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Epidemiological Studies of Childhood Wheeze
Risk Factors and Long-term Outcome
Emma Goksör
Department of Paediatrics
Institute of Clinical Sciences
Sahlgrenska Academy
University of Gothenburg
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Risk Factors and Long-term Outcome
Emma Goksör
Department of Paediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg
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List of abbreviations!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!"10
Introduction!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!" 11
Wheezing and asthma: definitions... 12
Wheezing phenotypes... 13
Transient and persistent wheezing... 13
Episodic viral wheeze and multiple-trigger wheeze... 14
Cohort studies exploring asthma and allergy development... 15
Birth cohorts... 15
Cross-sectional studies... 17
Prospective studies of virus-induced bronchiolitis or
obstructive bronchitis... 18
Definitions... 18
Finnish post-bronchiolitis study... 20
Finnish viral wheeze study... 21
Wheezing bronchitis follow-up... 21
Swedish post-RSV study... 22
Predicting persistent asthma... 23
Asthma Predictive Index, API... 23
Isle of Wight and PIAMA indices... 23
Hospital API for severe viral wheeze... 25
Identifying risk factors and protective factors... 25
Viral infections... 25
Heredity... 28
Other allergic manifestations... 30
Gender... 31 Obesity... 32 Smoking... 33 Antibiotics... 35 Paracetamol... 36 Fish... 37 Vitamin D... 38 Breast-feeding... 40
Methods... 45
Children of Western Sweden Study: Papers ! and !!...
45Participants... 45
Ethical approval... 45
Procedures... 45
Response rate... 45
Questionnaire... 45
Swedish Medical Birth Register (MBR)... 47
Outcome variables... 47
Statistics – background... 48
Statistics – Papers ! and !!... 50
Wheezing bronchitis follow-up: Papers !!!, !" and "...
52Participants... 52
Ethical approval... 52
Procedures... 52
Questionnaire... 52
Data on smoke exposure... 53
Allergy testing... 53
Airway function testing... 53
Outcome variables... 54
Statistics... 55
Results and Discussion... 57
Children of Western Sweden Study: Papers ! and !!...
57Prevalence... 57
Heredity... 59
Other allergic manifestations... 60
Gender... 62 Smoke exposure... 63 Neonatal antibiotics... 64 Paracetamol... 66 Fish... 67 Breast-feeding... 70
Other factors of interest... 71
Phenotype differences... 73
Representativeness of the sample... 73
Asthma prevalence in adolescence... 75
Airway function in adolescence... 77
Virus or host... 79
Heredity... 80
Other allergic manifestations... 81
Gender... 83
Pre- and postnatal smoke exposure... 86
Current smoke exposure... 88
Other factors of interest... 89
Pathogenic model... 91
Strengths and weaknesses... 92
General Discussion... 95
Virus or host?... 95
Family history and development of allergic disease... 95
Gender... 95
Window of opportunity... 95
Smoking habits 1983-2003... 96
!!
Introduction
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Wheezing and asthma: definitions
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Wheezing phenotypes
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Transient and persistent wheezing
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Episodic viral wheeze and multiple-trigger wheeze
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Cohort studies exploring asthma and allergy development
Birth cohorts
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Prospective studies of virus-induced bronchiolitis or
obstructive
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Special features Pneumonia group, n = 44 - - Treatment at admission: cromolyn group, budesonide group or control group
Control group 72 no atopic heredity, no wheeze < 2 y 294 Age matched at 17-20 y 93 Age and gen
-der matched, no early RSV
-Re- investigations 2-3 y, 4.4-6 y, 8-10 y, 14.9 y, 18-21 y, 27 y 3-4.5 y, 10 y, 17-20 y, 26 y (mean, ongoing) Mean 1 y, 3 y, 7.5 y, 13.4 y, 18 y 1.5 m, 4 m, 8 m, 12 m, 3 y, 6 y and 11 y after admission (me
-dian age 12.3 y at last re-invest)
Viral agents (RSV%)
All
(40%) All (28%) RSV only (100%) All (31%)
First wheezing episode in
74% 56% 98% 87%
Bronchiolitis/wheezing bronchitis definition Wheezing or prolonged expiration during respira
-tory infection Wheezing, retraction, rhonchi,
tachypnea
during
respiratory infection Tachypnea, prolonged expiration, dyspnea, and wheezing during respira
-tory infection Wheezing and respiratory distress, during acute respiratory tract infection
Age at inclusion < 24 mo. (median = 10 m) < 24 mo. (median = 10 m) < 12 months (mean = 116 days) > 24 months (median = 10 m)
Male % 67% 61% 45% 72%
No. included
83 101 47 100
Started year 1981-82 1984-85 1989-91 1992-93
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Finnish post-bronchiolitis study
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Finnish viral wheezing study
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Wheezing bronchitis follow-up
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Predicting persistent asthma
Asthma Predictive Index, API
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Asthma Predictive Index (API) from the Tucson Study
Major criteria
Doctor-diagnosed parental asthma Doctor-diagnosed eczema in child
Minor criteria
Doctor-diagnosed allergic rhinitis in child Wheezing in between colds
Eosinophilia
*One major or two minor criteria required for positive index
Modified Asthma Predictive Index (API)
Major criteria
Doctor-diagnosed parental asthma Doctor-diagnosed eczema in child Sensitisation to aeroallergens
Minor criteria
Allergic sensitisation to milk, eggs or peanuts Wheezing in between colds
Eosinophilia
Hospital Asthma Predictive Index from the Korppi group
Major criteria
Doctor-diagnosed parental asthma
Doctor-diagnosed eczema and/or food allergy in child Parental (especially maternal) smoking
Minor criteria
Sensitisation to aeroallergens Wheezing due to non-RSV infection
Eosinophilia or lack of eosinophilic response during viral infection
Predictive Index from the Isle of Wight Study
Family history of asthma
Recurrent chest infections in second year of life Atopic sensitisation at age 4 years
Absence of recurrent nasal symptoms first year
Predictive Index from the PIAMA Study
Male gender Post-term delivery Parental education Inhaled medication Wheezing frequency
Wheezing or dyspnea apart from colds Respiratory tract infections
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Hospital API for severe viral wheeze
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Identifying risk factors and protective factors
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425/617-46336.7-:(36.=-Viral infections
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Increased risk of asthma
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Age at infection and viral load
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Allergy and viral infection
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Gender and genes
Other allergic manifestations
Allergic march
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Impact on persistence of viral wheeze
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Gender
Course of wheezing in boys and girls
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Smoking
Impact of exposure to tobacco smoke
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Allergy and smoking
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Antibiotics
Impact on wheeze and asthma
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Marker of asthma?
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Effect on immune system
Breast-feeding
Effect on immune system?
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Aims
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Children of Western Sweden Study, Papers ! and !!
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Wheezing bronchitis follow-up, Papers !!!, !" and#"
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Data on smoke exposure
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Allergy testing
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Airway function testing
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Airway function measurements
FEV1 Forced expiratory volume in 1 second FVC1 Forced vital capacity
FEV1/FVC Ratio of forced expiratory volume in 1 second over forced vital capacity MEF50 Maximum expiratory flow at 50% of the FVC
MEF25 Maximum expiratory flow at 25% of the FVC R5Hz Airway resistance measurements at 5Hz
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Outcome variables
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Statistics
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Multivariate models for asthma
Current factors Allergy
BHR Active smoking Gender
All factors Allergy
BHR Active smoking Gender
Family history of atopy Early passive smoking
Infantile factors Gender
Family history of atopy Early passive smoking
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Multivariate model for abnormal airway function
Cohort
Infantile factors GenderPrenatal smoking Intense disease in early life
Cohort
All factors GenderPrenatal smoking Intense disease in early life Current asthma
Current allergic sensitisation Current BHR
Current active smoking
Study group
Infantile factors GenderSevere wheezing in early life (belonging to the cohort)
Study group
All factors GenderSevere wheezing in early life (belonging to the cohort) Current asthma
Current allergic sensitisation Current BHR
Current active smoking
Y)A*&#Z3
Multivariate models for pre- and postnatal smoke exposure
Outcomes Asthma
BHR
Allergic sensitisation Active smoking
Adjustments Family history of atopy
Gender
Results and Discussion
Children of Western Sweden Study, Papers ! and !!
Prevalence – Papers !#and !!
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Proxy for asthma
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Corresponding prevalence
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Heredity – Paper !
Increased risk of wheeze
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Parental asthma, eczema and rhinoconjunctivitis
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6):&# :(2&*# /('# '&3$''&"%# .0&&7&# )%# 5'&630((*# );&+# X"# )22!%!("I# '&6$*%6# )'&# 5'&6&"%&2# /('# '&3$''&"%#:$*%!5*&4%'!;;&'#)"2#&5!6(2!3#-!')*#.0&&7&+#^"5$A*!60&2#2)%)+ Recurrent wheeze aOR; 95% CI Multiple-trigger wheeze aOR; 95% CI Episodic viral wheeze aOR; 95% CI Parental asthma 1.7; 1.2-2.5 1.4; 0.8-2.5 1.9; 1.1-3.2 Parental eczema 2.0; 1.4-2.8 3.0; 1.7-5.1 1.5; 0.996-2.4 Parental rhinoconjunctivitis 1.0; 0.7-1.4 1.4; 0.8-2.4 0.9; 0.5-1.3 P2]$6%:&"%6#.&'&#:)2&#/('#5)'&"%)*#&2$3)%!("#*&-&*I#:)*&#;&"2&'I#6:(_!";#2$'!";#5'&;")"38I#:)%&'")*# :&2!3)%!("#2$'!";#5'&;")"38I#;&6%)%!(")*#);&#`#Da#.&&_6I#3)&6)'&)"#6&3%!("I#%'&)%:&"%#.!%0#)"%!A!(%!36# GXULQJWKH¿UVWZHHNRIOLIHEUHDVWIHHGLQJPRQWKVRUPRUHGRFWRUGLDJQRVHGIRRGDOOHUJ\GXULQJ¿UVW \HDURIOLIHHF]HPDGXULQJWKH¿UVW\HDURIOLIHWKHLQWURGXFWLRQRI¿VKEHIRUHPRQWKVRIDJHDQG¿VK ("3&#)#:("%0#('#:('&#)%#G#8&)'#(/#);&+
Other allergic manifestations – Paper !
Allergic manifestations in infancy
Allergic manifestations at preschool age
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allergy# Allergy test positive
Peanut
allergy# Eczema# Eczema treated ##
Eczema
ever Symp-toms of allergic rhinitis Allergic rhinitis# No re-current wheeze 4.0% 7.6% 0.7% 8.3% 14.6% 30.0% 4.4% 1.4% Re- current wheeze 13.0%*** 27.0%*** 2.5%*** 14.0%** 24.0%*** 51.0%*** 25.0%*** 7.0%*** MTW 23.0%*** 43.0%*** 5.0%*** 19.4%*** 28.0%*** 57.0%*** 47.0%*** 14.6%*** EVW 5.1% 13.2%* 0.7% 9.5% 20.4% 44.5%** 8.8%* 1.5%
Gender – Paper !
Increased risk of wheeze
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Smoke exposure – Paper#!
Prevalence
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No significant effect on preschool wheeze