An Australian COVID-19 respiratory care unit experience.

BACKGROUND: Coronavirus disease (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with a heterogeneous presentation ranging from severe pneumonitis to asymptomatic infection. International studies have demonstrated the utility of respiratory care units (RCUs) to facilitate the delivery of non-invasive ventilation techniques to patients with COVID-19 pneumonitis. AIMS: This study aims to describe the patient characteristics, flow and outcomes of admissions to the Royal Melbourne Hospital (RMH) COVID-19 RCU (CRCU) during its initial period of operation. METHODS: Single-centre retrospective cohort study, all patients admitted to CRCU between 17 September and 10 December 2021 were included in this study. Patient demographics, including comorbidities and limitations of medical treatment, were analysed. Admission source and discharge destination were reviewed. Length of stay was recorded. Finally, in-hospital and CRCU mortality were analysed. RESULTS: Ninety-seven patients, comprising 111 admissions, occurred during the study period with median age of 65 years (48% female). Most patients were admitted from and discharged to the ward. Twenty patients died in hospital (21%), with age, 4C score, comorbidity and presence of obstructive lung disease predicting mortality (area under the curve (AUC) 0.85, P < 0.001). Mortality was significantly higher in those over 65 years of age compared to those under 65 (P < 0.001), or those deemed not for intubation compared to those for intubation (P = 0.0019). CONCLUSIONS: This study demonstrates the feasibility of operating a CRCU within an Australian tertiary healthcare setting.

Post-COVID-19 syndrome/condition or long COVID: Persistent illness after acute SARS CoV-2 infection.

BACKGROUND: Approximately 10 million Australians have had confirmed SARS-CoV-2 infection. The waves of infection in the population have been succeeded by smaller waves of people affected by persistent illness following acute infection. Post-COVID-19 symptoms may extend for months following infection. There is a range of symptoms causing mild to debilitating impairment. OBJECTIVE: This article summarises what is currently understood about the pathophysiology, risk factors, symptoms and how to approach both the assessment and care of people with post-COVID-19 sequelae. DISCUSSION: Currently recommended is a person-centred approach from a multidisciplinary team, with general practitioners centrally coordinating care. As the understanding of post-acute COVID-19 is evolving, regularly updated or 'living guidelines' will be crucial for those affected to be provided with best care within the health system.

The COVID Positive Pathway: a collaboration between public health agencies, primary care, and metropolitan hospitals in Melbourne.

OBJECTIVES: To assess the capacity of the COVID Positive Pathway, a collaborative model of care involving the Victorian public health unit, hospital services, primary care, community organisations, and the North Western Melbourne Primary Health Network, to support people with coronavirus disease 2019 (COVID-19) isolating at home. DESIGN, SETTING, PARTICIPANTS: Cohort study of adults in northwest Melbourne with COVID-19, 3 August - 31 December 2020. MAIN OUTCOME MEASURES: Demographic and clinical characteristics, and social and welfare needs of people cared for in the Pathway, by care tier level. RESULTS: Of 1392 people referred to the Pathway by the public health unit, 858 were eligible for enrolment, and 711 consented to participation; 647 (91%) remained in the Pathway until they had recovered and isolation was no longer required. A total of 575 participants (81%) received care in primary care, mostly from their usual general practitioners; 155 people (22%) received care from hospital outreach services, and 64 (9%) needed high tier care (hospitalisation). Assistance with food and other basic supplies was required by 239 people in the Pathway (34%). CONCLUSIONS: The COVID Positive Pathway is a feasible multidisciplinary, tiered model of care for people with COVID-19. About 80% of participants could be adequately supported by primary care and community organisations, allowing hospital services to be reserved for people with more severe illness or with risk factors for disease progression. The principles of this model could be applied to other health conditions if regulatory and funding barriers to information-sharing and care delivery by health care providers can be overcome.

COVID-19 pandemic 2020: a tertiary Melbourne hospital's experience.

BACKGROUND: The COVID-19 pandemic has affected different parts of Australia in distinct ways across 2020 and 2021. In 2020, Melbourne was the epicentre of COVID-19. As one of the key tertiary centres caring for the patients affected by the outbreaks, the Royal Melbourne Hospital (RMH) managed the majority of the Victorian inpatient caseload. AIMS: To review the demographics, management and outcomes of patients with COVID-19 cared for by the RMH services in 2020. METHODS: A single health service retrospective cohort analysis of demographics, interventions and outcomes was conducted to characterise the RMH experience in 2020. RESULTS: From January to December 2020, 433 patients required admission more than 24 h. The demographics of affected patients and outcomes changed over the course of the study. Overall, 47% (203/433) required oxygen, most frequently (36%; 154/433) with low-flow devices (nasal prongs or hudson mask), and 11% (47/433) of patients required admission to intensive care. We recorded a 30-day mortality of 24% (104/433) mortality overall, rising to over 50% in patients aged over 80 years. CONCLUSIONS: The experience of this health service in 2020 demonstrated changing demographics over time, with associated differences in outcomes; notably marked mortality in older populations, frequent complications and limited inter-site transfer possible with mobilised resources.

The knowns & unknowns of pulmonary toxicity following immune checkpoint inhibitor therapies: a narrative review.

Since their discovery immune checkpoint inhibitors (ICI) have dramatically changed the treatment landscape for many cancers. In addition to their efficacy they are generally well tolerated, however, they have led to a new range of immune-related adverse events (irAEs) including pneumonitis. While not the most frequently reported immune-related adverse event in the clinical trial setting, recent real-world data suggests a significantly higher rate of pneumonitis leading to treatment suspension or cessation. It also appears to disproportionately contribute to immune-related mortality, particularly with anti-PD-1/PD-L1 treatment. While indicators have emerged regarding risk factors, incomplete prospective recording of patient characteristics hampers strong conclusions. Presenting symptoms are non-specific and the differential diagnosis is broad, made more complex by concomitant treatment with traditional chemotherapy or radiotherapy. Radiological findings are diverse and inconsistent terminology makes comparison and more complete characterization difficult. Further, little is known about the role of baseline testing or surveillance for early detection of pneumonitis, or the real-world role of bronchoscopy or biopsy in assessment. Scant literature exists to direct these complex decisions, so treatment guidelines have been published based on expert consensus. Here we provide a narrative review of what is known about ICI pneumonitis and propose key questions to enhance our understanding into the future.

A narrative review of combined stereotactic ablative radiotherapy and immunotherapy in metastatic non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) have significantly improved overall survival (OS) in metastatic non-small cell lung cancer (m-NSCLC). However, not all patients with m-NSCLC benefit from ICIs, and resistance to ICIs is an emerging challenge. The tumour microenvironment (TME) is immunosuppressive, and provides a myriad of mechanisms to facilitate escape of cancer cells from immune surveillance. The TME may also dampen the response to ICIs by inhibiting T cell effector responses. The poor prognosis of m-NSCLC has led to investigation of ICIs combined with other treatments with the intention of modulating the TME and sensitizing tumours to the effects of ICIs. Stereotactic ablative radiotherapy (SABR) in combination with ICIs is an area of intense interest. SABR is thought to evoke a pro-immunogenic response in the TME, with the capacity to turn a "cold", unresponsive tumour to "hot" and receptive to ICI. In addition to improved local response, SABR is postulated to produce a heightened systemic immune response when compared to conventional radiotherapy (RT). Preclinical studies have demonstrated a synergistic effect of SABR + ICIs, and clinical studies in m-NSCLC showed safety and promising efficacy compared to systemic therapies alone. To optimize ICI + SABR, ICI choice, combinations, dosing and length of treatment, as well as sequencing of ICI + SABR all require further investigation. Appropriate sequencing may depend on the ICI(s) being utilized, with differing sites of metastases possibly eliciting differing immune responses. Single versus multisite radiation is controversial, whilst effects of irradiated tumour volume and nodal irradiation are increasingly recognized. Taken together, there is strong preclinical and biological rationale, with emerging clinical evidence, supporting the strategy of combining SABR + ICIs in m-NSCLC.

Bereaved families' experiences of end-of-life decision making for general medicine patients.

BACKGROUND: Family involvement in decision making for hospitalised patients is associated with improved end-of-life care. Yet, these discussions can be challenging for physicians and families and associated with distress, confusion and conflict. There is a need to understand how best to support families involved in decisions regarding the transition from active to palliative treatment in hospital settings. AIM: To explore bereaved families' experiences of end-of-life decision making for general medicine patients. DESIGN: A qualitative exploratory study framed by social constructionism using semistructured interviews and thematic analysis. SETTING AND PARTICIPANTS: The general medicine units of one large public hospital in Melbourne, Australia. We recruited 28 bereaved family members of patients who had received end-of-life care. FINDINGS: Patients and families depended on physicians to explain clinical complexity and treatment beneficence; however, trust in medical judgement was mediated by participant's own interpretations of clinical progress. Families sought to be respected as advocates and experienced distress if physicians disregarded their perspectives and insight concerning patient preferences. Ideally, families supported patients to express their preferences to physicians. Otherwise, families contextualised treatment decisions through their knowledge of patient's values and quality of life. Families often felt burdened by or excluded from medical decision making and experienced distress and confusion regarding their rights to request or refuse treatment. CONCLUSION: Our study highlights how families contribute to decision making to ensure end-of-life care treatments reflect patient preferences. Physicians can ease families' distress around treatment withdrawal by providing a meaningful explanation of complex clinical issues, clarifying decision-making roles and acknowledge families' desire to protect and advocate for their loved one.

The efficacy and safety of varenicline alone versus in combination with nicotine lozenges for smoking cessation among hospitalised smokers (VANISH): study protocol for a randomised, placebo-controlled trial.

INTRODUCTION: Smoking is a leading cause of premature deaths globally. The health benefits of smoking cessation are many. However, majority of quit attempts are unsuccessful. One way to potentially improve success rates is to evaluate new combinations of existing smoking cessation therapies that may work synergistically to decrease the intensity of withdrawal symptoms and cravings. AIMS: To evaluate the feasibility, efficacy and safety of the combination of varenicline and nicotine replacement therapy (NRT) lozenges versus varenicline alone in assisting hospitalised smokers to quit. METHODS AND ANALYSIS: This is a multicentre, randomised, placebo-controlled trial. Adults with a history of smoking ≥10 cigarettes per day on average in the 4 weeks prior to their hospitalisation will be recruited. Participants will be randomly assigned to either the intervention group and will receive varenicline and NRT lozenges, or the control group and will receive varenicline and placebo lozenges. All participants will be actively referred to behavioural support from telephone Quitline. Participants are followed up at 1 and 3 weeks and 3, 6 and 12 months from the start of treatment. The primary outcome is carbon monoxide validated prolonged abstinence from 2 weeks to 6 months after treatment initiation. Secondary outcomes include self-reported and biochemically validated prolonged and point prevalence abstinence at 3, 6 and 12 months, self-reported adverse events, withdrawal symptoms and cravings, adherence to treatment, Quitline sessions attended and others. According to the Russell Standard, all randomised participants will be accounted for in the primary intention-to-treat analysis. ETHICS AND DISSEMINATION: The trial will be conducted in compliance with the protocol, the principles of Good Clinical Practice, the National Health and Medical Research Council National Statement on Ethical Conduct in Human Research (updated 2015) and the Australian Code for the Responsible Conduct of Research (2018). Approval will be sought from the Human Ethics Committees of all the participating hospitals and the university. Written informed consent will be obtained from each participant at the time of recruitment. TRIAL REGISTRATION NUMBER: Australia New Zealand Clinical Trials Registry (ACTRN12618001792213).

Electronic cigarettes: A position statement from the Thoracic Society of Australia and New Zealand.

The TSANZ develops position statements where insufficient data exist to write formal clinical guidelines. In 2018, the TSANZ addressed the question of potential benefits and health impacts of electronic cigarettes (EC). The working party included groups focused on health impacts, smoking cessation, youth issues and priority populations. The 2018 report on the Public Health Consequences of E-Cigarettes from the United States NASEM was accepted as reflective of evidence to mid-2017. A search for papers subsequently published in peer-reviewed journals was conducted in August 2018. A small number of robust and important papers published until March 2019 were also identified and included. Groups identified studies that extended, modified or contradicted the NASEM report. A total of 3793 papers were identified and reviewed, with summaries and draft position statements developed and presented to TSANZ membership in April 2019. After feedback from members and external reviewers, a collection of position statements was finalized in December 2019. EC have adverse lung effects and harmful effects of long-term use are unknown. EC are unsuitable consumer products for recreational use, part-substitution for smoking or long-term exclusive use by former smokers. Smokers who require support to quit smoking should be directed towards approved medication in conjunction with behavioural support as having the strongest evidence for efficacy and safety. No specific EC product can be recommended as effective and safe for smoking cessation. Smoking cessation claims in relation to EC should be assessed by established regulators.

Incidental Pulmonary Nodules Are Common on CT Coronary Angiogram and Have a Significant Cost Impact.

BACKGROUND: Computed tomography (CT) coronary angiogram (CTCA) is commonly used for diagnostic evaluation of low-moderate risk patients due to its excellent performance and cost-effectiveness. However, previous cost analyses have not factored in the burden of management of pulmonary nodules, which are a common occurrence. We sought to describe the frequency and characteristics of lung nodules on CTCA in an Australian tertiary hospital, and to assess cost impacts. METHODS: Consecutive CTCAs performed in the calendar year 2012 were retrospectively identified from the imaging department database. Subjects were excluded if they were under the age of 35, had known malignancy or findings identified prior to CTCA. Patients were stratified on smoking history and nodule size. RESULTS: Of the 2479 CTCAs included, full-field imaging revealed nodules in 358 patients (13.9%). The nodules were generally small (73% <6mm), multiple (63%) and in the lower lobe (83.4%). There was no significant difference when stratified for smoking, with 60% of nodules detected in never-smokers. A minimum of 445 subsequent scans was required for nodule surveillance, resulting in an additional overall cost of $63.62 per CTCA. Limited-Field-of-View (L-FOV) would have identified only 22 nodules, with a cost of $6.14 for every CTCA performed, a cost saving of $57 per patient. CONCLUSIONS: Indeterminate pulmonary nodules are a common incidental finding on CTCA and prevalence appears to be independent of smoking status. There is a consequent significant cost burden that has not previously been recognised. Use of L-FOV reduces the number of nodules identified, with a significant cost benefit, but this has to be balanced against the ethical and medico-legal issues inherent in not reconstructing the irradiated lung.

Outcomes following resection of non-small cell lung cancer in octogenarians.

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.

Consensus minimum data set for lung cancer multidisciplinary teams: Results of a Delphi process.

BACKGROUND AND OBJECTIVE: While multidisciplinary team (MDT) care in lung cancer is widely practiced, there are few guidelines for MDT on best data collection strategies. MDT meetings need ready access to information for the provision of optimal treatment recommendations (the primary purpose of the meeting), audit of team performance and benchmarking. This study aimed to develop a practical data set designed for these goals through a recognized consensus process with health professionals who participate in formal MDT settings. METHODS: A modified Delphi process with three iterations (two surveys and one consensus conference) was carried out involving over 100 Australian lung cancer MDT health professionals. RESULTS: In total, 122 lung cancer MDT health professionals responded to the Round 1 survey from over 350 invitees. Of the 122, 98 were available for invitation to Round 2. Of 98, 52 (53%) invitees responded to the Round 2 survey. After two rounds, 51 data elements across 8 domains (patient demographics, risk factors, biopsy data, staging, timeliness, treatment, follow-up and patient selection) achieved consensus, defined as 80% agreement. For Round 3, 33 MDT lead clinicians were invited to participate in a consensus conference. Of 33, 14 (42%) invitees distilled the 47 data elements into 23 elements across 8 domains to address the study objectives. CONCLUSION: A practical data set for lung cancer MDT to use for optimal treatment recommendations and to evaluate team performance was developed through recognized consensus methodology. Access to streamlined, relevant and feasible data collection strategies may improve MDT decision-making, audit of team performance and facilitate benchmarking.

In vivo evidence that RBM5 is a tumour suppressor in the lung.

Cigarette smoking is undoubtedly a risk factor for lung cancer. Moreover, smokers with genetic mutations on chromosome 3p21.3, a region frequently deleted in cancer and notably in lung cancer, have a dramatically higher risk of aggressive lung cancer. The RNA binding motif 5 (RBM5) is one of the component genes in the 3p21.3 tumour suppressor region. Studies using human cancer specimens and cell lines suggest a role for RBM5 as a tumour suppressor. Here we demonstrate, for the first time, an in vivo role for RBM5 as a tumour suppressor in the mouse lung. We generated Rbm5 loss-of-function mice and exposed them to a tobacco carcinogen NNK. Upon exposure to NNK, Rbm5 loss-of-function mice developed lung cancer at similar rates to wild type mice. As tumourigenesis progressed, however, reduced Rbm5 expression lead to significantly more aggressive lung cancer i.e. increased adenocarcinoma nodule numbers and tumour size. Our data provide in vivo evidence that reduced RBM5 function, as occurs in a large number of patients, coupled with exposure to tobacco carcinogens is a risk factor for an aggressive lung cancer phenotype. These data suggest that RBM5 loss-of-function likely underpins at least part of the pro-tumourigenic consequences of 3p21.3 deletion in humans.

IL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis.

Oncogenic KRAS mutations occur frequently in lung adenocarcinoma. The signaling pathways activated by IL6 promote Kras-driven lung tumorigenesis, but the basis for this cooperation is uncertain. In this study, we used the gp130(F/F) (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRAS-driven lung tumorigenesis. Malignant growths in the gp130(F/F):Kras(G12D) model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental Kras(G12D) mice, where STAT3 was not hyperactivated. Among IL6 family cytokines, only IL6 was upregulated in the lung. Accordingly, normalization of pulmonary STAT3 activity, by genetic ablation of either Il6 or Stat3, suppressed the extent of lung cancer in the model. Mechanistic investigations revealed elevation in the lung of soluble IL6 receptor (sIL6R), the key driver of IL6 trans-signaling, and blocking this mechanism via interventions with an anti-IL6R antibody or the inhibitor sgp130Fc ameliorated lung cancer pathogenesis. Clinically, expression of IL6 and sIL6R was increased significantly in human specimens of lung adenocarcinoma or patient serum. Our results offer a preclinical rationale to clinically evaluate IL6 trans-signaling as a therapeutic target for the treatment of KRAS-driven lung adenocarcinoma.

Inosine-mediated modulation of RNA sensing by Toll-like receptor 7 (TLR7) and TLR8.

RNA-specific adenosine deaminase (ADAR)-mediated adenosine-to-inosine (A-to-I) editing is a critical arm of the antiviral response. However, mechanistic insights into how A-to-I RNA editing affects viral infection are lacking. We posited that inosine incorporation into RNA facilitates sensing of nonself RNA by innate immune sensors and accordingly investigated the impact of inosine-modified RNA on Toll-like receptor 7 and 8 (TLR7/8) sensing. Inosine incorporation into synthetic single-stranded RNA (ssRNA) potentiated tumor necrosis factor alpha (TNF-α) or alpha interferon (IFN-α) production in human peripheral blood mononuclear cells (PBMCs) in a sequence-dependent manner, indicative of TLR7/8 recruitment. The effect of inosine incorporation on TLR7/8 sensing was restricted to immunostimulatory ssRNAs and was not seen with inosine-containing short double-stranded RNAs or with a deoxy-inosine-modified ssRNA. Inosine-mediated increase of self-secondary structure of an ssRNA resulted in potentiated IFN-α production in human PBMCs through TLR7 recruitment, as established through the use of a TLR7 antagonist and Tlr7-deficient cells. There was a correlation between hyperediting of influenza A viral ssRNA and its ability to stimulate TNF-α, independent of 5'-triphosphate residues, and involving Adar-1. Furthermore, A-to-I editing of viral ssRNA directly enhanced mouse Tlr7 sensing, when present in proportions reproducing biologically relevant levels of RNA editing. Thus, we demonstrate for the first time that inosine incorporation into immunostimulatory ssRNA can potentiate TLR7/8 activation. Our results suggest a novel function of A-to-I RNA editing, which is to facilitate TLR7/8 sensing of phagocytosed viral RNA.

Deregulated Stat3 signaling dissociates pulmonary inflammation from emphysema in gp130 mutant mice.

Interleukin (IL)-6 is a potent immunomodulatory cytokine that is associated with emphysema, a major component of chronic obstructive pulmonary disease (COPD). IL-6 signaling via the gp130 coreceptor is coupled to multiple signaling pathways, especially the latent transcription factor signal transducer and activator of transcription (Stat)3. However, the pathological role of endogenous gp130-dependent Stat3 activation in emphysema is ill defined. To elucidate the role of the IL-6/gp130/Stat3 signaling axis in the cellular and molecular pathogenesis of emphysema, we employed a genetic complementation strategy using emphysematous gp130(F/F) mice displaying hyperactivation of endogenous Stat3 that were interbred with mice to impede Stat3 activity. Resected human lung tissue from patients with COPD and COPD-free individuals was also evaluated by immunohistochemistry. Genetic reduction of Stat3 hyperactivity in gp130(F/F):Stat3(-/+) mice prevented lung inflammation and excessive protease activity; however, emphysema still developed. In support of these findings, Stat3 activation levels in human lung tissue correlated with the extent of pulmonary inflammation but not airflow obstruction in COPD. Furthermore, COPD lung tissue displayed increased levels of IL-6 and apoptotic alveolar cells, supporting our previous observation that increased endogenous IL-6 expression in the lungs of gp130(F/F) mice contributes to emphysema by promoting alveolar cell apoptosis. Collectively, our data suggest that IL-6 promotes emphysema via upregulation of Stat3-independent apoptosis, whereas IL-6 induction of lung inflammation occurs via Stat3. We propose that while discrete targeting of Stat3 may alleviate pulmonary inflammation, global targeting of IL-6 potentially represents a therapeutically advantageous approach to combat COPD phenotypes where emphysema predominates.