Reviews and feature article
Long-term studies of the natural history of asthma in childhood

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Segmentation of children with asthma and other wheezy disorders remains the main research challenge today, as it was when described 2 centuries ago. Early childhood wheezy disorders follow different temporal trajectories, probably representing different underlying mechanisms (endophenotypes). Prospective identification of endophenotypes allowing accurate prediction of the clinical course is currently not possible. The variability of the clinical course remains an enigma and difficult to predict. Three of 4 school-aged children with asthma have outgrown disease by midadulthood. The risk of persistence increases with severity, sensitization, smoking, and female sex. Genetic risk variants might help disentangle the heterogeneity of asthma and other wheezy disorders. At early school age, children with asthma have reduced lung function. It is an important and unresolved question whether the airflow limitation associated with asthma already existed at birth or developed along with symptoms. Likewise, the association between the infant's bronchial responsiveness and development of asthma and other wheezy disorders is unclear. Neither primary prevention through manipulation of environmental factors nor secondary prevention through the use of inhaled corticosteroids can effectively halt the long-term disease progression in childhood. In conclusion, the natural history of asthma and the associated airway changes is still poorly understood, and we have not managed to translate findings from long-term studies into a deeper understanding of the underlying endophenotypes or improved disease management. We propose the need for a translational research approach based on long-term clinical studies of birth cohorts with comprehensive and objective assessments of intermediate phenotypes and environmental exposures combined with interdisciplinary basic research and a systems biology approach.

Section snippets

Natural history of symptoms in children with asthma and other wheezy disorders

  • Early childhood wheezy disorders follow different temporal trajectories probably reflecting different endophenotypes.

  • There is no available evidence allowing prospective identification of these temporal patterns of early childhood wheeze.

  • 3:4 of school aged children with asthma have outgrown disease by mid-adulthood.

  • Risk of persistence increases with severity, sensitization, smoking and female gender.

Natural history of lung function in children with asthma and other wheezy disorders

  • It is the important research question if the early loss of lung function in asthma is a cause or a consequence of the disease.

  • It is unclear if persistent wheeze during preschool age is preceded by neonatal airflow limitation or if such airflow limitation develops along with symptoms.

  • Children with asthma have reduced lung function by early school age. Thereafter the lung function tracks at a fixed percentile with no evidence of a further decline in lung function.

Asthma at school age is

Natural history of bronchial responsiveness in children with asthma and other wheezy disorders

  • The association between infant bronchial responsiveness and asthma and other wheezy disorders is unclear.

  • Infant bronchial responsiveness is probably not associated with atopy as opposed to bronchial responsiveness later in life.

It is a challenging question whether premorbid abnormal bronchial hyperresponsiveness is a determinant factor for children to have asthma and other wheezy disorders or whether bronchial hyperresponsiveness develops as part of the asthmatic pathophysiology.

Two cohorts

Risk factors

  • The main environmental risk factors known from long-term studies to be associated with asthma and other wheezy disorders are genetics, virus, bacteria, tobacco exposure, and allergic sensitization.

Long-term studies on risk factors influencing the natural history of asthma generally belong to the more recent birth cohort studies, reflecting a changing paradigm in the past decades. While the pioneering long-term studies described above primarily focused on disease presentation, recent cohort

Modifying the natural history of asthma

  • Neither primary prevention through manipulation of environmental factors nor secondary prevention through use of ICS can effectively halt the long-term disease progression in childhood asthma or the progression from episodic to persistent wheezing.

It is an attractive hypothesis that remodeling of the airways developing over years of persistent asthma could evoke an irreversible airway obstruction phenotype. However, there is little evidence to support this concept, and there is currently no

Strengths and limitations of long-term studies

  • Long-term, classical epidemiological studies are at high risk of misclassification with imprecise outcome and exposure assessments.

  • Long-term clinical cohort studies gain power from deep phenotyping with accurate time-of-onset and objective clinical information and exposure assessments.

Prospective long-term studies aim to describe disease progression and identify unbiased associations between specified exposures and subsequent development of disease outcomes with the aim of establishing causal

Future long-term studies of the natural history of asthma in childhood

The burden of uncontrolled asthma reflects in part the failure of previous segmented research strategies. Indeed, the extent to which it will be possible to relate findings at the molecular level to clinical phenotypes is a central and general problem for current medical science.100

Large-scale, long-term observational studies have provided much insight into the nature of asthma and wheezy disorders. However, very little of the research has affected clinical management. New research alliances

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