1. Diagnosing and Management of Asthma in Children Four years and Younger John D. Mark MD Clinical Assoc Professor of Pediatrics Pediatric Pulmonary Medicine Lucile Packard Children’s Hospital at Stanford

2. Objectives To better understand how to differentiate between infants who wheeze and go on to develop asthma and those who wheeze but do not go on to have asthma To discuss management strategies for treating children with a high risk of developing asthma To discuss possible prevention therapies for asthma in children four years old or younger

3. What is Asthma? Disease of chronic inflammatory disorder of the airways Characterized by Airway inflammation Airflow obstruction Airway hyperresponsiveness http://health.allrefer.com/health/asthma-normal-versus-asthmatic-bronchiole.html Cookson W. Nature 1999; 402S: B5-11

4. Asthmatic Inflammation Normal Airway Mast Cells Alveolar macrophages Recruitment and activation of inflammatory cells Subacute/Chronic Inflammation Neural & vascular effects Late Asthmatic Response Early Asthmatic Response chemotactic factors cytokines Inhaled trigger

5. Figure 2. Inflammatory and remodelling responses in asthma with activation of the epithelial mesenchymal trophic unit Lancet, Vol 368, 2006-1 September 2006, Pages 780-793

6. What Causes Asthma? Asthma is a complex trait Heritable and environmental factors contribute to its pathogenesis. Viral infections appears have an expanding role as well. Onset appears early in life and severity remains constant Multiple interacting genes At least 20 distinct chromosomal regions with linkage to asthma and asthma related traits have been identified: Chromosome 5q, ADAM33, PHF11

7. Potential Risk Factors 1 Host factors Genetic predisposition Atopy Airway hyperresponsiveness Gender Race/Ethnicity Environmental factors Indoor allergens Outdoor allergens Occupational sensitizer Environmental factors (cont) Tobacco smoke Air pollution Respiratory infections Socioeconomic status Family size Diet and drugs Obesity 1 Masoli M, et al. The Global Burden of Asthma: Executive Summary of the GINA Dissemination Committee Report. Allergy 2004; 59: 469-78.

8. Diagnosing Asthma-Not Easy Clinical diagnosis supported by the certain historical, physical and laboratory findings History of episodic symptoms of airflow obstruction (e.g.. breathlessness, wheezing, and COUGH)-response to therapy! Physical: wheeze, hyperinflation Laboratory: exhaled nitric oxide (eNO), spirometry Exclude other possibilities

9. Differential Diagnosis Wheezing Asthma Congenital Anomalies with airway impingement: Vascular rings, tracheobronchial obstruction, mediastinal mass Bronchopulmonary dysplasia Cystic fibrosis Gastroesophageal reflux Aspiration Foreign Body Aspiration Heart Failure Sinusitis and allergic rhinitis Bronchiolitis Pertussis Tuberculosis Immune system Disorders

10. Wheezing in Infants Group 1: Low Lung function: children improve within a few years and "outgrow" their asthma Group 2: Non-Atopic, viral-induced asthma: also outgrow asthma after a somewhat longer period of time (nonatopic wheezing). Group 3: Atopic Asthma: in contrast, children who will go on to develop persistent wheezing beyond infancy and early childhood usually have a family history of asthma and allergies and present with allergic symptoms very early in life (atopy-associated asthma).

11. Diagnosing Asthma in Young Children – Asthma Predictive Index > 4 episodes/yr of wheezing lasting more than 1 day affecting sleep in a child with one MAJOR or two MINOR criteria Major criteria Parent with asthma Physician diagnosed atopic dermatitis Minor criteria Physician diagnosed allergic rhinitis Eosinophilia (>4%) Wheezing apart from colds 1 Adapted from Castro-Rodriquez JA, et al. AJRCCM 2000; 162: 1403

12. Asthma Diagnosis Made Identify precipitating factors (pets, ETS, mold) Identify comorbid conditions that may aggravate asthma (GERD, allergies etc) Assess the patient/families knowledge and self management skills Classify asthma severity using the Guidelines from the NHLBI (Expert Panel)

13. Assessing Asthma Severity Use Impairment and Risk Impairment Symptoms: night time symptoms, reliever use (SABA), miss school/work, quality of life, ACT screen Lung function- spirometry (FEV0.5), eNO Risk Recurrent exacerbations including ED visits and hospitalization (may be normal between events) At times, hard to differential between impairment and risk

14. Classifying Asthma Severity in Children 0-4 Years of Age Break down into intermittent, mild, moderate, or severe persistent asthma depending on symptoms of impairment and risk Once classified, use the 6 steps depending on the severity to obtain asthma control with the lowest amount of medication Controller medications (inhaled steroids) should be considered if >4 exacerbations/year, 2 episodes of oral steroids in 6 months, or use of SABA’s (albuterol) more then twice a week

15. Steps of Therapy 0-4 Years Step 1: intermittent- use SABA prn Step 2: mild persistent-use low dose ICS OR montelukast OR cromolyn alternatives Step 3: moderate persistent: moderate dose of ICS Step 4: moderate persistent: moderate dose of ICS and add either montelukast or LABA Step 5: severe persistent: high dose ICS and montelukast or LABA Step 6: severe persistent: high dose ICS and montelukast or LABA plus oral steroids Consult asthma specialist if step 3 or higher (consider at step 2)

16. Maintaining Control Monitor carefully- every 6 months if stable, more often if not If stable after 3 months, try to reduce therapy (usually by 25-50%) Inhaled steroids are safe even in the young at mild to moderate doses with only a slight decrease in growth velocity. Higher doses have been shown to affect growth, cause cataracts and reduce bone density Response to therapy is very important in this age group!

17. Inhaled Corticosteroid Preferred treatment alone or in combination for all persistent categories of asthma Safe when use is monitored Reduces asthma symptoms, bronchial hyperreactivity, exacerbations and hospitalizations, need for rescue medications Improves lung function, quality of life May prevent airway remodeling…Probably no longer true

18. ICS Are More Effective at Decreasing Asthma Exacerbations Than Anti-leukotriene Agents Results not affected by type of medication, methods, analysis, publication status or funding source. Insufficient evidence in children. * No exacerbations reported Maspero Baumgartner Busse Hughes (BUD)* Hughes (FP) Laviolette* Skalky Williams Bleecker Busse Fixed Effects Pooled Relative Risk 0.1 -15-10-50+5+10+15+10 Relative Risk (95% CI) Ducharme FM, BMJ 2003; 326: 621 Favors anti-leukotrienesFavors inhaled glucocorticoids 1 Kim 1.6

19. Role of ICS in Asthma Trials show that among children with asthma (or at risk for asthma), controller therapy with ICS is efficacious in controlling asthma symptoms However, ICS, do not change the natural clinical course of the disease. PEAK trial 285 children aged 2 to 3 years at high risk for asthma were randomized to therapy with either an ICS (fluticasone, 88 μg twice daily for 2 years) or placebo Results showed significantly better clinical outcomes and lung function outcomes in children treated with fluticasone than in those treated with placebo However, clinical differences between groups rapidly disappeared a few weeks after discontinuation of regular treatments. Guilbert et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma, N Engl J Med 354 (2006), pp. 1985–1997

20. FDA Approved Therapies ICS budesonide nebulizer solution (1-8 years) ICS fluticasone DPI (4 years of age and older) LABA and LABA/ICS combination DPI and MDI (4 years of age and older) Montelukast chewables (2-4 years), granules (down to 1 year of age) Cromolyn sodium nebulizer (2 years and older)

21. Is Environmental Control Helpful? Single allergen reduction not effective “…Treatment by means of allergen avoidance requires the definition of what patients are allergic to, and additional measures beyond the use of mattress covers and education” Thomas Platts-Mills http://health.allrefer.com/health/asthm a-common-asthma-triggers.html

22. Tailored Environmental Intervention Morgan et al, 2004 1 Randomized, controlled trial of environmental intervention Intervention resulted in Reduction in asthma symptoms, disruption in caretakers plans, caretaker’s and child’s sleep, asthma-related visits to the ER or clinic Reduction in asthma symptoms were correlated to reduction in allergens No difference in reduction of allergens in homes with carpets or without carpets 1 Morgan WJ, et al. N Engl J Med 2004; 351: 1068-80.

23. A Potential Gap in Patient-Provider Communications Asthma Practices- Two Perspectives: Patients and Doctors 1 Base: All patients (unweighted N=2509), all doctors (unweighted N=512). 27% 70% 28% 83% 35% 70% 55% 92% 90% 97% PatientDoctor 1 Adapted from http://www.asthmainamerica.com/slides/powerpoint/slide27.ppt

24. Neuroendocrine Mechanisms- Stress and Asthma Common clinical observations of adverse relationship between stress and human disease Adverse effects of psychological stress on asthma have been documented. Depression and stress can augment humoral immunity and favor production of IgE Immunological changes may shift from TH1 to TH2 and promote allergic responses Growing set of data provide evidence for association between chronic psychological stress and the pathogenesis of atopy and asthma Marshall G, Ann Allergy Asthma Immunol. 2004;93:S11-S17

25. Asthma: Goals of Treatment 1 Control chronic and nocturnal symptoms Maintain normal activity levels and exercise Maintain near-normal pulmonary function Prevent acute episodes of asthma Minimize emergency department (ED) visits and hospitalizations Avoid adverse effects of asthma medications 1 Global Initiative for Asthma. GINA workshop report: global strategy for asthma management and prevention. Available at: http://www.ginasthma.org. Accessed October 13, 2006. http://www.ginasthma.org

26. Asthma Prevention There has been remarkable progress in pharmacotherapy, education and environmental measures in treating asthma However, no single action has been demonstrated to decrease the risk of developing asthma Genetic and environmental influences-key! Exposure to microbial products- Hygiene? Low level of lung function present in preschoolers with asthma Prevention will depend on factors influencing the development and progression of asthma

27. Hypothetical representation of 2 separate developmental pathways present in persistent asthma Martinez, F, JACI, 119:30-33, January 2007

28. Next Steps There is a need to develop therapeutic modalities that, initiated even earlier in life and before the development of the first asthma-like symptoms, will prevent progression along the pathways to airway dysfunction. If a group of children with asthma in whom the disease is confirmed, early genetic and phenotypic markers are needed to target them for the development of specific therapies that will thwart that progression. It is essential to determine whether in children with mild persistent asthma, whether intermittent, symptom-triggered anti-inflammatory therapy might be as effective as daily continuous therapy with controller medications in decreasing exacerbations and improving quality of life.

29. That’s Enough!