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Voriconazole is an antifungal treatment with central neurotoxicity. Modifications of the electroretinogram can explain some of its visual complications: visual hallucination, blurred vision, altered visual perception or photophobia. However, reports from the literature or the French pharmacovigilance centers evoked toxic optic neuropathy due to voriconazole. The aim of this report is to analyze the role of voriconazole in the occurrence of toxic optic neuropathy or the role of the combination of voriconazole with other neurotoxic drugs.We report the case of a 15-year-old young boy treated with voriconazole and ethambutol for a severe lung infection due to aspergillosis and mycobacterium tuberculosis in the mucoviscidosis and pulmonary transplantation who developed a toxic optic neuropathy. A review of the literature on the role of ethambutol on the activity of CYP2C19 and its relationship with the serum concentration of voriconazole was conducted.In our patients, visual acuity recovered after discontinuation of voriconazole. Other cases of toxic optic neuropathy due to voriconazole were reported in pharmaco-vigilance databases, often in association with ethambutol.Ethambutol can reduce the activity of CYP2C19 leading to an increase of voriconazole concentration. Thus, it potentiates its risk of adverse event. Such mechanism leading to this neuro ophthalmological adverse effect would have an important clinical involvement. It would require a stricter monitoring and screening of patients treated by combination of neurotoxic molecules and VRZ to detect an adverse event.

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.

Background Homeostatic turnover of the extracellular matrix conditions the structure and function of the healthy lung. In lung transplantation, long-term management remains limited by chronic lung allograft dysfunction, an umbrella term used for a heterogeneous entity ultimately associated with pathological airway and/or parenchyma remodeling. Objective This study assessed whether the local cross-talk between the pulmonary microbiota and host cells is a key determinant in the control of lower airway remodeling posttransplantation. Methods Microbiota DNA and host total RNA were isolated from 189 bronchoalveolar lavages obtained from 116 patients post lung transplantation. Expression of a set of 11 genes encoding either matrix components or factors involved in matrix synthesis or degradation (anabolic and catabolic remodeling, respectively) was quantified by real-time quantitative PCR. Microbiota composition was characterized using 16S ribosomal RNA gene sequencing and culture. Results We identified 4 host gene expression profiles, among which catabolic remodeling, associated with high expression of metallopeptidase-7, -9, and -12, diverged from anabolic remodeling linked to maximal thrombospondin and platelet-derived growth factor D expression. While catabolic remodeling aligned with a microbiota dominated by proinflammatory bacteria (eg, Staphylococcus, Pseudomonas, and Corynebacterium), anabolic remodeling was linked to typical members of the healthy steady state (eg, Prevotella, Streptococcus, and Veillonella). Mechanistic assays provided direct evidence that these bacteria can impact host macrophage-fibroblast activation and matrix deposition. Conclusions Host-microbes interplay potentially determines remodeling activities in the transplanted lung, highlighting new therapeutic opportunities to ultimately improve long-term lung transplant outcome., Graphical abstract

Progress in transplantation technique has offered a growing number of solid organ transplant recipients the opportunity to travel to tropical and low-income countries. The issue of vaccine-preventable diseases is a challenging question in immunocompromised patients including those with solid organ transplant. Since the response to vaccines is weakened in case of chronic organ failure, candidates should be vaccinated early in the course of the disease. Clinicians should implement a vaccinal strategy until the patient is scheduled for transplantation and monitor its efficacy by serological assays. Live attenuated vaccines (such as yellow fever, measles-mumps-rubella, or chicken pox) are contra-indicated in solid organ transplant recipients and, when indicated, should be administered prior to transplantation, particularly in foreign-born patients highly likely to visit friends and relatives in endemic areas. Vaccinations for transplant recipients considering international travel should be realized according to the risk of acquiring vaccine-preventable diseases but also on both tolerance and immune response which are affected by degree and duration of immunosuppression, comorbidities, and type of organ transplanted. Routine and specific vaccinations for solid organ transplant recipients, as well as travel-related vaccination (such as hepatitis A, typhoid, meningococcal meningitis, rabies, tick-born encephalitis, Japanese encephalitis, and cholera) should be considered during a specific pretravel medical consultation. However, vaccination should be avoided in the 6 months following transplantation when patients are usually receiving the highest doses of immunosuppressive drugs. In this comprehensive review, we provide vaccination schedules based on published studies and guidelines for vaccination of solid organ transplant recipients.

Background The optimal management of Mycobacterium chelonae disease in immunocompromised patients remains unclear. A combination of antimicrobial agents is recommended as monotherapy with clarithromycin has been associated with clinical failures due to acquired resistance. Objectives We aim to report the efficacy and tolerability of linezolid in association with clarithromycin for the treatment of M. chelonae infections in immunocompromised patients. Methods We describe four immunocompromised patients treated by linezolid and clarithromycin for cutaneous M. chelonae disease. Results This combination was associated with rapid clinical efficacy in all patients with no relapse observed after a median follow-up of 2.25 years (1.4 years). However, this treatment was responsible for frequent adverse events including thrombocytopaenia, myalgia and mitochondrial toxicity. All adverse effects were reversible after linezolid discontinuation. Conclusions We therefore suggest linezolid/clarithromycin combination as the initial therapeutic strategy for M. chelonae skin infections in immunocompromised patients.

The safety and efficacy of amphotericin B lipid complex (ABLC) were evaluated in a retrospective study of 46 paediatric patients with invasive infections. The study included a large proportion of patients who were refractory to or intolerant of conventional antifungal therapy. The mean age of the children was 9.7 +/- 4.8 years. Primary underlying conditions included mainly haematopoietic stem cell transplantation, leukaemia and lung transplantation. The mean daily dose given was 4.11 mg/kg for a mean duration of 38.7 days. At the end of therapy, 38 of 46 (83%) patients responded successfully to treatment with ABLC, including 18 of 23 (78%) with aspergillosis and 17 of 19 (89%) with candidiasis. ABLC was well tolerated, with a low incidence of adverse events. The mean creatinine value was 74.5 microl/mol/l at baseline and 78.2 micromol/l at the end of therapy. These results support the use of ABLC in the treatment of invasive fungal infections in children, including patients who have previously failed, or are intolerant of, traditional antifungal regimens.

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.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%).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).Lung transplantation among children under 18 years have similar outcome to those of adult patients.

Resume • Objectif : Evaluer les effets hemodynamiques et respiratoires d'un immunosuppresseur par le muromonab CD3 (Orthoclone OKT3®) administre pendant les trois jours suivant la transplantation cardiaque, pour la prevention du rejet precoce de greffe. • Type d'etude : Etude clinique prospective. • Patients : Douze patients dont les resistances arterielles pulmonaires avant transplantation etaient inferieures a 400 dyn·s·cm −5 et dont les parametres hemodynamiques postoperatoires, en l'absence d'un traitement inotrope majeur, etaient stables depuis au moins 4 heures. • Methode : Patients, sous ventilation mecanique avec FiO 2 = 0,6 a j0, puis en ventilation spontanee, sous air enrichi en oxygene a j1 et j2, recevant isoprenaline 0,05 g·kg −1 ·min −1 et dopamine 3 g·kg −1 ·min −1 et dont le traitement immunosuppresseur comportait azathioprine 5 m·kg −1 a j0, puis 3 mg·kg −1 a j1 et j2, et methylprednisolone 720 mg a j0 et 240 mg a j1 et j2. L'OKT3 etait administre par voie i.v. a la dose de 5 mg toutes les 24h. Les variables hemodynamiques et respiratoires obtenues avant (=T0), puis 30 min (=T1) et 360 min (=T3) apres l'injection d'OKT3 a j0, j1 et j2. • Resultats : Aucune repercussion clinique ni radiologique n'a ete decelee. A T2 de j0, la frequence cardiaque s'est elevee et la PaO 2 ainsi que la SaO 2 ont diminue. Les autres parametres sont restes inchanges. A T1 de j1 et de j2, la PaO 2 a egalement diminue. Le shunt a augmente a j2 de pres de 3 %. • Conclusions : Dans les conditions de l'etude, l'administration d'OKT3 n'a eu qu'un retentissement modere sur l'hematose, surtout net a j2. Cette bonne tolerance peut etre attribuee d'une part a la selection des patients, exempts d'hypertension arterielle pulmonaire et, d'autre part aux fortes doses de corticoides administrees.

Tacrolimus (TRL) is an immunosuppressive drug characterized by a narrow therapeutic index, low bioavailability, and pharmacokinetic variability. Intravenous (IV) 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 IV. 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.

Summary 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

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.

Objective Heart or lung transplantation is a complex intervention requiring medication adherence. The objective of this systematic review is to estimate the prevalence of non-adherence (NA) with post-transplantation medication in heart or lung recipients and to assess its clinical impact. We examined in the selected studies if the authors considered the patient's perspective in their evaluations. Methods The electronic database MEDLINE, EMBASE and The Cochrane Central Register were searched. Only studies that reported the number of non-adhere subjects were eligible. The different methods of measurement, the ways in which authors defined NA and if authors had integrated patient's perspective in their secondary objectives were also assessed. Results The range frequency of NA was 1–42.9% for all drugs. Non-adherent patients tend to experience worse outcomes compared to adherent patients. The patient's perception of drug side-effects is the most reported patient-related factor for impairing adherence. Conclusion NA after heart or lung transplantation is an important issue and concerns not only immunosuppressant treatments. The main striking point of the selected studies is the lack of patient perspective and the omission of patients–healthcare providers’ relationship. Practice implications Future research must focus on patients’ motivation for the medication-taking behaviour.

Immunoglobulin abnormalities in serum from 76 heart-transplant recipients were examined by cellulose acetate and agarose gel electrophoresis. Monoclonal components were typed by immunofixation. IgG, IgA, and IgM and total kappa and lambda light chains were quantified by immunonephelometry. We confirm that both monoclonal and oligoclonal immunoglobulin banding are common in serum from these patients. Of the 149 serum samples examined, 21 (15%) had one monoclonal component and 53 (35%) had two or more. These monoclonal immunoglobulins were generally present at a low concentration and were transient. The class of immunoglobulins most commonly involved was IgG (about sevenfold more numerous than IgM); monoclonal IgA components and free light chains were not detected. The nephelometric kappa/lambda and heavy chain/light chain ratios were poor indicators of these abnormalities. Immunoglobulin abnormalities were not correlated with the sex and age of recipients, the pre-existing cardiopathy, the time since transplantation, or plasma concentrations of cyclosporine, but did correlate with plasma immunoglobulin concentration, biopsy findings, and viral infections, especially cytomegalovirus (CMV). A monoclonal IgG purified from a patient with a high titer of anti-CMV antibodies did not react with CMV antigens. The origin of these immunoglobulin abnormalities is unclear. Our data suggest that the presence of monoclonal or oligoclonal banding in heart-transplant recipients is of limited prognostic significance.

Progress in transplantation technique has offered a growing number of solid organ transplant recipients the opportunity to travel to tropical and low-income countries. The issue of vaccine-preventable diseases is a challenging question in immunocompromised patients including those with solid organ transplant. Since the response to vaccines is weakened in case of chronic organ failure, candidates should be vaccinated early in the course of the disease. Clinicians should implement a vaccinal strategy until the patient is scheduled for transplantation and monitor its efficacy by serological assays. Live attenuated vaccines (such as yellow fever, measles-mumps-rubella, or chicken pox) are contra-indicated in solid organ transplant recipients and, when indicated, should be administered prior to transplantation, particularly in foreign-born patients highly likely to visit friends and relatives in endemic areas. Vaccinations for transplant recipients considering international travel should be realized according to the risk of acquiring vaccine-preventable diseases but also on both tolerance and immune response which are affected by degree and duration of immunosuppression, comorbidities, and type of organ transplanted. Routine and specific vaccinations for solid organ transplant recipients, as well as travel-related vaccination (such as hepatitis A, typhoid, meningococcal meningitis, rabies, tick-born encephalitis, Japanese encephalitis, and cholera) should be considered during a specific pretravel medical consultation. However, vaccination should be avoided in the 6 months following transplantation when patients are usually receiving the highest doses of immunosuppressive drugs. In this comprehensive review, we provide vaccination schedules based on published studies and guidelines for vaccination of solid organ transplant recipients.

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.

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.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.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.

Mechanical circulatory assistances now belong to the therapeutic stock in case of advanced heart failure. Their mainspring lays on the substitution of the failing left and/or right ventricle function with a pump. The goal being to maintain or restore the system main functions. Their main indication is a bridge to transplant mechanical circulatory assistance, allowing the patient to await transplantation. However, indications for definitive implantation appear in case of transplantation counter indication, mechanical circulatory assistances already emerging as a possible alternative to transplantation. For over 10 years, we have used pulsatile flow assistances, either with pneumatic ventricles or electro-mechanic implantable left ventricles. We henceforth observe the development of a new generation of implantable assistance providing a non-pulsatile flow. These are axial pumps. We evaluated the first model, the DeBakey axial pump which became the most used axial pump worldwide. We now observe the development of other axial pumps as well as the development of new implantable centrifugal pumps.

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.

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.

Extracorporeal photochemotherapy (ECPC) has been investigated experimentally and in clinical conditions in transplant rejection treatment and prevention. Repeated injections of photochemically modified syngeneic alloreactive T cells prior to transplant significantly delay rejection in a mouse skin graft model as well as in a heterotopic heart transplant model in rats. In the latter, we found this effect to be dependent on 3 main parameters, i.e., treatment intensity (number of injections), schedule (injections before and after transplant), and associated immunosuppression (because there is no detectable effect in animals without immunosuppression). In human beings, ECPC was first used for the treatment of acute rejection episode after heart transplantation. At least 2 studies provided evidence that ECPC is as effective as high dose corticosteroids in controlling moderate acute rejections, and several case reports showed that ECPC could be effective in recurrent and/or steroid resistant rejections. ECPC has also been investigated in an open trial to prevent rejection episodes after heart transplantation in patients at high risk of acute rejection because of human leukocyte antigen (HLA) immunization and/or a second or third transplant and found to be successful. In heart transplant recipients at standard risk of rejection episodes, a small scale randomized trial showed a reduction in both rejection episodes and infections in the ECPC treated vs. the standard group. Beyond these studies and other isolated case reports, several large scale randomized trials in heart, lung, and even kidney transplantations (some of them already ongoing), will enable us to define the role of ECPC in the management of transplant recipients.

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.

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.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.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.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.

We investigated extracorporeal photochemotherapy--which consists of the collection of blood mononuclear cells by means of a cell separator, their exposure to ultraviolet A light in the presence of a photoactivatable molecule such as 8-methoxypsoralen, and their intravenous reinjection into the patient--for the treatment of an acute lung rejection episode in a severely infected patient, assuming that its mechanism of action is an immunomodulation rather than an actual immunosuppression.Three weeks after the simultaneous beginning of antiinfectious and extracorporeal photochemotherapy treatments, the patient improved clinically. Acute lung rejection was no longer detectable histologically 4 weeks after the beginning of extracorporeal photochemotherapy. Twenty-two months after the beginning of extracorporeal photochemotherapy (47 months after transplantation), the patient was living a normal life.We believe this treatment may be considered for further studies not only in acute lung rejection therapy when intensive immunosuppression is contraindicated but also as a means of rejection prevention.

Treatment of transplant rejection with muromonab CD3 (Orthoclone OKT3) may result in haemodynamic instability and pulmonary oedema, which would question its prophylactic use. The aim of this study was to the evaluate haemodynamic and respiratory tolerance of prophylactic treatment of cardiac rejection with OKT3.Prospective clinical study.Twelve patients, whose pulmonary arterial resistances before transplantation were less than 400 dyn.s.cm-5, with haemodynamic and respiratory stability during the 4 hours before OKT3 administration.Patients under preventive haemodynamic support with isoprenaline 0.05 micrograms.kg-1.min-1 and dopamine 3 micrograms.kg-1.min-1. Immunosuppressive treatment with azathioprine 5 mg.kg-1 at d0 and 3 mg.kg-1 at d1 and d2 and with methylprednisolone 720 mg at d0 and 240 mg at d1 and d2. OKT3, 5 mg administered i.v. at d0, d1, d2. Respiratory and haemodynamic variables were recorded prior to (T0), 30 min (T1) and 360 min (T2) after injection of OKT3.Neither clinical nor radiological changes were observed after the OKT3 injections. At d0, T2, the heart rate increased and PaO2 and SaO2 decreased. At d1 and d2, T1, PaO2 decreased, and QS2QT at T1 d2 increased by nearly 3%.OKT3 does not result in major circulatory and haematosis changes, provided patients are selected, especially free of pretransplantation pulmonary hypertension. Prior to the treatment with OKT3, they should be in a satisfactory haemodynamic and respiratory status and receive high doses of corticosteroids.

To follow an heart transplantation, EBCT is more precise than ultrasonography and scintigraphy to calculate a stroke volume. In lung transplantation, it is important before surgery to know the value of right ventricule stroke volume in order to choice the surgical protocol. After lung transplantation SFE helps to follow the patient to look after complications, to drain a collection or to guide a biopsy. SFE contribution is discussed in rejection, infectious diseases, detection of immuno-induced carcinomas, in bronchiolitis obliterans and recurrence of the primitive disease.

The increase of organ transplantations during the last decades conjointly with the prescription of heavy immunosuppressive drugs, has led to an increased incidence of new invasive aspergillosis (IA). This study is a report of the Broussais Hospital experience from 1968 to 1993 on kidney, heart and heart and lungs transplantations. It concerns 21 IA cases. Incidence was 0.5% for kidney, 4.5% for heart and 18% for heart and lungs transplantations. The most important risk factors were the increase of immunosuppressive therapy (66% of the cases), neutropenia (19%), and renovation of the hospital wards (36%). Lung was the most frequent site of infection (95% of the cases), clinical symptoms were no significant. Diagnosis procedures were realised on biopsy (23%) and on bronchoalveolar lavage (66%). Usual amphotericin B treatment was disappointing: mortality rate of 77%, the liposomal preparation of the drug seemed to be more efficient: mortality rate of 50%. Itraconazole appeared to be used in succession with a careful adaptation of posology. Prophylactic amphotericin B in a local way (sprays and aerosols) led to a good efficiency jointly with the patient isolation during constructions in the hospital area.

Extracorporeal photochemotherapy is a recently developed immunomodulator treatment against heart and lung graft rejection. The recipient's mononuclear cells are screened and irradiated with UV-A in the presence of 8-methoxy-psoralene (8-MOP), then reinjected. We treated 4 patients who had begun to reject their heart and/or lung grafts, with this technique, using one session per week for 4 weeks, followed by one session every 2 weeks for 2 months, then one session per month. In all cases, extracorporeal photochemotherapy appeared to improve the clinical and biological status of these patients. Episodes of rejection which could not be reversed with immunosuppressor treatment alone were controlled.

Immunocubes can detect very low HCMV IgG levels with at least the same sensitivity as the reference technique: ELISA. Samples containing bacteria showed no particular interference on the test, and results for non-infected material were in agreement with those of ELISA. The rapid test did not give any false positive reactions even with samples from patients with very high antiherpes immunoglobulins levels. Samples from transplant patients at the beginning of seroconversion or diluted to IgG titers corresponding to ELISA cut-off values were always detected as positive by immunocubes. In view of the rapidity of the test, its high specificity, its ability to detect levels corresponding to extremely low IgG signals in ELISA, and the possibility of conserving objective proof of the test, we conclude that this rapid immunocube technique is of great interest for current serologic screening in an emergency context, especially for transfusion and organ transplantation.

Cytomegalovirus (CMV) infection is a major cause of morbidity and death in heart transplant recipients. Cardiac graft involvement in CMV infection is a matter of controversy, considering its frequency and its relationship with acute or chronic rejection. Four heart transplant patients were selected because of a severe CMV infection (systemic, gastrointestinal, ophthalmic, and neurologic involvement). Immunoglobulin M and increased immunoglobulin G CMV antibodies developed. Twenty-two routine endomyocardial biopsies (EMB; mean: 5.5 EMB per patient; range, 3 to 9) from these patients were selected covering the period of CMV infection. Grading of rejection showed 12 biopsies with "no evidence of rejection (grade 0)," nine biopsies with "mild acute rejection (grade 1B)," and one biopsy with "moderate acute rejection (grade 3A)." One EMB exhibited a single CMV inclusion in an endothelial cell detectable by light microscopy. The EMB were assessed for CMV infection using in situ hybridization (ISH) for the detection of CMV genome with a biotinylated CMV probe and immunohistochemistry (IHC) for the detection of CMV immediate-early antigen with the monoclonal antibody E13. ISH and IHC detected a single CMV-infected cell, respectively, in one and two EMB from two patients. The patient with a CMV inclusion determined by light microscopy was also positive with both techniques. Positive ISH and IHC were always in enlarged inclusion-bearing cells, which were easily observable with routine staining. One EMB had mild acute rejection, and the other one had no rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

This technique is original in that it involves a single site (the ascending aorta) easily accessible to cannulation. Following lateral clamping of the ascending aorta, a bifurcate Dacron prosthesis is anastomosed. The draining cannula is introduced through one of the branches of the prosthesis and manually guided through the aortic sigmoid leaflets down to the left ventricular ejection outlet. The perfusion cannula is introduced through the outer branch of the prosthesis. The end of this cannula is positioned at the origin of the prosthesis to avoid a possible bend in the fork. This technique is a simple and effective means of providing left ventricular support.

Immunoglobulin abnormalities in serum from 76 heart-transplant recipients were examined by cellulose acetate and agarose gel electrophoresis. Monoclonal components were typed by immunofixation. IgG, IgA, and IgM and total kappa and lambda light chains were quantified by immunonephelometry. We confirm that both monoclonal and oligoclonal immunoglobulin banding are common in serum from these patients. Of the 149 serum samples examined, 21 (15%) had one monoclonal component and 53 (35%) had two or more. These monoclonal immunoglobulins were generally present at a low concentration and were transient. The class of immunoglobulins most commonly involved was IgG (about sevenfold more numerous than IgM); monoclonal IgA components and free light chains were not detected. The nephelometric kappa/lambda and heavy chain/light chain ratios were poor indicators of these abnormalities. Immunoglobulin abnormalities were not correlated with the sex and age of recipients, the pre-existing cardiopathy, the time since transplantation, or plasma concentrations of cyclosporine, but did correlate with plasma immunoglobulin concentration, biopsy findings, and viral infections, especially cytomegalovirus (CMV). A monoclonal IgG purified from a patient with a high titer of anti-CMV antibodies did not react with CMV antigens. The origin of these immunoglobulin abnormalities is unclear. Our data suggest that the presence of monoclonal or oligoclonal banding in heart-transplant recipients is of limited prognostic significance.

To evaluate the incidence, risk factors and effects of systemic hypertension on renal function and left ventricular hypertrophy after heart transplantation, 85 recipients under triple drug low low dosage immunosuppressive therapy were studied. After a mean follow-up of 12.5 +/- 8.7 months, high incidence of hypertension was observed in 67% of the patient and 71% had developed de novo hypertension. None of the pre-transplant nor post-transplant cardiovascular risk factors were significantly associated with post-transplant hypertension. Faster deterioration of renal function, as assessed by intraindividual variations of serum creatinine values, was demonstrated in hypertensive patients and appeared as an early indicator of cyclosporine nephrotoxicity in patients at risk for hypertension. [table: see text] Serial (early, intermediate, late) echocardiographic evaluations demonstrated early increase in left ventricular mass and in fractional shortening in both hypertensive and normotensive heart transplant recipients with sustained enhanced contractility in hypertensive patients. [table: see text] Further studies will help to determine the exact relationship between cyclosporine dosages and hypertension, and their respective roles in the development of renal insufficiency and left ventricular hypertrophy after heart transplantation.