Olivier Brugière

Survival benefit of lung transplantation for patients with idiopathic pulmonary fibrosis

OBJECTIVE Although lung transplantation is viewed as an acceptable option for patients with end-stage idiopathic pulmonary fibrosis, the survival benefit of this approach is still debated. This study examined whether there was a survival benefit of lung transplantation in a cohort of patients referred to our transplant center with a diagnosis of idiopathic pulmonary fibrosis according to American Thoracic Society criteria. METHODS Forty-six patients accepted for lung transplantation during a 12-year period with a diagnosis of idiopathic pulmonary fibrosis form the basis of this study. Survival benefit offered by lung transplantation was assessed using Cox proportional-hazards modeling, with patients on a waiting list as the control group. RESULTS Twenty-eight patients underwent lung transplantation (27 single and 1 double), 16 patients died while waiting, and 2 patients remained on the active waiting list. Diagnosis of idiopathic pulmonary fibrosis was made on histologic examination of the explanted lung or lung biopsy before lung transplantation. There was a pattern of usual interstitial pneumonia in 31 cases (67%). The 15 remaining patients fulfilled all American Thoracic Society criteria for idiopathic pulmonary fibrosis. The median waiting time for organs was 51 days. Survival after lung transplantation was 79.4% at 1 year, 63.5% at 2 years, and 39% at 5 years. The multivariable analysis showed that lung transplantation reduced the risk of death by 75% (95% confidence interval, 8%-86%; P =.03) after adjustment on potential confounding variables. CONCLUSIONS Lung transplantation is effective in improving the survival of selected patients affected by idiopathic pulmonary fibrosis.

Survival Benefit of Lung Transplant for Cystic Fibrosis since Lung Allocation Score Implementation

RATIONALE The survival benefit of lung transplantation (LT) in adult patients with cystic fibrosis (CF) is debated. OBJECTIVES We sought to assess the survival benefit of LT in adult patients with CF. METHODS We used data from the United Network for Organ Sharing Registry to identify adult patients with CF on a wait list for LT in the United States between 2005 and 2009. Survival times while on the wait list and after LT were modeled by use of a Cox model that incorporated transplantation status as a time-dependent covariate. Evolution in lung allocation score (LAS) while on the wait list was used as a surrogate for disease severity. We fitted a model for the joint distribution of survival and longitudinal disease process (LAS over time). MEASUREMENTS AND MAIN RESULTS A total of 704 adult patients with CF were registered on a wait list during the study period. The cumulative incidence of LT was 39.3% (95% confidence interval, 35.6-42.9%) at 3 months and 64.7% (61.0-68.4%) at 12 months, whereas the incidence of death while on the wait list at the same times was 8.5% (6.4-10.6%) and 12.9% (10.3-15.5%), respectively. Survival after LT was 96.5% (94.7-98.2%) at 3 months; 88.4% (85.1-91.8%) at 12 months; and 67.8% (59.9-76.8%) at 3 years. LT conferred a 69% reduction in the instantaneous risk of death (51-80%). The interaction between LAS and LT was significant: the higher the LAS, the greater the survival benefit of LT (P < 0.001). CONCLUSIONS LT confers a survival benefit for adult patients with CF.

Preventive effect of inhaled nitric oxide and pentoxifylline on ischemia/reperfusion injury after lung transplantation.

Background. The preventive effect of inhaled nitric oxide (NO) and pentoxifylline (PTX) administered during reperfusion has been demonstrated on experimental models of lung ischemia/reperfusion (I/R) injury but this strategy is not validated in clinical lung transplantation. The aim of this study was to assess retrospectively the protective effect of inhaled NO and PTX after lung transplantation. Methods. Twenty-three consecutive patients who received inhaled NO (10 ppm) and PTX (NO-PTX group) at the time of reperfusion were compared retrospectively with (1) 23 consecutive patients transplanted just before the use of NO-PTX (control group 23); (2) 95 patients representing all the patients of the series who did not receive NO-PTX (control group 95), with respect to I/R injury related complications. In particular, the incidence of pulmonary reimplantation edema and early hemodynamic failure, the PaO2/FIO2 ratio as well as the duration of mechanical ventilation and the 2-month mortality rates were compared. Results. Reimplantation edema was observed in 6/23 patients (26%) in the NO-PTX group vs. 13/23 patients (56%) in the control group 23 (P =0.035) and 48/95 patients (50%) in the control group 95 (P =0.035). The worst PaO2/FIO2 ratio during the first three postoperative days was 240±102 mmHg in the NO-PTX group vs. 162±88 mmHg (P =0.01) and 176±107 mmHg (P =0.01) in the control group 23 and the control group 95, respectively. The duration of mechanical ventilation was 2.1±2.4 days in the NO-PTX group vs. 7±9 days in the control group 23 (P =0.02) and 6±7 days in the control group 95 (P =0.01). The 2-month mortality rate was 4.3% in the NO-PTX group vs. 26% (P =0.04) and 21% (P =0.07) in the control group 23 and the control group 95, respectively. Conclusions. The marked decrease in the incidence of allograft dysfunction compared with two historical control groups suggests that PTX and inhaled NO given before and throughout reperfusion are protective against I/R injury in the setting of clinical transplantation.

Immunohistochemical Study of HLA‐G Expression in Lung Transplant Recipients

Human leukocyte antigen‐G (HLA‐G), a nonclassical HLA class I protein, promotes immune tolerance of solid‐organ allografts, yet its role in lung transplantation (LTx) is unknown. We examined the expression of HLA‐G in lung allografts through immunohistochemistry by a cross‐sectional study of 64 LTx recipients, classified into four groups (stable patients, acute rejection [AR], bronchiolitis obliterans syndrome [BOS] and symptomatic viral shedders). A marked expression of HLA‐G in bronchial epithelial cells (BEC) was frequently observed in stable recipients (n = 18/35 [51%]), but not in patients with AR (n = 14) or with BOS (n = 8). HLA‐G was also expressed by 4 of 7 symptomatic viral shedders. In addition, HLA‐G‐positive patients from the stable group (n = 35) experienced lower incidence of resistant AR and/or BOS during long‐term follow‐up, as compared with their HLA‐G‐negative counterparts. Finally, in vitro data showed that interferon‐γ, a cytokine present in lung allograft microenvironment, upregulated HLA‐G mRNA and protein expression in primary cultured human BEC. We conclude that HLA‐G expression in the bronchial epithelium of lung allograft is elevated in some LTx recipients in association with their functional stability, suggesting a potential role of HLA‐G as a tolerance marker.

Exhaled NO may predict the decline in lung function in bronchiolitis obliterans syndrome

Bronchiolitis obliterans syndrome (BOS) remains the leading cause of morbidity/mortality following lung transplantation. In recipients with BOS, markers predicting the decline in lung function are needed. The aim of this longitudinal study was to determine whether exhaled nitric oxide fraction (FeNO) measurements provide useful information for discriminating patients with unstable BOS from those with stable BOS. During a 14-month period, 145 FeNO measurements were performed in 50 lung transplant recipients. Among them, 16 recipients with BOS (32 FeNO measurements) were analysed. For each FeNO measurement, the patients were classified into three groups according to the decline in forced expiratory volume in one second (FEV1) within the following 6 months: 1) stable BOS free; 2) stable BOS (decline in FEV1 of <5%); and 3) unstable BOS (decline in FEV1 of ≥15%). The mean FeNO in patients with unstable BOS was significantly increased compared with that in stable BOS-free patients (18.4±5.7 versus 9.7±3.7 ppb) and that in patients with stable BOS (18.4±5.7 versus 9.7±3.3 ppb). The present findings suggest that, in patients with bronchiolitis obliterans syndrome, a raised exhaled nitric oxide fraction may predict the development of worrisome functional impairment during long-term follow-up.

Pulmonary hypertension following hepatopulmonary syndrome in a patient with cirrhosis

We report the case of a patient with liver cirrhosis who successively developed hepatopulmonary syndrome and portopulmonary hypertension. Initially, the patient presented with severe dyspnea and hypoxemia at rest. Technetium-99 macroaggregated albumin lung perfusion scan demonstrated right-to-left shunt, and hemodynamic study revealed a hyperdynamic state with low pulmonary vascular resistance, thus confirming the diagnosis of hepatopulmonary syndrome. More than 2 years after the onset of pulmonary symptoms, a marked improvement in dyspnea and gas exchange was observed. Lung perfusion scan did not disclose any right-to-left shunt and right-sided heart catheterization showed evidence of severe pulmonary hypertension. We conclude that hepatopulmonary syndrome and portopulmonary hypertension are not mutually exclusive. We hypothesize that, by reversing the phenomenon of intrapulmonary vasodilatation, the development of portopulmonary hypertension interfered with each of the potential causes of hypoxemia in hepatopulmonary syndrome (ventilation-perfusion inequalities, intrapulmonary shunting, oxygen diffusion limitation) and, as a result, led to a correction of hypoxemia.

Lung transplantation in patients with pretransplantation donor-specific antibodies detected by Luminex assay.

Background New methods of solid-phase assays, such as Luminex assay, with high sensitivity in detecting anti–human leukocyte antigen (HLA) antibodies (Abs), have increased the proportion of sensitized candidates waiting for lung transplantation (LTx). However, how to apply these results clinically during graft allocation is debated: strict exclusion of candidates with Luminex-positive results can lead to lost opportunities for Tx. We retrospectively analyzed the clinical impact of pre-LTx Luminex-detected Abs on post-LTx outcomes for patients who underwent LTx before the availability of Luminex assay. Methods We analyzed data for 56 successive patients who underwent LTx before 2008 and were considered to not have anti-HLA Abs by then-available methods of detection at the date of their LTx. Pre-LTx sera from these patients were retested by Luminex assay. Using log-rank test, freedom from bronchiolitis obliterans syndrome (BOS) and graft survival were compared between patients with and without pre-LTx Luminex-detected anti-HLA Abs classes I and II and donor-specific Abs (DSA) classes I and II. Results Freedom from bronchiolitis obliterans syndrome was lower, and mortality was higher for patients with than those without pre-LTx Luminex-detected DSA class II (P=0.004 and P=0.007, respectively) but did not differ for patients with and without DSA class I or anti-HLA Abs class I or II. Conclusions It suggests to avoid attributing graft with forbidden antigens to sensitized candidates with Luminex-detected DSA class II and to evaluate the role of specific posttransplantation protocols for LTx candidates who require emergency LTx.

Morbidity and mortality related to the native lung in single lung transplantation for emphysema

It has been advocated that a major drawback of single lung transplantation (SLT) is the risk of serious complications arising from the native lung. The morbidity and mortality related to the native lung in 46 patients who underwent SLT for pulmonary emphysema in Clichy from 1988 to 1997 were reviewed retrospectively. In particular, infectious complications and native lung hyperinflation were searched. Complications arising from the native lung are not unusual after SLT for subjects with emphysema, and it was concluded they are not responsible for a substantial mortality.

Coccidioidomycosis in a Lung Transplant Recipient Acquired From the Donor Graft in France

Coccidioidomycosis is an endemic mycosis in the southwest of United States, and Central and South America, resulting from the inhalation of arthrospores present in desert soil (1). Reactivation of latent Coccidioides immitis infection likely represents the majority of coccidioidomycosis posttransplant cases, primarily occurring in patients who had resided in or visited these areas (2). We report here a case of coccidioidomycosis in a French lung transplant recipient who had never traveled to endemic areas and has, thus, acquired the fungus from the donor graft. The patient, a 58-year old man, underwent a single lung transplant for severe idiopathic pulmonary fibrosis in 2001. Immunosuppression included cyclosporine, azathioprine, and prednisone. Itraconazole (400 mg/day) was prescribed during the first 6 months for a bronchial colonization with Aspergillus fumigatus. Postoperative events included two acute rejection episodes, treated with methylprednisone (15 mg/kg/day for 3 days), resulting in a satisfactory graft function at 3 months. At month 11 posttransplant, itraconazole was administered again for a suspected diagnosis of invasive aspergillosis based on the presence of peripheral infiltrate on thoracic computed tomography (CT) scan. Itraconazole was stopped 1 year later with stable and minimal sequelae on CT scan. Outcome was then uneventful, until month 35 posttransplant where a graft dysfunction occurred, without any new opacity on chest CT scan. Repeated cultures of bronchial specimens remained negative for bacteria, viruses, and fungi. Despite normal transbronchial biopsies, a late acute rejection was also evoked, but a therapeutic test with high-dosage steroids resulted in no change. Because of the graft dysfunction’s persistence, a surgical repair of a documented gastroesophageal reflux was performed (month 40). Day 2 postsurgery, a routine culture of the bronchial aspiration showed surprising growth of C. immitis. The diagnosis was further confirmed at the French National Reference Center Mycology and Antifungal Agents. Thoracic CT scan did not show new opacity in the graft or any modification in the native lung. There was no other localization (normal cerebrospinal fluid and normal cerebral magnetic resonance imaging, and no skin lesions). The presence of antibodies to C. immitis was determined by immunoelectrophoresis in sequential serum samples including retrospective sera (Fig. 1). Serologic immunoelectrophoresis testing was positive with two specific arcs at the time coccidioidomycosis was diagnosed (40 months post-Tx) and was negative before Tx and at 11 months post-Tx. The serum sample obtained from the donor at the time of death showed one nonspecific arc. Itraconazole (400 mg/day) was started again, and subsequent cultures of bronchial aspiration sampled after 1 month of therapy were negative. Three years after the diagnosis, no recurrence had occurred under itraconazole (400 mg/ day), and a stabilization of the pulmonary functional status has been obtained, attributed to the surgical repair of the gastroesophageal reflux. Repeated antibody testing, every 6 months, showed persistently positiveserologywithonearc.Acquisitionof C. immitis was eventually attributed to a transmission from the donor graft to the recipient based on the following evidences: (1) the recipient has never traveled outside metropolitan France; (2) the donor had visited Arizona a few months before organ donation, and his serology at the time of death showed a nonspecific arc, which in our experience are seen early after contamination before switching to specific arcs; and (3)thesuccessiveadministrationsofitraconazole from the time immunosuppression was started till the diagnosis of coccidioidomycosis may well explain the lack of symptoms and the delayed diagnosis in the recipient. We may also hypothesize that the earlier course of presumptive aspergillosis, treated with itraconazole, may have been coccidioidomycosis. Once the diagnosis established, we inquired after the outcome of other solid-organ transplant recipients from the same donor.

Relative Impact of Human Leukocyte Antigen Mismatching and Graft Ischemic Time After Lung Transplantation

BACKGROUND Recent data strongly suggest that human leukocyte antigen (HLA) mismatching has a negative impact on development of bronchiolitis obliterans syndrome (BOS) and survival after lung transplantation (LTx). Because HLA matching is sometimes achieved by extending ischemic time in other solid-organ transplantation models and ischemic time is a risk factor per se for death after LTx, we sought to compare the theoretical benefit of HLA matching with the negative impact of lengthened ischemic time. METHODS In this collaborative study we compared the relative impact of HLA mismatching and ischemic time on BOS and survival in 182 LTx recipients. RESULTS Using multivariate analyses, we observed a lower incidence of BOS (hazard ratio [HR] = 1.70, 95% confidence interval [CI]: 1.1 to 2.7, p = 0.03) and enhanced survival (HR = 1.91, 95% CI: 1.24 to 2.92, p = 0.01) in patients with zero or one HLA-A mismatch compared with those having two HLA-A mismatches. This beneficial effect on survival was equivalent to a reduction of ischemic time of 168 minutes. CONCLUSIONS We observed a reduced incidence of BOS and a better survival rate in patients well-matched at the HLA-A locus, associated with an opposite effect of an enhanced ischemic time. This suggests that graft ischemic time should be taken into account in future studies of prospective HLA matching in LTx.