Asthma.docx

Asthma DIAGNOSIS AND EVALUATION ■■APPROACH A presumptive diagnosis of asthma can usually be made based on a compatible history of recurrent wheezing, shortness of breath, chest tightness, or cough related to common bronchoconstrictor precipitants when appropriate components of the differential diagn...

Asthma DIAGNOSIS AND EVALUATION ■■APPROACH A presumptive diagnosis of asthma can usually be made based on a compatible history of recurrent wheezing, shortness of breath, chest tightness, or cough related to common bronchoconstrictor precipitants when appropriate components of the differential diagnosis have been considered and/or eliminated. In some cases, a therapeutic trial of low-dose inhaled corticosteroid (ICS) may be considered. In all but the mildest cases, the diagnosis should be confirmed with pulmonary function testing or demonstration of airway hyperresponsiveness. Unfortunately, the diagnosis may be difficult to confirm after initiation of therapy since airway obstruction and hyperresponsiveness may be mitigated with therapy. A trial of tapering medications may be necessary. Studies have shown that more than one-third of patients with a physician diagnosis of asthma do not meet the criteria for the diagnosis. Adjunctive evaluation, as outlined below, should be undertaken to identify precipitating factors and underlying mechanisms that may be amenable to specific therapies (e.g., allergen avoidance). Cases that require more than a daily moderate-dose ICS combined with a long-acting β2-agonist (LABA) (together known as ICS/LABA) should undergo more formal evaluation to assess comorbidities that may make asthma difficult to control and a reassessment of any possible confounding diagnoses that may mimic asthma symptoms (see Table 287-3). ■■PRIMARY ASSESSMENT TOOLS FOR ESTABLISHING A DIAGNOSIS History Patients with asthma most commonly complain of episodes of wheezing, shortness of breath, chest tightness, mucus production, or cough upon exposure to triggers listed in Table 287-2. Symptoms may be worse on arising in the morning. Some may have nocturnal symptoms alone. However, such patients should be evaluated for postnasal drip or GERD if that is their sole presenting symptom. Patients frequently complain of symptoms with rapid changes of temperature or humidity. Exercise-induced symptoms are common with increased sensitivity to cold air. As compared to cardiac sources of dyspnea, exercise symptoms tend to develop more slowly after initiation of exercise and tend to resolve more slowly unless a β2-agonist is administered after the onset of symptoms. A careful exposure history should be obtained for home (e.g., pets, molds, dust, direct or secondhand smoke), work (work environment and exposure to occupational sensitizers), and recreational (e.g., hobbies, recreational inhalants) exposures. Allergen-sensitized patients may complain of symptoms on exposure to known allergens such as animals and may complain of increased symptoms during specific pollen seasons. Up to two-thirds of patients with asthma will be atopic (as opposed to half of the U.S. population), and almost half will have a history of rhinitis, with many complaining of intermittent sinusitis. In patients with adult-onset asthma, a careful occupational history should be obtained and a history of reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) or use of new medications, such as beta blockers (including ophthalmic preparations) and ACE inhibitors (due to potential cough), should be elicited. Physical Examination In between acute attacks, physical findings may be normal. Many patients will have evidence of allergic rhinitis with pale nasal mucus membranes. Five percent or more of patients may have nasal polyps, with increased frequency in those with more severe asthma and aspirin-exacerbated respiratory disease. Some patients will have wheezing on expiration (less so on inspiration). During an acute asthma attack, patients present with tachypnea and tachycardia, and use of accessory muscles can be observed. Wheezing, with a prolonged expiratory phase, is common during attacks, but as the severity of airway obstruction progresses, the chest may become “silent” with loss of breath sounds. Pulmonary Function Tests Effective reduction of the airway lumen in asthma produces increased resistance to airflow, which can be detected as a reduction in expiratory airflow during forced expiratory maneuvers. The peak expiratory flow rate (PEFR), forced expiratory volume in 1 s (FEV1), and the FEV1/forced vital capacity (FVC) ratio are reduced below the lower limit of normal. The flow-volume loop may show a characteristic scalloping (see Chap. 286). These findings may not be present during acute attacks or on therapy (especially after recent use of bronchodilators). Reversibility is defined as a ≥12% increase in the FEV1 and an absolute increase of ≥200 mL at least 15 min after administration of a β2-agonist or after several weeks of corticosteroid therapy. Diurnal peak flow variability of >20% has also been proposed as an indicator of reversible airways disease, but it is less reliable due to difficulties with quality control and variability of home assessments. Lung volumes and diffusing capacity should be normal in uncomplicated asthma. Assessment of Airway Responsiveness In cases where pulmonary function tests are nonconfirmatory and the diagnosis remains in doubt, testing to demonstrate increased reactivity to provocative stimuli in the laboratory can be undertaken. Methacholine, a cholinergic agonist, inhaled in increasing concentrations is most commonly used. A provocative dose producing a 20% drop in FEV1 (PD20) is calculated, with a value ≤400 μg indicative of airway reactivity. Mannitol is used as well, and occasionally, hypertonic saline may be used. Challenge with exercise and/or cold, dry air can be performed, with a positive response recorded if there is a ≥10% drop in FEV1 from baseline. In the case of suspected environmental/occupational exposures, specific allergen challenges may be undertaken in highly specialized labs. ■■ADJUNCTIVE ASSESSMENT TOOLS Eosinophil Counts A large proportion of asthma patients not treated with oral or high-dose ICSs will have eosinophil counts ≥300 cells/μL. Eosinophil counts correlate with severity of disease in population studies. Their presence in patients with severe asthma indicates a likelihood that the patient would respond to medications targeted at type 2 inflammation. Extremely elevated levels should prompt consideration of eosinophilic granulomatosis with polyangiitis or primary eosinophilic disorders. IgE, Skin Tests, and Radioallergosorbent Tests Total serum IgE levels are useful in considering whether patients with severe asthma would be eligible for anti-IgE therapy. Levels >1000 IU/mL should prompt consideration of ABPA. Skin tests, or their in vitro counterparts that detect IgE directed at specific antigens (radioallergosorbent test [RAST]), can be useful in confirming atopy and suggesting allergic rhinitis, which can complicate asthma management. Allergy investigations may be useful, when correlated with a history of reactions, in identifying environmental exposures that may be aggravating asthma. Exhaled Nitric Oxide Fraction of exhaled nitric oxide (FeNO) in exhaled breath is an approximate indicator of eosinophilic inflammation in the airways. It is easily suppressed by ICSs and, thus, can be used to assess adherence in patients in whom it was initially elevated. Elevated levels (>35–40 ppb) in untreated patients are indicative of eosinophilic inflammation. Levels >20–25 ppb in patients with severe asthma on moderate- to high-dose ICS indicate either poor adherence or persistent type 2 inflammation despite therapy. ■■ADDITIONAL EVALUATION IN SEVERE/POORLY RESPONSIVE ASTHMA In patients with poorly responsive asthma, additional evaluations for comorbidities (see Table 287-3) may be necessary, including sinus radiographic studies (even in those who have no symptoms of sinus disease) and esophageal studies in those who have symptoms of reflux. In patients with nonreversible disease, many obtain a serum α1 antitrypsin level. Additionally, the following evaluations may be of utility in poorly responsive asthma. Chest Radiography Chest CT can be useful to assess for the presence of bronchiectasis and other structural abnormalities that could produce airway obstruction. New image analysis tools are being used in the research setting to assess airway properties such as airway wall thickness, airway diameter, and evidence of air trapping. Sputum Induced sputum may be used in more specialized centers to help characterize type 2 and non–type 2 inflammation by detection of eosinophils and neutrophils, respectively. In severe asthma, there is some evidence that some patients may have localized persistent eosinophilic airway inflammation despite lack of peripheral eosinophils on blood analysis. TREATMENT Asthma GOALS OF ASTHMA THERAPY AND ASSESSMENT OF CONTROL Goals of asthma therapy in terms of achieving control of symptoms and reducing risk (as reflected in frequency of asthma exacerbations) are listed in Table 287-4. The therapeutic agents used in treatment are discussed below, and an integrated approach to care is discussed subsequently. A comprehensive treatment approach involves avoiding and reducing asthma triggers and, if necessary, the adjunctive use of medications. Asthma medications are primarily divided into those that relax smooth muscle and produce a fairly rapid relief of acute symptoms and those that target inflammation or mediator production. The former medications are commonly referred to as reliever medications, and the latter are known as controller medications. REDUCING TRIGGERS Mitigation As shown in Tables 287-1 and 287-2, triggers and exposures can cause asthma and make it difficult to control. In the case of those with occupational exposures, removal from the offending environment may sometimes result in complete resolution of symptoms or significant improvement. Secondhand smoke exposure and frequent exposure to combustion products of cannabis are remediable environmental exposures as well. The removal of pets that are clearly associated with symptoms can reduce symptoms. Pest control at home and in the school in those with evidence of IgE-mediated sensitivity (skin test or IgE RAST) may also be beneficial. The effect of dust or mold control in reducing asthma symptoms has been more variable. There is moderate evidence that dust control (impermeable mattress and pillowcase covers) in those patients with symptoms and sensitization may be effective in reducing symptoms only when conducted as part of a comprehensive allergen mitigation strategy. Allergen Immunotherapy Allergen immunotherapy reduces IgEmediated reactions to the allergens administered. It clearly reduces the symptoms of allergic rhinitis and thus may be helpful in reducing this comorbidity. The evidence for its effectiveness in isolated asthma in those who are sensitized and have clinical symptoms is variable. Due to the risk of anaphylaxis, guidelines generally recommend immunotherapy only in patients whose asthma is under control and who have mild to moderate asthma. The evidence base for the effectiveness of sublingual allergen immunotherapy in the treatment of asthma is not substantial. Vaccination Respiratory infections are a major cause of asthma exacerbations. Patients with asthma are strongly advised to receive both types of currently available pneumococcal vaccines and yearly influenza vaccines. COVID-19 vaccination is advised, as well. MEDICATIONS Bronchodilators Bronchodilators relax airway smooth muscle. There are three major classes of bronchodilators, β2-agonists, anticholinergics, and theophylline. a2-Agonists Available in inhaled or oral form, these agents activate β2-receptors present on airway smooth muscle. Such receptors are also present on mast cells, but they contribute little to the efficacy of these agents in asthma. β2-receptors are G protein–coupled receptors that activate adenyl cyclase to produce cyclic AMP, which results in relaxation of smooth muscle. Use β2-Agonists are primarily used in inhaled forms to provide relief of bronchospasm or to reduce the degree of bronchospasm anticipated in response to exercise or other provocative stimuli. Regular use has been associated with tachyphylaxis of the bronchoprotective effect and possible increased airway reactivity. This may be more common in patients with a polymorphism at the 16th amino acid position of the β2-receptor. Frequent short-acting β-2 agonist use has been associated with increased asthma mortality resulting in decreased enthusiasm for use in isolation without inhaled corticosteroids. Short-Acting a2-Agonists Albuterol (also known as salbutamol) is the most commonly used agent. Bronchodilation begins within 3–5 min of inhalation, and effects generally last 4–6 h. It is most commonly administered by metered-dose inhaler. Solutions for nebulization are also used, especially for relief of bronchospasm in children. Oral forms are available but are not commonly used. TABLE 287-4 Goals of Asthma Therapy 1. Reduction in symptom frequency to ≤2 times/week 2. Reduction of nighttime awakenings to ≤2 times/month 3. Reduction of reliever use to ≤2 times a week (except before exercise) 4. No more than 1 exacerbation/year 5. Optimization of lung function 6. Maintenance of normal daily activities 7. Satisfaction with asthma care with minimal or no side effects of treatment Long-Acting a2-Agonists Salmeterol and formoterol are the two available LABAs. They have an ~12-h duration of action. Formoterol has a quick onset comparable to the short-acting β2-agonists. Salmeterol has a slower onset of action. These agents can be used for prophylaxis of exercise-induced bronchospasm. In contrast to their use in chronic obstructive pulmonary disease (COPD), these agents are not recommended for use as monotherapy in the treatment of asthma. Their use in asthma is generally restricted to use in combination with an ICS. Ultra-Long-Acting a2-Agonists These agents (indacaterol, olodaterol, and vilanterol) have a 24-h effect. They are only used in combination with ICSs in the treatment of asthma. Safety β2-Agonists are fairly specific for the β2-receptors, but in some patients and especially at higher doses, they can produce tremor, tachycardia, palpitations, and hypertension. They promote potassium reentry into cells, and at high doses, they can produce hypokalemia. Type B (nonhypoxic) lactic acidosis can also occur and is thought to be secondary to increased glycogenolysis and glycolysis and increased lipolysis, leading to a rise in fatty acid levels, which can inhibit conversion of pyruvate to acetyl-coenzyme A. Increased asthma mortality was associated with highpotency β2-agonists in Australia and New Zealand. Increased use of β2-agonists for relief of bronchospasm is a clear marker of poor asthma control and has been associated with increased mortality. Questions had been raised as to whether adding LABAs to ICS might be associated with severe adverse asthma outcomes, but several studies have not detected such outcomes in comparison to maintaining the ICS dose. Anticholinergics Cholinergic nerve–induced smooth-muscle constriction plays a role in asthmatic bronchospasm. Anticholinergic medications can produce smooth-muscle relaxation by antagonizing this mechanism of airway narrowing. Agents that have been developed for asthma have been pharmacologically designed to be less systemically absorbed so as to minimize their systemic anticholinergic effects. The long-acting agents in this class are known as long-acting muscarinic antagonists (LAMAs). Use The short-acting agents in this class can be used alone for acute bronchodilation. They appear to be somewhat less effective than β2-agonists and have a slower onset of action as well. Safety Dry mouth may occur. At higher doses and in the elderly, acute glaucoma and urinary retention have been reported. There was a numerical (but not significant) difference in mortality in African Americans treated with ICS/LAMA versus ICS/LABA for asthma. Theophylline Theophylline, an oral compound that increases cyclic AMP levels by inhibiting phosphodiesterase, is now rarely used for asthma due to its narrow therapeutic window, drug-drug interactions, and reduced bronchodilation as compared to other agents. Controller (Anti-Inflammatory/Antimediator) Therapies So-called “controller” therapies reduce asthma exacerbations and improve long-term control, decreasing the need for intermittent use of bronchodilator therapies. None of these therapies have yet been shown to prevent progression of airway remodeling or the more rapid decline in lung function that can occur in a subset of asthma patients. Corticosteroids Corticosteroids are particularly effective in reducing type 2 inflammation and airway hyperresponsiveness. Corticosteroids bind to a cytoplasmic glucocorticoid receptor to form a complex that translocates to the nucleus. The complex binds to positive and negative response elements that result in inhibition of T-cell activation; eosinophil function, migration, and proliferation; and proinflammatory cytokine elaboration and activation of nuclear factor-κB. It also attaches to other transcription factors, resulting in deactivation of other proinflammatory pathways. Use Corticosteroids reduce airway hyperresponsiveness, improve airway function, prevent asthma exacerbations, and improve asthma symptoms. Corticosteroid use by inhalation (ICSs) minimizes systemic toxicity and represents a cornerstone of asthma treatment. ICS and ICS/LABA ICSs are the cornerstone of asthma therapy. They take advantage of the pleiotropic effects of corticosteroids to produce salutary impact at levels of systemic effect considerably lower than oral corticosteroids. Their use is associated with decreased asthma mortality. They are generally used regularly twice a day as first-line therapy for all forms of persistent asthma. Doses are increased, and they are combined with LABAs to control asthma of increasing severity. European guidelines now recommend their intermittent use even in intermittent asthma. Combining them with LABAs permits effective control at lower ICS dose. Longer-acting preparations permitting once-a-day use are available. Their effects can be noticeable in several days, but continued improvement may occur over months of therapy, with the majority of improvement evident within the first month of regular use. Adherence to regular therapy is generally poor, with as few as 25% of total annual prescriptions being refilled. Very high doses are sometimes used to reduce oral corticosteroid requirements. Not all patients respond to ICS. Increasing evidence suggests that the most responsive patients are those with significant type 2–mediated asthma. Oral Corticosteroids Chronic oral corticosteroids (OCSs) at the lowest doses possible (due to side effects) are used in patients who cannot achieve acceptable asthma control without them. Alternate- day dosing may be preferred, and pneumocystis pneumonia prophylaxis should be administered for those maintained on a daily prednisone dose of ≥20 mg. OCSs are also used to treat asthma exacerbations, frequently at a dose of 40–60 mg/d of prednisone or equivalent for 1–2 weeks. Since they are well absorbed, they may also be used for managing hospitalized patients. Intravenous Corticosteroids Intravenous preparations are frequently used in hospitalized patients. Patients are rapidly transitioned to OCS once their condition has stabilized. Intramuscular Corticosteroids In high-risk, poorly adherent patients, intramuscular triamcinolone acetonide has been used to achieve asthma control and reduce exacerbations. Safety Chronic administration of systemic corticosteroids is associated with a plethora of side effects including diabetes, osteoporosis, cataracts and glaucoma, bruising, weight gain, truncal obesity, hypertension, ulcers, depression, and accelerated cardiac risk, among others. Appropriate monitoring and infectious (pneumocystis pneumonia prophylaxis for those treated chronically with ≥20 mg prednisone/d) and bone health prophylaxis are necessary. Intermittent “bursts” of systemic corticosteroids to treat asthma exacerbations are associated with reduced side effects, but observational studies have suggested that the cumulative dose over time is associated with deleterious side effects. ICSs have dramatically reduced side effects as compared to OCSs. At higher doses, bruising occurs and osteoporosis can accelerate. There is a small increase in glaucoma and cataracts. Local effects include thrush, which can be reduced by use of a spacer and gargling. Hoarseness may be the result of a direct myopathic effect on the vocal cords. Rare patients exhibit side effects even at moderate doses of ICS. Children may experience growth suppression. Leukotriene Modifiers Agents that inhibit production of leukotrienes (zileuton, an inhibitor of 5-lipoxygenase) or the action of leukotrienes at the CysLT1 receptor (montelukast and zafirlukast) are moderately effective in asthma. They can improve airway function and reduce exacerbations but not to the same degree as bronchodilators or ICS, respectively. They are also effective in reducing symptoms of allergic rhinitis and, thus, can be used in patients with concomitant allergic rhinitis. Montelukast, in particular, is frequently used in children with mild asthma due to concerns of ICS-related growth suppression. Montelukast use may decrease due to safety warnings regarding depression with this compound. Leukotriene modifiers are effective in preventing exercise-induced bronchoconstriction without the tachyphylactic effects that occur with regular use of LABAs. Leukotriene modifiers are particularly effective in aspirin-exacerbated respiratory disease, which is characterized by significant leukotriene overproduction. They have also shown modest effect as add-on therapy in patients poorly controlled on high-dose ICS/LABA. CysLT1 Antagonists Montelukast and zafirlukast are administered orally once or twice daily, respectively. The onset of effect is rapid (hours), with the majority of chronic effectiveness seen within 1 month. 5-Lipoxygenase Inhibition Zileuton in its extended form is administered orally twice a day. Safety Montelukast is well tolerated, but an association with suicidal ideation has now resulted in a warning label from the U.S. Food and Drug Administration. Zileuton increases liver function tests (transaminases) in 3% of patients. Intermittent monitoring is suggested. It inhibits CYP1A2, and appropriate dose adjustments of concomitant medications may be necessary. Cromolyn Sodium Cromolyn sodium is an inhaled agent believed to stabilize mast cells. It is only available by nebulization and must be administered two to four times a day. It is mildly to modestly effective and appears to be helpful for exercise-induced bronchospasm. It is used primarily in pediatrics in those concerned about ICS side effects. Anti-IgE Omalizumab, a monoclonal antibody to the Fc portion of the IgE molecule, prevents the binding of IgE to mast cells and basophils. Reduction in free IgE that can bind to effector cells blocks antigen-related signaling, which is responsible for production or release of many of the mediators and cytokines critical to asthma pathobiology. In addition, through feedback mechanisms, reduction in IgE production occurs as well. Anti-IgE has been shown to increase interferon production in rhinovirus infections, decrease viralinduced asthma exacerbations, and reduce duration and peak viral shedding. This effect is believed to be due to IgE’s ability to reduce interferon γ production in response to viral infections. Use In asthma, anti-IgE has been tested in patients with a circulating IgE ≥30 IU/mL and a positive skin test or RAST to a perennial allergen. It is generally used in patients not responsive to moderate- to high-dose ICS/LABA. It reduces exacerbations by 25–50% and can reduce asthma symptoms but has minimal effect on lung function. Anti-IgE is dosed based on body weight and circulating IgE and is administered subcutaneously every 2–4 weeks depending on the calculated dose. In the United States, the maximum dose is 300 mg every 2 weeks, which generally restricts the drug to those with a body weight ≤150 kg. Most effects are generally seen in 3–6 months. Retrospective studies have suggested that patients with an exhaled nitric oxide approximately ≥20 ppb or circulating eosinophils ≥260/μL have the greatest response as ascertained by reduction in exacerbations. FeNO is slightly reduced by treatment, but circulating IgE, as measured by available clinical tests, is not affected since these tests measure total circulating IgE, not free IgE. Safety The incidence of side effects is low. Anaphylaxis has been reported in 0.2% of patients receiving the drug. IL-5–Active Drugs Mepolizumab and reslizumab are monoclonal antibodies that bind to IL-5, and benralizumab binds to the IL-5 receptor. They rapidly (within a day) reduce circulating eosinophils. Use In patients symptomatic on moderate- to high-dose ICS/ LABA, generally with two or more exacerbations that require OCS per year and with an eosinophil count of ≥300/μL, IL-5–active drugs reduce exacerbations by about half or more. FEV1 and symptoms improve moderately as well. In patients who are not on chronic OCSs, these drugs are less effective in those with eosinophil counts <300/μL. They are also effective in reducing the need for chronic OCSs regardless of circulating eosinophil count (presumably due to the fact that many of those patients have type 2 inflammation but their circulating eosinophils have been suppressed by the systemic OCS). FeNO and IgE are relatively unaffected by these drugs. Most clinical effects are usually seen within 3–6 months. Safety These drugs are associated with minimal side effects. Mepolizumab and benralizumab are approved for home administration. Anti–IL-4/13 The IL-4 and IL-13 receptors are heterodimers that share a common subunit, IL-4 receptor α. Dupilumab binds to this subunit and, thus, blocks signaling through both receptors. Use In addition to effectiveness in the phenotype of patients who respond to anti–IL-5 therapies, poorly controlled patients on moderate- to high-dose ICS/LABA with an FeNO of 20–25 ppb also appear to respond to dupilumab even if their peripheral eosinophils are not elevated. Dupilumab reduces exacerbations by ≥50%, decreases symptoms, and may produce more of an effect on FEV1 than anti–IL-5 drugs. It gradually reduces FeNO and IgE levels. Paradoxically, circulating eosinophil counts may initially temporarily increase. Most effects are seen by 3–6 months of therapy. Safety Side effects are minimal but cases of serious systemic eosinophilia associated with the reduction of oral corticosteroids have been noted. This drug is also approved for home administration and is also approved for atopic dermatitis. Bronchial Thermoplasty, Alternative Therapies, and Therapies Under Development • Bronchial Thermoplasty This procedure involves radiofrequency ablation of the airway smooth muscle in the major airways administered through a series of three bronchoscopies for patients with severe asthma. There is some evidence that it may reduce exacerbations in very select patients. The procedure may be accompanied by significant morbidity, and most guidelines do not recommend it other than in the context of clinical trials or registries. Alternative Therapies Alternative therapies such as acupuncture and yoga have not been shown to improve asthma in controlled trials. Studies with placebo have demonstrated that there may be a significant response to placebo. Therapies in Development Trials are underway targeting pathways and receptors shown in Fig. 287-3. Those in more advanced stages of development include therapies targeting TSLP, IL-33, and CRTH2. Studies targeting IL-17 and TNF-α have not shown efficacy, but it is unclear if they were appropriately targeted. Whether these interventions might prove useful for particular endotypes of asthma is unclear. Proof-of-concept studies targeting mast cells via inhibition of tyrosine kinase have suggested efficacy in severe asthma. APPROACH TO THE PATIENT Asthma U.S. (National Asthma Education and Prevention Program [NAEPP]) and World Health Organization (Global Initiative for Asthma [GINA]) guidelines advise a symptomatic approach to asthma treatment assuming that appropriate measures have been taken to address asthma triggers, exposures, and comorbidities enumerated in Tables 287-2 and 287-3. Additionally, adherence and inhaler techniques need to be addressed. Poor adherence or poor inhaler technique has been identified as the cause of poor asthma control in up to 50% of patients referred for poorly controlled asthma. The stepwise approach to intensifying and reducing asthma therapy is outlined in Table 287-5. It involves “stepping” therapy up or down based on assessment of whether asthma is controlled by the criteria listed in Table 287-4. Assuming comorbidities have been addressed, adherence has been evaluated, education regarding avoiding triggers has been performed, and inhaler technique is verified, the cornerstone of preferred therapy is the intensification of ICS therapy in conjunction with the use of a LABA to achieve greater control at lower ICS doses. A major change in the stepwise approach, advocated for more than two decades, has occurred. Evidence has accumulated that as-needed ICS can be used instead of regular ICS in milder asthma and that the trigger for such use could be patient perception of the need to use a reliever inhaler. Since formoterol is a LABA with a rapid onset, combination ICS/formoterol has been used as a single agent in multiple studies: as needed without background therapy in milder asthma, and as needed in addition to twice daily ICS/formoterol in more severe asthma. Since asthma mortality can occur even in mild asthma (albeit at lower rates than more severe asthma), GINA, as part of a comprehensive strategy of asthma management, recommends ICS/formoterol be used as the reliever in all steps of asthma severity, including intermittent asthma (Step 1). NAEPP guidelines utilizing evidence-based studies recommend that ICS/ formoterol be used as the reliever medication in patients requiring step 3 and 4 therapy (see Table 287-5) and that as-needed concomitant ICS and short-acting β-agonist (SABA) can be used as a therapy in step 2. For the sake of simplicity, an adapted GINA approach is outlined in Table 287-5 with footnotes identifying the major differences from the NAEPP. Leukotriene receptor antagonists (LTRAs) are alternative medications in step 2, which may be used in those concerned about the minimal ICS side effects. However, recent warnings about suicidal ideation associated with montelukast may make this approach less appealing. Leukotriene modifiers and long-acting anticholinergics are possible add-on (adjunctive) therapies in those requiring step 4 and/or 5 therapies. Biologics are incredibly effective in their specific endotypes (type 2 with exacerbations and specific biomarkers, as previously described), but their high cost currently relegates them to step 5 therapy or beyond. TREATMENT Asthma Attacks Asthma deteriorations of mild to moderate severity can be initially treated with a β2-agonist administered up to every 1 h. Increasing the dose of ICSs by four- to fivefold may be helpful as well. If patients fail to achieve adequate control and continue to require β2-agonists hourly for several hours, they should be referred for urgent care. In the urgent care setting, PEFR or FEV1 should be assessed, and patients are usually treated with nebulized β2-agonists up to every 20 min. Those with PEFR >60% of predicted will frequently respond to β2-agonists alone. If they fail to respond in 1–2 h, intravenous corticosteroids should be administered. Supplemental oxygen is usually administered to correct hypoxemia. An LTRA and magnesium are sometimes given as well. Nebulized anticholinergics can be administered to produce additional bronchodilation. Failure to achieve PEFR >60% or persistent severe tachypnea over 4–6 h should prompt consideration of admission to the hospital. In-hospital treatment may include continuous bronchodilator nebulization. Noninvasive positive-pressure ventilation to assist with respiratory exhaustion is sometimes used to prevent a need for intubation, and helium-oxygen mixtures may be used to decrease the work of breathing. Antibiotics should be administered only if there are signs of infection. Mechanical ventilation may be difficult in patients with status asthmaticus due to high positive pressures in the setting of high resistance to airflow due to airway obstruction. Most patients with asthma attacks present with hypocapnia due to a high respiratory rate. Normal or near-normal Pco2 in a patient with asthma in respiratory distress should raise concerns of impending respiratory failure and need for mechanical ventilation. Mechanical ventilation should aim for low respiratory rates and/or ventilation volumes to decrease peak airway pressures. This can frequently be achieved by “permissive hypercapnia”—allowing the Pco2 to rise and, if necessary, temporarily correcting critical acidosis with administration of fluids to increase the pH. Neuromuscular paralysis may sometimes be beneficial. Bronchoscopy to clear mucus plugs has been described but may be dangerous in the setting of difficulties with mechanical ventilation. SPECIAL CONSIDERATIONS ■■HIGH-RISK ASTHMA PATIENTS Three to four thousand people die from asthma in the United States each year. Table 287-6 lists characteristics of patients at high risk for asthma death. These characteristics should be considered in evaluating and treating patients who present with asthma. ■■EXERCISE-INDUCED SYMPTOMS In many cases, the degree of exercise intolerance may reflect poor asthma control. Treatment involves step therapy of asthma as outlined in Table 287-5. In other cases, however, asthma may be well controlled in all other respects, but patients may report that they cannot undertake the level of exercise they desire. Some increase in exercise capacity can be achieved by starting at lower levels of exercise (warming up) and by using a mask in colder weather to condition the air. Pretreatment with an SABA can increase the threshold of ventilation required to induce bronchoconstriction. LABAs may extend the period of protection, but their use alone in asthma is to be discouraged. For occasional exercise, ICS/LABA can be used, but regular use may expose the patient to unnecessary doses of ICS. If regular exercise is undertaken, then LTRAs may provide protection and can be used regularly. A SABA (or ICS/formoterol) should always be available for quick relief. Exercise-induced airway narrowing in elite athletes may be related to direct epithelial injury. In addition to the above, conditioning of incoming air may be of major assistance. Ipratropium has been reported to be of utility as well. TABLE 287-6 Patients at Greater Risk for Asthma Mortality 1. History of intensive care unit admission for asthma 2. History of intubation for asthma 3. Illicit drug use 4. Depression 5. New diagnosis 6. ≥2 emergency unit visits in past 6 months 7. Severe psychosocial problems 8. Lower socioeconomic status 9. On daily prednisone prior to admission PREGNANCY Asthma may improve, deteriorate, or remain unchanged during pregnancy. Poor asthma control, especially exacerbations, is associated with poor fetal outcomes. The general principles of asthma management and its goals are unchanged. Avoidance of triggers, especially smoking environments, is critical in view of the risk of loss of control and, in the case of smoking, its clear effects on risk of development of asthma in the child. There is extensive experience suggesting the safety of inhaled albuterol, beclomethasone, budesonide, and fluticasone, with reassuring information on formoterol and salmeterol in pregnancy. Animal studies have not suggested toxicity for montelukast, zafirlukast, omalizumab, and ipratropium. Antibodies cross the placenta, and there are few human data on the safety of IL-5–active drugs or anti–IL-4Rα. Chronic use of OCS has been associated with neonatal adrenal insufficiency, preeclampsia, low birth weight, and a slight increase in the frequency of cleft palate. However, it is clear that poorly controlled asthma during pregnancy carries greater risk to the fetus and mother than these effects. There should be no hesitancy in administering routine pharmacotherapy for acute exacerbations. Initiation of allergen immunotherapy or omalizumab during pregnancy is not recommended. In cases where prostaglandins are needed to manage pregnancy, PGF2-α should be avoided since it is associated with bronchoconstriction. ■■ASPIRIN-EXACERBATED RESPIRATORY DISEASE A subset of patients (5–10%) present in adulthood with difficult-tocontrol asthma and type 2 inflammation with eosinophilia, sinusitis, nasal polyposis, and severe asthma exacerbations that are precipitated by ingesting inhibitors of cyclooxygenase, with aspirin being the most prominent of such inhibitors. Such patients, classified as having aspirin-exacerbated respiratory disease, overproduce leukotrienes in response to inhibition of cyclooxygenase-1, probably secondary to inhibition of PGE2. These patients should avoid inhibitors of cyclooxygenase-1, (aspirin and NSAIDs) but can generally tolerate inhibitors of cyclooxygenase-2 and acetaminophen. They should be treated with leukotriene modifiers. Aspirin desensitization can be undertaken to decrease upper respiratory symptoms and to allow chronic administration of aspirin or NSAIDs for those that require it. Dupilumab and the IL-5–active biologics appear to be particularly helpful and appear to be superseding aspirin desensitization in management except when chronic administration of aspirin or NSAIDs is required for another therapeutic indication. ■■SEVERE ASTHMA Severe and difficult-to-treat asthma, which composes ~5–10% of asthma, is defined as asthma that, having undergone appropriate evaluation for comorbidities and mimics, education, and trigger mitigation, remains uncontrolled on step 5 therapy or requires step 5 therapy for its control. Severe asthma can account for almost 50% of the cost of asthma care in the United States. A significant proportion of these patients have trouble with adherence and/or inhaler technique, and these factors need to be investigated vigorously. Almost half of these patients have evidence of persistent eosinophilic inflammation as evidenced by peripheral blood eosinophils and/or induced sputum. Those with recurrent exacerbations have a substantially increased likelihood of responding to the type 2 targeted biologics. Treatment for those with mixed inflammation, isolated neutrophilic inflammation, or pauci-granulocytic inflammation remains to be determined. Some data suggest that many of these patients may have aberrations in the pathways responsible for resolution of inflammation. A rare patient may have biochemical abnormalities that interfere with steroid response pathways. Macrolides are of use in a subset. Studies targeting mast cells, IL-6, IL-33, and other pathways illustrated in Fig. 287-3 are underway. Therapies aimed at improving pro-resolving pathways may also be promising. ■■ELDERLY PATIENTS WITH ASTHMA Asthma may present at or persist into older age. The mortality of asthma in those >65 years old is five times greater than that of younger cohorts even when adjusting for comorbidities. Many of these patients had asthma as children, some with quiescent periods as they entered adulthood. Of those with new-onset asthma, almost half were smokers or are currently smoking. One-quarter of adult-onset asthma is believed to be due to occupational exposure. Patients presenting with eosinophilic inflammation appear to have more severe asthma. Besides investigations of comorbidities, these patients may require adjustment to step therapy based on intolerance of β2-agonist therapy due to arrhythmia or tremulousness. The coexistence of COPD needs to be carefully considered (see below). ■■ASTHMA-COPD OVERLAP Most clinicians agree that asthma-COPD overlap is not a syndrome, but rather recognize that it may be useful to identify patients who present with symptoms related to airway dysfunction that may be due to simultaneous coexistence of both asthma and COPD. From an asthma perspective, recognition that COPD and smoking can alter the response to asthma therapies may be important. Smoking can blunt the response to ICS. Further, it has been difficult to demonstrate the effectiveness of biologic agents targeted at type 2 inflammation in patients with COPD despite the presence of ≥300 circulating eosinophils/μL. Additionally, in patients with both diseases, earlier initiation of anticholinergics may be considered.