Non-Infectious Complications in B-Lymphopenic Common Variable Immunodeficiency.

BACKGROUND AND OBJECTIVE: Common variable immunodeficiency (CVID) is considered the most symptomatic type of inborn errors of immunity in humans. Along with infectious complications, which have numerous consequences, non-infectious complications are also a major challenge among CVID patients. METHODS: All registered CVID patients in the national database were included in this retrospective cohort study. Patients were divided into two groups based on the presence of B-cell lymphopenia. Demographic characteristics, laboratory findings, non-infectious organ involvements, autoimmunity, and lymphoproliferative diseases were evaluated. RESULTS: Among 387 enrolled patients, 66.4% were diagnosed with non-infectious complications; however, 33.6% had only infectious presentations. Enteropathy, autoimmunity, and lymphoproliferative disorders were reported in 35.1%, 24.3%, and 21.4% of patients, respectively. Some complications, including autoimmunity and hepatosplenomegaly, were reported to be significantly higher among patients with B-cell lymphopenia. Among organ involvement, dermatologic, endocrine and musculoskeletal systems were predominantly affected in CVID patients with B-cell lymphopenia. Among autoimmune manifestations, the frequency of rheumatologic, hematologic, and gastrointestinal autoimmunity was reported to be higher compared to other types of autoimmunity independent from the B cell-lymphopenia. Furthermore, hematological cancers, particularly lymphoma, were slightly introduced as the most common type of malignancy. Meanwhile, the mortality rate was 24.5%, and respiratory failure and malignancies were reported as the most common cause of death in our patients without significant differences between the two groups. CONCLUSION: Considering that some of the non-infectious complications might be associated with B-cell lymphopenia, therefore, regular patient monitoring and follow-up along with proper medications (besides immunoglobulins replacement therapy) are highly recommended to prevent further sequels and increase the patients' quality of life.

The spectrum of inborn errors of immunity: a single tertiary center retrospective study in Alborz, Iran.

Summary: Background. Inborn errors of immunity (IEIs) are a group of heterogeneous disorders with inherited faults in the immune system that increase susceptibility to infections, malignancies, lymphoproliferation, and autoimmune/autoinflammatory disorders. Methods. We retrospectively studied the demographic characteristics, clinical features, and immunological profiles of the 90 IEIs patients, who were diagnosed and classified according to the European Society for Immunodeficiencies (ESID) and International Union of Immunological Societies (IUIS) criteria from July 2010 to June 2021. The study was carried out in the Non-communicable Diseases Research Center, Imam Ali Hospital, Alborz, Iran. Results. Within a period of 11 years, 53 (58.9%) males and 37 (41.1%) females were diagnosed and followed up for 20 IEI disorders. The median (IQR) age of onset, age of clinical diagnosis and diagnostic delay was 0.7 (0.08-2.0), 3.18 (1.0-8.0) and 1.5 (0.17-5.0) years, respectively. Twelve patients (36.4%) had a positive family history of IEI, and the majority of patients (84.5%) had recurrent infections. Pneumonia (51.7%) was the most common clinical manifestation among IEI patients, followed by skin complications (46.2%). The most frequently diagnosed IEI was immunoglobulin A deficiency (IgAD) (14.4%) and severe combined immunodeficiency (SCID) (11.1%). Predominantly antibody deficiencies group (36.7%) was the most common category, followed by combined immunodeficiencies with associated or syndromic features group (27.8%). Conclusions. IEIs have different patterns within populations with high consanguinity. There is a need to search for underlying genetic and epigenetic factors in most common IEIs in Alborz.

Evaluation of patients with primary immunodeficiency associated with Bacille Calmette-Guerin (BCG)-vaccine-derived complications

BACKGROUND: Bacille Calmette-Guerin (BCG) vaccination has a great impact on the prevention of severe complications of tuberculosis. However, in patients with primary immunodeficiencies (PID), it can lead to severe complications such as severe combined immunodeficiency, chronic granulomatous disease, and Mendelian susceptibility to mycobacterial disease. This study highlights the demographics, clinical complications and laboratory parameters among PID patients associated with BCG vaccination side effects. METHODS: One hundred and thirty-seven PID patients with BCGosis were evaluated in this study, based on the complications following BCG vaccination. RESULTS: The mean age of the patients with BCG complications at the time of the first visit was five years. The within-group comparison of patients showed a highly significant incidence of pneumonia and hepatomegaly in severe combined immunodeficiency patients. Furthermore, the immunologic data showed an increase in the overall rates of lymphocytes such as CD3+, CD4+ and CD8 + T cells in Mendelian susceptibility to mycobacterial disease patients. The level of immunoglobulins has also increased in chronic granulomatous disease patients. CONCLUSION: The high rate of undiagnosed PIDs predisposes individuals to a high risk of severe side effects as a result of BCG vaccination, as well as infants that are less than one month of age. Therefore, there is a need for early screening and diagnosis of PIDs before exposing unknown PID status patients to BCG vaccination. The benefits of screening and early diagnosis of PID cannot be overemphasized, especially in patients with a previous family history of immunodeficiency

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Evaluation of patients with primary immunodeficiency associated with Bacille Calmette-Guerin (BCG)-vaccine-derived complications.

BACKGROUND: Bacille Calmette-Guerin (BCG) vaccination has a great impact on the prevention of severe complications of tuberculosis. However, in patients with primary immunodeficiencies (PID), it can lead to severe complications such as severe combined immunodeficiency, chronic granulomatous disease, and Mendelian susceptibility to mycobacterial disease. This study highlights the demographics, clinical complications and laboratory parameters among PID patients associated with BCG vaccination side effects. METHODS: One hundred and thirty-seven PID patients with BCGosis were evaluated in this study, based on the complications following BCG vaccination. RESULTS: The mean age of the patients with BCG complications at the time of the first visit was five years. The within-group comparison of patients showed a highly significant incidence of pneumonia and hepatomegaly in severe combined immunodeficiency patients. Furthermore, the immunologic data showed an increase in the overall rates of lymphocytes such as CD3+, CD4+ and CD8 + T cells in Mendelian susceptibility to mycobacterial disease patients. The level of immunoglobulins has also increased in chronic granulomatous disease patients. CONCLUSION: The high rate of undiagnosed PIDs predisposes individuals to a high risk of severe side effects as a result of BCG vaccination, as well as infants that are less than one month of age. Therefore, there is a need for early screening and diagnosis of PIDs before exposing unknown PID status patients to BCG vaccination. The benefits of screening and early diagnosis of PID cannot be overemphasized, especially in patients with a previous family history of immunodeficiency.

Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management.

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by hypogammaglobulinemia and increased susceptibility to recurrent bacterial infections. It is the most frequent symptomatic antibody deficiency, with a wide variety of infectious and noninfectious complications. Numerous studies have demonstrated that immunological and genetic defects are involved in the pathogenesis of CVID. However, in most cases, the genetic background of the disease remains unidentified. This review aims to discuss various aspects of CVID, including epidemiology, pathogenesis, symptoms, diagnosis, classification, and management.

Common variable immunodeficiency: epidemiology, pathogenesis, clinical manifestations, diagnosis, classification, and management

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by hypogammaglobulinemia and increased susceptibility to recurrent bacterial infections. It is the most frequent symptomatic antibody deficiency, with a wide variety of infectious and noninfectious complications. Numerous studies have demonstrated that immunological and genetic defects are involved in the pathogenesis of CVID. However, in most cases, the genetic background of the disease remains unidentified. This review aims to discuss various aspects of CVID, including epidemiology, pathogenesis, symptoms, diagnosis, classification, and management

La inmunodeficiencia variable común (CVID) es un trastorno heterogéneo caracterizado por una hipogammaglobulinemia y por una mayor susceptibilidad a infecciones bacterianas recurrentes. Se trata de la inmunodeficiencia humoral sintomática más frecuente y cursa con una extensa variedad de complicaciones infecciosas y no infecciosas. En la patogenia de la CVID están involucrados diferentes defectos inmunológicos y genéticos. Sin embargo, en la mayoría de los casos, el fondo genético de la enfermedad permanece sin identificar. Esta revisión tiene como objetivo discutir diferentes aspectos de la CVID, incluyendo epidemiología, patogenia, síntomas, diagnóstico, clasificaciones y tratamiento de la enfermedad

Mendelian susceptibility to mycobacterial disease: Clinical and immunological findings of patients suspected for IL12RBeta1 deficiency

Background: Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by increased susceptibility to weakly virulent mycobacteria (Bacillus Calmette-Guérin [BCG] vaccines and environmental mycobacteria), Mycobacterium tuberculosis, Candida spp. and Salmonella spp. The aim of this study is to evaluate clinical features and immunological findings of MSMD patients with interleukin 12 receptor beta 1 (IL12Rβ1) deficiency. Methods: Among 117 screened patients with BCG infection following vaccination, 23 suspected MSMD subjects were recruited to this study by the exclusion of severe combined immunodeficiencies and chronic granulomatous diseases. Flow cytometric assessment for surface expression of IL12Rβ1 was performed. Moreover, the clinical and immunological data from the patients was evaluated. Results: A significant decrease (less than 1%) in the surface expression of IL12Rβ1 was reported in six cases which showed a significant increase in the count of lymphocytes (p = 0.009) and CD8+ T cells (p = 0.008) as compared to MSMD subjects with normal expression of surface IL12Rβ1. The frequency of disseminated BCGosis (50% vs. 20%, p = 0.29), recurrent infection (83.3% vs. 40%, p = 0.14) and salmonellosis (33.3% vs. 0.0%, p = 0.07) was higher in IL12Rβ1 deficient subjects than IL12Rβ1 sufficient individuals. Conclusion: MSMD patients with childhood onset of mycobacteriosis (mostly after BCG vaccination) and recurrent salmonellosis could be evaluated for IL12Rβ1 expression with flow cytometry for punctual diagnosis

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Mendelian susceptibility to mycobacterial disease: Clinical and immunological findings of patients suspected for IL12Rß1 deficiency.

BACKGROUND: Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by increased susceptibility to weakly virulent mycobacteria (Bacillus Calmette-Guérin [BCG] vaccines and environmental mycobacteria), Mycobacterium tuberculosis, Candida spp. and Salmonella spp. The aim of this study is to evaluate clinical features and immunological findings of MSMD patients with interleukin 12 receptor beta 1 (IL12Rß1) deficiency. METHODS: Among 117 screened patients with BCG infection following vaccination, 23 suspected MSMD subjects were recruited to this study by the exclusion of severe combined immunodeficiencies and chronic granulomatous diseases. Flow cytometric assessment for surface expression of IL12Rß1 was performed. Moreover, the clinical and immunological data from the patients was evaluated. RESULTS: A significant decrease (less than 1%) in the surface expression of IL12Rß1 was reported in six cases which showed a significant increase in the count of lymphocytes (p=0.009) and CD8+ T cells (p=0.008) as compared to MSMD subjects with normal expression of surface IL12Rß1. The frequency of disseminated BCGosis (50% vs. 20%, p=0.29), recurrent infection (83.3% vs. 40%, p=0.14) and salmonellosis (33.3% vs. 0.0%, p=0.07) was higher in IL12Rß1 deficient subjects than IL12Rß1 sufficient individuals. CONCLUSION: MSMD patients with childhood onset of mycobacteriosis (mostly after BCG vaccination) and recurrent salmonellosis could be evaluated for IL12Rß1 expression with flow cytometry for punctual diagnosis.

The profile of IL-4, IL-5, IL-10 and GATA3 in patients with LRBA deficiency and CVID with no known monogenic disease: Association with disease severity

Background: Common variable immunodeficiency (CVID) is the most common symptomatic form of primary immunodeficiency (PID). LPS-responsive beige-like anchor protein (LRBA) deficiency is an autosomal recessive disease characterized by a CVID-like phenotype. T cell abnormality was reported in patients with CVID and LRBA deficiency. The study's aim was to evaluate IL-4, IL-5, IL-10 and GATA3 expression in patients with LRBA deficiency and CVID with no known monogenic disease, and further evaluate its relevance with immunological futures and clinical complications of patients. Methods: The study population comprised patients with CVID, LRBA deficiency and age-sex matched healthy controls. Mutation analysis was done by whole exome sequencing in CVID patients to rule out monogenic PIDs. After CD4+ T cell stimulation with anti-CD3 and anti-CD28 monoclonal antibodies, gene expression of IL-4, IL-5, IL-10 and transcription factor GATA3 was evaluated by real-time polymerase chain reaction. The protein of mentioned cytokines was assessed by enzyme-linked immunosorbent assay. Results: The main clinical presentations of CVID patients were infections only and lymphoproliferations phenotypes, but in LRBA patients were autoimmune and enteropathy phenotype. The frequencies of CD4+ T cells were significantly reduced in LRBA and CVID patients. There were no statistically significant differences among GATA3, IL4, and IL5 gene expressions by CD4+ T cells of patients and controls, however, the IL10 expressions in CVID patients was significantly lower than in LRBA patients and HCs. As compared with HCs, CVID patients showed a prominent decrease in IL-4 and IL-10 production by CD4+ T cells. Conclusions: Our findings demonstrated that patients with CVID and LRBA deficiency (even with severe infectious and inflammatory complications) have not imbalance in Th2 response, which is in parallel with lower frequency of allergy and asthma in these patients

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The profile of IL-4, IL-5, IL-10 and GATA3 in patients with LRBA deficiency and CVID with no known monogenic disease: Association with disease severity.

BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic form of primary immunodeficiency (PID). LPS-responsive beige-like anchor protein (LRBA) deficiency is an autosomal recessive disease characterized by a CVID-like phenotype. T cell abnormality was reported in patients with CVID and LRBA deficiency. The study's aim was to evaluate IL-4, IL-5, IL-10 and GATA3 expression in patients with LRBA deficiency and CVID with no known monogenic disease, and further evaluate its relevance with immunological futures and clinical complications of patients. METHODS: The study population comprised patients with CVID, LRBA deficiency and age-sex matched healthy controls. Mutation analysis was done by whole exome sequencing in CVID patients to rule out monogenic PIDs. After CD4+ T cell stimulation with anti-CD3 and anti-CD28 monoclonal antibodies, gene expression of IL-4, IL-5, IL-10 and transcription factor GATA3 was evaluated by real-time polymerase chain reaction. The protein of mentioned cytokines was assessed by enzyme-linked immunosorbent assay. RESULTS: The main clinical presentations of CVID patients were infections only and lymphoproliferations phenotypes, but in LRBA patients were autoimmune and enteropathy phenotype. The frequencies of CD4+ T cells were significantly reduced in LRBA and CVID patients. There were no statistically significant differences among GATA3, IL4, and IL5 gene expressions by CD4+ T cells of patients and controls, however, the IL10 expressions in CVID patients was significantly lower than in LRBA patients and HCs. As compared with HCs, CVID patients showed a prominent decrease in IL-4 and IL-10 production by CD4+ T cells. CONCLUSIONS: Our findings demonstrated that patients with CVID and LRBA deficiency (even with severe infectious and inflammatory complications) have not imbalance in Th2 response, which is in parallel with lower frequency of allergy and asthma in these patients.

Infectious etiology of chronic diarrhea in patients with primary immunodeficiency diseases.

Summary: Background.Primary immunodeficiency diseases (PIDs) are life-threatening disorders, which manifest commonly with gastrointestinal (GI) signs, mainly as chronic diarrhea. Objective. To investigate and compare infectious etiology of chronic diarrhea in different PIDs. Patients and methods. Assessing clinical features, obtaining immunological profiles, as well as characterizing infectious etiology of diarrhea were performed in 38 PID patients with chronic diarrhea. Stool samples and/or biopsy specimens were checked using culture, microscopic examination, RT-PCR, and PCR, as appropriate. The patients were diagnosed to have common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID), X-linked agammaglobulinemia (XLA), and hyper-IgM (HIgM) syndrome. Results. In 32 patients we identified 41 infectious agents including 16 parasitic (39.0%, the most common Giardia lamblia), 11 bacterial (26.8%, the most common salmonella spp), 8 viral (19.5%, the most frequent group A rotavirus), and 6 fungal organisms (14.7%, the most common Candida albicans). From 6 of the patients, no infectious agent was isolated. In CVID bacteria and parasites, in SCID bacteria and viruses, in XLA parasites, and in individuals with HIgM syndrome parasites were the leading causes of chronic diarrhea. Infection with giardia and cryptosporidium were more frequent in XLA and HIgM, respectively. Conclusion. The current study suggests considering both usual and unusual pathogens in laboratory investigation and in the empiric treatment of chronic diarrhea. Opportunistic pathogens should be taken into account when no other pathogen is identified, especially in patients on long-term treatment or prophylaxis with antifungals/antibiotics and in those from geographical locations that favor pathogenicity of these organisms.

NC13D deficiency associated with epileptic seizures and antibody deficiency: the first case from the Iranian National Registry

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Autoimmunity and its association with regulatory T cells and B cell subsets in patients with common variable immunodeficiency

Background: Common variable immunodeficiency (CVID) is one of the most prevalent symptomatic primary immunodeficiencies (PIDs), which manifests a wide clinical variability such as autoimmunity, as well as T cell and B cell abnormalities. Methods: A total of 72 patients with CVID were enrolled in this study. Patients were evaluated for clinical manifestations and classified according to the presence or absence of autoimmune disease. We measured regulatory T cells (Tregs) and B-cell subsets using flow cytometry, as well as specific antibody response (SAR) to pneumococcal vaccine, autoantibodies and anti-IgA in patients. Results: Twenty-nine patients (40.3%) have shown at least one autoimmune manifestation. Autoimmune cytopenias and autoimmune gastrointestinal diseases were the most common. A significant association was detected between autoimmunity and presence of hepatomegaly and splenomegaly. Among CVID patients, 38.5% and 79.3% presented a defect in Tregs and switched memory B-cells, respectively, whereas 69.0% presented CD21low B cell expansion. Among patients with a defect in Treg, switched memory and CD21low B cell, the frequency of autoimmunity was 80.0%, 52.2% and 55.0%, respectively. A negative correlation was observed between the frequency of Tregs and CD21low B cell population. 82.2% of patients had a defective SAR which was associated with the lack of autoantibodies. Conclusions: Autoimmunity may be the first clinical manifestation of CVID, thus routine screening of immunoglobulins is suggested for patients with autoimmunity. Lack of SAR in CVID is associated with the lack of specific autoantibodies in patients with autoimmunity. It is suggested that physicians use alternative diagnostic procedures (AU)

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Rheumatologic complications in a cohort of 227 patients with common variable immunodeficiency.

Common variable immunodeficiency (CVID) is the most prevalent symptomatic type of human primary immunodeficiency diseases (PID). Clinically, CVID is characterized by increased susceptibility to infections and a wide variety of autoimmune and rheumatologic disorders. All patients with CVID registered in Iranian PID Registry (IPIDR) were enrolled in this retrospective cohort study. We investigated the frequency of rheumatologic diseases and its association with immunological and clinical phenotypes in patients with CVID. A total of 227 patients with CVID were enrolled in this study. The prevalence of rheumatologic disorders was 10.1% with a higher frequency in women than men. Most common rheumatologic manifestations were juvenile idiopathic arthritis (JIA) and adult rheumatoid arthritis (RA) followed by juvenile spondyloarthritis (JSpA) and undifferentiated inflammatory arthritis (UIA). Septic arthritis in patients with CVID with a history of RA and JIA was higher than patients without rheumatologic complication. Patients with CVID with a history of autoimmunity (both rheumatologic and non-rheumatologic autoimmunity) had lower regulatory T cells counts in comparison with patients without autoimmune disorders. There was an association between defect in specific antibody responses and negative serologic test results in patients with rheumatologic manifestations. JIA, RA, JSpA and UIA are the most frequent rheumatologic disorders in patients with CVID. Due to antibody deficiency, serologic tests may be negative in these patients. Therefore, these conditions pose significant diagnostic and therapeutic challenges for immunologists and rheumatologists in charge of the care for these patients.

Systematic investigation for underlying causes of recurrent infections in children: surveillance of primary immunodeficiency.

Summary: Recurrent infections seem to be a common complaint in children who are referred to general practitioners and pediatricians offices. Detection of primary immunodeficiencies (PID) etiology is very important for achieving appropriate diagnosis and treatment of these patients. The absence of appropriate treatment could lead to subsequent complications, in a hospital inpatient and/or outpatient settings. This study was performed in a group of children with recurrent infections to identify patients with underlying PID. A cross-sectional study was designed to evaluate the final clinical diagnosis obtained in 100 pediatric patients with a history of recurrent infections referred to Children s Medical Center, Tehran, Iran, during one year (2011-2012). History taking and physical examination, complementary laboratory tests including immunological investigations were done to confirm the main causes of disease according to our previously published stepwise approach to recurrent infections. Among all studied patients, 21% (11 males and 10 females) were diagnosed to have PID. Parental consanguinity (p = 0.001) and soft tissue infections (p = 0.004) were significantly higher in PID group, comparing to other causes of recurrent infections. Gender and location of infections were also linked to the type of PID including antibody deficiency, combined immunodeficiency and phagocytosis disorders. The real rate of PID as a cause of recurrent infection appears to be much higher than what is generally considered in a se-lected group of pediatric patients; so, following the suggested stepwise guideline can im-prove timely diagnosis and appropriate treatment of these patients.