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Chronic kidney disease (CKD) patients have an increased risk of morbidity and mortality following SARS-CoV-2 infection. Vaccination in these patients is prioritized, and monitoring of the immune response is paramount to define further vaccination strategies. This prospective study included a cohort of 100 adult CKD patients: 48 with kidney transplant (KT) and 52 on hemodialysis without prior COVID-19. The patients were assessed for humoral and cellular immune responses after four months of an anti-SARS-CoV-2 primary two-dose vaccination scheme (CoronaVac or BNT162b2) and one month after a booster third dose of BNT162b2 vaccine. We identified poor cellular and humoral immune responses in the CKD patients after a primary vaccination scheme, and these responses were improved by a booster. Robust polyfunctional CD4+ T cell responses were observed in the KT patients after a booster, and this could be attributed to a higher proportion of the patients having been vaccinated with homologous BNT162b2 schemes. However, even after the booster, the KT patients exhibited lower neutralizing antibodies, attributable to specific immunosuppressive treatments. Four patients suffered severe COVID-19 despite three-dose vaccination, and all had low polyfunctional T-cell responses, underscoring the importance of this functional subset in viral protection. In conclusion, a booster dose of SARS-CoV-2 mRNA vaccine in CKD patients improves the impaired humoral and cellular immune responses observed after a primary vaccination scheme.
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INTRODUCCIÓN: La inmunodeficiencia combinada severa (IDCS) corresponde a una de las formas más graves de inmunodeficiencia primaria, existiendo escasos datos nacionales sobre ésta. OBJETIVO: describir la epidemiología, complicaciones, pronóstico y uso de la vacuna BCG en pacientes chilenos con IDCS. PACIENTES Y MÉTODO: Estudio retrospectivo de pacientes diagnosticados con IDCS entre los años 1999 y 2020 por médicos inmunólogos a lo largo de Chile. El diagnóstico de IDCS se realizó conforme a los criterios propuestos por Shearer: linfocitos T (CD3+) < 300 células/μL y prolife ración 10% del límite de normalidad en respuesta a fitohemaglutinina o presencia de linfocitos T de origen materno. Se obtuvieron de la ficha clínica los datos correspondientes a: sexo, edad al diagnóstico, consanguinidad, región de origen, subpoblaciones linfocitarias, diagnóstico genético, complicaciones infecciosas y no infecciosas, vacunación BCG y sus complicaciones, edad de deriva ción al centro de TPH y causa de mortalidad no relacionada al TPH. RESULTADOS: se diagnosticaron 25 casos de IDCS en 22 familias entre los años 1999-2020. 78% varones, la edad media a la primera manifestación fue 2.3 meses (0-7), mientras que la edad media al diagnóstico fue de 3.4 meses (0 7). Un 16% de los casos tenía un antecedente familiar de IDCS. Un 40% de los casos fueron diag nosticados en la Región Metropolitana. El inmunofenotipo más frecuente fue T-B-NK+ (48%). Se realizaron estudios genéticos en 69,5% de los casos, siendo los defectos genéticos en RAG2 (39%) la causa más frecuente. Un 88% de los casos recibió la vacuna Bacillus Calmette-Guerin (BCG) previo al diagnóstico, incluidos 2 pacientes con historia familiar positiva, 36% de los vacunados experimentó complicaciones de la BCG. La edad media a la derivación a trasplante fue de 7,4 meses (5-16). De los 25 pacientes, 11 fallecieron previo a la derivación a un centro de trasplante. CONCLUSIÓN: En Chile existe un retraso clínicamente significativo entre las primeras manifestaciones y el diagnóstico de IDCS, así como un importante retraso en la derivación a centros de trasplante. La mayoría de los pacientes con IDCS reciben la vacuna BCG, pese a tener antecedentes familiares, y experimentan frecuentemente complicaciones de la vacuna.
INTRODUCTION: Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency. To date, there is little local information about this disease. OBJECTIVE: To describe the epidemiology, complications, prognosis, and use of the BCG vaccine in Chilean patients with SCID. PATIENTS AND METHOD: Retrospective review of the clinical records of patients diagnosed with SCID by clinical immunologists between 1999 and 2020 throughout Chile. SCID was diagnosed according to the cri teria proposed by Shearer: T lymphocytes (CD3+) < 300 cells/μL and proliferation 10% of the limit of normality in response to phytohemagglutinin or presence of T lymphocytes of maternal origin. Data collected from the clinical records were: sex, age at diagnosis, consanguinity, region of origin, lymphocyte subpopulations, genetic diagnosis, infectious and non-infectious complications, BCG vaccination and its complications, age at referral to the bone marrow transplant (BMT) center, and cause of non-BMT-related mortality. RESULTS: Between 1999 and 2020, 25 patients were diagnosed with SCID. 78% of them were male, mean age at first manifestation of the disease was 2.3 months (0-7), while the mean age at diagnosis was 3.4 months (0-7). 16% of patients had a family history of SCID. 40% of cases were diagnosed within the Metropolitan Region. The most frequent immuno- phenotype was T-B-NK+ SCID (48%). Genetic studies were done in 69.5% of cases, mutations in the RAG2 gene were the most common etiology of SCID (39%). 88% of SCID patients received the Bacillus Calmette-Guerin (BCG) vaccine before diagnosis, including 2 cases with a known family history of SCID. 36% of those who received the vaccine had BCG-related complications. The mean age at referral to a bone marrow transplant center was 7.4 months (5-16). 11/25 patients died before being transferred to a transplant center. DISCUSSION: There is a clinically significant delay between the first manifestations and the diagnosis of SCID in Chilean patients, as well as an important time gap between the diagnosis of SCID and referral to a center for BMT. Most SCID cases in Chile receive the BCG vaccine, despite a known family history of the disease, and frequently develop vaccine-related complications.
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Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Vacina BCG/administração & dosagem , Vacinação/estatística & dados numéricos , Imunodeficiência Combinada Severa/epidemiologia , Prognóstico , Fatores de Tempo , Proteínas Nucleares/genética , Vacina BCG/efeitos adversos , Linfócitos T/imunologia , Chile , Estudos Retrospectivos , Transplante de Medula Óssea/estatística & dados numéricos , Vacinação/efeitos adversos , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Proteínas de Ligação a DNA/genética , Diagnóstico Tardio , MutaçãoRESUMO
INTRODUCTION: Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency. To date, there is little local information about this disease. OBJECTIVE: To describe the epidemiology, complications, prognosis, and use of the BCG vaccine in Chilean patients with SCID. PATIENTS AND METHOD: Retrospective review of the clinical records of patients diagnosed with SCID by clinical immunologists between 1999 and 2020 throughout Chile. SCID was diagnosed according to the cri teria proposed by Shearer: T lymphocytes (CD3+) < 300 cells/µL and proliferation 10% of the limit of normality in response to phytohemagglutinin or presence of T lymphocytes of maternal origin. Data collected from the clinical records were: sex, age at diagnosis, consanguinity, region of origin, lymphocyte subpopulations, genetic diagnosis, infectious and non-infectious complications, BCG vaccination and its complications, age at referral to the bone marrow transplant (BMT) center, and cause of non-BMT-related mortality. RESULTS: Between 1999 and 2020, 25 patients were diagnosed with SCID. 78% of them were male, mean age at first manifestation of the disease was 2.3 months (0-7), while the mean age at diagnosis was 3.4 months (0-7). 16% of patients had a family history of SCID. 40% of cases were diagnosed within the Metropolitan Region. The most frequent immuno- phenotype was T-B-NK+ SCID (48%). Genetic studies were done in 69.5% of cases, mutations in the RAG2 gene were the most common etiology of SCID (39%). 88% of SCID patients received the Bacillus Calmette-Guerin (BCG) vaccine before diagnosis, including 2 cases with a known family history of SCID. 36% of those who received the vaccine had BCG-related complications. The mean age at referral to a bone marrow transplant center was 7.4 months (5-16). 11/25 patients died before being transferred to a transplant center. DISCUSSION: There is a clinically significant delay between the first manifestations and the diagnosis of SCID in Chilean patients, as well as an important time gap between the diagnosis of SCID and referral to a center for BMT. Most SCID cases in Chile receive the BCG vaccine, despite a known family history of the disease, and frequently develop vaccine-related complications.
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Vacina BCG/administração & dosagem , Imunodeficiência Combinada Severa/epidemiologia , Vacinação/estatística & dados numéricos , Vacina BCG/efeitos adversos , Transplante de Medula Óssea/estatística & dados numéricos , Chile , Proteínas de Ligação a DNA/genética , Diagnóstico Tardio , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Proteínas Nucleares/genética , Prognóstico , Estudos Retrospectivos , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Linfócitos T/imunologia , Fatores de Tempo , Vacinação/efeitos adversosRESUMO
Nuclear factor kappa-B subunit 2 (NF-κB2/p100/p52), encoded by NFKB2 (MIM: 164012) belongs to the NF-κB family of transcription factors that play a critical role in inflammation, immunity, cell proliferation, differentiation and survival. Heterozygous C-terminal mutations in NFKB2 have been associated with early-onset common variable immunodeficiency (CVID), central adrenal insufficiency and ectodermal dysplasia. Only two previously reported cases have documented decreased natural killer (NK) cell cytotoxicity, and little is known about the role of NF-κB2 in NK cell maturation and function. Here we report a 13-year-old female that presented at 6 years of age with a history of early onset recurrent sinopulmonary infections, progressive hair loss, and hypogamaglobulinemia consistent with a clinical diagnosis of CVID. At 9 years of age she had cytomegalovirus (CMV) pneumonia that responded to ganciclovir treatment. Functional NK cell testing demonstrated decreased NK cell cytotoxicity despite normal NK cell numbers, consistent with a greater susceptibility to systemic CMV infection. Research exome sequencing (ES) was performed and revealed a novel de novo heterozygous nonsense mutation in NFKB2 (c.2611C>T, p.Gln871*) that was not carried by either of her parents. The variant was Sanger sequenced and confirmed to be de novo in the patient. At age 12, she presented with a reactivation of the systemic CMV infection that was associated with severe and progressive nephrotic syndrome with histologic evidence of pedicellar effacement and negative immunofluorescence. To our knowledge, this is the third NF-κB2 deficient patient in which an abnormal NK cell function has been observed, suggesting a role for non-canonical NF-κB2 signaling in NK cell cytotoxicity. NK cell function should be assessed in patients with mutations in the non-canonical NF-κB pathway to explore the risk for systemic viral infections that may lead to severe complications and impact patient survival. Similarly NF-κB2 should be considered in patients with combined immunodeficiency who have aberrant NK cell function. Further studies are needed to characterize the role of NF-κB2 in NK cell cytotoxic function.