Mycophenolate Research Articles

365.6: Mycophenolate mofetil (MMF) effect on anti-HLA donor-specific antibody (DSA) after pediatric living donor transplantation.

365.6: Mycophenolate mofetil (MMF) effect on anti-HLA donor-specific antibody (DSA) after pediatric living donor transplantation.

P.330: Rapid reduction of mycophenolate mofetil and calcineurin inhibitor dose for treating BK polyomavirus virus infection in renal transplant patients.

P.330: Rapid reduction of mycophenolate mofetil and calcineurin inhibitor dose for treating BK polyomavirus virus infection in renal transplant patients.

The importance of determining the concentration of myco- phenolic acid in children with steroid-dependent nephrotic syndrome

Despite the significant effectiveness of steroid therapy, specialists face serious difficulties in managing patients with steroid-dependent nephrotic syndrome, which requires the prescription of immunosuppressive therapy. Among the available adjuvant drugs, mycophenolate mofetil stands out as a preferred option due to its safety profile, good tolerability, and high efficacy. Currently, only a few studies are presented in the literature on the effectiveness of the use of mycophenolic acid in children with nephrotic syndrome, which is explained by the complexity of the pharmacokinetics of the drug. The article presents the results of a study whose purpose was to evaluate the value of determining mycophenolic acid in patients with steroid-dependent nephrotic syndrome to maintain stable clinical and laboratory remission of the disease. The study examined 78 patients aged 1 to 18 years with steroid-dependent nephrotic syndrome. The results demonstrated that determination of mycophenolic acid concentrations in children with steroid-dependent nephrotic syndrome is an effective method for monitoring therapy for nephrotic syndrome in aunts. Determining the concentration of mycophenolic acid at the C0 point is a highly specific and sensitive method for predicting the development of relapses of the disease, while a mycophenolic acid concentration level of more than 3.2 μg/ml can serve as a minimum guideline for monitoring the use of mycophenolic acid in children with steroid-dependent nephrotic syndrome.

Effect of Immunosuppressive Therapy After Liver Transplantation and the Relationship Between Changes in the Gut Microbiome and Graft Rejection

Solid organ transplantation, particularly liver transplantation, necessitates the use of immunosuppressive therapy to prevent organ rejection. However, these agents profoundly affect the gut microbiota, whose altered state can significantly impact transplant outcomes. This review synthesizes current knowledge on the interactions between immunosuppressants and the gut microbiota and explores the mechanisms by which these interactions affect graft survival and rejection. Immunosuppressive drugs, including cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, prednisone, and azathioprine, are known to cause dysbiosis by decreasing microbial diversity and favoring pathogenic bacteria and fungi. This disruption can lead to increased susceptibility to infections, chronic inflammation, impaired drug metabolism, and direct effects on graft rejection. The review also discusses the potential of modifying the gut microbiota to improve transplant outcomes through dietary interventions, probiotics, prebiotics, and fecal microbiota transplantation (FMT). These interventions aim to restore a healthy microbial balance, enhance immune tolerance, and reduce the incidence of graft rejection. The paper highlights the need for integrated approaches that consider the microbiome’s role in transplantation and outlines future directions for research and clinical practice, aiming to optimize the management of transplant recipients. By understanding and manipulating the gut microbiome, new therapeutic strategies could revolutionize transplant medicine, reducing complications and improving the quality of life for recipients.

CAST Regimen for GvHD Prophylaxis: A CIBMTR Propensity Score-Matched Analysis

Previously, we reported excellent results with the combination of post-transplant cyclophosphamide (PTCy), abatacept, and a short course of tacrolimus (CAST) for the prevention of graft-versus-host disease (GvHD) following peripheral blood haploidentical transplantation. To further substantiate these results, we performed a propensity score-matched analysis. Patients enrolled in the CAST trial were matched with patients from a contemporaneous cohort from the Center for International Blood and Marrow Transplant Research database who received PTCy, tacrolimus, and mycophenolate mofetil, using nearest neighbor propensity score matching. An excellent balance between pairs was achieved as measured by the density distribution and standardized differences of covariates (median 0.09). The rates of acute GvHD grades II to IV at day +120 and 1-year GvHD- and relapse-free survival were 16.7% and 66.7% in the CAST cohort versus 28.6% and 47.6% in the control group, respectively. This trend did not reach statistical significance (P = .14 and .07), possibly due to the small numbers of patients and events. On the other hand, CAST was associated with a statistically significant reduction in the incidence of relapse (9.5% versus 26.2%, P = .045) with improved disease-free survival (85.7% versus 61.9%, P = .01). Our data provides a strong impetus to examine CAST in a randomized clinical trial.

Association Between Baseline Macular Morphologic Features on Optical Coherence Tomography and Visual Outcomes in Patients with Vogt-Koyanagi-Harada Disease.

The choroidal thickening and serous retinal detachments that characterize Vogt-Koyanagi-Harada (VKH) disease can be imaged in detail using spectral domain optical coherence tomography (SD-OCT). Whether specific qualitative and quantitative SD-OCT features at presentation were associated with visual outcomes in a randomized controlled trial comparing methotrexate to mycophenolate for steroid-sparing control of uveitis were evaluated. An exploratory subanalysis of data from the FAST trial in which SD-OCT images from VKH participants were analyzed for presence/absence of bacillary detachments, retinal pigment epithelium (RPE) folds, and internal limiting membrane (ILM) fluctuations was performed. A modified RPE undulation index was calculated to provide a quantifiable surrogate marker for choroidal folds. SD-OCT images were available from 158 eyes with VKH. At baseline, bacillary detachments were present in 23.5% of eyes, RPE folds in 22.8% of eyes, and ILM fluctuations in 35.2% of eyes. For each 0.1 unit increase in modified RPE undulation index, there was an associated 0.13 increase in mean logMAR BSCVA at baseline. None of the SD-OCT features were associated with BSCVA at the 6-month primary endpoint. Indeed, mean final BSCVA was similar in those with and without the SD-OCT features of interest at baseline, and was between 0.1 and 0.2 logMAR (Snellen visual acuity 20/25 to 20/30). While eyes with VKH may present with a variety of SD-OCT imaging pathology prior to starting immunosuppression with methotrexate or mycophenolate mofetil, final visual outcome in our study was excellent. With appropriate immunosuppression, good visual outcomes are possible in VKH.ClinicalTrials.gov Identifier NCT01829295Date of Registration: April 11, 2013.

In vitro mechanistic study on mycophenolate mofetil drug interactions: effect of prednisone, cyclosporine, and others.

The metabolism- and transporter-based drug-drug interactions (DDIs) between mycophenolate mofetil (MMF) and co-administered medications may be key factors for the high individual variability in MMF exposure. This study systematically assessed the influence of co-medications on the mycophenolic acid (MPA) pharmacokinetic (PK) process in vitro, particularly to provide mechanistic evidence of the metabolic interaction among steroids, cyclosporine (CsA), and MMF. Based on a previous study, we hypothesized that there are three main DDI pathways affecting MMF PK in vivo. A human hepatocyte induction study, transporter substrate/inhibition study using human embryonic kidney 293 cells, and multidrug resistance-associated protein 2 (MRP2) substrate/inhibition study using vesicle membrane were conducted to assess the mechanistic evidence of the metabolic interaction in triple therapies. The potential DDI risks associated with seven medications commonly co-administered with MMF in clinical practice were further evaluated. The in vitro results suggested that prednisolone, the active metabolite of prednisone, induces the enzymatic activity of uridine 5'-diphospho-glucuronosyltransferase (UGT), particularly the UGT1A9 and UGT2B7 isoforms, resulting in increased metabolism of MPA to MPA glucuronide (MPAG). This induction potential was not observed in CsA-treated human hepatocytes. CsA inhibits organic anion-transporting polypeptide (OATP) 1B1- and OATP1B3-mediated MPAG. Prednisolone and CsA showed no inhibitory effect on MRP2-mediated MPAG efflux. Salvia miltiorrhiza significantly inhibited organic anion-transporting polypeptide and OAT 3 activities, suggesting that it affects the hepatic uptake and renal excretion of MPAG, causing increased MPAG exposure in vivo. These identified factors may contribute to the high inter-individual variability in MMF exposure and facilitate further development of mechanistic MMF PK models and individualized therapies.

An enhanced electrochemical sensor using ZnO nanoparticles to measure mycophenolate mofetil: A cyclic voltammetric investigation

Zinc oxide nanoparticles (ZnO Nps) were prepared in the current work utilizing a chemical co-precipitation technique with the aim of electrochemically detecting mycophenolate mofetil (MMF). The synthesized nanoparticles showed increased crystallinity with particle diameters of roughly 25.26 nm when analyzed using X-ray diffraction (XRD), scanning electron microscopy (SEM), and EDAX tests. Throughout the research, the physiological pH of 7.4 was kept constant. ZnO Nps-incorporated carbon paste electrode exhibits a significant electroactive surface area (0.0378 cm2), better sensitivity, and consistent current responses as compared to the bare carbon paste electrode (0.0285 cm2). Furthermore, a multitude of additional experiments were carried out, such as sweep rate, concentration, and pH studies, which demonstrated decreased LOD and LOQ, or 0.6 and 1.99 µM, respectively. The modified electrode showed superior stability at 94 % by maintaining its activity. The designed electrode showed a greater recovery of mycophenolate mofetil (MMF) in the 96–98.5 % range, when tested further for an actual sample analysis of MMF in a human urine research.

Incidence, risk factors and therapy response of acute graft-versus-host disease after myeloablative hematopoietic stem cell transplantation with posttransplant cyclophosphamide.

Posttransplant cyclophosphamide, sirolimus and mycophenolate mofetil (PTCy/siro/MMF) constitutes an innovative and well-tolerated acute graft-versus-host disease (aGVHD) prophylaxis after allogeneic stem cell transplantation (allo-HSCT), but risk factors for aGVHD incidence and therapy failure in this setting are scarce. This study prospectively registered all consecutive adult patients with hematologic malignancies who received a myeloablative allo-HSCT using PTCy/siro/MMF prophylaxis at our institution between 2017 and 2023. A total of 385 patients were included, of whom 44%, 34% and 22% were transplanted from matched sibiling, matched unrelated and haploidentical donors, respectively. The 180-day cumulative incidence of aGVHD was 21% (95% confidence interval [CI] 17-25%) for grade II-IV and 11% (95% CI 8-14%) grade III-IV aGVHD. The use of haploidentical donors was associated with an increased risk of severe aGVHD. Among 75 patients receiving first-line systemic corticosteroids, 49% achieved a sustained complete response, while 23% and 24% developed steroid-dependent (SD-aGVHD) and steroid-refractory aGVHD (SR-aGVHD), respectively. SR-aGVHD was associated with worse salvage treatment response and overall survival compared to SD-aGVHD. The 1-year cumulative incidence of aGVHD-related mortality was 5.4% (95% CI, 3.3-8.1). Risk factors for aGVHD-related mortality included haploidentical donors, older donors, diagnosis of myeldysplastic neoplasms, and grade IV aGVHD. This study confirms a low incidence aGVHD with PTCy/siro/MMF prophylaxis. SR-aGVHD showed poorer response to salvage therapies and worse survival, while haploidentical donors and older donor age were negative predictors for aGVHD-related deaths.

The Consequences of HLA Screening in the Prevention of Graft-Versus-Host Disease in Living Donor Liver Transplantation.

To study the effects of routine HLA screening and the policy of avoiding donor-dominant one-way HLA match to prevent graft-versus-host disease (GVHD) after living donor liver transplantation (LDLT). The records of potential living liver donors and recipients who attended our center between 2007 and 2018 were reviewed retrospectively. Of the 149 patients who underwent LDLT and survived longer than 3 months, two developed GVHD despite our strict policy. The first patient presented with grade II GVHD limited to the skin. She was treated successfully by briefly discontinuing immunosuppression and switching to everolimus. In the second case, the policy had been relaxed due to the availability of a single donor for ABO-incompatible transplantation without any intervention to decrease anti-A antibody levels (special case: A2 to O). Nevertheless, the patient presented with grade I GVHD limited to skin and was treated successfully by adding oral methylprednisolone to tacrolimus and mycophenolate mofetil. To the best of our information, this is the second reported case who recovered from GVHD after LDLT from a donor, homozygous at HLA A, B and DR and a recipient, heterozygous for all. Sixteen potential donors (1.2% of all candidates) of 14 recipients were disqualified solely on the basis of the HLA results; five of these patients died due to unavailability of another donor. The results support the policy of avoiding HLA combinations that preclude immune recognition of graft lymphocytes as foreign to decrease the risk of GVHD after LDLT.

Graft Versus Host Disease Prophylaxis in Matched Donor Stem Cell Transplantation: Post-transplantation Cyclophosphamide Combinations Versus Methotrexate/Tacrolimus

BackgroundThe use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft versus host disease (GVHD) for haploidentical allogeneic hematopoietic stem cell transplantation (allo-HSCT). There is limited data on the role of PTCy as GVHD prophylaxis in matched-sibling and fully matched-unrelated donor (MSD/MUD) allo-HSCT. MethodsOur single-center retrospective study aims to compare outcomes of PTCy alone or in combination with mycophenolate mofetil and tacrolimus (PTCy/MMF/TAC) relative to methotrexate and tacrolimus (MTX/TAC). The primary endpoint of our study was GVHD-free, relapse free survival (GRFS). Secondary endpoints were overall survival (OS), disease free survival (DFS), and incidence of severe acute and chronic GVHD. We identified 74 adult patients who underwent MSD/MUD allo-HSCT at our institution from 2015 to 2023. ResultsWithin our cohort, 33.8% (n = 25) received MTX/TAC, while 54.0% (n = 40) received PTCy/MMF/TAC, and 12.2% (n = 9) received PTCy alone. Patients receiving PTCY had the longest time to neutrophil engraftment relative to MTX/TAC (15 days vs. 12 days, P = .010). PTCy/MMF/TAC was associated with improved GRFS relative to MTX/TAC (hazard ratio [HR] = HR 0.42, 95% CI 0.19-0.93, P = .031), which persisted when controlling for age. Incidence of chronic GVHD was lower in the PTCy/MMF/TAC group compared to MTX/TAC (1-year 9.0% vs. 30.1%, HR 0.19, 95% CI 0.06-0.59, P = .005). However, OS and DFS were comparable across all groups. ConclusionsOur results demonstrate decreased rates of severe chronic GVHD resulting in improved GRFS when using PTCy/TAC/MTX as GVHD prophylaxis compared to MTX/TAC in MSD/MUD.

Evaluation of dupilumab on the disease burden in children and adolescents with atopic dermatitis: A population-based cohort study.

Dupilumab is the first and only biologic agent approved for the treatment of atopic dermatitis (AD) in pediatric patients aged from 6 months to 17 years. The study aimed to evaluate the impact of dupilumab on the occurrence of comorbidities in pediatric patients with AD. In this population-based cohort study, we utilized electronic healthrecords from multiple healthcare organizations across the United States. Pediatric patients (<18 years of age) with a diagnosis of AD initiating dupilumab were propensity-score matched 1:1 to those initiating other systemic agents (azathioprine, cyclosporine, methotrexate, mycophenolate mofetil, or systemic corticosteroids). The primary outcomes were new-onset comorbidities emerging during the study period measured by the risk ratio (RR) and its confidence interval (CI). Subgroup analyses were stratified by age (0-5 years, 6-11 years, and 12-17 years), sex, and race. A total of 3575 pediatric patients with AD treated with dupilumab were matched to 3575 patients treated with other systemic agents. The dupilumab cohort was associated with a lowered risk of new-onset atopic comorbidities (including asthma [RR, 0.72; 95% CI, 0.59-0.89] and allergic rhinitis [RR, 0.62; 95% CI, 0.52-0.74]), infections (e.g., skin and soft tissue infection [RR, 0.70; 95% CI, 0.63-0.76] and respiratory tract infection [RR = 0.56; 95% CI, 0.51-0.61]), psychiatric disorders (e.g., mood disorder [RR, 0.52; 95% CI, 0.39-0.70] and anxiety [RR, 0.57; 95% CI, 0.46-0.70], sleep disturbance [RR, 0.60; 95% CI, 0.47-0.77]), neurologic and developmental disorders (e.g., attention deficit hyperactivity disorder [RR, 0.54; 95% CI, 0.38-0.75]). Furthermore, the positive effects are found to be more pronounced in younger children (aged 0-5 years) with AD. Treatment with dupilumab compared to systemic agents resulted in reductions in AD-related comorbidities in pediatric patients.

Efficacy of Disease-Modifying Antirheumatic Drugs in Primary Sjögren's Syndrome-related Interstitial Lung Disease

Objectives: To evaluate the treatment modalities and their effects in primary Sjögren's syndrome (pSS) patients with interstitial lung disease (ILD)Methods: In this chart review study, patients diagnosed with pSS-related ILD (pSS-ILD) between January 2004 and August 2022 were screened. Glucocorticoid use and administered disease-modifying antirheumatic drugs (DMARDs) were determined. The difference between forced vital capacity (FVC) and diffusion capacity of the lungs for carbon monoxide (DLCO) before and after treatment was evaluated.Results: ILD was present in 44 of 609 patients (7.2%) diagnosed with pSS. In 27 patients included in the study, steroid usage was 81.5%. There was a statistically insignificant increase in FVC% (from 80.20±22.1 to 81.6±23.0) and a decrease in DLCO% (53.7±15.3 to 52.2±19.3) with DMARD treatment (p=0.434 and p=0.652, respectively). There was no significant difference between the treatment groups (azathioprine [AZA], mycophenolate mofetil [MMF], and rituximab [RTX]) in terms of the change in FVC% and DLCO% compared with baseline levels. The effect of treatment on FVC and DLCO was similar in UIP and NSIP patterns.Conclusions: AZA, MMF, and RTX have similar effects on pulmonary functions in pSS-ILD and provide disease stabilization.

Use of immunomodulators in non-infectious uveitis: lights and shadows.

Non-infectious uveitis (NIU) is one of the leading causes of sight impairment worldwide. Corticosteroids are the mainstay treatment for acute NIU, although their known systemic and ocular side effects limit their long-term use. The most common types of immunosuppressants used as steroid-sparing treatment are non-biologic drugs, particularly antimetabolites (methotrexate, mycophenolate mofetil, and azathioprine) and biologic drugs, mainly TNF-α inhibitors such as Adalimumab or Infliximab. Antimetabolites have shown their effectiveness in the treatment of NIU in individual and comparative studies, being methotrexate and mycophenolate mofetil usually preferred over azathioprine. The choice of which antimetabolite to use at first is not well defined, and decisions usually depend on the patient's characteristics and the physician's preferences. Treatment of NIU with biologic drugs, and particularly TNF-α inhibitors, has significantly increased in the last years and is considered an important alternative in patients not responding to first-line immunomodulators such as antimetabolites. However, data regarding how different immunomodulators or biologic drugs perform in different NIU is still limited, and little is known about the optimization of both biologic and non-biologic drugs when used in NIU. Further randomized clinical trials and comparative studies are required to achieve more understanding and better results when addressing complicated NIU. The purpose of this review is to provide a comprehensive overview of the use of non-biologic and biologic drugs in NIU, which may be useful for clinicians in their daily practice, and to address those aspects that are less known about these treatments as well as their weaknesses.

Management and outcomes of hidradenitis suppurativa in solid organ transplant recipients.

This case series includes patients with hidradenitis suppurativa (HS) who underwent solid organ transplant with subsequent transplant-related immunosuppression. Most patients in this case series experienced improvement of their HS following the initiation of transplant immunosuppressive treatment, particularly with the majority on tacrolimus and mycophenolate mofetil.

Severity and organ distribution of graft-versus-host disease with post-transplant cyclophosphamide versus calcineurin inhibitor plus methotrexate/mycophenolate mofetil or sirolimus in allogenic HLA-matched or single-allele mismatched stem cell transplantation.

This retrospective single center study aims to describe changes in the severity and organ-specific distribution of GvHD, by comparing the outcomes of 3 distinct GvHD prophylaxis approaches. Between January 2012 and June 2022, 226 patients underwent allogeneic hematopoietic stem cell transplantation from HLA-matched or 1-allele mismatched related or unrelated donors. Fifty-eight (26%) received prophylaxis with calcineurin inhibitor in combination with mycophenolate mofetil or a short course of methotrexate (Cohort-1), 87 (38%) tacrolimus plus sirolimus (Cohort-2), and 81 (36%) post-transplant cyclophosphamide (PTCy) plus tacrolimus (Cohort-3). The incidence of grade II-IV aGvHD was 69% vs. 41.4% vs. 27.2%; p < .01. The most significant reduction with PTCy was observed in both stage 3-4 skin and lower gastrointestinal (GI) involvement (p < .01). The incidence of moderate-to-severe cGvHD at 12 months was 34.5% vs. 34.5% vs. 6.2%; p < .01. Moderate-to-severe skin and GI cGvHD was less common after PTCy (p < .01). The 1-year GvHD-free/relapse-free survival was higher with PTCy (p < .01). Our study indicates that PTCy-based GvHD prophylaxis reduces the frequency and severity of both acute and chronic GvHD, with a notable decrease in severe GI and cutaneous manifestations. The higher GRFS may result in lower GvHD-related mortality, leading to an improved quality of life among survivors.

Mycophenolate Mofetil for the Treatment of Warm Autoimmune Haemolytic Anaemia Post-Rituximab Therapy: A Case Series.

Warm autoimmune haemolytic anaemia (wAIHA) is an acquired haemolytic disorder most commonly treated with a combination of corticosteroids, rituximab and/or splenectomy. Third-line therapies for refractory cases include immunosuppressive agents. Mycophenolate mofetil is frequently used in these scenarios, although its use is supported by small studies and anecdotal evidence rather than large-scale data. We describe three cases of refractory warm autoimmune haemolytic anaemia successfully treated with mycophenolate mofetil. Case 1: A persistent case of autoimmune haemolytic anaemia in a 56-year-old was ultimately managed with mycophenolate mofetil, leading to successful steroid tapering and stable haemoglobin levels without relapse. Case 2: A woman with a complex oncological history, including lymphoma and breast cancer, achieved remission with mycophenolate therapy, maintaining stability post-steroid treatment. Case 3: Mycophenolate proved effective for a 63-year-old with cirrhosis after recurrent autoimmune anaemia and deep vein thrombosis, enabling cessation of steroids and maintaining remission. Management of this condition can be challenging and balancing the available treatments is crucial to reduce potential complications from long-term therapies that appear to be ineffective. Our case series demonstrates anecdotal experience on successful use of mycophenolate mofetil for complex refractory cases of wAIHA. Warm autoimmune haemolytic anaemia can be a challenging condition to manage. Refractory cases that are steroid-dependent can benefit from trialling steroid-sparing agents such as mycophenolate.Anti-CD20 agents such as rituximab can be very effective in refractory cases, however there is a small percentage of patients that might not be responsive to this monoclonal antibody.Autoimmune haemolytic anaemias can be frequently complicated by thrombotic events, and part of the backbone treatment is establishing good thromboprophylaxis.

The Use of Immunomodulators, Biologic Therapies, and Small Molecules in Patients With Inflammatory Bowel Disease and Solid Organ Transplant.

Patients with inflammatory bowel diseases (IBDs) may require solid organ transplants (SOTs) for multiple reasons, making its prevalence slightly higher than the general population. Although immunosuppression used in SOT may help control IBD-related inflammation, many patients still require additional immunosuppressive medications. We aim to assess the effectiveness and safety of the combination of SOT-related immunosuppression and IBD medications in patients with liver, kidney, or heart transplantation. We conducted a clinical review using PubMed, Scopus, MEDLINE, Embase, and Google Scholar databases for our search. We included data from systematic reviews, meta-analyses, case series, and case reports to assess the safety, effectiveness, and side effect profile of immunomodulators, biologic therapies, and small molecules in patients with SOT. Our review encompassed 25 liver, 6 kidney, and 1 heart transplant studies involving patients with IBD. Common liver transplant immunosuppressants included tacrolimus, mycophenolate mofetil, cyclosporine, and steroids. Anti-TNF agents, widely used in all SOT types, showed no significant safety issues, though infections and malignancies were noted. Patients with liver transplant on tacrolimus responded well to anti-integrins and ustekinumab without major complications. For kidney transplants, cyclosporine and tacrolimus were prevalent, and their combination with anti-TNF or ustekinumab was generally safe, with rare reports of malignancy or infection. Hence, the use of anti-TNF, anti-integrin agents, and ustekinumab appears to be safe in patients with SOT, regardless of their transplant related immunosuppression. More studies are needed in patients with kidney and heart transplants and in patients treated with small molecules for their IBD.

Advances in understanding and managing pediatric heart failure and transplant.

This article highlights the most recent advances in a review of the current literature in the field of pediatric heart failure and transplantation. Diagnostically, the identification of new genetic factors has contributed to a deeper understanding of cardiomyopathy in children. Novel medications like sacubitril/valsartan and Sodium-Glucose cotransporter-2 (SGLT2) inhibitors, which are now standard in the adult population are being studied in pediatric population and offer new promise of pediatric heart failure treatment. Ventricular assist devices are more commonly used in cardiomyopathy patients and single ventricle patients as a bridge to transplant. Recent pediatric heart transplant society (PHTS) data demonstrated that waitlist survival improved significantly over the past decades (i) and new treatments such as daratumumab and eculizumab have been used in high-risk populations and demonstrate promising results. TEAMMATE trial is the first multicenter randomized clinical trial (RCT) in pediatric heart transplant (HT) to evaluate the safety and efficacy of everolimus (EVL) and low-dose tacrolimus (TAC) compared to standard-dose TAC and mycophenolate mofetil (MMF). It will provide valuable information about the safety and efficacy of EVL, TAC, and MMF (ii).Donor cell-free DNA has been used more in pediatric transplant recipients and has significantly decreased invasive EMB (iii). This past 5 years have witness dramatic progress in the field of pediatric heart failure and transplantation including more use of mechanical support in heart failure patients with various underlying etiology, especially use of mechanical support in single ventricle patients and the use of sacubitril/valsartan and SGLT2 inhibitors in the pediatric population. The problem of the highly sensitized transplant recipient remains, although novel therapeutics have been added to our toolbox of options to maintain healthy allograft function. Ongoing research aims to further enhance our understanding and management of pediatric heart failure, emphasizing the need for continued innovation in this complex field.

Reversible cerebral vasoconstriction syndrome post-cardiac transplantation: a therapeutic dilemma: case report

BackgroundReversible cerebral vasoconstriction syndrome (RCVS) is characterized by diffuse, multifocal segmental narrowing of cerebral arteries and can result in ischaemic stroke. Causal factors, identified in 60% of cases, include immunosuppressant pharmacotherapy. The few reports following heart transplantation are almost all in Asian recipients. We report on a Caucasian Australian patient with immunotherapy induced RCVS post heart transplantation to highlight the state of knowledge of the condition and the treatment dilemma it poses.Case presentationA 51-year-old female underwent orthotopic heart transplantation at our institution. Induction immunotherapy comprised basiliximab, mycophenolate mofetil and methylprednisolone. On day 6 post-transplantation the patient was transitioned to oral prednisolone and tacrolimus. On day 7 the patient began to experience bilateral, severe, transient occipital and temporal headaches. On day 9 tacrolimus dose was up-titrated. A non-contrast computed tomography brain (CTB) was normal. Endomyocardial biopsy on day 12 demonstrated moderate Acute Cellular Rejection (ACR), which was treated with intravenous methylprednisolone. That evening the patient experienced a 15-minute episode of expressive dysphasia. The following morning she became confused, aphasic, and demonstrated right sided neglect and right hemianopia. A CT cerebral perfusion scan demonstrated hypoperfusion in the left middle cerebral artery (MCA) territory and cerebral angiography revealed widespread, focal multi-segmental narrowing of the anterior and posterior circulations. A diagnosis of RCVS was made, and nimodipine was commenced. As both steroids and tacrolimus are potential triggers of RCVS, cyclosporin replaced tacrolimus and methylprednisolone dose was reduced. A further CTB demonstrated a large left MCA territory infarct with left M2 MCA occlusion. The patient made steady neurological improvement. She was discharged 34 days post-transplantation with mild residual right lower limb weakness and persistent visual field defect on verapamil, cyclosporine, everolimus, mycophenolate mofetil and prednisolone.ConclusionReversible cerebral vasoconstriction syndrome is rare after orthotopic heart transplantation. Until now, RCVS has been almost exclusively described in Asian recipients, and is typically caused by immunotherapy. The condition may lead to permanent neurological deficits, and in the absence of definitive treatments, early recognition and imaging based diagnosis is essential to provide the opportunity to remove the causal agent(s). Co-existent ACR, can pose unique treatment difficulties.