Environmental Asthma and Allergic - All about Asthma, Asthma Treatments, Asthma Medication, Asthma Clinical, Asthma Introduction

Synonyms and related keywords: reactive airways disease, RAD, occupational asthma, reversible airway obstruction, increased bronchial reactivity, airway inflammation, passive smoke inhalation, allergic disease, aeroallergen exposure, viral respiratory illness, allergen-specific immunoglobulin E, allergen-specific IgE, airway hyperreactivity, AHR, airway remodeling, status asthmaticus, atopy, asthma triggers, nonallergic rhinitis, early allergic response, EAR, late allergic response, LAR, mite antigens, cockroach antigens, occupation-induced airway disease, occupation-induced asthma, industry-induced airway disease, industry-induced asthma, industrial asthma, occupational asthma, seasonal pollen allergens, mold spore allergens, dust mite allergens, animal allergens, food allergens, breath-actuated inhaler, BDI, dry-powder inhaler, DPI, metered-dose inhaler, MDI, breath actuated inhaler, dry powder inhaler, metered dose inhaler

ASTHMA INTRODUCTION

Background

Asthma is a clinical syndrome characterized by episodic reversible airway obstruction, increased bronchial reactivity, and airway inflammation. Asthma results from complex interactions among inflammatory cells, their mediators, airway epithelium and smooth muscle, and the nervous system. In genetically susceptible individuals, these interactions can lead to symptoms of breathlessness, wheezing, cough, and chest tightness.

Risk factors for asthma include a family history of allergic disease, the presence of allergen-specific immunoglobulin E (IgE), viral respiratory illnesses, exposure to aeroallergens, obesity, and lower socioeconomic status.

Environmental exposure in sensitized individuals is a major inducer of airway inflammation, which is a hallmark finding in the asthmatic lung. Although triggers induce inflammation through different pathways, the resulting effects all lead to increased bronchial reactivity.

Exposure to dust mites within the first year of life is associated with later development of asthma and, possibly, atopy. Mite and cockroach antigens are common, and exposure and sensitization has been shown to increase asthma morbidity. Allergies trigger asthma attacks in 60-90% of children and in 50% of adults. Approximately 75-85% of patients with asthma have positive (immediate) skin test results. In children, this sensitization is associated with disease activity. The level of IgE is associated with the prevalence and severity of airway hyperresponsiveness (AHR) and asthma.

Although most people with asthma have aeroallergen-induced symptoms, some individuals manifest symptoms with nonallergic triggers. As many as 3-10% of people with asthma are sensitive to nonsteroidal anti-inflammatory drugs (NSAIDs). Approximately 5-10% of people with asthma have occupation- or industry-induced airway disease. Many individuals develop symptoms after viral respiratory tract infections.

Allergen avoidance and other environmental control efforts are feasible and effective. Symptoms, pulmonary function test findings, and AHR improve with avoidance of environmental allergens. Removing even one of many allergens can result in clinical improvement. However, patients frequently are not compliant with such measures.

Asthma Pathophysiology

The allergic response in the airway is the result of a complex interaction of mast cells, eosinophils, T lymphocytes, macrophages, dendritic cells, and neutrophils. Inhalation-challenge studies with allergens reveal an early allergic response (EAR), which occurs within minutes and peaks at 20 minutes following inhalation of the allergen. Clinically, the manifestations of the EAR in the airway include bronchial constriction, airway edema, and mucus plugging. These effects are the result of mast cell–derived mediators. Four to 10 hours later, one sees the late allergic response, which is characterized by infiltration of inflammatory cells into the airway and is most likely caused by cytokine-mediated recruitment and activation of lymphocytes and eosinophils.

Antigen-presenting cells (ie, macrophages, dendritic cells) in the airway capture, process, and present antigen to helper T cells, which, in turn, become activated and secrete cytokines. Helper T cells can be induced to develop into T_H1 (ie, interferon-gamma, interleukin [IL]–2) or T_H2 (ie, IL-4, IL-5, IL-9, IL-13). Allergens drive the cytokine pattern towards T_H2, which promotes B-cell IgE production and eosinophil recruitment. Subsequently, IgE binds to the high-affinity receptor for IgE, Fc-epsilon-RI, on the surface of mast cells and, with subsequent exposure to the allergen, the IgE is cross-linked. This leads to degranulation of the mast cell. Preformed mast cell mediators, such as histamine and proteases, are released, leading to the EAR.

Newly formed mediators such as leukotriene C₄ and prostaglandin D₂ also contribute to the EAR. Proinflammatory cytokines (IL-3, IL-4, IL-5, tumor necrosis factor-alpha) are released from mast cells and are generated de novo after mast cell activation. These cytokines contribute to the late allergic response by attracting neutrophils and eosinophils. The eosinophils release major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase into the airway, causing epithelial denudation and exposure of nerve endings. The lymphocytes that are attracted to the airway continue to promote the inflammatory response by secreting cytokines and chemokines, which further potentiate the cellular infiltration into the airway. The ongoing inflammatory process eventually results in hypertrophy of smooth muscles, hyperplasia of mucous glands, thickening of basement membranes, and continuing cellular infiltration. These long-term changes of the airway, referred to as airway remodeling, can ultimately lead to fibrosis and irreversible airway obstruction in some, but not most, patients.

Frequency

United States

Prevalence is difficult to determine because definitions and survey methods vary, but it is likely increasing as a result of greater sensitization to common allergens and the redefinition of some nonatopic wheezing as asthma. From 1982-1992, the average age-adjusted prevalence rate increased 42% (from 34.7/1000 to 49.4/1000). Asthma may affect 31 million people, including 9.2 million children (7.2% of adults by self-report).

International

Asthma affects more than 100 million people worldwide. Some reports suggest asthma prevalence has peaked at 8-12%, perhaps because of improved management or because asthma has already been induced in the maximal number of genetically available individuals.

Mortality/Morbidity

• The death rate from asthma is 17.7 deaths per million people. Mortality has increased, especially in children who live in inner-city areas, despite advances in disease understanding and therapy. The number of deaths annually decreased from 5067 (1960-1962) to a low of 1870 (1975-1978) and then increased to 5429 (1993-1995).



• Annually, asthma is responsible for 1.5 million emergency department (ED) visits, 500,000 hospital admissions (third leading preventable cause), and 100 million days of restricted activity. Medical expenses and lost work and productivity cost an estimated $12.7 billion in 1998. Increased morbidity is multifactorial and may include increased exposure to indoor allergens, less exposure to viral infections early in life, more environmental pollution, overuse of short-acting beta-2 agonists, underuse of anti-inflammatory medications, and limited access to, or education about, health care.

Race

• Females, ethnic minorities, people with a low annual family income ($20,000/y in the United States), and persons with poor access to, or education about, health care have worse outcomes than other individuals.

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• Hospitalization and death rates are 3 times greater in African Americans.

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• Asthma is rare in Eskimos.

Sex

• Boys have been shown to be at greater risk for asthma than girls. In children younger than 14 years, the prevalence is twice as high in boys compared with girls.

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• The difference narrows with age, and women aged 40 years have a greater prevalence than men of the same age.

Age

• Disease onset can occur in persons of any age, but children often present when younger than 6 years. Asthma is the most common chronic disease of childhood.



• Many young children “outgrow” asthma, especially boys who have no personal or family history of atopy. However, clinical experience shows that many teenagers who become asthma-free develop asthma again in their 20s and 30s. Perinatal exposure to allergens or passive smoke has been postulated to make outgrowing asthma less likely.

CLINICAL ASTHMA

History

The classic history consists of wheeze, cough, and dyspnea. The predictive value of any single parameter is approximately 30% but is much higher when parameters are combined. Chest discomfort (eg, pain, tightness, congestion, inability to take a full breath) is also common. Some patients may have cough without other symptoms. Recurrent or refractory chest colds may also suggest the diagnosis.

• Record the following:
  
  
  • Age of onset
  
  
  
  • Frequency and severity of daytime and nocturnal symptoms
  
  
  
  • Symptom triggers, such as exercise, animals, irritants (smoke), and occupation (worse on workdays)
  
  
  
  • Seasonal and geographic variation
  
  
  
  • Limits on activity, lost work or school days, and quality of life
  
  
  
  • Number of ED and urgent clinic visits, hospital admissions, intensive care unit (ICU) stays, and need for mechanical ventilation
  
  
  
  • Past treatments, including oral and inhaled steroids, frequency of rescue inhaler use, immunotherapy, and environmental avoidance
  
  
  
  • Family history of asthma
  
  
  
  • Personal or family history of atopy, allergy, rhinitis (including nonallergic rhinitis), or sinusitis
  
  
  
  • Gastroesophageal reflux symptoms
  
  
  
  • Food allergy
  
  
  
  • Growth (children)
  
  
  
  • Atopic dermatitis
    
• All patients should be asked about or should complete a questionnaire regarding exacerbation of symptoms, as follows:
  
  
  • Allergic
    
    
    • Perennial symptoms - Pet in the home (especially in the bedroom, bed, or both), school, day care, or work environment; moisture, dampness, and humidifier use; mold and musty odors in any part of the home; cockroaches in the home; worsening of symptoms after vacuuming rugs (typical of dust mite allergen)
    
    
    
    • Seasonal symptoms (may extend beyond one season in temperate or tropical climates) - Early spring (trees), late spring and summer (grasses), summer and fall (dry molds), and fall (weeds)
      
  • Environmental
    
    
    • Personal or secondary tobacco smoke exposure in or out of the home
    
    
    
    • Stoves, fireplaces, or heaters used in home
    
    
    
    • Sprays or chemical agents at work, home, or with hobbies
    
    
    
    • Symptoms only at one place (ie, at work during week with no symptoms on weekends)
    
    
    
    • School or business associates with similar problems
    
    
    
    • Symptoms after eating (seafood or dried, canned, or processed food)
    
    
    
    • Medications such as beta-blockers (including eye drops), aspirin, or other NSAIDs

Physical

Physical examination findings are often normal.

• Head and neck: Nasal mucosal swelling, discharge, polyps, or sinus percussion tenderness may suggest associated allergic rhinitis or sinusitis. Wheezing heard only or mostly over the neck may suggest vocal cord dysfunction (VCD) or other laryngeal abnormality, though VCD can be present without a localizing wheeze.



• Cardiac: Findings are normal. Patients with status asthmaticus may have a pulsus paradoxus greater than 10 mm Hg.



• Respiratory: During an acute asthma exacerbation, lung examination findings may include wheezing, rhonchi, hyperinflation, or prolonged expiratory time. With severe disease, lung auscultation may reveal absent breath sounds (indicating poor air movement) or signs of respiratory distress and failure (eg, nasal flaring, grunting, accessory muscle use, cyanosis). Focal wheezing may indicate foreign body or other airway obstruction such as a tumor.



• Skin: Check the patient for atopic dermatitis.



• Extremities: Digital clubbing should not be present.

Causes

The etiology of asthma is likely multifactorial. Genetic factors may control individual predispositions to asthma and responses to medications. Genetics alone cannot account for the significant increases in prevalence, as genetic factors take several generations to develop, and asthma and atopy are not always co-inherited. Several environmental or lifestyle factors have been implicated.

• A hygienic hypothesis proposes that cleaner environments have led to less immunological stresses, preventing the development of an asthma-protective T_H1 cytokine phenotype.



• Measles infection, BCG vaccine administration, hepatitis A seropositivity, and other stimuli that increase production of interferon-gamma and IL-12 may inhibit the T_H2 allergic response.



• In selected series, vaccinations, fewer childhood infections, liberal use of antibiotics, more processed food in diets, smaller families, and less exposure to day care environments have been associated with increased atopy and asthma. Asthma, atopy, and AHR are more prevalent in western Germany, while bronchitis is more common in eastern Germany.



• One theory to explain the increased prevalence of allergic disease is that with fewer infectious stimuli in the environment, the in utero T_H2 allergic cytokine state never switches to the T_H1 state.



• Causes or triggers of asthma can be divided as follows:
  
  
  • Allergic: Aeroallergens can include seasonal pollen, mold spores, dust mites, animal allergens, and food (especially in children). Monosodium glutamate does not appear to be an allergen.
  
  
  
  • Nonallergic: These may include smoke, odors, cold air and weather, chemicals, medications (eg, aspirin, other NSAIDs, beta-blockers), exercise, hormonal changes (eg, pregnancy, menstrual cycle), and bisulfite food additives.

WORKUP ASTHMA

Lab Studies

• The most important tests are pulmonary function tests (see Other Tests). The serum IgE level is elevated only approximately half the time in patients with allergic disease. Checking IgE levels is not indicated in most patients with asthma. Levels greater than 1000 ng/mL (1 IU= 2.4 ng) may suggest an alternate diagnosis, such as allergic bronchopulmonary aspergillosis



• Sputum and serum eosinophilia tests are not routinely performed or required for diagnosis. Decrease in sputum eosinophilia may suggest asthma control or responsiveness to inhaled steroids. Note that a finding of greater than 15% serum eosinophilia can indicate parasites, drug allergies, or eosinophilic pulmonary disorders.



• Exhaled nitric oxide may also predict airway inflammation and asthmatic control but is more expensive to measure.



• In older patients, an elevated serum brain natriuretic peptide (BNP) level may help suggest heart failure as a primary or contributing cause of dyspnea and wheezing.



• Skin testing is one of the most useful ways to determine specific allergen sensitivity. A skin test or in vitro radioallergosorbent assay test (RAST) is very useful in advising patients about allergen avoidance techniques.

Imaging Studies

• Chest radiographs: These are taken only if pneumonia, large airway lesions, or heart failure is suggested or if symptoms are atypical or refractory to therapy, if the patient has unilateral or focal wheezing, or if the patient has new adult-onset asthma.



• Modified or limited sinus CT scans: Consider CT scans of the sinuses if chronic sinusitis is suggested. About 65% of people with severe asthma have concomitant sinusitis.



• Chest CT scans: These are indicated in select patients to help exclude interstitial lung disease, bronchiectasis, bronchiolitis, or infection.



• Echocardiograms: These are performed if congestive heart failure is suggested based on history and physical examination findings.

Other Tests

• Symptom improvement with asthma therapy is suggestive but not diagnostic of asthma. Symptoms alone do not necessarily reflect asthma severity. Infants may be treated empirically. In patients older than 5 years, objectively demonstrating reversible airflow obstruction with pulmonary function tests is possible and essential.
  
  
  • Obstruction is defined as a ratio less than 70% of forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC). FEV₁ is normally greater than 80% of values predicted by age. Young patients with a supranormal FVC can sometimes have a reduced FEV₁-to-FVC ratio without having obstructive lung disease.
  
  
  
  • Reversibility can be shown by administering a short-acting beta-2 agonist inhaler with a resultant 10-12% and more than 200-mL improvement in FEV₁ or FVC. If no response, 2-3 weeks of oral or inhaled corticosteroids (20 mg twice daily for the average patient) may be required to demonstrate an improvement in airflow. Note that airflow obstruction in some patients with chronic obstructive pulmonary disease may be partially reversible.
  
  
  

  • A 15% drop in FEV₁ after 6 minutes of running or other exercise can be diagnostic of exercise-induced bronchospasm.

  • A 20% variation in the peak expiratory flow rate (PEFR) between high and low values is highly suggestive of asthma, but formal pulmonary function testing (as above) is recommended because the PEFR is extremely effort-dependent.

  • An asthma specialist can perform bronchoprovocation testing with exercise, histamine, methacholine, or eucapnic voluntary hyperventilation. The results from these tests have a very high negative predictive value and are useful for excluding the diagnosis of asthma. The authors most commonly use a challenge with increasing doses of inhaled methacholine. A 20% decline in FEV₁ with a methacholine concentration of 8 mg/mL or less is considered a positive (abnormal) test result. This testing should be avoided during pregnancy because of the risk of precipitating an asthma attack and because methacholine is a class C drug.

• Allergen-inhalation challenges can be performed in selected patients but are generally not needed or recommended. This test requires an available allergen solution and specialized centers able to handle potentially significant reactions. A negative test finding may allow continued exposure to an allergen (eg, family pet); a positive test finding can dramatically indicate that the patient should avoid a particular allergen. This test is often needed to help diagnose occupational asthma.



• A trial of allergen avoidance may be diagnostic and therapeutic.



• If restrictive or other lung disease is suggested by history, physical examination, or pulmonary function testing findings, additional data must be obtained, including complete lung volumes, respiratory muscle strength, diffusion capacity, and a high-resolution CT scan.



• Perform a barium swallow, endoscopy, or 24-hour pH probe (the Bravo study is now possible in selected centers) to help diagnose gastroesophageal reflux disease (GERD) if a patient’s condition is refractory to asthma therapy. Empiric medical therapy is often tried without performing these tests, especially if a patient has symptoms of GERD.



• Measure oxygenation (ie, with pulse oximetry or arterial blood gas testing) in selected patients.



• Perform sweat chloride testing for cystic fibrosis or immunoglobulin level testing for immunodeficiency if these conditions are suggested.



• Skin testing should be performed to help detect the presence of allergen-specific IgE against environmental triggers that are suggested based on the patient's questionnaire answers and history information.
  
  
  • Testing is recommended for antigens to which the patient is exposed rather than testing with a standard panel.
  
  
  

  • Skin test findings have very high positive and negative predictive values; however, a negative test finding does not rule out the possibility that an allergen is having an impact on the patient’s asthma. Conversely, a positive test finding does not mean that a patient is exposed to an allergen or that he or she will react to it in a natural exposure.

  • Antihistamine medications, but not short courses of oral glucocorticoids at moderate doses, interfere with allergy skin testing.

  • Testing should not be performed during an asthma exacerbation, and the testing site should be equipped for the treatment of rare life-threatening reactions.
  
  
  

  • Skin testing is performed with controls (eg, histamine and saline) to avoid false-positive (dermatographism) or false-negative results.

  • Identification of allergen triggers can assist in formulating an environmental control strategy.

• An RAST may be used in place of skin testing if dermatologic disease is generalized, antihistamine or tricyclic antidepressant (TCA) use cannot be suspended (these will not interfere with RAST results), or skin testing is relatively contraindicated. However, skin testing is more specific, more sensitive, and usually less expensive than the RAST.

• Staining nasal secretions with Hansel stain is sometimes used to assess for nasal eosinophilia, which is suggestive of allergy, but the sensitivity and specificity of this stain are low.

Procedures

• Direct and indirect laryngoscopy are indicated if VCD or another laryngeal abnormality is suggested. A flow-volume curve on pulmonary function test may demonstrate extrathoracic obstruction, supporting the diagnosis of VCD.



• Cardiac stress testing, cardiopulmonary exercise testing, or both may be indicated if the etiology of dyspnea cannot be determined.

Histologic Findings

The diagnosis of asthma is not made histologically. However, autopsy and bronchoscopic biopsy findings include mucus plugging, inflammatory cell infiltrates and debris, vascular permeability, mucosal edema, and epithelial exfoliation. Remodeling, consisting of hypertrophy of smooth muscle, squamous and goblet cell metaplasia, mucous gland hypertrophy, and basement membrane thickening due to collagen and other matrix protein deposition, is present.

Sputum analysis results show creola bodies (ie, bronchial regenerative cells with nuclear atypia), Charcot-Leyden crystals (ie, residual product of eosinophils), and Curschmann spirals (ie, concentric layers of mucous and debris).

Staging

The National Asthma Education and Prevention Program, Expert Panel Report 2 (1997) from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes Health suggests the following stepwise approach to the diagnosis and treatment of adults and children older than 5 years. Updates were published in 2002. In addition, see Medication.

• Step 1 - Mild intermittent
  
  
  • Daytime symptoms 2 or fewer times per week
  
  
  
  • Nocturnal symptoms 2 or fewer times per month
  
  
  
  • PEFR or FEV₁ equal to 80% of normal or better
  
  
  
  • PEFR variation less than 20%
  
  
  
  • Treatment with short-acting inhaled bronchodilators only as needed
  
  
  
  • Systemic glucocorticoids for severe exacerbations
    
• Step 2 - Mild persistent
  
  
  • Daytime symptoms more than twice per week, but not daily
  
  
  
  • Nocturnal symptoms more than twice per month
  
  
  
  • PEFR or FEV₁ equal to 80% of normal or better
  
  
  
  • PEFR variation 20-30%
  
  
  

  • Treatment with daily low-dose inhaled glucocorticoids and short-acting inhaled bronchodilators as needed

  • Alternative daily therapy - Mast cell stabilizers (cromolyn or nedocromil) can be considered before inhaled steroids, especially in children. Leukotriene pathway modifier agents and even low-dose sustained release theophylline can also be considered, though these are less firmly established. In selected patients, allergy immunotherapy may be useful.
    
• Step 3 - Moderate persistent
  
  
  • Daily symptoms
  
  
  
  • Nocturnal symptoms more than once per week
  
  
  
  • PEFR or FEV₁ equal to 60-80% of normal
  
  
  
  • PEFR variation more than 30%
  
  
  
  • Treatment with daily low-to-medium–dose inhaled glucocorticoids - A recent warning from the US Food and Drug Administration (FDA) about possible adverse effects observed with combinations of inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA) indicates that some caution should be applied with the use of these products. However, experience indicates that combinations of inhaled CCS and LABA are extremely effective in step 3 asthmatics. All patients require short-acting bronchodilators as needed.
  
  
  

  • Alternate daily therapy - Increase inhaled glucocorticoids (to medium dose) or low-to-medium–dose inhaled glucocorticoids and either a leukotriene modifier or theophylline

  • Leukotriene synthesis inhibitors, such as zileuton

  • Allergy immunotherapy for appropriately selected patients

• Step 4 - Severe persistent
  
  
  • Continual daytime symptoms
  
  
  
  • Frequent nocturnal symptoms
  
  
  
  • PEFR or FEV₁ less than or equal to 60% of normal
  
  
  
  • PEFR variation more than 30%
  
  
  

  • Treatment with daily high-dose inhaled glucocorticoids and daily long-acting inhaled beta-agonist and short-acting bronchodilators as needed

  • Additionally, if needed, oral glucocorticoids at lowest dose and for the shortest duration required for relief
    
    
  • Zileuton (may be helpful in some patients)
  
  
  
  • Omalizumab (anti-IgE), in allergic patients requiring high-dose inhaled or oral CCS
    
• For children younger than 5 years, the guidelines also indicate the preferred therapy for moderate and severe persistent asthma consists of inhaled corticosteroids with the addition of long-acting beta-agonists.

ASTHMA TREATMENT

Medical Care

The goals of treatment are to minimize symptoms, improve quality of life, decrease need for urgent care or hospitalizations, normalize pulmonary function test results, and decrease the inflammatory process that leads to airway remodeling. For this discussion, treatment is divided into pharmacotherapy, environmental control, allergen immunotherapy, antibodies against IgE, and education.

• Pharmacotherapy
  
  
  • The most important facet of medical care is the use of anti-inflammatory medication (usually inhaled glucocorticoids) in patients at all stages beyond mild intermittent asthma. These medications improve the long-term outcomes for children with asthma and do not appear to have significant adverse effects at moderate doses (eg, on growth, bone density, eyes, adrenal sufficiency). Unfortunately, in some series, fewer than half the patients admitted to the hospital for asthma were receiving the recommended anti-inflammatory medications.
  
  
  
  • NHLBI guidelines suggest that initial medical care should be aggressive to rapidly gain control and then should be tapered as tolerated.
  
  
  
  • Severe exacerbations require standard care that includes supplemental oxygen (goal PaO₂ >60 mm Hg, arterial oxygen saturation >90%), nebulized medications, intravenous fluids, and even noninvasive or invasive ventilatory support. Heliox (helium-oxygen gas mixture) is an option but has not been systematically shown to be helpful.
  
  
  
  • Antibiotics offer no added benefit during an asthma exacerbation.
  
  
  

  • In emergency situations, nebulized magnesium sulfate during acute asthma attacks—when added to short-acting beta-2 agonists—may improve pulmonary function and reduce admissions, based on a limited number of studies.

  • All patients should receive assistance with quitting tobacco use. While smoking cessation is essential for a number of reasons, it particularly appears to increase corticosteroid responsiveness in patients with asthma.

  • All patients should receive an annual flu shot. A pneumococcal pneumonia vaccination is not required unless indicated based on age (ie, >65 y). Asthma symptoms do not increase after these shots because the antigens in the vaccinations are not alive.

  • Evaluating and treating patients for associated conditions (eg, rhinitis, GERD, sinusitis) can be important components of therapy. In one study, treating the GERD symptoms of patients with asthma with a proton pump inhibitor for 6 months reduced asthma exacerbations and improved quality of life but did not improve asthma symptoms or pulmonary function or reduce albuterol usage.

  • In addition, see Staging and Medication.
    
• Environmental control
  
  

  • Allergen avoidance takes different forms depending on the specific allergen size and characteristic. Improvement in symptoms after avoidance of the allergen may take 1-6 months.

  • Efforts should focus on the home, where 30-60% of time is spent. Patients should clean and dust their homes regularly. If patients cannot avoid vacuuming, they should use a face mask or a double-bagged vacuum with a high-efficiency particulate air filter. Consideration can be given to moving to a higher floor in the house (less dust and mold) or different neighborhood (fewer cockroaches) if possible. Active smoking and exposure to passive smoke must be avoided. Room air ionizers have not been proven effective to help persons with chronic asthma and the generation of ozone by these machines may be harmful to some. Other factors related to the home include the following:
    
    

    • Dust mites (Dermatophagoides pteronyssinus or "dead skin feeders," size 30 µm): The primary allergen is an intestinal enzyme on fecal particles. The allergen settles on fabric because of its relatively large size; therefore, air filtration is not as important. Measures to avoid dust mites include using impervious covers (eg, on mattresses, pillows, comforters), washing other bedding in hot water (130°F [54.4°C] most effective), removing rugs from the bedroom, limiting upholstered furniture, reducing the number of window blinds, and putting clothing away in closets and drawers. Minimize the number of soft toys, and wash them weekly or periodically put them in the freezer. Decrease room humidity;
      
      
    • Cats and other animals (dander or saliva, urine, or serum proteins, size 1-20 µm): Because of its small size, this allergen is predominantly an airborne indoor allergen. Avoidance involves removing animals from the home (or at least from the bedroom), using dense filtering material over heating and cooling duct vents, and washing cats and dogs as often as twice weekly.
    
    
    
    • Cockroaches (size 30 µm): Twenty percent of homes without visible infestation still produce sensitizing levels of allergen. Successful allergen elimination measures are difficult, especially in poor living conditions. To control cockroaches, exterminate and use poison baits and traps, keep food out of the bedroom, and never leave food out in the open.
    
    
    
    • Wet molds (size 1-150 µm): Avoidance includes keeping areas dry (eg, remove carpets from wet floors), removing old wallpaper, cleaning with bleach products, and storing firewood outdoors.
    
    
    
    • Pollen (size 1-150 µm): Avoidance includes closing windows and doors, using air conditioning and high-efficiency particulate air filters in the car and home, staying inside during the midday and afternoon when pollen counts are highest, wearing glasses or sunglasses, and wearing a face mask over the nose and mouth when mowing the lawn. In addition, consider increasing medications preseason and vacationing out of the area.
      
• Allergen immunotherapy
  
  
  • Repeated injections of small doses of allergen have been used for more than 90 years to treat allergic rhinitis. This treatment is clearly effective, and positive effects may persist even years after treatment is stopped. This treatment is also considered mandatory for life-threatening bee and wasp sting reactions. The role of repeated allergen injections in patients with asthma has been more controversial, ranging from a relative indication to no indication. Benefit has been shown in individuals with allergy-induced asthma.
  
  
  
  • Supporters argue that compliance can be ensured, and evidence shows that the underlying disease process can be modified or even prevented (eg, preventing asthma in children with allergic rhinitis).
  
  
  
  • In a 2003 review of 75 randomized controlled trials, Abramson et al reported that immunotherapy decreased asthma symptoms and need for medication. Another study showed improved PEFR and decreased use of medications in a highly selected group of children, but only for the first year of therapy.
  
  
  

  • The cost may be $800 for the first year and then $170/y thereafter (1996 estimate). No direct comparisons with medical therapy have been made to allow a cost-benefit analysis.

  • Allergen immunotherapy should be considered if specific allergens have a proven relationship to symptoms; the individual is sensitized (ie, positive skin test or RAST findings); the allergen cannot be avoided and is present year-round (eg, industrial); or symptoms are poorly controlled with medical therapy, and a vaccine to the allergen is available. As discussed above, this treatment is especially useful if asthma is associated with allergic rhinitis.

  • Referral to an allergist is required. The patient must commit to a course of 3-5 years of therapy (although a trial of several months can be considered).

  • Precautions include serious adverse reactions (occurring in 1 per 30-500 people, usually within 30 min). The estimated crude annual death rate is 0.7 deaths per million population. Monitoring and resuscitation personnel and equipment are required. Also, allergen immunotherapy should be avoided if the patient is taking beta-blockers or is having an asthma exacerbation

  • Dosing of allergen extracts is in bioequivalent allergy units (BAU), weight per volume (w/v), or protein nitrogen units (PNU), but "major allergen content" may be a more standardized and reliable method of dosing and characterizing allergen extracts.

  • Sublingual immunotherapy has been shown to improve allergic rhinitis symptoms, but effectiveness compared with the standard injection type is unclear. Sublingual immunotherapy and allergoids (modified or peptide-associated allergens) are not currently used in the United States.

• Antibodies to IgE antibody - Omalizumab
  
  

  • Omalizumab (Xolair) was approved by the FDA in 2003 for adults and adolescents (>12 y) with moderate-to-severe persistent asthma who have a positive skin test result or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids.

  • This is a humanized murine IgG antibody against the Fc component of the IgE antibody (the part that attaches to mast cell surfaces). Use of this antibody prevents IgE from binding directly to the mast cell surface, thereby preventing cell degranulation.

  • Therapy has been shown to decrease IgE antibody levels by 99% and cell receptor sites for IgE antibody by 97%. This decrease, in turn, is associated with reduced histamine production (90%), early-phase bronchospasm (40%), and late-phase bronchospasm (70%) and a decrease in the number, migration, and activity of eosinophils. levels drop quickly and remain low for at least a month.

  • This therapy is also effective for allergic rhinitis.
  
  
  
  • Multiple phase 3 trials show that, compared to placebo injections, treatment is associated with larger median inhaled steroid dose reduction (83% vs 50%), higher percentage of discontinuation of inhaled steroids (42% vs 19%), and fewer asthma exacerbations (approximately 15% vs 30%). Quality of life and use of rescue inhaler and the emergency department may also be improved. Omalizumab is approved for reduction of exacerbations.
  
  
  

  • Adverse effects are rare and include upper respiratory infection symptoms, headache, urticaria (2%) without anaphylaxis, and anaphylaxis (0.1%). Transient thrombocytopenia has also been noted but not in humans. Antibodies are formed against the anti-IgE antibody, but these do not appear to cause immune-complex deposition or other significant problems. To date, decreased IgE levels have not been shown to inhibit one’s ability to fight infection (including parasites). Registration trials raised a question of increased risk of malignancy, but this has not been seen in the postmarketing data.

  • Omalizumab is given by subcutaneous injection every 2-4 weeks based on initial serum IgE level and body weight. Patients are usually treated for a trial period lasting at least 12 weeks. Costs may be $12,000/y, so omalizumab is likely to be cost-effective only in patients with severe persistent asthma who have frequent exacerbations requiring hospitalization.
    
• Education: See Patient Education.

Consultations

• Consult a pulmonologist, allergist/immunologist, or both for any of the following:
• • Difficulty controlling disease after 3-6 months, including frequent attacks, need for rescue inhaler (>1 rescue inhaler used per mo), use of oral steroids more than 2 times per year, or step 4 therapy required
    
    
  • Poor quality of life
  
  
  
  • Immunotherapy under consideration
  
  
  
  • Intensive education needed
  
  
  
  • Refractory cough
  
  
  
  • Abnormal chest radiograph findings
  
  
  
  • Life-threatening asthma exacerbation
  
  
  
  • Patient or parent request
  
  
  



• Appropriate referral is needed if significant psychological, social, or family problems are present.

Diet

Aside from avoiding known food allergens or additives, diet is not restricted.

Activity

Maintaining physical activity and exercise is essential to avoid deconditioning. Susceptible individuals should decrease outdoor activity during midday and afternoon when pollen counts are highest. A short-acting beta-2 agonist and/or cromolyn metered-dose inhaler (MDI) can be used 15-30 minutes before exercise if needed.

ASTHMA MEDICATION

Anti-inflammatory medications (especially inhaled glucocorticosteroids) are now the mainstay of therapy and the single most effective therapy for adults with asthma. Anti-inflammatory medications are proven to improve lung function (ie, FEV₁, AHR) and to decrease symptoms, exacerbation frequency, and the need for rescue inhalers.

Short-acting inhaled beta-2 agonists, as needed, are most effective for rapid relief of asthma symptoms. No benefit and some risk of developing tolerance occur with regular long-term use. These agents should still be available to the patient, even if he or she is using a long-acting beta-2 agonist (eg, salmeterol).

Of note, the list of medications that combine 2 drugs in a single delivery device in an effort to increase patient convenience and compliance is expanding. These include a combination of albuterol and ipratropium bromide (Combivent) and a combination of fluticasone and salmeterol (Advair). Another combination product, composed of formoterol and budesonide (Symbicort), may be approved in the United States within 2 years.

Glucocorticoids may increase cell beta-2 agonist receptors, which, in turn, may enhance the action of the combination products.

According to the 1998 Leukotriene Working Group, leukotriene pathway modifiers may be useful as first-line therapy for mild persistent asthma or as an add-on or glucocorticoid-sparing medication in others. These agents are less effective than glucocorticoid inhalers but tend to improve compliance because dosing is oral and once daily, and usage appears more reasonable for those unable or unwilling to take glucocorticoids. Leukotriene synthesis inhibitors montelukast, zafirlukast, and zileuton are available.

When adding to a medication regimen for asthma (referred to as stepping up therapy), consider adding LABA for persistent symptoms with impaired FEV₁. Patients with symptoms but normal lung function (especially those with symptomatic allergic rhinitis) might benefit first from a leukotriene pathway modifier. Of course, some patients will ultimately be treated with both types of medications for optimum management.

Mast cell stabilizers can also be used. Cromolyn sodium (Intal) indirectly blocks calcium influx into mast cells, preventing inflammatory mediator release. Adults can use it in an MDI (2-4 puffs 3-4 times daily) or in a nebulized form (1 ampule 3-4 times daily). Because of its safety profile, this agent is often tried in children; however, it may take a month to work. The pediatric dose is 1-2 puffs via an MDI 3-4 times daily or 1 ampule via a nebulizer 3-4 times daily. Cromolyn sodium tends to work best in young and highly allergic patients.

Nedocromil (Tilade) has similar effects, although it is structurally distinct. The adult dose is 2-4 puffs via an MDI 2-3 times daily. The pediatric regimen is 1-2 puffs via an MDI 2-4 times daily. MDIs may be used with a spacer as necessary (mask if less than 2 y). Patients should activate the MDI while breathing in slowly, and then they should hold their breath for 10 seconds if possible.

Using a spacer or holding the inhaler 2 inches from the mouth may improve delivery. The recent change from chlorofluorocarbon to hydrofluoroalkane propellants with smaller particle size may help deliver more medication. The only reliable way to determine if the inhaler is empty is to count the number of doses. Patients should rinse their mouths with water and spit after glucocorticoid inhaler use to prevent oral thrush and dysphonia. An alcohol-containing mouthwash may be more effective than water.

Breath-actuated inhalers are easier to use for less-coordinated individuals. A dry-powder inhaler (DPI) allows rapid inhalation. These devices also often have built-in dose counters.

Consider recommending a nebulizer if the patient is younger than 2 years or is unable to use an MDI or DPI because of cough, severe dyspnea, or poor coordination.

Additionally, recombinant DNA-derived humanized immunoglobulin G monoclonal antibodies to IgE are now available to treat moderate-to-severe persistent asthma in patients who react to perennial allergens and whose symptoms are not controlled by inhaled corticosteroids.

Drug Category: Bronchodilators

Provide immediate relief of bronchospasm. Preferentially (but not exclusively) bind beta2-adrenergic receptors, resulting in conversion of ATP to cyclic AMP, relaxation of bronchial smooth muscle, and decreased release of inflammatory mediators. Anticholinergic agent ipratropium is included here because it has an additive beneficial effect when given with bronchodilators in acute, severe asthma.

Drug Name	Albuterol (Proventil, Ventolin, Airet)
Description	Beta-agonist. Relaxes bronchial smooth muscle by action on beta-2 receptors with little effect on cardiac muscle contractility.
Adult Dose	4 mg PO q12h; not to exceed 32 mg/d MDI: 1-2 puffs q4-6h prn; not to exceed 12 puffs/d Nebulizer: 2.5 mg tid/qid
Pediatric Dose	PO less than 12 years: 0.3-0.6 mg/kg/d, not to exceed 8 mg/d >12 years: Administer as in adults MDI less than 4 years: Not established >4 years: Administer as in adults Nebulizer 2-12 years: 0.1-0.15 mg/kg/dose, not to exceed 2.5 mg tid/qid prn >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders; used regularly during pregnancy; can cause paradoxical bronchospasm; increasing need for this rescue medication may indicate clinical destabilization that requires medical reevaluation

Drug Name	Ipratropium (Atrovent)
Description	DOC for beta-2 agonist-induced bronchospasm. Chemically related to atropine and has antisecretory properties. Inhibits vagally mediated reflexes by increasing cyclic GMP, causing local bronchial smooth muscle dilation. Not effective for exercise-induced symptoms. Additive to, but slower than, effects of beta-2 agonists.
Adult Dose	Nebulizer: 1 U dose vial (500 mcg) q30min for 3 doses, then q2-4h prn MDI: 4-8 puffs prn initially; not to exceed 12 puffs/d
Pediatric Dose	Nebulizer: 250 mcg q20min for 3 doses, then q2-4h prn MDI: 4-8 puffs prn initially; not to exceed 6 puffs/d
Contraindications	Documented hypersensitivity
Interactions	Drugs with anticholinergic properties (eg, dronabinol) may increase toxicity; albuterol may increase effects
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Not indicated for acute episodes of bronchospasm; caution in narrow-angle glaucoma, prostatic hypertrophy, and bladder neck obstruction

Drug Name	Bitolterol (Tornalate); Pirbuterol (Maxair)
Description	Stimulates beta-2 receptors directly to relax bronchial smooth muscle, relieving bronchospasm and reducing airway resistance.
Adult Dose	Bitolterol: 2 puffs q8h prn Pirbuterol: 1-2 puffs q4-6h prn
Pediatric Dose	less than 12 years: Not established >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; tachycardia resulting from cardiac arrhythmia
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders; can cause paradoxical bronchospasm; increased need for this rescue medication may indicate clinical destabilization that requires medical reevaluation

Drug Name	Metaproterenol (Alupent, Metaprel)
Description	Relaxes bronchial smooth muscle by action on beta2-adrenergic receptors with little effect on cardiac muscle contractility. Generally not recommended because of excessive cardiac stimulation, especially in high doses.
Adult Dose	MDI: 2-3 puffs q3-4h prn Nebulizer: 0.01 mg/kg; not to exceed 0.3 mL of 5% solution q4h prn PO: 20 mg tid/qid
Pediatric Dose	less than 6 years: 2 mg/kg/d PO 6-9 years: 10 mg PO tid/qid >9 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders; can cause paradoxical bronchospasm; increased need for this rescue medication may indicate clinical destabilization that requires medical reevaluation

Drug Name	Terbutaline (Brethaire, Brethine, Bricanyl)
Description	Acts directly on beta-2 receptors to relax bronchial smooth muscle, relieving bronchospasm and reducing airway resistance.
Adult Dose	MDI: 2 puffs q4-6h prn SC: 0.25 mg PO: 5 mg tid
Pediatric Dose	less than 12 years: Not established 12-15 years: 2.5 mg PO tid >15 years: Administer as in adults
Contraindications	Documented hypersensitivity; tachycardia resulting from cardiac arrhythmias
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Through intracellular shunting, may decrease serum potassium levels, which can produce adverse cardiovascular effects; decrease is usually transient and may not require supplementation

Drug Name	Salmeterol (Serevent)
Description	Long-acting bronchodilator - works by relaxing smooth muscles of bronchioles and relieving bronchospasms. Effect may also facilitate expectoration. Inhaler does not replace anti-inflammatory medications but can be added to decrease rescue inhaler use. Evening dose may be useful for nocturnal symptoms. SR PO albuterol has greater systemic sympathomimetic adverse effects and is considered an alternate therapy only. WARNING: Data from a large placebo-controlled US study (SMART trial) that compared the safety of salmeterol or placebo added to usual asthma therapy showed a small but significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks) versus those on placebo (3 of 13,179).
Adult Dose	PO: 4 mg q12h MDI: 2 puffs (or 1 blister pack) q12h
Pediatric Dose	PO: 0.3-0.6 mg/kg/d; not to exceed 8 mg MDI: 1-2 puffs (or 1 blister pack) q12h
Contraindications	Documented hypersensitivity; angina, tachycardia, and cardiac arrhythmia associated with tachycardia
Interactions	Concomitant use of beta-blockers may decrease bronchodilating and vasodilating effects of beta-agonists; concurrent administration with methyldopa may increase pressor response; coadministration with oxytocic drugs may result in severe hypotension; ECG changes and hypokalemia due to diuretics may worsen
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not indicated to treat acute asthmatic symptoms; sympathomimetic responses (tremor, tachycardia) can occur and may be significant in some patients with cardiovascular disease; onset of action can be delayed (does not preclude need for short-acting bronchodilators)

Drug Name	Theophylline (Theo-24, Theolair, Theo-Dur, Slo-bid)
Description	Structurally classified as a methylxanthine, it acts as a bronchodilator. Potentiates exogenous catecholamines and stimulates endogenous catecholamine release and diaphragmatic muscular relaxation, which, in turn, stimulates bronchodilation. For bronchodilation, near toxic (>20 mg/dL) levels are usually required. Less effective than glucocorticoids but may be glucocorticoid-sparing agent. Routine drug level monitoring required (goal: 5-15 mcg/mL).
Adult Dose	10 mg/kg/d (not to exceed 300 mg) PO initially; not to exceed 800 mg/d maintenance
Pediatric Dose	less than 1 year: 0.2 (times age in wk) plus 5 (estimated in mg/kg/d) maximum PO >1 year: 16 mg/kg/d PO; not to exceed 400 mg/d; alternatively, 10 mg/kg/d IV
Contraindications	Documented hypersensitivity; uncontrolled arrhythmia; peptic ulcers; hyperthyroidism; uncontrolled seizure disorders
Interactions	Aminoglutethimide, barbiturates, carbamazepine, ketoconazole, loop diuretics, charcoal, hydantoins, phenobarbital, phenytoin, rifampin, isoniazid, and sympathomimetics may decrease effects Effects may increase with allopurinol, beta-blockers, ciprofloxacin, corticosteroids, disulfiram, quinolones, thyroid hormones, ephedrine, carbamazepine, cimetidine, erythromycin, macrolides, propranolol, and interferon
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in peptic ulcer, hypertension, tachyarrhythmia, hyperthyroidism, and compromised cardiac function; do not inject IV solution >25 mg/min; patients diagnosed with pulmonary edema or liver dysfunction are at greater risk of toxicity because of reduced drug clearance

Drug Category: Monoclonal antibodies

Recombinant, DNA-derived agents inhibit IgE binding to the high-affinity IgE receptor on mast cells and basophils, causing a decrease in release of mediators of the allergic response.

Drug Name	Omalizumab (Xolair)
Description	Recombinant, DNA-derived, humanized IgG monoclonal antibody that binds selectively to human IgE receptor on surface of mast cells and basophils. By inhibiting IgE binding, release of mediators of allergic response is inhibited. Indicated for moderate-to-severe persistent asthma in patients who react to perennial allergens in whom symptoms are not controlled by inhaled corticosteroids.
Adult Dose	150-375 mg SC q2-4wk; inject slowly over 5-10 seconds due to viscosity; not to exceed 150 mg/injection site Precise dose and frequency established by serum total IgE level (IU/mL)
Pediatric Dose	less than 12 years: Not established >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not effective to treat acute asthma; do not abruptly discontinue inhaled corticosteroids when initiating omalizumab; malignancy rate among treated patients (0.5%) was numerically higher than among control patients (0.2%); malignancies varied, and further long-term observation needed to fully assess risk; may cause injection-site reaction

Drug Category: Glucocorticoids

Maintenance medications that decrease inflammatory mediators to limit airway remodeling. Must be taken regularly to be beneficial. Do not relieve acute bronchospasm; short-acting bronchodilators must be available. The multiple formulations are not equivalent on a per-dose or per-mcg basis. Inhaled corticosteroids are one of the most important developments in asthma management because they decrease inflammation. Proven to improve lung function (ie, FEV₁, airway hyperactivity) and decrease symptoms, exacerbation frequency, and need for rescue inhalers. Dose ranges as recommended by NHLBI.

Drug Name	Beclomethasone (Beclovent, Vanceril)
Description	Inhibits bronchoconstriction, produces direct smooth muscle relaxation, decreases number and activity of inflammatory cells, and decreases airway hyperresponsiveness.
Adult Dose	Low dose: 2-6 puffs (84-mcg MDI) or 4-12 puffs (42-mcg MDI) Medium dose: 6-10 puffs (84-mcg MDI) or 12-20 puffs (42-mcg MDI) High dose: >10 puffs (84-mcg MDI) or >20 puffs (42-mcg MDI)
Pediatric Dose	Low dose: 1-4 puffs (84-mcg MDI) or 2-8 puffs (42-mcg MDI) Medium dose: 4-8 puffs (84-mcg MDI) or 8-16 puffs (42-mcg MDI) High dose: >8 puffs (84-mcg MDI) or >16 puffs (42-mcg MDI)
Contraindications	Documented hypersensitivity; bronchospasm, status asthmaticus, other types of acute episodes of asthma
Interactions	Coadministration with ketoconazole may increase plasma levels but does not appear to be clinically significant
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not for acute attack; weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma

Drug Name	Budesonide (Pulmicort Respules, Pulmicort Turbuhaler, Rhinocort Aqua Intranasal)
Description	Inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness.
Adult Dose	DPI Low dose: 200-600 mcg Medium dose: 600-1200 mcg High dose: 1200 mcg
Pediatric Dose	Inhalation suspension for children Low dose: 0.5 mg Medium dose: 1 mg High dose: 2 mg
Contraindications	Documented hypersensitivity; bronchospasm, status asthmaticus, other types of acute episodes of asthma
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma

Drug Name	Flunisolide (AeroBid)
Description	Inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness.
Adult Dose	Low dose: 2-4 puffs Medium dose: 4-8 puffs High dose: >8 puffs
Pediatric Dose	Low dose: 2-3 puffs Medium dose: 4-5 puffs High dose: >5 puffs
Contraindications	Documented hypersensitivity: bronchospasm, status asthmaticus, other types of acute episodes of asthma
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma

Drug Name	Fluticasone (Flovent)
Description	Has extremely potent vasoconstrictive and anti-inflammatory activity. Has a weak hypothalamic-pituitary-adrenocortical axis inhibitory potency when applied topically.
Adult Dose	MDI Low dose: 88-264 mcg Medium dose: 264-660 mcg High dose: >660 mcg DPI Low dose: 100-300 mcg Medium dose: 300-600 mcg High dose: >600 mcg
Pediatric Dose	MDI Low dose: 88-176 mcg Medium dose: 176-440 mcg High dose: >440 mcg DPI Low dose: 100-200 mcg Medium dose: 200-400 mcg High dose: >400 mcg
Contraindications	Documented hypersensitivity; bronchospasm, status asthmaticus, other types of acute episodes of asthma
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma

Drug Name	Triamcinolone (Azmacort)
Description	Decreases inflammation by suppressing migration of PMN leukocytes and reversing capillary permeability.
Adult Dose	Low dose: 4-10 puffs Medium dose: 10-20 puffs High dose: >20 puffs
Pediatric Dose	Low dose: 4-8 puffs Medium dose: 8-12 puffs High dose: >12 puffs
Contraindications	Documented hypersensitivity, bronchospasm, status asthmaticus, other types of acute episodes of asthma
Interactions	Coadministration with barbiturates, phenytoin, and rifampin decreases effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma

Drug Name	Prednisone (Deltasone, Orasone)
Description	Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Goal is lowest dose and shortest duration effective for disease control. Conversion: methylprednisolone (Medrol) dose equal to four fifths of desired prednisone dose. Prednisolone (Prelone, Pediapred) dose equal to prednisone dose.
Adult Dose	40-60 mg/d PO for 3-10 d as burst; 5-60 mg/d PO qd or qod for long-term use prn for disease control; divided doses (20 mg tid) are more effective than 60 mg qd but are also associated with more adverse effects
Pediatric Dose	1-2 mg/kg/d PO for 3-10 d as burst; not to exceed 60 mg/d; 0.25-2 mg/kg qd or qod for long-term use prn for disease control
Contraindications	Documented hypersensitivity; peptic ulcer disease, hepatic dysfunction; viral infection, connective tissue infections, fungal or tubercular skin infections; GI disease
Interactions	Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Category C for methylprednisolone and prednisolone; abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, weight gain, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur; qod therapy lessens adverse effects

Drug Category: Leukotriene-modifying agents

Consist of leukotriene receptor antagonists (eg, zafirlukast and montelukast) and synthesis inhibitors (eg, zileuton).

Drug Name	Zafirlukast (Accolate), montelukast (Singulair), zileuton (Zyflo)
Description	Leukotriene pathway inhibitors. Not for use in acute episodes of asthma.
Adult Dose	Zafirlukast: 20 mg PO bid Montelukast: 10 mg PO qd Zileuton: 600 mg PO qid
Pediatric Dose	less than 12 years (zafirlukast and zileuton): Not established >6 years (montelukast): 5 mg PO qd
Contraindications	Documented hypersensitivity
Interactions	Warfarin and theophylline levels must be followed closely if coadministered with zafirlukast or zileuton; do not take with food
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category C for zileuton; association with Churg-Strauss vasculitis (zileuton), although may be unrelated and only reflect coincidental corticosteroid withdrawal; monitor liver enzymes; not a bronchodilator; have appropriate rescue medication available

FOLLOW-UP

Further Inpatient Care

• Consider admission to a hospital if the patient develops refractory symptoms with a marked decrease in spirometry or borderline oxygenation. Intravenous or oral corticosteroids (3- to 10-d course) may be required.
  
  

  • A reduced FEV₁ or PEFR to less than 50% of the patient’s personal best, normocapnia or hypercapnia, severe symptoms, or mental status changes warrants admission to an ICU.

  • If the patient responds to therapy, examination findings are normal 1 hour after the last medication dose, and the FEV₁ or PEFR is greater than 70% of patient’s personal best, consider discharging the patient home on therapy to include oral steroids and scheduling a follow-up visit within 1 week.

Further Outpatient Care

• Medical office visits should occur every 6-12 months (every 1-6 mo if severe) and should include the following assessments:
  
  
  • Reassess severity, compliance, and response to therapy. Consider giving patients a written questionnaire. (See ACT scorecard.)
  
  
  
  • Objectively measure pulmonary function; initially check office spirometry, then measure peak flow and review peak-flow log at each visit.
  
  
  
  • Reinforce inhaler technique and asthma management plan.
  
  
  
  • Ensure compliance with environmental avoidance techniques, and consider additional efforts (add one at a time).
  
  
  
  • Consider arranging a home visit to screen for environmental exposures and assess compliance with avoidance measures.

Prognosis

• Signs that may indicate a poor prognosis (ie, risk factors for death) are as follows:
• • Severe exacerbations - Intubation, ICU stay, 2 or more hospitalizations per year, 3 or more urgent clinic or ED visits per year

  • More than 2 short-acting beta-2 agonist MDIs per month

  • Glucocorticoid dependence

  • Poor patient perception of airflow obstruction

  • Significant medical comorbidities

  • Psychiatric disease

  • Illicit drug use

  • Sensitivity to Alternaria species (a mold)

Patient Education

• The American Lung Association has recently endorsed the Asthma Control Test (ACT), a 5-question self-assessment tool for patients. The ACT asks about symptoms experienced during the previous 4 weeks. Scores of 19 or less (out of a possible 25) suggest inadequate asthma control worthy of discussion with a physician.



• Patient compliance rates for medications can be as low as 50%. Compliance with environmental measures, including mattress covers for dust mites, may be even worse. Physicians and other health care professionals are also at fault, with only 63% of internists and only 81% of asthma specialists prescribing inhaled glucocorticoids according to recommended guidelines. In one study, more than 40% of patients did not feel that their asthma was well-controlled. Education reduces ED visits, but objective evidence for other outcome measures is limited. Adequate education programs for parents and/or patients include the following:
  
  
  • Asthma disease description
  
  
  
  • Proper medication use: Take off the cap and shake the inhaler (not needed for DPI). Breathe out deeply and hold the inhaler with lips pursed around the orifice or as far as 2 inches from the face or use a spacer. Depress the inhaler concurrent with slow inspiration. Hold breath for 10 seconds. Repeat until the desired dose is achieved (wait 1 min for short-acting beta-agonists).
  
  
  
  • How to identify and control environmental triggers
  
  
  
  • Upper airway allergic symptoms: These can be an early warning system for allergic asthma.
  
  
  
  • Written self-management plan according to PEFR, exposure, and symptoms: For example, a drop below 80% is considered the yellow zone, and additional intervention is needed; a drop below 50% is considered the red zone (severe exacerbation), and the patient should seek medical assistance.
  
  
  
  • Parents with a history of allergies: These parents should be advised that some evidence suggests that environmental control measures may potentially prevent sensitization in their children. Simple but unproven measures include reducing the number of bedroom carpets, avoiding passive smoke exposure, venting unvented gas appliances, increasing fish and vegetable intake, and allowing breastfeeding.
    
• Additional resources for physicians and other health care professionals are available on the Internet and include the following:
  
  
  • American Academy of Allergy, Asthma, and Immunology
  
  
  
  • American College of Allergy, Asthma and Immunology
  
  
  
  • Lung information from the NHLBI
  
  
  
  • American Lung Association
  
  
  
  • National Library of Medicine Breath of Life Program
  
  
  
  • National Asthma Education Program
  
  
  
  • National Jewish Medical and Research Center
  
  
  
  • American Academy of Family Physicians
    
• For excellent patient education resources, visit eMedicine's Asthma Center. Also, see eMedicine's patient education articles Asthma, Asthma FAQs, Occupational Asthma, and Understanding Asthma Medications.

MISCELLANEOUS

Medical/Legal Pitfalls

• Failure to recognize conditions in the differential diagnosis (eg, foreign body aspiration in a child)

• 
  
• Failure to provide sufficient treatment for pregnant women

• 
  
• Failure to provide short-term rescue agents (eg, inhaled beta-2 agonists) and long-term maintenance medications

• 
  
• Failure to refer patients whose conditions are refractory to treatment to specialists and subjecting them to inappropriate long-term treatment (eg, long-term prednisone when the patient actually has VCD)

Special Concerns

• Patients dependent on glucocorticoids: These individuals should be referred to a specialist. The goal is the lowest glucocorticoid dose for the shortest duration possible. Patients must be screened and then referred or treated for complications such as cataracts (optometry/ophthalmology screening annually) and osteoporosis (bone densitometry, supplemental calcium and vitamin D at a minimum if not contraindicated). Excluding problems that can mimic asthma, such as VCD in "refractory" glucocorticoid-dependent cases, is important. A truncated inspiratory flow-volume loop on pulmonary function tests suggests possible VCD.



• Infants and children younger than 5 years: Pulmonary function testing is difficult to perform because cooperation can be limited and reference ranges are not standardized. Fewer medications have been studied and approved for patients in this age group.



• Elderly patients: These patients frequently have other medical diseases that can mimic asthma and are more likely to experience adverse effects from asthma medications.



• Pregnant patients: Asthma affects up to 8% of pregnant women, and these patients should be treated similarly and possibly even more aggressively than other patients, given the detrimental effects of hypoxia on maternal and fetal outcomes. Generally during pregnancy, AHR is stable to improved 69% of the time and worse 31% of the time. The following are specific interventions:
  
  
  • Theophylline may be associated with drug toxicity in the newborn because of poor clearance.
  
  
  
  • Beclomethasone is an older and therefore better-studied inhaled steroid for use during pregnancy. However, budesonide is the only inhaled corticosteroid with an FDA pregnancy rating of B and should, thus, be the drug of choice.
  
  
  

  • Systemic glucocorticoids may increase the risk of preeclampsia and decreased birth weight but should be used if asthma exacerbation is severe because untreated asthma bears its own risks on the pregnancy.

  • Leukotriene pathway medications generally should not be used because of a lack of safety information, although montelukast is a category B drug.
  
  
  
  • Immunotherapy should not be started nor dosage escalated during pregnancy, given the rare but significant risk of anaphylaxis.