Immunodeficiency Disorders In Children Research Articles

Whole-exome sequencing to identify undiagnosed primary immunodeficiency disorders in children with community-acquired sepsis, admitted in the pediatric intensive care unit.

Whole-exome sequencing (WES) provides a powerful diagnostic tool for identifying primary immunodeficiency diseases (PIDs). This study explores the utility of this approach in uncovering previously undiagnosed PIDs in children with community-acquired sepsis (CAS), with a medical history of recurrent infections or a family history of PIDs. We performed WES on DNA samples extracted from the blood of the 34 enrolled patients, followed by bioinformatic analysis for variant calling, annotation, and prioritization. We also performed a segregation analysis in available family members to confirm the inheritance patterns and assessed the potential impact of the identified variants on protein function. From 34 patients enrolled in the study, 29 patients (85%) with previously undiagnosed genetic diseases, including 28 patients with PIDs and one patient with interstitial lung and liver disease, were identified. We identified two patients with severe combined immunodeficiency (SCID), patients with combined immunodeficiency (CID), six patients with combined immunodeficiency with syndromic features (CID-SF), four patients with defects in intrinsic and innate immunity, four patients with congenital defects of phagocyte function (CPDF), and six patients with the disease of immune dysregulation. Autoinflammatory disorders and predominantly antibody deficiency were diagnosed in one patient each. Our findings demonstrate the potential of WES in identifying undiagnosed PIDs in children with CAS. Implementing WES in the clinical evaluation of CAS patients with a warning sign for PIDs can aid in their timely diagnosis and potentially lead to improved patient care.

Primary Immunodeficiency Disorders in children with Non-Cystic Fibrosis Bronchiectasis.

Introduction. Primary immunodeficiency diseases (PID) are common in patients with non-cystic fibrosis bronchiectasis (NCFB). Our objective was to determine ratio/types of PID in NCFB. Methods. Seventy NCFB patients followed up in a two-year period were enrolled. Results. Median age was 14 years (min-max: 6-30). Male/female ratio was 39/31; parental consanguinity, 38.6%. Most patients with NCFB (84.28%) had their first pulmonary infection within the first year of their lives. Patients had their first pulmonary infection at a median age of 6 months (min-max: 0.5-84), were diagnosed with bronchiectasis at about 9 years (114 months, min-max: 2-276). PID, primary ciliary dyskinesia (PCD), bronchiolitis obliterans, rheumatic/autoimmune diseases, severe congenital heart disease and tuberculosis were evaluated as the most common causes of NCFB. About 40% of patients (n=16) had bronchial hyperreactivity (BH) and asthma. Twenty-nine patients (41.4%) had a PID, and nearly all (n=28) had primary antibody deficiency, including patients with combined T and B cell deficiency. PID and non-PID groups did not differ according to gender, parental consanguinity, age at first pneumonia, age of onset of chronic pulmonary symptoms, bronchiectasis, presence of gastroesophageal reflux disease (GERD), BH and asthma (p greater-than 0.05). Admission to immunology clinic was about 3 years later in PID compared with non-PID group (p less-than 0.001). Five patients got molecular diagnosis, X-linked agammaglobulinemia (n=2), LRBA deficiency (n=1), RASGRP1 deficiency (n=1), MHC Class II deficiency (n=1). They were given monthly IVIG and HSCT was performed for three patients. Conclusions. PID accounted for about 40% of NCFB. Early diagnosis/appropriate treatment have impact on clinical course of a PID patient. Thus, follow-up in also immunology clinics should be a routine for patients who experience pneumonia in the first year of their lives and those with NCFB.

Pulmonary manifestations of primary immunodeficiency disorders in children.

Primary immunodeficiencies (PIDs) are inherited disorders in which one or several components of immune system are decreased, missing, or of non-appropriate function. These diseases affect the development, function, or morphology of the immune system. The group of PID comprises more than 200 different disorders and syndromes and the number of newly recognized and revealed deficiencies is still increasing. Their clinical presentation and complications depend on the type of defects and there is a great variability in the relationship between genotypes and phenotypes. A variation of clinical presentation across various age categories is also presented and children could widely differ from adult patients with PID. Respiratory symptoms and complications present a significant cause of morbidity and also mortality among patients suffering from different forms of PIDs and they are observed both in children and adults. They can affect primarily either upper airways (e.g., sinusitis and otitis media) or lower respiratory tract [e.g., pneumonia, bronchitis, bronchiectasis, and interstitial lung diseases (ILDs)]. The complications from lower respiratory tract are usually considered to be more important and also more specific for PIDs and they determinate patients’ prognosis. The spectrum of the causal pathogens usually demonstrates typical pattern characteristic for each PID category. The respiratory signs of PIDs can be divided into infectious (upper and lower respiratory tract infections and complications) and non-infectious (ILDs, bronchial abnormalities – especially bronchiectasis, malignancies, and benign lymphoproliferation). Early diagnosis and appropriate therapy can prevent or at least slow down the development and course of respiratory complications of PIDs.

Delayed Diagnosis of Common Variable Immunodeficiency

Source: Urshel S, Kayikci L, Wintergerst U, et al. Common variable immunodeficiency disorders in children: delayed diagnosis despite typical clinical presentation. J Pediatr. 2009;154(6):888–894; doi:10.1016/j.jpeds.2008.12.020To characterize the clinical presentation of children with early-onset common variable immunodeficiency (CVID), investigators from Munich, Germany, surveyed patients and reviewed their medical records. To identify study participants, the investigators screened data collected between 1990 and 2004 by the immunology laboratory and the immunodeficiency clinic of a tertiary care center. Study patients had IgG and IgM levels or IgA levels reduced more than two standard deviations (SD) from mean values, evidence of impaired increase of specific antibody titers after vaccination, and recurrent infections. Those with other primary immunodeficiency disorders were excluded.A total of 32 patients with early-onset CVID were analyzed. Among the 32 study patients, 17 were female. The median age at diagnosis was 10.4 years. Most patients had a history of chronic or recurrent infections including bronchitis (88%), pneumonia (78%), sinusitis (78%), otitis media (69%), fungal infections (47%), and various gastrointestinal, skin, oral, and parasitic infections (3%–10%). Eight study children had a history of meningitis and five had culture-proven sepsis. Other clinical manifestations included allergy or allergy-like symptoms (38%); autoimmune diseases were found in 31% of study patients, including hemolytic anemia, thrombocytopenia, arthritis, vasculitis, gluten-sensitive enteropathy, diabetes mellitus, vitiligo, and psoriasis.Overall, 80% of the patients underwent surgical procedures before the diagnosis of CVID was made. Nearly half of the patients had findings suggestive of immunologic disease such as diffuse lymphadenopathy or splenomegaly. Four patients (13%) subsequently developed lymphomas; all survived following chemotherapy. Nine affected children (28%) showed significant growth retardation; of these nine, all had a history of recurrent bronchitis, seven had a history of recurrent pneumonia, and five had a history of allergies and/or diarrhea.At the time of diagnosis, all subjects had serum IgG levels 2 SD or more below the mean; IgM concentrations were reduced in 30 of 32. IgA concentrations were normal in one patient and below detection in 15 of 32. Reduced serum levels of all three immunoglobulin classes were found in 29 of 32 patients. The median duration between symptoms and the definitive diagnosis was 5.8±4.2 years.The authors conclude that CVID’s effects on growth and development are unique to pediatrics but the symptoms and disorders of CVID in children are comparable to the manifestations in adults. Marked delay of diagnosis may be due to the overlap with common pediatric disorders along with lack of familiarity with CVID in children.Dr Nimmagadda has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.CVID is second only to selective IgA deficiency among humoral immunodeficiencies and is thought to have a prevalence of 1:10,000 to 1:50,000. It affects males and females equally.1 CVID is part of a group of genetic disorders that results primarily in hypogammaglobulinemia or failure of antibody production. Patients typically present with recurrent infections, particularly of the respiratory tract, although gastrointestinal disease, autoimmune and inflammatory features, and lymphoma are frequent. Onset of symptoms can occur at any age, although there are peaks in the first and third decades of life. In about 10–20% of patients, other family members are affected.1Over the past few decades, studies on the cells of the immune system in patients with CVID have revealed a spectrum of lymphocyte abnormalities.2 Most patients appear to have normal numbers of B-lymphocytes, but they fail to undergo normal maturation into plasma cells capable of making the different types of immunoglobulins and antibodies. Other patients lack enough function from helper T-lymphocytes necessary for a normal antibody response. A third group of patients have excessive numbers of cytotoxic T-lymphocytes, although the role of these cells in the disease is unclear.The current study highlights the importance of clinical awareness of CVID in younger patients and the frequency of diagnostic delay. CVID usually presents in children as recurrent respiratory infections such as bronchitis, pneumonia, and otitis media, which are managed by primary care physicians until the frequency increases or a sentinel event occurs, prompting further investigation. CVID is under-recognized and underdiagnosed, with an average diagnostic delay of four to seven years from onset of symptoms. These delays in diagnosis often result in long-term sequelae, most commonly bronchiectasis and chronic sinusitis. This permanent damage is responsible for most of the chronic ill health and mortality associated with CVID.3,4The treatment of CVID is similar to that of other disorders characterized by low levels of serum immunoglobulins. In the absence of a significant T-lymphocyte defect or organ damage, immunoglobulin replacement therapy almost always brings improvement of symptoms. Thus, early recognition and diagnosis is critical to optimize the long-term outcome of these patients.

Common Variable Immunodeficiency Disorders in Children: Delayed Diagnosis Despite Typical Clinical Presentation

To characterize common variable immunodeficiency disorder (CVID) in childhood. We retrospectively investigated clinical findings in 32 children with primary CVID by questionnaire and file review. Clinical presentation included recurrent or chronic respiratory tract infections (88%), sinusitis (78%), otitis media (78%), and intestinal tract infections (34%), mainly with encapsulated bacteria. Meningitis was found in 25%, sepsis in 16%, and pyelonephritis in 16% of patients. Poliomyelitis after vaccination occurred in 2 patients and opportunistic infections occasionally. Allergic disorders were present in 38%, and autoimmune disease in 31% of patients. Eighty percent of the patients underwent surgical procedures because of recurrent infections. Growth retardation was seen in 28% of patients, and 16% showed retarded mental development. Bronchiectasis developed in 34%, and lymphoid proliferative disease in 13%. Incidence of allergic and autoimmune diseases was increased in first-degree relatives with normal immunologic findings. Mean time between symptoms and induction of immunoglobulin substitution therapy was 5.8 years (0.2-14.3). CVID in children presents with comparable symptoms and disorders as in adults. We found a significant influence on growth and development. The marked delay of diagnosis may be due to overlap with common pediatric disorders, while also reflecting insufficient awareness of these disorders.

Periodontal Manifestation of Leukocyte Adhesion Deficiency Type I

Leukocyte adhesion deficiency type I (LAD-I) is an autosomal recessive immunodeficiency disorder characterized by defects in the integrin receptors of white blood cells that lead to impaired adhesion and chemotaxis. Affected patients are susceptible to recurrent bacterial and fungal infections, impaired pus formation, delayed wound healing, and periodontitis. A case of generalized advanced periodontal destruction of the permanent and deciduous dentition in a young Jordanian girl with a severe phenotype of LAD-I is presented in this report. The medical diagnosis was made based on the characteristic clinical and laboratory findings, in particular the total absence of CD18, CD11b, and CD11c as determined by flow cytometry sorting. Periodontal findings in this patient include the early onset of the disease, which affected the primary teeth and permanent dentitions, the intense redness and inflammation of the gingiva, and the rapid periodontal destruction that seems refractory to conventional non-surgical periodontal therapy. This report emphasizes the importance of the differential diagnosis of severe immunodeficiency disorders in children and adolescents and mandates the importance of combined care by medical and dental practitioners to prevent tooth loss and control oral infection.

The Prevalence and Distribution of Primary Immunodeficiency Disorders in Children in Kuwait

The Prevalence and Distribution of Primary Immunodeficiency Disorders in Children in Kuwait

Overview of clinical occurrence of primary immunodeficiency disorders in children

More than one hundred primary immunodeficiency disorders have been discovered so far. But the incidence of these disorders in our country is still not clear, so we analyzed the clinical data of 93 children with primary immunodeficiency disorders seen in our hospital in recent 30 years to understand the occurrence of primary immunodeficiency disorders in children, to promote the clinicians to become familiar with these disorders, to improve the nationwide registry system and to establish the basis for the treatment and prevention in future. To analyze the constituent ratio of the 93 children with primary immunodeficiency disorders seen in our hospital from 1974 to 2003, diagnostic and classification criteria were set by taking the proposal by International Union of Immunological Societies (IUIS) PID classification committee in 2003 into account. All the data were analyzed retrospectively. In the 93 children with primary immunodeficiency disorders, antibody deficiencies were the most frequent (39.8%) finding, followed by combined immunodeficiency, combined T- and B-cell disorders (22.6%), and T lymphocytic deficiencies alone (14.0%). Immunodeficiency with other major defects accounted for 12.9%, phagocytic disorders 9.7%, and complement deficiencies 1.1%. Thus, there seemed to be a tendency that the incidence increased with time. The incidence of these disorders has increased significantly as shown by 50 diagnosed cases in children with these disorders since 1996. Sixteen children died, with the highest mortality occurred with combined immunodeficiency. Seven children developed bronchiectasis. Two children suffered from persistent diarrhea while one of the two was complicated with persistent intestinal fistula. One child developed juvenile rheumatoid arthritis, another one with granulocytopenia and iridocyclitis, and the other with allergic purpura. The boys: girls ratio for all disorders was 3:1. The age of onset ranged from 10 days to 37 years of age. There are vast variety of primary immunodeficiency disorders in our area and antibody deficiency is the most common abnormality. Combined immunodeficiency has early onset age and high mortality rate. With the great improvement of the diagnostic techniques, these disorders have become a group of important disorders and all the clinicians should pay great attention to these disorders.

Evaluating Immunodeficiency Disorders in Children

Evaluating Immunodeficiency Disorders in Children

Primary immunodeficiency disorders in children: Prompt diagnosis can lead to lifesaving treatment

Primary immunodeficiencies in children are rare, but an early diagnosis can improve long-term quality of life and prevent rapid deterioration of the immune system. More than 70 immunodeficiency diseases have been identified and are classified according to the areas of the immune system that are compromised. When a suspicious history or an uninterrupted pattern of infections leads the practitioner to suspect immunodeficiency, it is essential that proper immunologic testing be initiated as soon as possible. Once a diagnosis is established, the practitioner and a team of experts all are involved in the multidisciplinary treatment, counseling, and longitudinal care of children with primary immunodeficiency. J Pediatr Health Care. (2002). 16, 16-21.

Primary immunodeficiency disorders in children: Prompt diagnosis can lead to lifesaving treatment

<h2>Abstract</h2> Primary immunodeficiencies in children are rare, but an early diagnosis can improve long-term quality of life and prevent rapid deterioration of the immune system. More than 70 immunodeficiency diseases have been identified and are classified according to the areas of the immune system that are compromised. When a suspicious history or an uninterrupted pattern of infections leads the practitioner to suspect immunodeficiency, it is essential that proper immunologic testing be initiated as soon as possible. Once a diagnosis is established, the practitioner and a team of experts all are involved in the multidisciplinary treatment, counseling, and longitudinal care of children with primary immunodeficiency. J Pediatr Health Care. (2002). <i>16,</i> 16-21.

Neuropsychological Functioning in Children with Immunodeficiency Disorders

A small group of children with various types of immunodeficiency disorders, examined on a battery of neuropsychological and intellectual tests, was found to be impaired on perceptual speed, visuospatial sequencing, and visual attention span capacities when compared to a control group of closest aged siblings and normal children matched for age, education, and IQ. The results suggest that cerebral dysfunction may be associated with immunodeficiency disorders in children, although these findings are tentative since other factors, such as the effects of chronic illness, could not be excluded in this small cohort of patients.

Primary immunodeficiency disorders in Sweden: cases among children, 1974-1979.

A nationwide survey of symptomatic primary immunodeficiency disorders in children in Sweden during the 6-year period 1974-1979 resulted in 201 reported cases. The reported data for 174 children were analyzed. Antibody deficiencies were the most frequent (45.0%), followed by phagocytic disorders (22.0%) and combined T- and B-cell disorders (20.8%). Thirty-two children (18.4%) died, with the highest mortality for combined T- and B-cell defects. The sex ratio for all disorders was 2:1 for boys:girls. Neutropenia was significantly more common in the northern part of Sweden.