Clinical, Laboratory, and Molecular Findings for 63 Patients With Severe Combined Immunodeficiency: A Decade´s Experience.

BACKGROUND: Severe combined immunodeficiency (SCID) is a life-threatening pediatric disease. We report on the clinical evaluation, immunological assessment, molecular analysis, and outcomes of SCID patients in a tertiary referral center in Iran. METHODS: From January 2006 to December 2015, we performed a prospective cohort study in which initial screening and advanced immunological tests were carried out on patients suspected of having SCID. Genetic analysis was also performed to confirm the diagnosis. RESULTS: A total of 63 patients were diagnosed with SCID (43 male [68.3%]). The median age at onset and diagnosis and diagnostic delay were 40 and 110 and 60 days respectively. A total of 49 patients (77.8%) had a history of BCG vaccination, and of these, one-third experienced BCG-associated complications. The most common clinical manifestations were pneumonia, recurrent oral candidiasis, chronic diarrhea, and failure to thrive. Of the thirteen patients who underwent hematopoietic stem cell transplantation, 8 survived and 5 died before they could receive the transplant. Most patients (34.9%) were classified as having T-B-NK+ SCID and had a mutation in the RAG2 or RAG1 gene. CONCLUSIONS: Autosomal recessive SCID is the most common type in Iranian patients. Providing high-quality training to physicians and patients' families to reduce the diagnostic delay should be prioritized. It is also important to raise awareness of live vaccination and to expand stem cell donor registries to speed up the transplantation process.

Clinical, laboratory, and molecular findings for 63 patients with severe combined immunodeficiency: a decade's experience

Introduction: Severe combined immunodeficiency (SCID) is a life-threatening pediatric disease. We report on the clinical evaluation, immunological assessment, molecular analysis, and outcomes of SCID patients in a tertiary referral center in Iran. Methods: From January 2006 to December 2015, we performed a prospective cohort study in which initial screening and advanced immunological tests were carried out on patients suspected of having SCID. Genetic analysis was also performed to confirm the diagnosis. Results: A total of 63 patients were diagnosed with SCID (43 male [68.3%]). The median age at onset and diagnosis and diagnostic delay were 40 and 110 and 60 days respectively. A total of 49 patients (77.8%) had a history of BCG vaccination, and of these, onethird experienced BCG-associated complications. The most common clinical manifestations were pneumonia, recurrent oral candidiasis, chronic diarrhea, and failure to thrive. Of the thirteen patients who underwent hematopoietic stem cell transplantation, 8 survived and 5 died before they could receive the transplant. Most patients (34.9%) were classified as having T-B-NK+ SCID and had a mutation in the RAG2 or RAG1 gene. Conclusion: Autosomal recessive SCID is the most common type in Iranian patients. Providing high-quality training to physicians and patients’ families to reduce the diagnostic delay should be prioritized. It is also important to raise awareness of live vaccination and to expand stem cell donor registries to speed up the transplantation process (AU)

Introducción: La inmunodeficiencia combinada severa (SCID) es una grave enfermedad pediátrica que puede comprometer la vida del paciente. El artículo recoge la evaluación clínica e inmunológica, el análisis molecular y la supervivencia de los pacientes con SCID atendidos en un hospital de referencia de Irán. Métodos: Desde enero de 2006 a diciembre de 2015, se realizó un estudio prospectivo en los pacientes con SCID en el que se realizó un screening inicial junto a diferentes análisis inmunológicos. Se realizó un análisis genético para confirmar el diagnóstico. Resultados: Sesenta y tres pacientes fueron diagnosticados de SCID, cuarenta y tres (63,8%) de los mismos eran varones. La mediana de la edad de inicio de la enfermedad, diagnóstico y retraso en su diagnóstico, fueron de 40, 110 y 60 días respectivamente. Cuarenta y nueve pacientes (77,8%) recibieron vacunación con BCG y un tercio de los mismos presentó complicaciones como consecuencia de la misma. Las manifestaciones clínicas más frecuentes de estos pacientes fueron: neumonía, candidiasis oral recidivante, diarrea crónica y retraso en el crecimiento. Ocho de los treces pacientes que recibieron trasplante de progenitores hematopoyéticos, lograron sobrevivir. Los restantes pacientes fallecieron antes de poder recibir dicho trasplante. El 34,9% de los pacientes tuvieron T-B-NK+ SCID y la mayoría de los pacientes eran portadores de mutaciones en los genes RAG2 o RAG1. Conclusión: La variante autosómica recesiva de la SCID es la forma más común en los pacientes iraníes. Se debe considerar prioritario proporcionar una formación adecuada a los médicos y las familias para reducir el retraso en el diagnóstico. Es igualmente importante concienciar para evitar la vacunación con gérmenes vivos y expandir los registros de donantes de células madre para agilizar el trasplante de estos pacientes (AU)

Cytokine production by activated T cells in common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic antibody deficiency. It is characterized by hypogammaglobulinemia, increased susceptibility to recurrent infections, autoimmunity, and malignancies. OBJECTIVES: To determine whether patients with CVID have cytokine production defects after T-cell activation and to assess whether or not these are correlated with markers of severe disease. METHODS: Twenty-seven patients with CVID and 17 healthy volunteers were investigated. Peripheral blood mononuclear cells were cultured under standard conditions in the presence and absence of phytohemagglutinin. Subsequent cell proliferation and cytokine release were measured and compared between stimulated and unstimulated cells. RESULTS: A general enhancement in cytokine production was observed in both CVID patients and controls after stimulation. However, we detected a lower production of interferon-gamma in CVID patients than in controls (P = .026). A production defect for at least 1 cytokine was observed in 12 patients. Ten of these failed to generate protective titers in response to the polysaccharide vaccine, and the frequency of bronchiectasis in this group of patients was 91.7%. Cytokine release correlated strongly with cell proliferation. CONCLUSIONS: This study indicates that some CVID patients have T-cell proliferation and secretory defects and that these may be associated with severe manifestations of disease. Screening for such defects could permit more effective monitoring and therapeutic strategies for CVID patients.

T- helper 1 and 2 cytokine assay in patients with common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous group of disorders, characterized by decreased immunoglobulin levels in serum and increased susceptibility to recurrent infections, autoimmunity, and malignancy. The pathogenesis of CVID is still unknown. OBJECTIVES: This study was performed to investigate T-helper (T(H)) 1 and 2 cytokine levels in patients with CVID. MATERIAL AND METHODS: Twenty-four cases of CVID were studied. Cytokine levels of interleukin (IL)-2, IL-4, IL-10, and interferon gamma were measured in the serum of the patients and compared with those of healthy controls. RESULTS: T(H)2 cytokine levels (IL-4 and IL-10) were significantly higher in the patient group than in the controls (median: 64.5 vs 0.0 pg/mL, P=.016 for IL-4 and 321.1 vs. 0.0 pg/mL, P=.001 for IL-10). However, there were no significant differences in T(H)1 cytokines between the 2 groups (median, 116.5 vs. 104.5 pg/mL, P=.22 for IL-2 and 50.5 vs. 42.3 pg/mL, P=.32 for IFN-gamma). CONCLUSIONS: Increased levels of IL-4 and IL-10 could indicate high activation of T(H)2 lymphocytes in this group of patients and consequently supports the concept of a bias towards T(H)2-type responses.

Altered dendritic cell function in response to sera of common variable immunodeficiency patients.

OBJECTIVE: CVID is characterized by hypogammaglobulinemia and T cell disorder in most cases. Dendritic cells might be severely perturbed in differentiation and maturation but it is not clear whether this perturbation is intrinsic or because of alterations in microenvironmental factors. We evaluated the effects of CVID patient's sera as a source of microenvironmental factors on monocyte-derived DCs (MDCs). METHODS: Monocyte derived DCs (MDCs) were generated in the presence of GM-CSF, IL-4 and 10% concentration of CVID (n = 10) and healthy control (n = 8) serum samples. MDCs were matured with monocyte conditioned medium and TNF-alpha. Mature MDCs were used for: (i) immunophenotyping, (ii) MLR, (iii) co-culture with allogeneic lymphocytes for cytokine production assays and (iv) DC-cytokine production assays after stimulation with CD40L. RESULTS: Treatment of MDCs with sera derived from CVID patients as compared to control sera: (i) causes lower surface expression of HLA-DR after maturation, (ii) leads to production of higher amounts IL-18 by activated MDCs and, (iii) results in lower allostimulatory capacity of MDCs in MLR assays. CONCLUSIONS: Our findings argue for constitutive presence/absence of soluble factors e. g. cytokines in CVID patients' sera steering the immune response toward the cellular rather than the humoral arm. Our observations deserve further studies to identify these factors.