Uncontrolled asthma and Cushing's syndrome: Where does anti-IgE fit in?

Jeffrey Ceresnak, MD

Resident Physician

Department of Internal Medicine

Mary Lee-Wong, MD

Attending Physician

Department of Allergy, Asthma and Immunology

Beth Israel Medical Center

New York, NY

Asthma is a common illness worldwide. Steroids are part of the standard treatment of uncontrolled asthma, but many side effects are associated with frequent use of these drugs, including Cushing's syndrome. Physicians need to be vigilant in monitoring patients for these side effects and should consider alternatives for those with uncontrolled asthma and steroid intolerance. One alternative is omalizumab (Xolair), an anti-immunoglobulin E (anti-IgE) antibody.

We report a case of allergy-induced asthma in a patient who was receiving chronic oral steroid therapy and subsequently developed Cushing's syndrome. The patient became increasingly intolerant to steroid therapy and was weaned from these drugs. Omalizumab treatment was initiated, and her asthma exacerbations and cushingoid features resolved.

CASE PRESENTATION

A 30-year-old woman with a history of asthma, nasal polyps, and environmental allergies to trees, weeds, dogs, cats, dust, cockroaches, and mites presented to our allergy clinic for management of her symptoms. She reported persistent, unrelieved congestion, shortness of breath, and expectoration of clear phlegm. The patient's medical history was significant for asthmatic symptoms for many years, which had resulted in multiple hospitalizations. The patient's social history included infrequent alcohol use and smoking half a pack of cigarettes daily for the past 15 years. Her family history was significant for seasonal allergies and asthma in both parents. Her medications included fluticasone/salmeterol (Advair Diskus) and albuterol (Proventil). She noted that aspirin caused her to develop diffuse hives, but she had never undergone aspirin allergy testing. We advised her to consider this test because the combination of asthma, nasal polyps, and aspirin sensitivity is known as Samter's triad (also referred to as aspirin-exacerbated respiratory disease). Confirmation of an aspirin allergy would allow aspirin desensitization to be considered, which has been shown to improve respiratory symptoms and decrease steroid requirements.¹ A review of systems found no abnormalities, but discussions with the patient revealed the possibility of multiple precipitating factors in her home, including plants, cockroaches, dogs, cats, and birds.

Physical examination revealed a slightly overweight woman with prominent nasal polyps bilaterally. An examination of her chest was normal, and no wheezing or crackles were discernable on auscultation. Chest radiographs revealed no effusions, infiltrates, or abnormalities. The patient was advised to quit smoking and address the environmental precipitating factors in her home. Over the next few months, the patient was given a variety of medications by multiple physicians, including a budesonide inhaler (Pulmicort Respules); levalbuterol (Xopenex); fluticasone/salmeterol; montelukast (Singulair); albuterol; fexofenadine (Allegra); triamcinolone nasal (Nasacort); olopatadine ophthalmic (Patanol); cetirizine (Zyrtec); and prednisone (Deltasone), 10 mg by mouth daily. Despite these medications, she continued to experience asthma exacerbations.

The patient returned to our institution for follow-up 2 weeks after a 10-day hospitalization at another medical center. According to the hospital records, she presented to the emergency department with chest tightness, shortness of breath, and wheezing. Chest radiographs taken on admission showed no consolidation congestion or effusions and the endotracheal tube that had been placed was found to be in good position. She was intubated for 6 days for "asthma exacerbation and respiratory failure." A post-hospitalization complete blood count revealed an elevated white blood cell count of 15.1 x 10⁹/L (normal, 4.5-10.8 x 10⁹/L) normal hemoglobin and hematocrit levels and a normal platelet count. Complete metabolic and thyroid function panels were normal. Her anti-nuclear antibody (ANA) test was negative; and the rheumatoid factor test, which used the quantitative nephelometric method, was borderline elevated at 23.3 IU/mL (normal, 0-19 IU/mL). Her serum complement level had been normal on a previous visit. Immunoglobulin A (IgA) and immunoglobulin M (IgM) serum levels were normal, but her immunoglobulin E (IgE) was elevated at 176 kU/L (normal, ≤ 114 kU/L) and immunoglobulin G (IgG) was borderline low at 671 mg/dL (normal, 700-1,600 mg/dL).

Physical examination revealed a well-groomed, overweight woman with moon facies, a buffalo hump, central obesity with abdominal striae, peripheral wasting, and increased acneiform eruptions (Figure 1). Although oral steroid use provided intermittent improvement in her asthma symptoms, she had frequent exacerbations and became increasingly unable to tolerate these drugs; thus, the patient was considered glucocorticoid-intolerant. All steroid medications were slowly tapered, and she was started on a trial of omalizumab. She experienced no complications with this drug, and after several months on this therapy, her cushingoid features disappeared and her asthma was well-controlled, without any further exacerbations.

Figure 1—Photographs of the patient showing features characteristic of Cushing's syndrome, which is associated withchronic steroid use. These features include moon facies (A), buffalo hump (B), central obesity and abdominal striae (C), andacne flares (D).

DISCUSSION

Asthma is a common disease. According to the World Health Organization, over 300 million people suffer from asthma worldwide.² Its prevalence in Europe doubled over the past decade, and it is estimated that asthma is poorly controlled in more than 5% of those cases.³ According to the Centers for Disease Control and Prevention, the self-reported 12-month prevalence of asthma in the United States increased 73.9% from 1980 to 1996, and over 22 million US children and adults suffered from the disease in 2005.^4,5Physician office and hospital outpatient visits increased from 5.9 million in 1980 to 10.8 million in 1999.⁴ A May 2000 report by the Pew Environmental Health Commission projects that if asthma continues to spread unchecked, it will strike 1 in 14 Americans and affect 1 in 5 US families by 2020.⁵ These numbers are very concerning given the extensive morbidity and the mortality rates associated with this disease; approximately 5,000 deaths in the United States are attributable to asthma annually.^4,5

Patients with asthma always should be initially treated according to the accepted guidelines (Figure 2), which includes the administration of inhaled steroids and beta(2)-adrenoceptor agonists (bronchodilators). Those who experience frequent exacerbations despite this treatment may be given high-dose glucocorticoid therapy. This treatment has a high frequency of side effects, some of which include cataracts, diabetes, osteoporosis, skin atrophy, emotional lability, cushingoid habitus, increased appetite, and weight gain.⁶

Our patient developed many of the features characteristic of Cushing's syndrome (Figure 1). Iatrogenic Cushing's syndrome is usually caused by the use of large amounts of synthetic steroids that may regulate adipose-tissue differentiation, function, and distribution,⁷ as well as suppress cortisol-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secretion. This syndrome has been associated with morbidity and a significant increase in mortality risk.⁸

Many studies have been done on alternative and complementary treatments for uncontrolled asthma that could eliminate or reduce the need for dangerous steroid therapy. A large focus of this research has been anti-IgE therapy. IgE binds to high-affinity IgE receptors on the surface of mast cells and basophils. On exposure to allergens, an allergic cascade begins that ultimately results in the release of preformed mediators such as histamine from the mast cells. IgE plays a large part in causing airway inflammation and hyperresponsiveness in allergic asthmatics by stimulating the release of these mediators through the aforementioned mechanism.⁹ Anti-IgE helps block this cascade by binding to free IgE molecules. This decreases serum IgE, preventing IgE molecules from attaching to mast cells or basophils and inhibiting release of their cellular contents.¹⁰ By decreasing serum IgE and preventing attachment to mast cells, omalizumab fosters "attenuation of both early and late asthmatic responses to allergen inhalation, reduced eosinophil count in the sputum, decreased airway hyperresponsiveness, and improved symptom control in patients with allergic asthma."⁶

New England Journal of Medicine

A 2001 study showed that there were 58% fewer exacerbations per patient during the stable steroid phase and 52% fewer exacerbations during the steroid-reduction phase with omalizumab versus placebo.⁶ In this study, omalizumab simultaneously decreased asthma exacerbations and steroid requirements. A study published in the 2 years earlier showed that omalizumab improved asthma control and allowed for a reduction in both inhaled and oral corticosteroids.¹¹ In another study of high-risk patients with allergic asthma, omalizumab cut the rate of asthma exacerbations in half.¹² Multiple other studies have shown that omalizumab reduces asthma exacerbations, unscheduled outpatient visits, emergency department treatment,¹³ and the use of rescue medications and inhaled corticosteroids.¹⁴ A 2004 study found that patients who had been taking high doses of steroids or had poor lung function and frequent asthma exacerbations benefited the most from omalizumab.¹⁰

Figure 2—The Global Initiative for Asthma management approach. Reprinted with permission from: Global Initiative for Asthma. Pocket Guide for Asthma Management and Prevention: A Pocket Guide for Physicians and Nurses (Revised 2007). Figure 4.3-2. Available at: www.ginasthma.com. Accessed February 16, 2008.

Most asthma is well-controlled with bronchodilators and inhaled corticosteroids. Continued exacerbations or intolerable side effects from steroids should prompt physicians to consider anti-IgE therapy. The main drawback of omalizumab treatment is its cost, which is currently well over $1,000 per month. Omalizumab also has several side effects, and it may be too early to realize all the long-term effects of this relatively new medication. In July 2007, a boxed warning was added to the product label citing an increased risk of life-threatening anaphylaxis for as long as 24 hours after receiving a dose of the drug. Although no deaths have been reported and the warning is not expected to significantly hamper the prescription of omalizumab, its cost-benefit ratio and risks must be weighed carefully. Other asthma medications should still be considered as first-line treatment, but if omalizumab seems necessary, it is imperative that the patient be counseled on the drug's risks and is capable of initiating appropriate self-treatment for anaphylaxis.

CONCLUSION

Patients with asthma should be treated according to currently accepted guidelines, and physicians must be vigilant in monitoring their asthmatic patients closely for the many side effects of chronic steroid use. These could include cushingoid features, which patients may not be aware of, such as buffalo hump. Patients whose asthma remains uncontrolled despite appropriate therapy or who are unable to tolerate the side effects of steroids should be offered alternative management. Anti-IgE therapy with omalizumab is highly effective and may be a viable alternative to traditional steroid treatment for moderate-to-severe asthma sufferers.

Acknowledgement

We would like to thank Merhunisa Karagic and Jill Gregory for their significant assistance with this paper and for providing the accompanying photographs.

ASTHMA AND ALLERGY STATISTICS

• Asthma and allergies strike 1 out of 4 Americans. Approximately 20 million Americans have asthma.
• 9 million US children under 18 years of age have asthma.
• More than 70% of people with asthma also suffer from allergies.
• 10 million Americans suffer specifically from allergic asthma.
• In 2004, there were 13.6 million physician office visits and 1 million outpatient department visits due to asthma.
• Asthma accounts for 25% of all emergency department visits in the United States annually.
• Approximately 44% of all asthma hospitalizations are for children.
• Direct health care costs for asthma in the United States total more than $10 billion annually; indirect costs (lost productivity) add another $8 billion, for a total of $18 billion.
• Over $5 billion annually is spent on prescription drugs to treat asthma.
• Asthma prevalence is 39% higher in African Americans than in whites.
• In 2003, the prevalence of asthma in women was 35% greater than in men.
• Approximately 40% of children who have asthmatic parents will develop asthma.
• Every day in America 40,000 people miss school or work, 30,000 people suffer an asthma attack, 5,000 people visit the emergency department, 1,000 people are admitted to the hospital, and 11 people die due to asthma.
• The prevalence of asthma increased 75% from 1980 to 1994; during the same period, asthma rates in children under 5 years old increased 160%.

Source:

American Academy of Allergy Asthma & Immunology. Asthma Statistics. Available at www.aaaai.org/media/resources/media_kit/asthma_statistics.stm.

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