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Asthma. Mark A. Brown, MD Arizona Respiratory Center mabrown@arc.arizona.edu. Tucson Pediatric Pulmonary Center. Definition. Intermittent lower-airway obstruction that is reversible either spontaneously or as the result of treatment Inflammation and edema Bronchial smooth-muscle spasm

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  1. Asthma Mark A. Brown, MD Arizona Respiratory Center mabrown@arc.arizona.edu Tucson Pediatric Pulmonary Center

  2. Definition • Intermittent lower-airway obstruction that is reversible either spontaneously or as the result of treatment • Inflammation and edema • Bronchial smooth-muscle spasm • Mucous plugging

  3. Definitions • Asthma exacerbation: symptoms that require a change in medication from baseline • Status asthmaticus: increasingly severe asthma that is not responsive to drugs that are usually effective

  4. Epidemiology • 10% of children in the US: 5 million children under the age of 18 • Prevalence is increasing • Asthma morbidity and mortality is increasing • 50% have family history of asthma, rhinitis, eczematous dermatitis, or urticaria

  5. Onset of Symptoms in Children With Asthma 20% 30% 1-2 years <1 year 20% 2-3 years 30% >3 years McNicol and Williams. BMJ 1973;4:7-11; Wainwright et al. Med J Aust 1997;167:218-222.

  6. Natural History of Childhood Asthma Transient earlywheezers Non-atopicwheezers IgE-associatedwheeze/asthma Wheezing Prevalence 0 3 6 11 Age (Years) Martinez. J Allergy Clin Immunol 1999;104:S169-S174.

  7. Asthma Prevalence in US Children SOURCE: US EPA (NCHS, 2006-2010).

  8. Asthma Ambulatory Visits Akinbami LJ, et al. Pediatrics, 2009; 123:S131-S145

  9. Childhood Asthma Deaths Akinbami LJ, et al. Pediatrics, 2009; 123:S131-S145

  10. Deaths/100,000 population Arizona vs. US Asthma Age-Adjusted Mortality Rate 1991-98

  11. Risk Factors • Previous attack with: • Severe unexpected or rapid deterioration • Respiratory Failure (ICU/Intubation) • Seizure or loss of consciousness • Recent use of oral steroids or decrease in ICS • Frequent use of short acting -agonist

  12. Risk Factors • Two or more hospitalizations in the last year • Hospitalization or ED in the last month • 3 or more ED visits in the last year

  13. Psychosocial Denial or failure to perceive severity Depression Nonadherence Dysfunctional family Inner-city resident Risk Factors

  14. Inflammation in Mild Asthma Subject Without Asthma Patient With Mild Asthma Busse and Lemanske. N Engl J Med. 2001;344:350-62.

  15. CXR

  16. Airway Remodeling 30 20 10 0 P<.003 P<.01 SubepithelialLayerThickness (µm) * Severe Moderate Mild Healthy (n=6) (n=14) (n=14) (n=8) *P<.001, healthy subjects vs patients with asthma. Chetta et al. Chest. 1997;111:852-7.

  17. Frequent Use of B2 Agonists Increased Likelihood of Asthma-related Hospitalizations 8 7 6 5 4 3 2 1 0 Inhaled Steroids ß2-agonists Total Age 0-17 Total Age 0-17 Relative Risk of Hospitalization None 0-1 1-2 2-3 3-5 5-8 8+ Prescriptions per Person-Year Adapted from Donahue et al. JAMA. 1997;277:887-891.

  18. fibroblast adhesion molecules IL-8 monocyte CPLA2 GRO- dendritic cell IL-16 macrophage ICAM-1 IL-11 NO FGF IL-12 MCP-1 G-CSF SCF CGRP collagenase LTC-4 ICAM-1 GM-CSF LTB-4 IGF-I eotaxin VCAM-1 IFN- MCP-2 TNF- PDGF IL-1 0 species IL-5 IL-2 PGE2 IL-12 RANTES GM-CSF GM-CSF IFN- PGF2 EAF IL-1 TNF- ICAM-1/3 IL-1 IL-1 MIP-1 15-LT5 IL-6 TXA2 TGF- TNF- iNOS PGE2 MCP-3 CD8 IL-1 IL-3 IL-4 IL-6 COX2 IL-8 PGE2 IL-11 IL-8 NEP IL-5 IL-6 PAF CD4 MCP-1 ET-1 SLPI GM-CSF IL-3 antigen presentation iNOS IL- MIP-1 15-LD VIP RANTES RANTES IL-1 IL-3 9/13 HODE MIP-1 COLLAGEN I, II, V 0 species LTB-4 cytokines IL-5 15-HETE IL-12 MCP-3 NO IL-10 eotaxin IL-6 IL-10 eotaxin MIP-1 protease RANTES TNF- IL-17 PDGF LTB-4 ICAM-1 PGE2 IL-10 IL-8 TGF-1 eosinophil epithelial cell IL-8 Th-1 IFN- PAF IL-6 O2 IL-3 CR-3 RANTES TNF- EDN LTD-4 IFN- EDP histamine endothelial cell ECP IL-1 protease cytokines MBP TXA2 GM-CSF IL-2 MCP-1 LTD-4 IL-6 G-CSF MPO IL-4 LTC-4 PGS IL-5 BIP L-selectin IL-1 LTC-4 MCP-3 O species TNF- LTD-4 IL-13 IL-13 neutrophil IL-8 IFN- IL-1 ET-2 LTE-4 MIP-1 PGS LTC-4 GM-CSF TNF- TGF IL-4 GM-CSF PAF ET-1 ICAM-1 IgE IL-10 IL-6 IL-4 IL-8 GM-CSF PAF HB-EGF Th-0 basophil ICAM-1 IL-6 TXB-2 IL-2 adhesion molecules 0 species IL-5 tryptase IL-1 PDGF-B RANTES IL-4 NCF MCP-2 15-HETE IL-2 GM-CSF MIP-1 MCP-3 IgE LTC-4 IL-10 neurone IL-14 MCP-1 IL-13 IL-4 cytokines PGE2 mast cell IL-4 RANTES IgE LTD-4 IL-1 IL-3 IL-8 MCP-2 LTE-4 IL-5 TNF- GM-CSF SCF IL-8 GM-CSF C-kit MCP-3 B cell Th-2 TNF- IFN- IL-6 eotaxin IL-6 IFN- PAF IL-13 SCF GM-CSF IL-3 neurokinins Mediator release modified smooth muscle cell LTB-4 chemokines myofibroblast eotaxin IL-6 histamine PGD2 Effects of Corticosteroids on Inflammatory Cells

  19. 2.5 2.0 1.5 1.0 0.5 0.0 2 4 6 8 10 12 ICS May Prevent Death From Asthma Rate Ratio for Death From Asthma Number of Canisters of Inhaled Corticosteroids Used in the Year Before Death From Asthma Suissa et al. N Engl J Med. 2000;343:332-6.

  20. Effects of Inhaled Corticosteroidson Inflammation Pre- and post- 3 month treatment with budesonide(BUD) 600 mcg BID; E = epithelium, BM = basement membrane Laitinen. J Allergy Clin Immunol.1992;90:32-42.

  21. Health Resource Utilization Greater reductions in the need for emergency care Budesonide Nedocromil Placebo P<.001 30 P=.02 22 20 No./100 Person-Year 16 P=.04 12 10 4.3 4.4 2.5 0 Urgent Care Visits Hospitalizations Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343:1054-63.

  22. CAMP: ICS Reduced Oral Prednisone Use • First Course of Prednisone 1.00 Budesonide Nedocromil 0.75 Placebo Cumulative Probability 0.50 P<.001 budesonide vs placeboP=.32 nedocromil vs placebo 0.25 0.00 2 0 1 3 4 Time (y) CAMP = Childhood Asthma Management Program. Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343:1054-63.

  23. Prednisone Use Budesonide Nedocromil Placebo P<.001 P=.01 122 125 102 100 No./100 Person-Year 70 75 50 25 0 Prednisone Courses Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343:1054-63.

  24. Corticosteroid Dose Response Curves for Various Outcomes 100 80 60 Symptoms (reduction) % of Maximum FEV1 (increase) Exercise (FEV1) (increase) 40 Nitric oxide (reduction) FEF25-75% (increase) 20 0 800 0 200 400 600 Daily Dose of Budesonide (g) Barnes et al. Am J Respir Crit Care Med. 1998;157:S1-S53.

  25. Lower Doses Are Associated With Fewer Risks Therapeutic Effects Favorable Benefit:Risk Ratio Response Undesirable Effects Dose Pedersen et al. Allergy. 1997;52:1-34.

  26. Budesonide Nedocromil Placebo Budesonide Nedocromil Placebo Long Term Effects of Budesonide and Nedocromil On Growth Standing Height Standing-Height Velocity 6.5 160 155 6.0 150 5.5 145 140 5.0 135 cm cm/yr 4.5 130 0 0 0 1 2 3 4 0 1 2 3 4 Time (yr) Time (yr) Number of Patients Remaining in the Study Number of Patients Remaining in the Study • 286 288 275 • 291 278 266 • 400 388 379 370 308 294 293 289 280 309 303 293 284 271 414 400 392 386 379 Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:1054-1063.

  27. = Girls •  = Boys Predicted and Measured Adult Height Agertoft L & Pedersen S. NEJM 343:1064, 2000

  28. Important Additional Steps • Asthma education • Triggers, Adherence, Follow-up • Identify and treat comorbidities • Allergies, Sinus Disease, Reflux • Address Barriers to Care

  29. Childhood Asthma • Serious, common disease • Inflammation • Inhaled steroids are effective • Environmental and social factors are very important

  30. He who knows and knows that he knows is conceited; avoid him. He who knows not and knows not that he knows not is a fool; instruct him.He who knows and knows not that he knows is asleep; awaken him.But he who knows not and knows that he knows not is a wise man; follow him.— Arab proverb

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