Courtney M. Rowan

Background: Veno‐occlusive disease (VOD) is a common complication post‐hematopoietic stem cell transplant (HSCT) and is associated with increased mortality. Factors predictive of outcomes are lacking. Albumin–bilirubin (ALBI) score is used to quantify liver function and prognosticate but has not been investigated in VOD. Methods: Single‐center retrospective study investigating the ALBI score in children aged 0–26 years who underwent HSCT from 2019 to 2024 and developed VOD. Primary outcome was hospital mortality. ALBI score was calculated at time points chosen a priori spanning preconditioning to post‐VOD diagnosis. Results: Forty‐three patients developed VOD. Most were transplanted for cancer ( n = 33, 77%). Seven (16%) died. Preconditioning median ALBI scores did not differ between survivors and non‐survivors. Median ALBI scores significantly increased from preconditioning −3.00 (IQR: −3.10, −2.80) to VOD diagnosis −1.70 (IQR: −2.00, −1.50), p < 0.001. In the week after VOD diagnosis, ALBI scores improved in survivors but worsened in non‐survivors. ALBI scores 7 days post‐VOD diagnosis were higher in non‐survivors ( p = 0.008, AUC = 0.83). Using an established cutoff, severe ALBI on day 7 post‐VOD diagnosis had greater mortality odds (OR = 8.3 [95% CI: 1.4, 48.5], p = 0.02). Those who died trended toward higher ALBI 3 days prior to VOD diagnosis than those who survived, −1.70 (IQR: −1.90, −1.30) versus −2.10 (IQR: −2.40, −1.80), p = 0.16. Conclusions: In this cohort, ALBI score worsened with VOD diagnosis and at 7 days post‐diagnosis was associated with mortality. The ALBI score is easily obtained and may aid in VOD prognostication.

Background: Heated, humidified, high‐flow nasal cannula (HFNC) before intubation has been associated with increased mortality in children with immunocompromising conditions (ICC). Objectives: We sought to describe HFNC failure (intubation) rate and aimed to develop a novel score associated with HFNC failure. Methods: This is a single center, retrospective cohort. Patients (aged 0–26 years) with ICCs who used HFNC between 2021 and 2023 were included. Results: Forty‐four (47.3%) of 93 included subjects failed HFNC. PICU mortality was 14% ( n = 13). The median duration of HFNC was 18.7 h (IQR: 6.0, 40.4). We developed the novel FLOX ((flow in Liters/minute)/weight (kg)*FiO ₂ ) score. Median FLOX score was higher with HFNC failure at initiation ( p = 0.04), 2 h ( p = 0.03), 4 h ( p = 0.05), and 6 h ( p = 0.05). Adjusting for acuity, the odds of HFNC failure with a FLOX score (≥0.20) were as follows: Initiation OR = 2.5 (95%CI: 1.03, 5.9), p = 0.042); 2 h of HFNC, OR = 4.3 ((95%CI: 1.7, 10.9), p = 0.002); 4 h of HFNC, OR = 6.5 (95%CI: 2.5, 16.8), ( p < 0.001); and 6 h of HFNC, OR = 4.9 (95%CI: 1.9, 12.7), ( p = 0.001). Conclusion: In children with ICCs, almost half fail HFNC. Mortality was high in those who fail HFNC. The FLOX score, specifically a FLOX ≥ 0.20 is associated with increased odds of failing HFNC in our ICC cohort.

We sought to identify potential early risk biomarkers for lung disease in children post‐allogeneic HCT. Patients with pulmonary function tests 3 months post‐transplant and plasma samples between days 7 and 14 post‐HCT were included. Six of 27 subjects enrolled had reduced forced expiratory volume 1 (FEV1) z scores. Biomarker medians were higher in those with a reduced FEV1 z score ([WFDC1: 48,098 vs. 27,086 pg/mL, p = 0.062, AUC = 0.75], [TNFR1: 5,771 vs. 3,034 pg/ml, p = 0.078, AUC = 0.71], [MMP‐2: 380 vs. 290 ng/mL, p = 0.065, AUC = 0.75] and [SPD: 19.0 vs. 10.3 ng/mL, p = 0.049, AUC = 0.77]). This hypothesis‐generating study yields promising results for early risk biomarkers for lung disease post‐HCT.

Assessment of risk biomarkers of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) in pediatric patients is lacking. We conducted a prospective study of 318 patients (129 children aged ≤10 years and 189 children/adults aged >10 years). Six plasma biomarkers (C-X-C motif chemokine ligand 9 [CXCL9], interleukin-1 receptor-like 1 [IL1RL1], regenerating islet–derived 3-α [REG3α], matrix metallopeptidase-3 [MMP3], dickkopf-WNT signaling pathway inhibitor-3 [DKK3], and sCD163) were assessed at day 100 after HCT. We performed day-100 landmark analyses for cGVHD, stratifying at age ≤10 years vs >10 years and dichotomizing markers using the Youden index. IL1RL1 associated with future cGVHD in both age groups, as did DKK3. CXCL9, REG3α, and MMP3 are associated with cGVHD in patients aged >10 years. This 5-marker panel has an area under the curve (AUC) of 0.71 in children aged ≤10 years and 0.72 in children/adults aged >10 years for cGVHD risk, and an AUC of 0.86 in children aged ≤10 years and 0.80 in children/adults aged >10 years for moderate/severe cGVHD risk. A 5-biomarker panel (IL1RL1, REG3α, MMP3, DKK3, and sCD163) was associated with transplant-related mortality (TRM) in both age groups. Biomarkers measured 3 months post-HCT predict susceptibility and/or are prognostic for cGVHD and TRM in both children aged ≤10 years and children/adults aged >10 years, allowing for additional risk stratification.

Background/Objectives Pneumatosis intestinalis (PI) is a potential life-threatening complication following hematopoietic stem cell transplant (HSCT) in children. There is limited data on PI in this patient population, no consensus on its management, and limited data on recurrent PI. Identifying the outcomes, risk factors, and management of patients diagnosed with PI following HSCT can aid in its future clinical management. Design/Methods We conducted a retrospective cohort study of patients who received a HSCT at Riley Hospital for Children from 2014-2024. Results Twenty-two of 297 patients who underwent a HSCT were diagnosed with PI (7.4%). Four patients (18%) had recurrent episodes of PI, totaling 32 episodes in the cohort. All patients with PI were continued on (53%) or started on (47%) broad spectrum antibiotics. Management varied in duration of bowel rest, length of antibiotic course, consultation with surgery and x-ray frequency. The median time to resolution was 4 days (range 1-21). Patients with recurrent PI had a median of 3 episodes (range 3-5) and median time to recurrence after previous episode was 43 days (range 8-451). Previous diagnosis of graft-versus-host disease (GVHD) or thrombotic microangiopathy (TMA) significantly increased the rate of recurrent PI (p=0.01 and p=0.03 respectively). Conclusion The pathogenesis of PI in patients who received a HSCT is multifactorial. No uniform approach to treatment of PI was followed, suggesting an opportunity to standardize care through clinical guidelines in patients following HSCT. In addition, the significance of GVHD and TMA in recurrent PI suggests focused monitoring of this patient population to prevent recurrences.

Hematopoietic stem cell transplantation (HCT) is a potentially life-saving therapy but can lead to lung injury due to chemoradiation toxicity, infection, and immune dysregulation. We previously showed that bronchoalveolar lavage (BAL) transcriptomes representing pulmonary inflammation and cellular injury can phenotype post-HCT lung injury and predict mortality. To test whether peripheral blood might be a suitable surrogate for BAL, we compared 210 paired BAL and blood transcriptomes obtained from 166 pediatric HCT patients at 27 hospitals. BAL and blood RNA abundance showed minimal correlation at the level of individual genes, gene set enrichment scores, imputed cell fractions, and T- and B-cell receptor clonotypes. Instead, we identified significant site-specific transcriptional programs. In BAL, pathways related to immunity, hypoxia, and epithelial mesenchymal transition were tightly co-expressed and linked to mortality. In contrast, in blood, expression of endothelial injury, DNA repair, and cellular metabolism pathways was associated with mortality. Integration of paired BAL and blood transcriptomes dichotomized patients into two groups with significantly different rates of hypoxia and clinical outcomes within 1 week of BAL. These findings reveal a compartmentalized injury response, where BAL and blood transcriptomes provide distinct but complementary insights into local and systemic mechanisms of post-HCT lung injury.

Background: Pediatric respiratory syncytial virus (RSV)–related acute lower respiratory tract infection (LRTI) commonly requires hospitalization. The Clinical Progression Scale–Pediatrics (CPS-Ped) measures level of respiratory support and degree of hypoxia across a range of disease severity, but it has not been applied in infants hospitalized with severe RSV-LRTI. Methods: We analyzed data from a prospective surveillance registry of infants hospitalized for RSV-related complications across 39 pediatric intensive care units in the United States from October through December 2022. We assigned CPS-Ped (0 = discharged home at respiratory baseline to 8 = death) at admission and days 2–7, 10, and 14. We identified predictors of clinical improvement (CPS-Ped ≤2 or 3-point decrease) by day 7 using multivariable log-binomial regression models and estimated the sample size (80% power) to detect 15% between-group clinical improvement with CPS-Ped versus hospital length of stay (LOS). Results: Of 585 hospitalized infants, 138 (23.6%) received invasive mechanical ventilation (IMV) and 1 died. Failure to clinically improve by day 7 occurred in 205 (35%) infants and was associated with age <3 months, prematurity, underlying respiratory condition, and IMV in the first 24 hours in the multivariable analysis. The estimated sample size per arm required for detecting a 15% clinical improvement in a potential study was 584 using CPS-Ped clinical improvement versus 2031 for hospital LOS. Conclusions: CPS-Ped can be used to capture a range of disease severity and track clinical improvement in infants who develop RSV-related critical illness and could be useful for evaluating therapeutic interventions for RSV.

Hematopoietic cell transplantation (HCT) uses cytotoxic chemotherapy and/or radiation followed by intravenous infusion of stem cells to cure malignancies, bone marrow failure and inborn errors of immunity, hemoglobin and metabolism. Lung injury is a known complication of the process, due in part to disruption in the pulmonary microenvironment by insults such as infection, alloreactive inflammation and cellular toxicity. How microorganisms, immunity and the respiratory epithelium interact to contribute to lung injury is uncertain, limiting the development of prevention and treatment strategies. Here we used 278 bronchoalveolar lavage (BAL) fluid samples to study the lung microenvironment in 229 pediatric patients who have undergone HCT treated at 32 children’s hospitals between 2014 and 2022. By leveraging paired microbiome and human gene expression data, we identified high-risk BAL compositions associated with in-hospital mortality (P = 0.007). Disadvantageous profiles included bacterial overgrowth with neutrophilic inflammation, microbiome contraction with epithelial fibroproliferation and profound commensal depletion with viral and staphylococcal enrichment, lymphocytic activation and cellular injury, and were replicated in an independent cohort from the Netherlands (P = 0.022). In addition, a broad array of previously occult pathogens was identified, as well as a strong link between antibiotic exposure, commensal bacterial depletion and enrichment of viruses and fungi. Together these lung–immune system–microorganism interactions clarify the important drivers of fatal lung injury in pediatric patients who have undergone HCT. Further investigation is needed to determine how personalized interpretation of heterogeneous pulmonary microenvironments may be used to improve pediatric HCT outcomes.

We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care. 55 hospitals in 30 U.S. states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients <21 years admitted March 12, 2020–December 30, 2021 to the pediatric intensive care unit (PICU) or high acuity unit for acute COVID-19 were included Of 1,274 patients, 105 (8.2%) had an ICC including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid organ transplantation, 16 (15.2%) solid tumors and 13 (12.4%) autoimmune disorders. Patients with ICCs were older, had more underlying renal conditions, and had lower white blood cell and platelet counts than those without ICCs, but had similar clinical disease severity upon admission. In-hospital mortality from COVID-19 was higher (11.4% vs. 4.6%, p = 0.005) and hospitalization was longer (p = 0.01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, p = 0.40). In patients with ICC, bacterial co-infection was more common in those with life-threatening COVID-19. In this national case series of patients <21 years of age with acute COVID-19 admitted for intensive care, existence of a prior ICCs were associated with worse clinical outcomes. Reassuringly, most patients with ICCs hospitalized in the PICU for severe acute COVID-19 survived and were discharged home without new severe morbidities.

OBJECTIVES: To characterize immunocompromised-associated pediatric acute respiratory distress syndrome (I-PARDS) and contrast it to PARDS. DESIGN: This is a secondary analysis of the 2016–2017 PARDS incidence and epidemiology (PARDIE) study, a prospective observational, cross-sectional study of children with PARDS. SETTING: Dataset of 145 PICUs across 27 countries. PATIENTS: During 10 nonconsecutive weeks (from May 2016 to June 2017), data about immunocompromising conditions (ICCs, defined as malignancy, congenital/acquired immunodeficiency, posttransplantation, or diseases requiring immunosuppression) were collected. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 708 subjects, 105 (14.8%) had ICC. Before the development of I-PARDS, those with ICC were more likely to be hospitalized (70% vs. 35%, p < 0.001), have more at-risk for PARDS (p = 0.046), and spent more hours at-risk (20 [interquartile range, IQR: 8–46] vs. 11 [IQR: 4–33], [p = 0.002]). Noninvasive ventilation (NIV) use was more common in those with ICC (p < 0.001). Of those diagnosed with PARDS on NIV (n = 161), children with ICC were more likely to be subsequently intubated (n = 28/40 [70%] vs n = 53/121 [44%], p = 0.004). Severe PARDS was more common (32% vs 23%, p < 0.001) in I-PARDS. Oxygenation indices were higher at diagnosis and had less improvement over the first 3 days of PARDS (p < 0.001). Children with I-PARDS had greater nonpulmonary organ dysfunction. Adjusting for Pediatric Risk of Mortality IV and oxygenation index, children with I-PARDS had a higher severity of illness-adjusted PICU mortality (adjusted hazard ratio: 3.0 [95% CI, 1.9–4.7] p < 0.001) and were less likely to be extubated alive within 28 days (subdistribution hazard ratio: 0.47 [95% CI, 0.31–0.71] p < 0.001). CONCLUSIONS: I-PARDS is a unique subtype of PARDS associated with hospitalization before diagnosis and increased: time at-risk for PARDS, NIV use, hypoxia, nonpulmonary organ dysfunction, and mortality. The opportunity for early detection and intervention seems to exist. Dedicated study in these patients is imperative to determine if targeted interventions will benefit these unique patients with the ultimate goal of improving outcomes.