[Show abstract][Hide abstract] ABSTRACT: Chronic Obstructive Pulmonary Disease (COPD) is a progressive airway disease characterised by neutrophilic airway inflammation or bronchitis. Neutrophilic bronchitis is associated with both bacterial colonisation and lung function decline and is common in exacerbations of COPD. Despite current available therapies to control inflammation, neutrophilic bronchitis remains common. This study tested the hypothesis that azithromycin treatment, as an add-on to standard medication, would significantly reduce airway neutrophil and neutrophils chemokine (CXCL8) levels, as well as bacterial load. We conducted a randomised, double-blind, placebo-controlled study in COPD participants with stable neutrophilic bronchitis.
PLoS ONE 08/2014; 9(8):e105609. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypoxic pulmonary vasoconstriction (HPV) is an adaptive response unique to the lung whereby blood flow is diverted away from areas of low alveolar oxygen to improve ventilation-perfusion matching and resultant gas exchange. Some previous experimental studies have suggested that the HPV response to hypoxia is blunted in acute pulmonary embolism (APE), while others have concluded that HPV contributes to elevated pulmonary blood pressures in APE. To understand these contradictory observations, we have used a structure-based computational model of integrated lung function in 10 subjects to study the impact of HPV on pulmonary hemodynamics and gas exchange in the presence of regional arterial occlusion. The integrated model includes an experimentally-derived model for HPV. Its function is validated against measurements of pulmonary vascular resistance in normal subjects at four levels of inspired oxygen. Our results show that the apparently disparate observations of previous studies can be explained within a single model: the model predicts that HPV increases mean pulmonary artery pressure in APE (by 8.2 ± 7.0% in these subjects), and concurrently shows a reduction in response to hypoxia in the subjects who have high levels of occlusion and therefore maximal HPV in normoxia.
Annals of Biomedical Engineering 04/2014; · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clot load scores have previously been developed with the goal of improving prognosis in acute pulmonary embolism (PE). These scores provide a simple estimate of pulmonary vascular bed obstruction, however they have not been adopted clinically as they have poor correlation with mortality and right ventricular (RV) dysfunction. This study performed a quantitative analysis of blood flow and gas exchange in 12 patient-specific models of PE, to understand the limitations of current clot load scores and how their prognostic value could be improved. Prediction of hypoxemia in the models when using estimated baseline (non-occluded) minute ventilation and cardiac output correlated closely with clinical metrics for RV dysfunction, whereas the clot load score had only a weak correlation. The model predicts that large central clots have a greater impact on function than smaller distributed clots with the same total clot load, and that the partial occlusion of a vessel only has a significant impact on pulmonary function when the vessel is close to completely occluded. The effect of clot distribution on the redistribution of blood from its normal pattern - and hence the magnitude of the potential effect on gas exchange-is represented in the model but is not included in current clot load scores. Improved scoring systems need to account for the expected normal distribution of blood in the lung, and the impact of clot on redistributing the blood flow.
[Show abstract][Hide abstract] ABSTRACT: Abstract Background: COPD is often regarded as a smoker's disease. In fact, up to 50% of COPD could be attributable to other causes. Relatively little is known about COPD among nonsmokers, and this group is usually excluded from studies of COPD. Methods: In this cross-sectional case-comparison study, smokers and nonsmokers aged over 45 with COPD (post-bronchodilator FEV1 ≤ 70% predicted, FEV1/FVC ratio < 0.7) were recruited from specialist outpatient clinics and from primary care. Subjects completed a questionnaire and interview, and underwent spirometry, venesection, exhaled nitric oxide (ENO) measurement, allergen skinprick testing, formal lung function testing and high resolution CT. Results: 48 nonsmokers and 45 smokers participated. Asthma was nearly universal among nonsmokers and was the commonest identifiable cause of COPD in that group. Nonsmokers also exhibited a high prevalence of objective eosinophilic inflammation (raised ENO and eosinophil counts, positive skinprick tests). Smokers had more severe airflow obstruction, but respiratory symptom prevalences were similar between groups. Nonsmokers reported greater lifetime burdens of respiratory disease. Nonsmokers' HRCT results showed functional small airways disease, with no significant emphysema in any subject. Previously undiagnosed bronchiectasis was common in both groups (31% and 42%). Conclusions: Asthma is a very common cause of COPD among nonsmokers. Radiological bronchiectasis is common in COPD; the clinical significance of this finding is unclear.
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT BACKGROUND: Inhaled dry powder mannitol (DPM) enhanced mucus clearance and improved quality of life over two weeks in non-cystic fibrosis bronchiectasis. This study's objective was to investigate efficacy and safety of DPM over 12 weeks. METHODS: Subjects with bronchiectasis, confirmed by high resolution computer tomography (HRCT), aged 15-80 years, with FEV1 ≥ 50% predicted and ≥ 1L, participated in a randomised, placebo-controlled, double-blind study. Subjects with a negative mannitol provocation test were randomised to inhale 320mg mannitol (n=231) or placebo (n=112) twice daily for 12 weeks. To further assess safety, the same mannitol dose/frequency was administered to a patient subset in an open-label extension (OLE) over 52 weeks. Primary endpoints: changes at 12 weeks from baseline in 24-hour sputum weight and St George's Respiratory Questionnaire (SGRQ) score. RESULTS: There was a significant difference between mannitol and placebo in terms of change in sputum weight over 12 weeks 4.3g (95% CI: 1.64, 7.00; p=0.002) however this was largely driven by a decrease in sputum weight in the placebo group. This was in turn associated with more antibiotic use in the placebo group (50/112 (45%) vs. inhaled mannitol 85/231 (37%)).There was no statistical difference between the groups (p = 0.304) for total SGRQ score (Mannitol -3.4 points (95% CI: -4.81, -1.94) versus placebo -2.1 points (95% CI: -4.12,-0.09)). In a subgroup study (n=82) Mannitol subjects showed less small airway mucus plugging on HRCT at 12 weeks compared to placebo (p=0.048). Compliance rates were high and mannitol was well tolerated with similar adverse events to placebo. CONCLUSION: As the difference in sputum weights appears to be associated with increased antibiotic use in the placebo group, a larger controlled study is now required to investigate the long-term mannitol effect on pulmonary exacerbations and antibiotic use.ClinicalTrials.gov Number NCT0027753.
[Show abstract][Hide abstract] ABSTRACT: Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulatory properties. We tested the hypothesis that azithromycin would decrease the frequency of exacerbations, increase lung function, and improve health-related quality of life in patients with non-cystic fibrosis bronchiectasis.
We undertook a randomised, double-blind, placebo-controlled trial at three centres in New Zealand. Between Feb 12, 2008, and Oct 15, 2009, we enrolled patients who were 18 years or older, had had at least one pulmonary exacerbation requiring antibiotic treatment in the past year, and had a diagnosis of bronchiectasis defined by high-resolution CT scan. We randomly assigned patients to receive 500 mg azithromycin or placebo three times a week for 6 months in a 1:1 ratio, with a permuted block size of six and sequential assignment stratified by centre. Participants, research assistants, and investigators were masked to treatment allocation. The coprimary endpoints were rate of event-based exacerbations in the 6-month treatment period, change in forced expiratory volume in 1 s (FEV(1)) before bronchodilation, and change in total score on St George's respiratory questionnaire (SGRQ). Analyses were by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000641493.
71 patients were in the azithromycin group and 70 in the placebo group. The rate of event-based exacerbations was 0·59 per patient in the azithromycin group and 1·57 per patient in the placebo group in the 6-month treatment period (rate ratio 0·38, 95% CI 0·26-0·54; p<0·0001). Prebronchodilator FEV(1) did not change from baseline in the azithromycin group and decreased by 0·04 L in the placebo group, but the difference was not significant (0·04 L, 95% CI -0·03 to 0·12; p=0·251). Additionally, change in SGRQ total score did not differ between the azithromycin (-5·17 units) and placebo groups (-1·92 units; difference -3·25, 95% CI -7·21 to 0·72; p=0·108).
Azithromycin is a new option for prevention of exacerbations in patients with non-cystic fibrosis bronchiectasis with a history of at least one exacerbation in the past year.
Health Research Council of New Zealand and Auckland District Health Board Charitable Trust.
The Lancet 08/2012; 380(9842):660-7. · 39.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute thromboembolic pulmonary embolism (PE) is a life threatening condition that can lead to pulmonary hypertension and right ventricular dysfunction or failure. There is typically an increase in ventilation rate and cardiac output as a response to PE prior to cardiac failure, which is at least in part due to systemic hypoxemia. Here we assess the response of the lungs to changes in these parameters using anatomically-based computational models of pulmonary perfusion, ventilation and gas exchange. We show that increases in ventilation and cardiac output improve overall gas exchange in PE. However, this comes at the cost of an increased pulmonary blood pressure, which may contribute to pulmonary hypertension as a result of PE.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 08/2012; 2012:6657-60.
[Show abstract][Hide abstract] ABSTRACT: Pulmonary disease is a well recognised and important extra-articular manifestation of rheumatoid arthritis (RA). The objective of this study was to determine the prevalence of airway and parenchymal abnormalities in newly diagnosed patients with RA and to correlate these with clinical measures of RA severity and laboratory tests.
60 patients with a new (symptom duration <12 months) diagnosis of RA (43 females, 42 European, mean age 54, 33 ever smoker, (17 current) underwent lung function testing and high resolution computed tomography (HRCT) scored by two independent radiologists.
Eighteen (30%) patients reported respiratory symptoms: dyspnoea (11), cough (11), and wheeze (8). Twelve (20%) patients had physiologic evidence of airflow obstruction and 24 (40%) had reduced gas transfer. The prevalence of HRCT abnormalities (in any lobe) was as follows: decreased attenuation 67%, bronchiectasis 35%, bronchial wall thickening 50%, ground glass opacification 18%, reticular changes 12%. All abnormalities were more common in the lower lobes. With the exception of reduced DLCO, there were no significant differences in the prevalence of HRCT patterns or lung function parameters between smokers and non smokers. Anti-CCP antibodies and rheumatoid factor (RF) correlated strongly with DLCO and variably with other physiologic measures but poorly with radiologic abnormalities.
Patients with newly diagnosed RA have a moderate prevalence of airway and parenchymal abnormalities on HRCT and lower than predicted lung function parameters which cannot entirely be explained by smoking. These data suggest that pulmonary involvement is present early in the disease course in RA.
Respiratory medicine 07/2012; 106(10):1441-6. · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vertebral fractures are the most common osteoporotic fracture and predict subsequent fracture and mortality. We undertook an audit (Auckland City Hospital, Auckland, New Zealand) to determine whether targeted assessment for incidental vertebral fractures on computed tomography (CT) examinations of the chest or abdomen in older people would detect previously unidentified vertebral fractures. In 175 consecutive patients aged >65 years, sagittal images of the spine were obtained by reformatting data from CT examinations of the chest or abdomen. Vertebral fractures were assessed using a semi-quantitative technique. The prevalence of vertebral fractures was 13%, with 41 vertebral fractures identified in 22 patients; 12/22 (55%) had vertebral fracture mentioned in the formal CT report, and 2/12 patients with contemporaneous plain films had vertebral fracture mentioned in the X-ray report. The vertebral fracture was newly identified in 17 (77%) patients, but vertebral fracture and osteoporosis were each listed in the relevant discharge summary or clinic letter for only 14% of patients, and only 31% of patients with fracture subsequently received osteoporosis treatment. In summary, assessing sagittal spine images reformatted from CT examinations of the chest or abdomen detects previously unidentified vertebral fractures, offering an undervalued opportunity to assess fracture risk and intervene with treatments that prevent fractures and reduce mortality.
The New Zealand medical journal 02/2012; 125(1350):45-50.
[Show abstract][Hide abstract] ABSTRACT: Obstructive airflow limitation is the most common physiological impairment in sarcoidosis. This study determined the prevalence of airway hyperresponsiveness (AHR) in sarcoidosis, the correlation between responses to direct (using histamine) and indirect (using hypertonic saline) bronchial challenge, and the clinical, physiological and radiological predictors of AHR.
Subjects with sarcoidosis and a baseline forced expiratory volume in 1 s (FEV(1)) >35% predicted underwent hypertonic and histamine challenge, lung function testing and high resolution computed tomography (HRCT) of the chest. AHR was defined as a 15% fall in FEV(1) to hypertonic saline and a 20% fall in FEV(1) to histamine.
The 52 subjects had well-preserved lung function (FEV(1) = 2.8 ± 0.7 L, 87% predicted). AHR was detected in 5/47 (11%) to hypertonic saline and 19/43 (44%) to histamine challenge. On univariate analysis, response to histamine challenge was predicted by conglomerate fibrosis (P = 0.02) and reticular pattern (P = 0.03) on HRCT. The baseline % predicted forced expiratory volume in 1 s was significantly inversely associated with AHR on univariate (P = 0.004) and multivariate analysis (P = 0.01) when adjusted by HRCT patterns.
The higher prevalence of AHR using histamine challenge than hypertonic saline challenge and the association with baseline % predicted FEV(1) suggest that the AHR in sarcoidosis may reflect the consequences of airway remodelling following inflammation.
[Show abstract][Hide abstract] ABSTRACT: The six-minute walk test (6MWT) is a validated field test in the assessment of interstitial lung disease but may not be so useful in scleroderma (SSc) lung disease. The aim of this study was to determine the reliability of the 6MWT in patients with SSc and correlate results with morphological and functional measures of disease severity.
Thirty patients (24 female, mean age 47, mean diffusing capacity of carbon monoxide 65%, vital capacity 77% predicted) with American College of Rheumatology classification of SSc performed two 6MWT using various oximetry sites, 1 week apart, and underwent SSc-specific disease severity and quality-of-life measurements, lung function, high-resolution computed tomography and echocardiography.
There was good reliability between the two 6MWT (distance; intraclass correlation coefficient 0.95, r = 0.89, Borg; intraclass correlation coefficient 0.85, r = 0.91, both P < 0.00 for r), and Bland Altman plots demonstrate good agreement between measures 1 week apart. Forehead and finger oximetry were more reliable than earlobe (intraclass correlation coefficient 0.64, 0.60, 0.24; r = 0.46, 0.47, 0.14; n = 22, 17, 7, respectively). Forehead desaturation correlated with forced expiratory volume in 1 s (r = 0.55, P = 0.01) and forced vital capacity (r = 0.59, P = 0.01). Distance correlated with all physiological measures: forced expiratory volume in 1 s (r = 0.55, P = 0.01), forced vital capacity (r = 0.61, P = 0.01) and diffusing capacity of carbon monoxide (r = 0.42, P = 0.05). Computed tomography extent and patterns of disease correlated poorly with 6MWT measures, and global measures of SSc correlated only with post-test Borg score.
The 6MWT is feasible and reliable in SSc lung disease, but forehead oximetry should be used. The test measurements correlate reasonably but variably with functional and morphological measures of disease severity.
[Show abstract][Hide abstract] ABSTRACT: The most common cause of acute pulmonary hypertension is pulmonary embolism (PE). Classification of PE severity can be based on obstruction indices that are estimated from clinical imaging, however, as patients with apparently similar levels of obstruction can have quite different clinical outcomes, obstruction indices currently have limited use clinically. Embolus size and location affects patient response, as well as the existance of prior pulmonary disease, but neither of these factors is accounted for in current obstruction indices. To fully assess the importance of embolus size and location, patient-specific models of the functional response to PE must be matched to individual clinical outcomes. Here we describe the use of patient-specific imaging-based models of PE to provide insight into the mechanisms that are important in determining PE severity, and to correlate pathology with (dys)function.
[Show abstract][Hide abstract] ABSTRACT: Pulmonary embolism (PE) is the most common cause of acute pulmonary hypertension, yet it is commonly undiagnosed, with risk of death if not recognized promptly and managed accordingly. Patients typically present with hypoxemia and hypomania, although the presentation varies greatly, being confounded by co-morbidities such as pre-existing cardio-respiratory disease. Previous studies have demonstrated variable patient outcomes in spite of similar extent and distribution of pulmonary vascular occlusion, but the path physiological determinants of outcome remain unclear. Computational models enable exact control over many of the compounding factors leading to functional outcomes and therefore provide a useful tool to understand and assess these mechanisms. We review the current state of pulmonary blood flow models. We present a pilot study within 10 patients presenting with acute PE, where patient-derived vascular occlusions are imposed onto an existing model of the pulmonary circulation enabling predictions of resultant haemodynamic after embolus occlusion. Results show that mechanical obstruction alone is not sufficient to cause pulmonary arterial hypertension, even when up to 65 per cent of lung tissue is occluded. Blood flow is found to preferentially redistribute to the gravitationally non-dependent regions. The presence of an additional downstream occlusion is found to significantly increase pressures.
Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences 11/2011; 369(1954):4255-77. · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pulmonary hypertension is an increasingly recognised complication of sarcoidosis that arises from a variety of physiological mechanisms, including pulmonary fibrosis, granulomatous vasculitis, and circulating vasoactive mediators. We present the case of a young man with sarcoidosis complicated by fatal pulmonary hypertension due to extrinsic compression of the major pulmonary vessels by mediastinal granulomatous inflammation and lymphadenopathy.