L'Orf est une zoonose due à un Parapoxvirus, involuant généralement de manière spontanée en quelques semaines chez les patients immunocompétents. Chez les patients immunodéprimés, l'Orf peut être persistant et difficile à traiter. Nous rapportons, à notre connaissance, le premier cas d'Orf traité par injections intralésionnelles de cidofovir après échec des autres thérapeutiques. Un homme de 40 ans a consulté en août 2020 pour une lésion du 5e doigt de la main gauche, apparue 10 jours après la fête de l'Aïd, et 1 jour après sa transplantation rénale pour néphropathie indéterminée. Son traitement immunosuppresseur (TIS) comportait prednisolone10 mg/j, mycophénolate mofétil 2000 mg/j et tacrolius 12 mg/j. Le diagnostic d'Orf a été confirmé histologiquement. Deux séances de cryothérapie puis un traitement par imiquimod topique se sont avérés inefficaces. Une exérèse chirurgicale avec reconstruction de la perte de substance par greffe de peau totale a alors été réalisée avec reprise du traitement par imiquimod en préventif dès l'ablation des fils. Une récidive de l'Orf 3 semaines après l'opération a été constatée, avec à nouveau une lésion à croissance très rapide. Nous avons alors décidé de réaliser des injections intra-lésionnelles de cidofovir (disponible en ATU), à la dose de 3,75 mg, toutes les 2 semaines, sous anesthésie locale. Une guérison complète a été obtenue en 4 injections. Il a été observé par la suite 2 nouvelles lésions, auto-inoculées, sur l'hémilèvre blanche supérieure droite puis sur l'index droit, respectivement 3 et 8 semaines après le début du traitement, également efficacement traitées par injections intra-lésionnelles de cidofovir. La tolérance clinique et biologique était bonne. En parallèle, une modification de son TIS (remplacement du mycophénolate par un inhibiteur de mTOR) a été effectuée. Aucune récidive n'a été notée à 3 mois. Plusieurs cas d'Orf avec évolution rapide et échec des traitements classiques chez des patients greffés d'organe ont été décrits. Les traitements rapportés dans ces cas sont la cryothérapie, l'imiquimod topique et la chirurgie, associés à une baisse du TIS. Le cidofovir a également été rapporté efficace dans l'Orf par voie topique (mais la pénétration transcutanée aurait été limitée sur la volumineuse lésion de notre patient), et par voie systémique (mais avec un risque d'effets secondaires, notamment de toxicité rénale). Nous avons donc choisi d'effectuer des injections intra-lésionnelles, en se référant au protocole utilisé dans les papillomatoses laryngées. Le cidofovir intra-lésionnel, associé à une révision du TIS, peut être une alternative thérapeutique efficace en cas d'Orf d'évolution rapide, résistant aux traitements classiques, chez un patient greffé d'organe.

Risk-to-benefit analysis of upper extremity allotransplantation (UEA) warrants a careful assessment of immunosuppression-related complications. This first systematic report of infectious complications after UEA aimed to compare incidence and pattern of infections to that observed after kidney transplantation (KT). We conducted a matched cohort study among UEA and KT recipients from the International Registry on Hand and Composite Tissue Transplantation and the French transplant database DIVAT. All UEA recipients between 1998 and 2016 were matched with KT recipients (1:5) regarding age, sex, cytomegalovirus (CMV) serostatus and induction treatment. Infections were analyzed at three posttransplant periods (early: 0-6 months, intermediate: 7-12 months, late: >12 months). Sixty-one UEA recipients and 305 KT recipients were included. Incidence of infection was higher after UEA than after KT during the early period (3.27 vs. 1.95 per 1000 transplant-days, P = 0.01), but not statistically different during the intermediate (0.61 vs. 0.45/1000, P = 0.5) nor the late period (0.15 vs. 0.21/1000, P = 0.11). The distribution of infectious syndromes was significantly different, with mucocutaneous infections predominating after UEA, urinary tract infections and pneumonia predominating after KT. Incidence of infection is high during the first 6 months after UEA. After 1 year, the burden of infections is low, with favorable patterns.

BACKGROUND:Informing kidney transplant recipients of their prognosis and disease progression is of primary importance in a patient-centred vision of care. By participating in decisions from the outset, transplant recipients may be more adherent to complex medical regimens due to their enhanced understanding.METHODS:We proposed to include repeated measurements of serum creatinine (SCr), in addition to baseline characteristics, in order to obtain dynamic predictions of the graft failure risk that could be updated continuously during patient follow-up. Adult recipients from the French Données Informatisées et VAlidées en Transplantation (DIVAT) cohort transplanted for the first or second time from a heart-beating or living donor and alive with a functioning graft at 1 year post-transplantation were included.RESULTS:The model was composed of six baseline parameters, in addition to the SCr evolution. We validated the dynamic predictions by evaluating both discrimination and calibration accuracy. The area under the receiver operating characteristic curve varied from 0.72 to 0.76 for prediction times at 1 and 6 years post-transplantation, respectively, while calibration plots showed correct accuracy. We also provided an online application tool (https://shiny.idbc.fr/DynPG).CONCLUSION:We have created a tool that, for the first time in kidney transplantation, predicts graft failure risk both at an individual patient level and dynamically. We believe that this tool would encourage willing patients into participative medicine.

BACKGROUND: The use of the immunosuppressant sirolimus in kidney transplantation has been made problematic by the frequent occurrence of various side effects, including paradoxical inflammatory manifestations, the pathophysiology of which has remained elusive. METHODS: 30 kidney transplant recipients that required a switch from calcineurin inhibitor to sirolimus-based immunosuppression, were prospectively followed for 3 months. Inflammatory symptoms were quantified by the patients using visual analogue scales and serum samples were collected before, 15, 30, and 90 days after the switch. RESULTS: 66% of patients reported at least 1 inflammatory symptom, cutaneo-mucosal manifestations being the most frequent. Inflammatory symptoms were characterized by their lability and stochastic nature, each patient exhibiting a unique clinical presentation. The biochemical profile was more uniform with a drop of hemoglobin and a concomitant rise of inflammatory acute phase proteins, which peaked in the serum 1 month after the switch. Analyzing the impact of sirolimus introduction on cytokine microenvironment, we observed an increase of IL6 and TNFα without compensation of the negative feedback loops dependent on IL10 and soluble TNF receptors. IL6 and TNFα changes correlated with the intensity of biochemical and clinical inflammatory manifestations in a linear regression model. CONCLUSIONS: Sirolimus triggers a destabilization of the inflammatory cytokine balance in transplanted patients that promotes a paradoxical inflammatory response with mild stochastic clinical symptoms in the weeks following drug introduction. This pathophysiologic mechanism unifies the various individual inflammatory side effects recurrently reported with sirolimus suggesting that they should be considered as a single syndromic entity.

Background: Enhancing vaccine immunogenicity in kidney transplant recipients, particularly against influenza, is required since the immunosuppression used to prevent graft rejection limits vaccine immunogenicity. We therefore investigated the immunogenicity and safety of a double dose non-adjuvanted vaccination regimen against influenza H1N1pdm2009 in kidney transplant adult recipients.Methods: A prospective single-arm study was conducted including 121 renal transplant recipients under triple immunosuppressive regimen. Patients received 2 injections (day 0, day 21) of an inactivated, non-adjuvanted H1N1pdm2009 vaccine. Immunogenicity (hemagglutination-inhibition [HI] antibodies and anti-hemagglutin [HA] specific T cells) was evaluated after one and two injections (day 21, day 42) and at 6 months (day 182).Results: The seroprotection rate (HI antibody titer >= 1/40) was 19% at day 0 (n =119), 53% at day 21 (n = 118), 60% at day 42 (n = 116)(p = 0.013; day 42 vs. day 21) and 56% at day 182 (n = 113). The seroconversion rate was 24% and 32%, the geometric mean fold rise was 3.7 and 4.6 after the first and second injections, respectively. T-cell immunity to the H1N1pdm2009 vaccine showed a two-fold increase from baseline, though not statistically significant, in H1N1pdm2009-HA-specific CD4+ and CD8+ T cells in 34% and 48% of cases, respectively. No rejection episodes related to vaccination were observed while the donor-specific antibodies and creatinine clearance remained unchanged throughout the study.Conclusion: Administration of two doses of the non-adjuvanted influenza H1N1pdm2009 vaccine in renal transplant patients is safe and induces a significant seroprotection, not strong enough yet to meet European or US requirements for adults below 60 years, but comparable to seroprotection levels usually observed in the non immunosuppressed elderly population or conferred by a single dose of adjuvanted vaccine in solid organ transplant recipients. These results provide useful indications for future strategies required to improve immunogenicity of vaccines against influenza in transplanted patients. (C) 2012 Elsevier Ltd. All rights reserved.

Background: The use of the immunosuppressant sirolimus in kidney transplantation has been made problematic by the frequent occurrence of various side effects, including paradoxical inflammatory manifestations, the pathophysiology of which has remained elusive. We undertook the prospective tricentric SIRolimus Inflammation LYon GREnoble (SIRILYGRE) study to characterize more precisely the clinical and biological profiles of sirolimus-induced inflammatory syndrome and to gain insight into its pathophysiology. Design of the study: Thirty renal transplanted patients, that required a switch from calcineurin inhibitor to sirolimus-based immunosuppression, were prospectively followed in 3 French transplantation centers. Inflammatory symptoms were quantified by the patients using visual analogue scales and serum samples were collected before, 15, 30, and 90 days after the switch. Results and discussion: 79% of patients reported at least 1 inflammatory symptom, cutaneo-mucosal and digestive manifestations being the most frequent. Clinical presentation was essentially characterized by its lability and stochastic nature, each patient exhibiting a unique clinical presentation. The biochemical profile was more uniform with a drop of hemoglobin and a concomitant rise of inflammatory acute phase proteins (including CRP, fibrinogen, and haptoglobin), which peaked in the serum 1 month after the switch. Analyzing the impact of sirolimus on cytokine microenvironment, we observed a destabilization of the inflammatory cytokine balance, namely an increase of IL6 and TNFα without apparent compensation of the negative feedback loops dependent on IL10 and soluble TNF receptors. These findings are in line with recent experimental studies, which reported that blockade of mTOR pathway reduces STAT3 activity and in turn IL-10 production but releases the brakes on the transcription factor NF-κB, the master regulator of proinflammatory responses. The changes of IL6 and TNFα correlated with the biochemical and clinical inflammatory manifestations in a linear regression model. Conclusion: Our study shows that sirolimus triggers a destabilization of the inflammatory cytokine balance in transplanted patients that leads to a paradoxical inflammatory response with mild stochastic clinical symptoms in the weeks following drug introduction. This pathophysiologic mechanism unifies the various individual inflammatory side effects recurrently reported with sirolimus and suggests that it would make more sense to consider them as a single syndromic entity. The fact that sirolimus interferes with the negative feed back loops controlling inflammatory response indicates that glucocorticoid may efficiently prevent sirolimus-induced inflammatory syndrome.

Seasonal influenza epidemics are associated with high morbidity and mortality particularly in high-risk patients. Conventionally administered influenza vaccines show reduced efficacy in populations with weakened immune systems such as solid-organ transplant patients. This study assesses the safety and immunogenicity of an intradermally administered influenza vaccine in renal transplant patients previously identified as non-responders to a licensed trivalent inactivated influenza vaccine (TIV). Renal transplant patients with low or no hemagglutination inhibiting (HI) antibody response to an A influenza (H3N2) vaccine strain were enrolled in a descriptive phase II, open-label, randomized, multicentre trial: 31 received an investigational intradermal TIV, and 31 received a conventionally administered TIV. Both vaccines contained 15 μg hemagglutinin (HA) per strain. The 62 study subjects were selected from 201 renal transplant patients aged 18-60 years who had been vaccinated in the previous year with a conventionally administered TIV. Vaccination was safe and well tolerated by each administration route. The immunogenicity results of this descriptive study showed ID TIV vaccination to induce HI antibody responses that trended higher in renal transplant patients than conventionally administered TIV. Our results suggest that ID influenza vaccination may offer enhanced immunogenicity and protection in persons who do not respond well to conventional TIV. Further studies should be conducted in immunocompromised populations to validate the trends for higher efficacy of ID vs. conventional route of immunization against influenza.