La storia naturale dell’asma

fernando maria de benedictis

AOU “Ospedali Riuniti” - AnconaOspedale Materno-Infantile di Alta Specializzazione “G. Salesi”

SOD Pediatria

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

Yunginger, ARRD 1992;146:888

Remission rates of asthma symptoms during adolescence in cohort studies

70% 67%

45%50%

Nicolai, 2001 Anderson, 1986 Peat, 1989 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

50%

18%10% 10%

27%

% o

f as

thm

a at

tack

s in

th

e p

revi

ou

s ye

arUK cohort of 18.553 subjects followed from birth until 33 yrs

Strachan, BMJ 1996;312;1195

880 children who had wheezing before the age of 7 yrs

The Melbourne asthma study (1964-1999)

Longitudinal study of 403 subjects from the age of 7 yrs to 42 yrs

Phelan, JACI 2002;109:189

- Eczema- Hay fever- Atopy

The New Zealand asthma study

Cohort study of 1037 unselected subjects from age 9 to 26 yrs

15%

15%

12%

9%

21%

28%

Sears, NEJM 2003;349:1414

27%

Female sexSmokingEarly age of onsetAtopyBHR

Prevalence of current wheeze in children with any wheezing episode at school age stratified for atopy at school age

Non-atopicAtopic

No difference

Illi, Lancet 2006;368:763

German Multicenter Allergy Study

815 unselected newborns and 499 at high risk of atopy followed from birth to 13 yrs

46%

10%

CAMP study

1041 asthmatic children 5 to 12 yrsTrial of anti-inflammatory treatments for 5 yrs, and then a 4-year follow up

Covar, JACI 2010;125:359

55%

39%

6%

Severity of asthmaAllergic sensitizationLow lung function BHR

CAMP study

1041 asthmatic children 5 to 12 yrsTrial 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

Limb, JACI 2005;115:61

85 subjects with asthma in childhood evaluated 17 to 30 years after immunotherapy

2.1O

R f

or

asth

ma

at a

ge

22 y

rs1.4

4.6

7.4

4.1

14.0

Stern, Lancet 2008;372:1058

Tucson Children Respiratory Study

Cohort of 846 subjects followed from birth to 22 years

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

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.

Cohort study of 1037 unselected subjects followed from birth until 26 yrs

Sears, NEJM 2003;349:1414

Tucson Children Respiratory Study

Morgan, AJRCCM 2005;172:1253

Cohort of 425 subjects followed from birth to 16 years

Stern, Lancet 2008;372:1058

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

• 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

Determinants the progressive loss of lung function in asthmatics

Baseline lung function at different ages stratified for wheezing at 5-7 years

p<0.05* atopic wheeze vs no wheeze* atopic wheeze vs non-atopic wheeze

FV

C %

ME

F7

5 %

ME

F5

0 %

FE

V1

%

FV

C/F

EV

1 %

ME

F2

5 %

* * *

*

** ** *

****

** ** ** **

7 yr 10 yr 13 yr 7 yr 10 yr 13 yr 7 yr 10 yr 13 yr

German Multicenter Allergy Study

815 unselected newborns and 499 at high risk of atopy followed from birth to 13 yrs

Illi, Lancet 2006;368:763

The differences in pulmonary function between the different classes persist after bronchodilator

Adolescents with clinical remission of asthma, inflammation and bronchial hyperreactivity

21 with active asthma; 21 with asthma remission; 18 controlsMCH 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

De Marco, JACI 2002;110:228

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).

Gender differences for the incidence and pattern of asthma

MalesFemales

Inci

den

ce o

f as

thm

a/10

0.00

0 p

ts

Osman, Arch Dis Child 2003;88:5879

The New Zealand asthma study

Sex differences in childhood- and adolescent-onset wheeze

The influence of parental atopy on the development of wheeze differs between males and females and between childhood- and adolescent-onset wheeze

Wheeze by age 10

Wheeze between ages 10 and 26

Mandhane, AJRCCM 2005;172:45

M vs F, p <0.001

F vs M, p <0.001

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