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. 2023 Jul;78(7):643-652.
doi: 10.1136/thorax-2021-217032. Epub 2022 Aug 3.

Asthma exacerbations are associated with a decline in lung function: a longitudinal population-based study

Seyi Soremekun  1 , Liam G Heaney  2 , Derek Skinner  3   4 , Lakmini Bulathsinhala  3   4 , Victoria Carter  3   4 , Isha Chaudhry  3   4 , Naeimeh Hosseini  3   4 , Neva Eleangovan  3   4 , Ruth Murray  3   4 , Trung N Tran  5 , Benjamin Emmanuel  5 , Esther Garcia Gil  6 , Andrew Menzies-Gow  7 , Matthew Peters  8 , Njira Lugogo  9 , Rupert Jones  4   10 , David B Price  11   12   13
Affiliations

Asthma exacerbations are associated with a decline in lung function: a longitudinal population-based study

Seyi Soremekun et al. Thorax. 2023 Jul.

Abstract

Rationale: Progressive lung function (LF) decline in patients with asthma contributes to worse outcomes. Asthma exacerbations are thought to contribute to this decline; however, evidence is limited with mixed results.

Methods: This historical cohort study of a broad asthma patient population in the Optimum Patient Care Research Database, examined asthma patients with 3+eligible post-18th birthday peak expiratory flow rate (PEF) records (primary analysis) or records of forced expiratory flow in 1 s (FEV1) (sensitivity analysis). Adjusted linear growth models tested the association between mean annual exacerbation rate (AER) and LF trajectory.

Results: We studied 1 09 182 patients with follow-up ranging from 5 to 50 years, of which 75 280 had data for all variables included in the adjusted analyses. For each additional exacerbation, an estimated additional -1.34 L/min PEF per year (95% CI -1.23 to -1.50) were lost. Patients with AERs >2/year and aged 18-24 years at baseline lost an additional -5.95 L/min PEF/year (95% CI -8.63 to -3.28) compared with those with AER 0. These differences in the rate of LF decline between AER groups became progressively smaller as age at baseline increased. The results using FEV1 were consistent with the above.

Conclusion: To our knowledge, this study is the largest nationwide cohort of its kind and demonstrates that asthma exacerbations are associated with faster LF decline. This was more prominent in younger patients but was evident in older patients when it was related to lower starting LF, suggesting a persistent deteriorating phenotype that develops in adulthood over time. Earlier intervention with appropriate management in younger patients with asthma could be of value to prevent excessive LF decline.

Keywords: asthma.

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Conflict of interest statement

Competing interests: DS, VC and NE are employees of Optimum Patient Care, and SS, LB, IC and NH were employees of Optimum Patient Care. Optimum Patient Care is a co-funder of the International Severe Asthma Registry. LGH declares he has received grant funding, participated in advisory boards and given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim, Circassia, Hoffmann la Roche, GlaxoSmithKline, Novartis, and Teva; he has taken part in asthma clinical trials sponsored by Boehringer Ingelheim, Hoffmann la Roche, and GlaxoSmithKline for which his institution received remuneration; he is the Academic Lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma which involves industrial partnerships with a number of pharmaceutical companies including Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann la Roche, and Janssen. TNT and BE are employees of AstraZeneca, and EGG was an employee of AstraZeneca. AstraZeneca is a co-funder of the International Severe Asthma Registry. AM-G has attended advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi and Teva, and has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, Roche, Teva and Vectura. He has participated in research with AstraZeneca for which his institution has been remunerated and has attended international conferences with Teva. He has had consultancy agreements with AstraZeneca, Sanofi, and Vectura. MP declares personal fees and non-financial support from AstraZeneca and GlaxoSmithKline. NL consulted for AstraZeneca and GSK; served on protocol committee with AstraZeneca; and served on advisory board with AstraZeneca, GSK, Sanofi, Novartis, Genentech and Teva. RJ reports grants, personal fees, and non-financial support from AstraZeneca and OPRI, personal fees and non-financial support from Boehringer Ingelheim, grants, personal fees, and non-financial support from GSK, grants and non-financial support from Novartis, non-financial support from Nutricia, and personal fees from Pfizer outside the submitted work. DBP has advisory board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; funding for patient enrolment or completion of research from Novartis; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline.

Figures

Figure 1
Figure 1
Patient disposition. COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in one second; LF, lung function; PEF(R), peak expiratory flow rate; QoF, quality outcome framework-defined asthma diagnosis read codes. **≥2 separate prescriptions on ≥occasions during follow-up. ***Smoothing methods described in online supplement.
Figure 2
Figure 2
(A) Adjusted 20-year PEF trajectories (L/year) by annual exacerbation rate (AER; n=109 182). (B) Adjusted 20-year per cent-predicted PEF trajectories (%/year) by annual exacerbation rate (AER; n=109 182). Final models are adjusted for age at baseline, gender, fixed smoking status at baseline, time-varying smoking status during follow-up, BMI at baseline, length of follow-up, lung function at baseline and time-varying height. AER, annual exacerbation rate; BMI, body mass index; PEF, peak expiratory flow.
Figure 3
Figure 3
Adjusted 20-year PEF trajectories (L/year) by annual exacerbation rate (AER) stratified by patient age at baseline (18–24 years, n=16 482; 25–39 years, n=32 892;≥40 years, n=59 808). Final models are adjusted for age at baseline, gender, fixed smoking status at baseline, time-varying smoking status during follow-up, BMI at baseline, length of follow-up, lung function at baseline, and time-varying height. AER 0/year- no exacerbations, AER >0-1/yr - greater than 0 and up to 1 exacerbation per year, AER >1-2/yr - greater than 1 and up to 2 exacerbations per year, AER >2/yr - greater than 2 exacerbations per year. BMI, body mass index; PEF, peak expiratory flow rate.
Figure 4
Figure 4
20-year PEF trajectories (L/year) by annual exacerbation rate (AER) stratified by mean daily ICS dose (33.3% centiles); lowest dose: n=37 652; medium dose: n=37 770; highest dose: n=33 760). Final models are adjusted for age at baseline, gender, fixed smoking status at baseline, time-varying smoking status during follow-up, BMI at baseline, length of follow-up, lung function at baseline, and time-varying height. AER 0/year, no exacerbations; AER >0-1/yr, greater than 0 and up to 1 exacerbation per year; AER >1-2/yr, greater than 1 and up to 2 exacerbations per year; AER >2/yr, greater than 2 exacerbations per year; BMI, body mass index; PEF, peak expiratory flow.
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