Management of infectious disease syndromes in thoracic organ transplants and mechanical circulatory device recipients: a Delphi panel.

PURPOSE: Antimicrobial misuse contributes to antimicrobial resistance in thoracic transplant (TTx) and mechanical circulatory support (MCS) recipients. This study uses a modified Delphi method to define the expected appropriate antimicrobial prescribing for the common clinical scenarios encountered in TTx and MCS recipients. METHODS: An online questionnaire on managing 10 common infectious disease syndromes was submitted to a multidisciplinary Delphi panel of 25 experts from various disciplines. Consensus was predefined as 80% agreement for each question. Questions where consensus was not achieved were discussed during live virtual live sessions adapted by an independent process expert. RESULTS: An online survey of 62 questions related to 10 infectious disease syndromes was submitted to the Delphi panel. In the first round of the online questionnaire, consensus on antimicrobial management was reached by 6.5% (4/62). In Round 2 online live discussion, the remaining 58 questions were discussed among the Delphi Panel members using a virtual meeting platform. Consensus was reached among 62% (36/58) of questions. Agreement was not reached regarding the antimicrobial management of the following six clinical syndromes: (1) Burkholderia cepacia pneumonia (duration of therapy); (2) Mycobacterium abscessus (intra-operative antimicrobials); (3) invasive aspergillosis (treatment of culture-negative but positive BAL galactomannan) (duration of therapy); (4) respiratory syncytial virus (duration of antiviral therapy); (5) left ventricular assist device deep infection (initial empirical antimicrobial coverage) and (6) CMV (duration of secondary prophylaxis). CONCLUSION: This Delphi panel developed consensus-based recommendations for 10 infectious clinical syndromes seen in TTx and MCS recipients.

Treatment of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis: A position statement from the Thoracic Society of Australia and New Zealand 2023 revision.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease leading to significant morbidity and mortality. In 2017 the Thoracic Society of Australia and New Zealand (TSANZ) and Lung Foundation Australia (LFA) published a position statement on the treatment of IPF. Since that time, subsidized anti-fibrotic therapy in the form of pirfenidone and nintedanib is now available in both Australia and New Zealand. More recently, evidence has been published in support of nintedanib for non-IPF progressive pulmonary fibrosis (PPF). Additionally, there have been numerous publications relating to the non-pharmacologic management of IPF and PPF. This 2023 update to the position statement for treatment of IPF summarizes developments since 2017 and reaffirms the importance of a multi-faceted approach to the management of IPF and progressive pulmonary fibrosis.

Incidence of Nonmelanoma Skin Cancers in Alberta, Canada, From 2007 to 2018.

BACKGROUND: Nonmelanoma skin cancer (NMSC) is the most common malignancy affecting Caucasian populations and has been seeing steady increases in incidence globally for decades. Our previous study (from Alberta, Canada) had shown a plateau in the incidence rates for NMSC. This contrasts with data from other regions within Canada and throughout the world that indicated a continued increase in incidence rates of NMSCs. OBJECTIVES: The objective of this study was to provide an update on the trends in incidence of NMSC in Alberta, Canada, from 2007 to 2018. METHODS: A retrospective analysis of patients from Alberta diagnosed with NMSC from 2007 to 2018 inclusive was conducted with data retrieved from Alberta Cancer Registry. Sex-, age-, anatomical location-, NMSC subtype-, stage-specific incidence rates and trends were examined. RESULTS: From 2007 to 2018, overall incidence rates of NMSC increased by 36%. Invasive squamous cell carcinoma (SCC) and in situ SCC demonstrated the most significant increase, invasive SCC [annual percentage change (APC) 3.48, P = .014] and in situ SCC (APC 5.61, P = .0001). In addition, we were able to determine that females had the most significant increases in NMSC incidence rates from 2007 to 2018 particularly invasive SCC (APC 3.03, P = <.0001) and in situ SCC (APC 5.08, P = <.0001). CONCLUSIONS: After initial levelling of NMSC incidence in Alberta in the early part of 21st century, the incidence of NMSC continues to increase over the past decade. The reasons for this change are not clear and likely multifactorial.

Immunological Landscapes in Lung Transplantation: Insights from T Cell Profiling in BAL and PBMC.

Lung transplant recipients frequently encounter immune-related complications, including chronic lung allograft dysfunction (CLAD). Monitoring immune cells within the lung microenvironment is pivotal for optimizing post-transplant outcomes. This study examined the proportion of T cell subsets in paired bronchoalveolar lavage (BAL) and peripheral PBMC comparing healthy (n = 4) and lung transplantation patients (n = 6, no CLAD and n = 14 CLAD) using 14-color flow cytometry. CD4+ T cell proportions were reduced in CD3 cells in both PBMC and BAL, and positive correlations were discerned between T cell populations in peripheral PBMC and BAL, suggesting the prospect of employing less invasive PBMC sampling as a means of monitoring lung T cells. Furthermore, regulatory T cells (Tregs) were enriched in BAL when compared to peripheral PBMC for transplant recipients. A parallel positive correlation emerged between Treg proportions in BAL and peripheral PBMC, underscoring potential avenues for monitoring lung Tregs. Finally, the most promising biomarker was the Teff (CD8+Granzyme B+)-Treg ratio, which was higher in both the PBMC and BAL of transplant recipients compared to healthy individuals, and increased in the patients with CLAD compared to no CLAD and healthy patients. Conclusions: Distinct T cell profiles in BAL and peripheral PBMC underscore the significance of localized immune monitoring in lung transplantation. The Teff (CD8+granzyme B+)-Treg ratio, particularly within the context of CLAD, emerges as a promising blood and BAL biomarker reflective of inflammation and transplant-related complications. These findings emphasize the imperative need for personalized immune monitoring strategies that tailored to address the unique immunological milieu in post-transplant lungs.

Mycoplasma hominis and Ureaplasma urealyticum infections in the immediate post-lung transplant period: A case series and literature review.

Mycoplasma hominis and Ureaplasma species infections in the post-transplant setting are believed to be donor-derived and can be associated with poor outcomes. Difficulty in culturing and identifying these organisms is a significant barrier to diagnosis and early intervention. Tetracyclines, macrolides and fluoroquinolones are the mainstay treatments to cure these infections; however, there are increasing reports of antibiotic resistance. In this case series, we report our single-centre experience with M. hominis and U. urealyticum infection after lung transplantation (9 recipients, all men, mean age 56 years). Delayed diagnosis was common. Young donor age (mean age 23 yrs) and high-risk donor social history (67%) were repeatedly noted in these cases, and all infections were associated with significant morbidity (anastomosis and sternal wound infection, empyema, mediastinitis, pericarditis). Two patients died; with one directly related to Ureaplasma urealyticum infection. In conclusion post lung transplant M. hominis, and U. urealyticum infections are challenging and carry high morbidity. More prospective studies are required to assess the true prevalence, full spectrum of complications and utility of molecular diagnostics to aid early diagnosis and identify antibiotic susceptibility of Mycoplasma and Ureaplasma infections in the post-lung transplant setting.

Clinical utility of a standardized chronic hypersensitivity pneumonitis exposure questionnaire.

BACKGROUND AND OBJECTIVE: Identification of an exposure is integral to the diagnosis, management, and prognostication of chronic hypersensitivity pneumonitis (CHP). Standardized questionnaires may aid in the identification of exposures, however, there currently are no evidence-based patient-validated questionnaires available. Key qualifiers (including duration and frequency) which indicate exposure relevance are also poorly defined. This study assessed the use of a standardized CHP exposure questionnaire in the identification of exposures and diagnostic confidence of CHP. METHODS: People with a multi-disciplinary meeting (MDM) diagnosis from five Australian interstitial lung disease (ILD) expert centres who provided informed consent were included. Participants completed a previously developed standardized CHP Exposure Questionnaire. Responses were collected with the participant's MDM data, including diagnosis, diagnostic confidence, and clinician-elicited exposures. RESULTS: One hundred thirty participants (IPF = 58, CHP = 24, CTD-ILD = 17, unclassifiable = 19, other = 12) were included. In 33% of CHP participants, a standardized questionnaire elicited an exposure where the clinician did not. 63% of these had provisional low confidence CHP; and an exposure history would have increased the diagnostic confidence in these cases. Using the standardized questionnaire, 96% of CHP participants reporting any exposure, compared with 75% of non-HP ILD participants. CHP participants were 3.5 times more likely (p = 0.004) to report their symptoms improved on avoidance, and 2.3 times more likely (p = 0.018) to report daily frequent exposure, compared with non-HP ILDs. CONCLUSION: A standardized questionnaire which elicits exposure characteristics in addition to presence or absence of relevant exposures can increase the diagnostic confidence of CHP and reduce the proportion of antigen-indeterminate CHP.

Phase 2B Study of Inhaled RVT-1601 for Chronic Cough in Idiopathic Pulmonary Fibrosis: A Multicenter, Randomized, Placebo-controlled Study (SCENIC Trial).

Rationale: Chronic cough remains a major and often debilitating symptom for patients with idiopathic pulmonary fibrosis (IPF). In a phase 2A study, inhaled RVT-1601 (cromolyn sodium) reduced daytime cough and 24-hour average cough counts in patients with IPF. Objectives: To determine the efficacy, safety, and optimal dose of inhaled RVT-1601 for the treatment of chronic cough in patients with IPF. Methods: In this multicenter, randomized, placebo-controlled phase 2B study, patients with IPF and chronic cough for ⩾8 weeks were randomized (1:1:1:1) to receive 10, 40, and 80 mg RVT-1601 three times daily or placebo for 12 weeks. The primary endpoint was change from baseline to end of treatment in log-transformed 24-hour cough count. Key secondary endpoints were change from baseline in cough severity and cough-specific quality of life. Safety was monitored throughout the study. Measurements and Main Results: The study was prematurely terminated owing to the impact of the coronavirus disease (COVID-19) pandemic. Overall, 108 patients (mean age 71.0 years, 62.9% males) received RVT-1601 10 mg (n = 29), 40 mg (n = 25), 80 mg (n = 27), or matching placebo (n = 27); 61.1% (n = 66) completed double-blind treatment. No statistically significant difference was observed in the least-square mean change from baseline in log-transformed 24-hour average cough count, cough severity, and cough-specific quality of life score between the RVT-1601 groups and the placebo group. The mean percentage change from baseline in 24-hour average cough count was 27.7% in the placebo group. Treatment was generally well tolerated. Conclusions: Treatment with inhaled RVT-1601 (10, 40, and 80 mg three times a day) did not provide benefit over placebo for the treatment of chronic cough in patients with IPF.

A Phase IIb Randomized Clinical Study of an Anti-αvß6 Monoclonal Antibody in Idiopathic Pulmonary Fibrosis.

Rationale: Treatment options for idiopathic pulmonary fibrosis (IPF) are limited. Objectives: To evaluate the efficacy and safety of BG00011, an anti-αvß6 IgG1 monoclonal antibody, in the treatment of patients with IPF. Methods: In a phase IIb randomized, double-blind, placebo-controlled trial, patients with IPF (FVC ⩾50% predicted, on or off background therapy) were randomized 1:1 to once-weekly subcutaneous BG00011 56 mg or placebo. The primary endpoint was FVC change from baseline at Week 52. Because of early trial termination (imbalance in adverse events and lack of clinical benefit), endpoints were evaluated at Week 26 as an exploratory analysis. Measurements and Main Results: One hundred six patients were randomized and received at least one dose of BG00011 (n = 54) or placebo (n = 52). At Week 26, there was no significant difference in FVC change from baseline between patients who received BG00011 (n = 20) or placebo (n = 23), least squares mean (SE) -0.097 L (0.0600) versus -0.056 L (0.0593), respectively (P = 0.268). However, after Week 26, patients in the BG00011 group showed a worsening trend. Eight (44.4%) of 18 who received BG00011 and 4 (18.2%) of 22 who received placebo showed worsening of fibrosis on high-resolution computed tomography at the end of treatment. IPF exacerbation/or progression was reported in 13 patients (all in the BG00011 group). Serious adverse events occurred more frequently in BG00011 patients, including four deaths. Conclusions: The results do not support the continued clinical development of BG00011. Further research is warranted to identify new treatment strategies that modify inflammatory and fibrotic pathways in IPF. Clinical trial registered with www.clinicaltrials.gov (NCT03573505).

Single-Cell Profiling of Cells in the Lung of a Patient with Chronic Hypersensitivity Pneumonitis Reveals Inflammatory Niche with Abundant CD39+ T Cells with Functional ATPase Phenotype: A Case Study.

This study investigated immune cell characteristics in chronic hypersensitivity pneumonitis (HP), focusing on CD39-expressing cells' impact on inflammation and tissue remodelling. Lung tissue from an HP patient was analysed using single-cell transcriptomics, flow cytometry, and gene expression profiling. The tissue revealed diverse cell types like macrophages, T cells, fibroblasts, and regulatory T cells (Tregs). CD39-expressing Tregs exhibited heightened ATP hydrolysis capacity and regulatory gene expression. CD39hi cells displayed markers of both Tregs and proinflammatory Th17 cells, suggesting transitional properties. Communication networks involving molecules like SPP1, collagen, CSF1, and IL-1ß were identified, hinting at interactions between cell types in HP pathogenesis. This research provides insights into the immune response and cell interactions in chronic HP. CD39-expressing cells dual nature as Tregs and Th17 cells suggests a role in modulating lung inflammation, potentially affecting disease progression. These findings lay the groundwork for further research, underscoring CD39-expressing cells as potential therapeutic targets in HP.

A Methodological Approach to Identify Natural Compounds with Antifibrotic Activity and the Potential to Treat Pulmonary Fibrosis Using Single-Cell Sequencing and Primary Human Lung Macrophages.

Idiopathic pulmonary fibrosis (IPF) is the most common and lethal form of the interstitial pneumonias. The cause of the disease is unknown, and new therapies that stop or reverse disease progression are desperately needed. Recent advances in next-generation sequencing have led to an abundance of freely available, clinically relevant, organ-and-disease-specific, single-cell transcriptomic data, including studies from patients with IPF. We mined data from published IPF data sets and identified gene signatures delineating pro-fibrotic or antifibrotic macrophages and then used the Enrichr platform to identify compounds with the potential to drive the macrophages toward the antifibrotic transcriptotype. We then began testing these compounds in a novel in vitro phenotypic drug screening assay utilising human lung macrophages recovered from whole-lung lavage of patients with silicosis. As predicted by the Enrichr tool, glitazones potently modulated macrophage gene expression towards the antifibrotic phenotype. Next, we assayed a subset of the NatureBank pure compound library and identified the cyclobutane lignan, endiandrin A, which was isolated from the roots of the endemic Australian rainforest plant, Endiandra anthropophagorum, with a similar antifibrotic potential to the glitazones. These methods open new avenues of exploration to find treatments for lung fibrosis.

Demographic, exposure and clinical characteristics in a multinational registry of engineered stone workers with silicosis.

OBJECTIVES: To investigate differences in workplace exposure, demographic and clinical findings in engineered stone (ES) workers from a multinational consortium using the Engineered Stone Silicosis Investigators (ESSI) Global Silicosis Registry. METHODS: With ethics board approval in Israel, Spain, Australia and the USA, ES workers ages 18+ with a physician diagnosis of work-related silicosis were enrolled. Demographic, occupational, radiologic, pulmonary function and silica-related comorbidity data were compared cross-sectionally among countries using analysis of variance, Fisher's exact tests and logistic regression. RESULTS: Among 169 ES workers with silicosis, most were men, with mean age 51.7 (±11.4) years. Mean work tenure in stone fabrication or masonry was 19.9 (±9.8) years. Different methods of case ascertainment explained some inter-country differences, for example, workers in Queensland, Australia with a state-based surveillance program were likely to be identified earlier and with shorter work tenure. Overall, 32.5% of workers had progressive massive fibrosis, the most severe form of dust-related pneumoconiosis, of whom 18.5% reported ≤10 years of work tenure. Lung function impairment including restriction, reduced diffusion capacity and hypoxaemia was common, as was autoimmunity. CONCLUSIONS: Findings from a multinational registry represent a unique effort to compare demographic, exposure and clinical information from ES workers with silicosis, and suggest a substantial emerging population of workers worldwide with severe and irreversible silica-associated diseases. This younger worker population is at high risk for disease progression, multiple comorbidities and severe disability. The ESSI registry provides an ongoing framework for investigating epidemiological trends and developing prospective studies for prevention and treatment of these workers.

Alveolar crystal burden in stone workers with artificial stone silicosis.

BACKGROUND AND OBJECTIVE: An epidemic of silicosis has emerged due to a failure to control risks associated with exposure to high-silica content respirable dust generated while working with artificial stone products. Methods for quantification of alveolar crystal burden are needed to advance our understanding of the pathobiology of silica-related lung injury as well as assisting in the diagnosis, clinical management and prognostication of affected workers. The objective of this study was to develop and validate novel methods to quantify alveolar crystal burden in bronchoalveolar lavage (BAL) fluid from patients with artificial stone silicosis. METHODS: New methods to quantify and analyse alveolar crystal in BAL from patients with artificial stone silicosis were developed. Crystals were isolated and counted by microscopy and alveolar crystal burden was calculated using a standard curve generated by titration of respirable α-Quartz. The utility of the assay was then assessed in 23 patients with artificial stone silicosis. RESULTS: Alveolar crystal burden was greater in patients with silicosis (0.44 picograms [pg]/cell [0.08-3.49]) compared to patients with other respiratory diagnoses (0.057 pg/cell [0.01-0.34]; p < 0.001). Alveolar crystal burden was positively correlated with years of silica exposure (ρ = 0.49, p = 0.02) and with decline in diffusing capacity of the lungs for carbon monoxide (ρ = -0.50, p = 0.02). CONCLUSION: Alveolar crystal burden quantification differentiates patients with silicosis from patients with other respiratory disorders. Furthermore, crystal burden is correlated with the rate of decline in lung function in patients with artificial stone silicosis.

A Stanford Conference on Social Media, Ethics, and COVID-19 Misinformation (INFODEMIC): Qualitative Thematic Analysis.

BACKGROUND: The COVID-19 pandemic continues to challenge the world's population, with approximately 266 million cases and 5 million deaths to date. COVID-19 misinformation and disinformation led to vaccine hesitancy among the public, particularly in vulnerable communities, which persists today. Social media companies are attempting to curb the ongoing spread of an overwhelming amount of COVID-19 misinformation on their platforms. In response to this problem, the authors hosted INFODEMIC: A Stanford Conference on Social Media and COVID-19 Misinformation (INFODEMIC) to develop best practices for social media companies to mitigate online misinformation and disinformation. OBJECTIVE: The primary aim of this study was to develop recommendations for social media companies to address the COVID-19 infodemic. We report the methods used to execute the INFODEMIC conference, conference attendee engagement and analytics, and a qualitative thematic analysis of the conference presentations. The primary study outcomes were the identified themes and corresponding recommendations. METHODS: Using a constructivist paradigm, we conducted a thematic analysis of the 6-hour conference transcript to develop best practice recommendations. The INFODEMIC conference was the study intervention, the conference speakers were the study participants, and transcripts of their presentations were the data for this study. We followed the 6-step framework for thematic analysis described by Braun and Clarke. We also used descriptive statistics to report measures of conference engagement including registrations, viewership, post-conference asynchronous participation, and conference evaluations. RESULTS: A total of 26 participants spoke at the virtual conference and represented a wide array of occupations, expertise, and countries of origin. From their remarks, we identified 18 response categories and 4 themes: trust, equity, social media practices, and interorganizational partnerships. From these, a total of 16 best practice recommendations were formulated for social media companies, health care organizations, and the general public. These recommendations focused on rebuilding trust in science and medicine among certain communities, redesigning social media platforms and algorithms to reduce the spread of misinformation, improving partnerships between key stakeholders, and educating the public to critically analyze online information. Of the 1090 conference registrants, 587 (53.9%) attended the live conference, and another 9996 individuals viewed or listened to the conference recordings asynchronously. Conference evaluations averaged 8.9 (best=10). CONCLUSIONS: Social media companies play a significant role in the COVID-19 infodemic and should adopt evidence-based measures to mitigate misinformation on their platforms.

Pretransplant Cytomegalovirus-Specific Cellular Immunity and Risk of Viral Reactivation Following Lung Transplantation: A Prospective Cohort Study.

Cytomegalovirus (CMV) remains a significant burden in lung transplant recipients. Deficiencies in T-cell immunity posttransplant increase the risk of CMV-associated complications. However, it is not clear if underlying poor pretransplant immunity increases risk. To assess this, we recruited 39 prospective lung transplant patients and performed QuantiFERON-CMV on their peripheral blood. More than a third of prospective CMV-seropositive transplant recipients were CMV non-immune reactive (CMV-NIR) pretransplant. CMV-NIR status was associated with a significantly higher incidence of CMV reactivation posttransplant, demonstrating that dysfunctional CMV immunity in prospective lung transplant recipients is associated with an increased risk of viral reactivation posttransplant.

Diagnosis and management of connective tissue disease-associated interstitial lung disease in Australia and New Zealand: A position statement from the Thoracic Society of Australia and New Zealand.

Pulmonary complications in CTD are common and can involve the interstitium, airways, pleura and pulmonary vasculature. ILD can occur in all CTD (CTD-ILD), and may vary from limited, non-progressive lung involvement, to fulminant, life-threatening disease. Given the potential for major adverse outcomes in CTD-ILD, accurate diagnosis, assessment and careful consideration of therapeutic intervention are a priority. Limited data are available to guide management decisions in CTD-ILD. Autoimmune-mediated pulmonary inflammation is considered a key pathobiological pathway in these disorders, and immunosuppressive therapy is generally regarded the cornerstone of treatment for severe and/or progressive CTD-ILD. However, the natural history of CTD-ILD in individual patients can be difficult to predict, and deciding who to treat, when and with what agent can be challenging. Establishing realistic therapeutic goals from both the patient and clinician perspective requires considerable expertise. The document aims to provide a framework for clinicians to aid in the assessment and management of ILD in the major CTD. A suggested approach to diagnosis and monitoring of CTD-ILD and, where available, evidence-based, disease-specific approaches to treatment have been provided.

High intensity interval training versus moderate intensity continuous training for people with interstitial lung disease: protocol for a randomised controlled trial.

BACKGROUND: Interstitial lung disease is a debilitating condition associated with significant dyspnoea, fatigue, and poor exercise tolerance. Pulmonary rehabilitation is an effective and key intervention in people with interstitial lung disease. However, despite the best efforts of patients and clinicians, many of those who participate are not achieving clinically meaningful benefits. This assessor-blinded, multi-centre, randomised controlled trial aims to compare the clinical benefits of high intensity interval exercise training versus the standard pulmonary rehabilitation method of continuous training at moderate intensity in people with fibrotic interstitial lung disease. METHODS: Eligible participants will be randomised to either a standard pulmonary rehabilitation group using moderate intensity continuous exercise training or high intensity interval exercise training. Participants in both groups will undertake an 8-week pulmonary rehabilitation program of twice-weekly supervised exercise training including aerobic (cycling) and strengthening exercises. In addition, participants in both groups will be prescribed a home exercise program. Outcomes will be assessed at baseline, upon completion of the intervention and at six months following the intervention by a blinded assessor. The primary outcome is endurance time on a constant work rate test. Secondary outcomes are functional capacity (6-min walk distance), health-related quality of life (Chronic Respiratory Disease Questionnaire (CRQ), St George's Respiratory Questionnaire idiopathic pulmonary fibrosis specific version (SGRQ-I), breathlessness (Dyspnoea 12, Modified Medical Research Council Dyspnoea Scale), fatigue (fatigue severity scale), anxiety (Hospital Anxiety and Depression Scale), physical activity level (GeneActiv), skeletal muscle changes (ultrasonography) and completion and adherence to pulmonary rehabilitation. DISCUSSION: The standard exercise training strategies used in pulmonary rehabilitation may not provide an optimal exercise training stimulus for people with interstitial lung disease. This study will determine whether high intensity interval training can produce equivalent or even superior changes in exercise performance and symptoms. If high intensity interval training proves effective, it will provide an exercise training strategy that can readily be implemented into clinical practice for people with interstitial lung disease. Trial registration ClinicalTrials.gov Registry (NCT03800914). Registered 11 January 2019, https://clinicaltrials.gov/ct2/show/NCT03800914 Australian New Zealand Clinical Trials Registry ACTRN12619000019101. Registered 9 January 2019, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376050&isReview=true.

Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells.

Growing evidence demonstrates that human mesenchymal stromal cells (MSCs) modify their in vivo anti-inflammatory actions depending on the specific inflammatory environment encountered. Understanding this better is crucial to refine MSC-based cell therapies for lung and other diseases. Using acute exacerbations of cystic fibrosis (CF) lung disease as a model, the effects of ex vivo MSC exposure to clinical bronchoalveolar lavage fluid (BALF) samples, as a surrogate for the in vivo clinical lung environment, on MSC viability, gene expression, secreted cytokines, and mitochondrial function were compared with effects of BALF collected from healthy volunteers. CF BALF samples that cultured positive for Aspergillus sp. (Asp) induced rapid MSC death, usually within several hours of exposure. Further analyses suggested the fungal toxin gliotoxin as a potential mediator contributing to CF BALF-induced MSC death. RNA sequencing analyses of MSCs exposed to either Asp+ or Asp- CF BALF samples identified a number of differentially expressed transcripts, including those involved in interferon signaling, antimicrobial gene expression, and cell death. Toxicity did not correlate with bacterial lung infections. These results suggest that the potential use of MSC-based cell therapies for CF or other lung diseases may not be warranted in the presence of Aspergillus.

Silica-related diseases in the modern world.

Silicosis is an ancient and potentially fatal pneumoconiosis caused by exposure to respirable crystalline silica. Silicosis is historically a disease of miners; however, failure to recognize and control the risk associated with silica exposure in contemporary work practices such as sandblasting denim jeans and manufacturing of artificial stone benchtops has led to re-emergence of silicosis around the world. This review outlines the mineralogy, epidemiology, clinical and radiological features of the various forms of silicosis and other silica-associated diseases. Perspective is provided on the most recent studies shedding light on pathogenesis, including the central role of innate immune effector cells and subsequent inflammatory cascades in propagating pulmonary fibrosis and the extrapulmonary manifestations, which uniquely characterize this pneumoconiosis. Clinical conundrums in differential diagnosis, particularly between silicosis and sarcoidosis, are highlighted, as is the importance of obtaining a careful occupational history in the patient presenting with pulmonary infiltrates and/or fibrosis. While silicosis is a completely preventable disease, unfortunately workers around the world continue to be affected and experience progressive or even fatal disease. Although no treatments have been proven, opportunities to intervene to prevent progressive disease, founded in a thorough cellular and molecular understanding of the immunopathology of silicosis, are highlighted.

Diagnosis and treatment of lung disease associated with alpha one-antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand.

AATD is a common inherited disorder associated with an increased risk of developing pulmonary emphysema and liver disease. Many people with AATD-associated pulmonary emphysema remain undiagnosed and therefore without access to care and counselling specific to the disease. AAT augmentation therapy is available and consists of i.v. infusions of exogenous AAT protein harvested from pooled blood products. Its clinical efficacy has been the subject of some debate and the use of AAT augmentation therapy was recently permitted by regulators in Australia and New Zealand, although treatment is not presently subsidized by the government in either country. The purpose of this position statement is to review the evidence for diagnosis and treatment of AATD-related lung disease with reference to the Australian and New Zealand population. The clinical efficacy and adverse events of AAT augmentation therapy were evaluated by a systematic review, and the GRADE process was employed to move from evidence to recommendation. Other sections address the wide range of issues to be considered in the care of the individual with AATD-related lung disease: when and how to test for AATD, changing diagnostic techniques, monitoring of progression, disease in heterozygous AATD and pharmacological and non-pharmacological therapy including surgical options for severe disease. Consideration is also given to broader issues in AATD that respiratory healthcare staff may encounter: genetic counselling, patient support groups, monitoring for liver disease and the need to establish national registries for people with AATD in Australia and New Zealand.

Autologous Adoptive T-cell Therapy for Recurrent or Drug-resistant Cytomegalovirus Complications in Solid Organ Transplant Recipients: A Single-arm Open-label Phase I Clinical Trial.

Background: Opportunistic infections including cytomegalovirus (CMV) are a major cause of morbidity and mortality in solid organ transplant (SOT) recipients. The recurrent and protracted use of antiviral drugs with eventual emergence of drug resistance represents a significant constraint to therapy. Although adoptive T-cell therapy has been successfully used in hematopoietic stem cell transplant recipients, its extension to the SOT setting poses a considerable challenge because of the inhibitory effects of immunosuppressive drugs on the virus-specific T-cell response in vivo and the perceived risk of graft rejection. Methods: In this prospective study, 22 SOT recipients (13 renal and 8 lung and 1 heart transplants) with recurrent or ganciclovir-resistant CMV infection were recruited, and 13 of them were treated with in vitro-expanded autologous CMV-specific T cells. These patients were monitored for safety, clinical symptoms, and immune reconstitution. Results: Autologous CMV-specific T-cell manufacture was attempted for 21 patients, and was successful in 20. The use of this adoptive immunotherapy was associated with no therapy-related serious adverse events. Eleven (84%) of the 13 treated patients showed improvement in symptoms, including complete resolution or reduction in DNAemia and CMV-associated end-organ disease and/or the cessation or reduced use of antiviral drugs. Furthermore, four of these patients showed coincident increased frequency of CMV-specific T cells in peripheral blood after completion of T-cell therapy. Conclusions: The data presented here demonstrate for the first time the clinical safety of CMV-specific adoptive T-cell therapy and its potential therapeutic benefit for SOT recipients with recurrent and/or drug-resistant CMV infection or disease. Clinical Trials Registration: ACTRN12613000981729.