[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.

Very late heart transplant rejection is associated with microvascular injury, complement deposition and progression to cardiac allograft vasculopathy.

In heart transplants, the significance of very late rejection (after 7 years post-transplant, VLR) detected by routine endomyocardial biopsies (EMB) remains uncertain. Here, we assessed the prevalence, histopathological and immunological phenotype, and outcome of VLR in clinically stable patients. Between 1985 and 2009, 10 662 protocol EMB were performed at our institution in 398 consecutive heart transplants recipients. Among the 196 patients with >7-year follow-up, 20 (10.2%) presented subclinical ≥3A/2R-ISHLT rejection. The VLR group was compared to a matched control group of patients without rejection. All biopsies were stained for C4d/C3d/CD68 with sera screened for the presence of donor-specific antibodies (DSAs). In addition to cellular infiltrates with myocyte damage, 60% of VLR patients had evidence of intravascular macrophages. C4d and/or C3d-capillary deposition was found in 55% VLR EMB. All cases of VLR associated with microcirculation injury had DSAs (mean DSA(max) -MFI = 1751 ± 583). This entity was absent from the control group (p < 0.0001). Finally, after a similar follow-up postreference EMB of 6.4 ± 1 years, the mean of CAV grade was 0.76 ± 0.18 in the control group compared to 2.06 ± 0.26 in the VLR group respectively, p = 0.001). There was no difference in patient survival between study and control groups. In conclusion, VLR is frequently associated with complement-cascade activation, microvascular injury and DSA, suggesting an antibody-mediated process. VLR is associated with a dramatic progression to severe CAV in long-term follow-up.

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.

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.

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.

Renal histopathological lesions after lung transplantation in patients with cystic fibrosis.

We have analyzed the evolution of renal status beyond the perioperative period in patients with cystic fibrosis (CF) undergoing lung transplantation and presented histological analysis of 15 patients biopsied for an episode of accelerated renal function loss (RFL). Episodes of accelerated RFL after the perioperative period occurred in 32.5% of patients and significantly raised the risk of end-stage renal disease (ESRD) (p < 0.001). The histologic lesions associated with these episodes differed according to the time of onset. Early onset (10 cases) was associated with tubulointerstitial lesions in the form of oxalate nephropathy (50%) and/or a pigmented tubulopathy (80%). This latter was correlated with treatment with antiviral agents (p = 0.002) and aminoside and glycopeptide antibiotics (p = 0.03) administered in the month preceding biopsy. Lesions in late episodes of accelerated RFL (5 cases) were principally vascular: arteriosclerosis and arteriolosclerosis (p = 0.007, p = 0.00002), correlated with diabetic glomerulosclerosis or focal segmental glomerulosclerosis in the absence of prominent diabetic changes. Specific calcineurin-inhibitor nephrotoxicity was present in 93.3% of biopsies associated with thrombotic microangiopathy in 46.7% of cases. The identification of specific etiologies of progressive kidney disease in patients with CF after lung transplantation should permit more effective post-transplant care of these patients.

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.

Acute oxalate nephropathy: A new etiology for acute renal failure following nonrenal solid organ transplantation.

Acute renal insufficiency (ARI) is a frequent complication of nonrenal solid organ transplantation and may be responsible for an unfavorable outcome, particularly if dialysis is required. The etiology of post-transplantation ARI is poorly understood, with only isolated clinical cases being reported, most imputed to drug toxicity. We report here, the first three observations of irreversible ARI associated with acute oxalate nephropathy (AON) in the course of nonrenal organ transplants: a lung transplant and a lung-liver transplant in two patients with mucoviscidosis, and a cardiac transplant. The diagnosis of AON was made histologically. In all three cases, the ARI supervened after prolonged consumption of antibiotics capable of interfering with the colonic flora, and leading to enteric hyperoxaluria. The recognition of AON as a cause of post-transplantation, ARI underlines hyperoxaluria and digestive hyperabsorption of oxalate as specific risk factors for AON and should permit better posttransplant care of these patients.

[Voriconazole photosensitivity: 7 cases]. / Photosensibilisation au voriconazole: 7 cas.

BACKGROUND: Voriconazole is a new second-generation fluconazole-derived triazole. With greater potency against susceptible species and a broader spectrum of activity than fluconazole, it is the treatment of choice for invasive pulmonary aspergillosis and other fungal infections (Fusarium, Scedosporium/Pseudalleschezria) is indicated in a visit Candida infections refractory to fluconazole. We describe 7 cases of photosensitivity during treatment with voriconazole in a setting of immunodepression. CASE REPORTS: The patients comprised 5 women and 2 men with a mean age of 38 years (17-67 years). Five had undergone pulmonary transplantation for mucoviscidosis, one had undergone kidney transplantation for lupus nephroangiosclerosis and one was on long-term systemic steroid treatment for Sjögren's syndrome. All patients had very severe immunosuppression and were receiving voriconazole for pulmonary aspergillosis (6 cases) or Scedosporium infection (1 case). Photosensitization appeared within 5 weeks to 14 months after the start of treatment, and in all cases followed exposure to sun, occasionally at low levels. In all cases, cutaneous lesions rapidly disappeared on discontinuation of treatment. DISCUSSION: There have been reports in the literature, although rare, of photosensitivity with voriconazole. Patients must be informed of the possibility of this adverse effect and sun protection must be recommended when voriconazole is prescribed, particularly during periods of intensive exposure.

Colonization and infection of pulmonary artery catheter in cardiac surgery patients: epidemiology and multivariate analysis of risk factors.

OBJECTIVE: To assess the incidence and etiology of colonization and infection of pulmonary artery catheters inserted in cardiac surgery patients. To determine the influence of some variables on the risk of developing pulmonary artery catheter colonization and infection. DESIGN: Prospective observational study of pulmonary artery catheters inserted into the internal jugular vein that were in place for >48 hrs over a 13-month period. Data collected included age, gender, nature of the cardiac surgery intervention, duration of extracorporeal circulation, date of insertion and removal, subsequent infection, and curative antimicrobial therapy. End points were pulmonary artery catheter colonization with >or=10(3) colonies on quantitative cultures and pulmonary artery catheter-related bacteremia. Risk factors for colonization were determined by multiple logistic regression. SETTING: A 17-bed cardiac surgery intensive care unit in a 480-bed teaching hospital in Paris. PATIENTS: Patients undergoing cardiac surgery procedures between May 1, 1997, and May 31, 1998. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 164 pulmonary artery catheters inserted in 157 patients, 19 (11.6%) and 1 (0.6%) were associated with colonization (mean duration of catheterization, 7.5 +/- 2.8 days) and bacteremia, respectively. These data represent an incidence of 17.7 and 0.93 episodes per 1000 catheterization-days, respectively. Pulmonary artery catheter colonization was caused by Gram-positive cocci in 48% (67% were coagulase-negative staphylococci), Gram-negative rods in 48%, and Candida albicans in 4%. From multivariate analysis, >4 days of catheterization was the single variable associated with a significantly increased risk of pulmonary artery catheter colonization (odds ratio, 9.81; 95% confidence interval, 1.24-77.5, p = .03). CONCLUSIONS: Our data show that the risk of pulmonary artery catheter-related colonization and bacteremia is quite low despite the use of a high-risk insertion site. In cardiac surgery patient populations, a trial evaluating the impact of a systematic pulmonary artery catheter removal after 4 days is warranted.

Implication of HLA-G molecule in heart-graft acceptance.

HLA-G found in five of 31 heart-transplant recipients was associated with a decrease of acute and chronic rejection episodes.

Neosynthesized IgG detected by Western blotting in Toxoplasma-seropositive heart or lung transplant recipients.

Toxoplasmosis is a life-threatening disease in heart- or lung transplant recipients that can result either from the reactivation of a latent infection or from an organ-transmitted infection. The diagnosis of acute toxoplasmosis is easy in cases of seroconversion following a mismatch. However, when the recipient is Toxoplasma-seropositive before transplantation, usual serological techniques do not allow the differentiation between endogenous and organ-related reinfection. The aim of this study was to determine whether western blotting could contribute to this differentiation. Sequential sera from two heart- and one liver- and lung transplant patients whose anti-Toxoplasma antibody titers strongly increased after transplantation, were analyzed by western blotting. Neosynthesized IgG were observed on blots incubated with the sera from two patients who had received transplants from Toxoplasma-seropositive donors, whereas no neosynthesized IgG was detected on blots from the patient who had received a transplant from a Toxoplasma-seronegative donor. Our results suggest that the detection of neosynthesized IgG in the recipient may be related to the recognition of a new parasite strain possibly brought by the transplant from a Toxoplasma-seropositive donor.

Single breath exhaled nitric oxide in lung transplant patients: a preliminary clinical study.

Exhaled nitric oxide is considered as a marker of airway inflammation. We report here our preliminary experience with single-breath exhaled nitric oxide measured in lung transplant patients with and without bronchiolitis obliterans syndrome and in cardiac transplant patients. Peak and end-expiratory nitric oxide concentrations did not differ between groups, but single-breath exhaled nitric oxide recordings were strikingly different in patients suffering from bronchiolitis obliterans syndrome, with a slower decrease from peak to end-expiratory nitric oxide concentration. Further studies are required in order to determine whether theses abnormalities reflect the inflammatory process of bronchiolitis obliterans syndrome.

[Importance of dual isotope myocardial tomoscintigraphy in the detection of coronary disease in the graft among 96 heart transplant recipients]. / Intérêt de la tomoscintigraphie myocardique double isotope dans la détection de la maladie coronaire du greffon chez 96 transplantés cardiaques.

With a survival rate of 70% at 3 years, cardiac transplantation is the best treatment for end-stage heart disease. However, progressive development of graft atherosclerosis is frequent. Diagnosis of transplant coronary disease remains difficult and non-invasive tests have proved relatively insensitive. Therefore, coronary angiography performed annually is still the gold-standard test for the detection of heart transplant vasculopathy. We analyzed the records of 96 patients (82 men and 14 women) who were transplanted from 1986 to 1996. Mean age was 53 +/- 2.7 and time elapsed from transplantation was mean 5.3 +/- 10 years. All patients had rest myocardial TI 201 perfusion SPECT, followed by MIBI gated SPECT after exercise. MIBI gated SPECT allows simultaneous evaluation of perfusion, regional LV function and global ejection fraction. Angiocoronarography, performed in all patients during the six months following radionuclide investigation, showed the presence of coronary heart vasculopathy in nine (9.3%). Seven of these patients had abnormal dual isotope imaging and 2 of them had normal perfusion but altered LV regional function. Sensitivity of dual isotope scintigraphy was 77% and specificity was 97.7%. Dual isotope scintigraphy is helpful to detect coronary vasculopathy in heart transplant recipients and may reduce indications of angiocoronarography.

Disseminated Fusarium solani infection with endocarditis in a lung transplant recipient.

Eleven days after double lung transplantation for cystic fibrosis, an 18-year-old patient developed a disseminated Fusarium solani infection with tricuspid valve endocarditis. This infection occurred under fluconazole and immunosuppressive therapy with cyclosporin, prednisone and azathioprine, with a normal leucocyte count. Liposomal amphotericin B allowed blood culture negativation. The patient died from a bacterial septic shock.

[Immunosuppression: a case of mucoviscidosis]. / Immunosuppression: cas particulier de la mucoviscidose.

Cystic fibrosis is a recessive disease that causes changes in mucus secretions, affecting different systems: respiratory, digestive, pancreatic, hepatic; resulting in obstructions and secondary infections. Transplantation may be used for the most severe forms and is then complicated by the pediatric context, the existence of malabsorption and secondary infections and the type of transplantation (pulmonary and/or hepatic). The follow-up is characterized by pulmonary infections and pulmonary chronic rejection. In our experience, the initiation of the immunosuppressive treatment must avoid corticoids in the early post-transplantation days and have recourse to intravenous cyclosporin (CyA) 2 mg/kg/day, given on average for one month in an oral form. In case of persistent acute rejection, tacrolimus (FK 506) is instituted. Oral CyA (10-12 mg/kg/day) seems more sensitive to malabsorption syndrome than FK 506 (0.2 mg/kg/day). In both cases, the development of an inhibitory metabolic interaction in the presence of itraconazole must be taken into account: used against aspergillosis, itraconazole is metabolized as CyA and FK 506 by Cyt P450 3A4. The intensity of the interaction is twofold for CyA versus fivefold for FK 506. The strategy for the use of other recently available immunosuppressives such as mycophenolate is under evaluation.

[Pregnancy after organ transplantation]. / Grossesse après greffes d'organe.

In the past twenty years, the increased number of organ transplant recipients and better immunosuppressive regims have enhanced transplant survival, and several transplant recipients may conceive pregnancy or paternity after the graft. There is no French registry of posttransplant pregnancies, but analysis of the international literature reports 2300 pregnancies after kidney transplantation, 100 pregnancies after heart and 3 after heart-lung transplantation, 90 pregnancies after liver transplantation. Paternity after the graft may occur with no increased incidence of malformations, nor teratogenic and immunosuppressive effects due to the therapeutic regimen. All pregnancies after transplantation have to be considered at high risk, underlying the need for simultaneous follow-up by the gyneco-obstetrical team for the baby and the pregnancy and by the transplant team for the graft and the mother. Outcome is generally excellent for the mother and the baby. However, transplant recipients with either high blood pressure, diabetes, serum creatinine above 160 mumol/l or within less than 1 year after the graft should be considered at too high risk to conceive a pregnancy with no deleterious effect on the mother and/or on the foetus.

Influence of acute or chronic rejection on myocardial collagen density in serial endomyocardial biopsy specimens from cardiac allografts.

BACKGROUND: The knowledge of long-term changes in the transplanted heart is still incomplete. Among these changes that could potentially have an adverse effect on long-term cardiac function, myocardial fibrosis is of great concern. The aim of this study was to investigate the possible influence of acute or chronic rejection on the development of myocardial fibrosis in cardiac allografts. METHODS: We used light microscopic computer-assisted morphometry of collagen density in 200 right ventricular endomyocardial biopsy specimens taken routinely in 21 heart transplant recipients during a mean follow-up period of 36 months (range, 12 to 84). The 21 patients were divided into two groups according to the presence of chronic rejection assessed by coronary angiography. The first group consisted of 11 patients with no chronic rejection; the second group consisted of 10 patients with chronic rejection. Both groups were divided into four subgroups according to the highest grade of acute rejection reached during the follow-up period (subgroup 1, no acute rejection or grade 1A; subgroup 2, grade 1B; subgroup 3, grades 3A or 3B; subgroup 4, grade 4). Patients of both groups were selected on the basis of similarity patterns in clinical characteristics and mean follow-up time. RESULTS: Patients with no chronic rejection had relatively little variation in serial determinations of myocardial collagen density. During the prechronic and chronic phases in patients with chronic rejection, we found no overall increase in myocardial collagen density. In both the chronic rejection and no chronic rejection groups there was no consistent relationship between myocardial collagen density and severity of acute rejection. In both groups there were occasional strikingly elevated myocardial collagen density values that were well above the other serial determinations. These elevated values of collagen density were mainly a result of scars, the sequellae of prior myocyte damage, because neither interstitial nor perivascular fibrosis could be detected. CONCLUSION: During this long-term follow-up study of endomyocardial biopsy samples, we found no significant association between either acute or chronic rejection and the later increase in myocardial collagen density.