Asthma Treatment & Management

Medical care includes treatment of acute asthmatic episodes and control of chronic symptoms, including nocturnal and exercise-induced asthmatic symptoms. Pharmacologic management includes the use of control agents such as inhaled corticosteroids, long-acting bronchodilators (beta-agonists and anticholinergics), theophylline, leukotriene modifiers, and more recent strategies such as the use of anti-immunoglobulin E (IgE) antibodies (omalizumab), anti–IL5 antibodies, and anti–IL4/IL13 antibodies in selected patients. Relief medications include short-acting bronchodilators, systemic corticosteroids, and ipratropium.

For all but the most severely affected patients, the ultimate goal is to prevent symptoms, minimize morbidity from acute episodes, and prevent functional and psychological morbidity to provide a healthy (or near healthy) lifestyle appropriate to the age of child.

A stepwise (step-up if necessary and step-down when possible) approach to asthma management continues to be used in the current guidelines and is now divided into 3 groups based on age (0-4 y, 5-11 y, 12 y and older). ^[2]

For all patients, quick-relief medications include rapid-acting beta₂ agonists as needed for symptoms. The intensity of treatment depends on the severity of symptoms. If rapid-acting beta₂ agonists are used more than 2 days a week for symptom relief (not including use of rapid-acting beta₂ agonists for prevention of exercise-induced symptoms), stepping up on treatment may need be considered.

A study by Price et al randomly assigned patients to 2 years of open-label therapy with leukotriene antagonists (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and a leukotriene antagonist (170 patients) or long-acting beta-agonists (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial. ^[73] The results of these two trials suggests that a leukotriene antagonist is equivalent to both comparison drugs with regard to asthma-related quality of life at 2 months, but equivalence was not proven at 2 years.

A Cochrane review found that inhaled corticosteroids are superior to anti-leukotrienes when used as monotherapy in adults and children with persistent asthma. The superiority of inhaled corticosteroids is most pronounced in asthma patients with moderate airway obstruction. ^[74] The 2019 Global Initiative for Asthma (GINA) guidelines identify inhaled corticosteroids as the preferred controller medication of choice for children and adults.

In general, patients should be assessed every 1-6 months for asthma control. At every visit, adherence, environmental control, and comorbid conditions should be checked. If the patient has good control of their asthma for at least 3 months, treatment can be stepped down; however, the patient should be reassessed in 2-4 weeks to make sure that control is maintained with the new treatment.

A study by Bruzzese et al assessed the Asthma Self-Management for Adolescents (ASMA) approach, which is a school-based intervention for adolescents and medical providers. ^[75] The study found that ASMA helped improve self-management and reduced morbidity and urgent health care use in low-income, urban, minority adolescents.

Environmental exposures and irritants can play a strong role in symptom exacerbations. Therefore, in patients who have persistent asthma, the use of skin testing or in vitro testing to assess sensitivity to perennial indoor allergens is important. Once the offending allergens are identified, counsel patients on avoidance from these exposures. In addition, education to avoid tobacco smoke (both first-hand and second-hand exposure) is important for patients with asthma.

Allergen avoidance takes different forms, depending on the specific allergen size and characteristic. Improvement in symptoms after avoidance of the allergen should result rather rapidly, though the allergen itself (eg, cat dander) may linger in the environment for months after primary removal of the source. A multifaceted approach is necessary, as individual interventions are rarely successful by themselves.

Comprehensive allergen avoidance during the first year of life effectively prevents the onset of asthma in individuals with a high genetic risk, with the effect occurring early in childhood and persisting through adulthood, according to one study. In the trial, 120 children at high risk for allergic disorders were randomized into prophylactic (n=58) and control (n=62) groups. The infants in the intervention group were either breast fed (with the mother on a low allergen diet) or given an extensively hydrolyzed formula. The control group followed standard advice. At age 18, a significantly lower prevalence of asthma was observed in the intervention arm compared to the control group (10.7% and 25.9%, respectively). An overall reduction in asthma prevalence from 1 to 18 years was also observed in assessments performed at ages 1, 2, 4, 8 and 18 years. ^[76]

Efforts should focus on the home, where 30-60% of time is spent. Patients should clean and dust their homes regularly. ^[77] If a patient cannot avoid vacuuming, he or she should use a face mask or a double-bagged vacuum with a high-efficiency particulate air filter. If possible, consideration can be given to moving to a higher floor in the house (less dust and mold) or different neighborhood (fewer cockroaches). Active smoking and exposure to passive smoke must be avoided. Room air ionizers have not been proven to be effective for people with chronic asthma, and the generation of ozone by these machines may be harmful to some. Specific factors related to the home include dust mites, animals, cockroaches, mold, and pollen (see Indoor Aeroallergens for more details).

Air pollution caused by traffic may increase the risk of asthma and wheezing, especially in individuals with EPHX1 gene and enzyme activity. ^[78] This can be mediated through airway oxidative stress generation.

Dust mites

In the case of dust mites (Dermatophagoides pteronyssinus and farina, size 30 μm), the primary allergen is an intestinal enzyme on fecal particles. The allergen settles on fabric because of its relatively large size; therefore, air filtration is not very effective. Measures to avoid dust mites include using impervious covers (eg, on mattresses, pillows, comforters, the most important intervention), washing other bedding in hot water (130°F [54.4°C] most effective), removing rugs from the bedroom, limiting upholstered furniture, reducing the number of window blinds, and putting clothing away in closets and drawers. Minimize the number of soft toys, and wash them weekly or periodically put them in the freezer. Decrease room humidity (< 50%).

A Cochrane Review noted that most trials to date have been small and of poor methodologic quality. Therefore, clinicians cannot easily offer definitive recommendations on the role of house dust mite avoidance measures in the management of perennial allergic rhinitis that is sensitive to house dust mites. Conclusions from this analysis suggest that acaricides and extensive bedroom-based environmental control programs may help reduce rhinitis symptoms. If such measures are considered appropriate, they should be the interventions of choice. However, analysis also indicated that isolated use of bedding that is impermeable to house dust mites is not likely to be effective in reducing rhinitis symptoms caused by dust mites. ^[79]

Animals

Because of the small size (1-20 μm) of dander, saliva, urine, or serum proteins of cats and other animals, these allergens are predominantly airborne indoor allergens. Avoidance involves removing animals from the home (or at least from the bedroom), using dense filtering material over heating and cooling duct vents, and washing cats and dogs as often as twice weekly. The antigens may remain in a home for 6 months or more after cats are removed from the home, and cat antigen may be found in homes and offices where cats were never present, highlighting the importance of frequent cleaning.

Cockroaches

Twenty percent of homes without visible infestation still produce sensitizing levels of cockroach allergen (size 30 μm). Successful allergen elimination measures are difficult, especially in poor living conditions. To control cockroaches, exterminate and use poison baits and traps, keep food out of the bedroom, and never leave food out in the open.

Mold

For indoor molds (size 1-150 μm), avoidance includes keeping areas dry (eg, remove carpets from wet floors), removing old wallpaper, cleaning with bleach products, and storing firewood outdoors.

Pollen

Pollen (size 1-150 μm) avoidance is difficult or impossible, but efforts to reduce exposure include closing windows and doors, using air conditioning and high-efficiency particulate air filters in the car and home, staying inside during the midday and afternoon when pollen counts are highest, wearing glasses or sunglasses, and wearing a face mask over the nose and mouth when mowing the lawn. In addition, consider increasing medications preseason and vacationing in a different ecosystem during pollen season.

The use of immunotherapy for the treatment of asthma is controversial. Several large, well-conducted studies did not demonstrate any benefit, but a meta-analysis of 75 randomized controlled trials confirmed efficacy in asthma. ^[80] The National Asthma Education and Prevention Program Expert Panel Report recommends that immunotherapy be considered if the following criteria are fulfilled:

• A relationship is clear between symptoms and exposure to an unavoidable allergen to which the patient is sensitive.

• Symptoms occur all year or during a major portion of the year.

• Symptoms are difficult to control with pharmacologic management because the medication is ineffective, multiple medications are required, or the patient is not accepting of medication.

Repeated injections of small doses of allergen have been used for more than almost 100 years to treat allergic rhinitis. This treatment is clearly effective, and positive effects may persist even years after treatment is stopped. This treatment is also considered mandatory for life-threatening bee and wasp sting (hymenoptera venom) reactions. The role of repeated allergen injections in patients with asthma has been more controversial, ranging from a relative indication to no indication. Benefit has been shown in individuals with allergy-induced asthma. ^[81]

Supporters argue that compliance can be ensured, and evidence shows that the underlying disease process can be modified or even prevented (eg, preventing asthma in children with allergic rhinitis). Acquisition of new sensitivities can be reduced or eliminated with immunotherapy of monosensitized or oligosensitized children.

Immunotherapy decreased asthma symptoms and the need for medication in a 2003 meta-analysis of 75 randomized controlled trials by Abramson et al. ^[82] Another study showed improved peak expiratory flow rate (PEFR) and decreased use of medications in a highly selected group of children, but only for the first year of therapy.

Patients receiving subcutaneous immunotherapy (SCIT) demonstrated improved medical outcomes and cost savings in one study designed to evaluate the cost-effectiveness of SCIT in addition to symptomatic therapy (ST), compared with ST alone. ^[80]

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

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

Precautions include serious adverse reactions (occurring in 1 per 30-500 people, usually within 30 min). The estimated crude annual death rate is 0.7 deaths per million population. Monitoring and resuscitation personnel and equipment are required. Also, allergen immunotherapy should be avoided if the patient is taking beta blockers or is having an asthma exacerbation (ie, PEFR < 70% of patient’s personal best) or has moderate or worse fixed obstruction. A major risk factor for immunotherapy-related fatalities includes uncontrolled asthma; therefore, appropriate caution should be exercised.

Dosing of allergen extracts is in bioequivalent allergy units (BAU), weight per volume (w/v), or protein nitrogen units (PNU), but "major allergen content" may be a more standardized and reliable method of dosing and characterizing allergen extracts; however, not all allergens have been standardized. Extracts with modifications that decrease allergenicity (adverse reactions) without reducing immunogenicity (effectiveness) are under investigation.

Sublingual immunotherapy (SLIT) has been shown to improve allergic rhinitis symptoms, including in pediatric patients and allergic asthma. While adverse reactions do occur, SLIT is safe enough for home administration. Based on limited data, sublingual therapy, at least in the short term, may be about half as effective as traditional subcutaneous injection. While SLIT is widely used in European, South American, and Asian countries, as of early 2016, it is not FDA approved and remains off-label use in the United States.

Omalizumab

Omalizumab is indicated for adults and children aged 6 years or older with moderate-to-severe persistent asthma who have a positive skin test result or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Patients should have IgE levels between 30 and 700 IU and should not weigh more than 150 kg.

This is a humanized murine IgG antibody against the Fc component of the IgE antibody (the part that attaches to mast cell surfaces). Use of this antibody prevents IgE from binding directly to the mast cell receptor, thereby preventing cell degranulation without causing degranulation itself.

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

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

Prescribers must be prepared and equipped to recognize and treat anaphylaxis should it occur. Adverse effects are rare and include upper respiratory infection symptoms, headache, urticaria (2%) without anaphylaxis, and anaphylaxis (0.1% in studies and 0.2% in postmarketing surveillance). Transient thrombocytopenia has also been noted but not in humans. Antibodies are formed against the anti-IgE antibody, but these do not appear to cause immune complex deposition or other significant problems. To date, decreased IgE levels have not been shown to inhibit one’s ability to fight infection (including parasites). Registration trials raised a question of increased risk of malignancy, but this has not been seen in the postmarketing data.

Omalizumab is given by subcutaneous injection every 2-4 weeks based on initial serum IgE level and body weight. Patients are usually treated for a trial period lasting at least 12 weeks. Costs may be $6,110 to $36,600 annually, so omalizumab is a second-line therapy for patients with moderate-to-severe persistent allergic asthma that is not fully controlled on standard therapy. ^[83]

A study by Busse et al found that omalizumab further improved asthma control, nearly eliminated seasonal exacerbation peaks, and reduced the need for other medications to control asthma when added to a regimen of guidelines-based therapy in inner-city children, adolescents, and young adults. ^[84]

A study by Hanania et al found that omalizumab provided additional benefit in patients with severe allergic asthma that is insufficiently controlled with inhaled corticosteroids and long-acting beta2-agonists. ^[85] However, the results of the study were limited by early patient discontinuation (20.8%) and were limited because the study was not powered to detect rare safety events or treatment effect in the corticosteroid group.

Mepolizumab

Mepolizumab is a humanized IgG1 kappa monoclonal antibody specific for interleukin 5 (IL-5). Mepolizumab binds to IL-5 and therefore stops IL-5 from binding to its receptor on the surface of eosinophils. Inhibiting IL-5 binding to eosinophils reduces blood, tissue, and sputum eosinophil levels. It is indicated for add-on maintenance treatment of patients with severe asthma aged 12 years or older and with an eosinophilic phenotype.

Approval was based on three key phase 3 trials (DREAM, MENSA, and SIRIUS). Each trial demonstrated statistically significant improvement in decreasing asthma exacerbations and emergency department visits or hospitalization. Mean reduction in glucocorticoid use was 50% in the mepolizumab group, while also reducing the asthma exacerbation rate. Significant improvement in FEV₁ was also observed compared with placebo. ^{[86, 87, 88]}

Reslizumab

Reslizumab is an IgG kappa monoclonal antibody that inhibits IL-5. It was approved by the FDA in March 2016 and is indicated for add-on maintenance treatment of patients with severe asthma aged 18 years and older with an eosinophilic phenotype. It is administered as an intravenous infusion every 4 weeks. Approval was based on three multicenter, international trials in patients with asthma who had elevated eosinophils. In two of these studies (n = 953), patients who received reslizumab had a significant reduction in the frequency of asthma exacerbations of up to 59% (study 1: rate ratio, 0.50 [95% confidence interval, 0.37-0.67]; study 2: rate ratio, 0.41 [95% confidence interval, 0.28-0.59]; both P < .0001) compared with those receiving placebo. ^[89]

Benralizumab

Benralizumab is an IL-5 receptor, alpha-directed cytolytic mAb (IgG1, kappa) approved by the FDA in November 2017. The IL-5 receptor is expressed on the surface of eosinophils and basophils. Benralizumab reduces eosinophils and basophils through antibody-dependent cell-mediated cytotoxicity (ADCC). It is indicated for add-on maintenance treatment of severe asthma in patients aged 12 years or older who have an eosinophilic phenotype.

Approval was based on results from the WINDWARD clinical trial program, including the phase III exacerbation trials, SIROCCO and CALIMA, and the phase III oral corticosteroid (OCS)–sparing trial, ZONDA. ^{[90, 91, 92]}

Results for the 8-week benralizumab dosing regimen from these trials showed the following:

• Up to 51% reduction in the annual asthma exacerbation rate (AAER) compared with placebo
• Significant improvement in lung function as measured by forced expiratory volume in one second (FEV ₁) of up to 159 mL compared with placebo
• Seventy-five percent median reduction in daily OCS use and discontinuation of OCS use in 52% of eligible patients

Dupilumab

Approval for dupilumab was based on the LIBERTY QUEST (n=1902) and VENTURE (n=210) phase 3 clinical trials.

In the LIBERTY QUEST trial, patients with moderate-to-severe uncontrolled asthma were administered dupilumab add-on therapy to current maintenance therapy every 2 weeks or matched placebo. Those receiving a 200-mg dose demonstrated a 47.7% lower rate of annualized severe asthma exacerbations compared with placebo add-on (P< .001). The 300-mg dose showed a similar response. ^[93]

In the LIBERTY VENTURE trial, patients with oral corticosteroid–dependent severe asthma were administered dupilumab add-on therapy or matched placebo to current maintenance therapy every 2 weeks for 24 weeks or matched placebo. Corticosteroid doses were gradually decreased from week 4 to week 20 and then maintained for 4 weeks. Patients receiving dupilumab had a 70.1% greater corticosteroid dose reduction compared with 41.9% for placebo add-on (P< .001). Additionally, patients receiving dupilumab had a 59% (95% confidence interval, 37-74) lower rate of severe asthma exacerbations than those taking placebo add-on. ^[94]  

Tezepelumab

Tezepelumab is a first-in-class human monoclonal antibody immunoglobulin G2-lambda that inhibits thymic stromal lymphopoietin (TSLP) approved in December 2021. It is indicated as add-on maintenance treatment for severe asthma in adults and adolescents aged 12 years and older. 

Approval was based on the NAVIGATOR phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients (aged 12 to 80 years) were randomly assigned to receive tezepelumab (210 mg) or placebo subcutaneously every 4 weeks for 52 weeks. Among 1061 patients who underwent randomization, 529 were assigned to receive tezepelumab and 532 to receive placebo. The annualized rate of asthma exacerbations was 0.93 with tezepelumab and 2.10 with placebo (P < 0.001). Additionally, patients with a blood eosinophil count less than 300 cells per microliter, the annualized rate was 1.02 with tezepelumab and 1.73 with placebo (P < 0.001). At week 52, improvements were greater with tezepelumab than with placebo with respect to the prebronchodilator FEV1 (0.23 vs. 0.09 liters; P < 0.001). ^[95]  

Bronchial thermoplasty (BT) is a novel intervention for asthma in which controlled thermal energy is delivered to the airway wall during a series of bronchoscopy procedures.

A group of patients (AIR2 Trial Study Group) with severe asthma who remained symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting beta₂ agonists underwent BT and showed superior improvement from baseline in their score on the Asthma Quality of Life Questionnaire (AQLQ) (BT, 1.35±1.10; sham, 1.16±1.23). Changes in AQLQ of 0.5 or greater were seen in 79% of BT and in 64% of sham subjects. Although the hospitalization rate was 6% higher among BT subjects during the treatment period (up to 6 wk after BT), in the posttreatment period (6-52 wk after BT), the BT group experienced fewer severe exacerbations, emergency department visits, and days missed from work/school compared with the sham group. ^[96]

Further results from the AIR2 study showed lasting efficacy at 5 years, as well as a reduction in maintenance treatment and healthcare utilization. The study also highlights the possibility that more patients may benefit from this treatment. ^[97]

Wechsler and colleagues examined the long-term safety and effectiveness of bronchial thermoplasty in 162 patients with severe persistent asthma from the Asthma Intervention Research 2 (AIR2) trial, which showed a 32% reduction in severe asthma exacerbations, an 84% reduction in respiratory symptom-related emergency department visits, a 73% reduction in hospitalizations for respiratory symptoms, and a 66% reduction in time lost from work/school/other daily activities because of asthma symptoms. ^{[98, 99]}

Prehospital care

The mainstay of ED therapy for acute asthma is inhaled beta₂ agonists. The most effective particle sizes are 1-5 μm. Larger particles are ineffective because they are deposited in the mouth and central airways. Particles smaller than 1 μm are too small to be effective because they move in the airways by Brownian motion and do not reach the lower airways.

Although studies in patients with COPD reported increased rates of pneumonia associated with inhaled corticosteroid use, a study by O’Byrne et al found no increased risk in patients with asthma in clinical trials using budesonide. ^[100]

Standard delivery systems and routes

Albuterol is administered 2.5-5 mg every 20 minutes for 3 doses, then 2.5-10 mg every 1-4 hours as needed; dilution of 2.5 mg in 3-4 mL of saline or use of premixed nebules is standard. Oxygen or compressed air delivery of the inhaled beta agonists should be at a rate of 6-8 L/min. For children, use 0.15 mg/kg (minimum dose 2.5 mg) every 20 minutes for 3 doses, then 0.15-0.3 mg/kg up to 10 mg every 1-4 hours as needed.

An equivalent method of beta-agonist delivery in mild-to-moderate exacerbations is the metered-dose inhaler (MDI) used in conjunction with a spacer or holding chamber. For severe exacerbations, it is less clear if nebulized versus MDI/spacer delivery is truly equivalent. Each puff delivers a standard 90 μg of albuterol. The dose is 4-8 puffs every 20 minutes up to 4 hours, then every 1-4 hours as needed. A potential advantage of the MDI/holding chamber is that it requires little or no assistance from the respiratory therapist once the patient understands how to use the medication; the patient can be discharged from the ED with the same spacer and albuterol canister. This modality is especially effective in areas where patients may be unable to afford their inhaled beta agonists.

Side effects may include tremor and a slight tendency toward tachycardia. However, many patients who present with acute asthma and tachycardia actually decrease their heart rate with inhaled beta-agonist therapy. In addition, inhaled beta agonists decrease potassium by an average of 0.4 mEq/L.

Patients who respond poorly or not at all to an inhaled beta-agonist regimen may respond to parenteral beta₂ agonists, such as 0.25 mg terbutaline or 0.3 mg of 1:1000 concentration of epinephrine administered subcutaneously. This treatment should be reserved for patients who are seriously ill and not responding to serial treatments with inhaled beta-agonist/anticholinergic therapy and other more established therapies.

Ipratropium 0.5 mg has had variable benefit in controlled trials, demonstrating most consistent efficacy in children and smokers with comorbid COPD. The current NAEPP guidelines (2007) recommend its use in severe exacerbations only. ^[2] Ipratropium should be given in combination with albuterol every 20 minutes for 3 doses, then as needed. The addition of ipratropium has not been shown to provide further benefit once the patient is hospitalized.

Nebulizer therapy

Continuous nebulization may be superior to the MDI/holding chamber method in a patient with severe exacerbations (eg, PEF < 200 L/min). The dose of albuterol is 10-15 mg in 70 mL of isotonic saline. For children, this method is reserved for severe asthma at an albuterol dose of 0.5 mg/kg/h. Based on meta-analyses, there is no advantage of intravenous albuterol over inhaled albuterol, even in severe asthma. However, the role of parenteral beta agonists in addition to inhaled beta-agonist treatments is uncertain.

A study by Dhuper et al found no evidence that nebulizers were more effective than MDI/spacer beta agonist delivery in emergency management of acute asthma in an inner-city adult population. ^[101] Thus, because they are more cost effective, MDI/spacer may be a better alternative to nebulizer delivery for some individuals.

Intravenous/oral steroids

Although use of systemic corticosteroids is recommended early in the course of acute exacerbations in patients with an incomplete response to beta agonists, oral administration is equivalent in efficacy to intravenous administration. Corticosteroids speed the resolution of airway obstruction and prevent a late-phase response. ^{[102, 103]}

In children, long-term use of high-dose steroids (systemic or inhaled) may lead to adverse effects that include growth failure. However, long-term use of inhaled steroids (budesonide) was shown to have no sustained adverse effect on growth in children, according to the Childhood Asthma Management Program (CAMP). ^{[104, 105]}

In preschool children with asthma, 2 years of inhaled corticosteroid therapy did not change the asthma symptoms or lung function during a third, treatment-free year. This suggests that no disease-modifying effect of inhaled corticosteroids is present after the treatment is discontinued. ^[106]

Complications of long-term corticosteroid use may include osteoporosis, immunosuppression, cataracts, myopathy, weight gain, addisonian crisis, thinning of skin, easy bruising, avascular necrosis, diabetes, and psychiatric disorders.

Heliox

Heliox is a helium-oxygen (80:20 or 70:30) mixture that may provide dramatic benefit for ED patients with severe exacerbations. Helium is about 10% as dense as room air and, consequently, travels more easily down narrowed passages. This property makes heliox of particular value to patients at risk of intubation—by quickly decreasing the work of breathing and, when the gas mixture is used to drive the nebulizer, by better delivery of the inhaled bronchodilator.

Despite considerable promise, the literature shows mixed results. Potential explanations include the large number of small trials (low statistical power) and suboptimal delivery of albuterol to the patient. Briefly, heliox-driven nebulizer treatments should have the gas set at a rate of 8-10 L/min and with double the usual amount of albuterol. These adjustments result in the delivery of the appropriate amount of albuterol to the patient but with particles being delivered in the heliox mixture instead of oxygen or room air. When patients need supplemental oxygen, one can deliver it via nasal prong. Of course, as the supplemental oxygen is increased, the benefits of using heliox decrease. Oxygen requirements should determine the ideal mix. The role of heliox in acute asthma remains under investigation.

Indications for intubation

Despite the best efforts of the ED, some patients require endotracheal intubation. Approximately 5-10% of all hospital admissions for asthma are to an intensive care unit—for further care of already intubated patients or for close supervision of patients at very high risk of intubation. Mechanical ventilation of patients with acute asthma presents special challenges, such as the risk of high pressures lowering systemic blood pressure (auto-PEEP) and, less commonly, complications such as barotrauma, pneumothorax, or pneumomediastinum. The role of permissive hypercapnia goes beyond the scope of this article but is a ventilator strategy used in the ICU management of some patients with severe asthma exacerbations.

Indications for hospitalization

Indications for hospitalization are based on findings from the repeat assessment of a patient after the patient receives 3 doses of an inhaled bronchodilator. The decision whether to admit is based on the following:

• Duration and severity of asthma symptoms

• Severity of airflow obstruction

• Course and severity of prior exacerbations

• Medication use and access to medications

• Adequacy of support and home conditions

• Presence of psychiatric illness

Admit the patient to the ICU for close observation and monitoring in certain situations, such as the following:

• Rapidly worsening asthma or a lack of response to the initial therapy in the emergency department

• Confusion, drowsiness, signs of impeding respiratory arrest, or loss of consciousness

• Impending respiratory arrest, as indicated by hypoxemia (PO₂< 60 mm Hg) despite supplemental oxygen and/or hypercarbia with PCO₂ greater than 45 mm Hg

• Intubation is required because of the continued deterioration of the patient's condition despite aggressive treatments.

Status asthmaticus

Status asthmaticus, or an acute severe asthmatic episode that is resistant to appropriate outpatient therapy, is a medical emergency that requires aggressive hospital management. This may include admission to an ICU for the treatment of hypoxia, hypercarbia, and dehydration and possibly for assisted ventilation because of respiratory failure.

Asthma complicates 4-8% of pregnancies. Mild and well-controlled moderate asthma can be associated with excellent maternal and perinatal pregnancy outcomes. Severe and poorly controlled asthma may be associated with increased prematurity and other perinatal complications, to include maternal morbidity and mortality. Optimal management of asthma during pregnancy includes objective monitoring of lung function, avoiding or controlling asthma triggers, patient education, and individualized pharmacologic therapy. Inhaled corticosteroids are the preferred medication for all levels of persistent asthma during pregnancy. For pregnant women with asthma, it is safer to be treated with asthma medications than to have asthma symptoms and exacerbations. The ultimate goal of asthma therapy is to maintain adequate oxygenation of the fetus by prevention of hypoxic episodes in the mother.

With the exception of alpha-adrenergic compounds other than pseudoephedrine and some antihistamines, most drugs used to treat asthma and allergic rhinitis have not been shown to increase any risk to the mother or fetus. The National Institute of Health stated that albuterol (Proventil HFA), beclomethasone (QVAR), budesonide (Pulmicort Flexhaler or Respules), prednisone (Deltasone, Orasone), and theophylline, when clinically indicated, are considered appropriate for the treatment of asthma in pregnancy.

The American College of Obstetrics and Gynecology issued updated clinical guidelines for 2008. ^[55] Poorly controlled asthma can result in low birth weight, increased prematurity, and increased perinatal mortality.

The presence of acid in the distal esophagus, mediated via vagal or other neural reflexes, can significantly increase airway resistance and airway reactivity. Patients with asthma are 3 times more likely to also have GERD. ^[16] Aggressive antireflux therapy may improve asthma symptoms and pulmonary function in selected patients. Treatment with proton pump inhibitors, antacids, or H2 blockers may improve asthma symptoms or unexplained chronic cough.

The treatment of asthma with agents such as theophylline may lower esophageal sphincter tone and induce GERD symptoms. Some people with asthma have significant gastroesophageal reflux without esophageal symptoms.

Of patients with asthma, 50% have concurrent sinus disease. Sinusitis is the most important exacerbating factor for asthma symptoms. Either acute infectious sinus disease or chronic inflammation may contribute to worsening airway symptoms. Treatment of nasal and sinus inflammation reduces airway reactivity. Treatment of acute sinusitis requires at least 10 days of antibiotics to improve asthma symptoms. ^[21]

Nocturnal asthma is a significant clinical problem that should be addressed aggressively. Peak-flow meters should be used to allow objective evaluation of symptoms and interventions. Sleep apnea, symptomatic GERD, and sinusitis should be controlled when present. Medications should be appropriately timed, and consideration should be given to the use of a long-acting inhaled or oral beta₂ agonist and a leukotriene modifier with inhaled corticosteroids. A once-daily sustained-release theophylline preparation and changing the timing of oral corticosteroids to midafternoon can be also be used.

For all patients with asthma, monitoring should be performed on a continual basis based on the following parameters, which helps in the overall management of the disease:

• Regarding monitoring of asthma signs and symptoms, patients should be taught to recognize inadequate asthma control, and providers should assess control at each visit.

• To monitor pulmonary function, regularly perform spirometry and peak-flow monitoring.

• For quality of life and functional status, inquire about missed work or school days, reduction in activities, sleep disturbances, or change in caregiver activities.

• To monitor the history of asthma exacerbations, determine whether patients are monitoring themselves to detect asthma exacerbations and if these exacerbations are self-treated or treated by health care providers.

• Regarding monitoring pharmacotherapy, ensure compliance with medications and usage of short-acting beta agonists.

• Monitor patient-provider communication and patient satisfaction

Perform a functional assessment of airway obstruction with a measurement of the FEV₁ or peak expiratory flow (PEF) initially to assess the patient's response to treatment. PEF measurement is inexpensive and portable. Serial measurements document response to therapy and, along with other parameters, are helpful in the ED setting for determining whether to admit the patient to the hospital or discharge from the ED. A limitation of PEF is that it is dependent on effort by the patient. FEV₁ is also effort dependent but less so than PEF.

A study by van den Berge examined the increased interest in small airway disease and new insights that have been gained about the contribution of small airways to the clinical expression of asthma and COPD. New devices enable drugs to target the small airways and may have implications for treatment of patients with asthma, particularly those who do not respond to large-particle inhaled corticosteroids and patients with uncontrollable asthma. ^[107]

Asthma-related complications associated with surgery include acute bronchoconstriction resulting from intubation, impaired cough, hypoxemia, hypercapnia, atelectasis, respiratory tract infection, and exposure to latex. The likelihood of these complications occurring depends on the severity of the underlying asthma, the type of surgery (thoracic and upper abdominal), and the type of anesthesia. ^[108]

Patients with asthma should have an evaluation before surgery that includes a review of asthma symptoms, medication use (particularly oral systemic corticosteroids for longer than 2 wk in the past 6 mo), and measurement of pulmonary function. If possible, attempts should be made to improve lung function preoperatively to either predicted values or the personal best level. A short course of oral systemic corticosteroids may be necessary to optimize lung function.

If evidence of airflow obstruction (< 80% of baseline values) is present, a brief course of corticosteroids is recommended. Patients who have received oral corticosteroids for an asthma exacerbation in the past 6 months should receive systemic corticosteroids (100 mg hydrocortisone IV q 8 h) in the perioperative period.

Activity is generally limited by patients' ability to exercise and their response to medications. No specific limitations are recommended for patients with asthma, although they should avoid exposure to agents that may exacerbate their disease.

A significant number of patients with asthma also have exercise-induced bronchoconstriction, and baseline control of their disease should be adequate to prevent exertional symptoms. The ability of patients with exercise-induced bronchoconstriction to exercise is based on the level of exertion, degree of fitness, and environment in which they exercise.

Many patients have fewer problems when exercising indoors or in a warm, humid environment than they do outdoors or in a cold, dry environment

Information from prospective cohort studies and population-based studies in the past several years suggests an association between asthma and obesity. Patients with an elevated body mass index have an increased risk for developing asthma. A prospective cohort study of almost 86,000 adult women in the Nurses' Health Study II observed for 5 years showed a linear relationship between body mass index and the risk of developing asthma. ^[12] The 2019 GINA guideline adds that obese patients with asthma have lower lung function and more comorbidities than asthma patients who are of normal weight. ^[109] Asthma is more difficult to control in obese patients, but weight loss of 5-10% can improve asthma control and quality of life. ^[110]

No special diets are generally indicated. Food allergy as a trigger for asthma is uncommon. Unless compelling evidence for a specific allergy exists, milk products do not have to be avoided. Avoidance of foods is recommended after a double-blind food challenge that yields positive results. Sulfites have been implicated in some severe asthma exacerbations and should be avoided in sensitive individuals.

Refer any patient with moderate-to-severe persistent asthma that is difficult to control to a pulmonologist or allergist to ensure proper stepwise asthma management, or refer for further evaluation to help rule out other diagnoses such as VCD/ILO. Also, abnormalities found on chest radiography screening should prompt referral to a specialist for further evaluation.

Refer patients to an allergist or immunologist for skin testing to guide indoor allergen mitigation efforts and consideration of immunotherapy to treat seasonal allergic rhinitis.

Refer patients to a pulmonologist for evaluation of symptoms consistent with exercise-induced bronchoconstriction (EIB). These patients should undergo either exercise or bronchoprovocation testing to document evidence of airway hyperreactivity and response to exercise.

Refer patients to an otolaryngologist for treatment of nasal obstruction from polyps, sinusitis, or allergic rhinitis or for the diagnosis of upper airway disorders.

Control of factors contributing to asthma severity is an essential component in asthma treatment. Exposure to irritants or allergens has been shown to increase asthma symptoms and cause exacerbations. Clinicians should evaluate patients with persistent asthma for allergen exposures and sensitivity to seasonal allergens. Skin testing results should be used to assess sensitivity to perennial indoor allergens, and any positive results should be evaluated in the context of the patient's medical history.

All patients with asthma should be advised to avoid exposure to allergens to which they are sensitive, especially in the setting of occupational asthma. Other factors may include the following:

• Environmental tobacco smoke

• Exertion during high levels of air pollution

• Use of beta blockers

• Avoidance of aspirin and other nonsteroidal anti-inflammatory drugs if the patient is sensitive

• Avoidance of sulfites or other food items/additives to which the patient may be sensitive

• Occupational exposures