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Bronchiectasis is a chronic respiratory condition with a wide spectrum of disease severity. There is a pressing need for randomised controlled trials in bronchiectasis to help guide management of this condition which is associated with increased morbidity and mortality. There is paucity of data in this respiratory condition but it is a rapidly progressive field. Most studies are conducted in more severe disease (colonised with Pseudomonas aeruginosa, 3 or more exacerbations/year, reduced lung function) as they experience more exacerbations which in turn reduces quality of life and increases mortality. However, the vicious cycle of bronchiectasis implies this is a progressive disease whereby infection leads to a destructive inflammatory response which destroys the mucociliary escalator which in turn leads to a build-up of stagnant mucus and further perpetuates the cycle by predisposing to further infection. Treatment strategies are being aimed at breaking different part of this vicious cycle and should aim to prevent exacerbations. A logical starting point for treatment could be in those with less severe disease and thereby hope to prevent progression to more severe disease. Yet, little is known about outpatient exacerbations which could be classed as less severe exacerbations of bronchiectasis. The aim of this thesis was to phenotype outpatient bronchiectasis exacerbations. In particular, the aim was to investigate the importance of bacterial load in these exacerbations to see whether they could have influence the diagnosis and management of outpatient exacerbations. There are few clinical endpoints in bronchiectasis that have been validated for use in bronchiectasis that could assess treatment response. Further endpoints are urgently needed to help assess randomised controlled trials which could investigate novel treatment options to guide evidence based management plans. This thesis also aimed to assess the incremental shuttle walk test, a marker of functional capacity, as a validated clinical endpoint for use in bronchiectasis. This thesis reported several clinical markers that could correlate with the Bronchiectasis Severity Index in a cohort of 207 patients with bronchiectasis. Sputum colour, 24 hr sputum volume, incremental shuttle walk test, parameters of lung function, quality of life assessments, serum inflammatory markers and sputum inflammatory markers all correlated with Bronchiectasis Severity Index tertiles of increasing disease severity. Further work is necessary in a larger cohort to assess whether these clinical endpoints could be additive to the BSI in predicting hospital admission and 30-day mortality rates. This thesis examined 94 exacerbations of bronchiectasis that were all managed as an outpatient with 14 days of oral antibiotics based on previous sputum microbiology results. All clinical parameters assessed (sputum colour, spontaneous sputum volume, 24-hour sputum volume, the Leicester Cough Questionnaire score, the St George's Respiratory Questionnaire score, FEV1 and FVC actual and predicted scores, serum inflammatory markers; white cell count, neutrophil count, erythrocyte sedimentation rate and C-reactive protein, sputum inflammatory markers myeloperoxidase and trends in neutrophil elastase) all deteriorated from baseline to start of exacerbation. Bacteriology was investigated and demonstrated an increase in culture positive sputum samples for pathogenic bacteria with a change in dominant pathogen in over 53% of samples. There was a 2-log increase in bacterial load CFU/ml from baseline to start of exacerbation overall but when sub-analysed, this was only present when the dominant pathogen changed, i.e. there was no increase in bacterial load if the dominant pathogen stayed the same. This is the first study to demonstrate a change in dominant pathogen leads to an increase in bacterial load. The clinical significance of a 1log or more rise in bacterial load was explored and found to be associated with increased severity markers of 10% or more decline in actual and predicted FEV1, 5% or more reduction in incremental shuttle walk test score, increase in 24hour sputum volume, increase in sputum inflammatory markers myeloperoxidase and neutrophil elastase, doubling of white cell count and 50% increase in neutrophil count at start of exacerbation. A rise of 1 or more log unit in bacterial count CFU/ml was also associated with a symptom complex of chest pain, increased sputum volume and the absence of headache. This symptom complex is more specific for a rise in bacterial load than either the British Thoracic Society or European consensus definition of an exacerbation. Lastly, this thesis assessed the incremental shuttle walk test as a validated clinical endpoint for use in patients with bronchiectasis. Its reliability, validity and responsiveness were demonstrated with no change in incremental shuttle walk test over 6 months of clinical stability, correlation with other validated endpoints (including the St George's Respiratory Questionnaire (SGRQ) total and activity score, the MRC dyspnoea score, the Bronchiectasis Severity Index score and physical activity duration and sedentary time recorded on activity monitors) and improvement with different antibiotic therapies for exacerbations and stable bronchiectasis with intravenous, oral and nebulised antibiotics. The minimum clinically important difference was found to a 5% improvement in walk distance as this took patient's variable baseline functional capacity into account as well as correlating well with patients who had a clinically important improvement in SGRQ score (4 or more unit improvement). This thesis provides interesting results which require further investigation to help manage patients with bronchiectasis in the outpatient setting. Larger randomised controlled trials are needed to assess the clinical importance of a rise in bacterial load and to differentiate at which threshold colonisation becomes infection and requires treatment. This could ultimately lead onto randomised controlled trials that manage exacerbations based on bacterial load and symptoms, such as is currently the case in treating urinary tract infections. Once a rise in bacterial load has been further clarified, it could also provide insight into the duration of antibiotics needed in a cohort of patients that rely heavily on antibiotic therapy and antibiotic stewardship in a climate where there is a finite amount of available treatment options. Further external validation of the incremental shuttle walk test would strengthen its recommendation for use in routine clinical practice and research studies to assess response to existing and new therapies. |
