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Pulmonary Disorders and Adult Immunizations Table 6. Pharmacologic Agents Used for Asthma and COPD (Cont’d) Generic Brand Dose Adverse Effects Tezspire 210 mg SC every 4 wk Pharyngitis Arthralgia Back pain Comments TSLP blocker Tezepelumab FDA approval in 2021 Add-on maintenance treatment...

Pulmonary Disorders and Adult Immunizations Table 6. Pharmacologic Agents Used for Asthma and COPD (Cont’d) Generic Brand Dose Adverse Effects Tezspire 210 mg SC every 4 wk Pharyngitis Arthralgia Back pain Comments TSLP blocker Tezepelumab FDA approval in 2021 Add-on maintenance treatment of patients with severe asthma age 12 years and older Improved response is strongly correlated with higher blood eosinophil counts and FeNO levels BID = twice daily; COPD = chronic obstructive pulmonary disease; CV = cardiovascular; DPI = dry powder inhaler; DVT = deep venous thrombosis; ER = extended release; FDA = U.S. Food and Drug Administration; FeNO = fractional exhaled nitric oxide; GI = gastrointestinal; GINA = Global Initiative for Asthma; HA = headache; HFA = hydrofluoroalkane; HTN = hypertension; ICS = inhaled corticosteroid; IgE = immunoglobulin E; IV = intravenous(ly); LAMA = long-acting anticholinergic/muscarinic antagonist; LFT = liver function test; MDI = metered dose inhaler; MI = myocardial infarction; N/V = nausea and vomiting; PE = pulmonary embolism; PRN = as needed; QID = four times daily; SABA = short-acting β2-agonist. SAMA = short-acting anticholinergic/muscarinic antagonist; SC = subcutaneously; TIA = transient ischemic attack; TID = three times daily; TSLP = thymic stromal lymphopoietin; URTI = upper respiratory tract infection. Table 7. Inhaled Corticosteroid Daily Dosing in Children and Adults Inhaled Corticosteroids: Available Products and Strengths (mcg unless noted) Age group (yr) Beclomethasone QVAR HFA 40, 80 Budesonide Pulmicort DPI 90, 180 Budesonide suspension for nebulization Low-Dose (mcg/day) Medium-Dose (mcg/day) 0–5 6–11 ≥ 12 0–5 6–11 ≥ 12 50 50–100 100–200 200 > 100–200 > 200–400 (age 5 only) (age 5 only) High-Dose (mcg/day) 0–5 6–11 ≥ 12 N/A > 200 > 400 N/A 100–200 200–400 N/A > 200–400 > 400–800 N/A > 400 > 800 500 250–500 N/A 1000 > 500–1000 N/A > 1000 N/A N/A 80 80–160 N/A > 80–160 > 160–320 > 160–320 > 160 > 320 50 (age ≥ 4) 50–100 100–250 100 (age ≥ 4) > 100–200 > 250–500 N/A > 200 > 500 Flovent DPI 50, 100, 250 N/A 50–100 100–250 N/A > 100–200 > 250–500 N/A > 200 > 500 Fluticasone furoate Arnuity Ellipta 50, 100, 200a,c N/A 50 100 N/A N/A N/A N/A N/A 200 Mometasone 110 110 110–220 220 (age ≥ 4) > 220 – < 440 > 220–440 N/A > 440 > 440 100 200–400 N/A N/A N/A N/A 200 > 400 Pulmicort Respules 250, 500, 1000 Ciclesonidea,b Alvesco HFA 80, 160 Fluticasone propionate Flovent HFA 50, 125, 250 Asmanex Twisthaler DPI 110, 220 (age ≥ 4) Asmanex HFA 50, 100, 200 100 (age 5 only) N/A Doses are estimated from package insert. Ciclesonide was not available when the National Asthma Education and Prevention Program guidelines were published. The dose ranges are estimated from the package insert. c Once daily. DPI = dry powder inhaler; HFA = hydrofluoroalkane; N/A = not available. Adapted from: Global Initiative for Asthma (GINA): Global Strategy for Asthma Management and Prevention 2022. Available at www.ginasthma.org/. a b ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-369 Pulmonary Disorders and Adult Immunizations Patient Cases Questions 1–3 pertain to the following case. A 23-year-old woman has been coughing and wheezing about twice weekly, and she wakes up at night about three times per month. She has never been given a diagnosis of asthma and has not been to a physician, she says, “in years.” She uses her roommate’s albuterol inhaler, but having recently run out of refills, she is seeking care. Her activities are not limited by her symptoms. Spirometry today reveals FEV1 82% of predicted. 1. According to the NAEPP guidelines, which is the best classification of her asthma? A. Intermittent. B. Mild persistent. C. Moderate persistent. D. Severe persistent. 2. According to GINA guidelines, which medication is best to recommend for her, in addition to budesonide/ formoterol MDI every 4–6 hours as needed? A. No additional therapy needed. B. Oral montelukast 10 mg/day. C. Mometasone DPI 220 mcg/puff 2 puffs daily. D. Budesonide/formoterol MDI 80/4.5 mcg per puff 2 puffs twice daily. 3. At first, the patient’s symptoms were well controlled on your recommended therapy. However, when winter arrived, her symptoms were no longer well controlled, and she started using her budesonide/formoterol MDI 3 or 4 days per week during the day. Which is the preferred treatment change? A. No change in therapy is needed. B. Add budesonide/formoterol MDI 80/4.5 mcg per puff 2 puffs twice daily. C. Add montelukast orally 10 mg daily. D. Add mometasone DPI to 220 mcg/puff 2 puffs daily. H. Types of Inhalation Devices (Table 8) Table 8. Different Types of Inhalation Devices Type and Namea Specifics Type of Inhalation Shake or Prime Dose Counter Advantages and Limitations Drug is mixed with a propellant Press down canister at the start of a slow, deep inhalation Prime: Yes Yes, except Proventil, Xopenex, Alvesco Benefits: Slow, deep breath is easier than forceful, quick breath; may be used with a spacer or holding chamber MDIs HFA inhalers: ProAir, Ventolin, Proventil, Xopenex, Flovent, Alvesco, Asmanex HFA, Symbicort, Dulera, Advair HFA, Atrovent, Aerosphere (Bevespi, Breztri) Shake: Yes Limitation: Requires coordination; many people have difficulty with technique Breath Actuated (QVAR RediHaler) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-370 Pulmonary Disorders and Adult Immunizations Table 8. Different Types of Inhalation Devices (Cont’d) Type and Namea Specifics Type of Inhalation Shake or Prime Dose Counter Advantages and Limitations Inhalation should be a steady and deep breath, enough to hear the whirring sound of the capsule rattling. Inhalation does not need to be as forceful as with some DPIs. May take a second inhalation if powder remains in the capsule Prime: No No Shake: No But not needed Benefit: Inhalation is easier because it does not have to be forceful Multiple doses are included in each device, either as a reservoir or a multiunit dose; each device lasts about 1 mo Inhalation is quick, forceful, and deep; deeper and more forceful than in single-dose systems Prime: No, except Yes Flexhaler Different multidose system; 2 separate blister strips that dispense inhalation powder Inhalation is deep and slow, not fast and forceful as with other DPIs Prime: No Deep breath; quickly and deeply with enough force for the medication to be released Cannot be used with a spacer or holding chamber Contraindicated in severe hypersensitivity to milk proteins Prime: No Shake: No Single Dose System DPIs HandiHaler (Spiriva) Individual gelatin capsules containing drug must be inserted Neohaler and pierced before (Arcapta, Utibron, each use and removed Seebri) after each use Limitation: Need to load and pierce each capsule before use Preloaded Multidose DPIs Pressair (Tudorza, Duaklir) Twisthaler (Asmanex) Flexhaler (Pulmicort) Diskus Shake: No Limitation: Inhalation is more difficult to do correctly because it must be quick and forceful (Advair, Flovent, Serevent) Ellipta (Anoro, Breo, Arnuity, Incruse) Benefit: No need to load capsules before each inhalation Yes Benefits: Easier inhalation than with other DPIs; no need to load capsules before each inhalation; oncedaily dosing with only 1 inhalation each time, all medications that come in the Ellipta device are 1 inhalation once daily Yes Benefit: No need to coordinate breath with actuation as with all other albuterol devices (MDIs) Shake: No Contraindicated in severe hypersensitivity to milk protein Breath-Actuated DPI Respiclick (ProAir) Digihaler (ProAir, AirDuo, AromonAir) Medication is automatically released on inhalation; canister is not pressed Digihaler is the first digital inhaler with built-in sensors that measure inspiratory flow and detect inhaler use when the cap is opened or the patient inhales. Information is sent wirelessly to the companion mobile app using Bluetooth technology ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-371 Pulmonary Disorders and Adult Immunizations Table 8. Different Types of Inhalation Devices (Cont’d) Type and Namea Specifics Type of Inhalation Shake or Prime Dose of drug is in solution and is released through a nozzle with jets of mist Lung deposition and amount of drug delivered are independent of the patient’s effort Inhalation is slow and Prime: Yes deep Each new inhaler needs to be assembled, readied, and primed before first use; this is somewhat complicated If not used in 3 days, prime with 1 inhalation released into air Full repriming needed if not used in 21 days. Shake: No Dose Counter Advantages and Limitations Yes Benefits: Ease of inhalation, consistent drug delivery Limitation: Complicated steps to ready and prime inhaler each month and after not using for 21 days Soft Mist Inhaler Respimat (Combivent, Spiriva, Striverdi, Stiolto) a For generic names and drug class, see Table 6. DPI = dry powder inhaler; HFA = hydrofluoroalkane. I. Adjusting Asthma Treatment 1. Control-based asthma management: a. Continuous cycle of treatment adjustment that involves assessment, treatment, and review i. Assess: Confirm diagnosis, symptom control and modifiable risk factors, comorbidities, inhaler technique, patient goals ii. Adjust: Treatment of modifiable risk factors and comorbidities, nonpharmacologic strategies, education and skills training, asthma medications iii. Review response: Symptoms, exacerbations, adverse effects, lung function, patient satisfaction b. Change in treatment on the basis of features of poor symptom control with or without other risk factors c. Accounts for both symptom control and future risk when choosing an asthma treatment d. Recommended approach to monitoring and adjusting treatment e. Alternative strategies for adjusting treatment i. In adults, leads to reduced exacerbations and similar levels of symptom control ii. Limited availability of routine sputum analysis iii. Recommended for adults with moderate or severe asthma who are in treatment centers that have experience with this technique 2. FeNO a. In children/young adults, has been associated with reduced exacerbations b. In nonsmoking adults, no significant reduction in exacerbations c. Further study needed to identify populations most likely to benefit from FeNO-guided treatment J. Single Maintenance and Reliever Therapy (SMART) 1. Also called Maintenance and Reliever Therapy (MART) in GINA guidelines 2. SMART therapy with ICS-formoterol reliever reduces severe exacerbation risk compared with regimens including a SABA reliever ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-372 Pulmonary Disorders and Adult Immunizations K. L. Use of Long-Acting Antimuscarinic Antagonists (LAMAs) for Asthma 1. Tiotropium Respimat is the only LAMA indicated for long-term treatment of asthma. 2. Tiotropium is approved as add-on therapy in patients with asthma age 6 years and older. 3. Recommended as an alternative add-on in step 4 because of insufficient evidence compared with ICS plus long-acting β2-agonist (LABA) 4. A preferred add-on in step 5 5. Evidence shows improved lung function and increased time to severe exacerbation. Pharmacologic Treatment of Patients with Clinical Features of Asthma and COPD 1. If there are more features of asthma, use the treatment strategy for asthma. 2. If there are more features of COPD, use the treatment strategy for COPD. 3. If the clinical presentation includes features of both asthma and COPD, start with a low- or moderate-dose ICS and usually add a LABA or LAMA (www.ginasthma.org). M. Long-Acting β2-Agonists (FDA Drug Safety Communication 2010): 1. Use of a LABA alone without a long-term asthma control drug such as an ICS is contraindicated because of an increased risk of severe worsening of asthma symptoms, leading to hospitalization and death in some children and adults. 2. LABAs should not be used in patients whose asthma is adequately controlled by low- or medium-dose ICSs. 3. LABAs should be used only as additional therapy for patients who are currently taking, but whose asthma is not adequately controlled by, a long-term asthma control agent (e.g., an ICS). An FDA review found no significant increase in risk of serious asthma outcomes with LABA use in combination with ICS (FDA Drug Safety Communication 2017) 4. Once asthma control is achieved and maintained, patients should be assessed at regular intervals and stepped down (e.g., LABAs discontinued), if possible, and the patients should continue to be treated with a long-term asthma control agent (e.g., an ICS). 5. Pediatric and adolescent patients who need a LABA and an ICS should use a combination product to ensure adherence to both medications. N. Exercise-Induced Bronchospasm: Diagnosis, Prevention, and Treatment of Symptoms 1. History of cough, shortness of breath, chest pain or tightness, wheezing, or endurance problems during exercise are suggestive of exercise-induced bronchospasm. 2. Diagnosis is made with an exercise challenge in which a 15% decrease in FEV1 or peak expiratory flow occurs before and after exercise, measured at 5-minute intervals for 20–30 minutes. 3. Long-term control therapy, if otherwise appropriate (initiate or step-up), should be used, particularly if exercise-induced bronchospasm is frequent or severe. 4. Pretreatment with SABA or low-dose ICS-formoterol and as needed for symptom relief is recommended. 5. Leukotriene receptor antagonists (LTRAs) can attenuate symptoms in 50% of patients, but onset is hours after administration. O. Monitoring 1. Peak flow monitoring a. Symptom-based and peak flow–based monitoring have similar benefits; either is appropriate for most patients. Symptom-based monitoring is more convenient. b. Daily home peak flow monitoring may be considered for moderate to severe persistent asthma if the patient has a history of severe exacerbations or has poor perception of worsening of asthma symptoms. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-373 Pulmonary Disorders and Adult Immunizations c. Personal best peak expiratory flow rate (PEFR), not predicted PEFR, should be determined if a peak flow–based asthma action plan is being used. i. Personal best PEFR is the highest number attained after daily monitoring for 2 weeks twice daily when asthma is under good control. ii. Predicted PEFR is based on population norms for sex, height, and age. 2. Spirometry (only used in patients 5 years and older) a. At initial assessment b. After treatment is started and symptoms are stabilized (3–6 months) c. If prolonged or progressive loss of asthma control d. At least every 2 years or more often, depending on response to therapy P. Asthma Action Plan (Table 9) 1. Usually symptom based (equal benefits of symptom-based and peak flow–based monitoring) 2. Permits home treatment of an asthma exacerbation 3. For all patients with early/mild symptoms: a. Increase reliever b. Provide early increase in controller c. Review response 4. For late/severe symptoms if peak expiratory flow or FEV1 less than 60% best, or symptoms not improving after 48 hours: a. Continue reliever b. Continue controller c. Add prednisone 40–50 mg/day d. Contact physician 5. After initial treatment, immediate medical attention is needed if patient is at high risk of a fatal attack. Risk factors: asthma-related (history of severe attack [previous intubation or intensive care unit admission for asthma], ≥ 2 hospitalizations for asthma in past year, ≥ 3 ED visits for asthma in the past year, hospitalization or ED visit for asthma in the past month, using > 2 canisters of SABA a month, difficulty perceiving asthma symptoms), social (low socioeconomic status or inner-city residence, illicit drug use, major psychosocial problems), and comorbidities (cardiovascular disease, other chronic lung disease, chronic psychiatric disease). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-374 Pulmonary Disorders and Adult Immunizations Table 9. Asthma Action Plan Zone Green Signs and Symptoms Doing well; no or minimal symptoms of coughing, wheezing, or dyspnea PEFR 80%–100% of personal best Yellow Treatment Take long-term asthma control agent only (if one is prescribed) Use reliever inhaler 5–15 min before exercise if exerciseinduced asthma and before known triggers Avoid things that make asthma worse Getting worse; increased frequency Increase usual reliever (low-dose ICS-formoterol; increase of symptoms (e.g., coughing, frequency to max of 72 mcg formoterol/day; SABA: 2–4 puffs wheezing, chest tightness, or by MDI or 1 nebulizer treatment and repeat in 20 min, if needed). dyspnea); nighttime awakenings; If complete response at 1 hr, contact clinician for follow-up decreased ability to engage in instructions and consider OCS bursta normal activities If incomplete response in 1 hr (still some coughing, wheezing, PEFR 50%–79% of personal best or dyspnea), repeat SABA and add OCS burst; contact clinician that day for further instructions If poor response in 1 hr (e.g., marked coughing, wheezing, or dyspnea), repeat SABA immediately; add OCS burst; contact clinician immediately; proceed to the ED if the distress is severe and unresponsive to treatment; consider calling 911 Red Medical alert (e.g., marked coughing, wheezing, or dyspnea); inability to speak more than short phrases; use of accessory respiratory muscles; drowsiness PEFR < 50% of personal best May continue to use SABA every 3–4 hr regularly for 24–48 hr Begin treatment and consult clinician immediately Increase usual reliever (low-dose ICS-formoterol; increase frequency to max of 72 mcg formoterol/day; SABA: 2–6 puffs by MDI or 1 nebulizer treatment) If incomplete or poor response, repeat SABA immediately; proceed to the ED or call 911 if distress is severe and unresponsive to treatment Call 911 or go to the ED immediately if lips or fingernails are blue or gray or if there is trouble walking or talking because of shortness of breath Continue using SABA every 3–4 hr regularly for 24–48 hr a OCS burst: prednisone (or equivalent) 40–60 mg/day for 5–7 days (adults) or 1–2 mg/kg/day (maximum 40 mg/day) for 3–5 days (children). ED = emergency department; ICS = inhaled corticosteroid; MDI = metered dose inhaler; OCS = oral corticosteroid; PEFR = peak expiratory flow rate; SABA = short-acting β2-agonist. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-375 Pulmonary Disorders and Adult Immunizations Q. Managing Exacerbations: Initial—Emergency Department (ED) or Hospital (Table 10) Table 10. Classifying Severity of Asthma Exacerbations in the Urgent or Emergency Care Settinga Severity Mild or moderate Severe Lifethreatening Symptoms and Signs Talks in phrases, prefers sitting to lying, respiratory rate increased, heart rate 100–120 beats/min, Sao2 (room air) 90%–95% Dyspnea at rest; interferes with conversation; sits hunched forward; agitated; heart rate > 120 beats/ min; respiratory rate > 30 breaths/min; use of accessory muscles; Sao2 (room air) < 90% Too dyspneic to speak, perspiring; drowsy; confused Initial PEF or FEV1b > 50% predicted or personal best ≤ 50% of predicted or personal best Clinical Course Usually cared for at home or office visit; relief from frequently inhaled SABA; likely short course of OCS; some symptoms last 1–2 days after treatment begins Usually requires ED visit and likely hospitalization Partial relief from frequent inhaled SABA Oral systemic corticosteroids; some symptoms last > 3 days after treatment is begun < 25% of predicted or personal best Adjunctive therapies are helpful Requires ED or hospitalization, possible ICU Little or no relief from frequent inhaled SABAs IV corticosteroids Adjunctive therapies are helpful For all ages. b Lung function measures (PEF or FEV1) may be useful for children ≥ 5 yr but may not be attainable in children during an exacerbation. ED = emergency department; ICU = intensive care unit; OCS = oral corticosteroid; PEF = peak expiratory flow; SABA = short-acting β2-agonist.. Adapted from: Global Initiative for Asthma (GINA): Global Strategy for Asthma Management and Prevention 2022. Available at www.ginasthma.org/. a 1. Mild to moderate exacerbation (FEV1 of 50% or more) a. Oxygen to achieve oxygen saturation (Sao2) of 93%–98% (greater than 95% in pregnant women and those with concomitant heart disease) b. Inhaled SABA (MDI with valved holding chamber or nebulizer) up to three doses in the first hour i. Adult dose: albuterol MDI 4–10 puffs every 20 minutes for up to 4 hours, then every 1–4 hours as needed or by nebulizer 2.5–5 mg every 20 minutes for three doses, then 2.5–10 mg every 1–4 hours as needed ii. Pediatric dose (12 years or younger): albuterol MDI 4–8 puffs every 20 minutes for three doses, then every 1–4 hours as needed; use holding chamber (add mask if younger than 4 years) or by nebulizer 0.15 mg/kg (minimal dose 2.5 mg) every 20 minutes for three doses, then 0.15–0.3 mg/kg up to 10 mg every 1–4 hours as needed c. OCS if no response immediately or if patient recently took an OCS 2. Severe exacerbation (FEV1 of 50% or less) a. Oxygen to achieve Sao2 of 93%–98% (more than 95% in pregnant women and those with concomitant heart disease) b. High-dose inhaled SABA plus ipratropium by MDI plus valved holding chamber or nebulizer every 20 minutes or continuously for 1 hour ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-376 Pulmonary Disorders and Adult Immunizations c. Oral corticosteroids i. Adult dose: prednisone 40–50 mg/day in one or two divided doses until peak expiratory flow reaches 70% of predicted ii. Pediatric dose (12 years or younger): prednisone 1–2 mg/kg in two divided doses (maximum 40 mg/day) until peak expiratory flow reaches 70% of predicted d. Consider adjunctive therapies (intravenous magnesium, intravenous ketamine, or heliox) if the patient is still unresponsive. 3. Impending or actual respiratory arrest a. Intubation and mechanical ventilation with oxygen 100% b. Nebulized SABA plus ipratropium c. Intravenous corticosteroids d. Consider adjunctive therapies (intravenous magnesium or heliox) if the patient is still unresponsive to therapy. e. Admission to intensive care R. Managing Exacerbations: ED or Hospital After Repeat Assessment 1. Moderate exacerbation (FEV1 greater than 50%) a. Inhaled SABA every 60 minutes b. Oral corticosteroid c. Continue treatment for 1–3 hours if improvement 2. Severe exacerbation (FEV1 of 50% or less); no improvement after initial treatment a. Oxygen b. Nebulized SABA plus ipratropium; hourly or continuous c. Consideration of adjunctive therapies 3. If good response to above treatment and maintained for at least 60 minutes a. Continue inhaled SABA. b. Continue OCS course. c. Consider initiating an ICS (if patient is not already taking one). d. Discharge home. 4. If incomplete response, admit to hospital ward a. Continuation of inhaled SABA b. Systemic corticosteroids (oral or intravenous) c. Consideration of adjunctive therapies 5. If poor response, admit to intensive care a. Continuation of inhaled SABA, hourly or continuously b. Intravenous corticosteroid c. Consideration of adjunctive therapies d. Possible intubation and mechanical ventilation Patient Case 4. A 25-year-old man presents to the ED with shortness of breath at rest. He is having trouble with conversation. He used 4 puffs of albuterol MDI at home, with no resolution of symptoms. His FEV1 is 38% of predicted. Which therapy, in addition to oxygen, is best for him initially in the ED? A. Oxygen alone is sufficient. B. Give albuterol MDI 8 puffs every 20 minutes for 1 hour. C. Give albuterol plus ipratropium by nebulizer every 20 minutes for 1 hour, plus oral corticosteroids. D. Give albuterol plus ipratropium by nebulizer every 20 minutes for 1 hour, plus intravenous corticosteroids. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-377 Pulmonary Disorders and Adult Immunizations S. Additional Vaccines: Adults with asthma (19–64 years) should receive: 1. One dose of 20-valent pneumococcal conjugate vaccine (PCV20) alone or one dose of 15-valent pneumococcal conjugate vaccine (PCV15) followed by one dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23) at least 1 year later. 2. Influenza vaccine every fall or winter. Asthma in patients 5 years of age and older is considered a precaution for administration of the live, attenuated influenza vaccine (LAIV). T. Asthma in Pregnancy 1. Asthma may worsen, improve, or stay the same during pregnancy. 2. Asthma may increase the risk of perinatal mortality, hyperemesis, vaginal hemorrhage, preeclampsia, complicated labor, neonatal mortality, prematurity, and low-birth-weight infants, especially if it is uncontrolled. Risks are small and are not shown in all studies. 3. Medications a. The preferred controller is budesonide ICS; however, if asthma is well controlled on another ICS before pregnancy, it may be continued. b. The preferred rescue inhaler is albuterol. c. LABAs have less clinical experience. Use during pregnancy is reasonable if necessary for asthma control. Salmeterol is the preferred LABA. d. LTRAs have limited data; most data are with montelukast, and are reassuring. These are considered an alternative therapy. e. Prednisone: potential adverse effects in pregnancy are cleft palate, preeclampsia, gestational diabetes, low birth weight, and prematurity. However, few studies involved patients with asthma, and women might have been exposed to longer-term prednisone use. Prednisone should be used, if necessary, for acute exacerbations in pregnancy. II. CHRONIC OBSTRUCTIVE PULMONARY DISEASE Guidelines: Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of COPD 2023. Available at www.goldcopd.org/. A. Definition: COPD is a common, preventable, and treatable syndrome of persistent limitation in expiratory airflow encompassing both small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema). Airflow obstruction may be accompanied by airway hyperresponsiveness and may not be fully reversible. Airway and alveolar abnormalities are usually caused by significant exposure to noxious particles. 1. Chronic bronchitis consists of persistent cough plus sputum production for most days of 3 months in at least 2 consecutive years and is an independent disease entity that may occur before or after the development of airflow limitation. 2. Emphysema is abnormal permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis. Emphysema is only one of several structural abnormalities in patients with COPD. B. Diagnosis and Assessment 1. The clinical diagnosis of COPD is based on a history of exposure to risk factors and the presence of airflow limitation that is not fully reversible, with the presence of symptoms. a. Symptoms: Dyspnea (described by patients as “increased effort to breathe,” “heaviness,” “air hunger,” or “gasping”), poor exercise tolerance, chronic cough, sputum production, wheezing ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-378 Pulmonary Disorders and Adult Immunizations b. GOLD guidelines: Perform spirometry and consider COPD if a patient is older than 40 and has any of the following: i. Dyspnea that is progressive (worsens over time), persistent (present every day), and worse with exercise or on exertion ii. Chronic cough that is present intermittently or every day; often present throughout the day; seldom only nocturnal; may be nonproductive iii. Recurrent wheeze iv. Recurrent respiratory tract infections v. History of exposure to risk factors, especially tobacco smoke (most common risk factor), occupational dusts and chemicals, and smoke from home cooking and heating fuels c. American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society (ACP/ACCP/ATS/ERS) guidelines: The single best predictor of airflow obstruction is the presence of all three of the following: i. Smoking history of more than 55 pack-years ii. Wheezing on auscultation iii. Patient’s self-report of wheezing 2. For the diagnosis and assessment of COPD, spirometry is the gold standard. a.  Spirometry revealing an FEV1/FVC less than 70% of predicted is the hallmark of COPD. Bronchodilator reversibility testing is no longer recommended. b. Measurement of arterial blood gas tension should be considered for all patients with FEV1 less than 50% of predicted or clinical signs suggestive of respiratory failure or right heart failure. c. On the basis of the spirometry result, a GOLD grade is assigned. The GOLD grade is primarily used to direct nonpharmacologic interventions (e.g., pulmonary rehabilitation, lung reduction surgery). i. GOLD 1: Mild FEV 80% or greater of predicted ii. GOLD 2: Moderate FEV 50%–79% of predicted iii. GOLD 3: Severe FEV 30%–49% of predicted iv. GOLD 4: Very severe FEV less than 30% of predicted 3. Assess the frequency of exacerbations in the past 12 months: a. Less severe: 0 or 1 exacerbation (not leading to hospital admission) b. More severe: 2 or more exacerbations, or 1 or more exacerbation leading to hospital admission 4. Use validated symptom scales or questionnaires: a. The COPD Assessment Test (CAT) measures health status impairment in COPD (www.cateston line.org). i. Measures symptoms beyond breathlessness, such as cough, sputum production, chest tightness, limitation of activities, sleep, energy level, and confidence to leave house ii. Scale of 5 to more than 30 (a) 5 is upper limit of normal. (b) Less than 10 is low impact on life. (c) More than 30 is high impact on life; can barely leave the house b. mMRC breathlessness scale for assessing severity of breathlessness (Thorax 1999;54:581-6) i. Measures severity of shortness of breath or breathlessness ii. Scale of 0–4 (a) 0 = least symptoms; breathless only with strenuous exercise (b) 4 = too breathless to leave house; breathless even when dressing ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-379 AL GRAWANY Pulmonary Disorders and Adult Immunizations C. Factors Determining Severity of COPD 1. Severity of airflow limitation (FEV1) 2. Frequency and severity of exacerbations 3. Severity of symptoms (mMRC, CAT) 4. Presence of comorbidities that may restrict activity (e.g., heart failure, heart disease, musculoskeletal disorders, depression) D. Therapy Goals 1. Relieve symptoms. 2. Reduce the frequency and severity of exacerbations. 3. Improve exercise tolerance. 4. Improve health status. 5. Minimize adverse effects from treatment. E. Management of Stable COPD 1. Description of levels of evidence or grades of recommendations (Table 11) Table 11. Grades for Strength of Recommendations for COPD Guidelines GOLD Guidelines A B C D Randomized clinical trials Rich body of data Randomized clinical trials Limited body of data Nonrandomized trials Observational studies Panel judgment consensus COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease. 2. Existing medications for COPD have not been shown to modify the long-term decline in lung function, the hallmark of this disease (level of evidence A). Therefore, pharmacotherapy for COPD is used to decrease symptoms, complications, or both. 3. Smoking cessation is a critical component of COPD management for patients who are actively using tobacco. 4. Basic Principles of Pharmacotherapy a. Bronchodilator medications are central to the symptomatic management of COPD (level of evidence A). b. Primary mechanism of bronchodilators in COPD is through changes to smooth muscle tone that result in airway widening c. Bronchodilators can be given as needed or on a scheduled basis to prevent and reduce symptoms d. Principal bronchodilator treatments are: β2-agonists, muscarinic antagonists, and a combination of these drugs e. Inhaled therapy is preferred to oral therapies because of less systemic exposure f. Combining agents from different classes may improve efficacy compared with increasing the dose of a single bronchodilator g. Short- or long-acting bronchodilator is recommended as initial treatment for all COPD groups (Table 12). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-380 Pulmonary Disorders and Adult Immunizations h. Treatment with a LAMA delays first exacerbation, reduces the overall number of COPD exacerbations and related hospitalizations, improves symptoms and health status (level of evidence A), and improves the effectiveness of pulmonary rehabilitation (level of evidence B). i. No effect on the rate of lung function decline (no consistent or significant FEV1 improvement) ii. Initial tiotropium studies reported increased cardiovascular risk, but currently available studies do not reproduce the findings. i. LABAs improve health status, quality of life, and FEV1 and decrease COPD exacerbation rate (level of evidence A). i. No effect on mortality or rate of lung function decline ii. Do not have the same potential safety concerns as in asthma management iii. Salmeterol significantly reduces hospitalization rate and treatment of exacerbations (level of evidence B). iv. Indacaterol has significantly greater bronchodilator effect than salmeterol, similar to that of tiotropium (level of evidence A). j. LAMAs versus LABAs i. POET-COPD trial: Tiotropium was more effective than salmeterol as initial bronchodilator therapy in moderate to very severe COPD regarding time to first exacerbation and annual number of exacerbations (N Engl J Med 2011;364:1093-103). ii. Cochrane review: Tiotropium is more effective than LABAs in preventing COPD exacerbations and COPD-related hospitalization, but not in overall hospitalizations or mortality. Symptom and lung function improvement were similar. However, studies are sparse. Fewer serious adverse events and withdrawals from studies occurred with tiotropium than with LABAs (Cochrane Database Syst Rev 2012;9:CD009157). iii. FLAME trial: LABA/LAMA (indacaterol/glycopyrrolate) had greater efficacy than LABA/ ICS (salmeterol/fluticasone) in preventing COPD exacerbations in patients with a history of exacerbations in the previous year (N Engl J Med 2016;374:2222-34). k. ICSs in Stable COPD i. Not recommended as monotherapy and may increase risk of mortality compared with use in combination treatment ii. Theoretically work as anti-inflammatory agents to decrease airway inflammation iii.  Blood eosinophil counts may predict the magnitude of ICS effect in preventing future exacerbations (a) Some studies have found a greater risk of exacerbation after withdrawal of ICS when eosinophil count was greater than 300 cells/mcL (N Engl J Med 2014;371:1285-94; Am J Respir Crit Care Med 2018;198:329-39), whereas other studies have found no link between ICS withdrawal and increased exacerbation risk (Thorax 2005;60:480-7; Respir Res 2014;15:77). (b) Effect of an ICS on lung function, health status, and exacerbations is decreased when eosinophils are < 100 cells/mcL. Evidence is less clear regarding the efficacy of ICS with continued tobacco use. iv. Use is associated with an increased risk of pneumonia, oral candidiasis, and hoarse voice. v. Use of LABA/ICS in COPD is not encouraged. Triple therapy (LABA + LAMA + ICS) is preferred when ICS is indicated based on improved outcomes compared with LABA/ICS. vi. Group E: Consider LABA + LAMA + ICS if blood eosinophil count is ≥ 300 cells/mcL l. Triple therapy: i. Shown to improve lung function and health-related quality of life while reducing the number of exacerbations ii. Two fixed-dose combination inhalers available (Table 6) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-381 Pulmonary Disorders and Adult Immunizations iii. The FULFIL trial showed improvements in FEV1 and moderate to severe exacerbations with triple therapy compared to ICS/LABA Am J Respir Crit Care Med 2017;196:438-46). iv. IMPACT further demonstrated benefits of triple therapy compared to ICS/LABA and LAMA/ LABA through lower rate of moderate to severe COPD exacerbations compared to both dual treatments and lower rate of COPD hospitalizations than LAMA/LABA. N Engl J Med 2018;378:1671-80). v. In certain patients, adding tiotropium to a LABA/ICS combination (triple therapy) improves lung function and health-related quality of life and reduces the number of exacerbations (level of evidence B). vi. The ETHOS trial and a secondary analysis of IMPACT evaluated mortality in symptomatic COPD patients with a history of frequent and/or severe exacerbations as a prespecified outcome, although not the primary endpoint. All-cause mortality in the fixed-dose triple therapy arm was significantly lower compared to LABA/LAMA (only with higher dose ICS in ETHOS trial) and no differences were found in all-cause mortality when compared with LABA/ICS in both studies. 5. Patient assessment and selection of therapy a. GOLD guidelines combine symptoms (based on symptom scores) and frequency of exacerbations in the previous 12 months to determine patient risk group and recommend initial treatment (Figure 1 and Table 12). b. Maintenance therapy adjustments are recommended according to the predominant treatable trait of dyspnea (Table 13) or exacerbations (Table 14). These recommendations do not depend on the ABE assessment at diagnosis and focus on current treatment. If both exacerbations and dyspnea need to be targeted, the exacerbation pathway should be followed. c. De-escalation strategies are suggested for patients who experience adverse effects or lack of clinical efficacy with ICS or generally have symptom improvement that may require less therapy. d. Peak inspiratory flow rate (PIFR) measured against the simulated resistance of a dry powder inhaler (DPI) is emerging as a way to further guide therapy and provide a patient-centered product recommendation. PIFR less than 60 mL/minute is considered suboptimal and may identify those with a suboptimal response to a DPI. Assessment of airflow limitationa FEV1 (% predicted) GOLD 1 ≥ 80 GOLD 2 50–79 GOLD 3 30–49 GOLD 4 < 30 Exacerbation history (past 12 mo) ≥ 2 or ≥ 1 leading to hospital admission 0 or 1 (not leading to hospital admission) Assessment of symptoms/risk of exacerbationsb E A B mMRC 0–1 mMRC ≥ 2 CAT < 10 CAT ≥ 10 Symptoms Figure 1. GOLD guidelines: refined assessment of COPD severity and risk. Post-bronchodilator FEV1 should be used. CAT score is preferred, but any can be used. CAT = COPD Assessment Test (validated questionnaire); GOLD = Global Initiative for Chronic Obstructive Lung Disease; mMRC = Modified Medical Research Council breathlessness scale (validated questionnaire). Adapted from: Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of COPD. 2023 Update. Available at www.goldcopd.org/. a b ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-382 Pulmonary Disorders and Adult Immunizations Table 12. GOLD Guidelines: Initial Pharmacologic Treatment Patient Group A B E Symptoms and Exacerbations Few symptoms (CAT score < 10) No hospitalizations ≤ 1 exacerbation in the past year Many symptoms (CAT score ≥ 10) No hospitalizations ≤ 1 exacerbations in the past year Few or many symptoms ≥ 1 COPD-related hospitalization or ≥ 2 exacerbations in the past year Recommended Initial Treatment Bronchodilator (short- or long-acting) LABA + LAMAa LABA + LAMAa LABA + LAMA +ICSa,b Single inhaler may be more convenient and effective than multiple inhalers. Consider if eosinophils > 300 cells/mcL. CAT = COPD Assessment Test (validated questionnaire); COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; ICS = inhaled corticosteroid; LABA = long-acting b2-agonist; LAMA = long-acting anticholinergic/muscarinic antagonist. Information from: Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease, 2023. a b Table 13. Maintenance Therapy Modifications for the Predominant Treatable Trait of Dyspnea Current Treatment LABA or LAMA LABA + LAMAa Recommended Treatment Change(s) LABA + LAMAa If ineffective: consider changing inhaler devices or molecules, and investigate other causes of dyspnea Consider changing inhaler devices or molecules, implement or escalate nonpharmacologic treatments or investigate and treat other causes of dyspnea Single inhaler may be more convenient and effective than multiple inhalers. LABA = long-acting β2-agonist; LAMA = long-acting anticholinergic/muscarinic antagonist. Information from: Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease, 2023. a ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-383