RESUMO
This analysis reports on the outcomes of two different steroid sparing immunosuppression protocols used in the management of 120 highly sensitised patients (HSPs) with cRF>85% receiving Alemtuzumab induction, 53 maintained on tacrolimus (FK) monotherapy and 67 tacrolimus plus mycophenolate mofetil (FK + MMF). There was no difference in the median cRF or mode of sensitisation between the two groups, although the FK + MMF cohort received more poorly matched grafts. There was no difference in one-year patient or allograft survival, however rejection free survival was inferior with FK monotherapy compared with FK + MMF at 65.4% and 91.4% respectively, p < 0.01. DSA-free survival was comparable. Whilst there was no difference in rates of BK between the cohorts, CMV-free survival was inferior in the FK + MMF group at 86.0% compared with 98.1% in the FK group, p = 0.026. One-year post-transplant diabetes free survival was 89.6% and 100.0% in the FK and FK + MMF group respectively, p = 0.027, the difference attributed to the use of prednisolone to treat rejection in the FK cohort, p = 0.006. We report good outcomes in HSPs utilising a steroid sparing protocol with Alemtuzumab induction and FK + MMF maintenance and provide granular data on immunological and infectious complications to inform steroid avoidance in these patient groups.
Assuntos
Imunossupressores , Transplante de Rim , Humanos , Alemtuzumab/uso terapêutico , Imunossupressores/uso terapêutico , Tacrolimo/uso terapêutico , Transplante de Rim/métodos , Terapia de Imunossupressão/métodos , Esteroides , Ácido Micofenólico/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Sobrevivência de EnxertoRESUMO
Patients with end stage kidney disease receiving in-center hemodialysis (ICHD) have had high rates of SARS-CoV-2 infection. Following infection, patients receiving ICHD frequently develop circulating antibodies to SARS-CoV-2, even with asymptomatic infection. Here, we investigated the durability and functionality of the immune responses to SARS-CoV-2 infection in patients receiving ICHD. Three hundred and fifty-six such patients were longitudinally screened for SARS-CoV-2 antibodies and underwent routine PCR-testing for symptomatic and asymptomatic infection. Patients were regularly screened for nucleocapsid protein (anti-NP) and receptor binding domain (anti-RBD) antibodies, and those who became seronegative at six months were screened for SARS-CoV-2 specific T-cell responses. One hundred and twenty-nine (36.2%) patients had detectable antibody to anti-NP at time zero, of whom 127 also had detectable anti-RBD. Significantly, at six months, 71/111 (64.0%) and 99/116 (85.3%) remained anti-NP and anti-RBD seropositive, respectively. For patients who retained antibody, both anti-NP and anti-RBD levels were reduced significantly after six months. Eleven patients who were anti-NP seropositive at time zero, had no detectable antibody at six months; of whom eight were found to have SARS-CoV-2 antigen specific T cell responses. Independent of antibody status at six months, patients with baseline positive SARS-CoV-2 serology were significantly less likely to have PCR confirmed infection over the following six months. Thus, patients receiving ICHD mount durable immune responses six months post SARS-CoV-2 infection, with fewer than 3% of patients showing no evidence of humoral or cellular immunity.
Assuntos
Anticorpos Antivirais/análise , COVID-19/imunologia , Falência Renal Crônica/terapia , Diálise Renal/efeitos adversos , SARS-CoV-2/imunologia , Teste para COVID-19 , Feminino , Humanos , Imunidade , Masculino , Pandemias , Reação em Cadeia da Polimerase , Reinfecção , SARS-CoV-2/isolamento & purificação , Testes Sorológicos/métodosRESUMO
OBJECTIVE: There is an urgent need to assess the impact of immunosuppressive therapies on the immunogenicity and efficacy of SARS-CoV-2 vaccination. METHODS: Serological and T-cell ELISpot assays were used to assess the response to first-dose and second-dose SARS-CoV-2 vaccine (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in 140 participants receiving immunosuppression for autoimmune rheumatic and glomerular diseases. RESULTS: Following first-dose vaccine, 28.6% (34/119) of infection-naïve participants seroconverted and 26.0% (13/50) had detectable T-cell responses to SARS-CoV-2. Immune responses were augmented by second-dose vaccine, increasing seroconversion and T-cell response rates to 59.3% (54/91) and 82.6% (38/46), respectively. B-cell depletion at the time of vaccination was associated with failure to seroconvert, and tacrolimus therapy was associated with diminished T-cell responses. Reassuringly, only 8.7% of infection-naïve patients had neither antibody nor T-cell responses detected following second-dose vaccine. In patients with evidence of prior SARS-CoV-2 infection (19/140), all mounted high-titre antibody responses after first-dose vaccine, regardless of immunosuppressive therapy. CONCLUSION: SARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays, although the response is impaired compared with healthy individuals. B-cell depletion following rituximab impairs serological responses, but T-cell responses are preserved in this group. We suggest that repeat vaccine doses for serological non-responders should be investigated as means to induce more robust immunological response.
Assuntos
Doenças Autoimunes/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Hospedeiro Imunocomprometido/imunologia , Imunogenicidade da Vacina/imunologia , Adulto , Idoso , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Doenças Autoimunes/tratamento farmacológico , Feminino , Humanos , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Imunossupressores/imunologia , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , SARS-CoV-2 , Linfócitos T/imunologiaRESUMO
BACKGROUND: Strategies to minimize the risk of transmission and acquisition of COVID-19 infection in patients with ESKD receiving in-center hemodialysis have been rapidly implemented across the globe. Despite these interventions, confirmed COVID-19 infection rates have been high in the United Kingdom. Prevalence of asymptomatic disease in an adult hemodialysis population has not been reported. Also, to our knowledge, the development of humoral response to SARS-CoV-2 has not been previously reported in this population. Although serologic testing does not provide information on the infectivity of patients, seroprevalence studies may enable investigation of exposure within dialysis units and hence, assessment of current screening strategies. METHODS: To investigate the seroprevalence of SARS-CoV-2 antibodies in a hemodialysis population, we used the Abbott IgG assay with the Architect system to test serum samples from 356 patients receiving in-center hemodialysis for SARS-CoV-2 antibodies. RESULTS: Of 356 patients, 121 had been symptomatic when screened before a dialysis session and received an RT-PCR test; 79 (22.2% of the total study population) tested positive for COVID-19. Serologic testing of all 356 patients found 129 (36.2%) who tested positive for SARS-CoV-2 antibodies. Only two patients with PCR-confirmed infection did not seroconvert. Of the 129 patients with SARS-CoV-2 antibodies, 52 (40.3%) had asymptomatic disease or undetected disease by PCR testing alone. CONCLUSIONS: We found a high seroprevalence of SARS-CoV-2 antibodies in patients receiving in-center hemodialysis. Serologic evidence of previous infection in asymptomatic or PCR-negative patients suggests that current diagnostic screening strategies may be limited in their ability to detect acute infection.
Assuntos
Anticorpos Antivirais/sangue , Infecções Assintomáticas/epidemiologia , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Diálise Renal , Idoso , COVID-19 , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2 , Estudos Soroepidemiológicos , Testes SorológicosRESUMO
Malignant pleural mesothelioma (MPM) is an aggressive malignancy with limited effective treatment options. Focal adhesion kinase (FAK) inhibitors have been shown to efficiently suppress MPM cell growth initially, with limited utility in the current clinical setting. In this study, we utilised a large collection of MPM cell lines and MPM tissue samples to study the role of E-cadherin (CDH1) and microRNA on the efficacy of FAK inhibitors in MPM. The immunohistochemistry (IHC) results showed that the majority of MPM FFPE samples exhibited either the absence of, or very low, E-cadherin protein expression in MPM tissue. We showed that MPM cells with high CDH1 mRNA levels exhibited resistance to the FAK inhibitor PND-1186. In summary, MPM cells that did not express CDH1 mRNA were sensitive to PND-1186, and MPM cells that retained CDH1 mRNA were resistant. A cell cycle analysis showed that PND-1186 induced cell cycle disruption by inducing the G2/M arrest of MPM cells. A protein-protein interaction study showed that EGFR is linked to the FAK pathway, and a target scan of the microRNAs revealed that microRNAs (miR-17, miR221, miR-222, miR137, and miR148) interact with EGFR 3'UTR. Transfection of MPM cells with these microRNAs sensitised the CHD1-expressing FAK-inhibitor-resistant MPM cells to the FAK inhibitor.
Assuntos
Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/genética , Caderinas/metabolismo , Quinase 1 de Adesão Focal/antagonistas & inibidores , Mesotelioma Maligno/tratamento farmacológico , Mesotelioma Maligno/genética , MicroRNAs/fisiologia , Inibidores de Proteínas Quinases/farmacologia , Aminopiridinas/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Mapas de Interação de ProteínasRESUMO
Chemotherapy and hematopoietic stem cell transplantation are effective treatments for most Hodgkin lymphoma patients, however there remains a need for better tumor-specific target therapy in Hodgkin lymphoma patients with refractory or relapsed disease. Herein, we demonstrate that membrane CD83 is a diagnostic and therapeutic target, highly expressed in Hodgkin lymphoma cell lines and Hodgkin and Reed-Sternberg cells in 29/35 (82.9%) Hodgkin lymphoma patient lymph node biopsies. CD83 from Hodgkin lymphoma tumor cells was able to trogocytose to surrounding T cells and, interestingly, the trogocytosing CD83+T cells expressed significantly more programmed death-1 compared to CD83-T cells. Hodgkin lymphoma tumor cells secreted soluble CD83 that inhibited T-cell proliferation, and anti-CD83 antibody partially reversed the inhibitory effect. High levels of soluble CD83 were detected in Hodgkin lymphoma patient sera, which returned to normal in patients who had good clinical responses to chemotherapy confirmed by positron emission tomography scans. We generated a human anti-human CD83 antibody, 3C12C, and its toxin monomethyl auristatin E conjugate, that killed CD83 positive Hodgkin lymphoma cells but not CD83 negative cells. The 3C12C antibody was tested in dose escalation studies in non-human primates. No toxicity was observed, but there was evidence of CD83 positive target cell depletion. These data establish CD83 as a potential biomarker and therapeutic target in Hodgkin lymphoma.
Assuntos
Antígenos CD/sangue , Biomarcadores Tumorais/sangue , Doença de Hodgkin/tratamento farmacológico , Imunoglobulinas/sangue , Glicoproteínas de Membrana/sangue , Terapia de Alvo Molecular/métodos , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antígenos CD/imunologia , Feminino , Doença de Hodgkin/diagnóstico , Humanos , Imunoglobulinas/imunologia , Masculino , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Terapia de Salvação/métodos , Linfócitos T/citologia , Adulto Jovem , Antígeno CD83RESUMO
CD83 is a member of the Ig gene superfamily, first identified in activated lymphocytes. Since then, CD83 has become an important marker for defining activated human dendritic cells (DC). Several potential CD83 mRNA isoforms have been described, including a soluble form detected in human serum, which may have an immunosuppressive function. To further understand the biology of CD83, we examined its expression in different human immune cell types before and after activation using a panel of mouse and human anti-human CD83 mAb. The mouse anti-human CD83 mAbs, HB15a and HB15e, and the human anti-human CD83 mAb, 3C12C, were selected to examine cytoplasmic and surface CD83 expression, based on their different binding characteristics. Glycosylation of CD83, the CD83 mRNA isoforms, and soluble CD83 released differed among blood DC, monocytes, and monocyte-derived DC, and other immune cell types. A small T cell population expressing surface CD83 was identified upon T cell stimulation and during allogeneic MLR. This subpopulation appeared specifically during viral Ag challenge. We did not observe human CD83 on unstimulated human natural regulatory T cells (Treg), in contrast to reports describing expression of CD83 on mouse Treg. CD83 expression was increased on CD4+, CD8+ T, and Treg cells in association with clinical acute graft-versus-host disease in allogeneic hematopoietic cell transplant recipients. The differential expression and function of CD83 on human immune cells reveal potential new roles for this molecule as a target of therapeutic manipulation in transplantation, inflammation, and autoimmune diseases.
Assuntos
Antígenos CD/metabolismo , Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunoglobulinas/metabolismo , Glicoproteínas de Membrana/metabolismo , Monócitos/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Doença Aguda , Animais , Antígenos CD/genética , Antígenos Virais/imunologia , Células Cultivadas , Glicosilação , Humanos , Imunoglobulinas/genética , Ativação Linfocitária , Glicoproteínas de Membrana/genética , Camundongos , Isoformas de RNA/genética , RNA Mensageiro/genética , Transplante Homólogo , Antígeno CD83RESUMO
Malignant pleural mesothelioma (MPM) is a deadly cancer that is caused by asbestos exposure and that has limited treatment options. The current standard of MPM diagnosis requires the testing of multiple immunohistochemical (IHC) markers on formalin-fixed paraffin-embedded tissue to differentiate MPM from other lung malignancies. To date, no single biomarker exists for definitive diagnosis of MPM due to the lack of specificity and sensitivity; therefore, there is ongoing research and development in order to identify alternative biomarkers for this purpose. In this study, we utilized primary MPM cell lines and tested the expression of clinically used biomarker panels, including CK8/18, Calretinin, CK 5/6, CD141, HBME-1, WT-1, D2-40, EMA, CEA, TAG72, BG8, CD15, TTF-1, BAP1, and Ber-Ep4. The genomic alteration of CDNK2A and BAP1 is common in MPM and has potential diagnostic value. Changes in CDKN2A and BAP1 genomic expression were confirmed in MPM samples in the current study using Fluorescence In situ Hybridization (FISH) analysis or copy number variation (CNV) analysis with digital droplet PCR (ddPCR). To determine whether MPM tissue and cell lines were comparable in terms of molecular alterations, IHC marker expression was analyzed in both sample types. The percentage of MPM biomarker levels showed variation between original tissue and matched cells established in culture. Genomic deletions of BAP1 and CDKN2A, however, showed consistent levels between the two. The data from this study suggest that genomic deletion analysis may provide more accurate biomarker options for MPM diagnosis.
Assuntos
Biomarcadores Tumorais/normas , Inibidor de Quinase Dependente de Ciclina p18/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Cultura Primária de Células/normas , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina , Deleção de Genes , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Mesotelioma Maligno , Pessoa de Meia-Idade , Cultura Primária de Células/métodosAssuntos
COVID-19 , Transplante de Rim , Vacinas contra COVID-19 , Humanos , SARS-CoV-2 , TransplantadosAssuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/imunologia , Imunidade Humoral/efeitos dos fármacos , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/efeitos dos fármacos , Adulto , Idoso , Vacina BNT162 , ELISPOT , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The discovery of hepcidin, the hormone regulating iron absorption and transport, has improved the understanding of anemia and erythropoietin treatment. Excessive hepcidin signaling causes anemia in chronic inflammatory conditions by restricting iron delivery to the bone marrow. Hepcidin is normally eliminated in the urine, and the high levels seen in renal failure are thought to contribute to renal anemia and resistance to erythropoietin. METHODS: Clearance of hepcidin by hemodialysis was investigated in this study by measurement of plasma hepcidin before and after a single dialysis session in 204 patients. Results: Dialysis significantly reduced circulating hepcidin (p < 0.001) with median (IQR) clearance 47.7 (34.2 - 61.0)%. Dialytic hepcidin clearance was correlated with spKt/V (R = 0.202, p = 0.006), but not related to session length or membrane flux. There was also a strong correlation between hepcidin clearance and erythropoietin dose (R = -0.193, p = 0.007), sufficient to displace more traditional markers of erythropoietin resistance in a linear regression model, suggesting that increased dialytic removal of hepcidin could improve erythropoietin sensitivity. CONCLUSIONS: Hemodialysis reduces circulating hepcidin. Greater hepcidin clearance, which is related to spKt/V, is strongly associated with reduced erythropoietin requirement. This further implicates hepcidin in the pathogenesis of renal anemia and suggests that hepcidin could be a useful therapeutic target for dialysis patients.â©.
Assuntos
Anemia/tratamento farmacológico , Eritropoetina/uso terapêutico , Hepcidinas/farmacocinética , Diálise Renal , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Biomarcadores/sangue , Feminino , Humanos , Ferro/metabolismo , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Diálise Renal/efeitos adversosRESUMO
Human plasmacytoid dendritic cells (pDCs) were considered to be a phenotypically and functionally homogeneous cell population; however, recent analyses indicate potential heterogeneity. This is of major interest, given their importance in the induction of anti-viral responses and their role in creating immunologically permissive environments for human malignancies. For this reason, we investigated the possible presence of human pDC subsets in blood and bone marrow, using unbiased cell phenotype clustering and functional studies. This defined two major functionally distinct human pDC subsets, distinguished by differential expression of CD2. The CD2(hi) and CD2(lo) pDCs represent discontinuous subsets, each with hallmark pDC functionality, including interferon-alpha production. The rarer CD2(hi) pDC subset demonstrated a significant survival advantage over CD2(lo) pDC during stress and upon exposure to glucocorticoids (GCs), which was associated with higher expression of the anti-apoptotic molecule BCL2. The differential sensitivity of these two human pDC subsets to GCs is demonstrated in vivo by a relative increase in CD2(hi) pDC in multiple myeloma patients treated with GCs. Hence, the selective apoptosis of CD2(lo) pDC during stress represents a novel mechanism for the control of innate responses.
Assuntos
Antígenos CD2/metabolismo , Células Dendríticas/metabolismo , Estresse Fisiológico , Apoptose/efeitos dos fármacos , Medula Óssea/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Glucocorticoides/farmacologia , Humanos , Ligantes , Linfonodos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores Imunológicos/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Receptores Toll-Like/metabolismoAssuntos
COVID-19 , Humanos , Programas de Rastreamento , Pandemias , Prevalência , Diálise Renal , SARS-CoV-2Assuntos
Doença Antimembrana Basal Glomerular/epidemiologia , Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Glicoproteína da Espícula de Coronavírus/imunologia , Imunidade Adaptativa , Adulto , Idoso , Doença Antimembrana Basal Glomerular/diagnóstico , Doença Antimembrana Basal Glomerular/imunologia , Doença Antimembrana Basal Glomerular/virologia , Anticorpos Antivirais/imunologia , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Feminino , Membrana Basal Glomerular/imunologia , Membrana Basal Glomerular/patologia , Humanos , Incidência , Londres/epidemiologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , RNA Viral/isolamento & purificação , SARS-CoV-2RESUMO
Corticosteroid use after transplantation is associated with an increased incidence of cardiovascular events and death. Cerebrovascular disease is a common cause of morbidity and mortality post-renal transplantation; however, a dedicated analysis of cerebrovascular disease in recipients of a steroid sparing protocol has not been reported. The aim of this study was to examine the incidence, risk factors, and outcomes of CVA in transplant recipients receiving a steroid sparing protocol. We retrospectively analyzed 1237 patients who received a kidney alone or a simultaneous pancreas and kidney (SPK) transplant. Fifty-six of 1237 (4.53%) patients had a CVA post-transplant. All-cause mortality was significantly higher in the CVA group compared with the non-CVA group, OR: 3.4 (1.7-7.0), p < 0.001. Factors found to be associated with increased risk of CVA by multivariate analysis were older age, HR: 1.07 (1.04-1.09), p < 0.001; diabetes at the time of transplantation, HR: 2.83 (1.42-5.64), p = 0.003; corticosteroid use pre-transplant, HR: 3.27 (1.29-8.27), p = 0.013 and recipients of a SPK, HR: 4.03 (1.85-8.79), p < 0.001. This study has identified subgroups of patients who are at increased risk of CVA post-transplant in patients otherwise receiving a steroid sparing immunosuppression protocol.
Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Transplante de Rim , Complicações Pós-Operatórias/etiologia , Acidente Vascular Cerebral/etiologia , Corticosteroides/efeitos adversos , Adulto , Idoso , Seguimentos , Humanos , Incidência , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Transplante de Pâncreas , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controle , Resultado do TratamentoRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (<380 AU ml-1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Vacinas contra COVID-19 , Vacina BNT162 , ChAdOx1 nCoV-19 , Vacinação , Anticorpos AntiviraisRESUMO
BACKGROUND: This study examined the association between overall survival and Glutathione S-transferase Pi (GST Pi) expression and genetic polymorphism in stage C colon cancer patients after resection alone versus resection plus 5-fluourouracil-based adjuvant chemotherapy. METHODS: Patients were drawn from a hospital registry of colorectal cancer resections. Those receiving chemotherapy after it was introduced in 1992 were compared with an age and sex matched control group from the preceding period. GST Pi expression was assessed by immunohistochemistry. Overall survival was analysed by the Kaplan-Meier method and Cox regression. RESULTS: From an initial 104 patients treated with chemotherapy and 104 matched controls, 26 were excluded because of non-informative immunohistochemistry, leaving 95 in the treated group and 87 controls. Survival did not differ significantly among patients with low GST Pi who did or did not receive chemotherapy and those with high GST Pi who received chemotherapy (lowest pair-wise p = 0.11) whereas patients with high GST Pi who did not receive chemotherapy experienced markedly poorer survival than any of the other three groups (all pair-wise p <0.01). This result was unaffected by GST Pi genotype. CONCLUSION: Stage C colon cancer patients with low GST Pi did not benefit from 5-fluourouracil-based adjuvant chemotherapy whereas those with high GST Pi did.
Assuntos
Neoplasias do Colo/genética , Neoplasias do Colo/mortalidade , Expressão Gênica , Glutationa S-Transferase pi/genética , Idoso , Quimioterapia Adjuvante , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Resultado do TratamentoRESUMO
Background: People with end-stage kidney disease, including people on haemodialysis, are susceptible to greater COVID-19 related morbidity and mortality. This study compares the immunogenicity and clinical effectiveness of BNT162B2 versus ChAdOx1 in haemodialysis patients. Methods: In this observational cohort study, 1021 patients were followed-up from time of vaccination until December 2021. All patients underwent weekly RT-PCR screening. Patients were assessed for nucleocapsid(anti-NP) and spike(anti-S) antibodies at timepoints after second(V2) and third(V3) vaccinations. 191 patients were investigated for T-cell responses. Vaccine effectiveness (VE) for prevention of infection, hospitalisation and mortality was evaluated using the formula VE=(1-adjustedHR)x100. Findings: 45.7% (467/1021) had evidence of prior infection. There was no difference in the proportion of infection-naïve patients who seroconverted by vaccine type, but median anti-S antibody titres were higher post-BNT162b2 compared with ChAdOx1; 462(152-1171) and 78(20-213) BAU/ml respectively, p<0.001. Concomitant immunosuppressant use was a risk factor for non-response, OR 0.12[95% CI 0.05-0.25] p<0.001. Post-V3 (all BNT162b2), median anti-S antibody titres remained higher in those receiving BNT162b2 versus ChAdOx1 as primary doses; 2756(187-1246) and 1250(439-2635) BAU/ml respectively, p=0.003.Anti-S antibodies waned over time. Hierarchical levels of anti-S post-V2 predicted risk of infection; patients with no/low anti-S being at highest risk. VE for preventing infection, hospitalisation and death was 53% (95% CI 6-75), 77% (95% CI 30-92) and 93% (95% CI 59-99) respectively, with no difference seen by vaccine type. Interpretation: Serum anti-S concentrations predict risk of breakthrough infection. Anti-S responses vary dependent upon clinical features, infection history and vaccine type. Monitoring of serological responses may enable individualised approaches to vaccine boosters in at risk populations. Funding: National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London.