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Backgrounds Victoria (Australia) and Denmark have comparable population sizes and high-quality healthcare systems. Lung cancer surgery, however, is performed in more than 20 Victorian hospitals compared to four in Denmark. Such differences in centralization may influence outcomes. We engaged clinical quality registries to enable international benchmarking by exploring patterns of lung cancer surgery including mortality and survival. Methods All patients undergoing lung cancer surgery between 2015 and 2018 registered in the Victorian Lung Cancer Registry and the Danish Lung Cancer Registry were included. Analyses on stage concordance, 30 and 90-day mortality, and overall survival were restricted to a selected subgroup with NSCLC and no neo-adjuvant therapy or metastatic disease and only one operation. Results We included 1554 Victorian and 4319 Danish patients. The resection rate was 26.3% in Victoria and 28% in Denmark, but a higher proportion of Victorian patients underwent wedge resection (19.1% versus 8.8%). Stage concordance was 59.6% and 54.9% in Victoria and Denmark, respectively. The 30- and 90-day mortality was 1.3% and 2.6% in Victoria, compared to 1.4% and 2.8% in Denmark with no difference in overall survival (p = 0.28) or risk-adjusted survival (HR: 1.10 (95% CI: 0.89-1.37); p = 0.38). Conclusion High-quality surgical lung cancer care was confirmed by similar high resection and low mortality rates including no overall survival difference. The drivers and consequences of stage discordance and differences in patterns of resection deserve further exploration. This study provides a model for international benchmarking using clinical quality registries, although caution remains in the interpretation given disparities in data completeness.

Background Chronic rhinosinusitis affects 62% of adults with bronchiectasis and is linked to greater bronchiectasis severity. However, the impact of symptoms of chronic rhinosinusitis on disease‐specific and cough‐related quality of life is unknown. Methods In this cross‐sectional study, adults with stable bronchiectasis and chronic rhinosinusitis symptoms completed the sinonasal outcome test‐22 (SNOT‐22), quality of life–bronchiectasis questionnaire, and Leicester cough questionnaire. Bronchiectasis severity was assessed using the bronchiectasis severity index (BSI) and chest high‐resolution computed tomography (HRCT). Results Sixty participants with bronchiectasis (mean [SD] forced expiratory volume in 1 s of 73.2 [25.5] %predicted) were included. Greater severity of chronic rhinosinusitis symptoms (based on SNOT‐22) was moderately associated with impaired cough‐related quality of life (according to the Leicester cough questionnaire; all r > −.60) and impaired bronchiectasis‐specific quality of life (based on the quality of life–bronchiectasis questionnaire), with impaired physical function (r = −.518), less vitality (r = −.631), reduced social function (r = −.546), greater treatment burden (r = −.411), and increased severity of respiratory symptoms (r = −.534). Chronic rhinosinusitis symptoms were unrelated to disease severity according to the BSI (r = .135) and HRCT scoring (all r

BACKGROUND Multidisciplinary meeting (MDM) discussion and early palliative care are recommended in lung cancer management. The literature is unclear whether MDM discussion leads to early palliative care and improved end-of-life care. AIMS To evaluate impacts of discussion at an Australian lung MDM on palliative care referral, and MDM and early palliative care on aggressive end-of-life care. METHODS A retrospective, cross-sectional study was conducted of 352 patients diagnosed with primary lung cancer from 2017 to 2019 at the Alfred Hospital, Melbourne. The primary question was whether MDM discussion influenced palliative care referrals. Secondary questions were whether MDM discussion and early palliative care reduced aggressive treatment (chemotherapy, hospitalisation, emergency department visits, intensive care admission and in-hospital death) during the last 30 days of life. Multivariable logistic regression was used to determine independent association between MDM discussion and palliative care referral. RESULTS MDM discussion did not independently impact palliative care referral. There was reduced likelihood of MDM presentation in patients with metastatic disease (P

Introduction Patients with NSCLC may be treated with curative intent, yet they remain at high risk of both disease recurrence and second primary lung cancer (SPLC) and increased risk of early death. Guidelines provide recommendations for follow-up, but there is little consensus, and review of available evidence is necessary. The use of a systematic follow-up strategy for the detection of disease recurrence or SPLC after curative-intent treatment of NSCLC may increase the proportion of patients available for retreatment and increase the survival of patients with surveillance detection. Methods We performed a systematic review and meta-analysis of prospective studies on follow-up of NSCLC after curative-intent treatment to answer the following three questions: What is the effect of follow-up on detection of recurrence or SPLC? What is the effect of surveillance detection on curative-intent retreatment? What is the survival impact? Results Recurrence or SPLC was observed in 17.8% to 71% of patients. Scheduled imaging-detected recurrence in 60% to 100% of cases, yet neither computed tomography–based (OR = 2.31, 95% confidence interval [CI]: 0.27–19.49, p = 0.44) nor positron emission tomography-computed tomography–based follow-up (OR = 1.431, 95% CI: 0.92–2.22, p = 0.12) was statistically superior to standard follow-up strategies. Detection of disease recurrence/SPLC significantly increased the odds of curative-intent retreatment (OR = 4.31; 95% CI: 2.10–8.84, p Conclusions The early detection of disease recurrence/SPLC may increase the likelihood of curative-intent retreatment and prolong survival. There is a clear need for prospective randomized controlled studies of follow-up to confirm effectiveness of available follow-up modalities.

Treatment of elderly patients with lung cancer is significantly hindered by concerns about treatment tolerability, toxicity and limited clinical trial data in the elderly; potentially giving rise to treatment nihilism amongst clinicians. This study aims to describe survival in elderly patients with lung cancer and explore potential causes for excess mortality. Patients diagnosed with lung cancer in the Victorian Lung Cancer Registry between 2011–2018 were analysed (n=3481). Patients were age-categorised and compared using Cox-regression modelling to determine mortality risk, after adjusting for confounding. Probability of being offered cancer treatments was also determined, further stratified by disease stage. The eldest patients (≥80 years old) had significantly shorter median survival compared with younger age groups (, Treatment strongly determines lung cancer survival, yet nihilism may threaten treatment provision and survival outcomes. Older patients in this cohort had reduced multidisciplinary presentation, less treatment (OR 0.24) and 28% increased mortality risk. https://bit.ly/2ZGotj0

Background TrumenbaTM, a bivalent, factor-H binding protein meningococcal serogroup B (MenB-fHBP) vaccine was authorized for use in Canada in October 2017 for the prevention of invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup B in individuals 10-25 years of age. The National Advisory Committee on Immunization (NACI) provides recommendations regarding the use of meningococcal vaccines to the Public Health Agency of Canada. Objective To summarize NACI recommendations regarding the use of MenB-fHBP vaccine in Canada. Methods The NACI Meningococcal Disease Working Group developed a predefined search strategy to identify all eligible studies, assessed the quality of these studies, and summarized and analyzed the findings. According to the NACI evidence-based process, the working group then proposed recommendations and identified the grade of evidence that supported them. In light of the evidence, the recommendations were then considered and approved by NACI. Results The two serogroup B meningococcal vaccines currently authorized for use in Canada are not interchangeable as they contain different antigens and there are no published studies on the immunogenicity resulting from a vaccination series combining the two products. Following the review of evidence, NACI recommends that MenB-fHBP vaccine may be considered as an option for use in individuals 10 years of age and older in situations when a serogroup B meningococcal vaccine should be offered: 1) during serogroup B meningococcal disease outbreaks or with the emergence of hyperendemic N. meningitidis strains that are predicted to be susceptible to the vaccine; 2) for individuals who are close contacts with a case of invasive meningococcal disease caused by serogroup B N. meningitidis; 3) for individuals with underlying medical conditions that would put them at higher risk of meningococcal disease than the general population; or 4) for individuals at higher risk of exposure to serogroup B meningococcal isolates than the general population. NACI also recommends that MenB-fHBP vaccine may be considered as an option for individuals 10-25 years of age who are not at higher risk of meningococcal disease than the general population, but who wish to reduce their risk of invasive serogroup B meningococcal disease. Conclusion NACI recommends immunization against serogroup B IMD for all individuals who are at a higher risk of disease due to an underlying medical condition or an increased risk of exposure. In addition to providing guidance to public health decision-makers (i.e. provinces/territories making decisions for publicly-funded immunization programs), these NACI recommendations provide information to individuals, vaccine providers and organizations about vaccines that may not currently be included in publicly funded immunization programs. NACI continues to recommend against the use of the serogroup B vaccines in routine universal immunization programs in Canada at this time.

Introduction: Non-small-cell lung cancer outcomes are poor but heterogeneous, even within stage groups. To improve prognostic precision we aimed to develop and validate a simple prognostic model using patient and disease variables. Methods: Prospective registry and study data were analysed using Cox proportional hazards regression to derive a prognostic model (hospital 1, n=695), which was subsequently tested (Harrell’s c-statistic for discrimination and Cox–Snell residuals for calibration) in two independent validation cohorts (hospital 2, n=479 and hospital 3, n=284). Results: The derived Lung Cancer Prognostic Index (LCPI) included stage, histology, mutation status, performance status, weight loss, smoking history, respiratory comorbidity, sex, and age. Two-year overall survival rates according to LCPI in the derivation and two validation cohorts, respectively, were 84, 77, and 68% (LCPI 1: score⩽9); 61, 61, and 42% (LCPI 2: score 10–13); 33, 32, and 14% (LCPI 3: score 14–16); 7, 16, and 5% (LCPI 4: score ⩾15). Discrimination (c-statistic) was 0.74 for the derivation cohort, 0.72 and 0.71 for the two validation cohorts. Conclusions: The LCPI contributes additional prognostic information, which may be used to counsel patients, guide trial eligibility or design, or standardise mortality risk for epidemiological analyses.

We addressed the uncertainty of comorbidity as a prognosticator by evaluating comorbidity and the Simplified Comorbidity Score (SCS) as predictors of overall survival in non-small cell lung cancer (NSCLC).A prospective study included patients in whom NSCLC was diagnosed at an Australian cancer hospital between 2012 and 2014. Patients were assessed for SCS at recruitment and followed up every 3 months until death.The cohort included 633 patients; their median age was 67 years (range 28-93), 63% were male, and 86% were ever-smokers. The median SCS at enrolment was 8 (range 0-19); 20% had an SCS higher than 9, and 11% had an SCS of 0. An SCS higher than 9 was associated with male sex, age older than 75 years, an Eastern Cooperative Oncology Group performance status of 2 or higher, and fewer cancer treatments. The 1-year overall survival rate was 62% (95% confidence interval: 58-66). In multivariate analysis, the strongest associations with mortality were metastatic disease (hazard ratio [HR] = 2.8, p0.01), Eastern Cooperative Oncology Group performance status of 2 or higher (HR = 2.0, p0.01), male sex (HR = 1.6, p0.01), more than 10% weight loss at diagnosis (HR = 1.5, p0.01), and age older than 75 years (HR = 1.5, p = 0.01). An SCS higher than 9 was not associated with overall survival (HR = 1.0, p = 0.8), and the effect of continuous SCS (HR = 1.1, p0.01) was explained by smoking status.In this cohort of patients with NSCLC the SCS was not a clinically significant predictor of overall survival over and above basic patient and disease factors.

BACKGROUND: Acid gastroesophageal reflux is a common problem in non-cystic fibrosis bronchiectasis and COPD. Invasive methods are used to diagnose gastroesophageal reflux, but the ability to detect pulmonary microaspiration of gastric contents using this method is unclear. A noninvasive option to detect pulmonary microaspiration is to measure pepsin in exhaled breath condensate (EBC), but this has not been related to esophageal pH monitoring in these lung conditions. This study aimed to measure pepsin concentrations and pH in EBC and to determine the relationship to gastroesophageal reflux in bronchiectasis or COPD. METHODS: Subjects with bronchiectasis ( n = 10) or COPD ( n = 10) and control subjects ( n = 10) completed 24-h esophageal pH monitoring for detection of acid gastroesophageal reflux, measuring the percentage of reflux time in the proximal esophagus and the DeMeester score (DMS). Concurrently, 3 samples of EBC were collected from each subject, and pH was measured and pepsin concentrations were analyzed by enzyme-linked immunosorbent assay. RESULTS: EBC pepsin was detected in subjects with bronchiectasis (44%) or COPD (56%) and in control subjects (10%). A diagnosis of gastroesophageal reflux was not associated with a higher concentration of EBC pepsin in bronchiectasis ( P = .21) or COPD ( P = .11). EBC pepsin concentration did not correlate with DMS (rs = 0.36) or proximal reflux index (rs = 0.25) in subjects with bronchiectasis or with DMS (rs = 0.28) or proximal reflux index (rs = 0.21) in patients with COPD. EBC and sputum pepsin concentrations were moderately correlated in bronchiectasis (rs = 0.56) and in COPD (rs = 0.43). CONCLUSIONS: Pepsin is detectable in EBC samples in bronchiectasis and COPD. Although no association was found between pepsin concentrations and a diagnosis of gastroesophageal reflux, a moderate relationship between sputum and EBC pepsin concentrations suggests that EBC pepsin may be a useful noninvasive marker of pulmonary microaspiration.

Background and objective The aims of this observational study were (i) to examine the prevalence of symptomatic and clinically silent proximal and distal gastro-oesophageal reflux (GOR) in adults with chronic obstructive pulmonary disease (COPD) or bronchiectasis, (ii) the presence of gastric aspiration, and (iii) to explore the possible clinical significance of this comorbidity in these conditions. Methods Twenty-seven participants with COPD, 27 with bronchiectasis and 17 control subjects completed reflux symptom evaluation and dual-channel 24 h oesophageal pH monitoring. In those with lung disease, pepsin levels in sputum samples were measured using enzyme-linked immunosorbent assay, with disease severity (lung function and high-resolution computed tomography) also measured. Results The prevalence of GOR in COPD was 37%, in bronchiectasis was 40% and in control subjects was 18% (P = 0.005). Of those diagnosed with GOR, clinically silent reflux was detected in 20% of participants with COPD and 42% with bronchiectasis. While pepsin was found in 33% of COPD and 26% of bronchiectasis participants, the presence of pepsin in sputum was not related to a diagnosis of GOR based on oesophageal pH monitoring in either condition. Neither a diagnosis of GOR nor the presence of pepsin was associated with increased severity of lung disease in COPD or bronchiectasis. Conclusions The prevalence of GOR in COPD or bronchiectasis is twice that of the control population, and the diagnosis could not be based on symptoms alone. Pepsin was detected in sputum in COPD and bronchiectasis, suggesting a possible role of pulmonary aspiration, which requires further exploration.

Patients with chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU) often continue to experience symptoms despite receiving standard-of-care therapy with H1-antihistamines along with 1 or more add-on therapies.We sought to evaluate the safety and efficacy of 24 weeks of treatment with omalizumab in patients with persistent CIU/CSU despite treatment with H₁-antihistamines at up to 4 times the approved dose plus H₂-antihistamines, leukotriene receptor antagonists, or both.In this phase III study patients were randomized to receive 6 subcutaneous injections at 4-week intervals of either 300 mg of omalizumab or placebo, followed by a 16-week observation period. The primary objective of the study was to evaluate the overall safety of omalizumab compared with placebo. Efficacy (itch severity, hive, and urticaria activity scores) was evaluated at weeks 12 and 24.The overall incidence and severity of adverse events and serious adverse events were similar between omalizumab and placebo recipients; the safety profile was consistent with omalizumab in patients with allergic asthma. At week 12, the mean change from baseline in weekly itch severity score was -8.6 (95% CI, -9.3 to -7.8) in the omalizumab group compared with -4.0 (95% CI, -5.3 to -2.7) in the placebo group (P.001). Significant improvements were seen for additional efficacy end points at week 12; these benefits were sustained to week 24.Omalizumab was well tolerated and reduced the signs and symptoms of CIU/CSU in patients who remained symptomatic despite the use of H₁-antihistamines (up to 4 times the approved dose) plus H₂-antihistamines, leukotriene receptor antagonists, or both.

Background Inhaled dry powder mannitol enhanced mucus clearance and improved quality of life over 2 weeks in non-cystic fibrosis bronchiectasis. This study's objective was to investigate the efficacy and safety of dry powder mannitol over 12 weeks. Methods Patients with bronchiectasis confirmed by high-resolution CT (HRCT) scan, aged 15 to 80 years, with FEV 1 ≥ 50% predicted and ≥ 1 L participated in a randomized, placebo-controlled, double-blind study. Patients with a negative mannitol provocation test were randomized to inhale 320 mg mannitol (n = 231) or placebo (n = 112) bid for 12 weeks. To further assess safety, the same mannitol dose/frequency was administered to a patient subset in an open-label extension over 52 weeks. Primary end points were changes from baseline at 12 weeks in 24-h sputum weight and St. George's Respiratory Questionnaire (SGRQ) score. Results There was a significant difference of 4.3 g in terms of change in sputum weight over 12 weeks (95% CI, 1.64-7.00; P = .002) between mannitol and placebo; however, this was largely driven by a decrease in sputum weight in the placebo group. This was associated, in turn, with more antibiotic use in the placebo group (50 of 112 [45%]) than in the inhaled mannitol group (85 of 231 [37%]). There was no statistical difference between the groups ( P = .304) in total SGRQ score (mannitol, −3.4 points [95% CI, −4.81 to −1.94] vs placebo, −2.1 points [95% CI, −4.12 to −0.09]). In a subgroup study (n = 82), patients receiving mannitol showed less small airway mucus plugging on HRCT scan at 12 weeks compared with patients receiving placebo ( P = .048). Compliance rates were high, and mannitol was well tolerated with adverse events similar to those of placebo. Conclusion Because 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. Trial registry ClinicalTrials.gov; No.: NCT0027753; URL: www.clinicaltrials.gov

Summary Background and aims Inhalation of hypertonic saline (HTS) has short term positive effects on airways clearance in non-cystic fibrosis (CF) bronchiectasis, however its long term effects are unknown. The aim of this study was to determine the effect of HTS 6% on exacerbations, quality of life (QOL) and respiratory function over 12 months in non-CF bronchiectasis. Methods Forty patients were randomised to inhale isotonic saline (IS) 0.9% or HTS 6% daily for 12 months. Participants recorded their symptoms in a daily diary. Quality of life and respiratory function were measured after three, six and 12 months. Number of exacerbations and changes in sputum colonisation were recorded at 12 months. Participants, assessors and clinicians were blinded to group allocation. Results The exacerbation rate at 12 months was similar in the two groups and similar clinically significant improvements in QOL were seen in both groups. The FEV 1 increased in both groups after six months (mean 90 ml, 95% confidence interval 11–169 ml) with no difference between groups ( p = 0.394). The FEF 25–75% significantly improved at all time points (mean increase at 12 months 187 ml, 69–304 ml) with no difference between groups ( p = 0.705). There was a reduction in sputum colonisation in both groups ( p = 0.046). Conclusions Inhalation of HTS or IS has similar effects on exacerbations, QOL, sputum colonisation and respiratory function over 12 months in non-CF bronchiectasis. The trial was registered with both Clinical Trials.gov – NCT00484263 and Australian New Zealand Clinical Trials Registry – ACTRN12607000367448.

Background and aims: Intragam® 10 NF is the next generation 10% intravenous immunoglobulin with three pathogen reduction steps and a noncarbohydrate stabiliser. This open label, cross-over study in patients with primary immunodeficiency was designed to evaluate whether Intragam 10 NF differed in its pharmacokinetics (PK) compared with Intragam P and to assess Intragam 10 NF safety and tolerability. Methods: Nineteen primary immunodeficiency patients were administered one cycle of their existing Intragam P dose (0.2–0.8 g/kg 3–4 weekly), followed by seven cycles of Intragam 10 NF administered at the same dosing schedule as Intragam P. The primary objective was to compare serum immunoglobulin G (IgG) trough levels. Secondary endpoints were PK variables, safety and tolerability. Results: There was no significant within-patient difference in the average trough immunoglobulin G concentration between Intragam P and Intragam 10 NF (8.76 g/L, 8.55 g/L respectively) (geometrical mean ratio 1.034; 95% confidence interval 0.996–1.073; P = 0.079). Mean PK parameters for both products were similar, with all 95% confidence interval encompassing 1.0 except for time to maximum concentration. Time to maximum concentration occurred earlier with Intragam 10 NF compared with Intragam P, with a shorter infusion time (mean 1.75 h vs 2.52 h respectively; P

BACKGROUND: In February 2007, a general surgeon in Charlottetown, Prince Edward Island, tested positive for hepatitis C virus (HCV). The surgeon’s infection onset date could not be determined; however, episodic hepatic enzyme elevations were first detected in November 2004 and again in February 2007. HCV transmission during surgery, alhough rare, has been documented. A phased look-back HCV screening program was conducted to detect HCV transmission from this surgeon to patients who underwent the highest-risk procedures in the three years before his positive test.METHODS: Highest-risk procedures were defined as exposure-prone procedures (EPP) in which exposure to the surgeon’s blood was most likely. EPP patients from January 2004 to February 2007 were identified using hospital and administrative records. Linkages with the provincial notifiable disease for HCV was performed, and death records for deceased EPP patients were reviewed. Eligible patients were invited for screening.RESULTS: Of 6248 patients seen in phase 1, 272 (4.4%) were identified to be EPP. Of the 272 patients, 248 (91.1%) were invited for HCV testing and 24 (8.8%) were deceased. To date, 231 of 248 (93.1%) patients have presented for screening. Two patients (one alive, one deceased) were HCV positive before their EPP. Viral sequence of the surgeon’s isolate is unrelated to the first patient; the second individual has a resolved infection (polymerase chain reaction negative). No new transmission events were identified in the screened patients. The 95% CI of the transmission probability was estimated to be 0 to 0.016.INTERPRETATION: HCV transmission from the surgeon during a 38-month look back was unlikely. In the absence of protocols for investigating HCV transmission from infected health care workers, screening was initially prioritized to the highest-risk patients. The investigation has been satisfactorily terminated based on these results.

Background. Available data on the etiology of community-acquired pneumonia (CAP) in Australia are very limited. Local treatment guidelines promote the use of combination therapy with agents such as penicillin or amoxycillin combined with either doxycycline or a macrolide. Methods. The Australian CAP Study (ACAPS) was a prospective, multicenter study of 885 episodes of CAP in which all patients underwent detailed assessment for bacterial and viral pathogens (cultures, urinary antigen testing, serological methods, and polymerase chain reaction). Antibiotic agents and relevant clinical outcomes were recorded. Results. The etiology was identified in 404 (45.6%) of 885 episodes, with the most frequent causes being Streptococcus pneumoniae (14%), Mycoplasma pneumoniae (9%), and respiratory viruses (15%; influenza, picornavirus, respiratory syncytial virus, parainfluenza virus, and adenovirus). Antibiotic-resistant pathogens were rare: only 5.4% of patients had an infection for which therapy with penicillin plus doxycycline would potentially fail. Concordance with local antibiotic recommendations was high (82.4%), with the most commonly prescribed regimens being a penicillin plus either doxycycline or a macrolide (55.8%) or ceftriaxone plus either doxycycline or a macrolide (36.8%). The 30-day mortality rate was 5.6% (50 of 885 episodes), and mechanical ventilation or vasopressor support were required in 94 episodes (10.6%). Outcomes were not compromised by receipt of narrowerspectrum β-lactams, and they did not differ on the basis of whether a pathogen was identified. Conclusions. The vast majority of patients with CAP can be treated successfully with narrow-spectrum β-lactam treatment, such as penicillin combined with doxycycline or a macrolide. Greater use of such therapy could potentially reduce the emergence of antibiotic resistance among common bacterial pathogens. Members of the study group are listed at the end of the text.

Systematic evaluation is advocated for difficult asthma, but how best to deliver such care is unclear and outcome data are scarce.We describe our institution's structured approach to difficult asthma management and report on the outcomes of such an approach.Eighty-two consecutive patients with difficult asthma referred to our clinic from respiratory specialists were evaluated in 3 key areas: diagnostic confirmation, comorbidity detection, and inflammatory phenotyping. We then optimized treatment including relevant comorbidity interventions. The outpatient protocol was supported by comorbidity questionnaires, an electronic clinic template, and standardized panel discussion. Asthma outcomes were assessed at 6 months.Sixty-eight patients completed follow-up. Asthma diagnosis was refuted in 3 patients and the remaining 65 patients were included in the study analysis. There was no overall escalation of inhaled or oral corticosteroids. Patients had a median of 3 comorbidities, and a median of 3 comorbidity interventions. Control of chronic rhinosinusitis and dysfunctional breathing improved among patients with these diagnoses (22-item Sino-Nasal Outcome Test score from 47 ± 20 to 37 ± 22, P = .017; Nijmegen score from 32 ± 6 to 25 ± 9, P = .003). There were overall improvements in the Asthma Control Test score (from 14 ± 5 to 16 ± 6, P.001), the Asthma Quality of Life Questionnaire (from 4.29 ± 1.4 to 4.65 ± 1.5, P = .073), and the frequency of exacerbations over 6 months (from 2 [interquartile range, 0-4] to 0 [interquartile range, 0-2], P.001).In patients referred with difficult asthma from respiratory specialists, a structured approach coupled with targeted comorbidity interventions improved control of key comorbidities and enhanced asthma outcomes.

BACKGROUND Patients with difficult asthma suffer chronic moderate to severe persistent asthma symptoms despite high doses of inhaled and oral corticosteroid therapy. These patients suffer a high level of treatment and disease related morbidity but little is known about the degree of airway inflammation in these patients. METHODS Fifty two patients were examined to assess levels of exhaled nitric oxide (NO) as a surrogate marker of inflammatory activity in this condition. From this group, 26 patients were defined with severe symptoms and current physiological evidence of reversible airway obstruction requiring high dose inhaled (⩾2000 μg beclomethasone dipropionate (BDP) equivalent) or oral steroid therapy to maintain disease control. RESULTS Exhaled NO levels were higher in subjects with difficult asthma (mean 13.9 ppb, 95% CI 9.3 to 18.5) than in normal controls (7.4 ppb, 95% CI 6.9 to 7.8; p CONCLUSIONS Exhaled NO may serve as a useful complement to lung function and symptomatology in the assessment of patients with chronic severe asthma, and in the control and rationalisation of steroid therapy in these patients.

Background The diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in asthma is often made in patients with total serum IgE levels greater than 1,000 IU/mL in conjunction with evidence of Aspergillus sensitization. The specificity of total serum IgE for the diagnosis of ABPA is low even when combined with serum Aspergillus specific IgE. Objective To determine the prevalence of ABPA and to identify alternative clinical predictors for ABPA among asthmatic patients with a total serum IgE level greater than 1,000 IU/ml. Methods This study was conducted in a tertiary hospital in Melbourne, Australia, with a large asthma and allergy service. Patients with asthma and total serum IgE levels greater than 1,000 IU/ml from January 1, 2005, through December 31, 2014, were included. Patients were considered to have concomitant allergic conditions if they had atopic eczema, allergic rhinitis, or both. The diagnosis of ABPA was based on the managing physician's documented diagnosis and referenced to criteria proposed by the International Society for Human and Fungal Mycology. Results The prevalence of ABPA in our cohort was 15.8%. Older age, elevated total serum IgE level, reduced lung function, and the absence of other concomitant allergic conditions increased the risk of ABPA. After multivariate logistic regression, patients without concomitant allergic conditions had an odds ratio of 4.4 (95% confidence interval, 1.9–10.1; P = .001) for ABPA when compared with patients with allergic conditions. Conclusion The absence of atopic eczema and allergic rhinitis in these patients increases the likelihood of ABPA. Eliciting an accurate allergy history may be a useful bedside clinical tool when considering the diagnosis of ABPA.

SummaryBackgroundThe 6-Minute Walk Test (6MWT) is a widely used measurement of functional exercise capacity in chronic lung disease. While exercise intolerance has been identified in patients with bronchiectasis, the clinical determinants of the 6MWT in this population have not been examined. The aim of this study was to 1) establish the relationship between the 6-Minute Walk Distance (6MWD), disease severity and Health-Related Quality of Life (HRQOL) and 2) identify predictors of exercise tolerance in adults with bronchiectasis.MethodsThe 6MWT was performed in 27 patients with bronchiectasis (mean [SD] FEV1 73.9% predicted [23.4]). Disease severity was assessed using spirometry and HRCT scoring while HRQOL was evaluated using the St George's Respiratory Questionnaire (SGRQ) and the Short-Form 36 (SF-36). The relationships were evaluated using correlation and multiple regression.ResultsThe 6MWD correlated positively with FVC (r=0.52, p0.5, p

The airways in patients with cystic fibrosis (CF) are characterized by the accumulation of tenacious, dehydrated mucus that is a precursor for chronic infection, inflammation, and tissue destruction. The clearance of mucus is an integral component of daily therapy. Inhaled mannitol is an osmotic agent that increases the water content of the airway surface liquid, and improves the clearance of mucus with the potential to improve lung function and respiratory health. To this end, this study examined the efficacy and safety of therapy with inhaled mannitol over a 2-week period.This was a randomized, double-blind, placebo-controlled, crossover study. Thirty-nine subjects with mild-to-moderate CF lung disease inhaled 420 mg of mannitol or placebo twice daily for 2 weeks. Following a 2-week washout period, subjects were entered in the reciprocal treatment arm. Lung function, respiratory symptoms, quality of life, and safety were assessed.Mannitol treatment increased FEV(1) from baseline by a mean of 7.0% (95% confidence interval [CI], 3.3 to 10.7) compared to placebo 0.3% (95% CI, - 3.4 to 4.0; p0.001). The absolute improvement with mannitol therapy was 121 mL (95% CI, 56.3 to 185.7), which was significantly more than that with placebo (0 mL; 95% CI, - 64.7 to 64.7). The forced expiratory flow in the middle half of the FVC increased by 15.5% (95% CI, - 6.5 to 24.6) compared to that with placebo (increase, 0.7%; 95% CI, - 8.3 to 9.7; p0.02). The safety profile of mannitol was adequate, and no serious adverse events related to treatment were observed.Inhaled mannitol treatment over a period of 2 weeks significantly improved lung function in patients with CF. Mannitol therapy was safe and well tolerated.(ClinicalTrials.gov) Identifier: NCT00455130.

We have recently published two manuscripts on the effects of interleukin (IL)-5 administration to patients with mild asthma in the American Journal of Respiratory & Critical Care Medicine 1 and in Thorax .2 We are addressing this letter to the Editors of both journals. The data described in both papers have been obtained from one experiment performed in the same group of patients with mild asthma. While the paper in the American Journal of Respiratory & Critical …

Asthma is characterized by the accumulation of activated T cells and eosinophils within the airway. Eosinophils derive from CD34(+) bone marrow progenitor cells under the influence of hematopoietic growth factors, subsequently migrating to the airways under the cooperative influence of interleukin (IL)-5 and chemokines, including eotaxin. We compared the relative effects of systemic versus local IL-5 on progenitor-cell mobilization and mature eosinophil phenotype by using flow cytometry, following the administration of intravenous (2 microg) or inhaled (15 microg) IL-5 to nine patients with mild asthma. Intravenous IL-5 induced a rapid reduction in circulating eosinophil counts followed by prolonged blood eosinophilia. Both intravenous (p0.002) and inhaled (p0.05) IL-5 significantly increased CD34(+)/CD45(+) lymphoblastoid eosinophil progenitors. Intravenous IL-5 increased mature eosinophil CCR3 expression from a baseline mean fluorescence intensity (MFI) of 658 +/- 51.7 to 995 +/- 93.2 at 24 h (p0.05), but had no effect on interleukin-5 receptor subunit alpha or CD11b expression. Lymphocyte CCR3 MFI was increased by intravenous IL-5 from 38.5 +/- 13.6 at baseline to 73.6 +/- 14.3 at 24 h (p0.05). Systemic IL-5 increased circulating eosinophil progenitors, suggesting a key role for systemic IL-5 in eosinophil mobilization. Further, IL-5 causes terminal maturation of the eosinophil by increasing CCR3 expression, potentially affecting CCR3-dependent chemotaxis by eosinophils and lymphocytes.

Objective To develop reference intervals (RIs) for sweat chloride and sodium in healthy children, adolescents, and adults. Study design Healthy, unrelated subjects aged from 5 to >50 years and subjects who were pancreatic insufficient with cystic fibrosis (CF) were recruited. Sweat collection was performed on all subjects with the Wescor Macroduct system. Sweat electrolytes were analyzed with direct ion selective electrodes. ΔF508 mutation analysis was performed on the healthy subjects ≥15 years old. Results A total of 282 healthy and 40 subjects with CF were included for analysis. There was no overlap of sweat chloride between the group with CF and the group without CF, but there was some overlap of sweat sodium. Sweat chloride increased with age, with the rate of increase slowing progressively to zero after the age of 19 years. The estimated median (95% RI) for sweat chloride were: 5 to 9 years, 13 mmol/L (1-39 mmol/L); 10 to 14 years, 18mmol/L (3-47 mmol/L); 15 to 19 years, 20 mmol/L (3-51mmol/L); and 20+ years 23 mmol/L (5-56mmol/L). Conclusions We have successfully developed the age-related RI for sweat electrolytes, which will be useful for clinicians interpreting sweat test results from children, adolescents, and adults.