We included patients with lymphoma above the age of 18 years who received two doses of the BNT162b2 Pfizer vaccine and collected clinical and demographics data. T-cell immune response to the vaccine was analysed in patients' blood samples stimulated by spike antigen and quantified by two methods: (1) Interferon-gamma (IFNg)- release assay (IGRA, EuroImmun, Germany)- IFNg was quantified by ELISA (DuoSet, R and D Systems, Minneapolis, Minnesota, USA) and response above 50 pg/ml was considered positive. (2) Flow cytometry- Quantification of the T cell activation markers, CD134+ CD25+CD4+ T-cells was performed (Act-T4 CellTM kit, Cytognos, Spain), and any response above 0 was considered positive. Humoral response was measured by SARS-CoV-2 IgG II Quant (Abbott©) assay. The positive cut-off was set at 50AU/ml. Blood samples were drawn approximately 4 months after the second vaccination. Results: Sixty-nine lymphoma patients, treated with two vaccine doses, were included in this study. Median age was 66 (range: 30-84) and 39 (57%) were males. Sixty-two patients (90%) had non-Hodgkin lymphoma (NHL) including 18 with DLBCL, 26 with follicular lymphoma and 14 with marginal zone lymphoma. Seven (10%) patients had Hodgkin lymphoma. In this cohort, 70% (n=49) of the patients received anti CD20 MoAb, and 35% of them (n=27) were still on anti CD20 treatment. Thirteen patients received bendamustine-based immunochemotherapy. At the time of assessment (median 4.8 months after the 2nd vaccine) anti-spike antibodies were detected in only 42% (N = 29) of patients. In comparison, there was an increase in specific T cell response by any assay (IGRA and Flow) in 49% of patients (n = 34). The correlation between the IGRA and flow data was 0.7 (pearson correlation, P = 0.01). However, no correlation between humoral (qualitative and quantitative) and T cell response was shown, regardless of the assay applied. Cellular response was not corelated with the time elapsing from last immunochemotherapy. In the anti-CD20 MoAb treated cohort, of which 27 patients were still on active treatment at the time of vaccination, only 2 patients (7%) developed a humoral immune response, while cellular immunity was elicited in 52% (N = 15) patients (ELISA assay). In the Bendamustine treated cohort, with a median time from end of treatment to vaccination of 23 months (1-106 months), humoral but not cellular response correlated positively with the time from treatment completion to vaccination (p=0.04). Summary/Conclusion: The rate of cellular and humoral response to two doses of the BNT162b2 Pfizer vaccine in lymphoma patients was found to be significantly abrogated. In this small cohort, 49% of patients developed a cellular response despite a severely abrogated humoral immunity. These findings suggest that vaccine administration should be considered even early after anti CD20 therapy despite the reduced humoral immunity. These findings should be validated in studies with a higher number of patients.

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