INTRODUCTION

Power-Pak’s Pharmacotherapy Reviews series provides annual updates for major areas of therapeutics with an emphasis on conditions seen in the community and ambulatory settings. In addition to this program on respiratory disorders, Pharmacotherapy Reviews planned for 2021 cover cardiovascular conditions, infectious diseases, and oncology.

Respiratory disorders are major causes of morbidity and mortality for people everywhere. In this program, pharmacotherapy of chronic obstructive pulmonary disease (COPD) and asthma are reviewed.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Patient case: TG is a 67-year-old man with a past medical history significant for hypertension and hyperlipidemia who presents for his annual physical with his primary care provider (PCP) with a new complaint of dyspnea that has worsened over the last 6 months. TG also complains of a chronic cough that is sometimes productive. TG denies any treatment within the last year with antibiotics or oral steroids for respiratory infection. He reports a 35 pack–year history of smoking but quit approximately 3 years ago. What is the best action for the pharmacist to take in management of TG’s newly reported symptoms?

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) releases an updated guideline annually that provides a comprehensive strategy for the diagnosis, management, and prevention of COPD.¹ The goal is to produce recommendations for the management of COPD based on the best scientific information available. These guidelines are used worldwide as a tool to implement effective management programs based on local health care systems.

According to the World Health Organization (WHO), COPD was the third leading cause of death in the world in 2016 across all ages and sexes.² COPD is a significant contributor to chronic morbidity and mortality in the world, but the condition is preventable and treatable.

During the ongoing pandemic, individuals with COPD have been at an increased risk of severe illness from coronavirus disease 2019 (COVID-19). Patients should continue to take their current medications, making sure to keep at least a 30-day supply on hand. They should also avoid triggers that worsen symptoms and contact their health care provider if they have concerns.³ Many people suffer with COPD for years and prematurely die from COPD or its complications, or concomitant conditions such as lung cancer, depression, and respiratory infections.⁴

Diagnosis and Initial Assessment

COPD is defined as persistent respiratory symptoms and airflow limitation caused by airway or alveolar abnormalities usually caused by significant exposure to noxious particles or gases. The 2020 GOLD Guidelines provide several key indicators for considering a diagnosis of COPD¹:

1. Dyspnea that is progressive over time, persistent, and worse with exercise
2. Chronic cough that may be intermittent and unproductive with recurrent wheezing
3. Chronic sputum production of any pattern
4. Recurrent lower respiratory tract infections
5. History of risk factors
   1. Indoor and outdoor air pollution, occupational exposures, and tobacco use
   2. Genetic factors (hereditary alpha-1 antitrypsin deficiency)
   3. Nonmodifiable factors (older age, female sex)
   4. Lower socioeconomic status
   5. Asthma/hyperreactive airways and history of chronic bronchitis
6. Family history of COPD and/or childhood factors such as low birthweight, poor lung growth or development during gestation, or recurrent respiratory infections

If any of these key indicators are present in an individual over the age of 40, the guidelines recommend performing spirometry or pulmonary function tests (PFTs) to establish a diagnosis of COPD.⁵ Spirometry aids in diagnosis, prognosis, therapeutic decisions, and identification of rapid decline. The ratio of the forced expiratory volume in the first second (FEV₁) to the forced vital capacity (FVC) of the lungs is determined through PFTs. The normal FEV₁/FVC ratio is 0.75–0.85, and values of less than 0.70 suggest COPD.⁶

Goals of the initial COPD assessment include determining the level of airflow limitation, the airflow limitation’s impact on the patient’s health, and the risk of future events (exacerbations, hospitalizations, or death) to guide initial and future management. Classification of severity of airflow limitation is characterized as GOLD grades 1–4 based on post-bronchodilator FEV₁ values (Table 1). There is only a weak correlation between FEV₁, symptoms, and impairment of a patient’s health status, which is why a formal symptomatic assessment is required to guide further management.^7,8

The 2020 GOLD Guidelines provide 2 tools to formally assess a patient’s COPD symptoms. The first is the Modified Medical Research Council Dyspnea Scale (mMRC), which is graded 0–4; higher numbers indicate more severe dyspnea.⁹ The mMRC is a quick assessment that can be scored after only a few questions asked by a member of the health care team. The COPD Assessment Test (CAT) is a patient questionnaire that consists of 8 questions, scored 0–5, with higher scores indicating more severe symptoms.¹⁰ Because the CAT covers a more comprehensive list of symptoms compared to the mMRC, the assessment may take longer to perform, but it can provide specific details about the patient’s symptoms.

Preventive and Wellness Interventions

Smoking cessation, vaccinations, and pulmonary rehabilitation are important interventions that can reduce symptoms and decrease the risk of future COPD-related events (exacerbations, hospitalizations, or death).

Smoking cessation has the greatest impact on the course of COPD. It decreases the risk of disease progression, cardiovascular disease, and lung cancer in patients with mild-to-moderate COPD, and reduces total mortality in more severe cases.¹¹

Vaccinations can improve overall outcomes as well. Receiving an annual influenza vaccination can reduce serious illness¹² and death in patients with COPD.¹³ The 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been shown to reduce the risk of community-acquired pneumonia in those 65 years of age and older with an FEV₁ ≤40% predicted.¹⁴ The 13-valent conjugated pneumococcal vaccine (PCV13) demonstrated a reduction in risk of bacteremia and serious invasive pneumococcal disease in those 65 years of age and older.¹⁵

Pulmonary rehabilitation is recommended in all patients with COPD who have relevant symptoms (dyspnea, anxiety, depression, fatigue)¹ and/or a high risk of exacerbation. Pulmonary rehabilitation can improve dyspnea, health status, and exercise tolerance¹⁶ as well as reduce hospitalization risk in those with recent exacerbations (within the prior 2 weeks).¹⁷ In a recent retrospective analysis, patients with COPD who initiated pulmonary rehabilitation within 90 days of discharge had a lower rate of 1-year mortality than those who started rehabilitation after 90 days or not at all (7.3% vs. 19.6%).¹⁸

Initial Pharmacologic Management

Initial pharmacologic management of stable COPD is based on the Refined ABCD Assessment Tool, which incorporates exacerbation history and symptom severity (via the mMRC or CAT) to determine placement into 4 intensity groups labeled as A, B, C, or D.¹ Patients in all 4 groups should be prescribed short-acting bronchodilators for rescue use when immediate symptom relief is needed. The combination of a short-acting beta-2 agonist (SABA) and a short-acting muscarinic antagonist (SAMA) is superior to either agent alone in improving FEV₁ and symptoms.¹⁹ The combination of SAMA and long-acting muscarinic antagonist (LAMA) should be avoided due to minimal benefits and increase risk of anticholinergic side effects.

For patients in Group A [few symptoms (mMRC 0–1/CAT <10), low risk of exacerbation (0 or 1 without hospitalization)], a bronchodilator (short- or long-acting) should be initially offered and continued if benefit is observed. For those in Group B [more symptoms mMRC ≥ 2/CAT ≥10], low risk of exacerbation (0 or 1 without hospitalization)), initial therapy should consist of a long-acting bronchodilator.^20,21 Little evidence is available to recommend one class of long-acting bronchodilators (long-acting beta agonist [LABA] or long-acting muscarinic antagonist [LAMA]) over another for patients in Group B. For patients in Group C [few symptoms (mMRC 0–1/CAT <10), high risk of exacerbation (≥2, or ≥1 hospitalization)], a single long-acting bronchodilator is recommended. In this group, a LAMA is preferred over a LABA.^22,23 Lastly, patients in Group D [more symptoms (mMRC ≥2/CAT ≥10), high risk of exacerbation (≥2, or ≥1 hospitalization)] should be started on a LAMA, combination LAMA with LABA if highly symptomatic, or combination LABA with inhaled corticosteroid (ICS) when elevated blood eosinophils or history of asthma are present. Inhaled corticosteroids are reserved for specific patients — such as those with pneumonia — because of the risk of potentially serious adverse effects.²⁴

Table 2 provides a list of commonly used maintenance medications for the treatment of COPD. It is important to confirm correct inhaler technique when dispensing any of these medications, whether new or refill prescriptions, to ensure that the inhaled medication is reaching the site of action. If patients are having difficulty timing inhalations when using a metered dose inhaler (MDI), a spacer could be beneficial. Refer to the initial pharmacologic treatment algorithm in the GOLD guidelines for more information.¹

One of the most significant changes in the COPD guidelines over the last few years involves the use of ICS. Due to mounting evidence regarding risks of pneumonia, recommendations have changed. The 2020 GOLD Guidelines recommend considering several factors when initiating ICS treatment. ¹

• Strong support for use
  • History of hospitalization(s) for COPD exacerbations
  • ≥2 moderate COPD exacerbations per year
  • Blood eosinophils >300 cells/µL
  • History of asthma
• Consider use:
  • 1 moderate COPD exacerbation per year
  • Blood eosinophils 100–300 cells/µL
• Avoid use:
  • Repeated pneumonia events
  • Blood eosinophils <100 cells/µL
  • History of mycobacterial infections

Patient Case: TG underwent initial spirometry and was determined to have an FEV₁/FVC of 0.58. His FEV₁ was 67% predicted. His mMRC score was 2, and his CAT score was 11. What factors support a diagnosis of COPD? What is his GOLD grade for classification of airflow limitation? What is his group? What could the pharmacist recommend as initial therapy for TG based on the above information?

TG returns to his PCP 6 months after being initiated on a LABA to manage COPD. He reports a slight increase in dyspnea and is wondering if there is anything that can be done to improve his feelings of breathlessness. What adjustments could the pharmacist recommend to TG’s current inhaler regimen?

Follow-up Pharmacologic Management

Follow-up management should be guided by 3 principles: review (symptoms and exacerbation risk), assess (inhaler technique and adherence, and role of wellness and preventive therapies), and adjust therapy (if needed). The GOLD guidelines provide 2 algorithms for follow-up pharmacologic treatment based on the patient’s needs: a dyspnea pathway and an exacerbation pathway.¹ For patients with persistent dyspnea/exercise intolerance on a single long-acting bronchodilator, the addition of a second long acting bronchodilator is suggested. For those maintained on LABA/ICS therapy, the addition of a LAMA can be made. The exacerbation pathway differs slightly from the dyspnea pathway. For those with a history of exacerbation maintained on long acting bronchodilator therapy alone, escalation to LABA/LAMA or LABA/ICS (preferred if history of asthma, elevated blood eosinophils, or high exacerbation risk). Also, in the exacerbation algorithm, the addition of roflumilast is recommended in 2 instances. If patients have continued exacerbations on combination LABA + LAMA therapy and blood eosinophils are less than 100 cells/µL or for those patients established on triple therapy with LABA, LAMA, and ICS who have persistent exacerbations, an FEV₁ ≤50%, and chronic bronchitis.

Azithromycin could be considered as maintenance add-on therapy for former smokers who continue to have exacerbations despite optimal inhaler therapy.

Follow-up management may include de-escalation of ICS therapy if appropriate. ICS discontinuation can be considered if complications such as pneumonia occur or if efficacy is lacking. Appropriate patient selection for discontinuation of ICS therapy is important. For example, a patient has an elevated blood eosinophil count (>300 cells/µL) is at the greatest risk of experiencing exacerbations after ICS discontinuation and should be monitored closely.¹ See the 2020 GOLD Guidelines for more detailed information regarding the treatment intensification pathways.

Patient Case: TG is referred to a new pharmacist-managed COPD clinic for more frequent follow-up and focused care. During his first appointment, TG complains of shortness of breath at rest and coughing up green phlegm. These symptoms have worsened over the previous 2 weeks. He is found to have a heart rate of 110 bpm, blood pressure of 132/72 mm Hg, respiratory rate of 34 inhalations per minute, oxygen saturation 88% on room air, and temperature of 38.3° C. Is TG experiencing disease progression or a COPD exacerbation? In what setting should he be treated? What interventions can the pharmacist perform in the outpatient setting?

Recognizing COPD Exacerbations

COPD exacerbations are associated with long-term consequences, including disease progression.²⁵ About 20% of patients do not fully recover to their baseline status even 8 weeks post-exacberation.²⁶ After an exacerbation requiring hospitalization, the likelihood of survival to 5 years is only 50%.²⁷ For these reasons, early recognition and treatment of COPD exacerbations is essential for improving both acute and long-term patient outcomes.

COPD exacerbation is defined by the GOLD guidelines as any “acute worsening of respiratory symptoms that results in additional therapy.”¹ The exacerbation severity is classified based on the treatment required (Table 3). More than 80% of exacerbations are considered mild or moderate and can be treated in the outpatient setting. Mild exacerbations are managed with short-acting bronchodilators alone, while moderate exacerbations require antibiotics and/or corticosteroids. Severe exacerbations require hospitalization or emergency department (ED) visits and are further classified based on the presence of respiratory failure.¹

COPD exacerbations are associated with decreased quality of life, increased inflammation, faster disease progression, increased likelihood of hospitalization and recurrent exacerbations, and increased mortality.²⁸ Despite these poor outcomes, as many as 70% of COPD exacerbations go unreported.²⁹ These unreported episodes are often clinically significant and are associated with adverse outcomes, including decreased health-related quality of life.³⁰ For this reason, it is important to educate patients on the signs and symptoms of exacerbations. Common symptoms are nonspecific (Table 4) and may mimic other cardiopulmonary conditions, such as pneumonia, pulmonary edema, pulmonary embolism, or arrhythmias.

The most common cause of COPD exacerbations is respiratory viral infections. Bacterial infections and environmental triggers can also lead to irritation and swelling of the airways, resulting in exacerbations.³¹

Patient Case: Based on his pharmacist’s recommendations, TG presents to the ED and is admitted to the general hospital floor with a severe COPD exacerbation associated with non-life-threatening acute respiratory failure. What treatments should be initiated for TG? What are the goals of therapy?

Treatment of COPD Exacerbations

Treatment goals are 2-fold: (1) minimize negative consequences of the acute exacerbation and (2) prevent subsequent exacerbations from occurring.¹ Respiratory support with supplemental oxygen, high-flow oxygen therapy, or noninvasive or invasive mechanical ventilation should be used to treat respiratory failure. Pharmacologic considerations include short-acting beta₂-agonists and anticholinergics, systemic corticosteroids, antibiotics, vitamin D, and adjunctive therapies.

Bronchodilators. Short-acting beta-2 agonists with or without short-acting anticholinergics are the mainstay of therapy. Short-acting bronchodilators are recommended as the initial treatment for acute COPD exacerbations in the outpatient or inpatient setting and for all severities of exacerbations.¹ Bronchodilators can be administered via metered-dose inhaler (MDI) or nebulization.³² Bronchodilators should typically be administered hourly for 2 to 3 hours and then every 2 to 4 hours depending on response.

Corticosteroids. Prednisone 40 mg daily for 5 days is recommended for patients with moderate-to-severe COPD exacerbations.^1,33 Glucocorticoids have been demonstrated to reduce recovery time, improve oxygenation, and reduce hospital length of stay, among other benefits.³⁴ Longer courses of corticosteroids have been associated with pneumonia, sepsis, and mortality.³⁵ Thus, steroid-sparing treatment strategies have been proposed. These include the use of inhaled corticosteroids (as opposed to systemic) and approaches to select patients likely to have the greatest benefit from glucocorticoid therapy. While more research on these strategies is needed before widespread implementation, initial data suggests that inhaled corticosteroids may be a suitable substitute for systemic therapy in select patients and may also be useful in preventing exacerbations.³⁶ Further, initial evidence suggests that corticosteroids may have a benefit only in patients with higher levels of blood eosinophils.³⁷

Antibiotics: In an effort to practice antimicrobial stewardship and to avoid unnecessary exposure to antibiotics, antibiotics should be administered only to patients with suspected bacterial infections. Antibiotic are recommended for COPD exacerbations with the following features¹:

• Presence of all 3 cardinal symptoms: increase in dyspnea, sputum volume, and sputum purulence
• Increase in sputum purulence plus either increase in dyspnea or increase in sputum volume
• Requiring invasive or noninvasive mechanical ventilation

When antibiotics are used, treatment choice should be based on local antibiotic resistance patterns and may include an aminopenicillin with clavulanic acid, macrolide, or tetracycline. The antibiotic should be continued for 5 to 7 days.¹ The use of biomarkers, such as C-reactive protein and procalcitonin, for initiating or discontinuing antibiotics in COPD exacerbations is controversial. Earlier studies failed to identify an association between CRP levels and bacterial infection in COPD exacerbations, but more recent evidence demonstrates decreased antibiotic use when CRP is low.^38,39 Given the greater specificity for bacterial versus viral infections, procalcitonin is gaining favorability. Evidence suggests that procalcitonin-guided initiation of antibiotics is associated with decreased antibiotic prescribing without affecting clinical outcomes.⁴⁰

Vitamin D. Supplementation in patients with severe vitamin D deficiency has been associated with decreased COPD exacerbations and hospital admissions.⁴¹ Patients hospitalized with COPD exacerbations who have severe deficiency (i.e., <10 ng/mL) should receive vitamin D supplements.¹

Patient Case: The next day, TG develops increased work of breathing and worsening tachypnea with a respiratory rate of 42/min. An arterial blood gas is obtained, and it reveals oxygen saturation of 82% and Pco₂ of 64 mm Hg. The decision is made to transfer TG to the intensive care unit for a higher level of care. Does TG meet the criteria for mechanical ventilation? What changes should be made to his medication profile?

Special Considerations for the Intensive Care Unit

Indications for admission to the intensive care unit (ICU) include severe respiratory failure (i.e., need for invasive mechanical ventilation or dyspnea, hypoxemia, or respiratory acidosis that responds inadequately to supplemental oxygen or noninvasive ventilation), hemodynamic instability requiring vasopressors, or changes in mental status.¹ Types of respiratory support are reviewed in Table 5.

Antibiotic Therapy in the ICU. In the ICU setting, sputum cultures may be feasible and can help guide de-escalation of therapy. Sputum cultures are specifically recommended in patients with frequent exacerbations, severe airflow limitations, or requiring mechanical ventilation, as resistant pathogens may be present.⁴² In patients requiring mechanical ventilation, broader empiric therapy with antipseudomonal coverage may be considered. Procalcitonin-guided antibiotic therapy has been associated with reduced antibiotic exposure with no effect on treatment failure for COPD exacerbations in some populations. In the ICU setting, however, procalcitonin-guided algorithms for initiating or discontinuing antibiotics for COPD exacerbations have been associated with increased mortality and therefore should not be used.⁴³

Corticosteroid Therapy in the ICU. The GOLD Guidelines do not provide specific recommendations for corticosteroid therapy in patients requiring treatment in the ICU. For these patients, it may be prudent to consider intravenous therapy with an agent such as methylprednisolone. High doses of corticosteroids in critically ill patients have been proposed, but data have shown inconsistent results, with higher doses typically associated with worse clinical outcomes, including increased length of stay, prolonged mechanical ventilation, and increased rates of hyperglycemia.⁴⁴

Discharge Planning

Early follow-up within 1 month of hospital discharge has been associated with decreased COPD-related admissions and decreased mortality.⁴⁵ This initial follow-up should include a review of ongoing oxygen requirements as well as medication optimization. Additional follow-up should occur 3 months after discharge to ensure the patient’s return to baseline and to assess long-term prognosis.¹ After an acute exacerbation, maintenance medications should be optimized to reduce the risk of recurrent exacerbations. Other interventions to reduce the frequency of exacerbations should be considered, such as smoking cessation, rehabilitation, vaccines, lung volume reduction, and vitamin D.¹

ASTHMA

Patient Case: DG is a 15-year-old boy who presents to his PCP reporting intermittent symptoms of wheezing, shortness of breath, and chest tightness. He states that symptoms worsen with exercise and are present several days a week, and he has woken up twice in the last month due to shortness of breath. What could be the cause of his symptoms? What should a pharmacist recommend as initial therapy and why?

The Global Initiative for Asthma (GINA) updates guidelines annually for the management of asthma. The goal of these guidelines is to increase awareness about asthma among health care professionals, public health authorities and local communities to improve prevention and management of asthma through a coordinated worldwide effort.⁴⁶ These guidelines also provide a comprehensive and integrated approach to asthma management that can be adapted for local conditions and for individual patients. The National Heart, Lung, and Blood Institute (NHLBI) has also published guidelines on asthma, which were last fully update in 2012. The 2 guidelines differ in their classification of asthma severity and also have slight differences in treatment recommendations (Table 6).^46,47 This review focuses on the 2020 GINA Guidelines.

Asthma is a respiratory condition characterized by wheezing, shortness of breath, chest tightness, and expiratory airflow limitations that vary over time in their occurrence, frequency, and intensity. ⁴⁸ There are numerous factors that may trigger or exacerbate asthma symptoms. These include viral pathogens, tobacco smoke, allergens, exercise, and stress.⁴⁶

Diagnosis and Assessment

Pulmonary function tests (PFTs) are used in the diagnosis is asthma. Findings characteristic of asthma include FEV₁/FVC below normal limits, high degree of lung function variation (typically greater than 10% decrease from baseline⁴⁶), and the reversibility of these findings with bronchodilator administration (bronchodilator reversibility may be absent if a viral infection is present or if the patient is in a severe exacerbation).⁴⁶ These PFT components combined with a history of variable respiratory symptoms are consistent with a diagnosis of asthma.

Assessing a patient with asthma should include a review of symptom control over the last 4 weeks, specifically daytime symptoms, nighttime awakenings, SABA use, and activity limitation. Based on the assessment of asthma symptoms and identification of risk factors for poor asthma outcomes, the level of asthma control can be determined. All risk factors for poor asthma outcomes should be identified and modifiable risk factors should be addressed if possible. PFTs should be performed before starting treatment, 3–6 months later, and at least yearly thereafter.⁴⁶

Uncontrolled asthma is an important risk factor for exacerbations and poor outcomes.⁴⁹ Potentially modifiable risk factors according to the 2020 GINA Guidelines include⁴⁶:

• Medications: ICS not prescribed, poor adherence, incorrect inhaler technique, high SABA use
• Comorbidities: obesity, chronic rhinosinusitis, gastroesophageal reflux disease, food allergy, pregnancy
• Exposures: smoking, allergen, air pollution
• Setting: lower socioeconomic status
• Lung function: low FEV₁, especially if <60% predicted; higher reversibility
• Other tests: sputum/blood eosinophilia; elevated fractional exhaled nitric oxide in adults with allergic asthma on ICS

Patients with asthma may develop an accelerated decline in lung function that may not be fully reversible. Risk factors for developing persistent airflow limitation according to the 2020 GINA Guidelines include⁴⁶:

• Preterm birth, low birth weight, and higher rate of infant weight gain
• Lack of ICS treatment
• Exposures: tobacco smoke, noxious chemicals, occupational exposures
• Low FEV₁
• Chronic mucus hypersecretion
• Sputum/blood eosinophilia

Risk factors for medication side effects include frequent oral corticosteroids; long-term, high dose and/or potent ICS; coadministration of cytochrome P450 inhibitors; and poor inhaler technique.

Initial Pharmacologic Management

The Asthma Management Cycle is used to assess symptoms, adjust treatment, and review response in an attempt to reduce exacerbation risk and improve symptom control. Every patient should have a reliever inhaler prescribed for immediate symptom relief, with as-needed, low-dose ICS/formoterol being the preferred reliever for adults aged 12 years or older. For children 6–11 years old, SABA as needed is the preferred reliever. The major change to asthma management, made in the 2019 update of the GINA guidelines, is that SABA alone is no longer the preferred reliever. Rather, SABAs should only be used in combination with an ICS, both taken regularly or as needed for symptoms.²⁹ While a SABA provides quick relief of symptoms, regular use increases the allergic response and airway inflammation, which reduces the bronchodilator response to SABA. SABA overuse is associated with an increased risk of exacerbations and asthma-related death.⁴⁶

Recommendations for initial asthma treatment for adults and adolescents aged 12 years or older is summarized in Table 7. Most patients can be started with either daily low-dose ICS or low-dose ICS-formoterol as needed.⁴⁶ Asthma management centers around ICS dosing (high, medium, or low dose) in combination with a LABA. There are a few add-on therapies to discuss such as tiotropium and montelukast.

Tiotropium is the only approved LAMA for use to treat asthma and could be considered as add-on therapy to ICS-LABA as it modestly improves lung function and reduces exacerbation risk for adults in later phases of therapy. There is insufficient evidence to support its use in combination with an ICS over ICS+LABA, which is why it is add-on therapy only.²⁹

Montelukast is a leukotriene receptor antagonist (LTRA). Based on the new black box warning regarding the risk of serious mental health adverse effects, practitioners should consider risk versus benefit and properly counsel about the neuropsychiatric event risk before prescribing. Montelukast can be used as add-on therapy for those with concomitant allergic rhinitis or as a nonpreferred controller therapy alone or in combination with an ICS for adults.

Therapy can be escalated or deescalated depending on the severity of presenting symptoms. Table 8 provides dosing information of inhaled corticosteroids.

The treatment algorithms for children aged 6–11 years and adolescents/adults are similar with a few exceptions. Since the focus of this paper is treatment of adults and adolescents, please refer to the GINA guidelines for more specific recommendations regarding treatment of asthma in children aged 6–11 years.⁴⁶

Patient Case: DG is initiated on low-dose budesonide taken daily with low-dose budesonide-formoterol prescribed to be taken as needed. DG has a follow-up visit with his PCP to reassess his asthma control after 3 months of therapy. DG reports that his symptoms have not improved, and he continues to have wheezing and shortness of breath several days a week, which he treats with as-needed, low-dose ICS-formoterol. Does DG need a step-up in therapy? How would a pharmacist determine this?

Follow-up Pharmacologic Management

Asthma severity is assessed retrospectively from the level of treatment required to control symptoms. Asthma that requires steps 1–2 on the algorithm is considered mild asthma, step 3 is considered moderate asthma, and steps 4–5 is considered severe asthma.⁴⁶

When investigating uncontrolled asthma, it is important to ensure appropriate inhaler technique and adherence to prescribed therapy, discuss barriers to care, confirm the diagnosis of asthma, remove potential risk factors, and treat comorbidities that could influence asthma control.⁴⁶ Once these are assessed and no issues are noted, then a step-up in therapy should be considered. When a step-up or step-down in therapy is made, the patient should self-monitor symptoms and/or peak flow to determine the effect of this therapy change.

The GINA guidelines provide alternative methods for stepping up therapy, including a sustained step-up lasting at least 2–3 months, a short-term step-up lasting 1–2 weeks, or a day-to-day adjustment. A short-term step-up is usually in response to a viral infection or allergen exposure. Day-to-day adjustment is usually reserved for patients with mild asthma on as-needed, low-dose ICS-formoterol or scheduled daily low-dose ICS-formoterol.⁴⁶ Table 9 provides more detail regarding preferred therapeutic options when stepping up therapy.

When considering a step-down in therapy, an appropriate time should be chosen (e.g., not travelling, sick, or pregnant). The goal of stepping down therapy is to reduce the ICS dose 25%–50% over 2–3-month intervals without stopping ICS therapy completely.⁴⁶ Patient-specific risk factors should be assessed and baseline status documented. Refer to the 2020 GINA Guidelines for more specific recommendations regarding stepping down therapy according to a patient’s current treatment step.⁴⁶

Health care team members should provide a written asthma action plan, monitor patients closely, and follow-up in an appropriate time frame after changes in therapy. An asthma action plan is an integral component of asthma self-management. The action plan provides patients with instructions on how to make short-term adjustments to their treatment in response to changes in the peak flow readings or their asthma symptoms. It also describes how and when to access medical care.^50,51 The action plan should be reviewed regularly and updated if the level of asthma control or treatments have changed.⁵² Templates are available online from organizations such as the Centers for Disease Control and Prevention/National Institutes of Health and Asthma and Allergy Foundation of America with model asthma action plans for reference.

Management of Asthma–COPD Overlap

There are distinct differences in the management of asthma and COPD. In COPD, long-acting bronchodilators are used as initial treatment and ICS therapy is generally reserved for patients with a high exacerbation risk, but for patients with asthma, ICS therapy is essential, either as monotherapy or in combination with a long-acting bronchodilator to reduce the risk of severe exacerbations and death. Patients with asthma–COPD overlap should be managed as asthma with no use of long-acting bronchodilators alone without ICS due to the increased risk of severe exacerbations and death. The 2020 GINA Guidelines have additional information regarding this issue. ⁴⁶

Patient Case: DG presents with his father to his local community pharmacy and request a refill of his albuterol MDI. As the pharmacist, you notice that the prescription was filled 10 days prior. What information does the pharmacist need to determine whether DG is experiencing an asthma exacerbation? What questions should the pharmacist ask to determine whether to refer DG to self-manage using his asthma action plan, to consult with his PCP, or to report to the ED for rapid treatment?

Recognizing Asthma Exacerbations

Asthma exacerbations are defined simply by the American Thoracic Society/European Respiratory Society as “events characterized by a change from the patient’s previous status.”⁵³ This includes progression of symptoms, such as shortness of breath, cough, wheezing or chest tightness, and a corresponding decrease in lung function.⁴⁶ Severe exacerbations require urgent action to prevent hospitalization or death, whereas moderate exacerbations require a change in treatment but are not life-threatening.⁵³ Asthma action plans should be used to help identify exacerbations based on changes in symptoms or changes in peak expiratory flow (PEF) or FEV₁.

Asthma exacerbations usually occur result from poor adherence with controller medications or exposure to external agents, such as viral respiratory infections, environmental or food allergens, air pollution, or seasonal changes.^46,54,55 Typical presenting signs and symptoms include dyspnea, tachypnea, tachycardia, hypoxia, chest tightness, and wheezing.

Asthma exacerbations can be self-managed by patients using an asthma action plan or treated across the spectrum of health care settings. Patients with mild or moderate exacerbations (PEF >50% predicted or best, no use of accessory muscles, heart rate <120 bpm, oxygen saturation 90%–95%) can be treated in the primary care setting, whereas those with severe exacerbations (tachypnea >30/minute, heart rate >120 bpm, accessory muscle use, oxygen saturation <90% or PEF ≤50% predicted) should be transferred to an acute care facility. Some patients can be treated adequately in the ED, while others with persistent severe symptoms will require admission to an inpatient hospital ward. Patients with drowsiness, confusion, or silent chest (tightening of lungs to the point that airflow is so limited that there is no wheezing) should be admitted to the intensive care unit.⁴⁶

Patient-specific factors that increase the risk of asthma-related death include a history of asthma exacerbations requiring mechanical ventilation, acute care utilization for asthma within the past year, current/recent use of oral corticosteroids, lack of maintenance ICS, overuse of SABAs, history of psychiatric disease, poor adherence with maintenance medications and/or asthma action plan, and history of food allergy.^56,57 Patients possessing these risk factors should undergo more frequent assessment by their PCP.⁴⁶

Patient Case: Upon further discussion with DG and his father, the pharmacist discovers that he has been using his albuterol inhaler every 3–4 hours for the past 3 days. His PEF was 70% of his personal best this morning. He does not appear to be in any acute distress nor does he appear to be using accessory muscles. His heart rate is 82 bpm, and respiratory rate is 22/minute. The pharmacist decides to refer DG to his PCP for outpatient treatment of an acute asthma exacerbation. What therapies should be initiated for treatment in the primary care setting?

Treatment of Asthma Exacerbations

Mild asthma exacerbations can be self-managed by the patient according to their asthma action plan. When a clinically noticeable change in the level of asthma control occurs, patients should increase the frequency of their reliever medication and increase the dose of their controller medication.⁴⁶ Increasing the dose of ICS-formoterol as the reliever has been demonstrated to reduce the rate of progression to severe exacerbation by two-thirds compared with initial treatment with SABA alone.⁵⁸ The dose of maintenance ICS should be quadrupled for a period of 2 to 4 weeks in order to decrease progression to severe exacerbation and to decrease the need for systemic corticosteroids. For patients who fail to respond to these changes in 2–3 days, have a PEV or FEV₁ <60% of personal best, or have a history of sudden severe exacerbations, prednisolone 40–50 mg/day should be initiated for 5–7 days. Patients who self-manage an asthma exacerbation should follow-up with their PCP within 1–2 weeks.⁴⁶

Interventions for use in the primary and/or acute care setting are described in Table 10.⁴⁶ Clinical status and lung function 1 hour after initiating treatment should be used to determine hospital admission or discharge from the ED. Patients with pretreatment PEF or FEV₁ <25% predicted or with posttreatment PEF or FEV₁ <40% predicted should be admitted to the hospital. Patients with posttreatment PEF or FEV₁ >60% predicted should be discharged home with follow-up in 2–7 days. Discharge medications should include initiation or dose escalation of maintenance ICS, continuation of oral corticosteroids to complete a 5- to 7-day course, and a reliever medication to be used as needed for symptoms. Discharge management should also include comprehensive education on self-management skills and a written asthma action plan.

CONCLUSION

By applying the clinical strategies summarized in this program, patients with COPD and/or asthma can enjoy the best possible health-related quality of life and reduced medical expenditures. Pharmacists have an important role to play in this care, one that is enhanced by staying current on pharmacotherapeutic and other options and annually reviewing available guidelines for management of these respiratory conditions.

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