Interprofessional Team-based Care of the Hematopoietic Cell Transplantation Patient With Hepatic Veno-occlusive Disease/Sinusoidal Obstruction Syndrome.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a well-recognized complication of allogeneic and autologous hematopoietic cell transplantation (HCT). The diagnosis and treatment of VOD/SOS require the involvement of multiple specialists covering a wide range of expertise. Interprofessional team-based medical care is standard practice for patients undergoing HCT and has been shown to improve patient and provider satisfaction, enhance efficiency, and improve patient outcomes, particularly for patients in complex medical situations like those with VOD/SOS post-HCT. Interdisciplinary team-based models focus on the synthesis and harmonization of knowledge and methods from different disciplines to create an integrative approach to patient care that both maximizes the expertise of each involved specialist and encourages thought beyond each specialist's discipline. Multidisciplinary team members provide additive support and work collaboratively with the core team to provide knowledge from their field. The composition of the interdisciplinary HCT team should center on the needs of the patient and institutional resources and involve the expertise of additional multidisciplinary team members based on clinical needs. This review focuses on interdisciplinary and multidisciplinary team-based care of patients with VOD/SOS post-HCT and provides an example of a collaborative VOD/SOS team that includes transplant physicians, nurses, pharmacists, nutrition/dietary specialists, and intensive care teams.

Risk Factors for Noninvasive Ventilation Failure in Children Post-Hematopoietic Cell Transplant.

RATIONALE: Little is known on the use of noninvasive ventilation (NIPPV) in pediatric hematopoietic cell transplant (HCT) patients. OBJECTIVE: We sought to describe the landscape of NIPPV use and to identify risk factors for failure to inform future investigation or quality improvement. METHODS: This is a multicenter, retrospective observational cohort of 153 consecutive children post-HCT requiring NIPPV from 2010-2016. RESULTS: 97 (63%) failed NIPPV. Factors associated with failure on univariate analysis included: longer oxygen use prior to NIPPV (p=0.04), vasoactive agent use (p<0.001), and higher respiratory rate at multiple hours of NIPPV use (1hr p=0.02, 2hr p=0.04, 4hr p=0.008, 8hr p=0.002). Using respiratory rate at 4 hours a multivariable model was constructed. This model demonstrated high ability to discriminate NIPPV failure (AUC=0.794) with the following results: respiratory rate >40 at 4 hours [aOR=6.3 9(95% CI: 2.4, 16.4), p<0.001] and vasoactive use [aOR=4.9 (95% CI: 1.9, 13.1), p=0.001]. Of note, 11 patients had a cardiac arrest during intubation (11%) and 3 others arrested prior to intubation. These 14 patients were closer to HCT [14 days (IQR:4, 73) vs 54 (IQR:21,117), p<0.01] and there was a trend toward beginning NIPPV outside of the PICU and arrest during/prior to intubation (p=0.056). CONCLUSIONS: In this cohort respiratory rate at 4 hours and vasoactive use are independent risk factors of NIPPV failure. An objective model to predict which children may benefit from a trial of NIPPV, may also inform the timing of both NIPPV initiation and uncomplicated intubation.

Chimeric Antigen Receptor, Teamwork, Education, Assessment, and Management (CAR-TEAM): A Simulation-Based Inter-professional Education (IPE) Intervention for Management of CAR Toxicities.

Chimeric antigen receptor (CAR) therapies such as tisagenlecleucel, indicated for children and young adults with relapsed and/or refractory CD19+ acute lymphoblastic leukemia (ALL), have been associated with striking treatment outcomes and overall survival. Yet, they are also associated with unique and potentially life-threatening complications. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are generally reversible complications of CAR therapies, but many patients may require critical care support especially if they are not promptly recognized and appropriately managed by frontline healthcare staff. As CAR therapies become more widely available, it is important that inter-professional staff members be aware of general principles regarding diagnosis and management. We hypothesized that an inter-professional education (IPE) simulation-based education intervention (CAR-TEAM) would improve knowledge base and confidence regarding complications of CAR therapies among inter-professional staff. Here, we demonstrate that following CAR-TEAM training, >90% of participants demonstrated knowledge proficiency and confidence in the IPE content area. CAR-TEAM training may serve as an important tool to establish initial and continued competency among sites introducing CAR therapies.

Respiratory pathogens associated with intubated pediatric patients following hematopoietic cell transplant.

BACKGROUND: We describe organisms found in the respiratory tracts of a multicenter cohort of pediatric hematopoietic cell transplant (HCT) recipients with respiratory failure. METHODS: Twelve centers contributed up to 25 pediatric allogeneic HCT recipients requiring mechanical ventilation for respiratory failure to a retrospective database. Positive respiratory pathogens and method of obtaining sample were recorded. Outcomes were assessed using Mann-Whitney U test or chi-squared analysis. RESULTS: Of the 222 patients in the database, ages 1 month through 21 years, 34.6% had a positive respiratory culture. 105 pathogens were identified in 77 patients; of those, 48.6% were viral, 34.3% bacterial, 16.2% fungal, and 1% parasitic. PICU mortality with a respiratory pathogen was 68.8% compared to 54.9% for those without a respiratory pathogen (P = .045). Those with a positive respiratory pathogen had longer PICU length of stay, 20 days (IQR 14.0, 36.8) vs 15 (IQR 6.5, 32.0), P = .002, and a longer course of mechanical ventilation, 17 days (IQR 10, 29.5) vs 8 (3, 17), P < .0001. Method of pathogen identification, type of pathogen, and the presence of multiple pathogens were not associated with changes in PICU outcomes. CONCLUSIONS: In this multicenter retrospective cohort of intubated pediatric post-HCT patients, there was high variability in the respiratory pathogens identified. Type of pathogen and method of detection did not affect PICU mortality. The presence of any organism leads to increased PICU mortality, longer PICU stay, and increased duration of mechanical ventilation suggesting that early detection and treatment of pathogens may be beneficial in this population.

Diagnosis, grading, and treatment recommendations for children, adolescents, and young adults with sinusoidal obstructive syndrome: an international expert position statement.

Sinusoidal obstructive syndrome, also known as hepatic veno-occlusive disease, is a potentially life-threatening complication that occurs in children undergoing haemopoietic stem-cell transplantation (HSCT). Differences in the incidence of genetic predisposition and clinical presentation of sinusoidal obstructive syndrome between children and adults have rendered the historical Baltimore and Seattle diagnostic criteria insufficient for children. In 2017, the European Society for Blood and Marrow Transplantation (EBMT) proposed the first paediatric diagnostic and severity grading guidelines for sinusoidal obstructive syndrome, intended for implementation across European centres. However, universally accepted paediatric criteria are needed to ensure prompt diagnosis, definitive treatment, and improved outcomes for children, adolescents, and young adults with sinusoidal obstructive syndrome, and to facilitate international clinical research collaboration. We convened an international panel of multidisciplinary experts including physicians with expertise in HSCT, paediatric intensive care, nephrology, hepatology, radiology, pathology, and transfusion medicine; HSCT advanced-practice providers and medical trainees; pharmacists; and translational and basic science researchers from the Pediatric Acute Lung Injury and Sepsis Investigators Network, the EBMT, the Pediatric Blood and Marrow Transplant Consortia, and several other institutions with extensive experience in sinusoidal obstructive syndrome. Panellists convened at The University of Texas, MD Anderson Cancer Center (Houston, TX, USA) in February, 2019, to evaluate the available evidence. In this expert position statement paper, we provide consensus recommendations for the international implementation of guidelines for the diagnosis, severity grading, and treatment of sinusoidal obstructive syndrome among children, adolescents, and young adults. We endorse universal adoption of paediatric diagnostic guidelines for sinusoidal obstruction syndrome as proposed by the EBMT, and provide implementation guidance for standardisation across centres; we have further proposed adjunctive use of age-appropriate organ-specific toxicity criteria for severity grading and provided prophylaxis and treatment considerations among children and adolescent and young adult patients. Key recommendations include: (1) liver biopsy, portal venous wedge pressure, and reversal of portal venous flow on Doppler ultrasonography should not be used for the routine diagnosis of sinusoidal obstructive syndrome in children, adolescents, and young adults; (2) platelet refractoriness can be defined as a corrected count increment of less than 5000-7500 following at least two sequential ABO-compatible fresh platelet transfusions; (3) hepatomegaly is best defined as an absolute increase of at least 1 cm in liver length at the midclavicular line; and if a baseline measurement is not available, hepatomegaly can be defined as greater than 2 SDs above normal for age; and (4) the presence and volume of ascites can be categorised as mild (minimal fluid by liver, spleen, or pelvis), moderate (<1 cm fluid), or severe (fluid in all three regions with >1 cm fluid in at least two regions).

Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy.

In 2017, an autologous chimeric antigen receptor (CAR) T cell therapy indicated for children and young adults with relapsed and/or refractory CD19+ acute lymphoblastic leukaemia became the first gene therapy to be approved in the USA. This innovative form of cellular immunotherapy has been associated with remarkable response rates but is also associated with unique and often severe toxicities, which can lead to rapid cardiorespiratory and/or neurological deterioration. Multidisciplinary medical vigilance and the requisite health-care infrastructure are imperative to ensuring optimal patient outcomes, especially as these therapies transition from research protocols to standard care. Herein, authors representing the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Stem Cell Transplantation (HSCT) Subgroup and the MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program have collaborated to provide comprehensive consensus guidelines on the care of children receiving CAR T cell therapy.

Acute Respiratory Failure in Pediatric Hematopoietic Cell Transplantation: A Multicenter Study.

OBJECTIVES: Acute respiratory failure is common in pediatric hematopoietic cell transplant recipients and has a high mortality. However, respiratory prognostic markers have not been adequately evaluated for this population. Our objectives are to assess respiratory support strategies and indices of oxygenation and ventilation in pediatric allogeneic hematopoietic cell transplant patients receiving invasive mechanical ventilation and investigate how these strategies are associated with mortality. DESIGN: Retrospective, multicenter investigation. SETTING: Twelve U.S. pediatric centers. PATIENTS: Pediatric allogeneic hematopoietic cell transplant recipients with respiratory failure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two-hundred twenty-two subjects were identified. PICU mortality was 60.4%. Nonsurvivors had higher peak oxygenation index (38.3 [21.3-57.6] vs 15.0 [7.0-30.7]; p < 0.0001) and oxygen saturation index (24.7 [13.8-38.7] vs 10.3 [4.6-21.6]; p < 0.0001), greater days with FIO2 greater than or equal to 0.6 (2.4 [1.0-8.5] vs 0.8 [0.3-1.6]; p < 0.0001), and more days with oxygenation index greater than 18 (1.4 [0-6.0] vs 0 [0-0.3]; p < 0.0001) and oxygen saturation index greater than 11 (2.0 [0.5-8.8] vs 0 [0-1.0]; p < 0.0001). Nonsurvivors had higher maximum peak inspiratory pressures (36.0 cm H2O [32.0-41.0 cm H2O] vs 30.0 cm H2O [27.0-35.0 cm H2O]; p < 0.0001) and more days with peak inspiratory pressure greater than 31 cm H2O (1.0 d [0-4.0 d] vs 0 d [0-1.0 d]; p < 0.0001). Tidal volume per kilogram was not different between survivors and nonsurvivors. CONCLUSIONS: In this cohort of pediatric hematopoietic cell transplant recipients with respiratory failure in the PICU, impaired oxygenation and use of elevated ventilator pressures were common and associated with increased mortality.

A multicenter investigation of respiratory syncytial viral infection in children with hematopoietic cell transplantation.

BACKGROUND: Hematopoietic cell transplant (HCT) may be a risk factor for morbidity and mortality from respiratory syncytial virus (RSV). Previous studies have been limited by small sample size. We took a multicenter approach with the goal of better understanding the epidemiology, risk factors, treatment, morbidity, and mortality associated with RSV infections among children with HCT in the United States. METHODS: A retrospective, multicenter, cohort study of pediatric HCT recipients were diagnosed with RSV infection between January 2010 and December 2014. RESULTS: Of the 1522 HCT, 47 (3%) patients were diagnosed with RSV. Of those with RSV, 9 (19.1%) were admitted to the pediatric intensive care unit (PICU), 6 (12.8%) received invasive mechanical ventilation, and 1 died. Prophylactic palivizumab was uncommon. All who required critical care received ribavirin vs 7.3% of those who did not (P = .004). Cobacterial infections were found in 16 patients and were not associated with the need for critical care. We examined potential risk factors for severity of RSV disease. In those who received invasive ventilation, 100% had one of the preidentified risk factors. Half of those requiring mechanical ventilation were diagnosed with RSV during their conditioning for transplant as opposed to only 2.4% of those that did not require invasive mechanical ventilation (P = .005). CONCLUSIONS: In this multicenter cohort, RSV was not common in children following HCT. Few children infected with RSV required critical care and mortality was low. Those diagnosed with RSV during conditioning for transplant were at higher risk for invasive mechanical ventilation.

High-Frequency Oscillatory Ventilation Use and Severe Pediatric ARDS in the Pediatric Hematopoietic Cell Transplant Recipient.

INTRODUCTION: The effectiveness of high-frequency oscillatory ventilation (HFOV) in the pediatric hematopoietic cell transplant patient has not been established. We sought to identify current practice patterns of HFOV, investigate parameters during HFOV and their association with mortality, and compare the use of HFOV to conventional mechanical ventilation in severe pediatric ARDS. METHODS: This is a retrospective analysis of a multi-center database of pediatric and young adult allogeneic hematopoietic cell transplant subjects requiring invasive mechanical ventilation for critical illness from 2009 through 2014. Twelve United States pediatric centers contributed data. Continuous variables were compared using a Wilcoxon rank-sum test or a Kruskal-Wallis analysis. For categorical variables, univariate analysis with logistic regression was performed. RESULTS: The database contains 222 patients, of which 85 subjects were managed with HFOV. Of this HFOV cohort, the overall pediatric ICU survival was 23.5% (n = 20). HFOV survivors were transitioned to HFOV at a lower oxygenation index than nonsurvivors (25.6, interquartile range 21.1-36.8, vs 37.2, interquartile range 26.5-52.2, P = .046). Survivors were transitioned to HFOV earlier in the course of mechanical ventilation, (day 0 vs day 2, P = .002). No subject survived who was transitioned to HFOV after 1 week of invasive mechanical ventilation. We compared subjects with severe pediatric ARDS treated only with conventional mechanical ventilation versus early HFOV (within 2 d of invasive mechanical ventilation) versus late HFOV. There was a trend toward difference in survival (conventional mechanical ventilation 24%, early HFOV 30%, and late HFOV 9%, P = .08). CONCLUSIONS: In this large database of pediatric allogeneic hematopoietic cell transplant subjects who had acute respiratory failure requiring invasive mechanical ventilation for critical illness with severe pediatric ARDS, early use of HFOV was associated with improved survival compared to late implementation of HFOV, and the subjects had outcomes similar to those treated only with conventional mechanical ventilation.

Pediatric Acute Respiratory Distress Syndrome in Pediatric Allogeneic Hematopoietic Stem Cell Transplants: A Multicenter Study.

OBJECTIVE: Immunodeficiency is both a preexisting condition and a risk factor for mortality in pediatric acute respiratory distress syndrome. We describe a series of pediatric allogeneic hematopoietic stem cell transplant patients with pediatric acute respiratory distress syndrome based on the recent Pediatric Acute Lung Injury Consensus Conference guidelines with the objective to better define survival of this population. DESIGN: Secondary analysis of a retrospective database. SETTING: Twelve U.S. pediatric centers. PATIENTS: Pediatric allogeneic hematopoietic stem cell transplant recipients requiring mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the first week of mechanical ventilation, patients were categorized as: no pediatric acute respiratory distress syndrome or mild, moderate, or severe pediatric acute respiratory distress syndrome based on oxygenation index or oxygen saturation index. Univariable logistic regression evaluated the association between pediatric acute respiratory distress syndrome and PICU mortality. A total of 91.5% of the 211 patients met criteria for pediatric acute respiratory distress syndrome using the Pediatric Acute Lung Injury Consensus Conference definition: 61.1% were severe, 27.5% moderate, and 11.4% mild. Overall survival was 39.3%. Survival decreased with worsening pediatric acute respiratory distress syndrome: no pediatric acute respiratory distress syndrome 66.7%, mild 63.6%, odds ratio = 1.1 (95% CI, 0.3-4.2; p = 0.84), moderate 52.8%, odds ratio = 1.8 (95% CI, 0.6-5.5; p = 0.31), and severe 24.6%, odds ratio = 6.1 (95% CI, 2.1-17.8; p < 0.001). Nonsurvivors were more likely to have multiple consecutive days at moderate and severe pediatric acute respiratory distress syndrome (p < 0.001). Moderate and severe patients had longer PICU length of stay (p = 0.01) and longer mechanical ventilation course (p = 0.02) when compared with those with mild or no pediatric acute respiratory distress syndrome. Nonsurvivors had a higher median maximum oxygenation index than survivors at 28.6 (interquartile range, 15.5-49.9) versus 15.0 (interquartile range, 8.4-29.6) (p < 0.0001). CONCLUSION: In this multicenter cohort, the majority of pediatric allogeneic hematopoietic stem cell transplant patients with respiratory failure met oxygenation criteria for pediatric acute respiratory distress syndrome based on the Pediatric Acute Lung Injury Consensus Conference definition within the first week of invasive mechanical ventilation. Length of invasive mechanical ventilation, length of PICU stay, and mortality increased as the severity of pediatric acute respiratory distress syndrome worsened.

Invasive Mechanical Ventilation and Mortality in Pediatric Hematopoietic Stem Cell Transplantation: A Multicenter Study.

OBJECTIVE: To establish the current respiratory practice patterns in pediatric hematopoietic stem cell transplant patients and investigate their associations with mortality across multiple centers. DESIGN: Retrospective cohort between 2009 and 2014. SETTING: Twelve children's hospitals in the United States. PATIENTS: Two hundred twenty-two pediatric allogeneic hematopoietic stem cell transplant recipients with acute respiratory failure using invasive mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PICU mortality of our cohort was 60.4%. Mortality at 180 days post PICU discharge was 74%. Length of PICU stay prior to initiation of invasive mechanical ventilation was significantly lower in survivors, and the odds of mortality increased for longer length of PICU stay prior to intubation. A total of 91 patients (41%) received noninvasive ventilation at some point during their PICU stay prior to intubation. Noninvasive ventilation use preintubation was associated with increased mortality (odds ratio, 2.1; 95% CI, 1.2-3.6; p = 0.010). Patients ventilated longer than 15 days had higher odds of death (odds ratio, 2.4; 95% CI, 1.3-4.2; p = 0.004). Almost 40% of patients (n = 85) were placed on high-frequency oscillatory ventilation with a mortality of 76.5% (odds ratio, 3.3; 95% CI, 1.7-6.5; p = 0.0004). Of the 20 patients who survived high-frequency oscillatory ventilation, 18 were placed on high-frequency oscillatory ventilation no later than the third day of invasive mechanical ventilation. In this subset of 85 patients, transition to high-frequency oscillatory ventilation within 2 days of the start of invasive mechanical ventilation resulted in a 76% decrease in the odds of death compared with those who transitioned to high-frequency oscillatory ventilation later in the invasive mechanical ventilation course. CONCLUSIONS: This study suggests that perhaps earlier more aggressive critical care interventions in the pediatric hematopoietic stem cell transplant patient with respiratory failure requiring invasive mechanical ventilation may offer an opportunity to improve outcomes.

A review of graft versus host disease.

Children undergoing hematopoietic stem cell transplant often require intensive care support due to their underlying disease, sepsis, infection, hemorrhage, respiratory failure and organ dysfunction. The majority of children requiring intensive care support have an allogeneic donor. These children carry a higher likelihood of graft versus host disease complicating their medical management. Understanding the process of graft versus host disease is important in the shared care of these children between pediatric intensive care physicians and the bone marrow transplant team.

A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases.

Reduced-intensity conditioning (RIC) regimens have the potential to decrease transplantation-related morbidity and mortality. However, engraftment failure has been prohibitively high after RIC unrelated umbilical cord blood transplantation (UCBT) in chemotherapy-naïve children with nonmalignant diseases (NMD). Twenty-two children with a median age of 2.8 years, many with severe comorbidities and prior viral infections, were enrolled in a novel RIC protocol consisting of hydroxyurea, alemtuzumab, fludarabine, melphalan, and thiotepa followed by single UCBT. Patients underwent transplantation for inherited metabolic disorders (n = 8), primary immunodeficiencies (n = 9), hemoglobinopathies (n = 4) and Diamond Blackfan anemia (n = 1). Most umbilical cord blood (UCB) units were HLA-mismatched with median infused total nucleated cell dose of 7.9 × 10(7)/kg. No serious organ toxicities were attributable to the regimen. The cumulative incidence of neutrophil engraftment was 86.4% (95% confidence interval [CI], 65% to 100%) in a median of 20 days, with the majority sustaining > 95% donor chimerism at 1 year. Cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV by day 180 was 27.3% (95% CI, 8.7% to 45.9%) and 13.6% (95 CI, 0% to 27.6%), respectively. Cumulative incidence of extensive chronic GVHD was 9.1% (95% CI, 0% to 20.8%). The primary causes of death were viral infections (n = 3), acute GVHD (n = 1) and transfusion reaction (n = 1). One-year overall and event-free survivals were 77.3% (95% CI, 53.7% to 89.8%) and 68.2% (95% CI, 44.6% to 83.4%) with 31 months median follow-up. This is the first RIC protocol demonstrating durable UCB engraftment in children with NMD. Future risk-based modifications of this regimen could decrease the incidence of viral infections. (www.clinicaltrials.gov/NCT00744692).

Clinical outcomes of children receiving intensive cardiopulmonary support during hematopoietic stem cell transplant.

OBJECTIVE: We investigated the short-term and 1-year clinical outcomes of 129 children who received intensive cardiopulmonary support during hematopoietic stem cell transplant. Intensive cardiopulmonary support was defined as receiving at least one of the following interventions: continuous positive pressure ventilation, dopamine infusion greater than or equal to 10 mcg/kg/minute, or the use of any other vasoactive infusion. Duration of intensive cardiopulmonary support, survival to hospital discharge, and predictors of these outcome variables were compared with 387 hematopoietic stem cell transplant patients who did not receive intensive support during the same period. We also report the 1-year survival; presence of chronic graft-versus-host disease; and renal, cardiac, and pulmonary function for all patients. DESIGN: A multicenter retrospective cohort study. SETTING: The ICU and hematopoietic stem cell transplant unit of nine pediatric tertiary care centers. PATIENTS: Children undergoing hematopoietic stem cell transplant who required intensive cardiopulmonary support. INTERVENTIONS: None. RESULTS: Predictors of the need for intensive support included unrelated donor allogeneic transplant, glomerular filtration rate less than 85 mL/minute/1.73 m, and nonmalignant disease as the indication for transplant. The survival to discontinuation of intensive support for all patients was 62% and 58% for patients who received invasive mechanical ventilatory support. The duration of mechanical ventilation was not predictive of survival. Predictors of intensive support mortality included macroscopic bleeding, engraftment, and pediatric logistic organ dysfunction score greater than one in two domains. Survival to hospital discharge was 50% for the intensive support group and 99% for the nonintensive support group. Overall 1-year survival was 40% in the intensive support population and 65% in the nonintensive support group. There were no significant differences in the survival, rates of chronic graft-versus-host disease, creatinine, forced expiratory volume in 1-minute, cardiac shortening fraction, or performance status in intensive and nonintensive support patients who survived to hospital discharge. CONCLUSION: Intensive cardiopulmonary support plays an important and potentially life-saving role in the care of pediatric stem cell transplant patients. Survivors of intensive support do not have compromised 1-year survival or organ function compared with children who did not receive intensive support.