Q:

4/25/2013
I have a patient, 40 yo M, IgE total 150-200 with normal Eosinophils; Chronic rhinosinusitis, recently with removal of a pyogenic granuloma from his frontal sinus, no asthma, non atopic per skin testing, intradermals and sIGE serology. I read the chapter on IgE in Middleton's and did a search on the Ask the Expert site here, but many of the references are not showing up. Most of the entries here have to do with eosinophilia and elevated total IgE combined, not without eosinophilia. Can it be insignificant and to be ignored? Thank you.

A:

Thank you for your inquiry.

As you know, I have sent you, in response to a previous inquiry regarding this patient, copies of entries from our website. We usually only keep the most recent three years posted on the website.

However, I think more germane to your patient are the references noted below.

The most reasonable explanation for your patient’s elevated IgE is probably, according to the work of Bachert, et al., due to IgE anti-staphylococcal antigens. The references copied below will discuss this issue in detail and also give you suggestions for therapy.

Like intrinsic or nonallergic asthma, some patients with chronic rhinosinusitis who are not atopic exhibit elevated IgE levels. There may be multiple reasons for this, but the one which appears to be most prominent is the tendency for such patients to develop specific IgE against staphylococcal antigens as discussed in the references copied below.

Thank you again for your inquiry and we hope this information is helpful to you.

J Intern Med. 2012 Aug;272(2):133-43. doi: 10.1111/j.1365-2796.2012.02559.x.
Chronic rhinosinusitis and asthma: novel understanding of the role of IgE 'above atopy'.
Bachert C, Zhang N.
Source
Upper Airway Research Laboratory, Department of Oto-Rhino-Laryngology, Ghent University Hospital, Ghent, Belgium.
Abstract
Chronic rhinosinusitis (CRS) affects more than 10% of the European population and is often associated with asthma. Phenotypes of CRS can be differentiated based on mucosal remodelling and inflammatory patterns. Understanding the role of central mediators, such as interleukin-5, in these different phenotypes may lead to the development of specific therapeutic approaches. The impact of staphylococcal superantigens has been shown to further modify the immune response, contributing to persistent severe disease via the activation of T and B cells and the formation of local IgE. It is clear that these mechanisms are involved in the systemic spread of upper airway disease with resulting asthma comorbidity, when IgE antibodies to staphylococcal enterotoxins are present at measurable levels in serum. Recent findings point to superantigens as possible causal agents in the intrinsic form of severe asthma, and an anti-IgE strategy has shown promising therapeutic potential in nonatopic patients with nasal polyps and asthma. These findings should lead to a clinically relevant endotyping of patients with upper and lower airway disease and to a new understanding of the role of IgE 'above atopy'.

Role of staphylococcal superantigens in upper airway disease.
Bachert C, Zhang N, Patou J, van Zele T, Gevaert P.
Source
Upper Airway Research Laboratory, Ear Nose and Throat Department, University Hospital Ghent, Ghent, Belgium.
Abstract
Purpose of Review: Chronic rhinosinusitis with nasal polyps often represents a chronic severe inflammatory disease of the upper airways and may serve as a model for lower airway diseases such as late-onset intrinsic asthma. Enterotoxins derived from Staphylococcus aureus have been implicated in the pathophysiology of nasal polyps as disease-modifying factors; recent findings using therapeutic proof-of-concept approaches support this hypothesis.
Recent Findings: Nasal polyps (chronic rhinosinusitis with nasal polyps) are characterized by a T-helper-2 dominated cytokine pattern that includes interleukin-5 and formation of immunoglobulin E. This is in contrast to chronic rhinosinusitis without polyps, which exhibits T-helper-1 biased cytokine release. It is now evident that the cytokine environment is decisive regarding the impact of S. aureus derived enterotoxins, which function as superantigens. S. aureus enterotoxin B further shifts the cytokine pattern in nasal polyps toward T-helper-2 cytokines (increases greater than twofold for interleukin-2, interleukin-4 and interleukin-5), but it disfavours the T-regulatory cytokines interleukin-10 and transforming growth factor-beta1. Furthermore, S. aureus derived enterotoxins influence local immunoglobulin synthesis and induce polyclonal immunoglobulin E production, which may contribute to severe inflammation via activation of mast cells.
Summary: From this new understanding of chronic rhinosinusitis with nasal polyps, new therapeutic approaches emerge such as anti-interleukin-5, anti-immunoglobulin E, and antibiotic treatment. These may enlarge the nonsurgical armentarium.

J Allergy Clin Immunol. 2013 Apr 12. pii: S0091-6749(13)00367-9. doi: 10.1016/j.jaci.2013.02.036. [Epub ahead of print]
Endotypes and phenotypes of chronic rhinosinusitis: A PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology.
Akdis CA, Bachert C, Cingi C, Dykewicz MS, Hellings PW, Naclerio RM, Schleimer RP, Ledford D.
Source
Swiss Institute of Allergy and Asthma Research, University of Zurich, Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland.
Abstract
Chronic rhinosinusitis (CRS) is a complex disease consisting of several disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of CRS and improving treatment. It is generally agreed that there are clinically relevant CRS phenotypes defined by an observable characteristic or trait, such as the presence or absence of nasal polyps. Defining the phenotype of the patient is useful in making therapeutic decisions. However, clinical phenotypes do not provide full insight into all underlying cellular and molecular pathophysiologic mechanisms of CRS. Recognition of the heterogeneity of CRS has promoted the concept that CRS consists of multiple groups of biological subtypes, or "endotypes," which are defined by distinct pathophysiologic mechanisms that might be identified by corresponding biomarkers. Different CRS endotypes can be characterized by differences in responsiveness to different treatments, including topical intranasal corticosteroids and biological agents, such as anti-IL-5 and anti-IgE mAb, and can be based on different biomarkers that are linked to underlying mechanisms. CRS has been regarded as a single disease entity in clinical and genetic studies in the past, which can explain the failure to identify consistent genetic and environmental correlations. In addition, better identification of endotypes might permit individualization of therapy that can be targeted against the pathophysiologic processes of a patient's endotype, with potential for more effective treatment and better patient outcomes.

J Allergy Clin Immunol. 2012 Aug;130(2):376-81.e8. doi: 10.1016/j.jaci.2012.05.012. Epub 2012 Jun 26.
Specific IgE against Staphylococcus aureus enterotoxins: an independent risk factor for asthma.
Bachert C, van Steen K, Zhang N, Holtappels G, Cattaert T, Maus B, Buhl R, Taube C, Korn S, Kowalski M, Bousquet J, Howarth P.
Source
Upper Airway Research Laboratory (URL), Ghent University Hospital, Ghent, Belgium.
Abstract
Background: The role of IgE in patients with severe asthma is not fully understood.
Objective: We sought to investigate whether IgE to Staphylococcus aureus enterotoxins might be relevant to disease severity in adult asthmatic patients.
Methods: Specific IgE antibody concentrations in serum against enterotoxins, grass pollen (GP), and house dust mite allergens and total IgE levels were measured in adult cohorts of 69 control subjects, 152 patients with nonsevere asthma, and 166 patients with severe asthma. Severe asthma was defined as inadequately controlled disease despite high-dose inhaled corticosteroids plus at least 2 other controller therapies, including oral steroids.
Results: Enterotoxin IgE positivity was significantly greater in patients with severe asthma (59.6%) than in healthy control subjects (13%, P< .001). Twenty-one percent of patients with severe asthma with enterotoxin IgE were considered nonatopic. Logistic regression analyses demonstrated significantly increased risks for enterotoxin IgE-positive subjects to have any asthma (OR, 7.25; 95% CI, 2.7-19.1) or severe asthma (OR, 11.09; 95% CI, 4.1-29.6) versus enterotoxin IgE-negative subjects. The presence of GP or house dust mite IgE antibodies was not associated with either significantly increased risk for asthma or severity. Oral steroid use and hospitalizations were significantly increased in patients with enterotoxin IgE and nonatopic asthma. GP IgE was associated with a higher FEV(1) percent predicted value, and enterotoxin IgE was associated with a lower FEV(1) percent predicted value.
Conclusions: Staphylococcal enterotoxin IgE antibodies, but not IgE against inhalant allergens, are risk factors for asthma severity. We hypothesize that the presence of enterotoxin IgE in serum indicates the involvement of staphylococcal superantigens in the pathophysiology of patients with severe asthma.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology