Asthma is of great interest to physicians, scientist researchers, epidemiologists, and public health experts. The National Asthma Education and Prevention Pro-gram’s 440-page updated and expanded EPR-3 published in October 2007 describes in detail the contemporary approach to the treatment of asthma.
The report advises healthcare providers to treat asthma by incorporating four key components into their daily practice. The components are assessment and monitoring of asthma sever-ity and of asthma control at every visit; education for a partnership between the person with asthma (or care-givers) and the clinician that includes self-management support; control of environmental factors and comorbid conditions that affect asthma; and the stepwise use of medications.
Currently available asthma medicines are highly effective for the majority of persons diagnosed with asthma and have an excellent safety record.
As mentioned in Question 58, the inhaled route of administration is preferred, putting the medicine exactly where it is needed, while ensuring that as little active drug as possible enters other organs. It is not surprising to learn, therefore, that many recent advances relate to refining drug-delivery devices. Dry-powder inhalers were developed several decades ago and are now in widespread use worldwide.
More recently, the asthma community has seen the successful development and introduction to market of the “greener” HFA (hydrofluoroalkane) propellants in MDIs, as out-lined in Questions 59 and 60. As far as medications that help control and treat asthma, new approaches include the introduction of inhaled drug combinations and the development of novel drugs to treat the severest forms of persistent asthma. Combination inhalers generally contain both an ICS (an inhaled corticosteroid) and a LABA (a long-acting β2 agonist) bronchodilator.
Examples include Advair, which contains fluticasone + salmeterol, and Symbicort, made up of budesonide + formoterol. One puff delivered from those inhalers contains two long-term daily use medicines, enhancing medication adherence and efficacy.
According to the National Heart, Lung, and Blood Institute (NHLBI) of the U.S. National Institutes of Health, Approximately 5 to 10% of asthma patients have severe asthma that is not well controlled by long-term controller medications, such as high-dose inhaled corticosteroids, or oral prednisone. These patients may also be classified as having refractory or steroid-resistant asthma.
It emphasizes that, “new therapies are desperately needed for severe asthmatics who are poorly controlled despite . . . standard medications.” One such new approach to treatment, omalizumab (Xolair), is the result of our better understanding of asthma and allergy at the molecular level. Omalizumab (Xolair) is the first clinically available drug in a new class of medicine called IgE blockers, a type of immunomodulators.
Immunoglobulin E, abbreviated IgE, is a protein that was first identified in the mid-1960s. IgE is an anti-body produced by the body in minute quantities and normally circulates in the bloodstream in very small amounts, as mentioned in Question 47. Under certain conditions, however, the body’s (blood or serum) level of IgE can rise significantly. High serum IgE levels have been associated with persistent wheezing, allergy, and bronchial hyperresponsiveness.
IgE plays a pivotal role in allergy, in asthma, and in the other atopic dis-eases, such as eczema, seasonal allergic rhinitis, peanut allergy, anaphylaxis, and hives. To better understand the central role of IgE, it is important to first review our understanding of the body’s allergic response. When a person has a medically confirmed allergy to a specific allergen, that allergy has developed over time.
In order for the allergy to have emerged, several steps had to have first taken place. The initial event was allergen expo-sure, occurring earlier in their lifetime. Exposure then persisted over time, allowing the development of sensitization as a next step. Since the sensitized allergic individual then had a potential to react allergically, ongoing exposure to the allergen in the setting of that potential ultimately led to a clinical allergic response.
The genesis of a specific allergy in an individual with certain innate genetic characteristics thus requires at least two preliminary steps: exposure followed by sensitization. Those two steps are necessary, but not sufficient for an allergy to emerge. Most individuals are not “allergy prone,” meaning that even though they may have repeated, frequent allergen exposure, their immune system does not become sensitized, and allergic symptoms never develop.
Consider two siblings who live in a home with a cat. The older child, a boy, has no allergic symptoms. His sister however, experiences itchy eyes, runny nose, chest tightness, and wheezing when at home, and particularly when in direct contact with the family cat. The younger child was previously sensitized to the cat and now has developed allergic rhinitis and asthma triggered by her cat allergy. Her immune system has responded to the continued exposure and sensitization to cat allergen by producing antibodies directed against cat proteins. The antibodies made in the course of an allergic response are IgE antibodies, in our example, anti-cat IgE proteins. The IgE directed against cat protein is the culprit in the allergic response, causing sneeze, cough, and wheeze.
Total serum IgE level is easy to measure with a simple blood test. An elevated serum IgE level directed against a specific antigen indicates that sensitization against that antigen has occurred, but it does not automatically indicate that an allergy to that antigen is present as well. It is possible to have both an elevated total serum IgE level in the blood and no allergy symptoms at all. Before you can state that someone is allergic to something, both a positive test for the suspected allergen and a history of rele-vant symptoms must be present. Neither one alone is sufficient to confirm allergy. More information about testing for suspected allergy is presented in Question 46.
Scientists have been able to study and analyze the effects of IgE in humans at the cellular level. Researchers have been able to determine how the IgE interacts with effec-tor cells in our bodies, such as macrophages, T cells, B cells, basophils, and activated mast cells, leading, in turn, to the release of substances that bring about the symp-toms of an allergic response. The sophisticated research has not only advanced our understanding of how allergy and asthma develop, but has also suggested pathways for new asthma and allergy medications.
In particular, a novel medication, omalizumab (Xolair), was developed specifically for patients with IgE-mediated asthma and allergy. Omalizumab binds IgE circulating in the body and so treats asthma by a unique and completely different mechanism from other existing asthma medicines. Since most of the IgE becomes bound to the omalizumab, free IgE levels are reduced. Less free IgE is available to attach to receptors found on the surface of effector cells (mast cells and basophils), which limits the degree of release of mediators of the allergic response. Since mediator release becomes hindered, asthma and allergy symptoms are lessened.
The FDA granted Xolair its approval in June of 2003, and the medicine became available in the United States by prescription a month later . It is approved by the FDA for treatment of moderate and severe persistent asthma in adolescents and adults who meet two additional specific criteria. One is the presence of a positive skin test, or RAST blood test for a year-round allergen, such as dust mite or mold, for example. The second criterion requires that inhaled corticosteroid treatment be ineffective in adequately controlling the patient’s asthmatic symptomatology.
A non-pharmacologic approach to the treatment of severe asthma, bronchial thermoplasty, is currently under investigation in Australia, Brazil, Canada, the Netherlands, the United Kingdom, and in the United States in a series of studies, collectively called the AIR trials. Bronchial thermoplasty is a minimally invasive outpatient proce-dure that targets airway smooth muscle with radio-frequency–generated heat. It is performed over three sessions through bronchoscopy (see Question 31 for more on bronchoscopy). Bronchial thermoplasty has been investi-gated in persons with severe persistent asthma that is not controlled despite high doses of inhaled corticosteroids (ICS) and long-acting β2 agonist bronchodilators (LABA).
The First in a New Class of Asthma Treatments:
IgE Blockers Omalizumab (Xolair), a medication that binds immunoglobulin E, is the prototype of a novel unique class of asthma treatment, the IgE blockers. Omazilumab is:
a humanized monoclonal antibody
administered by injection, right under the skin (subcutaneous)
taken every 2 to 4 weeks, in a doctor’s office, under direct medical supervision
dosed based on body weight and the IgE level
FDA approved for persons 12 years of age and older indicated in adolescents and adults with:
severe persistent asthma who also have significant allergy
a positive skin test to a specific allergen
a positive RAST to a specific allergen uncontrolled or poorly controlled asthma despite the use of inhaled corticosteroids
never used in acute or emergency treatment of an exacerbation
The results of a large safety and effectiveness study (AIR-2) enrolling 297 persons at 30 sites in six countries who were followed for 1 year were published in the American Journal of Respiratory and Critical Care Medicine in October 2009, by the AIR2 Trial Study Group. The authors explain, “Bronchial thermoplasty (BT) is a novel intervention for asthma that delivers controlled thermal energy to the airway wall during a series of bronchoscopy procedures, resulting in a prolonged reduction in airway smooth muscle (ASM) mass.”
Since the amount of airway smooth muscle mass is reduced, the hypothesis is that less muscle leads to less airway narrowing from muscle constriction, which, in turn, leads to fewer exacerbations and better asthma control. The study has demonstrated that the group of persons treated with bronchial thermoplasty had “clinically meaningful improvements in severe exacerbations requiring corticosteroids, ED visits, and time lost from work/school during the post-treatment period . . . together with improvements in quality of life.”
The data look promising, and as of this writing, an FDA panel has recommended that the agency approve the bronchial thermoplasty device called Alair. Once approved by the FDA, it will become another treatment option for refractory, steroid-resistant asthma. Because severe persistent asthma is currently so difficult to treat, it continues to be the target of ongoing research. The work will undoubtedly not only continue to yield helpful treatments for those most severely targeted by the disease, but will ultimately provide insights into the underlying processes in asthma that will benefit anyone with asthma of any severity.