Selective IgA Deficiency and Allergy: A Fresh Look to an Old Story

Selective IgA deficiency (SIgAD) is the most common human primary immune deficiency (PID). It is classified as a humoral PID characterized by isolated deficiency of IgA (less than 7 mg/dL but normal serum IgG and IgM) in subjects greater than 4 years of age. Intrinsic defects in the maturation of B cells and a perturbation of Th cells and/or cytokine signals have been hypothesized to contribute to SIgAD pathogenesis. The genetic basis of IgA deficiency remains to be clarified. Patients with SIgAD can be either asymptomatic or symptomatic with clinical manifestations including allergy, autoimmunity and recurrent infections mainly of the respiratory and gastrointestinal tract. Studies analyzing allergy on SIgAD patients showed prevalence up to 84%, supporting in most cases the relationship between sIgAD and allergic disease. However, the prevalence of allergic disorders may be influenced by various factors. Thus, the question of whether allergy is more common in SIgAD patients compared to healthy subjects remains to be defined. Different hypotheses support an increased susceptibility to allergy in subjects with SIgAD. Recurrent infections due to loss of secretory IgA might have a role in the pathogenesis of allergy, and vice versa. Perturbation of microbiota also plays a role. The aim of this review is to examine the association between SIgAD and atopic disease and to update readers on advances over time at this important interface between allergy and SIgAD.

Clinical picture in a child who often gets sick (a new look at the origin, diagnosis and treatment). Report 2. Diagnosis and treatment

Objective: to determine the clinical picture in children who often get sick, taking into account the currently available data from the medical literature and authors’ observations accumulated over the past 25 years of clinical practice. Materials and methods. The design of the study was clinical and diagnostic and included the search for ways to diagnose and treat pathological conditions that compose the current clinical picture of children who often get sick. The studies were prospective and retrospective, longitudinal, with long-term follow-up of a certain part of the same patients for 1–10 years after diagnosis of “frequently ill child” and appropriate treatment. In terms of the effectiveness of the results, the researches were direct, because it undoubtedly contributed to the recovery of the child with the improvement/normalization of his general state and quality of life. The studies were multicenter, conducted in an outpatient setting at the premises of two clinics specialized in the field of chronic infectious diseases, with full laboratory researches and the department of pediatric infectious diseases of the medical university. The participants were children from infancy to 14 years of age, whose parents in 2009–2020 consulted with complaints about frequent illnesses of their children. Results. In 2010–2020, the authors supervised 3,547 children, who often get sick (6–12 episodes a year and even more: 1–2 diseases a month), and the period of each episode of their illness lasted more than 5–7 days. There were 862/3,547 (24.3 %) children under 3 years of age, 1,295/3,547 (36.5 %) from 3 to 7 years of age, and 1,390/3,547 (39.2 %) from 7 to 14 years of age. Given the clinically dominant symptoms, which are often intertwined into one holistic picture of these common diseases, children were divided into two large groups of observations. Group I, which was conventionally called “Clinical picture of frequently ill children with purulent-inflammatory diseases”, included 1,595/3,547 patients (45 %). Another 1,952/3,547 (55 %) individuals were included in group II with a conditional name “Clinical picture of frequently ill children with dominant toxic manifestations”. The second group of patients who often get sick also includes patients with fever not associated with acute purulent-inflammatory conditions or their recurrences. This group under supervision consisted of 1,952/3,547 (55 %) children — from infancy to 14 years with thermoregulatory disorders, including persistent low-grade fever — 1,206/1,952 (61.8 %), febrile seizures — 721/1952 (36.9 %) and 25/1,952 (1.3 %) children of mostly school age with fever at the level of 38–40 ºC and above for several months to 4 years and other symptoms of chronic bacterial intoxication syndrome. All children were examined bacteriologically (nasopharyngeal, oral swab culture, etc., as well as warm urine tests three times, three days in a row), toxicologically using Toxicon diagnostic system; they also underwent general clinical exa­minations, enzyme-linked immunosorbent assay and polymerase chain reaction, determination of immunological status, according to indicators — instrumental examination. Two foci of chronic bacterial infection were found to be present in all frequently ill children: in the nasopharynx, which in 3,467/3,547, or 97.7 % of cases, was associated with S.aureus, and in the kidneys (nephrodysbacteriosis), which was dominated by enterococci and Escherichia coli accounted for almost 2/3 (3,312/5,313, or 63 %) of all isolated urinary strains and detected in the urine of a total of 3,312/3,547 (93.4 %) children. Based on toxicological examination of the blood, severe toxemia was found in the vast majority of children (77/96, or 80.2 %), 16/96 (16.7 %) had moderate and only 3/96 (3.1 %) — mild form. The form of intoxication was mainly compensated in 87/96 (90.6 %) patients, another 9/96 (9.4 %) had generalization stage. When determining the immune status studied in 2,160/3,547 (60.1 %) of frequently ill children from infancy to 14 years of age in both observation groups, it was found that cellular and humoral immunity was usually either within normal limits or often even higher than normal. Only in 67/2,160 (3.1 %) cases, mild cellular immunodeficiency was detected, and in 7/2,160 (0.3 %) children — selective IgA deficiency. Treatment of all 3,547 frequently ill children of both observation groups was performed using bacterial autovaccines made from strains isolated during bacteriological examination. The number of children who underwent treatment the consequences of which can be considered established and not associated with concomitant use of antibacterial drugs was 3,159/3,547, or 89.1 %. In total, 3,093/3159, or 97.9 % of frequently ill children, recovered completely within 6–24 months after starting antibiotic-free bacterial autovaccine treatment. Conclusions. The clinical picture of a child who often gets sick is currently collective and consists of symptoms of recurrent respiratory diseases or recurrent acute respiratory viral infections, recurrent purulent-inflammatory diseases of the nose, pharynx, mouth, ears, eyes and bronchopulmonary system, as well as clinical manifestations of chronic bacterial intoxication syndrome developed on the background of nephrodysbacteriosis. The etiological and pathogenetic diagnosis is confirmed by the results of bacteriological and toxicological examinations. Standard treatment of frequently ill children using antibiotics is not effective. A positive clinical effect can be achieved in 97.9 % of children with complete recovery after the use of bacterial autovaccines made from strains isolated during bacteriological examination.

Clinical picture in a child who often gets sick (a new look at the origin, diagnosis and treatment). Report 1. Origin and clinical picture

Objective: to determine the clinical picture in children who often get sick, taking into account the currently available data from the medical literature and authors’ observations accumulated over the past 25 years of clinical practice. Materials and methods. The design of the study was clinical and diagnostic and included the search for ways to diagnose and treat pathological conditions that compose the current clinical picture of children who often get sick. The studies were prospective and retrospective, longitudinal, with long-term follow-up of a certain part of the same patients for 1–10 years after diagnosis of “frequently ill child” and appropriate treatment. In terms of the effectiveness of the results, the resear­ches were direct, because it undoubtedly contributed to the reco­very of the child with the improvement/normalization of his general state and quality of life. The studies were multicenter, conducted in an outpatient setting at the premises of two clinics specialized in the field of chronic infectious diseases, with full laboratory researches and the department of pediatric infectious diseases of the medical university. The participants were children from infancy to 14 years of age, whose parents in 2009–2020 consulted with complaints about frequent illnesses of their children. Results. In 2010–2020, the authors supervised 3,547 children, who often get sick (6–12 epi­sodes a year and even more: 1–2 disea­ses a month), and the period of each episode of their illness lasted more than 5–7 days. There were 862/3,547 (24.3 %) children under 3 years of age, 1,295/3,547 (36.5 %) from 3 to 7 years of age, and 1,390/3,547 (39.2 %) from 7 to 14 years of age. Given the clinically dominant symptoms, which are often intertwined into one holistic picture of these common diseases, children were divided into two large groups of observations. Group I, which was conventionally called “Clinical picture of frequently ill children with purulent-inflammatory diseases”, included 1,595/3,547 patients (45 %). Another 1,952/3,547 (55 %) individuals were included in group II with a conditional name “Clinical picture of frequently ill children with dominant toxic manifestations”. The second group of patients who often get sick also includes patients with fever not associated with acute purulent-inflammatory conditions or their recurren­ces. This group under supervision consisted of 1,952/3,547 (55 %) children — from infancy to 14 years with thermoregulatory disorders, including persistent low-grade fever — 1,206/1,952 (61.8 %), febrile seizures — 721/1952 (36.9 %) and 25/1,952 (1.3 %) children of mostly school age with fever at the level of 38–40 °C and above for several months to 4 years and other symptoms of chronic bacterial intoxication syndrome. All children were examined bacteriologically (nasopharyngeal, oral swab culture, etc., as well as warm urine tests three times, three days in a row), toxicologically using Toxicon diagnostic system; they also underwent gene­ral clinical examinations, enzyme-linked immunosorbent assay and polymerase chain reaction, determination of immunological status, according to indicators — instrumental examination. Two foci of chronic bacterial infection were found to be present in all frequently ill children: in the nasopharynx, which in 3,467/3,547, or 97.7 % of cases, was associated with S.aureus, and in the kidneys (nephrodysbacteriosis), which was dominated by enterococci and Escherichia coli accounted for almost 2/3 (3,312/5,313, or 63 %) of all isolated urinary strains and detected in the urine of a total of 3,312/3,547 (93.4 %) children. Based on toxicological examination of the blood, severe toxemia was found in the vast majority of children (77/96, or 80.2 %), 16/96 (16.7 %) had moderate and only 3/96 (3.1 %) — mild form. The form of intoxication was mainly compensated in 87/96 (90.6 %) patients, another 9/96 (9.4 %) had generalization stage. When determining the immune status studied in 2,160/3,547 (60.1 %) of frequently ill children from infancy to 14 years of age in both observation groups, it was found that cellular and humoral immunity was usually either within normal limits or often even higher than normal. Only in 67/2,160 (3.1 %) cases, mild cellular immunodeficiency was detected, and in 7/2,160 (0.3 %) children — selective IgA deficiency. Treatment of all 3,547 frequently ill children of both observation groups was performed using bacterial autovaccines made from strains isolated during bacteriological examination. The number of children who underwent treatment the consequences of which can be considered established and not associated with concomitant use of antibacterial drugs was 3,159/3,547, or 89.1 %. In total, 3,093/3159, or 97.9 % of frequently ill children, recovered completely within 6–24 months after starting antibiotic-free bacterial autovaccine treatment. Conclusions. The clinical picture of a child who often gets sick is currently collective and consists of symptoms of recurrent respiratory diseases or recurrent acute respiratory viral infections, recurrent purulent-inflammatory diseases of the nose, pharynx, mouth, ears, eyes and bronchopulmonary system, as well as clinical manifestations of chronic bacterial intoxication syndrome developed on the background of nephrodysbacteriosis. The etiological and pathogenetic diagnosis is confirmed by the results of bacteriological and toxicological examinations. Standard treatment of frequently ill children using antibiotics is not effective. A positive clinical effect can be achieved in 97.9 % of children with complete recovery after the use of bacterial autovaccines made from strains isolated during bacteriological examination.

STXBP6 and B3GNT6 Genes are Associated With Selective IgA Deficiency

Immunoglobulin A Deficiency (IgAD) is a polygenic primary immune deficiency, with a strong genetic association to the human leukocyte antigen (HLA) region. Previous genome-wide association studies (GWAS) have identified five non-HLA risk loci (IFIH1, PVT1, ATG13-AMBRA1, AHI1 and CLEC16A). In this study, we investigated the genetic interactions between different HLA susceptibility haplotypes and non-MHC genes in IgAD. To do this, we stratified IgAD subjects and healthy controls based on HLA haplotypes (N = 10,993), and then performed GWAS to identify novel genetic regions contributing to IgAD susceptibility. After replicating previously published HLA risk haplotypes, we compared individuals carrying at least one HLA risk allele (HLA-B*08:01-DRB1*03:01-DQB1*02:01 or HLA-DRB1*07:01-DQB1*02:02 or HLA-DRB1*01-DQB1*05:01) with individuals lacking an HLA risk allele. Subsequently, we stratified subjects based on the susceptibility alleles/haplotypes and performed gene-based association analysis using 572,856 SNPs and 24,125 genes. A significant genome-wide association in STXBP6 (rs4097492; p = 7.63 × 10−9) was observed in the cohort carrying at least one MHC risk allele. We also identified a significant gene-based association for B3GNT6 (PGene = 2.1 × 10–6) in patients not carrying known HLA susceptibility alleles. Our findings indicate that the etiology of IgAD differs depending on the genetic background of HLA susceptibility haplotypes.

The Role of HLA in the Association between IgA Deficiency and Celiac Disease

Selective IgA deficiency (SIgAD) is the most frequent primary immune defect. Since SIgAD is not characterized by relevant infectious issues in most cases, it is often diagnosed during the diagnostic work up of several and different autoimmune disorders, which are associated with this primary immune defect. The genetic background of SIgAD is complex and three HLA haplotypes resulted to be more frequently associated with it; in detail, two of them include HLA-DQB 1 ∗ 02 allelic variants, which are essential predisposing factors to develop Celiac Disease (CD). Here, we discuss the evidence regarding the role of HLA in the etiopathogenesis of SIgAD and its association with CD. Actually, the HLA region seems to play a modest role in the genetic predisposition to SIgAD and we may speculate that the association with the HLA-DQB 1 ∗ 02 alleles (or haplotypes including them) could derive from its link with CD. Indeed, SIgAD and some related immunological alterations are likely to predispose to several autoimmune diseases (with and despite different HLA backgrounds), including CD, which is relatively common and directly associated with the HLA-DQB 1 ∗ 02 allelic variants coding the DQ2 heterodimer. Further and specific studies are needed to make final conclusions in this regard.

Clinical case of congenital CMV neuroinfection in a child with selective IgA deficiency

Congenital CMV infection is thought to occur in at least 1 % of infants, although recent clinical studies indicate that these lesions account for 8 % of all neonates. The severity of clinical symptoms of nervous system damage of CMV-etiology depends on the duration of intrauterine infection. In early infection, during the first trimester of the fetal period, severe CNS malformations develop, including anencephaly, porencephaly, schizencephaly, lissencephaly, micropolygyria, and pachygyria. At later infection, during the 2nd–3rd trimesters of pregnancy, there are milder manifestations — ventriculomegaly, impaired myelination of the white matter of the brain, cysts in the poles of the temporal lobes, hypogenesis of the corpus callosum, periventricular calcifications, and lesions of the cochleovestibular nerves. The article presents the medical history of a 5-year-old boy with typical clinical and instrumental signs of congenital CMV infection. The child had deep spastic tetraparesis, severe mental retardation, refractory epileptic syndrome with polymorphic seizures, disorders of pelvic organs, inability to move independently. MRI of the brain showed typical radiological signs of congenital CMV infection: cortical atrophy, ventriculomegaly, periventricular gliosis, demyelination fields in the white matter of the hemispheres, cysts in the poles of the temporal lobes, hypoplasia of the corpus callosum. During the neonatal period, specific IgM to CMV in serum was observed. Blood leukocyte PCR revealed the CMV DNA in a 5-year-old child at the time of admission to the clinic. This infection led to genera-lized lymphadenopathy, hepatosplenomegaly, thrombocytopenia, and lymphomonocytosis. The assessment of immune status showed the presence of selective IgA deficiency, which was associated with the development of this opportunistic infection. Typical mistakes in the clinical management of children with congenital CMV infection and ways to avoid them are discussed.

Unexpected cause of dyspnoea in a patient with allergic rhinitis

A defect in one part of the immune system may affect the whole system. As a result, there may be a myriad of immunological diseases, which are often masked with the one disease that has the most prominent symptoms. This case report presents a patient with long-lasting allergic rhinitis who recently developed dyspnoea in exertion with suspected asthma development. After extensive diagnostic processing, asthma was dismissed, and diagnosis of selective IgA deficiency and coeliac disease with consequential iron deficiency anaemia was established. The patient was treated with parenteral iron and a gluten-free diet, which corrected her anaemia and led to the disappearance of dyspnoea. This paper aims to show the interplay between different immunological disorders and the possible causal connection between them.