Multi-site placebo-controlled randomised clinical trial to assess protection following oral immunisation with inactivated non-typeable Haemophilus influenzae in chronic obstructive pulmonary disease.

BACKGROUND: Previous studies identified factors that modify response to an oral non-typeable Haemophilus influenzae (NTHi) vaccine in chronic obstructive pulmonary disease (COPD): severe COPD, moderate-severe exacerbations as end-point and a threshold prevalence of NTHi in the study population. More data are needed to confirm parameters that influence clinical outcomes. AIMS: The primary aim was to determine the efficacy of an oral NTHi vaccine (HI-164OV) in reducing the rate of exacerbations requiring systemic corticosteroids or hospitalisation in COPD. Secondary aims included effect on the proportion of patients experiencing such exacerbations, severity of infections and quality of life (St George Respiratory Questionnaire for COPD patients (SGRQ-C)). METHODS: This multi-centre, double-blind, placebo-controlled study was conducted at 21 Australian sites for 9 months in 2011. RESULTS: Three-hundred and twenty subjects with COPD, FEV1 <60% predicted and ≥1 moderate-severe exacerbations in the previous 12 months were recruited. The primary and secondary end-points for the intention-to-treat population aged 40-88 years were not achieved, and only 5% of subjects had an H. influenzae-positive sputum sample. Subsequent exploratory analysis of patients <65 years (91 subjects) indicated protection with respect to the primary and most of the secondary end-points, with SGRQ-C symptom scores lower at 3 and 6 months. CONCLUSION: Patients aged 40-88 years with moderate to severe COPD and low rates of H. influenzae-positive sputum were not protected against exacerbations by HI-1640V. Further studies are needed to confirm protection in subjects aged <65 years. Older age and low colonisation rates appear to affect adversely response to this vaccine.

Beta-blockers are under-prescribed in patients with chronic obstructive pulmonary disease and co-morbid cardiac disease.

The use of beta-blockers in patients with chronic obstructive pulmonary disease and co-morbid cardiovascular disease is controversial, despite increasing evidence to support their use as safe and efficacious. This study retrospectively assessed the rates of beta-blocker prescription in patients admitted to two Australian tertiary hospitals for acute exacerbation of chronic obstructive pulmonary disease. This revealed that less than half of patients (45%) with known cardiac indications were receiving beta-blocker therapy, evident across all degrees of airways disease severity. Further work is needed to ensure that medical management of this patient group is optimised.

Suboptimal management of unfractionated heparin compared with low-molecular-weight heparin in the management of pulmonary embolism.

BACKGROUND: Both low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) have been shown to be equivalent in efficacy and safety profiles for the management of pulmonary embolism (PE). AIMS: To assess the real world management of anticoagulation in PE in a tertiary hospital setting. METHODS: An audit of patients with a new diagnosis of PE from March 2011 to March 2012. Data collected included patient demographics, anticoagulant, complication, mortality, time to first administration, frequency of monitoring and dose adjustment for UFH, time to therapeutic range for UFH (based on activated partial thromboplastin time) and length of hospital stay. RESULTS: Of the 211 patients who were included, 139 were admitted through the Emergency Department, and 45 were managed with UFH. There was no significant difference in time to initial dose between those treated with LMWH and UFH (192 vs 98 min, P = 0.16). For UFH, average time to therapeutic range was 594 min (range 87­2257 min). During the course of UFH therapy, only 22% of activated partial thromboplastin time was within therapeutic range, while 44% was above and 33% was below therapeutic range. Average number of UFH dose adjustment was 5. Increasing weight and higher baseline fibrinogen levels significantly delayed time to therapeutic range for patients on UFH (P = 0.02 and 0.04 respectively). Up to 18 months following PE, overall mortality rate was 28%, with no significant difference between LMWH and UFH (28% vs 29%). CONCLUSION: PE was predominantly managed with LMWH. UFH was suboptimally managed when used, although there was no impact on mortality rate.

Advances in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation in the presence of identifiable risk factors. Inflammation is the central pathological feature in the pathogenesis of COPD. In addition to its pulmonary effects, COPD is associated with significant extrapulmonary manifestations, including ischaemic heart disease, osteoporosis, stroke and diabetes. Anxiety and depression are also common. Spirometry remains the gold standard diagnostic tool. Pharmacologic and non-pharmacologic therapy can improve symptoms, quality of life and exercise capacity and, through their effects on reducing exacerbations, have the potential to modify disease progression. Bronchodilators are the mainstay of pharmacotherapy, with guidelines recommending a stepwise escalating approach. Smoking cessation is paramount in managing COPD, with promotion of physical activity and pulmonary rehabilitation being other key factors in management. Comorbidities should be actively sought and managed in their own right. Given the chronicity and progressive nature of COPD, ongoing monitoring and support with timely discussion of advanced-care planning and end-of-life issues are recommended.

Association between severe pandemic 2009 influenza A (H1N1) virus infection and immunoglobulin G(2) subclass deficiency.

BACKGROUND: . Severe pandemic 2009 influenza A virus (H1N1) infection is associated with risk factors that include pregnancy, obesity, and immunosuppression. After identification of immunoglobulin G(2) (IgG(2)) deficiency in 1 severe case, we assessed IgG subclass levels in a cohort of patients with H1N1 infection. METHODS: Patient features, including levels of serum IgG and IgG subclasses, were assessed in patients with acute severe H1N1 infection (defined as infection requiring respiratory support in an intensive care unit), patients with moderate H1N1 infection (defined as inpatients not hospitalized in an intensive care unit), and a random sample of healthy pregnant women. RESULTS: Among the 39 patients with H1N1 infection (19 with severe infection, 7 of whom were pregnant; 20 with moderate infection, 2 of whom were pregnant), hypoabuminemia (P < .001), anemia (P < .001), and low levels of total IgG (P= .01), IgG(1) (P= .022), and IgG(2) (15 of 19 vs 5 of 20; P= .001; mean value +/- standard deviation [SD], 1.8 +/- 1.7 g/L vs 3.4 +/- 1.4 g/L; P= .003) were all statistically significantly associated with severe H1N1 infection, but only hypoalbuminemia (P= .02) and low mean IgG(2) levels (P= .043) remained significant after multivariate analysis. Follow-up of 15 (79%) surviving IgG(2)-deficient patients at a mean (+/- SD) of 90 +/- 23 days (R, 38-126) after the initial acute specimen was obtained found that hypoalbuminemia had resolved in most cases, but 11 (73%) of 15 patients remained IgG(2) deficient. Among 17 healthy pregnant control subjects, mildly low IgG(1) and/or IgG(2) levels were noted in 10, but pregnant patients with H1N1 infection had significantly lower levels of IgG(2) (P= .001). CONCLUSIONS: Severe H1N1 infection is associated with IgG(2) deficiency, which appears to persist in a majority of patients. Pregnancy-related reductions in IgG(2) level may explain the increased severity of H1N1 infection in some but not all pregnant patients. The role of IgG(2) deficiency in the pathogenesis of H1N1 infection requires further investigation, because it may have therapeutic implications.

Interventions to reduce the frequency of exacerbations of chronic obstructive pulmonary disease.

Frequent exacerbations of chronic obstructive pulmonary disease (COPD) are associated with impaired quality of life, and hospital admissions for exacerbations account for a large proportion of the expenditure of COPD. An important objective when treating COPD is to reduce the frequency of exacerbations. Studies published in the last few years have increased our knowledge on how to prevent exacerbations, but a number of questions remain unanswered. Tiotropium, inhaled steroids and long-acting inhaled beta agonists reduce the frequency of exacerbations, but further studies are necessary to determine if combining tiotropium with the other inhaled medicines is more effective than using them separately. There is evidence that mucolytics and prophylactic antibiotics reduce exacerbations, but there is uncertainty how these treatments should be used. Both influenza and pneumococcal vaccination are recommended in guidelines, although evidence for the latter remains controversial. Other interventions including oral bacterial extracts and self-management programmes warrant further study.

Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease.

BACKGROUND: Interstitial lung disease (ILD) is characterised by exertional dyspnoea, exercise limitation and reduced quality of life. The role of exercise training in this diverse patient group is unclear. The aims of this study were to establish the safety of exercise training in ILD; its effects on exercise capacity, dyspnoea and quality of life; and whether patients with idiopathic pulmonary fibrosis (IPF) had similar responses to those with other types of ILD. METHODS: 57 subjects with ILD (34 IPF) were randomised to receive 8 weeks of supervised exercise training or weekly telephone support. The 6 min walk distance (6MWD), incremental exercise test, modified Medical Research Council (MRC) dyspnoea score and Chronic Respiratory Disease Questionnaire (CRDQ) were performed at baseline, following intervention and at 6 months. RESULTS: 80% of subjects completed the exercise programme and no adverse events were recorded. The 6MWD increased following training (mean difference to control 35 m, 95% CI 6 to 64 m). A significant reduction in MRC score was observed (0.7 points, 95% CI 0.1 to 1.3) along with improvements in dyspnoea (p = 0.04) and fatigue (p<0.01) on the CRDQ. There was no change in peak oxygen uptake; however, exercise training reduced heart rate at maximum isoworkload (p = 0.01). There were no significant differences in response between those with and without IPF. After 6 months there were no differences between the training and control group for any outcome variable. CONCLUSIONS: Exercise training improves exercise capacity and symptoms in patients with ILD, but these benefits are not sustained 6 months following intervention.

Characterization of M1/M2 Tumour-Associated Macrophages (TAMs) and Th1/Th2 Cytokine Profiles in Patients with NSCLC.

Lung cancer is one of the most commonly reported cancers, and is known to be associated with a poor prognosis. The function of tumour-associated macrophages (TAMs) in lung cancer patients is multifaceted and the literature shows conflicting roles. (I) To analyze the Th1 and Th2 cytokine levels that contribute to the differentiation of M1 and M2 macrophage populations in the serum of patients with NSCLC versus non-cancer controls; and (II) To characterize the M1 and M2 macrophage populations within TAMs in different subtypes of NSCLC compared to non-tumour tissue. The Th1 and Th2 cytokine levels were analyzed in serum using the Bio-Plex assay. In addition, TAMs subsets from non-tumour and tumour tissues were analyzed using immunohistochemistry (IHC). The level of IL-1ß, IL-4, IL-6 and IL-8 was found to be increased in the serum of patients with large cell carcinoma but not in other NSCLC subtypes compared to non-cancer controls. In addition, the expression of CD68 and M2 marker CD163 was found to be increased (P ≤ 0.0001) in all NSCLC subtypes compared to non-tumour tissues. In contrast, the expression of iNOS (M1 marker) was decreased in the tumour tissue of patients with adenocarcinoma (P ≤ 0.01) and squamous carcinoma (P ≤ 0.05) but not in large cell carcinoma compared to non-tumour tissue. The results of this study indicate that NSCLC might have the ability to alter phenotype within the lung tumour areas in the local environment (TAMs) but not in the bloodstream in the systemic environment (serum) except for large cell carcinoma.

Surface CD4 is critical to in vitro HIV infection of human alveolar macrophages.

The CD4 glycoprotein is the major cellular receptor for HIV. CD4 surface expression of monocytes decreases with time in culture while their susceptibility to HIV-1 increases. Our aim was to investigate whether this phenomenon occurs in macrophages that have differentiated in vivo by investigating CD4 expression and HIV-1 infection of human alveolar macrophages (AMs). Using flow cytometry to detect CD4 expression by Leu-3a labeled indirectly with fluorescein isothiocyanate or allophycocyanin, we found that CD4 was expressed at low but detectable levels, despite the high background autofluorescence well described in AMs. This finding was supported by the detection of CD4 mRNA in AMs using RT-PCR. T cell contamination of mRNA extracts of AMs was excluded by amplifying in parallel with primers to the constant region of the T cell receptor. Despite this low level of surface CD4, recombinant soluble CD4 and anti-CD4 antibody completely inhibited HIV-1 infection of AMs. We conclude that CD4, although expressed at low levels on the surface of AMs, appears to be critical to HIV-1 infection of these cells.

Defective cytostatic activity of pulmonary alveolar macrophages in primary lung cancer.

Macrophages are thought to play an important immune effector cell role in antitumor host defense. It remains unclear whether PAM antitumor activity in patients with lung cancer is normal or impaired. We examined PAM cytostasis in patients with lung cancer and in control subjects and determined whether the in vitro PAM response could be enhanced by gamma-interferon. Nineteen patients with primary lung carcinoma and 15 control patients underwent BAL. Five patients with cancer underwent lavage of both lungs to assess whether any abnormality found related to tumor proximity or was part of a more generalized defect. Cytostatic activity was assessed by measuring inhibition of incorporation of tritiated thymidine into the target cell U937. There was a significant difference in baseline cytostatic activity between patients with cancer (mean +/- SE, 59 +/- 7 percent) and control patients (92 +/- 2 percent) (p less than 0.0002). The increase in cytostatic function after stimulation with gamma-interferon (1,250 units/ml) was higher in the group with cancer (28 +/- 5 percent increase from baseline) than in controls (5 +/- 1 percent) (p less than 0.0005). Cytostasis after stimulation was not significantly different between the groups. In the bilaterally lavaged group, baseline cytostatic activity was not different between cancerous and noncancerous lungs and was again significantly lower than in control subjects. These results indicate (a) that PAM baseline cytostatic activity in patients with cancer is lower than in controls, (b) that gamma-interferon can significantly augment cytostatic function in patients with cancer, to levels comparable with those achievable in control patients, and (c) that the PAM abnormality is part of a generalized immune defect in lung cancer and does not simply reflect a local response to the carcinoma. It may be inferred from these results that PAMs from patients with primary lung cancer are not fully stimulated in vivo and that a defect of T cell lymphokine production may underlie the macrophage dysfunction.

Comparison of outpatient nebulized vs metered dose inhaler terbutaline in chronic airflow obstruction.

Eighteen patients (nine asthmatic patients and nine with poorly reversible airflow obstruction) with stable, severe chronic airflow obstruction, completed a four-week randomized, doubled-blind, placebo-control, crossover trial comparing the acute and chronic effects of terbutaline administered by metered-dose inhaler (MDI) and nebulizer (NEB). Equipotent doses of terbutaline were selected from the comparison of separate cumulative dose-response curves for MDI and NEB. The MDI and NEB given acutely produced similar bronchodilatation and improvement in exercise performance. Spirometric indices, 6 min walking distance, symptom scores and extra beta-agonist use were no different between MDI and NEB treatment fortnights in the outpatient study. We conclude that the degree of bronchodilatation achieved in these patients is a reflection of the dose of bronchodilator administered and not the mode of administration. There is no justification for the preferred outpatient use of nebulized bronchodilators in patients with stable chronic airflow obstruction who can use adequate doses of bronchodilators via a metered-dose inhaler.

Benzodiazepine-opiate antagonism--a problem in intensive-care therapy.

A 14-year-old previously fit schoolboy was admitted with staphylococcal pneumonia secondary to influenza A infection. His condition deteriorated as he developed adult respiratory distress syndrome (ARDS); during a stormy recovery exceptionally high doses of benzodiazepines and opiates were given in order to suppress voluntary breathing during a successful period of assisted ventilation. It is possible that benzodiazepine-opiate antagonism developed. Subsequent studies in laboratory mice indicate that the respiratory depressant effects of morphine can be antagonized by prior treatment with lorazepam.

Respiratory impairment in inflammatory bowel disease: does it vary with disease activity?

Serial assessments of respiratory function were made in 44 patients with inflammatory bowel disease. Pulmonary function tests were performed at the initial assessment and after three months to see if abnormality was associated with alteration in disease activity, drug therapy or with evidence of immunological disturbance. Fourteen patients (32%) had some abnormality of respiratory function when first investigated. Seven (16%) had a reduced gas transfer factor but these abnormalities were not related to disease activity, drug therapy or any immunological variable. Elevation of both functional residual capacity and residual volume was found in nine (20%) patients at the initial assessment. These abnormalities appeared to be associated with active inflammatory bowel disease and in four of these patients lung volumes returned to normal at 3 months when the bowel disease was in remission.

Adult domiciliary oxygen therapy: position statement of the Thoracic Society of Australia and New Zealand.

Evidence shows that patients with chronic obstructive pulmonary disease and a stable daytime PaO2 of 55 mm Hg or less will have longer life expectancy if given supplemental oxygen to keep the PaO2 above 60 mm Hg, preferably for longer than 15 hours a day, including sleep. There is some evidence for improved quality of life. It is reasonable to offer this therapy for other lung diseases which cause chronic hypoxaemia, and there are also less well defined indications for supplemental oxygen during exercise, sleep and air travel.

Breath testing in patients with respiratory disability.

The presence of chronic respiratory disease is sometimes claimed as a defence by drivers who refuse or fail a breath test. Trials have been conducted with two breath analysis instruments used in the state of Victoria, Australia in order to determine the respiratory parameters compatible with a satisfactory test. Patients with restrictive and obstructive conditions participated in the trial that was conducted in the respiratory unit of a large teaching hospital. The results showed that the evidential breath analyzer currently used in Victoria was able to accept breath samples from subjects at the limit of respiratory function likely to be encountered in drivers. It was also found that a subject capable of providing a breath sample for the current screening device should also be able to provide an evidential sample. The trials provided useful information in evaluating defences of inability to provide a breath sample due to respiratory incapacity.

Minimal important difference in field walking tests in non-cystic fibrosis bronchiectasis following exercise training.

BACKGROUND: The 6-min walk distance (6MWD) and incremental shuttle walk distance (ISWD) are clinically meaningful measures of exercise capacity in people with non-cystic fibrosis (CF) bronchiectasis, but the change in walking distance which constitutes clinical benefit is undefined. This study aimed to determine the minimal important difference for the 6MWD and ISWD in non-CF bronchiectasis. METHODS: Thirty-seven participants with mean FEV1 70% predicted completed both field walking tests before and after an 8-week exercise program. The minimal important difference was calculated using a distribution-based and anchor-based method, with the global rating of change scale used. RESULTS: The mean change in 6MWD in participants who reported themselves to be unchanged was 10 m, compared to 36 m (small change) and 45 m (substantial change) (p = 0.01). For the ISWD, the mean change in participants who reported themselves to be unchanged was 33 m, compared to 54 m (small change) and 73 m (substantial change) (p = 0.04). The anchor-based method defined the minimal important difference for 6MWD as 24.5 m (AUC 0.76, 95% CI 0.61-0.91) and for ISWD as 35 m (AUC 0.88, 95% CI 0.73-0.99), based on participant's global rating of change. The distribution-based method indicated a value of 22.3 m for the 6MWD and 37 m for the ISWD. There was excellent agreement between the two methods for the 6MWD (kappa = 0.91) and the ISWD (kappa = 0.92). CONCLUSIONS: Small changes in 6MWD and ISWD may represent clinically important benefits in people with non-CF bronchiectasis. These data are likely to assist in the interpretation of change in exercise capacity following intervention.

Exercise intervention to improve exercise capacity and health related quality of life for patients with Non-small cell lung cancer: a systematic review.

CONTEXT: The role of exercise intervention for patients with Non-small cell lung cancer (NSCLC) has not been systematically reviewed to date. OBJECTIVE: To identify, evaluate and synthesize the evidence examining (1) the effect of exercise intervention on exercise capacity, health related quality of life (HRQoL), physical activity levels, cancer symptoms and mortality for patients with NSCLC; and (2) the safety and feasibility of exercise intervention for a population with NSCLC. DATA SOURCES: A systematic review of articles using the electronic databases MEDLINE (1950-2010), CINAHL (1982-2010), EMBASE (1980-2010), TRIP (1997-2010), Science Direct (1994-2010), PubMed (1949-2010), Cochrane Library (2010), Expanded Academic ASAP (1994-2010), Meditext Informit (1995-2010), PEDRO (1999-2010) and DARE (2010). Additional studies were identified by manually cross referencing all full text reports and personal files were searched. No publication date restrictions were imposed. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised controlled trials (RCTs), case-control studies and case series assessing exercise intervention to improve exercise capacity, HRQoL, level of daily physical activity, cancer symptoms or mortality of patients with NSCLC were included. Only articles available in English and published in a peer reviewed journal were included. DATA EXTRACTION: A data collection form was developed by one reviewer and data extracted. Data extraction was cross checked by a second reviewer. RESULTS AND DATA SYNTHESIS: 16 studies on 13 unique patient groups totalling 675 patients with NSCLC met the inclusion criteria. The majority of studies were case series (n=9) and two RCTs were included. Studies exercising participants pre-operatively reported improvements in exercise capacity but no change in HRQoL immediately post exercise intervention. Studies exercising participants post-treatment (surgery, chemotherapy or radiotherapy) demonstrated improvements in exercise capacity but conflicting results with respect to the impact on HRQoL immediately post exercise intervention. Heterogeneity among studies was observed and a meta-analysis was deemed inappropriate. PRISMA guidelines were followed in reporting this systematic review. CONCLUSION: Exercise intervention for patients with NSCLC is safe before and after cancer treatment. Interventions pre-operatively or post-cancer treatment are associated with positive benefits on exercise capacity, symptoms and some domains of HRQoL. The majority of studies are small case series therefore results should be viewed with caution until larger RCTs are completed. Further research is required to establish the effect of exercise during and after cancer treatment and in the advanced stage of disease, the optimum type of exercise training and the optimum setting for delivery.