COVID-19 Vaccination Responses with Different Vaccine Platforms in Patients with Inborn Errors of Immunity.

Patients with inborn errors of immunity (IEI) in Argentina were encouraged to receive licensed Sputnik, AstraZeneca, Sinopharm, Moderna, and Pfizer vaccines, even though most of the data of humoral and cellular responses combination on available vaccines comes from trials conducted in healthy individuals. We aimed to evaluate the safety and immunogenicity of the different vaccines in IEI patients in Argentina. The study cohort included adults and pediatric IEI patients (n = 118) and age-matched healthy controls (HC) (n = 37). B cell response was evaluated by measuring IgG anti-spike/receptor binding domain (S/RBD) and anti-nucleocapsid(N) antibodies by ELISA. Neutralization antibodies were also assessed with an alpha-S protein-expressing pseudo-virus assay. The T cell response was analyzed by IFN-γ secretion on S- or N-stimulated PBMC by ELISPOT and the frequency of S-specific circulating T follicular-helper cells (TFH) was evaluated by flow cytometry.No moderate/severe vaccine-associated adverse events were observed. Anti-S/RBD titers showed significant differences in both pediatric and adult IEI patients versus the age-matched HC cohort (p < 0.05). Neutralizing antibodies were also significantly lower in the patient cohort than in age-matched HC (p < 0.01). Positive S-specific IFN-γ response was observed in 84.5% of IEI patients and 82.1% presented S-specific TFH cells. Moderna vaccines, which were mainly administered in the pediatric population, elicited a stronger humoral response in IEI patients, both in antibody titer and neutralization capacity, but the cellular immune response was similar between vaccine platforms. No difference in humoral response was observed between vaccinated patients with and without previous SARS-CoV-2 infection.In conclusion, COVID-19 vaccines showed safety in IEI patients and, although immunogenicity was lower than HC, they showed specific anti-S/RBD IgG, neutralizing antibody titers, and T cell-dependent cellular immunity with IFN-γ secreting cells. These findings may guide the recommendation for a vaccination with all the available vaccines in IEI patients to prevent COVID-19 disease.

Outcomes for Nitazoxanide Treatment in a Case Series of Patients with Primary Immunodeficiencies and Rubella Virus-Associated Granuloma.

PURPOSE: Nitazoxanide was recently reported as having in vitro effectiveness against the rubella virus. Immunodeficiency-related vaccine-derived rubella occurs in some patients who have an inherited immunodeficiency and who received the MMR vaccine. This study investigated the in vivo effectiveness of nitazoxanide therapy. METHODS: This is a retrospective analysis of seven patients treated with nitazoxanide as salvage therapy for immunodeficiency-related vaccine-derived rubella infection. The patients were recruited from an ongoing rubella detection surveillance project. RESULTS: Seven patients with persistent rubella were treated with nitazoxanide and one demonstrated significant clinical improvement. Two additional patients exhibited diminished viral capsid production with one patient having transient slowing of progression. The cohort overall generally had low T cell counts and had a high burden of comorbidities. There were three deaths. Two deaths were from PML and one was related to hematopoietic stem cell transplantation. CONCLUSIONS: Nitazoxanide has limited in vivo anti-viral effects for immunodeficiency-related vaccine-derived rubella. Most patients did not exhibit clinical improvement.

[Recommendations for care, prevention of infections and chemoprophylaxis in inborn errors of immunity]. / Recomendaciones para el cuidado, prevención de infecciones y quimioprofilaxis en los errores innatos de la inmunidad.

Inborn errors of immunity, previously named primary immunodeficiency are a heterogeneous group of genetic defects of different components of the immune system. Patients present high susceptibility to an only or several microorganisms, developing recurrent infections; the severity is related to the specific genetic type of immunity defect. The main strategy on the management of these illness is the prevention of infections. These consensus guidelines made by the Pediatric Immunology Work Group of Sociedad Argentina de Pediatría, givese main approaches of infection prevention in order to provide a useful tool for all practitioners who are involved in the management of these patients, based on scientific evidence and broad consensus of a specialized panel expert..

Los errores innatos de la inmunidad (EII), antes llamados inmunodeficiencias primarias (IDP), son un grupo heterogéneo de trastornos genéticos con defectos en uno o más componentes del sistema inmune. Los pacientes afectados por EII presentan aumentada susceptibilidad a microorganismos únicos o múltiples que se manifestará con infecciones recurrentes de diferente tipo y gravedad dependiendo del tipo de la localización del defecto. La prevención de infecciones es uno de los pilares fundamentales en el abordaje integral de los pacientes con EII. En este trabajo se resumen las conclusiones consensuadas en el Grupo de Trabajo de Inmunología Pediátrica de la Sociedad Argentina de Pediatría, sobre la base de la revisión de la evidencia disponible, respecto a los principios esenciales para el cuidado, la prevención de infecciones y la quimioprofilaxis en los errores innatos de la inmunidad para la orientación del pediatra y especialista dedicados al seguimiento de estas enfermedades.

Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement.

Importance: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management. Objective: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2. Evidence Review: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence. Findings: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined. Conclusions and Relevance: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2.

Recomendaciones para el cuidado, prevención de infecciones y quimioprofilaxis en los errores innatos de la inmunidad / Recommendations for care, prevention of infections and chemoprophylaxis in inborn errors of immunity

Los errores innatos de la inmunidad (EII), antes llamados inmunodeficiencias primarias (IDP), son un grupo heterogéneo de trastornos genéticos con defectos en uno o más componentes del sistema inmune. Los pacientes afectados por EII presentan aumentada susceptibilidad a microorganismos únicos o múltiples que se manifestará con infecciones recurrentes de diferente tipo y gravedad dependiendo del tipo de la localización del defecto. La prevención de infecciones es uno de los pilares fundamentales en el abordaje integral de los pacientes con EII. En este trabajo se resumen las conclusiones consensuadas en el Grupo de Trabajo de Inmunología Pediátrica de la Sociedad Argentina de Pediatría, sobre la base de la revisión de la evidencia disponible, respecto a los principios esenciales para el cuidado, la prevención de infecciones y la quimioprofilaxis en los errores innatos de la inmunidad para la orientación del pediatra y especialista dedicados al seguimiento de estas enfermedades.

Inborn errors of immunity, previously named primary immunodeficiency are a heterogeneous group of genetic defects of different components of the immune system. Patients present high susceptibility to an only or several microorganisms, developing recurrent infections; the severity is related to the specific genetic type of immunity defect. The main strategy on the management of these illness is the prevention of infections. These consensus guidelines made by the Pediatric Immunology Work Group of Sociedad Argentina de Pediatría, givese main approaches of infection prevention in order to provide a useful tool for all practitioners who are involved in the management of these patients, based on scientific evidence and broad consensus of a specialized panel expert.

Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood.

OBJECTIVE: We aimed to test the relevance of deficiency of adenosine deaminase 2 (DADA2) in patients with antibody deficiency and describe the clinical picture of the disease in adulthood. METHODS: We screened for DADA2 in a cohort of 181 patients with antibody deficiency with or without vascular lesions using next-generation sequencing and targeted Sanger sequencing. All mutations were confirmed by determining the ADA2 enzymatic activity levels in dried plasma spots. Clinical data and laboratory values were collected in a standardized format. RESULTS: Following the diagnosis of 2 siblings in the index family, we identified 9 additional affected patients with compound heterozygous or homozygous CECR1 mutations, containing 6 novel and 4 previously published mutations. The patients' age at evaluation ranged from 13 to 51 years, with a median age of 22 years. Clinically, we saw a broad phenotype, ranging from isolated antibody deficiency to recurrent strokes. All but 1 patient had low numbers of memory B cells. Moreover, B cell function seemed to correlate with inflammation. CONCLUSION: Taken together, our findings indicate that DADA2 presents not only with vasculopathy but also with an immunodeficiency of the B cell compartment. Therefore, patients with antibody deficiency should be screened for DADA2. Anti-tumor necrosis factor treatment might improve immunologic features over time and might be considered in patients without vascular manifestations but with elevated inflammation markers. Conservative management has so far proven to be the choice for our less severely affected adolescent and adult DADA2 patients; however, in patients with severe cytopenias and bone marrow failure, hematopoietic stem cell transplantation should be considered.

Human natural killer cell maturation defect supports in vivo CD56(bright) to CD56(dim) lineage development.

Two populations of human natural killer (NK) cells can be identified in peripheral blood. The majority are CD3(-)CD56(dim) cells while the minority exhibits a CD3(-)CD56(bright) phenotype. In vitro evidence indicates that CD56(bright) cells are precursors of CD56(dim) cells, but in vivo evidence is lacking. Here, we studied NK cells from a patient that suffered from a melanoma and opportunistic fungal infection during childhood. The patient exhibited a stable phenotype characterized by a reduction in the frequency of peripheral blood CD3(-)CD56(dim) NK cells, accompanied by an overt increase in the frequency and absolute number of CD3(-)CD56(bright) cells. These NK cells exhibited similar expression of perforin, CD57 and CD158, the major activating receptors CD16, NKp46, NKG2D, DNAM-1, and 2B4, as well as the inhibitory receptor CD94/NKG2A, on both CD56(bright) and CD56(dim) NK cells as healthy controls. Also, both NK cell subpopulations produced IFN-γ upon stimulation with cytokines, and CD3(-)CD56(dim) NK cells degranulated in response to cytokines or K562 cells. However, upon stimulation with cytokines, a substantial fraction of CD56(dim) cells failed to up-regulate CD57 and CD158, showed a reduction in the percentage of CD16(+) cells, and CD56(bright) cells did not down-regulate CD62L, suggesting that CD56(dim) cells could not acquire a terminally differentiated phenotype and that CD56(bright) cells exhibit a maturation defect that might result in a potential altered migration pattern. These observations, support the notion that NK cells of this patient display a maturation/activation defect that precludes the generation of mature NK cells at a normal rate accompanied by CD56(dim) NK cells that cannot completely acquire a terminally differentiated phenotype. Thus, our results provide evidence that support the concept that in vivo CD56(bright) NK cells differentiate into CD56(dim) NK cells, and contribute to further understand human NK cell ontogeny.