New medications and devices fit into a general management plan

Twitchy airways is a term used by some doctors to describe the lungs of people with asthma. The term is apt: It is possible that one minute an asthmatic is breathing freely, and the next, he or she is gasping for air.     Some trigger, which varies according to the individual, causes the tissue within the bronchi and bronchioles of the lungs to become inflamed while the muscles on the outside of the airways contract. Mucus enters the now swollen airways, making breathing a labored process. Some sort of intervention, whether self-administered or provided by a doctor, will likely be necessary before the asthmatic suffering such an attack will be able to take a deep breath.

The experience of being unable to breathe is both traumatic and life threatening. Management of this ailment focuses on preventing episodes such as this from ever occurring. Science has produced new drugs within the past few years to help, and an update to the 1997 Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma (EPR-2) has made new recommendations based on research conducted over the past 5 years.

Whether incorporating new medications or sticking to the old, the primary and most successful method of control continues to be a managed program created in conjunction with a physician and monitored by the patient.

Statistics Show Asthma on the Rise
The need for new treatments for asthma has increased with the rise in prevalence that has been noted since the early 1980s across all age, sex, and racial groups. Asthma is the only chronic disease, besides AIDS and tuberculosis, with an increasing death rate. The Centers for Disease Control and Prevention (CDC) reports a 75% increase in prevalence from 1980–1994; for children under the age of 5, asthma rates increased more than 160% in the same period.

According to Asthma Prevalence, Health Care Use, and Mortality, 2000–2001, published by the National Center for Health Statistics at the CDC, in 2001, 20.3 million Americans reported having asthma. This same publication reported:

• 6.3 million children under 18 indicated asthma;
• 12 million people experienced an asthma attack in 2000;
• 10.4 million asthma-related visits to private physician offices and hospital clinics occurred in 2000, with 4.6 million of these involving children under 18;
• 1.8 million asthma-related visits to emergency departments occurred in 2000, with more than 728,000 of these involving children under 18;
• 465,000 asthma-related hospitalizations occurred in 2000, 214,000 of which were children under 18; and
• 4,487 people died from asthma in 2000, of which 223 were children under 18.

The CDC’s March 29, 2002, Surveillance for Asthma — United States, 1980-1999, found that asthma annually accounts for 14 million missed school days for children and 14.5 million missed workdays for adults.

The American Lung Association estimates that direct health care costs for asthma in the United States total more than $8.1 billion annually, with indirect costs, such as lost productivity, adding another $4.6 billion (Trends in Asthma Morbidity and Mortality, February 2002). Similarly, the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) estimate asthma-related health care costs at $14 billion annually.

Though asthma is seen in all ages, sexes, and racial groups, its incidence has been found to be statistically higher in African Americans, with the American Lung Association reporting prevalence rates 21.6% higher in this group than in Caucasians in 1999.
Risk Factors

Research has been unable to determine why certain groups show higher rates of incidence, nor why the prevalence of asthma has been increasing for all. Correlation has been seen with poverty, urban air quality, crime, indoor allergens, a lack of patient education, and inadequate medical care, but no definitive links have been proven.

According to the Mayo Foundation for Medical Education and Research (MFMER), researchers have identified a number of factors that increase one’s likelihood of developing asthma. These include:

• Residence in a large urban area, which may increase exposure to environmental pollutants;
• Exposure to secondhand smoke;
• Exposure to occupational triggers, such as the chemicals used in farming or hairdressing;
• One or both parents also having asthma;
• Respiratory infections in childhood;
• Low birth weight;
• Obesity; and
• Gastroesophageal reflux disease (GERD).

Asthma resulting from triggers in the workplace is classified as occupational asthma and may occur as a direct response to an irritant or from long-term sensitization. These substances generally fall into one of five categories: chemicals; enzymes; animal allergens and proteins; flour, grain, and food allergens; and respiratory irritants.

Exercise-induced asthma is another classification in which the airways become constricted during vigorous exercise; however, not as much inflammation results as in normal asthmatics.

Triggers, Warning Signs, and Symptoms
Asthma can develop at any age and frequently results from a combination of allergic and nonallergic responses. Symptoms can be instigated by any of a large number of triggers, including allergens and cold air (see sidebar).

The symptoms themselves can also range. Patients may have occasional episodes with moderate, short-lived symptoms, or they may experience constant wheezing that worsens with exposure to triggers and leaves the patient gasping for breath. MFMER reports that attacks frequently occur between 2:00 am and 4:00 am.

All attacks, however, provide warnings signs, and it is these which patients are taught to look for and monitor in their efforts to prevent severe episodes. MFMER lists warning signs for both adults and children:

• Adult asthmatics may experience increased shortness of breath or wheezing; disturbed sleep caused by shortness of breath, coughing, or wheezing; chest tightness or pain; an increased need to use bronchodilators; and a fall in peak flow rates as measured by a peak flow meter.
• Child asthmatic warning signs include an audible whistling or wheezing during exhalation; coughing, particularly frequently and in spasms; waking during the night with coughing or wheezing; shortness of breath; and a tight feeling in the chest.

Diagnosing Asthma
These symptoms may be the cause of a request for diagnosis, or a patient may require medical help during an asthmatic episode. Asthma, particularly in adults, may be difficult to confirm as it can be confused with other lung conditions, such as emphysema or vocal cord dysfunction.

Food and Asthma Food allergies and/or intolerance may also provide asthma triggers. According to John Kernohan, director of York Nutritional Laboratories Inc, certain foods can cause asthma symptoms in adults as a result of the IgG antibody response. Once these person-specific foods are identified and eliminated from the diet, patients experience immediate relief. It is not currently standard for doctors to run food allergy tests in relation to asthma, so patients may need to ask, but the results may be worth it. One of the method’s biggest supporters is Marie John, MD, department head of pediatrics at Navy Hospital in Pensacola, Fla, who was cured of asthma after eliminating IgG-reactive foods from her diet.

The NHLBI defines asthma as a “chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, Tlymphocytes, macrophages, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli.”

Diagnosis of this condition begins with a complete medical history and physical examination. Lab tests may include chest x-rays, blood and allergy tests, and pulmonary, or lung, function tests. Lung function tests are frequently completed both before and after the patient is given a bronchodilator, which opens the airways; patients showing improvement on these tests after taking this medication are considered likely to have asthma. Specific examples of these tests include the peak flow meter, which measures the rate at which the patient expels air, and spirometry, which measures the amount of air the patient is able to exhale. The doctor may also do a methacholine bronchial challenge. Inhalation of methacholine by an asthmatic will cause mild constriction of the airways.

According to Norman Edelman, MD, consultant for scientific affairs at the American Lung Association, new diagnostic methods are currently in use and feature quantification of airway inflammation and measurement of the nitrous oxide by inflammatory cells. “In addition, more and better screening tools are being developed, including specific questionnaires,” says Edelman.

Once diagnosed, asthma can then be classified in four stages: mild intermittent, where symptoms are exhibited less than twice a week and exacerbation is brief; mild persistent, where symptoms occur more than twice a week but less than once a day with exacerbations that may affect activity; moderate persistent, with daily symptoms and exacerbations more than twice a week, which may last days; and severe persistent, which features continual symptoms causing limited physical activity.

Disease Management Plan
Whichever group patients fall within, they will need to develop a disease management plan in conjunction with a physician. The written plan includes step-by-step procedures for monitoring and reacting to asthma symptoms, including preventive measures and medications. The plan should be reevaluated over time as a person’s triggers, symptoms, and medication responsiveness can change.

The March/April 2002 issue of the California Journal of Health-System Pharmacy (“Update on the Management of Asthma,” Edna M. Chan, PharmD) identifies three federal initiatives from 2000 that provide a framework for the nation’s fight against asthma: the Children’s Health Act of 2000, Healthy People 2010, and the report Action Against Asthma: A Strategic Plan for the Department of Health and Human Services. Together these aim to expand research, prevention, and treatment efforts to tackle asthma. To further their objectives, all three promote the use of the guidelines established by the EPR-2. The guidelines are now available for downloading off the Internet onto PalmOS-compatible handheld devices for easy accessibility.

The goal of asthma therapy, as stated in the update to the EPR-2, is control, which is defined as minimal or no chronic symptoms, day or night; minimal or no exacerbations; no limitations on activities (no school or work missed); minimal use of a short-acting, inhaled beta-agonist; and minimal or no adverse effects from medications.

To achieve this, the guidelines continue to recommend the use of written action plans as part of the overall effort to educate patients in self-management. The plan outlines the actions patients are to take depending upon their signs and symptoms.

Patients oversee their own conditions by paying close attention to warning signs and/or utilizing a peak flow meter to help monitor pulmonary performance. The EPR-2 guidelines continue to recommend “peak flow monitoring for patients with moderate or severe persistent asthma as it may enhance clinician-patient communications and may increase patient and caregiver awareness of the disease status and control.”

Peak Flow Meters
Children as young as 3 years of age have been able to help manage their asthma with peak flow meters. Peak flow meters can measure changes in the airways before the patient feels them, helping to ward off severe episodes. They can also be used to identify specific triggers and/or evaluate a course of therapy.

Measurements can be taken multiple times daily or only when the patient senses a change in symptoms. Results are compared against personal normals. Flows in the green zone are typically within 80%–100% of the normal rate. Those in the yellow zone are at 50%–80% of the normal rate and will likely require a response. The red zone indicates less than 50% of a patient’s normal flow and signals a medical alert; typically, a patient would respond with immediate dosing of rescue medications.

Bronchodilators
There are two types of asthma medications: long-term control medicines, or anti-inflammatories, and bronchodilators, which prevent episodes or relieve acute symptoms.

Bronchodilators open up constricted airways, relaxing the muscles. They may be short acting (lasting 2–4 hours) or long acting (lasting up to 12 hours). Bronchodilators are safe when used properly, but when overused, side effects can include a fast heart rate, tremors, or even death. This group includes beta-agonists, ipratropium bromide, and burst corticosteroids.

The most common of these medications, short-acting beta-agonists, such as albuterol (Proventil, Ventolin) and pirbuterol (Maxair), act quickly to relieve symptoms and can also be used preventively. Taken in their inhaled form, these medications cause few systemic adverse effects.

New to this group is levalbuterol (Xopenex), which has been shown to have similar efficacy and safety as racemic albuterol in both adults and children. Another new bronchodilator is formoterol (Foradil Aerolizer), a long-acting beta-agonist with a shorter onset than salmeterol (Serevent), 3 to 5 minutes versus 10 to 20 minutes. Formoterol, like salmeterol, is a bronchodilator that may be used for long-term prevention of symptoms, particularly at night.

Ipratropium (Atrovent) is an antocholinergic not typically recommended for immediate relief of asthma symptoms, though it is an alternative for patients with intolerance to beta-agonists.

Asthma Triggers Some of the most frequent asthma triggers include: • Allergens, such as pollen, animal dander, cockroaches, and molds; • Air pollutants and irritants; • Tobacco smoke, inhaled as primary or secondhand; • Respiratory infections, including the common cold; • Physical exertion, including exercise; • Cold air; • Certain medications, such as beta-blockers, aspirin, and other non-steroidal anti-inflammatory drugs; • Sulfites; • Emotional stress; • GERD; and • Sinusitis

Anti-Inflammatories
Anti-inflammatories or long-term control medicines include inhaled or oral corticosteroids, cromolyn and nedocromil, long-acting beta-agonists, methylxanthines, and leukotriene modifiers. Taken on a daily basis to continually curb attacks, these medications suppress inflammation of the airways over days, weeks, or months, as well as prevent blood vessels from leaking fluid or mucus into airway tissues.

Though not the preferred first line of treatment, leukotriene modifiers, according to Edelman, have established themselves in the market as effective. Montelukast (Singulair) is one of the newest in this group. According to Chan, “Montelukast sodium is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor. Montelukast sodium is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 2 years of age and older.”

Corticosteroids: Preferred First-Line Therapy
The EPR-2 update recommends “inhaled corticosteroids as a safe, effective, and preferred first-line therapy for children as well as adults with persistent asthma.” In addition to controlling and preventing asthma symptoms, inhaled corticosteroids, which treat chronic inflammation of the airways, have been found to improve lung function and quality of life. Research has also shown that corticosteroids reduce the dosage of other medications required to control symptoms.

Corticosteroids currently on the market include Prednisone, Prednisolone, Cortisone, Hydrocortisone, beclomethasone (Vanceril, Beclovent), fluticasone (Flovent), budesonide (Pulmicort), and flunisolide (Aerobid).

Those taken orally or intravenously over long periods can produce serious side effects, including decreased resistance to infection, osteoporosis, muscle weakness, high blood pressure, and thinning of the skin. However, when taken as an aerosol, either through the nose or mouth, the regular, smaller dosage reduces the threat of adverse effects so that the benefits outweigh the risks. Long-term aerosol use carries a small risk of side effects, which include increased threat of glaucoma, cataracts, osteoporosis, easy bruising, and growth suppression in children. Intranasal corticosteroids have the added benefits of relieving the stuffy nose, nasal irritation, and other discomfort of allergies.

Combination Therapies
When inhaled, steroids alone do not work. The update to the EPR-2 found that rather than increasing the dosage of one medication, adding long-acting beta-agonists to inhaled steroids was more effective treating patients more than 5 years of age with moderate or severe persistent asthma. Stan Szefler, MD, head of pediatric clinical pharmacology at the National Jewish Medical and Research Center, says, “Combinations take the most effective classes of drugs and combine them. The newest one in this group is Advair, which combines an inhaled steroid and a long-acting beta-agonist.”

The Advair Diskus contains a dry powder mixture of fluticasone and salmeterol. Chan’s article states, “In separate studies comparing low-strength or mid-strength Advair, fluticasone alone, salmeterol alone or placebo, combination treatment provided significantly greater improvement in lung function, … asthma symptom scores, nighttime awakenings, and rescue albuterol use than placebo, fluticasone or salmeterol.” In addition, the inhaler itself incorporates new techniques, as it is activated by breath and indicates how many doses are left. Szefler states this is a benefit for asthmatics who want to monitor their available medication.

Combining two medications may reduce the risk of side effects that can result from taking one drug at a higher dosage. Combinations currently feature an inhaled corticosteroid with an inhaled bronchodilator, leukotriene modifiers, or theophylline. The specific combination is dependent upon the severity of the patient’s condition as well as the treatment goals. Other new combinations include albuterol sulfate and iprotropium bromide inhalation solution (DuoNeb) and an iprotropium bromide and albuterol sulfate inhalation aerosol (Combivent), both of which are used to treat symptoms of chronic obstructive pulmonary disease (COPD).

Antibody Defense
Severe asthma, which cannot be treated effectively with traditional medication or newer treatments, has a new line of defense in omalizumab (Xolair), developed by Genentech Inc, Novartis Pharmaceuticals Corporation, and Tanox Inc. Approved by the US Food and Drug Administration this summer, the new medication is the first approved humanized therapeutic antibody for asthma treatment, which targets IgE, an underlying cause of symptoms in allergy-related asthma.

Asthma medications include anti-inflammatories and bronchodilators.

According to Paul Dichtel, registered pharmacist with Option Care, one of five specialty pharmacies that will distribute the subcutaneously injected medication, “Use is indicated for adults and adolescents with moderate-to-severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids.”

Xolair has been found to significantly reduce asthma exacerbations and related symptoms. It does so by binding to the high-affinity receptors for IgE, thereby blocking the binding of the antibody to cell-membrane receptors and preventing the release of mediators, such as histamine, which can cause inflammatory responses in the body.

Significant side effects have thus far been few, with the most frequent reported to be injection-site reactions. “For this reason, and the potential for a severe allergic reaction, patients are monitored on site for two hours after injection,” says Dichtel.
Future Directions

Xolair is the newest asthma drug available, but Edelman notes that others are in the pipeline. “One interesting class to watch is the phosphodiesterase 4 (PDE4) inhibitors, which seem to have anti-inflammatory action,” he says.

Szefler points out that researchers are also developing more potent forms of current drugs, particularly inhaled steroids, that are more effective in the airways and require less absorption by the body, therefore reducing side effects. He also notes that asthma treatment is exploring new directions, with doctors trying to diagnose and treat the ailment earlier. “In most patients, the disease presents in early childhood with wheezing episodes. Doctors are beginning to understand the difference between wheezing due to viral infections and the early signs of asthma, and researchers are developing profiles on these patients. The next 5 to 10 years will also see the application of genetics and more sophisticated testing to evaluate the severity of the asthma and to direct treatment.”

Edelman adds, “It has become clear that management of asthma is a complicated issue, and its treatment requires patient knowledge and cooperation with physicians. Patients cannot simply take medications.”

Renee DiIulio is a contributing writer for Clinical Lab Products.