Search

The outbreak of the COVID-19 pandemic in late 2019 and in 2020 presented challenges to healthcare workers (HCW) around the world that were unexpected and dramatic. The relentless progress of infection, starting in China and rapidly spreading to Europe, North America and elsewhere gave more remote countries, like Australia, time to prepare but also time for unease. HCW everywhere had to readjust and change their work practices to cope. Further waves of infection and transmission with newer variants pose challenges to HCW and health systems, even after mass vaccination. Respiratory medicine HCW found themselves at the frontline, developing critical care services to support intensive care units and grappling with unanticipated concerns about safety, risk and the need to retrain. Several studies have addressed the need for rapid changes in the healthcare workforce for COVID-19 and the impact of this preparation on HCW themselves. In this paper, we present a scoping review of the literature on preparing HCW for the pandemic, explore the Australian experience of building the respiratory workforce and propose evidence-based recommendations to sustain this workforce in an unprecedented high-risk environment.

Though clinical guidelines recommend influenza vaccination for chronic obstructive pulmonary disease (COPD) patients and other high-risk populations, it is unclear whether current vaccination strategies induce optimal antibody responses. This study aimed to identify key variables associated with strain-specific antibody responses in COPD patients and healthy older people. 76 COPD and 72 healthy participants were recruited from two Australian centres and inoculated with influenza vaccine. Serum strain-specific antibody titres were measured pre- and post-inoculation. Seroconversion rate was the primary endpoint. Antibody responses varied between vaccine strains. The highest rates of seroconversion were seen with novel strains (36-55%), with lesser responses to strains included in the vaccine in more than one consecutive year (27-33%). Vaccine responses were similar in COPD patients and healthy participants. Vaccine strain, hypertension and latitude were independent predictors of seroconversion. Our findings reassure that influenza vaccination is equally immunogenic in COPD patients and healthy older people; however, there is room for improvement. There may be a need to personalise the yearly influenza vaccine, including consideration of pre-existing antibody titres, in order to target gaps in individual antibody repertoires and improve protection.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is established as the preferred method of mediastinal lymph node (LN) staging in non-small cell lung cancer (NSCLC). Selective (targeted) LN sampling is most commonly performed however studies in early stage NSCLC and locally advanced NSCLC confirm systematic EBUS-TBNA evaluation improves accuracy of mediastinal staging. This study aims to establish the rate of detection of positron emission tomography (PET)-occult LN metastases following systematic LN staging by EBUS-TBNA, and to determine the utility of systematic mediastinal staging for accurate delineation of radiation treatment fields in patients with locally advanced NSCLC. METHODS: Consecutive patients undergoing EBUS-TBNA for diagnosis/staging of locally advanced NSCLC will be enrolled in this international multi-centre single arm study. Systematic mediastinal LN evaluation will be performed, with all LN exceeding 6 mm to be sampled by TBNA. Where feasible, endoscopic ultrasound staging (EUS-B) may also be performed. Results of minimally invasive staging will be compared to FDG-PET. The primary end-point is proportion of patients in whom systematic LN staging identified PET-occult NSCLC metastases. Secondary outcome measures include (i) rate of nodal upstaging, (ii) false positive rate of PET for mediastinal LN assessment, (iii) analysis of clinicoradiologic risk factors for presence of PET-occult LN metastases, (iv) impact of systematic LN staging in patients with discrepant findings on PET and EBUS-TBNA on target coverage and dose to organs at risk (OAR) in patients undergoing radiotherapy. DISCUSSION: With specificity of PET of 90%, guidelines recommend tissue confirmation of positive mediastinal LN to ensure potentially early stage patients are not erroneously denied potentially curative resection. However, while confirmation of pathologic LN is routinely sought, the exact extent of mediastinal LN involvement in NSCL

BACKGROUND: Peripheral pulmonary lesion (PPL) incidence is rising because of increased chest imaging sensitivity and frequency. For PPLs suspicious for lung cancer, current clinical guidelines recommend tissue diagnosis. Radial endobronchial ultrasound (R-EBUS) is a bronchoscopic technique used for this purpose. It has been observed that diagnostic yield is impacted by the ability to accurately manipulate the radial probe. However, such skills can be acquired, in part, from simulation training. Three-dimensional (3D) printing has been used to produce training simulators for standard bronchoscopy but has not been specifically used to develop similar tools for R-EBUS. OBJECTIVE: We report the development of a novel ultrasound-compatible, anatomically accurate 3D-printed R-EBUS simulator and evaluation of its utility as a training tool. METHODS: Computed tomography images were used to develop 3D-printed airway models with ultrasound-compatible PPLs of "low" and "high" technical difficulty. Twenty-one participants were allocated to two groups matched for prior R-EBUS experience. The intervention group received 15 minutes to pretrain R-EBUS using a 3D-printed model, whereas the nonintervention group did not. Both groups then performed R-EBUS on 3D-printed models and were evaluated using a specifically developed assessment tool. RESULTS: For the "low-difficulty" model, the intervention group achieved a higher score (21.5 ± 2.02) than the nonintervention group (17.1 ± 5.7), reflecting 26% improvement in performance (P = 0.03). For the "high-difficulty" model, the intervention group scored 20.2 ± 4.21 versus 13.3 ± 7.36, corresponding to 52% improvement in performance (P = 0.02). Participants derived benefit from pretraining with the 3D-printed model, regardless of prior experience level. CONCLUSION: 3D-printing can be used to develop simulators for R-EBUS education. Training using these models significantly improves procedural performance and is effective in both novice an

OBJECTIVES: To design and evaluate 3D-printed nasal swabs for collection of samples for SARS-CoV-2 testing. DESIGN: An iterative design process was employed. Laboratory evaluation included in vitro assessment of mock nasopharyngeal samples spiked with two different concentrations of gamma-irradiated SARS-CoV-2. A prospective clinical study compared SARS-CoV-2 and human cellular material recovery by 3D-printed swabs and standard nasopharyngeal swabs. SETTING, PARTICIPANTS: Royal Melbourne Hospital, May 2020. Participants in the clinical evaluation were 50 hospital staff members attending a COVID-19 screening clinic and two inpatients with laboratory-confirmed COVID-19. INTERVENTION: In the clinical evaluation, a flocked nasopharyngeal swab sample was collected with the Copan ESwab and a mid-nasal sample from the other nostril was collected with the 3D-printed swab. RESULTS: In the laboratory evaluation, qualitative agreement with regard to SARS-CoV-2 detection in mock samples collected with 3D-printed swabs and two standard swabs was complete. In the clinical evaluation, qualitative agreement with regard to RNase P detection (a surrogate measure of adequate collection of human cellular material) in samples collected from 50 hospital staff members with standard and 3D-printed swabs was complete. Qualitative agreement with regard to SARS-CoV-2 detection in three pairs of 3D-printed mid-nasal and standard swab samples from two inpatients with laboratory-confirmed SARS-CoV-2 was also complete. CONCLUSIONS: Using 3D-printed swabs to collect nasal samples for SARS-CoV-2 testing is feasible, acceptable to patients and health carers, and convenient.

OBJECTIVES: PD-L1 immunohistochemistry (IHC) is an essential predictive biomarker for patients with non-small cell lung cancer (NSCLC), required to inform treatment decisions regarding anti-PD-1 immune checkpoint inhibitor therapy. This study aims to investigate the concordance between PD-L1 IHC assessed on NSCLC cytology and histology specimens and to determine the impactce of tumour cellularity. METHODS: Matched cytology and histology NSCLC specimens were retrieved from the archives of the Royal Melbourne Hospital and the Royal Prince Alfred Hospital. PD-L1 IHC was performed concurrently on both specimens at the Peter MacCallum Cancer Centre using the SP263 assay kit on the Ventana Benchmark Ultra staining platform and scored by two experienced pathologists. RESULTS: Overall agreement between matched cytology and histology specimens was good (intraclass correlation coefficient = 0.653, n = 58); however, markedly increased when the analysis was limited to cell-blocks with >100 tumour cells (intraclass correlation coefficient = 0.957, n = 29). Specificity at both 1% and 50% cut-offs was high regardless of cellularity; however, sensitivity decreased in samples with <100 tumour cells. CONCLUSIONS: PD-L1 IHC on cytology cell-block specimens in NSCLC is an acceptable alternative to histological specimens, provided adequate tumour cells are present. Clinicians and pathologists should be mindful of the risk of false negative PD-L1 IHC in samples with low tumour cellularity, to avoid excluding patients from potentially beneficial treatment.

BACKGROUND: The Infectious Diseases Society of America influenza guidelines no longer require fever as part of their influenza case definition in patients requiring hospitalization. However, the impact of fever or lack of fever on clinical decision-making and patient outcomes has not been studied. METHODS: We conducted a retrospective review of adult patients admitted to our tertiary health service between April 2016 and June 2019 with laboratory-confirmed influenza, with and without fever (≥37.8ºC). Patient demographics, presenting features, and outcomes were analyzed using Pearson's chi-square test, the Wilcoxon rank-sum test, and logistic regression. RESULTS: Of 578 influenza inpatients, 219 (37.9%) had no fever at presentation. Fever was less likely in individuals with a nonrespiratory syndrome (adjusted odds ratio [aOR], 0.44; 95% CI, 0.26-0.77), symptoms for ≥3 days (aOR, 0.53; 95% CI, 0.36-0.78), influenza B infection (aOR, 0.45; 95% CI, 0.29-0.70), chronic lung disease (aOR, 0.55; 95% CI, 0.37-0.81), age ≥65 (aOR, 0.36; 95% CI, 0.23-0.54), and female sex (aOR, 0.69; 95% CI, 0.48-0.99). Patients without fever had lower rates of testing for influenza in the emergency department (64.8% vs 77.2%; P = .002) and longer inpatient stays (median, 2.4 vs 1.9 days; P = .015). These patients were less likely to receive antiviral treatment (55.7% vs 65.6%; P = .024) and more likely die in the hospital (3.2% vs 0.6%; P = .031), and these differences persisted after adjustment for potential confounders. CONCLUSIONS: Absence of fever in influenza is associated with delayed diagnosis, longer length of stay, and higher mortality.

Rationale: Chronic bronchitis (CB) is characterized by productive cough with excessive mucus production, resulting in quality-of-life impairment and increased exacerbation risk. Bronchial rheoplasty uses an endobronchial catheter to apply nonthermal pulsed electrical fields to the airways. Preclinical studies have demonstrated epithelial ablation followed by regeneration of normalized epithelium.Objectives: To evaluate the feasibility, safety, and initial outcomes of bronchial rheoplasty in patients with CB.Methods: Pooled analysis of two separate studies enrolling 30 patients undergoing bilateral bronchial rheoplasty was conducted. Follow-up through 6 months (primary outcome) and 12 months included assessment of adverse events, airway histology, and changes in symptoms using the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test and St. George's Respiratory Questionnaire (SGRQ).Measurements and Main Results: Bronchial rheoplasty was performed in all 30 patients (63% male; mean [SD] age, 67 [7.4]; mean [SD] postbronchodilator FEV1, 65% [21%]; mean [SD] COPD Assessment Test score 25.6 [7.1]; mean [SD] SGRQ score, 59.6 [15.3]). There were no device-related and four procedure-related serious adverse events through 6 months, and there were none thereafter through 12 months. The most frequent nonserious, device- and/or procedure-related event through 6 months was mild hemoptysis in 47% (14 of 30) patients. Histologically, the mean goblet cell hyperplasia score was reduced by a statistically significant amount (P < 0.001). Significant changes from baseline to 6 months in COPD Assessment Test (mean, -7.9; median, -8.0; P = 0.0002) and SGRQ (mean, -14.6; median, -7.2; P = 0.0002) scores were observed, with similar observations through 12 months.Conclusions: This study provides the first clinical evidence of the feasibility, safety, and initial outcomes of bronchial rheoplasty in symptomatic patients with CB.Clinical trial registered with www.anzctr.org.au (ACTRN 1

Smoke exposure from bushfires, such as those experienced in Australia during 2019-2020, can reach levels up to 10 times those deemed hazardous. Short-term and extended exposure to high levels of air pollution can be associated with adverse health effects, although the most recent fires have brought into sharp focus that several important knowledge gaps remain. In this article, we briefly identify and discuss the existing Australian evidence base and make suggestions for future research.

The SARS-CoV-2 pandemic is unprecedented in our professional lives and much effort and resources will be devoted to care of patients (and HCW) affected by this illness. We must also continue to aim for the same standard of care for our non-COVID respiratory patients, while minimizing risks of infection transmission to our colleagues. This commentary addresses the key paired issues of minimizing performance of diagnostic/staging bronchoscopy in patients with suspected/known lung cancer while maximizing the safety of the procedure with respect to HCW transmission of COVID-19.

Introduction Endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA) represents a minimally invasive approach in the evaluation of mediastinal/hilar lymphadenopathy. Diagnostic performance of EBUS‐TBNA in lymphoma using standard 22‐gauge (22G) needle is limited by sample volumes that are often inadequate for histopathological assessment. Objectives To evaluate the diagnostic utility of 19‐gauge (19G) EBUS‐TBNA needle in the evaluation of suspected lymphoma. Methods We prospectively collected clinical and procedural information for patients undergoing EBUS‐TBNA with 19G needle at Royal Melbourne Hospital for investigation of mediastinal/hilar lymphadenopathy, where lymphoma was considered in the differential diagnosis. All consecutive patients between June 15, 2016 and July 10, 2019 were included. If definitive diagnosis was not achieved on EBUS‐TBNA, final diagnosis was determined through subsequent investigation or a minimum of 6 months radiologic surveillance. Results Thirty‐nine patients underwent EBUS‐TBNA using 19G needle for evaluation of suspected lymphoma. Thirteen patients had a prior diagnosis of lymphoma (33%). Lymphoma was ultimately diagnosed in 23 patients (59%). Of these, 10 had a prior diagnosis of lymphoma (43%). 19G EBUS‐TBNA demonstrated lymphoma in 19 patients, with a sensitivity of 83% (95% CI 66‐93) for detection of lymphoma. Four patients required surgical biopsy to definitively characterise lymphoma subtype. Therefore, sensitivity of 19G EBUS‐TBNA for definitive diagnosis of lymphoma was 65% (95% CI 45‐81). In patients with a prior diagnosis of lymphoma, sensitivity for definitive diagnosis of lymphoma was 80% (95% CI 48‐95). Conclusion Diagnostic performance of 19G EBUS‐TBNA appears similar to standard 22G needle in detection and definitive diagnosis of lymphoma. Further invasive testing remains necessary following non‐diagnostic EBUS‐TBNA procedures.

Our understanding of genomic heterogeneity in lung cancer is largely based on the analysis of early-stage surgical specimens. Here we used endoscopic sampling of paired primary and intrathoracic metastatic tumors from 11 lung cancer patients to map genomic heterogeneity inoperable lung cancer with deep whole-genome sequencing. Intra-patient heterogeneity in driver or targetable mutations was predominantly in the form of copy number gain. Private mutation signatures, including patterns consistent with defects in homologous recombination, were highly variable both within and between patients. Irrespective of histotype, we observed a smaller than expected number of private mutations, suggesting that ancestral clones accumulated large mutation burdens immediately prior to metastasis. Single-region whole-genome sequencing of from 20 patients showed that tumors in ever-smokers with the strongest tobacco signatures were associated with germline variants in genes implicated in the repair of cigarette-induced DNA damage. Our results suggest that lung cancer precursors in ever-smokers accumulate large numbers of mutations prior to the formation of frank malignancy followed by rapid metastatic spread. In advanced lung cancer, germline variants in DNA repair genes may interact with the airway environment to influence the pattern of founder mutations, whereas similar interactions with the tumor microenvironment may play a role in the acquisition of mutations following metastasis.

Objectives: Patients suitable for radical chemoradiotherapy for lung cancer routinely have radiotherapy (planning) volumes based on positron emission tomography (PET)-computed tomography (CT) imaging alone. Endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) can identify PET-occult malignancy and benign PET-avid regions. We investigated the impact of EBUS-TBNA on curative-intent radiotherapy in non-small cell lung cancer (NSCLC). Methods: A prospective multicentre trial was undertaken, investigating the impact of systematic EBUS-TBNA in addition to PET-CT for patients considered for radical chemoradiotherapy with NSCLC. A subset analysis of patients with discordant findings between PET-CT and EBUS-TBNA was performed. Radiotherapy plans investigated tumour coverage and dose to critical organs at risk (OARs) using PET-CT alone in comparison to PET-CT and EBUS-TBNA. Results: Of 30 patients enrolled, 10 had discordant findings between PET-CT and EBUS-TBNA. EBUS-TBNA-derived plans allowed for reduction in dose to OARs in patients downstaged by EBUS-TBNA, and reduced the risk of geographic miss in treating PET-occult disease in four patients where EBUS-TBNA identified malignant involvement of PET-negative lymphadenopathy. With the addition of EBUS-TBNA to radiotherapy planning, reductions were noted of 5.7%, 3.7% and 12.5% for the risks of symptomatic pneumonitis, mean heart dose and mean oesophageal dose, respectively. Conclusions: This study demonstrates for the first time that systematic EBUS-TBNA prior to radical-intent radiotherapy significantly improves coverage of subclinical disease through detection of PET-occult metastases. Identification of false-positive lymph node involvement in highly selected cases may reduce radiation dose to critical structures, and risk of organ toxicity.

BACKGROUND: The treatment of choice for early stage non-small cell lung cancer (NSCLC) is surgical resection. Little is known about the short- and long-term outcomes among very elderly patients. We sought to determine predictors of short- and long-term survival among octogenarians undergoing curative-intent resection for NSCLC in Victoria, Australia. METHODS: We retrospectively reviewed data from all patients aged ≥80 years who underwent curative-intent resection for NSCLC over 12 years (January 2005-December 2016) across five tertiary centres. We examined effect of age, stage of disease, extent of surgery and lung function on short- and long-term survival. RESULTS: Two hundred patients aged ≥80 years underwent curative-intent resections. Mortality at 30 and 120 days was 2.9% and 5.9%, respectively. Increased early mortality was observed among those ≥83 years, at 30 days (6.8% versus 0.8%, P = 0.044) and 120 days (12.2% versus 2.3%, P = 0.0096). Early mortality was highest among patients ≥83 years requiring lobectomy, compared to sub-lobar resection at 120 days (17% versus 3.8%, P = 0.019). Long-term survival was predicted by age and stage of disease. Among patients with Stage I disease aged <83 years, lobectomy was associated with superior 5-year survival, compared to sub-lobar resection (83% versus 61%, P = 0.02). CONCLUSION: In carefully selected elderly patients undergoing curative-intent resection of early stage NSCLC, both short- and long-term outcomes appear consistent with younger historical cohorts. Early mortality was associated with lobectomy in those with advanced age. Older patients undergoing lobectomy appeared to be at highest risk for early mortality, while younger patients with Stage I disease undergoing at least lobectomy appear to have the best long-term survival.

BACKGROUND AND OBJECTIVE: Non-invasive ventilation (NIV) improves clinical outcomes in hypercapnic acute exacerbations of COPD (AECOPD), but the optimal model of care remains unknown. METHODS: We conducted a prospective observational non-inferiority study comparing three models of NIV care: general ward (Ward) (1:4 nurse to patient ratio, thrice weekly consultant ward round), a high dependency unit (HDU) (1:2 ratio, twice daily ward round) and an intensive care unit (ICU) (1:1 ratio, twice daily ward round) model in three similar teaching tertiary hospitals. Changes in arterial blood gases (ABG) and clinical outcomes were compared and corrected for differences in AECOPD severity (Blood urea > 9 mmol/L, Altered mental status (Glasgow coma scale (GCS) < 14), Pulse > 109 bpm, age > 65 (BAP-65)) and co-morbidities. An economic analysis was also undertaken. RESULTS: There was no significant difference in age (70 ± 10 years), forced expiratory volume in 1 s (FEV1 ) (0.84 ± 0.35 L), initial pH (7.29 ± 0.08), partial pressure of CO2 in arterial blood (PaCO2 ) (72 ± 22 mm Hg) or BAP-65 scores (2.9 ± 1.01) across the three models. The Ward achieved an increase in pH (0.12 ± 0.07) and a decrease in PaCO2 (12 ± 18 mm Hg) that was equivalent to HDU and ICU. However, the Ward treated more patients (38 vs 28 vs 15, P < 0.001), for a longer duration in the first 24 h (12.3 ± 4.8 vs 7.9 ± 4.1 vs 8.4 ± 5.3 h, P < 0.05) and was more cost-effective per treatment day ($AUD 1231 ± 382 vs 1745 ± 2673 vs 2386 ± 1120, P < 0.05) than HDU and ICU. ICU had a longer hospital stay (9 ± 11 vs 7 ± 7 vs 13 ± 28 days, P < 0.002) compared with the Ward and HDU. There was no significant difference in intubation rate or survival. CONCLUSION: In acute hypercapnic Chronic obstructive pulmonary disease (COPD) patients, the Ward model of NIV care achieved equivalent clinical outcomes, whilst being more cost-effective than HDU or ICU models.

Solid pulmonary nodules are a common finding requiring serial computed tomography (CT) imaging. We sought to explore the detection and measurement accuracy of an ultralow-dose CT (ULDCT) protocol compared with our standard low-dose CT (LDCT) nodule follow-up protocol.In this pragmatic single-center pilot prospective cohort study, patients scheduled for clinically indicated CT surveillance of 1 or more known solid pulmonary nodules >2 mm underwent ULDCT immediately after routine LDCT. The Bland-Altman 95% limits of agreement for diameter and volumetry were calculated.In all, 57 patients underwent 60 imaging episodes, with 170 evaluable nodules. ULDCT detected all known solid pulmonary nodules >2 mm. Bland-Altman analyses demonstrated clinically agreement for both nodule diameter and volume, both of which fell within prespecified limits.This single-center pilot study suggests that ULDCT may be of use in surveillance of known solid pulmonary nodules >2 mm.

BACKGROUND: Transoesophageal endobronchial ultrasound (EBUS) video-bronchoscope insertion provides pulmonologists access to conduct endoscopic fine-needle aspiration (EUS-B-FNA) of mediastinal lymph node (LN) lesions and also assist in lung cancer staging by sampling left adrenal gland (LAG) lesions. Limited literature has described additional diagnostic value whilst maintaining patient safety. To elicit whether combining endoscopic transoesophageal fine-needle aspiration using convex probe bronchoscope (EUS-B-FNA) and EBUS bronchoscopy enhances the diagnostic yield of mediastinal nodal staging in lung cancer, whilst maintaining safety. METHODS: All eligible patients with paraoesophageal lesions on thoracic computed tomography (CT) underwent pulmonologist-performed EUS-B-FNA at two tertiary centres and were included in this prospective observational cohort study. RESULTS: EUS-B-FNA sampling was performed at 69 mediastinal LN lesion sites, including 17 sites inaccessible to bronchoscopic sampling. Four LAG lesions were sampled via EUS-B-FNA. There were no complications. EBUS-TBNA was augmented by EUS-B-FNA because of accessibility of sampling lesions otherwise unamenable bronchoscopically, thereby increasing diagnostic utility. Diagnostic sensitivity of EUS-B-FNA for malignancy in mediastinal LN lesions was 88% (51 of 58). For mediastinal LN lesions not amenable to EBUS-TBNA, the sensitivity for diagnosis of malignancy via EUS-B-FNA was 88% (15 of 17). Diagnostic sensitivity of EUS-B-FNA for malignancy in LAG lesions was 50% (2 of 4). CONCLUSION: EUS-B-FNA is a precise and safe approach in the evaluation and staging of lung cancer when performed by a pulmonologist. It complements and increases the diagnostic utility of EBUS-TBNA by further coverage of mediastinal LN stations and access to LAG lesions.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD) and co-morbid cardiovascular disease, emerging evidence suggests a benefit in commencing cardioselective beta-blockers. AIM: Our objective was to determine the safety of beta-blocker commencement during hospitalisation for acute exacerbation of COPD. METHODS: A retrospective cohort study of 1071 patients hospitalised for acute exacerbation of COPD was conducted across two tertiary hospitals over a 12-month period. We identified 36 patients in whom beta-blocker therapy was commenced during admission. The primary outcome of the study was to assess cardiovascular and respiratory adverse events related to the commencement of beta-blocker therapy. RESULTS: The most common indications for beta-blockers were atrial fibrillation (53%) and acute coronary syndrome (36%). Metoprolol was the most commonly prescribed beta-blocker (75%). No patients suffered clinically significant declines of respiratory function following the commencement of a beta-blocker, including worsening respiratory symptoms, oxygen, bronchodilator or ventilation requirements. These results were demonstrable in patients with reversible airways disease and advanced COPD. Only one patient (2.8%) experienced symptomatic hypotension after 48 h of therapy. CONCLUSION: The commencement of cardioselective beta-blockers during acute exacerbations of COPD appears to be well-tolerated.

Matrix metalloproteinase-9 (MMP-9) is increased in a number of pathological lung conditions, where the proteinase contributes to deleterious remodelling of the airways. While both lung cancer and COPD are associated with increased MMP-9 expression, the cellular and molecular drivers of MMP-9 remain unresolved. In this study, MMP-9 transcript measured within the tumour region from patients with non-small-cell lung cancer (NSCLC) and coexisting COPD was found to be uniformly increased relative to adjacent tumour-free tissue. MMP-9 gene expression and immunohistochemistry identified tumour-associated neutrophils, but not macrophages, as a predominant source of this proteinase. In addition, PTEN gene expression was significantly reduced in tumour and there was evidence of epithelial MMP-9 expression. To explore whether PTEN can regulate epithelial MMP-9 expression, a small interfering (si)RNA knockdown strategy was used in Beas-2B bronchial epithelial cells. PTEN knockdown by siRNA selectively increased MMP-9 expression in response to lipopolysaccharide in a corticosteroid-insensitive manner. In summary, tumour-associated neutrophils represent an important source of MMP-9 in NSCLC, and loss of epithelial PTEN may further augment steroid-insensitive expression.

The development of easily accessible tools for human immunophenotyping to classify patients into discrete disease endotypes is advancing personalized therapy. However, no systematic approach has been developed for the study of inflammatory lung diseases with often complex and highly heterogeneous disease etiologies. We have devised an internally standardized flow cytometry approach that can identify parallel inflammatory alveolar macrophage phenotypes in both the mouse and human lungs. In mice, lung innate immune cell alterations during endotoxin challenge, influenza virus infection, and in two genetic models of chronic obstructive lung disease could be segregated based on the presence or absence of CD11b alveolar macrophage upregulation and lung eosinophilia. Additionally, heightened alveolar macrophage CD11b expression was a novel feature of acute lung exacerbations in the SHIP-1(-/-) model of chronic obstructive lung disease, and anti-CD11b antibody administration selectively blocked inflammatory CD11b(pos) but not homeostatic CD11b(neg) alveolar macrophages in vivo. The identification of analogous profiles in respiratory disease patients highlights this approach as a translational avenue for lung disease endotyping and suggests that heterogeneous innate immune cell phenotypes are an underappreciated component of the human lung disease microenvironment.

Despite known limitations of positron emission tomography (PET) for mediastinal staging of non-small cell lung cancer (NSCLC), radiation treatment fields are generally based on PET-identified disease extent. However, no studies have examined the accuracy of FDG-PET/CT on a per-node basis in patients being considered for curative-intent radiotherapy in NSCLC.In a prospective trial, patients with NSCLC being considered for definitive thoracic radiotherapy (± systemic chemotherapy) underwent minimally invasive systematic mediastinal evaluation with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) following noninvasive staging with integrated PET-CT.Thirty patients underwent EBUS-TBNA, with TBNA performed from a mean 2.5 lymph node (LN) stations per patient (median 3, range 1-5). Discordant findings between PET-CT and EBUS-TBNA were observed in 10 patients (33%, 95% CI 19%-51%). PET-occult LN metastases were demonstrated by EBUS in 4 patients, whereas a lesser extent of mediastinal involvement, compared with FDG-PET, was demonstrated by EBUS in 6 patients, including 2 patients downstaged from cN3 to pN2. LNs upstaged by EBUS were significantly smaller than nodes downstaged by EBUS, 7.5 mm (range 7-9) versus 12 mm (range 6-21), P = 0.005.A significant proportion of patients considered for definitive radiotherapy (+/-chemotherapy) undergoing systematic mediastinal evaluation with EBUS-TBNA in this study have an extent of mediastinal NSCLC involvement discordant with that indicated by PET-CT. Systematic EBUS-TBNA may aid in defining the extent of mediastinal involvement in NSCLC patients undergoing radiotherapy. Systematic EBUS-TBNA has the potential to contribute significantly to radiotherapy planning and delivery, by either identifying occult nodal metastases, or demonstrating FDG-avid LNs to be disease-free.

Patient-derived xenograft (PDX) models generated from surgical specimens are gaining popularity as preclinical models of cancer. However, establishment of PDX lines from small cell lung cancer (SCLC) patients is difficult due to very limited amount of available biopsy material. We asked whether SCLC cells obtained from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) could generate PDX lines that maintained the phenotypic and genetic characteristics of the primary tumor. Following successful EBUS-TBNA sampling for diagnostic purposes, we obtained an extra sample for cytologic analysis and implantation into the flanks of immunodeficient mice. Animals were monitored for engraftment for up to 6 months. Histopathologic and immunohistochemical analysis, and targeted next-generation re-sequencing, were then performed in both the primary sample and the derivative PDX line. A total of 12 patients were enrolled in the study. EBUS-TBNA aspirates yielded large numbers of viable tumor cells sufficient to inject between 18,750 and 1,487,000 cells per flank, and to yield microgram quantities of high-quality DNA. Of these, samples from 10 patients generated xenografts (engraftment rate 83%) with a mean latency of 104 days (range 63-188). All but one maintained a typical SCLC phenotype that closely matched the original sample. Identical mutations that are characteristic of SCLC were identified in both the primary sample and xenograft line. EBUS-TBNA has the potential to be a powerful tool in the development of new targeting strategies for SCLC patients by providing large numbers of viable tumor cells suitable for both xenografting and complex genomic analysis.

Immunisation programs are designed to reduce serious morbidity and mortality from influenza, but most evidence supporting the effectiveness of this intervention has focused on disease in the community or in primary care settings. We aimed to examine the effectiveness of influenza vaccination against hospitalisation with confirmed influenza. We compared influenza vaccination status in patients hospitalised with PCR-confirmed influenza with patients hospitalised with influenza-negative respiratory infections in an Australian sentinel surveillance system. Vaccine effectiveness was estimated from the odds ratio of vaccination in cases and controls. We performed both simple multivariate regression and a stratified analysis based on propensity score of vaccination. Vaccination status was ascertained in 333 of 598 patients with confirmed influenza and 785 of 1384 test-negative patients. Overall estimated crude vaccine effectiveness was 57% (41%, 68%). After adjusting for age, chronic comorbidities and pregnancy status, the estimated vaccine effectiveness was 37% (95% CI: 12%, 55%). In an analysis accounting for a propensity score for vaccination, the estimated vaccine effectiveness was 48.3% (95% CI: 30.0, 61.8%). Influenza vaccination was moderately protective against hospitalisation with influenza in the 2010 and 2011 seasons. © 2013 Cheng et al.

Immunisation programs are designed to reduce serious morbidity and mortality from influenza, but most evidence supporting the effectiveness of this intervention has focused on disease in the community or in primary care settings. We aimed to examine the effectiveness of influenza vaccination against hospitalisation with confirmed influenza. We compared influenza vaccination status in patients hospitalised with PCR-confirmed influenza with patients hospitalised with influenza-negative respiratory infections in an Australian sentinel surveillance system. Vaccine effectiveness was estimated from the odds ratio of vaccination in cases and controls. We performed both simple multivariate regression and a stratified analysis based on propensity score of vaccination. Vaccination status was ascertained in 333 of 598 patients with confirmed influenza and 785 of 1384 test-negative patients. Overall estimated crude vaccine effectiveness was 57% (41%, 68%). After adjusting for age, chronic comorbidities and pregnancy status, the estimated vaccine effectiveness was 37% (95% CI: 12%, 55%). In an analysis accounting for a propensity score for vaccination, the estimated vaccine effectiveness was 48.3% (95% CI: 30.0, 61.8%). Influenza vaccination was moderately protective against hospitalisation with influenza in the 2010 and 2011 seasons.

Neutrophilic inflammation persists in COPD despite best current therapies and it is particularly resistant to inhaled glucocorticosteroids. Persistent neutrophil activation not only contributes to matrix breakdown, but can maintain inflammation through the release of endogenous damage associated molecule patterns (DAMPs). Inhibiting excessive neutrophilic inflammation is challenging as many pathogen recognition receptors can initiate migration and the targeting of downstream signaling molecules may compromise essential host defense mechanisms. Here, we discuss new strategies to combat this inflammation in COPD by focusing on the anti-inflammatory role of ALX/FPR2 receptors. ALX/FPR2 is a promiscuous G-protein coupled receptor (GPCR) responding to lipid and peptide agonists that can either switch on acute inflammation or promote resolution of inflammation. We highlight this receptor as an emerging target in the pathogenesis of COPD because known ALX/FPR2 endogenous agonists are enriched in COPD. Serum Amyloid A (SAA) has recently been discovered to be abundantly expressed in COPD and is a potent ALX/FPR2 agonist that unlike almost all other inflammatory chemoattractants, is induced by glucocorticosteroids. SAA not only initiates lung inflammation via ALX/FPR2 but can allosterically modify this receptor so that it no longer transduces pro-resolving signals from endogenous lipoxins that would otherwise promote tissue healing. We propose that there is an imbalance in endogenous and microbial ALX/FPR2 receptor agonists in the inflamed COPD lung environment that oppose protective anti-inflammatory and pro-resolution pathways. These insights open the possibility of targeting ALX/FPR2 receptors using synthetic agonists to resolve persistent neutrophilic inflammation without compromising essential host defense mechanisms.

OBJECTIVES: To systematically review the instruments used to assess postural control and fear of falling in people with chronic obstructive pulmonary disease (COPD), and to synthesize and evaluate their breadth of content and measurement properties. DATA SOURCES: MEDLINE, EMBASE, Web of Science, CINAHL, CENTRAL, PsycINFO, PEDro, and OTSeeker databases searched in September 2012. STUDY SELECTION: Two independent reviewers performed the selection of articles, the ICF linking process and quality assessment. Only quantitative studies were included, irrespective of language or publication date. DATA EXTRACTION: This systematic review comprised two phases. Phase 1 aimed to identify the commonly used instruments to assess postural control and fear of falling in the COPD literature. The breadth of content of each instrument was examined based on the International Classification of Functioning, Disability and Health (ICF). In phase 2, a measurement property search filter was adopted and used in four electronic databases to retrieve properties reported in the COPD population. The COSMIN checklist was used to assess the methodological quality of each measurement property reported. DATA SYNTHESIS: Seventeen out of 401 publications were eligible in phase 1. Seventeen instruments were identified including 15 for postural control and 2 for fear of falling assessment. The Berg Balance Scale, the Short Physical Performance Battery, and the Activities-specific Balance Confidence (ABC) scale were the most frequently used instruments to assess postural control and fear of falling respectively. The ICF categories covered varied considerably among instruments. The Balance Evaluation Systems test and ABC presented the greatest breadth of content. Measurement properties reported included criterion predictive validity (4 instruments), construct validity (11 instruments) and responsiveness (1 instrument), with inconsistent findings based on 'fair' and 'poor' quality studies. CONCLUSIONS: Dif

BACKGROUND: Asthma exacerbations remain a major unmet clinical need. The difficulty in obtaining airway tissue and bronchoalveolar lavage samples during exacerbations has greatly hampered study of naturally occurring exacerbations. This study was conducted to determine if mRNA profiling of peripheral blood mononuclear cells (PBMCs) could provide information on the systemic molecular pathways involved during asthma exacerbations. METHODOLOGY/PRINCIPAL FINDINGS: Over the course of one year, gene expression levels during stable asthma, exacerbation, and two weeks after an exacerbation were compared using oligonucleotide arrays. For each of 118 subjects who experienced at least one asthma exacerbation, the gene expression patterns in a sample of peripheral blood mononuclear cells collected during an exacerbation episode were compared to patterns observed in multiple samples from the same subject collected during quiescent asthma. Analysis of covariance identified genes whose levels of expression changed during exacerbations and returned to quiescent levels by two weeks. Heterogeneity among visits in expression profiles was examined using K-means clustering. Three distinct exacerbation-associated gene expression signatures were identified. One signature indicated that, even among patients without symptoms of respiratory infection, genes of innate immunity were activated. Antigen-independent T cell activation mediated by IL15 was also indicated by this signature. A second signature revealed strong evidence of lymphocyte activation through antigen receptors and subsequent downstream events of adaptive immunity. The number of genes identified in the third signature was too few to draw conclusions on the mechanisms driving those exacerbations. CONCLUSIONS/SIGNIFICANCE: This study has shown that analysis of PBMCs reveals systemic changes accompanying asthma exacerbation and has laid the foundation for future comparative studies using PBMCs.

BACKGROUND: Known inflammatory markers have limited sensitivity and specificity to differentiate viral respiratory tract infections from other causes of acute exacerbation of COPD (AECOPD). To overcome this, we developed a multi-factorial prediction model combining viral symptoms with inflammatory markers. METHODS: Interleukin-6 (IL-6), serum amyloid A (SAA) and viral symptoms were measured in stable COPD and at AECOPD onset and compared with the viral detection rates on multiplex PCR. The predictive accuracy of each measure was assessed using logistic regression and receiver operating characteristics curve (ROC) analysis. RESULTS: There was a total of 33 viruses detected at the onset of 148 AECOPD, the majority 26 (79%) were picornavirus. Viral symptoms with the highest predictive values were rhinorrhoea [Odds ratio (OR) 4.52; 95% CI 1.99-10.29; P < 0.001] and sore throat (OR 2.64; 95% CI 1.14-6.08; P = 0.022), combined the AUC ROC curve was 0.67. At AECOPD onset patients experienced a 1.6-fold increase in IL-6 (P = 0.008) and 4.5-fold increase in SAA (P < 0.001). The addition of IL-6 to the above model significantly improved diagnostic accuracy compared with symptoms alone (AUC ROC 0.80 (P = 0.012). CONCLUSION: The addition of inflammatory markers increases the specificity of a clinical case definition for viral infection, particularly picornavirus infection.