*5.2. Minor Infections*

Children with recurrent and severe infections present a diagnostic challenge [67]. Four or more ear infections and two or more serious sinus infections or episodes of pneumonia within one year are warning signs for primary immunodeficiencies in children [68].

Secretory IgA plays an important role in maintaining the equilibrium of the body, as it takes part in the mucosal immune system and serves as the interface between the body and the microbiome. In the human body, the largest mucosal systems are the gastrointestinal tract and respiratory system, and therefore, decreased level of IgA will affect mostly them.

Symptomatic patients with minor infection usually present recurrent upper respiratory tract infections (40–90%), mainly viral, less frequently bacterial (with encapsulated bacteria etiology, such as Streptococcus pneumoniae, Hemophilus Influenzae) [7,8,69,70]. Bacterial bronchitis and pneumonia are much less common, but these infections may be complicated by bronchiectasis [71]. Infections of the ear, sinuses, conjunctiva, nose, and throat mucosa may occur. Most often, these infections are mild, not requiring hospitalization and their treatment does not differ significantly from the treatment of a patient without sIgAD. It was found that patients with sIgAD have a compensatory increase in secretory IgM level [9,72], however, these IgM cannot replace all functions of IgA [73]. In the intestines of sIgAD patients, there is 65–75% of Ig-containing plasma cells with the ability to produce IgM in comparison to about 6% in healthy volunteers, possibly due to the homology in structure and function between those two isotypes [74–77]. Besides, patients with sIgAD suffer from urinary tract infections (UTI) and gastrointestinal tract infections with viruses and bacteria. Moreover, intermittent or chronic diarrhea due to Giardia Lamblia is common, because the attachment and proliferation of this parasite on the gastrointestinal mucous are facilitated due to lack of IgA [78,79]. It is important to mention that in patients with recurrent UTI, bronchitis and pneumonia, defects in the urinary and respiratory systems should be excluded.

The diagnosis of selective IgA deficiency mostly does not significantly influence the therapeutic management of patients. Treatment of infections should be adequate to their etiology, patient's age, and clinical condition. Treatment of comorbidities and prevention of complications remain the basis. There are no clear guidelines that would suggest the need for longer and more aggressive antibiotic therapy in this disease than in patients without sIgAD. There is also no consensus on the use of antibacterial prophylaxis in this immunodeficiency, but its usage was suggested in more severe cases, at least periodically [34,48,80]. Vaccinations play a significant role in minimizing the risk of infections [48]. It is advisable to extend the standard calendar with vaccination against *S. pneumoniae*, *N. meningitidis*, *H. influenzae,* and annual vaccination against influenza [34]. It is not typically recommended to initiate IgG (i.v, s.c) replacement therapy in patients without the

coexistence of other immune-related diseases, acute, severe infections, or coexistence of specific antibodies deficiency [81]. According to one of the latest meta-analyses covering the effects of oral probiotics, parabiotics, and synbiotics on immunoglobulin levels, it has been shown that their supplementation increases significantly salivary IgA secretion, without a significant effect on the level of other immunoglobulins and with no effect on the serum IgA [82]. In addition, there are reports of an increase in the amount of IgA+ cells in the intestines of lamina propria in mice after oral ingestion of Lactobacillus-based preparations [83,84]. One prospective, randomized study demonstrated the validity of the use of oral immunomodulator bacterial extract (OM-85 BV) in patients with sIgAD and/or IgG subclass deficiency, resulting in a lower one-year infection rate [85]. A suggestion has been made to use oral IgA in patients with sIgAD, since this deficiency is associated with dysbiosis and chronic inflammation, and the present inflammation is inversely correlated with systemic anticommensal IgG response, which acts as "second line of defense" [86,87].

The importance of the IgA was raised again because of the ongoing global pandemic of coronavirus disease 2019 (COVID-19). When looking for the reasons for the varied course of the disease, questions arose on whether deficiency of IgA could be the reason for disease severity, vaccine failure, and prolonged viral shedding [88]. As mentioned above, the prevalence of sIgAD differs in various countries and the same was found for COVID-19. Naito et al. compared the number of cases of COVID-19 with the prevalence of selective IgA deficiency in different countries [89]. They found "a strong positive correlation between the frequency of sIgAD and the COVID-19 infection rate per population". It was then concluded that one of the factors contributing to the low death rate from COVID-19 infection in Japan could be the low incidence of sIgAD in the country. As primary immunodeficiencies are a group of rare diseases, there is little data on the coexistence of sIgAD and COVID-19 infection. Nevertheless, literature data showing an extremely significant effect of class A immunoglobulins on early protection against SARS-CoV-2 virus also suggest a potentially more severe/complicated course of the disease [88,90]. This thesis is supported by the aforementioned literature data: a positive correlation between a high number of COVID-19 infections and a high incidence of sIgAD has been demonstrated, and an inverse relationship was observed in the extreme example of Japan [88]. In Israel, during two "so-called" waves, 20 patients with PID were affected by COVID-19 and none of them was diagnosed with sIgAD [91]; importantly, the relationship between the development of autoimmune diseases in the course of COVID-19 in patients with sIgAD—AIHA and Guillain-Baree syndrome [92]. Researchers also point to the risk of a poor response against SARS-CoV-2 after immunization in this group of patients [88].

#### *5.3. Autoimmunity*

There is an association between IgA deficiency and a higher prevalence of autoimmune disease [93,94]. Based on extended research in that field, the prevalence of autoimmune disease in this group rises to 31.7% [95]. According to Azizi et al. the median age of the onset of the first episode of autoimmunity was 7 [95]. Among diseases with higher prevalence in sIgAD subjects, we differentiate systemic lupus erythematosus, hypo- and hyperthyroidism, type 1 diabetes mellitus, Crohn's disease, ulcerative colitis, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, and vitiligo. Whereas other diseases like scleroderma, celiac disease, autoimmune hepatitis, immune thrombocytopenic purpura, and autoimmune hemolytic anemia, occur less often but still with higher prevalence than in the general population [96].

The mechanism of autoimmunity in sIgAD is still not fully understood. There are six hypotheses that try to explain these phenomena, each based on a different mode of autoimmunity, such as human leukocyte antigen, cytogenic, monogenic, molecular mimicry, lingering inflammation and immune complexes, dysregulation of molecular pathways [96]. Some studies suggest that various mechanisms are likely to play concurrently. It has been found that there is also a higher incidence of autoimmunity in first-degree relatives of sIgAD patients [97].

In a recent case reported by Pfeuffer et al., authors stated that the presence of other acute diseases could induce autoimmunity in SIgAD patients [98]. In their case, it was Guillain-Barré syndrome induced by COVID-19.

#### *5.4. Allergy*

Allergy has long been a component of immune deficiency; however, allergic burden differs in different types of immunological disorders. Both PID and allergy are associated with impaired reactions of the immune system. In the case of PID, malfunctioning of some of its components will lead to infectious susceptibility. Atopy, on the other hand, is a hypersensitivity reaction of the immune system and a form of misdirected immunity.

The true prevalence of allergy among patients with sIgAD is still under debate since studies from different countries present inconsistent results. Therefore, it suggests that the prevalence varies depending on the ethnic background. There is even controversy in the scientific world whether the coexistence of IgA deficiency and allergic diseases is, in fact, true. Most publications support the relationship between sIgAD or low-IgA levels and allergic diseases [10,99–103], but some researchers deny it [104,105]. This connection has been the subject of medical research for over 50 years. In 1975, Buckley suggested that about half of the patients with sIgAD presented atopic diseases and related findings have been published later by Kemola [106,107]. A similar observation has been done in Ankara more recently, in 2017, where 45.7% of the patients diagnosed with sIgAD presented one of the following: asthma, rhinitis, eczema, atopic dermatitis, and interestingly the prevalence of allergy in a close family of this patients rose up to 43.2% [101]. Aghamohammadi, in his study on Iranian patients, revealed that allergy was observed in 84% of patients with sIgAD [10]. In a study from China, 17.6% of patients had allergic symptoms, however, most of them were allergic reactions to drugs (mostly penicillin) [108]. These results were inconsistent with typical allergies reported in other countries, such as asthma, rhinitis, food allergy, and atopic dermatitis [108]. On the other hand, there is a study with a prevalence of allergy in children with sIgAD on the percentage of 13% [70].

Many clinicians point out the frequent coexistence of IgA deficiency with bronchial asthma, allergic rhinitis, and atopic dermatitis in everyday practice but it is unclear whether it is the immunoglobulin A deficiency that promotes an allergic reaction, or the allergic reaction weakening the mucous membranes and consequently leading to a secondary IgA deficiency. There are plenty of possible explanations of this phenomenon. The connection between IgA deficiency and allergies may be caused by increased levels of circulating antigens, due to increased permeability at mucosal surfaces. It could also be a result of the inability to induce ITAMi signaling, due to decreased level of monomeric serum IgA, which, consequently, causes overactivation of the immunological system [79,109]. Another hypothesized mechanism is the deficiency of TGF-beta response. TGF-beta has properties to induce IgA synthesis, as well as inhibiting proliferation of Th2-cells. Th2-response is involved in the pathogenesis of atopic diseases [110–112]. Interestingly, there are allergenspecific A immunoglobulins, but their role in the pathogenesis of allergic diseases is unclear [113]. We do not know whether they are responsible for exacerbation or silencing the symptoms, but what we know is that they are observed in healthy people without allergic symptoms and low or undetectable IgE-levels [114,115]. Moreover, children with a tendency to allergic diseases have a more pronounced physiological IgA deficiency in the neonatal period and the lower these concentrations are, the greater is the severity of symptoms (although they usually remain within the reference values for age).

The American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) developed practice parameters to guide the management of primary immunodeficiencies [116]. It is stated there that atopic diseases should be treated aggressively in patients with sIgAD. Since allergic inflammation facilitates the development of respiratory tract infections, it is crucial to treat allergy using all standard modalities, like avoidance of allergens, medication, and immunotherapy [116]. Our clinical experience shows that treating atopic diseases in patients with immunodeficiency is difficult and requires special attention and scrupulousness. In addition to the commonly used anti-histamine drugs, beta-mimetics, and glucocorticosteroids, in the case of treatment-resistant atopic diseases, biological drugs such as omalizumab and dupilumab might be helpful. Omalizumab is an anti-IgE antibody that is FDA approved for the treatment of moderate to severe allergic asthma, while dupilumab is an IL-4 receptor blocking antibody and is FDA approved for the treatment of moderate to severe atopic dermatitis in patients with the refractory disease [117–119]. The use of omalizumab in a young adult patient diagnosed with CVID, who suffered from chronic spontaneous urticaria, and did not respond either to an immunoglobulin substitution in immunomodulatory doses, anti-H1 and anti-H2 antihistamines, as well as leukotriene receptor antagonists, has been described. Only the inclusion of omalizumab resulted in a significant improvement in the condition of the skin and quality of life [120]. However, data suggest that such treatment could carry a risk of possible side effects—Banh et al. described a case of a 24-year-old patient diagnosed with asthma and CVID, where treatment with omalizumab might have increased the level of white blood cells and elevated myeloid cell count. Serious disorders, e.g., malignancy or severe infections were excluded. Importantly blood test results returned to normal levels shortly after drug discontinuation [121]. The use of dupilumab has been described in the context of a patient with CVID suffering from severe skin lesions such as erythematoussquamous and generalized infiltrated rash with exacerbation in sun-exposed zones and severe recurrent infections, in whom no improvement in skin condition was observed after treatment with glucocorticoids or cyclosporine. The introduction of dupilumab resulted in a reduction in the severity of skin lesions and the addition of IgG replacement therapy lowered the frequency of infections [122]. In our opinion, based on experience from other immunodeficiencies with predominantly antibody deficiency, it is possible to use the above-mentioned monoclonal antibodies in the treatment of severe allergic complications in patients with SIgAD.
