The All Age Asthma Cohort (ALLIANCE)

From Early Beginnings to Chronic Disease: A Longitudinal Cohort Study

Oliver Fuchs; Thomas Bahmer; Markus Weckmann; Anna-Maria Dittrich; Bianca Schaub; Barbara Rösler; Christine Happle; Folke Brinkmann; Isabell Ricklefs; Inke R. König; Henrik Watz; Klaus F. Rabe; Matthias V. Kopp; Gesine Hansen; Erika von Mutius


BMC Pulm Med. 2018;18(140) 

In This Article


The ALL Age Asthma Cohort is a large integrative and interdisciplinary framework containing data on n = 623 patients with wheeze and asthma and n = 172 healthy controls at baseline. With its comprehensive, standardized molecular approach in a prospective and identical fashion for children and adults, ALLIANCE aims at (a) identification of biomarkers and predictors to decode the complex mechanisms that may underlie the development of distinct childhood wheeze and asthma trajectories as well as their transition into and further course during adulthood, and at (b) translation of this into clinical practice for individual patients.

In addition to the comprehensive and prospective approach across all ages, ALLIANCE has several methodological strengths, which are its prime features: the prospective, observational approach with standardized data and comprehensive biomaterial collection across all ages during each study visit in a multi-centre setting to delineate the different wheeze and asthma phenotypes; the accurate and standardized measurements of lung function and markers of airway inflammation, and the stringent quality control measures involved for every single data point.

In a broad approach, ALLIANCE aims at decoding the complex mechanisms that may underlie the development of distinct childhood wheeze and asthma phenotypes and their transition into adulthood as well as later adult asthma phenotypes. As we hypothesize that specific molecular phenotypes are associated with distinct wheeze/asthma trajectories, this includes the meticulous longitudinal collection of routine clinical and epidemiological data and exhaustive examination of phenotype components that go beyond medical chart data. Thereby, underlying mechanisms as well as predictors and biomarkers for such traits can be identified. For children, this is being applied to study both participants with established diagnoses and those possibly on controller therapy, as well as in children which are steroid- and LTRA-naïve, ideally at the earliest possible disease state.

Thus, we follow a thorough and comprehensive deep phenotyping approach in cases and healthy controls. This includes extensive quality control during data collection. In this respect, besides the fact that all measurements are performed according to current guidelines where available, more than 50 standard operating procedures (SOPs) for data or biomaterial collection as well as their processing, shipment, and analyses have been developed. All data collection is being performed in a standardized way at any age, using the same technique and equipment on every subsequent occasion in the same order and according to the numerous harmonized SOPs. Adherence to these SOPs is ensured by regular field and lab audits. In addition, structured site visits and team meetings across all involved centres are performed regularly.

To explain the association of lung mechanics during early and late childhood as well as adult age with wheeze and asthma phenotypes as part of a physiological phenotyping, overall lung function, small airway function, and markers for ventilation inhomogeneity are measured. This is complemented by qualitative and quantitative assessments of airway inflammation and analyses of exhaled breath. Lung function tests are performed at several time points covering important phases of lung development (further growth of airways and alveoli) during early and later childhood.[34] Relevant confounders such as physical activity and auxological as well as developmental features are prospectively assessed and will be included in all analyses. All lung function and eNO measurements are performed according to the latest ERS/ATS recommendations, if available.[19,20,28,29,31–33]

There is still limited knowledge on the genetic impact on childhood wheeze and asthma as well as adult asthma. This is particularly true for cell- or target-tissue specific up- or downstream events involving epigenetic control as well as gene expression. Therefore, in addition to genotyping, the assessment of transcriptomics and epigenomics both in whole blood, cell-specific (blood cell sub-populations) and tissue-specific analyses (primary cells of the upper airways and biosamples from induced sputum) is part of the deep phenotyping strategy of ALLIANCE. Another hallmark hypothesis of the consortium is that individuals at risk for exacerbations can be identified by clinical and molecular biomarkers, which might become novel targets for therapy and secondary prevention. Therefore, exacerbations will be assessed by numbers (children and adults) as well as triggers, severity and clinical features (children only) via questionnaires at all visits.

So far, our attrition rates are comparable to other studies.[35,36] This may be due to the regular follow-up in the clinical setting. The drawback of such a detailed, time-consuming longitudinal study is that it can only be done on a limited number of participants due to the significant workload regarding logistics, data collection and analyses. This extensive biomaterial collection and the number of different analyses and hypotheses is also the reason, why a single power calculation for the whole cohort is not feasible. Sample size for both study arms is therefore based on pragmatism and clinical experience from comparable cohorts.

A significant limitation of ALLIANCE is the inclusion of cases into the study earliest at the time-point of disease manifestation, which renders assessment of prior or even causal determinants acting before disease onset impossible. Such assessments can only be performed by population-based birth cohort studies. Moreover, in contrast to cross-sectional comparisons, the lack of prospective follow-up of healthy controls identical to the setup performed for cases hinders comparability over time across both strata. Lastly, data on environmental exposures (e.g. allergen or microbial exposure) are only collected by questionnaires and not by objective sampling and measurement. Methodology in both study arms was harmonized as far as possible. However, both study arms are also used to answer individual research questions of paediatric and adult pulmonologists, while other measurements are not feasible or scientifically reasonable. Therefore some objective measurements are performed in one arm only.

So far, all involved study participants for the paediatric arm were recruited in participating hospital centres and private practices of registered paediatricians in the regions of Luebeck, Hannover, Munich, and for the adult arm in participating hospitals and research centres in Grosshansdorf and Borstel near Hamburg. Transition clinics will be established in all three sites to secure continuous follow-up across the otherwise often neglected gap between paediatric and adult pneumologist care. New study centres for the paediatric arm (Marburg, Cologne) have started recruitment in 2017. While the main reasons for non-participation especially of early-onset wheezers is lacking information about the study as well as the amount of data and biomaterial that is being collected, all participants are likely to be biased towards a well-educated middle-class population, which is the case with numerous studies bringing along detailed data collection. Moreover, this is an observational study within a clinical setting with desirable results to be applied in such environments. Hence, results will be less applicable for the general population than for individuals presenting to seek medical care in the case of wheeze and asthma.

In this clinical context, ALLIANCE offers improved endo-phenotyping in children and adults identically to delineate different underlying pathophysiological pathways across asthma phenotypes in a longitudinal way. With its standardised and unique dataset of detailed epidemiological, physiological, and deep phenotyping of a comprehensive range of biomaterials across all ages in a considerable number of study participants, it will enable to decode mechanisms underlying the asthma syndrome, as well as their translation to well-defined patient groups and possibly even the individual patient.