Pulmonary microbiome and transcriptome signatures reveal distinct pathobiologic states associated with mortality in two cohorts of pediatric stem cell transplant patients.

Lung injury is a major determinant of survival after pediatric hematopoietic cell transplantation (HCT). A deeper understanding of the relationship between pulmonary microbes, immunity, and the lung epithelium is needed to improve outcomes. In this multicenter study, we collected 278 bronchoalveolar lavage (BAL) samples from 229 patients treated at 32 children's hospitals between 2014-2022. Using paired metatranscriptomes and human gene expression data, we identified 4 patient clusters with varying BAL composition. Among those requiring respiratory support prior to sampling, in-hospital mortality varied from 22-60% depending on the cluster (p=0.007). The most common patient subtype, Cluster 1, showed a moderate quantity and high diversity of commensal microbes with robust metabolic activity, low rates of infection, gene expression indicating alveolar macrophage predominance, and low mortality. The second most common cluster showed a very high burden of airway microbes, gene expression enriched for neutrophil signaling, frequent bacterial infections, and moderate mortality. Cluster 3 showed significant depletion of commensal microbes, a loss of biodiversity, gene expression indicative of fibroproliferative pathways, increased viral and fungal pathogens, and high mortality. Finally, Cluster 4 showed profound microbiome depletion with enrichment of Staphylococci and viruses, gene expression driven by lymphocyte activation and cellular injury, and the highest mortality. BAL clusters were modeled with a random forest classifier and reproduced in a geographically distinct validation cohort of 57 patients from The Netherlands, recapitulating similar cluster-based mortality differences (p=0.022). Degree of antibiotic exposure was strongly associated with depletion of BAL microbes and enrichment of fungi. Potential pathogens were parsed from all detected microbes by analyzing each BAL microbe relative to the overall microbiome composition, which yielded increased sensitivity for numerous previously occult pathogens. These findings support personalized interpretation of the pulmonary microenvironment in pediatric HCT, which may facilitate biology-targeted interventions to improve outcomes.

Bleeding in Critically Ill Children With Malignancy or Hematopoietic Cell Transplant: A Single-Center Prospective Cohort Study.

OBJECTIVES: To determine the incidence of bleeding in critically ill children with malignancy and to describe associated patient characteristics, interventions, and clinical outcomes. DESIGN: Prospective cohort study. SETTING: PICU in a specialized cancer hospital. PATIENTS: Children with malignancy or hematopoietic cell transplant 0-18 years of age were admitted to the PICU from November 2020 to November 2021. INTERVENTIONS: None. MEASUREMENTS: Patient demographic data, laboratory values, and PICU outcome data were collected. Bleeding was classified according to the Bleeding Assessment Scale in Critically Ill Children. MAIN RESULTS: Ninety-three bleeding patients were enrolled, and a total of 322 bleeding days were recorded. The median (interquartile range [IQR]) age was 5.8 (2.9-11.8) years and 56% (52/93) of the patients were male. There were 121 new bleeding episodes, in 593 at-risk person-days, translating into a 20% incidence rate per day (95% CI, 17-24%). The incidence of severe, moderate, and minimal bleeding was 2% (95% CI, 1-3), 4% (95% CI, 3-6), and 14% (95% CI, 12-17), respectively. Of the new bleeding episodes, 9% were severe, 25% were moderate and 66% were minimal. Thrombocytopenia was the only laboratory value independently associated with severe bleeding ( p = 0.009), as compared to minimal and moderate bleeding episodes. History of radiation therapy was independently associated with severe bleeding ( p = 0.04). We failed to identify an association between a history of stem cell transplant ( p = 0.49) or tumor type ( p = 0.76), and bleeding severity. Patients were transfused any blood product on 28% (95% CI, 22-34) of the bleeding days. Severe bleeding was associated with increased length of mechanical ventilation ( p = 0.003), longer PICU stays ( p = 0.03), and higher PICU mortality ( p = 0.004). CONCLUSIONS: In this prospective cohort of children with malignancy, the incidence rate of bleeding was 20%. Most events were classified as minimal bleeding. Low platelet count and radiation therapy were variables independently associated with severe bleeding episodes.

Epidemiology of Bleeding in Critically Ill Children With an Underlying Oncologic Diagnosis.

OBJECTIVES: Critically ill children with malignancy have significant risk of bleeding but the exact epidemiology is unknown. We sought to describe severe bleeding events and associated risk factors in critically ill pediatric patients with an underlying oncologic diagnosis using the newly developed Bleeding Assessment Scale in Critically Ill Children definition. DESIGN: Retrospective cohort study. SETTING: PICU in comprehensive cancer center. PATIENTS: Children ages 28 days to 18 years with an underlying oncologic diagnosis admitted to the PICU during 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two-hundred sixty-seven admissions met inclusion criteria. Sixty-four percent (171/267) were male, with a median (interquartile range) age of 6.3 years (3.1-12.1 yr). Nine percent (23/267) had at least one severe bleeding event during their PICU admission. There were no significant differences between those with severe bleeding and those without, with respect to gender (p = 0.07), age (p = 0.66), weight (p = 0.76), or transplant status (p = 0.18). There was a difference in the frequency of severe bleeding based on underlying oncologic diagnosis (p = 0.009). For patients with severe bleeding, the median (interquartile range) platelet count and international normalized ratio on the day of bleeding were 102 × 109/L (40-181 × 109/L) and 1.36 (1.26-1.51), respectively. Eighty-seven percent patients (20/23) with severe bleeding received at least one blood component in response to bleeding. Two patients received antifibrinolytics. Patients with severe bleeding had significantly fewer PICU-free days (p = 0.001), fewer ventilator-free days (p < 0.001), and higher 28-day mortality (p = 0.003). CONCLUSIONS: Severe bleeding occurred in nearly one-tenth of critically ill children with an underlying oncologic diagnosis without severe thrombocytopenia or coagulopathy. The vast majority received blood component therapy, but few received hemostatic medication. Studies are needed to guide the treatment of severe bleeding in this vulnerable patient population.

Stepwise Strategic Mitigation Planning in a Pediatric Oncology Center During the COVID-19 Pandemic.

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) first reached the United States in January 2020. Located in New York City (NYC), MSK Kids, at Memorial Sloan Kettering Cancer Center services, is one of the largest pediatric cancer centers in the U.S., caring for children, teenagers, and young adults with cancer, immune deficiencies, and blood disorders. Methods: Implementation for infection mitigation and ongoing care of patients included: (1) the creation of a strategic planning team of physicians, advanced practice providers, nurses, and administrators to develop guidance and workflows, (2) continuous reassessment of patients' needs for hospital services and visit frequency, (3) the use of telemedicine to replace in-person visits, (4) the use of satellite regional centers to manage patients living outside NYC, (5) pre-screening of patients prior to visits for risks and symptoms of coronavirus disease 2019 (COVID-19) infection, (6) day-of-service screening for risks or symptoms of COVID-19 infection, (7) surveillance testing of children and their caregivers, and (8) creation of cohort plans for the management of COVID-19 positive and uninfected patients within the same institution, in both the outpatient and inpatient settings. Results: We describe the timeline for planning mitigation during the first weeks of the pandemic, and detail in a stepwise fashion the rationale and implementation of COVID-19 containment efforts in the context of a large pediatric oncology program. Discussion: Our experience offers a model on which to base strategic planning efforts at other pediatric oncology centers, for continued preparedness to combat the threat posed by SARS-CoV-2 worldwide.

A pragmatic multi-institutional approach to understanding transplant-associated thrombotic microangiopathy after stem cell transplant.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication of hematopoietic stem cell transplantation (HSCT). A single-center prospective screening study has shown that the incidence of TA-TMA is much higher than prior retrospective studies that did not systematically screen. These data have not been replicated in a multicenter study. Our objective was to determine the incidence and risk factors for TA-TMA and compare outcomes of pediatric HSCT patients with and without TA-TMA. Patients were prospectively screened for TA-TMA at participating centers using a simple to implement and inexpensive strategy from the start of the preparative regimen through day +100. TA-TMA was diagnosed if ≥4 of 7 laboratory/clinical markers diagnostic for TA-TMA were present concurrently or if tissue histology showed TA-TMA. A total of 614 patients (359 males; 58%) received prospective TA-TMA screening at 13 pediatric centers. TA-TMA was diagnosed in 98 patients (16%) at a median of 22 days (interquartile range, 14-44) posttransplant. Patients with TA-TMA had significantly increased bloodstream infections (38% [37/98] vs 21% [107/51], P ≤ .001), mean total hospitalization days (68; 95% confidence interval [CI], 63-74 vs 43; 95% CI, 41-45; P ≤ .001), and number of days spent in the intensive care unit (10.1; 95% CI, 6.4-14; vs 1.6; 95% CI, 1.1-2.2; P ≤ .001) in the first 100 days after HSCT compared with patients without TA-TMA. Overall survival was significantly higher in patients without TA-TMA (93%; 490/516) compared with patients with TA-TMA (78%; 76/98) (P ≤ .001). These data support the need for systematic screening for TA-TMA and demonstrate the feasibility and efficacy of an easy to implement strategy to do so.

Rapid Transition of a PICU Space and Staff to Adult Coronavirus Disease 2019 ICU Care.

OBJECTIVES: We describe the process by which a PICU and a PICU care team were incorporated into a hospital-wide ICU care model during the coronavirus disease 2019 pandemic. DESIGN: A descriptive, retrospective report from a single-center PICU. SETTING: Twenty-three bed, quaternary PICU, within an 862-bed hospital. PATIENTS: Critically ill adults, with coronavirus disease 2019-related disease. INTERVENTIONS: ICU care provided by pediatric intensivists with training and support from medical intensivists. MEASUREMENTS AND MAIN RESULTS: Within the context of the institution's comprehensive effort to centralize and systematize care for adults with severe coronavirus disease 2019 disease, the PICU was transitioned to an adult coronavirus disease 2019 critical care unit. Nurses and physicians underwent just-in-time training over 3 days and 2 weeks, respectively. Medical ICU physicians and nurses provided oversight for care and designated hospital-based teams were available for procedures and common adult emergencies. Over a 7-week period, the PICU cared for 60 adults with coronavirus disease 2019-related critical illness. Fifty-three required intubation and mechanical ventilation for a median of 18 days. Eighteen required renal replacement therapy and 17 died. CONCLUSIONS: During the current and potentially in future pandemics, where critical care resources are limited, pediatric intensivists and staff can be readily utilized to meaningfully contribute to the care of critically ill adults.

Critical Care for Coronavirus Disease 2019: Perspectives From the PICU to the Medical ICU.

OBJECTIVES: To describe the unique perspective of pediatric intensivists caring for critically ill adults during the coronavirus disease 2019 pandemic. DESIGN: Observational study. SETTING: Academic medical center in New York City. PATIENTS: Coronavirus disease 2019 positive adults requiring admission to an ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In late March 2020, New York Presbyterian Hospital centralized all of its inpatient pediatric units (n = 4) from across the network to a single center, in order to create space to accommodate the increasing number of critically ill adults with coronavirus disease 2019. Within 1 week, the PICU at New York Presbyterian Hospital-Weill Cornell Medicine transferred or discharged all inpatients, underwent a transformation of the physical space, and began admitting adults of all ages with coronavirus disease 2019 related acute respiratory failure. The New York Presbyterian Hospital-Weill Cornell Medicine PICU physician group continued to lead this unit. PICU nurses, respiratory therapists, social workers, and child life specialists joined their PICU physician colleagues to care for these critically ill adults. CONCLUSIONS: In the coronavirus disease 2019 pandemic, PICU physicians are well poised to care for adult patients in a surge capacity, and bring a unique perspective to the experience.

QT Interval Prolongation in the Pediatric Oncologic Population on Methadone.

Studies have been conducted on adults prescribed with methadone to determine the necessary frequency of QTc monitoring but no consensus has been reached and no similar research has been conducted in the pediatric population. The objective of this retrospective study was to determine the occurrence rate of QTc interval prolongation associated with methadone use in a pediatric oncologic population. In total, 18% of patients developed QTc interval prolongation. These patients had longer baseline QTc intervals and were on more QTc interval-prolonging medications. Our data suggest that these variables may be able to risk stratify patients who require more frequent monitoring.

Spinal Fusion for Scoliosis in Rett Syndrome With an Emphasis on Respiratory Failure and Opioid Usage.

Our objective was to characterize our experience with 8 patients with Rett syndrome undergoing scoliosis surgery in regard to rates of respiratory failure and rates of ventilator-acquired pneumonia in comparison to patients with neurologic scoliosis and adolescent idiopathic scoliosis. This study was a retrospective chart review of patients undergoing scoliosis surgery at a tertiary children's hospital. Patients were divided into 3 groups: (1) adolescent idiopathic scoliosis, (2) neurologic scoliosis, and (3) Rett syndrome. There were 133 patients with adolescent idiopathic scoliosis, 48 patients with neurologic scoliosis, and 8 patients with Rett syndrome. We found that patients with Rett syndrome undergoing scoliosis surgery have higher rates of respiratory failure and longer ventilation times in the postoperative period when compared with both adolescent idiopathic scoliosis and neurologic scoliosis patients. There is insufficient evidence to suggest a difference in the incidence of ventilator-acquired pneumonia between the Rett syndrome and the neurologic scoliosis group. We believe our findings are the first in the literature to show a statistically significant difference between these 3 groups in regard to incidence of respiratory failure.

Serial Measurement of Amino-Terminal Pro-B-Type Natriuretic Peptide Predicts Adverse Cardiovascular Outcome in Children With Primary Myocardial Dysfunction and Acute Decompensated Heart Failure.

OBJECTIVES: In children, elevated amino-terminal pro-B-type natriuretic peptide levels are associated with impaired heart function. The predictive value of serial monitoring of amino-terminal pro-B-type natriuretic peptide levels in acute decompensated heart failure is unclear. DESIGN: Prospective observational study. SETTING: Single, tertiary referral pediatric critical care unit. PATIENTS: Patients aged 0-21 years with primary myocardial dysfunction and acute decompensated heart failure. INTERVENTIONS: Amino-terminal pro-B-type natriuretic peptide levels were obtained on enrollment, day 2, and day 7. Clinical, laboratory, and imaging data were collected on enrollment. Adverse cardiovascular outcome was defined as heart transplant, ventricular assist device placement, extracorporeal membrane oxygenation, or death at 1 year after admission. Aminoterminal pro-B-type natriuretic peptide levels and the percent change from day 0 to day 2 and day 0 to day 7 were calculated and compared between those with and without adverse cardiovascular outcome. MEASUREMENTS AND MAIN RESULTS: Sixteen consecutive patients were enrolled. Adverse cardiovascular outcome occurred in six patients (37.5%, four heart transplant and two ventricular assist device). In patients with an adverse cardiovascular outcome, median amino-terminal pro-B-type natriuretic peptide levels at day 7 were significantly higher (7,365 vs 1,196 pg/mL; p = 0.02) and the percent decline in amino-terminal pro-B-type natriuretic peptide was significantly smaller (28% vs 73%; p = 0.02) compared with those without an adverse cardiovascular outcome. Receiver operating curve analysis revealed that a less than 55% decline in amino-terminal pro-B-type natriuretic peptide levels at day 7 had a sensitivity and specificity of 83% and 90%, respectively, in predicting an adverse cardiovascular (area under the curve, 0.86; 95% CI, 0.68-1.0; p = 0.02). CONCLUSIONS: In conclusion, children with primary myocardial dysfunction and acute decompensated heart failure, a persistently elevated amino-terminal pro-B-type natriuretic peptide, and/or a lesser degree of decline in amino-terminal pro-B-type natriuretic peptide during the first week of presentation were strongly associated with adverse cardiovascular outcome. Serial amino-terminal pro-B-type natriuretic peptide monitoring may allow the early identification of children at risk for worse outcome.

Arrhythmias in the paediatric intensive care unit: a prospective study of the rates and predictors of arrhythmias in children without underlying cardiac disease.

OBJECTIVE: Arrhythmias are common in patients admitted to the paediatric intensive care unit. We sought to identify the rates of occurrence and types of arrhythmias, and determine whether an arrhythmia was associated with illness severity and paediatric intensive care unit length of stay. DESIGN: This is a prospective, observational study of all patients admitted to the paediatric intensive care unit at the Children's Hospital at Montefiore from March to June 2012. Patients with cardiac disease or admitted for the treatment of primary arrhythmias were excluded. Clinical and laboratory data were collected and telemetry was reviewed daily. Tachyarrhythmias were identified as supraventricular tachycardia, ventricular tachycardia, and arrhythmias causing haemodynamic compromise or for which an intervention was performed. RESULTS: A total of 278 patients met the inclusion criteria and were analysed. There were 97 incidences of arrhythmia in 53 patients (19%) and six tachyarrhythmias (2%). The most common types of arrhythmias were junctional rhythm (38%), premature atrial contractions (24%), and premature ventricular contractions (22%). Tachyarrhythmias included three supraventricular tachycardia (50%) and three ventricular tachycardia (50%). Of the six tachyarrhythmias, four were related to placement or migration of central venous lines and two occurred during aminophylline infusion. Patients with an arrhythmia had longer duration of mechanical ventilation and paediatric intensive care unit stay (p<0.001). In multivariate analysis, central venous lines (odds ratio 3.1; 95% confidence interval 1.3-7.2, p=0.009) and aminophylline use (odds ratio 5.1; 95% confidence interval 1.7-14.9, p=0.003) were independent predictors for arrhythmias. CONCLUSIONS: Arrhythmias were common in paediatric intensive care unit patients (19%), although tachyarrhythmias occurred rarely (2%). Central venous lines and use of aminophylline were identified as two clinical factors that may be associated with development of an arrhythmia.

Anti-factor Xa assay is a superior correlate of heparin dose than activated partial thromboplastin time or activated clotting time in pediatric extracorporeal membrane oxygenation*.

OBJECTIVE: To assess the utility of activated clotting time, activated partial thromboplastin time, and anti-Factor Xa assay for the monitoring and dosing of heparin in pediatric patients requiring support with extracorporeal membrane oxygenation. DESIGN: Retrospective chart review. SETTING: PICU in a single, tertiary care, academic children's hospital. PATIENTS: Seventeen patients (age 1 d to 13.9 yr, median 0.83 yr) managed on pulmonary and cardiac extracorporeal membrane oxygenation between March 2010 and August 2012 by a single surgeon. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twice daily measurements of anti-Factor Xa assay, activated clotting time, and activated partial thromboplastin time were determined from the same blood specimen. Data were analyzed using SAS system v9.2. Fourteen patients (82.4%) were successfully weaned from extracorporeal membrane oxygenation and 12 (70.6%) were discharged from the hospital. Pearson correlations were used to compare heparin dose and activated clotting time, activated partial thromboplastin time, and anti-Factor Xa assay. Analysis showed negative Pearson correlations in 11 of 17 patients between the activated clotting time and heparin, as compared with seven of 17 for activated partial thromboplastin time and only one for heparin and anti-Factor Xa assay. Only four patients had moderate to strong positive correlations between activated clotting time and heparin as compared with a moderate to strong positive correlation in 10 patients for anti-Factor Xa assay and heparin. CONCLUSIONS: The anti-Factor Xa assay correlated better with heparin dosing than activated clotting time or activated partial thromboplastin time. Activated clotting time has a poor correlation to heparin doses commonly associated with extracorporeal membrane oxygenation. In pediatric extracorporeal membrane oxygenation, anti-Factor Xa assay may be a more valuable monitor of heparin administration.

Myocardial dysfunction in pediatric septic shock.

OBJECTIVE: To evaluate the prevalence and significance of myocardial dysfunction in children with septic shock. STUDY DESIGN: Thirty patients with septic shock were evaluated by transthoracic echocardiography within 24 hours of admission to a pediatric critical care unit. Transthoracic echocardiography evaluation included left ventricular (LV) size and function, mitral valve inflow velocities in early and late diastole, mitral valve annular velocities in systole and early and late diastole, and LV myocardial performance index. LV systolic dysfunction was defined as an ejection fraction or shortening fraction z-score <-2, and LV diastolic dysfunction was defined as a mitral valve inflow velocity/annular velocity in early diastole ratio z-score >2. Secondary outcomes included troponin I concentration, acute kidney injury, and 28-day mechanical ventilation-free duration. RESULTS: Mortality for the 30 patients (mean age, 9.5 ± 7 years) was 7%. The prevalence of LV systolic and/or diastolic dysfunction was 53% (16 of 30). Eleven patients (37%) had systolic dysfunction, 10 (33%) had diastolic dysfunction, and 5 (17%) had both. Systolic and/or diastolic dysfunction was significantly associated with troponin I level (P = .007) and acute kidney injury (P = .02), but not with ventilation-free duration (P = .12). Kaplan-Meier analyses for pediatric critical care unit and hospital length of stay identified no differences between patients with and those without myocardial dysfunction. CONCLUSION: Myocardial dysfunction occurs frequently in children with septic shock but might not affect hospital length of stay.

Blood transfusion in sickle cell disease leading to posterior reversible encephalopathy syndrome (PRES).

Children with sickle cell disease have a very high risk of lifelong neurologic morbidity and mortality. Cerebrovascular accidents are a known complication in children with sickle cell disease. Posterior reversible encephalopathy syndrome is a constellation of acute neurologic findings increasingly recognized in pediatric critical care population with evidence of vasogenic edema on brain imaging possibly due to cerebral vascular endothelial cell dysfunction. This report, for the first time, describes a young adult with sickle cell disease who developed posterior reversible encephalopathy syndrome following blood transfusion.

Massive pulmonary embolism in children.

We present 3 children with massive pulmonary embolism and review 17 recent pediatric reports. Malignancies were a frequent cause (40%), and sudden death was common (60%). Compared with adults, diagnosis was more likely to be made at autopsy (P < .0001), more children were treated with embolectomy/thrombectomy (P = .0006), and mortality was greater (P = .03).

Children undergoing heart transplant are at increased risk for postoperative vasodilatory shock.

OBJECTIVE: To determine the incidence of vasodilatory shock (VDS) in children after cardiopulmonary bypass (CPB), and to describe this syndrome of post-CPB VDS in children. DESIGN: Prospective, observational. SETTING: Pediatric and neonatal intensive care units in a tertiary care, children's hospital. PATIENTS: Three hundred children undergoing CPB. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Three hundred subjects undergoing CPB were evaluated for clinical evidence of VDS following CPB. The incidence of post-CPB VDS was 3%. Characteristics of children who developed VDS: higher peak lactate (6.2 +/- 2.6 vs. 3.0 +/- 2.1 mmol/L; p = 0.0002), higher peak serum blood urea nitrogen (18.5 +/- 4.6 vs. 15.6 +/- 7.2 mg/dL; p = 0.04), lower urine output (1.7 +/- 0.8 vs. 2.6 +/- 0.2 mL/kg/hr; p = 0.04), and fewer intensive care unit free days (14.9 +/- 9.0 vs. 21.1 +/- 7.2 days; p = 0.01). Univariate predictors for the development of post-CPB VDS included children who had heart transplantation (HT) (relative risk [RR], 9.8; 95% confidence interval [CI], 2.7-35.2) or ventricular assist device (VAD) placed (RR, 17.9; 95% CI, 3.8-84.1), a cardiomyopathy diagnosis (RR, 8.5; 95% CI, 2.3-31), age >12 years (RR, 4.5; 95% CI, 1.2-17.0), CPB time >180 minutes (RR, 7.1; 95% CI, 1.9-26.2), and preoperative ventricular dysfunction (RR, 3.7; 95% CI, 1.0-13.4). By stratified analysis, the only independent predictor for the development of VDS was undergoing HT/VAD. CONCLUSIONS: Post-CPB VDS is uncommon in children. However, children who undergo HT or VAD placement are at high risk for developing post-CPB VDS. Recognition that the overall incidence of post-CPB is low-except in the HT/VAD population-may help guide therapy in the pediatric post-CPB patient.