Late Consequences of Childhood Asthma

Andrew Bush MB BS (Hons) MA MD FRCP FRCPCH FERS

Professor of Paediatrics and Head of Section (Paediatrics), Imperial College

Professor of Paediatric Respirology, National Heart and Lung Institute

Consultant Paediatric Chest Physician, Royal Brompton Harefield NHS Foundation Trust.

Correspondence: Department of Paediatric Respiratory Medicine, Royal Brompton Hospital,

Sydney Street, London SW3 6NP, UK.

AB was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London

* Tel: -207-351-8232 * Fax: -207-351-8763 * e mail:- [email protected] Introduction The final outcomes in adult life of children who have had asthma are comprised of (a) the causes of the underlying asthma; (b) the consequences of asthma itself; and (c) the consequences of treatment. Treatment consequences also include treatment for associated conditions such as eczema and allergic rhinitis, which may also increase the burden of steroid therapy. These cannot readily be unpicked, and, since treatment has changed over the decades, the long-term outcomes of today’s asthmatics may be different. Finally, the really long-term cohorts (Melbourne, Aberdeen) did not have the modern ability to phenotype early asthma. The considerations of airway disease discussed in my bronchopulmonary dysplasia talk could not be applied, and sterile umbrella terms have to be accepted.

Early airflow obstruction, long term issues The Global Lung Initiative (www.lungfunction.org/) has produced spirometry equations covering the entire life span; briefly, the threshold for respiratory symptoms and disability as the lung ages depends on being born with normal lung function; growing the lungs at a normal rate to a plateau age 20-25 years; and then the rate of decline in the ensuing decades is normal. Irrespective of the presence of asthma or wheeze, airflow obstruction shortly after birth tracks into the third decade, and will likely track thereafter as well. Early airflow obstruction is also a risk factor for the development of asthma.

Early wheeze, impaired lung growth The CAMP study which compared asthma treatment with 400 mcg budesonide, 16 mg nedocromil or placebo daily for 4–6 years in children with asthma aged 5– 13 years first identified that around one third of mild-moderate asthmatics had impaired development of airway function, irrespective of treatment. This was taken forward by the Manchester group, who used unsupervised techniques to study four wheeze phenotypes (none, transient, late onset and persistent) and five atopy phenotypes (none, dust mite, non-dust mite, multiple early an multiple late) and showed that impaired airway development was associated only with persistent wheeze and multiple early atopy combined. Acute asthma attacks also predicted a bad trajectory.

Early wheeze, later rate of decline of spirometry The data are controversial. The Aberdeen cohort showed that those with asthma did not attain a normal first second forced expired volume (FEV 1) plateau, and had an accelerated rate of FEV1 decline. Interestingly, those with ‘wheezy bronchitis’, which we would now describe as having episodic viral wheeze, had a normal FEV1 plateau but an accelerated decline in FEV1. An accelerated rate of decline predisposes to ‘COPD’ in adult life, but the TORCH and ECLIPSE studies have both shown that many COPD patients have a normal rate of change of FEV1, so accelerated decline is not a pre-requisite for the diagnosis. By contrast, the Melbourne cohort, who recruited normal and mild and moderate asthmatics age 7, and enriched the cohort with severe asthmatics at age 10, and followed them to the sixth decade, showed that rate of change of FEV1 was the same and ran on parallel tracks for normal and all degrees of severity of asthma; thus the long-term differences were all determined in the very early years, before the children were recruited. There was no evidence of a difference in the rate of decline in FEV1 (mL/y, 95% CI) between the severe asthma group (15 mL/y [95% CI, 9-22 mL/y]) and all the other recruitment groups: control (16 mL/y [95% CI, 12-20 mL/y]), mild wheezy bronchitis (14 mL/y [95% CI, 8-19 mL/y]), wheezy bronchitis (16 mL/y [95% CI, 11-20 mL/y]), and persistent asthma (19 mL/y [95% CI, 13-24 mL/y]). The question of asthma and COPD is discussed below. This group has the best outcome data relating severity of asthma to likelihood of remission. Asthma remission at the age of 50 years was 64% in those with wheezy bronchitis, 47% for those with persistent asthma, and 15% for those with severe asthma in childhood. Multivariable analysis identified severe asthma in childhood (odds ratio [OR] 11.9 [95% CI, 3.4-41.8]), female sex (OR 2.0 [95% CI, 1.1-3.6]), and childhood hay fever (OR 2.0 [95% CI, 1.0-4.0]) as risk factors for "current asthma" at age 50 years.

Does asthma ever truly remit? Asthmatics clearly become asymptomatic off all treatment, and a proportion of these remain symptom-free. A challenging study from the Netherlands showed that adolescents and young adults with asthma in remission still had eosinophilic airway inflammation and remodelling to the same degree as those with ongoing symptomatic asthma. It is still unclear what this means for treatment and prognosis.

COPD and asthma The current definition of COPD, requiring an FEV1/FVC ration of <0.7, irrespective of age, is clearly flawed. So for women aged 30, FEV1/FVC ratio of 75% is wildly abnormal; above age

50, increasing numbers of normal people will have FEV1/FVC ratio <70%; and above age 70, >30% of normal people will have FEV1/FVC ratio <70%. Furthermore, the umbrella term COPD assumes (with no evidence) that the pathway to airflow obstruction is the same in a long term smoker as an asthmatic as a woman lifelong exposed to biomass fuels in the developing world. Having said that, nearly 50% of their severe asthmatics at age 10 had an FEV1/FVC ratio <70% in their fifties, and this was a stronger signal than smoking in this group. The odds ratio for adult COPD with severe asthma age 10 years was a staggering 32(3.4-269), much more than for smoking. Those with COPD in their fifties had the worst lung function at age 10, from which time spirometry ran parallel with the other groups.

What about treatment? The chief concern is adult height. The best data are from the CAMP study. In the budesonide but not the nedocromil group, there was a deficit in adjusted mean adult height compared with placebo of 1.2 cm; the deficit was greater for women (−1.8 cm, p<0.001) than for men (−0.8 cm, p=0.10). The deficit developed in the first 2 years of treatment, and growth velocity thereafter was similar in all three groups. There was a dose effect, with a decrement of 0.1 cm for each mcg/kg daily dose of ICS, but no effect of cumulative prednisolone dosage. Longer duration of asthma at trial entry and atopy (any positive skin test) were also risk factors for reduced adult height, implying that asthma itself and possibly the treatment for other atopic conditions (above) was important.

Summary and conclusions Early asthma has profound lifelong implications. Focus on the key antenatal and pre-school time period is essential if long term lung health is to be improved. Further reading

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