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1.
Hematology, Transfusion and Cell Therapy ; 44(Supplement 2):S681, 2022.
Article in English | EMBASE | ID: covidwho-2179248

ABSTRACT

Objetivos: A COVID-19 e uma doenca infecciosa, onde a maioria dos infectados desenvolve quadros leves, no entanto, idosos e individuos com comorbidades estao relacionados aos casos mais graves. A fim de conter a propagacao da doenca, foram desenvolvidas vacinas com a finalidade de inducao de memoria imunologica. Entretanto, estudos sobre a efetividade da imunizacao em idosos ainda sao escassos e nao se sabe exatamente como sera o comportamento nessa populacao. Dessa forma, o objetivo desta pesquisa foi avaliar esta resposta imune celular em idosos de Instituicoes de Longa Permanencia (ILPS) no estado de Sergipe, Brasil, induzida pela vacina CoronaVac. Material e Metodos: Este estudo prospectivo foi realizado com idosos (grupo idosos-GI) e profissionais (grupo controle-GC) de ILPS. Todos receberam a vacina CoronaVac e as analises foram feitas 30 dias apos a administracao da segunda dose da vacina. Respeitando-se os aspectos eticos e legais, os participantes foram submetidos a um questionario estruturado, e foram coletadas amostras de sangue periferico para analise das populacoes de linfocitos T CD4+ e CD8+ e os subtipos de memoria que foram avaliados por citometria de fluxo multiparametrica. Resultados: Foram avaliados 28 individuos, sendo 23 idosos (GI) e cinco profissionais (GC). No GI, nove eram do sexo feminino e 14 do masculino, com medias de idade 81,6 (67-89) e 74,1 (64-89), respectivamente. O grupo GC foi composto por duas mulheres e tres homens, e as medias de idades foram de 36,5 (24 e 49) para as mulheres e 45,0 (30-64) para os homens. Foi observado aumento da expressao dos linfocitos TCD3+ e TCD4+ nos idosos vacinados (p=0,0010 e p=0,0383) em comparacao ao GC. Os idosos tambem apresentaram aumento de LTCD4+ e LTCD8+, ambos de memoria efetora (CD45RA-CCR7-) demonstrando p=0,0471 e 0,0138, respectivamente. Avaliando as diferencas entre os sexos dos idosos, observou-se que os homens apresentaram aumento no numero total de LTCD8+ (p=0,0464) e LTCD8+ de memoria efetora (p=0,0199);e diminuicao nos LTCD4+ de memoria central (CD45RA-CCR7+) quando comparados com as mulheres (p= 0,0440). Discussao: Apesar de todos os avancos no controle da doenca e melhoria nos desfechos dos pacientes mais graves, inumeras questoes ainda permanecem sem resposta: As vacinas conferem a mesma protecao da infeccao ou sao fatores sinergicos? Idosos apresentam a mesma resposta aos imunizantes que os jovens? Nas infeccoes por SARS-CoV-2, as respostas dos LT sao detectadas em quase todos os casos, sendo as respostas das LT CD4+ mais proeminentes do que as respostas dos LT CD8+. Diferentemente das situacoes relatadas apos a infecao pelo SARS-CoV-2, avaliando a resposta ao imunizante CoronaVac, o presente trabalho demonstrou que idosos apresentaram maior producao de LTCD4+ quando comparados aos jovens. Entretanto, apesar de os LTCD8+ nao terem respostas diferentes entre os grupos (idosos e jovens), apresentaram maior resposta nos idosos do sexo masculino. Conclusao: Neste trabalho, foi observado que os homens parecem apresentar memoria efetora rapida maior que das mulheres, entretanto, as mulheres apresentaram memoria central maior, sugerindo imunidade prologada maior nas mulheres idosas do que nos homens. Copyright © 2022

2.
Hematology, Transfusion and Cell Therapy ; 44(Supplement 2):S658-S659, 2022.
Article in English | EMBASE | ID: covidwho-2179214

ABSTRACT

A resposta imune a infeccao por SARS-CoV-2 durante o periodo gravidico puerperal e as alteracoes que podem aumentar o risco de complicacoes maternas, fetais e neonatais ainda nao sao bem caracterizadas. Para isso, foram determinados, atraves de citometria de fluxo, niveis perifericos de linfocitos T-totais (CD3+), T-auxiliar (CD3+/CD4+), T-citotoxico (CD3+/CD8+), linfocitos B (CD19+), celulas NK (CD16+/56+) e NKT (CD3+/CD16-56+) em gestantes e puerperas com suspeita de COVID-19 com o objetivo de identificar potenciais alteracoes imunologicas induzidas pelo coronavirus. Foram utilizadas amostras de sangue periferico de mulheres que realizaram RT-PCR para COVID-19 entre maio de 2021 e marco de 2022. As amostras foram coletadas em tres maternidades publicas do Rio Grande do Norte na admissao para parto e no puerperio imediato nos casos suspeitos. O sangue foi coletado em tubos contendo EDTA para a realizacao da citometria de fluxo, utilizando o analisador de fluorescencia celular ativado (FACScan) e o software Cell Quest. Os linfocitos foram identificados por alta expressao de CD45 e baixa dispersao lateral, utilizando as seguintes combinacoes de 3 cores de anticorpo monoclonal: isotiocianato de uoresceina (FITC), ficoeritrina (PE) e Proteina Clorofila Piridina (PerCP). Cinquenta mulheres precisaram realizar o RT-PCR e 32 (64%) testaram positivo para COVID-19. Gestantes e puerperas infectadas pelo SARS-CoV-2 apresentaram niveis elevados de celulas T citotoxicas, mediana (ME) = 495,0;intervalo interquartil (IIQ) = 391,5, quando comparadas com pacientes nao infectadas, ME=356,2;IIQ=297,8;p=0.032. Com relacao a quantidade das celulas NK, ME=159,1;IIQ=220,4, e dos linfocitos B, ME=126,7;IIQ=186.4, as contagens foram significativamente mais baixas no grupo com menos de 30 dias de infeccao, em comparacao com o grupo em que o RT-PCR foi negativo, ME=280,8;IIQ=214,9;p=0,021 e ME=323,9;IIQ=365,5;p=0,045, respectivamente. Gestantes e puerperas com COVID-19 apresentam maior numero de linfocitos T citotoxicos no sangue periferico e menor numero de celulas NK e linfocitos B. Considerando que gravidez e pos-parto alteram fisiologicamente o sistema imunologico e que esse estudo transversal nao permite analisar causalidade entre infeccao e alteracoes celulares, mais estudos sao necessarios para elucidar as alteracoes causadas pela COVID-19 no sistema imunologico durante o periodo gravidico puerperal, para confirmar se a infeccao viral compromete a imunidade, aumentando o risco de complicacoes para o binomio mae-feto. Declaramos que nao houve apoio financeiro e (ou) material recebido para o desenvolvimento deste trabalho. Copyright © 2022

3.
Hematology, Transfusion and Cell Therapy ; 44(Supplement 2):S121, 2022.
Article in English | EMBASE | ID: covidwho-2179116

ABSTRACT

Objetivo: Descrever dois casos com desfechos diferentes de linfoma hepatoesplenico de celulas T gamma-delta (LHECTGD), entidade rara que corresponde a menos de 1% dos linfomas nao-Hodgkin. Caso clinico: Caso 1: Feminina, 71 anos, portadora de artrite reumatoide, HAS e glaucoma, internada por pancitopenia e pneumonia bacteriana sobreposta a infeccao por COVID-19. Fazia seguimento ha 2 anos com hematologia por anemia e plaquetopenia, sem exames diagnosticos. Em avaliacao medular, imunofenotipagem de medula compativel com linfoma T hepatoesplenico (LTHE). Devido intercorrencias infecciosas, paciente evoluiu para obito antes do tratamento da doenca hematologica. Caso 2: Masculino, 47 anos, avaliado em servico de hematologia devido hepatoesplenomegalia, baco ate 15cm do rebordo costal esquerdo (RCE), pancitopenia com neutropenia grau IV em hemograma inicial, descartadas infeccoes virais e leishmaniose visceral. Em avaliacao medular, biopsia de medula ossea evidenciou infiltracao por doenca linfoproliferativa B e imunohistoquimica inconclusiva. Imunofenotipagem de aspirado de medula ossea compativel com infiltracao por LTHE. O paciente recebeu tratamento com 6 ciclos de CHOEP e encontra-se com normalizacao de hemograma apos ultimo nadir, resposta clinica (reducao do baco para 3cm RCE e melhora dos sintomas B), alem de resposta em imagem no exame PET-CT. Atualmente, transplante autologo em andamento no intuito de consolidacao de resposta. Discussao: O LHECTGD tem pico de incidencia em adolescentes e adultos jovens e uma razao homem/mulher de 9:1. E uma doenca rara, visto que a maioria dos linfomas de celulas T expressa receptores alfa-beta e apenas 2-4% expressam receptores gamma-delta. Atualmente ha pouco mais de cem casos descritos na literatura, sendo definido como um linfoma de proliferacao maligna de celulas T nos sinusoides do figado, na polpa vermelha do baco e na medula ossea. O fenotipo frequentemente exposto e de celulas T CD2+, CD3+, CD4-, CD5-, CD7+-, CD8-, com expressao de receptor celula T gama delta ou alfa beta. Dentre as anormalidades citogeneticas associadas, inclui-se o isocromossomo 7q com ou sem trissomia do 8. Clinicamente, os pacientes apresentam sintomas B, alem de hepatoesplenomegalia acentuada, sem adenomegalias suspeita, o que aumenta o desafio diagnostico e leva a inferencias diagnosticas infecciosas e de hipertensao portal antes do diagnostico hematologico. O tratamento engloba desde a intervencao cirurgica, como a esplenectomia - no intuito de controlar o hiperesplenismo e evitar uma das principais causas de obito, a ruptura esplenica -, alem de quimioterapias baseadas em regimes que contenham etoposideo, sem esquemas com relato de superioridade na literatura. O transplante autologo (e em alguns relatos, o alogenico) foram indicados para consolidacao quando ha resposta ao tratamento. Conclusao: O LHETGD e uma doenca rara, de prognostico reservado, com multiplos relatos de atraso diagnostico devido a ausencia de sintomas especificos da doenca. Recomenda-se, assim, que, diante de paciente jovens, com quadro de trombocitopenia ou alteracoes de outras linhagens e hepatoesplenomegalia, a hipotese diagnostica de LHECTGD deve ser considerada. Em relacao ao arsenal terapeutico disponivel atualmente, novos estudos mostram-se necessarios, objetivando melhorar a expectativa e qualidade de vida dos pacientes. Copyright © 2022

4.
Pediatrics ; 150, 2022.
Article in English | ProQuest Central | ID: covidwho-2162658

ABSTRACT

PURPOSE OF THE STUDY: T cell lymphopenia is prevalent in severe coronavirus disease 2019 (COVID-19). This study evaluated associations with homeostatic and functional T cell responses in COVID-19 with the goal of identifying immunologic features of severe disease. STUDY POPULATION: Patients aged 18 years and older with symptomatic, real time-quantitative polymerase chain reaction confirmed SARS-CoV-2 (mild, n = 54;severe, n = 49) were recruited at 4 hospitals in the Canton of Zurich, Switzerland from April 2 to August 19, 2020, and a group of healthy controls recruited for comparison (n = 27). A subset (mild, n = 28;severe, n = 38, healthy, n = 22) had comprehensive T cell characterization. METHODS: In this prospective, observational, cross-sectional study, symptomatic participants with mild and severe COVID-19 and healthy controls were sampled at a single time point. Phenotypic and functional characteristics of T cells were evaluated using 40-parameter mass cytometry, flow cytometry, targeted proteomics, and functional assays. RESULTS: Compared with mild disease, severe COVID-19 was associated with T cell lymphopenia and redistribution of T cell populations, including loss of naïve and memory CD4+ and CD8+ T cells, skewing toward CD4+ T follicular helper cells and cytotoxic CD4+ T cells, and expansion of activated and exhausted T cells. Individuals with severe disease and T cell lymphopenia had signs of tissue migration, extensive T cell apoptosis, and impaired T cell responses to common viral antigens. Patients with severe disease also showed elevated interleukin-7 and increased T cell proliferation. Those sampled longest after symptom onset had higher T cell counts and improved antiviral T cell responses. CONCLUSIONS: Severe COVID-19 is characterized by extensive T cell dysfunction. Reduced naïve T cells and virus-specific memory T cell numbers are associated with severe disease and impaired T cell responses to viral antigens, particularly early in the disease. Increased T follicular helper cells may contribute to a robust antibody response often observed in COVID-19. T cell apoptosis is associated with lymphopenia and homeostatic T cell proliferation and T cell recovery in the later stages of disease.

5.
Clinical and Experimental Rheumatology ; 40(10):82-83, 2022.
Article in English | EMBASE | ID: covidwho-2067782

ABSTRACT

Objectives. The peripheral lymphocyte compartment of patients with primary Sjogren's syndrome (pSS) differs strongly from healthy individuals. Whether this altered lymphocyte composition also abnormally changes during immune reactions, especially in the context of novel mRNA-vaccines, is unknown. Methods. Peripheral blood samples from 26 pSS patients were compared to 6 healthy controls before Coronavirus-2 (CoV-2) vaccination (BNT162b2, ChAdOx1, mRNA-1273) and 7 days after secondary vaccination. Spike. 1 (S1)-receptor binding domain (RBD)-neutralizing IgG antibodies were measured in serum samples. Within peripheral blood mononuclear cells (PBMC), lymphocytes were characterized using spectral flow cytometry and B and T cell subpopulations were phenotypically analyzed. Results. Immunization induced CoV-2 specific serum antibodies in all pSS and healthy participants. When analyzing pSS and healthy individuals together, frequencies of circulating IgG+ RBD-binding antibody-secreting cells (ASC) and anti-CoV-2 serum titers correlated (r=0.42, p=0.022). Previously described alterations of peripheral B cells in pSS patients (like reduced memory B cells, increased naive and transitional B cells and higher maturity of ASCs) remained stable during vaccination. Also the subset distribution of CD4+ and CD8+ T cells mainly stayed unchanged. However, CD4+CXCR5-PD-1+ T cells phenotypically mimicking peripheral helper TPH cells increased in pSS patients comparing pre- and post-vaccination (p=0.020), while circulating CD4+CXCR5+PD-1+ follicular helper TFH cells declined (p=0.024). Conclusions. An immune reaction induced by vaccination with the novel mRNA technology yields adequate antibody production and vaccine specific lymphocytes in pSS patients and controls. However, no major changes within the typical composition of lymphocyte subpopulations of pSS patients were observed despite small changes in TPH and TFH subsets.

6.
American Journal of Transplantation ; 22(Supplement 3):1102, 2022.
Article in English | EMBASE | ID: covidwho-2063518

ABSTRACT

Purpose: Vaccination against SARS-CoV-2 is essential. Complicating this effort are reports of a suboptimal response to the SARS-CoV-2 spike protein in patients on immunosuppressive medications and possible thrombotic microangiopathy (TMA) in renal transplant patients who receive the mRNA type vaccines. Method(s): 48 year old male with end stage renal disease who received a living unrelated transplant in 2015. Pre-operative creatinine was 10.42 mg/dL and decreased to 2.48 mg/dL within a week. Patient received Basiliximab induction and maintained on tacrolimus and mycophenolate (MMF). One month post-transplant patient was diagnosed with TMA. Tacrolimus was stopped and patient was switched to Sirolimus and continued on MMF. Patient was followed closely by transplant nephrology for the next 5 years with a baseline creatinine of 1.9 mg/dL, protein to creatinine ratio below 0.5 mg/mg and well controlled diabetes. No DSA Class I or II detected on regular testing. Patient was compliant with all prescribed medications. On January 25 2021 patient received Pfizer Vaccine. Second Pfizer vaccine administered on February 18 2021. A week later creatinine was noted to be 3.44 mg/dL. Repeat creatinine of 4.27 mg/dL. Biopsy revealed diffuse lymphocytic interstitial inflammation, peritubular capillaritis, and C4D negative. Findings consistent with chronic TMA. DSA testing revealed Class II DSA:DQ2 (SI-5933), Allosure 1.2 %. BK < 500 and CMV undetected. Patient received therapeutic plasma exchange, IV Ig infusion and steroids while on MMF and sirolimus. His creatinine decreased to 2.9 mg/dL on discharge. Over the next 6 months graft function deteriorated. He is now CKD stage 5 and under evaluation for a second transplant. Result(s): There are case reports of COVID-19 vaccine administration and transplant graft dysfunction. A possible mechanism involves the mRNA lipid nanoparticleencapsulated platform producing such a robust CD4 and CD8 T-cell response that pro-inflammatory cytokines are activated or that immune complex associated glomerular disease occurs resulting in the development of TMA in susceptible patients. Conclusion(s): A possible link between SARS CoV-2 vaccination and kidney transplant TMA warrants the implementation of close surveillance of vaccinated transplant patients, particularly susceptible individuals. More research is needed to determine if this link exists.

7.
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.

8.
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.

9.
American Journal of Transplantation ; 22(Supplement 3):1059, 2022.
Article in English | EMBASE | ID: covidwho-2063485

ABSTRACT

Purpose: The purpose of this study was to evaluate long term humoral and cellular immunity generated following SARS-CoV-2 infection in solid organ transplant recipients (SOTR). Method(s): Patients included had an active graft of an organ transplant as an adult, a positive polymerase chain reaction nasopharyngeal swab for SARS-CoV-2 after transplant, and had not received convalescent plasma, vaccination, or monoclonal antibody for SARS-CoV-2. Whole blood was obtained 6 months (+/- 1 month) after infection. Serology measured IgG and IgM titer to the SARS-CoV-2 spike protein receptor binding domain, reported as signal/ cut-off ratio (s/co). CD4+ and CD8+ T-cell reactivity was measured by Activation Induced Marker assays following stimulation of peripheral blood mononuclear cells with SARS-CoV-2 peptide pools encompassing the SARS-CoV-2 spike protein. Result(s): Of 25 subjects, 19 (76.0%) were hospitalized, 4 (16.0%) developed hypoxia, but none required mechanical ventilation. Biopsy-proven graft rejection occurred in 3 (12.0%), but none had graft loss. At 6 months, 8 (16%) had persistent symptoms and 2 (4.0%) were re-infected within one year. In the immunity study, 22 (88.0%) had reactive IgG testing and 11 (44.0%) had reactive IgM testing. Median IgG titer was 3.68 s/co (range 0.19-36.44) and IgM titer was 0.79 s/co (range 0.02-16.41). Virus-specific CD4+ T-cell reactivity was noted in 23 (92%), but only 10 (40.0%) had reactive CD8+ T-cell testing. Moderate correlation was observed between IgG and IgM titer (r=.51, p= 0.009) and between IgG titer and percent virus-specific CD4+ T-cells (r=.46, p=0.02). CD8+ T-cell reactivity was correlated with greater illness severity (p=0.043). Use of Tacrolimus, mycophenolate, or corticosteroids at time of infection was not associated with T-cell or antibody reactivity. Conclusion(s): In summary, this cohort of SOTR evaluated six months after noncritical COVID-19 illness demonstrated robust IgG and CD4+ T-cell responses, and CD8+ T-cell reactivity was correlated with higher disease severity.

10.
American Journal of Transplantation ; 22(Supplement 3):1066, 2022.
Article in English | EMBASE | ID: covidwho-2063484

ABSTRACT

Purpose: The purpose of this study was to study our cohort of adult solid organ transplant recipients who had been infected with SARS-CoV-2 to describe the incidence density of SARS-CoV-2 re-infection, as well as the clinical features and convalescent immunity profile. Method(s): Incidence density was calculated as the total cases of re-infection divided by total days after initial diagnosis with active graft. We included those with initial infection diagnosed by polymerase chain reaction before or after transplantation, and cycle threshold values were obtained when possible. Two recipients had immunity evaluated in the weeks prior to re-infection, by measuring IgG antibody titer to the SARS-CoV-2 receptor binding domain and virus-specific CD4+ and CD8+ T-cell reactivity following stimulation with SARS-CoV-2 peptide pools and using activation induced marker assays. Result(s): Out of 210 infected recipients, 5 (2.4%) developed re-infection, including two that had received full mRNA vaccination, but none developed hypoxia. The incidence density was 9.4 (95% confidence interval 3.9-22.6) cases/100,000 patient days. Two cases of re-infection had participated in our immunity study and had convalescent immunity data from a blood draw approximately six months after initial infection and prior to re-infection. Both mounted virus specific CD4 T cell responses prior to re-infection (1.19% and 0.28% of total CD4 T cells) and both had reactive IgG testing (1.30 and 4.99 signal/cut off ratio). Conclusion(s): This suggests that SOT recipients infected with SARS-CoV-2 remain at high risk for re-infection even after generating reactive cellular and humoral immune responses.

11.
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.

12.
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.

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.
American Journal of Transplantation ; 22(Supplement 3):441, 2022.
Article in English | EMBASE | ID: covidwho-2063376

ABSTRACT

Purpose: To evaluate post-vaccination cellular and antibody (Ab) immunity after COVID-19 vaccination in single blood samples from 17 kidney transplant (KT) recipients who had received COVID-19 vaccination Methods: We measured frequencies of peripheral blood T- and B-cells which expressed the inflammatory marker CD154 after overnight stimulation with peptide mixtures representing the spike protein S, its S2 component which is conserved between SARS-CoV-2 and human coronaviruses, and the S1 component, which is specific to SARS-CoV-2 and also contains its receptor binding domain (RBD). Serum from each sample was assayed for anti-RBD and anti-S IgG Abs with ELISA. Optical density at 450nm (OD450) of 0.45 or greater implied presence of either Ab. Frequencies of monocytic and polymorphonuclear (PMN) myeloid-derived suppressor cell were also measured with flow cytometry. Result(s): Median age was 40 yrs (range 25 to 83), male:female gender distribution was 7:8. All recipients received mRNA vaccination. Anti-S-IgG and anti-RBD-IgG were detected in 11 (Ab+) and were absent in four (Ab-). Compared with Ab+ KT recipients, those who were Ab- had lower frequencies of S2-reactive and S-reactive B-cells (p<0.05), CD4+ and CD8+ T-cells (Table 1, Fig 1). S1-reactive T-cell and B-cells were non-detectable. Frequencies of PMN-MDSC were numerically higher in Ab- compared with Ab+ KT recipients (Mean +/- SEM 38.9+/-8.1 vs 19.4+/-1.8, p-value 0.1, NS). Significant negative correlation was observed between PMN-MDSC frequencies and strength of anti-RBD IgG and anti-SPIKE IgG (Fig 1). Conclusion(s): COVID-19 vaccination results in spike antigen reactive T- and B-cells in KT recipients who develop Abs after vaccination. Failure of an Ab response is associated with impaired B-cell responses to the spike antigen and an increase in circulating polymorphonuclear myeloid derived suppressor cells. (Table Presented).

15.
American Journal of Transplantation ; 22(Supplement 3):441-442, 2022.
Article in English | EMBASE | ID: covidwho-2063342

ABSTRACT

Purpose: Correlates of protection for SARS-CoV-2 vaccines are not well-established in kidney transplant recipients(KTRs). Studies have highlighted the importance of neutralizing antibodies(Abs), however data suggests T cell responses may play a secondary role in preventing reinfection. We performed a longitudinal assessment of immunogenicity, T and B cell response in KTRs following SARS-CoV-2 vaccination. Method(s): KTRs eligible for SARS-CoV-2 vaccination from 3/12/21 were enrolled. Baseline and weekly blood samples were collected for routine lab, SARS-CoV-2 spike protein Ab titers and cellular phenotyping for 12 weeks. Ab response was defined as a 10-fold increase in total binding IgG titers. To determine if T cell responses were induced by vaccination, we considered the proportion of activated non-naive CD4+ and CD8+ T cells post-vaccination. Result(s): 49 KTRs were enrolled ( Demographics -Table 1). 10 patients (20.4%) mounted an Ab response following vaccination. A history of COVID-19 was associated with an increased likelihood of developing an Ab response (OR: 18.3, 95% CI 3.2, 105.0, p=0.0005). For non-naive CD8+ T cells, a subset co-expressing CD38+Ki67+ was induced 1 week after the 1st immunization in some SARS-CoV- 2-naiive patients (P=0.12 versus P=0.14 for SARS-CoV-2-experienced adults, Fig 1A/B). For non-naive CD4+ T cells, induction of a subset co-expressing CD38+Ki67+ was observed at 1 week after the 1st immunization for SARS-CoV-2-naive participants (P = 0.09 for SARS-CoV-2-naive, P=0.03 for SARS-CoV-2-experienced adults, Fig 1C/D). For CD8+ and CD4+ T cells, dose 2 stimulated weak induction of the CD38+Ki67+ subset in the SARS-CoV-2-naive patients only (Fig 1A-D). Conclusion(s): Quantitative Ab responses were strongly associated with prior SARS-CoV-2 infection. Activated CD4+ and CD8+ T cell responses were evident in most patients irrespective of history of COVID-19. Further studies are needed to determine whether these activated CD4+ and CD8+ T cell responses were antigenspecific or confer immunity. (Table Presented).

16.
Chest ; 162(4):A865-A866, 2022.
Article in English | EMBASE | ID: covidwho-2060714

ABSTRACT

SESSION TITLE: Studies on COVID-19 Infections Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/18/2022 01:30 pm - 02:30 pm PURPOSE: Latent Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are commonly reactivated in critically ill patients with severe infections. This study aimed to evaluate the proportion of reactivation of EBV and CMV and its impact on length of stay, need for ventilation, and Ichikado CT scores in patients with coronavirus disease 2019 (COVID-19). METHODS: A retrospective study was conducted comprising adult patients admitted to our hospital with COVID-19 infection from June 2021 to September 2021. Patients were divided into groups: virus-free, EBV-only, CMV-only, and EBV and CMV detected. Primary outcomes were length of stay, need for ventilation, and Ichikado CT score. Descriptive statistics, one-way ANOVA, Games-Howell, and Kruskal-Wallis tests were used. RESULTS: 189 patients were included with a median age of 51 years [41 – 66], 80 (42.3%) were female and 109 (57.7%) were male. CD4(+) counts were lower in all viral reactivation groups. EBV-only (157 cell/µl [93 – 279.2] ), CMV-only (82.5 cell/µl [65.5 – 323.7] ), both viruses (62.5 cell/µl [47.5 – 135.5]) and virus-free (221 cell/µl [117 – 318]), (H(3) = 12.029, p = < 0.01). A significant increase in the Ichikado CT score was seen in the viral reactivation groups. EBV 186.5 [43.6], CMV 177.5 [41.6], both-viruses group 204 [50.3] vs. virus-free 161 [45.8],( H(3) = 15.770, p = < 0.01). There was an increase in days of hospitalization when comparing the virus-free and the viral reactivation groups. EBV (9 days [5.5-15.5]), CMV (17 days [3-33]), both viruses (23 days [8-31]) vs. virus-free (5 days [3.5-9]), (H(3) = 15.487, p = < 0.01). Regarding the need for assisted ventilation, there was no difference between groups. 7 (9.1%) patients in the virus-free group, 29 (29.9%) patients in the EBV group, 2 (33.3%) patients in the CMV group, and 2 (22.2%) patients in the both-viruses group needed mechanical ventilation (X2 (3, N=189) = 11.699, p= 0.08). Additionally, a statistically significant decrease in albumin levels on admission was found in the EBV-only patients compared to the virus-free group, (3.4 g/dL [0.44] vs 3.75 g/dL [0.46], F(3,185) = 5.483, p = < 0.01). CONCLUSIONS: Viral reactivation is associated with lower CD4(+) count, an increase in length of stay, and higher Ichikado CT scores. CLINICAL IMPLICATIONS: EVB and CMV reactivation is associated with low CD4(+) counts and longer hospital stay. DISCLOSURES: No relevant relationships by David Akinwale No relevant relationships by Angelica Almaguer No relevant relationships by Sushen Bhalla No relevant relationships by Ailine Canete Cruz No relevant relationships by Ndiya Emeaba Speaker/Speaker's relationship with johnson and johnson Please note: approx year 2000 Added 03/31/2022 by Joseph Gathe, value=Honoraria clinical research relationship with gilead Please note: since 1990 Added 03/31/2022 by Joseph Gathe, value=Grant/Research clinical research relationship with ansun Please note: 2020 Added 03/31/2022 by Joseph Gathe, value=Grant/Research Support clinical research relationship with regeneron Please note: 2020 Added 03/31/2022 by Joseph Gathe, value=Grant/Research Support No relevant relationships by Jesus Salvador Gonzalez Lopez No relevant relationships by Najia Hussaini No relevant relationships by Claudia Ramirez No relevant relationships by Salim Surani No relevant relationships by Daryelle Varon No relevant relationships by Joseph Varon No relevant relationships by Mohamed Ziad

17.
Chest ; 162(4):A859-A860, 2022.
Article in English | EMBASE | ID: covidwho-2060711

ABSTRACT

SESSION TITLE: Biological Markers in Patients with COVID-19 Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/18/2022 01:30 pm - 02:30 pm PURPOSE: A significant reduction of CD4(+) cells and marked inflammatory activity in moderate and severe COVID-19 cases are seen, both associated with a poor prognosis. This study aimed to assess the association of low CD4(+) counts with inflammatory markers, length of stay, and ICKIKADO scores in COVID-19 patients. METHODS: A retrospective study of adult patients admitted to our hospital with COVID-19 infection from June 2021 to September 2021. CD4(+) count was obtained and patients were divided into two categories: less than 200 cells/μl and more than 200 cells/μl. Ferritin, c-reactive protein (CRP), erythrocyte sedimentation rate (ESR), troponin, Lactate dehydrogenase (LDH), and d-Dimer values were also recorded. Primary outcomes were hospital length of stay (LOS), Ichikado CT scores, and correlation of CD4(+) count and inflammatory markers. Descriptive statistics, and Mann-Whitney-U methods were used. RESULTS: 264 patients were included, median age was 50 years [41-61]. 143(54.2%) were male. There was a statistically significant difference in LOS for patients with CD4(+) counts <200 cells/μl vs > 200 cells/μl CD4(+) (9 days [5-18]vs 6 days [4-9]), U=(111,107)=4330, z=-3.466, p <0.01). The Ichikado CT score was significantly different between groups (190[150-220]vs 160[128.7-192.5], U=(106,102)=3706.5, z=-3.923, p<0.01). IL-10 values and IL-6 values were higher in those patients with CD4(+) less than 200 cells/μl, as compared to higher CD4(+) counts. median IL-10 was (25.2 pg/ml [17-72.45 ] vs 15.7 pg/ml [9.4-26.8 ], U=(109,100)=3463, z=-4.550, p<0.01), and median IL-6 was (23 pg/ml [10.5-99] vs 12 pg/ml [3.77-39], U=(104, 96)=3444.5, z=-3.785, p<0.01). Ferritin was increased in patients with CD4(+) counts lower than 200 cells/μl when compared to counts more than 200 cells/μl (850.2 ng/mL [373.3-1600] vs 541.5 ng/mL [245.1-1034.6], U=(110,106) =4543.5, z=-2.813, p=<0.01). CRP had a similar pattern (82 mg/L[49.5-138.2] vs 60.8 mg/L[30-114.2]), U=(111,105)=4478, z=-2.940, p=<0.01), d-Dimer (2.2 mg/L[0.55-7.14] vs 0.7mg/L[0.37-1.75], U=(111,107)=3992.5, z=-4.180, p<0.01), LDH (630 IU/L[371-888] vs 381 IU/L[276-520.2], U=(102,92)=2631.5,z=-5.227, p<0.01) and troponin (0.024 ng/mL[0.012-0.048] vs 0.012 ng/mL[0.007-0.027], U=(91,90)=2925, z=-3.321,P<0.01). The only inflammatory marker that was not statistically significant different was ESR (86 mm/hr[60-110] vs 72 mm/hr[50-100], U(111-107)=5113, z=-1.773,P=0.076). CONCLUSIONS: CD4(+) counts below 200 cells/μl are associated with increased inflammatory markers, a longer hospital stay, and higher Ichikado CT scores. CLINICAL IMPLICATIONS: CD4(+) count below 200 cells/μl is other indicator of disease severity in COVID-19 DISCLOSURES: No relevant relationships by David Akinwale No relevant relationships by Angelica Almaguer No relevant relationships by Sushen Bhalla No relevant relationships by Ailine Canete Cruz No relevant relationships by Ndiya Emeaba Speaker/Speaker's relationship with johnson and johnson Please note: approx year 2000 Added 03/31/2022 by Joseph Gathe, value=Honoraria clinical research relationship with gilead Please note: since 1990 Added 03/31/2022 by Joseph Gathe, value=Grant/Research clinical research relationship with ansun Please note: 2020 Added 03/31/2022 by Joseph Gathe, value=Grant/Research Support clinical research relationship with regeneron Please note: 2020 Added 03/31/2022 by Joseph Gathe, value=Grant/Research Support No relevant relationships by Jesus Salvador Gonzalez Lopez No relevant relationships by Najia Hussaini No relevant relationships by Claudia Ramirez No relevant relationships by Salim Surani No relevant relationships by Daryelle Varon No relevant relationships by Joseph Varon No relevant relationships by Mohamed Ziad

18.
Chest ; 162(4):A562-A563, 2022.
Article in English | EMBASE | ID: covidwho-2060632

ABSTRACT

SESSION TITLE: COVID-19 Co-Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Pneumocystis jirovecii pneumonia (PJP) remains a significant cause of morbidity and mortality in the immunocompromised population. It can be difficult to discern the radiographic imaging of COVID-19 from PJP. This case describes a noncompliant HIV positive male with remote history of PCP pneumonia and COVID-19 pneumonia who presents with simultaneous recurrence of both disease processes. CASE PRESENTATION: A 45-year-old male with PMH of HIV/AIDS noncompliant on ART (CD4+ 10) presented for evaluation of exertional dyspnea and productive cough for the past 2 weeks. Of note, patient had a history of covid-19 pneumonia about 15 months ago when he was treated with remdesivir and steroids and required supplemental oxygen support. He was also admitted about 8 months prior for PJP pneumonia and underwent treatment with steroids and TMP-SMX for 21 days also requiring supplemental oxygen support. During this presentation, initial vital signs showed: T 36.5 C HR 98 BP 112/63 RR 20 saturating 95% breathing ambient air. ABG on presentation showed PaO2 65 while breathing room air. Physical exam suggested bilateral crackles diffusely with chest radiography significant for increased interstitial markings bilaterally. CT chest showed bilateral groundglass changes suggestive of inflammatory process. He was initially started on antibiotic coverage with azithromycin, ceftriaxone, and TMP-SMX as the initial differential included PJP recurrence since he was noncompliant on secondary prophylaxis after recent infection. He was also started on steroids due to low PaO2. SARS-CoV-2 PCR returned positive however, the low CD4+ count, and a positive serum B-D-glucan assay prompted us to schedule a bronchoscopy to evaluate for PJP pneumonia. BAL showed positive silver stain along with bronchial wash was elevated PCR for PJP (5.6 million copies/mL). A diagnosis of concurrent COVID-19 pneumonia and PJP pneumonia was made. Patient did not receive remdesivir during this admission since his oxygenation began to improve during the hospitalization. Patient was discharged on appropriate regiment for PJP pneumonia and continued steroid taper. He was seen as a follow-up in outpatient clinic about 2 months later compliant on his ART regimen and secondary PJP prophylaxis (CD4 120). DISCUSSION: If it wasn't for the serum B-D-glucan, we likely would not have pursued further causes for hypoxia in an otherwise COVID-19 positive patient with characteristic radiographic findings. The sheer co-incidence and concurrent nature of presentation of these two disease processes make our case extremely unique. Going forward, it is reasonable to keep PJP in the differential when treating a hypoxic immunocompromised patient even if an alternative cause for hypoxia is present. CONCLUSIONS: Herein we present a case of a patient with remote history of COVID-19 pneumonia and PJP pneumonia now presenting with a simultaneous co-infection. Reference #1: Mouren, D., Goyard, C., Catherinot, E., Givel, C., Chabrol, A., Tcherakian, C., Longchampt, E., Vargaftig, J., Farfour, E., Legal, A., Couderc, L. J., & Salvator, H. (2021). COVID-19 and Pneumocystis jirovecii pneumonia: Back to the basics. Respiratory medicine and research, 79, 100814. https://doi.org/10.1016/j.resmer.2021.100814 Reference #2: Huang, L., Cattamanchi, A., Davis, J. L., Boon, S. d., Kovacs, J., Meshnick, S., Miller, R. F., Walzer, P. D., Worodria, W., & Masur, H. (2011). HIV-associated Pneumocystis pneumonia. Proceedings of the American Thoracic Society, 8(3), 294–300. https://doi.org/10.1513/pats.201009-062wr Reference #3: Tasaka, S. (2015). pneumocystis pneumonia in human immunodeficiency virus–infected adults and adolescents: Current concepts and Future Directions. Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine, 9s1. https://doi.org/10.4137/ccrpm.s23324 Group, T. R. C. (2020). Dexamethasone in hospitalized patients with covid-19. (2021). New England Journal of Medicine, 384(8), 693–704. https://doi.org/10.1056/nejmoa2021436 KOLDITZ, M., HALANK, M., BANDT, D., SPORNRAFT-RAGALLER, P., & HÖFFKEN, G. (2009). Early recurrence ofPneumocystis jirovecipneumonia in two HIV-infected patients: Linking infection relapse and immune reconstitution syndrome. Respirology, 14(6), 910–912. doi:10.1111/j.1440-1843.2009.01583.x Mussini C, Pezzotti P, Antinori A, Borghi V, Monforte Ad, Govoni A, De Luca A, Ammassari A, Mongiardo N, Cerri MC, Bedini A, Beltrami C, Ursitti MA, Bini T, Cossarizza A, Esposito R;Changes in Opportunistic Prophylaxis (CIOP) Study Group. Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients: a randomized trial by the CIOP Study Group. Clin Infect Dis. 2003 Mar 1;36(5):645-51. doi: 10.1086/367659. Epub 2003 Feb 12. PMID: 12594647. DISCLOSURES: No relevant relationships by Mourad Ismail No relevant relationships by Carlos Palacios No relevant relationships by Rutwik Patel

19.
Chest ; 162(4):A480, 2022.
Article in English | EMBASE | ID: covidwho-2060605

ABSTRACT

SESSION TITLE: COVID-19 Case Report Posters 3 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Exposure to anti-CD20 treatment affects B cell functions involved in anti-COVID immunity and impacts the clinical course of infection. We present two patients with persistent respiratory symptoms and persistent SARS-COv-2 PCR positivity months after initial infection. The aim of presenting these cases is to highlight how exposure to Rituximab can result in patients having significantly prolonged SARS-CoV-2 infections that may require special treatment compared to immunocompetent patients. CASE PRESENTATION: Patient A is a 46-year-old man with a history of marginal zone lymphoma, who was treated with six cycles of bendamustine with rituximab and monthly maintenance rituximab. He has been hypoxic for 7 months after COVID infection with ground glass opacities on imaging, elevated CRP of 58.4, positive PCR, undetectable CD3/CD4 and low cycle threshold of 28, suggesting rapid active viral replication. COVID IGG was negative. T cell subsets counts were undetectable. IgG 351, IgA 59, IgM less than 10. He was treated with a 10-day course of Remdesevir and steroids. Given lack of humoral immunity, he was given convalescent plasma. At discharge he developed positive COVID IgG and remained COVID positive by PCR. He had complete resolution of hypoxia. Patient B is a 68-year-old man with a history of chronic lymphocytic leukemia, who was treated with six years of rituximab maintenance therapy, last rituximab was three years ago. He was diagnosed with SARS-CoV-2 three months prior to admission with worsening hypoxia. He remained PCR positive with persistent respiratory symptoms. At readmission his imaging showed ground glass opacities, CRP 6.6 and cycle threshold was 27.8. The follow studies were abnormally low:IgG 541, IgA 25, IgM 14, absolute CD3 171, absolute CD4 68. He was treated with remdesivir, steroids, granulocyte colony stimulating factor and sotrovimab. Despite these therapies, his hypoxia worsened, and he pursued comfort care. DISCUSSION: There are reports of patients receiving B cell depleting therapy who have persistent shedding of viable SARS-CoV. Persistent viral infection may be suspected in patients with relapsing symptoms, elevated CRP, D-dimer and active ground glass changes imaging. Low T cell subsets and low immunoglobulin levels indicate a CD20 related impairment of adaptive immunity. Time to viral clearance appears to be prolonged compared to general population in immunocompromised patients. There is some published experience using convalescent plasma in this setting. SARS-CoV-2 viremia has been demonstrated to predict adverse outcomes. Median cycle threshold has been shown to be lower, reflecting a high viral load comparable with acute infectious phase of COVID. CONCLUSIONS: To achieve stable clinical responses this subset of patients may benefit from early administration of combination regimens, including both passive immunotherapy and prolonged antiviral treatment. Reference #1: Furlan A, Forner G, Cipriani L, Vian E, Rigoli R, Gherlinzoni F, Scotton P. COVID-19 in B Cell-Depleted Patients After Rituximab: A Diagnostic and Therapeutic Challenge. Front Immunol. 2021 Nov 3;12:763412. doi: 10.3389/fimmu.2021.763412. PMID: 34804051;PMCID: PMC8595333. DISCLOSURES: No relevant relationships by Cheryl Augenstein Primary Investigator relationship with Boehringer Ingelheim Please note: 2/2022-2/2024 Added 04/01/2022 by A. Thanushi Wynn, value=Grant/Research Support

20.
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.

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