Medication Regimens for Managing Stable Asthma Susanne Meghdadpour FNP PhD and Njira L Lugogo MD Introduction Asthma Phenotypes and Endotypes Review of a Stepwise Approach for Managing Stable Asthma Assessment of Contributing Factors Asthma Follow-up, Assessing Adherence, and Education Are Essential to Asthma Outcomes New Approaches to Managing Stable Asthma Intermittent Dosing of Controllers Therapies in Asthma Alternative Medications for the Management of Asthma Long Acting Muscarinic Antagonists (Long-Acting Anticholinergic): Tiotropium and Umeclidinium Phosphodiesterase-4 Inhibitor: Roflumilast 5-Lipooxygenase Antagonists: Zileuton Macrolide Antibiotic: Azithromycin Special Population Considerations Asthma COPD Overlap African-American Patients and Safety of LABAs Summary Recommendations for Clinicians Providing Care to Patients With Stable Asthma Guideline-based management of asthma was developed as a means of standardizing asthma ther- apies and of improving outcomes. The National Asthma Education and Prevention Program and the Global Initiative for Asthma guidelines provide recommendations to care providers about the routine management of asthma. There has been rapid development of new therapies for asthma, specifically with the advent of new drug delivery devices and biologic therapies for severe asthma. We are increasingly recognizing that asthma is a heterogenous disease with a diverse underlying pathophysiology, and therefore, it is imperative for care providers to begin to understand asthma phenotypes and endotypes, and the implications of these classifications on management, especially of severe refractory asthma. This article serves as a review of guideline-based therapy for asthma and includes updates on alternative therapies, new approaches that use previously recognized therapies, and special populations with asthma. Key words: asthma; management; phenotypes; guide- lines. [Respir Care 2018;63(6):759–772. © 2018 Daedalus Enterprises] Introduction as a way of summarizing the best available evidence on the management of asthma. The National Asthma Edu- Asthma is a heterogeneous disease that is character- cation and Prevention Program1 (NAEPP) and the Global ized by both inflammation and airways hyper-respon- Initiative for Asthma2 (GINA) guidelines are meant to siveness. Asthma affects millions of adults and children empower care providers with tools to help manage worldwide and is associated with a significant degree of asthma, with specific recommendations about selecting morbidity. Guideline-based management of asthma has initial therapies, systematically assessing response, and been recommended since the 1990s as a means of stan- adjusting therapies based on the individual response to dardizing asthma treatment across the age spectrum and medications. RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 759 MEDICATIONS FOR STABLE ASTHMA The NAEPP guidelines1 were last updated in 2007 and asthma. These classifications may significantly impact the included a key change in asthma management priorities. The management of asthma, especially refractory asthma.1,2 NAEPP 2007 guidelines1 shifted from a focus on severity- based asthma treatment recommendations to one that is fo- Asthma Phenotypes and Endotypes cused on achieving optimal asthma control regardless of un- derlying severity. Asthma severity is an inherent feature of Asthma is a heterogeneous disease composed of a com- the disease, and there has been increased recognition that bination of symptoms, inflammation, and lung function severity cannot always be altered; however, asthma control impairments. However, it is being increasingly recognized can be optimized regardless of the underlying severity of that a variety of pathophysiologic mechanisms lead to the disease. Per the NAEPP guidelines,1 good control for patients manifestation of asthma symptoms. Phenotypes are de- Ͼ12 y old includes the following: asthma symptoms Յ2 days/ fined as the observable properties of an organism that are Յ ␤ wk, nighttime awakenings 2 times a month, short-acting 2 produced by the interaction of genotype and the environ- agonist (SABA) use Յ2 days/wk, no interference with nor- ment. Endotype is proposed to be a subtype of a condition Ն 3 mal activity, and FEV1 of 80% predicted. defined by a distinct pathophysiologic mechanism. For The current guidelines1,2 recommend systematic ap- example, eosinophilic asthma is the phenotype but the proaches to determining the degree of asthma symptoms endotype would be late onset eosinophilic asthma driven and then assessing impairments caused by these symptoms by interleukin-5. The primary inflammatory mediator of with standardized questionnaires such as the Asthma Con- asthma was previously thought to be underlying allergic trol Test and the Asthma Control Questionnaire. These and eosinophilic inflammation, and led to the recommen- instruments can be administered during clinician visits, dation that inhaled steroids should be the cornerstone of and adjustments in therapy are made based on the degree therapy in persistent asthma. to which the individual patient’s asthma is controlled or We now understand that a large proportion of patients uncontrolled. The GINA guidelines2 (2017) included the with asthma (up to 50% of patients with mild-to-moderate addition of newer asthma therapies that were not in the asthma) do not have underlying eosinophilic inflamma- previous guidelines, including the use of tiotropium and tion, which makes it unlikely that a response to inhaled anti-interleukin-5 targeted therapies. Both guidelines are steroids will occur.4-6 This indicates that a significant num- consistent in the recommendation that corticosteroid-based ber of patients would benefit more from initial therapy anti-inflammatory therapies are the baseline treatment for with bronchodilators, such as long acting muscarinic an- all patients with asthma, with the addition of bronchodi- tagonists monotherapy, or by using alternative anti-inflam- lators (both short acting and long acting), leukotriene an- matory therapies, such as theophylline, roflumilast, or leu- tagonists, and targeted biologic therapies as adjunctive ther- kotriene modifiers. Although, the evidence that supports apies if asthma control is not achieved.1,2 This paper reviews alternative approaches is mounting, it is too early to make current recommendations and approaches to care per the changes to the asthma guidelines. The fact that patients current guidelines, and suggests that treatment, both now may receive therapies that are both expensive and highly and in the future, should also be driven by consideration of unlikely to be beneficial underscores the importance of phenotypes and endotypes associated with an individual’s correctly identifying asthma phenotypes, particularly in severe asthma when targeted therapies can be adminis- tered. The key barrier to correct identification of asthma phe- Dr Lugogo is affiliated with Division of Pulmonary and CRITICAL CARE Medicine, Department of Medicine, University of Michigan, Ann Arbor, notypes and endotypes in clinical settings is the inability to Michigan. Dr Meghdadpour is affiliated with Division of Pulmonary, access a readily available clinical test that accurately cat- Department of Pediatrics, Allergy and Sleep Medicine, Duke University, egorizes the type of inflammation present in the lungs of Durham, North Carolina. patients with asthma. Sputum remains the accepted stan- Dr Lugogo discloses relationships with Sanofi, AstraZeneca, GlaxoSmith- dard to identify the presence of eosinophils and neutro- Kline, Merck, and Teva. Dr Meghdadpour has disclosed no conflicts of phils in the lungs of patients with asthma, but, with few interest. exceptions, sputum testing remains a research tool, and many centers do not have the capability to perform sputum Dr Lugogo presented a version of this paper at the 56th RESPIRATORY differential cell counts in patients with asthma as a means CARE Journal Conference, Respiratory Medications for COPD and Adult Asthma: Pharmacologic Actions to Clinical Applications, held June 22– of guiding therapy. Until these challenges can be addressed 23, 2017 in St Petersburg, Florida. and further evidence to guide medical decision-making can be accumulated, there is little chance that personalized Correspondence: Njira L Lugogo MD, 300 North Ingalls St Suite 2C40, Ann Arbor, MI 48109-5400. E-mail: [email protected]. medicine in asthma management will be fully realized. Alternative approaches to help identify phenotypes and DOI: 10.4187/respcare.05957 endotypes of asthma are being developed, including the use 760 RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 MEDICATIONS FOR STABLE ASTHMA Persistent asthma: daily medication Intermittent Consult with asthma specialist if step 4 care or higher is required. asthma Consider consultation at step 3. STEP 6 STEP 5 PREFERRED STEP 4 PREFERRED Step up if needed PREFERRED (first, check STEP 3 High-dose ICS High-dose ICS adherence, Medium-dose + LABA + oral environmental + LABA PREFERRED ICS + LABA corticosteroid control, and STEP 2 comorbid Medium-dose ALTERNATIVE AND conditions) PREFERRED ICS AND STEP 1 OR ASSESS Low-dose ICS Low-dose ICS + Medium-dose CONTROL PREFERRED LABA ICS + either Consider ALTERNATIVE LTRA, Consider ALTERNATIVE omalizumab theophylline, or omalizumab Step down if SABA PRN for patients Low-dose ICS + zileuton for patients possible Cromolyn, either LTRA, who have nedocromil, who have theophylline, or allergies (and asthma is LTRA, or zileuton allergies well-controlled