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1 Special consideration in management of childhood asthma Chung Shan Medical University Hospital Department of Pediatrics Ko-Huang Lue MD. PhD. 參

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4 The T h1 -T h2 immune system around birth. Genetics in utero postnatal T h2 priming boosting immune deviation T h2 placenta BIRTH T h1 Allergen exposure - Bacterial load + Ex. Hepatitis A, TB baccili, Meases,...

5 BIRTH Th-2 Amplification of the Immune response Allergen Th-2 Education Airways inflammation Allergen Process of repair/ remodeling BHR ASTHMA Immune deviation Th-1 Education Absence of allergic symptoms IN UTERO CHILDHOOD

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10 Differential Diagnosis of Young Children With wheezing Age Common Uncommon Rare Less than 6 months Bronchiolitis Gastro-esophageal reflux Aspiration pneumonia Bronchopulmonary dysplasia Asthma Foreign body aspiration Congestive heart failure 6 months-2 years Bronchiolitis Foreign body aspiration 2-5 years Asthma Foreign body aspiration Aspiration pneumonia Asthma Bronchopulmonary dysplasia Gastro-esophageal reflux Gastro-esophageal reflux Viral pneumonia Congestive heart failure Cystic fibrosis Aspiration pneumonia Bronchiolitis Congestive heart failure Gastro-esophageal reflux Cystic fibrosis

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15 Different phenotype of wheezing at different ages

16 Natural History of asthma (Infancy) Asthma may develop during the first few months of life, but it is often difficult to make a definite diagnosis until the child is older. Small lungs may be responsible for some infant wheezing that resolves with child s growth Wheezing in the first year of life is not a prognostic indicator for asthma or for more severe asthma later in childhood While viruses appear to be more important than allergens in infancy, allergen take on a greater role as children approach school age GINA April, 2002

17 Asthma & wheezing in the first six years of life (NEJM 332:133-8,1995) 1/3 3 Y/O children had LRTI with wheezing Wheezing in the first 3 years of life had a rather benign prognosis 60% of these children had stopped wheezing by the age of six years Wheezing in early life and persisted to 6 years old Mother Hx of asthma More frequent symptoms during 1 st year of life ( 3) Elevated serum IgE levels Normal pulmonary function in 1 st year of life and elevated IgE with diminish pulmonary function at 6 Y/O

18 RSV-Induced Bronchiolitis May Consist of Several Phases Phase I Phase II Phase III Long term Viral infection Acute phase Persistent wheezing Wheezing and asthma Days Weeks Months (Not to scale) 18

19 RSV Is a Common Virus Causing Bronchiolitis in Children In a clinical study in Argentina, RSV was the most common virus isolated from a sample of children aged <5 years with acute lower respiratory infection 7.8% 6.8% 6.5% 0.7% RSV Adenovirus 78.2% Parainfluenza Influenza A Influenza B Carballal G et al. J Med Virol 2001;64:

20 Relation of viral infections, Healthy infant wheezing, and asthma RSV PIV Wheezing illness Resolution Atopy Child or adult with asthma Early childhood infections Measles(-), TB(-), RSV(+) Rhinovirus Exacerbation of asthma

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25 Factors Predicting Persistent Asthma Family history of asthma (maternal>paternal) Atopy (IgE/positive skin test, eczema, rhinitis) Allergen exposure (dust mites/animals) (>2yr) Viral (RSV) infection (<2yr) Gender (males>females) Smoking (passive or active) Severity in childhood

26 Early exposure House dust collected at 1.5 and 3 yr Cord IgE of 2178 newborn, total IgE and specific IgE of 374 children at 1.5 yr Exposure to house dust mite Der p I in infancy and the incidence of allergic diseases at 3 years of age 1 g/g of dust (n=760) < 1 g/g of dust (n=38) p Bronchial asthma 84 (11.1%) 3 (7.9%) Wheezing ever 363 (47.8%) 14 (36.8%) Atopic dermatitis 164 (21.6%) 2 (5.3%) * Urticaria 56 (7.4%) 1 (2.6%) Huang JL. Pediatr Allergy Immunol 2001;12:11-6

27 Early exposure Presence of Der p, cow s milk and egg white specific IgE at 1.5 y and the occurrence of allergic disease at 3 y Der p 1 Cow s milk Egg white <0.35 IU/ml (n=282) 0.35 IU/ml (n=282) p <0.35 IU/ml (n=219) 0.35 IU/ml (n=282) P <0.35 IU/ml (n=295) 0.35 IU/ml (n=282) P asthma 28 (10%) 21 (26.6%) (11.4%) 24 (16.9%) (13.2%) 10 (15.4%) Wheezing ever 148 (52.5%) 32 (40.5%) (49.8%) 71 (50.0%) (50.3%) 31 (47.0%) Atopic dermatitis 61 (21.6%) 21 (26.6%) (21.9%) 34 (24.0%) (20.3%) 22 (33.8%) Urticaria 19 (6.7%) 4 (5.1%) (6.4%) 9 (6.3%) (6.8%) 3 (4.6%) Huang JL. Pediatr Allergy Immunol, 2001;12:11-6

28 Genetic and environment Boys Girls Prevalen ce (%) OR 95% CI PAR (%) ao R PAR (%) Prevalence (%) OR 95% CI PAR (%) aor PAR (%) Hereditary factors ** ** ** ** Indoor environmen tal factors * * Outdoor environmen tal factors ** * ** * Lee YL. Pediatrics 2003;122:e389-95

29 Factors Associated with the Development of Persistent Asthma (Asthma Predictive Index) Key Recurrent wheezing, defined as >3 wheezing episodes in the past year 1,2 Minor Eosinophilia 2 Wheezing apart from colds 2 Food sensitivity 2 Increased IgE 2 Major Eczema 1,2 Airborne allergen sensitization 2,3 Maternal asthma 1,2,4 1. Martinez FD, et al. N Engl J Med. 1995;332: Martinez FD. Pediatr Pulmonol Suppl. 1997;15: Platt-Mills TAE, et al. J Allergy Clin Immunol. 2000;S503-S Raby BA, et al. Pediatrics. 2004;114:e327-e Smith L. J Allergy Clin Immunol. 1998;101:S370-S Wainwright C et al. MJA. 1997;167: Other Male gender 1,4 Details of pregnancy and delivery 4,5 Tobacco smoke 1,6 Allergic rhinitis 1 76% of children with a positive index had active asthma during 1 school year >95% of children with a negative index never had asthma between ages 6 and 13 years

30 The influence of atopy on the natural history of asthma in childhood Prevalence % Atopic Non-atopic Age years Illi S et al Lancet 2006; 368:

31 Recurrent wheezing in infants and young children still comprise a heterogeneous conditions with different risk factors and prognosis Management of infants and small children with asthma is a challenging task because of the many issues unique to this age group that deserve special consideration

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35 Over the years, the symptoms and FEV1 in each of these groups continued reflect the differences in initial severity. The overall severity increased between the age of 7 and 10 years, but then improved until age 28 years, after which it remained stable. Only 1 subject died of asthma. By age 42 years, some of the subjects in each group were free of asthma, and some had frequent or persistent asthma. The more severe the asthma at age 7 years, the more likely it was to persist to age 42 years (Table I) These subjects were reviewed at ages 10, 14, 21, 28, 35, and 42 years. REDUCED LUNG FUNCTION AT AGE 7 YEARS was associated with continuing symptoms in adult life, and the lung function continued to be reduced, but did not appear to decline more rapidly than the control or mild groups with normal FEV1. PRESENCE OF HAY FEVER, ECZEMA, OR POSITIVE SKIN TEST RESULTS increased the risk of more severe asthma in adult life. Several conclusions seem reasonable. The SEVERITY OF ASTHMA in early childhood substantially determines the SEVERITY OF THE SYMPTOMS in later years. Children with atopy have more severe and persistent asthma than children whose episodes are provoked only by respiratory infection.

36 Diagnosis of Childhood Asthma Questionnaire Have you/has your child had wheezing or whistling in the chest in the last 12 months? In the last 12 months, have you/has your child had a dry cough at night, apart from a chough associated with a cold or chest infection? Do you/does your child have a history of hay fever eczema? Is there a family history of asthma in your (child s) first-degree relatives? Have you/has your child received more than three courses of antibiotics for respiratory symptoms (both upper and lower respiratory tract) in the last 12 months? In the last 12 months, has your (Child s) chest sounded wheezy during or after exercise? In the last 12 months, has your (Child s) sleep been disturbed due to wheezing? In the last 12 months, has wheezing ever been severe enough to limit your (Child s) speech to only one or two words at a time between breaths? In the Last 12 Months, have you/has your child been to a doctor, an emergency room, or a hospital for wheezing?

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43 Treatment of Asthma in Young Children Asthma is the most common chronic disease of childhood 50% to 80% of asthmatic children develop symptoms before the age of 5 years Ref 1, p 3A Ref 2, pp 1A, 94A Currently available therapies have troublesome limitations for children Adapted from Boner AL et al. Eur Respir Rev 1997;7:3-7; National Institutes of Health, NIH Publication No SGA 99-W-6373-SS Slide 1

44 Challenging Issues to Management of Wheezing Kids Early Prediction & Prevention Genetic Maternal environment (LGG) Hygiene hypothesis LP-33?? Transgenic plant (tomato) Diagnosis Definition Laboratroy parameter (IgE, specific IgE, ECP,.) Pulmonary function or eno Treatment Bronchodilator ICS Leukotriene receptor antagonist

45 Asthma severity in Taiwan AIRIAP total Taiwan Subjects Severe persistent 12% 11% Moderate persistent 16% 14% Mild persistent 20% 18% Mild intermittent 53% 57% AIRIAP study

46 REDUCE INCREASE TREATMENT STEPS CONTROLLER OPTION

47 What s the character?

48 Those who responded to montelukast alone were significantly younger and had shorter durations of asthma (median, 4 years) than those who responded to neither medication. Szefler S, et al. J Allergy Clin Immunol. 2005;115:

49 Inhaled corticosteroids control but do not influence the natural history of asthma in small children Fluticosone, 88µg bd Placebo N=285, aged 2-3 yrs Guilbert TW et al N Eng J Med 2006; 354:

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54 Duration and Adjustments to Treatment Full benefit of each treatment step may only be evident after 3 or 4 months Bateman ED et al. Am J Respir Crit Care Med 2004;170: Reddel H et al. Lancet 1999;353: In severe and chronically under-treated disease benefit can take longer Sont JK et al. Am J Respir Crit Care Med 1999;15):

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63 REDUCE INCREASE TREATMENT STEPS CONTROLLER OPTION

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66 REDUCE INCREASE TREATMENT STEPS CONTROLLER OPTION

67 Thank You For Your Attention!