Selective IgA Deficiency a Probable Risk of Recurrent Chest Infections in Asthmatics

Introduction

Asthma is a chronic inflammatory condition of the airways portrayed by its clinical heterogeneity due to the high intricacy of its pathophysiology. Several risk factors predispose to airway hyperresponsiveness and the limitation of the airflow. However, the exact etiology has yet not been fully elucidated.¹ The role of infections as triggering and exacerbating factors in asthma are widely recognized. The mechanisms underlying increased risk of microbial infections in asthmatic patients are unknown.^2,3 Recently, studies suggest that asthma is associated with impaired innate^4–6 and adaptive⁷ immunity, accounting for an increased susceptibility to infection. An additional probable etiology, other than immune inadequacy, for the increased risk of microbial infections in asthmatic patients is the existence of selective IgA deficiency (sIgAD).⁸ Selective immunoglobulin A (IgA) deficiency is characterized by a high incidence of both recurrent infections and atopic diseases. It is defined as an isolated deficiency of IgA less than 0.07 g/L in a patient above 4 years old.⁹ When serum IgA level is more than 7 mg/dL, but two standard deviations beneath normal for age, it is called partial IgA deficiency.³¹ The current study aims at investigating the prevalence of selective immunoglobulin A deficiency in Egyptian asthmatic patients and its correlation with recurrent infections in those patients.

Methodology

Subjects and Setting

The study was a case–control study which included 80 subjects attending the outpatient clinic of allergy and clinical immunology at Ain Shams University hospital during the period 2019−2020.

Study population: 80 Patients were divided into 3 groups:

1. Group A included 20 Asthmatic patients with recurrent chest infections;
2. Group B included 20 Asthmatic patients without recurrent chest infections;
3. Group C included 40 healthy controls who fulfill the same exclusion criteria as the patients.

They were health workers recruited from the hospital staff members.

• Recurrent chest infections were defined as the occurrence at least 3 lower respiratory tract infections (viral or bacterial) in a 1-year period, with at least 2 episodes of pneumonia with radiographic evidence (viral or bacterial).

Inclusion Criteria

1. Age above 18 years old;
2. Mild-to-moderate Asthmatic patients according to GINA 2019.

Exclusion Criteria

1. Smoking in order to exclude asthmatic bronchitis;
2. Patients with chronic diseases and other causes of secondary immune deficiency which could explain the recurrent chest infections, such as diabetes hypertension, pregnancy and malignancy;
3. Patients taking medications which are known to cause IgA deficiency including anti epileptics Sulfasalazine, D penicillamine, Gold, Thyroxine, Captopril, Levamisole, systemic corticosteroids and Cyclosporine;
4. History of immunosuppressive medications intake that may result in recurrent chest infections;
5. Comorbid conditions that are characterized by selective IgA deficiency such as rheumatoid arthritis, lupus, celiac disease, or inflammatory bowel disease to avoid confounding effect.

Each Patient is Subjected to the Following

1. Full detailed history and examination to exclude any comorbid condition (diabetes, hypertension, or any other system affection) or any drug intake that affects the results of the study;
2. History of inhaled corticosteroids intake;
3. Full detailed allergic history, and skin prick test to common allergens;
4. Clinical examination of the respiratory system;
5. Chest x-ray was done to exclude other lung pathology;
6. Pulmonary function tests with special emphasis on FEV1, FEV1/FVC to confirm the diagnosis of Asthma using SPIROMETRICS;
7. Serum immunoglobulins for each patient including total serum IgE which was done using enzyme-linked immunosorbent assay kit (ELISA) supplied by Bioss, USA, and Serum IgA, IgG, IgM which were tested by immunoturbidimetric assay using Cobas c311 analyzer by Roche Diagnostics, Germany. Anti-immunoglobulin antibodies react with the antigen in the sample to form a complex which is measured turbidimetrically;
8. Measure of total leucocytic count with differential using hematology analyzer LH 750 Beckman Coulter, USA;
9. All patients were on demand short acting reliever inhalers.

Statistical Analysis

The collected data were processed and coded before being analyzed using the IBM SPSS program (Statistical Package for Social Sciences) for Windows Version 20.0. Qualitative data were presented using numbers and percentages. Quantitative data were presented using means, standard deviations and ranges. The comparison between two groups with qualitative data was done by using Chi-square test. Fisher exact test was used instead of Chi-square test when the expected count in any cell was found less than 5. The comparison between more than two groups with quantitative data and parametric distribution was done by using One Way Analysis of Variance (ANOVA). Pearson’s correlation was used to find out relationship between two quantitative variables. The confidence interval was set to 95% and the margin of error accepted was set to 5%. So, the p-value was considered significant only when it was <0.05.

Results

According to (Table 1), there was a statistically significant difference between Group A and Group C regarding the mean of age (Figure 1). Group A had a higher mean age than Group C (p2 = 0.022*). Both groups, A and B, were comparable regarding the history of inhaled corticosteroids (p = 0.077). On comparing Groups A & B with respect to the duration of asthma and asthma control test results, there were non-significant differences between both groups (p = 0.659 and 0.968, respectively). Regarding total leucocyte count, there was a significant difference between the three groups (overall p = <0.001). Group A showed a significantly higher mean total leucocyte count than Group B and Group C (p1 < 0.001*, p2 < 0.001, respectively).

Table 1 Comparison Between the Three Studied Groups According to Demographic Data, Asthma Control, Duration of Asthma, Drug History and CBC Parameters

Figure 1 Comparison between the three studied groups according to Age (years). Group A had a higher mean age than Group C (p = 0.022). Group A: Asthmatic patients with recurrent chest infections. Group B: asthmatic patients without recurrent chest infections. Group C: healthy controls.

Regarding the Eosinophilic count, there was a significant difference between the 3 groups (overall p = <0.001). Group A showed a statistically significantly higher mean Eosinophilic count than group C. Besides, the mean Eosinophilic count was statistically significantly higher in group B than in C (p3 < 0.001). Nonetheless, there was no statistically significant difference between group A and B (p2 < 0.001, P1 = 0.619, respectively).

Table 2 summarizes the comparison between the 3 studied groups as per the different serum immunoglobulin levels. According to serum IgE, there was a statistically significant difference between the three groups (overall p = ˂0.001). The mean serum IgE was statistically higher in Group A&B than in controls (Figure 2). The mean value of serum IgE was significantly higher in Group A and B than in Group C (p2,3 <0.001 and <0.001*, respectively). Yet, there was a non-significant difference between Group A and B (p1 = 0.117).

Table 2 Comparison Between the Three Studied Groups According to Different Serum Immunoglobulin Levels

Figure 2 Comparison between the three studied groups according to serum IgE IU/mL. The mean serum IgE was statistically higher in Group A and B than in controls (p = ˂0.001). The mean value of serum IgE in Group A was 300.9 ± 131.8IU/ mL while in Group B was 220.1 ± 72.0 IU/mL and in the Group C was 94.75 ± 55.35 IU/mL.

As per serum IgA, there was a statistically significant difference between the three groups where the mean serum IgA was statistically significantly lower in Group A&B than in controls (overall p = ˂0.001) as shown, in Table 2 and Figure 3. The mean value of serum IgA was significantly lower in Group A than in Groups B and in C (p1,2 <0.002 and <0.001*, respectively). There was a statistically non-significant difference between Groups B and C (p = 1).

Figure 3 Comparison between the three studied groups according to serum IgA. The mean serum IgA was statistically significantly lower in Group A and B than in controls (p = ˂0.001). The mean value of serum IgA in group A was 84.25 ± 51.10 mg/dl while in Group B was 179.9 ± 90.81 mg/dl and in Group C was 219.6 ± 78.78 mg/dl. The mean value of serum IgA was statistically significantly lower in Group A than in Groups B and C (p1,2 <0.002 and <0.001, respectively). There was a statistically non-significant difference between Groups B and C (p = 1). Group A: Asthmatic patients with recurrent chest infections. Group B: Asthmatic patients without recurrent chest infections. Group C: healthy controls.

Furthermore, there was a non-significant difference between the three groups with respect to the mean serum IgM and serum IgG level with a p-value equal to 0.778 and 0.067, respectively.

Concerning the percentage of selective IgA deficiency or partial IgA deficiency in asthmatic patients, 26 patients (56%) of all asthmatic patients had a selective IgA deficiency or a partial deficiency as shown in Table 3. On comparing the percentage of selective IgA deficiency and partial deficiency in Group A&B, Group A showed a statistically significant higher percentage of selective/partial IgA deficiency. Seventeen patients in Group A (85%) had a selective or a partial IgA deficiency, while 9 patients in Group B (45%) had a selective or a partial IgA deficiency. Among patients with selective/partial IgA deficiency in asthmatics, Group A had a significant higher proportion of subject with complete IgA deficiency, while group B had a significantly higher proportion of partial selective IgA deficiency (p = 0.03), as shown in Table 3.

Table 3 Comparison Between the Two Studied Groups According to the Percentage of Selective/Partial IgA Deficiency

Table 4 shows correlations between IgA and different statistically significant parameters in asthmatic patients. There was a non-significant positive correlation between the duration of asthma and absolute eosinophilic count and Serum IgA, while there was a significant positive correlation between asthma control test and serum IgA (r s = 0.314 p = 0.048*). As the asthma control test results increased in value there was a corresponding significant increase in serum IgA.

Table 4 Summarizes the Correlation Between Serum IgA and Statistically Significant Parameters in Asthmatic Patients

There was a non-significant negative correlation between age and serum IgA on the one hand and serum IgE and serum IgA on the other in asthmatic patients. Nonetheless, there was a significant negative correlation between total leucocytic count and serum IgA (r s =−0.418 p = 0.007*). As total leucocytic count increased there was a corresponding significant decrease in serum IgA in asthmatic patients, as shown in Figure 4. Moreover, serum IgA level was significantly lower in patients taking inhaled corticosteroids (p = 0.03), as shown in Table 5 and Figure 5.

Table 5 Comparison Between Patients Who are Taking Inhaled Corticosteroids and Those are Not with Respect to Serum IgA Level

Figure 4 Correlation between serum IgA (71–360 mg/dl) and Total leucocyte count (TLC). A significant negative correlation between total leucocytic count and serum IgA was noted (r s =−0.418p=0.007). As total leucocytic count increased there was a corresponding significant decrease in serum IgA in asthmatic patients.

Figure 5 Comparison between patients who are taking inhaled corticosteroids and those are not with respect to serum IgA level.

Discussion

The current study has reached finding concerning the evaluation of serum IgA level and its correlation to recurrent infections in Asthmatic patients. In addition, the results of this study lend further support to the fact that serum IgE significantly increases in Asthmatic patients.

Firstly, regarding the correlation between serum IgA and the recurrent infections in asthmatics, asthma is associated with risk of serious pneumococcal disease and microbial infections affecting patients’ quality of life. Recent evidence suggests that asthma can influence patients’ susceptibility to infections. Yet, research in this domain has been limited.^10,11 Most previous studies evaluated the prevalence of allergic diseases, especially asthma, among patients having sIgAD (15% to 83%).^32–34 There are, however, limited number of studies which indicate that low or deficient serum IgA levels were more common among asthmatics than among non-asthmatics.^35,36 Based on the results of this study, it was found that there was a statistically significant difference between the three groups (A,B and C) regarding serum IgA where serum IgA level was statistically significantly lower in the asthmatic patients than in the control patients. Besides, serum IgA was statistically significantly lower in the patients with recurrent chest infections than in both asthmatic patients without recurrent chest infections and the healthy controls. Moreover, the percentage of selective /partial IgA deficiency was statistically significantly high among asthmatic patients where Group A showed a higher statistically significant percentage of selective /partial IgA deficiency than Group B. Group A had a significant higher proportion of subject with complete IgA deficiency, while group B had a significant higher proportion of partial selective IgA deficiency. Serum IgA showed negative correlations to age, serum IgE level and total leucocytic count, while displaying positive correlations with absolute eosinophilic count, duration of asthma and asthma control test results. The correlations between serum IgA levels and total leucocytic count and asthma control test results were of statistical significance. Moreover, serum IgA level was significantly lower in patients taking inhaled corticosteroids.

The pathogenesis for the association between asthma and sIgAD is undiscovered. Some studies have speculated that the variability of TNFRSF13B molecular deficiency probably shared in the etiopathogenesis of sIgAD.^37,38 Although the position of TNFRSF13B gene mutations in the development of asthma or allergy is not fully investigated, a recent study revealed that Swedish children with TNFRSF13B mutations were liable to a 2-fold rise in the risk of wheezing at the age of 2 and 4 and a 2.5-fold increased risk of developing asthma at 4 years of age regardless of serum IgE levels.³⁹

On reviewing the studies conducted in the field, it was found that the results of most studies matched our results, while very few did not. Urm et al agree with the current results. They conducted a population-based case–control study to ascertain the correlation between the history of asthma and the diagnosis of selective IgA deficiency (sIgAD)/common variable immunodeficiency (CVID). They concluded that asthmatic patients are more prone to suffer from sIgAD/CVID than non-asthmatic subjects. This correlation may possibly be the reason for the increased risks of bacterial infections in asthmatic individuals.⁸

In addition, Živković et al investigated the association between sIgAD subtypes and the incidence of respiratory and allergic disorders. They also assessed the connection between the changes in lung functions among children with sIgAD subtypes and respiratory and allergic disorders in a case–control study. Children in the case group were divided into severe sIgAD and partial IgAD patients. Their results revealed that both groups with severe IgAD as well as partial IgAD demonstrated a higher prevalence of allergic diseases and a total number of infections in comparison with controls. Their results are in alliance with the current results.¹²

Likewise, Erkoçoğlu et al evaluated the incidence of allergic diseases and autoimmune disorders among children with sIgAD and their first-degree relatives (FDRs). They revealed that there was an increased incidence of allergic and autoimmune disorders among those patients and their FDRs suggesting a probable common influencing genetic element for sIgAD and autoimmunity in those families.¹³

The negative significant correlation between serum IgA and the total leucocytic count revealed by the current study is attributable to the fact that low serum IgA levels is associated with recurrent infections in which total leucocytic count is elevated.^25–29

Shkalim et al evaluated the clinical and immunological characteristics of selective IgA deficiency in children in Israel. They indicated that the percentage of Allergic diseases among those patients was 31.7% and asthma was the most prevalent, followed by allergic rhinitis. Besides, they concluded that IgA deficiency was one of the immunodeficiencies that might be associated with elevated serum IgE levels and attributed their results to the fact that the increase in serum IgE levels was because of increased mucosal permeability to foreign antigens resulting in enhanced antigen stimulation in patients with IgA deficiency.²⁵

Similar results were achieved by Shahin et al who revealed an inverse significant correlation between serum IgA levels and serum IgE levels (r = –0.314, p < 0.001). However, their study was conducted on a population different from the population of the present study as they investigated the prevalence of IgA deficiency among Egyptian patients with food allergy.²⁴

Nonetheless, Kim et al disagreed with the current results regarding the correlation between serum IgA and serum IgE and age. They declared that serum IgE level was positively related to serum IgA level. They explained their results by suggesting that this correlation was due to the individual variances in functioning plasma cells due to aging or parasitic infestations which increase in adults.²³ Besides their study revealed a significant positive correlation between the mean age and serum IgA (r = 0.140, p = 0.000). Their study examined the relationship between serum IgA levels (within the normal range) and sensitization to house dust mites (HDM) or airway hyper-responsiveness (AHR).²³ They explained this correlation by denoting that repeated infections in adulthood induce a progressive increase in serum IgA levels with age. This disagreement could be due to their large sample size as their study was conducted on 1136 adult patients. Moreover, their study was done on a western population retaining a healthier lifestyle, with lower infection rates in low age groups “Hygiene hypothesis,” unlike the current study population.

As for the positive correlation between serum IgA and asthma control test results, several studies agreed with the current results. Balzar et al noticed that the prevalence of moderate/severe Asthma was also significantly inversely related to the IgA level in asthmatics. Moreover, higher sIgA was positively correlated with lung function. Hence, as the degree of asthma severity improved and the patients reached better control, serum IgA level increased.³⁰ Similar results were also reached by Kim et al.²³

In the present study, serum IgA level was significantly lower among patients using inhaled corticosteroids. No previous studies were conducted to assess the effect of inhaled corticosteroids on the serum IgA level. However, Fukushima et al assessed the difference salivary IgA concentration among asthmatic patients who had oral candidiasis and were using inhaled corticosteroids and those who did not have oral candidiasis and also used inhaled corticosteroids. Their results showed that inhaled corticosteroids may potentially reduce salivary IgA.⁴⁰ Their results reinforce the current results.

Secondly, regarding the fact that serum IgE level increases in asthmatic patients, the results of several studies as well as the current one have corroborated it.^{14–17,20–22}

Davila et al conducted a multicenter, retrospective, observational study including 383 patients with allergic asthma adult patients. They aimed to evaluate the association between serum total IgE levels and disease severity in adult patients with persistent allergic asthma and to explore the main predictors of IgE levels. They found that serum total IgE levels in adult patients with persistent allergic asthma were high (two-thirds with levels >150 IU/mL) and extremely variable.¹⁹

Besides, a retrospective cross-sectional real-life study by Lababidi et al was conducted on 142 patients attending adult refractory asthma outpatient clinic between 2015 and 2018.They investigated the concurrence of high eosinophil count and elevated serum IgE levels in patients with severe refractory asthma and found that serum IgE and eosinophilic count were concurrently elevated in 110 patients (78%).¹⁸

Study Limitations

One of the limitations of the current study was the small size of its sample. Moreover, it did not assess whether asthmatic patients are predisposed to development of diagnosis of sIgAD in time or whether asthma was a phenotypic subgroup of sIgAD. Moreover, it did not assess the correlation between lung function parameters and serum IgA concentration.

Hence, it is recommended for future research to conduct larger studies to further investigate the association between sIgAD and asthma and to assess whether asthma is a predisposing factor to sIgAD or a phenotypic subgroup of sIgAD. Moreover, larger studies assessing the effect of inhaled corticosteroids on serum IgA are also required.