Asthma in Non-Affluent Communities Renato T. Stein Pontifícia Universidade Católica RS Porto Alegre, Brazil

Worldwide Prevalence of Asthma Symptoms: ISAAC Phase I Data ISAAC Study. Lancet 1998; 351: 1225–32.

Asthma Phenotypes Stein R et al. Thorax 1997

Risk for Recurrent Wheeze in Children Infected by RSV Early in Life Stein R et al, Lancet 1999

ISAAC Phase II Thirty study centers in 22 countries Parental questionnaires (n=54,439) Skin prick tests (n=31,759) Serum IgE levels (n=8,951) Economic development assessed by gross national income per capita (GNI) Weinmayr G et al. AJRCCM 2007 (Atopic sensitisation and the international variation of asthma symptom prevalence in children)

OR for the association of current wheeze with skin prick test reactivity Odds ratio with 95%-confidence

OR for the association of current wheeze with allergen-specific IgE (0.35 kUA/L) Odds ratio with 95%-confidence

ISAAC – Phase II Data, Brazil Cross sectional study with questionnaires, skin tests, stool examinations for parasites, BHR Population n=1199 Age: 10.1 (+ 0.8) Non-atopic asthma is associated with helminth infections and bronchiolitis in poor children Pereira M et al. ERJ June 2007

Brazil data: ISAAC-II Wheeze past yr: 26% >4 asthma attacks: 6.5% Asthma ever: 12.7% Positive skin tests: 13.3% Atopic wheeze past yr: 5.4% Non-atopic wheeze: 20.9%

ISAAC II - Brazil Current asthma: 9.4% (29% atopic) Bronchiolitis <2y (E.R. or hospitalized) 6.1%

Analysis for children w questionnaires, SPTs, parasitology tests 495 (49.0) 865 (88.6) 93 (9.6) 852 (84.7) 322 (31.9) 195 (19.3)* 730 (72.2) 474 (46.9) 956 (94.7)* 78 (7.7) 58 (5.8) 273 (27.0) 93 (9.2) 131 (13.0) 63 (6.3) 70 (6.9) Male gender Birth weight ≥ 2500 Born before term Breast feeding ≥ 6 months Current maternal smoking ≥ 8y of maternal schooling ≥ 1 Sibling Humid household Poor neighborhood Maternal asthma Paternal asthma Wheeze past 12 months Active asthma Atopy Bronchiolitis < 2 y.o. Severe asthma (≥ 4 attacks) Pereira M et al. ERJ 2007 (accepted for publication)

Risk factors for wheeze and asthma Multivariate logistic regression Pereira M et al. ERJ 2007 (accepted for publication)

Asthma Phenotypes Stein R et al. Thorax 1997

Inflammatory characteristics in asthmatic children: Induced Sputum Atopic asthma (AA): asthma ever and wheeze in past year + SK+ve Non-atopic asthma (NAA): asthma ever and wheeze in past year + SK-ve Non-atopic no-asthma (NANA): no asthma/no wheeze ever + SK-ve Drews A, et al 2007

IS Eosinophil concentration in asthma phenotypes Median (IQ) Drews A, et al 2007

IS Eosinophil >3% in asthma phenotypes Drews A, et al 2007

IS Neutrophil concentration in asthma phenotypes Drews A, et al 2007

Conclusions Non-atopic asthma may be the most common phenotype in Latin America Main risk factor for asthma at age 10y: “Bronchiolitis” (RSV & Rhinovirus) early in life Mostly neutrophilic inflammation

Hypertonic Saline Study 2000 children with ISAAC phase II questionaires answered 1199 skin prick tests AND stool samples colected 50 with positive current asthma history in the past 12 months 50 with no history of current asthma AND no history of asthma ever

Bronchoprovocation 4.5% Hypertonic saline PFTs BHR positive: > 15% decline of FEV1

MAIN RESULTS 17 (17.5%) positive for BHR. 10 (20.4%) Current wheeze. 7 (14.6%) Control (non-wheeze). OR (CI 95%) = 1.5 (0.5 – 4.3) ns

RESULTS Variables n/M % OR (CI95%) Current asthma no 13/80 16.3 1.5 (0.4 – 5.6) yes 4/17 23.5 SPT+ve 13/82 15.9 2.1 (0.5 – 7.8) 4/14 28.6

Giardia lamblia infection Parasitosis vs. BHR n/N % OR (IC95%) Helminth infection neg 11/73 15.1 1.5 (0.4 – 5.0) pos 5/23 21.7 High helminth load 12/87 13.8 5.0 (1.1 – 21.3) 4/9 44.4 Giardia lamblia infection 16/83 19.2 0.8 (0.7 – 0.9) 0/13

Synergistic interaction between atopy and wLRI in y1 for persistent asthma 8 6 4 2 Odds Ratios for Asthma Number wLRI in first year 0 1 ≥2 non atopic @ 6yrs atopic @ 6yrs Sly, P et al.

Maturation of Immune Responses in Infancy Non-Asthmatic Interferon gamma responses (Th1) Atopic Asthmatic Non-Atopic Asthmatic 24-48 Age (months) Holt P, Sly P

IMMATURE IMMUNE SYSTEM Slow TH1 Environment Genetic Predisposition ALLERGIC PATHWAY Allergen exposure Airway Inflammation Altered Aw Function Th2-driven Immunity ASTHMA IMMATURE IMMUNE SYSTEM Slow TH1 Environment Intensification & low clearance LRTI/ Bronchiolitis Airway Inflammation Altered Aw Function NON-ATOPIC/VIRUS PATHWAY Genetic Predisposition