Trimethoprim-sulfamethoxazole acute respiratory distress syndrome requiring lung transplantation.

Trimethoprim-sulfamethoxazole (TMP-SMX) acute respiratory distress syndrome (ARDS) is a rare, but severe complication of a commonly prescribed antibiotic. TMP-SMX typically affects young, otherwise well patients with a specific human leukocyte antigen type (HLA-B*07:02 and HLA-C*07:02). The condition is poorly understood with a unique pathological appearance and mechanism that remains unclear. Mortality rate is greater than one third. We describe the case of a previously well 18-year-old woman treated with a prolonged course of TMP-SMX for a complex urinary tract infection who developed rapidly progressive respiratory failure requiring prolonged intensive care admission, extra-corporeal membranous oxygenation, and eventual lung transplantation. No targeted treatment exists, further research is required to better understand disease pathogenetic mechanisms and potential therapeutic interventions.

Multidisciplinary meeting review in nonsmall cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Lung cancer diagnosis, staging and treatment may be enhanced by multidisciplinary participation and presentation in multidisciplinary meetings (MDM). We performed a systematic review and meta-analysis to explore literature evidence of clinical impacts of MDM exposure. METHODS: A study protocol was registered (PROSPERO identifier CRD42021258069). Randomised controlled trials and observational cohort studies including adults with nonsmall cell lung cancer and who underwent MDM review, compared to no MDM, were included. MEDLINE, CENTRAL, Embase and ClinicalTrials.gov were searched on 31 May 2021. Studies were screened and extracted by two reviewers. Outcomes included time to diagnosis and treatment, histological confirmation, receipt of treatments, clinical trial participation, survival and quality of life. Risk of bias was assessed using the ROBINS-I (Risk of Bias in Non-randomised Studies - of Interventions) tool. RESULTS: 2947 citations were identified, and 20 studies were included. MDM presentation significantly increased histological confirmation of diagnosis (OR 3.01, 95% CI 2.30-3.95; p<0.00001) and availability of clinical staging (OR 2.55, 95% CI 1.43-4.56; p=0.002). MDM presentation significantly increased likelihood of receipt of surgery (OR 2.01, 95% CI 1.29-3.12; p=0.002) and reduced the likelihood of receiving no active treatment (OR 0.32, 95% CI 0.21-0.50; p=0.01). MDM presentation was protective of both 1-year survival (OR 3.23, 95% CI 2.85-3.68; p<0.00001) and overall survival (hazard ratio 0.63, 95% CI 0.55-0.72; p<0.00001). DISCUSSION: MDM presentation was associated with increased likelihood of histological confirmation of diagnosis, documentation of clinical staging and receipt of surgery. Overall and 1-year survival was better in those presented to an MDM, although there was some clinical heterogeneity in participants and interventions delivered. Further research is required to determine the optimal method of MDM presentation, and address barriers to presentation.

Nebulised granulocyte-macrophage colony-stimulating factor (GM-CSF) in autoimmune pulmonary alveolar proteinosis: a systematic review and meta-analysis.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) results from impaired macrophage-mediated clearance of alveolar surfactant lipoproteins. Whole lung lavage has been the first-line treatment but recent reports suggest the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF). We aimed to review the efficacy and safety of nebulised GM-CSF in aPAP. METHODS: We conducted a systematic review and meta-analysis searching Embase, CINAHL, MEDLINE and Cochrane Collaborative databases (1946-1 April 2022). Studies included patients aged >18 years with aPAP receiving nebulised GM-CSF treatment and a comparator cohort. Exclusion criteria included secondary or congenital pulmonary alveolar proteinosis, GM-CSF allergy, active infection or other serious medical conditions. The protocol was prospectively registered with PROSPERO (CRD42021231328). Outcomes assessed were St George's Respiratory Questionnaire (SGRQ), 6-min walk test (6MWT), gas exchange (diffusing capacity of the lung for carbon monoxide (D LCO) % predicted) and arterial-alveolar oxygen gradient. RESULTS: Six studies were identified for review and three for meta-analysis, revealing that SGRQ score (mean difference -8.09, 95% CI -11.88- -4.3, p<0.0001), functional capacity (6MWT) (mean difference 21.72 m, 95% CI -2.76-46.19 m, p=0.08), gas diffusion (D LCO % predicted) (mean difference 5.09%, 95% CI 2.05-8.13%, p=0.001) and arterial-alveolar oxygen gradient (mean difference -4.36 mmHg, 95% CI -7.19- -1.52 mmHg, p=0.003) all significantly improved in GM-CSF-treated patients with minor statistical heterogeneity (I2=0%). No serious trial-related adverse events were reported. CONCLUSIONS: Patients with aPAP treated with inhaled GM-CSF demonstrated significant improvements in symptoms, dyspnoea scores, lung function, gas exchange and radiology indices after treatment with nebulised GM-CSF of varying duration. There is an important need to review comparative effectiveness and patient choice in key clinical outcomes between the current standard of care, whole lung lavage, with the noninvasive treatment of nebulised GM-CSF in aPAP.

A Systematic Review of Joint Spatial and Spatiotemporal Models in Health Research.

With the advancement of spatial analysis approaches, methodological research addressing the technical and statistical issues related to joint spatial and spatiotemporal models has increased. Despite the benefits of spatial modelling of several interrelated outcomes simultaneously, there has been no published systematic review on this topic, specifically when such models would be useful. This systematic review therefore aimed at reviewing health research published using joint spatial and spatiotemporal models. A systematic search of published studies that applied joint spatial and spatiotemporal models was performed using six electronic databases without geographic restriction. A search with the developed search terms yielded 4077 studies, from which 43 studies were included for the systematic review, including 15 studies focused on infectious diseases and 11 on cancer. Most of the studies (81.40%) were performed based on the Bayesian framework. Different joint spatial and spatiotemporal models were applied based on the nature of the data, population size, the incidence of outcomes, and assumptions. This review found that when the outcome is rare or the population is small, joint spatial and spatiotemporal models provide better performance by borrowing strength from related health outcomes which have a higher prevalence. A framework for the design, analysis, and reporting of such studies is also needed.

Development of an Australia and New Zealand Lung Cancer Clinical Quality Registry: a protocol paper.

INTRODUCTION: Lung cancer is the leading cause of cancer mortality, comprising the largest national cancer disease burden in Australia and New Zealand. Regional reports identify substantial evidence-practice gaps, unwarranted variation from best practice, and variation in processes and outcomes of care between treating centres. The Australia and New Zealand Lung Cancer Registry (ANZLCR) will be developed as a Clinical Quality Registry to monitor the safety, quality and effectiveness of lung cancer care in Australia and New Zealand. METHODS AND ANALYSIS: Patient participants will include all adults >18 years of age with a new diagnosis of non-small-cell lung cancer (NSCLC), SCLC, thymoma or mesothelioma. The ANZLCR will register confirmed diagnoses using opt-out consent. Data will address key patient, disease, management processes and outcomes reported as clinical quality indicators. Electronic data collection facilitated by local data collectors and local, state and federal data linkage will enhance completeness and accuracy. Data will be stored and maintained in a secure web-based data platform overseen by registry management. Central governance with binational representation from consumers, patients and carers, governance, administration, health department, health policy bodies, university research and healthcare workers will provide project oversight. ETHICS AND DISSEMINATION: The ANZLCR has received national ethics approval under the National Mutual Acceptance scheme. Data will be routinely reported to participating sites describing performance against measures of agreed best practice and nationally to stakeholders including federal, state and territory departments of health. Local, regional and (bi)national benchmarks, augmented with online dashboard indicator reporting will enable local targeting of quality improvement efforts.

Pulmonary alveolar proteinosis with an unusual bronchoscopic complication.

Pulmonary alveolar proteinosis (PAP) is a rare respiratory syndrome, which can be challenging to diagnose given its non-specific presentation and imaging findings. While most primary cases of PAP have an autoimmune basis, the triggers for the disease are uncertain with occupational factors increasingly thought to be important. We report the unusual complication of pneumomediastinum and bilateral pneumothoraces following endobronchial ultrasound-guided transbronchial needle aspirate in the setting of PAP. We discuss the possible physiological mechanisms of this complication, which appears to be more common in conditions with reduced lung compliance.

Forecasting of Lung Cancer Incident Cases at the Small-Area Level in Victoria, Australia.

Predicting lung cancer cases at the small-area level is helpful to quantify the lung cancer burden for health planning purposes at the local geographic level. Using Victorian Cancer Registry (2001-2018) data, this study aims to forecast lung cancer counts at the local government area (LGA) level over the next ten years (2019-2028) in Victoria, Australia. We used the Age-Period-Cohort approach to estimate the annual age-specific incidence and utilised Bayesian spatio-temporal models that account for non-linear temporal trends and area-level risk factors. Compared to 2001, lung cancer incidence increased by 28.82% from 1353 to 1743 cases for men and 78.79% from 759 to 1357 cases for women in 2018. Lung cancer counts are expected to reach 2515 cases for men and 1909 cases for women in 2028, with a corresponding 44% and 41% increase. The majority of LGAs are projected to have an increasing trend for both men and women by 2028. Unexplained area-level spatial variation substantially reduced after adjusting for the elderly population in the model. Male and female lung cancer cases are projected to rise at the state level and in each LGA in the next ten years. Population growth and an ageing population largely contributed to this rise.

Excess mortality and undertreatment in elderly lung cancer patients: treatment nihilism in the modern era?

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 (<60 years: 2.0 years; 60-69 years: 1.5 years; 70-79 years: 1.6 years; ≥80 years: 1.0 years; p<0.001). Amongst those diagnosed with stage 1 or 2 lung cancer, there was no significant difference in adjusted-mortality between age groups. However, in those diagnosed with stage 3 or 4 disease, the eldest patients had an increased adjusted-mortality risk of 28% compared with patients younger than 60 years old (p=0.005), associated with markedly reduced probability of cancer treatment, after controlling for sex, performance status, comorbidities and histology type (OR 0.24, compared with <60 years old strata; p<0.001). Compared to younger patients, older patients with advanced-stage lung cancer have a disproportionately higher risk of mortality and lower likelihood of receiving cancer treatments, even when performance status and comorbidity are equivalent. These healthcare inequities could be indicative of widespread treatment nihilism towards elderly patients.

Effect of Follow-Up Surveillance After Curative-Intent Treatment of NSCLC on Detection of New and Recurrent Disease, Retreatment, and Survival: A Systematic Review and Meta-Analysis.

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 < 0.0001). Curative-intent retreatment prolonged survival in reported studies. 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.

Influence of timeliness and receipt of first treatment on geographic variation in non-small cell lung cancer mortality.

Mortality from non-small cell lung cancer (NSCLC) exhibits substantial geographical disparities. However, there is little evidence on whether this variation could be attributed to patients' clinical characteristics and/or socioeconomic inequalities. This study evaluated the independent and relative contribution of the individual- and area-level risk factors on geographic variation in 2-year all-cause mortality among NSCLC patients. In the Hierarchical-related regression approach, we used the Bayesian spatial multilevel logistic regression model to combine individual- and area-level predictors with outcomes while accounting for geographically structured and unstructured correlation. Individual-level data included 3330 NSCLC cases reported to the Victoria Lung Cancer Registry between 2011 and 2016. Area-level data comprised socioeconomic disadvantage, remoteness and pollution data at the postal area level in Victoria, Australia. With the inclusion of significant individual- and area-level risk factors, timely (≤14 days) first definitive treatment (odds ratio [OR] = 0.73, 95% credible interval [Crl] = 0.56-0.94) and multidisciplinary meetings (MDM) (OR = 0.74, 95% Crl = 0.59-0.93) showed an independent association with a lower likelihood of NSCLC 2-year all-cause mortality. Timely and delayed (>14 days) first nondefinitive treatment, no treatment, advanced clinical stage, smoking, poor performance status, public hospital insurance and area-level deprivation were independently associated with a higher likelihood of 2- and 5-year all-cause mortality. NSCLC's 2-year all-cause mortality exhibited substantial geographic variation, mainly associated with timeliness and receipt of first definitive treatment, no treatment followed by patient prognostic factors with some contribution from area-level deprivation, MDM and public hospital insurance. This study highlights NSCLC patients should receive the first definitive treatment within the recommended 14-days from diagnosis.

Association between Receipt of Guideline-Concordant Lung Cancer Treatment and Individual- and Area-Level Factors: A Spatio-Temporal Analysis.

BACKGROUND: Guideline-concordant treatment (GCT) of lung cancer has been observed to vary across geographic regions over the years. However, there is little evidence as to what extent this variation is explained by differences in patients' clinical characteristics versus contextual factors, including socioeconomic inequalities. METHODS: This study evaluated the independent effects of individual- and area-level risk factors on geographic and temporal variation in receipt of GCT among patients with lung cancer. Receipt of GCT was defined on the basis of the National Comprehensive Cancer Network guidelines. We used Bayesian spatial-temporal multilevel models to combine individual and areal predictors and outcomes while accounting for geographically structured and unstructured correlation and linear and nonlinear trends. RESULTS: Our study included 4,854 non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cases, reported to the Victorian Lung Cancer Registry between 2011 and 2018. Area-level data comprised socioeconomic disadvantage and remoteness data at the local government area level in Victoria, Australia. Around 60.36% of patients received GCT, and the rates varied across geographic areas over time. This variation was mainly associated with poor performance status, advanced clinical stages, NSCLC types, public hospital insurance, area-level deprivation, and comorbidities. CONCLUSIONS: This study highlights the need to address disparities in receipt of GCT among patients with lung cancer with poor performance status, NSCLC, advanced clinical stage, stage I-III SCLC, stage III NSCLC, public hospital insurance, and comorbidities, and living in socioeconomically disadvantaged areas. IMPACT: Two-year mortality outcomes significantly improved with GCT. Interventions aimed at reducing these inequalities could help to improve lung cancer outcomes.

The Victorian Lung Cancer Registry pilot: improving the quality of lung cancer care through the use of a disease quality registry.

BACKGROUND: Lung cancer remains a major disease burden in Victoria (Australia) and requires a complex and multidisciplinary approach to ensure optimal care and outcomes. To date, no uniform mechanism is available to capture standardized population-based outcomes and thereby provide benchmarking. The establishment of such a data platform is, therefore, a primary requisite to enable description of process and outcome in lung cancer care and to drive improvement in the quality of care provided to individuals with lung cancer. MATERIALS AND METHODS: A disease quality registry pilot has been established to capture prospective data on all adult patients with clinical or tissue diagnoses of small cell and non-small cell lung cancer. Steering and management committees provide clinical governance and supervise quality indicator selection. Quality indicators were selected following extensive literature review and evaluation of established clinical practice guidelines. A minimum dataset has been established and training and data capture by data collectors is facilitated using a web-based portal. Case ascertainment is established by regular institutional reporting of ICD-10 discharge coding. Recruitment is optimized by provision of opt-out consent. RESULTS: The collection of a standardized minimum data set optimizes capacity for harmonized population-based data capture. Data collection has commenced in a variety of settings reflecting metropolitan and rural, and public, and private health care institutions. The data set provides scope for the construction of a risk-adjusted model for outcomes. A data access policy and a mechanism for escalation policy for outcome outliers has been established. CONCLUSIONS: The Victorian Lung Cancer Registry provides a unique capacity to provide and confirm quality assessment in lung cancer and to drive improvement in quality of care across multidisciplinary stakeholders.

Phase 3 randomized study of the efficacy and safety of inhaled dry powder mannitol for the symptomatic treatment of non-cystic fibrosis bronchiectasis.

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 FEV1≥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.