Sternal wire fragmentation is a common radiographic finding. However, sternal wire displacement is a rare and often serious complication. We report the case of a 68-year-old man who was incidentally found to have sternal wire migration into his right ventricle 3 years after lung transplantation. Retrieval was attempted through a left parasternal approach, but the wires were not visible intraoperatively to facilitate removal. Because the patient was asymptomatic with no adverse outcomes and surgery was considered high risk, a decision was made not to pursue major surgery to remove the wires. Instead, the case was managed conservatively with ongoing surveillance for any further migration of the wires or associated complications.

A 60-year-old man deteriorated six weeks post bilateral lung transplantation and found to have concurrent Trichosporon inkin empyema and fungaemia. Diagnosis was confirmed via biochemical testing and pan-fungal rDNA sequencing. Management involved Interventional Radiology-guided drainage and voriconazole therapy, optimised via therapeutic drug monitoring with a final trough of 1.72 mg/L. This first reported case of concurrent T. inkin pleural and bloodstream infection underscores the necessity of molecular diagnostics and aggressive source control.

Background There are limited data on optimal management of chronic lung allograft dysfunction (CLAD). We aimed to describe the variability of diagnostic and therapeutic practices in Europe. Methods A structured questionnaire was sent to 71 centres in 24 countries. Questions were related to contemporary clinical practices for workup, monitoring and treatment of CLAD. The number of lung transplant procedures and patients in follow-up were collected. Results 44 centres (62%) responded from 20 countries, representing 74% of European activity. The prevalence of CLAD was estimated at 9.1 cases per million population (25th and 75th percentiles of 4.4, 15.7). Preferred initial workup for probable CLAD consisted of chest computed tomography (CT) (inspiratory 91% and expiratory 74%), donor-specific antibody (DSA) measurement (86%), bronchoalveolar lavage (BAL) (85%) and transbronchial biopsy (81%). For monitoring of definite CLAD, inspiratory CT (67%), DSA (61%) and BAL (43%) were preferred. Body plethysmography was unavailable for 16% of cases. Prophylaxis was based on preventing infections (cytomegalovirus 99%, inhaled antibiotics 70% and antifungals 65%), tacrolimus-based immunosuppression (96%), azithromycin (72%) and universal proton pump inhibitor treatment (84%). First-line treatment of CLAD was based on azithromycin (82%) and steroid augmentation (74%). Photopheresis was used in 26% of cases. Conclusion Current European practice CLAD detection is based on spirometry, inspiratory CT and DSA, with limited access to plethysmography and expiratory CT. Prophylactic treatment is based on azithromycin, tacrolimus-based immunosuppression and treatment of risk factors. No single treatment strategy is universally used, highlighting the need for an effective treatment of CLAD. The preferred first-line strategy is azithromycin and steroid augmentation.

Purpose: The 2015 ISHLT fungal guidelines recommend the use of BAL GM over serum GM in LTRs. Evidence for serum GM for diagnosis of invasive aspergillosis (IA) in LTRs is limited. GM testing costs €77.77 per test. The aim of our audit was to review our use of serum and BAL GM testing in our LTR cohort and assess its role in the diagnosis of IA.

Purpose: Two conceptual models of frailty, physical/frailty phenotype and cumulative deficits/frailty index, have both been associated with lung transplant outcomes. We aimed to compare the trajectories of physical and cumulative deficits frailty before and after lung transplantation (LTx). While physical frailty has been shown to improve post-LTx, we hypothesized that cumulative deficits would not improve as new deficits accrue after LTx.

The role of lung transplantation is to provide survival and quality of life benefits to patients with advanced lung disease. In this chapter, focusing on chronic obstructive pulmonary disease (COPD), we provide a comprehensive discussion of key aspects involved in the assessment of recipient suitability for transplantation. We discuss key issues such as timing of referral, donor evaluation, and organ allocation. We provide a detailed evaluation of the technical aspects of transplant surgery, evaluating the relative merits of both single and bilateral lung transplantation. In addition, we highlight how the transplant field is addressing donor shortfall, with expansion of acceptable donor criteria and the use of ex vivo lung perfusion to improve donor evaluation. Finally, we examine post-operative morbidity and mortality, discussing both early and late surgical complications and the adverse effects of long-term immunosuppression.

BACKGROUND:The 2015 International Society for Heart and Lung Transplant (ISHLT) fungal guidelines recommend the use of bronchoalveolar lavage (BAL) galactomannan over serum galactomannan for the diagnosis of invasive aspergillosis (IA) in lung transplant (LTx) recipients, based on limited evidence. Galactomannan testing is costly. METHODS:A single-center, retrospective cohort study reviewing all 814 serum and BAL galactomannan samples received from 184 LTx recipients in our center between 2021 and 2022 and assessing their diagnostic performance in the diagnosis of IA. RESULTS:Over the study period, 394 serum galactomannan samples were received from 144 patients and 420 BAL galactomannan samples from 143 patients. Using a cut-off of ≥ 1.0 for BAL galactomannan, the sensitivity and specificity were 65.9% and 98.4%, respectively. In total, 30 patients had positive BAL galactomannan. Antifungal therapy was commenced or continued in 29 of these patients either as targeted or pre-emptive treatment. Using a cut-off of ≥ 0.5 for serum galactomannan, the sensitivity and specificity were 9.7% and 99.7%, respectively. In total, four patients had a positive serum galactomannan. All four patients were either already on antifungal treatment for IA or were started before the serum galactomannan result was available, supported by laboratory, clinical, and radiological findings. A positive serum galactomannan was used to monitor treatment response in one patient. CONCLUSION:Serum galactomannan is not a valuable test in the diagnosis of IA in our LTx recipients, is costly, and does not remove the need for bronchoscopy and BAL galactomannan. This supports the ISHLT recommendation.

The long-term benefits of lung transplantation (LTx) are limited by pathogenic alloimmune responses that drive injury, inflammation, and chronic dysfunction. Human leukocyte antigen-G (HLA-G) plays a key role in the modulation of these pathways. This study assesses the impact of the HLA-G genotype on immunologic risk and survival following LTx. This retrospective cohort study included 289 bilateral LTx. Recipient and donor HLA-G genotypes were analyzed to identify associations with de novo donor-specific antibodies, acute rejection, chronic lung allograft dysfunction, and allograft survival. We further assessed these associations, both individually and in paired analysis, based on a grouped haplotype classification of HLA-G expression. Donor HLA-G single nucleotide polymorphisms were associated with allograft injury, the onset of chronic lung allograft dysfunction following injury, and allograft survival. Recipient HLA-G single nucleotide polymorphisms were associated with allograft injury, cellular rejection, and donor-specific antibody formation. "Low HLA-G expression" donor haplotypes were associated with impaired allograft survival, as were "low HLA-G expression" donor-recipient haplotype pairs. This study provides compelling evidence for the role of HLA-G in modulating immunologic risk after LTx. Our results highlight the importance of both donor and recipient HLA-G genotypes on the overall risk profile and underscore the lasting influence of donor genotype on lung transplant outcomes.

Background Morbidity and mortality in lung transplant recipients are often triggered by recurrent aspiration events, potentiated by oesophageal and gastric disorders. Previous small studies have shown conflicting associations between oesophageal function and the development of chronic lung allograft dysfunction (CLAD). Herein, we sought to investigate the relationship between oesophageal motility disorders and long-term outcomes in a large retrospective cohort of lung transplant recipients. Methods All lung transplant recipients at the Toronto Lung Transplant Program from 2012 to 2018 with available oesophageal manometry testing within the first 7 months post-transplant were included in this study. Patients were categorised according to the Chicago Classification of oesophageal disorders (v3.0). Associations between oesophageal motility disorders with the development of CLAD and allograft failure (defined as death or re-transplantation) were assessed. Results Of 487 patients, 57 (12%) had oesophagogastric junction outflow obstruction (OGJOO) and 47 (10%) had a disorder of peristalsis (eight major, 39 minor). In a multivariable analysis, OGJOO was associated with an increased risk of CLAD (HR 1.71, 95% CI 1.15–2.55, p=0.008) and allograft failure (HR 1.69, 95% CI 1.13–2.53, p=0.01). Major disorders of peristalsis were associated with an increased risk of CLAD (HR 1.55, 95% CI 1.01–2.37, p=0.04) and allograft failure (HR 3.33, 95% CI 1.53–7.25, p=0.002). Minor disorders of peristalsis were not significantly associated with CLAD or allograft failure. Conclusion Lung transplant recipients with oesophageal stasis characterised by OGJOO or major disorders of peristalsis were at an increased risk of adverse long-term outcomes. These findings will help with risk stratification of lung transplant recipients and personalisation of treatment for aspiration prevention.

Antibody-mediated rejection (ABMR) results from a pro-inflammatory cascade that occurs following the binding of circulating anti-HLA antibodies to HLA on donor endothelial cells. As such, pathogenic pathways of humoral immunity are considered key targets for diagnostic and therapeutic focus. As one example, antibody-dependent cell-mediated cytotoxicity (ADCC) is an important mechanism of ABMR, in which graft-bound anti-HLA antibodies activate innate leukocytes such as natural killer (NK) cells and monocytes via surface Fc gamma receptors for IgG1.

Purpose Lung transplant recipients are at elevated risk of aspiration and subsequent microbial colonization and infection of the lungs, which portend worse clinical outcomes. Although aspiration is thought to affect the right lung more commonly than the left lung due to anatomical factors, such association has not been shown in lung transplant recipients. We hypothesized that bronchoalveolar lavage (BAL) from right single lung transplants (SLT) have higher microbiological culture positivity compared to BAL from left SLT, leading to worse outcomes in right SLT recipients. Methods All first adult SLT performed at our institution up to June 2021 with at least one BAL microbiological culture result were included. All BAL from surveillance and clinically indicated bronchoscopies were included. By our protocol, BAL is obtained from the transplanted lung, either the right middle lobe or lingula, unless clinically indicated otherwise. Fisher's exact test and univariable Cox proportional hazards model were used to compare culture positivity and outcomes, respectively. Results 165 right SLT recipients with 1505 cultures and 164 left SLT recipients with 1450 cultures were included. Baseline patient characteristics were comparable. BAL from right SLT had 17% positivity for significant respiratory pathogens, compared to 12% from left SLT (p<0.0001). Right SLT had higher positivity for P. aeruginosa (7% right vs. 4% left, p<0.001) and S. aureus (2% right vs. 1% left, p=0.04). There was similar positivity for high commensal flora (34% right vs. 36% left, p=0.26). There was a trend towards lower risk of chronic lung allograft dysfunction (HR 0.77 [0.55-1.09], p=0.1) and death/retransplant (HR 0.76 [0.58-1.01], p=0.06) in right SLT recipients. Conclusion BAL from right SLT have higher BAL microbiological culture positivity for significant respiratory pathogens, P. aeruginosa, and S. aureus compared to BAL from left SLT, with no difference in outcomes between right and left SLT recipients.

Response to commentary by Dr Guillamet:

As of April 2022, the Mater Hospital serves 190 patients who have been the recipient of a lung transplant in Ireland. During the COVID-19 pandemic, solid organ transplant was recognised as a risk factor for progression to severe disease. In January 2022, the European Medicines Agency (EMA) approved the use of Sotrovimab for high risk patients. Sotrovimab is a monoclonal antibody which neutralises SARS-CoV-2 with recent data showing efficacy in reducing the risk of progression to severe disease in high risk patients1. We aim to describe our patient cohort and the rates of COVID-19 infection seen before and after the introduction of monoclonal antibody therapy. While likely reflecting emerging variants resulting in less severe disease, we observe variation in morbidity and mortality in this time. From March 2020 to April 2022, 116 post-lung transplant patients tested positive for COVID-19 infection. This represents 61% of our overall population. Since January 2022, coinciding with the surge of the omicron variant, 57 patients contracted COVID-19. 47 were deemed to be suitable for treatment with 10 presenting outside the window for therapeutic intervention. 3.5% (n=2) required ICU admission and 2 died directly as a result of COVID-19. Prior to this, 58 patients contracted COVID-19, 31 of which (53.5%) required hospital admission with 18 (58%) requiring ICU admission. Overall we saw 13 deaths representing 22.4% of this group and 6.8% of the overall population. 1. Gupta A, Gonzalez-Rojas Y, Juarez E, Crespo Casal M, Moya J, Falci DR, Sarkis E, Solis J, Zheng H, Scott N, Cathcart AL. Early treatment for Covid-19 with SARS-CoV-2 neutralizing antibody sotrovimab. New Englad Journal of Medicine. 2021 Nov18;386(21):1941-50

Purpose Chronic lung allograft dysfunction (CLAD) is a major cause of morbidity and mortality in lung transplant recipients and is often triggered by aspiration events, potentiated by esophageal and gastric disorders. The two major classes of esophageal disorders include: 1) disorders of peristalsis and 2) esophagogastric junction outflow obstruction (EGJOO). Previous small studies have shown conflicting relationships between esophageal function and the development of CLAD. Herein, we sought to investigate the relationship between esophageal disorders and long-term outcomes in a large retrospective cohort of lung transplant recipients. Methods All lung transplant recipients from 2000-2018 with available esophageal manometry testing within first 7 months post-transplant were included in this study. Subjects were categorized into three groups: 1) no esophageal disorders, 2) disorder of peristalsis, and 3) EGJOO (defined by the 2007 Chicago Classification System). Disorders of peristalsis were further divided into major disorder (absent contractions) and minor disorder (irregular contractions). Univariable Cox proportional hazards models were used to determine the relationship between esophageal disorders and the development of CLAD and allograft failure (death/retransplant). Results Of 487 subjects, 47 (10%) had a disorder of peristalsis (8 major, 39 minor) and 57 (12%) had EGJOO. Older subjects were more likely to have an esophageal disorder (p=0.001). A major disorder of peristalsis was associated with an increased risk of CLAD [HR 2.78 (95% CI 1.23-6.28); p=0.01] and allograft failure [HR 3.17 (95% CI 1.49-6.77); p=0.003]. A minor disorder of peristalsis was not significantly associated with CLAD or allograft failure. EGJOO was associated with an increased risk of CLAD [HR 1.63 (95% CI 1.11-2.40); p=0.01] and allograft failure [HR 1.73 (1.18-2.54); p=0.005]. Conclusion In a large retrospective cohort we observed that lung transplant recipients with major disorders of peristalsis and EGJOO were at an increased risk of CLAD and death/retransplant. In contrast, people with minor disorders of peristalsis were not at an increased risk of these outcomes. These findings will help with risk-stratification of lung transplant recipients and personalization of treatment for aspiration prevention. Chronic lung allograft dysfunction (CLAD) is a major cause of morbidity and mortality in lung transplant recipients and is often triggered by aspiration events, potentiated by esophageal and gastric disorders. The two major classes of esophageal disorders include: 1) disorders of peristalsis and 2) esophagogastric junction outflow obstruction (EGJOO). Previous small studies have shown conflicting relationships between esophageal function and the development of CLAD. Herein, we sought to investigate the relationship between esophageal disorders and long-term outcomes in a large retrospective cohort of lung transplant recipients. All lung transplant recipients from 2000-2018 with available esophageal manometry testing within first 7 months post-transplant were included in this study. Subjects were categorized into three groups: 1) no esophageal disorders, 2) disorder of peristalsis, and 3) EGJOO (defined by the 2007 Chicago Classification System). Disorders of peristalsis were further divided into major disorder (absent contractions) and minor disorder (irregular contractions). Univariable Cox proportional hazards models were used to determine the relationship between esophageal disorders and the development of CLAD and allograft failure (death/retransplant). Of 487 subjects, 47 (10%) had a disorder of peristalsis (8 major, 39 minor) and 57 (12%) had EGJOO. Older subjects were more likely to have an esophageal disorder (p=0.001). A major disorder of peristalsis was associated with an increased risk of CLAD [HR 2.78 (95% CI 1.23-6.28); p=0.01] and allograft failure [HR 3.17 (95% CI 1.49-6.77); p=0.003]. A minor disorder of peristalsis was not significantly associated with CLAD or allograft failure. EGJOO was associated with an increased risk of CLAD [HR 1.63 (95% CI 1.11-2.40); p=0.01] and allograft failure [HR 1.73 (1.18-2.54); p=0.005]. In a large retrospective cohort we observed that lung transplant recipients with major disorders of peristalsis and EGJOO were at an increased risk of CLAD and death/retransplant. In contrast, people with minor disorders of peristalsis were not at an increased risk of these outcomes. These findings will help with risk-stratification of lung transplant recipients and personalization of treatment for aspiration prevention.

Purpose Primary graft dysfunction (PGD) remains a major obstacle to lung transplantation (LT) success and is classified as severe (PGD3) in 10-15% of all LT recipients. Ex vivo lung perfusion (EVLP) allows for evaluation of donor lungs prior to LT and measurement of circulating cells and soluble factors in the perfusate. The contributions of donor cells to PGD are unknown, and whether specific cells might confer a risk of PGD is unclear. We hypothesized that larger quantities of donor myeloid cells in EVLP perfusate might predict PGD3. Methods In this retrospective study, we selected consecutive clinical EVLP cases and grouped them based on PaO2/FIO2 (P/F) ratio at 72h post-LT, resulting in two groups: PGD3 (n = 33, P/F = 183 ± 48mmHg) and PGD0/1 (n = 25, P/F = 395 ± 71mmHg). Cryopreserved perfusate cells from the first and last hour of EVLP were subjected to multiparameter flow cytometry to identify major leukocyte populations. Time and PGD-dependent differences were assessed by two-way ANOVA with post-hoc testing adjusted for multiple comparisons. Results In the first hour of EVLP, the total cells/mL was higher in the PGD3 group compared to PGD0/1 (12.1 × 105 versus 8.4 × 105 cells/ml, p = 0.0573) - the cell/ml decreased in both groups to similar densities by the end of EVLP (Fig A). In the PGD3 group, neutrophils (Fig B) and B cells (Fig C) were significantly higher than in the PGD0/1 group in the first hour and significantly decreased over time. Macrophages (Fig D) and classical monocytes (Fig E) were also elevated in PGD3 group in the first hour, although this observation did not reach statistical significance. Conclusion Neutrophils and B cells in the 1-hour perfusate are associated with PGD3 development at 72h post-LT. While these findings suggest that higher numbers of these donor cells may play a role in PGD pathogenesis, PGD3 developed even though these populations were reduced by the end of EVLP. Studies of cellular activation states will be conducted to validate these findings and explore donor cellular contributions to PGD.

AbstractObjectiveCOPA syndrome is a genetic disorder of retrograde cis‐Golgi vesicle transport that leads to upregulation of pro‐inflammatory cytokines (mainly IL‐1β and IL‐6) and the development of interstitial lung disease (ILD). The impact of COPA syndrome on post‐lung transplant (LTx) outcome is unknown but potentially detrimental. In this case report, we describe progressive allograft dysfunction following LTx for COPA‐ILD. Following the failure of standard immunosuppressive approaches, detailed cytokine analysis was performed with the intention of personalising therapy.MethodsMultiplexed cytokine analysis was performed on serum and bronchoalveolar lavage (BAL) fluid obtained pre‐ and post‐LTx. Peripheral blood mononuclear cells (PMBCs) obtained pre‐ and post‐LTx were stimulated with PMA, LPS and anti‐CD3/CD28 antibodies. Post‐LTx endobronchial biopsies underwent microarray‐based gene expression analysis. Results were compared to non‐COPA LTx recipients and non‐LTx healthy controls.ResultsMultiplexed cytokine analysis showed rising type I/II IFNs, and IL‐6 in BAL post‐LTx that decreased following treatment of acute rejection but rebounded with further clinical deterioration. In vitro stimulation of PMBCs suggested that myeloid cells were driving deterioration, through IL‐6 signalling pathways. Tocilizumab (IL‐6 receptor antibody) administration for 3 months (4 mg kg−1, monthly) effectively suppressed IL‐6 levels in BAL. Mucosal gene expression profile following tocilizumab suggested greater similarity to normal.ConclusionClinical effectiveness of IL‐6 receptor blockade was not observed. However, we identified IL‐6 upregulation associated with graft injury, effective IL‐6 suppression with tocilizumab and evidence of beneficial effect on molecular transcripts. This mechanistic analysis suggests a role for IL‐6 blockade in post‐LTx care that should be investigated further.