International Society for Heart and Lung Transplantation consensus statement for the standardization of bronchoalveolar lavage in lung transplantation

Martinu, T.; Koutsokera, Angela; Benden, Christian; Cantu, Edward; Chambers, Daniel C.; Cypel, Marcelo; Edelman, Jeffrey D.; Emtiazjoo, A.; Fisher, Andrew J.; Greenland, John R.; Hayes, Don; Hwang, David; Keller, Brian C.; Lease, Erika D.; Perch, Michael; Sato, Masaaki; Todd, Jamie L.; Verleden, Stijn E.; Thüsen, Jan von der; Weigt, S. Samuel; Keshavjee, S.

doi:10.1016/j.healun.2020.07.006

Cited by 54 publications

(46 citation statements)

References 116 publications

(192 reference statements)

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“…Despite the fact that no single clinically useful biomarker has been identified yet, several interesting markers have been linked to CLAD development in BAL, blood and lung tissue. Todd et al recently identified upregulation of amphiregulin, an epidermal growth factor receptor (EGFR) ligand with putative role in airway injury and repair regulation, in BAL fluid of CLAD patients (20). In situ hybridization of CLAD tissue identified abundant EGFR and amphiregulin transcript expression in the airway epithelial cells of fibrotic regions.…”

Section: Discussionmentioning

confidence: 99%

Connective Tissue Growth Factor Is Overexpressed in Explant Lung Tissue and Broncho-Alveolar Lavage in Transplant-Related Pulmonary Fibrosis

et al. 2021

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BackgroundConnective tissue growth factor (CTGF) is an important mediator in several fibrotic diseases, including lung fibrosis. We investigated CTGF-expression in chronic lung allograft dysfunction (CLAD) and pulmonary graft-versus-host disease (GVHD).Materials and MethodsCTGF expression was assessed by quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry in end-stage CLAD explant lung tissue (bronchiolitis obliterans syndrome (BOS), n=20; restrictive allograft syndrome (RAS), n=20), pulmonary GHVD (n=9). Unused donor lungs served as control group (n=20). Next, 60 matched lung transplant recipients (BOS, n=20; RAS, n=20; stable lung transplant recipients, n=20) were included for analysis of CTGF protein levels in plasma and broncho-alveolar lavage (BAL) fluid at 3 months post-transplant, 1 year post-transplant, at CLAD diagnosis or 2 years post-transplant in stable patients.ResultsqPCR revealed an overall significant difference in the relative content of CTGF mRNA in BOS, RAS and pulmonary GVHD vs. controls (p=0.014). Immunohistochemistry showed a significant higher percentage and intensity of CTGF-positive respiratory epithelial cells in BOS, RAS and pulmonary GVHD patients vs. controls (p<0.0001). BAL CTGF protein levels were significantly higher at 3 months post-transplant in future RAS vs. stable or BOS (p=0.028). At CLAD diagnosis, BAL protein content was significantly increased in RAS patients vs. stable (p=0.0007) and BOS patients (p=0.042). CTGF plasma values were similar in BOS, RAS, and stable patients (p=0.74).ConclusionsLung CTGF-expression is increased in end-stage CLAD and pulmonary GVHD; and higher CTGF-levels are present in BAL of RAS patients at CLAD diagnosis. Our results suggest a potential role for CTGF in CLAD, especially RAS, and pulmonary GVHD.

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Section: Discussionmentioning

confidence: 99%

Connective Tissue Growth Factor Is Overexpressed in Explant Lung Tissue and Broncho-Alveolar Lavage in Transplant-Related Pulmonary Fibrosis

et al. 2021

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“…The demographic characteristics of the study participants are provided in Table 1. BAL sample collection: Patients underwent bronchoscopy for surveillance or for diagnosis of ALAD. BAL was obtained according to a standard protocol in accordance with international guidelines (2). Two 50 mL-aliquots of saline were instilled with the bronchoscope in a wedged position in either the right middle lobe or lingula.…”

Section: Methodsmentioning

confidence: 99%

“…Lung transplantation (LT) is a life-saving treatment option for advanced lung diseases ( 1 ). However, long-term survival after LT remains significantly lower than after transplantation of other solid organs, despite a substantial improvement in recent years ( 2 ). The main factor limiting long-term survival is chronic lung allograft dysfunction (CLAD), a progressive fibrotic process that destroys the lung allograft and is driven by inflammation and alloimmunity.…”

Section: Introductionmentioning

confidence: 99%

Pro-inflammatory alveolar macrophages associated with allograft dysfunction after lung transplantation

Moshkelgosha

Wilson

Duong

et al. 2021

Preprint

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Purpose: Lung transplant (LT) recipients experience episodes of immune-mediated acute lung allograft dysfunction (ALAD). We have applied single-cell RNA sequencing (scRNAseq) to bronchoalveolar lavage (BAL) cells of stable and ALAD patients to determine key cellular elements in dysfunctional lung allografts. Our particular focus here is on studying alveolar macrophages (AMs) as scRNAseq enables us to elucidate their heterogeneity and possible association with ALAD where our knowledge from cytometry-based assays is very limited. Methods: Fresh bronchoalveolar lavage (BAL) cells from 6 LT patients, 3 with stable lung function and 3 undergoing an episode of ALAD were used for scRNAseq. R Bioconductor and Seurat were used to perform QC, dimensionality reduction, annotation, pathway analysis, and trajectory. Donor and recipient deconvolution was performed using single nucleotide variations. Results: Our data revealed that AMs are highly heterogeneous (12 transcriptionally distinct subsets in stable). We identified two AM subsets uniquely represented in ALAD. Based on pathway analysis and the top differentially expressed genes in BAL we annotated them as pro-inflammatory interferon-stimulated genes (ISG) and metallothioneins-mediated inflammatory (MT). Pseudotime analysis suggested that ISG AMs represent an earlier stage of differentiation which may suggest them as monocyte drive macrophages. Our functional analysis on an independent set of BAL samples shows that ALAD samples have significantly higher expression of CXCL10, a marker of ISG AM, as we as higher secretion of pro-inflammatory cytokines. Single nucleotide variation calling algorithm has allowed us to identify macrophages of donor origin and demonstrated that donor AMs are lost with time post-transplant. Conclusion: Using scRNAseq, we observed AMs heterogeneity and identified specific subsets that may be associated with allograft dysfunction. Further exploration with scRNAseq will shed light on LT immunobiology and the role of AMs in allograft injury and dysfunction.

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“…Follow-up bronchoscopies after treatment of ACR to confirm resolution is performed by 72.4% of centers. 116…”

Section: Clinical Presentation and Diagnosismentioning

confidence: 99%

“…A recent ISHLT consensus document provides recommendations for BAL standardization collection and processing and is expected to facilitate improvement and development of BAL-based diagnostics. 116 BAL cellular components: several studies have shown increased BAL cellularity and also increases leukocyte subtypes during ACR, although the findings are not sufficiently specific to allow diagnosis. [131][132][133][134][135] Interestingly, BAL cell immunophenotyping may discriminate between infection and acute rejection with CD25 þ cell, natural killer cell, monocyte, lymphocyte, and eosinophil percentages correlating with ACR.…”

Section: Promising Less-invasive Diagnostic Toolsmentioning

confidence: 99%

Acute Rejection in the Modern Lung Transplant Era

Renaud-Picard

Koutsokera

Cabanero

et al. 2021

Semin Respir Crit Care Med

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Acute cellular rejection (ACR) remains a common complication after lung transplantation. Mortality directly related to ACR is low and most patients respond to first-line immunosuppressive treatment. However, a subset of patients may develop refractory or recurrent ACR leading to an accelerated lung function decline and ultimately chronic lung allograft dysfunction. Infectious complications associated with the intensification of immunosuppression can also negatively impact long-term survival. In this review, we summarize the most recent evidence on the mechanisms, risk factors, diagnosis, treatment, and prognosis of ACR. We specifically focus on novel, promising biomarkers which are under investigation for their potential to improve the diagnostic performance of transbronchial biopsies. Finally, for each topic, we highlight current gaps in knowledge and areas for future research.

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International Society for Heart and Lung Transplantation consensus statement for the standardization of bronchoalveolar lavage in lung transplantation

Cited by 54 publications

References 116 publications

Connective Tissue Growth Factor Is Overexpressed in Explant Lung Tissue and Broncho-Alveolar Lavage in Transplant-Related Pulmonary Fibrosis

Connective Tissue Growth Factor Is Overexpressed in Explant Lung Tissue and Broncho-Alveolar Lavage in Transplant-Related Pulmonary Fibrosis

Pro-inflammatory alveolar macrophages associated with allograft dysfunction after lung transplantation

Acute Rejection in the Modern Lung Transplant Era

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