A new classification system for chronic lung allograft dysfunction

doi:10.1016/j.healun.2013.10.022

The Journal of Heart and Lung Transplantation

Volume 33, Issue 2, February 2014, Pages 127-133

https://doi.org/10.1016/j.healun.2013.10.022 Get rights and content

Although survival after lung transplantation has improved significantly during the last decade, chronic rejection is thought to be the major cause of late mortality. The physiologic hallmark of chronic rejection has been a persistent fall in forced expiratory volume in 1 second associated with an obstructive ventilatory defect, for which the term bronchiolitis obliterans syndrome (BOS) was defined to allow a uniformity of description and grading of severity throughout the world. Although BOS was generally thought to be irreversible, recent evidence suggests that some patients with BOS may respond to azithromycin with > 10% improvement in their forced expiratory volume in 1 second. In addition, a restrictive form of chronic rejection has recently been described that does not fit the strict definition of BOS as an obstructive defect. Hence, the term chronic lung allograft dysfunction (CLAD) has been introduced to cover all forms of graft dysfunction, but CLAD has yet to be defined. We propose a definition of CLAD and a flow chart that may facilitate recognition of the different phenotypes of CLAD that can complicate the clinical course of lung transplant recipients.

Section snippets

Lung allograft dysfunction

Lung allograft dysfunction may be an acute phenomenon (acute lung allograft dysfunction [ALAD]), leading to an acute decline in FEV₁ (with or without forced vital capacity [FVC] decline) and may be due to various conditions that affect the graft, including acute infection, pulmonary embolism, and acute rejection, among others. We acknowledge that in some of these conditions, spirometry will not be available, but ALAD may be diagnosed from other measures of acute graft dysfunction such as

Chronic lung allograft dysfunction

CLAD is a term that was first introduced in the lung transplant literature in 2010,⁸ although no precise definition currently exists. This document will propose such a definition in the attempt to draw together some disparate notions regarding this condition and standardize its use in describing loss of lung allograft function so that data on functional decline can be uniformly collected. The proposed definition of CLAD is based on expert clinical experience, review of available data, and

Obstructive CLAD: BOS

When the FEV₁ decline (≥ 20%) is not only persistent, this means in 2 measurements at least 3 weeks apart, but also obstructive (based on FEV₁/FVC ratio), we suggest that BOS should continue to be used as the preferred term to describe this phenotype of CLAD. Not every patient should or will go through a stage of suspected CLAD, because some patients may already have lost > 20% of their FEV₁ when they are diagnosed with allograft dysfunction.¹⁰ The revised definition of BOS, as given in the

Restrictive CLAD: Restrictive allograft syndrome

Recent publications have reported that some patients may experience a persistent decline in vital capacity and TLC that is accompanied by a decline in FEV₁ of > 20%, which has been termed restrictive allograft syndrome (RAS).³⁰ Compared with BOS, we also suggest that there should be 2 pulmonary function measurements at least 3 weeks apart showing this decline and that other causes (e.g., infection, rejection, etc) should be ruled out. Depending on the relative change among the FEV₁, the FEV₁

Limitations and future needs

We suggest that the term “suspected CLAD” is a suitable alternative to BOS Stage 0-p and that the detection of a FEV₁ and/or FVC decline of > 10% from a stable, best FEV₁and FVC value should trigger an evaluation that seeks to determine the cause(s) that explain the decline in lung function. However, we also recognize that not every patient can necessarily fit cleanly into a specific phenotype (e.g., BOS, RAS, ARAD) and that phenotypes may overlap significantly. So far, RAS is only described by

Disclosure statement

None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.

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Cited by (429)

Alveolar macrophage–CD8 T cell interactions after acute lung allograft dysfunction: Insights from single-cell RNA sequencing
2024, Journal of Heart and Lung Transplantation
Oversizing lung allografts deteriorates outcomes in patients with pulmonary fibrosis
2024, Journal of Heart and Lung Transplantation
Lung transplantation is the only curative treatment for patients with end-stage pulmonary fibrosis. It is still under debate whether over- or undersizing of lung allografts is preferably performed regarding the postoperative outcome. We therefore analyzed our data using predicted total lung capacity to compare size mismatches.
Patient records were retrospectively reviewed. Three groups were formed, 1 including patients with a donor-recipients pTLC ratio (DRPR) of <1.0 (undersized group), the second with a DRPR of ≥1.0 and <1.1 (size-matched group), and the third group with a DRPR of ≥1.1 (oversized group). Outcomes were evaluated using chi-square test and Kruskall-Wallis test as well as Kaplan-Meier analysis, competing risk analysis, and multivariable analysis, respectively.
Between January 2010 and May 2023, among the 1501 patients transplanted at our institution, 422 (28%) patients were included, 26 (2%) patients forming the oversized group (median DRPR: 1.14), 101 (7%) patients forming the size-matched group (median DRPR: 1.03), and 296 (20%) patients forming the undersized group (median DRPR: 0.92). Patients from the oversized group had a higher PGD grade 3 rate at 24 (p < 0.001), 48 (p < 0.001), and 72 (p = 0.039) hours after transplantation as well as a higher in-hospital mortality compared to the undersized group (p = 0.033). The long-term survival was also better in the undersized group compared to the oversized group (p = 0.011) and to the size-matched group (p = 0.01).
Oversizing lung allografts more than 10% deteriorated early postoperative outcomes and long-term survival in patients with pulmonary fibrosis.
Macrophage and CD8 T cell discordance are associated with acute lung allograft dysfunction progression
2024, Journal of Heart and Lung Transplantation
Acute lung allograft dysfunction (ALAD) is an imprecise syndrome denoting concern for the onset of chronic lung allograft dysfunction (CLAD). Mechanistic biomarkers are needed that stratify risk of ALAD progression to CLAD. We hypothesized that single cell investigation of bronchoalveolar lavage (BAL) cells at the time of ALAD would identify immune cells linked to progressive graft dysfunction.
We prospectively collected BAL from consenting lung transplant recipients for single cell RNA sequencing. ALAD was defined by a ≥10% decrease in FEV₁ not caused by infection or acute rejection and samples were matched to BAL from recipients with stable lung function. We examined cell compositional and transcriptional differences across control, ALAD with decline, and ALAD with recovery groups. We also assessed cell-cell communication.
BAL was assessed for 17 ALAD cases with subsequent decline (ALAD declined), 13 ALAD cases that resolved (ALAD recovered), and 15 cases with stable lung function. We observed broad differences in frequencies of the 26 unique cell populations across groups (p = 0.02). A CD8 T cell (p = 0.04) and a macrophage cluster (p = 0.01) best identified ALAD declined from the ALAD recovered and stable groups. This macrophage cluster was distinguished by an anti-inflammatory signature and the CD8 T cell cluster resembled a Tissue Resident Memory subset. Anti-inflammatory macrophages signaled to activated CD8 T cells via class I HLA, fibronectin, and galectin pathways (p < 0.05 for each). Recipients with discordance between these cells had a nearly 5-fold increased risk of severe graft dysfunction or death (HR 4.6, 95% CI 1.1–19.2, adjusted p = 0.03). We validated these key findings in 2 public lung transplant genomic datasets.
BAL anti-inflammatory macrophages may protect against CLAD by suppressing CD8 T cells. These populations merit functional and longitudinal assessment in additional cohorts.
Effect of once-per-day tacrolimus versus twice-per-day ciclosporin on 3-year incidence of chronic lung allograft dysfunction after lung transplantation in Scandinavia (ScanCLAD): a multicentre randomised controlled trial
2024, The Lancet Respiratory Medicine
Evidence is low regarding the choice of calcineurin inhibitor for immunosuppression after lung transplantation. We aimed to compare the use of tacrolimus once per day with ciclosporin twice per day according to the current definition of chronic lung allograft dysfunction (CLAD) after lung transplantation.
ScanCLAD is an investigator-initiated, open-label, multicentre, randomised, controlled trial in Scandinavia evaluating whether an immunosuppressive protocol based on anti-thymocyte globulin induction followed by tacrolimus (once per day), mycophenolate mofetil, and corticosteroids reduces the incidence of CLAD after de novo lung transplantation compared with a protocol using ciclosporin (twice per day), mycophenolate mofetil, and corticosteroids. Patients aged 18–70 years who were scheduled to undergo double lung transplantation were randomly allocated (1:1) to receive either oral ciclosporin (2–3 mg/kg before transplantation and 3 mg/kg [twice per day] from postoperative day 1) or oral tacrolimus (0·05–0·1 mg/kg before transplantation and 0·1–0·2 mg/kg from postoperative day 1). The primary endpoint was CLAD at 36 months post transplantation, determined by repeated lung function tests and adjudicated by an independent committee, and was assessed with a competing-risks analysis with death and re-transplantation as competing events. The primary outcome was assessed in the modified intention-to-treat (mITT) population, defined as those who underwent transplantation and received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02936505) and EudraCT (2015-004137-27).
Between Oct 21, 2016, and July 10, 2019, 383 patients were screened for eligibility. 249 patients underwent double lung transplantation and received at least one dose of study drug, and were thus included in the mITT population: 125 (50%) in the ciclosporin group and 124 (50%) in the tacrolimus group. The mITT population consisted of 138 (55%) men and 111 (45%) women, with a mean age of 55·2 years (SD 10·2), and no patients were lost to follow-up. In the mITT population, CLAD occurred in 48 patients (cumulative incidence 39% [95% CI 31–48]) in the ciclosporin group and 16 patients (13% [8–21]) in the tacrolimus group at 36 months post transplantation (hazard ratio [HR] 0·28 [95% CI 0·15–0·52], log-rank p<0·0001). Overall survival did not differ between groups at 3 years in the mITT population (74% [65–81] for ciclosporin vs 79% [70–85] for tacrolimus; HR 0·72 [95% CI 0·41–1·27], log-rank p=0·25). However, in the per protocol CLAD population (those in the mITT population who also had at least one post-baseline lung function test allowing assessment of CLAD), allograft survival was significantly better in the tacrolimus group (HR 0·49 [95% CI 0·26–0·91], log-rank p=0·021). Adverse events totalled 1516 in the ciclosporin group and 1459 in the tacrolimus group. The most frequent adverse events were infection (453 events), acute rejection (165 events), and anaemia (129 events) in the ciclosporin group, and infection (568 events), anaemia (108 events), and acute rejection (98 events) in the tacrolimus group. 112 (90%) patients in the ciclosporin group and 108 (87%) in the tacrolimus group had at least one serious adverse event.
Immunosuppression based on use of tacrolimus once per day significantly reduced the incidence of CLAD compared with use of ciclosporin twice per day. These findings support the use of tacrolimus as the first choice of calcineurin inhibitor after lung transplantation.
Astellas, the ALF-agreement, Scandiatransplant Organization, and Heart Centre Research Committee, Rigshospitalet, Denmark.
Telemonitoring: An opportunity in cystic fibrosis lung transplant recipients
2023, Heliyon
Telemedicine has been successfully employed in a wide range of conditions, such as such as chronic lung disease and COVID-19. This study evaluate the role of telemonitoring for the early diagnosis of acute lung allograft dysfunction in cystic fibrosis adults who underwent lung transplant (LuTx). Quality of life and functional level achieved during a 12 months follow up were assessed.
Patients were randomized into two groups; control group received traditional hospital-based follow-up, whereas patients in the intervention group received, on top of standard care, a telemonitoring device, with a pulse oximeter and a spirometer integrated. Telemonitoring data were digitally transmitted to our centre.
Sixteen patients were enrolled in each group. No statistically significant difference was found between the two groups in terms of incidence of allograft dysfunction, time from onset of symptoms to diagnosis and time of occurrence from LuTx. Moreover, both groups achieved similar quality of life and functional level. With reference to the telemonitoring group: 1) hospital reported data were consistent with those being remotely registered; 2) adherence to telemonitoring decreased during the follow up; 3) the majority of patients reported a high degree of satisfaction.
The COVID19 pandemic highlighted the necessity to investigate alternative practices to treat chronically ill individuals. Telemonitoring is a valuable tool to improve quality care to LuTx recipients.
Pulmonary epithelial markers in phenotypes of chronic lung allograft dysfunction
2023, Journal of Heart and Lung Transplantation
Airway epithelial injury is thought to be a key event in the pathogenesis of chronic lung allograft dysfunction (CLAD). We investigated whether markers of epithelial activity and injury in bronchoalveolar lavage fluid (BAL) correlate with CLAD diagnosis and major CLAD phenotypes: bronchiolitis obliterans syndrome (BOS) vs restrictive allograft syndrome (RAS)-related phenotypes (including RAS, mixed phenotype, and all other patients with RAS-like opacities).
CLAD status and phenotypes were retrospectively determined in a cohort of all consecutive adult, first, bilateral lung transplants performed 2010-2015, with available BAL samples. All patients with RAS-related phenotypes were included and 1:1 matched with BOS patients based on the time from transplant to CLAD-onset. Subjects who were CLAD-free for a minimum of 3 years post-transplant were 1:1 matched to CLAD patients and included as controls. Proteins that maintain the barrier function of the airway epithelial mucosa (club cell secretory protein, surfactant protein-D and epithelial mucins: MUC1, MUC5AC, MUC5B, MUC16), as well as epithelial cell death markers (M30&M65 representing epithelial cell apoptosis and overall death, respectively), were measured in BAL obtained within 6-months post CLAD onset using a double-sandwich ELISA or a multiplex bead assay. Protein levels were compared using Mann-Whitney-U-test. Association between protein levels and graft survival was assessed using Cox proportional hazards models, adjusted for CMV serology mismatch status and CLAD phenotype.
Fifty-four CLAD (27 BOS, 11 RAS, 7 mixed, 9 others with RAS-like opacities) patients and 23 CLAD-free controls were included. Median BAL levels were significantly higher in patients with CLAD compared to CLAD-free controls for M30 (124.5 vs 88.7 U/L), MUC1 (6.8 vs 3.2 pg/mL), and MUC16 (121.0 vs 30.1 pg/mL). When comparing CLAD phenotypes, M30 was significantly higher in patients with RAS-related phenotypes than BOS (160.9 vs 114.6 U/L). In multivariable models, higher M30 and MUC5B levels were associated with decreased allograft survival after CLAD onset independent of phenotype (p < 0.05 for all).
Airway epithelial mucins and cell death markers are enhanced in the BAL of patients with CLAD and can assist in differentiating between CLAD phenotypes and post-CLAD outcomes. Abnormal airway mucin expression and epithelial cell death may be involved in the pathogenesis of CLAD, and therefore their detection may aid in future selection of targeted therapies.

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A new classification system for chronic lung allograft dysfunction

Section snippets

Lung allograft dysfunction

Chronic lung allograft dysfunction

Obstructive CLAD: BOS

Restrictive CLAD: Restrictive allograft syndrome

Limitations and future needs

Disclosure statement

J Heart Lung Transplant

Chest

J Heart Lung Transplant

Chest

Transplant Immunol

J Heart Lung Transplant

Am J Transplant

J Heart Lung Transplant

J Heart Lung Transplant

Am J Transplant

J Heart Lung Transplant

J Heart Lung Transplant

Hum Pathol

Chest

Mod Pathol

J Heart Lung Transplant

Heart and Lung Transplantation J Heart Lung Transplant

Obliterative bronchiolitis after heart-lung transplantation: apparent arrest by augmented immunosuppression

Ann Intern Med

Evaluation of transbronchial lung biopsy specimens in the diagnosis of bronchiolitis obliterans after lung transplantation

J Heart Lung Transplant

A working formulation for the standardization of nomenclature for clinical staging of chronic dysfunction in lung allografts

J Heart Lung Transplant