Overview of Diagnosis and Management

An overview of the diagnosis and management of asthma is presented in Table 1. Topics are addressed in the sequence presented in the overview.

Diagnosis of Asthma

The steps to diagnose asthma are summarized in Table 1. Each step is described in more detail below.

Asthma Education

At all asthma visits, provide patient/family education by a member of the health care team. The key educational points to address are listed in Table 4. Patients with severe asthma (especially children) benefit from comprehensive education programs.

Emphasize how to recognize and treat exacerbations. Early treatment is the best strategy. The principal goal of treatment is to rapidly reverse airflow obstruction. When treatment for an exacerbation is needed, the initial approach is repetitive treatments with an inhaled beta agonist. For patients with severe attacks or who fail to respond promptly and completely to an inhaled beta agonist, administer systemic corticosteroids.

Patient education materials about asthma and its control are available at www.med.umich.edu/1info/fhp/practiceguides/. Information there includes how to use a metered dose inhaler (MDI), instructions for specific devices, and MDI dose counting charts to help patients be sure they are using inhalers containing active drug.

Environmental Control

Asthma triggers that induce airway inflammation or precipitate acute bronchospasm are listed in Table 5. The majority of patients with asthma are atopic, especially patients in the pediatric age group. Aeroallergen exposure and sensitivity contribute significantly to the development and persistence of asthma, particularly in patients with atopy.

In patients with persistent asthma, evaluate the role of allergens as contributing factors. Accurate identification of the triggering allergens will help patients avoid them. The only reliable way to determine sensitivities to allergens is to jointly consider the patient’s medical history and results of skin or in-vitro testing. Skin testing correlates with bronchial allergen challenge, and in many instances it can identify controllable environmental allergens.

For patients with mild to moderate persistent asthma and who are exposed to a triggering allergen. consider allergen immunotherapy.

Environmental tobacco smoke. For asthma patients who smoke and for children with asthma whose parents or family members smoke, strongly recommend smoking cessation. Smoking cessation is a critical first step for reducing inflammation in asthma patients who smoke or are exposed to smoke. Smoking also impairs the short-term response to both systemic and inhaled corticosteroids.

Recommend patients avoid passive smoke exposure if possible. Exposure to smoke can trigger asthma attacks or worsen lung function. Ask patients about passive exposure to smoke. High-efficiency particulate air (HEPA) filters can reduce the level of particulates in air that contains tobacco smoke.

Also recommend avoiding smoke from marijuana and vapor from electronic cigarettes. Although the data are not as clear, most evidence suggests both of these can make asthma worse.

Indoor allergens. For indoor allergens, recommend a comprehensive avoidance approach, particularly in the bedroom. Studies have shown that a single avoidance step is generally ineffective, but that a comprehensive approach can improve outcomes.

Bedroom. The bedroom is the most important continuous source of indoor allergen exposure. An important avoidance step is to control house dust mites. They are microscopic arachnids (spider family) that live in mattresses, bedding, furniture, and carpets. They thrive in high humidity and eat dead skin cells. High levels of dust mites can be found in dust from mattresses, pillows, carpets, upholstered furniture, bed covers, clothes, and soft toys. Effective dust mite control includes washing bedding materials in hot water to denature mite allergens ideally every week. Encasing the mattress, pillows and box spring reduces mite allergen levels and is also recommended for mite-allergic patients. Additional control measures include removing carpeting from the bedroom, reducing relative humidity to less than 50%, cleaning carpets once a week with a high-efficiency particulate air (HEPA) vacuum cleaner, and eliminating, minimizing, or washing children’s stuffed bed toys.

Pets. All warm-blooded pets – including cats, dogs, rodents, and birds – produce allergens that can trigger asthma. Removing animals to which the patient is allergic from the patient’s environment may provide a benefit. However, the perceived benefit may not be immediate because animal allergens can linger for months after the animal is removed. If removal of the animal is not acceptable, the pet should be kept out of the patient’s bedroom, and the bedroom door should be kept closed. Removing upholstered furniture and carpets or isolating the pets from these items will also be beneficial. HEPA vacuum cleaners can reduce the airborne level of pet allergens. The role of regular washing of the allergenic pet has not been established.

Molds and cockroaches. Exposure to molds and cockroaches can trigger asthma in sensitive individuals. Remove these allergens if possible. Mold spores can be reduced by using central HEPA filters in homes with forced air heating and cooling systems, repairing leaky pipes, and keeping relative humidity levels below 50%. Cockroaches can be removed by poison baits or traps, but professional pest management services may be needed.

Workplace. Numerous occupational allergens and irritants can precipitate asthma. Once a worker is sensitized to a particular allergen or irritant, the level of exposure necessary to induce symptoms may be very low. Monitoring of peak expiratory flow rates (PEFR) both on and off the job and review of Material Safety Data Sheets (which are required by the US Occupational Safety and Health Administration for all workplaces) can help identify occupational triggers. Attempts to reduce occupational trigger exposure have been successful in a number of industrial settings.

Outdoor allergens. Outdoor allergens (pollens and molds) are common triggers and impossible to avoid completely. Exposure may be reduced by staying indoors, closing windows and doors, and using air-conditioning and filtering devices, especially during peak pollen times (typically midday and afternoon). This may not be realistic for some patients, especially children.

Food triggers. Foods rarely trigger asthma. However, exposure to sulfites can trigger asthma in some patients. Sulfites are common preservatives found in wines, processed potatoes, shrimp, dried fruits, beer, and some medications. Ask patients about any association between exposure to these items and asthma symptoms. If an association is identified, advise patients to avoid foods and drugs that contain sulfites. Labels may list ingredients such as potassium bisulfite, potassium metabisulfite, sodium bisulfite, sodium metabisulfite, sodium sulfite, or sulfur dioxide.

Indoor air pollution. A variety of indoor air pollutants can trigger asthma, including smoke from various sources (eg, tobacco, wood stoves, or heating), aerosols, household sprays, volatile organic compounds, strong odors, and scents. Advise patients to avoid offending pollutants.

Medications. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) can cause severe exacerbations in some patients. Ask patients if they have ever had bronchospasm precipitated by drugs. The association is highest in those with severe persistent asthma or nasal polyps. Nonselective beta blockers can cause asthma symptoms, although cardioselective beta blockers can usually be tolerated. In a small portion of women, oral contraceptives or hormone replacement therapy can worsen asthma.

Infections. Viral infections cause the majority of asthma exacerbations in children, and they are also important in adults. Respiratory syncytial virus (RSV), rhinovirus, and influenza virus have all been implicated. Bacterial infections with mycoplasma and chlamydia may also contribute to asthma exacerbations and worsen disease chronicity and severity.

Concurrent medical conditions. Concurrent conditions that can exacerbate asthma include infections (eg, viral upper respiratory infections, bronchitis, sinusitis), allergic rhinitis, gastroesophageal reflux disease, allergic bronchopulmonary aspergillosis (ABPA), obesity, obstructive sleep apnea (OSA), stress, and depression. Addressing these conditions may improve asthma control. Additionally, many women notice a perimenstrual or perimenopausal worsening of asthma.

Exercise-induced bronchospasm (EIB). Exercise may trigger asthma symptoms in patients with either intermittent or persistent asthma. EIB is diagnosed by a 15% decrease in FEV₁ from pre- to post exercise. More information on exercise-induced bronchospasm is located in the Special Circumstances section of this document.

Initiating and Modifying Medical Therapy

Medications for asthma either reduce airway obstruction (bronchodilation) or reduce airway inflammation. Medications are divided into rescue medications, which are used as-needed for exacerbations, and control medications, which are used daily to prevent exacerbations.

Stepwise approach to managing asthma.¹³ Asthma therapy has traditionally followed a stepwise approach. The previous version of this guideline used the medical treatment framework of the National Asthma Education and Prevention Program (NAEPP),¹⁴ released in 2007. Recommendations in this guideline initially used the framework of the 2018 update of the Global Initiative for Asthma¹³. They were later addended using recommendations from the NHLBI 2020 Focused Update to the Asthma Management Guidelines and also the 2020 update of the Global Initiative for Asthma.^15,16

The 2019 update for the Global Initiative for Asthma (GINA 2019) introduced SMART (single maintenance and reliever therapy).¹⁷ SMART therapy consists of using an ICS in combination with formoterol, a rapid acting LABA, for both maintenance and rescue therapy. GINA 2019 recommended SMART therapy as the preferred rescue therapy for all stages of asthma, and recommended SMART as the controller therapy for mild persistent asthma. These guidelines recommendation were carried over into the GINA 2020 update. The US NHLBI 2020 update also recommended SMART therapy for mild through moderate persistent asthma. (GINA 2019, GINA 2020, NHLBI 2020 Focused Update to the Asthma Management Guidelines). ^15–17

SMART therapy has not yet received approval by the FDA. The authors of this guideline chose to addend this guideline in 2021 upon the release of the NHLBI 2020 update. SMART therapy has been shown to have improved outcomes (improved FEV1, fewer asthma exacerbations, decreased need for rescue medication use) compared to traditional ICS plus SABA.¹⁸

A stepwise approach to treating asthma taking SMART therapy into account is shown in table 7. Table 7 is based primarily on the US NHLBI 2020 update. While it includes SMART therapy, it also includes the more “traditional” approach of using an ICS and/or other “controller” medications for maintenance and a SABA for rescue.¹⁶

The NHLBI 2020 framework (outlined in Tables 6 and 7) includes:

• An assessment of asthma type, severity, and level of control, resulting in a stepwise approach to initial medical therapy and modifying medical therapy
  • Step 1: Mild intermittent asthma. As-needed SABA alone for rescue therapy
  • Step 2: Mild persistent asthma. SMART therapy or low-dose ICS with an as-needed SABA. Other controller medications can be considered.
  • Step 3: Moderate persistent asthma. SMART therapy with daily and as-needed therapy, or a medium dose ICS with an as-needed SABA. Other controller medications can be considered.
  • Step 4: Moderate persistent asthma. Higher dose SMART therapy with daily and as-needed therapy, or a medium dose ICS coupled with another controller medication with an as-needed SABA.
  • Step 5 and 6: Severe persistent asthma. Typically requires specialty care. Consider biologics. Higher dose ICS, typically couple with other controller medications, with an as-needed SABA

Initial assessment of severity and treatment. As detailed in Tables 6 and 7, the extent of symptoms determines the step of treatment at which a patient should start.

• Step 1: Mild intermittent asthma: symptomatic asthma no more than twice monthly, awakening with asthmatic symptoms no more than once monthly, and not requiring an oral corticosteroid for asthma within the past year. For these patients a rescue SABA alone can be sufficient.
• Step 2: Mild persistent asthma: symptomatic asthma more than twice monthly, awakening with asthma symptoms more than once monthly, and/or requiring an oral corticosteroid for asthma within the past year. Start these patients with as-needed SMART therapy (an ICS-formoterol combination). Alternatively, use a low-dose ICS (or a LTRA) as a controller medication, with an as-needed SABA as rescue therapy.
• Step 3: Moderate persistent asthma: symptomatic on most days or waking up with asthma symptoms once a week or more often. Start these patients with a daily scheduled ICS+formoterol, with additional doses of ICS+formoterol (SMART therapy) as needed for rescue. Alternatively, an ICS + LABA combination can be used for control in adults or children over 4, again with an as-needed SABA for rescue therapy.

Monitoring severity and modifying medications. After initial treatment:

• If patients have persistent symptoms and exacerbations (“not well controlled asthma,” as outlined in Table 10):
  • - Ensure that they are using medications as prescribed and using the inhalers with proper technique.
  • - If there are no adherence issues, increase medical therapy by providing the controller therapies of the next step in the step-wise model.
• If patients have well-controlled asthma (as outlined in Table 10) for at least 3 months, consider stepping down to a less aggressive controller.

While stepping up treatment to address increased severity is intuitive, providers may be concerned about stepping down patients who show good control. A 2017 systematic review showed no net benefit or harm in stepping down from a higher dose ICS to a lower dose ICS, although the authors noted that the quality of the included studies was relatively poor, and there was a trend to increased exacerbations.¹⁹ A recent randomized controlled trial published in 2016 found a 13% risk of exacerbation over 12 weeks with stepping down from an ICS + LABA combination to ICS therapy alone.²⁰ A 2016 cohort study found fewer exacerbations with stepping down from an ICS + LABA combination to an ICS alone as opposed to subsequently decreasing the ICS dose.²¹ There is some evidence that shows the risk of an exacerbation after stepping down therapy decreases with the duration of stability prior to the step down. The risk of exacerbation was 44% in patients with stability less than 4 months, and 21% with stability for more than 24 months.²²

Treatment of Acute Exacerbations

Short-acting beta agonists (SABA). Short-acting beta agonists (SABA) have long been the first step of treatment of acute asthma exacerbations. The dose and frequency of SABA therapy typically depend on the severity of exacerbation. Traditional doses for adults are 2-4 puffs (4-8 puffs for severe exacerbations) every 20 minutes for up to 3 doses. For children, the 2018 GINA guidelines were more aggressive and advise increasing SABA therapy to 4-10 puffs, repeated every 20 minutes for up to 3 doses (1 hour of therapy). Children under 5 have typically been treated by increasing their frequency of SABA use to every 4 to 6 hours for 24 hours. Use an asthma action plan to outline for patients the recommended treatments for exacerbations.

For severe acute exacerbations in an ambulatory setting, consider using the short-acting muscarinic antagonist (SAMA) ipratropium along with a SABA. Two systematic reviews of patients presenting to an emergency department with acute asthma exacerbations showed that combination therapy with a SAMA and a SABA decreased the rates of hospital admission for asthma. These studies did not include children ages 3 years and under. These studies were limited to emergency department presentations, did not look into patient self-treatment of acute exacerbations, and cannot be used to support supplying asthma patients with a SAMA to use along with a SABA at home.^23,24

GINA 2019 recommended ICS-based therapies for acute treatment of asthma exacerbations, either with formoterol-budesonide (“SMART” therapy) or using combination SABA-ICS products (not currently available in the US). The NHLBI 2020 Update recommends SMART therapy for acute treatment of mild to moderate persistent asthma. To date, these therapies not yet FDA-approved in the US. The goal of including the inhaled steroid is better prevent severe exacerbations.^{17,25,26 16}

Increased inhaled corticosteroids. The evidence argues against doubling the dose of ICS to treat acute exacerbations.²⁷ However, there is some evidence that supports quadrupling the dose of ICS to treat acute exacerbations.²⁸ This can be considered for up to 7 days in patients ≥ 5 years old. For children < 3 years old experiencing a mild asthma exacerbation, high-dose budesonide nebulizer is as effective as systemic steroid therapy.

Antibiotics. Antibiotics have no role in treating acute asthma exacerbations, unless secondary infection is a concern. A recent 2016 randomized controlled trial found no improvement in patients whose asthma exacerbation treatment included azithromycin.²⁹

Oral Steroids. In patients with acute exacerbations who fail to respond to SABA therapy, consider a short course of oral corticosteroids. Suggested dosing strategies are outlined in table 8. Systemic steroids have a number of adverse effects when used over a long duration, so oral corticosteroid therapy should be used only as second line therapy and only for a limited duration. There is some evidence, based on a systematic review, that in children under 5, oral corticosteroid therapy decreases the need for hospital admission when these children present to the emergency department, but when used outside the emergency department, oral corticosteroid therapy is associated with higher rates of admission.³⁰

Pharmacologic therapy in urgent care settings. More aggressive pharmacologic therapy for acute flares of asthma (or status asthmaticus) may be given urgently under clinical supervision, typically in the emergency department or inpatient setting. These treatments are beyond the scope of ambulatory care addressed in this guideline.

Classes of Medications

Medications used to manage asthma are described below. Table 7 indicates classes of drugs to use for various levels of severity. Table 8 presents examples of specific drugs used for chronic asthma management, including dosing and cost.

Inhaled short-acting beta agonists (SABA). SABAs have been and remain a therapy of first choice for relief of acute symptoms and prevention of exercise-induced bronchospasm in infants, children, and adults. Frequent use is a clinical indicator of uncontrolled asthma, and should trigger change in the treatment plan.

Intermittent use of an inhaled SABA alone is frequently effective in controlling the symptoms of mild asthma. Occasional as-needed SABA therapy is acceptable as long as asthma symptoms are well controlled. Avoid chronic SABA use.

For patients experiencing difficulty with traditional MDI technique, other SABA delivery options include use of a breath-activated MDI (Autohaler), dry powder inhaler (DPI), (Respiclick),^31,32 or nebulizer. Similar to corticosteroid DPIs, these delivery systems offer an advantage to patients who cannot coordinate activation and inhalation. Activation is dependent upon a rapid, deep inhalation by the patient. Therefore, breath-activated mechanisms are not recommended for small children.

Several epidemiologic studies found an association between excess use of beta-agonist (short- and long-acting) inhalers and asthma mortality. A causal relationship has not been demonstrated, and beta-agonists may merely represent a marker for the severity of disease, since they are more frequently prescribed for patients with life-threatening asthma. If beta-agonists do have a causative role, it may be an indirect one, such as delaying presentation until airway obstruction is more severe. While important to recognize, such an association does not necessarily mandate a change in prescribing practices. A number of prospective studies have failed to demonstrate any alteration in airway hyper-responsiveness with chronic beta-agonist use. In addition, tolerance to the effects of beta -agonists with chronic use has been hard to demonstrate, suggesting that significant down regulation of beta-receptors likely does not occur.

Inhaled corticosteroids (ICS). ICS help control inflammation, and they are the mainstay of therapy in persistent asthma. These medications help to reduce the airway response to allergens and irritants, and they prevent repeated and dangerous exacerbations. Strong evidence from clinical trials demonstrates that inhaled corticosteroids improve outcomes in persistent asthma.

For patients who use an ICS once daily, administration in the evening is preferred; improvements in lung function are better compared to every morning dosing.³³

The risks of topical adverse effects with high-dose inhaled corticosteroids can be minimized by having the patient rinse their mouth immediately after inhalation, spit out the rinse water, and by always using a spacer device, preferably a valved holding chamber (VHC). Using a VHC also reduces the amount of inhaled corticosteroid from MDIs that can be swallowed and potentially available for systemic absorption. When a VHC is used with a mask, instruct patients to wash the facial skin under the mask with mild soap and water after drug administration to prevent topical adverse effects.

Inhaled corticosteroids may have an adverse effect on linear growth in children, reducing height by about 1 cm in pubertal growth stages, less prepubertally.^34,35 This effect must be balanced against the risk that uncontrolled asthma will delay growth. The efficacy of ICS is generally sufficient to outweigh concerns about growth or other systemic effects. Management of children requiring long-term inhaled corticosteroids includes counseling on the risk of growth impairment, nutritional supplementation of vitamin D and calcium at age-appropriate levels, maximizing asthma control with the lowest effective dose of ICS, and monitoring linear growth.

Studies of markers of bone deposition and absorption, and of bone mineral density, suggest that osteopenia is a concern with inhaled corticosteroids in the adult population and increases with dose and duration of use. Patients who take medium to high doses of inhaled corticosteroids long-term may need prophylactic measures (supplemental calcium with vitamin D) to reduce the potential development of osteoporosis. For more information on assessing risk and testing for osteoporosis, see the UMHS guideline Osteoporosis Prevention and Treatment.

The risk of cataracts increases with long-term use of inhaled corticosteroids. Periodic ophthalmologic exams should be considered based on dose and duration of use.

ICS use may contribute to adrenal suppression, increased risk of fracture, and increased risk of higher BMI. ^36–40

A long-acting beta-agonist (LABA) should be added to a medium-dose inhaled corticosteroid before using high dose inhaled corticosteroids. This combination therapy has been shown to have more favorable outcomes than high dose inhaled corticosteroids alone, while maintaining lower exposure to steroids.

Dry powder inhalers are available for select steroids (Pulmicort Flexhaler and Advair Diskus: Flovent/Serevent combination) in addition to traditional metered dose inhalers. Advantages of these devices include easier administration of doses and lack of chlorofluorocarbons. No coordination is necessary between device activation and inhalation; however, a minimal inspiratory flow rate is needed to activate the device, which may make usage difficult during exacerbations. The relative ease of use with these devices may make them more suitable for children ≥ 5 years of age and the elderly, who may experience difficulty with the MDI.

Combination products such as fluticasone propionate/salmeterol (Advair), and budesonide/fomoterol (Symbicort) allow simplification of the medication regimen. Simplification may be especially useful for adolescents or patients with adherence problems.

A small study evaluated dental hygiene in children age 7-17 years before and after 1 month of fluticasone propionate/salmeterol 100/50 mcg DPI (Advair Diskus) twice daily. The study reported a significant decrease in salivary flow and increase in dental plaque in the post-treatment group, suggesting that good dental hygiene and dental checks are important in this population.

Long-acting beta agonists (LABA). LABA inhalers are used in controlling moderate and severe persistent asthma in children (not infants) and adults.

Salmeterol, fomoterol, and vilanterol are the only LABA medications currently available for use in asthma patients. Salmeterol and formoterol demonstrate a 12-hour duration of action (5-hour with regular chronic use) while vilanterol’s duration of action is longer, only requiring once-daily dosing (Breo Ellipta).⁴² Salmeterol may be used twice daily for maintenance or before bedtime for nocturnal asthma symptoms. Safety and efficacy for salmeterol has been established in children as young as 4 years of age and for fomoterol as young as 5 years. However, salmeterol, fomoterol, and vilanterol are not indicated for acute bronchospasm. Make sure the patient always has a short-acting bronchodilator available for treating acute symptoms.

LABAs should always be administered in combination with an anti-inflammatory drug when used for maintenance therapy. Monotherapy is only FDA-approved for exercise-induced bronchospasm on a strict intermittent basis.

Traditionally LABAs have been used only for maintenance, not rescue therapy. Newer data now exists evaluating the LABA formoterol when used in conjunction with budesonide (Symbicort) as both a maintenance and a reliever therapy in adolescents and adults. This works as formoterol is a rapid-acting LABA. Formoterol’s onset of action is within 3 minutes, peak effect within 15 minutes, compared to salmeterol, with an onset of action 30-48 minutes and with peak effect at 3 hours, and vilanterol, with a median time to onset of action 16 minutes.⁴³ See the section on “SMART therapy” section under “Combined Inhaler Medications” for further details.^{17,25,43–46}

If stepping-up therapy to ICS and LABA is warranted in a patient, use a combination inhaler product rather than using two separate ICS and LABA inhalers. A combination inhaler simplifies and improves adherence, assures balanced dosing, and increased the odds of achieving overall asthma control.⁴¹

A secondary data analysis associated the use of LABAs with an increase in asthma deaths, though the numbers in the study were small and the interpretation is still a matter of controversy.

Caution patients not to discontinue their established LABA without consulting their health care provider.

Long-acting muscarinic antagonists (LAMA). LAMAs are anticholinergic medications that are used in controlling moderate and severe persistent asthma in children (not infants) and adults. However, recent data suggest that tiotropium (Spiriva Respimat) may be administered with a valved holding chamber in patients 1-5 years old with persistent asthma symptoms.⁴⁷ LAMAs act at acetylcholine receptors and contribute to bronchodilation in bronchial smooth muscle.

Consider LAMAs as add-on therapy in patients with uncontrolled asthma symptoms on medium-dose ICS + LABA with or without a leukotriene receptor antagonist (LTRA). As add-on therapy, LAMAs reduce risk of exacerbation requiring systemic steroids, emergency visits, hospitalizations. Theyimprove respiratory function, asthma control, and quality of life. LAMAs can also minimize requirements for high-dose ICS.^25,48–53 Of note, patients with high serum total IgE levels (>430 mcg/L) and high eosinophil count (>0.6 x 10⁹/L) were less likely to benefit from tiotropium.⁵⁴

Leukotriene modifiers. Leukotriene modifiers can be useful in controlling asthma in infants, children, and adults.

Current data suggest that monotherapy with leukotriene modifiers is more likely to be successful for prophylaxis in mild persistent asthma and exercise-induced bronchospasm, especially when allergic rhinitis is a comorbid condition. Leukotriene modifiers have not been studied as monotherapy for severe persistent asthma. They have been used as adjuvants to inhaled corticosteroids in severe persistent asthma, although not studied extensively for this purpose. Numerous studies have shown leukotriene modifiers to be less effective than long-acting beta-agonists (LABAs) when added to inhaled corticosteroids as a second-line agent.

Three leukotriene modifiers approved by the FDA are currently available for the treatment of chronic asthma. Zafirlukast (Accolate) and montelukast (Singulair) are leukotriene receptor antagonists (LTRA)and zileuton (Zyflo) is a 5-lipoxygenase inhibitor that interferes with leukotriene formation. These agents have been shown clinically to inhibit exercise-induced bronchoconstriction as well as reduce daytime symptom scores, nighttime asthma, rescue beta-agonist use. They also improve PEFR and FEV₁ in chronic asthma. In a controlled study comparing these agents to inhaled corticosteroids, beclomethasone 200 mg twice daily outperformed montelukast 10 mg daily.

Montelukast can be administered without regard to food, while zafirlukast must be dosed one hour before or 2 hours after eating. In children, zafilukast is approved for ages > 5 years and montelukast is approved for ages > 6 months using the oral granules. Zafirlukast can potentiate warfarin and theophylline as well as interact with several other medications. Drug interactions with montelukast are rare. Post marketing surveillance of adverse effects reported with montelukast includes psychomotor hyperactivity (including irritability, agitation, aggressive behavior, restlessness, and tremor), and seizures. With regard to LTRAs, the FDA states that "healthcare professionals should consider discontinuing these medications if patients develop neuropsychiatric symptoms." For this reason, the FDA required that montelukast be given a “black box” warning as of March 4, 2020.⁵⁵ Eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome) has rarely been reported in association with montelukast or zafirlukast in patients tapering chronic systemic corticosteroids. The FDA mandates monitoring hepatic enzymes in patients on zileuton.

Zileuton may be preferred over montelukast in acute asthma due to significant improvement in lung function, and reduction in the need for rescue medications.⁵⁶ However, when considering zileuton, take into account its high cost and adverse effects (mainly headache, dyspepsia, nausea, diarrhea, elevated ALT or AST, and hepatotoxicity).⁵⁷

In children with chronic cough-variant asthma, the combination of montelukast and budesonide is superior to budesonide use alone.⁵⁸

Mast cell stabilizers. These agents stabilize mast cells and inhibit release of inflammatory mediators, thereby controlling inflammation in asthma. Cromolyn and nedocromil are equivalent to low-dose ICS in patients with mild-to-moderate asthma, but not as effective as medium- to high-dose ICSs. They are rarely used due to their relatively low efficacy, need for frequent dose administration, and bitter taste despite an excellent safety profile. Efficacy is achieved after 2 to 4 weeks of consistent use. They are not effective for immediate relief of symptoms in acute asthma exacerbations.⁵⁹

Methylxanthines. These agents can be used to control symptoms in older children and adults with mild persistent asthma.

Theophylline exhibits only mild to moderate bronchodilator activity but has additional effects that may be beneficial in the management of asthma. It is useful for managing patients with variable or nocturnal symptoms not readily controlled with inhaled medication (anti-inflammatory and beta-agonist). Theophylline’s bronchodilator response is roughly linear with serum concentration. Traditionally, levels of 10-20 mcg/mL have been suggested as an optimal compromise between safety and efficacy. Recent data suggest that adverse effects are minimized and safety more easily maintained with levels between 5-15 mcg/mL.⁶⁰

Titrate theophylline by clinical response rather than by serum levels.⁶¹ Carefully screen for potential drug interactions and clearance-altering co-morbidities (heart and liver disease, smoking, erythromycin, cimetidine and others) before prescribing, and make dosage adjustments as needed. Current practice tends to use theophylline as an adjunct to inhaled corticosteroid therapy, not as the mainstay. Sustained release theophylline is a convenient way to maintain steady-state levels in the therapeutic range. Sustained release products should be chosen on the basis of cost. Scientific evidence does not support or reject the use of theophylline in severe acute asthma. Common side effects of theophylline include headache, nausea and vomiting, increased acid secretion, and gastroesophageal reflux.

To reduce medication cost, an option to consider is adding theophylline tablets to a fluticasone inhaler rather than using a fluticasone propionate/salmeterol inhaler. A study showed no difference in therapeutic effect or safety in patients with moderate-to-severe asthma.⁶²

Systemic (oral) corticosteroids. Systemic corticosteroids are used to treat exacerbations and as maintenance therapy in steroid-dependent severe persistent asthma.

Systemic corticosteroids have numerous significant and undesirable long term adverse effects for both adults and children. Their long-term use is undesirable and only recommended in the most severe cases. Refer patients in this category for evaluation by an asthma specialist.

The mechanism of action of corticosteroids in asthma is not entirely established, but includes: interference with arachidonic acid metabolism and the synthesis of leukotrienes; prevention of the directed migration and activation of inflammatory cells; and increased responsiveness of beta₂-receptors of the airway smooth muscle. No consensus exists on the specific type, dose, or duration of corticosteroid to be used in the treatment of asthma. Systemic corticosteroid bursts with or without a taper are generally used for acute exacerbations. If chronic long-term therapy is required, alternate day administration of oral corticosteroids is preferable to daily treatment. When oral corticosteroids are started, add inhaled corticosteroids to reduce or eliminate chronic long-term oral therapy. Administration of systemic corticosteroids within 1 hour of presentation to the emergency department for both adults and children with acute asthma significantly reduces rates of hospital admission. Benefits are greatest in patients with more severe asthma and those not currently receiving systemic steroids.

Chronic systemic corticosteroid therapy may be associated with obesity, moon facies, supraclavicular and nuchal fat pads, striae, easy bruisability, gastric ulcers or bleeds, weakness, hypertension, osteopenia, fracture, and glucose intolerance. Children may also exhibit growth failure.

Long-term (>2 weeks) systemic corticosteroid therapy may cause suppression of the hypothalamic-pituitary-adrenal axis. Full recovery of the axis can take up to 12 months, depending on the dose, frequency, and duration of the corticosteroid therapy. Symptoms and signs of secondary adrenal insufficiency include weakness, weight loss, and gastrointestinal discomfort. Adrenal insufficiency can evolve into acute adrenal crisis precipitated by severe infection, trauma, or surgery. The clinical presentation includes fever, dehydration, hypotension, nausea, vomiting, and hypoglycemia. Make sure that patients with asthma have their asthma under good control prior to surgery. This is especially important for those using inhaled or systemic corticosteroids. They may require a pre-operative stress dose or pharmacologic dose of a systemic corticosteroid to minimize the morbidity secondary to inflammation, bronchoconstriction, and potential adrenal insufficiency associated with endotracheal intubation. Long-term systemic corticosteroid therapy can cause osteopenia and osteoporosis.

The duration of action depends on the type of systemic corticosteroid. Oral dexamethasone has a longer duration of action (48-60 hours) than prednisone or prednisolone.⁶³ Oral prednisone’s duration of action is ~18-36 hours,⁶⁴ and oral prednisolone’s duration of action is ~3-36 hours.⁶⁵ No difference was found when dexamethasone was given for 2 doses compared to prednisone or prednisolone x 5 days in children and adolescents with acute asthma.^66–69 Dexamethasone was not more effective than prednisone x 5 days in adults.^70,71

Intramuscular steroids may be similarly effective to oral steroids in terms of reducing relapse and less adverse events. However, more data are required before intramuscular steroids can be considered an option.⁷²

Combined inhaler medications. Fixed-dose combination medications via inhalers allow multiple necessary inhaled medications to be taken at once, assisting with convenience and adherence for asthma patients. Using multiple medications via one inhaler such as ICS + LABA rather than via separate inhalers increases the odds of achieving overall better asthma control.⁴¹ The combination ICS + LABA inhalers and equivalent dosing are presented in Table 9.

Fluticasone propionate/salmeterol combination inhalers now come in 4 inhaler devices (2 DPI devices, MDI, and diskus DPI) with 2 formulations now available as generics (2 DPI devices). Other combination inhalers include budesonide/formoterol HFA (Symbicort), fluticasone furoate/vilanterol DPI (Breo Ellipta), and mometasone/formoterol HFA (Dulera).

In patients with mild asthma, taking ICS + LABA on a scheduled basis results in better control of asthma symptoms that taking the combination as needed. ^73,74

SMART therapy. In Europe, an approach called SMART (single maintenance and reliever therapy), consisting of as-needed use of a combination ICS plus formoterol inhaler, has been used for mild and moderate persistent asthma. Indeed, the GINA 2019 guidelines and the US NHLBI 2020 Update to the Asthma Management Guidelines recommend it. The LABA component of the ICS + LABA inhaler must be formoterol (Dulera or Symbicort, but mainly studied with Symbicort) because only formoterol of the LABAs has a quick onset of action (within 3 minutes, similar to albuterol). While currently only an off-label use – it is not currently FDA approved -- SMART is now recommended by the NHLBI in the US.^{22, 16 42–44}

The combination inhaler fluticasone furoate + vilanterol (Breo Ellipta) can be prescribed as a once daily medication. Compared to fluticasone propionate, fluticasone furoate has an enhanced affinity for the target receptor, and the LABA vilanterol has an inherent 24-hour duration of action. These factors allow the dosing interval to be just once daily. The effects on lung function and asthma control are similar to those of twice-daily combination products, with less frequent administration potentially resulting in better adherence.⁷⁵

Another combination inhaler to consider for off-label use in severe asthma exacerbations is ipratropium/albuterol (Combivent Respimat). Administering this combination via the inhaler may be more effective than using a nebulizer during an exacerbation. This was demonstrated in a study of children who had lower rate of hospital admission, improved clinical scores, and higher oxygen saturations. Compared to SABA alone, the ipratropium/albuterol combination was more effective in preventing hospitalization in adults with severe asthma exacerbations, and showed improved lung function and a lower likelihood of return to the emergency department for additional care. However, patients receiving the combination were also more likely to experience adverse effects (tremor, agitation, palpitations) compared to SABA alone.^23,24,76,77

Targeted biologic therapies for asthma. The number of biologic agents available for treating asthma has increased. Refer patients with severe asthma to a specialist in asthma care. Some patients may be candidates for treatment with biologic agents. Proper patient identification is important and basic phenotyping is essential in identifying patients that may benefit from biologic agents. Candidates include patients who are not well controlled on high-dose inhaled corticosteroids with a second controller, or those who are dependent on oral corticosteroids in addition to their inhaled therapies. Patients with frequent exacerbations (more than two per year) requiring oral corticosteroids are also potential candidates for biologic therapies, even if their asthma control is acceptable between exacerbations.

The FDA-approved biologic agents for the treatment of asthma are: benralizumab (Fasenra), dupilumab (Dupixent), omalizumab (Xolair), mepolizumab (Nucala), and reslizumab (Cinqair). These medications are typically managed in specialty clinics, and details about their mechanisms are beyond the scope of this guideline.

The most serious adverse effect of biologic agents is anaphylaxis, but it is extremely rare. All biologic agents are given in the clinic the first time with post-administration monitoring to ensure that no reactions occur. Hypersensitivity reactions associated with hives and throat irritation (but no hemodynamic collapse) occur in 1% of the population. Local skin reactions with redness, induration and pain at the injection site can occur and are treated with topical corticosteroids. For all patients on biologic agents, live virus vaccinations must be spaced out at least one week from the dose of biologic therapy. Dupilumab can result in transient increases in eosinophils and caution should be used in those with eosinophils greater than 1500cells/uL at baseline. Markedly elevated eosinophils can result in adverse events including pulmonary infiltrates, hypoxemia and cardiac complications.

Pediatric considerations. In managing pediatric patients, few recommendations guide the clinician and fewer criteria exist on which to base fundamental treatment decisions. The FDA has not approved the use of many effective anti-asthma drugs in the very young. However, in the absence of needed studies, “lack of approval” does not constitute “disapproval.”

Review Technique for Inhaled Medications

Optimal delivery of inhaled medications depends greatly on the way the specific delivery system is used. Both caregivers and patients must understand and master the proper technique for effective use of MDIs with valved holding chambers (VHC), DPIs, or nebulizers. Review proper technique with patients on a regular basis. See Instructions for various MDI delivery devices

Infants and children. For infants and children, use metered dose inhalers (MDIs) with valved holding chamber (VHCs) with either a mask or mouth piece. Infants and smaller children need MDI doses equivalent to adult doses because they inhale aerosols during tidal breathing without a breath hold, reducing retention time and decreasing the effective drug delivery to the lungs. Compressed-air-driven wet nebulizers are commonly available for home administration of beta-agonists, ipratropium bromide, and the corticosteroid budesonide. Complete nebulization of medication is time consuming, and the infant or young child must keep the mask in place for the duration of therapy. Older children may use a mouthpiece instead. Using a face mask made for delivering the medication is important. Attempting to short-cut the process by partially blocking one side of the nebulizer mouth piece and using the nebulizer machine to blow the medicine at the face and nose (ie, "blow by") is ineffective and must be avoided. Pediatric patients may be uncooperative with nebulized medication delivery. If proper administration is not tolerated by the child, use a metered-dose inhaler with a valved holding chamber (VHC) instead.

Administration of inhaled medication via MDIs, DPIs, and nebulizers requires deliberate patient and family education and their understanding of technique. Patient education is at http://pteducation.med.umich.edu/asthma_qi.

Home nebulizers. Home nebulizers are no more effective than MDIs in the management of asthma, and may be less effective than MDIs with valved holding chambers (VHC). Nebulizers may be helpful for the minority of patients who cannot use a metered dose inhaler or a VHC properly. Patients and caregivers need instruction on the proper mechanical use of the nebulizer; preferably by a clinician or respiratory therapist. Patients and care-givers must also be instructed regarding frequency, dose, and monitoring parameters for nebulized medications.

Inhaler device selection. Considerations for selecting an inhaler device choice include effectiveness, cost, patient preference, and ability to use the device correctly.⁷⁸ Certain newer inhaler devices have been developed that facilitate device mastery, such as breath-actuated dry powder inhalers that do not require the patient to coordinate canister pressing and inhalation as MDIs do. However, some MDIs produce a stronger anti-inflammatory and bronchodilation effect compared to DPIs.⁷⁹ Rates of asthma exacerbations are higher in MDI users compared to DPI users and a higher percentage of patients who use DPIs find them easier to use compared to MDIs.⁸⁰ Due to insurance coverage limitations and constant changes in prescription drug insurance formularies, it is reasonable to initially prescribe the most affordable inhaler and provide education about technique for optimal asthma control.

Inhaler device education. Proper inhaler use is very important for asthma treatment. Face-to-face demonstration with visual and verbal instruction and teach-to-goal instruction are ideal.^81,82 Video education can be a suitable substitute for face-to-face education.⁸³ Written instruction alone is inadequate.⁸⁴ Assess inhaler technique at every opportunity and reinforce proper technique.⁸⁵

Allergy Immunotherapy

Allergy immunotherapy is an effective treatment for patients with allergic asthma as demonstrated through skin or blood testing. It is effective in mild to moderate persistent asthma patients.

The principles of allergy immunotherapy are based on the induction of tolerance by exposure to slowly increasing amounts of an allergen through subcutaneous or sublingual routes. This can improve outcomes and decrease medication use. For allergen-sensitive patients with mild to moderate persistent asthma who are exposed to triggering allergens, consider referral to a specialist in allergen immunotherapy.

The benefits of allergen immunotherapy must be balanced against the inconvenience of coming in for immunotherapy shots and the small risk of a systemic reaction.^86,87

Bronchial Thermoplasty

Bronchial thermoplasty is a procedure that utilizes thermal energy to reduce the smooth muscle mass in the airway, thereby decreasing bronchoconstriction. It requires general anesthesia and three bronchoscopies three weeks apart.

Bronchial thermoplasty is indicated for adults age > 18 years with severe persistent asthma and recurrent exacerbations or oral steroid dependence. Patients who are candidates for biologic therapies must have demonstrated a partial response or non-response to biologic agents before proceeding with thermoplasty. Candidates must be adherent to a regimen of maximal inhaled therapies, including inhaled corticosteroids/long-acting bronchodilators and long-acting muscarinic antagonist therapies, have no alternative diagnosis, and have all comorbid conditions optimized prior to being offered thermoplasty.

Treatments for Comorbidities that Improve Asthma

In patients with asthma, drugs being considered for comorbid conditions may also be useful for treating asthma.

In adolescents and adults with comorbid asthma and COPD who experience status asthmaticus, anticholinergics are useful and have been approved as add-on maintenance therapy. Addition of a LAMA to an asthma regimen can reduce high-dose ICS requirements, minimizing ICS potential adverse effects. Note that patients with high serum total IgE levels and eosinophil counts are less likely to benefit from tiotropium.

In patients with comorbid asthma and allergic rhinitis, the addition of fluticasone nasal spray to asthma regimen is likely beneficial.

Vaccinations

Provide asthma patients with all the routine preventive care and vaccinations that are recommended for otherwise healthy children and adults. Patients with asthma are at increased risk for complications from pulmonary infections (eg, hospitalization, increased use of antibiotics). Therefore, the CDC Advisory Committee on Immunization Practices recommends all patients older than 6 months receive influenza vaccine and that all adults with asthma receive pneumococcal vaccine.

Provide influenza vaccination annually for all patients age ≥ 6 months (whether they have asthma or not). Influenza vaccination is typically administered in the fall to maximize protection during the winter flu season. Children age < 9 years receiving influenza vaccine for the first time should receive a booster dose 1 month after the first injection. Children who only receive 1 of the 2 recommended doses in their first year of vaccination should receive 2 doses the second year. Influenza vaccination does not reduce the frequency or severity of asthma exacerbations during the influenza season, and patients should not have this expectation.

Pneumococcal polysaccharide vaccine is recommended for asthma patients 19-65 years old and all adults ≥ 65 years. If the initial dose is given before age 65, a second dose should be administered when the individual is over 65 years old and more than 5 years have passed since the initial vaccination. As of 2020, the pneumococcal conjugate vaccine (PCV 13) is no longer routinely recommended in immunocompetent adults with asthma.

Self-Management Using an Asthma Action Plan

Provide patients with a written asthma action plan. This is a written guideline to help patients direct self-care based on symptoms and/or decreased peak flows. A commonly used asthma action plan has three “zones,” often labeled “doing well,” “caution,” and “medical alert.” These zones are also commonly labelled “green,” “yellow,” and “red.” Each zone carries instructions regarding the use of controller and rescue medications. At Michigan Medicine, this format of asthma action plan is integrated into the electronic medical record.

Self-management guided by an asthma action plan has been shown to reduce hospitalizations, emergency department visits, unscheduled office visits, and time off from work and school for both adults^88,89 and children over 5.^90–92 However, studies are not unanimous in their support of asthma action plans. A 2017 systematic review found neither benefit nor harm in using asthma action plans, although its authors noted the included trials enrolled only small numbers and were generally of poor quality.⁹³

Use either symptoms or peak expiratory flow rates. A systematic review found equal benefit from asthma action plans using symptoms versus using peak flows.⁹⁴ Practicing clinicians have often found that needing to determine a patient’s baseline peak flow can be a barrier to creating a peak-flow-based asthma action plan. The use of symptom-based asthma action plans allows clinicians to avoid that barrier.

Monitoring peak expiratory flow rate (PEFR). If patients are to use PEFR to monitor their status, they must be taught to perform the measurement appropriately.

PEFR is a simple quantitative method for monitoring asthma activity. PEFR monitoring provides objective information that can be used in adults and children older than 5 years, but measurements may be less reliable in children under age 8. PEFR is particularly useful for patients who have difficulty perceiving symptoms of worsening asthma.

The use of a peak flow monitor requires deliberate patient education and patient understanding of technique. Every time PEFR is measured, patients make three attempts and record the best value.

The personal best PEFR is the baseline value used in asthma action plans for patients who have difficulty perceiving symptoms of asthma. This value is determined by measuring peak flow rates twice daily over a 2-3 week period. The personal best is the highest value that is consistently recorded during this period. If the patient uses a bronchodilator, measure peak expiratory flow rates before and after bronchodilator. In children, reevaluate the personal best value annually to account for growth.

Advise patients and their families to record all measured PEFR values in a logbook with dates and times. Ask them to bring this logbook to every visit for review and discussion with the clinician. An example of a peak flow record chart is available at getasthmahelp.org/mark/Peak-Flow-Tracking-chart.pdf

Engaging members of the health care team. Many clinical practices have integrated pharmacists and patient educators into the management of chronic conditions such as diabetes and hypertension. Emerging data support the role of clinical pharmacists in assisting with the management of asthma. A 2018 systematic review of randomized control trials investigated the impact of community pharmacists supporting the self-management of adults with asthma. Pharmacist interventions included assistance in self-monitoring, provision of asthma action plans, and goal setting. These interventions resulted in improved asthma control, improved medication adherence, and improved quality of life measures.⁹⁵

Utilizing personal mobile technology. A role is also emerging for asthma self-management supported by personal mobile technology, such as mobile phone applications. Several studies provide evidence of improved medication adherence and improved asthma control in adults and adolescents who use this type of technology.^96–99

Follow Up Interval after Initiating Treatment

Assess Asthma Control, Severity, and Risk for Exacerbations

Assess asthma control. Assess asthma control at every encounter. Patients are typically classified as having well controlled, not well controlled, or very poorly controlled asthma. The assessment of asthma control is mainly based on symptom pattern.

• Well controlled asthma – While taking the prescribed therapy, the patient has no symptoms (day or night), and activity is not limited by asthma.
• Not well controlled asthma – The severity of symptoms is in between what has been described for well controlled asthma and very poorly controlled asthma.
• Very poorly controlled asthma – The patient has three or more days a week with asthma symptoms, or needs a short-acting beta agonist for symptomatic relief three or more days a week, or wakes due to asthma symptoms one or more nights a week.

When assessing asthma control, use spirometry for objective evaluation of pulmonary function. Spirometry is the only functional test that should be used for monitoring response to therapy. Spirometry can be reliably performed by adults and children over age 5 years. Perform spirometry at least once every 1-2 years to check function.

In adult patients with mild to moderate asthma, consider using a validated questionnaire to help assess asthma control. Questionnaires, like Asthma Control Test¹⁰⁰ (ACT) or Asthma Control Questionnaire¹⁰¹ (ACQ), have been primarily validated in patients with mild and moderate asthma. They can help quantify the level of symptoms in patients age 17 years and older. The cost-effectiveness of using validated pediatric questionnaires to monitor asthma control in children ages 5-16 years with asthma needs further investigation.

When evaluating asthma control, ask patients about specific types of symptoms, events, and actions. For patients who have difficulty perceiving symptoms of worsening asthma, consider recommending PEFR monitoring for self-management. While no evidence shows that self-monitoring of PEFR is better than symptom-based monitoring for asthma patients in general, symptom-based monitoring is likely less effective in patients who have difficulty perceiving symptoms.

Assess asthma severity. Asthma severity is determined retrospectively, based on the minimum level of treatment required to control symptoms and exacerbations. Assess severity at every encounter, once the patient has been on regular controller therapy and, if appropriate, a step down in treatment has been attempted (Tables 6 and 7). Asthma severity is classified as follows:

• Mild asthma is well controlled with as-needed use of short-acting beta agonists, low-dose inhaled corticosteroids, or leukotriene receptor antagonists.
• Moderate asthma is well controlled with combination low-dose inhaled corticosteroids and long-acting beta agonists, medium-dose inhaled corticosteroids, or low-dose inhaled corticosteroids plus another controller.
• Severe asthma is well controlled with a combination of high-dose inhaled corticosteroids and a long-acting beta agonist or another controller therapy, low-dose oral steroids, or biologic agents.

Assess risk for exacerbations. While lack of control is an important risk for exacerbation, even patients with few or no reported symptoms may be at risk for exacerbation. Risk factors include:

• Uncontrolled asthma symptoms.
• More than one exacerbation in the previous year
• A history of intubation or intensive care admission for asthma
• Non-adherence to asthma therapy
• High use of short-acting beta agonist
• Psychosocial problems
• Low FEV₁ (especially if <60% of predicted)
• High bronchodilator reversibility
• Eosinophilic asthma
• Pregnancy
• Exposure to tobacco smoke
• Exposure to identified triggering allergens.

Review Environmental Control

Check the patient’s understanding and identification of triggers. Find out what steps have been taken to avoid triggers and if these efforts have been successful. Address tobacco smoke exposure (both smoking and passive smoke exposure). When appropriate, provide advice regarding ways to reduce environmental exposures.

Review and Adjust Medical Therapy

Maintain or adjust medical therapy based on the level of asthma control, as shown in Table 6. Table 7 defines the treatment at each step.

• For “well controlled” asthma, maintain current therapy.
• For “not well controlled” asthma, step up therapy by 1 step.
• For “very poorly controlled” asthma, step up therapy by 1-2 steps and consider a short course of oral corticosteroids.

Increasing or frequent use of a SABA for “rescue” from exacerbations generally indicates inadequate control and the need to step up treatment. For all ages, consider stepping up treatment when the patient uses a SABA more than 2 days/week for symptoms (not exercise-induced).

On subsequent follow up visits, if asthma remains well controlled for 3 months or longer, consider reducing treatment by one step. (See section Initiating and Modifying Medical Therapy)

Review/Revise Self-Management and Asthma Action Plan

Review the patient’s understanding of and adherence to asthma self-management. Discuss their current asthma action plan, which should be based on their symptoms and/or peak flows. Review how to use both controller and rescue medications when in the green, yellow, and red zones

If the current level of asthma control:

• indicates a need for a step down or step up in recommended medical therapy, explain the change in management and write out a new asthma action plan. Place a written copy of the new plan in the patient record and provide a copy for the patient and family to use at home.
• Indicates no need to change medical therapy, reinforce use of the current plan. If no changes are made, rewrite the asthma action plan annually.

Vaccinations at Follow-Up

At each visit, review the status of vaccinations for influenza and for pneumococcal disease to be sure they have been administered.

Plan ahead for the annual influenza vaccination. If the patient does not have a visit scheduled for the fall, special notification may be sent in the fall to remind the patient to get an annual influenza vaccination.

When patients become age 65 years, review the date at which their pneumococcal polysaccharide vaccination occurred. If the initial dose was given before age 65 years, administer a second dose when the patient is over 65 years old and more than 5 years have passed since the initial vaccination.

Referral to Asthma specialist

Refer the patient to an asthma specialist when:

• The diagnosis is unclear, symptoms and signs are atypical, or if the differential diagnosis is problematic.
• There is inadequate response to asthma treatment, especially if more than two courses of oral steroids are needed in one year or if any emergency department or hospital treatment is required.
• Ongoing oral corticosteroid treatment is required.
• The patient has asthma with chronic obstruction and a consistently abnormal FEV₁ (less than 70% of predicted).
• The patient requires step 4 care (medium-dose ICS and LABA) or higher, or step 3 for children ages 0–4 years. Consider referral if the patient requires step 3 care (medium-dose ICS or low-dose ICS and LABA), or step 2 care for children ages 0–4 years.
• There are multiple confounding diagnoses.
• The patient may have allergic asthma requiring allergen testing and consideration of immunotherapy.
• The patient is a potential candidate for advanced therapies, such as biologic agents or bronchial thermoplasty.
• Occupational asthma is present.
• There are problems with adherence requiring a multidisciplinary team approach and additional education efforts.
• Comorbid psychosocial problems or disability interferes with adherence or treatment.
• The patient has had a life-threatening asthma exacerbation.

Follow-Up Intervals

Optimal intervals for follow up have not been specifically studied. General recommendations are:

• 4-6 weeks after initiation of treatment, significant changes in status, or stepping-up treatment
• 3 months after stepping-down treatment
• 3-6 months for patients with stable control and symptoms.

Consider modifying intervals based on disease severity and control.

• Severe asthma may require more frequent follow-up.
• Mild asthma with good control and no exacerbations may be followed annually.

Exercise-Induced Bronchospasm

Bronchospasm may occur during exercise as a result of hyperventilating environmental air that is cooler and drier than that of the respiratory system. A 15% drop in FEV₁ from pre- to post-exercise is consistent with exercise-induced bronchospasm. Consider alternative diagnoses in patients with exercise-induced bronchospasm symptoms, but no change in FEV₁ and no response to therapy.¹⁰²

Exercise-induced bronchospasm is most common in patients with asthma (either intermittent or persistent), but it may occur in those without asthma. Exercise-induced bronchospasm often presents with nonspecific symptoms such as cough, chest tightness, and shortness of breath. During exercise, hyperventilating air that is cooler and dryer than that of the respiratory system can result in a loss of heat, water, or both from the lung. Some studies suggest that inflammatory mediators are released. This process results in bronchospasm, airway obstruction, and symptoms.

Treat exercise-induced bronchospasm prior to exercise using a stepwise approach similar to that for asthma. Using a SABA 20 minutes before exercise will reduce the incidence and severity of bronchospasm in more than 80% of patients. Some patients may require a controller medication. Leukotriene receptor antagonists (LTRA) such as montelukast can attenuate exercise-induced bronchospasm in up to 50% of patients, but inhaled corticosteroids may be required. Training and sufficient warm up also reduce the incidence and severity of exercise-induced bronchospasm.

While exercise may be the only trigger of asthma symptoms for some patients, in many others exercise-induced bronchospasm is a marker of uncontrolled asthma. Monitor these patients closely to ensure that they are asymptomatic at rest. When assessing asthma control, frequent or severe episodes of exercise-induced bronchospasm suggest a need to step up medication for long-term control (Tables 6 and 7).

Occupational Asthma

Occupational asthma is characterized by classic asthma symptoms (eg, cough, difficulty breathing, chest tightness, wheezing) brought on by inhalation of an allergen or irritant in the work environment.¹⁰³

Evaluation includes a detailed history and physical. Diagnosis is most securely established by a specific inhalational challenge with the offending agent in an experienced center.¹⁰⁴ However, this type of testing may not be feasible and nonspecific airway sensitivity may act as a surrogate marker. A short medical removal period can assist with diagnosing patients with suspected work-related asthma, especially if their peak expiratory flow rates improve when away from work. Conversely, a negative methacholine challenge in a patient still exposed to the causative agent at work has a strong negative predictive value for the diagnosis of occupational asthma.¹⁰⁵

The Centers for Disease Control and Prevention (CDC) and the National Institute for Occupational Safety and Health (NIOSH) suggest that the plan for occupational asthma include avoiding triggers and medically controlling clinical symptoms. “Exposure cessation is the optimal approach, but exposure reduction through the use of workplace controls may benefit some workers with work-related asthma.”¹⁰⁶

Treating Comorbidities

Evidence is limited regarding whether treating comorbidities will improve asthma. For example, while asthma has general population correlations with gastroesophageal reflux disease (GERD), obesity, and social determinants of health, the extent to which managing those comorbidities will improve asthma in the general population is unclear.^107,108 However, clear evidence exists for treating those with “obesity-related asthma” and “asthma-COPD overlap syndrome.”

In patients with the obesity-related asthma phenotype, which is a non-type 2 asthma, weight loss can improve symptoms and lung function, as well as reduce both medication utilization and hospital admissions. In this population, consider recommending exercise, weight loss, and dietary interventions, instead of primarily focusing on disease control by stepping up asthma therapy.¹⁰⁹

The asthma-COPD overlap syndrome is the presence in a given patient of three elements: significant smoking exposure, chronic airflow limitation, and asthma. Diagnosis is confirmed when a patient age ≥ 35 years, who is a smoker or ex-smoker of more than 10 pack-years, presents with airflow limitation (post-bronchodilator FEV₁/FVC < 0.7) that persists after treatment with bronchodilators and inhaled corticosteroids (even after systemic corticosteroids in selected cases), and also has an objective current diagnosis of asthma.¹¹⁰ Please refer to the Michigan Medicine guideline on Chronic Obstructive Pulmonary Disease for further information.

Pregnancy and Breastfeeding

Pregnancy. There is limited evidence to guide the treatment of asthma in pregnant patients. A 2014 Cochrane review could make “no firm conclusions about optimal interventions for managing asthma in pregnancy.”¹¹¹ Asthma is generally managed similarly for pregnant and non-pregnant women. Good asthma control is associated with better pregnancy outcomes, with lower risks of mild prematurity, pre-eclampsia, and growth restriction.

Systematic reviews show that:

• Long and short-acting beta agonists are safe in pregnancy.
• Inhaled corticosteroids are safe in pregnancy and reduce the risk of pregnancy-associated exacerbations. The bulk of data on inhaled corticosteroids is from studies using budesonide; other inhaled corticosteroids have not been well studied. In contrast to inhaled corticosteroids, systemic corticosteroid use in the first trimester is associated with cleft lip and palate, and later in pregnancy it is associated with pregnancy-induced hypertension and possibly preeclampsia.
• Theophylline in high doses is associated with adverse pregnancy outcomes; while usual doses are considered safe, unacceptable adverse effects are frequent.
• Data are limited regarding leukotriene modifiers in pregnancy. No specific evidence exists for fetal risk, so these medicines may be a good option, especially for women who benefited from them prior to pregnancy.¹¹²

Breastfeeding. Breastfeeding is generally managed similarly for women who have and do not have asthma. All commonly used asthma medications are considered “probably compatible” with breastfeeding. This is based on extremely limited data, with most drugs having only information about low amounts excreted in breast milk (some have no data at all), and no reports of any problems.^113,114

Preparation for Surgery

For patients with asthma who plan to undergo elective surgery, the goal is for the asthma to be well controlled through optimal therapy prior to the procedure. This is accomplished by the usual classification of asthma severity and control, with stepped therapy when needed (see Tables 6 & 7). If the patient’s asthma is well controlled, no further intervention is necessary. Stress-dose steroids may be required for patients on chronic oral steroids.

Complementary and Alternative Treatments

Non-traditional treatments, including manual therapy, acupuncture, Vitamin C, herbal interventions, and avoidance of monosodium glutamate (MSG), have not shown significant beneficial effects for asthma.^115–118

National Guidelines

This guideline is consistent with the:

• National Institute for Health and Care Excellence (UK): Asthma – Diagnosis and Monitoring, 2017.
• National Institute for Health and Care Excellence (UK): Chronic Asthma Management, 2017.

Performance Measures

National and regional programs that have clinical performance measures for care often use data from the Healthcare Effectiveness Data and Information Set (HEDIS) approved by the National Committee for Quality Assurance (NCQA).

While programs may modify specific measurement details (eg, method of data collection, population inclusions and exclusions), the HEDIS measures relevant to asthma are:

Medication Management for People with Asthma: Assesses adults and children 5-64 years of age who were identified as having persistent asthma and were dispensed appropriate asthma-controlled medications that they remained on for at least 75% of their treatment period. (Blue Cross Blue Shield of Michigan)

Funding

The development of this guideline was funded by Michigan Medicine.

Guideline Development Team and Disclosures

The multidisciplinary guideline development team consisted of:

• Primary care physicians: Jeffery D. Smith, MD, General Internal Medicine, Scott A. Kelley, MD, Family Medicine, Jill A. Noble, MD, General Pediatrics.
• Specialists in asthma care: Manuel Arteta, MD, Pediatric Pulmonary Medicine, Alan P. Baptist, MD, MPH, Allergy & Clinical Immunology, Valerie A. Lindell, PharmD, BCACP, College of Pharmacy, Njira I. Lugogo, MD, Pulmonary & Critical Care Medicine.
• Guideline development methodologist: R. Van Harrison, PhD, Learning Health Sciences.
• Literature search services were provided by informationists at the Taubman Health Sciences Library, University of Michigan Medical School.

The University of Michigan Health System endorses the Guidelines of the Association of American Medical Colleges and the Standards of the Accreditation Council for Continuing Medical Education that the individuals who present educational activities disclose significant relationships with commercial companies whose products or services are discussed. Disclosure of a relationship is not intended to suggest bias in the information presented, but is made to provide readers with information that might be of potential importance to their evaluation of the information.

Systematic Review of Literature

A detailed description of the systematic search and review of literature upon which this guideline is based is presented in the associated UMHS document “Asthma, 2020: Literature Review Methods and Results.” The following section highlights major aspects of the literature search and review process.

Literature search. The team began the search of literature by accepting the results of systematic literature reviews performed for:

• Asthma – Diagnosis and Monitoring, National Institute for Health and Care Excellence, 2017 (literature searches through March 2017)
• Chronic Asthma Management, National Institute for Health and Care Excellence (UK), 2017 (literature searches through September 2016.

To update those results, we performed a systematic search of literature on Medline and in the Cochrane Database of Systematic Reviews for the following general topics and time periods:

• Asthma diagnosis and monitoring: January 2017 – January 2019
• Asthma management: July 2016 – January 2019
• Asthma – complementary medicine: January 2008 – January 2019

The major search term was asthma. The searches were for guidelines, controlled trials (including meta-analyses), and cohort studies, for literature on humans in the English language. Within these parameters individual searches were performed for the following topics:

Diagnosis – start Jan 2017

• 1. History (rhinitis, nasal polyps, atopic dermatitis, response to exercise) (for diagnosis)
• 2. Physical exam, signs, symptoms (normal, wheezing, intercostal retraction during inspiration, chest hyperinflation, prolonged expiratory phase) (for diagnosis)1.
• 3. Differential diagnosis – Exclusion on alternative diagnoses
• 4. Spirometry (include broncho-provocation/methacholine challenge, bronchodilator)
• 5. Peak flow meter – PEFR (for diagnosis, mostly used for assessment for treatment and monitoring)
• 6. Radiography (current practice – little role)
• 7. FENO (fractional excretion of nitric oxide)
• 8. Testing used specifically for candidacy for newer therapies (biologics) – peripheral eosinophilia, IgE levels, FENO (fractional excretion of nitric oxide)
• 9. Impedence oscillometry (not current practice)
• 10. Diagnosis, other references not included in 1–9.

Monitoring Asthma Control – start Jan 2017

• 11. Assessment of asthma control and severity (impairment and risk): peak expiratory flow rate (PEFR), spirometry, exacerbations (as risk for future)
• 12. Validated patient questionnaires: ACT (Asthma Control Test), ACQ (Asthma Control Questionnaire)

Treatment – Start July 2016

• 13. Patient education – exclude self-management and “action plan,” addressed in management – include improving adherence
• 14. Environmental control – avoid, control triggers (smoking, allergens, foods, indoor air pollution, medications, exercise, concurrent medical conditions, environmental control)
• 15. Stepwise approach with medications
• 16. Alternative treatment strategies (e.g., corticosteroid + LABA) as Single Maintenance and Reliever Therapy (SMART)
• 17. Exacerbations and acute severe exacerbations – approach
• 18. Short-acting beta agonists (SABA)
• 19. Inhaled corticosteroids
• 20. Long-acting beta agonists (LABA)
• 21. Long-acting muscarinic antagonists (LAMA) anticholinergics
• 22. Leukotriene receptor antagonists (LTRA)
• 23. Mast cell stabilizers
• 24. Systemic (oral corticosteroids)
• 25. Theophylline/methylxanthines
• 26. Combined inhaler medications
• 27. Biologic therapies (omalizumab, mepolizumab, reslizumab)
• 28. (search not performed)
• 29. Other pharmacotherapy agents, not in above
• 30. Pharmacotherapy adverse effects
• 31. Pharmacotherapy delivery devices, inhalers, spacers, home nebulizers
• 32. Immunization therapy
• 33. Self-management, peak expiratory flow rate (PEFR) and “action plans”
• 34. Immunizations (no separate search, using ACIP guidelines)
• 35. Follow up, consultation, referral

Special circumstances – Start July 2016 (except for complementary/alternative med)

• 36. Exercise-induced asthma
• 37. Occupational asthma
• 38. Treating contributing co-morbidities
• 39. Pregnancy and breast feeding
• 40. Complementary, alternative, and integrative medicine. No previous search – start Jan 2008
• 41. Treatment, management, monitoring – other references not included in 11-40.
• 42. Other references to asthma, but not in above

A more formal presentation of the inclusion and exclusion criteria is in Section II of the accompanying Literature Review Methods and Results.

The search was conducted in components of a formal problem structure (outlined above). The search was supplemented with very recent clinical trials known to expert members of the panel. The search was a single cycle. The number of publications identified is presented in the accompanying Literature Review Methods and Results.

Literature review and assessment. Members of the guideline team reviewed the publications identified to be relevant to specific topics in order to select those with best evidence. Criteria to identify overall best evidence included relevance of the study setting and population, study design, sample size, measurement methods (variables, measures, data collection), intervention methods (appropriateness, execution), appropriateness of analyses, and clarity of description.

In considering level of evidence based on study design, the classification was:

• A = systematic reviews of randomized controlled trials with or without meta-analysis
• B = randomized controlled trials
• C = systematic reviews of non-randomized controlled trials or observational studies, non-randomized controlled trials, group observation studies (cohort, cross-sectional, case-control)
• D = individual observation studies (case study or case series)
• E = expert opinion regarding benefits and harm

Beginning with best evidence identified by the previous systematic literature review, team members checked publications identified in the more recent search to determine whether better evidence was available. Team members also had the option of considering very recent literature (published since January 2019 in determining whether even better evidence was available.

The process of review and assessment is described in more detail in the accompanying Literature Review Methods and Results

Best evidence and recommendations. Team members identified articles or other publications with best evidence regarding specific topics.

The guideline team reviewed the evidence and determined the importance of performing or not performing key aspects of care (listed on the first page of this guideline). In the absence of empirical evidence, the guideline team-based recommendations on their expert opinion.

The strength of recommendations regarding care were categorized as:

• I = Generally should be performed
• II = May be reasonable to perform
• III = Generally should not be performed

The accompanying Literature Review Methods and Results presents a table of each recommendation and the source of best evidence on which the recommendation is based.

Review and Endorsement

A draft of this guideline was reviewed by units within UMHS to which the content is most relevant. A representative of Pharmacy Services performed the initial review. Then reviews occurred in clinical conferences or by distribution for comment within the following primary care clinical departments and divisions: Family Medicine, General Internal Medicine, General Pediatrics, and Geriatric Medicine, and the following specialty divisions: Allergy & Clinical Immunology, Pediatric Pulmonology, and Pulmonary & Critical Care Medicine. The draft was revised based on comments from these groups.

The final version of this guideline was endorsed by the Clinical Practice Committee of the University of Michigan Medical Group and by the Executive Committee for Clinical Affairs of the University of Michigan Hospitals and Health Centers.

Acknowledgements

The following individuals are acknowledged for their contributions to previous versions of this guideline.

1996: Cyril M. Grum, MD; James L. Baldwin, MD; Ann M Durnace, RN; Steven R. Erickson, PharmD; Lee A. Green, MD, MPH; Martin E. Hurwitz, MD; Sonya Mitrovich, MD; John G. Younger, MD.

2000 (and revised 2004): Lee A. Green, MD, MPH; James L. Baldwin, MD; Steven R. Erickson, PharmD; Cyril M. Grum, MD; Martin E. Hurwitz, MD; Sonya Mitrovich, MD; John G. Younger, MD.

2005 (and revised 2006): Lee A. Green, MD, MPH; James L. Baldwin, MD; F. John Brinley, MD; James A. Freer, MD; Cyril M. Grum, MD; Martin E. Hurwitz, MD; Cary E. Johnson, PharmD; Benjamin Song, MD.

2009: Annie Sy, PharmD, helped adapt NHLBI guidelines into Table 6 (initial classification) and Table 9 (follow-up classification).

2010: Sean K. Kesterson, MD; Joyce E. Kaferle, MD; Jill A. Noble, MD; Manuel Arteta, MD; Alan P. Baptist, MD, MPH; James A. Freer, MD; Cyril M. Grum, MD; Cary E. Johnson, PharmD; R. Van Harrison, PhD.

Data Availability

These links to Internal UMHS Guidelines contain proprietary information so are only accessible to appropriate Michigan Medicine staff. For more information, contact the authors or publisher.

Supplementary material can be found at http://www.uofmhealth.org/provider/clinical-care-guidelines

Internal UMHS Guidelines contain proprietary information so are only accessible to appropriate Michigan Medicine staff. For more information, contact the authors or publisher.