Iranian Primary Immunodeficiency Registry Research Articles

Historical Cohort of Severe Congenital Neutropenia in Iran: Clinical Course, Laboratory Evaluation, Treatment, and Survival.

Severe congenital neutropenia (SCN) is one of the primary immunodeficiency diseases developed by genetic alterations. Mutations in several genes including HAX-1 , G6PC3 , jagunal , and VPS45 account for autosomal recessive SCN. Patients with SCN registered in the Iranian Primary Immunodeficiency Registry and referred to our clinic at the Children's Medical Center were reviewed. Thirty-seven eligible patients with a mean age of 28.51 ± 24.38 months at the time of diagnosis were included. Nineteen cases had consanguineous parents and 10 cases had confirmed or unconfirmed positive family history. The most prevalent infectious symptoms were oral infections followed by respiratory infections. We identified HAX-1 mutation in 4, ELANE mutation in 4 cases, G6PC3 mutation in 1, and WHIM syndrome in 1 case. Other patients remained genetically unclassified. After the median follow-up of 36 months from the time of diagnosis, the overall survival was 88.88%. The mean event-free survival was 185.84 months (95% CI: 161.02, 210.66). Autosomal recessive SCN is more common in countries with high rates of consanguinity like Iran. The genetic classification was possible only for a few patients in our study. This might suggest that there are other autosomal recessive genes causative of neutropenia that have yet to be described.

Cardiac Complications in Patients with Common Variable Immune Deficiency: A Longitudinal Study

Background: The common variable immune deficiency (CVID) is known as the most prevalent symptomatic primary immune deficiency (PID) diseases, which is characterized by hypogammaglobulinemia with variable infectious and noninfectious manifestations. In this study, the researchers aimed to evaluate the frequency of cardiac disorders and investigate its association with other manifestations in CVID patients.
 Method: A total of 337 CVID patients registered in the Iranian Primary Immunodeficiency Registry were evaluated in this study. The questionnaire was completed for all patients to collect the participants’ demographic data, clinical manifestations and laboratory finding. The analysis was performed between the two groups of the study including CVID patients with cardiac manifestation and those without it.
 Results: The prevalence rate of cardiac manifestation was calculated to be 9.1%. pericardial and myocardial diseases and pulmonary hypertension were the most prevalent complications. CVID patients with a history of cardiac problem had significantly higher prevalence rates of otitis media, lymphoproliferative disorders, splenomegaly, hepatomegaly, failure to thrive and lower numbers of CD8+ T cells and CD19+ B cells compared to the patients without cardiac disorders. Notably, no significant differences were observed in immunoglobulins serum levels, CD3+ and CD4+ T cells between the patients with and without cardiac manifestation.
 Conclusion: Regular echocardiographic evaluation and of CVID patients for cardiac complications especially for inflammatory cardiac disease, heart failure and pulmonary hypertension, is critical to reduce the risk of heart disease.

Comparison of Demographic and Clinical Characteristics Among X-Linked and Autosomal Recessive Agammaglobulinemia

Background: Congenital agammaglobulinemia is an inborn error of immunity, resulting in the impairment of effective antibody production. Agammaglobulinemia may be due to X-linked or autosomal genetic abnormalities. The primary defect in X-Linked agammaglobulinemia (XLA) and autosomal recessive agammaglobulinemia (ARAG) is the B cell precursors’ failure to mature B-lymphocytes and, ultimately, plasma cells. This study aims to evaluate the differences in clinical and paraclinical characteristics of XLA and ARAG patients.
 Method: A total of 58 patients were enrolled in this retrospective study. The data were extracted from the Iranian primary immunodeficiency registry (IPIDR). Forty-eight of the patients were diagnosed with XLA, while the other ten were diagnosed with ARAG. Measures including demographic data, clinical manifestations, and laboratory data of the patients were compared between the groups.
 Results: Patients with ARAG, presented manifestations at an earlier age and had a lower diagnosis delay compared to XLA patients. However, the mortality rate was not significantly affected. The pattern of organ involvement also differed between the two groups, as patients with ARAG showed manifestations that are more chronic in nature (e.g., autoimmunity, lymphoproliferation, and allergy). In contrast, XLA patients were more prone to infections and other associated complications (e.g., meningitis, sinusitis, diarrhea, and bronchiectasis). Meningitis was exclusively observed in the XLA group. The number of CD19+ B cells was significantly higher in the ARAG group (P=0.002), While the level of IgM was significantly higher in the XLA group (P=0.045).
 Conclusion: Identifying the clinical presentations of XLA and ARAG, may assist clinicians in early diagnosis in the setting of limited available genetic studies.

Respiratory System Involvement in Patients with IgA Deficiency

Background: Selective IgA deficiency (SIgAD), is known as the most common antibody deficiency. This study, investigated the respiratory disorders among these patients.
 Method: In this retrospective descriptive study, the data of patients with SIgAD in “Iranian Primary Immunodeficiency Registry” were extracted. Then, demographic characteristics, frequency and type of respiratory disorders, in addition to immunologic findings were gathered and analyzed by SPSS software.
 Results: One hundred and twenty three patients with SIgAD (78 males/45 females), with the mean age of 18± 9.6 years old were investigated. Respiratory complications (recurrent cold, chronic cough and pneumonia), were the first presentation in 45% of the patients, and respiratory system involvement was detected among 66 patients (54.1%). The prevalence of pneumonia, otitis media and sinusitis, were 33.3%, 12.5% and 20.7%; respectively; which were significantly reduced after the diagnosis (PV<0.05). Bronchiectasis had also been found in five patients (4.1%).
 Conclusion: Respiratory problems were shown to be common presenting disorders in SIgAD. Early diagnosis and appropriate therapy could be crucial for better protection, and avoidance of severe respiratory complications in these patients.

Clinical and Mutation Description of the First Iranian Cohort of Infantile Inflammatory Bowel Disease: The Iranian Primary Immunodeficiency Registry (IPIDR)

ABSTRACT We describe a cohort of 25 Iranian patients with infantile inflammatory bowel disease (IBD), 14 (56%) of whom had monogenic defects. After proper screening, patients were referred for whole exome sequencing (WES). Four patients had missense mutations in the IL10 RA, and one had a large deletion in the IL10 RB. Four patients had mutations in genes implicated in host:microbiome homeostasis, including TTC7A deficiency, and two patients with novel mutations in the TTC37 and NOX1. We found a novel homozygous mutation in the SRP54 in a deceased patient and the heterozygous variant in his sibling with a milder phenotype. Three patients had combined immunodeficiency: one with ZAP-70 deficiency (T+B+NK−), and two with atypical SCID due to mutations in RAG1 and LIG4. One patient had a G6PC3 mutation without neutropenia. Eleven of the 14 patients with monogenic defects were results of consanguinity and only 4 of them were alive to this date.

Monogenic Primary Immunodeficiency Disorder Associated with Common Variable Immunodeficiency and Autoimmunity

Background: Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency disorder mainly characterized by recurrent bacterial infections besides other immunological defects including loss of or dysfunction of B cells and decreased immunoglobulin levels. In this study, our aim is to evaluate clinical, immunological, and molecular data of patients with a primary clinical diagnosis of CVID and autoimmune phenotype with a confirmed genetic diagnosis. Methods: Among 297 patients with CVID, who were registered in the Iranian Primary Immunodeficiency Registry at Children’s Medical Center Hospital in Iran, 83 patients have been genetically examined and 27 patients with autoimmunity and confirmed genetic mutations were selected for analysis. Whole-exome sequencing and confirmatory Sanger sequencing methods were used for the study population. A questionnaire was retrospectively filled for all patients to evaluate demographic, laboratory, clinical, and genetic data. Results: In the 27 studied patients, 11 different genetic defects were identified, and the most common mutated gene was LRBA, reported in 17 (63.0%) patients. Two patients (7.7%) showed autoimmune complications as the first presentation of immunodeficiency. Eleven patients (40.7%) developed one type of autoimmunity, and 16 patients (59.3%) progressed to poly-autoimmunity. Most of the patients with mono-autoimmunity (n = 9, 90.0%) primarily developed infectious complications, while in patients with poly-autoimmunity, the most common first presentation was enteropathy (n = 6, 37.6%). In 13 patients (61.9%), the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency. The most frequent autoimmune manifestations were hematologic (40.7%), gastrointestinal (48.1%), rheumatologic (25.9%), and dermatologic (22.2%) disorders. Patients with poly-autoimmunity had lower regulatory T cells than patients with mono-autoimmunity. Conclusion: In our cohort, the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency in most patients. This association highlights the fact that patients referring with autoimmune manifestations should be evaluated for humoral immunity.

Ataxia-Telangiectasia in Iran: Clinical and Laboratory Features of 104 Patients

Ataxia-telangiectasia is a multisystem disorder characterized by progressive neurologic impairment, variable immunodeficiency, impaired organ maturation, x-ray hypersensitivity, oculocutaneous telangiectasia, and a predisposition to malignancy. To evaluate clinical and immunologic features of Iranian patients with ataxia-telangiectasia, the records of 104 patients with ataxia-telangiectasia (54 male, 50 female) with the age range of 1.6-23.5 years were reviewed. The Iranian Primary Immunodeficiency Registry was used as the data source. Progressive ataxia was seen in all the patients. Other symptoms were eye movement disorders (n = 84), slurred speech (n = 70), mental retardation (n = 10), and ocular (n = 87) and cutaneous (n = 73) telangiectasia. Three patients developed leukemia and lymphoma, and 17 patients had family history of malignancy. Positive correlation was seen between clinical immunologic symptoms and immunoglobulin deficiencies (P = 0.004). The predominant infections were sinopulmonary and acute and recurrent infections (78 cases). Infections included pneumonia (56 patients), otitis media (34 patients), and sinusitis (50 patients). Average serum alpha-fetoprotein level was 149 +/- 137 ng/dL. The incidence of ataxia-telangiectasia in Iran is high, possibly due to familial marriages. Treatment should be focused on supportive management to prolong survival.

Frequency and Clinical Manifestations of Patients with Primary Immunodeficiency Disorders in Iran: Update from the Iranian Primary Immunodeficiency Registry

Primary immunodeficiency disorders (PID) are a heterogeneous group of diseases, characterized by an increased susceptibility to infections. A total of 930 patients (573 males and 357 females) are registered in Iranian PID Registry (IPIDR) during three decades. Predominantly antibody deficiencies were the most common (38.4%), followed by congenital defects of phagocyte number and/or function (28.3%), other well-defined immunodeficiency syndromes (17.7%), combined T- and B-cell immunodeficiencies (11.0%), complement deficiencies (2.4%), and diseases of immune dysregulation (2.3%). Common variable immunodeficiency was the most frequent disorder (20.8%), followed by chronic granulomatous disease, ataxia-telangiectasia, btk deficiency, selective IgA deficiency, and T-B-severe combined immunodeficiency. The frequency of other PID disorders was less than 50 in number (<5%). There is an increasing trend in recognition of more PID in the recent years. Construction of such registry is not only important for its epidemiological aspect but also for its role in increasing the physician's knowledge about such disorders.

Consanguinity in Primary Immunodeficiency Disorders; the Report from Iranian Primary Immunodeficiency Registry

Primary Immunodeficiency Disorders (PiD) are a heterogeneous group of genetic disorders, with different modes of inheritance. This study was accomplished in order to determine the frequency of consanguineous marriages in the families of patients with PiD. In this study, the records 515 Iranian PiD patients were reviewed during a 25-year period. The mean proportion of consanguineous marriages was 65.6% among PiD patients, while the overall rate was 38.6% in the country. The rate of consanguinity was 77.8% in cellular immunodeficiencies, 75.8% in combined immunodeficiencies, 72.5% in defects of phagocytic function, 58.6% in other immunodefiiencies, 54.1% in predominantly antibody deficiencies, and 50% in complement deficiencies. Moreover all patients with immunodeficiency associated with other diseases had consanguineous parents. Such marriages were most common in the parents of patients with Chediak-Higashi syndrome, severe combined immunodeficiencies, primary CD4 deficiency, ataxia-telangiectasia, selective IgG class deficiencies, chronic granulomatous disease, and Schwachman syndrome. It is important to inform the general population about the dangers of consanguinity, which is very common in some areas such as Iran. Premarital examination to avoid genetic diseases could be suggested, especially in a community where the rate of consanguineous marriage is high.

The clinical and laboratory survey of Iranian patients with Hyper-IgE syndrome

In order to determine the clinical and laboratory findings of Iranian patients with presumed hyper-immunoglobulin E syndrome (HIES), the medical records of 22 patients from 21 unrelated families, who had been registered in the Iranian Primary Immunodeficiency Registry, were observed. The median age of patients at the time of first symptom and at the time of diagnosis was 1 month and 52.5 months, respectively, with a median diagnosis delay of 70 months. 13 families had consanguineous marriages. IgE level was higher than 2000 IU/ml in all patients, ranging from >2000 to 80,000 IU/ml. The most commonly occurring manifestations were: eczema and dermatitis, pneumonia, upper respiratory tract infections, cutaneous abscesses, diarrhoea, deep abscesses, and otitis media. Other less frequent manifestations were: mucocutaneous candidiasis, sinusitis, cutaneous ulcers, Molluscum contagiosum, herpetic keratitis, onychomycosis, conjunctivitis, septic arthritis, and meningitis. Five patients were complicated by bronchiectasis due to recurrent pneumonia and 5 patients died because of severe infections and malignancy. The HIES is a multisystem disorder that affects especially cutaneous, respiratory, skeletal and the immune system. Although HIES is a rare condition, the recurrent infections should always raise a suspicion, which deserves further evaluation for detecting the syndrome.

Chronic Granulomatous Disease: A Clinical Survey of 41 Patients from the Iranian Primary Immunodeficiency Registry

Background: Chronic granulomatous disease (CGD) represents a group of inherited disorders of the phagocytic system, involving recurrent infections at different sites, especially the respiratory system. The present study was accomplished in order to determine the clinical spectrum of Iranian patients with CGD. Methods: Forty-one patients (29 males and 12 females) with CGD, who had already been referred to two immunodeficiency referral centers in Iran, were reviewed during a 22-year period (1980–2002). Results: These patients belonged to 34 families, and 56% of them were consanguineous. The median age at the time of study was 12 years (3 months to 22 years). The median age at onset of symptoms was 4 months (1 month to 12 years), and the median diagnostic age was 5.5 years (2 months to 20 years), with a diagnostic delay of 3 years on average. The most common presenting complaint in our CGD patients was lymphadenopathy (seen in 11 patients, 26.8%). The most common manifestations of CGD (in descending order) were lymphadenopathy (75.6%), pulmonary infections (65.9%) and skin involvement (63.4%) during their illness, followed by gastrointestinal (56.1%), skeletal (29.3%), upper respiratory tract (26.8%) and central nervous system (2.4%) involvement. Conclusions: Early diagnosis of the disease is crucial. In view of the possibility of timely treatment, i.e. prophylactic treatment of infection, CGD should be excluded in any patient with unexplained infections or granulomas.

Neutropenia in patients with primary antibody deficiency disorders.

Neutropenia is characterized by decrease in the absolute number of circulating neutrophils and an increase susceptibility to infections. The current study was performed in order to explain the clinical and laboratory findings of patients with antibody deficiency disorders associated neutropenia. The patients' records of 19 neutropenic cases out of 207 patients with antibody deficiencies, who had been referred to Children's Medical Center and enrolled in Iranian primary immunodeficiency registry, were reviewed. Nineteen cases (14 male and 5 female), with a mean age of 10.7+/-5.7 years, were associated with neutropenia (9.2%). The disorders with associated neutropenia were Hyper IgM syndromes (3 of 8), Common variable immunodeficiency (13 of 109), and X-linked agammaglobulinemia (3 of 45). The median age for the onset of disease and diagnosis age were 15 months (1-134) and 3.8 years (6 months-13 years), respectively. The most common infections during the course of illness were pneumonia (13 cases), diarrhea (12 cases), oral candidiasis (9 cases), otitis media (6 cases), sinusitis (6 cases), cutaneous infections (5 cases), and abscess (5 cases). Other less frequent infections were: conjunctivitis, oral ulcers, meningitis, and osteomyelitis. Three neutropenic patients died because of recurrent infections. Neutropenia may occur in any of the primary immunodeficiency disorders. Persistent or severe infections always pose a supposition, which deserves further evaluation for detecting an underlying immune deficiency syndrome and neutropenia, since a delay in diagnosis may result in a serious organ damage or even death of the patient.

Mortality in primary immunodeficient patients, registered in Iranian primary immunodeficiency registry.

Primary immunodeficiencies (PID) are a group of disorders, characterized by an unusual susceptibility to infections. Delay in diagnosis results in increased morbidity and mortality in affected patients. The purpose of this study was to determine the mortality rate of Iranian immunodeficient patients referred to Children Medical Center Hospital affiliated to Tehran University of Medical Sciences over a period of 20 years.In this study, records of 235 (146 males, 89 females) patients with immunodeficiency who were diagnosed and followed in our center, during 22 years period (1979-2001) were reviewed. The diagnosis of immunodeficiency was based on the standard criteria. The cause of death was determined by review of death certificates.Antibody deficiency was the most common diagnosis made in our patients. The overall five-year survival rate was 22.7% in our studied patient group; this was greatest in antibody deficiency. During the 22 year period of study, 32 patients died. As some of the patients could not be located, the true mortality rate ranged between 13.6% and 17.5%. The main leading cause of death were lower respiratory tract involvement in 14 cases (44%). The most common pathogenic microorganisms causing fatal infections were psudomonas and staphylococcus in 9 cases (28.1%) followed by E. coli in 7 (21.9%), tuberculosis in 13 (40.6%) and salmonella in 1 (3.1%).Based on our study, delay in diagnosis in patients with PID results in tissue and organ damage and several complications. Mortality and morbidity are increased in undiagnosed patients.

Clinical and laboratory findings in Iranian children with cyclic neutropenia.

Cyclic neutropenia is a rare immunodeficiency syndrome, characterized by regular periodic oscillations in the circulating neutrophil count from normal to neutropenic levels through 3 weeks period, and lasting for 3-6 days. In order to determine the clinical features of cyclic neutropenia, this study was performed. Seven patients with cyclic neutropenia (3 males and 4 females), who experienced neutropenic periods every 3 weeks (5 with severe and 2 with moderate neutropenia), were investigated in this study. They had been referred to Iranian Primary Immunodeficiency Registry during 23 years (1980-2003). The range of patients' ages was from 7 to 13 years (median 11 years). The median age at the onset of the disease was 12 months (1 month- 2 years) and the median age of diagnosis was 2 (1.5-5) years, with a median diagnosis delay of 1 year (2 months- 5 years). Neutropenia was associated with leukopenia (3 patients), anemia (3 patients), and thrombocytopenia (1 patient). Patients were asymptomatic in healthy phase, but during the episode of neutropenia suffered from aphthous ulcers, abscesses and overwhelming infections. The most commonly occurred manifestations were: otitis media (6 cases), oral ulcers (5 cases), abscesses (4 cases), pneumonia (3 cases), diarrhea (3 cases), oral candidiasis (3 cases), cutaneous infections (2 cases), and periodontitis (2 cases). One of these patients subsequently died because of recurrent infections. Unusual, persistent or severe infections should be the initiating factors to search for an immune deficiency syndrome such as cyclic neutropenia, because a delay in diagnosis may result in chronic infection, irretrievable end-organ damage or even death of the patient.

Respiratory manifestations of chronic granulomatous disease; a clinical survey of patients from Iranian primary immunodeficiency registry.

Chronic granulomatous disease represents a group of inherited disorders of phagocytic system wherein recurrent infections are seen at different sites especially in the respiratory system. To determine the clinical spectrum of respiratory manifestations in chronic granulomatous disease patients, in this retrospective study, we used data from Iranian Primary Immunodeticiency Registry. The diagnosis was based upon WHO criteria for chronic granulomatous disease. We reviewed the records of 38 patients (26 males, 12 females), related to 33 families, 73% of whom were consanguineous. The median age at the time of the study was 12yrs (3 months-22 years). The median onset age of symptoms was 4 months (l month-12 years), and that of diagnostic age was 5 years (l month-20 years), with a diagnostic delay of 4.15 years, on an average. Sixty three percent of our patients had respiratory involvement in the course of their illness, including pneumonia (18 pts, 75%), tuberculosis (llpts, 46%), aspergillosis (3 pts, 12.5%), pulmonary abscess (3 pts, 12.5%), and bronchiectasis (1 pt, 4%). Only 4 of our patients presented with respiratory problems as their first manitestation. Lymph nodes were the first common site and the lungs were the second sites of involvement in chronic granulomatous disease patients; however, it is noteworthy that only in a few of our patients, it was the first manifestation of the disease. Thus special attention should be paid to the pulmonary complications while managing this disease.