Factors Associated With Neurobehavioral Complications in Pediatric Abdominal Organ Transplant Recipients Identified Using Computable Composite Definitions.

OBJECTIVES: Neurologic complications occur in up to 40% of adult abdominal solid organ transplant recipients and are associated with increased mortality. Comparable pediatric data are sparse. This study describes the occurrence of neurologic and behavioral complications (neurobehavioral complications) in pediatric abdominal solid organ transplant recipients. We examine the association of these complications with length of stay, mortality, and tacrolimus levels. DESIGN: The electronic health record was interrogated for inpatient readmissions of pediatric abdominal solid organ transplant recipients from 2009 to 2017. A computable composite definition of neurobehavioral complication, defined using structured electronic data for neurologic and/or behavioral phenotypes, was created. SETTING: Quaternary children's hospital with an active transplant program. PATIENTS: Pediatric abdominal solid organ transplant recipients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Computable phenotypes demonstrated a specificity 98.7% and sensitivity of 63.0% for identifying neurobehavioral complications. There were 1,542 readmissions among 318 patients, with 65 (20.4%) having at least one admission with a neurobehavioral complication (total 109 admissions). Median time from transplant to admission with neurobehavioral complication was 1.2 years (interquartile range, 0.52-2.28 yr). Compared to encounters without an identified neurobehavioral complication, encounters with a neurobehavioral complication were more likely to experience ICU admission (odds ratio, 3.9; 2.41-6.64; p < 0.001), have longer ICU length of stay (median 10.3 vs 2.2 d; p < 0.001) and hospital length of stay (8.9 vs 4.3 d; p < 0.001), and demonstrate higher maximum tacrolimus level (12.3 vs 9.8 ng/mL; p = 0.001). Patients with a neurobehavioral complication admission were more likely to die (odds ratio, 5.04; 1.49-17.09; p = 0.009). In a multivariable analysis, type of transplant, ICU admission, and tacrolimus levels were independently associated with the presence of a neurobehavioral complication. CONCLUSIONS: Common electronic health record variables can be used to accurately identify neurobehavioral complications in the pediatric abdominal solid organ transplant population. Late neurobehavioral complications are associated with increased hospital resource utilization, mortality, and tacrolimus exposure. Additional studies are required to delineate the relationship between maximum tacrolimus level and neurobehavioral complications to guide therapeutic drug monitoring and dosing.

Development and Performance of Electronic Pediatric Risk of Mortality and Pediatric Logistic Organ Dysfunction-2 Automated Acuity Scores.

OBJECTIVES: Develop and test the performance of electronic version of the Children's Hospital of Pittsburgh Pediatric Risk of Mortality-IV and electronic version of the Children's Hospital of Pittsburgh Pediatric Logistic Organ Dysfunction-2 scores. DESIGN: Retrospective, single-center cohort derived from structured electronic health record data. SETTING: Large, quaternary PICU at a freestanding, university-affiliated children's hospital. PATIENTS: All encounters with a PICU admission between January 1, 2009, and December 31, 2017, identified using electronic definitions of inpatient encounter. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The main outcome was predictive validity of each score for hospital mortality, assessed as model discrimination and calibration. Discrimination was examined with the area under the receiver operating characteristics curve and the area under the precision-recall curve. Calibration was assessed with the Hosmer-Lemeshow goodness of fit test and calculation of a standardized mortality ratio. Models were recalibrated with new regression coefficients in a training subset of 75% of encounters selected randomly from all years of the cohort and the calibrated models were tested in the remaining 25% of the cohort. Content validity was assessed by examining correlation between electronic versions of the scores and prospectively calculated data (electronic version of the Children's Hospital of Pittsburgh Pediatric Risk of Mortality-IV) and an alternative informatics approach (Children's Hospital of Pittsburgh Pediatric Logistic Organ Dysfunction-2 score). The cohort included 21,335 encounters. Correlation coefficients indicated strong agreement between different methods of score calculation. Uncalibrated area under the receiver operating characteristics curves were 0.96 (95% CI, 0.95-0.97) for electronic version of the Children's Hospital of Pittsburgh Pediatric Logistic Organ Dysfunction-2 score and 0.87 (95% CI, 0.85-0.89) for electronic version of the Children's Hospital of Pittsburgh Pediatric Risk of Mortality-IV for inpatient mortality. The uncalibrated electronic version of the Children's Hospital of Pittsburgh Pediatric Risk of Mortality-IV standardized mortality ratio was 0.63 (0.59-0.66), demonstrating strong agreement with previous, prospective evaluation at the study center. The uncalibrated electronic version of the Children's Hospital of Pittsburgh Pediatric Logistic Organ Dysfunction-2 score standardized mortality ratio was 0.20 (0.18-0.21). All models required recalibrating (all Hosmer-Lemeshow goodness-of-fit, p < 0.001) and subsequently demonstrated acceptable goodness-of-fit when examined in a test subset (n = 5,334) of the cohort. CONCLUSIONS: Electronically derived intensive care acuity scores demonstrate very good to excellent discrimination and can be calibrated to institutional outcomes. This approach can facilitate both performance improvement and research initiatives and may offer a scalable strategy for comparison of interinstitutional PICU outcomes.

Survival and Long-Term Functional Outcomes for Children With Cardiac Arrest Treated With Extracorporeal Cardiopulmonary Resuscitation.

OBJECTIVES: To identify patient- and disease-related factors related to survival and favorable outcomes for children who underwent extracorporeal cardiopulmonary resuscitation after a refractory cardiac arrest. DESIGN: Retrospective observational study with prospective assessment of long-term functional outcome. PATIENTS: Fifty-six consecutive children undergoing extracorporeal cardiopulmonary resuscitation at our institution from 2007 to 2015. Median age at arrest was 3.5 months (interquartile range, 1-53). SETTING: Tertiary pediatric university hospital with a referral heart center. INTERVENTIONS: Health-related quality of life and family functioning assessment with the Pediatric Quality of Life Inventory and the McMaster Family Assessment Device. MEASUREMENTS AND MAIN RESULTS: Fifty-eight consecutive extracorporeal cardiopulmonary resuscitation episodes were included, with 46 (79.3%) related to primary cardiac conditions. Initial cannulation site was central in 19 (32.8%) and peripheral in 39 (67.2%). Survival to decannulation was 77.6% with survival at hospital discharge and at the end of the follow-up period being 65.5% and 62.1%, respectively. Time to follow-up was 38 months (interquartile range, 19-52). Patients who survived tended to be younger (3.5 mo [1 mo to 2 yr] vs 7 mo [1.25 mo to 17 yr]; p = 0.3) with decreased extracorporeal cardiopulmonary resuscitation times (28 min [15-47 min] vs 37.5 min [28.5-55 min]; p = 0.04). Those who received therapeutic hypothermia tended to have higher hospital survival (21/28 [75%] vs 16/29 [55%]; p = 0.08). Follow-up assessments of survivors demonstrated good quality of life and family functioning (Pediatric Quality of Life Inventory, 84 [76-89.5]; McMaster Family Assessment Device, 1.62 [1.33-1.83]). CONCLUSIONS: In this series, extracorporeal cardiopulmonary resuscitation was associated with relatively high survival rates and a good health-related quality of life and family functioning. Larger series are needed to assess whether this technique should be more broadly available in the pediatric critical care community.

A randomized controlled pilot trial of the functional assessment screening tablet to engage patients at the point of care.

BACKGROUND: Healthcare providers play an important role in encouraging healthy behaviors and improving health-related quality of life (HRQoL). They are most effective when they partner with informed, engaged patients. OBJECTIVE: To examine the impact of a new health-information technology intervention (FAST-Feedback) that provides patients with immediate, personalized, guideline-based feedback regarding tobacco use, physical activity, and HRQoL, and encourages patients to initiate discussions regarding these topics with their primary care physician. DESIGN: A pilot, randomized controlled trial clustered by resident physician, with patients as the unit of analysis. PARTICIPANTS: Resident physicians and their out-patients in a single academic health center between May and October 2011. INTERVENTION: Patients received (intervention) or did not receive (control) FAST-Feedback prior to the clinical encounter. MAIN OUTCOME MEASURES: Primary outcomes were patient reports of initiating any discussions regarding tobacco use, physical activity, and HRQoL. Subgroup analyses examined patient reports of discussions regarding tobacco use, physical activity, and HRQoL, respectively. KEY RESULTS: Thirty of the 36 eligible resident physicians (83%) agreed to participate; 173 of their 415 eligible patients (42%) expressed interest in the study and 99 (24%) consented to participate. Compared to controls, a higher percentage of intervention patients reported initiating any discussion with their resident physician, although this difference was not statistically significant (40% vs. 27%; p = 0.12). For subgroup analyses regarding specific topics of discussion, patients in the intervention group reported initiating more discussions regarding mental HRQoL than controls (23% vs. 0%; p = 0.02). There was no difference in patient reports of initiating discussions regarding smoking, physical activity or physical HRQoL. CONCLUSIONS: Providing patients with immediate, personalized, guideline-based feedback prior to the clinical encounter can increase patient-initiated discussions regarding mental HRQoL. Future work should test FAST-Feedback in a larger population and evaluate the impact on tobacco cessation, increased physical activity, and improvements in HRQoL.

Epitope discovery in West Nile virus infection: Identification and immune recognition of viral epitopes.

Cytotoxic T lymphocytes (CTL) play an important role in the control and elimination of infection by West Nile virus (WNV), yet the class I human leukocyte antigen (HLA)-presented peptide epitopes that enable CTL recognition of WNV-infected cells remain uncharacterized. The goals of this work were first to discover the peptide epitopes that distinguish the class I HLA of WNV-infected cells and then to test the T cell reactivity of newly discovered WNV epitopes. To discover WNV-immune epitopes, class I HLA was harvested from WNV (NY99 strain)-infected and uninfected HeLa cells. Then peptide epitopes were eluted from affinity-purified HLA, and peptide epitopes from infected and uninfected cells were comparatively mapped by mass spectroscopy. Six virus-derived peptides from five different viral proteins (E, NS2b, NS3, NS4b, and NS5) were discovered as unique to HLA-A*0201 of infected cells, demonstrating that the peptides sampled by class I HLA are distributed widely throughout the WNV proteome. When tested with CTL from infected individuals, one dominant WNV target was apparent, two epitopes were subdominant, and three demonstrated little CTL reactivity. Finally, a sequence comparison of these epitopes with the hundreds of viral isolates shows that HLA-A*0201 presents epitopes derived from conserved regions of the virus. Detection and recovery from WNV infection are therefore functions of the ability of class I HLA molecules to reveal conserved WNV epitopes to an intact cellular immune system that subsequently recognizes infected cells.

Influenza-like illness among university students: symptom severity and duration due to influenza virus infection compared to other etiologies.

OBJECTIVE: University students with influenza-like illness (ILI) were assessed to determine whether symptom severity, duration, or missed days of school or work varied according to etiology. PARTICIPANTS: Sixty persons presenting to a university health clinic with ILI symptoms during 3 consecutive influenza seasons completed baseline survey and viral testing; 51 (85%) completed follow-up. METHODS: Influenza viral culture and polymerase chain reaction and respiratory virus immunofluorescence assay testing were performed. Information collected at baseline and follow-up included symptom occurrence, severity, duration, and numbers of days of work and school missed. RESULTS: Influenza virus was confirmed in 63% of participants. Influenza-positive individuals were no more likely to report any symptom or miss more days of school or work. Self-reported severity and durations of symptoms were similar between groups. CONCLUSIONS: Students with influenza-associated ILI were similar to those with noninfluenza ILI with respect to severity, duration, and numbers of days of school and work missed.

Demographic and clinical factors associated with persistent symptoms after West Nile virus infection.

Prognosis varies among persons with West Nile virus (WNV) infection, but the most important factors associated with persistent symptoms are not clear. In this cross-sectional study, 265 persons with symptomatic WNV infection during 2006-2008 completed a survey a mean of 7.7 months after diagnosis. We determined the association of demographic and clinical characteristics to the most common symptoms. Of 214 persons infected ≥ 6 months, 53% reported one or more persistent symptoms, including fatigue, muscle aches, decreased activity, difficulty with memory, and difficulty concentrating. Persons with neuroinvasive disease, hypertension, or diabetes were significantly more likely to report persistent symptoms, whereas age, sex, and time since infection were not associated with persistent symptoms. In conclusion, persistent symptoms persisted in most persons for more than six months after symptomatic WNV infection. Improved strategies for prevention and treatment are needed.

Surface phenotype and functionality of WNV specific T cells differ with age and disease severity.

West Nile virus (WNV) infection can result in severe neuroinvasive disease, particularly in persons with advanced age. As rodent models demonstrate that T cells play an important role in limiting WNV infection, and strong T cell responses to WNV have been observed in humans, we postulated that inadequate antiviral T cell immunity was involved in neurologic sequelae and the more severe outcomes associated with age. We previously reported the discovery of six HLA-A*0201 restricted WNV peptide epitopes, with the dominant T cell targets in naturally infected individuals being SVG9 (Env) and SLF9 (NS4b). Here, memory phenotype and polyfunctional CD8+ T cell responses to these dominant epitopes were assessed in 40 WNV seropositive patients displaying diverse clinical symptoms. The patients' PBMC were stained with HLA-I multimers loaded with the SVG9 and SLF9 epitopes and analyzed by multicolor flow cytometry. WNV-specific CD8+ T cells were found in peripheral blood several months post infection. The number of WNV-specific T cells in older individuals was the same, if not greater, than in younger members of the cohort. WNV-specific T cells were predominantly monofunctional for CD107a, MIP-1ß, TNFα, IL-2, or IFNγ. When CD8+ T cell responses were stratified by disease severity, an increased number of terminally differentiated, memory phenotype (CD45RA+ CD27- CCR7- CD57+) T cells were detected in patients suffering from viral neuroinvasion. In conclusion, T cells of a terminally differentiated/cytolytic profile are associated with neuroinvasion and, regardless of age, monofunctional T cells persist following infection. These data provide the first indication that particular CD8+ T cell phenotypes are associated with disease outcome following WNV infection.