INTRODUCTION
Selective immunoglobulin A (IgA) deficiency (SIgAD) is a disease in the antibody deficiency subgroup of primary immunodeficiencies. It is the most prevalent form of primary immunodeficiency, with an estimated incidence ranging from approximately 1 : 3000 to 1 : 150, depending on the population, and it is more frequently diagnosed in males [1, 2]. SIgAD is defined when the serum IgA level is equal to or below 7 mg/dl in individuals older than 4 years with normal IgG and IgM levels, and an otherwise healthy immune system [3]. When the serum IgA level exceeds 7 mg/dl but is less than two standard deviations (SD) below the mean for age, it is termed partial or probable IgA deficiency [1]. SIgAD generally manifests sporadically, although patterns of autosomal recessive, autosomal dominant, and sporadic inheritance have all been observed [4]. The probability of familial inheritance of the disease is estimated to be approximately 20% [5].
Patients with SIgAD exhibit not only low serum IgA levels but also a reduction in secretory IgA. This deficit facilitates the colonization and penetration of pathogenic bacteria, making these patients more susceptible to recurrent infections. The absence of mucosal IgA may also contribute to the development of allergies by enabling the passage of aeroallergens and food antigens [6]. Allergies may present as the first symptom in up to 40% of SIgAD cases [7]. Therefore, SIgAD should be considered in patients with recurrent infections and in those presenting with atopic symptoms.
The clinical presentation of SIgAD patients varies widely, from asymptomatic individuals diagnosed incidentally through routine laboratory tests to symptomatic patients with diverse clinical phenotypes and varying degrees of disease severity. The most common and significant clinical manifestations include recurrent infections, particularly affecting the respiratory and gastrointestinal systems [4, 8, 9]. In children, the most frequent infections include pharyngotonsillitis, otitis, bronchitis, sinusitis, and less commonly, pneumonia [10–12].
SIgAD is also widely recognized to be associated with various atopic manifestations, including allergic rhinitis, asthma, urticaria, food allergies, and atopic dermatitis (AD) [6, 9].
AIM
The goal of our study was to investigate the relationship between immunodeficiency and respiratory and allergic diseases in children diagnosed with selective IgA deficiency.
MATERIAL AND METHODS
Patients aged 4–18 years, who were admitted to our pediatric allergy and immunology outpatient clinic between 2021 and 2024 and diagnosed with SIgAD were included in the study from the archive records. The study protocol was conducted in accordance with the ethical principles of the Declaration of Helsinki. The inclusion criterion was having SIgAD. The identification of SIgAD was based on the criteria established by the European Society for Immunodeficiencies (ESID) [13]. Severe IgAD was characterized by a serum IgA concentration of less than 7 mg/dl, with normal levels of serum immunoglobulin G (IgG) and immunoglobulin M (IgM) in children over the age of 4 [14, 15]. All participants underwent evaluation through clinical and laboratory tests, along with allergy-related data, including atopic dermatitis, allergic rhinitis, asthma, and urticaria. All diagnoses of allergic diseases were made by an allergist. The history of frequent illness was assessed according to the presence of at least 1 of the 10 criteria including infections and features that may be warning signs in terms of primary immunodeficiency reported by the Jeffrey Model Foundation Medical Advisory Board [16].
ImmunoCAP (Thermo Fisher Scientific, Uppsala, Sweden) was used for allergen-specific IgE measurements in patients evaluated for the presence of allergy, and inhaler and food allergen-specific IgE levels were measured. An allergen-specific IgE level of 0.35 kU/l and above was considered positive. Histamine (10 mg/ml) was used as a positive control and saline was used as a negative control in patients who underwent the skin prick test. In the absence of induration and/or dermographism in the negative control, tests with an induration of 3 mm or more were considered positive.
STATISTICAL ANALYSIS
The statistical analysis of the study data was performed using the SPSS 24.0 software package. Descriptive statistics in the research were presented using median, minimum, and maximum values, as well as counts (n) and percentages (%). The normality of continuous variables was assessed through histograms, probability plots, and analytical techniques. For data that did not follow a normal distribution, the Mann-Whitney U test was applied to compare the two groups. A p-value of less than 0.05 was considered to indicate statistical significance.
RESULTS
The median age of the 63 pediatric patients in the study was 79 months, while the minimum and maximum ages were 48 and 209 months, respectively. Of the patients who participated in the study, 49.2% were female and 50.8% were male. None of the patients had a family history of immunodeficiency. However, 87.3% of the patients reported no family history of atopy, while 12.7% had a family history of atopy. While 42.9% of the patients had no comorbidity, 7.9% had asthma, 12.7% had allergic rhinitis, and 15.9% had a combination of asthma and allergic rhinitis. Furthermore, 6.3% had urticaria, 7.9% had atopic dermatitis, 1.6% had asthma, allergic rhinitis and periodic fever-aphthous stomatitis-pharyngitis-adenitis (PFAPA) syndrome, 1.6% had systemic lupus erythematosus (SLE), and 1.6% had a combination of juvenile idiopathic arthritis (JIA) and allergic rhinitis. Finally, 71.4% of the patients had a history of frequent illness, while 28.6% had a history of frequent illness (Table 1).
TABLE 1
Clinical characteristics and gender data of the patients
Table 2 shows the haemogram parameters and immunoglobulin values of the patients who participated in the study. The median value for lymphocyte count was 3.33 × 103/Ul, with a minimum value of 1.27 and a maximum value of 9.03. The median value for neutrophil count was 4.41 × 103/Ul, the minimum value was 1.46 and the maximum value was 11.85. The median value for eosinophil count was 230 cells/μl and varied between a minimum of 30 and a maximum of 730. Eosinophil percentage was determined as median 2.60%, minimum 0.17% and maximum 8.40%. When immunoglobulin values were analyzed, the median IgA level was 0.04 g/l, minimum 0.00 g/l and maximum 0.07 g/l. The median value for IgM level was 1.28 g/l, with a minimum of 0.59 g/l and a maximum of 3.25 g/l. The median IgG concentration was 12.96 g/l, with values spanning from a minimum of 9.15 g/l to a maximum of 25.31 g/l. Additionally, the median IgE concentration was 54.00 IU/ml, ranging from a minimum of 0.00 IU/ml to a maximum of 898.00 IU/ml.
TABLE 2
Haemogram parameters and immunoglobulin values of the patients
When aeroallergen sensitization was evaluated, 19 (30.2%) children had aeroallergen sensitization, while 44 (69.8%) children had no allergen sensitization. Seventeen (27%) children were sensitized to house dust mites, 4 (6.3%) to cat dander, 2 (3.2%) to pollen and 1 (1.6%) to mold fungi. Five children had multiple allergen positivity. The characteristics of children with and without allergy were evaluated. The median age of the children with allergy was significantly older (p = 0.042). The median values of eosinophils (%), IgM, IgG and IgE were also significantly higher in children with allergy (p = 0.023, p = 0.040, p = 0.002 and p = 0.013, respectively) (Table 3).
TABLE 3
Effect of the presence of allergy on age and laboratory values
DISCUSSION
In our study, we examined the association between immunodeficiency and allergic and respiratory diseases in children with SIgAD. SIgAD is recognized as the most common primary immunodeficiency and is often linked to respiratory infections and various atopic conditions. In our study, the presence of atopic diseases in a significant proportion of patients diagnosed with SIgAD is remarkable. Especially respiratory allergies such as asthma and allergic rhinitis were frequently observed in this patient group.
In our study, 28.6% of children with SIgAD had a history of frequent illness, whereas 71.4% did not have this history. This suggests that patients with SIgAD may be more susceptible to infections. In addition, 57.1% of the patients had one or more comorbidities. This finding suggests that patients with SIgAD have a heterogeneous clinical presentation and some patients may be predisposed to additional pathologies such as allergic diseases in addition to immunodeficiency.
We found aeroallergen sensitization in 30.2% of our patients. According to a study in the literature, allergic symptoms were observed in 43.2% of 118 Turkish children with SIgAD [17]. Two studies conducted in Italy on independent pediatric cohorts reported that 39% of 184 and 38% of 103 SIgAD patients were diagnosed with allergies [11, 18].
In our study, house dust mite allergy was identified in 27% of the patients, confirming that dust mites are the most common allergen identified in SIgAD patients, apart from differences in seasonal allergens observed in different countries [11, 19, 20].
We found AD in 9.5% of our patients with SIgAD. In a study conducted by Gualdi et al. on 102 SIgAD patients, the prevalence of AD was reported to be 57.84% [21]. Magen et al. found that the prevalence of AD in SIgAD was 4.6% [22]. In a study in the literature, the prevalence of AD was found to be 11.1%, similar to our study [23]. It was found that 27% of our patients had asthma, 33.4% had AR, and 6.3% had urticaria complaints. Papadopoulou et al. suggested that the inadequate protection provided by respiratory mucosa lacking IgA in SIgAD children predisposes them to bronchial hypersensitivity and subsequently to asthma [19]. Another study conducted in Türkiye found that 34.6% of 81 SIgAD patients had asthma [23]. In the same study, the prevalence of allergic rhinitis in SIgAD patients was 27.2% [23], compared to 16.9% in Turkish school-age children [24]. According to that study, the prevalence of asthma and AR was elevated in SIgAD patients, and our study supports this finding. In a study conducted in Italy in which pediatric patients with selective IgA deficiency were investigated, Moschese et al. found allergic asthma in 10.67%, atopic dermatitis in 12.6% and AR in 18.45% [18]. The prevalence of allergies in SIgAD patients was reported to be 34% in a study by Cinicola et al., with 7 (10%) patients diagnosed with intermittent allergic asthma, 17 (25%) with allergic rhinitis, and ten (15%) with atopic dermatitis [25].
When immunoglobulin levels were evaluated, IgM, IgG and IgE levels were found to be significantly higher in children with allergy. These results suggest that high IgE levels in patients with SIgAD may be associated with allergic diseases. It is thought that IgE level may be an important marker especially in the diagnosis and management of atopic diseases. These findings suggest that patients with SIgAD are predisposed to developing allergies and these patients should be closely monitored for allergy.
CONCLUSIONS
The prevalence of recurrent infections and atopic diseases is high in children with SIgAD. In the management of these patients, not only immunodeficiency but also allergic diseases should be considered. Furthermore, the presence of high IgE levels in patients with SIgAD may increase their risk of developing allergies. Therefore, regular follow-up of children with SIgAD and early recognition of allergy symptoms are of great importance to improve the quality of life of patients.
