Association of continuous kidney replacement therapy timing and mortality in critically ill children.

BACKGROUND: Acute kidney injury (AKI) is a common complication of critical illness and associated with high morbidity and mortality. Optimal timing of continuous kidney replacement therapy (CKRT) in children is unknown. We aimed to measure the association between timing of initiation and mortality. METHODS: This is a single-center retrospective cohort study of pediatric patients receiving CKRT from 2013 to 2019. The primary exposure, time to CKRT initiation, was measured from onset of stage 3 AKI during hospitalization (defined using Kidney Disease: Improving Global Outcomes creatinine and urine output criteria) and analyzed as both a continuous and categorical variable. The primary outcome was ICU mortality. RESULTS: Ninety-nine patients met criteria for analysis. Overall mortality was 39% (39/99). Median time from stage 3 AKI onset to CKRT initiation was 1.5 days in survivors and 5.5 days in nonsurvivors (p < 0.001). In multivariable analysis, increased time to CKRT initiation was independently associated with mortality [OR 1.02 per hour (95% CI 1.01-1.04), p < 0.001]. Longer time to CKRT initiation was associated with higher odds of mortality in ascending time intervals. Patients started on CKRT > 2 days compared to < 2 days after stage 3 AKI onset had higher mortality (65% vs. 5%, p < 0.001), longer median ICU length of stay (25 vs. 12 d, p < 0.001), longer median CKRT duration (11 vs. 5 d, p < 0.001), and fewer AKI-free days (0 vs. 14 d, p < 0.001). CONCLUSIONS: Longer time to initiation of CKRT after development of severe AKI is independently associated with mortality. Consideration of early CKRT in this high-risk population may be a strategy to reduce mortality and improve recovery of kidney function. However, there remains significant heterogeneity in the definition of early versus late initiation and the optimal timing of CKRT remains unknown.

Interrogating the sepsis host immune response using cytomics.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2023. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2023 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901 .

Peri-Intubation Adverse Events in the Critically Ill Child After Hematopoietic Cell Transplant.

OBJECTIVES: Mechanically ventilated children post-hematopoietic cell transplant (HCT) have increased morbidity and mortality compared with other mechanically ventilated critically ill children. Tracheal intubation-associated adverse events (TIAEs) and peri-intubation hypoxemia universally portend worse outcomes. We investigated whether adverse peri-intubation associated events occur at increased frequency in patients with HCT compared with non-HCT oncologic or other PICU patients and therefore might contribute to increased mortality. DESIGN: Retrospective cohort between 2014 and 2019. SETTING: Single-center academic noncardiac PICU. PATIENTS: Critically ill children who underwent tracheal intubation (TI). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data from the local airway management quality improvement databases and Virtual Pediatric Systems were merged. These data were supplemented with a retrospective chart review for HCT-related data, including HCT indication, transplant-related comorbidity status, and patient condition at the time of TI procedure. The primary outcome was defined as the composite of hemodynamic TIAE (hypo/hypertension, arrhythmia, cardiac arrest) and/or peri-intubation hypoxemia (oxygen saturation < 80%) events. One thousand nine hundred thirty-one encounters underwent TI, of which 92 (4.8%) were post-HCT, while 319 (16.5%) had history of malignancy without HCT, and 1,520 (78.7%) had neither HCT nor malignancy. Children post-HCT were older more often had respiratory failure as an indication for intubation, use of catecholamine infusions peri-intubation, and use of noninvasive ventilation prior to intubation. Hemodynamic TIAE or peri-intubation hypoxemia were not different across three groups (HCT 16%, non-HCT with malignancy 10%, other 15). After adjusting for age, difficult airway feature, provider type, device, apneic oxygenation use, and indication for intubation, we did not identify an association between HCT status and the adverse TI outcome (odds ratio, 1.32 for HCT status vs other; 95% CI, 0.72-2.41; p = 0.37). CONCLUSIONS: In this single-center study, we did not identify an association between HCT status and hemodynamic TIAE or peri-intubation hypoxemia during TI.

The Use and Duration of Preintubation Respiratory Support Is Associated With Increased Mortality in Immunocompromised Children With Acute Respiratory Failure.

OBJECTIVES: To determine the association between preintubation respiratory support and outcomes in patients with acute respiratory failure and to determine the impact of immunocompromised (IC) diagnoses on outcomes after adjustment for illness severity. DESIGN: Retrospective multicenter cohort study. SETTING: Eighty-two centers in the Virtual Pediatric Systems database. PATIENTS: Children 1 month to 17 years old intubated in the PICU who received invasive mechanical ventilation (IMV) for greater than or equal to 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: High-flow nasal cannula (HFNC) or noninvasive positive-pressure ventilation (NIPPV) or both were used prior to intubation in 1,825 (34%) of 5,348 PICU intubations across 82 centers. When stratified by IC status, 50% of patients had no IC diagnosis, whereas 41% were IC without prior hematopoietic cell transplant (HCT) and 9% had prior HCT. Compared with patients intubated without prior support, preintubation exposure to HFNC (adjusted odds ratio [aOR], 1.33; 95% CI, 1.10-1.62) or NIPPV (aOR, 1.44; 95% CI, 1.20-1.74) was associated with increased odds of PICU mortality. Within subgroups of IC status, preintubation respiratory support was associated with increased odds of PICU mortality in IC patients (HFNC: aOR, 1.50; 95% CI, 1.11-2.03; NIPPV: aOR, 1.76; 95% CI, 1.31-2.35) and HCT patients (HFNC: aOR, 1.75; 95% CI, 1.07-2.86; NIPPV: aOR, 1.85; 95% CI, 1.12-3.02) compared with IC/HCT patients intubated without prior respiratory support. Preintubation exposure to HFNC/NIPPV was not associated with mortality in patients without an IC diagnosis. Duration of HFNC/NIPPV greater than 6 hours was associated with increased mortality in IC HCT patients (HFNC: aOR, 2.41; 95% CI, 1.05-5.55; NIPPV: aOR, 2.53; 95% CI, 1.04-6.15) and patients compared HCT patients with less than 6-hour HFNC/NIPPV exposure. After adjustment for patient and center characteristics, both preintubation HFNC/NIPPV use (median, 15%; range, 0-63%) and PICU mortality varied by center. CONCLUSIONS: In IC pediatric patients, preintubation exposure to HFNC and/or NIPPV is associated with increased odds of PICU mortality, independent of illness severity. Longer duration of exposure to HFNC/NIPPV prior to IMV is associated with increased mortality in HCT patients.

Risk of Mortality in Immunocompromised Children With Severe Sepsis and Septic Shock.

OBJECTIVES: To assess the prevalence of immunocompromised diagnoses among children with severe sepsis and septic shock, and to determine the association between immunocompromised diagnoses and clinical outcomes after adjustment for demographics and illness severity. DESIGN: Retrospective multicenter cohort study. SETTING: Eighty-three centers in the Virtual Pediatric Systems database. PATIENTS: Children with severe sepsis or septic shock admitted to a participating PICU between January 1, 2012, and December 31, 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Across 83 centers, we identified 10,768 PICU admissions with an International Classification of Diseases, 9th Revision, Clinical Modification code for severe sepsis or septic shock; 3,021 of these patients (28%) had an immunocompromised diagnosis. To evaluate variation across centers and determine factors associated with PICU mortality, we used mixed-effect logistic regression models. Among patients without hematopoietic cell transplant, congenital immunodeficiency (adjusted odds ratio, 1.90; 95% CI, 1.24-2.92), multiple prior malignancies (adjusted odds ratio, 1.86; 95% CI, 1.15-2.99), and hemophagocytic lymphohistiocytosis (adjusted odds ratio, 3.09; 95% CI, 1.91-4.98) were associated with an increased odds of PICU mortality. Among patients with prior hematopoietic cell transplant, liquid malignancy (adjusted odds ratio, 3.15; 95% CI, 2.09-4.74), congenital immunodeficiency (adjusted odds ratio, 6.94; 95% CI, 3.84-12.53), multiple prior malignancies (adjusted odds ratio, 3.54; 95% CI, 1.80-6.95), and hemophagocytic lymphohistiocytosis (adjusted odds ratio, 2.79; 95% CI, 1.36-5.71) were associated with an increased odds of PICU mortality. PICU mortality varied significantly by center, and a higher mean number of sepsis patients per month in a center was associated with lower PICU mortality (adjusted odds ratio, 0.94; 95% CI, 0.90-0.98). PICU resource utilization varied by immunocompromised diagnosis and history of hematopoietic cell transplant, and among survivors immunocompromised patients have shorter median PICU length of stay compared with patients without immunocompromised diagnoses (p < 0.001). CONCLUSIONS: Immunocompromised diagnoses are present in 28% of children with severe sepsis or septic shock. Multiple prior malignancies, hemophagocytic lymphohistiocytosis, congenital immunodeficiency, and hematopoietic cell transplant are independently associated with an increased odds of PICU mortality in children with severe sepsis or septic shock. Significant variation exists in PICU mortality among centers despite adjustment for immunocompromised diagnoses, known risk factors for sepsis-related mortality, and center-level sepsis volume.

Joining Datasets Without Identifiers: Probabilistic Linkage of Virtual Pediatric Systems and PEDSnet.

OBJECTIVES: To 1) probabilistically link two important pediatric data sources, Virtual Pediatric Systems and PEDSnet, 2) evaluate linkage accuracy overall and in patients with severe sepsis or septic shock, and 3) identify variables important to linkage accuracy. DESIGN: Retrospective linkage of prospectively collected datasets from Virtual Pediatrics Systems, Inc (Los Angeles, CA) and the PEDSnet consortium. SETTING: Single-center academic PICU. PATIENTS: All PICU encounters between January 1, 2012, and December 31, 2017, that were deterministically matched between the two datasets. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We abstracted records from Virtual Pediatric Systems and PEDSnet corresponding to PICU encounters and probabilistically linked using 44 features shared by the two datasets. We generated a gold standard deterministic linkage using protected health information elements, which were then removed from datasets. We then calculated candidate pair log-likelihood ratios for all pairs of subjects and selected optimal pairs in a two-stage algorithm. A total of 22,051 gold standard PICU encounter pairs were identified over the study period. The optimal linkage model demonstrated excellent discrimination (area under the receiver operating characteristic curve > 0.99); 19,801 cases (89.9%) were matched with 13 false positives. The addition of two protected health information dates (admission month, birth day-of-year) increased to 20,189 (91.6%) the cases matched, with three false positives. Restricting to patients with Virtual Pediatric Systems diagnosis of severe sepsis or septic shock (n = 1,340 [6.1%]) matched 1,250 cases (93.2%) with zero false positives. Increased number of laboratory values present in the first 12 hours of admission significantly increased log-likelihood ratios, suggesting stronger candidate pair matching. CONCLUSIONS: We demonstrated the use of probabilistic linkage to accurately join two complementary pediatric critical care datasets at a single academic PICU in the absence of protected health information. Combining datasets with curated diagnoses and granular measurements can validate patient acuity metrics and facilitate multicenter machine learning algorithms. We anticipate these methods will generalize to other common PICU diagnoses.

Comparison of Methods for Identification of Pediatric Severe Sepsis and Septic Shock in the Virtual Pediatric Systems Database.

OBJECTIVES: To compare the performance of three methods of identifying children with severe sepsis and septic shock from the Virtual Pediatric Systems database to prospective screening using consensus criteria. DESIGN: Observational cohort study. SETTING: Single-center PICU. PATIENTS: Children admitted to the PICU in the period between March 1, 2012, and March 31, 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the study period, all PICU patients were prospectively screened daily for sepsis, and those meeting consensus criteria for severe sepsis or septic shock on manual chart review were entered into the sepsis registry. Of 7,459 patients admitted to the PICU during the study period, 401 met consensus criteria for severe sepsis or septic shock (reference standard cohort). Within Virtual Pediatric Systems, patients identified using "Martin" (n = 970; κ = 0.43; positive predictive value = 34%; F1 = 0.48) and "Angus" International Classification of Diseases, 9th Edition, Clinical Modification codes (n = 1387; κ = 0.28; positive predictive value = 22%; F1 = 0.34) showed limited agreement with the reference standard cohort. By comparison, explicit International Classification of Diseases, 9th Edition, Clinical Modification codes for severe sepsis (995.92) and septic shock (785.52) identified a smaller, more accurate cohort of children (n = 515; κ = 0.61; positive predictive value = 57%; F1 = 0.64). PICU mortality was 8% in the reference standard cohort and the cohort identified by explicit codes; age, illness severity scores, and resource utilization did not differ between groups. Analysis of discrepancies between the reference standard and Virtual Pediatric Systems explicit codes revealed that prospective screening missed 66 patients with severe sepsis or septic shock. After including these patients in the reference standard cohort as an exploratory analysis, agreement between the cohort of patients identified by Virtual Pediatric Systems explicit codes and the reference standard cohort improved (κ = 0.73; positive predictive value = 70%; F1 = 0.75). CONCLUSIONS: Children with severe sepsis and septic shock are best identified in the Virtual Pediatric Systems database using explicit diagnosis codes for severe sepsis and septic shock. The accuracy of these codes and level of clinical detail available in the Virtual Pediatric Systems database allow for sophisticated epidemiologic studies of pediatric severe sepsis and septic shock in this large, multicenter database.

Pediatric In-Hospital Cardiac Arrest Secondary to Acute Pulmonary Embolism.

OBJECTIVES: Pulmonary embolism is a rarely reported and potentially treatable cause of cardiac arrest in children and adolescents. The objective of this case series is to describe the course of five adolescent patients with in-hospital cardiac arrest secondary to pulmonary embolism. DESIGN: Case series. SETTING: Single, large academic children's hospital. PATIENTS: All patients under the age of 18 years (n = 5) who experienced an in-hospital cardiac arrest due to apparent pulmonary embolism from August 1, 2013, to July 31, 2017. INTERVENTIONS: All five patients received systemic thrombolytic therapy (IV tissue plasminogen activator) during cardiac arrest or periarrest during ongoing resuscitation efforts. MEASUREMENTS AND MAIN RESULTS: Five adolescent patients, 15-17 years old, were treated for pulmonary embolism-related cardiac arrests during the study period. These accounted for 6.3% of all children and 25% of adolescents (12-17 yr old) receiving at least 5 minutes of in-hospital cardiopulmonary resuscitation during the study period. All five had venous thromboembolism risk factors. Two patients had known, extensive venous thrombi at the time of cardiac arrest, and one was undergoing angiography at the time of arrest. The diagnoses of pulmonary embolism were based on clinical suspicion, bedside echocardiography (n = 4), and low end-tidal CO2 levels relative to arterial CO2 values (n = 5). IV tissue plasminogen activator was administered during cardiopulmonary resuscitation in three patients and after the return of spontaneous circulation, in the setting of severe hemodynamic instability, in the other two patients. Four of five patients were successfully resuscitated and survived to hospital discharge. CONCLUSIONS: Pulmonary embolism was recognized as the etiology of multiple adolescent cardiac arrests in this single-center series and may be more common than previously reported. Recognition, high-quality cardiopulmonary resuscitation, and treatment with thrombolytic therapy resulted in survival in four of five patients.

The Influence of Adolescence on Parents' Perspectives of Testing and Discussing Inherited Cancer Predisposition.

Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome that may present with a first cancer before or during adolescence/young adulthood. Families offered LFS genetic testing for their children can inform our understanding of how the unique developmental context of adolescence influences parental perspectives about genetic testing and discussions of cancer risk. In this study, semi-structured interviews were conducted with 46 parents of children at risk for LFS to capture those perspectives. Analysis utilized summary descriptive statistics and inductive qualitative content coding. Most parents (33/46; 72%) expressed beliefs that adolescence influences the importance of LFS testing and/or discussions about genetic risk. Twenty-six parents related this influence to cognitive, physical, and social changes occurring during adolescence. Aspects of adolescence perceived as promoting LFS testing/discussion included developmental appropriateness, risks of cancer in adolescence, need for medical screening decisions, influence on behaviors, transition to adult health care, and reproductive risks. Aspects of adolescence perceived as complicating LFS testing/discussions included potential negative emotional impact, misunderstanding, added burden, and negative impact on self-image or future planning. Parents recognize the complex influence that adolescence has on LFS testing and conversations surrounding results. Further research is needed to understand the actual impact of genetic testing on young people, and how to best support parents and adolescents within the broader context of heritable diseases.

High Levels of Morbidity and Mortality Among Pediatric Hematopoietic Cell Transplant Recipients With Severe Sepsis: Insights From the Sepsis PRevalence, OUtcomes, and Therapies International Point Prevalence Study.

OBJECTIVES: Pediatric severe sepsis is a major cause of morbidity and mortality worldwide, and hematopoietic cell transplant patients represent a high-risk population. We assessed the epidemiology of severe sepsis in hematopoietic cell transplant patients, describing patient outcomes compared with children with no history of hematopoietic cell transplant. DESIGN: Secondary analysis of the Sepsis PRevalence, OUtcomes, and Therapies point prevalence study, comparing demographics, sepsis etiology, illness severity, organ dysfunction, and sepsis-related treatments in patients with and without hematopoietic cell transplant. The primary outcome was hospital mortality. Multivariable logistic regression models were used to determine adjusted differences in mortality. SETTING: International; 128 PICUs in 26 countries. PATIENTS: Pediatric patients with severe sepsis prospectively identified over a 1-year period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In patients with severe sepsis, 37/567 (6.5%) had a history of hematopoietic cell transplant. Compared with patients without hematopoietic cell transplant, hematopoietic cell transplant patients had significantly higher hospital mortality (68% vs 23%; p < 0.001). Hematopoietic cell transplant patients were more likely to have hospital acquired sepsis and had more preexisting renal and hepatic dysfunction than non-hematopoietic cell transplant patients with severe sepsis. History of hematopoietic cell transplant, renal replacement therapy, admission from inpatient floor, and number of organ dysfunctions at severe sepsis recognition were independently associated with hospital mortality in multivariable analysis; hematopoietic cell transplant conferred the highest odds of mortality (odds ratio, 4.00; 95% CI, 1.78-8.98). In secondary analysis of hematopoietic cell transplant patients compared with other immunocompromised patients with severe sepsis, history of hematopoietic cell transplant remained independently associated with hospital mortality (odds ratio, 3.03; 95% CI, 1.11-8.27). CONCLUSIONS: In an international study of pediatric severe sepsis, history of hematopoietic cell transplant is associated with a four-fold increased odds of hospital mortality after adjustment for potential measured confounders. Hematopoietic cell transplant patients more often originated from within the hospital compared to children with severe sepsis without hematopoietic cell transplant, possibly providing an earlier opportunity for sepsis recognition and intervention in this high-risk population.

Should Genetic Testing be Offered for Children? The Perspectives of Adolescents and Emerging Adults in Families with Li-Fraumeni Syndrome.

Whether children should be offered genetic testing for cancer risk is much debated but young voices are rarely heard in these conversations. The current study explored perspectives of genetic testing held by adolescents and emerging adults in families with Li Fraumeni syndrome (LFS). Twelve 12- to 25-year-olds in families with LFS completed qualitative interviews for this study. All believed that testing should be offered for children but many qualified this statement saying parental approval would be needed and testing should be optional. Genetic testing was seen as way to learn of risk status, allow for disease prevention efforts, and reduce uncertainty and anxiety. Perceived disadvantages included negative emotions associated with the testing result. Participants generally felt that children should be involved in the testing decision, but that parents could unilaterally decide to have a child tested in certain circumstances (e.g., young age, high risk). All who were aware of having been tested and of their test result (n = 7; 4 positive) said testing had no negative impact on their outlook and they agreed with the decision to undergo testing. Implications of these findings for clinical practice and future research are discussed.

Parent decision-making around the genetic testing of children for germline TP53 mutations.

BACKGROUND: Li-Fraumeni syndrome is a rare genetic cancer predisposition syndrome caused by germline TP53 mutations. Up to 20% of mutation carriers develop cancer during childhood. The benefits of TP53 mutation testing of children are a matter of debate and knowledge of parent decision-making around such testing is limited. The current study examined how parents make decisions regarding TP53 testing for their children. METHODS: Families offered and those pursuing TP53 testing for their children were identified across the study sites. Qualitative interviews with 46 parents (39 families) were analyzed to describe decision-making styles and perceived advantages and disadvantages of testing. RESULTS: TP53 mutation testing uptake was high (92%). Three decision-making styles emerged. Automatic decisions (44% of decisions) involved little thought and identified immediate benefit(s) in testing (100% pursued testing). Considered decisions (49%) weighed the risks and benefits but were made easily (77% pursued testing). Deliberated decisions (6%) were difficult and focused on psychosocial concerns (25% pursued testing). Perceived advantages of testing included promoting child health, satisfying a "need to know," understanding why cancer(s) occurred, suggesting family member risk, and benefiting research. Disadvantages included psychosocial risks and privacy/discrimination/insurance issues. CONCLUSIONS: Although empirical evidence regarding the benefits and risks of TP53 testing during childhood are lacking, the majority of parents in the current study decided easily in favor of testing and perceived a range of advantages. The authors conclude that in the context of a clinical diagnosis of Li-Fraumeni syndrome, parents should continue to be offered TP53 testing for their children, counseled regarding potential risks and benefits, and supported in their decision-making process.

Knowledge of diagnosis, treatment history, and risk of late effects among childhood cancer survivors and parents: The impact of a survivorship clinic.

BACKGROUND: Childhood cancer survivors are at risk for treatment-related adverse health outcomes, known as late effects. Through matched and longitudinal cohorts, we assessed the impact of survivorship care on patient and parent knowledge of treatment history and associated health risks. PROCEDURE: Childhood cancer survivors were recruited from a single-institution survivorship clinic and matched with survivors receiving routine follow-up care (controls) on diagnosis, age, and time off therapy. One hundred seventy-four participants completed telephone interviews assessing knowledge of diagnosis, treatment history, and risk of late effects. Additionally, 48 new survivorship patients were followed longitudinally with serial interviews for 18 months. RESULTS: In the case-control study, survivorship participants were more likely than controls to correctly report their diagnosis (98% vs. 90%, P = 0.039) and indicate a previous discussion of risk of late effects (99% vs. 62%, P<0.0001). Compared to controls, survivorship participants were 13% more sensitive reporting chemotherapeutics (95%CI 2.8-23.7%, P = 0.013) and 12% more sensitive reporting late effect risk (95%CI 7.3-16.6%, P<0.0001). In the longitudinal cohort, participants were 7% more sensitive reporting chemotherapeutics (95%CI 5.4-10.8%, P < 0.001) and 9% more sensitive reporting late effect risk (95%CI 5.6-23.8%, P<0.001) at 3 months compared to baseline. In regression analysis, baseline knowledge correlated with subsequent interview performance, and time since survivorship visit correlated with decreased knowledge of late effects, but not diagnosis or treatment history. CONCLUSIONS: Survivorship care was associated with increased knowledge of diagnosis, treatment history, and risk of late effects in both cohorts. Knowledge of late effects decreases with time, suggesting the need for additional educational strategies.

Development and validation of a prediction model for diagnosing blood stream infections in febrile, non-neutropenic children with cancer.

BACKGROUND: Pediatric oncology patients are at increased risk for blood stream infections (BSI). Risk in the absence of severe neutropenia (absolute neutrophil count [ANC] ≥500/µl) is not well defined. PROCEDURE: In a retrospective cohort of febrile (temperature ≥38.0° for >1 hr or ≥38.3°) pediatric oncology patients with ANC ≥500/µl, a diagnostic prediction model for BSI was constructed using logistic regression modeling and the following candidate predictors: age, ANC, absolute monocyte count, body temperature, inpatient/outpatient presentation, sex, central venous catheter type, hypotension, chills, cancer diagnosis, stem cell transplant, upper respiratory symptoms, and exposure to cytarabine, anti-thymocyte globulin, or anti-GD2 antibody. The model was internally validated with bootstrapping methods. RESULTS: Among 932 febrile episodes in 463 patients, we identified 91 cases of BSI. Independently significant predictors for BSI were higher body temperature (Odds ratio [OR] 2.36 P < 0.001), tunneled external catheter (OR 13.79 P < 0.001), peripherally inserted central catheter (OR 3.95 P = 0.005), elevated ANC (OR 1.19 P = 0.024), chills (OR 2.09 P = 0.031), and hypotension (OR 3.08 P = 0.004). Acute lymphoblastic leukemia diagnosis (OR 0.34 P = 0.026), increased age (OR 0.70 P = 0.049), and drug exposure (OR 0.08 P < 0.001) were associated with decreased risk for BSI. The risk prediction model had a C-index of 0.898; after bootstrapping adjustment for optimism, corrected C-index 0.885. CONCLUSIONS: We developed a diagnostic prediction model for BSI in febrile pediatric oncology patients without severe neutropenia. External validation is warranted before use in clinical practice. Pediatr Blood Cancer 2015;62:262-268. © 2014 Wiley Periodicals, Inc.

Diagnostic Performance of Whole-Body MRI as a Tool for Cancer Screening in Children With Genetic Cancer-Predisposing Conditions.

OBJECTIVE: Children with cancer-predisposing conditions are at increased risk to develop and die of cancer. Limited data exist on the utility of whole-body MRI as a cancer screening tool in children. In this study, we examined the diagnostic performance of whole-body MRI as a mechanism of tumor surveillance for children at increased genetic risk for cancer. MATERIALS AND METHODS: Twenty-four children (six boys and 18 girls) with a mean age of 11.2 years (range, 2.1-18.2 years) underwent 50 unenhanced whole-body MRI examinations over a 5-year period. Scans were retrospectively reviewed and assessed for image quality; sequences performed; and the presence of osseous, soft-tissue, or solid organ abnormalities. Findings suggestive of a malignancy were stratified by risk as low (< 20% chance for cancer), moderate (20-80%), or high (> 80%). MRI findings were correlated with medical records, biopsy results, or additional follow-up imaging; biopsy and follow-up were considered as the reference standards. RESULTS: Forty-eight of 50 (96%) examinations were of very good quality. Nine findings suspicious for malignancy were identified, including two high-risk, two moderate-risk, and five low-risk lesions. One high-risk lesion was proven by biopsy to be a papillary thyroid carcinoma, with the remaining lesions deemed nonmalignant. The sensitivity of whole-body MRI was 100%; specificity, 94%; positive predictive value, 25%; and negative predictive value (NPV), 100%. CONCLUSION: Unenhanced whole-body MRI is safe and produces excellent images. The high sensitivity, specificity, and NPV make whole-body MRI a valuable cancer screening tool in children with a genetic predisposition for cancer.

Dysregulated STAT3 signaling and T cell immunometabolic dysfunction define a targetable, high mortality subphenotype of critically ill children.

Sepsis is the leading cause of death of hospitalized children worldwide. Despite the established link between immune dysregulation and mortality in pediatric sepsis, it remains unclear which host immune factors contribute causally to adverse sepsis outcomes. Identifying modifiable pathobiology is an essential first step to successful translation of biologic insights into precision therapeutics. We designed a prospective, longitudinal cohort study of 88 critically ill pediatric patients with multiple organ dysfunction syndrome (MODS), including patients with and without sepsis, to define subphenotypes associated with targetable mechanisms of immune dysregulation. We first assessed plasma proteomic profiles and identified shared features of immune dysregulation in MODS patients with and without sepsis. We then employed consensus clustering to define three subphenotypes based on protein expression at disease onset and identified a strong association between subphenotype and clinical outcome. We next identified differences in immune cell frequency and activation state by MODS subphenotype and determined the association between hyperinflammatory pathway activation and cellular immunophenotype. Using single cell transcriptomics, we demonstrated STAT3 hyperactivation in lymphocytes from the sickest MODS subgroup and then identified an association between STAT3 hyperactivation and T cell immunometabolic dysregulation. Finally, we compared proteomics findings between patients with MODS and patients with inborn errors of immunity that amplify cytokine signaling pathways to further assess the impact of STAT3 hyperactivation in the most severe patients with MODS. Overall, these results identify a potentially pathologic and targetable role for STAT3 hyperactivation in a subset of pediatric patients with MODS who have high severity of illness and poor prognosis.

Obesity and insulin resistance in pediatric acute lymphoblastic leukemia worsens during maintenance therapy.

BACKGROUND: Pediatric acute lymphoblastic leukemia (ALL) survivors are at increased risk for the metabolic syndrome (MS). To establish the trajectory of development during active treatment, we followed patients longitudinally over the first year of maintenance therapy. PROCEDURE: In a prospective cohort of 34 pediatric ALL patients, followed over the first 12 months of ALL maintenance, we evaluated changes in body mass index (BMI), blood pressure, fasting insulin and glucose, lipids, Homeostatic Metabolic Assessment (HOMA), leptin, and adiponectin. RESULTS: Over the study time period, the median BMI z-score increased from 0.29 to 0.66 (P = 0.001), median fasting insulin levels increased from 2.9 to 3.1 µU/ml (P = 0.023), and the proportion of patients with insulin resistance by HOMA (>3.15) increased from 3% to 24% (P = 0.016). Median leptin increased from 2.5 to 3.5 ng/ml (P = 0.001), with levels correlated with BMI z-score. Median adiponectin level decreased from 18.0 to 14.0 µg/ml (P = 0.009), with levels inversely correlated to BMI z-score. No change in median total cholesterol and LDL levels was observed. Median triglycerides decreased (P < 0.001) and there was a trend to increase in HDL (P = 0.058). Blood pressure did not significantly change, although overall prevalence of systolic and diastolic hypertension was high (23.5% and 26.4%, respectively). CONCLUSIONS: Following patients over the first year of ALL maintenance therapy demonstrated that components of the MS significantly worsen over time. Preventive interventions limiting increases in BMI and insulin resistance during maintenance therapy should be targeted during this time period to avoid long-term morbidity associated with the MS in long-term survivors.

Immunocompromised Children With Acute Respiratory Distress Syndrome Possess a Distinct Circulating Inflammatory Profile.

Immunocompromised status, with and without stem cell transplant, confers a worse prognosis in pediatric acute respiratory distress syndrome. An improved understanding of the biochemical profile of immunocompromised children with acute respiratory distress syndrome would inform whether specific pathways are targetable, or merely bystanders, in order to improve outcomes in this high-risk subgroup. OBJECTIVES: We aimed to identify a biomarker profile of immunocompromised children, with and without stem cell transplant, independent of illness severity. DESIGN SETTINGS AND PARTICIPANTS: This was a secondary analysis of a prospective cohort study of intubated children with Berlin-defined acute respiratory distress syndrome with existing biomarker measurements conducted in a large academic PICU between 2014 and 2019. MAIN OUTCOMES AND MEASURES: Biomarker levels were compared between immunocompetent and immunocompromised children, with and without stem cell transplant, both prior to and after adjusting for severity of illness. RESULTS: In 333 children with acute respiratory distress syndrome, 84 were immunocompromised, of whom 39 had a stem cell transplant. Circulating neutrophil levels were strongly correlated with biomarkers, with 14 of 18 measured proteins differentially expressed in patients with versus without neutropenia. In order to identify biomarker levels independent of severity of illness, acute respiratory distress syndrome etiology, and neutrophil levels, we computed predicted (log-transformed) biomarker levels after adjusting for confounders using linear regression and then compared these severity-adjusted levels between immunocompetent and immunocompromised (with and without stem cell transplant) subjects using analyses of variance and post hoc Bonferroni. After multivariable adjustment, 11 biomarkers were higher in immunocompromised subjects without stem cell transplant, relative to immunocompetent, implicating endotheliopathy (angiopoietin-2), tissue damage (procollagen type III N-terminal peptide), and innate immunity. A single biomarker, C-C motif chemokine ligand 22, was lower in immunocompromised subjects with and without stem cell transplant. CONCLUSIONS AND RELEVANCE: Immunocompromised children with acute respiratory distress syndrome were characterized by elevations in pro-inflammatory and endothelial damage biomarkers. Our study provides insight into mechanisms underlying the molecular heterogeneity of this population and potentially identifies targetable pathways to mitigate their increased mortality risk.