Asthma is a chronic pulmonary disease that affects 17 million Americans - approximately five percent of the population. Morbidity and mortality from asthma have been increasing since 1980, although the understanding of its pathophysiology has improved and the amount of money focused on acute treatment has increased.^, Both hospitalization and mortality are higher in nonwhites, the socioeconomically underserved and those living in urban areas such as New York City. The explanation for these observations is not clearly understood, but may be due to increased exposure to environmental irritants, reduced access to good quality health care, poor understanding of the disease by the patient or differences in the drugs that are used in these populations. Since the treatment of asthmatic patients is often delivered by the primary care physician, it is important to understand the pathogenesis, diagnosis and management of the disease in order to become an effective provider.

Asthma is a disease characterized by variable and reversible airway obstruction. Although the exact mechanisms of asthma are not fully understood,^, a body of evidence suggests that airway obstruction is initiated when exposure to an allergen or stimulus, such as pollen, exercise or emotion, results in exaggerated bronchial hyperirritability. This leads to cell release of histamine and arachidonic acid metabolites, producing an intense inflammatory reaction. The result is bronchial hyperresponsiveness, increased vascular permeability, mucosal edema and increased mucus production. Later, hours after the initial trigger, there is an influx of additional cellular infiltration that includes lymphocytes (Th2), eosinophils, and mast cells that lead to further plugging and vasospasm, resulting in airway obstruction. The cascade of events is perpetuated, with IgE releasing factors amplifying the airway obstruction. Ultimately, alterations in non-cellular components of the airway can result in thickening of the basement membrane. This is called re-modeling, and may affect the rate of decline in lung function with age in some patients with asthma.⁸

TABLE 1: List of acronyms

The clinical spectrum of asthma is wide. Mild asthma may present as occasional episodes of wheezing, dyspnea, chest tightness with exercise, or nocturnal coughing. The classic presentation of wheezing when a patient is introduced to certain stimulants can make the diagnosis of asthma straightforward. There may not be one particular stimulus that triggers symptoms, however. Manifestations may resolve spontaneously or symptoms may start slowly and then worsen. It is essential to elicit a thorough medical history and to confirm the diagnosis with objective testing. A diagnosis of asthma requires the presence of episodic symptoms of airway obstruction, airflow obstruction that is at least partially reversible, and the exclusion of alternate diagnoses. ⁹

Medical history:

In the consideration of the diagnosis and treatment of asthma, it is crucial to review the profile of a typical exacerbation, its onset, duration and pattern of recurrence. Asthma "staging" is important – primary care providers should ascertain level of severity (see Table 2) in order to determine appropriate therapy and need for subspecialty referral. Nocturnal or early morning symptoms such as a cough are very common. Determining what precipitating factors induce exacerbations is critical to the management of the asthmatic patient. Stimulants such as perfume, laundry detergents, strong smells or cold air may trigger symptoms. Food additives that contain sulfites, dyes, and certain medications such as aspirin, nonsteroidal anti-inflammatory agents and beta blockers (including eye drops) may cause acute airway obstruction.

Identifying exposure to an allergen in the home includes reviewing the presence of pet dander, smoke, pollen and dust (which harbors dust mites). The occupation of the person with asthma is also important, since stimulants in the workplace often trigger symptoms (see occupational asthma, below). A careful medical history can often reveal rhinitis, sinusitis, nasal polyps, atopy and allergic disorders, all of which are associated with asthma. Atopy in the context of asthma has a strong family component. ^{10 11}

Physical examination:

Physical examination in the patient with asthma is often unrevealing, particularly in a patient with mild symptoms. Signs of atopy, allergic rhinitis, nasal polyps or sinusitis may suggest the disease in those who present with less classic symptoms.

Objective pulmonary function testing:

The diagnosis of asthma requires objective demonstration of episodic and reversible airway obstruction. This can be done by ordering routine pulmonary function tests with bronchodilators at a time when the patient is symptomatic. Alternatively, peak flow can be measured in the office or in the home.

Spirometric measurements (FEV1, FVC and FEV1/FVC ratio) are necessary laboratory tests when considering the diagnosis of asthma. In patients with reduced air flow, defined as an FEV1 of less than 75 percent of predicted value, and improvement of 15 percent or greater than baseline after inhalation of two puffs of a beta agonist confirms the diagnosis. Typically, FVC is normal, but the ratio of FEV1/FVC is reduced. As lungs empty during expiration, airway narrowing (and, therefore, resistance) has a more pronounced effect on airflow. This results in more impressive reductions in flows measured later in the forced expiratory effort. Lung volumes may be helpful when the FRC or RV are elevated with premature closing of involved airways and air-trapping. Although routine pulmonary function tests are extremely helpful, patients with mild asthma may have no objective evidence of reactive airflow obstruction. More sensitive laboratory assessments using methacholine or histamine challenge can help to confirm the diagnosis in these patients; ¹² these tests are not routinely indicated in our setting.

TABLE 2: Classification of asthma severity

The peak flow meter is an important tool for monitoring the asthmatic in the office and at home. The peak expiratory flow (PEFR) correlates with the FEV1 and can be useful for daily monitoring of airway function. It can also be used diagnostically in the office. Guidelines from a National Asthma Education Program expert panel suggest that asthmatics can benefit from a home peak flow meter as a simple and objective way to assess airway obstruction.¹³ The patient should be instructed to monitor PEFR values

twice daily for two weeks while receiving optimal therapy. This will determine the asthmatic’s personal best PEFR. The peak flow meter can then be used on a regular basis to measure daily PEFR, ideally before and after treatment. The results should be recorded. When the PEFR is between 80 and 100 percent of normal (green zone), no new intervention is needed. When the PEFR is between 50 and 80 percent (yellow zone), the patient is told to increase the use of medications and to call the physician. Patients should understand that when the PEFR is less than 50 percent (red zone) it is a true emergency. Peak flow meters are covered by Medicaid and require a simple prescription.

General guidelines for the treatment of the asthmatic patient are outlined by the 1997 NIH Expert Panel Report.¹⁴ The document, entitled Guidelines for the Diagnosis and Management of Asthma, represents the current standard of care. The entire 153-page document is available on-line at www.nhlbi.nih.gov/guides.html. Goals include regular objective assessments and education in order to establish a partnership of care between patient and physician, careful avoidance of asthma triggers and the establishment of a written, medication plan for chronic and acute management of symptoms.

Prevent chronic and troublesome symptoms

Maintain (near) "normal" pulmonary function

Maintain normal activity levels (including exercise and other physical activity)

Prevent recurrent exacerbations of asthma and minimize the need for emergency department visits or hospitalizations

Provide optimal pharmacotherapy with minimal or no adverse effects

Meet patients’ and families’ expectations of and satisfaction with asthma care

Available pharmacologic agents can be broken down into two broad categories: the quick-relief medications which relieve bronchoconstriction compared to the long-term, control medications, which prevent and reverse underlying inflammation.(See Table 6)

Beta2 agonists act to relax smooth muscle and to stabilize mast cells. They are not anti-inflammatory agents, instead acting to increase cyclic AMP and antagonizing bronchoconstriction. Inhaled short-acting beta2 agonists act in minutes to hours and are effective for mild to moderate symptoms of asthma.¹⁶ They are prescribed on an as-needed basis because of concerns about possible deleterious effects of heavy use. ¹⁷A recent trial comparing standing and as-needed beta2 agonists found no difference in effectiveness between these two strategies.¹⁸ Side effects include tachyphylaxis, rebound bronchoconstriction and, possibly, tolerance associated with escalating use.¹⁹ Long-acting beta2 agonists such as salmeterol (Serevent) are also available. Long-acting beta2 agonists are not indicated for the treatment of acute exacerbations. Asthma treatment guidelines recommend addition of a long acting beta2-agonist for asthma inadequately controlled by low-moderate dosages of an inhaled corticosteroid (ICS). One 28-week randomized, blinded, placebo controlled study of 164 patients using an inhaled corticosteroid, assigned patients to continue the ICS, switch to salmeterol or take placebo.²⁰ Those continuing ICS and salmeterol showed no objective evidence of deterioration. However, those taking only salmeterol showed more treatment failures and asthma exacerbations than those continuing ICS. The conclusion in this study and in general was that long-acting beta2 agonist monotherapy should not be substituted for ICS, but can be considered in addition to inhaled corticosteroids.

Spacer devices (Aerochamber, InspirEase) can be prescribed for patients using a metered dose inhaler and can facilitate particle delivery; we strongly recommend their use. Salmeterol also comes in diskus form, which may also help to improve delivery of drug therapy to the lungs. Explanations on how to correctly use the metered dose inhaler and spacer are in Tables 4 and 5. The diskus is easy to use: open, click, and inhale once two times daily.

TABLE 4: Using a metered-dosed inhaler

1. Remove cap and shake inhaler vigorously

2. Place MDI 2 inches in front of mouth, or at lips keeping mouth open

3. Breathe out, then slowly inhale, while pressing the top of the inhaler once

4. Hold breath for 5-10 seconds

5. Wait 1-2 minutes prior to second puff

6. Clean inhaler by rinsing with warm water

TABLE 5: Using a spacer with a metered-dose inhaler

1. Insert inhaler mouthpiece into universal gasket on one end of spacer

2. Shake unit

3. Place spacer mouthpiece in the mouth

4. Spray a puff from MDI into spacer

5. Inhale slowly over 5 seconds, holding breath for 10 seconds

6. Wait 1-5 minutes before second dose

7. Rinse spacer with warm water weekly

Anticholinergics such as ipatropium bromide also work as bronchodilators acutely. It may provider some additive benefit with inhaled beta2 agonists in asthma exacerbations.

Corticosteroids as inhaled or oral agents work as anti-inflammatory drugs promoting symptom control. Unlike beta2 agonists, the anti-inflammatory agents have the capacity to alter disease activity.²¹ The NIH Guidelines note that they are "the most potent and consistently effective long-term control medication for asthma."²² Inhaled corticosteroids are effective in reducing the frequency of days with symptoms, reducing the frequency of hospitalizations and decrease the risk of death from asthma.^{23 24 25}

Inhaled corticosteroids are important for prophylactic control of moderate to severe asthma and largely spare the patient the systemic side effects of oral prednisone²⁶; they should be routinely prescribed for patients who require beta-agonists more than twice a week. Inhaled steroids are used to facilitate the withdrawal of oral steroids, and can also be used to control exacerbations.

It is important to explain to patients that the peak effect of inhaled steroids ranges from 6 to 10 hours after use, and that there may be no immediately appreciable benefits. Different formulations have different inhaled steroid doses: beclomethasone (Vanceril, Beclovent) has 42 or 84 mcg/puff, triamcinolone (Azmacort) has 100 mcg/puff, flunisolide (Aerobid) has 250 mcg/puff, and fluticasone (Flovent) can be prescribed at 44, 110 or 220 mcg/puff. All of the inhaled corticosteroids are efficacious, but there is varying potency. Fluticasone is the most potent agent. The effects of steroids are dose-dependent. Most inhaled corticosteroids come in the meter dose form, and should be used with a spacer. Budesonide is available as a dry powdered inhaler, called the Turbohaler and does not require a spacer. With higher doses of any inhaled corticosteroid, side effects increase and can include oropharyngeal candidiasis, dysphonia and occasional cough. Mouth rinsing immediately after use of the inhaler prevents most of these adverse effects. Osteopenia, adrenal suppression and cataract formation have been reported at very high doses.^{27 28 29}

Inhaled mast cell stabilizing agents such as cromolyn sodium (Intal) and nedocromil sodium (Tilade) have anti-inflammatory effects and are occasionally referred to as the "inhaled NSAIDs."³⁰ These agents provide prophylaxis against symptoms, particularly in patients with exercise-induced asthma or seasonal allergies. They are not indicated alone for patients with moderate or severe asthma. A trial of four to six weeks is required to assess their effectiveness in an individual patient; they should not be used during an acute exacerbation. These agents have no significant side effects.

The use of theophylline has decreased somewhat recently, and this drug is now considered second-line therapy.³¹ In patients with nocturnal symptoms, the slow release form can be particularly helpful as a single dose. The therapeutic index of this drug is small and it is associated with numerous side effects, including nausea, headache and tremors. At doses above the therapeutic index, arrhythmias and seizures can occur. Careful monitoring of serum theophylline concentrations is required, and caregivers should be aware that numerous drugs (including erythromycin, coumadin, allopurinol, cimetidine and ritonavir) change serum theophylline levels.

Leukotriene modifiers are the first completely new class of anti-asthma medication since inhaled steroids were introduced in 1972. Leukotrienes, initially described as the "slow-reacting substance of anaphylaxis," have been implicated as important mediators of the inflammatory response in asthma, acting to increase vascular permeability, mucus production and cellular infiltration. They are also powerful bronchoconstrictors. Derived from arachidonic acid and produced by multiple classes of inflammatory cells - including neutrophils, mast cells, eosinophils and macrophages - leukotrienes have long been a target for researchers looking for new anti-asthma drugs.

Leukotriene synthesis inhibitors and receptor antagonists have been tested in a number of clinical trials. All of the available agents, zileuton(Zyflo), zafirlukast(Accolate) and montelukast(Singulair) have been shown to provide superior effect to placebo in the treatment of patients with mild to moderate asthma. Clinical trials of anti-leukotriene agents in chronic asthma have been relatively small and short. In a six-week double-blind randomized placebo-controlled trial of zafirlukast, patients given 20 mg/day reported significant improvement in morning peak flow rates, nighttime awakenings and daytime symptom scores when compared to patients in the 10 mg/day and placebo groups. ³² A 6-month double-blind placebo-controlled trial in patients with moderate asthma found zileuton improved FEV1, decreased asthma symptoms and reduced the use of inhaled beta2 agonists and inhaled steroids. ³³

One randomized double-blind, double-dummy placebo controlled trial compared inhaled corticosteroids at low dose to montelukast in patients with moderate persistent asthma. Both agents showed an improvement in FEV1, quality of life, reduced nocturnal awakenings and asthma attacks, and both agents were well tolerated.³⁴ Other studies have shown that a leukotriene receptor antagonist reduces the need for inhaled corticosteroids.³⁵ Also, adding montelukast to patients who have marginal control of their asthma on ICS may improve FEV1; although deterioration may occur in patients who are weaned from their ICS completely. ³⁶ Safety profiles show that these agents are well tolerated overall. Zileuton does show an increase in LFT’s in a small percentage of patients, although this has not been seen in the other leukotriene modifiers.

The data shows that leukotriene inhibitors and antagonists are a safe and well tolerated alternative to inhaled corticosteroids. They may improve compliance since they can easily be taken in tablet form. These agents are recommended for use when weaning oral steroids, and have been documented to be effective as add on therapy for patients on inhaled corticosteroids who are not controlled. At present, they may be considered alternatives to low-dose inhaled corticosteroids.^{37 38 39}

TABLE 6: Medications for asthma

Combination therapy: More recently, a combination agent of fluticasone/ salmeterol(Advair) has been marketed in diskus form. The diskus comes in three different doses, which are the equivalent of fluticasone at low(50/50), medium(100/50) and high dose(250/50). Salmeterol is the same dose for all three diskus. Several studies have shown that this combination drug may be more effective in controlling lung function than either medication alone. ^{40 41}

It is important to look for an allergen trigger or irritant in all asthmatics. This includes environmental irritants, infection such as sinusitis, tobacco, drugs, emotional stress and esophageal reflux. Removal of the trigger can lead to a dramatic improvement in symptoms. Environmental control measures alleviate the symptoms of asthma in a significant proportion of asthmatics. Allergens that trigger symptoms outside are pollen, ragweed, grass and mold. Moving inside, closing windows and using an air conditioner can help to alleviate symptoms. Indoor allergens include tobacco, smoke, pet dander, house dust mites and mold. Humidifiers can be harmful if not cleaned properly as they can actually increase allergen exposure.

Patients with persistent moderate or severe symptoms related to allergic triggers should be referred to Allergy Clinic for immunotherapy. If symptoms do improve, monthly treatment should continue for three to five years. Influenza and pneumococcal vaccinations are recommended for all patients with moderate or severe asthma. A recombinant humanized antibody, which binds IgE (omalizumab) with high affinity, has been developed for the treatment of allergic diseases. Although not licensed for clinical use in the United States, it may be effective in the future for patients with severe allergic asthma when administered by subcutaneous injections every 2-4 weeks.

Patient education is an extremely important component of effective treatment in asthma. Educating patients requires encouraging them to become active partners in the management of their disease. Education should include repeated explanations, written guidelines, use of home peak flow monitoring and recording, and the mutual evaluation of any action plan.

Mild intermittent asthma refers to infrequent, episodic symptoms less than twice a week. Exacerbations are brief (hours to days) and nocturnal symptoms are rare. Patients are asymptomatic and PEF is normal between exacerbations. A beta2 agonist alone on an as-needed basis is sufficient. If a patient is using daily beta2 agonists, this is considered moderate asthma, and further management with inhaled steroids on a fixed dose schedule should be instituted. Mild persistent asthma is a syndrome characterized by symptoms more than twice a week but less than once a day. Nocturnal symptoms occur more than twice a month, and FEV1 or PEF is greater than 80 percent predicted. Standing low-dose inhaled corticosteroids, or possibly a leukotriene modifier should be used for such patients. Some long term control medication should be instituted.

Moderate persistent asthma is characterized by daily symptoms that affect sleep and activity levels, result in exacerbations that last several days or reduce PEFR to 60-80 percent of a patient’s baseline. Moderate asthma should be treated with a medium-dose inhaled steroid on a fixed schedule. Alternatively, a low-medium dose inhaled steroid may be combined with a long-acting beta2 agonist, or leukotriene modifier. As needed short-acting inhaled beta2 agonists should also be used. If nocturnal symptoms are prominent, sustained-release theophylline may be considered. Acute exacerbations, such as those triggered by respiratory infections, may require a course of oral prednisone at 40-60 mg in single or divided doses. Early treatment with oral steroids may prevent emergency room visits and hospitalization.

Severe persistent asthma occurs when the asthmatic has daily wheezing, frequent exacerbations or requires multiple urgent visits to a physician or emergency room. If such patients are not well controlled on higher doses of inhaled corticosteroids with a long acting beta2 agonists, and/or leukotriene modifiers, an oral corticosteroids should be used (at the lowest effective dose). Immunotherapy may be an adjunct to maximal pharmacological treatment. All patients with severe persistent asthma should be evaluated by an asthma subspecialist.

Exercise-induced asthma is one of the most common precipitants for the asthmatic patient, causing bronchospasm without inflammation and often manifesting as cough or chest tightness. Definitive diagnosis can be made in a laboratory setting, or the patient can simply repeat the activity that causes symptoms and measure the PEFR with a peak flow meter. A decrease of 15 percent would confirm the diagnosis. The management goal is effective symptomatic treatment, and inhaled beta2 agonists are recommended five to 60 minutes prior to exercise. Long term control therapy such as a leukotriene modifier or long-acting b2agonist may alleviate the need for relief medication.

Occupational asthma is defined as a "disorder of variable obstruction and airway hyperresponsiveness attributable to a particular occupational situation."⁴² The mechanisms that lead to airflow obstruction can be immunologically mediated, and in some cases a work-related irritant may cause direct release of bronchoconstrictor substances. The patient often gives a characteristic history that includes initially feeling well at the exposure site but noting worsening symptoms throughout the day. Symptoms fade when the worker leaves the site of the stimulant. With sensitization, even minimal exposure can induce symptoms and long-term exposure can lead to persistent disease. Removal from exposure is the treatment of choice.⁴³

Asthma affects up to four percent of all pregnancies. Management is not substantially different than in the nonpregnant asthmatic. The main principle is to prevent maternal (and subsequent fetal) hypoxemia. Drug therapy safely includes short acting beta2 agonists, mast cell stabilizing agents, theophylline and corticosteroids.

There are not enough pulmonologists in the country to manage all 17 million asthmatics. Generalists manage most patients with asthma, although there are troublesome data to suggest that the care they provide may be inferior to that provided by asthma experts.^{44, 45} Given the prevalence of this disease in our setting, all primary care providers should make sure they are familiar with the latest recommendations for asthma treatment. The NIH Guidelines include criteria for referral to an asthma specialist, which are outlined in Table 7:

TABLE 7: Guidelines for referral to an asthma specialist⁴⁶

We thank Dr. Randolph Cole for his helpful comments and suggestions.