**1. Introduction**

A recently updated classification distributes innate errors of immunity into 10 groups, one of which is considered to be due to "antibody deficiencies" (Group 3) [1,2].

Immunoglobulins A (IgA), M (IgM), and G (IgG) are central in the humoral immune response and play a fundamental role in protecting against infections caused by all kinds of agents (viruses, bacteria, protozoa, parasites), and they represent the defense mediated by antibodies, which are part of the so-called acquired immunity [3].

Immunoglobulin E (IgE) has been conventionally related to the immune response against helminth infection, and its levels are particularly high in patients who suffer from a parasitic infestation [4]. IgE is also involved in type I hypersensitivity allergic reactions, which are diseases where it is also common to find high levels of specific IgE against allergens. Most IgE is found bound to its high-affinity receptor FcRI located on the surface of mast cells and basophils. The binding of the allergen to the specific IgE/FcRI complex triggers the degranulation of mast cells and basophils that release numerous substances (vasoactive, bronchoconstrictors, interleukins), which are ultimately responsible for the clinical manifestations of the allergic response (rhinitis, asthma, urticaria, angioedema, anaphylaxis) [5].

Various types of immunodeficiencies associated with low levels of one or a combination of IgA, IgG, and IgM immunoglobulins are recognized. [1,2]. The most studied combined form is known as "common variable immunodeficiency" (CVID), which is a disorder characterized by reduced serum levels of IgG, which can be combined with a reduction of IgA or IgM, or both, which is associated with recurrent sinopulmonary infections, autoimmune disorders, granulomatous diseases, and increased risk of malignancy and altered response of antibodies against infections [6,7].

Selective IgG deficiency (SIgGD) encompasses any subject with a serum IgG level below normal range with normal IgA and IgM levels. Studies comparing the SigGD and CVID patients found that the CVID group was more likely to have bronchiectasis, poorer responses to vaccines, and a higher incidence of autoimmune cytopenias, granulomas, splenomegaly, and lymphoid neoplasms than those with SigGD [8].

IgG subclass deficiency (IgGSD) is a heterogeneous subtype of primary immunodeficiency, which is defined as the triad of frequent or severe respiratory tract infections, subnormal levels of one or more of the four IgG subclasses, and decreased IgG response to pneumococcal polysaccharides. Many adults with IgGSD also have autoimmune conditions or atopy [9,10].

Selective IgA deficiency (SIgAD) [11,12], and selective IgM (SIgMD) [13,14] are diagnosed in a diverse group of patients, ranging from completely asymptomatic individuals to people with recurrent infections, allergic diseases, autoimmune processes, and malignant tumors.

The question is: are there any similar diseases associated with selective IgE deficiency (SIgED)? Conventionally, normal serum IgE values are considered to range between the technical detection limit (≤2 kU/L) and up to 100 kU/L. An excess of IgE (>100 kU/L) can be established but, in contrast to the other immunoglobulins, there is no generally accepted minimum level to establish an IgE deficiency. In various studies in the literature, different cut-off points have been used to define IgE deficiency [15–19]. Most clinicians do not attribute any pathological significance to very low IgE values, even those that are unquantifiable (≤2 kU/L), which are usually considered as "normal".

Low IgE is frequently associated with deficiencies in other immunoglobulins, particularly in patients with CVID [20–22]. Based on this observation, the use of routine IgE measurement has been proposed as the first step to detect the presence of CVID [21,22].

In the classification of primary immunodeficiencies attributed to antibody deficiency, the presence of low IgE values is mentioned, but it is always associated with deficiencies in some of the other immunoglobulins [1,2]. The possibility of an immunodeficiency associated only with an SIgED is not considered in the classification. However, a few

studies have reported that an SIgED may be the biomarker of an immunodeficiency with a significant clinical impact that has been overlooked until now [23–26].

The studies analyzing the potential role of SIgED are retrospective and include a limited number of cases. Furthermore, most of the patients included in these studies were selected from allergy units [23,26] or were patients having any allergy-related symptoms and/or requesting antiallergy medications [25], which is a bias that could have limited the spectrum of diseases found associated with SIgED. Despite these limitations, it is worth noting that these studies show that individuals with a low level of IgE, with normal values for the other immunoglobulins, present recurrent respiratory infections, suffer from autoimmune diseases, and upper and lower airway diseases [23–26], similar to those described in patients with CVID [6–8], IgGSD [9] or with SIgGD [8], SIgAD [11,12], and SIgM D [13,14].

The predisposition to develop neoplasms in patients with antibody deficiency, either in combination or due to selective deficits of IgA or IgM, is widely documented [27]. In the same way, the scientific information supports that IgE deficiency is a predisposing factor for the development of malignancies [28].

The hypothesis of this study establishes that isolated IgE deficiency is associated with diseases similar to that described in other antibody deficiencies, but its clinical spectrum has been underestimated.

This study is the first to research the effects of SIgED in the entire population in a hospital setting with a 2-year follow up and sought to delineate in detail the clinical aspects of SIgED.
