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  • Wilkinson JD
  • Allen U
  • Green M
  • Dipchand AI
  • Dharnidharka VR
  • et al.
Pediatr Transplant. 2024 Feb;28(1):e14333 doi: 10.1111/petr.14333.

The International Pediatric Transplant Association (IPTA) Consensus Conference on Practice Guidelines for the Diagnosis, Prevention, and Management of Post-Transplant Lymphoproliferative Disorders after Solid Organ Transplantation in Children took place on March 12-13, 2019, and the work of conference members continued until the end of December 2021. The goal was to produce evidence-based consensus guidelines on the definitions, diagnosis, prevention, and management of PTLD and related disorders based on the critical review of the literature and consensus of experts. This report describes the goals, organization, and methodology of the consensus conference and follow-up activities. The results of each working group (Definitions, Prevention, Management, and Epstein-Barr viral [EBV] load/Biomarker Monitoring) are presented in separate manuscripts within this volume of Pediatric Transplantation.

  • Hamilton AD
  • Prætorius HA
  • Praetorius HA
Dan Med J. 2024 Jan 15;71(2) doi: 10.61409/A06230424.
INTRODUCTION:

Renal transplant patients are prone to developing urinary tract infections (UTIs). However, the potential effect of a UTI on renal graft loss remains unclear.

METHODS:

We systematically surveyed the literature for a potential association between UTI and graft loss. Articles were identified in online databases using a specific search string, followed by post selection for meta-analysis following four inclusion criteria: 1) a clear definition of UTI and recurrent UTI, 2) n > 200, 3) patient age > 16 years and 4) inclusion of data on graft loss. Data on UTI and graft loss were extracted from the included studies for calculation of a combined weighted odds ratio (OR) using the Mantel-Haenszel method. This review was conducted according to the PRISMA 2020 statement.

RESULTS:

Unfortunately, only eight of 108 papers met the inclusion criteria. These studies reported between 276 and 2,368 patients, primarily male, aged around 50 years. The two-year incidence of overall UTI varied from 16.5% at a 27.5-month follow-up to 30.1% at a 24-month follow-up from transplantation. Seven papers were included in the OR analysis; two found an association between UTI and graft loss and five did not. However, in the meta-analysis, the weighted OR for all seven studies was 1.340 (95% confidence interval: 1.050-1.720).

CONCLUSIONS:

Filtering the literature for a strict definition of UTI allowed us to establish an association between UTI and graft loss in renal transplant patients. However, further investigation and stronger studies using the Goldman criteria are needed to allow stratification for UTI severity and effect on graft loss.

  • Schultz BG
  • Bullano M
  • Paratane D
  • Rajagopalan K
Transpl Infect Dis. 2024 Jan 14;e14216 doi: 10.1111/tid.14216.
BACKGROUND:

Cytomegalovirus (CMV) infections among hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients impose a significant health care resource utilization (HCRU)-related economic burden. Maribavir (MBV), a novel anti-viral therapy (AVT), approved by the United States Food and Drug Administration for post-transplant CMV infections refractory (with/without resistance) to conventional AVTs has demonstrated lower hospital length of stay (LOS) versus investigator-assigned therapy (IAT; valgancilovir, ganciclovir, foscarnet, or cidofovir) in a phase 3 trial (SOLSTICE). This study estimated the HCRU costs of MBV versus IAT.

METHODS:

An economic model was developed to estimate HCRU costs for patients treated with MBV or IAT. Mean per-patient-per-year (PPPY) HCRU costs were calculated using (i) annualized mean hospital LOS in SOLSTICE, and (ii) CMV-related direct costs from published literature. Probabilistic sensitivity analysis with Monte-Carlo simulations assessed model robustness.

RESULTS:

Of 352 randomized patients receiving MBV (n = 235) or IAT (n = 117) for 8 weeks in SOLSTICE, 40% had HSCT and 60% had SOT. Mean overall PPPY HCRU costs of overall hospital-LOS were $67,205 (95% confidence interval [CI]: $33,767, $231,275) versus $145,501 (95% CI: $62,064, $589,505) for MBV and IAT groups, respectively. Mean PPPY ICU and non-ICU stay costs were: $32,231 (95% CI: $5,248, $184,524) versus $45,307 (95% CI: $3,957, $481,740) for MBV and IAT groups, and $82,237 (95% CI: $40,397, $156,945) MBV versus $228,329 (95% CI: $94,442, $517,476) for MBV and IAT groups, respectively. MBV demonstrated cost savings in over 99.99% of simulations.

CONCLUSIONS:

This analysis suggests that Mean PPPY HCRU costs were 29%-64% lower with MBV versus other-AVTs.

  • Dellgren G
  • Lund TK
  • Raivio P
  • Leuckfeld I
  • Svahn J
  • et al.
Lancet Respir Med. 2024 Jan;12(1):34-44 doi: 10.1016/S2213-2600(23)00293-X.
CET Conclusion
Reviewer: Mr Keno Mentor, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: Tacrolimus has largely replaced ciclosporin as the calcineurin inhibitor of choice for immunosuppression therapy in lung transplant patients in most countries. This is based on evidence, which the Cochrane group graded as low quality, suggesting reduced rates of chronic rejection associated with tacrolimus-based protocols. This randomised controlled trial was based in Scandinavia, where ciclosporin use is still preferred. 249 patients were randomised to either tacrolimus or ciclosporin-based immunosuppression regimes. The primary outcome was rates of chronic lung allograft dysfunction (CLAD), an umbrella term which encompasses a range of syndromes which cause lung graft failure and is predominantly a result of chronic rejection. The authors argue that this is a more clinically relevant measure than the pathology-based assessments used in other studies. Importantly, the clinical assessment of CLAD was based on committee consensus who were blinded to the treatment groups. The rate of CLAD in the tacrolimus group was significantly lower than the ciclosporin group, with lower rates of acute rejection and graft survival at 3 years. As is true in other organ groups, this well-designed study supports the existing evidence that tacrolimus should be the calcineurin inhibitor of choice in immunosuppression therapy after lung transplantation.
Aims: This study aimed to examine the effect of using tacrolimus once per day versus ciclosporin twice per day on the cumulative incidence of chronic lung allograft dysfunction (CLAD) at 36 months following transplantation in de novo lung transplant recipients.
Interventions: Participants were randomised to either the tacrolimus group or the ciclosporin group.
Participants: 264 adult patients (18–70 years) planning to to undergo a de novo double lung transplantation
Outcomes: The primary endpoint was the cumulative incidence of CLAD at 36 months post transplantation. The secondary endpoints were the composite measure of freedom from treated acute rejection and CLAD, and patient and graft survival following transplantation.
Follow Up: 36 months
BACKGROUND:

Evidence is low regarding the choice of calcineurin inhibitor for immunosuppression after lung transplantation. We aimed to compare the use of tacrolimus once per day with ciclosporin twice per day according to the current definition of chronic lung allograft dysfunction (CLAD) after lung transplantation.

METHODS:

ScanCLAD is an investigator-initiated, open-label, multicentre, randomised, controlled trial in Scandinavia evaluating whether an immunosuppressive protocol based on anti-thymocyte globulin induction followed by tacrolimus (once per day), mycophenolate mofetil, and corticosteroids reduces the incidence of CLAD after de novo lung transplantation compared with a protocol using ciclosporin (twice per day), mycophenolate mofetil, and corticosteroids. Patients aged 18-70 years who were scheduled to undergo double lung transplantation were randomly allocated (1:1) to receive either oral ciclosporin (2-3 mg/kg before transplantation and 3 mg/kg [twice per day] from postoperative day 1) or oral tacrolimus (0·05-0·1 mg/kg before transplantation and 0·1-0·2 mg/kg from postoperative day 1). The primary endpoint was CLAD at 36 months post transplantation, determined by repeated lung function tests and adjudicated by an independent committee, and was assessed with a competing-risks analysis with death and re-transplantation as competing events. The primary outcome was assessed in the modified intention-to-treat (mITT) population, defined as those who underwent transplantation and received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02936505) and EudraCT (2015-004137-27).

FINDINGS:

Between Oct 21, 2016, and July 10, 2019, 383 patients were screened for eligibility. 249 patients underwent double lung transplantation and received at least one dose of study drug, and were thus included in the mITT population: 125 (50%) in the ciclosporin group and 124 (50%) in the tacrolimus group. The mITT population consisted of 138 (55%) men and 111 (45%) women, with a mean age of 55·2 years (SD 10·2), and no patients were lost to follow-up. In the mITT population, CLAD occurred in 48 patients (cumulative incidence 39% [95% CI 31-48]) in the ciclosporin group and 16 patients (13% [8-21]) in the tacrolimus group at 36 months post transplantation (hazard ratio [HR] 0·28 [95% CI 0·15-0·52], log-rank p<0·0001). Overall survival did not differ between groups at 3 years in the mITT population (74% [65-81] for ciclosporin vs 79% [70-85] for tacrolimus; HR 0·72 [95% CI 0·41-1·27], log-rank p=0·25). However, in the per protocol CLAD population (those in the mITT population who also had at least one post-baseline lung function test allowing assessment of CLAD), allograft survival was significantly better in the tacrolimus group (HR 0·49 [95% CI 0·26-0·91], log-rank p=0·021). Adverse events totalled 1516 in the ciclosporin group and 1459 in the tacrolimus group. The most frequent adverse events were infection (453 events), acute rejection (165 events), and anaemia (129 events) in the ciclosporin group, and infection (568 events), anaemia (108 events), and acute rejection (98 events) in the tacrolimus group. 112 (90%) patients in the ciclosporin group and 108 (87%) in the tacrolimus group had at least one serious adverse event.

INTERPRETATION:

Immunosuppression based on use of tacrolimus once per day significantly reduced the incidence of CLAD compared with use of ciclosporin twice per day. These findings support the use of tacrolimus as the first choice of calcineurin inhibitor after lung transplantation.

FUNDING:

Astellas, the ALF-agreement, Scandiatransplant Organization, and Heart Centre Research Committee, Rigshospitalet, Denmark.

  • Toniato de Rezende Freschi J
  • Cristelli MP
  • Viana LA
  • Ficher KN
  • Nakamura MR
  • et al.
Transplantation. 2024 Jan 1;108(1):261-275 doi: 10.1097/TP.0000000000004749.
CET Conclusion
Reviewer: Mr Keno Mentor, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: Mammalian target of rapamycin inhibitors (mTORi) have been increasingly investigated as alternate immunosuppression agents for kidney transplant patients to reduce the adverse effects of the current standard combination of mycophenolate and calcineurin inhibitor. Sirolimus and everolimus have distinct pharmacokinetic and pharmacodynamic properties and this trial sought to compare outcomes in kidney transplant patients utilising immunosuppression regimens based on each of these mTORi agents. A standard regimen group (mycophenolate/tacrolimus) was also included as a control. The primary outcome was the rate of CMV infection in the first year after transplantation. There were no significant differences in the rate of CMV infection nor in the secondary outcomes including BK virus infection, acute rejection and delayed graft function between the two mTORi agents. However, the study was limited by a small sample size and short follow-up period.
Aims: This study aimed to compare the outcomes of de novo sirolimus (SRL) versus everolimus (EVR) plus reduced-dose tacrolimus among renal transplant patients.
Interventions: Participants were randomised to one of three groups including the SRL group, the EVR group and the mycophenolate sodium (MPS) group.
Participants: 268 first kidney transplant recipients.
Outcomes: The primary outcome was the incidence of the first CMV infection/disease at 12 months posttransplantation. The secondary outcomes included BK polyomavirus (BKPyV) viremia, treatment failure, de novo donor-specific antibodies, 12-month protocol biopsies, kidney function and drug discontinuation.
Follow Up: 12 months
BACKGROUND:

Mammalian target of rapamycin inhibitors (mTORi), sirolimus (SRL) and everolimus (EVR), have distinct pharmacokinetic/pharmacodynamics properties. There are no studies comparing the efficacy and safety of de novo use of SRL versus EVR in combination with reduced-dose calcineurin inhibitor.

METHODS:

This single-center prospective, randomized study included first kidney transplant recipients receiving a single 3 mg/kg antithymocyte globulin dose, tacrolimus, and prednisone, without cytomegalovirus (CMV) pharmacological prophylaxis. Patients were randomized into 3 groups: SRL, EVR, or mycophenolate sodium (MPS). Doses of SRL and EVR were adjusted to maintain whole blood concentrations between 4 and 8 ng/mL. The primary endpoint was the 12-mo incidence of the first CMV infection/disease.

RESULTS:

There were 266 patients (SRL, n = 86; EVR, n = 90; MPS, n = 90). The incidence of the first CMV event was lower in the mTORi versus MPS groups (10.5% versus 7.8% versus 43.3%, P  < 0.0001). There were no differences in the incidence of BK polyomavirus viremia (8.2% versus 10.1% versus 15.1%, P  = 0.360). There were no differences in survival-free from treatment failure (87.8% versus 88.8% versus 93.3%, P  = 0.421) and incidence of donor-specific antibodies. At 12 mo, there were no differences in kidney function (75 ± 23 versus 78 ± 24 versus 77 ± 24 mL/min/1.73 m 2 , P  = 0.736), proteinuria, and histology in protocol biopsies. Treatment discontinuation was higher among patients receiving SRL or EVR (18.6% versus 15.6% versus 6.7%, P  = 0.054).

CONCLUSIONS:

De novo use of SRL or EVR, targeting similar therapeutic blood concentrations, shows comparable efficacy and safety. The reduced incidence of CMV infection/disease and distinct safety profile of mTORi versus mycophenolate were confirmed in this study.

  • Alghamdi AS
  • Alghamdi H
  • Alserehi HA
  • Babatin MA
  • Alswat KA
  • et al.
Saudi J Gastroenterol. 2024 Jan 1;30(Supp 1):S1-S42 doi: 10.4103/sjg.sjg_333_23.

Hepatitis C virus (HCV) infection has been a major global health concern, with a significant impact on public health. In recent years, there have been remarkable advancements in our understanding of HCV and the development of novel therapeutic agents. The Saudi Society for the Study of Liver Disease and Transplantation formed a working group to develop HCV practice guidelines in Saudi Arabia. The methodology used to create these guidelines involved a comprehensive review of available evidence, local data, and major international practice guidelines regarding HCV management. This updated guideline encompasses critical aspects of HCV care, including screening and diagnosis, assessing the severity of liver disease, and treatment strategies. The aim of this updated guideline is to assist healthcare providers in the management of HCV in Saudi Arabia. It summarizes the latest local studies on HCV epidemiology, significant changes in virus prevalence, and the importance of universal screening, particularly among high-risk populations. Moreover, it discusses the promising potential for HCV elimination as a public health threat by 2030, driven by effective treatment and comprehensive prevention strategies. This guideline also highlights evolving recommendations for advancing disease management, including the treatment of HCV patients with decompensated cirrhosis, treatment of those who have previously failed treatment with the newer medications, management in the context of liver transplantation and hepatocellular carcinoma, and treatment for special populations.

  • Kwa AL
  • Aninda Sidharta BR
  • Son DN
  • Zirpe K
  • Periyasamy P
  • et al.
Expert Rev Anti Infect Ther. 2024 Jan-Jun;22(1-3):45-58 doi: 10.1080/14787210.2023.2296066.
INTRODUCTION:

The South-East Asian (SEA) region and India are highly susceptible to antibiotic resistance, which is caused due to lack of antimicrobial stewardship (AMS) knowledge, uncontrolled use of antibiotics, and poor infection control. Nonadherence to national/local guidelines, developed to combat antimicrobial resistance, is a major concern. A virtual advisory board was conducted to understand the current AMS standards and challenges in its implementation in these regions.

AREAS COVERED:

Procalcitonin (PCT)-guided antibiotic use was discussed in various clinical conditions across initiation, management, and discontinuation stages. Most experts strongly recommended using PCT-driven antibiotic therapy among patients with lower respiratory tract infections, sepsis, and COVID-19. However, additional research is required to understand the optimal use of PCT in patients with organ transplantation and cancer patients with febrile neutropenia. Implementation of the solutions discussed in this review can help improve PCT utilization in guiding AMS in these regions and reducing challenges.

EXPERT OPINION:

Experts strongly support the inclusion of PCT in AMS. They believe that PCT in combination with other clinical data to guide antibiotic therapy may result in more personalized and precise targeted antibiotic treatment. The future of PCT in antibiotic treatment is promising and may result in effective utilization of this biomarker.

  • Zais IE
  • Sirotti A
  • Iesari S
  • Campioli E
  • Costantino A
  • et al.
Clin Transplant. 2024 Jan;38(1):e15218 doi: 10.1111/ctr.15218.
BACKGROUND:

Human-cytomegalovirus (hCMV) infection involving the gastrointestinal tract represents a leading cause of morbidity and mortality among kidney transplant (KT) recipients (KTRs). Signs and symptoms of the disease are extremely variable. Prompt anti-viral therapy administration and immunosuppression modification are key factors for optimizing management. However, complex work-up strategies are generally required to confirm the preliminary diagnosis. Unfortunately, solid evidence and guidelines on this specific topic are not available. We consequently aimed to summarize current knowledge on post-KT hCMV-related gastrointestinal disease (hCMV-GID).

METHODS:

We conducted a systematic review (PROSPERO ID: CRD42023399363) about hCMV-GID in KTRs.

RESULTS:

Our systematic review includes 52 case-reports and ten case-series, published between 1985 and 2022, collectively reporting 311 cases. The most frequently reported signs and symptoms of hCMV-GID were abdominal pain, diarrhea, epigastric pain, vomiting, fever, and GI bleeding. Esophagogastroduodenoscopy and colonoscopy were the primary diagnostic techniques. In most cases, the preliminary diagnosis was confirmed by histology. Information on anti-viral prophylaxis were extremely limited as much as data on induction or maintenance immunosuppression. Treatment included ganciclovir and/or valganciclovir administration. Immunosuppression modification mainly consisted of mycophenolate mofetil or calcineurin inhibitor minimization and withdrawal. In total, 21 deaths were recorded. Renal allograft-related outcomes were described for 26 patients only. Specifically, reported events were acute kidney injury (n = 17), transplant failure (n = 5), allograft rejection (n = 4), and irreversible allograft dysfunction (n = 3).

CONCLUSIONS:

The development of local and national registries is strongly recommended to improve our understanding of hCMV-GID. Future clinical guidelines should consider the implementation of dedicated diagnostic and treatment strategies.

  • Phan J
  • Eslick GD
  • Elliott EJ
J Infect. 2024 Jan;88(1):2-14 doi: 10.1016/j.jinf.2023.11.011.
BACKGROUND:

The sudden outbreak of severe acute hepatitis of unknown aetiology (SAHUA) in the first half of 2022 affected more than 1010 children in 35 countries worldwide. Dire clinical outcomes, such as acute liver failure necessitating transplantation, neurological symptoms, long-term sequelae, and death, highlight the need to determine the pathogenesis of this condition. Hypotheses on the aetiology include adenovirus and SARS-CoV-2 infections and an aberrant immune response to multiple pathogen exposure following lifting of lockdown measures but further investigation is required to reach an informed consensus.

METHODS:

A literature search was performed on MEDLINE and EMBASE in accordance with PRISMA guidelines for systematic reviews. Primary studies reporting data on severe acute hepatitis of unknown aetiology in children from the COVID-19 era were selected for inclusion in our review. Data on patient demographics, clinical presentation and outcomes, and diagnostic testing for coinfection were extracted. Meta-analysis used a random-effects model.

RESULTS:

The 33 included studies (30 case series and 3 case-control studies) described a total of 3636 cases of SAHUA (reported 1 January, 2019-31 December, 2022), with a median age of 3.5 years. Of these, 214 children (5.9%) received a liver transplant and 66 (1.8%) died. Whilst data on diagnostic testing was incomplete, the most frequently detected coinfections were with adenovirus and/or adeno-associated virus 2 (AAV2). Other common childhood respiratory and enteric pathogens, such as enterovirus, rhinovirus, and herpesviruses (EBV and HHV-6), were also identified.

CONCLUSION:

Coinfection with AAV2 and other common childhood pathogens may predispose children to develop this novel severe hepatitis. Altered susceptibility and response to such pathogens may be a consequence of immunological naivety following pandemic restrictions. Further investigations are needed to generate high-quality evidence on aetiology for different patient demographics and geographical areas.

  • Franceschini G
  • Talevi G
  • Maso S
  • Comparcini D
  • Porfiri M
  • et al.
Ann Ig. 2024 Jan-Feb;36(1):41-59 doi: 10.7416/ai.2023.2582.
BACKGROUND:

The implantation of ventricular assist devices is the only effective alternative to cardiac transplantation in patients with chronic heart failure, in terms of survival and quality of life. However, their implantation can lead to physical and psychological complications, potentially preventable, especially in the long term, through patients' education. This research aimed to summarize the current best evidence on educational strategies towards patients after implantation of ventricular assist devices, in home-care setting, to reduce the major related complications, namely driveline infections, gastrointestinal bleeding and psychological complications.

STUDY DESIGN:

Systematic review.

METHODS:

Title and abstract selection, full-text screening, study quality assessment, and data extraction followed the PRISMA protocol and the Cochrane Handbook for Systematic Reviews of Interventions. The search was conducted through consultation of databases such as Medline, Scopus, EMBASE, and Web of Science, during the period from March 2022 to December 2022, in relation to English-language articles, from search strings processing and inclusion and exclusion criteria.

RESULTS:

Of the 1,231 items identified, 9 were selected because consistent with the inclusion criteria. The most effective educational interventions toward patients with ventricular assist devices were identified, delivered by multidisciplinary teams coordinated by a professional expert in management of ventricular assist devices, and regularly conducted. In particular, gastrointestinal bleeding and driveline infections could be prevented and reduced by complex, multimodal educational interventions, including telephone and app interventions. Educational strategies based on verbal instructions, hands-on demonstrations, innovative technologies, and active involvement of families/caregivers were particularly effective in preventing psychological complications.

CONCLUSIONS:

Investing time and resources in educating patients with ventricular assist devices is mandatory, given the significant impact of educational outcomes on complications' reduction. Moreover, educational interventions geared towards patient's psychological well-being, brings positive outcomes on patient's compliance too, resulting in promising clinical outcomes. However, more in-depth research is needed, to support professionals in developing effective educational plans for such fragile and complex patients.