*6.1. IgA Deficiency and CVID*

Common variable immunodeficiency (CVID) is an immune disorder characterized by decreased serum levels of both IgG and IgA, with or without a decreased level of IgM, and poor antibody vaccine response or low switched memory B cells less than 70% of age-appropriate normal [158]. CVID most often presents with recurrent infections of the respiratory and gastrointestinal tract [159]. Symptomatic sIgAD and CVID have many similar features, moreover, some patients with sIgAD progress to CVID, especially if autoimmunity or IgG subclass deficiency is observed [149–164].

In patients with sIgAD, there is a significantly lower number of class-switched memory B cells and transitional B cells [165]. Preprint of another study showed an increased percentage of naive B cells and decreased percentage of switched memory B cells. Only one parameter correlated with the severity of the disease—CD21low cells. They were increased in patients with severe SIgAD as compared to those with mild severity [166]. Increased level of CD21low was previously described but without correlation to clinical status [167].

In CVID, there is a classification based on B-cell phenotype, which divides CVID patients into B − group and B + group, depending on the CD19 expression (lower or higher > 1%). B + patients may be further divided into groups smB + or smB-, based on a proportion of switched memory B-cell percentage (lower or higher >2%). Recently, an increase in transitional B cells and CD21low B-cells is used as a base to subdivide groups [168]. Some of the B-cell phenotype findings are similar between CVID and SIgAD. There is an interesting observation of an increased CD21low cells number in patients with severe sIgAD; a higher level of those cells in CVID patients is connected with autoimmune phenomena [169,170].

The major histocompatibility complex (MHC) represents the most common genetic susceptibility locus for CVID. However, non-MHC-associated single-gene mutations have been identified. These include the genes for ICOS, BAFF-R, TACI, CD19, CD21, CD81, CD20, LRBA, PKC-Delta, NF-kB1, NF-kB2, IL-21 [171]. Defects of these genes represent only approximately 2–10% of patients with CVID [172]. Some authors state that a common

genetic basis for IgAD and CVID can suggest that at least in some cases, IgAD and CVID may be part of a spectrum of diseases caused by a common genetic factor—for example, a mutation in the TACI—transmembrane activator CAML (calcium modulator and cyclophilin ligand) [173]. Another, slightly different thesis is the presence of autoantibodies against BAFF, APRIL, or IL21 as a common ground for CVID and sIgAD [174]. Both in CVID and sIgAD, there are reports of an increased level of BAFF and APRIL [175]. Increased apoptosis is also one of the mechanisms reported for both of these disorders [48]. An interesting observation indicating a similar genetic background of both diseases is their coexistence in families [176].

Besides, the relation between human leukocyte antigen (HLA) A1, B8, DR3, DQ2, or any part of this haplotype and IgA deficiency could indicate progression to CVID [159,161]. In patients with severe clinical manifestations, HLA typing could be helpful for the prediction of progression to CVID [160]. Moreover, in sIgAD subjects with simultaneous Ig subclass deficiency and bronchiectasis, the presence of hematologic autoimmunity could be another predictor of progression to CVID [94].

#### *6.2. Transfusion Selective IgA Deficiency*

One of the most dangerous complications of sIgAD is an anaphylactic transfusion reaction. It has been found that some patients with sIgAD are sensitized, which means that there are anti-IgA antibodies (IgG or IgE) present in their blood [34,177–179]. These autoreactive antibodies were found in 20–40% of patients with sIgAD [180]. After transfusion of blood containing IgA in such individuals, there is a risk of anaphylactoid reaction mediated by these immunoglobulins.

Rachid and Bonilla reviewed the articles reporting reactions to immunoglobulin products in patients with sIgAD [181]. The severity of adverse reactions with anti-IgA antibodies depends among others on the isotype (IgG or IgE), its specificity and serum concentration, the method of measurement. IgG anti-IgA antibodies are found in approximately one-third of sIgAD patients [181]. But only a few studies have reported anaphylactic transfusion reaction associated with IgE class. It has been also reported that IgE anti-IgA is less frequently studied than IgG anti-IgA. However, when both have been studied together, anti-IgA of the IgE class occurs much less frequently than IgG [182]. Burks et al. reported two patients (one with CVID and another with sIgAD) with IgE anti-IgA and IgG anti-IgA [177]. One of them had anaphylaxis with IVIG and another with IgA-deficient plasma. Ferreira et al. found IgE anti-IgA1 in a patient with CVID, which also had IgG anti-IgA [183].

The diagnosis of IgA-related anaphylaxis is made after transfusion-related anaphylaxis by measuring the levels of IgA and anti-IgA. The mechanism of anti-IgA production remains unexplained [184] and the clinically significant threshold of anti-IgA is still unknown [185]. However, the incidence of anaphylactic blood transfusion reactions is not very high and it occurs in one in 20,000–50,000 transfusions [186]. Moreover, some studies suggest that transfusion reactions occur less commonly than previously thought [187]. Only 17.5% of all blood samples coming from patients after transfusion reactions contained an IgA antibody, which indicates the presence of some other triggers [188].

There are no evidence-based guidelines regarding the proper approach while performing transfusion to patients with sIgAD. It is evident that patients with a history of anaphylactic transfusion reactions should not receive IgA-containing blood products [96]. These patients can receive blood products coming from donors with IgA deficiency, washed red blood cells, or platelet components. It is performed to remove residual plasma before transfusion and to decrease the risk of anaphylactic transfusion reactions in such patients [189]. There are also some cases that illustrate successful desensitization to IgA using IgA-enriched immunoglobulin preparations as a source of antigen [190].

#### *6.3. Malignancy*

There is a relationship between the occurrence of immune disorders and the overall risk of malignancy. This relationship is evident in some immunity disorders such as CVID [191,192]. It has been shown that the risk of malignant lymphoma among these patients is increased by 30 times, while the risk of gastric cancer is 47 times higher [193]. In the case of IgA deficiency, the association with the incidence of cancer is not that clear. There are studies that report the different incidences of malignancies among patients with sIgAD, especially adenocarcinoma of the gastrointestinal tract, and lymphomas. Such studies require a long-term follow-up to diagnose this kind of evolution, therefore there are not much data regarding this topic. In a review of 330 patients, the authors report a 1.5% prevalence of malignancy, and five patients who presented neoplasms had Hodgkin lymphoma, acute lymphoid leukemia, Wilms tumor, Burkitt lymphoma, and ganglioneuroma [132]. Another study that included 63 children from Israeli reports a much higher frequency of malignancy (4.8%) [99] and the following malignancies were present: astrocytoma, adenocarcinoma of the colon, Hodgkin's lymphoma, neuroblastoma. On the other hand, a combined Danish and Swedish study including 386 patients with sIgAD did show an elevated incidence of cancer compared to a healthy cohort, however, this increase was non-significant [194]. In 2015, Ludvigsson et al. performed a prospective nationwide population-based cohort study with 2320 individuals with IgA deficiency [195]. They concluded that there is a moderately increased risk of cancer, especially gastrointestinal one, and that the risk is highest after diagnosis of sIgAD.

#### **7. Atopic Diseases in Other PIDs**

Tuano et al. described the prevalence of asthma, allergic rhinitis, atopic dermatitis, and food allergy in a cohort of 2923 patients with PID in US population [123]. Atopic dermatitis and food allergy were most common in patients with CVID, combined immunodeficiency (CID), and hyper IgE syndrome. Patients with CID and sIgAD presented a higher percentage of food allergy symptoms than the healthy population; 33.3% in CID and 25% in SIgAD [123]. In CVID the prevalence rates of asthma, rhinitis, and documented food allergy have been established as 37.5%, 55.5%, and 11.25% respectively [196]. In the case of patients with hypogammaglobulinemia, prevalence rates of asthma, rhinitis, and atopic dermatitis were established at 20%, 22%, and 9% respectively. Interestingly, Szczawinska-Poplonyk assessed the incidence of food allergy as 74% in the pediatric population [131,197,198].

#### **8. Conclusions**

sIgAD is an antibody deficiency and it usually remains undiagnosed throughout the patient's life, due to its frequent asymptomatic course. If symptomatic, sIgAD is connected to more frequent viral and bacterial infections of upper respiratory, urinary, and gastrointestinal tracts, as well as allergic and autoimmune diseases. It was suggested that allergic diseases (e.g., eczema, rhinitis, asthma) are more common in patients diagnosed with this particular PID, however, the prevalence and severity of allergic manifestations can be associated with ethnic background.

Since there is a controversy in the scientific world whether the coexistence of IgA deficiency and allergic diseases is in fact true, further studies on a large group should be carried out. Atopy in sIgAD subjects is common, but is also possible that it is overlooked. Therefore, it is necessary to follow diagnostic criteria to make a diagnosis of any atopic disease. The possible reasons for different prevalence which is observed in different studies could be caused by different diagnostic criteria or inclusion of patients based on parentally reported symptoms in the children population.

Moreover, these patients can present with simultaneous atopic and infectious manifestations which can intensify the symptoms; therefore, atopic diseases should be treated aggressively in patients with sIgAD. It is necessary to provide these patients with a proper multi-disciplinary team of physicians.

Moreover, it is important to emphasize that the course of the disease may change and there are some serious complications of this disorder, among which there are progression to CVID, transfusion-related anaphylaxis, and malignancy. Although they do not happen very often, sIgAD remains the most common PID disease, therefore physicians should be aware of all possible complications to provide the best care for their patients.

**Author Contributions:** Conceptualization, I.M., A.M., E.G., K.Z.-O., and J.R.; methodology, S.K., D.B., R.H., and P.N.-R.; validation, R.B., H.P.-B., and B.B.; formal analysis, I.M., S.K., E.G., J.R., and P.N.-R.; investigation, I.M., S.K., D.B., R.H., R.B., and A.M.; data curation, I.M., S.K., D.B., E.G., and J.R.; writing—original draft preparation, I.M., S.K., D.B., R.H., R.B., A.M., H.P.-B., B.B., and K.Z.-O.; writing—review and editing, E.G., J.R., and P.N.-R.; visualization, R.H.; funding acquisition, J.R. and E.G.; supervision, P.N.-R., E.G., and J.R. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by Research Grant No. 2016/21/B/NZ6/02279 of the Polish National Science Centre (NCN) and Research Grant No. DS460 of the Medical University of Lublin.

**Conflicts of Interest:** The authors declare no conflict of interest.
