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UPDATE on ASTHMA: INFLAMMATION, ENVIRONMENT, and THERAPY Adrian M. Casillas, MD UCLA School of Medicine Division of Clinical Immunology and Allergy ASTHMA DEFINED 1952: “The presence of widespread narrowing of the airways which alters in severity either spontaneously or as a result of treatment” 1962: Presence of bronchial hyperesponsiveness added 1970’s: Autopsy studies revealed inflammation 1980’s: Bronchoscopic evidence of inflammation in vivo WHAT IS ASTHMA? 1995 Definition: • Chronic inflammatory disorder of the airways - Mast cells, eosinophils, T lymphocytes • Inflammation associated with: - Airways hyperresponsiveness - Airflow limitation (at least partially reversible) - Respiratory symptoms: wheezing, breathlessness, cough, chest tightness 1995 NHLBI/WHO Workshop Report Cardinal Features of Asthma • Hyper-reactive airways • Late phase reaction • Multicellular infiltrate Provocative Inhalation Challenge in Asthmatics 50 40 30 SEVERE 20 MODERATE MILD SLIGHT 10 Normal 0 0.01 0.1 Dose (mol) 1 10 % Fall in Baseline FEV1 Mediators in Early and Late Phase Responses 10 EPR 0 LPR -10 -20 LTB4, LTC4 PGE2 , PGD2 Histamine GM-CSF, IL-5 LTB4 LTB4 LTB4 PGD2 TX Histamine Tryptase LTC4 -30 -40 -50 0 1 2 3 4 5 6 Hours After Allergen Challenge 7 8 9 10 Busse WW and Lemanske RF. Asthma. NEJM. 2001. 344;350-362 Normal Asthma Inflammatory Cells in Bronchial Epithelium of Newly Diagnosed Asthmatics ** 120 Cells/mm2 ** Controls Asthmatics 612 ** 80 40 * 0 N E M MC L * p<0.05 ** p<0.001 Laitinen et al, ARRD 1993;147:697 Asthma Pathological Changes in the Airways of Asthmatics Vasodilatation Plasma leakage New vessels Plasma exudation Desquamation of epithelium Goblet cell hyperplasia Mucus plug Air passage Hyperplasia of mucus glands Edema Smooth muscle hypertrophy and contraction Basement membrane thickening Subepithelial fibrosis Neutrophil and eosinophil infiltration Chronic changes are identified in italics, the remainder are acute changes. Adapted from Cochrane GM, Jackson WF, Rees PJ. Asthma Mechanisms Underlying the Definitions of Asthma Environmental risk factors (causes) INFLAMMATION Airway hyperresponsiveness Airflow limitation Triggers Symptoms Adapted with permission from Stephen T. Holgate, M.D., D.Sc. Asthma IS THE PREVALENCE OF ASTHMA INCREASING? per 1000 population TRENDS IN ASTHMA PREVALENCE IN THE Trends in Asthma Prevalence UNITED STATES 80 70 60 50 40 30 20 10 0 all ages 0 to 4 5 to 14 15 to 34 35 to 64 65 + 1980 81 - 93 84 - 86 87 - 89 90 - 92 93 - 94 Years Source: MMWR 1998; 47:1-27 Per 100k population TRENDS IN U.S. ASTHMA MORTALITY RATES 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 AfricanAmerican Caucasian All persons 79 81 83 85 87 89 91 93 95 Year ASTHMA MORTALITY RATES (per 100k) COUNTRY 1975-77 1985-87 % INCREASE AUSTRALIA 0.86 1.42 65 CANADA 0.33 0.47 42 ENGLAND & WALES 0.57 0.90 58 FRANCE 0.24 0.51 113 JAPAN 0.44 0.59 34 SINGAPORE 0.75 0.88 17 SWEDEN 0.37 0.54 46 SWITZERLAND 0.31 0.45 45 UNITED STATES 0.19 0.40 111 WEST GERMANY 0.59 0.78 32 Beasley, et al. Ciba Symposium 206; 1997 RISK FACTORS for DEVELOPMENT of ASTHMA • GENDER • ATOPIC STATUS Lung and Immune system development Induction of atopy: Th1/Th2 • GENETIC FACTORS Susceptibility genes • RESPIRATORY INFECTIONS Viral respiratory disease (RSV) • ENVIRONMENT Pollution (DEP) IMMUNOLOGICAL DEVELOPMENT AND ATOPIC STATUS THE Th1/Th2 CELL PARADIGM Kay AB. Allergy and Allergic diseases. NEJM. 2001. 344;30-37 Busse WW and Lemanske RF. Asthma. NEJM. 2001. 344;350-362 TH1/TH2 PARADIGM PARADIGM TH1/TH2 TH1 TH2 IL-2 INF- IL-3 GM-CSF TNF- IL-4 (IL-13) IL-5 IL-3 GM-CSF TNF- DELAYED HYPERSENSITIVITY ALLERGIC INFLAMMATION Need a balance of TH1 and TH2; with asthma, a more “TH2-like” phenomenon is seen. Tang et al. Lancet 1994;344(8928):983-5; *Prescott S. et al. Lancet 1999;16;353(9148):196-200 THE ROLE OF IgE Busse WW and Lemanske RF. Asthma. NEJM. 2001. 344;350-362 IgE and ASTHMA Prevalence of Asthma (%) 40 Age 6 to < 35 Age 35 to < 55 Age 55 + 30 20 10 0 <-1.5 -1.5 to < -0.5 -0.5 to < 0.5 0.5 to < 1.5 Ranges of Serum IgE Z Score Prevalence of Asthma in Relation to IgE Z Scores standardized for Age and Sex. Burrows et al.NEJM 1989;320(5):271-7 1.5+ EXOGENOUS FACTORS: INFECTION AND ENVIRONMENT VIRAL RESPIRATORY ILLNESS: THE ROLE OF RSV RSV IN EARLY LIFE and RISK of WHEEZE and ALLERGY by AGE 13 YEARS Relative Risk 5 Infrequent wheeze 4 3 Frequent wheeze 2 Decreased FEV 1 0 5 yrs 6 yrs 11 yrs 13 yrs Atopic status Age RSV is a risk-factor early on, but there is a change in the asthma phenotype over time. Adapted from Stein RT, et al. Lancet 1999;354;9178 Why has there been such a remarkable change in the level of allergic airway disease the last two centuries? This is a complex problem • Industrialization • Change in antigens • Changes in childhood infections • Change in activities - Indoors - Inactivity •Smoking by infants care givers For every complex problem, there is a simple solution which is WRONG! H.L. Mencken ENVIRONMENTAL ISSUES: POLLUTION EXPERIMENTAL RESEARCHERS OF THE CAUSES AND NATURE OF CATARRHUS AESTIVUS (HAY-FEVER OR HAY-ASTHMA) BY CHARLES H. BLACKLEY, M.R.C.S.ENG LONDON DAWSON’S OF PALL MALL 1873 CHAPTER V ON THE GREATER PREVALANCE OF HAY-FEVER AND ON THE INCREASE OF ITS PREDISPOSING AND EXCITING CAUSES 162 Experimental Researchers on Hay-Fever and I have shown that large numbers of the people have been transferred from the country to the workshops and mills of the towns, and have thus been placed in circumstances where the predisposition to hay-fever would be most rapidly developed in those who rise to a place amongst the educated class. And lately, I have shown that the production of the exciting cause has of late years been largely increased. Taking all these circumstances into account it is a highly probable that hay-fever was at one time altogether unknown, and it is tolerably certain that it has not only been much more frequent of late, but that, as population increases and as civilization and education advance, the disorder will become more common than it is at the present time. PREVALENCE of ATOPIC DISEASE SINCE the INDUSTRIAL REVOLUTION 30 % GENETIC PREVALENCE LIMIT FOR ALLERGIC RHINITIS 20 % Airborne Allergen load 10 % Bostock Bostock 1 case 28 cases 1828 1819 Lloyd Common 1907 0 1800 1850 1900 1950 2000 DEP are made up of a carbonaceous core containing unburnt chemicals DEP + RW INDUCE a TH2-TYPE CYTOKINE PATTERN mRNA level (Units) 20 15 Pre-Challenge Post RW Post RW + DEP 10 5 0 IL-4 IL-5 IL-6 IFN- IL-2 Exacerbation of allergic response • Allergic subjects challenged nasally with pollen ± 0.3 mg DEP • Allergic antibody production is up to 50 times greater if DEP present Diaz-Sanchez et al., J Immunol. 1997; 158:2406-13. Secondhand smoke augments allergen-induced Th2 responses Secondhand smoke exposure exacerbates IgE responses Pharmacological Therapy of Asthma • Quick-relief medications – Short-acting inhaled ß2-agonists – Inhaled anticholinergics • Long-term control medications – – – – – – Antihistamines Corticosteroids Cromolyn sodium, nedocromil Long-acting inhaled ß2-agonists Methylxanthines Leukotriene modifiers Mechanism of Glucocorticoid Action Protein enzyme receptor cytokine Cytokine e.g. TNF-a GCS CyR Cell Membrane + + NF-kB GR Direct interaction mRNA AP-1 (Fos + Jun) Nucleus Target gene TRE kB GRE Cellular Effect of Glucocorticoids Inflammatory Cells Structural Cells Eosinophil Epithelial cells Numbers (apoptosis) Cytokines Mediators T-lymphocyte Cytokines Endothelial cell Mast Cell Glucocorticoids Leak Numbers Macrophage Airway smooth muscle Cytokines B2-recep. Dendritic cell Mucus gland Numbers Mucus secretion Summary • Asthma is a CHRONIC INFLAMMATORY disorder of the airways caused by immune cell activation – Hyper-reactivity, late phase response, multicellular infiltrate • Prevalence is increasing globally • Risk factors include gender, atopic status, genetics, respiratory infections, environmental effects • Anti-Inflammatory agents should be considered in treatment regimens where asthma is persistent • Among newer therapeutic agents currently available, steroids and anti-leukotrienes offer specific benefits