Noninfectious Complications in B-Lymphopenic Common Variable Immunodeficiency.

BACKGROUND: 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, noninfectious complications are a major challenge among CVID patients. METHODS: All CVID patients registered in the national database were included in this retrospective cohort study. Patients were divided into 2 groups based on the presence of B-cell lymphopenia. Demographic characteristics, laboratory findings, noninfectious organ involvement, autoimmunity, and lymphoproliferative diseases were evaluated. RESULTS: Among 387 enrolled patients, 66.4% were diagnosed with noninfectious complications and 33.6% with isolated 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 more frequent among patients with B-cell lymphopenia. As for organ involvement, the 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 than that of other types of autoimmunity not associated with B cell-lymphopenia. Furthermore, hematological cancers, particularly lymphoma, were the most common type of malignancy. The mortality rate was 24.5%, and respiratory failure and malignancies were the most common causes of death, with no significant differences between the 2 groups. CONCLUSIONS: Considering that some of the noninfectious complications might be associated with B-cell lymphopenia, regular patient monitoring and follow-up with proper medication (in addition to immunoglobulin replacement therapy) are highly recommended to prevent sequelae and increase patient quality of life.

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.

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.

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.

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.

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.

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.

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.

Circulating Helper T-Cell Subsets and Regulatory T Cells in Patients With Common Variable Immunodeficiency Without Known Monogenic Disease.

BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency (PID). It is characterized by heterogeneous clinical manifestations and defects in B cells and T cells. In the present study, we investigated helper T (TH) cell subsets and regulatory T (Treg) cells and their related cytokines and transcription factors in CVID patients with no definitive genetic diagnosis. METHODS: The study population comprised 13 CVID patients and 13 healthy controls. Mutation analysis was performed using whole exome sequencing in CVID patients to rule out monogenic PIDs. TH subsets and Treg were analyzed using flow cytometry. The expression of determinant cytokines (IFN-γ, IL-17, IL-22, and IL-10) and cell subset specific transcription factors was evaluated before and after stimulation. RESULTS: The main clinical presentations of these patients were infections only and lymphoproliferative phenotypes. No autoimmune or allergy phenotypes were recorded. The frequencies of CD4+ T cells, TH17, and Treg cells were significantly reduced in CVID patients; however, TH1, TH1-like TH17, and TH22 subsets were normal. After stimulation, expression of retinoic-acid-orphan-receptor-C (RORC), runtrelated transcription factor 1 (RUNX1), IL17, and IL10 was significantly lower in CVID patients than in the healthy controls. Moreover, the concentration of IL-17 and IL-10 in the cell culture supernatants of stimulated CD4+ T cells was lower in CVID patients than in healthy controls. CONCLUSIONS: Our findings demonstrate that the imbalance of TH17 and Tregs could be associated with infection and the lymphoproliferative phenotype in CVID patients without monogenic disorders.

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.

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.

Selective IgA Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management.

Selective immunoglobulin A deficiency (SIgAD) is the most common primary antibody deficiency. Although more patients with SIgAD are asymptomatic, selected patients suffer from different clinical complications such as pulmonary infections, allergies, autoimmune diseases, gastrointestinal disorders and malignancy. Pathogenesis of SIgAD is still unknown; however, a defective terminal differentiation of B cells and defect in switching to IgA-producing plasma cells are presumed to be responsible. Furthermore, some cytogenic defects and monogenic mutations are associated with SIgAD. There is no specific treatment for patients with symptomatic IgA deficiency, although prophylactic antibiotic therapy along with circumstantial immunoglobulin replacement with justification and supportive care (using a product that contains minimal IgA) could be helpful for patients with a severe phenotype. The epidemiology, pathogenesis, clinical phenotype, diagnosis, prognosis, management and treatment in patients with SIgAD have been reviewed.

A Comparison of Clinical and Immunologic Phenotypes in Familial and Sporadic Forms of Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency disease, and its prevalence varies significantly among different population. Minority of CVID patients present a familial aggregation suggesting a higher probability of heritable genetic defects. A total of 235 registered CVID patients were evaluated in this cohort study. Familial and sporadic patients were stratified, and demographic information, clinical records, laboratory and molecular data were compared among these two groups of patients. Multiple cases were identified in 12 families (30 patients) and sporadic presentation in 120 cases. The rate of parental consanguinity (83.3%) and clinical presentation of lymphoid malignancy (20.7%) were predominant in familial CVID patients, whereas significantly increased recurrent upper respiratory infections were recorded in sporadic patients (0.3 infections per year). Probands of familial group were presented with a higher severity score resulting in a profound mortality rate (41.7% after 30-year follow-up) comparing to the non-proband CVID patients in the same families with a lowered diagnostic delay. Familial CVID patients had a specific signature in clinical presentation and immunologic profile, and a high consanguinity in this group of patients suggests a Mendelian trait with an autosomal recessive inheritance pattern. Diagnosis of an index patient within a multiple case families significantly improves the diagnostic process and outcomes of the yet asymptomatic patients.

Approach to the Management of Autoimmunity in Primary Immunodeficiency.

Primary immunodeficiency diseases (PIDs) consist of a genetically heterogeneous group of immune disorders that affect distinct elements of the immune system. PID patients are more prone to infections and non-infectious complications, particularly autoimmunity. The concomitance of immunodeficiency and autoimmunity appears to be paradoxical and leads to difficulty in the management of autoimmune complications in PID patients. Therefore, management of autoimmunity in patients with PID requires special considerations because dysregulations and dysfunctions of the immune system along with persistent inflammation impair the process of diagnosis and treatment.

Infectious and Noninfectious Pulmonary Complications in Patients With Primary Immunodeficiency Disorders.

Primary immunodeficiency disorders (PIDs) are caused by 1 or more defects of the immune system. Patients are more likely to experience recurrent and/or severe infections and tend to develop a wide range of complications. Respiratory diseases are the main and initial manifestation in most cases and the most common complication. Pulmonary complications cause significant morbidity and mortality in patients with PIDs. Early diagnosis and appropriate treatment can prevent or at least slow the development of respiratory complications. Since the spectrum of pulmonary complications in PIDs is broad, we divided pulmonary complications into upper respiratory complications (eg, sinusitis, otitis media, and laryngeal angioedema) and lower respiratory complications (eg, pneumonia, bronchitis, bronchiectasis, interstitial lung diseases, organizing pneumonia, pulmonary adenopathies and malignancies, hyperreactive airway diseases, pulmonary dysgenesis, and adverse reactions to treatment). This review covers the main respiratory manifestations in patients with PIDs.

Comparison of various classifications for patients with common variable immunodeficiency (CVID) using measurement of B-cell subsets.

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous disease, characterised by hypogammaglobulinaemia leading to recurrent infections and various complications. The aim of this study was to classify CVID patients based on four known classifications (Paris, Freiburg, EUROclass, and B-cell patterns) by measurement of B-cell subsets and to assess the relation of each classification with clinical manifestations. METHODS: We measured all B-cell subsets as both absolute count and percentage in 30 CVID patients and 30 healthy individuals using four-colour flow cytometry. Moreover, we evaluated antibody responses to pneumococcal vaccine in patients. RESULTS: A significant reduction in percentage of terminal B-cell subsets (total, marginal zone-like, switched memory, IgM-only memory, total memory B-cells and plasmablast) and absolute count of all B-cell subsets along with a strong increase in CD21low B-cells has been observed in patients. Patients with splenomegaly and hepatomegaly clustered in group Ia, smB+21low and group 1 based on known classifications, and significantly tended to have a decreased transitional and marginal zone-like B-cells count, as well as an increase in CD21low B-cell counts. Patients with lymphadenopathy, bronchiectasis and allergy had a significant decrease in absolute count of total memory, switched memory and total B-cells, respectively. CONCLUSION: Classification of patients could provide useful information to guide clinicians in long-term follow-up of CVID patients. Our data demonstrate that it may be more accurate to use absolute counts of B-cell subpopulations in CVID patients because absolute counts of B-cell subsets are more associated with clinical manifestations compared with their percentage and also four known classifications.

Epidemiology and pathophysiology of malignancy in common variable immunodeficiency?

Common variable immunodeficiency (CVID) is a diagnostic category of primary immunodeficiency (PID) which may present with heterogeneous disorders including recurrent infections, autoimmunity, granulomatous diseases, lymphoid and other types of malignancies. Generally, the incidence of malignancy in CVID patients is around 1.5-20.7% and usually occurs during the 4th-6th decade of life. Non-Hodgkin lymphoma is the most frequent malignancy, followed by epithelial tumours of stomach, breast, bladder and cervix. The exact pathological mechanisms for cancer development in CVID are not fully determined; however, several mechanisms including impaired genetic stability, genetic predisposition, immune dysregulation, impaired clearance of oncogenic viruses and bacterial infections, and iatrogenic causes have been proposed to contribute to the high susceptibility of these patients to malignancies.

New therapeutic approach by sirolimus for enteropathy treatment in patients with LRBA deficiency.

SUMMARY: Purpose. To report the successful use of sirolimus for management of enteropathy in four patients with LPS-responsive beige-like anchor protein (LRBA) deficiency. Methods. Case series. Results. sirolimus therapy led to a complete improvement of symptoms including decrease in frequency and severity of diarrhea, as well as patients' weight gain. No signs of abdominal cramps and anorexia were also detected during the follow up period after treatment. Conclusions. sirolimus with its potential efficacy and immunomodulatory properties may be recommended for the treatment of severe enteropathy refractory to conventional therapy in patients with LRBA deficiency.