Asthma
GENERAL PRINCIPLES
Definition
Asthma is a common airway disease characterized by chronic airway inflammation and variable obstruction wherein patients frequently have paroxysms of cough, dyspnea, chest tightness, and wheezing.
Patients with asthma frequently have episodic acute exacerbations that are interspersed with periods of symptomatic variability. Exacerbations are characterized by a progressive increase in asthma symptoms that can last minutes to hours and are frequently associated with viral infections, allergens, and occupational exposures.
Classification
When treating asthma, severity should be carefully classified by the clinician based on both level of impairment (symptoms, lung function, daily activities, and rescue medication use) and risk (exacerbations, lung function decline, and medication side effects).
At the initial clinical evaluation, a clinician should determine a patient's asthma severity level. If the patient is not already on controller medications, severity is determined based on the most severe category in which any feature appears (Table 9-10). On subsequent visits, or if the patient is already on a controller medication at the initial encounter, severity is based on the lowest step of therapy required to maintain clinical control (Table 9-11).
TABLE 9-10
CLASSIFICATION OF ASTHMA SEVERITY ON INITIAL ASSESSMENT
| | Intermittent | Mild Persistent | Moderate Persistent | Severe Persistent |
| Daytime symptoms | ≤2 d/wk | ≥2 d/wk but not daily | Daily | Throughout the day |
| Nighttime symptoms Activity | ≤2?∕mo None | 3-4?∕mo Minor | ≥1?∕wk but not nightly Some | Nightly Extreme |
limitations
| Reliever medicine use | ≤2 d/wk | ≥2 d/wk but not daily | Daily | | Several times per day |
| FEV1 | ≥80% | ≥80% | 60%-80% | | 2 d/wk | Throughout the day |
| Nighttime symptoms | None | 1-3?Mk | ≥4?Mk |
| Activity limitations | None | Some | Extreme |
| Reliever medicine use | ≤2?Mk | >2?Mk | Frequent |
| FEV1 or PEF | ≥80% | 60%-80% | < 0.75 | ACT 16-19 ACQ > 1.5 | ACT ≤ 15 |
| Exacerbations | 0-1/y | ≥2?ty | ≥2?ty |
| Management | Maintain at lowest step possible Consider step down if well controlled for ≥3 mo | Step up one step | Step up one to two steps and consider short-course OCS |
| Follow-up | 1-6 mo | 2-6 wk | 2 wk |
| | | | | | | | |
Data from the 2020 GINA Report: Global Strategy for Asthma Management and Prevention.
Global Initiative for Asthma - GINA. Updated 2020. Accessed February 24, 2021. https://ginasthma.org/gina-reports/ and NAEPP Third Expert Panel on the Diagnosis and Management of Asthma. Accessed February 24, 2021, https://www.jacionline.org/action/showPdf?pii=S0091- 6749%2820%2931404-4 ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; FEV1, forced expiratory volume in 1 second; OCS, oral corticosteroids; PEF, peak expiratory flow.
The severity of an asthma exacerbation should be classified based on symptoms, signs, and objective measures of lung function (Table 9-12).
TABLE 9-12
CLASSIFICATION OF ASTHMA EXACERBATION SEVERITY
| | Moderate | Severe | Impending Respiratory Arrest |
| FEV1 or PEF predicted or personal best | 40%-69% | 42 mm Hg | Hypercapnia is a late sign |
| | | | | | | | |
Data from the 2020 GINA Report: Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma - GINA. Updated 2020. Accessed February 24, 2021. https://ginasthma.org/gina-reports/ and NAEPP Third Expert Panel on the Diagnosis and Management of Asthma. Accessed February 24, 2021. https://www.jacionline.org/action/showPdf?pii=S0091- 6749%2820%2931404-4
DOE, dyspnea on exertion; FEV1, forced expiratory volume in 1 second; HR, heart rate; O2sat, oxygen saturation; PEF, peak expiratory flow; RA, room air; RR, respiratory rate; SOB, shortness of breath.
While the majority of patients with asthma can achieve disease control with controller therapy, approximately 5% of patients with asthma have severe persistent disease that remains inadequately controlled despite adherence to standard treatments.
These patients carry a significant amount of the morbidity, mortality, and healthcare utilization that is associated with asthma. Epidemiology
In the US
Asthma is highly prevalent affecting more than 300 million people worldwide and approximately 8% of the American population.38
The prevalence of asthma is highest among African-Americans, is inversely associated with socioeconomic status, and is a well-recognized health inequity in the US.39
Etiology
Possible factors associated with asthma development can be broadly divided into host, genetic, and environmental factors.
There have been multiple genes, chromosomal regions, and epigenetic changes associated with the development of asthma. Racial and ethnic differences have also been reported in asthma and are likely the result of a complex interaction between genetic, socioeconomic, and environmental factors.
There are multiple environmental factors that contribute to the development and persistence of asthma. Severe viral infections early in life, particularly respiratory syncytial virus and rhinovirus, are associated with the development of asthma in childhood and play a role in its pathogenesis.
Childhood exposure and sensitization to a variety of aeroallergens and irritants (e.g., cigarette smoke, mold, pet dander, dust mites, cockroaches) may play a role in the development of asthma, but the exact nature of this relationship is not yet fully elucidated. By contrast, early-life exposure to indoor allergens together with certain bacteria (microbiota) may be protective for urban children. The prevalence of asthma in children raised in a rural setting is reduced, although the reason for this is not fully known.
Pathophysiology
Asthma is characterized by variable airflow obstruction, hyperinflation, and airflow limitation resulting from multiple processes including the following:
Acute and chronic airway inflammation characterized by infiltration of the airway wall, mucosa, and lumen by activated eosinophils, mast cells, macrophages, and T lymphocytes.
Components of innate immunity including natural killer T cells, neutrophils, and innate lymphoid lymphocytes are also implicated. Bronchial smooth muscle contraction resulting from mediators released by a variety of cell types
including inflammatory, local neural, and epithelial cells.
Epithelial damage manifested by denudation and desquamation of the epithelium leading to mucus plugs that obstruct the airway.
Airway remodeling characterized by the following findings:
๎ Subepithelial fibrosis, specifically thickening of the lamina reticularis from collagen deposition.
๎ Smooth muscle hypertrophy and hyperplasia.
๎ Goblet cell and submucosal gland hypertrophy and hyperplasia resulting in mucus hypersecretion.
๎ Airway angiogenesis.
๎ Airway wall thickening due to edema and cellular infiltration.
Risk Factors
A number of factors increase airway hyperresponsiveness and can cause an acute and chronic increase in the severity of asthma:
Allergens such as dust mites, cockroaches, pollens, molds, and pet dander in susceptible patients.
Viral upper respiratory tract infections.
Many occupational allergens and irritants such as perfumes, cleaners, or detergents, even in small doses.
Changes in weather (i.e., from warm to cold), strong emotional stimuli, and exercise.
Indoor and outdoor pollutants, such as nitrogen dioxide (NO2) and tobacco and wood smoke.
Obesity.
Medications such as β-blockers (including ophthalmic preparations), aspirin, and NSAIDs can cause the sudden onset of severe airway obstruction.
Prevention
Rigorous treatment adherence and appropriate follow-up can help prevent worsening of asthma control.
Identification and avoidance of risk factors (allergens, irritants) that exacerbate symptoms play a key role in prevention.
Recognition and management of comorbidities such as obesity, sinonasal diseases, gastroesophageal reflux disease (GERD), and psychiatric disorders is important.
Associated Conditions
Rhinosinusitis, with or without nasal polyps, is frequently present and should be treated with intranasal or oral corticosteroids, saline rinses, and/or antihistamines. Antibiotics should be reserved for superimposed bacterial infections.
Vocal cord dysfunction (VCD) or paradoxical vocal fold movement can coexist with or masquerade severe, uncontrolled asthma. Diagnosis often requires provocation testing with laryngoscopy by otolaryngology specialists. Treatment consists of speech and, if needed, behavioral therapy.
Symptomatic GERD can cause worsening asthma control and treatment with H2 blockers or proton pump inhibitors is recommended in these cases. However, empiric treatment of GERD in asymptomatic patients with uncontrolled asthma is not an effective strategy.
Obesity is increasingly recognized as an important comorbid condition and its presence is inversely correlated with asthma control. This association may be related to altered lung mechanics, altered respiratory patterns, or an increase in systemic infl ammation. Healthy weight loss should be an integral part of a comprehensive asthma treatment plan.
Smoking prevalence in patients with asthma is the same as the general population. Although no convincing evidence links tobacco use with developing asthma, it may make patients less responsive to ICS and more difficult to control. Tobacco cessation should be encouraged in all patients.
OSA may make asthma more difficult to control and should be addressed with an overnight polysomnogram if suspected.
DIAGNOSIS
Clinical Presentation
HISTORY
Recurring episodes of cough, dyspnea, chest tightness, and wheezing are suggestive of asthma. Symptoms are often worse at night or early morning, in the presence of potential triggers, and/or in a seasonal pattern.
A personal or family history of atopy increases the likelihood of an asthma diagnosis.
Patients older than 50 years presenting for the first time, patients with >20 pack-years of smoking, and patients with a lack of response to asthma therapy are features that make asthma less likely as the sole cause of respiratory symptoms.
Alternative diagnoses including COPD, ACO, and others should be carefully considered in these patients. PHYSICAL EXAMINATION
Chronic asthma
๎ Auscultation of wheezing and a prolonged expiratory phase can be present on examination, but a normal chest examination does not exclude asthma.
๎ Signs of atopy, such as eczema, rhinitis, or nasal polyps, often coexist with asthma. The presence of nasal polyps should prompt questioning regarding the possibility of aspirin-exacerbated respiratory disease (AERD).
Asthma exacerbation
ฐ During a suspected asthma exacerbation, a rapid assessment should be performed to identify patients who require immediate intervention (Table 9-12).
๎ The presence or intensity of wheezing is an unreliable indicator of the severity of an attack.
Diagnostic Criteria
In general, the diagnosis is supported by the presence of symptoms consistent with asthma combined with demonstration of variable expiratory airflow obstruction.
Adequate response to asthma treatment assists with making the diagnosis.
Methacholine challenge test can be considered when the diagnosis is in question. Note that airway hyperresponsiveness can be seen in diseases other than asthma (e.g., COPD, sarcoidosis) and effective asthma controller medications (such as ICS) can normalize the result (see Diagnostic Testing below).
Differential Diagnosis
Other conditions may present with wheezing and must be considered, especially in patients who are not responsive to therapy (Table 9-13).
TABLE 9-13
CONDITIONS THAT CAN PRESENT AS REFRACTORY ASTHMA
Upper Airway Obstruction
Tumor
Epiglottitis
Vocal cord dysfunction
Obstructive sleep apnea
Lower Airway Disease
Allergic bronchopulmonary aspergillosis
Chronic obstructive pulmonary disease
Cystic fibrosis α1-Antitrypsin deficiency
Bronchiectasis
Bronchiolitis obliterans
Tracheomalacia
Endobronchial lesion
Foreign body
Herpetic tracheobronchitis
Adverse Drug Reaction
Aspirin
β-Adrenergic antagonist
Angiotensin-converting enzyme inhibitors
Inhaled pentamidine
Congestive heart failure
Gastroesophageal reflux
Sinusitis
Hypersensitivity pneumonitis
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
Eosinophilic pneumonia
Hyperventilation with panic attacks
Dysfunctional breathlessness
Diagnostic Testing
LABORATORY STUDIES
Chronic asthma
๎ Although laboratory analysis is not necessary for a diagnosis, a complete blood count with cellular differential should be obtained to assist with clinical phenotyping (i.e., to identify those with predominant eosinophiliaabsolute peripheral blood eosinophil level of 0.3 ? 109∕mm3 or greater).
๎ A diagnosis of allergic bronchopulmonary aspergillosis (ABPA), which is due to a hypersensitivity reaction to Aspergillus fumigatus, should be carefully considered in each patient and is present in 1%-2% of asthma patients with persistent disease. Serum IgE levels, precipitating antibodies to A. fumigatus, or elevated A. fumigatus-specific antibodies should be tested to aid in the diagnosis.
๎ Allergy skin tests or immunoassays for allergen-specific IgE are helpful to identify sensitization to specific inhalant allergens when allergen exposures are being concerned as a trigger. Results of allergy tests must correlate with history and clinical presentation.
๎ Fractional concentration of exhaled nitric oxide (FeNO) may be used as a marker of eosinophilic airway inflammation in asthma. An FeNO level >50 parts per billion (ppb) is associated with a good response to ICS therapy.
Asthma exacerbation
๎ During an exacerbation, monitor oxygen saturation. ABG measurement should be considered in patients in severe distress or with an FEV1 of a proportionally smaller reduction in the FVC occur. This produces a decreased FEV1∕FVC ratio (generally 12% and 200 mL after two to four puffs of a short-acting bronchodilator. Bronchodilator response is helpful in the diagnosis of asthma, but absence will not exclude the diagnosis as some patients may need repeat testing to demonstrate reversibility.
๎ In patients with chronic, severe asthma, the airflow obstruction may no longer be completely reversible. In these patients, the most effective way to establish the maximal degree of airway reversibility is to repeat PFTs after a course of oral corticosteroids (usually 40 mg/day for 10-14 days) and to use the same criteria as above for reversibility. The lack of demonstrable airway obstruction or reactivity does not rule out a diagnosis of asthma.
๎ In cases in which spirometry is normal, the diagnosis can be made by showing heightened airway responsiveness to a methacholine challenge. A methacholine challenge is considered positive when a provocative concentration of 8 mg/mL or less causes a drop in FEV1 of 20% (PC20). If the patient is on an ICS, a PC20 of 8-16 mg/mL is considered borderline positive. A PC20 >16 mg/mL is considered a negative test. Repeat testing with the patient off of their ICS may be necessary.
An objective measurement of airflow obstruction is essential to the evaluation of an exacerbation. The severity of the exacerbation should be classified as follows:
๎ Mild (peak expiratory flow [PEF] or FEV1 >70% of predicted or personal best)
๎ Moderate (PEF or FEV1 40%-69%)
๎ Severe (PEF or FEV1 240-480
>480 | | Budesonide DPI (90, 180, or 200 pg/dose) | 180-600 | >600-1200 | >1200 |
| Budesonide nebulized respules (250, 500, or 1000 pg/respules) | 250-500 | >500-1000 | >1000 |
| Ciclesonide HFA (80 or 160 pg/puff) | 160-320 | >320-640 | >640 |
| Fluticasone propionate HFA (44, 110, or 220 pg/puff) | 88-264 | >264-440 | >440 |
| Fluticasone furoate (100, 220 pg/puff) | 100-300 | >300-500 | >500 |
| Mometasone furoate DPI (110 or 220 pg/puff) | 220 | 440 | >440 |
Data from the 2020 GINA Report: Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma - GINA. Updated 2020. Accessed February 24, 2021. https://ginasthma.org/gina-reports/ and NAEPP Third Expert Panel on the Diagnosis and Management of Asthma. Accessed February 24, 2021. https://www.jacionline.org/action/showPdf?pii=S0091- 6749%2820%2931404-4
DPI, dry powder inhaler; HFA, hydrofluoralkane; MDI, metered-dose inhaler.
Systemic corticosteroid absorption can occur in patients who use high doses of ICS. Consequently, prolonged therapy with high-dose ICS should be reserved for patients with severe disease or for those who otherwise require oral corticosteroids.
Pharmacological inhibitors of cytochrome P450 may reduce steroid elimination in patients on ICS, thus increasing steroid side effects.
Attempts should be made to decrease the dose of ICS every 2-3 months to the lowest possible dose to maintain control.
Traditionally, patients with mild persistent asthma are treated with a daily maintenance low-dose ICSs that are to be taken as prescribed regardless of symptoms. Patients are further instructed to take a SABA with symptoms.
COMBINATION THERAPY
Alternative regimens in moderate persistent asthma include a maintenance low-dose ICS/LABA (or medium-dose ICS) taken as a maintenance inhaler with a SABA used as needed.
In addition, the treatment of moderate persistent asthma can include a low-dose ICS/LAMA. At the moment tiotropium (Spiriva) is the only FDA-approved stand-alone muscarinic antagonist for asthma specifically.
A low-dose ICS plus a leukotriene modifier (LTM) or theophylline can be considered but is generally less preferred.
REGIMEN USING ICS/FORMOTEROL
Formoterol is a LABA, but it can provide relief of symptoms quickly (similar to SABAs) due to formoterol's rapid onset of action as compared to other LABAs. Using this characteristic, several as- needed options for ICS/formoterol have been studied and shown efficacy.41 However, at the moment, these treatment methods are still off-label in the US.
Low-dose ICS in combination with formoterol used as needed can be an option for treatment of mild asthma rather than a maintenance ICS and as-needed SABA.
Single maintenance and reliever therapy (SMART) uses a low- or medium-dose ICS combined with formoterol on a maintenance basis and as needed for relief of asthma symptoms. SMART has been shown to reduce exacerbations and is a preferred treatment for mild or mild to moderate persistent asthma.
LEUKOTRIENE AGENTS
Leukotrienes are mediators in the inflammatory cascade.
LTMs include montelukast and zafirlukast, which are oral leukotriene receptor antagonists (LTRA), and zileuton, which is an oral 5-lipoxygenase inhibitor.
These medications can be considered as an alternative first-line medication for mild persistent asthma and as an add-on to ICS for more severe forms of asthma.
In particular, these medications should be considered for patients with aspirin-sensitive asthma, exercise-induced bronchoconstriction, concurrent allergic rhinitis, or in individuals who cannot master the use of an inhaler.
Pharmacologic Therapies in Severe Persistent Asthma
Optimal treatment of severe persistent asthma is of the utmost importance given the high degree of morbidity and mortality in this group and deserves particular attention.
Treatment of severe persistent asthma generally involves the use of a medium-dose or high-dose ICS/LABA as a maintenance inhaler. However, use of a LAMA in the place of a LABA can be considered.
In patients not controlled on high-dose ICS/LABA therapy, consideration should be given to add-on therapy with tiotropium or an LTM.
Selected patients who have uncontrolled asthma despite the use of high-dose ICS/LABA therapy and in whom medication adherence is not an issue should be carefully considered for biologic therapy.
Biologic therapy with monoclonal antibodies against IgE and interleukin (IL)-4, IL-5, and IL-13 has been shown to be highly effective in certain patients with severe persistent asthma not controlled on high doses of ICS plus long-acting bronchodilators (see Table 9-15).
๎ Omalizumab is a monoclonal antibody against IgE that has been shown to reduce exacerbation rates, decrease emergency healthcare utilization, and improve asthma-related quality of life in patients with moderate to severe persistent allergic asthma with a demonstrable sensitivity to a perennial allergen and incomplete symptom control with ICS.42
TABLE 9-15
FDA-APPROVED BIOLOGICS FOR ASTHMA
| Biologic Medication | Mechanism of Action | Indication | Dosing and Administration |
| Omalizumab | Binds free | ≥6 y old with moderate to severe persistent | 150-375 mg |
| | IgE | asthma, an IgE level of 30-700 IU/mL (US ≥12 y) and 30-1300 IU/mL (US 6-11 y), and positive IgE specific tests or skin testing to a perennial allergen. | SC q2-4 weeks depending on IgE level |
| Mepolizumab | Binds to IL-5 ligand | ≥12 y old (US) or ≥6 y old (EU) with severe eosinophilic asthma unresponsive to GINA Step 4-5 therapy. Serum AEC ≥150-300 cells∕μL. | 100 mg SC q4wk |
| Reslizumab | Binds to IL-5 ligand | ≥18 y old with severe eosinophilic asthma unresponsive to GINA Step 4-5 therapy. Serum AEC ≥400 cells∕μL. | 3 mg/kg IV q4wk |
| Benralizumab | Binds to IL-5 receptor α | ≥12 y old with severe eosinophilic asthma unresponsive to GINA Step 4-5 therapy. Serum AEC ≥300 cells∕μL. | 30 mg SC q4wk for first three doses followed by 30 mg q8wk |
| Dupilumab | Binds to IL-4 receptor α; blocks signaling of IL-4 and IL- 13 | ≥12 y old with severe eosinophilic asthma unresponsive to GINA Step 4-5 therapy. Serum AEC ≥150 cells∕μL or FeNO ≥25 ppb. | 400-600 mg SC loading dose initially followed by 200-300 mg SC q2wk |
| | | | | | | | |
AEC, absolute eosinophil count; FeNO, fractional nitric oxide concentration in exhaled breath; GINA, Global Initiative for Asthma; IL, interleukin; IU, international unit.
๎ Mepolizumab and reslizumab are humanized monoclonal antibodies against IL-5, which reduce eosinophilic inflammation and have been shown to significantly reduce the frequency of exacerbations and hospitalizations in patients with severe asthma. Mepolizumab is delivered subcutaneously (and can now be self-administered at home), while reslizumab is delivered based on weight dosing intravenously.43,44
๎ Benralizumab is a monoclonal antibody directed against the α receptor of IL-5 that has been shown to significantly decrease exacerbations, improve lung function, and reduce systemic corticosteroid exposure in patients with severe, steroid-dependent asthma. Benralizumab can be self-administered at home and carries the benefit of every 8 week dosing (after the first three doses).45
๎ Dupilumab is a human monoclonal antibody against the α receptor of IL-4 that blocks signaling for IL-4 and IL-13. Among patients with uncontrolled severe asthma, dupilumab was shown to decrease the rate of severe exacerbation, improve lung function, and improve asthma control. This effect was most pronounced in patients with an eosinophil count >300 cells/mm3 or FeNO ≥25 ppb. Dupilumab can be self-administered at home and should be administered every 2 weeks.46
Management of Asthma Exacerbations
Management of an exacerbation requiring hospital-based care should follow a treatment algorithm to triage patients based on response to treatment.
๎ The response to initial treatment (three treatments with a short-acting bronchodilator every 20 minutes for 60-90 minutes) can be a better predictor of the need for hospitalization than the severity
of an exacerbation.
๎ Patients at high risk of asthma-related death should be advised to seek medical attention early in the course of an exacerbation.
๎ A low threshold for admission is appropriate for patients with recent hospitalization, a failure of aggressive outpatient management (with oral corticosteroids), or a previous life-threatening attack.
๎ During an exacerbation, reversal of airflow obstruction is achieved most effectively by frequent administration of an inhaled SABA.
■ For a mild to moderate exacerbation, initial treatment starts with two to six puffs of albuterol via MDI with a spacer or 2.5 mg via nebulizer and is repeated q20min until improvement is obtained or toxicity is noted.
■ For a severe exacerbation, albuterol 2.5-5 mg q20min with ipratropium bromide 0.5 mg q20min should be administered via nebulizer. Alternatively, albuterol 10-15 mg, administered continuously over an hour, may be more effective in severely obstructed adults. If used, telemetry monitoring is necessary.
■ Levalbuterol four to eight puffs or nebulized 1.25-2.5 mg q20min can be substituted for albuterol but has not been associated with fewer side effects in adults.
๎ During an exacerbation, systemic corticosteroids speed the resolution of exacerbations of asthma and should be administered promptly to all patients.
■ The ideal dose of corticosteroid needed to speed recovery and limit symptoms is not well defined. A single or divided daily dose equivalent to prednisone 40-60 mg is usually adequate. Oral corticosteroid administration seems to be as effective as IV administration if given in equivalent doses.
■ For maximal therapeutic response, tapering of high-dose corticosteroids should not take place until objective evidence of clinical improvement is observed (usually 36-48 hours or when PEF >70%). Initially, patients are given a daily dose of oral prednisone, which is then reduced slowly.
■ A 7- to 14-day tapering dose of prednisone is usually successful in combination with an ICS instituted at the beginning of the tapering schedule. In patients with severe disease or with a history of respiratory failure, a slower dose reduction is appropriate.
■ Patients discharged from the ED should receive oral corticosteroids. A dose of prednisone, 40 mg/day for 5-7 days, can be substituted for a tapering schedule in selected patients. Either regimen should be accompanied by the initiation of an ICS or an increase in the previous dose of ICS.
■ For selected patients having a mild or moderate exacerbation, an alternative to oral corticosteroids is a recommendation that patients having an exacerbation quadruple their ICS.
Other Asthma Therapies
Methylxanthines: Theophylline has historical utility in the management of asthma but should be a lastญline option given the wide variety of options with less toxicity.
IV magnesium sulfate: During a severe exacerbation refractory to standard treatment over 1 hour, one dose of 2 g IV over 20 minutes in the ED should be considered. It has been shown to acutely improve lung function especially in those with severe, life-threatening exacerbations.
Inhaled heliox: During a severe exacerbation refractory to standard treatment over 1 hour, heliox- driven albuterol nebulization in a mixture with oxygen (70:30) should be considered. It has been shown to acutely improve lung function, especially in those with severe, life-threatening exacerbations.47
Macrolides: Antibiotics have not been shown to have any benefit when used to treat asthma exacerbations. Although results are conflicting across trials, chronic azithromycin therapy can be considered in patients with severe persistent asthma who are poorly controlled despite maximal therapy.
SC allergen immunotherapy (SCIT) can be considered in allergic patients with mild to moderate disease with persistent symptoms despite adherence to allergen avoidance and medications. SCIT is relatively contraindicated in patients with severe or unstable asthma (chronic oral corticosteroid use or severe exacerbations requiring hospitalization or intubation in the previous 6 months).
Bronchial thermoplasty: Bronchial thermoplasty is a novel therapy for severe asthma in which a specialized radiofrequency catheter is introduced through a bronchoscope to deliver thermal energy to smaller airways to reduce smooth muscle mass surrounding the airways. Bronchial thermoplasty should be only performed in very selected patients by experienced bronchoscopists in conjunction with an asthma specialist, and ideally as part of a clinical registry.
Oxygenation and Mechanical Ventilation
Supplemental oxygen should be administered to the patient who is awaiting an assessment of arterial oxygen tension and should be continued to maintain an oxygen saturation >92% (95% in patients with coexisting cardiac disease or pregnancy).
Mechanical ventilation may be required for respiratory failure.
๎ General principles include use of a large endotracheal tube (≥7.5 mm), prolonged expiratory time with high inspiratory flows, and low respiratory rate. PEEP should be patient targeted and may need to be upwardly adjusted in some cases to avoid development of intrinsic PEEP.
๎ Ketamine and propofol may provide modest bronchodilatory effects in addition to sedation. After deep sedation, paralytics may have an advantage in decreasing muscular tone and minimizing patient-ventilator dyssynchrony.
๎ Recent trials have shown that NIV may be carefully used in patients with acute asthma exacerbations and decreases the risk of endotracheal intubation.48 Data on a survival benefit in using NIV in this group are conflicting.
ฐ Although prospective data are lacking, extracorporeal life support may be beneficial in cases of severe ventilatory failure associated with asthma exacerbations in patients who are deteriorating on mechanical ventilation.
Lifestyle/Risk Modification
DIET
There is no general diet that is known to improve asthma control. However, a small percentage of patients may have reproducible deterioration after exposure to dietary sulfites used to prevent discoloration in foods such as beer, wine, processed potatoes, and dried fruit. These foods should be avoided in patients if they have had prior reactions to them.
ACTIVITY
Patients should be encouraged to lead an active lifestyle. If asthma is well controlled, patients should expect to be as physically active as they desire. If exercise is a trigger, patients should be advised to continue physical activity after prophylactic use of an LTM (montelukast 10 mg 2 hours before exercise) or an inhaled β2-agonist (two to four puffs 15-20 minutes before exposure).
SPECIAL CONSIDERATIONS During pregnancy, patients should have more frequent follow-up because the severity of asthma often changes and requires medication adjustment. There is more potential risk to the fetus with poorly controlled asthma than with exposure to asthma medications, most of which are generally considered safe.
Occupational asthma requires a detailed history of occupational exposure to a sensitizing agent, lack of asthma symptoms before exposure, and a documented relationship with symptoms and the workplace. Beyond standard asthma medical treatment, exposure avoidance is crucial.
AERD: Patients with aspirin sensitivity and chronic rhinosinusitis with nasal polyps typically have onset of asthma in the third or fourth decade of life. Aspirin desensitization may be considered in patients with corticosteroid-dependent asthma or those requiring daily aspirin/NSAID therapy for other medical conditions.
Complications
Medication Side Effects
SABA: Sympathomimetic symptoms (tremor, anxiety, tachycardia), decrease in serum potassium and magnesium, mild lactic acidosis, prolonged QTc.
ICS
ฐ Increased risk for systemic effects at high doses (equivalent >1000 μg∕day of beclomethasone) including skin bruising, cataracts, elevated intraocular pressure, and accelerated loss of bone mass.
๎ Pharyngeal and laryngeal effects are common, such as sore throat, hoarse voice, and oral candidiasis. Patients should be instructed to rinse their mouth after each administration to reduce the possibility of thrush. A change in the delivery method and/or use of a valved holding chamber/spacer may alleviate the other side effects.
LABA
๎ Fewer sympathomimetic-type side effects.
๎ Associated with an increased risk of severe asthma exacerbations and asthma-related death when used without ICS based on the Salmeterol Multicenter Asthma Research Trial, which showed a very low but significant increase in asthma-related deaths in patients receiving salmeterol (0.01%- 0.04%).49
๎ Should only be used in combination with ICS. FDA recommends discontinuation of LABA once asthma control is achieved and maintained.
LTM
๎ Cases of newly diagnosed eosinophilic granulomatosis with polyangiitis (Churg-Strauss) after exposure to LTRA have been described, but it is unclear whether they are related to unmasking of a preexisting case with concurrent corticosteroid tapering or whether there is a causal relationship.
๎ Zileuton can cause a reversible hepatitis, so it is recommended that hepatic function be monitored at initiation once a month during the first 3 months, every 3 months for the first year, and then periodically.
Biologic therapy: All biologic therapies pose the risk of immunogenicity, hypersensitivity, or, rarely, anaphylaxis. Today most biologic therapies can safely be administered at home.
Methylxanthines
๎ Theophylline has a narrow therapeutic range with significant toxicities, such as arrhythmias and seizures, as well as many potential drug interactions, especially with antibiotics.
๎ Serum concentrations of theophylline should be monitored on a regular basis, aiming for a peak level of 5-10 μg∕mL; however, at the lower doses used for asthma, toxicity is much less likely.
Referral
Referral to a specialist should be considered in the following situations:
Patients who require step 4 (see Figure 9-1) or higher treatment, or patients who have had a lifeญthreatening asthma exacerbation.
Patients being considered for biologic therapy, bronchial thermoplasty, or other alternative treatments.
Patients with atypical signs or symptoms that make the diagnosis uncertain.
Patients with comorbidities such as chronic sinusitis, nasal polyposis, ABPA, VCD, severe GERD, severe rhinitis, or significant psychiatric or psychosocial difficulties interfering with treatment.
Patients requiring additional diagnostic testing, such as rhinoscopy or bronchoscopy, bronchoprovocation testing, or allergy skin testing.
Patients who need to be evaluated for allergen immunotherapy.