Asthma Nursing CE Course for APRNs

(GINA, 2023)

Nonpharmacological Treatment of Asthma

Asthma management has three components: nonpharmacological treatment, control medications, and reliever medications. The GINA guidelines emphasize a comprehensive list of treatments patients with asthma should be educated about. They recommend smoking cessation (if the patient smokes) or avoiding environmental exposure to secondhand smoke. Patients are also encouraged to engage in regular physical activity, regardless of whether or not the patient has exercise-induced symptoms. To prevent exercise-induced bronchoconstriction (EIB), the patient should be educated on prevention techniques such as completing a warm-up before strenuous activity and administering a SABA, ICS-SABA, or low-dose ICS-formoterol (Symbicort, Dulera) before exercise or wearing a mask or scarf if symptoms are cold-induced. Physical activity is associated with improved symptom control, cardiopulmonary function, and QOL. Another reason physical activity is important is that obesity has been shown to make asthma control more difficult to achieve. Patients who are obese should be strongly encouraged to attempt a comprehensive weight loss plan. All patients with asthma should be educated on the importance of a balanced diet to maintain a healthy weight (GINA, 2023).

Certain medications can cause worsening asthma symptoms, such as non-selective beta-blockers, nonsteroidal anti-inflammatory drugs (NSAIDs), and ACE inhibitors. If cardioselective beta blockers are indicated for treating or preventing coronary events, comorbid asthma is not an absolute contraindication, but the potential benefits versus risks must be weighed. NSAIDs should always be avoided in patients with aspirin-exacerbated asthma, although cyclooxygenase-2 (COX-2) inhibitors and acetaminophen (Tylenol) are usually well-tolerated (GINA, 2023).

Breathing exercises may be used with pharmacological treatment to improve symptoms and QOL. The American Lung Association has helpful patient education videos on their website regarding pursed-lip breathing (which involves breathing in through the nose and then out very slowly through pursed lips, making sure that the exhale lasts at least twice as long as the time spent inhaling), and diaphragmatic breathing (also known as belly breathing, where again the patient breathes in through the nose but places their hands or another object on their belly to reinforce filling the lungs by pulling down and out with the diaphragm into the abdomen, and then slowly exhaling, again taking two to three times the amount of time to exhale as the time spent on inhaling). Although these techniques can be helpful, they have not consistently improved lung function or decreased exacerbations (American Lung Association, 2022; GINA, 2023).

Decreasing stress has been shown to enhance asthma control and lung function beneficially. Patients with asthma should be educated on which stress-relief activity or program fits their lifestyle and personality best. There is insufficient evidence that one technique is more beneficial than another. Anxiety and depression may also lead to worse asthma control, poor adherence, and decreased QOL if not appropriately treated. Patients with symptoms of anxiety or depression affecting asthma control should be referred to a mental health specialist for treatment. GINA also recommends that all patients with asthma pay close attention to their vaccination records and ensure that all recommended vaccinations are current, especially for influenza and COVID-19. Insufficient evidence supports the routine use of pneumococcal and pertussis vaccinations in adults with asthma (GINA, 2023).

The GINA guidelines suggest that patients with asthma avoid exposure to known triggers when possible, especially if these are occupational, indoor allergens, or air pollution. Occupational asthma refers to patients triggered by chemical or environmental exposure during their regular workday, and it generally increases in severity over time. The primary goal of treatment is to limit exposure. Although many patients with asthma may not feel comfortable making drastic decisions such as changing their profession, switching schools, or moving to a rural area with less smog and air pollution, they can at least engage in a program to reduce exposure to indoor allergens in their own homes and schools (GINA, 2023).

An evidence summary conducted in preparation for the EPR-4 found a paucity of high-quality studies looking at the effectiveness of managing indoor allergen exposure and its effect on asthma morbidity and control. Studies that incorporate high-efficiency particulate air filter (HEPA) vacuums appear to decrease the rate of exacerbations and increase the patient's report of QOL. Mattress covers designed to reduce allergens improve non-validated measures of respiratory symptoms when combined with other interventions but have no clinical effect when tested independently. Consistent pest control service reduces the number of asthma exacerbations (Leas et al., 2018). For pediatric patients who spend a large portion of their waking hours in a school environment, a systematic review of multiple randomized control trials was conducted by Maciag and Phipatanakul to evaluate the exposure to environmental allergens and mitigating interventions. Unfortunately, some exposure to allergens is unavoidable, such as pet allergens brought into school on the clothing or belongings of other students. Mouse allergen proteins are also a problem in schools. One study in the review found that 98% of inner-city schools in the northeast US contained detectable amounts of mouse allergen. Exposure to mouse allergen in schools has been associated with an increased likelihood of the individual experiencing an asthma symptom day and a decrease in FEV₁ by 4%. The method to decrease mouse allergens is integrated pest management (IPM). Following IPM, studies showed a 75% reduction in mouse allergen correlated to increased lung growth in children. The presence of the cockroach allergens Bla g 1 and Bla g 2 is associated with decreased lung function and increased emergency room visits and hospitalizations in patients with asthma. The most effective intervention to remove cockroach allergens is IPM, which can reduce exposure risk by 90%; however, studies examining the impact of cockroach allergen reduction on asthma symptoms are mixed (Maciag & Phipatanakul, 2022).

The National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC) last published guidelines, called the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3), in 2007. In 2018, the National Heart, Lung, and Blood Advisory Council (NHLBAC) and NAEPPCC established a group to update these guidelines to EPR-4. In 2020, focused updates were released, concentrating on 19 recommendations addressing six topic areas. The NHLBAC also recommended that another 11 topics be acknowledged in the update, but no new recommendations were developed. One such topic was the definitions associated with asthma severity. Due to this lack of update, the original severity classification is still in use, including a practical algorithm for assessing asthma severity at initial diagnosis (see Table 3) based on the frequency of symptoms, nighttime awakenings, SABA use, and exacerbations combined with everyday impairment and spirometry results broken down by age group. Notice that symptoms and lung function testing results vary depending on whether the patient is under the age of 5, 5-11, or over the age of 12, which is typically classified as an adult in most asthma guidelines (NHLBI, 2020).

Table 3

Asthma Severity Classification by Age

(NHLBI, 2012, p. 5)

Once assessed, these severity levels correspond with a stepwise treatment algorithm outlined in the 2020 Asthma Management Guidelines and GINA updates. Step 1 refers to managing intermittent asthma, while steps 2-6 refer to persistent asthma ranging from mild to severe in ascending order. Each step has preferred and alternative treatment options based on patient presentation and preferences (GINA, 2023; NHLBI, 2020).

Immunotherapy

Immunotherapy for treating allergic asthma has become more commonplace and better studied in recent years. GINA guidelines (2023) list this particular therapy among the recommended nonpharmacological treatments that should be considered for patients with asthma. There are two approaches to immunotherapy: subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). SCIT involves the identification of allergens affecting the individual and then the administration of the extracts of those allergens in progressively higher doses to illicit desensitization. SCIT is associated with decreased symptoms, the need for medication intervention, and airway hyperresponsiveness. The 2020 updates recommend using SCIT as an adjunct therapy conditionally for patients older than 5 with mild to moderate asthma that is well controlled. There are concerns regarding the design of many of the studies conducted on the effectiveness of SLIT. Despite this, SLIT is recommended in patients with asthma and allergic rhinitis related to an established allergy to house dust mites that are suboptimally controlled despite ICS use and have an FEV₁ of at least 70% of predicted. SLIT is not recommended in the GINA guidelines or EPR-4 updates to treat allergic asthma specifically (Allergy & Asthma Network, n.d.; GINA, 2023; NHLBI, 2020).

Procedural Treatment Options

Bronchial thermoplasty is a device-based treatment option at step 5 (see Table 4) for adult patients with severe asthma that is uncontrolled despite a regimen of ICS and LABAs and a referral to a specialty asthma treatment center that either do not have access or do not qualify for treatment with biologics. Bronchial thermoplasty is delivered via the FDA-approved Alair system, which uses heat to reduce the amount of smooth muscle in the airways. This decrease in tissue impacts the ability of the airway to constrict, allowing for more airflow and ease of breathing during an asthma attack. GINA guidelines caution against this treatment as studies on the effectiveness are small, and patients did not have their medication regimen optimized before bronchial thermoplasty. The guidelines also cite a significant placebo effect and a transient increase in asthma exacerbations during the 3-month treatment period, followed by a subsequent reduction in exacerbations following treatment. They cited no impact on lung function testing or asthma symptoms compared with sham procedures. GINA guidelines recommend that bronchial thermoplasty only be performed in adults in an Institutional Review Board-approved clinical study until more information is gained on the overall effectiveness of the procedure (Boston Scientific, n.d.; GINA, 2023). Chupp and colleagues completed a study to determine the 5-year efficacy of bronchial thermoplasty on adult patients with severe asthma. A total of 284 subjects between 18 and 65 were included in the study, with 227 subjects completing the entire 5-year follow-up period. The researchers compared the results 5 years post-treatment to the 12 months before treatment. They found that the number of individuals that experienced severe exacerbations decreased from 77.8% to 42.2%, emergency room visits dropped from 29.4% to 7.9%, and hospitalization decreased from 16.1% to 4.8%. The percentage of participants taking oral maintenance corticosteroids also improved from 19.4% to 9.7% (Chupp et al., 2021).

Integration of Care

Asthma is best treated in an integrated, multidisciplinary manner. The School-Based Allergy, Asthma, and Anaphylaxis Management Program (SA³MPRO) is designed by the American Association of Allergy, Asthma, and Immunology (AAAAI) to assist students and their families in managing asthma consistently at home and at school (AAAI, n.d.). It involves four components:

Figure 5

 Sample Asthma Action Plan

(NHLBI, 2021)

Treatment Guidelines

The extensive pharmacological management options available to patients with asthma can overwhelm providers. Options include control medications, typically taken daily on a scheduled basis regardless of symptoms. ICS, LABAs, LTRAs, long-acting muscarinic antagonists (LAMA), theophylline (Theo-24, bronchodilator in pill form), and cromolyn sodium (Intal, a mast cell stabilizer) are control medications. For severe asthma, there are five biologics approved by the FDA. Reliever, quick-relief, or rescue medications work quickly to diminish symptoms, but most have a very short half-life. These include SABAs like albuterol (ProAir, Ventolin) and terbutaline (Bricanyl, Marex; not currently available as an inhaler in the US) or short-acting muscarinic antagonists (SAMA) such as ipratropium bromide (Atrovent). Formoterol fumarate (Symbicort, Dulera) is a longer-acting but rapid-onset LABA also used as a reliever (Sharma et al., 2023).

As previously discussed, the NAEPP last published full guidelines in 2007, with more recent updates in 2020. The original NAEPP guidelines included a practical algorithm to assess asthma severity at initial diagnosis (see Table 3 above) based on the frequency of symptoms, nighttime awakenings, SABA use, and exacerbations in combination with everyday impairment and spirometry results broken down by age group (NHLBI, 2012). Once assessed, these severity levels correspond with the updated EPR stepwise treatment algorithm that assists providers in determining the best medication regimen for their patient, broken down again by age group outlined in Table 4.

Table 4

NAEPP 2020 Asthma Treatment Algorithm

GINA Step Guidelines for ages 12+

(GINA, 2023)

Table 6

GINA Step Guidelines for ages 6 to 11 

(GINA, 2023)

The first step of the EPR-4 indicates using a SABA as needed for symptom management for all age groups. The severity of symptoms guides treatment intensity, but SABAs may be administered every 20 minutes up to three times. If the administration of intermittent SABA is required more than two days per week, a step up in treatment is indicated (NHLBI, 2020).

Step 2 of the EPR-4 includes preferred and alternative treatments. For all patients, regardless of age, the preferred treatment is the addition of a low-dose ICS administered daily. The alternative treatment for those ages 0-4 is the addition of daily montelukast (Singulair) or Comolyn. The alternative treatment for those ages 5 and older includes the addition of a daily dose of an LTRA, cromolyn sodium (Intal), nedocromil (Tilade), or theophylline (Theo-24). Another alternative option for those ages 12 and older is zileuton (Zyflo; NHLBI, 2020). Step two of the GINA guidelines for children ages 6-11 includes using a daily low-dose ICS. Other controller medications that can be used but are not preferred include daily LTRA or using a low-dose ICS whenever a SABA is used. For those ages 12 and older, the preferred treatment in step 2 is the same as step 1, specifically as needed low-dose ICS-formoterol (Symbicort, Dulera). The alternative therapy is daily low-dose ICS with an as-needed SABA as a reliever medication (GINA, 2023).

Step 3 of the EPR-4 for those ages 0-3 includes increasing the daily dose of ICS to a medium dose. If an escalation to step 4 is indicated, the preferred treatment is the addition of a LABA. The alternative treatment in step 4 includes the addition of montelukast (Singulair). For children that are 4 years old, steps 3 and 4 for those ages 5-11 should be followed. Therefore, step 3 therapy for those ages 4 and up is a low-dose daily and as-needed dose of ICS-formoterol (Symbicort, Dulera). For steps 3 and 4, the preferred quick-relief treatment for children 4-11 is ICS-formoterol (Symbicort, Dulera) 1 to 2 puffs as needed up to a daily maximum of 8 puffs or 36 mcg or a daily maximum of 12 puffs or 54 mcg for those 12 and up. Alternatives for step 3 include a medium dose of ICS with an as-needed SABA, a low dose of ICS-LABA daily, or a low dose of ICS daily plus an LTRA or theophylline (Theo-24) with an as-needed SABA. Step 4 calls for a daily medium dose of ICS-formoterol (Symbicort, Dulera), with an alternative of daily medium-dose ICS with a LABA, LTRA, or theophylline (Theo-24) plus an as-needed SABA. Step 5 treatment is based on daily high-dose ICS-LABA with a PRN SABA, while step 6 involves the addition of a systemic steroid. Alternatives include using an LTRA or theophylline instead of the LABA (NHLBI, 2020).

The primary therapies for Steps 3 and 4 in those over 12 mirror the treatments for 4-11-year-olds, but the alternatives vary some. Alternative step 3 treatments include a daily low dose ICS plus LAMA or zileuton (Zyflo) and a SABA as needed. If a step up is required to step 4 in a patient 12+, the dose of ICS-formoterol (Symbicort, Dulera) increases from a low dose to a medium dose in both the preferred and alternative treatment guidelines. Step 5 treatment is based on daily medium-high-dose ICS-LABA plus LAMA with a PRN SABA, while step 6 involves the addition of a systemic steroid. Alternatives include using an LTRA instead of the LABA (NHLBI, 2020).

Intermittent ICS dosing is defined as varying in dose, frequency, or duration of administration, such as initiating a temporary course of ICS or temporarily increasing the dose. For the 2020 EPR-4 update, an executive summary regarding intermittent ICS and LAMA use was published by Sobieraj and colleagues (2018b), discussing the efficacy of intermittent ICS use by age group. They reviewed 54 randomized controlled trials and two observational studies as part of their process. In patients aged 4 and under with recurrent wheezing, they found intermittent ICS use with SABA (vs. SABA alone) reduced the risk of exacerbation requiring oral steroids based on moderate strength of evidence and improved QOL based on low strength of evidence. In these patients, intermittent ICS reduced the risk of exacerbation requiring oral steroids, hospitalization, or rescue medication use versus regularly scheduled ICS controller use. There was insufficient evidence regarding intermittent ICS use versus nonpharmacological or no therapy in this age group. In patients aged 5 to 11 with persistent asthma, they found intermittent ICS use did not affect QOL or rescue medication use versus ICS controller use based on low strength of evidence, and there was insufficient evidence to assess the effect on the other outcomes in this age group. In patients with persistent asthma aged 12 and older, they found that the use of intermittent ICS dosing, either alone or with ICS controller dosing, versus ICS controller dosing alone, did not affect the risk of exacerbation based on low strength of evidence. However, using intermittent and controller ICS versus controller dosing alone decreased the number of asthma-related outpatient visits based on low strength of evidence (Sobieraj et al., 2018b).

Controller Medications

Inhaled Corticosteroids

ICS are the primary preferred controller medications used in both algorithms for persistent asthma. They reduce bronchial inflammation, prevent exacerbations, and often relieve cough. The onset of action is slow and gradual; therefore, the maximum benefit may take several days to weeks to be seen. There are different standard dosing ranges of ICS based on the age of the patient, the particular guideline followed, and the specific step within the guidelines (GINA, 2023; Liang & Chao, 2022; NHLBI, 2022). The standard low, medium, and high doses of ICS for the GINA and EPR-4 updated guidelines are outlined in Tables 7 and 8.

Table 7

Low, Medium, and High Doses of Inhaled Corticosteroids by Age per GINA

(GINA, 2023)

Table 8 

Low, Medium, and High Doses of Inhaled Corticosteroids by Age per NHLBI

(Mammen, 2021; NHLBI, 2012)

Since these drugs are administered via inhalation, they are delivered directly to the site of action. Due to this, decreased doses can be used due to the bypass of the first-pass metabolism process. They are traditionally dosed daily or twice daily, regardless of symptoms. Dysphonia is a commonly experienced side effect in 50% to 60% of patients. Dysphonia is reversible after ICS treatment is discontinued. Thrush is also a common side effect of ICS. This is especially true in older adults and those also taking oral steroids. However, the risk of thrush can be reduced significantly with diligent oral hygiene after medication administration and using a spacer or chamber (see Figure 6), which also helps with medication delivery when using a metered-dose inhaler (MDI). In older adults, ICS may also increase the rate of bone mineral loss and cause skin thinning, bruising, and adrenal suppression. Adult patients that have chronically used ICS should undergo bone density measurement. ICS has also been shown to slow growth rates in children by an average of 1 cm, although this is both non-progressive and not entirely predictable. Testing of bone density is not recommended in children; however, it is recommended that children taking ICS intake adequate amounts of calcium and vitamin D (Liang & Chao, 2022; NHLBI, 2022).

Figure 6

MDI with Attached Spacer Device

(FDA, 2012)

GINA guidelines recommend a lower dose of ICS earlier, as opposed to a higher dose, with more significant side effects later. With regular ICS use, an improvement in FEV₁ should be seen within days and usually plateaus in roughly 2 months. PEF readings usually increase to PB level after about 2 weeks of treatment, with variability diminishing after 3 months. They also list nasal spray corticosteroids as an alternative for patients with allergic rhinitis and a proven allergy instead of ICS. Patients with eosinophilic asthma typically require a higher dose of ICS for inflammation management, regardless of what may seem like adequate symptom control. Because inflammation can affect the entire respiratory tract, ICS alone may be insufficient in some patients. In severe asthma, systemic steroids may be added as a last resort but should be used cautiously since they carry significantly greater adverse effects (GINA, 2023).

Long-Acting Inhaled Beta 2 Agonists 

LABAs are only FDA-approved for use with an ICS (other than formoterol [Perforomist]) and not for acute symptom relief when used to treat asthma. Adding LABA to low-dose ICS in adult patients with asthma who are not well-controlled with low-dose ICS alone results in better control than doubling the ICS dose. However, using LABA alone has been shown to increase the risk of exacerbation and is not recommended. They work as bronchodilators by relaxing the smooth muscles surrounding the airway by selectively stimulating beta-2 adrenergic receptors. Examples of LABAs include salmeterol (Serevent, Advair), vilanterol (Breo Ellipta), and formoterol (Perforomist). Vilanterol's (Breo Ellipta) half-life is 16-21 hours (allowing once-daily dosing) with an onset of about 10 minutes, formoterol's (Perforomist) half-life is 10 hours with an onset of 5 minutes or less, and salmeterol's (Serevent, Advair) half-life is just 5.5 hours with an onset of about 15 minutes. EPR-4 recommends a maximum daily dose of 100 mcg of salmeterol (Serevent, Advair) or 54 mcg of formoterol (Perforomist). They work exceptionally well in patients with a lot of wheezing, SOB, and nocturnal symptoms or those patients found to be in the non-eosinophilic clinical phenotype characterized by severe symptoms but minimal inflammation. Side effects include tremors, vomiting, nausea, fever, headache, cough, dry mouth, and dyspepsia (NHLBI, 2020; Sharma et al., 2023).

Long-Acting Inhaled Muscarinic Antagonists

Tiotropium bromide (Spiriva) is the only LAMA FDA-approved for asthma patients over 11 in the US (although others are approved for treating COPD). It is an antagonist to muscarinic (M3) cholinergic receptors, causing bronchodilation, with a half-life of 25 hours. GINA states that in patients older than 6 with a history of exacerbations not well-controlled on low-dose ICS and LABA, the addition of tiotropium (Spiriva) can be considered in the 4th step. It has been shown to improve lung function and modestly increase the time to severe exacerbation. Dosing is 2 puffs of 1.25 mcg/actuation once daily. It may take 4 to 8 weeks to experience any improvement. The most common side effects experienced are a direct result of the anticholinergic effects of the medication and include urinary retention, dry mouth, headaches, and dizziness. Other side effects include bronchitis, sinusitis, dyspnea, back pain, cough, dyspepsia, and nausea (GINA, 2023; Sharma et al., 2023).

Sobieraj and colleagues (2018b) evaluated the research regarding using LAMA as part of the executive summary when preparing the updated EPR-4. They found that in patients over 11 with uncontrolled persistent asthma, adding LAMA to ICS versus placebo decreased the risk of exacerbation and improved spirometry results. They also compared the combination of LAMA and ICS versus doubling the dose of ICS and found no significant effect. They compared adding LAMA to ICS versus adding LABA and similarly found no significant impact. Finally, they reviewed what they termed "triple treatment," which included ICS, LABA, and LAMA. They found that adding LAMA improved FEV₁ based on high strength of evidence and improved asthma control scores based on low to moderate strength of evidence but saw no significant effect on the risk of exacerbation or hospitalization (Sobieraj et al., 2018b). Separately, a systematic review and meta-analysis of LAMA use published in 2018 included 15 randomized clinical trials and over 7,000 patients over 11, including 789 between the ages of 12-17. They found that adding LAMA to ICS versus placebo reduced the risk of exacerbation requiring systemic steroids and improved spirometry results. They found no significant difference between ICS-LABA and ICS-LAMA. Very similar to the results above, when they compared ICS-LABA with triple therapy (ICS/LABA/LAMA), they found an improvement in FEV₁ as well as QOL scores but saw no decrease in exacerbation risk (Sobieraj et al., 2018a).

Leukotriene Receptor Antagonists

The EPR-4 and GINA guidelines both list LTRAs such as montelukast (Singulair), zafirlukast (Accolade), or zileuton (Zyflo) as alternative options for persistent asthma treatment in patients aged 5 and above. They are available as once-daily oral tablets, and montelukast (Singulair) is also available in a granule packet. Zileuton (Zyflo) also has a slightly different mechanism of action, working as a 5-lipoxygenase inhibitor to interfere with leukotriene formation, while montelukast (Singulair) and zafirlukast (Accolade) both function as selective LTRAs blocking the leukotriene portion of the inflammatory cascade (Sharma et al., 2023).

GINA specifies that these oral medications may be an appropriate daily controller choice in patients who experience intolerable adverse effects related to ICS or may have concomitant allergic rhinitis and as an alternative in EIB. It is an alternative adjunct to ICS treatment but is less effective than adding LABA. It can also be considered an optional adjunct therapy in patients with aspirin-sensitive asthma (GINA, 2023). EPR-4 specifies that montelukast (Singulair) may be used in children as young as 1, while zafirlukast (Accolade) and zileuton (Zyflo) should not be used in patients under 5. They further specify that both zafirlukast (Accolade) and zileuton (Zyflo) require liver function monitoring regularly. They also suggest LTRAs as an alternative to treating EIB (NHLBI, 2020).

Before prescribing these medications, providers must weigh the benefits versus the risks of adverse effects. Side effects of these medications include headaches, eczema, laryngitis, pharyngitis, dental pain, dyspepsia, cough, sinusitis, hepatitis, and allergic granulomatous angiitis (Churg-Strauss syndrome). Montelukast (Singulair) can cause neuropsychiatric events such as hostility, aggressive behavior, agitation, dream abnormalities, hallucinations, and suicidal behavior, and as of 2020, the FDA has required a black box warning for this serious mental health effect. Due to hepatoxicity risk, LTRAs are contraindicated in patients with hepatic dysfunction (Fanta & Barrett, 2023; Sharma et al., 2023).

Theophylline

Theophylline (Theo-24) is a xanthine derivative administered orally that functions by antagonizing adenosine receptors and increasing cyclic adenosine monophosphate (cAMP), and decreasing the production and release of pro-inflammatory signals, specifically TNF-alpha and leukotriene, thereby causing smooth muscle relaxation and bronchodilation. It can be beneficial with nocturnal symptoms. EPR-4 guidelines recommend theophylline (Theo-24) as an alternative to low-dose ICS in step 2 treatment, an alternative adjunct to ICS or ICS-LABA in steps 3, 4, and 5, or step 6 in conjunction with ICS-LABA in an attempt to avoid a course of oral corticosteroids. It is available in liquid, capsule, or sustained-release tablet form. It is typically dosed at 10 mg/kg per day initially (NHLBI, 2020).

GINA guidelines offer theophylline (Theo-24) as an alternative initial controller medication in adolescents and adults with initial presentation of asthma symptoms, or SABA use more than twice weekly, but note that this is typically less effective than low-dose ICS. They also mention that short-acting theophylline (Theo-24) should not be used as a reliever medication due to its poor efficacy, slower onset of action, and higher risk of adverse effects than SABAs. GINA guidelines also list theophylline (Theo-24) as an adjunct treatment option with ICS or ICS-LABA in adolescents and adults but do not recommend its use in children (GINA, 2023). Potential side effects of theophylline (Theo-24) include headaches, insomnia, irritability, restlessness, seizures, tremors, tachycardia, cardiac arrhythmias, urinary retention, and acute myocardial infarction. Theophylline (Theo-24) may worsen GERD symptoms via lower esophageal sphincter relaxation. Theophylline (Theo-24) also has a narrow therapeutic range and requires serum blood level monitoring at least every 6 months (Sharma et al., 2023).

Cromolyn sodium

Cromolyn sodium (Intal) is a mast cell stabilizer that decreases the degranulation of pro-inflammatory mediators such as histamine and leukotrienes, thereby blocking the cellular response to inhaled antigens that can trigger asthma exacerbations. Cromolyn sodium (Intal) can be administered via MDI or nebulizer; however, a significant limitation of cromolyn sodium (Intal) is needing a nebulizer and needing to be dosed four times daily to be effective. Adverse effects vary based on the route of administration. Effects of inhalation are throat irritation, laryngeal edema, drowsiness, dizziness, bronchial irritation, cough, hoarseness, and cough (Minutello & Gupta, 2023). Cromolyn sodium (Intal) is listed in EPR-4 as an alternative controller medication in step 2; however, insufficient research demonstrates its safety and efficacy in children under 2. It is also one of the options that may be used to pre-treat EIB before exercise (NHLBI, 2020). The updated GINA (2023) guidelines did not mention cromolyn sodium (Intal) or other mast cell stabilizers.

Biologics

For severe asthma, there are six biologics approved by the FDA that work by diminishing or blocking the effects of various steps in the inflammatory cascade, such as omalizumab (Xolair, an antibody that binds IgE), dupilumab (Dupixent, an antibody to IL-4), mepolizumab (Nucala, an antibody to IL-5), benralizumab (Fasenra, an antibody to IL-5), reslizumab (Cinqair, an IL-5 antagonist), and tezepelumab (Tezspire, an anti-thymic stromal lymphopoietin [anti-TSLP]). Omalizumab (Xolair) is the only biologic recommended in the EPR-3 treatment guidelines; when the EPR-4 updates were released, biologic agents were listed as an emerging topic and were not included in the update (NHLBI, 2020). GINA guidelines include all six biologics as an optional adjunct treatment in step 5 for patients over 6 with moderate or severe allergic asthma uncontrolled on step 4 treatment (GINA, 2023).

Omalizumab (Xolair) 

Omalizumab (Xolair) is an FDA-approved medication for moderate to severe allergic asthma in patients aged 6 and older with elevated IgE levels. It functions as a monoclonal antibody that binds IgE. Treatment with omalizumab (Xolair) may decrease the frequency of asthma exacerbations, the need for corticosteroids, and symptoms. It is delivered as a subcutaneous injection every 2-4 weeks. The dose is between 75 and 375 mg based on the patient's weight and IgE levels before starting treatment. The manufacturer has a table and tool to calculate dosing based on individual patient values. Adverse effects of omalizumab (Xolair) include headaches, fatigue, peripheral edema, abdominal pain, leg pain, injection site reaction, myocardial infarction, and pulmonary embolism (Ortega & Izquierdo, 2022b; Woods, 2023).

Dupilumab (Dupixent)

Dupilumab (Dupixent) is a monoclonal antibody to the IL-4-alpha subunit receptor that has been shown to significantly reduce exacerbations and improve lung function and asthma control in patients older than 6 with moderate to severe asthma with an eosinophilic phenotype or those that are oral corticosteroid dependent. It is thought to function by inhibiting IL-4 and IL-13 activity. It is given via subcutaneous injection every 2 weeks. There are two dosing schedules. In the first, the initial dose is 400 mg, followed by 200 mg administered every other week. In the second, the initial dose is 600 mg, followed by 300 mg administered every other week. The higher dosing schedule is reserved for patients dependent on oral corticosteroids to reduce the dose or eliminate their use. Side effects include pain or redness at the injection site, sore throat, fever, dizziness, facial rash, diarrhea, toothache, insomnia, eosinophilia, and oral sores (Ortega & Izquierdo, 2022b; Woods, 2023).

Mepolizumab (Nucala) 

Mepolizumab (Nucala) is a humanized monoclonal antibody to IL-5 that is FDA-approved for adjunctive therapy for severe eosinophilic asthma in patients 6 and older. Dosing for patients ages 6 to 11 is 40 mg, and for patients 12 and older is 100 mg, administered via subcutaneous injection every 4 weeks. Clinical trials showed that treatment is most effective when serum eosinophil counts are above 0.15 x 10⁹/L; however, this value can be affected by long-term oral corticosteroid use. Mepolizumab (Nucala) has effectively reduced or eliminated the need for treatment with oral corticosteroids. Side effects of treatment include headaches, injection site reactions, abdominal pain, pruritus, eczema, fatigue, and hypersensitivity reactions (GINA, 2023; Ortega & Izquierdo, 2022b; Sharma et al., 2023).

Benralizumab (Fasenra) 

Benralizumab (Fasenra) is a humanized monoclonal antibody that binds to the IL-5-alpha receptor, inhibiting eosinophils' proliferation in the bone marrow. It is an FDA-approved adjunctive therapy for patients with severe eosinophilic asthma 12 and older. It has been shown to reduce or eliminate the need for oral corticosteroids and decrease the frequency of exacerbations. The recommended dose is 30 mg administered subcutaneously every 4 weeks for three doses, then every 8 weeks. Potential side effects include headaches, pyrexia, pharyngitis, and hypersensitivity reactions (GINA, 2023; Ortega & Izquierdo, 2022b; Sharma et al., 2023).

Reslizumab (Cinqair) 

Reslizumab (Cinqair) is a humanized monoclonal IgG4 antibody to IL-5 that is FDA-approved as adjunctive therapy for patients over 18 with uncontrolled severe asthma with an eosinophilic phenotype. It has been shown to decrease oral corticosteroid use and the frequency of exacerbations. It is administered over 20 to 50 minutes via IV infusion at a 3 mg/kg dose every 4 weeks. Possible side effects include oropharyngeal pain, myalgia, muscle spasms and fatigue, chest and neck pain, elevated creatine phosphokinase (CPK), antibody development, and anaphylaxis (GINA, 2023; Ortega & Izquierdo, 2022b; Sharma et al., 2023).

Tezepelumab (Tezspire) 

Tezepelumab (Tezspire) is a novel biologic IgG2 monoclonal antibody that blocks the effects of thymic-stromal lymphopoietin (TSLP). This cytokine is released when the epithelium is irritated by an allergen or another antigen one step upstream from IL-4 and IL-13. It was approved by the FDA in December 2021 for use in patients 12 and older as an adjunct in treating severe uncontrolled asthma. The recommended tezepelumab (Teszpire) dose is 210 mg, administered subcutaneously every 4 weeks. In clinical trials, the most commonly reported adverse effects included pharyngitis, arthralgia, and back pain. There is also a risk for hypersensitivity reactions (AstraZeneca, 2023).

Azithromycin (Zithromax) 

For severe asthma, the GINA guidelines recommend adding azithromycin (Zithromax) 500 mg three times weekly after a specialist referral and initiation of high-dose ICS-LABA (Step 5). Before initiating azithromycin (Zithromax), the provider should obtain a sputum sample to test for atypical mycobacteria and an ECG to assess for a prolonged QT interval (this should be repeated after a month of treatment). When utilizing an antibiotic such as azithromycin (Zithromax), the potential for antimicrobial resistance should be considered and weighed against the benefits of treatment. The suggested treatment duration is 6 months, as clinical trials did not demonstrate an improvement after 3 months. The most commonly reported side effect is diarrhea (GINA, 2023).

Quick Reliever Medications

Reliever or rescue medications are used to treat asthma exacerbations or sudden onset of symptoms as needed. Examples of reliever medications include ICS-formoterol (Symbicort, Dulera), ICS-SABA, or SABA alone. Albuterol (Pro-Air, Ventolin) and levalbuterol (Xopenex) are bronchodilators that selectively stimulate beta-2 adrenergic receptors, similar to the previously mentioned LABAs, relaxing the airway smooth muscles. Their half-life is 2.7 to 6 hours. Both are available as MDIs or can be used in nebulizers, and albuterol (Pro-Air, Ventolin) can also be found in oral tablet form, extended-release oral tablet, or liquid syrup. Terbutaline (Bricanyl) is a SABA available in tablet form and a subcutaneous injection with a half-life of 3-4 hours. It is approved for use up to three times daily in patients over 5. EPR-4 and GINA guidelines suggest using SABAs like albuterol (Pro-Air, Ventolin) on an as-needed basis in patients with mild intermittent asthma. As mentioned, formoterol (Perforomist) is a quick-onset LABA with a 10-hour half-life. Ipratropium bromide (Atrovent) is a SAMA that creates bronchodilation by antagonizing acetylcholine receptors. It has a half-life of 2 hours and is available as a nebulizer solution that can be mixed with Albuterol (Pro-Air, Ventolin), levalbuterol (Xopenex), or an MDI that can be used independently. Both guidelines suggest utilizing the 'patient's report of reliever use frequency to help gauge the level of symptom control in patients with asthma (GINA, 2023; NHLBI, 2020; Sharma et al., 2023).

MART/SMART

In the GINA treatment guidelines (2023), low-dose ICS-formoterol (Symbicort, Dulera) is listed in steps 3-5 as an option for controller and reliever medication. This is known as maintenance and reliever therapy (MART) and can only be used with ICS-formoterol inhalers such as budesonide-formoterol (Symbicort, ages 12 to 17). The basic concept of MART is as follows: the traditional instructions to patients with asthma involve one or two inhalers for daily control/maintenance and separate reliever medication in another inhaler to be used as needed. Alternatively, the MART method instructs patients to utilize one inhaler, a combination of ICS and formoterol, a rapid-onset LABA, for maintenance and as-needed symptom control. Some also refer to MART as single-inhaler maintenance and reliever therapy (SMART; the GINA guidelines utilize the term MART and the NAEPP guidelines use the term SMART). MART is also the preferred treatment method in steps 3 and 4 for children ages 6 to 11. Studies have shown that the use of MART with low-dose ICS-formoterol reduces severe exacerbations and provides a similar level of control compared to ICS-LABA or a higher dose of ICS as maintenance medication in combination with a SABA as needed (Evidence level A indicating a large amount of supporting data). One meta-analysis demonstrated that switching patients in Step 3 with poorly controlled asthma to MART led to a reduction of severe exacerbations by 29% compared to an ICS-LABA maintenance dose plus an as-needed SABA (alternative Step 4) and a 30% reduction of symptoms compared to the alternative regimen of Step 3. There is currently no evidence about initiating MART in patients taking biologics; however, there is no contraindication for beginning a biologic in those patients already using MART (GINA, 2023).

The NAEPP also recommends utilizing MART (or SMART) in steps 3 and 4 for those individuals aged 4 to 11 and in step 4 for those older than 12. For individuals 5 to 11, the evidence supports using MART instead of an equivalent, low, or medium dose of ICS-LABA plus an as-needed SABA; however, the evidence was insufficient to make recommendations of MART compared to high-dose ICS-LABA. Three large, randomized control trials (RCTs), including 4,662 individuals older than 12, compared the difference between utilizing MART versus daily ICS (budesonide) plus an as-needed SABA. The results of the RCTs showed a reduction in the relative risk of exacerbations by 35% to 51%. These RCTs recommended the use of MART with a high certainty of evidence. Another analysis of three RCTs by O'Byrne and Colleagues included 224 children ages 4 to 11 who were already being treated with medium to high doses of ICS. Of the 224 participants, 118 were switched to MART, and the other 106 took budesonide (Pulmicort) with an as-needed SABA. In the group that followed MART, the relative risk of exacerbation, including the use of systemic corticosteroids, emergency room visits, hospitalization, and the need for increased medication doses, decreased by 57% compared to the control group. The MART group also demonstrated a significantly improved growth rate of 1 cm due to utilizing a lower dose of ICS (NHLBI, 2020; O'Byrne et al., 2018).

Per the EPR-4 expert panel, more research is needed to address this recommendation. The benefits versus risk of ICS use needs to be differentiated based on race and ethnicity. There also needs to be more research done on the effects on growth for those aged 0 to 4 that require short courses of ICS treatment to treat wheezing triggered by the presence of a respiratory tract infection. The effectiveness of using MART compared to high doses of ICS-LABA with a SABA as needed in children ages 4 to 11. There also needs to be more research done on the effectiveness of other rapid-onset LABAs in combination formulations used for both maintenance and reliever therapy (NHLBI, 2020).

Assessment of Asthma Control 

The key to utilizing this stepwise approach effectively is the accurate and consistent assessment of symptom control at each follow-up visit (see Table 9 below). During the follow-up visit, the provider should assess symptom control and frequency of exacerbations since the last visit, lung function, side effects, QOL, and overall patient satisfaction with asthma care. The patient should be asked about nighttime awakenings and daytime symptoms. Medication adherence should be discussed with non-judgmental and open-ended statements and questions. The inhaler technique should be assessed at each visit, and the presence of an AAP that is up-to-date and appropriate should be confirmed. These follow-up visits should occur every 2-6 weeks while the patient is gaining control, every 1-6 months to monitor if well-controlled, or every 3 months if a step-down in therapy is anticipated or being carried out. This follow-up should include spirometry on all patients over the age of 4 at least every year or two, as well as the use of validated symptom control tools in all patients over the age of 11, according to the NAEPP. Good control is a combination of decreased functional impairment and future exacerbation risk or damage (Fanta & Barrett, 2023; NHLBI, 2012).

According to GINA recommendations, follow-up visits to assess control should occur 1-3 months after the initial diagnosis, then every 3-6 months, depending on the level of control. A follow-up is also recommended within a week of an exacerbation requiring an emergency room visit and 3-6 weeks after any medication change. In children that have experienced an exacerbation and are at risk of a repeat exacerbation, a follow-up should be completed within 1-2 days and again in 1-2 months. FEV₁ should be reassessed 3-6 months after starting long-term control treatment to establish the patient's PB, and periodically after that, but at least every year or two in asthma patients over the age of 4. GINA guidelines point out persistent bronchodilator reversibility of greater than 12% or 200 mL in a patient on a long-term control medication or who was given a dose of SABA within the last 4 hours or LABA within the previous 24 hours when administered twice daily or 36 hours when administered once daily indicates uncontrolled asthma. Similarly, excessive variability in a patient's PEF readings indicates suboptimal control and an increased risk for exacerbations in the future (GINA, 2023).

Table 9

Follow-up Assessment of Asthma Control

(NHLBI, 2012, p. 6)

An FEV₁ less than 60% predicted is an independent predictor for future exacerbation risk and accelerated lung function decrease. This means that if there is a patient with a decreased FEV₁ but minimal symptoms, the provider needs to consider whether the patient is significantly limiting their lifestyle to avoid symptom provocation or has a poor perception of airflow limitation secondary to untreated airway inflammation. Conversely, if a patient presents with increased symptoms, but good or acceptable spirometry results, the provider must consider differential diagnoses such as undetected GERD, cardiac disease, or a cough related to post-nasal drip (GINA, 2023).

Asthma control is the extent to which the signs and symptoms of asthma can be observed in a particular patient and how impairments and risk of adverse effects are minimized due to treatment. Control is classified as well-controlled, not well-controlled, and very poorly controlled. The overall goal of asthma treatment is to achieve good control, which is possible in most patients. Patients that have their asthma controlled do not use their quick-reliever medications for more than two days per week, do not experience nighttime awakenings more than twice per month, their PEF or FEV1 is within 20% of their PB, and have not had more than a single exacerbation requiring urgent medical treatment or the use of oral glucocorticoids within the past year (Fanta & Barrett, 2023; Ortega & Izquierdo, 2022a). Asthma control has two facets: symptom control and the risk of future adverse events or exacerbations (GINA, 2023). Numerous screening tools can be used to assess asthma control in adolescents and adults, such as:

Patients with aspirin-exacerbated asthma typically present with nasal congestion and anosmia, leading to chronic rhinosinusitis with nasal polyps and, eventually, asthma. They usually describe acute exacerbations within 60-120 minutes of exposure to aspirin or other NSAIDs, along with rhinorrhea, nasal obstruction, conjunctival irritation, and flushing of the head and neck. If needed, it can be confirmed with an aspirin challenge test in a well-monitored environment with access to emergency equipment. NSAIDs should be avoided in these patients, but COX-2 inhibitors or acetaminophen (Tylenol) are typically well tolerated. Asthma symptoms can be treated with ICS, LTRA, with or without oral corticosteroids, and desensitization therapy (GINA, 2023).

Referral to a Specialist

Recognizing when a patient needs to be referred to a specialist for more advanced care should be of utmost concern to the provider. In patients aged 4 and under, the EPR-4 suggests referral with an asthma specialist if step 3 management or higher is reached, with consideration at step 2. In patients aged 5 and above, this threshold is step 4 or higher, with consideration in step 3 (NHLBI, 2020). GINA guidelines recommend referral to an asthma specialist at step 5 or in the following circumstances: