Rising Incidence of Asthma

Transcription

1 Controlling Severe Asthma through Advanced Diagnosis and Treatment Strategies James F. Donohue, MD Professor of Medicine Division of Pulmonary and Critical Care Medicine University of North Carolina at Chapel Hill Chapel Hill, NC Rising Incidence of Asthma US Population (%) 10.00% 9.00% 8.00% 7.00% 6.00% 5.00% 4.00% 3.00% 2.00% 1.00% 0.00% Incidence of Asthma in the US Population Loftus PA, Wise SK. Int Forum Allergy Rhinol. 2015;5(Suppl 1):S7 S10. 1

2 Severe Asthma Definition:* Asthma which requires treatment with high dose inhaled corticosteroids plus a second controller (and/or systemic corticosteroids) to prevent from becoming uncontrolled or which remains uncontrolled despite this therapy * Numerous definitions of severe asthma have been proposed by various organizations 1. Lang DM. Allergy Asthma Proc. 2015;36(6): Akinbami LJ. NCHS data brief, no 94. National Center for Health Statistics; Sadatsafavi M, et al. Can Respir J. 2010;17(2): Peters SP, et al. J Allergy Clin Immunol. 2007;119(6): All Asthma Sufferers Severe asthma: 5 10% Severe uncontrolled asthma: 50% Severe Asthma Among patients with severe, difficult to treat asthma: High rates of medication and healthcare utilization High rates of work absences Poor asthma control associated with poorer quality of life 1. Chipps BE, et al. J Allergy Clin Immunol. 2012;130(2): Cisternas MG, et al. J Allergy Clin Immunol. 2003;111(6):

3 Severe Asthma: Cost Comparison Facet of Care Asthma Severe Asthma Inpatient $174 $3,610 Outpatient $337 $1,417 Emergency Department $219 $1,693 Medications $2,130 $4,090 Total $2,860 $10,811 Although those with severe asthma represent only 5 10% of all asthma sufferers, they account for a significant portion of the economic cost associated with this condition 1. Chipps BE, et al. J Allergy Clin Immunol. 2012;130(2): Cisternas MG, et al. J Allergy Clin Immunol. 2003;111(6): Severe Asthma: Classification World Health Organization (WHO) classification schema for severe asthma Severe Asthma Untreated severe asthma Treatmentresistant severe asthma Difficult to treat asthma Patients who fail to achieve control on current medication Patients who achieve control on current medication 1. Bousquet J, et al. J Allergy Clin Immunol. 2010;126(5): Taylor DR, et al. Eur Respir J. 2008;32(3):

4 Severe Asthma: Classification Innovative Medicine Initiative (IMI) proposes term problematic asthma with 2 subgroups: Problematic asthma Difficult asthma: Poor adherence and poor treatment of confounders causes difficult to control asthma Severe refractory asthma: Persistent poor control and frequent exacerbations despite acceptable adherence to highintensity treatment and treatment of comorbidities Bel EH, et al. Thorax. 2011;66(10): Severe Asthma: IMI Diagnostic Criteria Requires confirmed diagnosis of asthma with adequate adherence and treatment of comorbidities Requires high intensity treatment managed by an asthma specialist to prevent patients from becoming uncontrolled High dose therapy: High dose inhaled corticosteroid (ICS) and long acting beta2 agonist (or leukotriene modifier) or systemic corticosteroids Definition of uncontrolled asthma: Poor symptom control as measured by Asthma Control Questionnaire (ACS, consistently >1.5) or not well controlled according to published guidelines Frequent or severe exacerbations Bel EH, et al. Thorax. 2011;66(10):

5 Asthma Immunopathology Lower airway inflammation arises from genetic predisposition, environmental exposures, and possible alterations in the microbiome Most asthmatics have Type 2 inflammation Named for the type 2 T helper cell lymphocyte Associated with certain cytokine profiles (interleukin [IL] 4, IL 5, IL 14) and inflammatory cells (eosinophils, mast cells, basophils, and immunoglobulin E [IgE] producing plasma cells) TH2 cytokine pathway is the main target for asthma treatment Mims JW. Int Forum Allergy Rhinol. 2015;5(Suppl 1):S2 S6. Asthma Immunopathology Airway cell types Epithelial cells Dendritic cells Goblet cell Lymphocytes Type 2 Inflammatory Changes Commonly Identified in Asthma Eosinophils Mast cells and basophils Mims JW. Int Forum Allergy Rhinol. 2015;5(Suppl 1):S2 S6. Inflammatory changes Increased IL 33, thymic stromal lymphopoietin Increased OX40L expression, lymph node migration affecting lymphocyte maturation Metaplasia, increased mucin stores Increased TH2 bias with downregulation of T regulatory cells Increased IL 4, IL 5, and IL 13 Increased IgE producing plasma cells IL 5 mediated accumulation Increased IgE binding and mediator storage. 5

6 Asthma Immunopathology From Chung KF. Lancet. 2015;386(9998): ; with permission. Tissue remodeling: Airway Remodeling Pathological alterations in the lower airways Primarily the mucosa and submucosa Histopathological Changes in Asthma Smooth muscle hypertrophy and hyperplasia Goblet cell hyperplasia Hypertrophy of subumcosal mucus glands Subepithelial fibrosis and collagen deposition Increased blood vessels in submucosa Inflammatory cell infiltrate and subumcosal edema Mims JW. Int Forum Allergy Rhinol. 2015;5(Suppl 1):S2 S6. 6

7 Phenotypes describes clinical and morphologic characteristics and unique responses to treatment Clinically relevant in terms of presentation, triggers, and treatment response Phenotypes do not necessarily relate to the underlying pathological mechanisms Phenotypes can overlap or change over time Asthma Phenotypes Clinically observable asthma characteristics From Agache I, et al. Allergy. 2012;67(7): ; with permission Asthma Phenotypes Allergic asthma Starts in childhood Often accompanied by allergic rhinitis and/or atopic eczema Initial symptoms driven by allergen exposure Leads to increased airway inflammation which can persist even in the absence of the allergen Histologic characterization Mucosal infiltration with eosinophils, CD4+ cells, mast cells Expression of high affinity IgE receptors (epithelial damage) Half desmosomes Goblet cell hyperplasia Reticular basal membrane thickening and smooth muscle hypertrophy Key pathogenic mechanism is Th2 driven inflammation Diagnosis requires determination of atopic status Agache I, et al. Allergy. 2012;67(7):

8 Asthma Phenotypes Intrinsic (nonatopic) asthma Often begins in the second half of life Often accompanied by chronic sinusitis, nasal polyps, and aspirin sensitivity Histologic characteristics Similar to allergic asthma (increased Th2 cells, mast cell activation, infiltration of eosinophils, etc) IL 2 and IFN gamma are increased in BAL fluid IL 4 not increased Suggests ongoing T cell stimulation Pathophysiology Key drivers of inflammation unknown Local IgE synthesis has been hypothesized No validated biomarkers Agache I, et al. Allergy. 2012;67(7): Asthma Phenotypes Noneosinophilic asthma Characterized by the absence of airway eosinophilia Neutrophilia can be observed in nearly 60% of symptomatic adults Pathogenesis Activation of innate immune responses Possible role of bacteria, viruses, and diet Activation of neutrophil elastase Impaired nuclear recruitment of histone deacetylase (HDAC) Increased factors promoting airway neutrophil variability in severe asthma Established biomarkers Il 8, IL 17A, LTB4 Key diagnostic tool is induced sputum Agache I, et al. Allergy. 2012;67(7):

9 Asthma Phenotypes Aspirin intolerant asthma (AIA) Affects 5 10% of adult asthmatics More common in nonatopic asthmatics Often starts in 3 rd decade of life Sometimes referred to as aspirin exacerbated respiratory disease (AERD) Common disease course: Rhinitis following viral respiratory illness Development of chronic nasal congestion, anosmia, rhinorrhea, nasal polyps Asthma and sensitivity to aspirin Histologic characterization Intense eosinophilic inflammation of nasal and bronchial tissues Altered eicosanoid metabolism Increased sensitivity to leukotrienes C4, D4 and E4 Pathogenesis Overproduction of cysteinyl leukotrienes (Cys LTs) Diagnose with lysine aspirin bronchial challenge test Agache I, et al. Allergy. 2012;67(7): Asthma Phenotypes Extensive remodeling asthma Extensive remodeling with minimal inflammation Subtypes include thickened small airways, alveolar detachment and loss of elastin, airway smooth muscle hypertrophy, etc Pathophysiology unclear Abnormal epithelial mesenchymal trophic unit with abnormal activation and inappropriate tissue repair mechanisms may be involved Possible altered expression and funciton of sarcoplasmic/endoplasmic reticulum Ca2+ pup Possible abnormal expression of tight junction proteins Diagnose with dynamic evaluation of airway physiology and high resolution computed tomography 9

10 Asthma Endotypes Endotypes: disease subtypes defined by an intrinsically distinct pathogenetic mechanism The Type 2 inflammatory complex has been proposed as a distinct asthma endotype that correlates to treatment response and disease outcomes Three major downstreatm effector pathways of the Type 2 asthma endotype Agache I, et al. Curr Allergy Asthma Rep. 2015;15(6):29. Asthma Endotypes Type 2 endotype biomarkers have been proposed, although the reliability and validity of such biomarkers are still being evaluated. Potential biomarkers include: Sputum and blood eosinophils Fractional exhaled NO (FeNO) Serum periostin Th2 gene signature (serpin B2, periostin, CLCA1 or CLC, CPA3, DNA SE1L3) in bronchial and nasal epithelial cells Sputum cell Th2 gene mean (IL 4, Il 5, IL 13) TSLP and mast cells in bronchial biopsies Salivary inflammatory profile Agache I, et al. Curr Allergy Asthma Rep. 2015;15(6):29. 10

11 Asthma Endotypes Endotypes describe disease subtypes defined by an intrinsically distinct pathogenetic mechanism Corresponding endotypes Allergic Asthma Eosinophilic Th2 driven inflammation Steroid responsive Responsive to allergen specific immunotherapy Anti IgE responsive Anti IL 5 responsive Anti Il 4/IL 13 responsive Corresponding endotypes Intrinsic Asthma Eosinophilic Neutrophilic Associated with autoantibodies and superantigens Steroid responsive Steroid resistant Agache I, et al. Allergy. 2012;67(7): Asthma Endotypes Corresponding endotypes Neutrophilic Asthma Activation of innate immune response HDAC2 abnormal recruitment Increased neutrophil survival Steroid resistant Responsive to antioxidants/antibiotics Anti TNF alpha responsive Responsive to HDAC regulators Corresponding endotypes AIA Eosinophilic Alteration in the eicosanoid metabolism/sensitivity to LTs C4, D4, and E4 Steroid responsive LTRA responsive Extensive Remodeling Asthma Corresponding endotypes Lack fo inflammation/extensive remodeling Abnormal EMTU activation Abnormalities of ASM Defective repair mechanisms Steroid resistant ASM, MMP targeted treatment responsive Agache I, et al. Allergy. 2012;67(7): Antiangiogeneic responsive 11

12 DREAM study Asthma Endotypes Successful trial of endotype driven therapy Patients selected based on their eosinophillic profile Efficacy of anti IL 5 intervention demonstrated Treatment lowered blood and sputum eosinophil counts Parvord ID, et al. Lancet. 2012;380(9842): General Management Approach: Severity Based Care Severity is assessed retrospectively from the level of treatment required to control symptoms and exacerbations Severe asthma STEP 2 STEP 3 STEP 4 STEP 5 Alternatives: Add low dose OCS; SABA or low dose ICS as needed Preferred: Med/high dose ICS/LABA Alternatives: Add tiotropium, high dose ICS+LTRA or theophyline; SABA or low dose ICS as needed Preferred: Low dose ICS/LABA Alternatives: Med/high dose ICS, Low dose ICS+LTRA or theophyline; SABA or lowdose ICS as needed Preferred: Low dose ICS Alternatives: LTRA, low dose theophyline; SABA as needed Preferred: Add on treatment (eg, omalizumab, mepolizumab) STEP 1 Preferred: Consider low dose ICS Alternatives: SABA as needed Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (2016 update). 12

13 General Management Approach: Severe vs. Uncontrolled Some patients will not achieve good symptom control and minimal exacerbations even on maximal therapy In these cases, it is important to distinguish between true severe, refractory asthma and uncontrolled asthma Uncontrolled asthma is a more common reason for persistent symptoms and exacerbations Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (2016 update). Pre Step Up Checklist Before stepping up therapy: Confirm diagnosis Age Condition (differential) Age Condition (differential) <40 years Chronic upper airway cough syndrome 40 years Vocal cord dysfunction Vocal cord dysfunction Hyperventilation, dysfunctional breathing Bronchiectasis Cystic fibrosis Congenital heart disease Alpha 1 antitrypsin deficiency Inhaled foreign body Hyperventilation, dysfunctional breathing COPD Bronchiectasis Cardiac failure Medication related cough Parenchymal lung disease Pulmonary embolism Central airway obstruction Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (2016 update). 13

14 Pre Step Up Checklist Before stepping up therapy: Evaluate triggers Investigate for persistent environmental exposure to tobacco smoke, allergens, or toxic substances Review potential comorbidities and complicating conditions Obesity, gastroesophageal reflux disease (GERD), anxiety/depression, food allergies, rhinitis, sinusitis, and nasal polyps all are commonly found in patients with asthma, particularly those with difficult to treat or severe asthma Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (2016 update). Pre Step Up Checklist Before stepping up therapy: Assess adherence Unintentional poor adherence Misunderstanding about instructions Forgetfulness Absence of a daily routine Cost Intentional poor adherence Perception that the treatment is unnecessary Denial or anger about asthma or its treatment Inappropriate expectations Concerns about side effects (real or perceived) Dissatisfaction with healthcare providers Stigmatization Cultural or religious issues Cost Medication/regimen factors Difficulty using inhaler device Burdensome regimen (eg, multiple doses per day) Multiple different inhalers Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (2016 update). 14

15 Conclusion The personal, social, and economic burden of severe asthma is disproportionately high New insights into asthma pathophysiology emphasize the role of type 2 inflammation Identification of distinct phenotypes and endotypes provide novel ways of categorizing asthma and open avenues for the potential of phenotype and endotype driven therapy It is important to distinguish between truly severe, refractory asthma and uncontrolled disease prior to therapeutic intensification 15