Asthma Treatment PDF

ADJUNCTIVE ASSESSMENT TOOLS  ADJUNCTIVE ASSESSMENT EOSINOPHIL COUNTS TOOLS IGE, SKIN TESTS, AND RADIOALLERGOSORBENT TESTS EXHALED NITRIC OXIDE A large...

ADJUNCTIVE ASSESSMENT TOOLS  ADJUNCTIVE ASSESSMENT EOSINOPHIL COUNTS TOOLS IGE, SKIN TESTS, AND RADIOALLERGOSORBENT TESTS EXHALED NITRIC OXIDE A large proportion of asthma Total serum IgE levels are useful Fraction of exhaled nitric oxide patients not treated with oral in considering whether patients (FeNO) in exhaled breath is an or high-dose ICSs will have with severe asthma would be approximate indicator of eosinophil counts ≥300 eligible for anti-IgE therapy. eosinophilic inflam- mation in cells/μL. Eosinophil counts Levels >1000 IU/mL should the airways. It is easily prompt consideration of ABPA. suppressed by ICSs and, thus, correlate with severity of Skin tests, or their in vitro can be used to assess disease in population studies. counterparts that detect IgE adherence in patients in whom Their presence in patients directed at specific antigens it was initially elevated. with severe asthma indicates (radioal- lergosorbent test a likelihood that the patient Elevated levels (>35–40 ppb) [RAST]), can be useful in would respond to medications in untreated patients are confirming atopy and indicative of eosinophilic targeted at type 2 suggesting allergic rhinitis, inflammation. Levels >20–25 inflammation. Extremely which can complicate asthma ppb in patients with severe elevated levels should prompt manage- ment. Allergy asthma on moderate- to high- consideration of eosinophilic investigations may be useful, dose ICS indicate either poor granulomatosis with when correlated with a history of reactions, in identifying adherenceor persistent type 2 polyangiitis or primary inflammation despite therapy. environmental exposures that  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 antit- rypsin level. Additionally, the following evaluations may be of utility in poorly responsive asthma.  Chest Sputum ADDITIONAL Radiography Chest CT can be useful Induced sputum may be used in more specialized to assess for the pres- EVALUATION ence of bronchiectasis centers to help characterize type 2 and and other structural IN abnormalities that non–type 2 inflammation by detection of could produce airway SEVERE/POO obstruction. New eosinophils and neutrophils, respectively. image analysis tools RLY are being used in the In severe asthma, there is some evidence that some research setting to RESPONSIVE assess airway patients may have localized persistent eosin- ASTHMA properties such as airway wall thickness, ophilic airway inflammation despite lack airway diameter, and of peripheral eosinophils evidence of air on blood analysis. trapping. 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 exacerba- tions) 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 produc- tion. The former medications are commonly referred to as reliever medications, and the latter are known as controller medications. REDUCING TRIGGERS  REDUCING TRIGGERS MITIGATION ALLERGEN IMMUNOTHERAPY VACCINATION Mitigation As shown in Tables 287-1 and 287- 2, triggers and exposures can cause asthma Allergen Immunotherapy Allergen Vaccination and make it difficult to control. In immunotherapy reduces IgE- mediated Respiratory infections the case of those with occupational exposures, reactions to the allergens are a major cause of removal from the offending environment may administered. It clearly reduces the asthma exacerbations. sometimes result in complete resolu- tion of symptoms of allergic rhinitis and thus Patients with asthma are symptoms or significant improvement. may be helpful in reduc- ing this strongly advised to Secondhand smoke exposure and frequent comorbidity. The evidence for its receive both types of exposure to combustion products of cann- abis are remediable environmental exposures as effectiveness in isolated asthma in currently available well. The removal of pets that are clearly those who are sensitized and have pneumococcal vaccines associated with symptoms can reduce symp- clinical symptoms is variable. Due to and yearly influenza toms. Pest control at home and in the school in the risk of anaphylaxis, guidelines vaccines. COVID-19 those with evidence of IgE-mediated sensitivity generally rec- ommend vaccination is advised, (skin test or IgE RAST) may also be beneficial. immunotherapy only in patients whose as well. The effect of dust or mold control in reducing asthma is under control and who have asthma symptoms has been more variable. There is moderate evidence that dust control mild to moderate asthma. The (impermeable mattress and pillowcase covers) evidence base for the effectiveness of in those patients with symptoms and sublingual allergen immunotherapy in sensitization may be effective in reduc- ing the treatment of asthma is not symptoms only when conducted as part of a substantial. comprehensive allergen mitigation strategy. MEDICATION S BRONCHODILA B2- USE TORS Bronchodilators relax airway smooth muscle. There are AGONIST Available in inhaled or Use β2-Agonists are primarily used oral form, these agents in inhaled forms to provide relief of three major classes of acti- vate β2-receptors bronchospasm or to reduce the bronchodilators, β2-agonists, present on airway degree of bronchospasm anticipated anticholinergics, and in response to exercise or other smooth muscle. Such theophylline. provocative stimuli. Regular use has receptors are also present on mast cells, been associated with tachyphylaxis but they contribute of the bron- choprotective effect and possible increase7d airway little to the effi- cacy of reactivity. This may be more these agents in common in patients with a asthma. β2-receptors polymorphism at the 16th amino are G protein–coupled acid position of the β2-receptor. receptors that activate Frequent short-acting β-2 agonist adenyl cyclase to use has been associated with produce cyclic AMP, increased asthma mortality resulting which results in in decreased enthusiasm for use in relaxation of smooth isolation without inhaled SHORT-ACTING B2- AGONISTS Albuterol (also known as salbuta- mol) 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.  Salmeterol and formoterol are the two LONG- available LABAs. They have an ~12-h duration of action. Formo- terol has a quick ACTING B2- onset comparable to the short-acting β2- agonists. Salmeterol has a slower onset of AGONISTS 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 treat- ment of asthma. Their use in asthma is generally restricted to use in combination with an ICS. ULTRA- These agents (indacaterol, LONG- olo- daterol, and ACTING B - vilanterol) have a 24-h AGONISTS effect. They are only used in 2 combination with ICSs in the treatment of asthma. Safety Anticholinergics Use β2-Agonists are fairly specific for the β2- Cholinergic nerve–ind The short-acting receptors, but in some patients and especially uced smooth-muscle agents in this at higher doses, they can pro- duce tremor, constriction plays a role in class can be tachycardia, palpitations, and hypertension. asthmatic bronchospasm. They promote potassium reentry into cells, and used alone for Anticholiner- gic at high doses, they can produce hypokalemia. acute medications can produce Type B (nonhypoxic) lactic acidosis can also smooth-muscle relaxation bronchodilation. occur and is thought to be secondary to by antago- nizing this They appear to increased glycoge- nolysis and glycolysis and mechanism of airway be somewhat increased lipolysis, leading to a rise in fatty acid narrowing. Agents that less effective levels, which can inhibit conversion of pyruvate have been developed for than β2-agonists to acetyl-coenzyme A. asthma have been and have a Increased asthma mortality was associated with pharmacologically slower onset of high- potency β2-agonists in Australia and New designed to be less action as well. Zealand. Increased use of β2-agonists for relief systemically absorbed so of bronchospasm is a clear marker of poor as to minimize their asthma control and has been associated with increased mortality. Questions had been raised systemic anticho- linergic as to whether adding LABAs to ICS might be effects. The long-acting associated with severe adverse asthma agents in this class are outcomes, but several studies have not known as long-acting Safety Theophylline Dry mouth may occur. At an oral compound that higher doses and in the increases cyclic AMP levels by elderly, acute glaucoma inhibiting phosphodiesterase, and urinary retention have is now rarely used for asthma been reported. There was a due to its narrow therapeutic numerical (but not window, drug-drug significant) difference in interactions, and reduced mortality in African bronchodilation as compared Americans treated with to other ICS/LAMA versus ICS/LABA agents. for asthma. 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 Use Corticosteroids are particularly Corticosteroids reduce airway effective in reducing type 2 hyperresponsiveness, improve inflammation and airway airway function, prevent asthma hyperresponsiveness. exacerbations, and improve Corticosteroids bind to a asthma symptoms. Corticosteroid cytoplasmic glucocorticoid use by inhalation (ICSs) receptor to form a complex that minimizes sys- temic toxicity and translocates to the nucleus. The represents a cornerstone of complex binds to positive and asthma treatment. negative response elements that result in inhibition of T-cell activation; eosinophil function, migration, and prolifera- tion; and proinflammatory cytokine ICS and ICS/LABA Oral Corticosteroids ICSs are the cornerstone of asthma therapy. They take Chronic oral corticosteroids advantage of the pleiotropic effects of corticosteroids to (OCSs) at the lowest doses produce salutary impact at levels of systemic effect possible (due to side effects) are consider- ably lower than oral corticosteroids. Their use is used in patients who cannot associated with decreased asthma mortality. They are achieve acceptable asthma generally used regularly twice a day as first-line therapy for control without them. Alter- nate- all forms of persistent asthma. Doses are increased, and they are combined with LABAs to control asthma of day dosing may be preferred, and increasing severity. European guidelines now recommend pneumocystis pneumonia their intermittent use even in intermittent asthma. prophylaxis should be Combining them with LABAs permits effective control at administered for those lower ICS dose. Longer-acting preparations permitting maintained on a daily prednisone once-a-day use are available. Their effects can be dose of ≥20 mg. OCSs are also noticeable in several days, but continued improvement used to treat asthma may occur over months of therapy, with the majority of exacerbations, frequently at a improvement evident within the first month of regular use. dose of 40–60 mg/d of Adherence to reg- ular therapy is generally poor, with as prednisone or equivalent for 1–2 few as 25% of total annual prescriptions being refilled. Very weeks. Since they are well high doses are sometimes used to reduce oral absorbed, they may also be used corticosteroid requirements. Not all patients respond to ICS. Intravenous Corticosteroids Intramuscular Corticosteroids Intravenous preparations are In high-risk, poorly adherent fre- quently used in hospitalized patients, intramuscular patients. Patients are rapidly triamcinolone acetonide has transi- tioned to OCS once their been used to achieve asthma condition has stabilized. control and reduce exacerbations. Safety Leukotriene Modifiers Chronic administration of systemic corticosteroids is Agents that inhibit production of leu- kotrienes associated with a plethora of side effects including (zileuton, an inhibitor of 5-lipoxygenase) or the diabetes, oste- oporosis, cataracts and glaucoma, action of leukotrienes at the CysLT1 receptor bruising, weight gain, truncal obesity, hypertension, (montelukast and zafirlukast) are moderately ulcers, depression, and accelerated cardiac risk, effective in asthma. among others. Appropriate monitoring and infectious They can improve airway function and reduce (pneu- mocystis pneumonia prophylaxis for those exacerbations but not to the same degree as treated chronically with ≥20 mg prednisone/d) and bronchodilators or ICS, respectively. They are also bone health prophylaxis are necessary. Intermittent effective in reducing symptoms of allergic rhinitis “bursts” of systemic corticosteroids to treat asthma and, thus, can be used in patients with concomitant exacerbations are associated with reduced side effects, allergic rhinitis. Montelu- kast, in particular, is but observa- tional studies have suggested that the frequently used in children with mild asthma due to cumulative dose over time is associated with concerns of ICS-related growth suppression. deleterious side effects. Montelukast use may decrease due to safety ICSs have dramatically reduced side effects as warnings regarding depression with this compound. compared to OCSs. At higher doses, bruising Leukotriene modifiers are effective in preventing occurs and osteoporosis can accel- erate. There exercise-induced bronchoconstriction without the is a small increase in glaucoma and cataracts. tachyphylactic effects that occur with regular use of Local effects include thrush, which can be LABAs. Leukotriene modifiers are particularly reduced by use of a spacer and gargling. effective in aspirin-exacerbated respiratory disease, Hoarseness may be the result of a direct which is characterized by significant leukotriene myopathic effect on the vocal cords. Rare overproduction. They have also shown modest patients exhibit side effects even at mod- erate 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 Cromolyn Anti-IgE Sodium Omalizumab, a monoclonal Montelukast is well Cromolyn sodium is an antibody to the Fc portion of tolerated, but an inhaled agent believed the IgE molecule, prevents the binding of IgE to mast cells and association with suicidal to stabilize mast cells. basophils. Reduction in free IgE ideation has now It is only available by that can bind to effector cells resulted in a warning nebulization and must blocks antigen-related signaling, which is responsible label from the U.S. Food be administered two for production or release of and Drug many of the mediators and to four times a day. It cytokines critical to asthma Administration. Zileuton is mildly to modestly pathobiology. In addition, increases liver function through feedback mechanisms, effective and appears reduction in IgE production tests (transaminases) in to be helpful for occurs as well. Anti-IgE has 3% of patients. been shown to increase exercise-induced Intermittent monitoring interferon production in is suggested. It inhibits bronchospasm. It is rhinovirus infections, decrease viral- induced asthma CYP1A2, and used primarily in exacerbations, and reduce appropriate dose pediatrics in those duration and peak viral concerned about ICS shedding. This effect is adjustments of believed to be due to IgE’s  Safety IL-5–Active Use Drugs In patients symptomatic on moderate- to The incidence Mepolizumab and high-dose ICS/ LABA, generally with two or of side effects reslizumab are more exacerbations that require OCS per is low. year and with an eosinophil count of monoclo- nal Anaphylaxis ≥300/μL, IL-5–active drugs reduce antibodies that bind has been exacerbations by about half or more. FEV1 reported in to IL-5, and and symptoms 0.2% of benralizumab binds improve moderately as well. In patients who are not on chronic OCSs, these drugs are less patients to the IL-5 receptor. effective in those with eosinophil counts receiving the They rapidly (within 60% of predicted will fre- quently 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 anticholin- ergics 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 neb- ulization. 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 neces- sary, temporarily correcting critical acidosis with administration of fluids to increase the pH. Neuromuscular paralysis may some- times be beneficial. Bronchoscopy to clear mucus plugs  HIGH-RISK ASTHMA PATIENTS SPECIAL CONSIDERATI ONS  EXERCISE-INDUCED SYMPTOMS In many cases, the degree of exercise intolerance may reflect poor asthma control. Treatment involves step therapy of asthma SPECIAL as outlined in Table 287-5. In other cases, however, asthma may be well controlled in all other respects, but patients may report CONSIDERATI that they cannot under- take the level of exercise they desire. Some increase in exercise capacity can be achieved by starting ONS 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 protec- tion, 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.  PREGNANCY Asthma may improve, deteriorate, or remain unchanged during preg- nancy. Poor asthma control, especially exacerbations, is associated SPECIAL with poor fetal outcomes. The general principles of asthma management and its goals are unchanged. Avoidance of triggers, CONSIDERATI 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 ONS 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 insuffi- ciency, preeclampsia, low birth weight, and a slight increase in the fre- quency 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 immu- notherapy 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  ASPIRIN-EXACERBATED RESPIRATORY DISEASE A subset of patients (5–10%) present in adulthood with difficult-to- control asthma and type 2 inflammation with SPECIAL eosinophilia, sinusitis, nasal polyposis, and severe asthma exacerbations that are precipitated by ingesting inhibitors of CONSIDERATI cyclooxygenase, with aspirin being the most prominent of such ONS inhibitors. Such patients, classified as hav- ing 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 man- agement 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 SPECIAL evaluation for comorbidities and mimics, education, and trigger mitigation, remains uncontrolled on step 5 therapy or requires step 5 CONSIDERATI therapy for its control. ONS 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 inflamma- tion, 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. SPECIAL mortality of asthma in >65 years old is 5x CONSIDERATI greater than that of younger coheven when ONS adjusting for comorbidities. 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. 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  ASTHMA-COPD OVERLAP SPECIAL Most clinicians agree that asthma-COPD overlap is not a syndrome, but rather recognize that it may CONSIDERATI be useful to identify patients who present with ONS 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 effec tiveness 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 anti- cholinergics may be considered.