ABSTRACT: Asthma is a chronic lung condition that involves inflammation of the airways in the lungs. Asthma can result from a number of environmental or genetic factors. Appropriate pharmacologic treatment and proper patient counseling are crucial to achieving asthma control. Some key roles of a pharmacist are to counsel patients on the proper use of medications and devices and to identify and prevent nonadherence.
In the United States, asthma affects more than 24 million people, and about 6 million of them are children.1 According to the 2015 National Health Interview Survey, the current asthma prevalence of children less than 18 years of age is 8.4%.1 Asthma is a chronic lung disease that inflames and narrows the airways in the lungs, causing periodic wheezing, shortness of breath, coughing, and chest tightness.2 In acute exacerbations of asthma, progressive narrowing of the airways and worsening of symptoms occur in response to exposure to a variety of stimuli, such as allergens or irritants. Exacerbations, mostly due to poorly managed asthma, may result in the need for additional medication and, if severe enough, urgent medical attention. This can pose a significant burden for patients and their families, including increased health costs and effect on quality of life.3
Asthma can result from a number of environmental or genetic factors. Risk factors include tobacco smoke exposure both in utero and in early childhood; allergen sensitization (such as animals with fur, house dust mites, mold, or changes in weather); viral respiratory infections; obesity; and stress.2 The application of genetic factors has yet to be fully understood. Several respiratory viruses during infancy have also been identified as risk factors in the development of asthma later in childhood.2
A diagnosis of asthma should be considered and spirometry performed if the following indicators are present: history of cough that is worse at night, recurrent wheeze, difficulty breathing or chest tightness in the presence of exercise, viral infection, and environmental factors.2 After other potential diagnoses are excluded, a diagnosis of asthma can be made when episodic symptoms of airflow obstruction or airway hyperresponsiveness are present and airflow obstruction is reversible.2
Asthma severity in the pediatric population is determined by the frequency of several components, such as nighttime awakenings; interference with normal activity; symptoms like shortness of breath, coughing, wheezing, and chest tightness; and the frequency of use of short-acting beta2-agonists (SABAs) for symptom control (excludes prevention of exercise-induced bronchospasms [EIB]). Lung-function measurements are also incorporated to classify severity of asthma in children aged 5 to 11 years.2 Lung function is measured by forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF), expressed as a percent of the predicted value. This provides important information about the level of airflow obstruction.2 Severity of asthma can be categorized as intermittent, persistent mild, persistent moderate, or persistent severe (see TABLE 1).
Pharmacotherapy Rescue Medications
All patients will require a rescue medication to be readily available in the event of an asthma attack. SABAs improve airflow via agonizing beta2 receptors, causing relaxation of bronchial smooth muscle and prompting an increase in airflow within 4 to 5 minutes of inhalation. Albuterol and levalbuterol have a duration of action of 2 to 6 hours.2,4 Studies have shown there to be no difference in the two medications. In the treatment of children with acute asthma exacerbation in the emergency department, no difference was shown when levalbuterol was compared to albuterol in improvement of asthma or percentage of predicted FEV1, number of SABA treatments given, length of care, rate of hospitalization, changes in pulse rate, respiratory rate, and pulse oximetry readings.5 The cost of levalbuterol greatly exceeds the cost of racemic albuterol. Side effects of SABAs may include tachycardia, jitteriness, nervousness, dizziness, or headache.2,4
Inhaled Corticosteroids: Inhaled corticosteroids (ICS) are the preferred medication for initiating long-term treatment in all ages and are the most effective treatment for persistent asthma. ICS work by suppressing airway inflammation.6 They have limited systemic bioavailability and are generally safe, especially when given at lower doses, even over long periods of time.2 General side effects include oral thrush, sore throat, hoarseness of the voice, and dry mouth. Growth suppression has been linked to long-term ICS use. A large meta-analysis found that ICS use for longer than 12 months in children has a limited effect—about 0.7% reduction—on annual growth rate. Also, the magnitude of the growth suppression was not progressive past 1 year of therapy.7 Serious side effects are more likely to occur with high, persistent doses; therefore, step-down therapy should be considered after 3 months of adequate asthma control.
Long Acting Beta2 Agonists: Chronic long-acting beta2 agonist (LABA) use in combination with ICS has been found to further improve lung function and decrease symptoms.2 LABAs work by binding selectively with the beta2 receptors in the lungs, resulting in a prolonged period of bronchial smooth-muscle relaxation. LABAs have a duration of action of about 12 hours after one dose. They have a black box warning for an increased risk of death caused by severe asthma exacerbations in some studies. Therefore, LABAs should never be used as monotherapy. In 2006, a large clinical trial showed an increased rate of asthma-related deaths in patients taking salmeterol (13 out of 13,176) versus placebo (3 out of 13,179).2 For most patients, the benefits of adding LABA therapy outweigh the risks in children 5 years of age who are inadequately controlled with low-dose inhaled corticosteroids.2
Leukotriene Modifiers: Leukotriene receptor antagonists (LTRAs) approved for use in children include montelukast (1 year of age) and zafirlukast (7 years of age). They are administered orally and prevent the activation of inflammatory cells, contraction of smooth muscle, and airway edema caused by leukotrienes. LTRAs are recommended as an alternative, but not a preferred option, in patients with mild persistent asthma. They have been shown to confer modest improvement in asthma control when used as monotherapy in adults and children as young as 2 years of age.2 LTRAs have also been shown to reduce EIB.2 They are typically well tolerated, and possible side effects include headache and behavioral changes such as insomnia or suicidal thoughts. In 2009, the FDA requested a labeling update of LTRAs to include neuropsychiatric events following postmarketing reporting of cases of behavioral effects such as agitation, aggression, depression, and anxiousness.8,9 The psychiatric adverse events are listed as a precaution for use, not as a black box warning, in the package insert. It is recommended that patients be evaluated for psychiatric problems at baseline and that they be reevaluated during treatment.10
Methylxanthines: Sustained-release theophylline is a mild-to-moderate bronchodilator that may have anti-inflammatory effects. It is recommended as an alternative, but not preferred, adjunctive therapy with ICS. In combination with ICS, studies have shown theophylline to improve lung function to a small degree, similar to that of doubling the ICS dose.2 In children with acute severe asthma, the use of IV aminophylline as adjunctive therapy was not shown to change the length of hospital stay, symptoms, frequency of nebulizer use, or mechanical-ventilation rates.11 Serum theophylline concentrations must be monitored to check for toxicity, if used.2
Mast Cell Stabilizers: Cromolyn sodium and nedocromil stabilize mast cells and alter chloride channel function. Mast cells store mediators, such as histamine, leukotrienes, and prostaglandins, that cause direct contraction of airway smooth muscle as a result of allergen exposure. They may be considered in mild persistent asthma as an alternative, but are not preferred. They may also be used to prevent EIB and before unavoidable allergen exposure.2
Monoclonal Antibodies: Currently available monoclonal antibodies used in asthma treatment include omalizumab, an anti-immunoglobulin E (IgE) antibody, and mepolizumab and reslizumab, anti-interleukin 5 (IL-5) antibodies.12 Omalizumab is approved for patients at least 6 years of age with severe allergic asthma, and it works by preventing IgE from binding to its receptors, which inhibits mast-cell degranulation. Mepolizumab and reslizumab are approved in the treatment of eosinophilic asthma in patients aged 12 years or older.13 It works by inhibiting IL-5 signaling to reduce the amount of inflammatory eosinophils in the body.12,13 These treatment options may be considered for patients with persistent symptoms or exacerbations despite being on two or more controllers.3
Asthma exacerbations are acute or subacute episodes of progressively worsening asthma symptoms, such as shortness of breath, coughing, wheezing, and/or chest tightness.2 Home management involves intensification of therapy by increasing the frequency of SABAs. Repetitive or continuous administration of SABAs is the most effective way of reversing airflow obstruction and bronchoconstriction. The absence of wheezing or dyspnea (or tachypnea in young children) and PEF 80% predicted or personal best is considered a good response to SABA treatment. If an incomplete response results, an oral systemic corticosteroid (OCS) may be needed along with the inhaled SABA.2 OCSs work by decreasing the pulmonary swelling and inflammation that cause the acute exacerbations. If poor response—characterized by marked wheezing and dyspnea—continues after initial treatment and PEF <50% predicted or personal best, the patient should proceed to the emergency room.2
Most severe exacerbations of asthma require the emergency department because these can potentially be life threatening.2 In the inpatient management of acute asthma exacerbation in children, all patients receive SABA treatment and most receive oxygen to maintain oxygen saturation 90%, ipratropium bromide, and systemic corticosteroids.2 Ipratropium bromide is an anticholinergic that provides bronchodilation by blocking the action of acetylcholine at parasympathetic sites in bronchial smooth muscle to cause smooth-muscle relaxation. Adding multiple doses of ipratropium bromide to a SABA produces additional bronchodilation, resulting in fewer hospital admissions.2,3 An OCS is given if the patient experiences no immediate response from initial treatment or if the patient already recently took an OCS. In severe cases of asthma exacerbations when FEV1 or PEF <40%, oxygen, inhaled SABA plus ipratropium, and OCS are given. If the patient is impending or has actual respiratory arrest, he or she will require intubation and mechanical ventilation with 100% oxygen, nebulized SABA and ipratropium, and intramuscular corticosteroid.2
Hospital discharge should be considered if the patient experiences a good response to therapy, FEV1 or PEF 70%, no distress, response sustained 60 minutes after last treatment, and a normal physical exam.
Pharmacologic treatments are selected after asthma severity is determined (see TABLE 1). Guidelines classify levels of therapy as steps. All pediatric patients with intermittent asthma may begin treatment at Step 1 with a SABA as needed.2
Ages 0 to 4: Patients with mild persistent asthma may begin treatment at Step 2 with a low-dose ICS or, alternatively, cromolyn or montelukast. The choice between using ICS or alternative options is based on effectiveness, any previous patient response to treatment, ability to correctly administer the medication, and individual patient or caregiver concerns.2 Patients with moderate-to-severe persistent asthma may begin treatment at Step 3 with a medium-dose ICS and may consider a short course of OCS. Level of control should be evaluated after 2 to 6 weeks, depending on asthma severity. In 4 to 6 weeks, changing therapy or reevaluating diagnosis should be considered if there has been no clear benefit from treatment.2
Ages 5 to 11: Patients with mild persistent asthma may begin treatment at Step 2 with a low-dose ICS or, alternatively, cromolyn, an LTRA, nedocromil, or theophylline. Patients with moderate-to-severe persistent asthma may begin treatment at Step 3 with a medium-dose ICS and may consider a short course of OCS. Severe persistent asthma patients may also start with combination therapy of an LABA plus medium-dose OCS. Level of control should be evaluated 2 to 6 weeks—depending on asthma severity—after initiating therapy.2
Goals of Treatment
Two goals of therapy in the treatment of asthma are reduction of impairment and reduction of risk.2 Reduction of impairment includes preventing symptoms, reducing use of inhaled SABA for quick relief (>2 days a week), maintaining pulmonary function and normal activity levels, and meeting expectations of and satisfaction with asthma care.2 Reduction of risk includes prevention of recurrent exacerbations of asthma, need for emergency department visits or hospitalizations, loss of lung function, and providing optimal pharmacotherapy with minimal or no adverse effects.2 Ultimate goals of therapy include a decrease in asthma burden, increase of quality of life, and decreased healthcare utilization.3
Appropriate treatment and continual patient counseling are crucial to attaining and maintaining asthma control. Four factors that must be reassessed at each opportunity include medication adherence, environmental control, inhaler technique, and comorbidities to minimize exacerbations.2 If asthma control is classified as well controlled for a period of at least 3 months, then patient-specific step-down treatment may be considered (TABLE 2).
Pharmacists can provide patient education and contribute to overall management of asthma.14 The difference between using long-term medications and quick-relief medications should be explained to all patients. An explanation of the reason for the daily use of preventive medications and the impact it will have on their asthma improves understanding of therapy and encourages adherence.2 For ICS, it is important to tell patients to rinse the mouth after each use to prevent oral thrush.2,15 OCS are generally difficult to administer due to poor palatability; however, the different formulations offer different flavorings.4 Pharmacists can also find alternative products with dosing regimens that better suit a patient’s schedule or help the patient obtain an additional medication supply to be kept at school or daycare. Pharmacists can aid in adherence by addressing formulary concerns and finding therapeutically affordable equivalents that will lessen the financial burden of therapy. Pharmacist assessment of inhaler technique and step-by-step demonstration of proper use ensure that patients maximize therapeutic response.16
Individual patient capabilities and needs must be considered when choosing any device.6 There are several different devices on the market: jet nebulizers, ultrasonic nebulizers, metered dose inhalers (MDIs) with or without valve-holding chambers (VHCs), and dry powder inhalers (DPIs). The use of nebulization is common in children because the technique is easy to learn. Children younger than 6 years of age may have difficulties producing the forcefulness required for proper use of a DPI. Studies show no difference in drug delivery and response to treatment between nebulizers and MDIs used with VHCs when proper technique was employed.2,17 A VHC with a mask (in patients <5 years old) or a mouthpiece should be used with MDIs in children to overcome potential coordination difficulties.16
A pharmacist may use an Asthma Action Plan (AAP) as a tool to educate patients on when and how to take their daily medications and when to adjust therapy based on symptoms. An AAP is a form that patients use to self-monitor asthma control.2,15 The form categorizes medications, their dosages, and signs and symptoms indicating worsening asthma. This encourages disease self-management and can improve patient outcomes.2 Inpatient pharmacists can use the AAP upon discharge to help patients understand any changes in medication therapy.16 Community pharmacists can reinforce the importance of adherence and using the written AAP by reminding patients and caregivers that taking medications as prescribed will improve their scores.16
Asthma in children is a prevalent and multifaceted chronic condition that requires continual patient and caregiver education at every patient-provider interaction. Pharmacists have a crucial role in asthma care due to the multiple factors that can affect patient outcomes, such as medication adherence, environmental control, inhaler technique, and comorbid conditions.
1. Centers for Disease Control and Prevention. 2014. Hyattsville, MD: National Health Interview Survey (NHIS 2014), National Center for Health Statistics (NCHS). www.cdc.gov/asthma/nhis/2014/data.htm. Accessed January 25, 2017.
2. National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung, and Blood Institute; 2007.
3. Global Initiative for Asthma. Global strategy for asthma management and prevention. www.ginasthma.org. Accessed April 4, 2017.
4. Lexicomp Online. Lexi-Drugs. Hudson, OH: Lexi-Comp, Inc; 2017. www.online.lexi.com. Assessed February 26, 2017.
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6. Hossny E, Rosario N, Lee BW, et al. The use of inhaled corticosteroids in pediatric asthma: update. World Allergy Org J. 2016;9:26.
7. Loke YK, Blanco P, Thavarajah M, Wilson AM. Impact of inhaled corticosteroids on growth in children with asthma: systematic review and meta-analysis. PLoS One. 2015;10(7):e0133428.
8. FDA. Updated Information on Leukotriene Inhibitors: Montelukast (marketed as Singulair), Zafirlukast (marketed as Accolate), and Zileuton (marketed as Zyflo and Zyflo CR). www.fda.gov/Dugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformation forHealthcareProfessionals/ucm165489.htm. Accessed April 24, 2017.
9. Calapai G, Casciaro M, Miroddi M, et al. Montelukast-induced adverse drug reactions: a review of case reports in the literature. Pharmacology. 2014;94(1-2):60-70.
10. Erdem SB, Nacaroglu HT, Unsalkarkiner CS. Side effects of leukotriene receptor antagonists in asthmatic children. Iranian Journal of Pediatrics. 2015;25(5):e3313.
11. Mitra A, Bassler D, Goodman K, et al. Intravenous aminophylline for acute severe asthma in children over two years receiving inhaled bronchodilators. Cochrane Database Syst Rev. 2005(2):CD001276.
12. Canonica GW, Senna G, Mitchell PD, et al. Therapeutic interventions in severe asthma. World Allergy Org J. 2016;9(1):40.
13. Nucala (mepolizumab) package insert. Philadelphia, PA: GlaxoSmithKline; 2015.
14. The Role of the Pharmacist in Improving Asthma Care. Bethesda, MD: National Lung, Heart and Blood Institute, 1995.
15. Lampkin SJ, Maslouski CA, Maisch WA, John BM. Asthma review for pharmacists providing asthma education. J Pediatr Pharmacol Ther. 2016;21(5):444-471.
16. Summary Report: National Asthma Education and Prevention Program Expert panel report III: Guidelines for the diagnosis and management of asthma. Bethesda, MD: National Heart, Lung, and Blood Institute, 2007.
17. Dolovich MB, Ahrens RC, Hess DR, et al. College of Chest Physicians. American College of Asthma, Allergy, and Immunology. Device selection and outcomes of aerosol therapy: evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest. 2005;127(1):335-371.
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