From Science to Practice in Severe AsthmaThe pathophysiology and management of severe asthma was a major topic of sessions at CHEST 2018, the annual meeting of the American College

A CME/CE-certified supplement to CHEST® Physician

From Science to Practice in Severe Asthma Matching Treatment With Pathophysiology

2 / FROM SCIENCE TO PRACTICE IN SEVERE ASTHMA: MATCHING TREATMENT WITH PATHOPHYSIOLOGY

Table of ContentsIntroduction .................................................................................................................... 4Diagnosis and Workup of Severe Asthma: Back to Fundamentals .............................................. 4 Is It Asthma? ................................................................................................................................... 5Comorbid Contributors ....................................................................................................................... 5Therapy Optimization and Patient Factors ............................................................................................... 5

Asthma Learning Snapshot ............................................................................................................7Advanced Therapies for Severe Asthma: Biologic Therapy and Bronchial Thermoplasty ..................8Anti-IgE .......................................................................................................................................... 8 Anti-IL-5 ......................................................................................................................................... 8Anti-IL-4/IL-13 ................................................................................................................................. 9Anti-TSLP .......................................................................................................................................10Bronchial Thermoplasty .....................................................................................................................10

Non-T2 Asthma: From New Pathways to Novel Therapies ............................................................ 11Biologic Pathways in Non–Type 2 Pediatric Asthma: The Role of Obesity........................................................11The Role of Stress and Depression in Asthma Development .......................................................................11Non-T2 Asthma: Treatment Strategies ..................................................................................................12

An Online Tool for Shared Decision Making in Severe Asthma Care .............................................. 15Posttest and Evaluation ................................................................................................... 16

F. Eun-Hyung Lee, MD Associate Professor of MedicineDivision of Pulmonary, Allergy, and Critical Care MedicineDirector, Asthma, Allergy, and Immunology Program The Emory Clinic, Emory University School of MedicineAtlanta, Georgia

Faculty

This activity is supported by an independent educational grant from Sanofi Genzyme and Regeneron Pharmaceuticals.

Jointly provided by

Neither the editors of CHEST® Physician nor the Editorial Advisory Board nor the reporting staff contributed to this content. The ideas and opinions expressed are those of the faculty and do not necessarily reflect the views of the supporters, American College of Chest Physicians (CHEST), Postgraduate Institute for Medicine, Global Academy for Medical Education, or the Publisher.

A CME/CE-certified supplement to CHEST® Physician

From Science to Practice in Severe Asthma Matching Treatment With Pathophysiology

Mario Castro, MD, MPHAlan A. and Edith L. Wolff Professor of Pulmonary and Critical Care MedicineProfessor of Medicine, Pediatrics, and RadiologyWashington University School of MedicineSt. Louis, Missouri

Nicola A. Hanania, MD, MS, FCCP Associate Professor of MedicineDirector, Airways Clinical Research CenterBaylor College of MedicineDirector, Asthma and COPD ClinicBen Taub HospitalHouston, Texas

Merin Kuruvilla, MDAssistant Professor of MedicineDivision of Pulmonary, Allergy, and Critical Care MedicineEmory University School of MedicineAtlanta, Georgia

FROM SCIENCE TO PRACTICE IN SEVERE ASTHMA: MATCHING TREATMENT WITH PATHOPHYSIOLOGY / 3

Original Release Date: February 15, 2019 Expiration Date: February 15, 2020 Estimated Time to Complete Activity: 1.0 hour Media: Printed supplement Method of Participation Participants should read the activity information, review the activity in its entirety, and complete the online posttest and evaluation. Upon completing this activity as designed and achieving a passing score on the posttest, you will be directed to a Web page that will provide you infor-mation on how to receive your certificate of credit via e-mail or print it out. The online posttest and evaluation can be accessed at: https://tinyurl.com/AsthmaChest18. Inquiries may be directed to Global Academy for Medical Education at [email protected] or (973) 290-8225 or Postgraduate Institute for Medicine at (720) 895-5357. CME Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the American College of Chest Physicians (CHEST) and Global Academy for Medical Education. The American College of Chest Physicians is accredited by the ACCME to provide continuing education for physicians. The American College of Chest Physicians designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Joint Accreditation Statement

In support of improving patient care, this activity has been planned and implemented by Postgraduate Institute for Medicine and Global Academy for Medical Education.

Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the health care team. Continuing Nursing Education The maximum number of hours awarded for this Continuing Nursing Education activity is 1.0 contact hours. Designated for 1.0 of pharmaco-therapy credit for Advanced Practice Nurses. Maintenance of Certification (MOC) Statement Successful completion of this CME activity enables the participant to earn up to 1 MOC points in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC points. Upon successful completion of this course, CHEST will submit your completion data to ABIM via ACCME's Program and Activity Reporting System (PARS) for MOC points. Please allow 30 business days for your points to be reflected on your ABIM record. Target Audience This activity is intended for pulmonologists, family practitioners, inter-nists, physician assistants, nurse practitioners, and other clinicians who treat patients with asthma. Learning ObjectivesAt the conclusion of this program, participants should be better able to:• List the steps in the assessment of a patient with poorly

controlled asthma• Explain the use of advanced therapies, including biologics and

bronchial thermoplasty• Describe recent research on non–type 2 asthma and appropriate

treatment strategies for it• Explain how to use decision aids and other tools with patients to

guide them in shared decision making

Statement of Need The advent of targeted therapies and biomarkers in recent years has the potential to improve the care of severe asthma, but it also increases the complexity of its management. New data on biomarkers and asthma endotypes can help physicians choose among treatment options for particular groups of patients. New tools can help busy physicians share decision making with their patients. Clinicians are challenged to remain current with recommendations for applying the latest advances to clinical care. This supplement summarizes selected presentations about the most recent clinical and pathophysiological evidence in severe asthma from the annual meeting of the American College of Chest Physicians.

Disclosure Declarations Individuals in a position to control the content of this educational activity are required to disclose: 1) the existence of any relevant financial rela-tionship with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients with the exemption of non-profit or government organizations and non-health care related companies, within the past 12 months; and 2) the identi-fication of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved. The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with ACCME-defined commercial interests related to the content of this CME activity: Mario Castro, MD, MPH, Consultant: 4D Pharma, Aviragen, Boston Scientific, Genentech, Mallinckrodt, Nuvaira, Sanofi-Aventis, Teva, Therabron, Theravance, and VIDA. Grant/Research Support: AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, and Sanofi-Aventis. Speakers Bureau: AstraZeneca, Boehringer Ingelheim, Boston Scientific, Genentech, and Teva. Royalty: Elsevier.Nicola A. Hanania, MD, MS, FCCP, Consultant: AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi Genzyme. Grant/Research Support: AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline.F. Eun-Hyung Lee, MD, Consultant: AstraZeneca. Receipt of Intellectual Property Rights/Patent Holder: MicroBplex, Inc. Merin Kuruvilla, MD, has nothing to disclose.American College of Chest Physicians (CHEST) staff have nothing to disclose. The Postgraduate Institute for Medicine planners and managers have nothing to disclose. Global Academy for Medical Education planners and managers have nothing to disclose.

Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medica-tions, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Copyright © 2019 by Global Academy for Medical Education, LLC, Frontline Medical Communications Inc., and its Licensors. All rights reserved. No part of this publication may be reproduced or transmitted in any form, by any means, without prior written permission of the Publisher. Global Academy for Medical Education, LLC and Frontline Medical Communications will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein.


Diagnosis and Workup of Severe Asthma: Back to Fundamentals

Asthma Workup: Laboratory Testing7

• Pulmonary function tests/spirometry with bronchodilator challenge• Exhaled nitric oxide • CBC with differential, including eosinophil count• Serum IgE• Allergy panel or skin prick tests• Consider chest x-ray or CT scan if concomitant pulmonary disease is suspectedCBC, complete blood count; CT, computed tomography; IgE, immunoglobulin E.

An estimated 5% to 10% of patients with asthma have severe disease, defined as asthma that (1) requires treatment with high-dose inhaled corticosteroids (ICS) and either a long-acting β-agonist (LABA) or a leu-kotriene modifier/theophylline for the previous year, or systemic corticoste-roids for at least 50% of the previous year to prevent it from becoming uncontrolled, or (2) remains uncon-trolled despite this therapy.1,2 Effective management of the care of these patients requires a careful workup to confirm the diagnosis of asthma and to identify comorbidities and their potential contributions to symptoms.

Patient factors such as knowledge of their disease, medication adherence, inhaler technique, insurance coverage, and environmental exposures also should be assessed, as these may

affect disease control. This article reviews these topics based on presen-tations at the CHEST Annual Meeting 2018 by Laren Tan, MD, FCCP, and Monica Kraft, MD, FCCP.3,4

IntroductionResearch into the pathophysiology of severe asthma has expanded substantially in recent years, identifying multiple potential targets for therapies for patients with type 2 inflammation who do not respond to standard care. The pathophysiology and management of severe asthma was a major topic of sessions at CHEST 2018, the annual meeting of the American College of Chest Physicians. This supplement reports on the highlights of selected sessions on severe asthma.

The first step in managing the care of patients with difficult-to-control asthma is to confirm the diagnosis, review adherence, and address potential exacerbating factors. In this supplement, we summarize information from presentations by Laren Tan, MD, FCCP, and Monica Kraft, MD, FCCP, briefly reviewing asthma diagnosis, common comorbidities, and optimization of standard therapy. Multiple biologic therapies are available for patients with markers for type 2 inflammation. Presentations by Nicola A. Hanania, MD, MS, FCCP, and Linda Rogers, MD, FCCP, reviewed the latest studies of anti-immunoglobulin E (IgE), anti-interleukin (IL)-5, and anti-IL-5/IL-13 agents in severe asthma, as well as a trial of the investigational anti-thymic stromal lymphopoietin. Bronchial thermoplasty may be appropriate for certain patients. Diego J. Maselli, MD, FCCP, summarized the evidence for this procedure in his presentation.

Knowledge of the etiology of asthma in those who do not respond to the recently introduced biologics is at an early stage. Deepa Rastogi, MD, reviewed studies by her group and others elucidating the inflammatory, pulmonary, and genetic characteristics of children with asthma and obesity. Erick Forno, MD, MPH, presented the evidence for associations between stress, depression, community violence, and asthma development. Joshua L. Denson, MD, MS, and Jay I. Peters, MD, FCCP, summarized data evaluating the use of long-acting muscarinic antagonist therapy or macrolide antibiotics.

A patient-clinician partnership is crucial for control of asthma. Tonya Winders, MBA, of the Allergy & Asthma Network introduced an online shared decision-making tool for patients with severe asthma and their clinicians at the annual meeting.

We hope that this information provides a valuable update to your clinical practice.


Is It Asthma?Asthma has many mimics; before choosing therapy, the clinician should determine that the patient with what appears to be difficult-to-treat asthma has been diagnosed correctly.1 The standard criteria for an asthma diag-nosis require a characteristic pattern of symptoms such as wheezing, dys-pnea, chest tightness or cough, and variable expiratory airflow obstruction with bronchodilator reversibility.5 Some patients with severe asthma have fixed obstruction.6 Laboratory testing does not con-firm but can support the diagnosis of asthma and can help differentiate between type 2 vs non–type 2 asthma (see Asthma Workup: Laboratory Testing7). This determination can guide choice of therapy.

Comorbid ContributorsSevere asthma is often associated with comorbidities that may cause or exac-erbate asthma symptoms.1 Common comorbidities in patients with asthma include the following:

Sinusitis/RhinitisAn estimated 80% to 90% of patients with asthma have allergic rhinitis.8 In one study, about 37% of patients with asthma had sinusitis.9 Computed tomography (CT) scoring identified extensive sinus disease in 24% of patients with severe asthma in another study.10 This relationship was most pronounced in subjects with late-onset asthma. CT scores were correlated with sputum and peripheral blood eosinophils as well as exhaled nitric oxide—all biomarkers for type 2 inflam-mation. Sinonasal mucosal thickness was directly related to bronchial inflam-mation.10 Chronic sinusitis with nasal polyps is, in particular, associated with late-onset severe asthma.11,12

Gastroesophageal Reflux DiseaseFrom 32% to 84% of patients with asthma have abnormal acid reflux, according to esophageal pH-monitoring studies. Proton pump inhibitor ther-apy did not improve asthma control in patients with asymptomatic acid reflux and poorly controlled asthma, in terms of objective outcomes (lung function and airway hyperresponsiveness) as well as exacerbations, symptoms, and quality of life.13

ObesityRates of obesity are higher among patients with severe asthma than in the general population. In the United States, obesity affects 19% of children and 40% of adults,14 but among those with severe asthma, it affects 31% of children and 57% of adults, according to the TENOR (The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens) study.15,16 Obesity has been associated with late-onset asthma in both males and females, with a more pronounced effect in women.16 Self-reported obesity, defined as a body mass index (BMI) ≥30 kg/m2, affected about 43% of older adults (≥65 years old) with asthma, in an analysis of the 2006-2010 Medical Expenditure Panel Survey data.17 Obese individuals who have asthma are known to have worse asthma control and increased rates of asthma-related health care utilization compared with nonobese individuals who have asthma.16

Anxiety and Depression SymptomsPrednisone maintenance treatment in severe asthma has been linked to higher rates of clinically significant depressive symptoms, compared with patients with severe asthma not taking prednisone (9% vs 0%, respectively; P=0.04). Patients with prednisone- dependent asthma also were more likely to have anxiety symptoms than those with severe non–prednisone- dependent asthma (19% vs 6.4%, respectively; P=0.01).18

Obstructive Sleep Apnea (OSA) Roughly 50% of adults with asthma have OSA, according to a meta- analysis. Adults with asthma are 2.64 times more likely than those without asthma to have OSA. A recent study found that adults with asthma who also have OSA had a significantly higher BMI than those without OSA.19

Vocal Cord Dysfunction (VCD) Paradoxical vocal fold motion or VCD can both be confused for and coexist with asthma. Overall, the true preva-lence of VCD in asthma is still unknown but was 19% among patients with asthma and 5% in controls (P<0.001) in one small series (n=20).20

Asthma and Chronic Obstructive Pulmonary Disease Overlap Syndrome (ACO) The term ACO is used to classify those with clinical features of both entities, such as patients with asthma who have fixed obstruction or neutrophilic inflammation, and patients with chronic obstructive pulmonary disease (COPD) who have airway eosinophilia. An estimated 27% of patients with COPD have features of asthma, according to a meta-analysis. These individuals are significantly younger than those with only COPD or with a higher BMI and are more likely to have poorly con-trolled disease. Patients with COPD and reversible obstruction (≥12% and ≥200 mL change in forced expiratory volume in 1 second from baseline [FEV1]), peak expiratory flow variability (≥20% change), or airway hyperresponsive-ness to methacholine or histamine were considered to have ACO.21

Therapy Optimization and Patient FactorsSome patients referred to specialists because of poorly controlled asthma have not received treatment with optimized doses of high-dose ICS and LABA or leukotriene modifier therapy, as recommended by the most recent guidelines.1,5 Reviewing inhaler tech-nique with patients may improve drug delivery. Asking patients when they take their medications and how they remember to take them (eg, after meals, before bedtime) may uncover adherence issues. Asking patients what complicates medication adherence may reveal inadequate insurance cover-age or lifestyle factors that interfere with taking the prescribed regimen. Addressing each of these issues may boost asthma control.If inadequate control persists despite these steps, consider adding a non-biologic therapy (eg, tiotropium), if appropriate. Patients whose disease remains poorly controlled should be referred to a specialist with exper-tise in managing severe asthma.5 If laboratory testing uncovers high levels of eosinophils or evidence of atopic dis-ease (eg, positive allergy skin test or specific immunoglobulin E), then a trial of biologic therapy may be considered in patients who are unresponsive to high-dose ICS and LABA or leukotriene modifier therapy.7


The Figure displays a suggested pathway once the clinician has con-firmed the diagnosis of asthma, ruled out or addressed the contributions of comorbidities, and addressed inhaler technique and adherence.

References1. Chung KF, Wenzel SE, Brozek JL, et al. International

ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014; 43(2):343-373.

2. Blaiss MS, Castro M, Chipps BE, Zitt M, Panettieri RA Jr, Foggs MB. Guiding principles for use of newer biologics and bronchial thermoplasty for patients with severe asthma. Ann Allergy Asthma Immunol. 2017;119(6):533-540.

3. Tan LD. Define and review updated guidelines provided for the workup of severe refractory asthma. Presented at: American College of Chest Physicians (ACCP) CHEST Annual Meeting 2018; October 8, 2018; San Antonio, TX.

4. Kraft M. Discuss available biologic therapy and share experience of the prior workup recommended before starting biologic therapy. Presented at: American College of Chest Physicians (ACCP) CHEST Annual Meeting 2018; October 8, 2018; San Antonio, TX.

5. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2018. www.ginasthma.org. Accessed January 14, 2019.

6. Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med. 2017;377(10):965-976.

7. Tan LD, Yoneda KY, Louie S, Hogarth DK, Castro M. Bronchial thermoplasty: a decade of experi-ence: state of the art. J Allergy Clin Immunol Pract. 2019;7(1):71-80.

8. Leynaert B, Neukirch F, Demoly P, Bousquet J. Epidemiologic evidence for asthma and rhinitis comorbidity. J Allergy Clin Immunol. 2000;106 (5 suppl):S201-S205.

9. Matsuno O, Ono E, Takenaka R, et al. Asthma and sinusitis: association and implication. Int Arch Allergy Immunol. 2008;147(1):52-58.

10. ten Brinke A, Grootendorst DC, Schmidt JT, et al. Chronic sinusitis in severe asthma is related to sputum eosinophilia. J Allergy Clin Immunol. 2002;109(4):621-626.

11. Lin DC, Chandra RK, Tan BK, et al. Association between severity of asthma and degree of chronic rhi-nosinusitis. Am J Rhinol Allergy. 2011;25(4):205-208.

12. Wu D, Bleier BS, Wei Y. Progression from nasal pol-yps to adult-onset asthma: a different process from atopic march? Rhinology Online. 2018;1:22-29.

13. Mastronarde JG, Anthonisen NR, Castro M, et al. Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med. 2009;360(15):1487-1499.

14. Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of obesity among adults and youth: United States, 2015–2016. NCHS Data Brief. 2017;(288):1-8.

15. Schatz M, Hsu JW, Zeiger RS, et al. Phenotypes determined by cluster analysis in severe or difficult-to-treat asthma. J Allergy Clin Immunol. 2014;133(6):1549-1556.

16. Tashiro H, Shore SA. Obesity and severe asthma. Allergol Int. 2018. doi.org/10.1016/j.alit.2018.10.004

17. Shah R, Yang Y. Health and economic burden of obe-sity in elderly individuals with asthma in the United States. Popul Health Manag. 2015;18(3):186-191.

18. Amelink M, Hashimoto S, Spinhoven P, et al. Anxiety, depression and personality traits in severe, prednisone-dependent asthma. Respir Med. 2014;108(3):438-444.

19. Kong DL, Qin Z, Shen H, Jin HY, Wang W, Wang ZF. Association of obstructive sleep apnea with asthma: a meta-analysis. Sci Rep. 2017;7(1):4088.

20. Yelken K, Yilmaz A, Guven M, Eyibilen A, Aladag I. Paradoxical vocal fold motion dysfunction in asthma patients. Respirology. 2009;14(5):729-733.

21. Alshabanat A, Zafari Z, Albanyan O, Dairi M, FitzGerald JM. Asthma and COPD overlap syndrome (ACOS): a systematic review and meta analysis. PLoS One. 2015;10(9):e0136065.

Figure. Workup for Patients With Poorly Controlled Asthma4

NO

Refer patient to an asthma specialist

Consider adding a non-biologic therapy• Tiotropium• Leukotriene modifier• Theophylline• Macrolide antibiotic• Oral glucocorticoid (short course)

• Exclude comorbid disorders and poor adherence to medication

• Step up to a high-dose ICS + LABA

Is asthma still uncontrolled* despite high-dose ICS + LABA

and a nonbiologic add-on therapy?

YES

Close follow-upReduce treatment

intensity after at least 3-6 months of stable,

good control, per GINA/NAEPP guidelines

Is asthma still uncontrolled* despite high-dose ICS + LABA?

NO

Determine inflammatory endotype• Start with noninvasive testing

(allergy testing, IgE level, blood eosinophil count, and FeNo level)

• If poor response to therapy continues, consider induced sputum differential for eosinophil and neutrophil counts and/or bronchoscopy with endo-bronchial biopsy and BAL

YES

ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; BAL, bronchoalveolar lavage; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; GINA/NAEPP, Global Initiative for Asthma/National Asthma Education and Prevention Program; ICS, inhaled corticosteroid; IgE, immunoglobulin E; LABA, long-acting β-agonist.

Key Teaching Points• Severe asthma accounts for a small proportion of patients with asthma. If asthma is uncontrolled despite high-dose ICS

and LABA, confirm the diagnosis, consider the possible contribution of comorbidities, optimize therapy in accordance with the guidelines, and consider patient factors (eg, adherence, inhaler technique, lifestyle, insurance coverage).1,5

• For patients who continue to meet criteria for severe asthma, consider adding nonbiologic or biologic therapy if appropriate or referral to a specialist with expertise in severe asthma.5

*Asthma is uncontrolled if:• Poor symptom control (ACQ >1.5, ACT <20, or per GINA/NAEPP guidelines), or • ≥2 bursts of systemic corticosteroids for asthma exacerbation in the past year, or• ≥1 hospitalization for asthma in the past year, or• FEV1 <80% predicted when not taking short- or long-acting bronchodilators

57%27%

10%4%

2%

Extremely confident

Very confident

Confident

Somewhat confident

Not confident

How confident are you in your ability to use biomarkers in selecting treatment for patients with severe asthma?

In late 2018, the first two activities in this educational series began educating clinicians about treating severe asthma:Severe Asthma Reference Guide: Phenotypes, Endotypes, Biomarkers, and Treatment http://bit.ly/SevereAsthmaCMECE

Uncontrolled Moderate-to-Severe-Asthma: Latest Data From the Floor of CHEST 2018 https://reachmd.com/programs/cme/uncontrolled-moderate-severe-asthma-latest-data-floor-chest-2018/10484/

After reading the monograph, the clinicians’ levels of knowledge improved. Only 4% reported that phenotypes were “key to choosing therapy” and 70% knew, correctly, that phenotypes can be clas-sified as patient demographics, triggers, or clinical presentation. Substantial majorities showed an understanding of endotypes and biomarkers, including eosinophils, neutrophils, and the cytokines interleukin (IL)-4 and IL-13.

Their lack of confidence seems to reflect their limited knowledge about biomarkers. Only 17% were aware that so far, despite much research, asthma phenotypes cannot be used to predict endotypes or treatment response.

Asthma Learning Snapshot


Can be used to predict endotypes in many patients

Are useful in predicting response to therapy

Can help identify candidates for dupilumab treatment

Cannot predict endotype or response to therapy*

32%

17%

17%

34%

Phenotypic clusters in severe asthma…

However, about half of the learners understood the role of one biomarker, serum immunoglobulin E (IgE), in selecting treatment with omalizumab, a biologic that has been in use in the United States since 2003.

Data collected from learners were used, in part, to shape the focus of this educational supplement. Learner gaps in knowledge and competence were assessed, and specific deficiencies received extra emphasis in this activity. Please take a moment to review the data of your peers and consider how they compare to your knowledge levels and opinions.Severe Asthma Reference Guide: Phenotypes, Endotypes, Biomarkers, and TreatmentIn questions posed before the activity, clinicians demonstrated their limited knowledge about biomarkers and their lack of confidence in using them clinically.Physicians expressed a lack of confidence in using biomarkers to select treatment: 84% reported that they were “not confident” or only “somewhat confident.”

Each phenotypic cluster is associated with a specific disease mechanism Phenotypes can be classified as patient demographics, triggers, or clinical presentation* Phenotypes and endotypes are synonymous; both denote mechanisms of underlying disease Phenotypes are key to choosing therapy

19%

70%

7%4%

Which of the following best characterizes phenotypes of severe asthma?

IL, interleukin.

Increased synthesis of IL-5 Increased synthesis of IL-4

High levels of neutrophils*

High levels of eosinophils

64%

5%11%

20%

Which of these is associated with non–type 2 inflammation?

FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E.

Serum periostin Serum IgE

FeNO

Eosinophils in sputum or blood*

64%7%

27%

3%

Which of the following biomarkers has been shown to predict response to anti-IL-5 therapies approved for treatment of severe asthma?

IL, interleukin.

IL-33 IL-25

IL-5

IL-4 and IL-13* 10%

12%

75%

3%

Which of the following cytokines is/are targeted by dupilumab?

46%

17%

24%

14%Contributes to identifying candidates for omalizumab treatment*Predicts response to omalizumab treatment

Predicts response to anti-IL-5 therapies in patients with allergic asthma

Is useful in neither choosing candidates for therapy nor in predicting therapeutic response

IL, interleukin.

The biomarker IgE...

*Correct answer

Our understanding of the diverse pathophysiology of severe asthma has expanded substantially in recent years, as have the therapies to treat this condition.1 This article reviews the data for biologic agents targeting immu-noglobulin E (IgE); interleukin (IL)-5, IL-4, and IL-13; and thymic stromal lymphopoietin (TSLP). The pivotal trials for these therapies measure efficacy as the annualized rate of asthma exacer-bations with these agents as compared with placebo when each is added to background therapy.2-8 Separate trials have assessed the effect of three biologic therapies (mepolizumab, benralizumab, and dupilumab) on the use of maintenance oral corti-costeroids.9-11 This article describes the use of these therapies, as well as bronchial thermoplasty. This article is based on presentations at the CHEST Annual Meeting 2018 by Nicola A. Hanania, MD, MS, FCCP; Linda Rogers, MD, FCCP; and Diego J. Maselli, MD, FCCP.12-14

Anti-IgE High levels of serum IgE signal allergic sensitization as well as type 2 inflam-mation.15 Elevated levels of serum IgE were found in roughly 53% of patients with severe asthma in a Belgian registry.16 The humanized anti-IgE monoclonal antibody omalizumab inter-rupts the allergic cascade by binding free IgE, thereby preventing IgE from binding with receptors on mast cells, antigen-presenting cells, and other inflammatory cells.17 Omalizumab also downregulates the expression of IgE receptors on mast cells and basophils.18 It was the first biologic approved for asthma by the US Food and Drug Administration (FDA), in 2003.Omalizumab reduced the annual relative risk of asthma exacerbation by 38% and the risk of emergency visits by 47% compared with controls, according to pooled data from seven randomized studies (P<0.0001 vs control for both comparisons; N=4,308 patients, 93% with severe persistent asthma). Patients with more severe asthma (ie, <60% forced expiratory volume in 1 second [FEV1] at baseline) appeared to derive the greatest abso-lute benefit.2 Omalizumab also reduced the number of systemic corticosteroid bursts (relative risk reduction of 43% compared with controls; P<0.001).19

An analysis of a real-world data set reports similar benefits, with omali-zumab effectiveness persisting for up to 2 years. Among 943 patients with uncontrolled persistent allergic asthma, 694 completed 2 years of follow-up. The proportion of patients with no clin-ically significant exacerbations rose from 6.8% during the year before starting omalizumab to 54.1% and 67.3% after 1 and 2 years of omalizumab therapy, respectively. Symptoms and rescue medication use fell by more than 50% after 2 years, compared with base-line. The use of oral corticosteroids as maintenance therapy decreased from 28.6% at baseline to 14.2% after 2 years of omalizumab therapy.20 Omalizumab therapy blunted the seasonal (spring/fall) spike in exac-erbations characteristic of allergic asthma, according to a post-hoc analysis of a study in inner-city children and young adults.21 This finding suggests that omalizumab may reduce the risk of viral infection, a major cause of seasonal asthma exacerbation, by dampening allergic inflammation. Recent studies have suggested that allergic inflammation itself can inhibit innate antiviral immune responses.22 Mechanistic studies indicate that omalizumab treatment augments plasmacytoid dendritic cell interferon-α responses while decreasing high- affinity Fcε receptor expression, providing evidence of the relation-ship between these effects.23 A study examining whether omalizumab can prevent the onset of asthma in preschool children at high risk for the disease is in progress (NCT02570984).Which patients are likely to respond to omalizumab? Data on this point are mixed. High levels of fractional exhaled nitric oxide (FeNO, ≥19 ppb), peripheral blood eosinophils (≥260/µL), or serum periostin (≥50 ng/mL) pre-dicted greater likelihood of response (ie, reduced exacerbations) in a post-hoc analysis of a clinical trial of patients with uncontrolled severe persistent allergic asthma.24 A real-world study in patients with severe allergic asthma did not support this finding; the rate of exacerbations with omalizumab was similar regardless of baseline eosinophil levels (blood eosino-phil count <300 or ≥300 cells/µL).25

Anti-IL-5High levels of eosinophils also charac-terize type 2 inflammation in severe asthma.16 The cytokine IL-5 is asso-ciated with eosinophil production, differentiation, maturation, activa-tion, and survival, as well as airway remodeling.15,26,27 Three therapies targeting IL-5 are FDA approved for use in patients with severe asthma and an eosinophilic endotype: the anti-IL-5 agents mepolizumab and reslizumab, and the IL-5 receptor-α antagonist benralizumab. All three medications have reduced exacerba-tions by roughly 50% compared with placebo in patients with severe asthma and high eosinophil levels, with the latter variously defined depending on the medication (Table 1).3-6,28-31 The overall rate of adverse events for all three medications was similar to that of placebo.3-6 Patients with certain characteristics derived more benefit from the anti-IL-5 therapies. In mepolizumab stud-ies, those with a baseline eosinophil count of at least 500 cells/µL showed a greater reduction in clinically signifi-cant exacerbations (by 79% vs placebo, compared with a 53% reduction for the overall mepolizumab group).3,9 With reslizumab, benefit was greater in those with late-onset (age of onset ≥40 years) rather than early-onset asthma (75% vs 42% relative reduc-tion in exacerbations vs placebo).32 For benralizumab, the degree of improve-ment (reduction in exacerbation risk) was significant for those with a history of more frequent exacerbations and baseline eosinophil levels ≥150 cells/µL, and rose proportionately with blood eosinophil thresholds.33

Mepolizumab therapy for 20 weeks enabled patients dependent on systemic glucocorticoids to reduce their oral steroid dose by a median of 50%. Despite reduced steroid dosage, patients randomized to mepolizumab experienced a 32% reduced annual rate of exacerbations compared with placebo.9 Benefits (reduced exacer-bation rate and oral corticosteroid use) and safety persisted at 1-year follow-up.34 Benralizumab reduced the median oral glucocorticoid dose by 75% from base-line to week 28 in steroid-dependent, eosinophilic patients (≥150 cells/µL

Advanced Therapies for Severe Asthma: Biologic Therapy and Bronchial Thermoplasty



at baseline). The annual exacerbation rate also improved significantly with benralizumab, by 55% or 70% (doses every 4 weeks and every 8 weeks, respectively) compared with placebo.10

The effects of mepolizumab and reslizumab on exacerbation rate have been studied only in patients with high eosinophil levels: for mepolizumab, defined as ≥150 cells/µL at screening or ≥300 cells/µL at some point during the prior year,3,35 and for reslizumab, ≥400 cells/µL.4 Eosinophil cut points were not among the inclusion criteria for benralizumab trials, but results were stratified by eosinophil count.5,6 A pooled analysis of the pivotal benralizumab trials reported a signif-icant reduction in exacerbation rate among those with ≥150 eosinophils/µL but not for patients with eosinophils <150 cells/µL at baseline.33 All anti-IL-5 agents produced what a Cochrane analysis termed a “small but statistically significant improve-ment” in mean prebronchodilator FEV1 (0.08-0.11 L).36 All anti-IL-5 agents substantially reduced blood eosinophil counts; benralizumab resulted in near depletion of eosinophils.36

Anti-IL-4/IL-13Dupilumab represents the most recently FDA-approved biologic therapy for severe asthma. It binds to the α subunit of the IL-4 receptor and inhibits both IL-4 and IL-13 signaling.37 IL-4 and IL-13 are both components of the type 2 inflammatory cascade in severe asthma. A phase 3 trial of dupilumab accepted patients regardless of baseline eosin-ophil count but reported results stratified by eosinophil count as well as for the overall population. At the two doses studied, dupilumab significantly reduced the annualized exacerbation rate compared with placebo in the overall population and even more prominently in those with ≥300 eosinophils/µL. For those with ≥150 to <300 cells/µL, the relative reduction in exacerbation rate with dupilumab was significant only with the higher dupilumab dose (Table 2).7,31 Patients with higher baseline FeNO (≥25 to <50 ppb or ≥50 ppb) also showed a greater reduction in exacerbation rate compared with those who had a lower baseline FeNO (<25 ppb).7

Dupilumab also significantly improved prebronchodilator FEV1 at week 12 by 0.14 L with the lower dose and by 0.13 L with the higher dose as com-pared with change from baseline FEV1 with matched placebo. Again, bene-fits were greater in those with higher baseline eosinophils (≥300 cells/µL) and FeNO (most marked at ≥50 ppb).7 Dupilumab enabled a significant reduction in the use of oral glucocor-ticoids in glucocorticoid-dependent patients with severe asthma. After 24 months of dupilumab treatment, the glucocorticoid dose was reduced by 28.2% compared with placebo (−70.1% and −41.9% with dupilumab and placebo, respectively; P<0.001). Nearly half (48%) of patients ran-domized to dupilumab in this study discontinued oral steroids, compared with a quarter (25%) of those receiv-ing placebo therapy. Reduction in glucocorticoid dose with dupilumab occurred regardless of baseline blood eosinophil count, but patients with higher baseline eosinophil counts showed greater benefits.11

Table 1. FDA-Approved Anti-IL-5 and Anti-IL-4/IL-13 Therapies: Pivotal Trials

Agent Patients Effect on Annualized Exacerbation Rate vs Placebo FDA-Approved Dosage

Mepolizumab (anti-IL-5)*

N=576; blood eosinophils ≥150/µL at screening or ≥300/µL within the prior year3

i53%; P<0.001 SC: 100 mg q4w28

Reslizumab (anti-IL-5)

N=953; 2 identical randomized controlled trials; blood eosinophils ≥400 cells/µL4

i50%, i59%; P<0.0001 IV infusion: 3 mg/kg q4w29

Benralizumab (anti-IL-5 receptor-α)

N=1205 and N=1306; 2 identical randomized controlled trials; no eosinophil criteria but in primary analysis population, blood eosinophils ≥300 cells/µL (n=809, n=728)5,6

Primary analysis population: i45%, q4w; i51%, q8w; P<0.0001, both comparisons5 i46%, q4w; P=0.002; i38%, q8w; P=0.0196

SC: 30 mg q4w SC for first 3 doses, then 30 mg q8w SC30

Dupilumab (anti-IL-4/IL-13)

N=1902; no eosinophil criteria7 Full study population: i48%, 200 mg q2w, i46%, 300 mg q2w vs placebo; P<0.001 ≥300 cells/µL: i66%, 200 mg q2w, i67%, 300 mg q2w vs placebo; P<0.001≥150-<300 cells/µL: i36%, 200 mg q2w; NS; i43%, 300 mg q2w

SC: Initial dose of 400 mg, then 200 mg q2w or initial dose of 600 mg, then 300 mg q2w31

FDA, US Food and Drug Administration; IL, interleukin; IV, intravenous; NS, not significant; q2w, every 2 weeks; q4w, every 4 weeks; q8w, every 8 weeks; SC, subcutaneous. *SC formulation.

Anti-TSLPAn epithelial cell–derived cytokine, TSLP has a pivotal role in trigger-ing allergic and nonallergic type 2 inflammation. The human anti-TSLP monoclonal antibody tezepelumab has effects upstream of the aforementioned biologic agents.15 In a phase 2 trial of 584 adults with poorly controlled severe asthma, tezepelumab significantly reduced the annualized exacerbation rate as compared with placebo after 52 weeks of therapy at all doses studied (relative reductions of 61%, 71%, and 66% with three tezepelumab doses as compared with placebo; P<0.001 for all comparisons). The benefit was similar regardless of baseline eosinophil count. Tezepelumab therapy significantly reduced serum IgE, blood eosinophils, and FeNO levels. The overall rate of adverse events with tezepelumab was similar to that of placebo.8 The FDA has designated tezepelumab as a breakthrough therapy,38 and phase 3 studies of tezepelumab are in progress (NCT03347279 and NCT03406078).

Bronchial ThermoplastyA procedural alternative for a subset of patients, bronchial thermoplasty involves heating a portion of the airways by threading a radiofrequency

catheter through a bronchoscope. This procedure is performed on an outpatient basis, three times at 3-week intervals for up to 45 minutes per session. The mechanism of action is, in part, a decrease in airway smooth muscle on the premise that smooth muscle hypertrophy can worsen bronchoconstriction.39 In a trial leading to FDA approval of this procedure, 297 patients with severe asthma were randomized to bronchial thermoplasty or a sham control procedure. Over a 12-month follow-up period, a significantly higher proportion of patients receiving the therapeutic intervention showed improved quality of life (79% vs 64%; Asthma Quality of Life Questionnaire [AQLQ] score of ≥0.5), though a sub-stantial placebo effect was reported. The rate of hospitalization within 6 weeks of treatment was 6% higher among those who underwent bronchial thermoplasty. The rates of severe exacerbations, emergency department visits, and days missed from work or school during the 52 weeks postpro-cedure were all significantly lower in the bronchial thermoplasty group.40 Reductions in exacerbations and emergency department visits lasted through 5 years of follow-up. However,

there was no effect on lung function as measured by spirometry following bronchial thermoplasty.41 Benefits were similarly sustained at 3-year follow-up of clinical trial participants and in 1-year post- procedure data from a real-world registry (Table 2).35,42 Lung function (prebronchodilator FEV1) remained unchanged from baseline through 3-year follow-up.35 Bronchial ther-moplasty was also associated with decreased asthma maintenance med-ication doses and increased quality of life.42 Bronchodilator responsiveness was not associated with the results of bronchial thermoplasty in a 42-patient series.43 A small (N=9) biopsy study demonstrated that a significant decrease in airway smooth muscle observed 3 weeks post–bronchial thermoplasty was comparable to one detected more than 27 months after the procedure.44 The treatment landscape for severe asthma has changed substantially since the FDA-approved bronchial ther-moplasty in 2010. Preferred criteria for patients undergoing bronchial thermo-plasty at one institution include FEV1 of at least 50% predicted, frequent exacerbations, and inability to use or unresponsiveness to biologic therapy.

Table 2. Bronchial Thermoplasty: Efficacy and Effectiveness

Study Patients, Follow-Up Severe Exacerbations* ED Visits* Hospitalizations*

AIR235 N=190, 3 years i37% i72% Up to i25%

PAS235 N=190, 3 years i45% i55% i40%

Bronchial Thermoplasty Global Registry42 N=159, 1 year i35% i65% i51%

AIR2, Asthma Intervention Research 2; ED, emergency department; FDA, US Food and Drug Administration; PAS2, Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma.*Compared with the 12 months preprocedure.

Key Teaching Points*• Biologics available to treat patients with evidence of type 2 inflammation include anti-IgE therapy with omalizumab,

anti-IL-5 therapy with mepolizumab and reslizumab, anti-IL-5 receptor-α therapy with benralizumab, and anti-IL-4/IL-13 therapy with dupilumab

• The anti-IL-5 and anti-IL-5 receptor-α therapies have demonstrated benefit in patients with high eosinophil counts• Dupilumab has demonstrated benefit across eosinophil counts, with greater benefit in those with higher eosinophil counts• The investigational anti-TSLP therapy tezepelumab appears to reduce exacerbations at a similar rate regardless of

baseline eosinophil count• Bronchial thermoplasty, designed to reduce airway smooth muscle and thereby alleviate smooth muscle

hyperreactivity, has demonstrated reduced exacerbations *IgE, immunoglobulin E; IL, interleukin; TSLP, thymic stromal lymphopoietin.


continued on page 14


Nearly half of patients with severe asthma have non–type 2 inflamma-tion,1 which often does not respond to standard therapy or approved biologics that largely target type 2 inflammation. This article summa-rizes recent evidence describing inflammatory, metabolic, and pulmo-nary characteristics of children and adolescents with early-onset, nonatopic, obesity-associated asthma. It also reviews the role of stress and depression in asthma and treatments for patients with non–type 2 asthma. It is based on presentations at the CHEST Annual Meeting 2018 by Deepa Rastogi, MD; Erick Forno, MD, MPH; Joshua L. Denson, MD, MS; and Jay I. Peters, MD, FCCP.2-5

Biologic Pathways in Non–Type 2 Pediatric Asthma: The Role of Obesity Childhood-onset asthma is classically associated with atopy and an inflam-matory state driven by T-helper type 2 (Th2) cells.6-8 Yet, not all children with asthma have allergies. Obesity, like asthma, is a chronic inflammatory state. It is characterized by high levels of leptin, an adipokine that promotes T-helper type 1 (Th1) cell differenti-ation.8,9 A 42-study review identified three studies evaluating the effect of comorbid overweight/obesity on the risk of nonatopic asthma in children, all of which identified a significant increase in risk.10 Biological evidence supports the hypoth-esis that children with asthma and obesity have different inflammatory and pulmonary function profiles from those of children who have asthma but not obesity. Rastogi and colleagues studied T-helper cell responses in children aged 7 to 11 years old with asthma and obesity (n=30), asthma but not obesity (n=30), obesity but not asthma (n=30), and neither asthma nor obesity (n=30).8 Compared with children who had asthma but not obe-sity, children with both conditions had significantly higher Th1 responses and significantly lower Th2 responses to two of three stimuli tested (tetanus toxoid, the polyclonal nonspecific mitogen phorbol 12-myristate 13-acetate, and Dermatophagoides farinae [house dust mite]). T-helper cell responses among children with obesity were similar regard-less of whether they also had asthma.8

Pulmonary function in children with asthma and obesity appears to correlate with obesity-mediated systemic inflam-matory patterns. Children with obesity and asthma had significantly lower forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) and residual volume/total lung capacity ratios compared with all the other study groups. FEV1/FVC, a measure of lower airway obstruction, correlated nega-tively with serum interferon-inducible protein 10 (a Th1 marker) in children with both asthma and obesity but not in those with asthma and no obesity. Residual volume/total lung capacity correlated negatively with interferon-γ levels only in children with both asthma and obesity.8 A study of adolescents (13-18 years old) with asthma and obesity, one of these conditions, or neither condition confirmed the presence of Th1 polar-ization in those with asthma and obesity, and linked it to metabolic parameters (serum homeostatic model assessment of insulin resistance and high-density lipoprotein cholesterol).11 To identify the pathways underlying these findings, Rastogi and col-leagues compared DNA methylation epigenome-wide in peripheral blood mononuclear cells from children with asthma and obesity, children with asthma but not obesity, children with obesity but not asthma, and con-trols with neither condition. Findings suggested that dysregulated DNA methylation was associated with the nonatopic inflammation observed in children with obesity and asthma, and that DNA methylation patterns in chil-dren with obesity and asthma differed from patterns in children with only one or neither of these conditions.12 To further investigate the mechanism of Th1-polarized inflammation in children with asthma and obesity, Rastogi and coworkers compared the CD4+ T-cell transcriptome in children with asthma and obesity (n=21) with those of nor-mal-weight children who had asthma (n=21). Results indicated that the genes associated with the protein CDC42 were upregulated in the T-helper cells of chil-dren with asthma and obesity. CDC42 is linked to T-cell activation and function. Counts of two CDC42-linked genes—CDC42EP4 and DOCK5—were inversely correlated with the FEV1/FVC ratio in children with asthma and obesity but

not in controls. Taken together, this implicates CDC42 in driving Th1 differ-entiation and pulmonary dysfunction in obesity-related asthma.13 The Figure summarizes the mecha-nisms suggested by these findings.8,11,13

The Role of Stress and Depression in Asthma Development Stress and depression have been caus-ally associated with the development of asthma as well as its concomitant presence in observational studies.14-18 Evidence is beginning to illuminate the pathophysiology of stress- or depres-sion-associated asthma.19 Preliminary findings suggest that the mechanisms are unrelated to type 2 inflammation but may occur through the modulation of lung development or through neu-roendocrine and autonomic responses in some cases,20 and may stem from type 2 inflammation in others through the potentiation of reactivity to allergens.19,21 Genetic and epigenetic factors in stress/depression-associated asthma have also been identified.22,23

Non-T2 Asthma: From New Pathways to Novel Therapies

Figure. Proposed Mechanism for the Relationship Between Obesity and Asthma

DyslipidemiaInsulin resistance

Obesity

Th1 polarizationCDC42 pathway

Pulmonary function deficits(aiway obstruction and low lung volumes)

Obesity-related asthma

Comorbid obesity in children and adolescents with asthma has been linked to Th1 polarization.8 Th1/Th2 responses in adolescents with asthma and obesity have been associated with metabolic parameters (insulin resistance, high-density lipoprotein cholesterol).11 Some measures of pulmonary function have been correlated with obesity-mediated systemic inflammatory patterns in children with asthma and obesity.8 CDC42 is linked to T-cell activation. FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; Th1, T-helper type 1 cell; Th2, T-helper type 2 cell.


Personal Stress, Depression, and AsthmaStressful life events in adolescence were associated with the subsequent development of asthma in the pro-spective, population-based Tucson Children’s Respiratory Study. The asso-ciation was significant only in males.14 Participants (n=318) completed the Life Events Questionnaire for Adolescents at age 16 and were followed there-after. A life event score signaling high stress at age 16 (ie, above the study population median) was signifi-cantly associated with higher risk of asthma at age 16 among males but not females. Among adolescents with no asthma through age 16, life event scores above the median were linked to a 4-fold higher risk of subsequently developing asthma between ages 18 and 29 years (adjusted relative risk, 4.07; 95% CI, 1.33-12.43; P=0.014). Again, when analyzed by gender, the risk was restricted to males.14 High school students with asthma were significantly more likely to report sui-cidal ideation, planning, attempt, and treatment for an attempt compared with those who did not have asthma. This association was no longer signifi-cant after adjustment for self-reported rates of 2-week sadness, however, suggesting that the higher rate of sadness among those with current or any history of asthma drove the higher rate of suicide-related measures. These findings come from an analysis of the US Centers for Disease Control and Prevention’s 2011 Youth Risk and Safety Behavior Survey of high school students (N=15,425).18 Major depression in adults was asso-ciated with a 3.4-fold higher risk of asthma compared with those reporting minimal or no depressive symptoms (95% CI, 2.6-4.5; P<0.01) in an analy-sis of data from the 2007-2012 National Health and Nutrition Examination Survey (N=20,272).16 Comorbid depression was associated with a 4.2% (95% CI, −7.5% to −0.8%; P=0.02) reduction in bronchodilator responsive-ness, compared with those who had asthma but minimal, moderate, or no depression.16

Maternal Stress/Depression and Childhood WheezingMaternal depression or stress during a child’s early life has been linked to higher rates of childhood wheezing. A mother’s depression in the 3 years

after giving birth was significantly associated with recurrent wheezing in the child at age 3, in an analysis of data from the Urban Environment and Childhood Asthma cohort (odds ratios [ORs] ranged from 1.30 to 1.54; all P<0.02). A mother’s perceived stress at years 2 and 3 after giving birth also was significantly associated with recurrent wheezing in the child at age 3 (ORs, 1.28-1.29; P=0.02-0.03).20

Neither maternal stress nor mater-nal depression was associated with enhanced type 2 cytokine responses in the child at age 3. In fact, mater-nal depression and perceived stress were negatively related to some type 2 responses in the child (interleukin [IL]-4, IL-5, and IL-13).20

Community Violence and AsthmaAsthma also has been linked to childhood exposure to community violence. In a study based on parents’ or guardians’ (n=1,232) responses to a questionnaire about community violence and children’s asthma symp-toms, exposure to violence was divided into quintiles. Children exposed to the highest rates of violence were nearly twice as likely to have asthma symp-toms as those not exposed to violence (asthma rates of 28.4% and 16.4%, respectively; adjusted OR, 1.94; 95% CI, 1.12-3.36).15 A case-control study (N=466) reported similar findings. Lifetime exposure to violence (defined as hearing a gunshot more than once and being afraid to leave their home because of violence) was linked to a 3.2-fold increased risk of asthma in children, compared with those exposed to neither form of violence (P<0.01). An exploratory analysis revealed that each 1-point increase in the composite score for violence exposure was significantly associated with 1.9-fold higher odds of asthma and atopy (ie, ≥1 positive immunoglobulin E [IgE] to allergens).17

How Might Stress Promote Asthma? Pathophysiology, Genetics, and EpigeneticsMultiple lines of evidence from animal and human studies suggest possible mechanisms linking stress and asthma. Studies in mice indicate that stress increases airway reactivity and aller-gen-induced airway inflammation.19 In children with a family history of atopy, parental stress during the first 6 months of life was associated with an increased allergen-specific response

and IgE production.24 In rats, prenatal exposure to stress was associated with lung hyperresponsiveness and increased expression of IL-5 and IL-13.21 Acute stress added to a background of chronic stress in children with asthma has been associated with a 5.5-fold reduced expression of glucocorticoid receptor mRNA and a 9.5-fold reduced expression of β2-adrenergic receptor mRNA compared with children who have asthma but did not experience such stress.25 Multiple clinical studies have reported a low hypothalamic- pituitary-adrenal (HPA) axis and reduced cortisol response to stress in patients with atopy, including patients with asthma treated with inhaled corticosteroids (ICS) and those not treated with ICS.19

Stress, Asthma, and Genetic/Epigenetic Changes The gene ADCYAP1R1 functions along with the HPA axis to regulate stress responses and has been associated with anxiety in children26 and posttraumatic stress disorder in women.27 Children exposed to violence had increased methylation of a CpG site in a sin-gle-nucleotide polymorphism (SNP) in the promoter of ADCYAP1R1 in one study. Increased methylation of this site also was associated with a higher risk of asthma (P=0.03).22 An SNP in the gene ADCYAP1R1 also has been associated with reduced bronchodilator response in children with asthma and with decreased expression of the gene for the β2-adrenergic recep-tor in CD4+ lymphocytes of patients with asthma. This same SNP also was linked to greater connectivity between the amygdala and the insula using brain magnetic resonance imaging. These regions of the brain have been associ-ated with anxiety in at-risk adults.23

Non-T2 Asthma: Treatment StrategiesStudies have evaluated the benefit of tiotropium and azithromycin in patients who do not have markers for type 2 asthma. Studies have also examined the effects of weight loss in patients with asthma and obesity. This section summarizes the data examining the use of these therapies.

Tiotropium A long-acting muscarinic antagonist (LAMA), tiotropium is the only drug in its class with an indication for asthma.

Adding tiotropium to patents who have poorly controlled asthma despite the use of ICS and long-acting β-agonist (LABA) therapy significantly increased the time to the first severe exacerba-tion, resulting in a 21% reduced risk of severe exacerbation over 48 weeks compared with placebo (P=0.03). It also improved peak FEV1 compared with placebo.28 Tiotropium reduced the risk of severe exacerbations and improved lung function irrespective of baseline eosinophil count or IgE level, in an exploratory analysis of four ran-domized phase 3 trials.29

AzithromycinThere is a mechanistic rationale for the use of antibiotics in asthma patients without evidence of infection. In addition to its anti-infective prop-erties, the macrolide erythromycin has been shown to inhibit activation of transcription factors nuclear fac-tor-kappa B and activator protein-1 and reduce levels of IL-8 (and thereby potentially neutrophil recruitment) in human bronchial cells.30 These transcriptional factors are ubiquitous inflammatory mediators that have been associated with asthma.31 Research on the use of antibiotics in asthma has had mixed results. A recent Cochrane analysis of six studies evaluated the efficacy of antibiotics given at the time of asthma exacerba-tion. Authors found limited evidence that such treatment may improve symptoms and peak expiratory flow rate. As findings were inconsistent and studies were heterogeneous, Cochrane review authors expressed “limited confidence in the results.”32 Studies on the use of azithromycin in asthma have reported positive findings with prolonged use. Azithromycin did

not demonstrate efficacy when given short-term (3 days) for treatment of patients seeking emergency care for an acute exacerbation of asthma.33 Six months of therapy with low-dose azith-romycin (250 mg/day for 5 days, then 250 mg 3 times/week) did not affect the primary outcome (rate of severe exacerbations and/or lower respiratory tract infections) in the study population as a whole (n=55, azithromycin; n=54, placebo) but did significantly reduce the primary outcome and the rate of exacerbations in the subgroup with noneosinophilic asthma.34 Long-term (48-week) therapy with higher-dose azithromycin (500 mg 3 times/week) reduced asthma exac-erbations in a large cohort of adults (N=420) who were symptomatic despite ICS and LABA therapy. Less than half (44%) of patients randomized to azithromycin experienced at least one exacerbation during the trial, compared with 61% of those receiving placebo (P<0.0001). More than half (57%) of the 420 patients in this trial had a noneosinophilic phenotype. The study population was mostly older (median age, ~60 years), with long-standing disease. Azithromycin significantly reduced exacerbations in those with and without eosinophilic asthma in a prespecified subgroup analysis. Benefit was also obtained in patients who were positive or negative for bacterial patho-gen isolation from sputum. There were also fewer respiratory infections with azithromycin overall. Of note, there was a nonsignificant increase in azithromy-cin-resistant bacteria in surveillance cultures of antibiotic-treated subjects.35 Some patients with refractory asthma may respond to antibiotics because of subclinical infection. In one study,

more than half (33/64; 52%) of patients with refractory asthma tested positive for Mycoplasma pneumoniae infection. Most (29/33) were identified using an ultrasensitive (not clinically available) assay for an inflammatory toxin associated with M. pneumoniae. About one-third (10/29) tested positive for the toxin multiple times over 633 days, suggesting chronic infection.36

Bronchoscopy, bronchoalveolar lavage, and cytology studies in a small group of patients suggest that subacute bacterial infection may be associated with neutrophilic asthma. Among 22 patients with Th2/Th17-low asthma, 45% had neutro-philic asthma, and 60% of those with neutrophilic asthma had evidence of subacute bacterial infection.37

References1. Schleich F, Brusselle G, Louis R, et al. Heterogeneity

of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR). Respir Med. 2014;108(12):1723-1732.

2. Rastogi D. Understanding new biologic pathways in non-Th2 asthma. Presented at: American College of Chest Physicians (ACCP) CHEST Annual Meeting 2018; October 8, 2018; San Antonio, TX.

3. Forno E. The role of stress and depression in asthma development. Presented at: American College of Chest Physicians (ACCP) CHEST Annual Meeting 2018; October 8, 2018; San Antonio, TX.

4. Denson JL. Novel therapies for non-Th2 asthma. Presented at: American College of Chest Physicians (ACCP) CHEST Annual Meeting 2018; October 8, 2018; San Antonio, TX.

5. Peters JI. Antibiotics in severe asthma: where do we stand? Presented at: American College of Chest Physicians (ACCP) CHEST Annual Meeting 2018; October 8, 2018; San Antonio, TX.

6. Eggleston PA, Rosenstreich D, Lynn H, et al. Relationship of indoor allergen exposure to skin test sensitivity in inner-city children with asthma. J Allergy Clin Immunol. 1998;102(4, pt 1):563-570.

7. Comberiati P, Di Cicco ME, D'Elios S, Peroni DG. How much asthma is atopic in children? Front Pediatr. 2017;5:122.

8. Rastogi D, Canfield SM, Andrade A, et al. Obesity-associated asthma in children: a distinct entity. Chest. 2012;141(4):895-905.

9. Ferrante AW Jr. Obesity-induced inflammation: a metabolic dialogue in the language of inflammation. J Intern Med. 2007;262(4):408-414.

10. Strina A, Barreto ML, Cooper PJ, Rodrigues LC. Risk factors for non-atopic asthma/wheeze in children and adolescents: a systematic review. Emerg Themes Epidemiol. 2014;11:5.

Key Teaching Points*• Comorbid obesity in children and adolescents with asthma has been associated with a pattern of Th1 polarization,

rather than the type 2 endotype more typically associated with childhood asthma.8 In adolescents with asthma and comorbid obesity, Th1/Th2 responses have been directly correlated with serum homeostatic model assessment of insulin resistance.11 Some measures of pulmonary function have been correlated with obesity-mediated systemic inflammatory patterns in children with asthma and obesity.8 Genes linked to a protein involved in T-cell activation have been inversely correlated with the FEV1/FVC ratio in children with asthma and obesity.13

• Evidence suggests that stress, violence, anxiety, and depression can affect asthma risk and reduce bronchodilator response. Early findings suggest that stress-related cytokines may lead to a hyporesponsive HPA axis and reduced response to corticosteroid and bronchodilator therapy.

• Data support the long-term use of tiotropium or azithromycin in refractory asthma. Further studies are needed to assess the role of subacute bacterial infection in chronic neutrophilic asthma.

*FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HPA, hypothalamic-pituitary-adrenal; Th1, T-helper type 1 cell; Th2, T-helper type 2 cell.



11. Rastogi D, Fraser S, Oh J, et al. Inflammation, met-abolic dysregulation, and pulmonary function among obese urban adolescents with asthma. Am J Respir Crit Care Med. 2015;191(2):149-160.

12. Rastogi D, Suzuki M, Greally JM. Differential epig-enome-wide DNA methylation patterns in childhood obesity-associated asthma. Sci Rep. 2013;3:2164.

13. Rastogi D, Nico J, Johnston AD, et al. CDC42-related genes are upregulated in helper T cells from obese asthmatic children [published correction appears in J Allergy Clin Immunol. 2018;142(6):2014]. J Allergy Clin Immunol. 2018;141(2):539-548.e7.

14. Oren E, Gerald L, Stern DA, Martinez FD, Wright AL. Self-reported stressful life events during adolescence and subsequent asthma: a longitudinal study. J Allergy Clin Immunol Pract. 2017;5(2):427-434.e2.

15. Alves Gda C, Santos DN, Feitosa CA, Barreto ML. Community violence and childhood asthma preva-lence in peripheral neighborhoods in Salvador, Bahia State, Brazil. Cad Saude Publica. 2012;28(1):86-94.

16. Han YY, Forno E, Marsland AL, Miller GE, Celedón JC. Depression, asthma, and bronchodilator response in a nationwide study of US adults. J Allergy Clin Immunol Pract. 2016;4(1):68-73.e1.

17. Ramratnam SK, Han YY, Rosas-Salazar C, et al. Exposure to gun violence and asthma among children in Puerto Rico. Respir Med. 2015;109(8):975-981.

18. Steinberg L, Aldea I, Messias E. Asthma, depression, and suicidality: results from the 2007, 2009, and 2011 Youth Risk Behavior Surveys. J Nerv Ment Dis. 2015;203(9):664-669.

19. Priftis KN, Papadimitriou A, Nicolaidou P, Chrousos GP. Dysregulation of the stress response in asthmatic children. Allergy. 2009;64(1):18-31.

20. Ramratnam SK, Visness CM, Jaffee KF, et al. Relationships among maternal stress and depression, type 2 responses, and recurrent wheezing at age 3 years in low-income urban families. Am J Respir Crit Care Med. 2017;195(5):674-681.

21. Barreto do Carmo MB, Righetti RF, Tibério IF, Hunziker MH. The effects of prenatal "psychological" stressor exposure on lung inflammation and hyperre-sponsiveness in adult rat offspring. Dev Psychobiol. 2016;58(8):1076-1086.

22. Chen W, Boutaoui N, Brehm JM, et al. ADCYAP1R1 and asthma in Puerto Rican children. Am J Respir Crit Care Med. 2013;187(6):584-588.

23. Brehm JM, Ramratnam SK, Tse SM, et al. Stress and bronchodilator response in children with asthma. Am J Respir Crit Care Med. 2015;192(1):47-56.

24. Wright RJ, Finn P, Contreras JP, et al. Chronic caregiver stress and IgE expression, allergen-in-duced proliferation, and cytokine profiles in a birth cohort predisposed to atopy. J Allergy Clin Immunol. 2004;113(6):1051-1057.

25. Miller GE, Chen E. Life stress and diminished expres-sion of genes encoding glucocorticoid receptor and β2-adrenergic receptor in children with asthma. Proc Natl Acad Sci U S A. 2006;103(14):5496-5501.

26. Jovanovic T, Norrholm SD, Davis J, et al. PAC1 receptor (ADCYAP1R1) genotype is associated with dark-enhanced startle in children. Mol Psychiatry. 2013;18(7):742-743.

27. Uddin M, Chang SC, Zhang C, et al. ADCYAP1R1 genotype, posttraumatic stress disorder, and depression among women exposed to childhood maltreatment. Depress Anxiety. 2013;30(3):251-258.

28. Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012;367(13):1198-1207.

29. Casale TB, Bateman ED, Vandewalker M, et al. Tiotropium Respimat add-on is efficacious in symp-tomatic asthma, independent of T2 phenotype. J Allergy Clin Immunol Pract. 2018;6(3):923-935.e9.

30. Desaki M, Takizawa H, Ohtoshi T, et al. Erythromycin suppresses nuclear factor-κB and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun. 2000;267(1):124-128.

31. Bennett BL, Manning AM. Activator protein-1 and Nuclear factor-kappa B. In: Hansel TT, Barnes PJ, eds. New Drugs for Asthma, Allergy and COPD. Prog Respir Res. Vol 31. Basel, Switzerland: Karger; 2001:337-341.

32. Normansell R, Sayer B, Waterson S, Dennett EJ, Del Forno M, Dunleavy A. Antibiotics for exacer-bations of asthma. Cochrane Database Syst Rev. 2018;6:CD002741.

33. Johnston SL, Szigeti M, Cross M, et al. Azithromycin for acute exacerbations of asthma: the AZALEA randomized clinical trial. JAMA Intern Med. 2016;176(11):1630-1637.

34. Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68(4):322-329.

35. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-con-trolled trial. Lancet. 2017;390(10095):659-668.

36. Peters J, Singh H, Brooks EG, et al. Persistence of community-acquired respiratory distress syndrome toxin-producing Mycoplasma pneumoniae in refrac-tory asthma. Chest. 2011;140(2):401-407.

37. Liu W, Liu S, Verma M, et al. Mechanism of TH2/TH17-predominant and neutrophilic TH2/TH17-low subtypes of asthma. J Allergy Clin Immunol. 2017;139(5):1548-1558.e4.

References1. Wechsler ME, Parulekar AD. Severe asthma reference

guide: phenotypes, endotypes, biomarkers, and treatment. October 1, 2018. https://www.globalacad-emycme.com/sites/default/files/73848_0088_lr_rev3.pdf. Accessed January 14, 2019.

2. Bousquet J, Cabrera P, Berkman N, et al. The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma. Allergy. 2005;60(3):302-308.

3. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198-1207.

4. Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with ele-vated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, pla-cebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3(5):355-366.

5. Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corti-costeroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115-2127.

6. FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128-2141.

7. Castro M, Corren J, Pavord ID, et al. Dupilumab effi-cacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378(26):2486-2496.

8. Corren J, Parnes JR, Wang L, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017;377(10):936-946.

9. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepoli-zumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189-1197.

10. Nair P, Wenzel S, Rabe KF, et al. Oral glucocor-ticoid-sparing effect of benralizumab in severe asthma. N Engl J Med. 2017;376(25):2448-2458.

11. Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of dupilumab in glucocorticoid-de-pendent severe asthma. N Engl J Med. 2018;378(26):2475-2485.

12. Hanania NA. Biologicals in asthma: targeting IgE and eosinophils. Presented at: American College of Chest Physicians (ACCP) CHEST Annual Meeting 2018; October 8, 2018; San Antonio, TX.

13. Rogers L. Targeting type 2 inflammation: IL-4, IL-13, TSLP, and beyond. Presented at: American College of Chest Physicians (ACCP) CHEST Annual Meeting 2018; October 8, 2018; San Antonio, TX.

14. Maselli DJ. Revisiting bronchial thermoplasty.

Presented at: American College of Chest Physicians (ACCP) CHEST Annual Meeting 2018; October 8, 2018; San Antonio, TX.

15. Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol. 2015;16(1):45-56.

16. Schleich F, Brusselle G, Louis R, et al. Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR). Respir Med. 2014;108(12):1723-1732.

17. Humbert M, Busse W, Hanania NA, et al. Omalizumab in asthma: an update on recent developments. J Allergy Clin Immunol Pract. 2014;2(5):525-536.e1.

18. Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C. The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation. J Allergy Clin Immunol. 2005;115(3):459-465.

19. Busse WW, Massanari M, Kianifard F, Geba GP. Effect of omalizumab on the need for rescue systemic corticosteroid treatment in patients with mod-erate-to-severe persistent IgE-mediated allergic asthma: a pooled analysis. Curr Med Res Opin. 2007;23(10):2379-2386.

20. Braunstahl GJ, Chen CW, Maykut R, Georgiou P, Peachey G, Bruce J. The eXpeRience registry: the 'real-world' effectiveness of omalizumab in allergic asthma. Respir Med. 2013;107(8):1141-1151.

21. Busse WW, Morgan WJ, Gergen PJ, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med. 2011;364(11):1005-1015.

22. Kloepfer KM, Gern JE. Virus/allergen interactions and exacerbations of asthma. Immunol Allergy Clin North Am. 2010;30(4):553-563, vii.

23. Gill MA, Liu AH, Calatroni A, et al. Enhanced plasmacytoid dendritic cell antiviral responses after omalizumab. J Allergy Clin Immunol. 2018;141(5):1735-1743.e9.

24. Hanania NA, Wenzel S, Rosén K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187(8):804-811.

25. Humbert M, Taillé C, Mala L, Le Gros V, Just J, Molimard M. Omalizumab effectiveness in patients with severe allergic asthma according to blood eosinophil count: the STELLAIR study. Eur Respir J. 2018;51(5). doi:10.1183/13993003.02523-2017

26. Papi A, Brightling C, Pedersen SE, Reddel HK. Asthma. Lancet. 2018;391(10122):783-800.

27. Long AA. Monoclonal antibodies and other bio-logic agents in the treatment of asthma. MAbs. 2009;1(3):237-246.

28. Nucala [package insert]. Philadelphia, PA: GlaxoSmithKline LLC; 2017.

29. Cinqair [package insert]. Frazer, PA: Teva Respiratory LLC; 2016.

30. Fasenra [package insert]. Södertälje, Sweden: AstraZeneca AB; 2017.

31. Dupixent [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals Inc; 2018.

32. Brusselle G, Germinaro M, Weiss S, Zangrilli J.

Reslizumab in patients with inadequately controlled late-onset asthma and elevated blood eosinophils. Pulm Pharmacol Ther. 2017;43:39-45.

33. FitzGerald JM, Bleecker ER, Menzies-Gow A, et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir Med. 2018;6(1):51-64.

34. Lugogo N, Domingo C, Chanez P, et al. Long-term effi-cacy and safety of mepolizumab in patients with severe eosinophilic asthma: a multi-center, open-label, phase IIIb study. Clin Ther. 2016;38(9):2058-2070.e1.

35. Chupp G, Laviolette M, Cohn L, et al. Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: a comparison of 3-year follow-up results from two prospective multi-centre studies [published correction appears in Eur Respir J. 2017;50(4):1700017]. Eur Respir J. 2017;50(2):1700017.

36. Farne HA, Wilson A, Powell C, Bax L, Milan SJ. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev. 2017;9:CD010834.

37. Parulekar AD, Diamant Z, Hanania NA. Role of biologics targeting type 2 airway inflammation in asthma: what have we learned so far? Curr Opin Pulm Med. 2017;23(1):3-11.

38. Tezepelumab granted breakthrough therapy designation by US FDA [press release]. AstraZeneca; September 7, 2018. https://www.astrazeneca.com/media-centre/press-releases/2018/tezepelumab-granted-break-through-therapy-designation-by-us-fda-07092018.html. Accessed November 30, 2018.

39. Blaiss MS, Castro M, Chipps BE, Zitt M, Panettieri RA Jr, Foggs MB. Guiding principles for use of newer biologics and bronchial thermoplasty for patients with severe asthma. Ann Allergy Asthma Immunol. 2017;119(6):533-540.

40. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, dou-ble-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010;181(2):116-124.

41. Wechsler ME, Laviolette M, Rubin AS, et al. Bronchial thermoplasty: long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol. 2013;132(6):1295-1302.

42. Torrego A, Herth F, Munoz AM, et al. Bronchial Thermoplasty Global Registry: one year results. Eur Respir J. 2018;52(suppl 62). doi:10.1183/13993003.congress-2018.OA1921

43. Langton D, Ing A, Fielding D, Wang W, Plummer V, Thien F. Bronchodilator responsiveness as a predictor of success for bronchial thermoplasty. Respirology. 2019;24(1):63-67.

44. Salem IH, Boulet LP, Biardel S, et al. Long-term effects of bronchial thermoplasty on airway smooth muscle and reticular basement membrane thickness in severe asthma. Ann Am Thorac Soc. 2016;13(8):1426-1428.

Advanced Therapies for Severe Asthma: Biologic Therapy and Bronchial Thermoplasty continued from page 10

Many reasons for poorly controlled asthma stem from issues that could be addressed through patient education and a patient-clinician partnership, eg, adherence to therapy, correct inhaler use, identifying and avoiding environmental triggers, and recognizing and responding to early warning signs of exacerbation. The Global Initiative for Asthma (GINA) guidelines recommend establishing a partnership with the patient to manage his or her disease. Such a relationship includes listening to and considering patient expectations, concerns, and preferences when choos-ing therapy and encouraging patient participation in treatment decisions.1 Shared decision making in asthma care has improved medication adherence in adults2 and quality of life and asthma control in children3 compared with usual care. An online shared decision-making tool for patients with severe asthma and their clinicians has been introduced by the Allergy & Asthma Network, the CHEST Foundation, and the American College of Allergy, Asthma, and Immunology (http://severeasthmatreat-ments.chestnet.org/). Tonya Winders, MBA, of the Allergy & Asthma Network, described the tool at the 2018 CHEST Annual Meeting.4

This interactive tool provides education in patient-friendly language and seeks

patient input about their concerns, attitudes, and priorities. A patient questionnaire asks about the ability to control exposure to triggers, frequency of using controller therapies, and openness to new therapies. Based on this information, FDA-approved therapies are recommended. Further screens include information in patient language about these therapies for severe asthma: anti-immunoglobulin E, anti-interleukin-5, long-acting mus-carinic antagonist therapy, macrolide antibiotics, and bronchial thermoplasty, as well as oral corticosteroids and the standard of care. The software can store individual patient responses. It is nonproprietary and could potentially be integrated into electronic medical record systems.The tool is suitable for in-office use, with a nurse or other clinical staff member walking the patient through the screens after the clinical portion of a visit. Obstacles raised to implement-ing shared decision making include time and fit into clinical systems. Figure 1 depicts a suggested flow for a patient visit that includes 10 minutes with the physician followed by a 10-minute ses-sion of education and shared decision making with a nurse or other clinical team member. Practices can code for an extended office visit to reflect time spent discussing issues with the patient.

A companion tool to support patient self-management is the Asthma Storylines app, developed by the Allergy & Asthma Network for patient use (Figure 2). It can track medications and symptoms, includes reminders about medications and appointments, and can record patient questions. More information is available at http://www.allergyasthmanetwork.org/outreach/patient-resources/asthma-storylines/.

References1. Global Initiative for Asthma. Global Strategy for Asthma

Management and Prevention, 2018. https://ginasthma.org/2018-gina-report-global-strategy-for-asthma-man-agement-and-prevention/. Accessed January 8, 2019.

2. Wilson SR, Strub P, Buist AS, et al. Shared treatment decision making improves adherence and outcomes in poorly controlled asthma. Am J Respir Crit Care Med. 2010;181(6):566-577.

3. Taylor YJ, Tapp H, Shade LE, Liu TL, Mowrer JL, Dulin MF. Impact of shared decision making on asthma quality of life and asthma control among children. J Asthma. 2018;55(6):675-683.

4. Winders TA. Asthma shared decision-making toolkit—best practices for clinicians. Presented at: American College of Chest Physicians (ACCP) CHEST Annual Meeting 2018; October 10, 2018; San Antonio, TX.

An Online Tool for Shared Decision Making in Severe Asthma Care

Key Teaching Point• Shared decision making is often recommended but challenging to implement in practice. An online tool specific

to patients with severe asthma, designed for in-office or at-home use and including patient-friendly information about the newest therapies, has been introduced by the Allergy & Asthma Network, the CHEST Foundation, and the American College of Allergy, Asthma, and Immunology


Figure 1. Integrating Shared Decision Making Into an Office Visit

SDM, shared decision making.

Staff and Patient• Registration• Questionnaires

Medical Assistant and Patient• Vital signs 5 minutes

Nurse and Patient• Review decision aids• Follow up

10 minutes

Physician and Patient• History/physical exam• Goals• Action/life plan• Initiate SDM 10 minutes

5 minutes

Figure 2. Asthma Storylines App

Steps to Shared Decision Making• Invite patient to participate• Present options• Provide information on benefits

and risks• Elicit patient preferences• Facilitate deliberation with family • Make the decision after the

patient has time to consider the options

• Assist with implementation

From Science to Practice in Severe Asthma: Matching Treatment With Pathophysiology-Posttest and Evaluation FormOriginal Release Date: February 15, 2019 • Expiration Date: February 15, 2020 Estimated Time to Complete Activity: 1.0 hourTo get instant CME/CE credits online, go to https://tinyurl.com/AsthmaChest18. Upon successful completion of the online test and evaluation form, you will be directed to a Web page that will provide you information on how to receive your certificate of credit via e-mail. If you have any questions or difficulties, please contact: Global Academy for Medical Education at [email protected] or (973) 290-8225.

FOR REVIEW PURPOSES ONLY. MUST BE COMPLETED ONLINE.

EVALUATION FORM Please indicate your profession/background: (check one) MD/DO MSN/BSN/RN PA APN/NP PharmD/RPh Resident/Fellow Researcher Administrator Student Other; specify _____________________________________________

If you do not feel confident that you can achieve the above objectives to some extent, please describe why not._____________________________________________________________________________________

Was the content of this activity fair, balanced, objective, and free of bias?Yes. If no, please explain _______________________________________________________

Based on the content of this activity, what will you do differently in the care of your patients/regarding your professional responsibilities? (check one)

Implement a change in my practice/workplace. Seek additional information on this topic.Do nothing differently. Current practice/job responsibilities reflect activity recommendations.Do nothing differently as the content was not convincing. Do nothing differently. System barriers prevent me from changing my practice/workplace.

If you anticipate changing one or more aspects of your practice/profes-sional responsibilities as a result of your participation in this activity, please briefly describe how you plan to do so._____________________________________________________________________________________

If you plan to change your practice/workplace, may we contact you in 2 months to see how you are progressing?

Yes. E-mail address: ____________________________________________________________No. I don’t plan to make a change.

If you are not able to effectively implement what you learned in this activity, please tell us what the system barriers are (eg, institutional systems, lack of resources, etc)._____________________________________________________________________________________

What topics do you want to hear more about, and what issue(s) regarding your practice/professional responsibilities will they address?_____________________________________________________________________________________

Please provide additional comments pertaining to this activity and any suggestions for improvement._____________________________________________________________________________________

OVERALL EVALUATION Strongly Agree Agree Somewhat Agree Disagree Strongly Disagree

The information presented increased my awareness/understanding of the subject. 5 4 3 2 1

The information presented will influence how I practice/do my job. 5 4 3 2 1

The information presented will help me improve patient care/my job performance. 5 4 3 2 1

The program was educationally sound and scientifically balanced. 5 4 3 2 1

Overall, the program met my expectations. 5 4 3 2 1

I would recommend this program to my colleagues. 5 4 3 2 1

Mario Castro, MD, MPHNicola A. Hanania, MD, MS, FCCP F. Eun-Hyung Lee, MD Merin Kuruvilla, MD

Authors demonstrated current knowledge of the topic. 5 4 3 2 1

Authors were organized in the written materials. 5 4 3 2 1

© 2019 Global Academy for Medical Education. All Rights Reserved.

LEARNING OBJECTIVES: Having completed this activity, you are better able to: Strongly Agree Agree Somewhat Agree Disagree Strongly Disagree

List the steps in the assessment of a patient with poorly controlled asthma 5 4 3 2 1Explain the use of advanced therapies, including biologics and bronchial thermoplasty 5 4 3 2 1Describe recent research on non–type 2 asthma and appropriate treatment strategies for it 5 4 3 2 1Explain how to use decision aids and other tools with your patients to guide them in shared decision making 5 4 3 2 1

POSTTEST CME/CE QUESTIONS1. In patients with asymptomatic acid reflux and poorly controlled

asthma, treatment with a proton pump inhibitor has been shown to:A. Improve lung function and airway hyperresponsivenessB. Decrease symptoms of anxietyC. Decrease exacerbationsD. Have no effect on symptoms of asthma or its comorbid disorders

2. Treatment with which medication results in near depletion of eosinophils?A. BenralizumabB. OmalizumabC. MepolizumabD. Reslizumab

3. Which agent has reduced the risk of severe exacerbations and improved lung function in patients with asthma irrespective of baseline eosinophil count or IgE level and might therefore be helpful for patients with non–type 2 asthma?A. DupilumabB. MontelukastC. TheophyllineD. Tiotropium

4. The shared decision-making tool available at http://severeasthmatreatments.chestnet.org will:A. Describe prescription and over-the-counter medicationsB. Educate patients about FDA-approved treatment optionsC. Provide information on alternative and complementary treatmentsD. Recommend the best treatment for a patient

Documents

From Science to Practice in Severe AsthmaThe pathophysiology and management of severe asthma was a major topic of sessions at CHEST 2018, the annual meeting of the American College