Asthma is a chronic pulmonary disease that affects 17 million Americans - approximately five percent of the population.[i] 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.[ii]^,[iii] Both hospitalization and mortality are higher in nonwhites, the socioeconomically underserved and those living in urban areas such as New York City.[iv] 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.[v] 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 remain unclear,[vi]^,[vii] 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 inflammatory cells, particularly eosinophils, that lead to further plugging and vasospasm, resulting in airway obstruction. The cascade of events is perpetuated, with more arachidonic acid metabolites and histamine releasing factors amplifying the airway obstruction, which can last for days.

There are provocative but inconclusive data linking asthma (and other chronic lung diseases) to infection with Chlamydia pneumonia. A recent systematic review of the 18 controlled studies seeking to find an association between infection and asthma and/or COPD reported that such associations were significant in 15 such studies.[viii] Similar theories associating asthma with viral upper respiratory infection have been proposed. 

TABLE 1: List of acronyms
 

B2 agonist	beta 2 agonist	MDI	metered dose inhaler
FEV1	forced expiratory volume in 1 second	MMFR	maximum midexpiratory flow rate
FVC	forced vital capacity	PEFR	peak expiratory flow rate
FEFmax	maximum forced expiratory flow rate	PFR	peak flow rate
FRC	functional residual capacity	PFT	pulmonary function test

Diagnosis

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.[ix]

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 recommended – 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.[x]^,[xi]

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. 

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;[xii] these tests are not routinely indicated in our setting. 

TABLE 2: Classification of asthma severity
 

	Symptoms (before treatment)	PM Symptoms	Lung Function
Mild intermittent (Step 1)	- Symptoms < 2 times/week - Asymptomatic and normal PEFbetween exacerbations - Exacerbations brief	< 2 times/month	- FEV1 or PEF > 80% predicted - PEF variability < 20%
Mild persistent (Step 2)	- Symptoms > 2 times/week but < 1 time/day - Exacerbations may affect activity	> 2 times/month	- FEV1 or PEF > 80% predicted - PEF variability 20-30%
Moderate persistent (Step 3)	-Daily symptoms -Daily use of inhaled short-acting b2 agonists -Exacerbations affect activity -Exacerbations > 2 times/week; may last days	> 1 time/week	- FEV1 or PEF 60%-80% predicted - PEF variability > 30%
Severe persistent (Step 4)	- Continual symptoms - Limited physical activity - Frequent exacerbations	Frequent	- FEV1 or PEF < 60% predicted - PEF variability > 30%
The presence of one of the features of severity is sufficient to place a patient in that category. An individual should be assigned to the most severe grade in which any feature occurs.

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.[xiii] 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.

General guidelines for the treatment of the asthmatic patient are outlined by the International Consensus Report for the Diagnosis and Treatment of Asthma,[xiv] and, more recently, by the 1997 NIH Expert Panel Report.[xv] The latter, 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 medication plan for chronic and acute management of symptoms.

TABLE 3: NIH Expert Panel - Goals of asthma therapy[xvi]

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.[xvii] They are prescribed on an as-needed basis because of concerns about possible deleterious effects of heavy use.[xviii] A recent trial comparing standing and as-needed beta2 agonists found no difference in effectiveness between these two strategies.[xix] Side effects include tachyphylaxis, rebound bronchoconstriction and, possibly, tolerance associated with escalating use.[xx] Long-acting beta2 agonists such as salmeterol (Serevent) are also available, although regular use may lead to tolerance.[xxi] Long-acting beta2 agonists are not indicated for the treatment of acute exacerbations. Spacer devices (Aerochamber, InspirEase) can be prescribed for patients and can facilitate particle delivery; we recommend their use. Explanations on how to correctly use the metered dose inhaler and spacer are in Tables 4 and 5.

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

Corticosteroids as inhaled or oral agents work as anti-inflammatory drugs promoting symptoms control. Unlike beta2 agonists, the anti-inflammatory agents have the capacity to alter disease activity;[xxii] the NIH Guidelines note that they are “the most potent and consistently effective long-term control medication for asthma.”[xxiii]Inhaled steroids are important for prophylactic control of moderate to severe asthma and largely spare the patient the systemic side effects of oral prednisone;[xxiv] 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 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. The different agents are not equivalent on a weight basis. The effects of steroids are dose-dependent. With higher doses, 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.[xxv]^{,[xxvi],[xxvii]}

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.”[xxviii] These agents provide prophylaxis against symptoms, particularly in patients with exercise-induced asthma or seasonal allergies. They are not indicated 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.[xxix] In patients with nocturnal symptoms, the slow release form can be particularly helpful, but 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 small clinical trials; while there are little data about long term use or combination with other classes of anti-asthma medication, early results are very encouraging. Both inhibitors and antagonists have been shown to block leukotriene-induced bronchoconstriction in test subjects, as well as to moderate clinical response to allergen challenge. In addition, they have been shown to be clinically effective in several short-term models such as cold-induced, exercise-induced and aspirin-triggered asthma.

Clinical trials of anti-leukotriene agents in chronic asthma have been relatively small and relatively short. In a six-week double-blind randomized placebo-controlled trial of oral zafirlukast (a leukotriene receptor antagonist whose trade name is Accolate), 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.[xxx] A 13-week randomized, double-blind, placebo-controlled trial demonstrated that patients on zafirlukast had 89 percent more days without use of beta2 agonists, 55 percent fewer health care contacts and 55 percent fewer days of absence from work or school.[xxxi]A 6-month double-blind placebo-controlled trial in patients with moderate asthma found zileuton (a leukotriene synthesis inhibitor, trade named Zyflo) improved FEV1, decreased asthma symptoms and reduced the use of inhaled beta2 agonists and inhaled steroids.[xxxii]

The optimal role of leukotriene inhibitors and antagonists in the clinical management of asthma has yet to be determined. At present, they may be considered alternatives to low-dose inhaled corticosteroids.[xxxiii]^{,[xxxiv],[xxxv]}

TABLE 6: Medications for asthma
 

Long-term-control medications: Corticosteroids Cromolyn sodium and nedocromil Long-acting beta2-agonists Methylxanthines (theophylline) Leukotriene modifiers

Quick-relief medications: Short-acting beta2-agonists Anticholinergics (ipratropium bromide) Systemic corticosteroids

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. 

Patient education is an extremely important component of effective treatment in asthma. Educating patients required 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 treatment 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 should be used for such patients.

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.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. Early treatment with oral steroids may prevent emergency room visits and hospitalization. For patients with prominent nocturnal symptoms, extended-release theophylline preparations can be useful.

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 steroids or a mast cell stabilizing agent with beta2 agonists, long term oral corticosteroids should be used (at the lowest effective dose). Immunotherapy may be an adjunct to maximal pharmacologic 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.

Occupational asthma is defined as a “disorder of variable obstruction and airway hyperreponsiveness attributable to a particular occupational situation.”[xxxvi] 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.[xxxvii]

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 beta2 agonists, mast cell stabilizing agents, theophylline and corticosteroids. Immunotherapy appears to be safe in pregnancy, although anaphylaxis can occur. If a patient is receiving immunotherapy and is deriving benefit from desensitization, treatment can be continued. 

Subspecialty referral

TABLE 7: Guidelines for referral to an asthma specialist[xl]

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