La storia naturale dell’asma fernando maria de benedictis AOU “Ospedali Riuniti” - Ancona Ospedale 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% 27% % of asthma attacks in the previous year UK cohort of subjects followed from birth until 33 yrs Strachan, BMJ 1996;312; children who had wheezing before the age of 7 yrs

The Melbourne asthma study ( ) 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% 12% 9% 21% 28% Sears, NEJM 2003;349: % Female sex Smoking Early age of onset Atopy BHR

Prevalence of current wheeze in children with any wheezing episode at school age stratified for atopy at school age Non-atopic Atopic 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 yrs Trial of anti-inflammatory treatments for 5 yrs, and then a 4-year follow up Covar, JACI 2010;125:359 55% 39% 6% Severity of asthma Allergic sensitization Low lung function BHR

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 Limb, JACI 2005;115:61 85 subjects with asthma in childhood evaluated 17 to 30 years after immunotherapy

2.1 OR for asthma at age 22 yrs Stern, Lancet 2008;372:1058 Tucson Children Respiratory Study Cohort of 846 subjects followed from birth to 22 years

The Melbourne asthma study ( ) * * * 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 FEV 1 :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 FVC % MEF75 % MEF50 % FEV1 % FVC/FEV1 % MEF25 % * * * * * * * * * * * * * * * * * * * * * 7 yr 10 yr13 yr 7 yr 10 yr13 yr 7 yr 10 yr13 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 controls MCH challenge and FeNO van den Toorn, AJRCCM 2000;162:953

Italian Study on asthma in young adults Cross-sectional study of 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 Males Females Incidence of asthma/ pts 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