Tanvi S. Sharma

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.

Attitudes Toward Transitioning in Youth With Perinatally Acquired HIV and Their Family Caregivers

&NA; This study investigated the preparedness and views of patients with perinatally acquired HIV and their family caregivers about transitioning to adult medical care. Fifteen participants (ages 15–24 years) with perinatally acquired HIV and eight family caregivers participated in structured interviews. All interviews were recorded and analyzed for themes using qualitative research methodology. Three major themes emerged: (a) perceived lack of readiness for transition, (b) fear of change and anxiety about entering the adult health care system, and (c) burgeoning personal responsibility that comes with age. Participants also offered suggestions to improve the transition experience, including starting the process early with specific guidelines. All patients and family caregivers wanted early knowledge about transition; these individuals could be an important resource to find potential solutions to guide the transition process. Clinical outcomes must be assessed in patients undergoing transition to determine the effect on management of medical disease, and protocols must be developed.

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.

CD8+ T-Cell Interleukin-7 Receptor Alpha Expression as a Potential Indicator of Disease Status in HIV-Infected Children

BACKGROUND Initiation and modification of antiretroviral therapy in HIV-infected children depend on viral load and CD4+ T-cell count. However, these surrogates have limitations, and complementary immunological markers to assess therapeutic response are needed. Our aim was to evaluate CD8+ T-cell expression of CD127 as a marker of disease status in HIV-infected children, based on adult data suggesting its usefulness. We hypothesized that CD127 expression on CD8+ T-cells is lower in children with more advanced disease. METHODS In a cross-sectional evaluation, we used flow cytometry to measure CD127+ expression on CD8+ T-cells in whole blood from HIV-infected children with varying disease status. This was compared with expression of CD38 on this subset, currently used in clinical practice as a marker of disease status. RESULTS 51 HIV-infected children were enrolled. There was a strong positive correlation between CD127 expression on CD8+ T-cells and CD4+ T-cell count, and height and weight z-scores, and a strong negative correlation between CD127 expression and viral load. In contrast, we found no association between CD38 expression and these disease status markers. CONCLUSIONS CD8+ T-cell CD127 expression is significantly higher in children with better HIV disease control, and may have a role as an immunologic indicator of disease status. Longitudinal studies are needed to determine the utility of this marker as a potential indicator of HIV disease progression.

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 mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors

Embryonal tumors with multilayered rosettes (ETMRs) have recently been described as a new entity of rare pediatric brain tumors with a fatal outcome. We show here that ETMRs are characterized by a parallel activation of Shh and Wnt signaling. Co-activation of these pathways in mouse neural precursors is sufficient to induce ETMR-like tumors in vivo that resemble their human counterparts on the basis of histology and global gene-expression analyses, and that point to apical radial glia cells as the possible tumor cell of origin. Overexpression of LIN28A, which is a hallmark of human ETMRs, augments Sonic-hedgehog (Shh) and Wnt signaling in these precursor cells through the downregulation of let7-miRNA, and LIN28A/let7a interaction with the Shh pathway was detected at the level of Gli mRNA. Finally, human ETMR cells that were transplanted into immunocompromised host mice were responsive to the SHH inhibitor arsenic trioxide (ATO). Our work provides a novel mouse model in which to study this tumor type, demonstrates the driving role of Wnt and Shh activation in the growth of ETMRs and proposes downstream inhibition of Shh signaling as a therapeutic option for patients with ETMRs.

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.

Allograft-Transmitted Histoplasma capsulatum Infection in a Solid Organ Transplant Recipient

Histoplasma capsulatum is a dimorphic fungus known to be endemic to the Mississippi and Ohio River valleys of North America. Infection is the result of exposure to the microconidia of the mold phase of the organism, and the degree of exposure and immunocompetency of the host are thought to be important determinants in the severity of consequent illness [1]. In most patients, histoplasmosis manifests as a self-limited respiratory illness with protean complaints that include fever, dry cough, and fatigue. The more severe form of the disease, progressive disseminated histoplasmosis, is far less common and is usually seen in very young, elderly, and immunosuppressed patients. Unfortunately, the diagnosis requires a high level of suspicion and is often delayed. We describe a case of progressive disseminated histoplasmosis in a pediatric orthotopic heart transplant recipient from a nonendemic area whose disease was acquired from the donor allograft and whose diagnosis was delayed because of an incomplete donor history.

Thresholds and interpretations: How clinical competency committees identify pediatric residents with performance concerns

Abstract Background: Clinical competency committee (CCC) identification of residents with performance concerns is critical for early intervention. Methods: Program directors and 94 CCC members at 14 pediatric residency programs responded to a written survey prompt asking them to describe how they identify residents with performance concerns. Data was analyzed using thematic analysis. Results: Six themes emerged from analysis and were grouped into two domains. The first domain included four themes, each describing a path through which residents could meet or exceed a concern threshold:1) written comments from rotation assessments are foundational in identifying residents with performance concerns, 2) concerning performance extremes stand out, 3) isolated data points may accumulate to raise concern, and 4) developmental trajectory matters. The second domain focused on how CCC members and program directors interpret data to make decisions about residents with concerns and contained 2 themes: 1) using norm- and/or criterion-referenced interpretation, and 2) assessing the quality of the data that is reviewed. Conclusions: Identifying residents with performance concerns is important for their education and the care they provide. This study delineates strategies used by CCC members across several programs for identifying these residents, which may be helpful for other CCCs to consider in their efforts.

Milestone Ratings and Supervisory Role Categorizations Swim Together, but is the Water Muddy?

OBJECTIVE This single-specialty, multi-institutional study aimed to determine 1) the association between milestone ratings for individual competencies and average milestone ratings (AMRs) and 2) the association between AMRs and recommended supervisory role categorizations made by individual clinical competency committee (CCC) members. METHODS During the 2015-16 academic year, CCC members at 14 pediatric residencies reported milestone ratings for 21 competencies and recommended supervisory role categories (may not supervise, may supervise in some settings, may supervise in all settings) for residents they reviewed. An exploratory factor analysis of competencies was conducted. The associations among individual competencies, the AMR, and supervisory role categorizations were determined by computing bivariate correlations. The relationship between AMRs and recommended supervisory role categorizations was examined using an ordinal mixed logistic regression model. RESULTS Of the 155 CCC members, 68 completed both milestone assignments and supervision categorizations for 451 residents. Factor analysis of individual competencies controlling for clustering of residents in raters and sites resulted in a single-factor solution (cumulative variance: 0.75). All individual competencies had large positive correlations with the AMR (correlation coefficient: 0.84-0.93), except for two professionalism competencies (Prof1: 0.63 and Prof4: 0.65). When combined across training year and time points, the AMR and supervisory role categorization had a moderately positive correlation (0.56). CONCLUSIONS This exploratory study identified a modest correlation between average milestone ratings and supervisory role categorization. Convergence of competencies on a single factor deserves further exploration, with possible rater effects warranting attention.