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Arne Høst, ledende overlæge, dr. med.
H. C. Andersen Børnehospital
Odense Universitetshospital
Hvad kan kohortestudier bruges til?
En prospektiv uselekteret fødselskohorte
født i Odense Kommune
01.11.98 – 30.11.99 (”DARC-Kohorten”)
Causality or coincidence ?
Associations are not causations!
Decreasing number of
storks & newborns
Prospective longitudinal birth
cohort studies
Natural history of disease and phenotypes
Risk factors, predictors, determinants
Incidence
Prevalence
Prospective evaluation of exposure (quantity,
duration)
Effect of genetic and environmental interaction
Temporality of events
The criteria for proving causality
between an environmental exposure
and a non-infectious illness
Biological plausible
Analogous associations
Temporality
Dose-response effect
Consistency
Decrease in effect when exposure ceases
Hill AB. The environment and disease: association
or causation? Proc R Soc Med 1965;58:295-3000
Evaluation of different kind of studies
Study Utility
Retrospective Not useful
Cross-sectional Not useful
Prospective non-interventional Generate hypotheses
Prospective interventional Proper confirmation
Assessment of cause-effect relationships between exposure
to allergens/adjuvant factors and the development of allergic
disease
Studies on development of allergic
diseases - important factors
• Prospective vs retrospective
• Randomisation + blind ascertainment
• Unselected vs. selected HR sample
• Age of the population
• Duration of intervention
• Pre-definition of outcome measures
• Well defined diagnostic criteria
• Investigation at onset of symptoms/disease
• Control for confounding
• Compliance and drop-out
• Duration of follow-up
• Sample size – power/adequate statistical analyses
Best evidence for
recommendations
Randomisation not possible:
• Breastfeeding
• Environmental tobacco smoke
Best evidence for recommendations
The randomised controlled trial is traditionally
the gold standard for judging the benefits of
treatment/intervention mainly because it is
conceptually easier to attribute any observed effect
to the treatment/intervention being compared
High quality observational studies may extend
evidence over a wider population and are likely to
be dominant in the identification of risk factors/
predictive factors and when randomised controlled
studies be unethical or impractical
Development of allergic disease
Genetic factors
Environmental exposure to allergens
Food allergens
Inhalant allergens
Other risk/protective factors e.g.
Tobacco smoke
Infections
Microbial flora
Other (antioxidants?)
The development and phenotypic expression of
allergic disease depends on an interaction between:
Age, dose and duration of exposure important
Synergistic effects
Increased prevalence of allergic diseases
Environmental factors ?
Western life-style ?• Increased exposure to allergens / adjuvants
• Changed exposure to infections / microbial
flora ? (Hygiene hypothesis)
• Changes in diets and obesity ?
Er forekomsten af allergi stigende?
Definition
Resultater fra danske undersøgelser
• Fødselskohorter fra 1985 og 1998-1999
• Nordborg Kommune 1990-1991 og 2001
Allergi - definition
Allergi er en overfølsomhedsreaktion udløst
af immunologiske mekanismer
(immunologisk mekanisme påvist eller stærkt
mistænkt)
A revised nomenclature for allergy
An EAACI position statement. Allergy 2001;56:813-824
WAO. JACI 2004;113:832-6
Atopi - definition
Atopi er en personlig eller familiær tendens
til at producere IgE antistoffer som respons
på lave doser af allergener, oftest
proteiner, og til at udvikle typiske
symptomer som astma, rhinoconjunctivitis,
eller eksem / dermatitis
A revised nomenclature for allergy
An EAACI position statement. Allergy 2001;56:813-824
WAO. JACI 2004;113:832-6
Overfølsomhed
Allergisk overfølsomhed(immunologisk mekanisme påvist
eller stærkt mistænkt)
Nonallergisk overfølsomhed
(immunologisk mekanisme
udelukket)
IgE-medieret Ikke IgE-medieret
Nonatopisk Atopisk T celle: f.eks. kontakt
dermatitis, celiaci
Eosinophile: f.eks.
gastroenteropati
IgG-medierede: f.eks.
allergisk alveolitis
Andre
Insekt stik
Orme
Lægemidler
Andre
A revised nomenclature for allergy. EAACI position statement. Allergy 2001;56:813-824; WAO. JACI
2004;113:832-6
Changes in asthma prevalence:
two surveys 15 years apart
Cross-sectional study 12 year old
1973 1988
n 818 n 965
Wheeze, ever 17% 22%
Asthma, ever 6% 12%
Asthma current 4% 9%
Eczema 5% 15%
Hay fever 9% 15%
BHR, PEF var. ≥ 15% 6.7% 7.7%
Burr ML et al. Arch Dis Child 1989;64:1452-56
Odense fødselskohorter
Odense
fødselskohorte
1985
Alle
1 år
1749
15 år
Prospektiv
Non-
intervention
Komælksallergi
(alle)
Allergisk sygdom
(n276)
DARC-
fødselskohorte
1998-1999
562
uselekterede
nyfødte
562
6 år
Prospektiv
Non-
intervention
Allergisk sygdom
Odense fødselskohortestudie 1985
* Udvalgt tilfældigt blandt hele studiepopulationen
Fødsels kohorte, Odense 1985: 1758 nyfødte
9 døde neonatalt
Uselekterede = stikprøve*: 276 børn (16%)
Follow-up ved 1½ year: 276 børn
Follow-up ved 5 years: 256 børn (93%)
Follow-up ved 10 years: 226 børn (82%)
Follow-up ved 15 years: 219 børn (79%)
Results
Odense birth cohort 1985
Prevalence (%(n)) of atopic symptoms
in unselected children18 mo
N 256*
5 years
N 256
10 years
N 223
15 years
N 216
Atopic dermatitis14% (36) 6% (14) 10% (23) 7% (16)
Food allergy7% (19) 4% (10) 8% (17) 4% (9)
Asthma2% (4) 5% (12) 8% (18) 9% (19)
Rhinoconjunctivitis0.4% (1) 2% (5) 6% (14) 12% (27)
* Only children who participated at 5 yrs are included.
Høst A et al. PAI 2002
1749 infants
210 (12%) no CM formula 1539 (88%) + CM formula (40-860
ml)
0 CMPA 39 CMPA (40-830 ml CM formula)
40 ml CM formula equals 0.4 g BLG
0.4 g BLG equals BLG of 8000 L Human milk
Høst A et al. Acta Paediatr 1988;77:663-70
Food Allergy and CMPA in two comparable
unselected birth cohorts in Odense, 14 years apart,
in young children 0-18 months
Cumulated incidence (95% CI)
1985
(n 1,749)
1999
(n 495)
FA 7.4% (6.2-8.6) 3.2% (1.8-5.0)
CMPA 2.2% (1.5-2.9) 1.0% (0.1-1.7)
Danish Allergy Research Centre
The DARC birth cohort
Observational / non-intervention study
562 unselected children
• Recruited from maternity ward OUH
Followed prospectively birth 6 years
(1998 2004)
• Inclusion data at birth + 6 ”follow-ups”
DARC KohortenPh.D.-afhandlinger
Lene Annette Norberg: Environmental factors and atopic
pre-disposition as predictors for the development of asthma,
rhinoconjunctivitis and other atopic diseases in mucous
membranes in childhood.
Hanne Jøhnke: A comparison between criteria for diagnosing AD
Morten Østerballe: The prevalence of food hypersensitivity in an
unselected population of children and adults
Henrik Kjær: The prevalence of allergic diseases in an unselected
group of 6 year old children. The DARC birth cohort study
Esben Eller: Food allergy and atopic dermatitis in childhood.
Longitudinal results from the DARC cohort.
Cumulated incidence of atopic diseases in two birth cohorts 14 years apart
Cumulated incidence
up to18 months
1999 1985
Recurrent wheeze 25.1% 21.4%
Asthma 5.1% 1.6%
Hay fever 0.4% 0.4%
Food allergy/intolerance 3.4% 7.4%
Cow’s milk allergy 0.9% 2.2%
Patterns of sensitization in infants and its relation to atopic dermatitis.
Jøhnke H, Norberg LA, Vach W, Høst A, Andersen KEPediatr Allergy Immunol. 2006 Dec;17(8):591-600
Sensitization ever to ≥ 1 allergen at 18 months of age
was 59%, 50% and 6% using HR, IgE and SPT,
respectively. A transient sensitization to ≥ 1 allergen
was found in 47%, 42% and 4% and a persistent
sensitization in 17%, 10% and 3%, respectively.
Sensitization to environmental allergens was
frequently observed in infancy when testing with HR
and IgE. Results of SPT gave much lower
frequencies. Reactivity to foods was more frequent
than to aeroallergens.
The dominant pattern was low-level transient
sensitization
Sensitization to cow’s milk and egg, CAP RAST
cl 1 (≥ 0.35) & cl 2 (≥ 0.7) up to 18 months of life
Norberg LA. Ph.D.Thesis 2003
Jønhke H. Ph.D. Thesis
N 470 Danish unselected children. DARC cohort
0
2
4
6
8
10
12
14
3mo 6 mo 12 mo 18 mo
Age
%
Cows milk cl 2
Cow's milk cl 1
Hens egg cl 2
Hens egg cl 1
Prevalence of food hypersensitivity - DARC
Questionnaire, SPT, HR, spec. IgE, oral challenge
FHS
486 children 3 years of age: 2.3%
1.6% egg
0.6% milk
0.2% peanut
301 children > 3 years of age 1.0%
936 adults 3.2%
0.4% peanut
Estimated FHS to pollen related foods in pollen sensitized adults 32%
Østerballe M et al. PAI 2005
DARC at 6 years, n 404
Current prevalence
AD 14.4% (11.3-18.1)
Asthma 6.2% (4.2-9.0)
ARC 5.7% (3.8-8.4)
Any allergic disease 25.7%
Food allergy 1.2% (0.4-3.0)
Kjær H, PAI 2008
Food sensitization and subsequent allergic disease
0
10
20
30
40
50
60
70
80
Asthma Atopic dermatitis Rhinoconjunctivitis Any
%
Never sensitized (n=243)
Early sensitized only (n=36)
Late sensitized only (n=26)
Persistently sensitized (n=20)
* p<0.05, ** p<0.01, *** p<0.001
NS
NS
NS
NS
NS
NS
***
******
***
*
**
Inhalant sensitization and subsequent allergic disease
* p<0.05, ** p<0.01, *** p<0.001
0
10
20
30
40
50
60
70
80
Asthma Atopic dermatitis Rhinoconjunctivitis Any
%
Never sensitized (n=225)
Early sensitized only (n=48)
Late sensitized only (n=35)
Persistently sensitized (n=17)
NS
NS
NS
NS
***
*
*** *** **
***
***
*
DARC Cohort
Development of asthma 0-6 years
In food allergics 4/15 (26.6%)*
In non-food allergics 21/389 (5.4%)*
*p< 0.01
Odds Ratio 6.4 (1.4-23.8)
Kjaer HF et al. PAI 2009
Point-Prevalence of FHS
0
1
2
3
4
3 6 12 18 36 72
Age (mo)
%
Peanut
Egg + Peanut
Egg
Milk + Egg
Milk
No children allergic to wheat, soy or fish!
(n) 2 6 16 13 5
Frequency of Atopic Dermatitis
0
5
10
15
20
25
3 6 12 18 36 72
Age (months)
%Line: cum. incidence
Bar: point-prevalence
Point-prevalence of AD and FHS
0
2
4
6
8
10
12
3 6 12 18 36 72
Age (months)
%
From birth to 6 yrs. of age:
23% have AD
4% have food
hypersensitivity
90% of children with
FHS have AD
15% of children with AD
develops FHS
Sensitization to food is a normal phenomenon in
children without food allergy
Irrelevant sensitization to foods in food-allergic
children
Children with AD, but without FHS, are neither
more frequently nor having higher levels of IgE
than children without AD
Sensitization
Strong association between allergic
sensitisation and childhood allergic diseases
Preventive Measures. Section 1: Early Interventions. Høst A, Boner A, Odhiambo J, Custovic A,
Lockey R. In Johansson SGO, Haahtela T (eds): Prevention of Allergy and Allergic Asthma. World
Allergy Organisation Project Report and Guidelines. Chem Immunol Allergy. Basel, Karger 2004,
vol. 84; 135-151
Allergen exposure sensitisation
Sensitisation allergic disease
Allergen exposure allergic disease
Foods - food allergy +
Inhalants - asthma?
- allergic asthma + (?)
Breastfed high risk infants differed from formula fed high risk infants regarding the following characteristics:
age at introduction of solid foods 5 vs 4 monthsexposure to tobacco smoke at home 28% vs 46%exposure to tobacco smoking by mother13% vs 29%exposure to pets 33% vs 42%socioeconomic class
Exposure to environmental factors in a birth cohort of atopic predisposed infants fed human milk or a
hydrolysed cow’s milk based formula
Halken et al. Pediatr Allergy Immunol 2000;11:149-161.
A prospective, randomized intervention study. N 478
Decreased exposure to ETS?
Comparable data from two Danish birth cohorts 13 years apart:
Year Numbers Exposure to ETS at home/daycare
1985 n 276* 66%
1998-1999 n 562 69%
During the same period the ”official” frequency of female smokers
decreased from 42% to 30%!
* Random sample of a one year birth cohort of 1746 newborns.
The reason for discrepancy?
”Official” TS data Method of TS registration
1985 birth cohort Questionnaire, selfreported
Structured interview
1998-1999 birth cohort Questionnaire, structured
interview + CO in exhaled air
of parents
Questionnaire data on TS may be invalidated by recall bias and/or
information
Norberg LA. Predictors of development of allergic diseases in mucous membranes. Ph.d. thesis.
University of Southern Denmark, Odense University, 2003: Odense, Denmark.
Christensen Estmann A. J Pediatr Epidem 2004.Smoking and Allergy. A prospective cohort study
of infants at hign risk for allergy development. Ph.d. thesis. University of Southern Denmark.
Odense University, 2004: Odense, Denmark.
Cross-sectional investigations
Nordborg 1990 and 2001
Results 1990-1991
(n=851)
2001
(n=939)
Asthma 4.0% 3.6% Ns
BHR 3.2% 2.0% Ns
Asthma and BHR 7.2% 5.6% Ns
Zilmer M et al. 2009 DPS
Prospective longitudinal birth
cohort studies
• Natural history of disease and phenotypes
• Risk factors, predictors, determinants
• Incidence
• Prevalence
• Prospective evaluation of exposure (quantity,
duration)
• Effect of genetic and environmental interaction
• Temporality of events
Many thanks to my colleagues:
- Lene Annette Norberg
- Hanne Jøhnke
- Morten Østerballe
- Henrik Fomsgaard Kjær
- Esben Eller
- Susanne Halken
- Carsten Bindslev-Jensen
Eller E et al. Development of atopic dermatitis in the DARC birth cohort.
PAI 2009.
Kjaer HF et al. The association between early sensitization patterns and
subsequent allergic disease. The DARC birth cohort study. PAI 2009.
Eller E et al. Food allergy and food sensitization in early childhood: results
from the DARC cohort. Allergy 2009.
Eller E et al. Meta-analysis of determinants for pet ownership in 12
European birth cohorts on asthma and allergies: a GA2LEN initiative.
Allergy 2008.
Kjaer HF. Spirometry in an unselected group of 6-year-old children: the
DARC birth cohort study. Pediatr Pulm 2008
Kjaer HF et al. The prevalence of allergic disease in an unselected group
of 6-year-old children. The DARC birth cohort study. PAI 2008.
Jøhnke H et al. Patterns of sensitization in infants and its relation to
atopic dermatitis. PAI 2006.
Keil T et al. European birth cohort studies on asthma and atopic
diseases: II. Comparison of outcomes and exposures – a GA2LEN
initiative. Allergy 2006.
Keil T et al. European birth cohort studies on asthma and atopic dieases:
I. Comparison of study designs – a GALEN initiative. Allergy 2006.
Osterballe M et al. The prevalence of food hypersensitivity in an
unselected population of children and adults. PAI 2005.
Jøhnke H et al. A comparison between criteria for diagnosing atopic
eczema in infants. Br J Dermatol 2005.
Jøhnke H et al. Reacitivity to patch tests with nickel sulfate and fragrance
mix in infants. Contact Dermatitis 2004.
Increase in allergic diseases
over 3-4 decades?
Asthma (A) +
Allergic/atopic
Non-atopic
Allergic rhinitis (AR) +
Atopic dermatitis (AD) ++
Food allergy (FA) -
Methodology to confirm an
increase
Same method/design 10-20 years apart,
same region
Questionnaires?
Questionnaires + interview?
Q+I + objective parameters (clin. exam.,
IgE, SPT, LF)
Grades of Recommendations - WHO
A. Requires at least one randomized controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation. (Evidence levels Ia, Ib)
B. Requires the availability of well-conducted controlled clinical studies without randomization. (Evidence levels IIa, IIb)
C. Requires evidence obtained from well designed descriptive studies, comparative studies, correlation studies and case studies. (Evidence level III)
D. Requires evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality. (Level IV)
Breastfeeding
• Exclusively breastfeeding 4 months is associated with a
lower cumulative incidence of FA/CMPA and eczema until
3 years and recurrent wheeze/asthma until 6 years
Prospective, observational non-interventional
studies have shown:
Muraro A, Dreborg S, Halken S, Høst A, Niggemann B, Aalberse R et al. Dietary prevention of
allergic diseases in infants and small children. Part III: Critical review of published peer-reviewed
observational and interventional studies and final recommendations. Pediatr Allergy Immunol.
2004 Aug;15(4):291-307.
Observational studies
• Disease related modification of exposure
– Mothers of children with allergic symptoms
before weaning tend to breastfeed longer
• May not be able to control for selection
bias and reverse causation as regards the
effect of BF on AD
Kull I. JACI 2004
Lauberau B. J. Pediatr 2004
Breastfeeding reduces the risk of asthma
during the first 4 yrs
Breastfeeding ≥ 4 moAsthma at 4 years
OR [95%CI]
All 0.72 [0.53-0.97]
Children with onset of wheeze
during lactation excluded0.64 [0.46-0.88]
Only breastfeeding before the onset
of wheeze0.52 [0.39-0.69]
Mothers of children with allergic symptoms before weaning
tend to breastfeed longer
Disease related modification of exposure
Kull I.JACI 2004:114:755-60. Prospective, n 4098
Foods
Exposure Sensitisation, Food Allergy
Exposure Food Allergy Eczema
Documentation: Pro-obs-non interv. studies and
RCT in HR infants.
Muraro A, Dreborg S, Halken S, Host A, Niggemann B, Aalberse
R et al. Dietary prevention of allergic diseases in infants and
small children. Part III: Critical review of published peer-
reviewed observational and interventional studies and final
recommendations. Pediatr Allergy Immunol. 2004
Aug;15(4):291-307.
Formulas containing hydrolysed protein
for prevention of allergy and
food intolerance in infants.
Cochrane review.
The Cochrane Library 2007, issue 2
• Conclusions
– HF not better than BF!
– In high risk infants limited evidence of effect of HF compared to CMF.
• No effect on A, R, AD
• Limited evidence that pHF reduces CMPA and eHF is better than pHF
• Limited evidence that eHF prevent allergy, AD
Osborn DA, Sinn J
Specific proliferative peripheral blood monuclear cell response
Development of allergic disease
Specific IgE
Neonatal/postnatal allergen exposure
Increased risk for development of clinical allergic disease
Particularly in high risk infants
In utero allergen stimulation
What came first ?
?
Disease related modification of exposure !!!
Barton S. Which clinical studies provide the best evidence? The best RCT still trumps the best observational
study. BMJ 2000;321(7256):255-6.
Eccles M, Freemantle N, Mason J. North of England based guidelines development project: Methods of
developing guidelines for efficient drug use in primary care. Education and debate. BMJ 1998;316:1232-35.
Nickel R, Niggemann B, Grüber C, Kulig M, Wahn U, Lau S. How should a birth cohort study be organised?
Experience from the German MAS cohort study. Paed Resp Rev 2002;3:169-76.
Høst A, Halken S. Can we apply clinical studies to real life? Evidence-based recommendations from studie on
development of allergic diseases and allergy prevention. Allergy 2002;57:389-97.
Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier B, Lockey R et al. A revised nomenclature for
allergy for global use. Report of the Nomenclature Review Committee of World Allergy Organisation, October
2003. J Allergy Clin Immunol 2004;113(5):832-6.
Johansson SGO, Haahtela T (eds): Prevention of Allergy and Allergic Asthma. World Allergy Organisation
Project Report and Guidelines. Chem Immunol Allergy. Basel, Karger 2004, vol. 84.
Muraro A, Dreborg S, Halken S, Høst A, Niggemann B, Aalberse R et al. Dietary prevention of allergic
diseases in infants and small children. Part II. Evaluation of methods in allergy prevention studies and
sensitization markers. Definitions and diagnostic criteria of allergic diseases. Pediatr Allergy Immunol. 2004
Jun;15(3):196-205.
Is early S-IgE positivity associated
to subsequent disease ?
Kulig M et al. Clin Exp Allergy 1998;28:1397-1403
Tariq SM et al Pediatr Allergy Immununol 2000;11:162-67
Retrospective view on sensitization status in children
with allergic disease at 6 years