Neutrophilic Reversible Allograft Dysfunction Research Articles

Update on Chronic Lung Allograft Dysfunction.

Chronic lung allograft dysfunction (CLAD) encompasses a range of pathologies that cause a transplanted lung to not achieve or maintain normal function. CLAD manifests as airflow restriction and/or obstruction and is predominantly a result of chronic rejection. Three distinct phenotypes of chronic rejection are now recognized: bronchiolitis obliterans, neutrophilic reversible allograft dysfunction, and restrictive allograft syndrome. Recent investigations have revealed that each phenotype has a unique pathology and histopathological findings, suggesting that treatment regimens should be tailored to the underlying etiology. CLAD is poorly responsive to treatment once diagnosed, and therefore the prevention of the factors that predispose a patient to develop CLAD is critically important. Small and large animal models have contributed significantly to our understanding of CLAD and more studies are needed to develop treatment regimens that are effective in humans.

Chronic lung allograft dysfunction

The recognition that chronic graft dysfunction after lung transplantation is a heterogeneous phenomenon has led to the introduction of a new term: chronic lung allograft dysfunction (CLAD). An International Society for Heart and Lung Transplantation working group will determine a definition of CLAD in 2014. It is thought that CLAD should not totally replace bronchiolitis obliterans syndrome (BOS), the conventional phenotype of chronic graft dysfunction, but that it should be a more comprehensive category that includes BOS as a purely obstructive disorder. Another phenotype to be included is restrictive allograft syndrome, a restrictive form of graft dysfunction that is distinct from BOS. Neutrophilic reversible allograft dysfunction may be included in CLAD as well. Further discussion is required before including other conditions associated with impaired pulmonary function after transplantation. Recent progress in the management of patients with CLAD includes the development of a series of diagnostic tests and recognition of the benefits of a trial of low-dose azithromycin. Further refinement of our understanding of the pathophysiology of CLAD and clinical care pathways is necessary.

Neutrophilic Reversible Allograft Dysfunction (NRAD) and Restrictive Allograft Syndrome (RAS)

Lung transplantation is currently considered as an ultimate live-saving treatment for selected patients suffering from end-stage pulmonary disease. Long-term survival, however, is hampered by chronic rejection, or chronic lung allograft dysfunction (CLAD). Recently, various phenotypes within CLAD have been identified, challenging the established clinical definition of bronchiolitis obliterans syndrome (BOS). Some patients with presumed BOS, for instance, demonstrate an important improvement in forced expiratory volume in the first second of expiration (FEV1) after treatment with azithromycin. These patients are characterized by the presence of excess (≥ 15%) bronchoalveolar lavage (BAL) neutrophils, in absence of concurrent infection. This phenotype of CLAD has been redefined as neutrophilic reversible allograft dysfunction (NRAD), and these patients generally have a very good prognosis after diagnosis. Another group of patients with CLAD develop a restrictive rather than an obstructive pulmonary function defect (defined as a decline in total lung capacity of at least 10%) and demonstrate persistent interstitial and ground-glass opacities on chest computed tomographic (CT) scan. This phenotype is called restrictive allograft syndrome (RAS), and patients with RAS have a much worse prognosis after diagnosis. This review further discusses both of these CLAD phenotypes that do not fit the classical definition of BOS. Potential pathophysiological mechanisms, etiology, diagnosis, prognosis, and treatments are discussed.

Chronic lung allograft dysfunction after lung transplantation: the moving target

Chronic lung allograft dysfunction is a major challenge in long-term management of lung transplant recipients. Both alloimmune-dependent factors (rejection) and alloimmune-independent factors contribute to the development of chronic lung allograft dysfunction. Thus, use of the term "chronic rejection" tends to be intentionally avoided among specialists in the field, although "chronic rejection" is still an acceptable lay word understood by many patients. Several different phenotypes have been identified in chronic lung allograft dysfunction, including restrictive allograft syndrome, neutrophilic reversible allograft dysfunction, and fibrous bronchiolitis obliterans syndrome. Restrictive allograft syndrome is characterized by restrictive physiology and peripheral foci of inflammation and fibrosis, which contrasts the obstructive physiology and pathological foci in small airways in conventional bronchiolitis obliterans syndrome. Among patients with bronchiolitis obliterans syndrome, there is a subpopulation that responds relatively well to azithromycin. Because these patients show airway neutrophilia, this subtype of chronic lung allograft dysfunction was named neutrophilic reversible allograft dysfunction. Conversely, patients with bronchiolitis obliterans syndrome unresponsive to azithromycin show airway fibrosis with less inflammation (fibrous bronchiolitis obliterans syndrome). In general, restrictive allograft syndrome shows poorer survival than does bronchiolitis obliterans syndrome, and early-onset bronchiolitis obliterans syndrome (within 2 years) shows a worse prognosis than does late-onset bronchiolitis obliterans syndrome. Until preventive and therapeutic options are refined, chronic lung allograft dysfunction will remain a major life-limiting factor. It has significant psychological, physical, social, and economic impacts. Early introduction of palliative care is another important strategy to improve patients' quality of life.

Exhaled Nitric Oxide: A Valuable Tool for Early Diagnosis and Phenotyping of Bronchiolitis Obliterans Syndrome

To the Editor: Thank you very much for the opportunity to write a letter of response with respect to the letter of Antus et al. regarding possible limitations of fraction of nitric oxide in exhaled breath (FeNO) for the early detection of chronic graft dysfunction after lung transplantation (LTX; Ref. 1). We speculate that several factors might have contributed to the lack of demonstration of clinical utility for FeNO in this relatively small cohort of LTX recipients. In our study, population underlying disease was not identified as a variable contributing to the variance of FeNO. However, the percentage of cystic fibrosis (CF) patients in our study cohort was only 16.7% in comparison to 43.3% in the Hungarian cohort. Although subgroup analysis of FeNO performance is limited because of the overall small sample size, we cannot definitely rule out a significant impact of the underlying disease on FeNO performance as a marker for bronchiolitis obliterans syndrome (BOS; Ref. 2). Despite the fact that FeNO readings of recipients with overt infection were excluded from the analysis, a significant rate of colonization and subclinical infections in CF patients may be important confounders for the interpretation of FeNO measurements (3). In accordance with the findings of Antus et al., our data demonstrated that a relevant percentage of patients displayed only slightly elevated FeNO values in spite of developing BOS. We suggest that dividing BOS patients on the basis of BAL neutrophilia into neutrophilic reversible allograft dysfunction and fibroproliferative BOS (fBOS) could reveal a lack of detectable FeNO increase in fBOS patients because FeNO is mainly a marker of airway inflammation (4). Moreover, Antus and colleagues do not report the prophylactic or therapeutic use of azithromycin in CF and nonCF recipients which is the standard of care in many centers for patients during early stages of BOS that might result in a significant reduction of FeNO (5). The authors report an impressively high number of FeNO measurements without finding an unambiguous association of FeNO and BOS during long-term follow-up. However, assessment of FeNO readings as a mean of all values recorded during 6-month intervals as depicted by Antus and colleagues might hamper the performance of FeNO as a predictive marker because the average time from FeNO readingto onsetofBOSwas only 117 ±9 days in ourstudy. In this respect, we wish to emphasize the high negative predictive value of elevated FeNO (96.9%) in comparison to its rather intermediate positive predictive value (69.0%) in our cohort. In summary, we clearly recognize the relevant limitations of FeNO as a predictive marker in the context of the overall highly variable course of BOS. Nevertheless, FeNO is a valuable tool to improve our understanding for different phenotypes of BOS with potentially important clinical applications.

Survival Determinants in Lung Transplant Patients With Chronic Allograft Dysfunction

Chronic lung allograft dysfunction (CLAD) remains the leading cause of mortality after lung transplantation. In this retrospective single-center study, we aimed to identify different phenotypes of and risk factors for mortality after CLAD diagnosis using univariate and multivariate Cox proportional hazard survival regression analysis. CLAD was diagnosed in 71 of 294 patients (24.2%) at 30.9±22.8 months after transplantation. Pulmonary function was obstructive in 51 (71.8%) of the CLAD patients, restrictive in 20 (28.2%) patients, of whom 17 had persistent parenchymal infiltrates on pulmonary computer tomography (CAT) scan. In univariate analysis, previous development of neutrophilic reversible allograft dysfunction (NRAD, P=0.012) and a restrictive pulmonary function (P=0.0024) were associated with a worse survival, whereas there was a strong trend for early development of CLAD and persistent parenchymal infiltrates on CAT scan (P=0.067 and 0.056, respectively). In multivariate analysis, early development of CLAD (P=0.0067), previous development of NRAD (P=0.0016), and a restrictive pulmonary function pattern (P=0.0005) or persistent parenchymal infiltrates on CAT scan (P=0.0043) remained significant. Although most CLAD patients develop an obstructive pulmonary function, 28% develop a restrictive pulmonary function, compatible with the recently defined restrictive allograft syndrome phenotype. Early-onset CLAD, previous development of NRAD, and the development of restrictive allograft syndrome are associated with worse survival after CLAD has been diagnosed.

Thin-section Computed Tomography findings before and after azithromycin treatment of neutrophilic reversible lung allograft dysfunction

ObjectivesRecently a novel subgroup of bronchiolitis obliterans syndrome (BOS) has been described in patients after lung transplantation with high neutrophil counts in broncho-alveolar lavage and recovery of lung functional decline with azithromycin treatment. We aimed to describe the thin-section computed tomography (CT) findings of these neutrophilic reversible allograft dysfunction (NRAD) patients before and after azithromycin.MethodsA cohort of 100 lung transplant recipients with BOS were treated with azithromycin and underwent lung function testing, broncho-alveolar lavage and CT before azithromycin treatment and during follow-up. The 200 CT data sets were scored for bronchial dilatation, mucus plugging, centrilobular abnormalities, airway wall thickening, consolidation, ground glass and end-expiratory air trapping.ResultsNRAD was characterized by more centrilobular abnormalities on CT (p = 0.03 for prevalence and p = 0.06 for severity) compared to non-responders. At follow-up NRAD patients showed improvement in all CT abnormalities including air trapping, but the degree of improvement in all CT abnormalities was significantly different between responders and non-responders (who showed progression of bronchus dilatation, consolidation and air trapping).ConclusionsWithin BOS patients those with NRAD differ from azithromycin non-responders by more centrilobular abnormalities on CT before azithromycin and improvement in bronchus dilatation, consolidation and air trapping during treatment.

Heterogeneity of chronic lung allograft dysfunction: Insights from protein expression in broncho alveolar lavage

Chronic lung allograft dysfunction (CLAD) remains a major risk factor for death after lung transplantation. Previous data suggested that within CLAD at least 2 phenotypes are present: a neutrophilic type (nCLAD or neutrophilic reversible allograft dysfunction [NRAD]), reversible with azithromycin therapy, vs a low neutrophilic type, non-responsive to azithromycin (fibrotic bronchiolitis obliterans syndrome [fBOS]). We aimed to further characterize this dichotomy by measuring multiple proteins in the bronchoalveolar lavage (BAL) fluid of 28 lung recipients. Patients were retrospectively subdivided by the absence or presence of CLAD and subsequently by their response to azithromycin, resulting in 3 groups: 10 stable, 9 responsive (nCLAD/NRAD), and 9 non-responsive (fBOS). Enzyme-linked immunosorbent assay was used to measure 32 different proteins. Protein variations were predominantly present in the nCLAD/NRAD group, whereas no differences were observed in the fBOS group compared with control. MCP-1 (p < 0.01), RANTES (p < 0.05), IL-1β (p < 0.01), IL-8 (p < 0.01), TIMP-1 (p < 0.01), MMP-8 (p < 0.01), MMP-9 (p < 0.01), HGF (p < 0.001), MPO (p < 0.01), and bile acid (p < 0.05) concentrations were upregulated in nCLAD/NRAD compared with fBOS, whereas PDGF-AA (p < 0.05) was downregulated. These data provide further evidence that within CLAD there is a heterogeneity of phenotypes with different mechanisms involved. Further investigation is warranted to unravel the pathophysiology of both phenotypes.

Lung allograft rejection: diagnosis and management

Rejection remains a common complication after lung transplantation and has adversely affected long-term outcomes. This manuscript reviews the various manifestations of rejection after lung transplantation and provides an update of recent developments. The grading scheme for lymphocytic bronchiolitis was updated in 2007, and recent studies demonstrate that this disease is an important and independent risk factor for chronic rejection. Furthermore, a role for humoral immunity has become more apparent in recent years, although this role remains enigmatic in lung transplantation. Finally, a new subtype of bronchiolitis obliterans syndrome, termed neutrophilic reversible allograft dysfunction, has been proposed based on the response to treatment with azithromycin. Acute rejection and lymphocytic bronchiolitis are major risk factors for chronic rejection, which remains the primary obstacle to better outcomes after lung transplantation.

206: A Retrospective Analysis of Long-Term Azithromycin Therapy for Bronchiolitis Obliterans Syndrome after Lung Transplantation

BOS is the most important cause of late mortality after LTx and is characterized by a neutrophilic inflammatory process leading to fibroproliferation and an irreversible decline in FEV1. The introduction of azithromycin (AZI) has challenged this definition. We previously hypothesized, opposed to the current belief, a dichotomy within BOS: Neutrophilic reversible Allograft Dysfunction (NRAD) on the one hand and fibropoliferative BOS (fBOS) on the other hand, based on the discrepancy in AZI response and observations within our center consisting of clinical, biochemical and cellular (BAL) analysis (Verleden et al AJRCCM, 2006 and Vanaudenaerde et al ERJ 2008).

The Leuven experience with a dichotomy in Bronchiolitis Obliterans Syndrome (BOS) after lung transplantation revealed by azithromycin

BOS is the most important cause of late mortality after LTx. Until 5 years ago, the prevalence was around 30% and 50%, 3 and 5 years after LTx. Introduction of azithromycin (AZI) improved the FEV1in 40% of BOS patients. AZI treatment may explain why in our center, the BOS prevalence at 3 years has decreased from 30% to 15% compared to the ISHLT registry. Opposed to the current belief about BOS, we hypothesize a dichotomy within BOS: Neutrophilic Reversible Allograft Dysfunction (NRAD) and fibropoliferative BOS (fBOS; table 1). This dichotomy is based on the discrepancy in AZI response and observations within our center consisting of clinical, biochemical and cellular (BAL) analysis.NRAD makes a re-evaluation of the BOS definition (irreversible FEV1decline, neutrophilic inflammation, fibroproliferation) indispensable. As it is reversible, NRAD should be excluded from BOS and accepted as innate (non-specific) inflammation and as an important risk factor for the development of BOS. So after exclusion of other complications such as acute rejection, infection, gastro-oesophageal reflux and after a trial with AZI, BOS will remain what it is now (the fBOS). This implements a re-evaluation of the neutrophilic inflammation, as it is a prerequisite for AZI responsiveness. BOS can then histologically be characterized as pure inactive OB, which is hardly responsive to any treatment.