AOU “Ospedali Riuniti” - Ancona
Ospedale Materno-Infantile di Alta Specializzazione “G. Salesi”
SOD Pediatria
La storia naturale dell’asma
fernando maria de benedictis
The natural history of asthma:
questions to answer
• When does asthma begin in childhood?
• Do children outgrow asthma?
• May asthma relapse after disappearance?
• What about late-onset asthma?
• Is there anything that can modify the course of asthma?
A community-based study of the epidemiology of asthma
Females
Males
Incidence rates/1000.000
4000
3000
2000
1000
0
<1
1-4
5-9
10-14
15-29
30-49
> 50
Age group, yr
Yunginger, ARRD 1992;146:888
Remission rates of asthma symptoms during adolescence
in cohort studies
80
70%
67%
60
50%
45%
% 40
20
0
Munich
Nicolai, 2001
UK
Anderson, 1986
Australia
Peat, 1989
UK
Withers, 1998
It is often not asthma that is outgrown,
but the paediatrician….
Levison, JACI 1991
The natural history of asthma:
the need of prospective, long-term studies
• May describe disease progression through its full course
• May identify unbiased associations between specified
exposures and subsequent development of disease outcomes
• May help to understand the effect of therapies on modifying
the course of the disease
British 1958 asthma and wheezing study
% of asthma attacks in the previous year
UK cohort of 18.553 subjects followed from birth until 33 yrs
80
60
880 children who had wheezing before the age of 7 yrs
50%
% 40
27%
18%
20
10%
10%
16
23
0
7
11
33
Years
Strachan, BMJ 1996;312;1195
The Melbourne asthma study (1964-1999)
Longitudinal study of 403 subjects from the age of 7 yrs to 42 yrs
- Eczema
- Hay fever
- Atopy
Phelan, JACI 2002;109:189
The New Zealand asthma study
Cohort study of 1037 unselected subjects from age 9 to 26 yrs
15%
15%
27%
12%
9%
Female
21% sex
Smoking
28% age of onset
Early
Atopy
BHR
Sears, NEJM 2003;349:1414
German Multicenter Allergy Study
815 unselected newborns and 499 at high risk of atopy followed from birth to 13 yrs
Non-atopic
Atopic
No difference
46%
10%
Prevalence of current wheeze in children with any wheezing episode at school age stratified for
atopy at school age
Illi, Lancet 2006;368:763
CAMP study
1041 asthmatic children 5 to 12 yrs
Trial of anti-inflammatory treatments for 5 yrs, and then a 4-year follow up
55%
Severity of asthma
Allergic sensitization
Low lung function
39%
BHR
6%
Covar, JACI 2010;125:359
CAMP study
1041 asthmatic children 5 to 12 yrs
Trial of anti-inflammatory treatments for 4 to 6 yrs and then a 4-year follow up
Covar, JACI 2010;125:359
Pattern of asthma in adults with a history of
childhood asthma
85 subjects with asthma in childhood evaluated 17 to 30 years after immunotherapy
Limb, JACI 2005;115:61
Tucson Children Respiratory Study
Cohort of 846 subjects followed from birth to 22 years
Newly diagnosed asthma (n. 49) Chronic asthma (n. 132)
OR for asthma at age 22 yrs
20
14.0
15
10
7.4
4.6
5
2.1
4.1
1.4
0
Transient Wheezing
Late onset Wheezing
Persistent Wheezing
Stern, Lancet 2008;372:1058
The Melbourne asthma study (1964-1999)
* *p <0.01 vs controls
*
At each year of review, the degree of lung function abnormality paralleled the initial
frequency of wheeze = The early loss of lung function did not appear to progress !
Phelan, JACI 2002;109:189
The New Zealand asthma study
Cohort study of 1037 unselected subjects followed from birth until 26 yrs
The slopes of change in FEV1:FVC were similar in each wheezing group (“tracking”),
thus indicating that impairment of lung function in patients with persistent asthma
occurred in early childhood, before the first measurement at the age of 9 years.
Sears, NEJM 2003;349:1414
Tucson Children Respiratory Study
Cohort of 425 subjects followed from birth to 16 years
Morgan, AJRCCM 2005;172:1253
Tucson Children Respiratory Study
Cohort of 846 subjects followed from birth to 22 years
FEV1/FVC ratio and asthma at age 22 yrs by age at first asthma diagnosis
Stern, Lancet 2008;372:1058
Determinants the progressive loss of lung function
in asthmatics
• In asthmatic children, reduced lung function becomes apparent
around school age
• In asthmatic subjects, there is no further progression of lung function
impairment from childhood up to adolescence and adulthood
(“tracking”)
• Airway inflammation and changes in airway structure (“remodeling”)
are considered to be responsible for reduced lung function
• Unknown factors between birth and school age determine the
progressive loss of pulmonary function in children with asthma
German Multicenter Allergy Study
815 unselected newborns and 499 at high risk of atopy followed from birth to 13 yrs
*
*
FVC/FEV1 %
FEV1 %
*
**
7 yr
*
10 yr
13 yr
**
7 yr
**
10 yr
**
13 yr
MEF25 %
**
**
*
The differences in pulmonary function between the different classes
persist after bronchodilator
MEF50 %
MEF75 %
FVC %
*
*
p<0.05
atopic wheeze vs no wheeze
atopic wheeze vs non-atopic wheeze
**
7 yr
*
10 yr
*
13 yr
Baseline lung function at different ages stratified for wheezing at 5-7 years
Illi, Lancet 2006;368:763
Adolescents with clinical remission of asthma, inflammation and
bronchial hyperreactivity
21 with active asthma; 21 with asthma remission; 18 controls
MCH challenge and FeNO
van den Toorn, AJRCCM 2000;162:953
Italian Study on asthma in young adults
Cross-sectional study of 18.837 young adults
Cumulative probability of remission
The minority of persons with early-onset asthma
who do not recover represents approximately 35%
of prevalent cases of the young adult population
(20-44 year of age).
De Marco, JACI 2002;110:228
Incidence of asthma/100.000 pts
Gender differences for the incidence and pattern of
asthma
Males
Females
Osman, Arch Dis Child 2003;88:5879
The New Zealand asthma study
Sex differences in childhood- and adolescent-onset wheeze
F vs M, p <0.001
Wheeze between ages 10 and 26
M vs F, p <0.001
Wheeze by age 10
The influence of parental atopy on the development of wheeze differs between
males and females and between childhood- and adolescent-onset wheeze
Mandhane, AJRCCM 2005;172:45
The natural history of asthma:
what do we know?
• Three of 4 school-aged children with asthma have outgrown
disease by mid-adulthood
• Risk of persistence/relapse increases with severity, sensitization,
smoking and female sex
• Children with asthma have reduced lung function by early school
age. The lung function seems to track at a fixed percentile.
• Neither primary (manipulation of environmental factors) nor
secondary (use of anti-inflammatory drugs) prevention can
effectively halt the long term disease progression of asthma
The natural history of asthma:
what is still unknown?
• Whether the early loss of lung function in asthma is a cause
or a consequence of the disease
• Which is the relationship between airflow limitation in the
neonates and development of asthma
• The direction of causality between infant bronchial responsiveness
and asthma
• Long term cohort studies starting before birth may gain power from
deep phenotyping with objective assessment of the disease
• Analytic approaches are needed to achieve more than just
interesting observations of statistically significant associations