Childhood respiratory cohort studies: do they generate useful outcomes?

Strengths and limitations of cohort studies

Given that there are so many different cohorts it is inevitable that there is a wide spectrum of study design (table 1). Variability in study design reflects lessons learnt from previous studies, advances in methods of assessment and also ethical considerations. The perfect study would follow up several thousand individuals from conception to grave and, during that time, assess all genetic variations and environmental exposures and relate these to robust indices of asthma. Life is not perfect and strengths and weaknesses of cohort studies are displayed in table 2. The practical challenges of participant recruitment and retention and limitation of finances often mean that most studies are only able to focus on one exposure/outcome; unfortunately asthma is a complex disease in which more than one gene or environmental exposure are implicated in causation. One limitation to cohort studies is that results may take many years to emerge and may not be relevant to current practice; for example, is it fair to extrapolate to children in 2012 the results from participants in the 1958 cohort who were assessed as children? People who come forward to participate in respiratory studies are not always typical of the general population [8], so results may not necessarily be generalisable even with low rates of drop out. However, drop out of participants is inevitable and introduces bias into the remaining study population (children of smoking and less affluent parents are more likely to drop out) and also reduces a study's power to detect the presence of an association and, even more so, the absence of an association. Further limitations are that once a study is underway it is very hard to retrospectively include additional exposures and that the associations described do not necessarily equate to causation. Finally, the flaw in every asthma study is that there is no gold standard test or definition for asthma, and different asthma definitions can invalidate direct comparison between studies. Given the lack of a gold standard phenotype for asthma and heterogeneity in genetic and environmental characteristics across the world's population, it is perhaps not surprising that different studies yield apparently inconsistent results; one example of this is the relationship between breast feeding and asthma which is positive in some studies but negative in others [9]. One alternative to the typical cohort is to use routinely acquired data and undertake “real world” whole population studies; while this is not without another series of limitations it has been advocated [10] and already used in Scandinavian countries.

What are the risk factors for asthma? Can we predict who will get asthma?

Asthma is a classical complex disease in which a series of genetic and environmental factors interact, often at critical stages of development. As for all complex diseases (e.g. cancer, ischaemic heart disease), the risk for developing asthma can be described for the population but not for the individual. A child at a high risk for developing asthma may never develop symptoms and, conversely, a child with no apparent risk factors may develop troublesome symptoms. It is not possible to predict who will and will not develop asthma; instead, what can be done instead is describe the relative risk (table 3). The truly novel insight which cohort studies have provided is the ability to identify when these factors become important. Many factors appear to be acting early in life, some even before birth, but the presence of adult-onset asthma is evidence that symptoms can appear at any time during life. To add a further dimension to the model, there are almost certainly interactions between factors, e.g. family history of atopy and breast feeding [19], atopy and early viral infection [23], and parental atopy and smoking [24].

What is the evidence that factors are acting early?

Cohort studies for which physiological measurements were made in asymptomatic infants or young children who were then followed up have demonstrated that the hallmarks of childhood asthma are present before the onset of symptoms; these features include atopy [31], reduced lung function [4], bronchial hyper-reactivity [13] and airway eosinophilia [32]. Further evidence that early influences are important to asthma is that reduced fetal size at ten weeks gestation has been linked to increased respiratory morbidity in 10-yr-olds [33]. There are at least two implications for these findings. First, for many children (and adults), asthma develops in early life and second there is a “pre-asthmatic” stage during which intervention might influence asthma outcome. table 3 summarises some of the early factors associated with asthma and their possible magnitude of effect.

Which factors are acting early?

Who grows out of asthma and can we predict prognosis? Will my child grow out of their asthma?

The prospective collection of questionnaire and physiological data over time allows cohort studies the luxury of hindsight and some have developed algorithms that predict outcomes of early wheeze. Unfortunately, whilst useful on a whole-population basis, these algorithms do lack precision. The three most consistent indices of persisting wheeze are frequent early wheeze, parental history of asthma and early onset atopy in the child; these three factors probably correspond to airway abnormality, genetic susceptibility and atopy respectively. table 4 summarises the relative risk for different risk factors described in cohort studies. Due to the challenge in measuring respiratory physiology in young children, all but one algorithm combines factors obtained from the history, some also include allergy testing [44] and one also includes allergen exposure [45]. At the time of writing, a single study has related lung function and nitric oxide in 4 yr olds to later symptoms and found limited evidence that these measurements may be useful [46].

Can we prevent asthma? What can I do to stop my other children from getting asthma?

There is no cure for asthma; however, a number of centres have introduced interventions aimed at reducing the risk for developing asthma. These pioneering studies have given important insight into asthma aetiology during infancy and highlighted the complexities and pitfalls in trying to prevent asthma. Single interventions have proven disappointing whereas multiple interventions have shown evidence in reducing asthma symptoms in childhood.

In Manchester, UK, a birth cohort of 251 infants at high risk for allergy was randomised to an intervention which very effectively removed house dust mites (HDM) from their environment for the first year [50]. At age 3 years, the intervention group were somewhat unexpectedly at increased risk for HDM sensitisation (OR 2.9; 95% CI 1.0–8.0). The intervention was associated with a reduction in airway resistance of approximately 20%. Outcomes beyond 3 years have not been reported despite the cohort having been followed up past age 5 years, so it is possible that the outcomes at 3 years did not persist. What this study demonstrates is that an apparently simple intervention can be far from simple. By reducing HDM exposure, there was an increase in IgE sensitisation but an unexpected improvement in lung function, the latter may have been due to exposure to an adverse exposure, e.g. lipopolysaccharide, which was inadvertently reduced by the intervention. A second intervention study in the Netherlands introduced the single intervention of HDM reduction and the intervention was associated with reduced recurrent wheeze during infancy but not at 2 years of age [11].

A study by Canadian researchers in Belarus randomised mothers attending 31 maternity hospitals to an educational intervention aimed at prolonging extended breast feeding. In total, 17,046 infants participated. After 1 year, mothers who had received the intervention had breastfed for longer and exclusively breastfed for longer compared with controls. Infants of mother who received the intervention were less likely to have diarrhoeal illnesses and eczema. At 6 years of age, those in the intervention group were more likely to be skin-prick positive (OR 2.0; 95% CI 1.1–3.4) but there was no increase or decrease in asthma symptoms [51].

A birth cohort of 120 infants at high risk for developing allergy was recruited in the Isle of Wight, UK. Infants were randomised to a complex allergen-avoidance intervention aimed at reducing exposure to HDM and cow’s milk. At 8 years of age, individuals who received the intervention were less likely to have current wheeze (OR 0.3; 95% CI 0.1–1.0) and atopy (OR 0.2; 95% CI 0.1–0.6) [52].

The Childhood Asthma Prevention Study (CAPS) in Sydney, Australia, sought to reduce the risk of asthma developing in 616 infants at higher risk for asthma. The intervention here was either HDM reduction or dietary supplementation with omega-3 and reduction of omega-6 fatty acids or both or neither. At 3 years of age, those children who had developed atopy but who had dietary supplementation had 10.0% (95% CI 3.7–16.4) reduction in the prevalence of cough. There was a 7.2% (95% CI 10.11–14.3) reduction in sensitisation to HDM in the active allergen avoidance group (p = 0.05; number needed to treat: 14) [53]. There are no published outcomes beyond 3 years despite the cohort being recruited in the late 1990s.

A randomised–controlled study tested the effect of a multifaceted intervention programme on the primary prevention of asthma in high-risk infants in Canada. Here, 545 infants with at least one parent with asthma were randomised to a complex intervention including four components: 1) reduction of house dust mite exposure; 2) reduction of exposure to pets; 3) reduced exposure to environmental tobacco smoke; and 4) avoidance of cow’s milk protein and delayed weaning. At 7 years of age, 469 children were followed up and the intervention was associated with a reduced risk for diagnosed asthma of 0.44 (95% CI, 0.25–0.79), the intervention was not associated with reduced atopy or BHR so the underlying mechanism is not clear but was not by delaying onset of atopy [17].

The outcomes of these studies can be summarised thus:

Conclusions and future research

Cohort studies continue to give insight into the timing of early exposures on asthma causation and their magnitude of effect. figure 1 demonstrates that these studies are mostly restricted to the developed world and similar studies would be welcomed in Asia and Africa. Given the changing nature of our environment and lifestyle, there is justification for more cohort studies to be recruited and these should carefully consider their study design to reflect clinically relevant questions. Whole population studies in Finland and Sweden validate the use of routinely acquired data as part of “real-world” studies and these have benefits of yielding rapid results at low cost. Genetic variations, sex, age and socioeconomic status are all associated with altered risk for asthma but are not modifiable; however, intervention studies can be designed to modify what can be changed, i.e. lifestyle, to prevent asthma developing.