11Adult Asthma

131

From: Current Clinical Practice: Disorders of the Respiratory Tract:

Common Challenges in Primary Care By: M. L. Mintz © Humana Press, Totowa, NJ

11 Adult Asthma

Dharti Patel and Matthew L. Mintz

C ^ONTENTS

C

ASE

P

RESENTATION

K

EY

C

LINICAL

Q

UESTIONS

L

EARNING

O

BJECTIVES

E

PIDEMIOLOGY

P

ATHOGENESIS

D

IFFERENTIAL

D

IAGNOSIS

D

IAGNOSIS

M

ONITORING

T

REATMENT

F

UTURE

D

IRECTIONS

R

EFERENCES

CASE PRESENTATION

A 23-year-old male with a childhood history of mild persistent asthma pre- sents to his primary care physician for an albuterol prescription refill earlier than expected. On further questioning, the patient reveals progressively worsening episodic shortness of breath following his evening runs as well as nighttime awakenings once or twice a week. His current medication regimen includes albuterol for acute attacks and a low dose of fluticasone proprionate for long- term control. The patient is worried about chronic steroid use because of side effects. Physical findings are unremarkable except for a slightly elevated respi- ratory rate of 25 and scattered wheezes.

KEY CLINICAL QUESTIONS

1. What factors determine asthma classification of severity?

2. What is triggering acute exacerbations in this patient?

3. Is the patient overusing his albuterol inhaler? What changes, if any, would you make to his medication regimen to assure control as well as compliance?

4. Is the patient’s concern about chronic corticosteroid use appropriate?

5. What recommendations would you make for monitoring and follow-up?

LEARNING OBJECTIVES

1. Understand the pathophysiology of asthma.

2. Learn how to diagnose, classify, and monitor asthma.

3. Be familiar with the updated evidence-based treatment recommendations.

4. Understand the importance of patient–provider communication in the manage- ment of asthma and learn tools for improvement.

EPIDEMIOLOGY

Asthma continues to be a growing burden in the United States despite the advent of multiple medications and an increased understanding of asthma patho- physiology. There are nearly 2 million emergency department (ED) visits and more than 10 million physician office visits each year. Females, children aged 14 or younger, and blacks as compared with whites have higher rates of office visits.

Blacks also share higher rates of asthma-related ED visits, hospitalizations, and deaths. The numeric increase over the years in numbers and rates of office and ED visits can largely be accounted for by an increase in prevalence. The lifetime prevalence of asthma in the United States is estimated at nearly 26.7 million people and a 12-month attack prevalence (persons with one or more attacks) estimated at nearly 11.1 million. Despite increased treatment options, the mor- bidity and mortality associated with asthma remains high. Asthma accounts for nearly 500,000 hospitalizations and 5000 deaths each year (1). Even patients with mild intermittent and persistent asthma were often identified in a review of asthma-related deaths during sports, underscoring the seriousness of asthma and suggesting possible undertreatment (2). In an effort to address such disparity between the availability of asthma treatment options and an increase in morbid- ity, the National Asthma Education and Prevention Program (NAEPP) updated clinical guidelines in 2002 to define a new standard of care (3).

PATHOGENESIS

Asthma is an obstructive airway disease characterized by episodic airway

narrowing that resolves either spontaneously or with treatment. Two major fac-

tors that contribute to such narrowing are (1) airway hyperresponsiveness to

stimuli, which otherwise elicit minimal to no bronchoconstrictor response in

nonasthmatics, and (2) chronic inflammation, which over time can lead to airway

remodeling and thus partial irreversibility in severe cases. Stimuli vary from

individual to individual and may include various allergens, respiratory viruses, exercise, cold air, stress, and/or occupational exposures.

The inflammation triggered in asthmatics is a complex multicellular process that leads to marked airway edema, mucus plug formation, increase in hyperresponsiveness, and airway remodeling, all of which contribute to airflow limitation. Acute airway obstruction results in paroxysms of wheezing, dyspnea, chest tightness, and cough, usually lasting minutes to hours. Symptoms are often worse at night and in the early morning. In rare cases, acute episodes can persist for days or weeks either with mild obstructive symptoms with or without super- imposed exacerbations or, in status asthmaticus, with continual severe obstruc- tive symptoms. During acute exacerbations, asthma can be potentially fatal.

Asthma develops more often in childhood than in adulthood. Atopy, a genetic predisposition to an immunoglobulin (Ig)E-mediated response to environmental stimuli, is a major risk factor for the development of asthma in childhood. The relationship between atopy and asthma is complex. For example, studies indicate that the link between asthma and rhinitis may go beyond shared risk factors, including genetic predisposition, because they failed to fully explain the strong association between the two. Patients with rhinitis were at a significantly increased risk for asthma and bronchial hypersensitivity than those without asthma, even after adjusting for total IgE, parental history of asthma, and aller- gen sensitization (4). Allergy and a family history of allergy also play an impor- tant role in adult-onset asthma. Adult-onset asthma can also be triggered by occupational exposures, for which symptoms can persist even after the elimina- tion of exposure. Although the mechanisms of the non-allergic, or intrinsic, form of adult-onset asthma are still unclear, it shares a similar inflammatory process to that of atopic asthma.

Inflammation is a key contributor to the onset and persistence of asthma, in which the Th2 lymphocytic cytokine profile including interleukin-4 and -5 plays a significant role. Primary players in the inflammatory process include mast cells, eosinophils, macrophages, T-lymphocytes, and epithelial cells. The release of inflammatory mediators from these cells following contact of the bronchial epithelium with stimuli serves to recruit more cells and potentiate the pathologi- cal response of airway narrowing. They affect airway tone, neural stimulation, mucus secretion, microvascular permeability and leakage, and over time, can affect the structural integrity of the tracheobronchial tree (Table 1). Long-stand- ing inflammation can lead to collagen deposition in the basement membrane and fibrosis of subbasement membrane tissues, which contributes to airway rigidity and persistent abnormalities in pulmonary function unresponsive to treatment.

Hence, early anti-inflammatory treatment is significant in that it may halt or slow

the development of such airway remodeling and modify the disease process. It

is further important to diagnose and treat asthma early because studies have

shown that active asthma can serve as a significant risk factor for the future development of chronic bronchitis, emphysema, and chronic obstructive pulmo- nary disease (COPD) (5).

The component of bronchial hyperresponsiveness is present apart from as well as potentiated by the inflammatory process. Bronchoconstriction contrib- utes significantly to the symptoms of wheezing and dyspnea and the degree of constriction correlates closely with clinical severity. Acute bronchoconstriction following allergen exposure results from IgE-dependent mast cell degranulation of mediators, such as histamine, tryptase, leukotrienes, and prostaglandins, whereas aspirin-induced bronchoconstriction results from non-IgE-dependent mediator release. The mechanism of airflow obstruction is less well understood for other stimuli, such as exercise, cold air, irritants, and stress.

DIFFERENTIAL DIAGNOSIS

Although asthma often presents with recurrent coughing and wheezing, there are multiple other diagnoses that can present with similar symptoms and some may require more urgent intervention (Table 2). It is important to entertain the differential diagnostic possibilities of asthma not only for patients with new onset of coughing and wheezing, but also for patients for whom the diagnosis of asthma has already been established. Some diagnoses to consider are congestive heart failure, pulmonary embolism, laryngeal or vocal cord dysfunction, pulmo- nary infiltration, mechanical obstruction with tumors, as well as medications such as angiotensin-converting enyzyme inhibitors. COPD (chronic bronchitis or emphysema), for which asthma is a significant risk factor, is also among the differential. Whether asthma and COPD are distinct entities or a spectrum remains to be determined, but primary care physicians should consider COPD in their patients with a history of asthma (5).

Table 1

Components of Airway Wall Remodeling That Lead to Permanent Air-Flow Limitation Airway smooth muscle hypertrophy

Angiogenesis

Epithelial cell destruction

Increased submucosal vascularity

Subepithelial collagen deposition

Thickening of the basement membrane

DIAGNOSIS

Asthma is a clinical diagnosis based on a compilation of findings from a detailed medical history, physical exam, and spirometry that establishes the presence of episodic obstructive pulmonary signs and symptoms, at least par- tially reversible airflow obstruction, and rules out differential diagnoses (Table 3).

History should detail symptoms, their severity, frequency, and triggers, as well as explore genetic predisposition to asthma and allergies. Key indicators that increase the likelihood of diagnosis of asthma are a history of recurrent wheez- ing, difficulty breathing, chest tightness, and/or cough as well as a history of these symptoms occurring or worsening at night or in the presence of triggers such as exercise, viral infections, dust mites, mold, smoke, pollen, weather, strong emotions, and menses. Physical exam findings that can assist in diagnosis, though nonspecific, are wheezing during normal respiration, prolonged forced exhalation, increased nasal secretion, mucosal swelling, nasal polyps, and atopic dermatitis or eczema. Symptoms vary from patient to patient, and thus clinical judgment should be utilized to assess for the presence of asthma. Spirometry can assist in making the diagnosis of asthma. Reduced forced expiratory volume in 1 second (FEV

₁

), peak expiratory flow (PEF) rate, and maximal mid-expiratory flow rate suggest airway obstruction. FEV

₁

, forced vital capacity (FVC), and FEV

₁

:FVC measurements should be taken before and after the use of an inhaled short-acting bronchodilator to demonstrate reversibility. an increase of more than 12% and 200mL in FEV

₁

after the use of a bronchodilator indicates reversibility of airflow obstruction. Use of spirometry is recommended for initial assessment over the use of peak-flow meters, which have a wide variability in reference values.

Table 2

Differential Diagnosis of Asthma in Adults Chronic obstructive pulmonary disease

Congestive heart failure Pulmonary embolism Laryngeal dysfunction

Mechanical obstruction of the airways (benign or malignant) Pulmonary infiltration with eosinophilia

Cough secondary to drugs (angiotensin-converting enzyme inhibitors) Vocal cord dysfunction

From ref. 7.

Table 3

Diagnosis of Asthma in Children and Adults Episodic symptoms of airflow obstruction are present

Difficulty breathing Chest tightness

Cough (particularly worse at night)

Symptoms occur or worsen at night, awakening the patient

Symptoms occur or worsen in the presence of exercise, viral infections, animals, dust mites, mold, smoke, pollen, changes in weather, strong emotions, chemicals, or menses

Wheezing

Airflow obstruction is at least partially reversible Diurnal variation of PEF more than 20% over 1–2 weeks

Increase of 12% or more and 200 mL FEV

₁

after bronchodilators indicates reversibility

Reduced FEV

₁

and FEV

₁

:FVC ratio using spirometry indicates obstruction Alternative diagnoses are excluded

Infants and Children Allergic rhinosinusitis Cystic fibrosis

Enlarged lymph nodes/tumor Foreign body

Heart disease Viral bronchiolitis Vocal cord dysfunction Adults

Chronic obstructive pulmonary disease Congestive heart failure

Cough secondary to angiotensin-converting enzyme inhibitors Mechanical obstruction of the airway

Pulmonary embolism

Pulmonary infiltration with eosinophilia Vocal cord dysfunction

PEF, peak expiratory flow; FEV

₁

, forced expiratory volume in 1 second; FVC, forced vital capacity.

If spirometry is normal, but the clinical suspicion for asthma is high, consider

measuring diurnal variation in PEF over 1 to 2 weeks or bronchoprovocation

testing. If there is a more than 20% difference in the morning PEF taken before

the use of a short-acting β-agonist and the early afternoon PEF taken after the use

of a β-agonist, then the diagnosis of asthma is likely. If spirometry testing con-

tinues to be unrevealing, consider bronchoprovocation testing with methacho-

line, histamine, cold air, or exercise challenge. Such testing should only be per- formed by a trained professional and done in individuals with a predicted FEV

₁

more than 65%.

Other objective findings that can suggest asthma are sputum and blood eosi- nophilia, elevated serum IgE levels, and chest hyperinflation. Nonetheless, these findings are nonspecific and chest radiographs are more commonly normal in asthma. Chest radiographs, allergy testing, evaluation of nose for polyps and sinuses for disease, and evaluation for gastroesophageal reflux can be useful in making an accurate diagnosis. If skin allergen sensitivities are found, it is impor- tant to keep in mind that they may not necessarily correlate with allergens that trigger asthma. Finally, once the diagnosis of asthma is made and before any therapy, it is important to classify its severity to guide appropriate management (Table 4).

MONITORING

Patient should follow up as often as the clinician deems appropriate to meet the goals of therapy (Table 5). Routine assessment should evaluate for symptom control over a short period of 2 to 4 weeks, pulmonary function, quality of life/

functional status, history of exacerbations, pharmacotherapy, and patient satis- faction. Spirometry is recommended at the initial assessment, after treatment initiation, and then every 1 to 2 years to monitor pulmonary function. Home peak-flow monitoring is recommended for moderate to severe persistent asth- matics at least every morning, more frequently if PEF is less than 80% of personal best (i.e., the highest PEF over a 2 to 3 week period when asthma is well-con- trolled), and during acute exacerbations to determine severity and guide treat- ment. Peak-flow monitoring can detect airway narrowing before the onset of symptoms and appropriate management can prevent full-blown exacerbations.

Although the significance of written action plans remains inconclusive, the NAEPP expert panel continues to recommend its use for asthma management, especially for patients with moderate to severe persistent asthma and for those with a history of severe exacerbations. All asthmatics should monitor symptoms and be trained to recognize inadequate control and early signs of deterioration.

Asthma control can be difficult to assess secondary to time and resource

constraints in busy medical practices and is often subject to overestimation by

both patients and physicians. Development of the asthma control test (ACT)

(Fig. 1) looks promising because it correlates extremely well with lung function

testing and can either supplement or replace lung function testing when it is not

readily available. ACT is a quick five-item patient-based tool that gauges asthma

symptoms, use of rescue medications, and functional impact to assess asthma

control. ACT was developed using asthma specialist-treated patients, who may

be better educated about asthma, and thus, still needs to be tested in a true primary

care setting (6).

138

Table 4 Asthma Classification and Preferred Medical Treatment Using a Stepwise Approach in Adults and Children Medications required to maintain long-term control Classify severity: clinical features Symptoms/day PEF or FEV

1

before treatment or adequate control Symptoms/night (for adults) Preferred medical treatment Step 1 <2 days/week ⱖ 80% No daily medication needed. Mild intermittent ⱕ 2 nights/month Step 2 <2 days/week ⱖ 80% Low-dose inhaled corticosteroid (with Mild persistent but <1 × /day nebulizer or pressurized metered dose >2 nights/month inhaler with holding chamber with or one per day without face mask or dry powder inhaler for children). Step 3 D aily >60%–80% Adults and children older than 5 years Moderate persistent >1 night/week Low- to medium-dose inhaled corticosteroids and long-acting inhaled β 2 agonists Children 5 years and under Low-dose inhaled corticosteroids and long- acting inhaled β 2 agonists or medium- dose inhaled corticosteroids. Step 4 Continual ⱕ 60% High-dose inhaled corticosteroids and long- Severe persistent Frequent acting inhaled β 2 agonists. Adapted from ref. 3 . All asthmatics should use short-acting bronchodilators on an as needed basis as “quick relievers” to diminish symptoms. Adults and children with persistent asthma should also be on a daily controller medications, intended to prevent asthma symptoms and exacerbations.

Table 5

The Goals of Asthma Therapy

• Maintain normal activity levels

• Maintain “normal” pulmonary function

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

• Prevent chronic symptoms

• Prevent recurrent exacerbations

• Provide optimal pharmacotherapy with minimal or no adverse events Adapted from ref. 3.

The importance of patient–physician communication cannot be overempha- sized. Open communication and education should begin at the time of diagnosis and continue at each follow-up visit. Patients should be taught basic facts of asthma, roles of rescue medications versus controller therapies, how to use inhal- ers and spacers, environmental control measures, and self-monitoring with peak- flow meters. Written materials and formal education programs should be used to supplement, not replace, education provided by physicians. Physicians should work together with the patients to formulate individualized written daily self- management and action plans that meet jointly established treatment goals. Goals should then be reviewed at each visit to assure that they are being met. Action plans and a daily asthma diary are especially important for patients with recurrent severe exacerbations and for those with moderate to severe asthma. Physicians should maintain cultural sensitivity and enlist family involvement where appro- priate.

TREATMENT

Although trigger control is important and the patient should be advised to eliminate or minimize exposure to the causative agent whenever applicable, a pharmacological regimen should be initiated based on the severity of asthma (Table 4). Currently available medications are targeted largely at either reducing airway obstruction via bronchodilation or toward reducing the inflammation that leads to airway narrowing. There are multiple classes of medications, and among them are those that provide quick relief for acute exacerbations and those that provide long-term relief for persistent symptoms.

In an attempt to address the disparity between the wide availability of treat-

ment options and the undertreatment of asthma, the NAEPP expert panel set forth

clinical guidelines to establish a standard of care (7). These guidelines were

recently updated in 2002 to address the safety of and preference for chronic

inhaled corticosteroid therapy, management of moderate persistent asthma,

asthma monitoring, and the controversial role of antibiotics (3). Current recom-

Fig. 1. Asthma Control Test.

mendations for long-term control hail the chronic use of inhaled corticosteroids

as safe and encourage their use as first-line treatment for all asthmatics with

persistent symptoms, including those with mild symptoms. Furthermore, it rec-

ommends the addition of a long-acting β2-agonist to achieve symptomatic con-

trol in moderate to severe asthmatics. For acute exacerbations, short-acting

β-agonists remain the mainstay and guidelines recommend short-term use of

systemic corticosteroids when bronchodilator treatment alone fails to achieve

symptomatic control. There are no benefits associated with the use of antibiotics

in treatment of acute exacerbations, and hence, are not recommended by the

NAEPP panel.

Acute Exacerbations S

HORT

-A

CTING

β2-A

^DRENERGIC

A

GENTS

Short-acting inhaled β2-adrenergic agents, such as albuterol, are currently the mainstay for acute exacerbations, mild-intermittent asthma, and the prevention of exercise-induced bronchospasm. They stimulate β2-receptors, which in turn activate adenylate cyclase and increase cyclic adenosine monophosphate to cause smooth muscle relaxation. With an onset of action generally within minutes, they promptly improve airflow and can sustain the effects for 4 to 6 hours. The more selective β2-agonists, such as albuterol, bitolbuterol, pirbuterol, and terbutaline, are preferred over the less selective isoproterenol, metaproterenol, isoetharine, and epinephrine to maximize the action on the respiratory tract and minimize unwanted cardiac side effects that may occur, especially at high doses of the latter medications. Inhalation is the preferred route of administration because of its faster onset, fewer adverse effects, and greater effectiveness than systemic routes.

Potential adverse effects include tachycardia, skeletal muscle tremor, hypokale- mia, lactic acidosis, headache, and hyperglycemia. Short-acting β2-agonists should be used on an as needed basis for exacerbations and not with a regular daily dosing schedule. Use of more than one canister per month may indicate poor control and warrants the initiation or adjustment of long-term controller therapy.

A

NTICHOLINERGICS

Anticholinergics, such as ipratroprium bromide, are the treatment of choice for β-blocker-induced bronchospasm and provide a good alternative for patients who are otherwise unable to tolerate β2-agonists, such as the elderly or those with co-existent cardiac disease. They provide an additive benefit when used in con- junction with inhaled β2-agonists in severe exacerbations, but are not effective for preventing exercise-induced bronchospasm. Ipratroprium bromide inhibits the effects of acetylcholine on intrapulmonary smooth muscle via competitive inhibition of muscarinic receptors. It reduces the intrinsic vagal tone in the air- ways and may work to decrease mucus production and to block reflex bronchoconstriction resulting from irritants or reflux esophagitis. Ipratroprium brominde helps with cough symptoms, but has a slow onset of action at about 60 to 90 minutes and is not as effective as short-acting β2-agonists in acute broncho- spasm. Adverse effects may include dry mouth and airways, increased wheezing, and blurred vision with exposure to the eyes. The use of atropine, an older anticholinergic, is rare and limited by central nervous system toxicity.

S

YSTEMIC

C

ORTICOSTEROIDS

Systemic corticosteroids, such as methylprenisolone, prednisolone, and pred-

nisone, are effective at reducing inflammation in moderate to severe exacerba-

tions in an otherwise mild asthmatic. They prevent the progression of exacerba- tion, speed recovery, and prevent early recurrence. Corticosteroids have multiple anti-inflammatory actions including blocking the late reaction to allergen, reduc- ing airway hyperresponsiveness, as well as inhibiting cytokine production, adhe- sion protein activation, and cell migration and activation. They also reverse β2-receptor downregulation and prevent microvascular leakage.

Systemic corticosteroids should be used in those patients whose symptoms fail to resolve after a trial of bronchodilator therapy. Steroids have a slow onset of action and improvement may not be seen for at least 4 to 6 hours, and therefore it is important to promptly start and continue aggressive bronchodilator therapy.

Steroid pulse therapy can be initiated at 40 to 60 mg per day and slowly tapered to zero over 7 to 14 days (the dose should be reduced by 50% every third to fifth day) as inhaled corticosteroids are started for long-term control. The goal of short-term systemic therapy is to achieve PEF more than 80%, personal best, or symptom resolution. If symptoms recur after pulse cessation, consider alternate- day corticosteroid therapy with morning dosing as opposed to daily therapy to minimize toxicity. Adverse effects associated with short-term use of systemic corticosteroids include alterations in glucose metabolism, increased appetite, fluid retention, weight gain, mood alteration, hypertension, peptic ulcer, and potentially aseptic necrosis of the femur. Use of systemic corticosteroids can exacerbate co-existent conditions, such as herpes virus infections, varicella, tuberculosis, hypertension, peptic ulcer, and Strongyloides. Adverse effects as- sociated with long-term use include adrenal axis suppression, growth suppres- sion, dermal thinning, hypertension, diabetes, Cushing’s syndrome, cataracts, muscle weakness, and immune suppression.

Long-Term Symptomatic Control I

NHALED

C

ORTICOSTEROIDS

The NAEPP recommends inhaled corticosteroid therapy as the first-line treat- ment for all asthmatics with persistent symptoms whether they are mild, moder- ate, or severe (Table 4). Corticosteroids are safe and effective anti-inflammatory agents with minimal systemic effects when used via inhalation. Although they may not prevent disease progression, they offer good long-term symptomatic control, reduce the need for oral steroids, minimize acute exacerbations, prevent hospitalizations, and dramatically decrease deaths from asthma. The mechanism of action of inhaled corticosteroids is similar to that of systemic use.

Inhaled corticosteroids include beclomethasone diproprionate, budesonide,

flunisolide, fluticasone proprionate, and triamcinolone acetonide. Dexametha-

sone is not recommended secondary to high systemic absorption resulting in

long-term side effects. The dosing is based on clinical severity and is not abso-

lutely interchangeable among the different inhaled corticosteroids. They can

take up to a week to show improvement, therefore systemic corticosteroid use should be considered if there is an urgent need for symptomatic control. Systemic therapy works well acutely when airway obstruction is not improving or wors- ening despite optimal bronchodilator therapy or used chronically in rare patients when standard therapy fails to achieve good control.

There has been considerable controversy regarding the safety of chronic in- haled corticosteroid use. After reviewing multiple studies examining bone mineral density, subcapsular cataracts, glaucoma, and hypothalamic–pituitary–adrenal axis suppression, the NAEPP panel found negligible adverse events from chronic inhaled corticosteroid use. They concluded that they are safe and that the benefits clearly outweighed the small potential risks. The more common adverse effects include oral candidiasis, hoarseness, and cough. Such adverse effects can be reduced with the use of aerosol spacers and rinsing the mouth after every dose.

L

^ONG

-A

^CTING

β2-A

^DRENERGIC

A

^GENTS

Long-acting β2-agonists, such as salmeterol and formoterol, stimulate intra- pulmonary β2-receptors to cause sustained bronchodilation that can last up to 12 hours. They are effective controller agents, especially for nocturnal symptoms and exercise-induced bronchospasm, but should not be used alone or in lieu of anti-inflammatory therapy. The NAEPP panel recommends its use in combina- tion with inhaled corticosteroids because such combination is superior to all other combinations as well as to higher dosages of inhaled corticosteroids alone for moderate to severe asthma. Long-acting β2-agonists should not be used to treat acute exacerbations as they have a slower onset of action (15–30 minutes).

Adverse effects include tachycardia, tremor, hypokalemia, and a prolonged QTc interval in overdose. Inhalation is the preferred route of administration because it produces more sustained effects with less adverse reactions than oral agents such as sustained-release albuterol.

Combination medications with long-acting β2-adrenergic agents are avail- able and serve as powerful agents in the asthma armamentarium to improve medication adherence, reduce morbidity and mortality, and health care expendi- tures. Recent studies demonstrate that the refill persistence for fluticasone proprionate and salmeterol combination was significantly more than for fluticasone proprionate taken alone or in combination with other controller thera- pies and that medication adherence was comparable to an oral agent (8).

L

EUKOTRIENE

M

ODIFIERS

This class of medications works either by inhibiting the enzyme 5-lipoxygenase

(zileuton) to prevent the synthesis of leukotrienes or by antagonizing leukotriene

receptors (montelukast, zafirlukast). Anti-leukotrienes are variably effective in

patients and thus, are considered alternative medications for mild persistent

asthma and should only be used in combination with inhaled corticosteroids for

more severe asthma. Review of current data demonstrates that the addition of anti-leukotrienes to inhaled corticosteroid therapy shows only modest improve- ment in lung function and are at best second-line agents when used alone com- pared with inhaled corticosteroids (9,10). Montelukast is a leukotriene receptor antagonist, specifically inhibiting the cysteinyl leukotriene (CysLT1) receptor.

It blocks leukotriene (LTD4)-mediated effects causing airway edema, broncho- spasm, and inflammation. Montelukast has milder side effects such as headache, muscle aches, abdominal pain, nasal congestion, rash, and fever compared with zileuton and zafirlukast, which can also cause elevation of hepatic enzymes and reduce the metabolism of drugs such as warfarin.

M

ETHYLXANTHINES

Methylxanthines, such as theophylline and aminophylline, are mild to mod- erate bronchodilators that act via phosphodiesterase inhibition. They are at best second-line medications for use either alone in mild persistent asthma or in combination with inhaled corticosteroids for moderate to severe persistent asthma. They are infrequently used as controller medications because of their wide variability in metabolism among individuals, which makes them prone to toxicity. If administered, they require close monitoring to maintain steady-state serum levels between 5 and 15 μg/mL, above which cardiac arryhthmias and seizures become more likely and can present without any milder symptoms.

C

^ROMOLYN

S

^{ODIUM AND}

N

^EDOCROMIL

Cromolyn sodium and nedocromil are nonsteroidal anti-inflammatory medi- cations indicated as alternative treatment for mild persistent asthma or as preven- tative treatment before exercise or known allergen exposure. They block chloride channels, stabilize mast cell membranes, and curb eosinophilic recruitment. They both block the early and late response to allergen, but nedocromil is more effec- tive at blocking the acute response to exercise and cold dry air. Their safety makes their use popular among the pediatric population.

FUTURE DIRECTIONS

Despite greater understanding of asthma pathophysiology and treatment op-

tions, asthma continues to remain underdiagnosed and undertreated. Although

the NAEPP has set forth guidelines to address this disparity and reduce asthma

exacerbations, asthma-related ED visits have remained elevated in the past

decade. Studies show that the asthmatic population are largely dependent on

rescue medications, such as short-acting bronchodilators and oral corticoster-

oids, but even more striking is that even an acute event such as an ED visit does

not result in significant change in long-term controller therapies (11). Given that

there are 2 million asthma-related events each year in the United States, this

should be a major focus for improving care. Furthermore, this study also showed

that in the 12 months before the ED event, 90% presented to a primary care physician, 50% with asthma-related complaints, but nearly 75% did not receive inhaled corticosteroid controller therapy, first-line treatment for persistent asthma (11). Underclassification of severity and inadequate treatment of asthma cannot be overemphasized because it is associated with a high level of morbidity and mortality, and particularly after an ED event, because continued inadequate management sustains the risk of future acute events, ED visits, and hospitaliza- tions. This calls for a better way of monitoring patient status. Although research data is inconclusive, the NAEPP continues to recommend written action plans, peak-flow monitoring, and routine office spirometry as means for monitoring in the hopes of preventing exacerbations.

Markers for asthma severity and inflammation are also an area of investiga- tion. Although pulmonary function tests are objective measures of lung function, they do not correlate perfectly for disease severity and are suboptimal for moni- toring disease status, such as a hemoglobin A1c for diabetes or systolic blood pressure for hypertension. Nitrous oxide (NO) is produced by inflammatory cells and exhaled NO might serve as such a marker for disease status. There is evi- dence that NO correlates with disease severity, but significantly more data is needed.

Finally, newer therapeutic agents will be helpful. Although the safety of inhaled corticosteroids has been established, newer and theoretically safer inhaled steroids are in development. Although the methylxanthines, once a mainstay of asthma therapy, have been relegated to third- or fourth-line options, newer more specific phosphodiesterase inhibitors may provide excellent bronchodilation without the associated side effects or narrow therapeutic win- dow. Lastly, different delivery devices and combination products will also come to the US market soon, including the combination of fomoterol (a long-acting bronchodilator) and budesonide (inhaled corticosteroids). The faster action of fomoterol over salmaterol may allow asthma control and relief in a single inhaler, possibly leading to improved compliance and control.

REFERENCES

1. Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC. Surveillance for asthma—1980–1999. MMWR Surveill Summ 2002;51:1–13.

2. Becker J, Rogers J, Rossini G, Mirchandani H, D’Alonzo GE, Jr. Asthma deaths during sports: report of a 7-year experience. J Allergy Clin Immunnol 2004;113:264–267.

3. National Asthma Educatoin and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma: update on selected topics—2002. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD, 1997; NIH publication no. 02-5074.

4. Leyhnaert B, Neukirch C, Kony S, et al. on behalf of the European Community Respiratory

Health Survey. Association between asthma and rhinitis according to atopic sensitization in

a population-based study. J Allergy Clin Immunnol 2004;113:86–93.

5. Silva G, Sherrill D, Guerra S, et al. Asthma as a risk factor for COPD in a longitudinal study.

Chest 2004;126:59–65.

6. Nathan RA, Sorkness CA, Kosinski M, et al. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunology 2004;113: 59–65.

7. National Asthma Education and Prevention Program. Guidelines for the diagnosis and man- agement of asthma: expert panel report 2. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Insti- tute, Bethesda, MD, 1997; NIH publication no. 97-4051.

8. Stoloff S, Stemple DA, Meyer J, Stanford RH, Carranza Rosenzweig JR. Improved refill persistence with fluticasone proprionate and salmeterol in a single inhaler compared with other controller therapies. J Allergy Clin Immunol 2004;113: 245–251.

9. Ducharme F, Di Salvio, F. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma and children. Cochrane Database Sys Rev 2005;4.

10. Ducharme F, Schwartz Z, Hicks G, Kakuma R. Addition of anti-leukotriene agents to inhaled corticosteroids for chronic asthma. Cochrane Database Sys Rev 2004;4:CD003133.

11. Stempel D, Roberts CS, Stanford RH. Treatment patterns in the months orior to and after

asthma-related emergency department visit. Chest 2004;126:75–81.