Approach to multidrug resistant infections in pediatric transplant recipients.

Introduction: There is increasing recognition of infections due to multidrug-resistant Gram negative (MDRGN) bacterial infections among children undergoing solid organ and hematopoietic cell transplantation, which may be associated with morbidity and mortality. Methods: We present two vignettes that highlight the clinical challenges of evaluation, management, and prevention of MDRGN bacterial infections in children prior to and after transplantation. The goal of this discussion is to provide a framework to help develop an approach to evaluation and management of these infections. Results: Source control remains the utmost priority in management of MDR infections and is paired with antibiotic selection guided by in vitro susceptibilities, adverse effect profiles, and clinical response. Identification and confirmation of resistance can be challenging and often requires additional testing for recognition of complex mechanisms. Current antimicrobial approaches to MDRGN infections include use of novel agents, prolonged infusion, and/or combination therapy. We also discuss preventative efforts including infection control, antimicrobial stewardship, targeted pre-emptive or prophylactic treatment, and decolonization. Discussion: The impact of MDRGN infections on patient and graft survival highlights the need to optimize treatment and prevention strategies.

Epidemiology and outcomes of invasive aspergillosis among pediatric immunocompromised patients: A 12-year single-center experience.

Invasive aspergillosis (IA) remains a common cause of mortality in pediatric immunocompromised populations. Much of our knowledge of IA stems from adult literature. We conducted a retrospective evaluation of cases of proven or probable IA, defined according to the 2019 EORTC/MSG criteria, in patients with underlying immunocompromising conditions at Boston Children's Hospital from January 1, 2007 to January 1, 2019. We estimated survival curves over 12 weeks using the Kaplan-Meier method for all-cause mortality, and we used univariate Cox proportional hazards modeling to evaluate for mortality risk factors. We identified 59 cases, 29% with proven and 71% with probable IA. Pulmonary IA was the most common presentation (78%). The median age at diagnosis was 11 years (range, 0.5-28). Hematopoietic cell transplantation (HCT) was the most frequent predisposing underlying condition (41%). Among affected patients, 44.8% were neutropenic and 59.3% were lymphopenic at diagnosis. The 12-week all-cause mortality rate was 25.4%; HCT recipients comprised the majority of deaths (9/15) with a hazard ratio of 2.47 [95% CI, 0.87-6.95]. No patients with congenital immunodeficiencies (n = 8) died within 12 weeks of IA diagnosis. Other risk factors that were significantly associated with mortality included mechanical ventilation at diagnosis, intensive care unit stay, and lymphopenia; treatment with an Aspergillus-active azole was associated with decreased mortality.In conclusion, our study found that in pediatric immunocompromised hosts, IA is associated with a high 12-week all-cause mortality rate, with a particular impact on the HCT population. LAY ABSTRACT: This study explores the epidemiology, outcomes and predictors of mortality of invasive aspergillosis (IA) at a high-volume pediatric center for immunocompromised hosts. Much of our understanding of pediatric IA is extrapolated from the adult literature. Our study found that IA is associated with a high 12-week all-cause mortality rate, with a particular impact on the hematopoietic cell transplantation study cohort.

Progressive multifocal leukoencephalopathy presenting with acute sensorineural hearing loss in an intestinal transplant recipient.

A 20-year-old male presented 3.5 years after intestinal transplantation with rapidly progressive sensorineural hearing loss. Initial brain imaging was consistent with inflammation and/or demyelination. Lumbar puncture was initially non-diagnostic and a broad infectious workup was unrevealing. Three months after presentation, a repeat LP detected JC virus for which tests had not earlier been conducted. He continued to deteriorate despite withdrawal of prior immunosuppression and addition of mirtazapine, maraviroc, and steroids. He died of progressive neurologic decompensation 5 months after his initial presentation. This case highlights progressive multifocal leukoencephalopathy (PML) as a rare complication after solid organ transplantation and acute sensorineural hearing loss as an unusual first presenting symptom of PML. JC virus should be considered in the differential diagnosis of acute sensorineural hearing loss in any immunocompromised patient.

Human T-cell lymphotrophic virus in solid-organ transplant recipients: Guidelines from the American society of transplantation infectious diseases community of practice.

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of Human T-cell lymphotrophic virus 1 (HTLV)-1 in the pre- and post-transplant period. HTLV-1 is an oncogenic human retrovirus rare in North America but endemic in the Caribbean and parts of Africa, South America, Asia, and Oceania. While most infected persons do not develop disease, <5% will develop adult T-cell leukemia/lymphoma or neurological disease. No proven antiviral treatment for established HTLV-1 infection is available. The effect of immunosuppression on the development of HTLV-1-associated disease in asymptomatically infected recipients is not well characterized, and HTLV-1-infected individuals should be counseled that immunosuppression may increase the risk of developing HTLV-1-associated disease and they should be monitored post-transplant for HTLV-1-associated disease. Currently approved screening assays do not distinguish between HTLV-1 and HTLV-2, and routine screening of deceased donors without risk factors in low seroprevalence areas is likely to result in significant organ wastage and is not recommended. Targeted screening of donors with risk factors for HTLV-1 infection and of living donors (as time is available to perform confirmatory tests) is reasonable.

Pediatric post-transplant hepatic kaposi sarcoma due to donor-derived human herpesvirus 8.

In areas of the world where human herpesvirus 8 (HHV-8) is endemic, Kaposi sarcoma (KS) is a common SOT-associated cancer. In the United States, where the virus is not prevalent, PTKS is rare, and there is little literature on pediatric PTKS. We present a North American female who underwent deceased donor, left lateral segment liver transplant for biliary atresia at age 11 months. The donor was a male with no known history of KS, originally from an HHV-8-endemic country. Three months after transplantation, the patient developed liver nodules and portal vein thrombosis. Analysis of needle biopsy established the diagnosis of KS and confirmed that the transformed cells were donor-derived. HHV-8 viremia was detected, and ganciclovir dosing (which had been started prophylactically) was increased. Immunosuppression was changed from tacrolimus to sirolimus. After further disease progression, 8 cycles of paclitaxel were administered. Under this treatment, her nodules regressed, HHV-8 viremia resolved, and she had marked clinic improvement. Notably, the adult recipient of the right liver lobe from the same donor also developed PTKS. This is one of few pediatric PTKS cases described in the literature. It contributes to the mechanistic understanding of PTKS development, illustrating the risk posed by donors from HHV-8-endemic countries, as well as the potential for strong PTKS correlation between multiple recipients of organs from a single shared donor.

A 5-Year Prospective Multicenter Evaluation of Influenza Infection in Transplant Recipients.

Background: Seasonal influenza infection may cause significant morbidity and mortality in transplant recipients. The purpose of this study was to assess the epidemiology of symptomatic influenza infection posttransplant and determine risk factors for severe disease. Methods: Twenty centers in the United States, Canada, and Spain prospectively enrolled solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) recipients with microbiologically confirmed influenza over 5 consecutive years (2010-2015). Demographics, microbiology data, and outcomes were collected. Serial nasopharyngeal swabs were collected at diagnosis and upto 28 days, and quantitative polymerase chain reaction for influenza A was performed. Results: We enrolled 616 patients with confirmed influenza (477 SOT; 139 HSCT). Pneumonia at presentation was in 134 of 606 (22.1%) patients. Antiviral therapy was given to 94.1% for a median of 5 days (range, 1-42 days); 66.5% patients were hospitalized and 11.0% required intensive care unit (ICU) care. The receipt of vaccine in the same influenza season was associated with a decrease in disease severity as determined by the presence of pneumonia (odds ratio [OR], 0.34 [95% confidence interval {CI}, .21-.55], P < .001) and ICU admission (OR, 0.49 [95% CI, .26-.90], P = .023). Similarly, early antiviral treatment (within 48 hours) was associated with improved outcomes. In patients with influenza A, pneumonia, ICU admission, and not being immunized were also associated with higher viral loads at presentation (P = .018, P = .008, and P = .024, respectively). Conclusions: Annual influenza vaccination and early antiviral therapy are associated with a significant reduction in influenza-associated morbidity, and should be emphasized as strategies to improve outcomes of transplant recipients.

A Prospective, International Cohort Study of Invasive Mold Infections in Children.

BACKGROUND: Invasive mold infections (IMIs) are a leading cause of mortality in immunocompromised children, yet there has never been an international epidemiologic investigation of pediatric IMIs. METHODS: This international, prospective cohort study was performed to characterize the epidemiology, antifungal therapy, and outcomes of pediatric IMIs. Children (≤18 years) with proven or probable IMIs were enrolled between August 2007 and May 2011 at 22 sites. Risk factors, underlying diagnoses, and treatments were recorded. Outcomes were assessed at 12 weeks after diagnosis using European Organization for Research and Treatment of Cancer/Mycoses Study Group response criteria. RESULTS: One hundred thirty-one pediatric patients with IMIs were enrolled; the most common IMI was invasive aspergillosis ([IA] 75%). Children with IA and those with other types of IMIs had similar underlying risk factors, except that children with IMIs caused by non-Aspergillus species were more likely to have received mold-active antifungal agents preceding diagnosis. The most commonly used antifungal classes after diagnosis were triazoles (82%) and polyenes (63%). Combination therapy was used in 53% of patients. Use of combination therapy was associated with an increased risk of adverse events (risk ratio, 1.98; 95% confidence interval, 1.06-3.68; P = .031), although there was no detectable difference in outcome. CONCLUSIONS: Although risk factors for IMIs are similar across specific subtypes, preceding antifungal therapy may be an important modifier. Combination antifungal therapy requires further study to determine its true risks and benefits.

Yield of fungal surveillance cultures in pediatric hematopoietic stem cell transplant patients: a retrospective analysis and survey of current practice.

BACKGROUND: Fungal surveillance cultures (FSCs) have been proposed as predictors for development of invasive fungal disease (IFD) and identifiers of the causative organism, although data supporting these are limited and predate universal initiation of antifungal prophylaxis. We aimed to define the epidemiology of fungal colonization and investigate the utility of FSCs for predicting IFD in recipients of pediatric hematopoietic stem cell transplantation (HSCT). METHODS: FSCs performed from 2007 to 2011 on HSCT patients and laboratory and clinical data were reviewed, and incidence of IFD was determined. Descriptive analyses of culture results were performed to determine the yield of FSCs and their utility. A Web-based survey of national pediatric HSCT providers was undertaken to evaluate current practice and the relevance of our results. RESULTS: Five thousand six hundred eighteen FSCs from nares, throat, and stool from 360 patients were processed. Of these, 14.8% were positive: 30.3% from stool, 13.2% from throat, and 0.9% from nares; 64.4% of patients had >1 positive FSCs. Thirty (8.3%) patients had IFD. IFD occurred in 7.9% and 10.1% of patients with positive and negative FSCs, respectively (P = .25). Antifungal coverage was changed in 69 patients (29.9%) after positive FSC; 8.6% developed IFD (n = 2 of 6 pathogen concordance with FSC) compared with 6.7% (P = .59) who had no treatment change (n = 3 of 11 concordance). The response rate to the survey was 70.8%; 40% of institutions reported performing routine FSC. Twenty-five percent of providers would not change management based on FSC results; overall rating of usefulness of FSCs was low. CONCLUSIONS: Although FSCs are commonly performed for pediatric HSCT patients, they have limited utility for predicting IFD.

Vancomycin Use for Pediatric Clostridium difficile Infection Is Increasing and Associated with Specific Patient Characteristics.

In adults with Clostridium difficile infection (CDI), enteral vancomycin is considered the preferred initial regimen for severe disease; however, patterns of antimicrobial use for children with CDI are unknown. We sought to describe trends in and predictors of vancomycin use for the treatment of children with CDI admitted to tertiary-care children's hospitals in the United States. We used a database of freestanding children's hospitals to identify patients 1 to 18 years old with CDI between January 2006 and June 2011. The first hospitalization with a diagnosis of CDI for each patient was identified, and CDI-directed therapy was assessed. Generalized estimating equations were used to identify predictors of vancomycin receipt, controlling for clustering within hospitals. Vancomycin use has increased significantly (P = 0.005), with substantial variability between hospitals (0 to 16%). In multivariate analyses, vancomycin use was more common in children age 7 to 13 years old (versus children 1 to 2 years old: adjusted odds ratio [AOR] = 1.57; 95% confidence interval [CI] = 1.13 to 2.18), 14 to 18 years old (AOR = 1.40; 95% CI = 1.11 to 1.76), in an ICU (AOR = 1.37; 95% CI = 1.05 to 1.80), or with chronic gastrointestinal conditions (AOR = 2.01; 95% CI = 1.44 to 2.81). Vancomycin use was less common in black (AOR = 0.53; 95% CI = 0.39 to 0.73) and Hispanic (AOR = 0.63; 95% CI = 0.47 to 0.84) patients and in children with malignancies (AOR = 0.57; 95% CI = 0.36 to 0.89). Despite a lack of empirical evidence to suggest superiority, vancomycin use for pediatric CDI is increasing. Furthermore, there is substantial variability in vancomycin use between hospitals. Further studies are needed to explore potential racial and ethnic differences in CDI management and to investigate clinicians' rationale for using vancomycin for initial therapy in selected populations.

Effect of titrated parenteral nutrition on body composition after allogeneic hematopoietic stem cell transplantation in children: a double-blind, randomized, multicenter trial.

BACKGROUND: Children undergoing hematopoietic stem cell transplantation (HSCT) often require parenteral nutrition (PN) to optimize caloric intake. Standard approaches to nutritional supplementation provide 130-150% of estimated energy expenditure, but resting energy expenditure (REE) may be lower than expected after HSCT. Provision of PN exceeding energy needs may lead to overfeeding and associated complications. OBJECTIVE: We conducted a blinded, randomized, controlled, multicenter trial in children undergoing HSCT to determine the effect on body composition of 2 different approaches of nutrition support: standard amounts of energy from PN (130-150% of REE) compared with PN titrated to match measured REE. DESIGN: Twenty-six children undergoing HSCT were randomly assigned to standard or titrated PN. Energy intake was monitored until day 30 after HSCT. Body-composition and anthropometric measures were obtained through day 100. The primary outcome variable was percentage body fat (%BF) measured by dual energy X-ray absorptiometry. RESULTS: The estimated change in %BF from baseline to day 30 was 1.2 ± 0.5% in the standard group and 0.1 ± 0.5% in the experimental group, but the overall time course of %BF did not differ significantly by treatment (P = 0.39 for time × treatment interaction). A profound loss of lean body mass (LBM) occurred in both groups during the intervention period and persisted through day 100. CONCLUSIONS: Parenteral energy intake titrated to energy expenditure does not result in a lower accumulation of BF than does standard energy intake. Neither titrated nor standard PN regimens during HSCT preserve LBM. Alternative approaches to preserve LBM are needed. This trial is registered at clinicaltrials.gov as 00115258.

Accelerated cardiovascular disease and myocardial infarction risk in patients with the human immunodeficiency virus.

Highly active antiretroviral therapy has greatly reduced mortality among human immunodeficiency virus (HIV)-infected patients by delaying, and possibly preventing, progression to AIDS. The risk of cardiovascular disease (CVD) is now an important consideration in these patients and may increase as they live longer. Risk factors for CVD, the inflammatory effects of HIV, and the metabolic complications of antiretroviral therapy may accelerate the onset of CVD. Death from myocardial infarction, however, is still rare compared with death from progression of HIV disease, and the benefits of antiretroviral therapy clearly outweigh any associated risk of CVD. In this review, the authors describe the risk of accelerated CVD in HIV-infected individuals, the proposed viral and therapy-related mechanisms of CVD, the clinical features of CVD in these patients, and monitoring and management guidelines to reduce CVD risk. Identifying, monitoring, and treating CVD risk factors in HIV-positive patients is vital to improving their lives and should become standard practice.