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.

BACKGROUND:

Invasive fungal infections are associated with high morbidity in solid organ transplant recipients. Risk factor modification may help with preventative efforts. The objective of this study was to identify risk factors for the development of fungal infections within the first year following solid organ transplant.

METHODS:

We searched for eligible articles through February 3, 2023. Studies published after January 1, 2001, that pertained to risk factors for development of invasive fungal infections in solid organ transplant were reviewed for inclusion. Of 3087 articles screened, 58 were included. Meta-analysis was conducted using a random-effects model to evaluate individual risk factors for the primary outcome of any invasive fungal infections and invasive candidiasis or invasive aspergillosis (when possible) within 1 y posttransplant.

RESULTS:

We found 3 variables with a high certainty of evidence and strong associations (relative effect estimate ≥ 2) to any early invasive fungal infections across all solid organ transplant groups: reoperation (odds ratio [OR], 2.92; confidence interval [CI], 1.79-4.75), posttransplant renal replacement therapy (OR, 2.91; CI, 1.87-4.51), and cytomegalovirus disease (OR, 2.97; CI, 1.78-4.94). Both posttransplant renal replacement therapy (OR, 3.36; CI, 1.78-6.34) and posttransplant cytomegalovirus disease (OR, 2.81; CI, 1.47-5.36) increased the odds of early posttransplant invasive aspergillosis. No individual variables could be pooled across groups for invasive candidiasis.

CONCLUSIONS:

Several common risk factors exist for the development of any invasive fungal infections in solid organ transplant recipients. Additional risk factors for invasive candidiasis and aspergillosis may be unique to the pathogen, transplanted organ, or both.

BACKGROUND:

Influenza-associated pulmonary aspergillosis (IAPA) increasingly is being reported in critically ill patients. We conducted this systematic review and meta-analysis to examine the prevalence, risk factors, clinical features, and outcomes of IAPA.

STUDY QUESTION:

What are the prevalence, risk factors, clinical features, and outcomes of IAPA in critically ill patients?

STUDY DESIGN AND METHODS:

Studies reporting IAPA were searched in the following databases: PubMed MEDLINE, CINAHL, Cochrane Library, Embase, Scopus, Cochrane Trials, and ClinicalTrials.gov. We performed one-group meta-analysis on risk factors, clinical features, morbidity, and mortality using random effects models.

RESULTS:

We included 10 observational studies with 1,720 critically ill patients with influenza, resulting in an IAPA prevalence of 19.2% (331 of 1,720). Patients who had undergone organ transplantation (OR, 4.8; 95% CI, 1.7-13.8; I2 = 45%), harbored a hematogenous malignancy (OR, 2.5; 95% CI, 1.5-4.1; I2 = 0%), were immunocompromised (OR, 2.2; 95% CI, 1.6-3.1; I2 = 0%), and underwent prolonged corticosteroid use before admission (OR, 2.4; 95% CI, 1.4-4.3; I2 = 51%) were found to be at a higher risk of IAPA developing. Commonly reported clinical and imaging features were not particularly associated with IAPA. However, IAPA was associated with more severe disease progression, a higher complication rate, and longer ICU stays and required more organ supports. Overall, IAPA was associated with a significantly elevated ICU mortality rate (OR, 2.6; 95% CI, 1.8-3.8; I2 = 0%).

INTERPRETATION:

IAPA is a common complication of severe influenza and is associated with increased mortality. Early diagnosis of IAPA and initiation of antifungal treatment are essential, and future research should focus on developing a clinical algorithm.

TRIAL REGISTRY:

International Prospective Register of Systematic Reviews; No.: CRD42022284536; URL: https://www.crd.york.ac.uk/prospero/.

Epstein-Barr Virus (EBV) diseases, including EBV-associated post-transplant lymphoproliferative disorder (PTLD) remain important causes of morbidity and mortality in children undergoing solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT). Despite progress in the prevention of EBV disease including PTLD (EBV/PTLD) in HCT, key questions in the prevention, and management of these infectious complications remain unanswered. The goal of this manuscript is to highlight key points and recommendations derived from the consensus guidelines published by the International Pediatric Transplant Association and the European Conference on Infections in Leukemia for children undergoing SOT and HCT, respectively. Additionally, we provide background and guidance on the use of EBV viral load measurement in the prevention and management of these children.

BACKGROUND:

Whether trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis prevents nocardiosis in solid organ transplant (SOT) recipients is controversial.

OBJECTIVES:

To assess the effect of TMP-SMX in the prevention of nocardiosis after SOT, its dose-response relationship, its effect on preventing disseminated nocardiosis, and the risk of TMP-SMX resistance in case of breakthrough infection.

METHODS:

A systematic review and individual patient data meta-analysis.

DATA SOURCES:

MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science Core Collection, and Scopus up to 19 September 2023.

STUDY ELIGIBILITY CRITERIA:

(a) Risk of nocardiosis between SOT recipients with and without TMP-SMX prophylaxis, or (b) sufficient details to determine the rate of TMP-SMX resistance in breakthrough nocardiosis.

PARTICIPANTS:

SOT recipients.

INTERVENTION:

TMP-SMX prophylaxis versus no prophylaxis.

ASSESSMENT OF RISK OF BIAS:

Risk Of Bias In Non-randomized Studies-of Exposure (ROBINS-E) for comparative studies; dedicated tool for non-comparative studies.

METHODS OF DATA SYNTHESIS:

For our primary outcome (i.e. to determine the effect of TMP-SMX on the risk of nocardiosis), a one-step mixed-effects regression model was used to estimate the association between the outcome and the exposure. Univariate and multivariable unconditional regression models were used to adjust for the potential confounding effects. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

RESULTS:

Individual data from three case-control studies were obtained (260 SOT recipients with nocardiosis and 519 uninfected controls). TMP-SMX prophylaxis was independently associated with a significantly decreased risk of nocardiosis (adjusted OR = 0.3, 95% CI 0.18-0.52, moderate certainty of evidence). Variables independently associated with an increased risk of nocardiosis were older age, current use of corticosteroids, high calcineurin inhibitor concentration, recent acute rejection, lower lymphocyte count, and heart transplant. Breakthrough infections (66/260, 25%) were generally susceptible to TMP-SMX (pooled proportion 98%, 95% CI 92-100).

CONCLUSIONS:

In SOT recipients, TMP-SMX prophylaxis likely reduces the risk of nocardiosis. Resistance appears uncommon in case of breakthrough infection.

The International Pediatric Transplant Association (IPTA) convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorder after solid organ transplantation in children. In this report from the Prevention Working Group, we reviewed the existing literature regarding immunoprophylaxis and chemoprophylaxis, and pre-emptive strategies. While the group made a strong recommendation for pre-emptive reduction of immunosuppression at the time of EBV DNAemia (low to moderate evidence), no recommendations for use could be made for any prophylactic strategy or alternate pre-emptive strategy, largely due to insufficient or conflicting evidence. Current gaps and future research priorities are highlighted.

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.

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.

(1) Background: Organ transplant recipients (OTRs) are vulnerable groups at risk of parasitic infections. This systematic review and meta-analysis aimed to evaluate the overall prevalence of Cryptosporidium sp. in OTRs and shed light on this potentially serious complication of organ transplantation. (2) Methods: We systematically searched studies on Cryptosporidium sp. infections in OTRs in four databases (Academia, PubMed, Scopus, and Science Direct). Random effects models were used to calculate pooled prevalence estimates with 95% confidence intervals (CIs). Sub-group and meta-regression analyses were conducted. A quality assessment of the included studies was also performed. (3) Results: Among 876 articles retrieved, 21 were included, accounting for 2,642 OTRs. Twenty studies were cross-sectional in design, of which seven reported data on a comparison group, and one was a retrospective cohort. The pooled prevalence of Cryptosporidium sp. in OTRs was 15% (95% CI: 7.4-24.6). Subgroup analysis revealed that the prevalence of Cryptosporidium sp. infection was higher in adults, symptomatics and developing countries and in studies using only non-molecular methods. However, substantial heterogeneity was reported. Low to moderate heterogeneity was observed in subgroups reporting lower prevalence Cryptosporidium sp. including children (5.8; 95% CI: 2.8-9.6), studies conducted in developed countries (5.8; 95% CI: 3.0-9.4) and studies using both molecular and non-molecular diagnostics (11.4; 95% CI: 6.4-17.4). The majority of the listed research reported low-medium quality scores. (4) Conclusion: Cryptosporidium sp. infection is a significant complication in OTRs with underreported prevalence. Preventive strategies to reduce the burden should include Cryptosporidium sp. routine screening for OTRs, particularly post-transplantation in patients with diarrhea. Additional well-designed research studies are required to determine the extent of the Cryptosporidium sp. burden in OTRs.