Asthma in Non-Asthma in Non-Affluent CommunitiesAffluent Communities

Renato T. SteinRenato T. Stein

Pontifícia Universidade Pontifícia Universidade Católica RSCatólica RS

Porto Alegre, BrazilPorto Alegre, Brazil

ISAAC Study. Lancet 1998; 351: 1225–32.

Worldwide Prevalence of Asthma Symptoms: ISAAC Phase I Data

Asthma PhenotypesAsthma Phenotypes

Stein R et al. Thorax 1997

Risk for Recurrent Wheeze in Risk for Recurrent Wheeze in Children Infected by RSV Early in Children Infected by RSV Early in LifeLife

Stein R et al, Lancet 1999

ISAAC Phase IIISAAC Phase II

Thirty study centers in 22 countries Thirty study centers in 22 countries Parental questionnaires (n=54,439)Parental questionnaires (n=54,439) Skin prick tests (n=31,759)Skin prick tests (n=31,759) Serum IgE levels (n=8,951)Serum IgE levels (n=8,951) Economic development assessed by Economic development assessed by

gross national income per capita gross national income per capita (GNI)(GNI)

Weinmayr G et al. AJRCCM 2007 (Atopic sensitisation and the international variation of asthma symptom prevalence in children)

West Sussex

Oestersund

Linkoeping

Valencia

Madrid

Cartagena

Almeria

Tromso

Hawkes Bay

Utrecht

Rome

Reykjavik

Thessaloniki

Athens

Munich

Dresden

Hong Kong

1 10

Ankara

Ramallah

Riga

Mumbai

Kintampo

Tbilisi

Tallinn

Pichincha

Guangzhou

Beijing

Uruguaiana

Tirana

Combined affluent

Combined non-affluent

Combined non-affluentwithout Guangzhou

58.9 [21.4;162.2]

0,6 12Odds ratio with 95%-confidence

OR for the association of current OR for the association of current wheeze with skin prick test wheeze with skin prick test reactivityreactivity

West Sussex

Östersund

Linköping

Tromso

Utrecht

Rome

Thessaloniki

Athens

Munich

Dresden

Valencia

Madrid

Almeria

Cartagena

1 10

Tbilisi

Mumbai

Tallinn

Tirana

Combined affluent

Combined non-affluent

0,6 12

OR for the association of OR for the association of current wheeze with allergen-current wheeze with allergen-specific IgE specific IgE ((0.35 kUA/L)0.35 kUA/L)

Odds ratio with 95%-confidence

ISAAC – Phase II Data, ISAAC – Phase II Data, BrazilBrazil Cross sectional Cross sectional

studystudy with with questionnairesquestionnaires, , skin testsskin tests, stool , stool examinations for examinations for parasitesparasites, BHR, BHR

Population Population n=1199 Age: 10.1 n=1199 Age: 10.1 ((++ 0.8) 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-IIBrazil data: ISAAC-II

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

ISAAC II - BrazilISAAC II - Brazil

Current asthma: 9.4% (Current asthma: 9.4% (29% 29% atopic)atopic)

Bronchiolitis <2y (E.R. or Bronchiolitis <2y (E.R. or hospitalized) 6.1%hospitalized) 6.1%

N=1011n (%)

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 genderBirth weight ≥ 2500Born before termBreast feeding ≥ 6 monthsCurrent maternal smoking≥ 8y of maternal schooling≥ 1 SiblingHumid householdPoor neighborhoodMaternal asthmaPaternal asthmaWheeze past 12 monthsActive asthmaAtopyBronchiolitis < 2 y.o.Severe asthma (≥ 4 attacks)

Analysis for children w Analysis for children w questionnaires, SPTs, parasitology questionnaires, SPTs, parasitology teststests

Pereira M et al. ERJ 2007 (accepted for publication)

Risk factors for wheeze and Risk factors for wheeze and asthma Multivariate logistic asthma Multivariate logistic regressionregression

Wheeze in previous 12m OR (95% C.I.)

Active Asthma OR (95% C.I.)

Maternal Hx Asthma 3.1 (1.8-5.3)*** 5.6 (2.8-11.1)*** Paternal Hx Asthma 3.9 (2.1-7.3)*** 3.6 (1.6-7.9)*** Bronchiolitis < 2y 5.4 (2.9-9.9)*** 18.1 (9.1-36.0)*** Any positive skin test 2.7 (1.8-4.1)*** 6.3 (3.4-11.8)*** Humid household 1.5 (1.1-2.1)** 2.2 (1.3-3.8)** Maternal smoking 1.2 (0.9-1.7) 1.1 (0.6-2.0) Born before term 1.4 (0.8-2.3) 0.7 (0.3-1.8) Years of maternal schooling 0.98 (0.92-1.0) 0.9 (0.8-0.9)* ? 2 Siblings 1.1 (0.8-1.5) 0.5 (0.3-0.9)* Higher-load Ascaris (?100eggs/g)

1.8 (0.98-3.4) 2.4 (1.0-6.1)*

Pereira M et al. ERJ 2007 (accepted for publication)

Asthma PhenotypesAsthma Phenotypes

Stein R et al. Thorax 1997

Inflammatory characteristics in Inflammatory characteristics in asthmatic children: Induced asthmatic children: Induced SputumSputum

55 children55 children– Atopic asthma (AA): asthma ever Atopic asthma (AA): asthma ever

and wheeze in past year + SKand wheeze in past year + SK+ve+ve

– Non-atopic asthma (NAA): asthma Non-atopic asthma (NAA): asthma ever and wheeze in past year + SKever and wheeze in past year + SK-ve-ve

– Non-atopic no-asthma (NANA): no Non-atopic no-asthma (NANA): no asthma/no wheeze ever + SKasthma/no wheeze ever + SK-ve-ve

Drews A, et al 2007

IS Eosinophil IS Eosinophil concentration in asthma concentration in asthma phenotypesphenotypes

Media

n (

IQ)

Drews A, et al 2007

IS Eosinophil >3% in IS Eosinophil >3% in asthma phenotypesasthma phenotypes

Drews A, et al 2007

IS Neutrophil IS Neutrophil concentration in asthma concentration in asthma phenotypesphenotypes

Drews A, et al 2007

Non-atopic asthma may be the Non-atopic asthma may be the most common phenotype in Latin most common phenotype in Latin AmericaAmerica

Main risk factor for asthma at age Main risk factor for asthma at age 10y: “Bronchiolitis” (RSV & 10y: “Bronchiolitis” (RSV & Rhinovirus) early in life Rhinovirus) early in life – Mostly neutrophilic inflammationMostly neutrophilic inflammation

ConclusionsConclusions

Hypertonic Saline StudyHypertonic Saline Study

2000 children with ISAAC phase II 2000 children with ISAAC phase II questionaires answeredquestionaires answered

1199 skin prick tests AND stool samples 1199 skin prick tests AND stool samples colectedcolected

50 with positive current asthma history in the

past 12 months

50 with no historyof current asthma AND no history of asthma

ever

Bronchoprovocation Bronchoprovocation

4.5% Hypertonic saline4.5% Hypertonic saline PFTsPFTs

BHR positive: > 15% decline of FEV1BHR positive: > 15% decline of FEV1

MAIN RESULTSMAIN RESULTS

17 (17.5%) positive for BHR.17 (17.5%) positive for BHR.– 10 (20.4%) Current wheeze.10 (20.4%) Current wheeze.– 7 (14.6%) Control (non-wheeze).7 (14.6%) Control (non-wheeze).

OR (CI 95%) = 1.5 (0.5 – 4.3)OR (CI 95%) = 1.5 (0.5 – 4.3) nsns

RESULTSRESULTS

VariablesVariables n/Mn/M %% OR (CI95%)OR (CI95%)

Current Current asthmaasthma

nono 13/813/800

16.16.33

1.5 (0.4 – 5.6)1.5 (0.4 – 5.6)yesyes 4/174/17 23.23.

55

SPTSPT+ve+ve

nono 13/813/822

15.15.99

2.1 (0.5 – 7.8)2.1 (0.5 – 7.8)yesyes 4/144/14 28.28.

66

Parasitosis vs. BHRParasitosis vs. BHRn/Nn/N %% OR (IC95%)OR (IC95%)

Helminth Helminth infectioninfection

negneg 11/711/733

15.15.11

1.5 (0.4 – 5.0)1.5 (0.4 – 5.0)pospos 5/235/23 21.21.

77

High helminth High helminth loadload

negneg 12/812/877

13.13.88 5.0 (1.1 – 5.0 (1.1 –

21.3)21.3)pospos 4/94/9 44.44.

44

Giardia Giardia lamblia lamblia

infectioninfection

negneg 16/816/833

19.19.22 0.8 (0.7 – 0.9)0.8 (0.7 – 0.9)

pospos 0/130/13 00

8

6

4

2

OddsRatiosforAsthma

Number wLRI in first year

0 1 ≥2

non atopic @ 6yrs

atopic @ 6yrs

Synergistic interaction between atopy and wLRI in y1 for persistent asthma

Sly, P et al.

Age (months)

Interferongammaresponses(Th1)

0 24-48

Non-AtopicAsthmatic

Non-Asthmatic

Maturation of Immune Responses Maturation of Immune Responses in Infancyin Infancy

AtopicAsthmatic

Holt P, Sly P

IMMATURE IMMUNE SYSTEM Slow TH1

Th2-driven

Immunity

Allergen exposure

Airway Inflammatio

n

Altered Aw

FunctionASTHMA

LRTI/ Bronchiolit

is

Airway Inflammatio

n

Altered Aw

Function

Intensification & low clearance

ALLERGIC PATHWAY

NON-ATOPIC/VIRUS PATHWAY

Environment

Genetic Predisposition

Genetic Predisposition