Clinical significance of isolated IgE deficiency

INTRODUCTION AND DEFINITION — Selective immunoglobulin (Ig)E deficiency is defined as a significant decrease in the levels of IgE (<2.5 international units/mL) in a patient whose other immunoglobulin levels, including IgG, IgG subclasses, and IgA levels, are normal. It is a laboratory finding that does not necessarily equate to a clinical disorder, and selective IgE deficiency has not been included in international classification systems for primary immunodeficiency diseases [1].

This topic review will present the information available about this subject.

●The normal production of IgE and the disorders associated with elevated IgE levels are discussed separately. (See "The biology of IgE" and "The adaptive humoral immune response".)

●The role of IgE in the pathogenesis of allergic disease has been extensively studied and is reviewed elsewhere. (See "The relationship between IgE and allergic disease".)

●Anti-IgE therapy for the treatment of asthma and allergic disease is discussed elsewhere. Of note, anti-IgE therapy reduces serum levels of free IgE but elevates serum levels of total IgE, so it induces a state that is distinct from IgE deficiency [2]. (See "Anti-IgE therapy".)

MEASUREMENT OF IgE — Accurate IgE levels may be obtained with the type of testing routinely performed by commercial laboratories. This usually involves a paper radioimmunosorbent test (PRIST) to measure total serum IgE. The detection range of this test is 0.5 to 800 kU/L. A level below 2.5 kU/L is considered deficient.

PREVALENCE — The prevalence of isolated IgE deficiency depends upon the population under study. The authors measured serum IgE levels in 500 blood donors, 974 allergy/immunology clinic patients, and 155 rheumatology clinic patients and found deficient levels in 2.6, 8.1, and 9.7 percent, respectively [3]. IgE deficiency was selective (ie, other immunoglobulin classes were normal) in 0.8, 3.1, and 1.3 percent, respectively, of these cohorts. Associated immunoglobulin deficiencies varied among the three populations (table 1) [3]. Three additional studies involving a total of 8280 patients found isolated IgE deficiencies in 2.4 percent of subjects (range 1 to 2.6 percent) [4-6].

PATHOGENESIS — The pathogenesis of a selectively low level of IgE deficiency is unclear. Defects in immunoglobulin class-switching have not been conclusively demonstrated [4].

ASSOCIATED DISORDERS — Information on disorders possibly associated with selective IgE deficiency is based upon a small number of studies, including a case-control study of 226 children and adults in a health care system and a retrospective review of 44 patients referred to the authors' allergy/immunology practice [3,7]. IgE deficiency may be associated with increased susceptibility to certain infections, sinopulmonary disease, nonallergic airway disease, immunodeficiency, autoimmunity, and malignancy.

Infections — There is some evidence that IgE antibodies play a protective role against viral and parasitic infections in humans [3,7-17]. However, due in part to the redundancy of the immune system, low or absent levels of IgE do not predispose people to severe parasitic infections [18]. IgE does not participate in the opsonization of bacteria, but it may play a role in mucosal defense against bacterial infections in other ways. IgE is predominantly a mucosal immunoglobulin. A potential association between IgE deficiency and increased sinopulmonary infections was noted in the two largest studies:

●In the authors' study, patients with selective IgE deficiency sought medical advice in the allergy/immunology clinic because of persistent sinopulmonary symptoms that were assumed by the patients to be allergic in origin, but sensitization to allergens was not found [3]. There was an increased prevalence of infections with common bacteria, including Streptococcus pneumoniae, Hemophilus influenzae, and Moraxella catarrhalis. A similar association was found in a study of 130 patients with isolated IgE deficiency [6].

●In children, IgE antibodies have been shown to provide some protection against Lyme disease (Borrelia burgdorferi infection), which persists throughout adulthood [11]. The prevalence of gastric infection with Helicobacter pylori has been reported to be significantly higher in dyspeptic patients with selective IgE deficiency as compared with dyspeptic patients with normal IgE levels [17].

Sinopulmonary disease — Several reports have documented a higher incidence of rhinitis, rhinosinusitis, and/or bronchitis in patients with selective IgE deficiency [3,7,14,15]. However, other groups have not found this association [16].

In the large case-control study of 226 patients with selective IgE deficiency mentioned earlier, there was a significantly higher prevalence of chronic rhinosinusitis and otitis media in both children and adults when compared with age-matched controls [7]. In the same cohort, the prevalence of gastric infection with H. pylori was significantly higher in dyspeptic patients with selective IgE deficiency (<2 kIU/mL) compared with dyspeptic patients with normal IgE levels [17].

Nonallergic airway disease — The authors reported a higher prevalence of nonallergic reactive airway disease in patients with selective IgE deficiency (<2.5 kIU/mL) compared with age- and sex-matched controls [3]. Other groups reported similar findings (<2 kIU/mL) [7].

The possibility that IgE may play a role in the regulation of the respiratory immune response is suggested by several studies in experimental animal models. Mice that are deficient in lymphotoxin alpha (LTalpha -/- mice) also exhibit diminished levels of IgE and reduced allergic airway responsiveness to both environmental and induced antigen challenge [19]. These mice develop inflammatory airway disease that is nonallergic and noninfectious and mediated by T helper type 1 (Th1) cells. The lung inflammation is alleviated by reconstitution of IgE. Furthermore, depletion of IgE in wild-type mice duplicates the lung pathologies of the LTalpha -/- mice and is also reversed by the administration of IgE.

These findings are consistent with the theory that the presence of subnormal levels of IgE impairs the ability of mast cells to respond normally to airway antigens and consequently, to produce cytokines that favor T helper type 2 (Th2) development (interleukin [IL]-4, IL-13). As a result, Th1 responses to the uncleared antigens predominate and lead to pathology.

Rather than merely priming mast cells to respond to specific antigens, IgE (in the absence of cross-linking antigens) may promote survival, receptor expression, and mediator release of mast cells and promote a healthy balance between Th1 and Th2 processes responses [20-24].

Immunodeficiencies — Low serum levels of IgE can accompany several well-defined immunodeficiency diseases, including common variable immunodeficiency (CVID), IgG subclass deficiencies, selective IgA deficiency, ataxia-telangiectasia, and agammaglobulinemia [3,25,26]. Most patients with CVID have very low levels of IgE, but the diagnosis also requires low IgG, plus low IgA or IgM. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults", section on 'Immunoglobulin levels' and "IgG subclass deficiency" and "Ataxia-telangiectasia".)

Autoimmune disease — There is an increased prevalence of autoimmune disease in persons with certain immunoglobulin deficiencies, particularly those with IgA deficiency, and the two largest studies of patients with selective IgE deficiency found a similar association [3,7]. Several other reports have documented a similar association of selective IgE deficiency and autoimmunity [6,17].

There are a number of potential mechanisms that could explain this finding [27-33]. Because IgE is predominantly a mucosal immunoglobulin, it may protect against autoimmunization by preventing the systemic absorption of mucosal antigens, similar to the proposed function of IgA [34]. Defective antigen exclusion at the mucosal barrier could allow exogenous antigens to induce autoimmune responses by:

●Stimulating autoreactive lymphocytes through molecular mimicry [27]

●Promoting immune complex formation [28]

●Super antigen-induced polyclonal activation of lymphocytes [29]

●Inducing a perturbation of the idiotypic network [30]

●Aberrant induction of major histocompatibility complex class II antigens [31]

If IgE promotes mast cell survival, receptor expression, and mediator release, it may also facilitate immune responses [20]. It is possible that IgE deficiency predisposes to autoimmunity by adversely effecting mast cell survival and function. In a mouse model, mast cells were shown to be essential intermediaries in regulatory T cell (Treg)-induced allograft tolerance [32].

Alternative hypotheses include:

●Common genetic factors predispose to both IgE deficiency and autoimmune disease.

●Low levels of IgE merely reflect an imbalance between Th1 and Th2 lymphocyte activity that, in turn, favors the development of Th1-mediated autoimmune diseases [32].

Antitumor activity — IgE has been shown to possess antitumor properties in vitro [35,36] and in experimental mice [37-40]. IgE has been shown to play an active role in tumor immunosurveillance in mice [41] and to induce human colon cancer cell apoptosis in vitro by enhancing cyp27b1 expression [42].

A large survey cohort study found that the incidence of prior malignancy was higher in persons with selective IgE deficiency as compared with those with normal IgE levels [43]. A similar observation was made in patients with CVID, with and without IgE deficiency [5]. The same researchers performed a longitudinal cohort study of 42 patients with IgE deficiency (one of whom had CVID), who were matched to patients with normal, high, or very high (≥1000 kIU/mL) IgE levels and prospectively followed for a median of 44 months [44]. The rate of newly diagnosed malignancy was significantly higher in the IgE-deficient group compared with patients without IgE deficiency (all other groups combined) (17.6 versus 3.8 percent) (odds ratio [OR] 5.4, 95% CI 1.3-22.9), although not when only compared to patients with normal levels. The types of malignancies included both hematologic and solid tumors. Although these data are not sufficient to understand any relationships that underlie an association with possible increased malignancy risk, potential explanations include that IgE itself has antitumor activity in humans, that IgE is being sequestered by malignant tissue, or that low IgE is an epiphenomenon of immune dysregulation. Larger prospective studies including longer periods of observation are needed.

Until more information is available, patients with isolated IgE deficiency should be advised to stay current with routine health maintenance, adhere to recommendations for exercise, diet, and weight control, stop smoking, and obtain age- and sex-appropriate cancer screening tests. (See "Overview of preventive care in adults", section on 'Cancer prevention' and "Overview of preventive care in adults", section on 'Cancer screening'.)

ASSOCIATED CLINICAL AND LABORATORY FEATURES — Most patients are identified when immunoglobulin analysis includes an IgE determination. Abnormally high or low levels should be verified by repeat testing. No further work-up is available or necessary to define a low IgE level. As noted above:

●IgE deficiency has been associated with other immunodeficiencies, rhinosinusitis, other respiratory ailments, and autoimmune disease. These should be evaluated as needed.

●In the authors' allergy/immunology clinic, the majority of 30 patients with selective IgE deficiency sought medical advice because of persistent sinopulmonary symptoms that were assumed by the patients to be allergic in origin but were found on skin or radioallergosorbent testing (RAST) to be nonallergic in origin [3]. Airway symptoms included sinus pain and congestion, nasal congestion and rhinorrhea, persistent or intermittent cough, and wheezing. Sinopulmonary infections, documented by culture, were more prevalent in patients with selective IgE deficiency than in those with normal IgE levels. These infections were less severe than those occurring in patients with IgE coupled with other immunoglobulin deficiencies.

●Data on vaccine responses in patients with selective IgE deficiency are lacking.

●In addition to nonallergic reactive airway disease, IgE-deficient patients were more likely to have one or more autoimmune diseases and to complain of arthralgias, chronic fatigue, and symptoms suggestive of airway infection (purulent sputum and/or nasal discharge) when compared to a sex- and age-matched control group from the same clinic with normal levels of IgE.

SUMMARY AND RECOMMENDATIONS

●Selective immunoglobulin (Ig)E deficiency is defined as a significant decrease in the levels of IgE (<2.5 international units/mL) in a patient whose other immunoglobulin levels, including IgA, IgG, and IgG subclasses, are normal. It is a laboratory finding that has not been demonstrated to equate to a clinical disorder, and selective IgE deficiency is not considered to be a primary immunodeficiency. (See 'Introduction and definition' above.)

●The prevalence of selective IgE deficiency is highly dependent on the population under study and can range from as low as 0.8 percent in blood donors to as high as 3.1 percent in rheumatology patients, with an overall prevalence of 2.4 percent. IgE deficiency can occur in isolation or in combination with other immunoglobulin deficiencies. (See 'Prevalence' above.)

●IgE-deficient patients can present with symptoms of reactive airway disease (rhinosinusitis, bronchitis, asthma), sinopulmonary infection, chronic fatigue, arthralgias, and serologic or clinical evidence of autoimmune disease. An association between very low serum IgE and malignancy has been noted in some studies. (See 'Associated disorders' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.