Protocol for the Wessex AsThma CoHort of difficult asthma (WATCH): a pragmatic real-life longitudinal study of difficult asthma in the clinic

The UHSFT Adult Asthma multidisciplinary team (MDT) is comprised of Consultants, Research Fellows, Specialist Nurses, Associate Practitioners, Clinical Psychologists, Physiotherapists and Dietitians. The service is provided via a dedicated Regional Severe/Difficult Asthma Clinic, Transitional/Young Asthma Patient Clinic, Isle of Wight Outreach Asthma Clinic, Biologics (Omalizumab, Mepolizumab, Reslizumab and Benralizumab) Clinic, Nurse-led Asthma Clinic, Clinical Psychology Clinic and Respiratory Physiotherapy Clinic. The team has a close working relationship with Allergy and Immunology services, Ear Nose & Throat (ENT) Department (providing ready access to Speech Therapy services), and Gastroenterology (GI) Department (providing ready access to Upper GI physiology testing plus dedicated medical/surgical MDT meetings). Support is also provided by UHSFT Pathology, Radiology and Respiratory Physiology Departments. Patients attending the UHSFT Adult or Transitional Regional Asthma Clinics are assessed by a physician and referred onto further MDT members and investigations, with clinical decisions supported by a weekly post-clinic MDT and monthly Biologics Referral MDT. This facilitates the extensive characterisation of each patient, which in turn enables the clinic to meet the standards of care described by NHSE.

WATCH is a prospective observational study of patients with difficult asthma attending the Difficult Asthma Clinic at UHSFT. The study is planned as a long-term research vehicle with no limit to enrolment or any time defined end. The study design, protocol and paperwork have been approved by West Midlands – Solihull Research Ethics Committee (REC reference: 14/WM/1226). Patients are recruited into the study by way of a discrete “Enrolment” Study Visit capturing core demographic and clinical information and the results of the characterisation process provided by the clinic. For new to clinic patients, an additional 3 month follow up visit is also undertaken. Critically, the standard clinical assessment for the immediate needs of management and the additional assessments for research needs are collected in sequence, with combined support from Trust staff and research personnel of the NIHR BRC. Thereafter, their records are continuously updated through annual “Follow Up” Study Visits and extraction from their electronic clinical records using the combined hospital clinical record system and research data collection resources in the BRC. This pragmatic, opportunistic approach to data collection takes full advantage of the broad multidisciplinary clinical approach to difficult asthma management without becoming too onerous for the patient, clinician or researcher (Fig. 2). Patients can complete all of their case report forms (CRF) during their clinic appointments for their convenience, but are also given the opportunity to complete their longer enrolment visit on a separate day if more convenient.

This is a dual centre study (UHSFT and a satellite outreach clinic on the Isle of Wight) that started recruitment in August 2015. The Difficult Asthma Clinic at UHSFT is a formally commissioned Regional Centre for Severe Asthma, providing support for patients across the South Central England region. At the end of 2017, the clinic looked after 922 patients, of which 459 (49.8%) were “tertiary patients” referred from other local hospitals.

All patients attending the UHSFT Difficult Asthma Clinic (newly referred and under existing follow up) are approached for enrolment into the WATCH study. In the past 5 years, the clinic has seen an average of 182 new referrals per year, with tertiary referrals accounting for just under 50% of the workload. Based on new referral rates to the clinic, plus the high proportion of the clinic population who met inclusion criteria, an expected minimum study recruitment rate of 100 new patients per year was anticipated for the first 5 years of the study. At the end of 2017, 375 patients had been enrolled. Study enrolment will be continual into the future aligned to the ongoing function of the clinical service with no discrete recruitment target or endpoint.

Data for the WATCH study are captured both through CRFs completed opportunistically during outpatient appointments and/or discrete study visits, as well as, extraction from hospital electronic clinical record systems after enrolment.

The initial enrolment CRF contains a large suite of questions that mirrors the extensive characterisation undertaken in clinical practice (summarised in Tables 1 and 2; detailed in Additional file 1). This is completed after the patient has received and read a patient study information sheet, a clinical or research member of the WATCH study team has received consent from the participant, and they have been assigned a study number. A clinical or research member of the WATCH team will then proceed to interview the participant, asking the questions from the Enrolment CRF (detailed in Additional file 1) and then filling in various health and disease related questionnaires with the participant (Table 2).

Should the participant not have time to complete all questionnaires at the enrolment visit, then they are completed at the subsequent 3 month follow up (if applicable) or annual follow up visits. They are dated with the date they were completed.

In addition to the questionnaires, objective measures and biological samples (Table 3) are collected during the enrolment process, with the latter being processed by the BRC scientists and technical staff.

Finally, additional objective clinical data from the hospital electronic systems are harnessed to provide retrospective and current investigation findings (Table 4).

Where patients are enrolled into the study on their initial visit to the Difficult Asthma clinic, they are likely to have a number of clinically requested investigations and changes in therapy. These patients are therefore invited to complete a 3 month post-enrolment CRF to capture any clinical changes during this period. All patients (regardless of whether they are new to clinic or not) are invited to complete Annual CRFs (Additional file 2). Both the 3 month and annual CRFs are more concise than the enrolment CRF. The annual CRF is repeated every year throughout the period of clinical observation and study participation. These CRFs aim to capture an update of asthma and co-morbid disease related information and objective markers (Table 5). Questionnaires completed at enrolment and found to be scored outside ‘normal’ range are repeated at these assessments.

Electronic clinical records are reviewed for any new or repeat investigations since the last CRF. These results are then extracted into the study database. If there are any outstanding clinically requested blood tests or lung function tests then these can be performed as part of the study visit.

The WATCH database captures results from clinically requested and processed investigations. These are performed by hospital departments in line with Standard Operating Procedures (SOPs) that conform to standards required of an NHS Hospital Service. A more detailed description of these investigations and departmental standards are provided in Additional file 3: Appendix A

Height and weight are measured by the study team from which BMI is calculated. Additionally, a Medical Body Composition Analyser (SECA, Hamburg Germany) is used to analyse body composition of adults based on Bioelectrical Impedance Analysis (BIA).

Clinically requested lung function tests are performed by the UHSFT Respiratory Physiology Department or Specialist Asthma Nurses, who operate in accordance with local department SOPs and the Association of Respiratory Technology and Physiology (ARTP) guidelines. Some lung function tests are repeated by the BRC research staff at study visits using local SOPs in accordance with ERS/ATS guidelines [30]. A more detailed description of lung function methodology is provided in Additional file 3: Appendix B.

At enrolment blood and urine is stored for biobanking. If a patient requires sputum induction or bronchoscopy for clinical purposes, they are asked to consent to additional samples being taken for the WATCH biobank, supported by the BRC. A more detailed description of biobanking methodology is provided in Additional file 3: Appendix C.

The data model used for WATCH tries, where possible, to adopt a truly longitudinal approach. Change over time is treated explicitly. In this model patients can be enrolled at any time during their clinical journey, and equally may also exit (via clinical discharge, death, or being lost to follow up) at any time. Between those two dates (enrolment and exit or last visit), they are regarded as being ‘under observation’. Data recorded on the CRFs are entered into a bespoke WATCH study database housed by the Southampton BRC. Study status reports, follow up CRFs that highlight areas of missing information/data and discrete datasets can be readily generated. The data capture is categorised as an episode or snapshot. Each CRF, questionnaire or investigation is considered a snapshot. Medication, pregnancy or inpatient stays are considered episodes within the observed period. Where the start date of existing medication is ambiguous or continues past the period of observation, episodes are considered left censored or open-ended respectively. All investigations added to the database are marked by the date of investigation.

Analysis of the whole dataset will be both cross-sectional and longitudinal according to specific study questions. Specific datasets can be extracted from the database to investigate specific hypotheses.

This cohort can also be interrogated for inclusion criteria towards additional trials occurring in parallel to the WATCH study. Participation in clinical trials will not exclude patients from the cohort, but may omit patients from some analysis depending upon the research question.

The primary objective of the “parent” WATCH study is a cross-sectional characterisation of a cohort of difficult asthma patients with secondary objectives including further endotypic and longitudinal characterisation. Data from around the participants’ enrolment and of later follow up can be extracted from the database into discrete datasets to satisfy these aims. Statistical analysis will be performed primarily in IBM SPSS 25 (NY, USA). Categorical data will be presented as counts and percentages, with differences between groups tested by Pearson χ². Continuous data with Gaussian distributions will be presented as mean and standard deviation, whilst continuous data with skewed distributions will be presented as median and interquartile ranges. Differences between groups will be measured by t-test and Wilcoxon rank-sum test for Gaussian and skewed continuous data respectively. Where more unbiased assessment of phenotypes is undertaken, techniques such as cluster analysis and topological data analysis will be deployed.