Strategies to delay progression of alpha-1 antitrypsin deficiency related lung disease

Ellis, Paul Robert (2022). Strategies to delay progression of alpha-1 antitrypsin deficiency related lung disease. University of Birmingham. Ph.D.

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Alpha-1 antitrypsin deficiency (AATD) is a major risk factor for chronic obstructive pulmonary disease (COPD) and specifically development of pulmonary emphysema at an accelerated rate.

The strong emphysema phenotype associated with AATD related lung disease would suggest that interventions which reduce emphysema decline are logical approaches. Such therapies are much needed with a paucity of new treatments in the last three decades. This thesis explores interventions that target two models of emphysema progression; 1) accelerated lung destruction from pulmonary exacerbations and 2) overall basal elastin degradation rate.

As with usual COPD, individuals with AATD often suffer with periodic worsening of symptoms known as exacerbations. Exacerbations contribute to reduced quality of life (QOL) for individual patients and are a significant financial and resource burden. They also accelerate emphysema decline. Most exacerbations present with a combination of breathlessness, increased sputum production and increased sputum purulence but it is not understood which exacerbation phenotypes lead to lung damage. Symptoms alone are unlikely to make this distinction.

The discovery of a specific biomarker that detects the start and recovery from an exacerbation, in combination with symptoms, would not only guide management options but identify pathophysiological pathways with potential discovery of novel drug targets. The first intervention involves the use of both detailed symptom monitoring and point of care (POC) biomarker tracking for the early detection and treatment of exacerbations. These interventions were assessed via the ‘Elastin degradation in exacerbations of AATD related lung disease’ study, an 18-month prospective cohort of 55 AATD patients with frequent exacerbations. The hypothesis was that prompt and appropriate treatment of exacerbations could limit their destructive effects and therefore slow emphysema progression. Since an enhanced monitoring approach is fairly novel, the main aim of this study was to assess feasibility and efficacy of an electronic symptom diary (eDiary) and POC urine lateral flow immune assay alongside identification of a suitable urinary biomarker. Promising results would then prompt assessment of whether emphysema progression is improved with such interventions.

Results showed that the use of an eDiary was feasible and was able to predict exacerbations, though not accurately enough to be used alone. The addition of urinary biomarkers was unable to improve the predictive algorithm. There were mean changes in CRP and TIMP1 across the time course of an exacerbation. The pilot data from the urine device has pioneered alterations to its design to improve its accuracy and reliability.

The second model of emphysema progression, basal elastin degradation rate, already has an established therapy. Alpha-1 antitrypsin (AAT) augmentation therapy has been shown to slow the rate of decline in CT lung density and is currently the only approved disease modifying therapy for AATD patients. The effect of augmentation therapy on more conventional outcomes such as mortality and QOL have not yet been established which has delayed approval of augmentation therapy in the UK.

This thesis explored the efficacy of AAT augmentation therapy via a large prospective study comparing two separate cohorts of AATD patients; one receiving AAT augmentation therapy and one standard COPD care alone. This was designed to investigate conventional outcomes that have not been addressed through randomised controlled trials. Results showed that the mortality benefit of AAT augmentation therapy remains uncertain, though there appears to be a reduction in rate of decline in QOL in the augmentation group compared to control. The cost effectiveness of augmentation therapy is also discussed.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Licence: All rights reserved
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Applied Health Research
Funders: Other
Other Funders: Alpha-1 Foundation
Subjects: R Medicine > R Medicine (General)


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