Background:Tracheobronchitis is an uncommon pattern of airway disease and is typically caused by infection, inhalation injury, infiltrative disorders and more rarely, systemic autoimmune disease. Rarer again is the development of bronchial webbing following tracheobronchitis. The underlying aetiology is usually identified through biopsy, culture or a detailed clinical history. We present a case of cryptogenic ulcerative tracheobronchitis with bronchial webbing being successfully managed by bilateral lung transplantation that has, however, been complicated by recurrence. Case Presentation:In 2019, Crowhurst et al. detailed the case of a patient who presented with dyspnoea and haemoptysis. Bronchoscopy revealed ulcerative tracheobronchitis and he subsequently formed recurrent web-like stenoses of the central bronchi, leading to rapidly progressive type 2 respiratory failure; he received bilateral sequential lung transplantation for definitive management. At the time of transplant, the presumed diagnosis was an inhalation injury that occurred while travelling in Vietnam, or exposure to the organophosphate pesticide Malathion several days prior. The explanted lung histology revealed ulcerating bronchitis with intense histiocytic infiltrates, bronchial luminal fibrosis and obstruction with scant, poorly formed granulomas. The patient thrived with stable lung function and had minimal complications initially post-transplantation. However, 6 years after lung transplantation and without re-exposure, the patient re-developed ulcerative tracheobronchitis, which shared similar histopathologic features to airway involvement of Crohn's disease. Gastrointestinal or other organ system involvement of Crohn's disease was not established despite extensive investigations. A decision for phenotypic treatment with the TNF-α inhibitor, infliximab, was made with subsequent rapid improvement in the tracheobronchitis. Conclusion:This is the first case documented in the literature of ulcerative tracheobronchitis followed by intense bronchial web-like stenoses caused by an unspecified autoimmune disease, treated by bilateral lung transplantation. The disease recurred after 6 years and responded to phenotypic management with the TNF-α inhibitor, infliximab. The patient will require careful monitoring given the risk of augmented immunosuppression and unknown disease trajectory.

BACKGROUND:Chronic lung allograft dysfunction (CLAD) remains the primary limitation to long-term survival after lung transplantation. We conducted a multicenter, phase 2, double-blind, randomized controlled trial of intravenous (IV) allogenic bone marrow-derived mesenchymal stromal cells (MSC) in lung transplant recipients with new-onset CLAD. METHODS:Participants (bilateral or single lung transplant, aged ≥18 years, >6 months post-transplant and with a persistent fall in forced expiratory volume in 1 second [FEV1] and/or forced vital capacity [FVC] >20% from best post-transplant values within 12 months) were randomized (1:1, target n = 41 per arm) to receive MSC (2 × 10⁶ cells/kg IV twice weekly for 2 weeks) or placebo. The primary end-point was progression-free survival at 12 months, defined as a composite of all-cause mortality and freedom from CLAD progression (fall in FEV1 decline >10%). RESULTS:Fifty-nine participants were randomized. Fifty-eight received treatment (31 placebo; 27 MSC). MSC treatment did not improve progression-free survival: Seventeen of 31 (55%) in the placebo arm vs 11 of 27 (41%) in the MSC arm (relative risk 0.74 (0.42-1.29), p = 0.30). Lung function decline was similar between groups. The FEV1 slope (95% CI) declined by 6.43 (-11.78, -1.08) ml/week in the MSC group and 9.14 (-14.29, -3.99) ml/week in the placebo group (difference: 2.56 (-4.88, 9.99) ml/week, p = 0.50). FVC declined by 4.58 (-7.51, -1.65) ml/week in the MSC group and by 4.19 (-6.97, -1.41) ml/week in the placebo group (difference: -0.39 (-4.43, 3.65) ml/week (p = 0.85). CONCLUSIONS:MSC treatment did not influence progression-free survival in lung transplant recipients with new-onset CLAD.

BACKGROUND:Chronic lung allograft dysfunction (CLAD), and especially bronchiolitis obliterans syndrome (BOS), remain dominant causes of morbidity and mortality after lung transplantation. Interest is growing in the forced oscillation technique, of which impulse oscillometry (IOS) is a form, as a tool to improve our understanding of these disorders. However, data remain limited and no longitudinal studies have been published, meaning there is no information regarding any capacity IOS may have for the early detection of CLAD. METHODS:We conducted a prospective longitudinal study enrolling a consecutive sample of adult bilateral lung transplant recipients with healthy lung allografts or CLAD and performed ongoing paired IOS and spirometry tests on a clinically determined basis. We assessed for correlations between IOS and spirometry and examined any predictive value either modality may hold for the early detection of BOS. RESULTS:We enrolled 91 patients and conducted testing for 43 mo, collecting 558 analyzable paired IOS and spirometry tests, with a median of 9 tests per subject (interquartile range, 5-12) and a median testing interval of 92 d (interquartile range, 62-161). Statistically significant moderate-to-strong correlations were demonstrated between all IOS parameters and spirometry, except resistance at 20 Hz, which is a proximal airway measure. No predictive value for the early detection of BOS was found for IOS or spirometry. CONCLUSIONS:This study presents the first longitudinal data from IOS after lung transplantation and adds considerably to the growing literature, showing unequivocal correlations with spirometry but failing to demonstrate a predictive value for BOS.

Purpose: Participants in the ASSIST CLAD study of mesenchymal stromal cell therapy in new-onset chronic lung allograft dysfunction (CLAD) participated in an optional bronchoalveolar lavage (BAL) sub-study, providing an opportunity to investigate relationships between longitudinal change in BAL biomarkers and subsequent CLAD outcome.

Chronic lung transplant rejection (termed chronic lung allograft dysfunction [CLAD]) is the main impediment to long-term survival after lung transplantation. Bone marrow-derived mesenchymal stromal cells (MSCs) represent an attractive cell therapy in inflammatory diseases, including organ rejection, given their relative immune privilege and immunosuppressive and tolerogenic properties. Preclinical studies in models of obliterative bronchiolitis and human trials in graft versus host disease and renal transplantation suggest potential efficacy in CLAD. The purpose of this phase 1, single-arm study was to explore the feasibility and safety of intravenous delivery of allogeneic MSCs to patients with advanced CLAD. MSCs from unrelated donors were isolated from bone marrow, expanded and cryopreserved in a GMP-compliant facility. Patients had deteriorating CLAD and were bronchiolitis obliterans (BOS) grade2 or grade 1 with risk factors for rapid progression. MSCs (2 x 10(6) cells per kilogram patient weight) were infused via a peripheral vein twice weekly for 2 weeks, with 52 weeks follow-up. Ten Patients (5 male, 8 bilateral, median [interquartile range] age 40 [30-59] years, 3 BOS2, 7 BOS3) participated. MSC treatment was well tolerated with all patients receiving the full dosing schedule without any procedure-related serious adverse events. The rate of decline in forced expiratory volume in one second slowed after the MSC infusions (120 ml/month preinfusion vs. 30 ml/month postinfusion, p=.08). Two patients died at 152 and 270 days post-MSC treatment, both from progressive CLAD. In conclusion, infusion of allogeneic bone marrow-derived MSCs is feasible and safe even in patients with advanced CLAD.

Background: Improvements in pulmonary diagnostic imaging and the development of lung cancer screening are increasing the prevalence of Solitary pulmonary nodules (SPNs). Fluoroscopically guided radial endobronchial ultrasound (EBUS) with transbronchial forceps biopsy (TB-FB) has been the conventional diagnostic method. Transbronchial cryobiopsy (TB-CB) is an alternative biopsy method. We sought to compare transbronchial cryobiopsy to transbronchial forceps biopsy for the diagnosis of SPNs. Methods: A prospective, single-centre, randomised controlled trial was conducted at the Royal Adelaide Hospital (RAH). Patients with SPNs were randomised to either 5 transbronchial forceps biopsies or one transbronchial cryobiopsy. Complete blinding of investigators and participants was not possible, as transbronchial cryobiopsy required general anaesthesia. The primary outcome was diagnostic yield with secondary outcomes of specimen size, diagnostic yield for subsets challenging to access with forceps and safety. Results: The overall diagnostic yield for the 28 enrolled subjects was 76.8%(22/28). The diagnostic yield was 91.7% (11/12 patients) for transbronchial cryobiopsy and 68.8% (11/16 patients) for forceps biopsy (p=0.14). Median biopsy sizes were consistently larger for the cryobiopsy arm at 7.0mm compared to 2.5mm(p<0.0001). An eccentric EBUS image signalling the probe was adjacent to the nodule occurred in 4/28 cases, and TB-CB confirmed a diagnosis in 3/3 randomised to this arm. There were no major complications with either technique. Conclusion: Transbronchial cryobiopsy under the guidance of fluoroscopy and radial EBUS facilitates larger biopsy specimens without a significant increase in major complications. Further research is required to confirm the effect on diagnostic yield; however, our study supports a role for TB-CB in the diagnosis of SPNs and small, nodule-adjacent biopsies. Clinical Trial Registration Number: Reference number of R20160213(HREC/16/RAH/37).

INTRODUCTION:Pro-inflammatory CD8+ T cells are increased in the lungs and also in the peripheral circulation of both smokers and chronic obstructive pulmonary disease (COPD) patients. The reason for this is unclear but has been described as a spillover from cells in the lungs that may cause the systemic inflammation noted in COPD. We have recently shown an increase in steroid-resistant CD28nullCD8+ senescent lymphocytes in the lungs and peripheral blood in COPD. Leukotreine B4 (LB4) receptor 1 (BLTR1) is involved in recruitment of CD8+ T cells to sites of inflammation, and we hypothesized that it may be involved in the migration of these senescent lymphocytes from the lungs in COPD.METHODS:Via flow cytometry and Western blot BLTR1, IFNγ, and TNFα expression were measured in peripheral blood, BAL, and large proximal and small distal airway CD28±, CD8± T, and NKT-like cells from COPD patients and healthy control subjects (±prednisolone) following in vitro stimulation. Chemotaxis of leucocyte subsets was determined (±LB4 ± prednisolone).RESULTS:There was an increase in BLTR1-CD28nullCD8+ lymphocytes in the lungs and blood in patients with COPD compared with controls. BLTR1-CD28nullCD8+ T and NKT-like cells produce more IFN/TNF than BLTR+ cells and fail to migrate to LTB4. Treatment with 1 µM prednisolone in vitro resulted in upregulation of BLTR1 expression in pro-inflammatory CD28nullCD8+ cells and migration to LB4.CONCLUSIONS:Loss of BLTR1 is associated with an increased inflammatory potential of CD28nullCD8+ T cells and may allow these pro-inflammatory steroid-resistant cells to migrate to peripheral blood. Treatment strategies that upregulate BLTR1 may reduce systemic inflammation and associated co-morbidity in patients with COPD.

We previously showed increased steroid resistant CD28null CD8+ senescent lymphocyte subsets in peripheral blood from COPD patients. These cells expressed decreased levels of the glucocorticoid receptor (GCR), suggesting their contribution to the steroid resistant property of these cells. COPD is a disease of the small airways. We therefore hypothesized that there would be a further increase in these steroid resistant lymphocytes in the lung, particularly in the small airways. We further hypothesized that the pro-inflammatory/cytotoxic potential of these cells could be negated using prednisolone with low-dose cyclosporin A. Blood, bronchoalveolar lavage, large proximal and small distal airway brushings were collected from 11 COPD patients and 10 healthy aged-matched controls. The cytotoxic mediator granzyme b, pro-inflammatory cytokines IFNγ/TNFα, and GCR were determined in lymphocytes subsets before and after their exposure to 1µM prednisolone and/or 2.5ng/mL cyclosporin A. Particularly in the small airways, COPD subjects showed an increased percentage of CD28null CD8 T-cells and NKT-like cells, with increased expression of granzyme b, IFNγ and TNFα and a loss of GCR, compared with controls. Significant negative correlations between small airway GCR expression and IFNγ/TNFα production by T and NKT-like cells (eg, T-cell IFNγ R= -.834, p=.031) and with FEV (R= -890) were shown. Cyclosporine A and prednisolone synergistically increased GCR expression and inhibited pro-inflammatory cytokine production by CD28null CD8- T and NKT-like cells. COPD is associated with increased pro-inflammatory CD28null CD8+ T and NKT-like cells in the small airways. Treatments that increase GCR in these lymphocyte subsets may improve morbidity in COPD patients.

Introduction Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. Coronavirus disease 2019 (COVID-19) is an acute respiratory infection that emerged as a pandemic worldwide before the start of the 2020 Australian influenza season. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza and COVID-19 during the 2020 influenza season in a sentinel surveillance system. Methods The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. Influenza and COVID-19 cases were defined as patients hospitalised at sentinel hospitals and confirmed by nucleic acid detection. Results There were 448 patients with COVID-19 admitted between 16 March and 31 December 2020, and only 20 patients with influenza admitted between 1 April and 30 November 2020, to one of 22 FluCAN hospitals. Of the COVID-19 cases, 173 (39%) were > 65 years of age, 36 (8%) were children (< 16 years), 6 (1%) were Aboriginal and Torres Strait Islander peoples, 4 (1%) were pregnant and 289 (65%) had chronic comorbidities. COVID-19 hospital admissions peaked between weeks 13 and 15 (first wave) nationally, and again between weeks 31 and 35 (Victoria), with most admissions represented by those above 40 years of age. Discussion There was an unusually low number of hospital admissions with laboratory-confirmed influenza in this season, compared to recent seasons. This is likely to be due to effective public health interventions and international border closures as a result of a rise in COVID-19 respiratory infections and associated hospitalisations.

Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2019 influenza season. The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. Cases were defined as patients hospitalised at any of the 17 sentinel hospitals with influenza confirmed by nucleic acid detection. Data were also collected on a frequency matched control group of influenza-negative patients admitted with acute respiratory infection. During the period 1 April to 31 October 2019 (the 2019 influenza season), there were 4,154 patients admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 44% were elderly ( ≥ 65 years), 21% were children (< 16 years), 7.7% were Aboriginal and Torres Strait Islander peoples, 1.7% were pregnant and 73% had chronic comorbidities. Most admissions were due to influenza A infection (85%). Estimated vaccine coverage was 75% in the elderly, 49% in non-elderly adults with medical comorbidities, and 27% in young children (< 5 years). The estimated vaccine effectiveness in the target adult population was 42% (95% confidence interval [95% CI]: 36%, 49%). There were a larger number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2019 than in 2018.

Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2019 influenza season. The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. Cases were defined as patients hospitalised at any of the 17 sentinel hospitals with influenza confirmed by nucleic acid detection. Data were also collected on a frequency matched control group of influenza-negative patients admitted with acute respiratory infection. During the period 1 April to 31 October 2019 (the 2019 influenza season), there were 4,154 patients admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 44% were elderly (≥ 65 years), 21% were children (< 16 years), 7.7% were Aboriginal and Torres Strait Islander peoples, 1.7% were pregnant and 73% had chronic comorbidities. Most admissions were due to influenza A infection (85%). Estimated vaccine coverage was 75% in the elderly, 49% in non-elderly adults with medical comorbidities, and 27% in young children (< 5 years). The estimated vaccine effectiveness in the target adult population was 42% (95% confidence interval [95% CI]: 36%, 49%). There were a larger number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2019 than in 2018.

Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. Coronavirus disease 2019 (COVID-19) is an acute respiratory infection that emerged as a pandemic worldwide before the start of the 2020 Australian influenza season. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza and COVID-19 during the 2020 influenza season in a sentinel surveillance system. patients hospitalised at sentinel hospitals and confirmed by nucleic acid detection. with most admissions represented by those above 40 years of age. There was an unusually low number of hospital admissions with laboratory-confirmed influenza in this season, compared to recent seasons. This is likely to be due to effective public health interventions and international border closures as a result of a rise in COVID-19 respiratory infections and associated hospitalisations.

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.

ABSTRACT BACKGROUND Immunosuppression therapy is ineffective at preventing bronchiolitis obliterans syndrome (BOS), primarily a disease of the small airways. Our previous reports show increased senescent CD28null T and NKT-like cells in the peripheral blood in patients with BOS and increased cytotoxic pro-inflammatory lymphocytes in the small airways. We hypothesized that the cytotoxic pro-inflammatory lymphocytes in the small airways would be steroid resistant senescent CD28null lymphocytes. METHODS Intracellular cytotoxic mediator granzyme b, IFNγ and TNFα pro-inflammatory cytokines and CD28 were measured in blood, bronchoalveolar lavage, large and small airway brushing T and NKT-like cells from 10 patients with BOS, 11 stable lung transplant patients and 10 healthy aged-matched controls. Small airway brushings were cultured in the presence of ± 1µM prednisolone ± 5 mg/L theophylline ± 2.5 ng/mL cyclosporine A and IFNγ and TNFα pro-inflammatory cytokines assessed using flowcytometry. RESULTS Increased small airway CD28null T and NKT-like cells were identified in BOS compared with controls and stable transplants. Loss of CD28 was associated with increased T and NKT-like cells expressing granzyme b, IFNγ and TNFα. Loss of CD28 expression by CD8+T cells was significantly associated with FEV1 (R=.655, p=.006) and with time post-transplant (R=-.552, p=.041). Treatment with predniosolone + theophylline + cyclopsorin A inhibited IFNγ and TNFα production by small airway CD28nullCD8+ T and NKT-like cells additively. CONCLUSIONS BOS is associated with loss of CD28 in small airway cytotoxic pro-inflammatory senescent T and NKT-like lymphocytes. Treatment options that target the pro-inflammatory nature of these cells in the small airways may improve graft survival.

BACKGROUND: Immunosuppression therapy is ineffective at preventing bronchiolitis obliterans syndrome (BOS), primarily a disease of the small airways (SAs). Our previous reports show increased senescent CD28null T and natural killer T (NKT)-like cells in the peripheral blood of patients with BOS and increased cytotoxic, proinflammatory lymphocytes in the SAs. We hypothesized that the cytotoxic, proinflammatory lymphocytes in the SAs would be steroid-resistant senescent CD28null lymphocytes. METHODS: Intracellular cytotoxic mediator granzyme B, interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha proinflammatory cytokines, and CD28 were measured in the blood, bronchoalveolar lavage, large airway, and SA brushing T and NKT-like cells from 10 patients with BOS, 11 stable lung transplant recipients, and 10 healthy age-matched controls. SA brushings were cultured in the presence of +/- 1 mmol/liter prednisolone, +/- 5 mg/liter theophylline, and +/- 2.5 ng/ml cyclosporine A, and IFN-gamma and TNF-alpha proinflammatory cytokines were assessed using flow cytometry. RESULTS: Increased SA CD28null T and NKT-like cells were identified in patients with BOS compared with that in the controls and stable transplant recipients. Loss of CD28 was associated with increased T and NKT-like cells expressing granzyme B, IFN-gamma, and TNF-alpha. Loss of CD28 expression by CD8+ T cells was significantly associated with forced expiratory volume in 1 sec (R = 0.655, p = 0.006) and with time after transplantation (R = -0.552, p = 0.041). Treatment with prednisolone + theophylline + cyclosporin A inhibited IFN-gamma and TNF-alpha production by SA CD28null CD8+ T and NKT-like cells additively. CONCLUSIONS: BOS is associated with the loss of CD28 in SA cytotoxic, proinflammatory senescent T and NKT-like lymphocytes. Treatment options that target the proinflammatory nature of these cells in the SAs may improve graft survival. (C) 2020 International Society for Heart and Lung Transplantation. All rights reserved.

BACKGROUND:Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system caused by JC virus (JCV). The disease occurs in the setting of significant immunocompromise and has now been reported in many different settings, although only very rarely after lung transplantation. The mortality rate is high and therapeutic options are limited.CASE PRESENTATION:We report a case of a 66-year-old man who presented with non-specific memory disturbance at 19 months after lung transplantation for chronic hypersensitivity pneumonitis. He had required methylprednisolone for acute allograft rejection but achieved good graft function. Physical examination was unremarkable. CT revealed hypodensity in the left frontal lobe. MR demonstrated significant hyperintense white-matter abnormalities on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, mainly focused on the periventricular region adjacent the frontal horn of the left lateral ventricle. Brain biopsy confirmed PML. The patient had his immunosuppression reduced but then developed antibody-mediated rejection four months later. Despite re-escalation of immunosuppression, he remains neurologically stable on mirtazapine at eight months post-diagnosis.CONCLUSIONS:This very rare case highlights the challenges presented by PML, especially in the lung transplant population. It reveals the difficult balance between reducing immunosuppression to protect the brain versus prevention of lung allograft rejection. It clearly highlights the need for improved therapeutic modalities.

While controversy abounds regarding the use of mTOR inhibitors during while listed for LTX in LAM patients, this case series suggest that continuation of mTOR inhibitor during waitlist phase before LTX is reasonable and safe. Programs should consider allowance of mTOR inhibition in LAM patients on the LTX waitlist. References: 1. McCormack FX et al. N Engl J Med. 2011;364(17):1595 2. King-Biggs MB et al. Transplantation 2003;75:1437 3. Groetzner J et al. J Heart Lung Transplant 2004;23:632 4. Dilling, DF et al. J Heart Lung Transplant. 2018 37(4), S457.