Clinical Outcomes of Human Rhinovirus/Enterovirus Infection in Pediatric Hemopoietic Cell Transplant Patients.

BACKGROUND: Respiratory viral infections are common among pediatric transplant patients, with human rhinovirus (HRV) being the most frequent. In pediatric patients undergoing hemopoietic cell transplant (HCT), infection with HRV has been associated with progression to lower respiratory tract infection (LRTI) and adverse outcomes. We describe the clinical presentation and outcomes of HRV infection in children undergoing HCT. METHODS: Single-center retrospective study. HCT recipients who were positive for HRV/EV (HRV+) or negative for any respiratory virus (VN) by BioFire® FilmArray® panel between October 2014 and December 2017, were included. Primary outcomes were progression to LRTI, ICU admission, all-cause mortality at 3 and 6 months, and respiratory event-related mortality at 6 months. RESULTS: 227 patients (160 allogeneic HCT) were included. Of all patients, 108/227 (47.6%) were HRV+. From all HRV+, 95/108 (88%) were symptomatic and 68/107 (63.6%) of the diagnosis were made pretransplant. The median age of HRV+ was significantly lower than VN patients (5 vs 10 years). Cough and rhinorrhea were more frequently observed in HRV+ (53.7 and 60% vs 19.8 and 22.8%, respectively). No differences were found between both groups pretransplant and overall in rates progression to LRTI, ICU admission, mechanical ventilation, all-cause within 3 and 6 months, and mortality related with respiratory failure. No significant association was found between the severity of respiratory disease and the type of conditioning, type of transplant, or absolute lymphocyte count. CONCLUSIONS: HRV infection is frequently detected in HCT recipients but is not associated with severity of respiratory disease, need for intensive care unit or mortality, including those diagnosed before transplant, suggesting that delaying HCT in this scenario may not be needed. Multicenter larger studies are required to confirm these findings.

Digital PCR to Measure SARS-CoV-2 RNA, Variants, and Outcomes in Youth.

BACKGROUND: The role of SARS-CoV-2 viral load in predicting contagiousness, disease severity, transmissibility, and clinical decision-making continues to be an area of great interest. However, most studies have been in adults and have evaluated SARS-CoV-2 loads using cycle thresholds (Ct) values, which are not standardized preventing consistent interpretation critical to understanding clinical impact and utility. Here, a quantitative SARS-CoV-2 reverse-transcription digital PCR (RT-dPCR) assay normalized to WHO International Units was applied to children at risk of severe disease diagnosed with COVID-19 at St. Jude Children's Research Hospital between March 28, 2020, and January 31, 2022. METHODS: Demographic and clinical information from children, adolescents, and young adults treated at St. Jude Children's Research Hospital were abstracted from medical records. Respiratory samples underwent SARS-CoV-2 RNA quantitation by RT-dPCR targeting N1 and N2 genes, with sequencing to determine the genetic lineage of infecting virus. RESULTS: Four hundred and sixty-two patients aged 0-24 years (median 11 years old) were included during the study period. Most patients were infected by the omicron variant (43.72%), followed by ancestral strain (22.29%), delta (13.20%), and alpha (2.16%). Viral load at presentation ranged from 2.49 to 9.14 log10 IU/mL, and higher viral RNA loads were associated with symptoms (OR 1.32; CI 95% 1.16-1.49) and respiratory disease (OR 1.23; CI 95% 1.07-1.41). Viral load did not differ by SARS-CoV-2 variant, vaccination status, age, or baseline diagnosis. CONCLUSIONS: SARS-CoV-2 RNA loads predict the presence of symptomatic and respiratory diseases. The use of standardized, quantitative methods is feasible, allows for replication, and comparisons across institutions, and has the potential to facilitate consensus quantitative thresholds for risk stratification and treatment.

Prediction of attributable mortality in pediatric patients with cancer admitted to the intensive care unit for suspected infection: A comprehensive evaluation of risk scores.

OBJECTIVE: To evaluate the performance of existing sepsis scores for prediction of adverse outcomes in children with cancer admitted to the ICU with suspected sepsis. DESIGN: Retrospective chart review using data available at 1, 6, 12, and 24 h after ICU admission to calculate the Pediatric Risk of Mortality 3 (PRISM-3), Pediatric Sequential Organ Failure Assessment (pSOFA), Paediatric Logistic Organ Dysfunction 2 (PELOD-2), and Quick Pediatric Sequential Organ Failure Assessment (qSOFA) scores. Area under the receiver operator characteristic curve (AUROC) was used to evaluate performance for prediction of attributable mortality. Sensitivity analyses included recalculation of scores using worst preceding values for each variable, excluding hematologic parameters, and prediction of alternative outcomes. SETTING: St. Jude Children's Research Hospital, a pediatric comprehensive cancer center in the USA. PATIENTS: Pediatric patients (<25 years of age) receiving conventional therapy for cancer admitted to the ICU with suspected sepsis between 2013 and 2019. RESULTS: Of 207 included episodes of suspected sepsis, attributable mortality was 16 (7.7%) and all evaluated sepsis scores performed poorly (maximal AUROC of 0.73 for qSOFA at 1 and 24 h). Sensitivity analyses did not identify an alternative approach that significantly improved prediction. CONCLUSIONS: Currently available sepsis scores perform poorly for prediction of attributable mortality in children with cancer who present to ICU with suspected sepsis. More research is needed to identify reliable predictors of adverse outcomes in this population.

Microbiota Predict Infections and Acute Graft-Versus-Host Disease After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Despite preventive measures, infections continue to pose significant risks to pediatric allogeneic hematopoietic cell transplantation (allo-HCT) recipients. The gut microbiota has been linked to clinical outcomes following adult allo-HCT. This study evaluated whether similar disruptions or differing microbiota patterns were associated with infection risk in pediatric allo-HCT. METHODS: In a prospective observational study, fecal samples were obtained from 74 children before conditioning and upon neutrophil recovery. Microbiome signatures identified through sequencing were examined for their associations with infections or acute graft-versus-host disease (aGVHD) in the first-year post-HCT using Cox proportional hazards analysis. RESULTS: Microbiome disruption in adults, did not predict infection risk in pediatric allo-HCT. Unique microbiota signatures were associated with different infections or aGVHD. A ratio of strict and facultative anaerobes (eg, Lachnoclostridium, Parabacteroides) prior to conditioning predicted bacteremia risk (Cox hazard ratio [HR], 3.89). A distinct ratio of oral (eg, Rothia, Veillonella) to intestinal anaerobes (eg, Anaerobutyricum, Romboutsia) at neutrophil recovery predicted likelihood of bacterial infections (Cox HR, 1.81) and viral enterocolitis (Cox HR, 1.96). CONCLUSIONS: Interactions between medical interventions, pediatric hosts, and microbial communities contribute to microbiota signatures that predict infections. Further multicenter study is necessary to validate the generalizability of these ratios as biomarkers.

Clinical Correlation of Adenoviral Load in the Respiratory Tract Measured by Digital PCR in Immunocompromised Children.

Immunocompromised patients can have life-threatening adenoviral infection. Viral load in blood and stool is commonly used to guide antiviral therapy. We developed and evaluated a digital polymerase chain reaction assay to quantify human adenovirus in the respiratory tract and showed that higher peak load correlates with disseminated infection, mechanical ventilation, and death.

Effects of an Online Education Program on Physical Therapists' Confidence in Weight Management for People With Osteoarthritis: A Randomized Controlled Trial.

OBJECTIVE: To evaluate effects of an online education program about weight management for osteoarthritis on physical therapists' self-reported confidence in knowledge and skills in weight management and attitudes toward obesity. METHODS: In a 2-group randomized controlled trial, 80 physical therapists (58 female physical therapists) were randomized to education or control groups. The theoretically informed and evidence-informed online self-directed training program covered biopsychosocial elements of obesity and weight management. The primary outcome was self-reported confidence in knowledge in weight management using a customized validated tool (scale 14-70, higher scores indicating higher confidence) assessed at baseline and 6 weeks. Secondary measures included confidence in nutrition care, clinical skills in weight management, and weight stigma. Process measures evaluated participant experience. Differences in change between groups were compared using linear regression models adjusted for baseline scores and stratifying variables (clinical setting; confidence in weight management). Moderation analysis was performed using an interaction approach in a linear regression model and multivariable fractional polynomial interaction approach. RESULTS: A total of 79 participants (99%) completed outcome measures at 6 weeks. The education group demonstrated greater improvement in confidence in knowledge than the control group (adjusted mean difference 22.6 units, 95% confidence interval 19.6, 25.5). Greater improvement in knowledge was associated with lower baseline values (interaction P = 0.002). Secondary outcomes showed greater improvements in confidence in skills and nutrition care and in weight stigma domains favoring the education group. Over 90% of participants would recommend the program to peers. CONCLUSION: An online education program improves physical therapists' short-term confidence in knowledge and skills in weight management for people with osteoarthritis and reduces weight-stigmatized attitudes.

Antibiotic prophylaxis and the gastrointestinal resistome in paediatric patients with acute lymphoblastic leukaemia: a cohort study with metagenomic sequencing analysis.

BACKGROUND: Although antibiotic prophylaxis with levofloxacin can reduce the risk of serious infection in immunocompromised patients, the potential contribution of prophylaxis to antibiotic resistance is a major drawback. We aimed to identify the effects of levofloxacin prophylaxis, given to paediatric patients with acute lymphoblastic leukaemia to prevent infections during induction chemotherapy, on antibiotic resistance in gastrointestinal microbiota after completion of induction and consolidation therapy. METHODS: This prospective, single-centre (St Jude Children's Research Hospital, Memphis, TN, USA) cohort study included children (≤18 years) receiving therapy for newly diagnosed acute lymphoblastic leukaemia and who received either primary levofloxacin prophylaxis or no antibacterial prophylaxis (aside from Pneumocystis jirovecii prophylaxis with trimethoprim-sulfamethoxazole) and provided at least two stool samples, including one after completion of induction therapy. We used metagenomic sequencing to identify bacterial genes that confer resistance to fluoroquinolones, trimethoprim-sulfamethoxazole, or other antibiotics, and to identify point mutations in bacterial topoisomerases (gyrA, parC) that confer resistance to fluoroquinolones. We then used generalised linear mixed models to compare the prevalence and relative abundance of antibiotic resistance gene groups after completion of induction and consolidation therapy between participants who had received levofloxacin and those who received no prophylaxis. FINDINGS: Between Feb 1, 2012, and April 30, 2016, 118 stool samples (32 baseline, 49 after induction, and 37 after consolidation) were collected from 49 evaluable participants; of these participants, 31 (63%) received levofloxacin prophylaxis during induction therapy and 18 (37%) received no antibacterial prophylaxis. Over the course of induction therapy, there was an overall increase in the relative abundance of trimethoprim-sulfamethoxazole resistance genes (estimated mean fold change 5·9, 95% CI 3·6-9·6; p<0·0001), which was not modified by levofloxacin prophylaxis (p=0·46). By contrast, the prevalence of topoisomerase point mutations increased over the course of induction therapy in levofloxacin recipients (mean prevalence 10·4% [95% CI 3·2-25·4] after induction therapy vs 3·7% [0·2-22·5] at baseline) but not other participants (0% vs 0%; p<0·0001). There was no significant difference between prophylaxis groups with respect to changes in aminoglycoside, ß-lactam, vancomycin, or multidrug resistance genes after completion of induction or consolidation therapy. INTERPRETATION: Analysing the gastrointestinal resistome can provide insights into the effects of antibiotics on the risk of antibiotic-resistant infections. In this study, antibiotic prophylaxis with trimethoprim-sulfamethoxazole or levofloxacin during induction therapy for acute lymphoblastic leukaemia appeared to increase the short-term and medium-term risk of colonisation with bacteria resistant to these antibiotics, but not to other drugs. More research is needed to determine the longer-term effects of antibacterial prophylaxis on colonisation with antibiotic-resistant bacteria. FUNDING: Children's Infection Defense Center at St Jude Children's Research Hospital, American Lebanese Syrian Associated Charities, and National Institutes of Health.

Fluoroquinolone prophylaxis does not increase risk of neuropathy in children with acute lymphoblastic leukemia.

BACKGROUND: Fluoroquinolone antibiotics are frequently utilized in pediatric oncology patients as prophylaxis or step-down therapy following broad spectrum beta-lactam therapy for febrile neutropenia. Concerns regarding neurotoxicity limit the use of these agents. No studies have evaluated the association between fluoroquinolone use and neurotoxicity in pediatric oncology patients receiving other neurotoxic agents such as vincristine. METHODS: An observational cohort study comprising patients aged 0-18 at diagnosis enrolled on a prospective study for treatment of acute lymphoblastic leukemia (ALL) at a pediatric comprehensive cancer center between October 2007 and November 2018. Data for neuropathic pain and sensory or motor neuropathy were collected prospectively, and a Cox proportional hazards regression model was used to evaluate associations between administration of fluoroquinolone antibiotics during induction therapy and subsequent development of vincristine-induced peripheral neurotoxicity (VIPN). RESULTS: A total of 598 participants were enrolled, including 338 (57%) who received fluoroquinolones during induction therapy; of these 470 (79%) were diagnosed with VIPN and 139 (23%) were diagnosed with high-grade (Grade 3+) VIPN. On unadjusted analyses, and analyses adjusted for age and race, there was no evidence of an association between fluoroquinolone exposure and subsequent VIPN (hazard ratio [HR] 0.8, 95% CI 0.5-1.04, P = .08) or high-grade VIPN (HR 1.1, 95% CI 0.4-2.2, P = .87). CONCLUSIONS: The results of this observational study do not show an association between exposure to fluoroquinolone antibiotics during induction therapy for ALL and subsequent development of vincristine-induced peripheral neuropathies, and suggest that a large increase in VIPN is unlikely.

Evaluation of Plasma Microbial Cell-Free DNA Sequencing to Predict Bloodstream Infection in Pediatric Patients With Relapsed or Refractory Cancer.

Importance: Bloodstream infection (BSI) is a common, life-threatening complication of treatment for cancer. Predicting BSI before onset of clinical symptoms would enable preemptive therapy, but there is no reliable screening test. Objective: To estimate sensitivity and specificity of plasma microbial cell-free DNA sequencing (mcfDNA-seq) for predicting BSI in patients at high risk of life-threatening infection. Design, Setting, and Participants: A prospective pilot cohort study of mcfDNA-seq for predicting BSI in pediatric patients (<25 years of age) with relapsed or refractory cancers at St Jude Children's Research Hospital, a specialist quaternary pediatric hematology-oncology referral center. Remnant clinical blood samples were collected during chemotherapy and hematopoietic cell transplantation. Samples collected during the 7 days before and at onset of BSI episodes, along with negative control samples from study participants, underwent blinded testing using a mcfDNA-seq test in a Clinical Laboratory Improvement Amendments/College of American Pathologists-approved laboratory. Main Outcomes and Measures: The primary outcomes were sensitivity of mcfDNA-seq for detecting a BSI pathogen during the 3 days before BSI onset and specificity of mcfDNA-seq in the absence of fever or infection in the preceding or subsequent 7 days. Results: Between August 9, 2017, and June 4, 2018, 47 participants (27 [57%] male; median age [IQR], 10 [5-14] years) were enrolled; 19 BSI episodes occurred in 12 participants, and predictive samples were available for 16 episodes, including 15 bacterial BSI episodes. In the 3 days before the onset of infection, predictive sensitivity of mcfDNA-seq was 75% for all BSIs (12 of 16; 95% CI, 51%-90%) and 80% (12 of 15; 95% CI, 55%-93%) for bacterial BSIs. The specificity of mcfDNA-seq, evaluated on 33 negative control samples from enrolled participants, was 82% (27 of 33; 95% CI, 66%-91%) for any bacterial or fungal organism and 91% (30 of 33; 95% CI, 76%-97%) for any common BSI pathogen, and the concentration of pathogen DNA was lower in control than predictive samples. Conclusions and Relevance: A clinically relevant pathogen can be identified by mcfDNA-seq days before the onset of BSI in a majority of episodes, potentially enabling preemptive treatment. Clinical application appears feasible pending further study. Trial Registration: ClinicalTrials.gov identifier: NCT03226158.

Treatment and secondary prophylaxis with ethanol lock therapy for central line-associated bloodstream infection in paediatric cancer: a randomised, double-blind, controlled trial.

BACKGROUND: Central line-associated bloodstream infections (CLABSIs) affect about 25% of children with cancer, and treatment failure is common. Adjunctive ethanol lock therapy might prevent treatment failure but high-quality evidence is scarce. We evaluated ethanol lock therapy as treatment and secondary prophylaxis for CLABSI in children with cancer or haematological disorders. METHODS: This randomised, double-blind, placebo-controlled superiority trial, with two interim futility and efficacy analyses (done when the first 46 and 92 evaluable participants completed study requirements), was done at two paediatric hospitals in the USA and Australia. Patients aged 6 months to 24 years, inclusive, with cancer or a haematological disorder and new CLABSI were eligible. Participants were randomly assigned (1:1) to receive either ethanol lock therapy (70% ethanol) or placebo (heparinised saline) for 2-4 h per lumen daily for 5 days (treatment phase), then for up to 3 non-consecutive days per week for 24 weeks (prophylaxis phase). The primary composite outcome was treatment failure, consisting of attributable catheter removal or death, new or persistent (>72 h) infection, or additional lock therapy during the treatment phase, and recurrent CLABSI during the prophylaxis phase. This trial is registered with ClinicalTrials.gov, number NCT01472965. FINDINGS: 94 evaluable participants were enrolled between Dec 14, 2011, and Sept 12, 2016, of whom 48 received ethanol lock therapy and 46 received placebo. The study met futility criteria at the second interim analysis. Treatment failure was similar with ethanol lock therapy (21 [44%] of 48) and placebo (20 [43%] of 46; relative risk [RR] 1·0, 95% CI 0·6-1·6; p=0·98). Some adverse events, including infusion reactions and catheter occlusion, were more frequent in the ethanol lock therapy group than in the placebo group. Catheter occlusion requiring thrombolytic therapy was more common with ethanol lock therapy (28 [58%] of 48) than with placebo (15 [33%] of 46; RR 1·8, 95% CI 1·1-2·9; p=0·012). Discontinuation of lock therapy because of adverse effects or patient request occurred in a similar proportion of participants in the ethanol lock therapy (nine [19%] of 48) and placebo groups (ten [22%] of 46; p=0·72). INTERPRETATION: Ethanol lock therapy did not prevent CLABSI treatment failure and it increased catheter occlusion. Routine ethanol lock therapy for treatment or secondary prophylaxis is not recommended in this population. FUNDING: American Lebanese Syrian Associated Charities to St Jude Children's Research Hospital and an Australian Government Research Training Scholarship.

A Standard Set of Value-Based Patient-Centered Outcomes for Breast Cancer: The International Consortium for Health Outcomes Measurement (ICHOM) Initiative.

A major challenge in value-based health care is the lack of standardized health outcomes measurements, hindering optimal monitoring and comparison of the quality of health care across different settings globally. The International Consortium for Health Outcomes Measurement (ICHOM) assembled a multidisciplinary international working group, comprised of 26 health care providers and patient advocates, to develop a standard set of value-based patient-centered outcomes for breast cancer (BC). The working group convened via 8 teleconferences and completed a follow-up survey after each meeting. A modified 2-round Delphi method was used to achieve consensus on the outcomes and case-mix variables to be included. Patient focus group meetings (8 early or metastatic BC patients) and online anonymized surveys of 1225 multinational BC patients and survivors were also conducted to obtain patients' input. The standard set encompasses survival and cancer control, and disutility of care (eg, acute treatment complications) outcomes, to be collected through administrative data and/or clinical records. A combination of multiple patient-reported outcomes measurement (PROM) tools is recommended to capture long-term degree of health outcomes. Selected case-mix factors were recommended to be collected at baseline. The ICHOM will endeavor to achieve wide buy-in of this set and facilitate its implementation in routine clinical practice in various settings and institutions worldwide.

Immunogenicity and safety of high-dose trivalent inactivated influenza vaccine compared to standard-dose vaccine in children and young adults with cancer or HIV infection.

BACKGROUND: Approaches to improve the immune response of immunocompromised patients to influenza vaccination are needed. METHODS: Children and young adults (3-21 years) with cancer or HIV infection were randomized to receive 2 doses of high-dose (HD) trivalent influenza vaccine (TIV) or of standard-dose (SD) TIV. Hemagglutination inhibition (HAI) antibody titers were measured against H1, H3, and B antigens after each dose and 9 months later. Seroconversion was defined as ≥4-fold rise in HAI titer comparing pre- and post-vaccine sera. Seroprotection was defined as a post-vaccine HAI titer ≥1:40. Reactogenicity events (RE) were solicited using a structured questionnaire 7 and 14 days after each dose of vaccine, and adverse events by medical record review for 21 days after each dose of vaccine. RESULTS: Eighty-five participants were enrolled in the study; 27 with leukemia, 17 with solid tumor (ST), and 41 with HIV. Recipients of HD TIV had significantly greater fold increase in HAI titers to B antigen in leukemia group and to H1 antigen in ST group compared to SD TIV recipients. This increase was not documented in HIV group. There were no differences in seroconversion or seroprotection between HD TIV and SD TIV in all groups. There was no difference in the percentage of solicited RE in recipients of HD TIV (54% after dose 1 and 38% after dose 2) compared to SD TIV (40% after dose 1 and 20% after dose 2, p=0.27 and 0.09 after dose 1 and 2, respectively). CONCLUSION: HD TIV was more immunogenic than SD TIV in children and young adults with leukemia or ST, but not with HIV. HD TIV was safe and well-tolerated in children and young adults with leukemia, ST, or HIV.

Monitoring Central Venous Catheter Resistance to Predict Imminent Occlusion: A Prospective Pilot Study.

BACKGROUND: Long-term central venous catheters are essential for the management of chronic medical conditions, including childhood cancer. Catheter occlusion is associated with an increased risk of subsequent complications, including bloodstream infection, venous thrombosis, and catheter fracture. Therefore, predicting and pre-emptively treating occlusions should prevent complications, but no method for predicting such occlusions has been developed. METHODS: We conducted a prospective trial to determine the feasibility, acceptability, and efficacy of catheter-resistance monitoring, a novel approach to predicting central venous catheter occlusion in pediatric patients. Participants who had tunneled catheters and were receiving treatment for cancer or undergoing hematopoietic stem cell transplantation underwent weekly catheter-resistance monitoring for up to 12 weeks. Resistance was assessed by measuring the inline pressure at multiple flow-rates via a syringe pump system fitted with a pressure-sensing transducer. When turbulent flow through the device was evident, resistance was not estimated, and the result was noted as "non-laminar." RESULTS: Ten patients attended 113 catheter-resistance monitoring visits. Elevated catheter resistance (>8.8% increase) was strongly associated with the subsequent development of acute catheter occlusion within 10 days (odds ratio = 6.2; 95% confidence interval, 1.8-21.5; p <0.01; sensitivity, 75%; specificity, 67%). A combined prediction model comprising either change in resistance greater than 8.8% or a non-laminar result predicted subsequent occlusion (odds ratio = 6.8; 95% confidence interval, 2.0-22.8; p = 0.002; sensitivity, 80%; specificity, 63%). Participants rated catheter-resistance monitoring as highly acceptable. CONCLUSIONS: In this pediatric hematology and oncology population, catheter-resistance monitoring is feasible, acceptable, and predicts imminent catheter occlusion. Larger studies are required to validate these findings, assess the predictive value for other clinical outcomes, and determine the impact of pre-emptive therapy. TRIAL REGISTRATION: Clinicaltrials.gov NCT01737554.

A framework for evaluating diagnostic discordance in pathology discovered during research studies.

CONTEXT: Little is known about the frequency of discordant diagnoses identified during research. OBJECTIVE: To describe diagnostic discordance identified during research and apply a newly designed research framework for investigating discordance. DESIGN: Breast biopsy cases (N = 407) from registries in Vermont and New Hampshire were independently reviewed by a breast pathology expert. The following research framework was developed to assess those cases: (1) compare the expert review and study database diagnoses, (2) determine the clinical significance of diagnostic discordance, (3) identify and correct data errors and verify the existence of true diagnostic discrepancies, (4) consider the impact of borderline cases, and (5) determine the notification approach for verified disagreements. RESULTS: Initial overall discordance between the original diagnosis recorded in our research database and a breast pathology expert was 32.2% (131 of 407). This was reduced to less than 10% after following the 5-step research framework. Detailed review identified 12 cases (2.9%) with data errors (2 in the underlying pathology registry, 3 with incomplete slides sent for expert review, and 7 with data abstraction errors). After excluding the cases with data errors, 38 cases (9.6%) among the remaining 395 had clinically meaningful discordant diagnoses (κ = 0.82; SE, 0.04; 95% confidence interval, 0.76-0.87). Among these 38 cases, 20 (53%) were considered borderline between 2 diagnoses by either the original pathologist or the expert. We elected to notify the pathology registries and facilities regarding discordant diagnoses. CONCLUSIONS: Understanding the types and sources of diagnostic discordance uncovered in research studies may lead to improved scientific data and better patient care.

No evidence of benefit from antibiotic lock therapy in pediatric oncology patients with central line-related bloodstream infection: results of a retrospective matched cohort study and review of the literature.

BACKGROUND: Long-term central venous catheters (CVCs) are essential to modern pediatric oncology practice, but central line-related bloodstream infection (CRBSI) is a frequent and important complication. CVC salvage is often attempted but treatment failure is common due to persistent infection, delayed catheter removal, or subsequent relapse of infection, which can be associated with significant morbidity and cost. Adjunctive antibiotic lock therapy (ALT) has been proposed to reduce the risk of treatment failure, but insufficient data are available to confirm efficacy of this intervention. PROCEDURE: We undertook a retrospective matched cohort study of ALT use for treatment of CRBSI in pediatric hematology/oncology patients at St. Jude Children's Research Hospital between 2006 and 2012. RESULTS: Thirty-eight eligible episodes of CRBSI treated with adjunctive ALT were identified and compared to 73 episodes treated with standard therapy (ST) alone, matched by catheter-type and organism. Overall, treatment failure was similar between ALT and ST groups (50.0 vs. 38.4%; P = 0.24), but the timing was different; in the ALT cohort, immediate CVC removal was less common (0.0 vs. 12.3%; P = 0.03) but delayed removal (4-13 days) and relapse of infection was more common (50.0 vs. 24.7%; P = 0.01). CONCLUSIONS: This retrospective study was unable to identify any benefit of adjunctive ALT in pediatric oncology patients with CRBSI. The available evidence does not support routine ALT use, and well-conducted prospective studies are needed.

Metabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children.

OBJECTIVES: HIV-infected children may be at risk for premature cardiovascular disease. We compared levels of biomarkers of vascular dysfunction in HIV-infected children (with and without hyperlipidaemia) with those in HIV-exposed, uninfected (HEU) children enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS), and determined factors associated with these biomarkers. METHODS: A prospective cohort study was carried out. Biomarkers of inflammation [C-reactive protein (CRP), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP1)], coagulant dysfunction (fibrinogen and P-selectin), endothelial dysfunction [soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM) and E-selectin], and metabolic dysfunction (adiponectin) were measured in 226 HIV-infected and 140 HEU children. Anthropometry, body composition, lipids, glucose, insulin, HIV disease severity, and antiretroviral therapy were recorded. RESULTS: The median ages of the children were 12.3 years in the HIV-infected group and 10.1 years in the HEU group. Body mass index (BMI) z-scores, waist and hip circumferences, and percentage body fat were lower in the HIV-infected children. Total and non-high-density lipoprotein (HDL) cholesterol and triglycerides were higher in HIV-infected children. HIV-infected children also had higher MCP-1, fibrinogen, sICAM and sVCAM levels. In multivariable analyses in the HIV-infected children alone, BMI z-score was associated with higher CRP and fibrinogen, but lower MCP-1 and sVCAM. Unfavourable lipid profiles were positively associated with IL-6, MCP-1, fibrinogen, and P- and E-selectin, whereas increased HIV viral load was associated with markers of inflammation (MCP-1 and CRP) and endothelial dysfunction (sICAM and sVCAM). CONCLUSIONS: HIV-infected children have higher levels of biomarkers of vascular dysfunction than do HEU children. Risk factors associated with higher biomarkers include unfavourable lipid levels and active HIV replication.

Immunogenicity and safety of inactivated monovalent 2009 H1N1 influenza A vaccine in immunocompromised children and young adults.

BACKGROUND: Influenza vaccination is recommended for immunocompromised patients. METHODS: Children (6 months to 21 years) with cancer, HIV infection, or sickle cell disease (SCD) received 1 or 2 doses of pandemic 2009 H1N1 monovalent influenza vaccine (H1N1 MIV). Safety and tolerability, hemagglutination inhibition (HI) and microneutralization (MN) antibody titers were measured against 2009 H1N1 influenza A virus after each dose. Seroprotection (SP) and seroconversion (SC) rates were determined. RESULTS: 103 participants were enrolled and 99 were evaluable (39 with HIV, 37 with cancer and 23 with SCD). Mean age (±SD) was 7.9 (±5.4) years for cancer participants, 18.0 (±3.5) for HIV, and 13.3 (±4.2) for SCD. 54% were males; 65% black; and 96% had received seasonal influenza vaccine. HIV-infected participants had a median CD4 count of 625 cells/mm(3) (range, 140-1260). 46% had an undetectable HIV viral load and 41% were perinatally infected. No participant had vaccine-related serious adverse events. None developed influenza A proven illness during the 6 months after the vaccine. Local injection reactions were reported in 29% and systemic reactions in 42% after the first dose of vaccine. SC and SP were achieved after the last dose in 48% and 52%, respectively, of participants with leukemia or lymphoma, 50% and 75% of participants with solid tumors, 63% and 92% of HIV-infected participants, and 74% and 100% of participants with SCD. CONCLUSION: H1N1 MIV was safe and well tolerated. H1N1 MIV resulted in an adequate immune response in children with SCD. It was only modestly immunogenic in cancer or HIV participants.

Safety and immunogenicity of live attenuated and inactivated influenza vaccines in children with cancer.

BACKGROUND: The safety and immunogenicity of live, attenuated influenza vaccine (LAIV) has not been compared to that of the standard trivalent inactivated vaccine (TIV) in children with cancer. METHODS: Randomized study of LAIV versus TIV in children with cancer, age 2-21 years, vaccinated according to recommendations based on age and prior vaccination. Data on reactogenicity and other adverse events and blood and nasal swab samples were obtained following vaccination. RESULTS: Fifty-five eligible subjects (mean age, 10.4 years) received vaccine (28 LAIV/27 TIV). Both vaccines were well tolerated. Rhinorrhea reported within 10 days of vaccination was similar in both groups (36% LAIV vs 33% TIV, P > .999). Ten LAIV recipients shed virus; the latest viral shedding was detected 7 days after vaccination. Immunogenicity data were available for 52 subjects, or 26 in each group. TIV induced significantly higher postvaccination geometric mean titers against influenza A viruses (P < .001), greater seroprotection against influenza A/H1N1 (P = .01), and greater seroconversion against A/H3N2 (P = .004), compared with LAIV. No differences after vaccination were observed against influenza B viruses. CONCLUSIONS: As expected, serum antibody response against influenza A strains were greater with TIV than with LAIV in children with cancer. Both vaccines were well tolerated, and prolonged viral shedding after LAIV was not detected. CLINICAL TRIALS REGISTRATION: NCT00906750.

Safety of live attenuated influenza vaccine in mild to moderately immunocompromised children with cancer.

BACKGROUND: The safety of intranasal live-attenuated influenza vaccine (LAIV) in immunocompromised children with cancer is unknown. The objective of this study was to describe the safety and immunogenicity of LAIV in mild to moderately immunocompromised children with cancer. METHODS: We conducted a multicenter, randomized, double-blind study of LAIV versus placebo in children aged 5-17 years with cancer. LAIV (frozen formulation) or allantoic fluid/buffer was administered intranasally. Reactogenicity, adverse events, blood for immune assays, and nasal swabs for viral shedding were obtained during 5 visits over the first 42 days postvaccination; information concerning serious adverse events (SAEs) was collected for 180 days. RESULTS: 20 subjects were enrolled (LAIV, n=10; placebo, n=10) with a mean age of 12.2 years. Ten subjects had hematologic malignancy (LAIV, n=4; placebo, n=6); 10 subjects had solid tumors (LAIV, n=6; placebo, n=4). One subject was excluded from immunogenicity analysis for not receiving a full dose of LAIV. LAIV resulted in an increased incidence of runny nose/nasal congestion occurring in all LAIV recipients; no related SAEs were observed. Four of 10 LAIV recipients shed vaccine virus, with none exceeding 7-10 days duration. LAIV demonstrated modest immunogenicity by hemagglutination inhibition (≥ 4 fold rise for any strain, 33%) and microneutralization assays (≥ 4 fold rise for any strain, 44%). CONCLUSION: In this small pilot study conducted in mild to moderately immunocompromised children with cancer, runny nose/nasal congestion was increased in LAIV recipients, no related SAEs occurred, and prolonged viral shedding was not detected. Moderate immunogenicity was demonstrated in this small group of individuals.

Recipients of vaccine against the 1976 "swine flu" have enhanced neutralization responses to the 2009 novel H1N1 influenza virus.

BACKGROUND. The world is facing a novel H1N1 influenza pandemic. A pandemic scare with a similar influenza virus in 1976 resulted in the vaccination of nearly 45 million persons. We hypothesized that prior receipt of the 1976 "swine flu" vaccine would enhance immune responses to the 2009 novel H1N1 influenza strain. METHODS. A prospective, volunteer sample of employees aged > or = 55 years at a children's cancer hospital in August 2009 was assessed for antibody responses to the 2009 pandemic H1N1 influenza virus and the 2008-2009 seasonal H1N1 influenza virus. RESULTS. Antibody responses by hemagglutination-inhibition assay were high against both the seasonal influenza virus (89.7% had a titer considered seroprotective) and pandemic H1N1 influenza virus (88.8% had a seroprotective titer). These antibodies were effective at neutralizing the seasonal H1N1 influenza virus in 68.1% of participants (titer > or = 40), but only 18.1% had detectable neutralizing titers against the pandemic H1N1 influenza virus. Of 116 participants, 46 (39.7%) received the 1976 "swine flu" vaccine. Receipt of this vaccine significantly enhanced neutralization responses; 8 (17.4%) of 46 vaccine recipients had titers > or = 160, compared with only 3 (4.3%) of 70 who did not receive the vaccine (P = .018 by chi(2) test). CONCLUSIONS. In this cohort, persons aged > or = 55 years had evidence of robust immunity to the 2008-2009 seasonal H1N1 influenza virus. These antibodies were cross-reactive but nonneutralizing against the 2009 pandemic H1N1 influenza strain. Receipt of a vaccine to a related virus significantly enhanced the neutralization capacity of these responses, suggesting homologous vaccination against the 2009 pandemic H1N1 influenza virus would have a similar effect.