Mark A. Brown, MD Arizona Respiratory Center mabrown@arc.arizona.edu 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 Mucous plugging Primary immune mechanism of asthma: antigen with immunoglobulin E bound to the cell surfaces which triggers the release of histamine and a variety of other factors that promote both bronchospasm and local inflammation Inflammation: --Lymphocytic and eosiophilic submucosal infiltrates seen on tracheal and bronchial biopsy specimens correlate with severity of disease --Mast cells, epithelial cells and T lymphocytes are activated and produce proinflammatory cytokines --Mediators such as histamine, leukotrienes, platelet-activating factor and others are found locally as well as systemically in increased conc Histamine: increases leakage of protein and fluid from venules increases airway secretions,can stimulate irritant receptors in the airway walls This leads to relex vagal release of acetylcholine near smooth muscles leading to further bronchoconstriction Antihistamines are not helpful in asthma Other factors besides histamine: --lipoxygenage products of arachidonate--leukotrienes--other bronshospasm mediators: platelet activating factor, bradykinin, substance P, oxidants Cholinergic nerves that travel in the vagus nerve may release acetylcholine Stimulation of these receptors is also responsible for cough Epithelial Destruction renders airways hyperirritable The hyperirritable and chronically inflamed airway is susceptible to acute obstruction triggered by such factor as allergen exposure, URI, environmental irritants, exercise, second hand smoke, emotional stress, GER, and drugs.

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 Review Article in Chest 2001. Status Asthmaticus in Children. A Review. Heinrich A Werner, MD

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 10 % of children in the US: the most common chronic illness of childhood in the US Reference: Pediatric Asthma:Promoting Best Practices. Guide for managing asthma in child, 1999 Prevalence is increasing—especially among children less than 12: Source: NCHS, national health interview survey, 1884-1996. Diagnostic shift (use of “asthma” for conditions classified differently) cannot fully account for this development—asthma prevalence is increasing world-wide Asthma morbidity is also on increase—rates have doubled for kids aged 1-4 About 50% of children with asthma improve or become symptom free on reaching early adulthood but a very early onset of disease is associated with a less favorable prognosis

Onset of Symptoms in Children With Asthma 20% 30% 1-2 years <1 year 20% 2-3 years 30% Slide 7. Onset of Symptoms in Children With Asthma Most children who experience wheezing before age 5 years are likely to receive an asthma diagnosis in childhood. Approximately 10% of young children are affected by asthma. Of these children, 30% will have an onset of symptoms within the first year of life. Approximately 50% of children with asthma experience symptom onset by age 2 years and 70% do by age 3 years. Dodge R, Martinez FD, Cline MG, Lebowitz MD, Burrows B. Early childhood respiratory symptoms and the subsequent diagnosis of asthma. J Allergy Clin Immunol 1996;98:48-54. Wainwright C, Isles AF, Francis PW. Asthma in children. Med J Aust 1997;167:218-222. McNicol KN,Williams HB. Spectrum of asthma in children. I. Clinical and physiological components. BMJ 1973;4:7-11. >3 years McNicol and Williams. BMJ 1973;4:7-11; Wainwright et al. Med J Aust 1997;167:218-222.

Natural History of Childhood Asthma Transient early wheezers Non-atopic wheezers IgE-associated wheeze/asthma Wheezing Prevalence Slide 8. Natural History of Childhood Asthma Childhood asthma often persists or recurs in adulthood, with approximately one third of children with asthma experiencing symptoms as adults.The occurrence of wheezing and other respiratory symptoms in children aged 3 to 4 years is significantly associated with future asthma. Most infants who wheeze have no increased risk of asthma or allergies later in life. However, for a minority of infants, early wheezing episodes may be related to future asthma.These children have elevated immunoglobulin E (IgE) levels during the first months of life and have lung function deficits by 6 years of age. Development of asthma may also be related to allergen sensitivity. Children who wheeze at age 6 years and who are skin-test positive to asthma-related allergens are more likely to have persistent symptoms and show hyperresponsiveness to methacholine beyond that age (and up to age 11 years). In contrast, children who wheeze at age 6 years and who are skin-test negative to allergens are much less likely to show persistent wheezing beyond the early school years. Oswald H, Phelan PD, Lanigan A, Hibbert M, Bowes G. Olinsky A. Outcome of childhood asthma in mid-adult life. BMJ 1994;309:95-96. Dodge R, Martinez FD, Cline MG, Lebowitz MD, Burrows B. Early childhood respiratory symptoms and the subsequent diagnosis of asthma. J Allergy Clin Immunol 1996;98:48-54. Martinez FD,Wright AL,Taussig LM, et al. Asthma and wheezing in the first six years of life. N Engl J Med 1995;332:133-138. Martinez FD. Present and future treatment of asthma in infants and young children. J Allergy Clin Immunol 1999;104:S169-S174. 0 3 6 11 Age (Years) Martinez. J Allergy Clin Immunol 1999;104:S169-S174.

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

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

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

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

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 Risk Factors for potentially fatal asthma Although several contributors to the mortality risk have been described—as many as one third of children who die from asthma may have only had mild asthma before and were not previously classified as high risk by any available criteria In the US : nonwhite children with poor access to health care have the highest risk for near-fatal and fatal asthma

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

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

Inflammation in Mild Asthma Slide 11. Inflammation in Mild AsthmaBusse and Lemanske N Engl J Med 2001/figure 1 Inflammation in asthma leads to structural airway changes, even in patients with mild to moderate disease.Busse 2001/350/2/1 This photograph, which appeared in a New England Journal of Medicine review, shows a specimen of bronchial mucosa from a subject without asthma and a patient with mild asthma. The epithelium is intact in the subject without asthma. Neither thickening of the sub-basement membrane nor cellular infiltrate is evident. In the patient with mild asthma, there is evidence of goblet-cell hyperplasia in the epithelial cell lining, sub-basement membrane thickening, collagen deposition in the submucosal area, and a cellular infiltrate.Busse 2001/351/Figure 1 Busse WW, Lemanske RF. Asthma. N Engl J Med. 2001;344:350-62. Subject Without Asthma Patient With Mild Asthma Busse and Lemanske. N Engl J Med. 2001;344:350-62.

CXR Heart has been shifted medially and inferiorly by the hyperexpansion of the lungs. Also can see this hyperexpansion with anterior air on lateral film

Airway Remodeling 30 P<.003 20 P<.01 10 P<.003 P<.01 Subepithelial Layer Thickness (µm) * Slide 29. Airway Remodeling Occurs Even in Patients With Mild AsthmaChetta 1997/855/figure 1 and 854/2/2 Airway remodeling, as determined by subepithelial layer thickness, is a characteristic pathologic finding in patients with asthma.Chetta 1997/853/1/3, 852/Abstract Airway biopsies were taken from 34 patients with asthma (aged 15–55 y) controlled only with inhaled 2-adrenergic agonists and 8 healthy volunteers.Chetta 1997/853/2/2 Patients with asthma were excluded if they required theophylline, corticosteroids, or sodium cromoglycate. Asthma severity was assigned based on symptoms, bronchodilator use, and peak expiratory flow variability, each of which was rated on a 0 to 4 scale.Chetta 1997/853/1/4 Differences in subepithelial layer thickness were computed for each biopsy. Differences were significant among the groups of asthma patients identified by disease severity (P<.003 for severe vs mild asthma; P<.01 for severe vs moderate asthma) and between all patients with asthma versus healthy controls (P<.001).Chetta 1997/854/2/2 In the figure shown, bars indicate the mean and circles indicate the individual values for subepithelial layer thickness in each group of patients with asthma and the group of healthy controls.Chetta 1997/855/1/ Figure 1 Chetta A, Forest A, Del Donno M, Bertorelli G, Pesci A, Olivieri D. Airways remodeling is a distinctive feature of asthma and is related to severity of disease. Chest. 1997;111:852-7. 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.

Frequent Use of B2 Agonists Increased Likelihood of Asthma-related Hospitalizations 8 7 6 5 4 3 2 1 ß2-agonists Inhaled Steroids Total Age 0-17 Total Age 0-17 Relative Risk of Hospitalization Overuse of rescue beta agonists may indicate worsening asthma. In this study by Donahue et al, The relative risk for hospitalization increased as the number of beta2-agonist prescriptions increased above approximately 3 prescriptions per person-year among non-recipients of inhaled corticosteroids. Regardless of the number of beta2-agonist prescriptions per person-year, the relative risk for hospitalization did not increase among recipients of inhaled corticosteroids. Inhaled corticosteroids were associated with a 50% reduction in the relative risk of hospitalization compared with people who were not dispensed an inhaled corticosteroid. 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.

Effects of Corticosteroids on Inflammatory Cells B cell IgE dendritic cell ICAM-1/3 IL-1 CD4 antigen presentation IL-12 CD8 mast MCP-3 IL-5 IL-6 NCF MIP-1 LTB-4 SCF IL-3 IL-14 tryptase GM-CSF LTC-4 RANTES TNF- IL-8 eotaxin IL-13 LTE-4 IFN- PGD2 histamine PAF chemokines LTD-4 IL-4 neurone neurokinins myofibroblast C-kit Th-2 IL-1 IL-10 Th-1 TNF- IL-2 Th-0 basophil cytokines PGS protease neutrophil TGF-1 TXA2 IL-1 MPO O species BIP endothelial cell adhesion molecules ICAM-1 L-selectin ET-2 ET-1 G-CSF fibroblast TGF- PDGF MIP-1 COLLAGEN I, II, V MCP-1 PGE2 collagenase IL-11 VCAM-1 eosinophil O2 PDGF-B ECP HB-EGF TGF TXB-2 EDP MBP 15-HETE 0 species CR-3 EDN MCP-2 macrophage IL- iNOS EAF epithelial cell 15-LD SLPI NEP COX2 15-LT5 PGF2 IGF-I CGRP FGF IL-16 CPLA2 GRO- NO VIP 9/13 HODE IL-17 smooth muscle cell Mediator release modified monocyte There are a multitude of cells, each capable of releasing a variety of mediators that participate in the inflammatory process of asthma. However, as can be seen from this slide, corticosteroids affect a significant number of the key inflammatory cells, and the release of their pro-inflammatory mediators.

ICS May Prevent Death From Asthma 0.0 0.5 1.0 1.5 2.0 2.5 2 4 6 8 10 12 Rate Ratio for Death From Asthma Slide 28. Low-Dose Inhaled Corticosteroids May Prevent Death From AsthmaSuissa 2000/335/figure 1 A study of 30,569 members (aged 5–44 y) of the Canadian Saskatchewan Health database examined whether the use of inhaled corticosteroids (ICS) could prevent deaths from asthma.Suissa 2000/332/1/3, 333/1/1 Those who received at least 3 prescriptions for an asthma medication in any 1-year period from 1975 to 1991 were included. A nested–case control design was used to match patients who died of asthma (n=66) with cohort controls (n=2681) according to the length of follow-up at death of the case patient (index date), date of study entry, and asthma severity.Suissa 2000/332/1/abstract; 333/results The figure shows the fitted rate ratio for death from asthma as a function of the number of canisters of ICS used during the year before the index date. The rate ratio was adjusted for the patient’s age and sex; the number of prescriptions for theophylline, nebulized and oral 2-adrenergic agonists, and oral corticosteroids in the year before the index date; the number of canisters of inhaled 2-adrenergic agonists dispensed in the year before the index date; and the number of hospitalizations for asthma during the 2 years before the index date.Suissa 2001/335/15/Figure 1 The rate of death from asthma among ICS users was reduced by 50% with the use of at least 6 canisters per year. Higher rates of death from asthma may be associated with sporadic ICS use (<4 canisters/y).Suissa 2000/335/1/1 For each additional canister of ICS used in the previous year, the rate of death decreased by 21% (adjusted rate ratio, 0.79; 95% confidence interval, 0.65–0.97).Suissa 2000/332/abstract, 334/table 1 Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med. 2000;343:332-6. 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.

Effects of Inhaled Corticosteroids on Inflammation Laitinen Study - Numerous studies in patients with asthma including the one above from Laitinen et al, have demonstrated that inhaled corticosteroids reduce airway inflammation. - Randomized, double-blind, parallel-group trial in 14 newly diagnosed mild asthmatics (mean duration of asthma was 7.4 months) - Subjects entered a 6-week baseline period, treated with terbutaline 375 mcg (three puffs) bid - Prior to randomization to either budesonide via MDI with spacer (600 mcg bid) or terbutaline (375 mcg bid) via MDI with spacer, subjects had a baseline bronchial biopsy - Bronchial biopsy was repeated after three months of (blinded) treatment - In the Figure are shown lymphocytes (arrow heads), eosinophils (thick arrows) and mast cells (thin arrow) - The histologic changes were associated with an improvement in lung function, asthma symptom scores, and bronchial responsiveness to inhaled histamine 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.

Health Resource Utilization Greater reductions in the need for emergency care Budesonide Nedocromil Placebo P<.001 30 P=.02 22 No./100 Person-Year 20 16 P=.04 12 Slide 52. Health Resource UtilizationCAMP 2002/1057/table 2 Compared with the placebo group, the budesonide group had a 45% lower rate of urgent care visits (P<.001). The nedocromil group had a 27% lower rate versus the placebo group (P=.02).CAMP 2000/1057/1/2 The hospitalization rate for the budesonide group was 43% lower (P=.04) than that for the placebo group. The rate of hospitalization with nedocromil treatment was similar to that with placebo.CAMP 2000/1057/1/2 The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med. 2000;343:1054-63. 10 4.3 4.4 2.5 Urgent Care Visits Hospitalizations Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343:1054-63.

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 placebo P=.32 nedocromil vs placebo 0.25 Slide 73. CAMP: Inhaled Corticosteroid Use Reduced Oral Prednisone UseCAMP 2000/1060/figure 2 The Childhood Asthma Management Program (CAMP) Research Group study compared the long-term effectiveness of budesonide and nedocromil versus placebo in 1041 children aged 5–12 years with mild to moderate persistent asthma.CAMP 2000/1054/abstract Children were randomized to treatment with 200 g budesonide (n=311), 8 mg nedocromil (n=312), or placebo (n=418), twice daily, for 4–6 years.CAMP 2000/1555/1/2 Asthma control was best in children treated with budesonide. Time to the first course of oral prednisone was significantly longer for the budesonide group versus the placebo group (P.001), but not for the nedocromil group versus the placebo group (P=.32).CAMP 2000/1057/2/2, 1060/figure 2   Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med. 2000;343:1054-63. 0.00 1 2 3 4 Time (y) CAMP = Childhood Asthma Management Program. Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343:1054-63.

Prednisone Use Budesonide Nedocromil Placebo P<.001 P=.01 122 125 102 100 No./100 Person-Year 70 75 Slide 53. Prednisone UseCAMP 2002/1057/table 2 The rate of use of prednisone courses was lowest in the budesonide group, with a 43% lower rate compared with that of the placebo group (P<.001).CAMP 2000/1057/1/2 The rate of use in the nedocromil group was 16% lower than that in the placebo group (P=.01).CAMP 2000/1057/1/2 The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med. 2000;343:1054-63. 50 25 Prednisone Courses Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343:1054-63.

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 Slide 20: Corticosteroid Dose Response Curves for Various Outcome ParametersBarnes 1998/S12/figure 8 This figure displays dose-response relationships for several asthma outcome parameters after treatment with inhaled budesonide. Desired effects on outcomes measuring asthma symptoms, lung function, and exhaled nitric oxide (a surrogate marker of inflammation), increase steeply with increasing doses of budesonide in the subclinical dose range, and plateau within the clinical dose range.Barnes1998/S12/Figure 8/peer group   Barnes PJ, Pedersen S, Busse WW. Efficacy and safety of inhaled corticosteroids: new developments. Am J Respir Crit Care Med. 1998;157:S1-S53. 200 400 600 800 Daily Dose of Budesonide (g) Barnes et al. Am J Respir Crit Care Med. 1998;157:S1-S53.

Lower Doses Are Associated With Fewer Risks Favorable Benefit:Risk Ratio Therapeutic Effects Response Undesirable Effects Slide 19: Lower Inhaled Corticosteroid Doses Are Associated With Fewer RisksPedersen 1997/28/figure 14 Unwanted systemic effects of inhaled corticosteroids (ICS) in the most commonly used dose range are only rarely of clinical significance.Pedersen 1997/27/2/4 Although lower ICS doses may be associated with systemic effects in some patients, unwanted effects in most patients occur at higher doses where the therapeutic dose-response curve has already plateaued.Pedersen 1997/27/2/5 In the figure shown, the dose range at which the benefit to risk ratio for an ICS is favorable is that at which the therapeutic effects “increase steeply with dose while the unwanted systemic effects increase only gradually.”Pedersen 1997/28/Figure 14 Pedersen S, O’Byrne P. A comparison of the efficacy and safety of inhaled corticosteroids in asthma. Allergy. 1997;52(suppl 39):1-34. Dose Pedersen et al. Allergy. 1997;52:1-34.

Long Term Effects of Budesonide and Nedocromil On Growth Standing Height Standing-Height Velocity 160 6.5 155 6.0 150 145 5.5 140 5.0 135 cm cm/yr 4.5 130 1 2 3 4 1 2 3 4 Time (yr) Time (yr) Number of Patients Remaining in the Study Number of Patients Remaining in the Study Budesonide Nedocromil Placebo The difference between the BUD and placebo groups in the rate of growth was evident primarily during the first year of treatment and did not increase later. All groups had similar rates of growth by the end of the treatment period. The difference between in height for the BUD and Placebo groups was 1.1cm. This difference did not increase over time. Calculations of projected final adult height suggest that the children in this study will reach similar adult heights. Some catch up growth may also occur during puberty. 308 294 293 289 280 309 303 293 284 271 414 400 392 386 379 Budesonide Nedocromil Placebo 286 288 275 291 278 266 400 388 379 370 Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:1054-1063.

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

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

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

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