ASTHMA. Epidemiology Pathophysiology Diagnosis Management Safe Bets. o AERD o ABPA o VCD o Pregnancy

Transcription

1 ASTHMA David M. Lang, MD Head, Allergy/Immunology Section Respiratory Institute Cleveland Clinic Foundation Member, Rock and Roll Hall of Fame (Roller Level)

2 Disclosure Consultant/Advisory Board: Hycor, Quest Speaker: Genentech, Novartis, GlaxoSmithKline, Merck Honorarium: Genentech, Novartis, GlaxoSmithKline, Merck Research Grant: Genentech, Novartis, Merck

3 Learning Objectives Upon completion of this session, participants should be able to: Describe recent asthma trends in the USA, and risk factors for asthma mortality. Relate the paradigm of asthma management proposed in EPR3 guidelines, specifically in terms of the assessment of asthma severity and asthma control. Describe key facts concerning conditions such as AERD, ABPA, VCD, and management of asthma during pregnancy

4 ASTHMA Epidemiology Pathophysiology Diagnosis Management Safe Bets o AERD o ABPA o VCD o Pregnancy

5 EPIDEMIOLOGY

6 The US Asthma Burden 2010: An estimated 25.7 million (8%) with current asthma, compared with 20 million (7%) in 2001 African Americans = 10.2% Whites = 7.6% Asthma cost the USA about $3,300 per person with asthma each year from 2002 to 2007 in medical expenses. 2007: $56 billion in annual costs including medical costs, lost school/work, and early deaths deaths (2010) o accessed January 11, 2014 o Mooreman et al. Surveillance for asthma United States, MMWR. 2007;56:1. o Akinbami L, Moorman J. National Health Statistics Reports, Number 32, January 12, 2011

7 2.5 2 Asthma Mortality per 100, Asthma M ortal ity per 100,000 Trends in US Asthma Mortality: Source:

8 Asthma Mortality Patterns in Philadelphia Asthma Mortality per 100, Poisson Regression Poverty African Americans Hispanic Americans p <.001 p =.032 p =.013 Lang DM, Polansky M. N Engl J Med 1994; 331: Low Mid High

9 Asthma Mortality - Risk Factors Past history of sudden, severe exacerbations Prior intubation and ICU management 2 hospitalizations for asthma in past year 3 ED visits for asthma in past year Hospitalization or ED visit for asthma in past month Use of 2 canisters of rescue inhaler per month Current use of or recent withdrawal from oral steroid Poor perception of dyspnea Psychologic co-morbidity Low socioeconomic status Inner city residence African-American race or Hispanic-American ethnicity Illicit drug use IgE-mediated potential to Alternaria Modified from: Restrepo R, Peters J. Curr Opinion Pulm Med 2008; 14:13-23.

10 Common Sources of Allergens in Inner-City Homes

11 Cockroach Dominant Allergen Associated with Asthma Morbidity p = p = 0.88 p = 0.81 Rosenstreich D, et al. N Engl J Med 1997; 336:

12 PATHOPHYSIOLOGY

13 Asthma is Heterogeneous Not a single disease entity It s a syndrome characterized by multiple phenotypes Age Gender Race/ethnicity Disease pattern Remission/relapse Persistence.

14 Airway Remodeling Changes to the formed elements of the airway contribute to pathophysiology Airway epithelium Mucus/sputum Airway smooth muscle Inflammation Angiogenesis Pascual RM, Peters SP. Airway remodeling contributes to progressive loss of lung function in asthma. J Allergy Clin Immunol. 2005;116:

15 Airway Remodeling Changes to the formed elements of the airway contribute to pathophysiology Airway epithelium Mucus/sputum Airway smooth muscle Inflammation Angiogenesis Pascual RM, Peters SP. Airway remodeling contributes to progressive loss of lung function in asthma. J Allergy Clin Immunol. 2005;116:

16 Pathology of Asthma Normal Lungs Asthma Source: What You and Your Family Can Do About Asthma by the Global Initiative For Asthma Created and funded by NIH/NHLBI

17 DIAGNOSIS

18 Airways of Asthmatics are Hyperresponsive Colasurdo G, Larson G. Airway hyperresponsiveness. In Busse, et al. Asthma and Rhinitis, 2nd Edition Blackwell Science,

19 Bronchoprovocation NON-SELECTIVE Direct (e.g., methacholine, histamine) Indirect (e.g., exercise, mannitol) SELECTIVE Immunologic (e.g., allergen) Non-Immunologic (e.g., aspirin)

20 Estimates of Sensitivity and Specificity Test Sensitivity Specificity Methacholine High Medium Mannitol Medium High FE NO High Medium Sputum EOS High Medium

21 What s New and What s Hot? Genetics Biomarkers Phenotypes/Endotypes Personalized management

22 Genetics What s Hot? Epigenetics: It s not genes, it s gene activation. Biomarkers eno Sputum EOS LTE 4 Periostin Personalized management profile severity and prognosis

23 Accessed January 11, 2014 at:

24 Fraction of Exhaled Nitric Oxide (FE NO )

25 FE NO : Diagnostic Properties Yes Asthma (n = 17) No Nonasthma (n = 30) Yes No Sensitivity (%) Specificity (%) Positive Predictive Value (%) Negative Predictive Value (%) Bronchodilator reversibility >12% Bronchial hyperresponsiveness <20 ml Peak flow variation >20% * NA 70 Peak flow improvement with steroid >15% * FEV 1 <80% predicted FEV 1 <90% predicted FEV 1 /FVC ratio <70% FEV 1 /FVC ratio <80% FEV 1 improvement with steroid >15% * Sputum eosinophils >3% 12 2* 3 23* FE NO >20 ppb Asthma diagnosed by bronchodilator reversibility and/or bronchial hyperresponsiveness (shown above purple line) Comparison of FE NO with other diagnostic tests is shown at bottom ppb = parts per billion. *Patient unable or unwilling to complete procedure. Technical difficulties prevented completion of FE NO measurements at 50 ml/second. Smith AD et al. Amer J Respir Crit Care Med. 2004;169:

26 FE NO : Possible Detection of Noncompliance With ICS FE NO (ppb) On ICS Off ICS Weeks Silkoff P et al. J Asthma. 1998;35:

27 Which of the following will increase the measurement of exhaled nitric oxide in a patient with asthma? A. Drinking 16 ounces of beer B. Eating a hot dog C. Running 3 miles D. Smoking a cigarette

28 Factors Affecting FE NO Levels Increase Viral URI Allergic Rhinitis Nitrate-rich diet Decrease Cystic Fibrosis Smoking Pulmonary Hypertension Alcohol consumption Spirometric maneuvers

29 Anti-IL13 and Periostin TH2 cells secrete IL-4 and IL-13, which induce B cells to produce IgE. IL-13 can mediate several features of asthma: Airways hyperresponsiveness Mucous metaplasia Eosinophilic inflammation Activation and proliferation of airway fibroblasts. High TH2 phenotype ( IL-13 signature surrogate ) recently described, associated with increased circulating levels of periostin, a matricellular protein induced by IL-13. Kraft M. N Engl J Med 2011; 365:

30 Kraft M. N Engl J Med 2011; 365:

31 Corren J. N Engl J Med 2011; 365:

32 14.0% 5.8% p=.03 * FEV 1 5.1% 3.5% p=.61 Corren J. N Engl J Med 2011; 365:

33 Which is the Best Biomarker For Detecting Eosinophilic Airway Inflammation? Presence of eosinophilic airway inflammation defines pathophysiologically and clinically distinct subgroups of asthma, and predicts salutary response to steroids and emerging therapies (e.g., anti-il5). Invasive sampling via bronchoscopy or sputum induction not feasible. Non-invasive biomarkers will have utility for identifying asthma subgroups responsive to Th2 targeted therapies. Woodruff PG, et al. AJRCCM 2009; 180: Nair P, et al. N Engl J Med 2009; 360:

34 What is the Best Biomarker For Detecting Eosinophilic Airway Inflammation? Jia G, et al. J Allergy Clin Immunol 2012; 130:

35 What is the Best Biomarker For Detecting Eosinophilic Airway Inflammation? Serum periostin: PPV = 93% Jia G, et al. J Allergy Clin Immunol 2012; 130:

36 Personalized Care Heterogeneity of asthma leads to differential responses to treatment. Several studies imply that genetic factors and biomarkers -- perhaps in combination, can direct asthma pharmacotherapy.

37 Lotvall J, et al. J Allergy Clin Immunol 2011; 127:

38 Lotvall J, et al. J Allergy Clin Immunol 2011; 127:

39 Meta analysis Prospective Epidemiologic Studies Compared with normal weight, elevated BMI confers increased odds of incident asthma. Beuther DA, Sutherland ER. Am J Resp Crit Care Med 2007; 175:

40 Meta analysis Prospective Epidemiologic Studies Dose response effect of overweight and obesity on incident asthma Beuther DA, Sutherland ER. Am J Resp Crit Care Med 2007; 175:

41 Weight Loss Interventions Medical Low calorie diets Exercise Behavioral Medications Surgical: Gastric bypass

42 Weight Loss Interventions for Asthma RCTs of interventions for overweight or obese asthmatics, compared with no intervention or alternative weight loss intervention 4 studies, N=197 Brazil, Mexico, Australia, Finland variety of medical interventions Serious methodologic issues Imprecision Selection bias Detection bias Conclusion: The benefit of weight loss as an intervention for asthma control remains uncertain, as such, clinicians should be prepared to help patients to make a decision that is consistent with their own values. Adeniyi FB, Young T. Cochrane Database accessed 1/2/14:

43 Mary is a 25 year-old woman with episodes of wheezing 3 days each week. She awakens out of sleep once every other week with wheezing and cough. Her only medication is albuterol inhaler prn, which she requires at least 3 days per week. She had a hospitalization at age 18 for asthma requiring ICU management. Her physical exam is normal, and spirometry shows no ventilatory impairment: FEV1 = 88% predicted, FVC = 94% predicted. How would you categorize the severity of Mary s asthma? A. Intermittent B. Mild persistent C. Moderate persistent D. Severe persistent

44 accessed January14, 2012

45 MANAGEMENT

46 Based on evidence from randomized, placebo-controlled, double blind studies, which of the following controller options is preferred for Mary? A. Low dose inhaled steroid monotherapy B. Medium dose inhaled steroid monotherapy C. Combination low dose inhaled steroid and long acting beta agonist D. Leukotriene modifier monotherapy

47 mild Asthma Control, Management, and Severity optimal good control Asthma Management A poor Severity severe B poor control modified from: Osborne M, et al. Chest 1999; 115:

48 Definitions Severity the intrinsic intensity of the disease process Measured most easily and directly in a patient not receiving long term control therapy Control The degree to which manifestations of asthma (symptoms, functional impairments, and risks of untoward events) are minimized and the goals of therapy are met. accessed January

49 Asthma Severity and Control: Impairment Domain Impairment = Frequency and Intensity of Symptoms and Functional Limitations Symptoms Nighttime awakenings Need for SA β 2 -agonists (SABAs) for quick relief Work/school days missed Ability to engage in normal and desired daily activities Quality-of-life assessments Lung Function Spirometry Peak flow Adapted from NHLBI Expert Panel Guidelines (EPR-3).

50 Assessing Asthma Control in Children 12 Years of Age and Adults: NAEPP Guidelines Impairment Components of Control Symptoms Nighttime awakenings Interference with normal activity SABA use for symptoms (not prevention of EIB) FEV 1 or peak flow Validated Questionnaires ATAQ ACQ ACT Well Controlled 2 days/week 2/month None 2 days/week >80% predicted/personal best Not Well Controlled >2 days/week 1-3/month Some limitation >2 days/week 60%-80% predicted/personal best Poorly Controlled Throughout the day 4/week Extremely limited Several times per day <60% predicted/personal best 3-4 N/A 15 Risk Exacerbations Progressive loss of lung function Treatment-related adverse effects 0-1 per year 2-3 per year >3 per year Evaluation requires long-term follow-up care Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in the overall assessment of risk. ACQ = Asthma Control Questionnaire; ACT = Asthma Control Test; ATAQ = Asthma Therapy Assessment Questionnaire; EIB = exercise-induced bronchospasm; FEV 1 = forced expiratory volume in 1 second; N/A = not applicable. accessed January 14, 2012

51 Validated Tools to Assess Asthma Control Asthma Control Questionnaire (ACQ) 1 Asthma Control Test (ACT) 2 Asthma Therapy Assessment Questionnaire (ATAQ) 3 1. Juniper EF, et al. Eur Respir J. 1999;14: Nathan RA, et al. J Allergy Clin Immunol. 2004;113: Vollmer WM, et al. Am J Respir Crit Care Med. 1999;160:

52 Patients on a controller are classified as having not well controlled asthma if they have any ONE of the following * : Albuterol use >2 days/week Asthma symptoms >2 days/week Nighttime awakenings 1-3x/week Some limitation of normal activity FEV 1 between 60%-80% of predicted ACT score < 20 ACT = Asthma Control Test. Asthma Control Test is a trademark of QualityMetric Incorporated. *Based on NIH asthma guidelines for adjusting therapy in patients 12 years. accessed January 14, 2010

53 Algorithm for Attaining Optimal Asthma Control Presentation with Asthma Classify Asthma Severity Assess Asthma Control Frequency of symptoms Frequency of rescue bronchodilator Frequency of night/morning symptoms Activity, work, school limitations Patient assessment Pulmonary Function Tests Periodic Assessment of Asthma Assess psychosocial status Assess adherence/compliance Assess medication s side effects Assess asthma triggers Review action plan Confirm/reconfirm diagnosis of asthma Asthma Well-controlled No Detailed asthma assessment Step-up therapy Yes Maintain or step-down therapy Attaining optimal asthma control: A practice parameter. J Allergy Clin Immunol. 2005;116:S3-11.

54 Intermittent Mild Persistent Moderate Persistent Severe Persistent Step 1 Preferred: SABA prn Step 2 Preferred: Low-Dose ICS (A) Alternative: Cromolyn (B), Nedocromil (B), LTRA (B), or Theophylline (B) Step 3 Preferred: Medium-Dose ICS (A) or Low-Dose ICS + LABA (A) Alternative: Low-Dose ICS and either LTRA (A), Theophylline (B), or Zileuton (D) Step 4 Preferred: Medium-Dose ICS + LABA (B) Alternative: Medium-Dose ICS and either LTRA (B), Theophylline (B), or Zileuton (D) Step 5 Preferred: High-Dose ICS + LABA (B) and Consider Omalizumab for Patients Who Have Allergies (B) Step 6 Preferred: High-Dose ICS + LABA + Oral Corticosteroid and Consider Omalizumab for Patients Who Have Allergies accessed January 14, 2010

55 Intermittent Mild Persistent Moderate Persistent Severe Persistent Step 6 Step 1 Preferred: SABA prn Step 2 Preferred: Low-Dose ICS (A) Alternative: LTRA (B), Cromolyn (B), Nedocromil (B), or Theophylline (B) Step 3 Preferred: Medium- Dose ICS (B) or Low-Dose ICS and either LABA (B), LTRA (B), or Theophylline (B) Step 4 Preferred: Medium-Dose ICS + LABA (B) Alternative: Medium-Dose ICS and either LTRA (B) or Theophylline (B) Step 5 Preferred: High-Dose ICS + LABA (B) Alternative: High-Dose ICS and either LTRA (B) or Theophylline (B) and Omalizumab May Be Considered for Patients Who Have Allergies Preferred: High-Dose ICS + LABA + Oral Corticosteroid (D) Alternative: High-Dose ICS and either LTRA or Theophylline and Oral Corticosteroid (D) and Omalizumab May Be Considered for Patients Who Have Allergies LTRA = leukotriene receptor antagonist. accessed January 14, 2010

56 Intermittent Mild Persistent Moderate to Severe Persistent Step 1 Preferred: SABA prn Step 2 Preferred: Low-Dose ICS (A) Alternative: Montelukast (A) or Cromolyn (B) Step 3 Preferred: Medium- Dose ICS (D) Step 4 Preferred: Medium-Dose ICS and either Montelukast or LABA (D) Step 5 Preferred: High-Dose ICS and either Montelukast or LABA (D) Step 6 Preferred: High-Dose ICS and either Montelukast or LABA and Oral Corticosteroids (D) accessed January 14, 2010

57 ASTHMA MEDICATIONS Inhaled short acting beta agonists Inhaled long acting beta agonists Oral anti-leukotrienes Oral Theophylline Inhaled anti-cholinergics Inhaled corticosteroids Oral corticosteroids Anti-IgE

58 Inhaled Steroid Is the Most Effective Controller for Asthma Sin DD, et al. JAMA. 2004;292:367-76

59 accessed January 14, 2010

60 SMART Salmeterol Multicenter Asthma Research Trial A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy plus Salmeterol Nelson HS et al. Chest. 2006;129:15-26.

61 Long-acting ß2-agonists Salmeterol, Formoterol SMART Implications Avoid LABA as monotherapy No use of LABA as reliever Arg/Arg at codon 16 of ADRB2 Worsening of lung function observed in association with regular use of albuterol No convincing evidence for this in association with LABA.

62 zileuton zafirlukast montelukast

63 Theophylline: Drug Interactions Increase Levels Decrease Levels - alcohol - aminoglutethamide - cimetidine - carbamazepine - ciprofloxacin - isoproterenol - clarithromycin - phenobarbital - erythromycin - phenytoin - oral contraceptives - rifampin - verapamil - sulfinpyrazone - zileuton - others

64 Paradoxical Vocal Cord Motion (Vocal Cord Dysfunction) Functional airway obstruction results from inappropriate motion of the vocal cords, usually during inspiration. Patients may present with dyspnea, throat tightness, choking, dysphonia, and/or cough. Occurs most commonly in women between the ages of Symptom onset may be spontaneous or provoked by exercise or irritant exposures. Gimenez L, Zafra H. Ann Allergy Asthma Immunol 2011;106:

65 Paradoxical Vocal Cord Motion (Vocal Cord Dysfunction) Gimenez L, Zafra H. Ann Allergy Asthma Immunol 2011;106:

66 PARADOXICAL VOCAL CORD MOTION Gimenez L, Zafra H. Ann Allergy Asthma Immunol 2011;106:

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69 Allergic Bronchopulmonary Aspergillosis Major criteria Asthma Roentgenographic infiltrates Proximal bronchiectasis Eosinophilia > 1000/mm3 Serum IgE markedly elevated Positive immediate skin test reaction to A. fumigatus IgG precipitins against Aspergillus antigens. Minor criteria Aspergillus in sputum History of expectorated brown plugs Delayed (Arthus) skin test reaction to Aspergillus antigen Greenberger P, Patterson R. Ann Allergy 1986;56:444-52

70 Wheal/Flare Reaction

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73 Asthma and Pregnancy Most common chronic condition in pregnancy, affecting 3.4% %. Physiologic changes Minute ventilation increases Normal: compensated respiratory alkalosis Related to increased circulating levels of progesterone Lung volume changes TV increases RV decreases FRC decreases Diagnosis of asthma can be confirmed in pregnancy -- similar to non-pregnancy -- with 12% increase in FEV1 after bronchodilator; methacholine challenge not recommended. Dombrowski MP. Asthma and pregnancy. Obstet Gynecol 2006; 108: Rey E, Boulet LP. Asthma in pregnancy. BMJ 2007; 334:

74 Asthma and Pregnancy Course of asthma Worse: 35% Same: 33% Improved: 28% More likely to worsen in women with severe (52-65%) compared with mild (8-13%) asthma Reverts to pre-pregnancy level within 3 months post-partum. Exacerbations most likely between weeks Most common: respiratory or urinary tract infection (69%) 2nd most common: non-adherence to ICS (29%) Rey E, Boulet LP. BMJ 2007; 334: Schatz M, et al. J Allergy Clin Immunol 1988; 81:

75 FDA Pregnancy Categories Category A B C D X Interpretation Controlled studies show no risk No evidence of risk in humans Risk cannot be ruled out Positive evidence of risk Contraindicated in pregnancy Gluck PA, Gluck JC. Curr Med Res Opin 2005; 21:

76 FDA Pregnancy Categories Drug Category Inhaled short acting beta agonists C Inhaled long acting beta agonists C Theophylline C Cromones B Leukotriene Modifiers B * Inhaled Corticosteroids C # Oral Corticosteroids C Anti-IgE B * Zileuton = C # Budesonide = B Yawn B, Knudtson M. J Am Board Fam Med 2007; 20:

77 The Future Will Be Better Tomorrow Dan Quayle