Table 1 Overview of trials investigating the effect of a (multidisciplinary) systematic assessment in difficult-to-treat or severe asthma

Irwin et al. 1993 [15]

Prospective, observational

★★★

42

Adult patients with difficult asthma referred for systematic assessment in Massachusetts between January 5, 1982 to October 1, 1990

▪ Systematic assessment:

▪ Diagnostic confirmation

▪ Identify poor adherence

▪ Identify poor inhaler technique

▪ Address comorbidities and contributing factors (sinusitis, medication/food additive sensitivity, environment/work-related triggers, ABPA)

▪ Assessment of why asthma was difficult to control and identification of the most helpful therapeutic interventions

3.5 years follow-up:

▪ 74% were no longer DTC after systematic assessment

▪ Improvement more likely if GERD was a factor

▪ Non-adherence most likely reason for maintaining DTCA

Heaney et al. 2003 [16]

Prospective, observational

★★★

73

Adult patients with uncontrolled asthma

referred for systematic assessment in Belfast, Ireland

▪ Systematic assessment:

▪ Diagnostic confirmation

▪ Inflammatory phenotyping: blood tests; induced sputum analysis

▪ Comorbidity and contributory factor detection: medical history; psychological status; skin prick testing; assessment inhaler technique; psychiatric assessment; HR-CT thorax; pulmonary function tests; ENT examination and/or imaging; oesophageal pH monitoring

▪ Self-management plan

▪ Peak flow record and asthma diary

▪ Outcome measure(s): AQLQ

▪ 39 responded to intervention and 34 had TRA

▪ High and similar prevalence of comorbidities in both groups

12 months follow-up:

▪ Significant AQLQ improvement in therapy-responsive asthma (3.2 to 4.4), but not in TRA (3.3 to 3.6)

Gibeon et al. 2015 [17]

Prospective, observational

★★★

346

Adult patients with difficult-to-treat asthma referred to one of the 11 centers within the National Registry for UK Difficult Asthma Services between April 2009 and December 2010

▪ Systematic assessment:

▪ Diagnostic confirmation

▪ Inflammatory phenotyping: blood tests

▪ Comorbidity and contributory factor detection: e.g. medical history; pulmonary function tests; allergy assessment

▪ Outcome measure(s): ACQ, HCU, FEV1, (m)OCS

Median 286 days follow-up:

▪ Significant improvement in AQLQ and ACQ (3.6 to 3.0, 3.4 to 2.8)

▪ Significant reduction in HCU

▪ No difference in required mOCS, but reduced steroid dose and short-burst steroids

Van der Meer et al. 2016 [18]

Prospective, observational

★★★

40

Adult patients with uncontrolled asthma referred for systematic assessment in Leeuwarden, The Netherlands, between June 2013 and June 2014

▪ Systematic assessment:

▪ Diagnostic confirmation

▪ Inflammatory phenotyping: blood tests; induced sputum analysis; FeNO

▪ Comorbidity and contributory factor detection: medical history; psychological status; HR-CT thorax; pulmonary function tests; adherence and inhaler technique; ENT examination/imaging; 6MWD

▪ Outcome measure(s): ACQ, AQLQ, HCU, exacerbations

12 months follow-up:

▪ Significant improvement in ACQ and AQLQ (2.6 to 1.8 and 4.8 to 5.4)

▪ Significant reduction exacerbation frequency (≥ 2) and HCU

Tay et al. 2017 [19]

Prospective, observational

★★★

65

Adult patients with difficult asthma referred for systematic assessment in Melbourne, Australia, between June 2014 and March 2016

1.5% were on biologicals at baseline (anti-IL5)

▪ Systematic assessment:

▪ Diagnostic confirmation

▪ Inflammatory phenotyping

▪ Comorbidity and contributory factor detection: obesity; allergic rhinitis; CRS; gastroesophageal reflux; obstructive sleep apnoea; anxiety or depression; dysfunctional breathing and vocal cord dysfunction; history of potential aggravating factors (e.g. environmental exposure); poor medication adherence and inhaler technique

▪ 15 patients used a smartinhaler measuring adherence

▪ Outcome measure(s): ACT, AQLQ, exacerbations

▪ Median of 3 comorbidities, and 3 comorbidity interventions

6 months follow-up:

▪ Overall improvements in ACT and AQLQ (14 to 16 and 4.3 to 4.7)

▪ Significant reduction exacerbation frequency (2 to 0)

▪ Median medication adherence rate measured with Smartinhaler (n = 15): 87%

Denton et al. 2019 [20]

Prospective, observational

★★★

161

Adult patients with difficult asthma referred for systematic assessment in Melbourne, Australia, between June 1, 2014, and December 31, 2017

6.0% were on biologicals at baseline, and 7.0% commenced treatment during the assessment period

▪ Systematic assessment:

▪ Diagnostic confirmation

▪ Inflammatory phenotyping

▪ Identify poor adherence (41% with electronic adherence monitor)

▪ Identify poor inhaler technique

▪ Comorbidity and contributory factor detection: adherence and inhaler technique; allergic rhinitis; CRS; OSA; GERD; dysfunctional breathing; VCD; psychiatric history

▪ Outcome measure(s): ACT, AQLQ, FEV1, mOCS, exacerbations

6 months follow-up:

▪ 87% improved in at least 1 domain

▪ 64% had a reduction in exacerbations, 54% achieved MID for ACQ and AQLQ, and 40% increased FEV1 ≥ 100 mL

▪ mOCS burden halved, comparable to results achieved with monoclonal biologicals

McDonald et al. 2020 [21]

Randomized, open-label, cross-sectional

★★★

55

Adult patients with severe asthma treated at a severe asthma clinic in Newcastle, Australia

▪ Intervention: 16-week treatment program with comprehensive multidimensional assessment across pulmonary, extrapulmonary, and behavioural/lifestyle domains, followed by targeted treatment

▪ Usual care: Treatment according to best available evidence by the pulmonologist

▪ Outcome measure(s): ACQ, AQLQ

▪ Mean of 10.44 traits per person: 3.01 pulmonary traits, 4.85 extrapulmonary traits, 2.58 behavioural/lifestyle traits

4 months follow-up:

▪ Individualised treatment targeting traits was feasible and significantly improved AQLQ (0.86 units) and ACQ (0.73 units)

Lin et al. 2023 [22]

Prospective, observational

★★★

241

Adult patients with difficult asthma referred for systematic assessment in Melbourne, Australia, between June 2014 and April 2022

7.5% were on biologicals at baseline

▪ Systematic assessment:

▪ Diagnostic confirmation

▪ Inflammatory phenotyping

▪ Comorbidity and contributory factor detection: obesity; allergic rhinitis; CRS; gastroesophageal reflux; obstructive sleep apnea; anxiety or depression; dysfunctional breathing and vocal cord dysfunction; history of potential aggravating factors (e.g. environmental exposure); poor medication adherence and inhaler technique

▪ Latent class analysis performed using 12 traits

▪ Outcome measure(s): ACT, AQLQ, FEV1, mOCS, exacerbations

▪ Worse baseline ACQ and AQLQ in non-airway-centric profiles

6 month follow-up:

▪ Overall improvements across all outcomes: ACQ (0.5 units), AQLQ (0.6 units), FEV1 (3.8%), mOCS dose (3.3 mg), exacerbation frequency (1.4 exacerbations)

▪ Airway-centric (early-onset with allergic rhinitis or adult onset with eosinophilia/CRS): more FEV1 improvement (trend)

▪ Non-airway-centric (comorbid, psychosocial or multi-domain): greater reduction in exacerbations