The refractory asthma patient: Thinking outside the box to - PowerPoint PPT Presentation


 The refractory asthma patient: 
 Thinking “outside the box” to phenotype and give specific directed therapy � Richard Martin, MD � Professor of Medicine, Pulmonary Disease Section � National Jewish Health � Denver, Colorado �

Learning Objectives Upon completion of this activity, the participant should be able to: • Describe how to “think outside the box” when consulted on a refractory asthma patient • Go through a differential diagnostic process; “all that wheezes is not asthma” • Determine what tests are useful to better phenotype refractory asthma patients • Describe how to use bronchoscopy to phenotype and give specific directed therapy • Outline how to use novel directed therapy to improve refractory asthmatics and use less “standard” asthma medications

Disclosures The following CME Committee Members/planners disclose the following: • Richard Martin. MD discloses he is a consultant for Teva, AZ, Novartis, MedImmune, Merck, Genentech, Amgen, LEK, and Sunovion. He is a speaker for Merck, Genentech, and the ACAAI. He receives a royalty from UpToDate. • Harold Nelson, MD is a consultant for Merck, Circassia, and Shionogi. He has received grant/research support from Lincoln Diagnostics, Circassia, Rigel, and NIH. • Sarah Meadows, MS, CCMEP has no relevant financial relationships to disclose. • The employees of CJP Medical Communications have no financial relationships to disclose.

REACT study: The prevalence of uncontrolled asthma (Real-world Evaluation of Asthma Control and Treatment) Uncontrolled Asthma † Controlled Asthma † 45% 55% (n=809) (n=1003) A US representative sample of 1812 (>18 years of age) patients with moderate-to-severe asthma. † ACT of 5-19 = uncontrolled asthma; 20-25 = controlled. Peters SP, et al. JACI 2007;119:1454-61

Limited change in asthma outcomes since 1998 - US Hospitalization Limited activity Limited work Missed work/school Acute Care 0% 10% 20% 30% 40% % of Adult Patients Asthma in America 1998 (n=1,788) Asthma insight and Management 2009 (n=2,294)

Patient History � • 51 y/o F, never smoker � • Asthma onset at age 30 years following a prolonged chest cold. � • Was under fair control with moderate dose of combination therapy (ICS + LABA) and rescue albuterol until four years ago. Progressive worsening. � ╺ Now on high dose combination and rescue 1-5 times a day for the last year �

Patient History � • Other medications � ╺ Prednisone bursts ~6 times a year (1 ED visit/year) � ╺ PPI � ╺ Allergy shots (grass, trees, weeds) � ╺ NSI and nasal steroids � ╺ Tried montelukast and theophylline without help. Tiotropium gave about a 5% increase in FEV1. � • No pets, no hobbies � • No longer working due to asthma �

Patient R.A.—PE � • V.S. normal, BMI 27.9 kg/m 2 � • HEENT: boggy nasal turbinates. Small oropharynx. � • CV: Neg � • Respiratory: scattered forced expiratory wheezes � • Rest of exam: negative �

Asthma Control Test (ACT) � x � x � x � x � x � 10 �

FeNO = 32 ppb �

Patient R.A.—Imaging � • CXR—hyperinflation, airway wall thickening � • Sinus CT—Pansinusitis represented by mild to moderate mucosal thickening. No acute change �

Discussion of case �

All that wheezes is not asthma • Asthma • GERD • Laryngeal dysfunction • AIDS – VCD, polyp, tumor • Angioedema • Psychosomatic • Bronchiolitis • Pulmonary embolism • Carcinoid syndrome • PIE • Central obstruction – ABPA − Tumor, aneurysm, – Chronic eos. goiter penumonia • COPD – Chrug-strauss • Cocaine toxicity syndrome – Loffler syndrome • CHF – Tropical pul. Eos. • Endobronch. TB • Sarcoidosis • Inhaled toxins − Fire, smoke

Vocal Cord Dysfunction 12 8 Predicted 4 Flow Baseline 0 2 4 6 8 10 12 -4 Volume -8

Vocal Cord Dysfunction (VCD) 
 Definition/Characteristics � • VCD is characterized by vocal cord closure, usually on inspiration, leading to airflow obstruction with “ wheezing ” or stridor. � • VCD frequently is inappropriately diagnosed as asthma. � • A number of different terms have been used to describe VCD which compounds the diagnostic difficulty. Furthermore, VCD and asthma are not mutually exclusive. �

Presentation of VCD � • Age � – Reported in patients 3-82 years old � – Most frequent 2nd - 4th decade � • Female predominance in adults � • Increased occurrence among health care workers in adults � • Among children/teenage, VCD has a strong link to participation in competitive sports and high achievement orientation � • Prevalence unknown, but in refractory asthma about 10% have VCD, and 33% have both VCD and asthma �

Typical VCD Patient � • Carries diagnosis of asthma unresponsive to therapy � • Episodic or recurrent wheezing/dyspnea usually sudden in onset and cessation � • Frequent ER visits and/or hospitalization � – Extreme case intubation or tracheostomy � • In adults obesity is a common feature which in part may be due to chronic oral steroid use �

Historical Clues (con ’ t.) � • Identify “ throat ” as the major site of obstruction during attacks � • Hoarseness and dysphonia � • Tightness upper chest or neck � • Irritants, e.g., dust, smoke, odors, exercise can trigger an attack � • Unlike asthmatics, VCD patients are rarely awakened from sleep by attacks �

Historical Clues (con ’ t.) � • In children and teens � – Attacks associated with sports or strenuous activity � – School exams � • Physical examination cannot rule in or out VCD versus asthma � – Since large airways are excellent conductors of distal airway sounds, asthmatics can have laryngeal wheezing � – Conversely, patients suspected of laryngeal stridor via auscultation can have normal vocal cord and upper airway exam �

Psychological Factors � • No specific psychological profile defines VCD � – Children - unusual to have � � � � psychological problem besides �� � stress � – Adults - may have various types of � psychological processes. Past � sexual abuse may be involved. �

Normal Respiration

Start of inspiration

Mid Inspiration

End Inspiration

PRE PRE 1 2 Flow Flow POST POST Volume Volume PRE 3 PRE 4 Flow Flow POST POST Volume Volume McFadden ER, et al. AJRCCM 1996;153:942-947

Laryngoscopy-Needed for diagnosis • Classic VCD presents as an anterior bowing of the vocal cords with a small posterior opening � • Be sure the inspiratory and expiratory phases of respiration are precisely defined. � – Assuming the vocal cord opening (abduction) corresponds to inspiration will lead to a missed diagnosis. A hand on the chest wall will help in determining the phase of respiration. � • During quiet respiration the vocal cords may function normally. � – Have the patient take three or more rapid deep breaths to TLC and blow out to RV � – Exercise, Mch challenge, or VC stimulation may be needed �

Adherence and technique �

Back to refractory asthma discussion �


 Stepwise Approach for Managing Asthma in Individuals ≥ 12 Years Old Intermittent � Persistent Asthma: Daily Medication � � � STEP 6 
 STEP 5 
 STEP 4 
 STEP 3 � � � � High-dose ICS + STEP 2 � High- Medium Low-dose LABA + Low- dose ICS ICS + LABA � ICS + systemic steroid � dose or � + LABA 
 LABA � � ICS. � STEP 1 � Medium- � or � Consider dose ICS � � � Consider ICS + or � omalizumab � LTRA, SABA prn � omaliz- LTRA, ICS + � nedoc, umab � theo, or LTRA, theo, or theo � zileuton � or zileuton � Each step: Patient education, environmental control, and management of comorbidities � Steps 2-4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma. � NAEPP Expert Panel Report 3 (EPR-3) Guidelines, 2007. �

Since asthma is an “airway” disorder, why not study the airway in refractory asthmatics to determine phenotypes and directed therapy? � Lower Airway � Upper Airway (Supraglottic) �

Refractory Asthma—ATS � • Major characteristics (1 needed) � ╺ Oral steroids ≥ 50% of year � ╺ High dose ICS, e.g., FP > 880mcg � • Minor characteristics (2 needed) � ╺ ICS + another controller � ╺ SABA ~ QD � ╺ FEV 1 < 80%; PEF variability >20% � ╺ ≥ 1 urgent care visits/year � ╺ ≥ 3 oral steroid bursts/year � ╺ Deterioration with ≤ 25% decrease in steroids � ╺ Near fatal asthma event � Proceedings of the ATS workshop on refractory asthma.AJRCCM 2000;162:2341-2351

In order to give personalized specific directed therapy for refractory asthma, phenotyping that truly separates groups needs to be developed �

Phenotyping � • The problem with most phenotyping studies is that they are focused on those patients that need to increase steroids � ╺ Exhaled nitric oxide (FeNO) � ╺ Sputum eosinophils � ╺ Other non-invasive surrogate markers of lung inflammation � • Refractory asthma patients are already on high ICS and/or oral steroids �

Cluster Phenotypes � Mild � Severe � AA � AA � AA � Fixed � Late � non-AA � Moore WC. 2010;181:315 �