Progression pattern of restrictive allograft syndrome after lung transplantation

doi:10.1016/j.healun.2012.09.026

The Journal of Heart and Lung Transplantation

Volume 32, Issue 1, January 2013, Pages 23-30

https://doi.org/10.1016/j.healun.2012.09.026 Get rights and content

Background

Restrictive allograft syndrome (RAS) is a novel form of chronic lung allograft dysfunction after lung transplantation. RAS is characterized by restrictive physiology and peripheral lung fibrosis. The purpose of the study is to analyze progression patterns of RAS.

Methods

Clinical information, pulmonary function test results and radiographic findings were reviewed for 25 RAS patients who received bilateral lung or heart–lung transplantation between January 2004 and December 2009.

Results

Average time from transplantation to RAS onset was 647±544 (mean±SD) days; RAS onset to end of observation (death or re-transplantation) was 490±417 days. RAS patients had 1 to 4 episodes of acute exacerbation (2.48±0.82 episodes/patient) that accompanied acute respiratory deterioration or distress, a sudden drop in pulmonary function, evidence of diffuse alveolar damage (DAD) on biopsies, and patchy or diffuse ground-glass opacities (GGO) with occasional consolidation on computed tomography scan. Patients were most frequently managed by high-dose steroid in combination with empirical antibiotics, with uncertain efficacy. Acute exacerbation was followed by an interval during which resolution of GGO and progression of consolidation, interstitial reticular shadows and traction bronchiectasis were frequently observed. The interval between episodes of acute exacerbation was 238±165 days. In 21 patients, the last episode of acute exacerbation led to death or urgent retransplantation.

Conclusions

RAS shows a “stair-step” pattern of progression. Acute lung injury represented by DAD and GGO is followed by an interval period during which graft fibrosis often progresses.

Section snippets

Definition of CLAD and RAS

CLAD and RAS were defined as described previously.¹ In brief, baseline forced expiratory volume in 1 second (FEV₁) was defined according to criteria recommended by the International Society for Heart and Lung Transplantation,⁴ and then the baseline values of other PFT parameters were taken as the average of the parameters measured at the time of the best FEV₁ measurements. CLAD was defined as an irreversible drop of FEV₁ to <80% of baseline. RAS was defined as a condition in which restrictive

Results

Patient demographics of the 25 RAS cases examined are shown in Table 1. Among them, 3 patients initially showed BOS phenotype and then developed RAS. Although the number of patients with cystic fibrosis was relatively large in this study, the original diagnosis was not significantly different among BOS, RAS and non-CLAD patients in our previous study using a larger cohort.¹

In all RAS cases analyzed, patients had at least 1 episode of acute exacerbation. None of the patients showed a steady

Case 1

A 62-year-old man received cadaveric bilateral lung transplantation for chronic obstructive pulmonary disease (COPD) (Figure 4). Although his early post-transplant course was uneventful, he had 3 episodes of acute exacerbation. After the first exacerbation, PFT showed a decline over time, whereas, after the second episode, PFT showed partial recovery. On CT scan, there were diffuse bilateral GGO and consolidation at the time of exacerbation. GGO resolved to some extent during intervals between

Case 2

A 28-year-old man with cystic fibrosis received cadaveric bilateral lung transplantation (Figure 5). His post-transplant recovery was excellent except for complications of supraventricular tachycardia and intracardiac thrombus formation. His chest remained clear until he had an initial episode of acute exacerbation, accompanied by extensive bilateral GGO, bilateral pneumothoraces and pneumomediastinum (Figure 5C). Although PFT indicated temporary recovery and the radiographic abnormalities

Case 3

A 52-year-old man received bilateral lung transplantation for idiopathic pulmonary fibrosis (Figure 6). His clinical course was excellent until the first episode of acute exacerbation, approximately 1 year after transplantation. His general condition, PFTs and CT scans showed gradual improvement over the next 16 months, when he had a second episode of acute exacerbation. He died 868 days after transplantation due to respiratory failure.

Discussion

In this study we have documented the progression pattern of RAS. In general, patients suffer multiple episodes of acute exacerbation (a “stair-step” progression pattern) characterized by GGO, with or without consolidation and interstitial shadow on CT scan, and histologic features of DAD on biopsies. Although some episodes of acute exacerbation were associated with acute rejection or infection, there was no uniform explanation for acute exacerbation. After acute exacerbations, patients

Disclosure statement

The authors have no conflicts of interest to disclose.

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Antithymocyte Globulin Treatment for Chronic Lung Allograft Dysfunction in Lung Transplant Recipients: Experience From a National Reference Transplant Center
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Chronic lung allograft dysfunction (CLAD) is the leading cause of mortality after the first year of transplantation and treatments can have little impact on CLAD progression in some cases. The objective of this study was to evaluate the effectiveness and safety of antithymocyte globulin (ATG) in lung transplant recipients with CLAD.
We reviewed all patients from our center that had undergone a lung transplant between 2008 and 2019 and selected those with CLAD who were treated with ATG. The closest lung function (forced expiratory volume in the first second) to the ATG administration was recorded, as well as the values 3, 6, and 12 months before and after treatment. We followed and recorded survival during the 12 months after treatment.
A total of 13 patients with CLAD received ATG treatment. A favorable positive response to treatment (improvement or stabilization on lung function) was achieved in half of the patients. Most patients (71%) who responded well to ATG were in CLAD stage 1 to 2. The fall slope of forced expiratory volume in the first second is better after treatment. The median survival was 27 months, and we found a trend toward better survival in early CLAD stages 1 to 2. There were also differences in survival between rapid decliners and nonrapid decliners.
ATG treatment could play a role in patient with CLAD who do not respond to conventional therapies. The effect of cytolytic therapy with ATG is clearly better in those patients in early stages, with little effect in those in CLAD stage 3.
Bronchiolitis obliterans after stem cell transplantation for hematologic malignancies rescued by lung transplantation: A report of two cases
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Bronchiolitis obliterans syndrome (BOS) occurring after hematopoietic stem cell transplantation (HSCT) for hematologic malignancies is a progressive and refractory disease, and lung transplantation (LTx) seems to be the only promising treatment. We report two cases of BOS after HSCT, which showed distinct clinical courses and were successfully treated with LTx. The respiratory symptoms and function of the two patients progressively deteriorated to a critical level during the waiting period. In one patient, recurrent and intractable pneumothoraxes consistent with thoracic air-leak syndrome (TALS) occurred, which were associated with pleuroparenchymal fibroelastosis. TALS could accelerate clinical deterioration, thus permitting a shorter waiting period for LTx.
Antibody-Mediated Rejection After Lung Transplantation
2021, Encyclopedia of Respiratory Medicine, Second Edition
An important role for donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) in lung allograft rejection has been recognized since the late 1990s. Early studies identified the development of HLA antibodies as a risk factor for chronic rejection. Recently, antibody-mediated rejection (AMR) has been increasingly recognized as a form of lung allograft rejection, and the International Society for Heart and Lung Transplantation proposed a consensus definition. However, experience with AMR after lung transplantation remains limited, and outcomes are poor with many patients dying of AMR or developing progressive chronic rejection after the diagnosis.
Longitudinal lung function measurements in single lung transplant recipients with chronic lung allograft dysfunction
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Phenotyping chronic lung allograft dysfunction (CLAD) in single lung transplant (SLTX) recipients is challenging. The aim of this study was to assess the diagnostic and prognostic value of longitudinal lung function tests in SLTX recipients with CLAD.
A total of 295 SLTX recipients were analyzed and stratified according to native lung physiology. In addition to spirometry, measurements of static lung volumes and lung capacities were used to phenotype patients and to assess their prognostic value. Outcome was survival after CLAD onset. Patients with insufficient clinical information were excluded (n = 71).
Of 224 lung transplant recipients, 105 (46.9%) developed CLAD. Time to CLAD onset (hazard ratio [HR]: 0.82, 95% CI: 0.74–0.90; p < 0.001), severity of CLAD at onset (HR: 0.97, 95% CI: 0.94–0.99; p = 0.009), and progression after onset of CLAD (HR: 1.03, 95% CI: 1.00–1.05; p = 0.023) were associated with outcome. Phenotypes at onset were bronchiolitis obliterans syndrome (BOS) (59.1%), restrictive allograft syndrome (RAS) (12.4%), mixed phenotype (6.7%), and undefined phenotype (21.9%). Survival estimates differed significantly between phenotypes (p = 0.004), with RAS and mixed phenotype being associated with the worst survival, followed by BOS and undefined phenotype. Finally, a higher hazard for mortality was noticed for RAS (HR: 2.34, 95% CI: 0.99–5.52; p = 0.054) and mixed phenotype (HR: 3.30, 95% CI: 1.20–9.11; p = 0.021) while controlling for time to CLAD onset and severity of CLAD at onset.
Phenotyping CLAD in SLTX remains challenging with a high number of patients with an undefined phenotype despite comprehensive lung function testing. However, phenotyping is of prognostic value. Furthermore, early, severe, and progressive CLADs are associated with worse survival.
Noninvasive methods for detection of chronic lung allograft dysfunction in lung transplantation
2020, Transplantation Reviews
Citation Excerpt :
RAS is characterized by inflammation and fibrosis in the alveoli, pleura, and interlobular septum of the lung parenchyma [9]. In addition to the above symptoms, RAS was reported to present with minimal coarse crackles, pleurisy and chest tightness in other studies [16,17,20]. Even when treated routinely, RAS eventually results in respiratory failure due to irreversible deterioration of pulmonary function [21].
Lung transplantation (LTx) is the only therapeutic option for end-stage lung diseases. Chronic lung allograft dysfunction (CLAD), which manifests as airflow restriction and/or obstruction, is the primary factor limiting the long-term survival of patients after surgery. According to histopathological and radiographic findings, CLAD comprises two phenotypes, bronchiolitis obliterans syndrome and restrictive allograft syndrome. Half of all lung recipients will develop CLAD in 5 years, and this rate may increase up to 75% 10 years after surgery owing to the paucity in accurate and effective early detection and treatment methods. Recently, many studies have presented noninvasive methods for detecting CLAD and improving diagnosis and intervention. However, the significance of accurately detecting CLAD remains controversial. We reviewed published studies that have presented noninvasive methods for detecting CLAD to highlight the current knowledge on clinical symptoms, spirometry, imaging examinations, and other methods to detect the disease.
Use of CT-SCAN score and volume measures to early identify restrictive allograft syndrome in single lung transplant recipients
2020, Journal of Heart and Lung Transplantation
Citation Excerpt :
BOS was defined by the classical International Society for Heart and Lung Transplantation definition.10,15 Spirometry was performed according to American Thoractic Society guidelines2 (refer to Supplementary Material available online at www.jhltonline.org). Only 5 out of 17 (28%) patients with RAS had performed TLC measures during follow-up within the period of RAS development, with only very few available measures in 3 of them, which did not allow us to use this criteria for the diagnosis of RAS.
Restrictive allograft syndrome (RAS) after lung transplantation (LTx) is associated with the poorer graft survival in patients with chronic lung allograft dysfunction (CLAD). Nevertheless, its diagnostic criteria have not been clearly defined after single-LTx (SLTx). Hence, we studied an SLTx cohort with CLAD to investigate the utility of both computed tomography (CT)-score/volume measures and functional spirometric criteria for the early identification of RAS in this population.
We included 51 patients with SLTx (17 RAS, 17 bronchiolitis obliterans syndrome [BOS], and 17 stable condition). The criteria for RAS diagnosis in SLTx included forced vital capacity (FVC) <80% baseline (BL) or forced expiratory volume in 1 second (FEV1) <80% BL with an FEV1/FVC ratio^{unchanged or >0.7} and persistent CT-scan-lung opacities. We defined 4 time points (T): T-baseline, T-onset (first CT-scan-opacities), T-follow-up, and T-last.
In patients with RAS, the spirometric criteria for RAS at T-onset were reached in only 47% (FVC decline <80% BL [(29%] or FEV1 <80% BL/ratio^{unchanged or >0.7} [41%]), whereas at the same T-onset date, the graft CT-score increased to 5 (4–6) vs 1 (0–2) at baseline (p < 0.001) (CT - score ≥2 at T-onset in 100% and ΔCT - score ≥2 in 74% of patients with RAS), and the median CT-scan graft volume decreased to 1,722 ml (vs 1,796 ml at T-baseline, p = 0.003) (decreased CT-graft - volume <90% BL in 50% of patients). In contrast, in patients with BOS, CT-score/volume were unchanged at T-onset vs T-baseline (p = 0.8, p = 0.68, respectively).
Our results suggest that the use of a simple CT-score and to a lesser extent, CT-volume measures, might allow for the early identification and/or prediction of RAS in SLTx rather than functional criteria.

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Featured articlesProgression pattern of restrictive allograft syndrome after lung transplantation

Background

Methods

Results

Conclusions

Section snippets

Definition of CLAD and RAS

Results

Case 1

Case 2

Case 3

Discussion

Disclosure statement

J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

Semin Thorac Cardiovasc Surg

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Progression pattern of restrictive allograft syndrome after lung transplantation