The Allergy Asthma Connection

A combination of genetic predisposition and environmental factors can trigger asthma in patients with allergies

Asthma is a common chronic disease in the United States and worldwide. According to the 2003 National Health Interview Survey,¹ there were an estimated 20.7 million adults diagnosed with asthma, a prevalence of 9.7%, and 8.9 million children diagnosed with asthma, a prevalence of 12%. The same survey reported 1.7 million asthma-related emergency department visits, 511,000 hospitalizations, 12.9 million outpatient office visits, and 4,261 deaths in 2002. Despite advances in knowledge of the pathophysiology and etiology of asthma, the availability of new medications, and the introduction of new formulations and drug-delivery methods, asthma is still a life-threatening disease. Asthma is a leading cause of absence from work and school. It is a significant economic burden on health care, and it affects quality of life negatively, limiting patients’ activity levels and imposing psychological stress on their families.

Asthma is a complex, variable disease. Symptoms can vary from cough alone (in cough-variant asthma) through inability to inhale deeply enough to chest tightness, wheezing, and respiratory distress. Some patients suffer from frequent symptoms and significantly limited physical activities, but maintain normal lung function. Others may have mild symptoms with significant decreases in lung function, but bronchodilators may reverse the associated obstruction.

Asthma is the result of interaction between complex genetic factors and the environment. Medicine is just beginning to understand how genetic predisposition affects the manifestations and severity of asthma and the individual’s response to pharmacotherapy. Variable degrees of inflammation are present in the airways of asthma patients. The inflammation leads to reversible airway obstruction and airway hyperresponsiveness.

Allergies trigger airway inflammation in approximately 90% of asthma patients,² but this may be less true of older patients. An inhaled allergen reaches the immune cells in the lung. Through a chain of steps, a specific immunoglobulin E (IgE) is produced. The allergen-specific IgE then binds to tissue mast cells and basophils for long periods—until it comes in contact with the same allergen again, which results in the activation of the mast cells and basophils in the lung.

The inflammatory process can be divided into early and late responses. In the early phase, histamine, tryptase, and cysteinyl leukotrienes (among other mediators) are released, causing an immediate decrease in forced expiratory volume in 1 second (FEV₁), followed shortly by the recovery of lung function. In the late phase, eosinophils are recruited to the lung tissue, in addition to other types of cells, and chronic inflammation begins (and goes on for years). The chronic inflammation gets a boost every time a new exposure occurs, and it persists even when asthma enters clinical remission.³

Exacerbations represent an acute increase in an existing, chronic inflammation of lung tissue (Figure). Airway inflammation can be triggered by exposure to allergens; air pollutants (such as dust, rubber particles, and ozone); tobacco smoke, whether inhaled actively or passively; irritants and sensitizers in the workplace (including fumes, cleaners, detergents, and sanitizers); and bacterial and viral infections.

Cold air and exercise can also trigger symptoms, especially if the patient’s asthma is suboptimally controlled. Exercise tolerance usually improves along with asthma control.

Asthma severity is described using four categories. Each category is determined using the patient’s single most severe feature, whether it involves diurnal or nocturnal symptoms, pulmonary function, or peak flows.⁵ The definition of asthma control is still being debated, but the goals of therapy, as stated by the National Asthma Education and Prevention Program Expert Panel Report ²⁵ published in 1997, are to:

• prevent symptoms,
• maintain near-normal lung function,
• maintain normal activities,
• prevent exacerbations,
• provide therapy with the lowest incidence of side effects, and
• meet patient expectations.

In other words, clinicians should strive to provide asthma control that gives patients normal or near-normal lives. Each patient has individual expectations, and each patient’s asthma is different, so treatment should be tailored for each individual. In a telephone survey of asthma patients, Fuhlbridge et al⁵ found that 77.3% of patients had moderate-to-severe persistent disease. The same survey also showed that fewer than 10% of US patients are in the mild intermittent category. The majority have persistent asthma and should be using controller (anti-inflammatory) medications, as recommended in the guidelines of the US National Heart, Lung, and Blood Institute (NHLBI).⁴

Asthma is a dynamic disease; even patients in the mild category are at risk for severe exacerbations and death. Exacerbations also occur with the best management. Stemple et al⁶ analyzed 3 years’ claim data for 6,300 asthma patients and found that patients moved in and out of control. Of the 57% who were in control in the first year, 53% lost control in the second or third year, as indicated by oral steroid use, emergency-department visits, hospitalization, or increased use of short-acting b-agonists.

The search continues for the perfect tool to assess or predict how well asthma is controlled. Measuring exhaled nitric oxide or sputum eosinophils seems promising, but each method has limitations. Neither test has reached clinical utility in office practice. In the office setting, patients should be asked about their use of rescue medications, functional status, missed work or school, frequency of diurnal and nocturnal symptoms, and emergency-department or urgent care visits. Information on self-reported control and lung-function measurement should be obtained by either peak-flow monitoring or office spirometry. An asthma-control survey has been developed commercially; it consists of five questions and is available in two versions (for patients older and younger than age 12).

Acute Asthma Management
Exacerbations are accompanied by increased airway inflammation. The severity of exacerbation reflects the degree of airflow obstruction. Symptoms and signs correlate poorly with the degree of airflow restriction. Only the peak expiratory flow rate (PEFR) or FEV₁, rather than clinical signs and symptoms, should be used to assess the severity of airflow obstruction and the patient’s response to treatment in the emergency department, the clinician’s office, or the patient’s home. Children younger than 7 years of age are usually incapable of performing these maneuvers reliably. They should be assessed using clinical signs and symptoms.

Most exacerbations are mild or moderate and are treated in outpatient settings. According to an Australian survey,⁷ only 2% of total exacerbations resulted in hospitalization or death. Even though death from asthma is rare, it still claims about 5,000 lives per year in the United States.

Several risk factors have been associated with asthma mortality. Black men living in inner cities have the highest case-fatality rate, as well as the highest rates of previous mechanical ventilation and recurrent hospitalization. Psychological disorders and noncompliance are also associated with increased risk. Fewer than 50% of patients who experience life-threatening episodes have these risk factors, however.⁸ Most asthma deaths occur at home, and access to an emergency department is a good predictor of survival.⁹

The NHLBI guidelines⁴ define a moderate exacerbation as an FEV₁ or PEFR of 50% to 80% of the predicted or personal-best value, with a severe exacerbation indicated by results of less than 50%. These measurements are not needed for cyanotic, confused, or exhausted patients. Pao₂ is usually normal in mild and moderate exacerbations, and Paco₂ is normal to low. Hypoxemia results from ventilation-perfusion mismatching, which occurs in severe exacerbations. Hypercarbia (Paco₂ of more than 40 mm Hg) generally develops only when the FEV₁ is less than 25% of the predicted value.

Arterial blood gases are not routinely assessed in asthma exacerbations. Chest radiographs are obtained only for patients with suspected complications such as pneumonia, congestive heart failure, pneumomediastinum, or pneumothorax.

Inhaled b₂-agonists are first-line therapy. Metered-dose inhalers (MDIs) used with spacers are as effective as nebulizer therapy, if used correctly by patients. The dose of b₂-agonist needed to reverse an asthma attack varies, depending on the degree of the obstruction and the response to the initial treatment. Typically, four to eight puffs from an MDI with a chamber are needed. The puffs should be given one at a time. Nebulizing three to four units of liquid b₂-agonist, intermittently or continuously, is as effective. The continuous method saves the RT time and does not subject the patient to increased side effects.

Subcutaneous epinephrine or intravenous terbutaline may be indicated for some patients (for example, those who have excessive coughing or who are too weak to inspire adequately). Adding ipratropium bromide to a b₂-agonist is superior to using a b₂-agonist alone, especially in severe exacerbations.¹⁰

Patients require hospitalization or die not because of bronchospasm, but due to significant inflammation. Instituting anti-inflammatory therapy early in the course of emergency-department management is, therefore, essential. Oral corticosteroids should be administered early, within the first hour, but how much should be given is uncertain. There is no clear evidence demonstrating more efficacy for high (versus moderate) doses.

The use of methylxanthines (such as theophylline) as additions to b₂-agonists has declined in acute asthma management, since evidence favoring their use is inadequate, at best.¹¹ The need for assisted ventilation increases as the FEV₁ or PEFR decreases below 25% of the predicted value. Endotracheal intubation is associated with complications, of course; noninvasive positive-pressure ventilation (NPPV) has been shown to reduce the likelihood of intubation, decrease work of breathing, and improve oxygenation.¹² NPPV is an attractive alternative to intubation when aggressive medical management fails.

Long-Term Management
Pharmacological maintenance treatment, also referred to as controller medication, has evolved. Anticholinergics such as atropine and other belladonna alkaloids were first-line treatment until the early 1970s. Now, a long-acting form is available as tiotropium bromide; it has a place in the long-term treatment of chronic obstructive pulmonary disease,¹³ but is not yet part of asthma management. Isoproterenol, salbutamol, and terbutaline have been used since the 1960s for bronchodilation. Isoproterenol was widely used until it was linked to the possibility of increased asthma mortality.¹⁴ Short-acting b-agonists were initially used on a scheduled daily basis, as controller and rescue medications. Now, they are used only as needed. In the past decade, two long-acting b₂-agonists (LABAs), formoterol and salmeterol, were introduced and used as controller medications. Adding LABAs to inhaled corticosteroids (ICS) improved asthma control better than increasing the dose of ICS.¹⁵ This led to the production of a fluticasone-salmeterol combination in the United States. LABAs should be used in combination with ICS, not alone, as controller therapy.

Several types of polymorphism of the b₂-agonist receptor have been identified. Individuals with one polymorphism in particular do not respond to b₂-agonists as well as individuals with other polymorphisms.¹⁶

ICS treatment is recommended as first-line therapy for persistent asthma because it has been most effective in decreasing symptoms, exacerbations, emergency-department visits, and hospitalizations, as well as in improving lung function and reducing mortality.^17,18

Leukotrienes are released during the inflammatory process in the airways. They cause bronchoconstriction and fuel inflammation, and may not be blocked by ICS. Several leukotriene modifiers are being used as controller medications. Zileuton works by blocking the production of leukotrienes, while zafirlukast and montelukast are receptor blockers. They are more effective than placebo, but less effective than ICS.¹⁹Adding a leukotriene modifier to an ICS regimen is more effective than increasing the dose of ICS, but the combination of LABAs and ICS is most effective.²⁰ The long-term safety of ICS and systemic exposure to ICS are major concerns. The safety of low-dose ICS is well established. Prolonged use of medium-to-high doses of ICS is accompanied by increased incidence of side effects such as oral candidiasis, hoarseness, and osteoporosis.²¹ The benefits of long-term ICS therapy appear to outweigh the associated risks. After asthma control is initially gained, the ICS dose should be tapered to the lowest level that maintains asthma control. Combination therapy can be used to achieve control at a lower ICS dose.

Individual responses to any controller medication vary significantly. Szefler et al²² examined variations in response to fluticasone and montelukast among children with mild-to-moderate persistent asthma. They found that 5% of children responded well to montelukast alone; 23%, to fluticasone alone; and 17%, to both medications—but 55% did not respond significantly to either medication. Younger children with shorter asthma duration responded more favorably to montelukast, while patients with more severe asthma and higher levels of inflammatory markers responded better to fluticasone.

Genetic inheritance is probably the determining factor in the varying therapeutic response to different agents. The time may come when it will be possible to select suitable medications for each patient after analyzing individual genetic polymorphisms that predict the response to therapy. Meanwhile, ICS treatment remains the foundation of asthma treatment for the near future.

Mometasone recently became available, and ciclesonide is expected to be approved by the US Food and Drug Administration soon. Several antibodies have been developed against specific mediators of allergic inflammation and are under investigation. The anti-IgE antibody omalizumab is being used to treat patients with moderate and severe asthma. Treated patients have been able to use lower doses of ICS while maintaining asthma control and experiencing fewer exacerbations.²³ Still, the clinical efficacy of the available antibodies has fallen below the levels initially hoped for, providing added evidence of the complexity of asthma.

Pharmacotherapy is one aspect of disease management. A more difficult aspect is persuading patients to carry out clinical recommendations. As for all chronic conditions, patient adherence to therapy is lower than it is for acute illnesses.²⁴ Lack of adherence and incorrect use of medication pose more challenges in clinical management than choosing the appropriate regimen. Educating patients about the disease, its triggers, the early recognition of exacerbations, and, most important, the correct use of medication is essential. Successful management starts with establishing a relationship and good communication, leading to partnership between the provider and the patient. The current restraints on health care delivery allow less time to be spent with patients and, as a result, less time for education. Improving adherence is also hampered by the mounting financial pressure on patients due to increasing insurance co-payments. Time spent educating patients and creating a partnership pays good dividends, however, and this is one of several significant parts for nurses, RTs, and other medical personnel to play in successful asthma management.

Joseph Fahhoum, MD, is clinical assistant professor of medicine and pediatrics, Department of Medicine, University of Tennessee Health Science Center, Memphis.

References
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