Retrospective analysis of veno-occlusive disease/sinusoidal obstruction syndrome in paediatric patients undergoing hematopoietic cell transplantation -a multicentre study.

Background: Sinusoidal obstruction syndrome is a potentially fatal complication following hematopoietic cell transplantation, high-intensity chemotherapies and increasingly seen with calicheamicin based leukemia therapies. Paediatric specific European Society for Blood and Marrow Transplantation (pEBMT) diagnostic criteria have demonstrated benefit in single center studies compared to historic criteria. Yet, the extent to which they have been universally implemented remains unclear. Methods: We conducted a retrospective multi-centre study to examine the potential impact of the Baltimore, modified Seattle and pEBMT criteria on the incidence, severity, and outcomes of sinusoidal obstruction syndrome among paediatric hematopoietic cell transplantation patients. Findings: The incidence of sinusoidal obstruction syndrome in this cohort (n = 488) was higher by pEBMT (21.5%) vs historic modified Seattle (15.6%) and Baltimore (7.0%) criteria (p < 0.001). Application of pEBMT criteria identified 44 patients who were not previously diagnosed with sinusoidal obstruction syndrome. Overall, 70.5% of all patients diagnosed with sinusoidal obstruction syndrome ultimately developed very severe disease and almost half of diagnosed patients required critical care support. Overall survival was significantly lower in patients who were diagnosed with sinusoidal obstruction syndrome vs those who were not. Interpretation: Taken together, pEBMT criteria may be a sensitive method for prompter diagnosis of patients who subsequently develop severe/very severe sinusoidal obstruction syndrome. To our knowledge, this is the first multi-centre study in the United States (US) to demonstrate that pEBMT guidelines are associated with earlier detection of sinusoidal obstruction syndrome. Since early initiation of definitive treatment for sinusoidal obstruction syndrome has been associated with improved survival in paediatric patients and implementation of pEBMT criteria appears feasible in the US, universal adoption should facilitate prompter diagnosis and lead to improved outcomes of children with sinusoidal obstruction syndrome. Funding: None.

Interventions Performed in Children With Immunocompromised Conditions in the Pediatric Intensive Care Unit Within 48 Hours of Death.

Background: Understanding interventions preceding death in children with immunocompromised conditions is important to ensure a peaceful and dignified perideath experience. The aim of this study was to describe the number of interventions performed in the pediatric intensive care unit (PICU) within the 48 hours before death in this population. Methods: This was a single-center, retrospective cohort study of all children with an underlying oncologic, hematologic, or immunologic diagnosis admitted to the PICU for at least 72 hours between 2014 and 2021. Medical records were reviewed for interventions within 48 hours preceding death and for palliative care involvement. Interventions were defined as new or escalations in respiratory support, cardiopulmonary resuscitation (CPR), vascular access, drains, and radiographic studies. Associations were evaluated using simple logistic regression. Results: A total of 55 patients were included in this study. The predominant PICU admission diagnoses were respiratory (51%), followed by shock (25%), and neurologic diagnoses (9%). These predominant diagnoses were similar perideath. At PICU admission, only 1 patient had a do-not-resuscitate (DNR) order. Forty-six percent had a DNR order 48 hours preceding death, and 91% had DNR orders in place at time of death. During the 48-hour period preceding death, 80% of children received at least one intervention. Radiographic studies were the most common, used in 78% of children, followed by respiratory (20%), vascular (16%), CPR (13%), and drain placement (7%). Palliative care was involved in 38% of cases and was associated with a decrease in the number of radiologic interventions (p = 0.028) and CPR (p = 0.026). Conclusions: Children in the PICU with underlying immunocompromised conditions frequently receive interventions within the 48-hour period preceding death. Palliative care involvement was associated with fewer radiographic studies and fewer occurrences of CPR. The impact of interventions on the dying experience warrants further investigation.

A fluid relationship: Calcineurin inhibitors and pericardial effusions.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a common and effective treatment for multiple malignant and non-malignant pediatric conditions. Graft-versus-host disease (GVHD) is a common complication of HSCT that can be prevented with prophylactic use of calcineurin inhibitor (CNI) immunosuppressants. A complication of HSCT and CNI use is pericardial effusion (PEF), which is frequently treated by CNI discontinuation with or without surgical intervention. No studies to date have evaluated the management of PEF without CNI discontinuation as a means of preventing GVHD flares. METHODS: In this single-center retrospective study, we reviewed the management of PEF in pediatric patients post-HSCT who received conservative or surgical intervention with or without CNI discontinuation between May 2012 and June 2022. RESULTS: Of the patients found to have PEF, all were given tacrolimus for GVHD prophylaxis. Management of PEF included surgical intervention for 83% of patients, and CNI was not discontinued for 83%. None of the patients developed GVHD during the management of PEF. CONCLUSIONS: Our results demonstrate that continuation of CNI therapy for GVHD prophylaxis did not negatively impact the disease course of PEF in post-HSCT patients.

Diagnostic yield of bronchoscopy in children with leukemia or post hematopoietic stem cell transplant.

BACKGROUND: The utility of bronchoscopy with bronchoalveolar lavage (BAL) in immunocompromised children is not well understood. We aim to describe the bronchoscopy diagnostic yield and complications and to investigate factors associated with diagnostic yield. METHODS: This is a single-center, retrospective cohort study of 60 children with leukemia or post-hematopoietic stem cell transplant who had a bronchoscopy with BAL between 2017 and 2021. Comparisons were done with regression analysis. RESULTS: Of the 60 bronchoscopies performed, 46 (77%) revealed diagnostic information: 39 (65%) identified a pathogen, 14 (23.3%) found secretions/mucus plugging, and 6 (10%) found pulmonary hemorrhage. BAL results changed antimicrobial therapy in 27 (45%) cases. Bronchoscopies were performed in the intensive care unit (27/60) or operating room (33/60), with the former having a higher diagnostic yield (96% vs. 60%, p = 0.001). Half (50%) of bronchoscopies found a new infectious diagnosis. Respiratory symptoms (n = 58, 97%), supplemental oxygen use (n = 39, 65%), and antibiotic use (n = 56, 93%) before bronchoscopy were all common. The median volume of fluid instilled during bronchoscopy was 1.3 mL/kg (interquatile range [IQR]: 0.7, 2.6). None of these factors were associated with the diagnostic yield. Complications were rare and minor with only one child having self-resolved bleeding and four children, previously in room air requiring a nasal cannula. For the 27 (45%) children on mechanical ventilation when the bronchoscopy was performed, there was no difference in ventilator settings pre- and post-bronchoscopy. CONCLUSION: Bronchoscopies with BAL are useful, safe, and important in the diagnostic management of pulmonary complications in this cohort of children.

A familial SAMD9 variant present in pediatric myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a rare pediatric diagnosis characterized by ineffective hematopoiesis with potential to evolve into acute myelogenous leukemia (AML). In this report, we describe a unique case of a 17-yr-old female with an aggressive course of MDS with excess blasts who was found to have monosomy 7 and a SAMD9 germline variant, which has not previously been associated with a MDS phenotype. This case of MDS was extremely rapidly progressing, showing resistance to chemotherapy and stem cell transplant, unfortunately resulting in patient death. It is imperative to further investigate this rare variant to aid in the future care of patients with this variant.

Multiple Organ Dysfunction and Critically Ill Children With Acute Myeloid Leukemia: Single-Center Retrospective Cohort Study.

OBJECTIVES: To describe the prevalence of multiple organ dysfunction syndrome (MODS) and critical care utilization in children and young adults with acute myeloid leukemia (AML) who have not undergone hematopoietic cell transplantation (HCT). DESIGN: Retrospective cohort study of MODS (defined as dysfunction of two or more organ systems) occurring any day within the first 72 hours of PICU admission. SETTING: Large, quaternary-care children's hospital. PATIENTS: Patients 1 month through 26 years old who were treated for AML from 2011-2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty patients with AML were included. These 80 patients had a total of 409 total non-HCT-related hospital and 71 PICU admissions. The majority 53 of 71 of PICU admissions (75%) were associated with MODS within the first 72 hours. MODS was present in 49 of 71 of PICU admissions (69%) on day 1, 29 of 52 (56%) on day 2, and 25 of 32 (78%) on day 3. The organ systems most often involved were hematologic, respiratory, and cardiovascular. There was an increasing proportion of renal failure (8/71 [11%] on day 1 to 8/32 [25%] on day 3; p = 0.02) and respiratory failure (33/71 [47%] to 24/32 [75%]; p = 0.001) as PICU stay progressed. The presence of MODS on day 1 was associated with a longer PICU length of stay (LOS) (ß = 5.4 [95% CI, 0.7-10.2]; p = 0.024) and over a six-fold increased risk of an LOS over 2 days (odds ratio, 6.08 [95% CI, 1.59-23.23]; p = 0.008). Respiratory failure on admission was associated with higher risk of increased LOS. CONCLUSIONS: AML patients frequently require intensive care. In this cohort, MODS occurred in over half of PICU admissions and was associated with longer PICU LOS. Respiratory failure was associated with the development of MODS and progressive MODS, as well as prolonged LOS.

Leukapheresis in Pediatric Acute Leukemia with Hyperleukocytosis: A Single-Center Experience.

Hyperleukocytosis in pediatric acute leukemia is associated with increased morbidity and mortality and at present there is no consensus on the use of leukapheresis (LPH) for its management. Our aim was to review characteristics and outcomes of newly diagnosed leukemia patients with hyperleukocytosis (HL) comparing those who received LPH and those who did not. An IRB approved retrospective case control study reviewed data from a single institution over a 10 year period. At our institution, LPH was used in 8 of 62 (13%) patients with hyperleukocytosis with minimal complications. Mean leukocyte count in patients who received LPH versus those who did not was 498 k cells/mm3 and 237 k cells/mm3, respectively. Patients who had symptoms of neurologic (63 vs. 17%) or pulmonary leukostasis (75 vs. 17%) were more likely to have undergone leukapheresis. The time from presentation to the initiation of chemotherapy was not different between those who received LPH and those who did not (mean of 35 h vs. 34 h). There was one death in the LPH group, that was the result of neurologic sequelae of hyperleukocytosis and not LPH itself. The use of LPH in patients with hyperleukocytosis is safe, well tolerated and does not alter time to chemotherapy at our institution.

Hypogammaglobulinemia in Adolescents and Young Adults with Acute Lymphoblastic Leukemia.

Hypogammaglobulinemia is a poorly described complication of chemotherapy in adolescents and young adults (AYAs, 15-39 years) with acute lymphoblastic leukemia (ALL). The majority of AYAs treated on a Berlin-Frankfurt-Munster-based ALL regimen experienced hypogammaglobulinemia (65.0% [13/20]). Febrile neutropenia episodes (throughout the treatment course) and infectious events during maintenance occurred more frequently in hypogammaglobulinemic patients compared with patients with normal immunoglobulin G levels (n = 7) (median 1.0 vs. 0.0, p = 0.02; 7.0 vs. 3.0, p = 0.02, respectively). Hypogammaglobulinemia did not impact overall or event-free survival. Further studies are needed to elucidate the etiology of hypogammaglobulinemia and to establish criteria for immunoglobulin replacement in these patients.

Factors associated with a prolonged hospital stay during induction chemotherapy in newly diagnosed high risk pediatric acute lymphoblastic leukemia.

BACKGROUND: High Risk (HR) or Very High Risk (VHR) acute lymphoblastic leukemia (ALL) treated with 4 drug induction chemotherapy is often associated with adverse events. The aim of this study was to identify risk factors associated with a prolonged inpatient length of stay LOS during induction chemotherapy. PROCEDURE: Data from patients (N = 73) (age<21 years) was collected through a retrospective chart review. Univariable and multivariable logistic regression was used to test for statistical significance. The overall survival and disease (leukemia)-free survival were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: Of the 73 patients, 42 (57%) patients were discharged on day 4 of induction (short LOS, group A), while 31 (43%) patients (group B) experienced a prolonged LOS or an ICU stay (16 ±â€¯27.7 days, median hospital stay = 8 days vs 4 days (group A), p = 0.02) due to organ dysfunction, infectious or metabolic complications. Group B patients were more likely to have a lower platelet count, serum bicarbonate, and a higher blood urea nitrogen (BUN) on day 4 of treatment (OR = 4.52, 8.21, and 3.02, respectively, p < 0.05). Multivariable analysis identified low serum bicarbonate (p = 0.002) and a platelet count<20,000/µL (p = 0.02) on day 4 of induction to be predictive of a prolonged LOS. Twenty six (group A (n = 16, 36%) and B (n = 11, 35%), p = 0.8) patients experienced unplanned admissions, within 30 days of discharge. CONCLUSIONS: A significant proportion of newly diagnosed HR or VHR pediatric ALL patients experience a prolonged LOS and unplanned re-admissions. Aggressive discharge planning and close follow up is indicated in this cohort of patients.

WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome.

BACKGROUND: Rare de novo mutations have been implicated as a significant cause of idiopathic intellectual disability. Large deletions encompassing 10p11.23 have been implicated in developmental delay, behavioural abnormalities and dysmorphic features, but the genotype-phenotype correlation was not delineated. Mutations in WAC have been recently reported in large screening cohorts of patients with intellectual disability or autism, but no full phenotypic characterisation was described. METHODS: Clinical and molecular characterisation of six patients with loss-of-function WAC mutations identified by whole exome sequencing was performed. Clinical data were obtained by retrospective chart review, parental interviews, direct patient interaction and formal neuropsychological evaluation. RESULTS: Five heterozygous de novo WAC mutations were identified in six patients. Three of the mutations were nonsense, and two were frameshift; all are predicted to cause loss of function either through nonsense-mediated mRNA decay or protein truncation. Clinical findings included developmental delay (6/6), hypotonia (6/6), behavioural problems (5/6), eye abnormalities (5/6), constipation (5/6), feeding difficulties (4/6), seizures (2/6) and sleep problems (2/6). All patients exhibited common dysmorphic features, including broad/prominent forehead, synophrys and/or bushy eyebrows, depressed nasal bridge and bulbous nasal tip. Posteriorly rotated ears, hirsutism, deep-set eyes, thin upper lip, inverted nipples, hearing loss and branchial cleft anomalies were also noted. CONCLUSIONS: Our case series show that loss-of-function mutations in WAC cause a recognisable genetic syndrome characterised by a neurocognitive phenotype and facial dysmorphism. Our data highly suggest that WAC haploinsufficiency is responsible for most of the phenotypic features associated with deletions encompassing 10p11.23.