Cumulative radiation dose after lung transplantation in patients with cystic fibrosis.

PURPOSE: The purpose of this study was first to evaluate the imaging-related cumulative post-transplantation radiation dose in cystic fibrosis (CF) lung transplantation (LT) recipients and second, to identify the occurrence and type of malignancies observed after LT. MATERIALS AND METHODS: A total of 52 patients with CF who underwent LT at our institution between January 2001 and December 2006 with at least 3 years of survival were retrospectively included. There were 27 men and 25 women with a mean age of 24.4±9.2 (SD) years (range: 7.6-52.9 years) at the time of LT. Calculation of cumulative effective and organ doses after LT were based on dosimetry information and acquisition parameters of each examination. Cumulative radiation doses were calculated until June 2016, but stopped at the time of de novomalignancy diagnosis, for patients developing the condition. RESULTS: Patients received a mean cumulative effective dose of 110.0±51.6 (SD) mSv (range: 13-261.3 mSv) over a mean follow-up of 8.1±3.6 (SD) years (range: 0.5-13.5 years), with more than 100mSv in 5 years in 19/52 patients (37%). Chest CT accounted for 73% of the cumulative effective dose. Mean doses to the lung, breast and thyroid were 152.8±61.1 (SD) mGy (range: 21.2-331.6 mGy), 106.5±43.2 (SD) mGy (range: 11.9-221.4 mGy) and 72.7±31.8 (SD) mGy (range: 9.5-165.0 mGy), respectively. Nine out of 52 patients (17%) developed a total of 10 de novo malignancies, all but one attributable to immunosuppression after a mean post-transplantation follow-up period of 11.1±3.5 (SD) years (range: 3.7-16.3 years). Six-month cumulative effective dose was not greater in patients with de novomalignancies than in those without de novomalignancies (28.9±14.5 (SD) mGy (range: 13.0-53.4) vs 25.6±15.3 (range: 5.0-69.7), respectively, P>0.05). CONCLUSION: The cumulative effective dose exceeded 100 mSv in 5 years in 37% of LT recipients, the reason why continuous efforts should be made to optimize chest CT acquisitions accounting for 73% of the radiation dose.

Factors associated with humoral immune response to pandemic A/H1N1(v) 2009 influenza vaccine in cystic fibrosis.

Influenza vaccination is recommended in cystic fibrosis patients. The objective of this study was to assess the immunogenicity of vaccination against 2009 pandemic A/H1N1 influenza and to study the factors associated with the immune response in patients with cystic fibrosis. 122 patients with cystic fibrosis were enrolled in a prospective study and received 1 dose of 2009/H1N1v adjuvanted vaccine, or for children <2 years and lung-transplanted patients, two doses of non-adjuvanted 2009/H1N1v vaccine administered 21 days apart. Hemagglutination inhibition antibodies were assessed before and 21 days after vaccination and at least 6 months after vaccination. After vaccination, 85% of the patients had an influenza antibody titer ≥1:40 and 69% seroconverted. 13% of the transplanted patients seroconverted compared with 72% of the non-transplanted patients. In this latter group, non-adjuvanted vaccine and low body mass index were independently associated with lower response to vaccination. 86% of the non-transplanted patients with normal BMI and receiving adjuvanted vaccine seroconverted. Persistence of seroprotection 10 months after vaccination was found in 50% of the patients. In patients with cystic fibrosis, malnutrition and receipt of non-adjuvanted vaccine were associated with lower immune response to pandemic influenza vaccination. Our data also suggest a potential defect in the immune response to influenza vaccination of patients with cystic fibrosis and raise the question of whether a different immunization strategy is needed.

[Pediatric lung transplantation in Broussais-HEGP: a 23-year experience (1990-2013)]. / Transplantation pulmonaire pédiatrique : expérience de l'équipe Broussais-HEGP de 1990 à 2013.

INTRODUCTION: Pediatric lung transplantations (LTx) remains a small part of LTx performed worldwide. The majority of these Tx concerns young adolescents, transplantations in infants being anecdotic. We conducted a retrospective study of LTx in children and adolescents in one center in Paris from the beginning of the 90's to 2013. METHODS: Data from Broussais then HEGP were collected retrospectively from 1990 to 2013: 380 LTx were reported in 368 patients including 111 LTx performed among children from 5 to 18 years of age (30%). RESULTS: One hundred and eleven patients received 121 LTx: 86 bilateral LTx, 13 combined lung-liver, 3 monopulmonary, 5 heart-lung and 4 combined heart-lung-liver Tx. Eighty-eight percent of the patients had cystic fibrosis. Median age was 14 years, weight 34 kg and height 144 cm. Median age of donors was 27 years, weight 60 kg and height 167 cm. Conditional survival for children was not different than adults: 72% at one year, 42% at 5 years, 37% at 10 years and 26% at 15 years. There was not overall early mortality after transplantation. Era graft survival was significantly higher after year 2000 (53% at 5 years vs 32% P=0.03). CONCLUSION: Lung transplantation among children under 18 years have similar outcome to those of adult patients.

Sublingual tacrolimus as an alternative to intravenous route in patients with thoracic transplant: a retrospective study.

Tacrolimus (TRL) is an immunosuppressive drug characterized by a narrow therapeutic index, low bioavailability, and pharmacokinetic variability. Intravenous (i.v.) TRL may be needed whenever the oral route is unavailable. The small amount of infusion formulation (5 mg/mL) results in a large dilution and need for careful technical management of the infusion. This study addressed the feasibility to provide sublingual (SL) as an alternative to i.v.. TRL for transplanted patients. In a substudy, we performed a retrospective analysis of 17 lung and heart transplant patients using SL TRL. It included therapeutic drug monitoring and 4 area under curve (AUC) measurements. Patients received SL TRL on a dose-to-dose basis from the oral formulation. The mean age of the subjects (14 male, 3 female) was 35.3 ± 15.6 years; 146 trough (C(0)) samples were collected during the SL period (15.8 ± 20.6 days) showing a conformity level of 90.4%. Mean dose, C(0), and AUC of SL tacrolimus were 0.116 ± 0.096 mg/kg, 12.9 ± 5 ng/mL, and 230 ± 74 ng·h/mL, respectively, with an average 1 hour time to peak concentration. Acute rejection episodes, renal toxicity, and drug interactions were not observed. This study supported the convenience of short-term SL TRL administration, even in unconscious patients. Further investigations are needed to validate the dose range of the SL route.

Clinical outcomes of lung-transplant recipients treated by voriconazole and caspofungin combination in aspergillosis.

BACKGROUND AND OBJECTIVE: Invasive pulmonary aspergillosis (IPA) is a serious cause of death among immune-compromised patients such as organ-transplant recipients. Recently, voriconazole has been approved for first-line therapy in IPA. Theoretically, optimal voriconazole blood level (superior to 1 mg/L according to recent studies) should be reached within 24 h. In practice, a significantly longer time seems to be needed in lung-transplant recipients. Therefore, caspofungin is now used in combination with voriconazole to provide cover against Aspergillus spp. infection during this gap. The first aim of this study was to investigate Aspergillus spp. infection treated with this combination and the atter's tolerability. The median time for attainment of apparently active blood levels in lung transplant recipients were compared between those with cystic fibrosis and those without. METHODS: Lung-transplant recipients who received a combination of voriconazole and caspofungin between 2002 and 2008 as primary therapy were identified retrospectively. The median number of days to reach active voriconazole blood levels was compared between cystic fibrosis and other patients by Student's t-test. Statistical significance was defined by P-value <0.05. RESULTS: Four patients were treated for Aspergillus colonization before transplantation and their culture were negative at 90 days. Eleven patients were treated for proven or probable invasive aspergillosis and 14 of them had a complete response. Hallucinations (n = 2) and significant hepatic toxicity (n = 2) were reported. Among the 15 studied transplant recipients, a median of 12.3 days was observed for active voriconazole blood levels to be reached. With cystic fibrosis patients, time tended to be longer than with other recipients (14.9 days vs. 8.3 days). Tacrolimus blood levels (between 5 and 15 ng/mL) may have been increased by voriconazole. CONCLUSION: This retrospective study describes practical experience in the management of this rare and severe disease in a referral centre for cystic fibrosis lung transplantation. Voriconazole and caspofungin combination was acceptably safe and was associated with good clinical outcomes in almost all patients. We showed that in 15 lung-transplant recipients a median of 12.3 days was required for voriconazole to reach high enough blood levels. Caspofungin in combination with voriconazole provides cover against Aspergillus infection during the period when voriconazole may be at subtherapeutic levels with good tolerability.

Valganciclovir prophylaxis for cytomegalovirus infection in thoracic transplant patients: retrospective study of efficacy, safety, and drug exposure.

Oral ganciclovir (GCV) was replaced by prodrug valganciclovir (vGCV) for cytomegalovirus (CMV) prophylaxis. We assessed retrospectively (2005-2007) vGCV effectiveness and safety during prophylaxis and 4 months after, in heart (HTx) and lung transplantation (LTx), including lung transplant for cystic fibrosis (CFTx). Patients with stable renal function received vGCV 900 mg daily during 3-6 and 8-12 months in HTx and LTx. Effectiveness was assessed by antigenemia (pp65Ag) and a GCV therapeutic drug monitoring to document exposure. A total of 32 patients (11 HTx, 7 LTx, and 14 CFTx) received vGCV for 106+/-67 days in HTx versus 270+/-85 days in LTx and CFTx. Doses were 700+/-225, 915+/-60, and 820+/-150 mg/24 h in HTx, LTx, and CFTx showing acceptable mean trough GCV 0.75+/-0.5 mg/L. Two of 9 cases of neutropenia were attributable to vGCV. Three CMV donor-positive/recipient-negative CFTx patients presented positive pp65Ag; 2 developed CMV disease (6%). We found that vGCV 900 mg, adapted to renal function, was effective and safe for long CMV prophylaxis together with efficient exposure in thoracic transplantation.

[Early postoperative management and immunosuppressive treatment following lung transplantation]. / Prise en charge postopératoire précoce et traitement immunosuppresseur dans la greffe pulmonaire.

Lung transplantation is now considered a valid option in the management of end-stage respiratory failure. The postoperative period remains a key stage that will influence the average long-term prognosis of the patients. Primary graft failure, postoperative bleeding, infection, acute rejection and complications linked to the surgery, and to vascular or bronchial anastomoses, are risk factors for mortality and morbidity. These must be taken care of quickly via collaboration with the surgical team. The immunosuppressive treatment essential for tolerance induction with regard to the transplanted organ will be introduced during the intraoperative period and continued for life. The combination of a calcineurin inhibitor, an antiproliferative agent and corticosteroids remains the conventional procedure. The role of new molecules as mTor inhibitors remains to be determined.

Voriconazole pharmacokinetic variability in cystic fibrosis lung transplant patients.

BACKGROUND: Aspergillosis is a high-risk complication in cystic fibrosis (CF) lung transplant patients. Azole antifungal drugs inhibit CYP3A4, resulting in significant metabolic drug-drug interactions. Voriconazole (VRZ) was marketed without therapeutic drug monitoring (TDM) recommendations, consistent with favorable pharmacokinetics, but regular determinations of plasma VRZ concentration were introduced in our center to manage interactions with calcineurin inhibitors and to document the achievement of therapeutic levels. METHODS: VRZ TDM data analysis for trough concentration (C0) and peak concentration (C2) was carried out, using validated liquid chromatography assay with ultraviolet detection, for 35 CF lung transplant patients (mean age 25 years, mean weight 47 kg, balanced sex ratio) since 2003. Therapeutic range (C0: 1.5 +/- 0.5 - C2 : 4.0 +/- 1.0 mg/L) was expressed relative to pivotal pharmacokinetic trial data. RESULTS: The duration of VRZ treatment ranged from 9 days to 22 months. The recommended standard dose of VRZ (200 mg twice a day, following the loading dose) resulted in significant plasma concentrations (>0.5 mg/L) in 20% of CF lung transplant patients. Therapeutic concentrations were obtained using higher doses (average 570 +/- 160 mg/day, +43%, P<0.01). Despite adaptation, C0 remained <0.5 mg/L (11%), even when the drug was administered intravenously, highlighting the variability of VRZ pharmacokinetics, possibly enhanced by CYP2C19 polymorphism. The risk of inefficacy during periods of underdosage was overcome by treatment with antifungal drug combinations (caspofungin, n=10). The therapeutic index was limited by neurologic effects (14%) and hepatic abnormalities (30%). VRZ concentrations correlated significantly (P<0.01) with aspartate aminotransferase levels but not with bilirubin levels. VRZ acted as a metabolic inhibitor of tacrolimus (C0 to dose ratio 5.8 +/- 2.6, n=31/VRZ versus 1.7 +/- 0.9 alone, P<0.001). Large changes in azole concentration affected the magnitude of the drug-drug interactions and adjustment requirements. CONCLUSIONS: TDM is required because VRZ levels are often undetectable in treated CF lung transplant patients, supporting the use of antifungal drug combinations until achievement of VRZ C0 at a steady state between 1 and 2 mg/L. Plasma VRZ concentrations should be determined for the quantitative, individualized management of drug-drug interactions in lung transplant patients, in particular immunosuppressant such as tacrolimus, considering VRZ to be both a target and an inhibitor of CYP3A4.

Single-lung transplantation for cystic fibrosis and metachronus pneumonectomy: case reports.

Three patients with end-stage cystic fibrosis (CF) underwent single lung transplantation (SLT) with contralateral pneumonectomy. In the first case, contralateral pneumonectomy (CP) was performed before SLT. The patient is alive with no signs of infection or rejection. For the other 2 cases, CP was performed after SLT. One patient died 8 months later with septicemia; the other patient died after 10 days because of complicated bronchopleural fistula and infection of the pneumonectomy space. SLT can be a good option for some patients with CF. The outcome is good when CP is done before SLT. However, CP must be done simultaneously with SLTX.

Clinical outcome following lung transplantation in patients with cystic fibrosis colonised with Burkholderia cepacia complex: results from two French centres.

BACKGROUND: Infection with Burkholderia cepacia complex (BCC) is a life threatening complication of cystic fibrosis (CF), often seen as a contraindication for lung transplantation. METHODS: A long term retrospective study was conducted of all patients with CF undergoing lung transplants from January 1990 to October 2006 in two French centres allowing transplantation in patients colonised with BCC. RESULTS: 22 of the 247 lung transplant patients with CF were infected with BCC (B. cenocepacia genomovar III (n = 8), B. multivorans genomovar II (n = 11), B. vietnamiensis genomovar V (n = 2) and B. stabilis genomovar IV (n = 1)). BCC colonisation was not associated with any significant excess mortality (HR 1.5, 95% CI 0.7 to 3.2; p = 0.58). However, early mortality rates tended to be higher in the BCC group than in the non-BCC group (3 month survival: 85% vs 95%, respectively; log rank p = 0.05). Univariate analysis showed that the risk of death was significantly higher for the eight patients infected with B. cenocepacia than for the other 14 colonised patients (HR 3.2, 95% CI 1.1 to 5.9; p = 0.04). None of the other risk factors tested-primary graft failure, late extubation, septicaemia-had a significant effect. The 5 year cumulative incidence rate of bronchiolitis obliterans syndrome was not significantly higher in the BCC group than in the non-BCC group (38% vs 24%, respectively; p = 0.35). CONCLUSION: Our results suggest that BCC infection with a non-genomovar III organism may not be associated with excess mortality after lung transplantation in patients with CF and should not be seen as sufficient reason to exclude lung transplantation. However, colonisation with B. cenocepacia remains potentially detrimental.

Neuromuscular painful disorders: a rare side effect of voriconazole in lung transplant patients under tacrolimus.

Voriconazole is an anti-fungal agent active against Aspergillus infection that is used for prophylaxis and curative treatment in lung transplant patients. We present nine cases of painful neuromuscular disorders, an unusual and rare side effect of high-dose voriconazole in association with tacrolimus.

[Moderately abundant hemoptysis revealing endobronchial hamartochondroma]. / Une hémoptysie de moyenne abondance révélant un hamartochondrome endobronchique.

Hemoptysis is rarely the inaugural sign of endobronchial hamartoma. Abundance may range from moderate to massive, and may be life-threatening. We report the case of a 44-year-old woman who was referred to our center with moderate and persistent hemoptysis. A left upper lobe lobectomy was performed. We discuss the therapeutic options in such cases.

[Bronchopulmonary disease in drug abusers]. / La pathologie bronchopulmonaire des toxicomanes.

Drug abuse is a growing problem in industrialized countries, opening the way to new diseases of the respiratory tract. It has been demonstrated that regular inhalation of cannabis has the same consequences as tobacco smoking. The same cannot be said for other drugs. Cocaine, amphetamines or crack expose the patient to particular toxic effects: in addition to barotrauma related to the administration route, syndromes of acute respiratory distress have been described. These result either from bronchial reactions, asthma exacerbation or eosinophil bronchopneumonia, or alveolar involvement: intra-alveolar bleeding, pulmonary edema or organized pneumonia. Respiratory complications induced by opiates, often used in injections, are related to central alveolar hypoventilation and/or the development of injury from pulmonary edema or pneumonia. The pathophysiology of these lesions is not perfectly understood. Besides these specific conditions, infection is a major problem in drug abusers, irrespective of the drug: bacterial pneumonia, tuberculosis, HIV infection are much more frequent in this high-risk group. Finally repeated intravenous injections of various drugs designed for oral intake can lead to severe complications such as pulmonary hypertension or toxic interstitial lung disease. Summarizing, respiratory diseases in drug abuses can take on a wide range of quite complex presentations. Occasional or regular use of illicit drugs can lead, not exceptionally, to severe respiratory complications requiring rapid management. Knowledge of the principal complications and the appropriate diagnostic procedures is indispensable.

Spectrum of CD4 to CD8 T-cell ratios in lymphocytic alveolitis associated with methotrexate-induced pneumonitis.

The present study was conducted to confirm the presence of severe lymphocytic alveolitis and to determine the factors responsible for the very different alveolar CD4 to CD8 T-cell ratios (CD4/ CD8) described in methotrexate-induced pneumonitis (MTX-pneumonitis). Clinical and radiologic findings, as well as bronchoalveolar lavage (BAL) data, including CD4 and CD8 subset analysis, were retrospectively reviewed for patients hospitalized between 1985 and 2000 for MTX-pneumonitis. BAL cell counts from patients with MTX-pneumonitis (cases) were compared with those from patients receiving MTX but who did not have evidence of MTX toxicity (MTX-exposed patients) and those from healthy subjects (control subjects). Nineteen BAL were performed in 14 consecutive cases of MTX-pneumonitis. MTX was given for various underlying diseases. All cases presented a subacute diffuse interstitial pneumonitis that recovered, with MTX discontinuation and/or initiation of adjunctive steroid therapy. At the time of diagnosis, BAL cell counts in MTX-pneumonitis indicated severe lymphocytic alveolitis when compared with MTX-exposed patients and control subjects and moderate neutrophil alveolitis compared with control subjects. The lymphocytic alveolitis resulted from an increase in both CD4 and CD8 lymphocyte cell counts. Nevertheless, alveolar CD4/ CD8 T-cell ratios ranged from 0.4 to 9.6. CD4/CD8 values correlated positively with lymphocyte counts but negatively with time elapsed between last MTX administration and BAL and with steroid cumulative dose received by the patients. Severe lymphocytic alveolitis was confirmed in our series of MTX-pneumonitis. The between-patient variation in CD4/CD8 T-cell ratios may reflect the large range of time intervals between last MTX administration and BAL evaluation and the use of adjunctive steroid therapy.

In situ expression of B7 and CD40 costimulatory molecules by normal human lung macrophages and epithelioid cells in tuberculoid granulomas.

Normal alveolar macrophages (AM) are not efficient in inducing the proliferation of resting T lymphocytes, and, rather, tend to inhibit pulmonary immune responses. In contrast, epithelioid cells (EC), activated macrophages that play an essential role in the course of granulomatous responses, appear to stimulate T cell proliferation efficiently. The inability of macrophages to deliver potent costimulatory signals through the B7/CD28 and CD40/CD40L pathways could explain their weak accessory cell activity. Using MoAbs and immunohistochemical techniques, however, we found that essentially all AM in normal human lung tissue expressed B7-1, B7-2 and CD40 molecules, and most of these cells were strongly positive. Pulmonary macrophages in other compartments also expressed these costimulatory molecules; no differences in expression were observed comparing macrophages from smokers and non-smokers. Most AM recovered by bronchoalveolar lavage from normal lung segments also strongly expressed B7-1, B7-2 and CD40 molecules. In comparison, resting blood monocytes were B7-1- and only moderately positive for B7-2. Activation of monocytes with lipopolysaccharide (LPS) induced expression of these costimulatory molecules to levels similar to that of AM from the control subjects. EC in granulomatous lesions also expressed easily detectable levels of B7-1, B7-2 and CD40. T lymphocytes within and surrounding the granulomas expressed CD28, the counter-receptor for B7, and many of these T cells also expressed B7-1 and B7-2. These findings suggest that both AM and EC can deliver costimulatory signals through B7-1, B7-2 and CD40 molecules, and indicate that the impairment in accessory cell activity observed for normal AM cannot be attributed to the absence of expression of these costimulatory molecules.

Expression of three members of the TNF-R family of receptors (4-1BB, lymphotoxin-beta receptor, and Fas) in human lung.

Receptors belonging to the tumour necrosis factor receptor (TNF-R) superfamily are implicated in a variety of important biological processes. Although messenger ribonucleic acid coding for many of these receptors has been detected in lung, little is known about their expression in this organ. In this study, immunohistochemical techniques were used to evaluate the expression of three receptors of this family (4-1BB, lymphotoxin-beta receptor (LTbeta-R), and Fas) in normal human lung, lung carcinomas and by tuberculous and sarcoid granulomas. The 4-1BB receptor was uniformly expressed by endothelial cells of small vessels and by basal epithelial cells within pseudostratified bronchial epithelium. LTbeta-R expression by parenchymal cells was limited to those of epithelial origin (bronchial and bronchiolar epithelium, hyperplastic alveolar epithelium and lung carcinomas). Fas was present on both fibroblasts and epithelial cells (bronchial and alveolar epithelium and most, but not all, carcinomas), but not on endothelial cells. A subpopulation of T-lymphocytes expressed these receptors, but only Fas was detected on normal alveolar macrophages and epithelioid cells. Thus, 4-1BB, LTbeta-R, and Fas have characteristic and only partially overlapping patterns of expression in the lung. The findings should facilitate further evaluation of their role in lung homeostasis and pathology.