Q:

2/4/2013
Hello, I have a 48 y/o woman who I, and the pulmonologist, are having difficulty controlling her asthma and urticaria. She has a h/o allergic rhinosinusitis in the spring since childhood who developed new onset asthma in June of 2011 with eosinophilia. She was treated with 3 courses of ABX but her asthma symptoms persist. She has documented diffuse insp/exp wheezing with obstructive spirometry which completely reverses with albuterol, DLCO is normal.
CBCD is normal except Eo's = 1400 (25%)
Total IgE is elevated at 388.
Bone Marrow bx= increased Eo's at 16% but otherwise normal
FISH normal
Normal values for IgG/A/M, LFT's, CMP, SPEP, UPEP,
stool O+P, ANA, hypersensitivity pneumonitis panel, ESR, Strongyloides titers
Skin testing was only positive to walnut and house dust, foods were also negative.
The hematologist thinks the cause of eosinophilia is her asthma and recommends starting prednisone 1mg/kg if her Eo count rises more than 5000. Currently, her asthma is not controlled with Symbicort 160/4.5 2p bid, Singulair and Zyflo failed. Not surprisingly, the only med that works is prednisone. I plan to try Xolair.

My questions are:
1. Do you agree with a trial of Xolair?
2. Do you agree her asthma is the cause of eosinophilia? I was under the impression her eosinophilia was the cause of her asthma.
3. Do you recommend an alternative med to prednisone to decrease the Eo's? She gains excessive wt with prednisone.
4. Would you wait until her Eo's reach 500 before starting long term prednisone?
5. Do you have any other ideas?

A:

Thank you for your inquiry.

First, I would like to mention for you other entries that have been posted on our Ask the Expert website which have dealt with similar questions - that is, patients presenting with recalcitrant asthma and hypereosinophilia, even in the absence of marked atopy as evidenced by the absence of multiple skin test reactivity.

These entries can be accessed by going to the Ask the Expert section of the website and typing “recalcitrant asthma” in the search box. Then do a separate search using eosinophilia as the search word.

The etiology of this type of asthma is unknown, but there are several theories as to its pathogenesis.

You have done due diligence in evaluating this patient, but I would suggest that you consider one more additional diagnosis - Churg-Strauss syndrome. I would therefore order antineutrophil cytoplasmic antibodies.

In any recalcitrant asthmatic, as you know, you should also consider the presence of sinus disease, and therefore a sinus CT might be indicated, and esophageal reflux.

Having said this, I will try and deal with your questions separately:

1. Do you agree with a trial of Xolair?

Yes. As you can see from the abstract copied below, Xolair has been reported to be effective in both nonallergic and allergic asthmatics. Your patient, although having a single positive skin test, is more than likely a nonallergic or “intrinsic” asthmatic. The article abstracted below postulates that there may be local IgE synthesis in the respiratory tract. Another explanation for this phenomenon is the presence of IgE anti-staphylococcal antigens in patients with asthma (J Allergy Clin Immunol 2012; 130:376-381).

Even patients with nondetectable significant allergy on skin testing could have an IgE-mediated response in part responsible for their symptoms. Thus, I feel a trial of Xolair is warranted.

2. Do you agree her asthma is the cause of eosinophilia?

Yes. Many such patients have been reported in the literature, and my own experience over the last four decades has resulted in a number of encounters with patients fitting this description.

3. Do you recommend an alternative med to pred to decrease the Eo's?

There are a number of alternative medications and procedures that have been used in prednisone-dependent asthma. A list of these is copied below. There are conflicting reports as to the efficacy of each one of these, but clearly there are case reports of patients having responded to each. If omalizumab was not helpful in your patient, then you could certainly consider the initiation of one of these alternative therapies, and perhaps the first choice would be tacrolimus. And she would be an ideal candidate fior anti-IL5 if it becomes available.

A. Methotrexate
B. Cyclosporin or tacrolimus
C. Gold
D. Hydroxychloroquine
E. High dose immunoglobulin replacement
F. Bronchial thermoplasty
G. Anti-TNF alpha
H. Anti-IL6
I. Anti-IL13
J. Aspirin desensitization if your patient has aspirin sensitivity

4. Would you wait until her Eo's reach 500 before starting long term pred?

My personal preference would be to use prednisone, not according to her eosinophil count, but according to her symptoms. The hematologist certainly has a reasonable rationale for treating eosinophilia since we know that sustained levels (greater than 1,500 per cubic mm over prolonged periods of time) can damage tissues (described in patients with primary hypereosinophilic syndrome). But, at least in my experience, asthmatics with the hypereosinophilic phenotype have not personally encountered any tissue damage from the eosinophilia with the possible exception of the lung which can undergo “remodeling”. However, I would deal with that possibility as best you can with topical inhaled steroids, and adjust the systemic steroids based upon her asthma and not the eosinophil level.

5. Do you have any other ideas?

I do not have any significant additions to the above comments, but some patients with this syndrome have been found to benefit by the addition of a small particle inhaled corticosteroid to the combination inhaled steroid and long-acting bronchodilator preparation they have been using (see abstract copied below).

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

J Allergy Clin Immunol. 2013 Jan;131(1):110-116.e1. doi: 10.1016/j.jaci.2012.07.047. Epub 2012 Sep 27.
Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma.
Gevaert P, Calus L, Van Zele T, Blomme K, De Ruyck N, Bauters W, Hellings P, Brusselle G, De Bacquer D, van Cauwenberge P, Bachert C.
Source
Upper Airways Research Laboratory, Department of Otorhinolaryngology, Ghent University Hospital, Ghent, Belgium.
Abstract
Background: Adult patients with nasal polyps often have comorbid asthma, adding to the serious effect on the quality of life of these patients. Nasal polyps and asthma might represent a therapeutic challenge; inflammation in both diseases shares many features, such as airway eosinophilia, local IgE formation, and a T(H)2 cytokine profile. Omalizumab is a human anti-IgE mAb with proved efficacy in patients with severe allergic asthma. Omalizumab could be a treatment option for patients with nasal polyps and asthma.
Objective: The goal of this study was to investigate the clinical efficacy of omalizumab in patients with nasal polyps and comorbid asthma.
Methods: A randomized, double-blind, placebo-controlled study of allergic and nonallergic patients with nasal polyps and comorbid asthma (n = 24) was conducted. Subjects received 4 to 8 (subcutaneous) doses of omalizumab (n = 16) or placebo (n = 8). The primary end point was reduction in total nasal endoscopic polyp scores after 16 weeks. Secondary end points included a change in sinus computed tomographic scans, nasal and asthma symptoms, results of validated questionnaires (Short-Form Health Questionnaire, 31-item Rhinosinusitis Outcome Measuring Instrument, and Asthma Quality of Life Questionnaire), and serum/nasal secretion biomarker levels.
Results: There was a significant decrease in total nasal endoscopic polyp scores after 16 weeks in the omalizumab-treated group (-2.67, P = .001), which was confirmed by means of computed tomographic scanning (Lund-Mackay score). Omalizumab had a beneficial effect on airway symptoms (nasal congestion, anterior rhinorrhea, loss of sense of smell, wheezing, and dyspnea) and on quality-of-life scores, irrespective of the presence of allergy.
Conclusion: Omalizumab demonstrated clinical efficacy in the treatment of nasal polyps with comorbid asthma, supporting the importance and functionality of local IgE formation in the airways.

J Allergy Clin Immunol 2012;130:376-81.
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 FEV1 percent predicted value, and enterotoxin IgE was associated with a lower FEV1 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.

Hydrofluoroalkane-134A Beclomethasone or Chlorofluorocarbon Fluticasone: Effect on Small Airways in Poorly Controlled Asthma
Journal of Asthma 2005, Vol. 42, No. 4 , Pages 257-263
Inflammation in asthma extends into the small airways (< 2 mm diameter). Most inhaled corticosteroids are suspensions with a particle size > 2 mm. Therefore, inflammation in the small airways of patients with asthma may not be adequately treated with these preparations. Some inhaled corticosteroids, on the other hand, are compounded with alcohol, resulting in a solution producing an aerosol that has a mean particle diameter of < 2 mm. This study was designed to compare the addition of equivalent amounts of two inhaled corticosteroids (one a suspension and one a solution) to the treatment of patients with asthma, which was uncontrolled despite treatment with moderate to high doses of inhaled corticosteroids and usually additional controller medications. The study was performed with 30 patients, ≥ 18 years of age. Subjects were randomized in a single-blind fashion to receive, in addition to their current asthma therapy, either CFC-FP 220 µg each morning and 110 µg each evening (n = 10) or HFA-BDP 160 mcg twice daily (n = 20). Pre- and postbronchodilator spirometry, single breath nitrogen washout for closing volume and residual volume by plethysmography were assessed before and after 3 months of therapy. In the subjects who received HFA-BDP, the ratio of closing volume (CV) to vital capacity (VC) and residual volume (RV) decreased significantly (p = 0.0214 and 0.0433, respectively), whereas forced expiratory flow over 25–75% of the vital capacity (FEF25–75%), forced expiratory volume in 1 second (FEV1), and morning peak flow improved significantly (p = 0.0014, 0.0184, and 0.0321). Improvements from baseline of CV, CV/VC, and postbronchodilator FEF25–75%, were statistically significant in the HFA-BDP group compared with the CFC-FP group (p = 0.0049, 0.0194, and 0.0355, respectively). These preliminary findings suggest that the addition of HFA-BDP, compared with CFC-FP in patients with poorly controlled asthma despite receiving moderate to high doses of inhaled steroids, has a greater effect on parameters reflecting small airway patency presumably secondary to reduction in inflammation.

Hydrofluoroalkane-134A Beclomethasone or Chlorofluorocarbon Fluticasone: Effect on Small Airways in Poorly Controlled Asthma

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology