Potential novel biomarkers for chronic lung allograft dysfunction and azithromycin responsive allograft dysfunction

Veraar, Cécilia; Kliman, Jonathan; Benazzo, Alberto; Oberndorfer, Felicitas; Laggner, Maria; Hacker, P.; Raunegger, Thomas; Janik, Stefan; Jaksch, Péter; Klepetko, Walter; Ankersmit, Hendrik Jan; Moser, Bernhard

doi:10.1038/s41598-021-85949-1

Cited by 12 publications

(15 citation statements)

References 29 publications

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“…They include multi-breath nitrogen wash-out to evaluate small airway function, different imaging modalities and analytic strategies (e.g. high-resolution computed tomography), novel assessments of immune cell counts, chemokines, cytokines, and circulating cell free DNA ( Belloli et al, 2021 ; Shtraichman and Diamond, 2020 ; Tissot et al, 2019 ; Veraar et al, 2021 ). Some groups are also investigating computational models to estimate a recipient’s risk of CLAD using clinical and multi-omic databases ( Koutsokera et al, 2017 ; Pison et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of chronic lung allograft dysfunction phenotypes using spectral and intrabreath oscillometry

Vasileva²,

Hanafi³

et al. 2022

Front. Physiol.

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Background: Chronic lung allograft dysfunction (CLAD) is the major cause of death beyond 2 years after lung transplantation and develops in 50% of all patients by 5 years post-transplant. CLAD is diagnosed on the basis of a sustained drop of 20% for at least 3 months in the forced expiratory volume (FEV1), compared to the best baseline value achieved post-transplant. CLAD presents as two main phenotypes: bronchiolitis obliterans syndrome (BOS) is more common and has better prognosis than restrictive allograft syndrome (RAS). Respiratory oscillometry is a different modality of lung function testing that is highly sensitive to lung mechanics. The current study investigated whether spectral and intrabreath oscillometry can differentiate between CLAD-free, BOS- and RAS-CLAD at CLAD onset, i.e., at the time of the initial 20% drop in the FEV1.Methods: A retrospective, cross-sectional analysis of 263 double lung transplant recipients who underwent paired testing with oscillometry and spirometry at the Toronto General Pulmonary Function Laboratory from 2017 to 2022 was conducted. All pulmonary function testing and CLAD diagnostics were performed following international guidelines. Statistical analysis was conducted using multiple comparisons.Findings: The RAS (n = 6) spectral oscillometry pattern differs from CLAD-free (n = 225) by right-ward shift of reactance curve similar to idiopathic pulmonary fibrosis whereas BOS (n = 32) has a pattern similar to obstructive lung disease. Significant differences were found in most spectral and intrabreath parameters between BOS, RAS, and time-matched CLAD-free patients. Post-hoc analysis revealed these differences were primarily driven by BOS instead of RAS. While no differences were found between CLAD-free and RAS patients with regards to spectral oscillometry, the intrabreath metric of reactance at end-inspiration (XeI) was significantly different (p < 0.05). BOS and RAS were differentiated by spectral oscillometry measure R5, and intrabreath resistance at end expiration, ReE (p < 0.05 for both).Conclusion: Both spectral and intrabreath oscillometry can differentiate BOS-CLAD from CLAD-free states while intrabreath oscillometry, specifically XeI, can uniquely distinguish RAS-CLAD from CLAD-free. Spectral and intrabreath oscillometry offer complementary information regarding lung mechanics in CLAD patients to help distinguish the two phenotypes and could prove useful in prognostication.

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Section: Discussionmentioning

confidence: 99%

Characterization of chronic lung allograft dysfunction phenotypes using spectral and intrabreath oscillometry

Vasileva²,

Hanafi³

et al. 2022

Front. Physiol.

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“…Interestingly, in an associated ex vivo study, they identified that activated T cells promote specific MMP‐9 production by bronchial epithelial cells trough the CCL2/CCR2 axis in synergy with TGF‐β and initiate epithelial-to-mesenchymal transition ( 40 ). Recently, increased expression of lipocalin-2, which stabilizes MMP-9 activity, was also proposed as potential biomarker to distinguish RAS from BOS patients and stable-LTx patients ( 41 ). TGF-β forms the most potent inducer of CTGF, and CTGF overproduction plays a crucial role in fibrosis development ( 42 , 43 ), but appears to induce fibrosis mostly in the co-presence of TGF-β ( 44 ).…”

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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“…Levels of alpha 2-macroglobulin, ceruloplasmin and antithrombin-3 could discriminate between CLAD and control patients [44]. Lipocalin is another marker involved in macrophage-related innate immunity and was increased in RAS compared with BOS and control [45]. Krebs von den Lungen 6 (KL-6) is produced by damaged pneumocytes, and higher serum concentrations could differentiate RAS from BOS patients, while BAL KL-6 concentrations showed no difference.…”

Section: Blood Biomarkersmentioning

confidence: 99%

Novel biomarkers of chronic lung allograft dysfunction: is there anything reliable?

Verleden

2021

Current Opinion in Organ Transplantation

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Purpose of reviewChronic lung allograft dysfunction (CLAD) remains a major barrier preventing long-term survival following lung transplantation. As our clinical knowledge regarding its definition and presentation has significantly improved over the last years, adequate biomarkers to predict development of CLAD, phenotype of CLAD or prognosis post-CLAD diagnosis are definitely needed. Recent findingsRadiological and physiological markers are gradually entering routine clinical practice. In-depth investigation of biological samples including broncho-alveolar lavage, biopsy and serum has generated potential biomarkers involved in fibrogenesis, airway injury and inflammation but none of these are universally accepted or implemented although progress has been made, specifically regarding donorderived cell-free DNA and donor-specific antibodies.

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Potential novel biomarkers for chronic lung allograft dysfunction and azithromycin responsive allograft dysfunction

Cited by 12 publications

References 29 publications

Characterization of chronic lung allograft dysfunction phenotypes using spectral and intrabreath oscillometry

Characterization of chronic lung allograft dysfunction phenotypes using spectral and intrabreath oscillometry

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

Novel biomarkers of chronic lung allograft dysfunction: is there anything reliable?

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