Author Identifier

Sanjay Ramakrishnan: http://orcid.org/0000-0002-3003-7918

Date of Award

2025

Document Type

Thesis

Publisher

Edith Cowan University

Degree Name

Doctor of Philosophy

School

School of Medical and Health Sciences

First Supervisor

Robert Newton

Second Supervisor

Carolyn McIntyre

Abstract

Background: Background Chronic Obstructive Pulmonary Disease (COPD) is a common chronic condition causing significant morbidity and mortality. Patients with COPD report sudden episodes of deteriorating respiratory symptoms called exacerbations, often presumed to be precipitated by infections. COPD is in the top 5 causes of death globally. COPD exacerbations drive a large proportion of these deaths. Despite this, there is no standardised model of care for the sickest patients who need hospitalisations for exacerbations. Meanwhile, treatment for COPD exacerbations continues to be guided by symptoms, instead of underlying biology. Most patients are treated with unnecessary and harmful systemic corticosteroids. During the COVID-19 pandemic, patients with COPD were found to be underrepresented in patients requiring hospitalisation for severe COVID-19. Among other explanations, the use of inhaled corticosteroids in this population has been hypothesised for this apparent reduction in risk.

Purpose: The objectives of this research were to:

  1. obtain a detailed European expert consensus on the assessment, investigation, management and follow up of patients hospitalised with an exacerbation of COPD;
  2. investigate the use of a point of care blood eosinophil count to determine the patients that need systemic corticosteroids in primary care treated COPD exacerbations; and
  3. investigate the use of inhaled budesonide to reduce the risk of clinical deterioration and subsequent hospitalisation in patients with early COVID-19.

Methods: Three studies were conducted: one Delphi survey of European COPD experts, a multi-centre double blind randomised controlled trial of patients presenting to primary care with COPD exacerbations, and an open label community trial of patients with early COVID-19.

For the Delphi study, 25 experts from 18 countries participated in a three round online Delphi survey. Experts were asked their opinion on over 700 individual components of clinical assessment, management and follow up of patients hospitalised for acute hospitalised exacerbation of COPD. Importance and feasibility of every item were assessed. Consensus and stability thresholds for opinions were pre-determined prior to survey commencement.

In the STARR2 clinical trial, 14 primary care practices in the UK randomised 144 exacerbations from 93 patients to blood eosinophil biomarker guided directed care or standard care. Patients who were allocated to the biomarker guided arm received 14 days of systemic corticosteroids if their blood eosinophil count was ≥2% of total white cell count on a point of care test. If they had a blood eosinophil count which was less than 2%, they received matching placebo. All patients in the standard care arm received 14 days of systemic corticosteroids regardless of blood eosinophil count. All allocation and treatments were delivered in a double-blind manner. The primary outcome was the need for any additional treatment to treat a COPD exacerbation at 30 days. STARR2 also assessed symptoms, lung function and quality of life recovery between groups.

In the STOIC clinical trial, 146 patients with symptoms suggestive of COVID-19 within 7 days of symptom onset were recruited. Patients were randomly allocated to receive inhaled budesonide 800 micrograms twice a day until symptoms resolved, or usual care. The primary endpoint was COVID-19-related urgent care visit, including emergency department assessment or hospitalisation. The secondary outcomes were self-reported clinical recovery, viral symptoms questionnaires, body temperature, blood oxygen saturation and SARS-CoV-2 viral load.

Results: In the Delphi study, experts agreed that a detailed history and examination were needed. Experts also agreed on which treatments are needed and how soon these should be delivered. Experts recommended that a full blood count, renal function, C-reactive protein, and cardiac blood biomarkers should be measured within 4 hours of admission and that the modified Medical Research Council dyspnoea scale and COPD Assessment Test should be performed at time of exacerbation and follow up. Experts encouraged COPD clinicians to strongly consider discussing palliative care, if indicated, at time of hospitalisation.

In the STARR2 trial, 144 exacerbations were included in the modified intention to treat analysis. There were 14 (19%) treatment failures in the biomarker guided treatment and 23 (32%) in the usual care arm. The analysis comparing biomarker guided care against standard care showed a large non-significant estimated effect (RR 0.60, 95% CI 0.33 to 1.04, p=0.070) in reducing treatment failures after a COPD exacerbation. The non-inferiority analysis confirmed that BET was non-inferior to ST. Frequency of adverse events were similar between the study arms.

In the STOIC trial, 146 participants were randomly assigned to usual care or inhaled budesonide. In the intention to treat population, the primary outcome occurred in 11 (15%) participants in the usual care group and two (3%) participants in the budesonide group (difference in proportions 0·123, 95% CI 0·033 to 0·213; p=0·009). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was eight. Clinical recovery was 1 day shorter in the budesonide group compared with the usual care group (median 7 days [95% CI 6 to 9] in the budesonide group vs 8 days [7 to 11] in the usual care group; log-rank test p=0·007).

Conclusions: COPD exacerbation care has not changed in over 30 years. All exacerbations are treated equally with little focus on the biological cause of the exacerbation. The Delphi study shows that there is a great deal of agreement among respiratory physicians on how patients should be assessed, cared for and followed up when they are hospitalised for a COPD exacerbation. The STARR2 study showed that blood eosinophil count assessment was safe and effective for identifying patients who needed systemic steroids for the treatment of COPD exacerbations treated in primary care. The time for change in COPD care has arrived. Early COVID-19 shares many similarities with COPD exacerbations. The use of inhaled budesonide in patients with early COVID-19 reduced the risk of clinical progression and improved symptom recovery. Early, accurate and standardised care is needed for patients with COPD exacerbations and COVID-19.

DOI

10.25958/9ggb-7311

Download

Included in

COVID-19 Commons

Share

 
COinS