Clinical manifestation for immunoglobulin A deficiency: a systematic review and meta-analysis

IgAD is a primary immunodeficiency described in patients older than 4 years, after excluding other causes of hypogammaglobulinemia and T cell defects [1]. In this study, we provided a comprehensive analysis of the clinical manifestations in IgAD patients and its three main subtypes: SIgAD, PIgAD, and the coexistence of IgAD and IgG subclass deficiency.

Although more than half of IgAD patients remain undiagnosed in their life [5], individuals with SIgAD, as the largest group of both IgAD and predominantly antibody deficiency, represented a wide range of clinical manifestations with various prevalence in different study populations [7]. Our analysis revealed infection to be the most common complication in SIgAD patients (64.8%) with respiratory (50.7%) and GI (15.7%) tract as the main target systems, which is in agreement with previous publications [1, 23‐27]. Interestingly, despite former studies insisting on encapsulated bacteria such as Streptococcus pneumonia and Haemophilus influenza [26], we detected fungal pathogens as the major invading agents (18.5%) highlighting the role of secretory IgA in mucosal immunity against fungi [28]; thus, it could be assumed that fungi are underacknowledged pathogens in SIgAD and patients with a definite diagnosis might benefit from fungal screening. Additionally, the rate of infection considerably varied in different studies; some reported lower [19, 25, 29‐31] or higher [16, 23, 32, 33] prevalence of infection than our pooled data. These controversial results could stem from the fact that many individuals may only represent mild infections and therefore not be screened for immunodeficiency. Plus, the lack of diagnostic facilities in developing countries might lead to improper treatment and eventually raise the prevalence of clinical presentations in IgAD.

The other major complications in SIgAD, in the order of prevalence, are allergy (29.16%), autoimmunity (22%), and malignancy (3.7%). IgAD is a heterogenous disease with maltitude pathogenic approaches; the major underlying cause of IgAD centers around B-cell proliferation, maturation, and ultimately immunoglobulin production [34]. Lack of IgA production tend to incite compensatory increase in secretory IgM [35]. Many studies have pointed out an increased risk of atopic diseases in IgAD including bronchial asthma, allergic rhinitis, and atopic dermatitis [25, 31, 36‐39]. Although we found allergic diseases far less prevalent than in former reports [16, 23, 31, 40], it ranked second in the clinical manifestations of patients. Asthma was the most prevalent atopy in our analysis of SIgAD cases. However, the association between asthma and SIgAD seems to be conflicting. Although asthma outbreak has been commonly reported in SIgAD patients [41], no significant difference was observed in the incidence of asthma among SIgAD patients and the control group [8]. It is thought that the impaired mucosal immunity in the absence of secretory IgA is mainly responsible for the sensitization against aeroallergens and food allergens in the respiratory and GI tracts [38, 42]. However, they still lack a clear cause-and-effect relationship; arguing whether IgAD promoted allergic reactions or the allergic reactions weakened the mucosal membranes and consequently generated a secondary IgAD [4]. Besides, the influence of nutrition, geographic locations, and genetics should also be taken into consideration, which might explain the low rate of allergy in Chinese patients with SIgAD [19, 32]. Importantly, patients with concomitant IgAD and allergic disease are inclined to develop severe manifestations, especially respiratory tract infections [43].

An association between IgAD and a higher prevalence of autoimmune diseases has been detected [10, 44]. We reported autoimmune diseases in 22% of our SIgAD patients which is substantially greater than the reported proportions from Spain (11.5%), Brazil (19%), Turkey (17.3%), and Israel (20.6%) [13, 25, 31, 45, 46]. This should be noted that these results are mainly from symptomatic cases, as undiagnosed individuals are less likely to be tested for autoimmune diseases or other disorders. Celiac disease (6.57%), inflammatory bowel disease (IBD) (4.01%), and rheumatoid arthritis (3.80%) were the most prevalent autoimmunity in SIgAD patients which is much lower than their prevalence in general population [1.4%, 0.32%, and 0.5-1.0%, respectively] [47‐49].

Similar to the prevailing data [10, 14, 25, 31, 33, 36, 45, 50‐54], celiac disease was the most frequent autoimmunity in our study. Celiac disease shares a Igfic significance with IgA deficiency possibly through certain HLA haplotypes [55]. Incidentally, due to the paucity of IgA antibodies in SIgAD, celiac disease could be misdiagnosed in the context of this immunodeficiency [56, 57]. Only 9.3% of SIgAD cases with biopsy-confirmed celiac disease had IgG antibodies against TTG, implying physicians need to rely on tissue biopsies in this population [14]. Of note, patients with concurrent celiac disease and IgAD are more likely to have an additional autoimmune disease than individuals with celiac disease alone (67% vs. 23.5%) as well as a lower frequency of GI symptoms (17.7% vs. 66.7%) [58].

PIgAD and the coexistence of IgA and IgG subclass deficiency shared close results in terms of clinical manifestations with SIgAD. Nonetheless, they both had a lower incidence of autoimmunity and allergic diseases without any report of malignancy. However, neither the disease severity nor the occurrence of infections and autoimmune diseases was stated to correlate with serum IgA level [59]. Despite some discrepancy [60], the frequency of severe infections tended to be greater in IgAD with concurrent IgG2 or IgG4 subclass deficiency and/or limited pneumococcal polysaccharide antibody response [29, 61]. Likewise, these patients had a higher rate of infection in the pooled analysis compared to the other groups. Currently, the same size of the PIgAD and concurrent IgA and IgG subclass deficiency prevents a precise conclusion.

In this regard, the pooled prevalence of infection, autoimmunity, and allergic disease in SIgAD were comparable to PIgAD patients. Respiratory tract infection was the most prevalent infection in both groups whereas, gastrointestinal and fungal infection infection had the second position in the PIgAD and SIgAD group. Similar results were also observed in the prevalence of autoimmune manifestations. Generally, the current study indicates that the spectrum of complications in patients with PIgAD and SIgAD has considerable similarities with minor differences in some presentations.

Noteworthily, common variable immunodeficiency (CVID) and IgAD have comparable clinical and immunological features and even IgAD can be seen early in the development of CVID [62]. Progression of IgAD to CVID is a rare phenomenon that has been occurred in several cases. However, presence of autoimmune disorders and IgG subclass deficiency in association with distinct HLA haplotypes could increase the risk of CVID induction in a genetically susceptible IgAD patient [63]. Thus, the screening of immunoglobulins is better implemented so that intravenous immunoglobulin (IVIG) therapy can be considered in case of disease progression towards CVID. Finally, the lack of an established screening method and the difficulty of diagnosis owing to the heterogeneity of the clinical presentation in PIgAD and SIgAD cloud a precise estimation of the patients in each category of IgA deficiency [64].

Moreover, new clinical manifestations might appear during patients’ follow-up, particularly in the presence of a positive family history [41], indicating that the age of patients and the course of the disease probably interfere with the reported frequency. In addition, periodic assessment in IgAD patients is warranted.

One of our limitations in the current study was the lack of information or incomplete data regarding the clinical manifestations and immunologic evaluations of IgAD cases in the published literature; information that could play a rather important role in categorizing different types of IgAD.

Overall, our study identified the infection as the most prevalent clinical presentation among IgAD patients, followed by allergic and autoimmune diseases. Due to the functional role of secretory IgA in maintaining the homeostasis of mucosal surfaces, these complications mainly involved respiratory and GI tracts. SIgAD patients tend to have altered intestinal and oropharyngeal microbiota that can be only partially compensated with IgM secretion [65, 66]. These microbial perturbations may play a role in developing or exacerbating immune dysregulations in the patients. The spectrum of clinical manifestations in PIgAD and SIgAD are mainly similar with a few minor discrepancies in allergic presentations. The coexistence of IgA and IgG subclass deficiency in patients may increase the susceptibility to infections. CVID and IgAD share clinical and immunological features; few IgAD patients progress toward CVID. Furthermore, new clinical manifestations could be detected in the course of the disease, implying the necessity of periodic assessment in these patients. However, the same size of the PIgAD and concurrent IgA and IgG subclass deficiency is small to conclude.