The 2022 Banff Meeting Lung Report.

The Lung Session of the 2022 16th Banff Foundation for Allograft Pathology Conference-held in Banff, Alberta-focused on non-rejection lung allograft pathology and novel technologies for the detection of allograft injury. A multidisciplinary panel reviewed the state-of-the-art of current histopathologic entities, serologic studies, and molecular practices, as well as novel applications of digital pathology with artificial intelligence, gene expression analysis, and quantitative image analysis of chest computerized tomography. Current states of need as well as prospective integration of the aforementioned tools and technologies for complete assessment of allograft injury and its impact on lung transplant outcomes were discussed. Key conclusions from the discussion were: (1) recognition of limitations in current standard of care assessment of lung allograft dysfunction; (2) agreement on the need for a consensus regarding the standardized approach to the collection and assessment of pathologic data, inclusive of all lesions associated with graft outcome (eg, non-rejection pathology); and (3) optimism regarding promising novel diagnostic modalities, especially minimally invasive, which should be integrated into large, prospective multicenter studies to further evaluate their utility in clinical practice for directing personalized therapies to improve graft outcomes.

CCR5 drives NK cell-associated airway damage in pulmonary ischemia-reperfusion injury.

Primary graft dysfunction (PGD) limits clinical benefit after lung transplantation, a life-prolonging therapy for patients with end-stage disease. PGD is the clinical syndrome resulting from pulmonary ischemia-reperfusion injury (IRI), driven by innate immune inflammation. We recently demonstrated a key role for NK cells in the airways of mouse models and human tissue samples of IRI. Here, we used 2 mouse models paired with human lung transplant samples to investigate the mechanisms whereby NK cells migrate to the airways to mediate lung injury. We demonstrate that chemokine receptor ligand transcripts and proteins are increased in mouse and human disease. CCR5 ligand transcripts were correlated with NK cell gene signatures independently of NK cell CCR5 ligand secretion. NK cells expressing CCR5 were increased in the lung and airways during IRI and had increased markers of tissue residency and maturation. Allosteric CCR5 drug blockade reduced the migration of NK cells to the site of injury. CCR5 blockade also blunted quantitative measures of experimental IRI. Additionally, in human lung transplant bronchoalveolar lavage samples, we found that CCR5 ligand was associated with increased patient morbidity and that the CCR5 receptor was increased in expression on human NK cells following PGD. These data support a potential mechanism for NK cell migration during lung injury and identify a plausible preventative treatment for PGD.

Interstitial lung disease progression after genomic usual interstitial pneumonia testing.

BACKGROUND: A genomic classifier for usual interstitial pneumonia (gUIP) has been shown to predict histological UIP with high specificity, increasing diagnostic confidence for idiopathic pulmonary fibrosis (IPF). Whether those with positive gUIP classification exhibit a progressive, IPF-like phenotype remains unknown. METHODS: A pooled, retrospective analysis of patients who underwent clinically indicated diagnostic bronchoscopy with gUIP testing at seven academic medical centres across the USA was performed. We assessed the association between gUIP classification and 18-month progression-free survival (PFS) using Cox proportional hazards regression. PFS was defined as the time from gUIP testing to death from any cause, lung transplant, ≥10% relative decline in forced vital capacity (FVC) or censoring at the time of last available FVC measure. Longitudinal change in FVC was then compared between gUIP classification groups using a joint regression model. RESULTS: Of 238 consecutive patients who underwent gUIP testing, 192 had available follow-up data and were included in the analysis, including 104 with positive gUIP classification and 88 with negative classification. In multivariable analysis, positive gUIP classification was associated with reduced PFS (hazard ratio 1.58, 95% CI 0.86-2.92; p=0.14), but this did not reach statistical significance. Mean annual change in FVC was -101.8 mL (95% CI -142.7- -60.9 mL; p<0.001) for those with positive gUIP classification and -73.2 mL (95% CI -115.2- -31.1 mL; p<0.001) for those with negative classification (difference 28.7 mL, 95% CI -83.2-25.9 mL; p=0.30). CONCLUSIONS: gUIP classification was not associated with differential rates of PFS or longitudinal FVC decline in a multicentre interstitial lung disease cohort undergoing bronchoscopy as part of the diagnostic evaluation.

The safety profile of a protocolized transbronchial cryobiopsy program utilizing a 2.4 mm cryoprobe for interstitial lung disease.

INTRODUCTION: Transbronchial lung cryobiopsy (TBLC) has emerged as a promising alternative to surgical lung biopsy for the diagnosis of interstitial lung disease. However, uncertainty remains regarding its overall complications due to a lack of procedural standardization including the size of cryoprobe utilized. METHODS: This is a prospective cohort study of a protocolized transbronchial cryobiopsy program utilizing a 2.4 mm cryoprobe. 201 consecutive subjects were enrolled at a single academic center. RESULTS: The average biopsy size was 106.2 ± 39.3 mm2. Complications included a total pneumothorax rate of 4.9% with 3.5% undergoing chest tube placement. Severe bleeding defined by the Nashville Working Group occurred in 0.5% of cases. There were no deaths at 30-days. DISCUSSION: A protocolized transbronchial cryobiopsy program utilizing a 2.4 mm cryoprobe in can achieve a high diagnostic yield with a favorable safety profile.

Risk Factors for Acute Rejection in the First Year after Lung Transplant. A Multicenter Study.

Rationale: Acute rejection, manifesting as lymphocytic inflammation in a perivascular (acute perivascular rejection [AR]) or peribronchiolar (lymphocytic bronchiolitis [LB]) distribution, is common in lung transplant recipients and increases the risk for chronic graft dysfunction.Objectives: To evaluate clinical factors associated with biopsy-proven acute rejection during the first post-transplant year in a present-day, five-center lung transplant cohort.Methods: We analyzed prospective diagnoses of AR and LB from over 2,000 lung biopsies in 400 newly transplanted adult lung recipients. Because LB without simultaneous AR was rare, our analyses focused on risk factors for AR. Multivariable Cox proportional hazards models were used to assess donor and recipient factors associated with the time to the first AR occurrence.Measurements and Main Results: During the first post-transplant year, 53.3% of patients experienced at least one AR episode. Multivariable proportional hazards analyses accounting for enrolling center effects identified four or more HLA mismatches (hazard ratio [HR], 2.06; P ≤ 0.01) as associated with increased AR hazards, whereas bilateral transplantation (HR, 0.57; P ≤ 0.01) was associated with protection from AR. In addition, Wilcoxon rank-sum analyses demonstrated bilateral (vs. single) lung recipients, and those with fewer than four (vs. more than four) HLA mismatches demonstrated reduced AR frequency and/or severity during the first post-transplant year.Conclusions: We found a high incidence of AR in a contemporary multicenter lung transplant cohort undergoing consistent biopsy sampling. Although not previously recognized, the finding of reduced AR in bilateral lung recipients is intriguing, warranting replication and mechanistic exploration.

Amphiregulin contributes to airway remodeling in chronic allograft dysfunction after lung transplantation.

Chronic lung allograft dysfunction (CLAD), a condition of excess matrix deposition and airways fibrosis, limits survival after lung transplantation. Amphiregulin (Areg) is an epidermal growth factor receptor (EGFR) ligand suggested to regulate airway injury and repair. We sought to determine whether Areg expression increases in CLAD, localize the cellular source of Areg induction in CLAD, and assess its effects on airway matrix deposition. Lung fluid Areg protein was quantified in patients with or without CLAD. In situ hybridization was performed to localize Areg and EGFR transcript in CLAD and normal lung tissue. Expression of hyaluronan, a matrix constituent that accumulates in CLAD, was measured in Areg-exposed bronchial epithelial cells in the presence or absence of an EGFR inhibitor. We demonstrated that lung fluid Areg protein was significantly increased in CLAD in a discovery and replication cohort. Areg and EGFR transcripts were abundantly expressed within CLAD tissue, localized to basally distributed airway epithelial cells overlying fibrotic regions. Areg-exposed bronchial epithelial cells increased hyaluronan and hyaluronan synthase expression in an EGFR-dependent manner. Collectively, these novel observations suggest that Areg contributes to airway remodeling and CLAD. Moreover these data implicate a role for EGFR signaling in CLAD pathogenesis, suggesting novel therapeutic targets.

Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies.

Lung transplantation has become an established therapeutic option for a variety of end-stage lung diseases. Technical advances in graft procurement, implantation, perioperative care, immunosuppression, and posttransplant medical management have led to significant improvements in 1-year survival, but outcomes after the first year have improved minimally over the last two decades. The main limitation to better long-term survival after lung transplantation is chronic lung allograft dysfunction (CLAD). CLAD also impairs quality of life and increases the costs of medical care. Our understanding of CLAD manifestations, risk factors, and mechanisms is rapidly evolving. Recognition of different CLAD phenotypes (e.g., bronchiolitis obliterans syndrome and restrictive allograft syndrome) and the unique pathogenic mechanisms will be important for developing novel therapies. In addition to alloimmune-mediated rejection, we now recognize the importance of alloimmune-independent mechanisms of injury to the allograft. CLAD is the consequence of dysregulated repair of allograft injury. Unfortunately, currently available therapies for CLAD are usually not effective. However, the advances in knowledge, reviewed in this manuscript, should lead to novel strategies for CLAD prevention and treatment, as well as improvement in long-term outcomes after lung transplantation. We provide an overview of the evolving terminology related to CLAD, its varying clinical phenotypes and their diagnosis, natural history, pathogenesis, and potential treatments.

CD4(+)CD25(hi)Foxp3(+) Cells Exacerbate Bleomycin-Induced Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis is a fatal lung disease with a median survival of 2 to 5 years. A decade of studies has downplayed inflammation contributing to its pathogenesis. However, these studies preceded the discovery of regulatory T cells (Tregs) and all of their functions. On the basis of human studies demonstrating Tregs can decrease graft-versus-host disease and vasculitides, there is consideration of their use to treat idiopathic pulmonary fibrosis. We hypothesized that Treg therapy would attenuate the fibroplasia involved in a preclinical murine model of pulmonary fibrosis. IL-2 complex was used in vivo to expand CD4(+)CD25(hi)Foxp3(+) cells in the lung during intratracheal bleomycin challenge; however, this unexpectedly led to an increase in lung fibrosis. More important, this increase in fibrosis was a lymphocyte-dependent process. We corroborated these results using a CD4(+)CD25(hi)Foxp3(+) cellular-based therapy. Mechanistically, we demonstrated that CD4(+)CD25(hi)Foxp3(+) cells undergo alterations during bleomycin challenge and the IL-2 complex had no effect on profibrotic (eg, transforming growth factor-ß) or type 17 immune response cytokines; however, there was a marked down-regulation of the type 1 and augmentation of the type 2 immune response cytokines from the lungs. Collectively, our animal studies show that a specific lung injury can induce Treg alterations, which can augment pulmonary fibrosis.

Idiopathic Pulmonary Fibrosis: Epidemiology, Clinical Features, Prognosis, and Management.

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic interstitial lung pneumonia associated with the histologic pattern of usual interstitial pneumonia (UIP). Although UIP is a distinct histologic lesion, this histologic pattern is not specific for IPF and can also be found in other diseases (e.g., connective tissue disease and asbestosis). Clinical features of IPF include progressive cough, dyspnea, restrictive ventilatory defect, and progressive fibrosis and destruction of the lung parenchyma. IPF is rare (13-42 cases/100,000), and primarily affects older adults (>50 years of age). The diagnosis of IPF often requires surgical lung biopsy, but the diagnosis can be affirmed with confidence in some patients provided the results of computed tomographic (CT) scans and clinical features are consistent. The clinical course is variable, but inexorable progression (typically over months to years) is typical. Mean survival from the onset of symptoms approximates 3 to 5 years. Medical treatment is only modestly effective, primarily by slowing the rate of disease progression. Lung transplantation is the best therapeutic option.

Banff study of pathologic changes in lung allograft biopsy specimens with donor-specific antibodies.

BACKGROUND: The diagnosis of antibody-mediated rejection (AMR) in the lung transplant is still an area under investigation. We performed a blinded multicenter study to determine if any statistically significant histologic findings in transbronchial biopsy specimens from lung transplant patients correlate with the presence of donor-specific antibodies (DSAs). METHODS: We asked 9 pathologists with experience in lung transplantation to evaluate 161 lung transplant biopsy specimens for various histologic parameters. The findings were correlated with antibody status positive for DSAs, positive for non-DSAs, and no antibodies (NABs) present. The significance of each histologic variable was reviewed. RESULTS: We found no statistically significant association with acute cellular rejection, airway inflammation, or bronchiolitis obliterans and the presence or absence of antibodies. However, biopsy specimens with DSAs had a statistically significant difference vs NABs in the setting of acute lung injury, with or without diffuse alveolar damage (p = 0.0008), in the presence of capillary neutrophilic inflammation (p = 0.0014), and in samples with endotheliitis (p = 0.0155). In samples with complement 4d staining, there was a trend but no statistically significant difference between specimens associated with DSAs and specimens with NABs. CONCLUSIONS: Capillary inflammation, acute lung injury, and endotheliitis significantly correlated with DSAs. The infrequently observed diffuse staining for complement 4d limits the usefulness of this stain.

Lung transplantation for cystic fibrosis: results, indications, complications, and controversies.

Survival in patients with cystic fibrosis (CF) has improved dramatically over the past 30 to 40 years, with mean survival now approximately 40 years. Nonetheless, progressive respiratory insufficiency remains the major cause of mortality in CF patients, and lung transplantation (LT) is eventually required. Timing of listing for LT is critical, because up to 25 to 41% of CF patients have died while awaiting LT. Globally, approximately 16.4% of lung transplants are performed in adults with CF. Survival rates for LT recipients with CF are superior to other indications, yet LT is associated with substantial morbidity and mortality (∼50% at 5-year survival rates). Myriad complications of LT include allograft failure (acute or chronic), opportunistic infections, and complications of chronic immunosuppressive medications (including malignancy). Determining which patients are candidates for LT is difficult, and survival benefit remains uncertain. In this review, we discuss when LT should be considered, criteria for identifying candidates, contraindications to LT, results post-LT, and specific complications that may be associated with LT. Infectious complications that may complicate CF (particularly Burkholderia cepacia spp., opportunistic fungi, and nontuberculous mycobacteria) are discussed.

Outcome and prognostic indicators of patients with hematopoietic stem cell transplants admitted to the intensive care unit.

The prognosis of patients with hematopoietic stem cell transplants (HSCTs) who require admission to the intensive care unit (ICU) has been regarded as extremely poor. We sought to re-evaluate recent outcomes and predictive factors in a retrospective cohort study. Among the 605 adult patients that received an HSCT between 2001 and 2006, 154 required admission to the ICU. Of these, 47% were discharged from the ICU, 36% were discharged from the hospital, and 19% survived 6 months. Allogeneic transplant, mechanical ventilation, vasopressor-use, and neutropenia were each associated with increased mortality, and the mortality of patients with all four characteristics was 100%. Hemodialysis was also associated with increased mortality in a Kaplan-Meier analysis but did not appear important in a multivariate tree analysis. A final Cox model confirmed that allogeneic transplant, mechanical ventilation, and vasopressor-use were each independent risk factors for mortality in the 6 months following ICU admission.

Usual interstitial pneumonia.

Usual interstitial pneumonia (UIP) is a distinct histological lesion observed in idiopathic pulmonary fibrosis (IPF) but can be found in other etiologies. The diagnosis of UIP can be established by surgical lung biopsy or by high-resolution thin-section computed tomographic (CT) scans (provided the radiographic features are classical). Historically, patients labeled as "IPF" encompassed a group of disorders, including UIP as well as other idiopathic interstitial pneumonias that differ from UIP in prognosis and responsiveness to therapy. Current recommendations from international consensus statements restrict the term IPF to patients with idiopathic UIP. The inciting cause(s) and pathogenesis of UIP have not been elucidated, but alveolar epithelial cell injury and dysregulation or altered phenotypic expression of fibroblasts are key elements. Inflammatory cells may play minor roles in initiating or propagating the fibrotic process. The prognosis of UIP is poor. Mean survival following diagnosis approximates 3 years. Current therapies are of unproven value. Corticosteroids or immunosuppressive agents have been most often used, but data affirming benefit are lacking. Lung transplantation is a viable option for patients failing medical therapy. This review discusses diagnostic criteria for UIP (both histopathological and radiographic), natural history and clinical course, and therapeutic approaches (both current and future).

Overview of lung transplantation and criteria for selection of candidates.

Lung or heart-lung transplantation is a viable option for diverse end-stage pulmonary parenchymal or pulmonary vascular disorders. However, mortality associated with lung transplant (LT) is appreciable, with 3 and 5 year survival rates of approximately 60 and 50%, respectively. Thus LT is reserved for patients with life-threatening disease refractory to medical therapy. Four diagnoses (i.e., chronic obstructive pulmonary disease; idiopathic pulmonary fibrosis; cystic fibrosis; alpha-1-antitrypsin deficiency emphysema) account for approximately 80% of LT recipients; diverse interstitial and pulmonary vascular disorders account for the remaining cases. Given the potential morbidity and mortality associated with LT, the decision to refer patients for LT is difficult. Which patients are acceptable candidates for LT? What are the projected benefits of LT? What criteria should be used to estimate mortality with medical therapy alone? Given the uncertainty of waiting time, when should patients be listed for LT? Identifying appropriate candidates for LT and determining when to list for LT is determined by a risk analysis of the likelihood of mortality during the projected waiting period versus the likely mortality following LT. In this review, we discuss the major diseases treated with LT and the appropriate criteria for LT.