Lung transplantation (LT) has gained widespread acceptance as a therapeutic option in a selected number of patients with end-stage lung disease refractory to other forms of treatment. Pulmonary Langerhans' cell histiocytosis (PLCH), an uncommon cause of infiltrative lung disease that occurs principally in young adults, is one of these diseases which have become a potential indication for LT (1). This disease of unknown origin, which develops predominantly in adult cigarettes smokers, belongs to the spectrum of Langerhans' cell histiocytosis, diseases characterized by an uncontrolled proliferation and infiltration of various organs by Langerhans' cells. In adult patients, the lung is the predominant target and is often the sole organ involved in the disease but other organs such as bone, skin, pituitary gland, and lymph nodes may also be involved. LT may be considered in a subgroup of PLCH patients who experience progressive respiratory impairment related to the extension of cystic lung destruction or to the development of severe pulmonary hypertension. To this date, several hundreds of PLCH patients have probably been transplanted worldwide, but with the exception of some postoperative cases of recurrence of the disease that have been reported postLT (2–4), little information on LT in PLCH is available. Therefore, we designed a retrospective multicenter study to obtain information on LT in PLCH patients with special emphasis on posttransplant survival and frequency of recurrence of the disease. Another aim of the study was to assess the functional characteristics of the PLCH patients considered for LT and more particularly to describe their pulmonary hemodynamic status which is believed to play a central role in end-stage disease (5, 6).
MATERIALS AND METHODS
In August 2004, a standardized questionnaire was sent to each of the 11 adult lung transplantation centers in France to collect all cases of patients with PLCH who underwent LT in our country. In all cases, a firm diagnosis of PLCH based on the results of histological examination of the lung (preoperative lung biopsy, analysis of the explanted lung) was mandatory. The questionnaire focused on several issues: smoking habit, extrathoracic involvement of Langerhans' cell histiocytosis, results of preoperative pulmonary function tests and right heart catheterization, prevalence of pulmonary hypertension, modalities of the diagnosis of PLCH, type of LT [single lung transplantation (SLT), double lung transplantation (DLT) or heart-lung transplantation (HLT)], intraoperative use of cardiopulmonary bypass, survival posttransplant, freedom from bronchiolitis obliterans syndrome (BOS), incidence of recurrence of PLCH, complications arising from the native lung in case of SLT, and incidence of malignancy.
Preoperative Pulmonary Functional Assessment
The results of Fletcher dyspnea score (7), FEV1, TLC, FVC, FEV1/FVC, carbon dioxide diffusing capacity per unit of alveolar volume (DLCO/VA), and blood gases on room air were retrieved from the questionnaires for each patient. Similarly, because right heart catheterization was routinely performed preoperatively in each participating center, the hemodynamic results of the patients were available. In all cases, right heart catheterization was performed at rest, in stable condition with patients in the supine position by means of a Swan-Ganz catheter. Oxygen was given if required in order to maintain arterial blood oxygen saturation >90% but the patients did not receive any vasodilators at the time of evaluation. Mean pulmonary artery pressure (PAPm) and right atrial pressure (RAP) were measured at end-expiration. Cardiac output and cardiac index (CI) were calculated by thermodilution. Total pulmonary vascular resistance index (iTPVR) was calculated as iTPVR=PAPm/CI×80 (dynes/sec/cm−5/m2). Pulmonary hypertension was defined as a PAPm above 25 mm Hg at rest and classified as mild (PAPm between 26 and 35 mm Hg), moderate (PAPm between 36 and 45 mm Hg) or severe (PAPm>45 mm Hg) (8).
Recurrence of PLCH posttransplant was defined by either the histological evidence of PLCH lesions, or the progressive development within the graft of nodules and/or cysts on CT scan associated with the absence of documented infection or neoplasm.
Descriptive statistics were used to analyze the patient chararacteristics. Normally distributed continuous data are expressed as mean ± standard deviation (SD). Medians with ranges are used when continuous data were not normally distributed. Recurrence rate of PLCH postLT and duration of follow-up in patients with and without extra-thoracic involvement were compared using Fisher exact test and student t test, respectively.
Kaplan-Meier analysis was used to assess survival and freedom from BOS in the whole group as well as in subgroups defined by the type of procedure, the presence of an extra-thoracic involvement and the development of a recurrence. Survival comparisons between subgroups were performed using the Mantel-Haenszel log-rank test.
From October 1988 to May 2003, 42 LT procedures were performed in 39 patients with end-stage PLCH at seven centers in France. Fifteen patients underwent SLT, whereas DLT and HLT were performed in 15 and 9 patients, respectively. Three patients were retransplanted at one center for bronchiolitis obliterans syndrome (BOS). In each of these cases, the redo LT procedure was a SLT (one after initial DLT and two after initial SLT).
The preoperative characteristics of the 39 patients are shown in Table 1.
Pulmonary function at the time of referral for LT is summarized in Table 2. The main disorders were obstructive pattern in 18 patients (47.5%) and combined restrictive and obstructive defects in 16 patients (42%). All the patients but one had a decreased DLCO/VA (mean value: 33% of predicted, range: 11–104). All patients presented with resting arterial oxygen desaturation on room air.
The results of right heart catheterization were available in 36 patients. Pulmonary hypertension (PAPm>25 mm Hg) was noted in 92% of them. Sixteen (44%) had severe pulmonary hypertension (Table 2). The median time interval between pulmonary hemodynamics measurement and LT was 263±230 days (range, 7–1058).
The survival of the patients after LT for PLCH is shown in Figure 1. The 1-year, 2-year, 5-year, and 10-year survival rates after LT were 76.9%, 63.6%, 57.2%, and 53.7%, respectively. No difference was found in terms of survival according to the type of LT, to the presence of an extra-thoracic involvement or to the development of a recurrence (see below).
The median duration of follow-up was 3.25 years (25th–75th percentile: 1.4–7.6 years) (186.9 patient-years). Table 3 shows the complications after LT. The early (one month) mortality was 7.7%. Three patients died during the first month, one from primary graft dysfunction, one from sepsis in relation with the dehiscence of the tracheal anastomosis and one from invasive aspergillosis. Among the patients surviving at one month, 50% experienced at least one episode of acute rejection. The mean number of acute rejection episodes per patient was 1.9±1.3 (range, 1–4). Bronchiolitis obliterans syndrome was diagnosed in 13.5% of the patients at one year, 21.3% at 2 years, 37% at 5 years and 83.5% at ten years. The cumulative incidence of BOS curve is shown in Figure 2. We failed to detect a relationship between freedom from BOS and both recurrence (see below) and extrathoracic involvement.
We observed two cases of malignant neoplasm after LT (5.3%). The first patient, a 32-year-old woman, developed an adenocarcinoma in the native lung after SLT. She died 6 months after the diagnosis despite chemotherapy. This patient had resumed smoking after LT. The second patient, a 36-year-old man, presented with a cutaneous carcinoma which was surgically resected. He is still alive thirteen years after LT.
In three SLT recipients, complications arose from the native lung. One patient developed lung carcinoma, one had two episodes of pneumothorax, and the last one developed aspergilloma.
Recurrence of PLCH within the transplant was observed in 8 patients (20.5%). The main characteristics of these patients are shown in Table 4. Three of them had resumed smoking after LT. Among the eight cases of recurrences, five were histologically proven (four by transbronchial biopsies and one by surgical lung biopsy). In the other patients, diagnosis of recurrence was based on the results of CT scan which identified the recent development of nodules (n=2) or cysts (n=1). The recurrence rate was significantly higher in patients with extra-pulmonary involvement (5/12, 41.7%) than in those without extrapulmonary involvement (3/27, 11.1%) (P=0.03), both groups having a similar duration of follow-up (P=0.7).
PLCH is an infiltrative lung disease of unknown pathophysiology, belonging to the spectrum of Langerhans' cell histiocytosis, diseases characterized by an uncontrolled infiltration and proliferation of various organs by Langerhans' cell (9). The disease develops in young adults and is strongly associated with smoking. In those who develop a severe pulmonary impairment, LT offers a potential therapeutic option. Many transplant centers have transplanted at least one patient with PLCH but LT has not been fully evaluated in this setting. The main results of our study which represents the first series assessing the results of LT for PLCH are the following: 1) preoperatively, the majority of patients present with moderate-to-severe pulmonary hypertension; 2) posttransplant survival is good; and 3) recurrence of PLCH may be observed in a fifth of the patients.
Our study gave us the opportunity to assess the clinical and functional characteristics of the PLCH patients at the end-stage of their disease. Before LT, all but one patient had a smoking history which is in keeping with what is already known on PLCH (9, 10). There were almost 5 times as many males in the group as females. The reported sex ratio has varied considerably in the different studies (10). Earlier studies have reported a clear male predominance while more recent ones have found a nearly equal male to female ratio. These variations may reflect smoking habits in the patients studied. Extrapulmonary involvement was present in 31% of cases, the main manifestations being diabetes insipidus and bone involvement. Our rate of extrapulmonary involvement appears to exceed the 17% rate reported by Vassalo and colleagues (11). The fact that our series is dealing with end-stage patients could explain this discrepancy. Obviously, the search of extrapulmonary involvement was not exhaustive in each center and it could have introduced a bias in our results. In terms of pulmonary functional status, obstructive, restrictive and mixed patterns have been reported to occur (5, 9, 11). The obstructive or mixed patterns were predominantly observed in our series and here again it could reflect the very advanced stage of the patients.
Pulmonary vascular involvement related to the extension of the PLCH lesions into adjacent vascular structure has also been underlined (6, 12, 13). According to some authors, this vascular involvement is even believed to play a central role in the exercise limitation experienced by the patients (5, 6, 14). In particular, Fartoukh and colleagues from Antoine Beclere Hospital who studied 21 consecutive patients with advanced PLCH found that all patients displayed severe pulmonary hypertension and that the level of pulmonary artery pressure was not related to the pulmonary function parameters (6). Our data are not in complete agreement with this study since severe PAPm (>35 mmHg) was observed in 72.5% of our PLCH patients. The fact that the Antoine Beclere Center is specialized in pulmonary hypertension could explain the discrepancy with our results. Whatever the prevalence of severe pulmonary hypertension may be, its presence in PLCH patients could be a risk factor for mortality after LT by analogy with what has been shown for primary pulmonary hypertension in the registry of the International Society for Heart and Lung Transplantation (1, 15).
The selection criteria for LT in the different centers have not specifically been studied but from Table 2, it is clear that the PLCH were not always transplanted on the basis of spirometric parameters. Almost all patients had a high degree of dyspnea which was probably related to several isolated or combined factors such as hypoxemia, pulmonary hypertension, and severe airway obstruction.
Concerning the survival of our PLCH patients, it was close to what is described in the ISHLT Registry over a similar transplant period, regardless of pretransplantation diagnosis (15). Posttransplant survival of PLCH patients was even quite similar to the survival rate for COPD and cystic fibrosis, indications that yield the best survival results after LT. Thus, our data strongly support the general impression that end-stage PLCH is a good indication of LT. Obviously, it would have been better to compare within the same seven centers the survival of our patients to that of the patients with more common indications, after adjustment on confounding variables. Unfortunately we are unable to perform this comparison since the questionnaires we sent to the seven centers focused only on the PLCH patients.
The potential recurrence of initial disease after LT has already been described for several types of end-stage lung diseases and it was also the case for PLCH. The reports on recurrence of PLCH after LT have been few (2–4), limited to several cases and the incidence of recurrence is therefore unknown. Etienne and colleagues (2) reported two cases of recurrence several months posttransplant among seven PLCH patients receiving LT. These two cases are included in the present study. In both cases, recurrence was observed after the patient had resumed smoking. Two other authors reported cases of recurrence of PLCH several years posttransplant but in those cases recurrence was not apparently related to resumption of smoking (3, 4). We found that the recurrence rate of PLCH was approximately 20% but this figure could have been higher if all the patients had survived LT and if a longer follow-up had been available. If we restrict the diagnosis of recurrence to the 5/8 patients with histological confirmation, the recurrence rate would be 12.8%. The other findings of our study are the fact that most often recurrence was not related to a resumption of smoking and that recurrence was associated with a preoperative extra-respiratory involvement.
Although we did not specifically compare PLCH patients to the general transplant population, the incidence of the usual posttransplant complications (Table 3) did not seem to be remarkable. In particular, given the uncertainties about the pathogenesis of PLCH, we aimed to verify that LT for PLCH was not associated with an increased incidence of BOS or acute rejection. Our data showing an incidence of BOS or acute rejection within the range of what is already known after LT in other indications, indicate that PLCH patients do not seem to be particularly prone to the development of these complications. Moreover, the presence of an extra-thoracic involvement, the development of a recurrence or the type of transplantation did not seem to influence the occurrence of BOS.
The potential development of a carcinoma is a well known complication after LT as well as after other forms of solid organ transplantation (16). Moreover, adult patients with PLCH seem to be at increased risk of developing malignant neoplasms (11). The incidence of carcinoma was low in our series (2/39 patients). Our data therefore suggest that LT for PLCH does not carry a special risk of developing neoplasms.
SLT, DLT and HLT have each been performed in our PLCH patients and we failed to demonstrate the superiority of one procedure over the others in terms of survival or incidence of BOS. Moreover, the incidence of complications arising from the native lung in case of SLT was low. We are thus unable to recommend any procedure of choice in these patients.
In summary, our data confirm that in end-stage PLCH patients considered for LT, severe pulmonary hypertension is frequently present suggesting that in this setting involvement of the pulmonary vasculature is an important contributor to the pulmonary disability. Despite a recurrence rate of the disease of approximately 20% after LT, the good postransplant survival results confirm that LT is a therapeutic option for end stage PLCH patients.
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