Implementing a behavioral physical activity program in children and adolescent survivors of childhood cancer: a pilot randomized controlled trial.

Purpose We aimed to document the acceptability (enrollment rate) and feasibility (phone call delivery rate) of implementing a behavioral PA intervention over 12 weeks, in addition to documenting its effects on patient-reported outcomes and physical functioning. This study also describes the costs of carrying out a behavioral PA intervention. A total of 40 participants were randomized in a 1:1 ratio. The tailored behavioral PA intervention was developed based on the most recent PA guidelines in pediatric oncology and on the COM-B framework to enact PA behavior changes. The prescription (frequency, intensity, time and type (FITT)) was adjusted each week during the weekly support calls. The control group did not receive the intervention. 26 males and 14 females (13.6 years old on average and 2.9 years post-cancer treatment on average) participated in our study. The acceptability rate was 90.9% and the feasibility rate was > 85%. We found that 85% improved PA frequency, 80% improved PA intensity, 100% improved PA time, and 50.0% achieved the recommended PA guidelines. No adverse events were reported over the duration of the intervention. Physical function improved with longer 6-minute walk distances in the intervention group (465.8 ± 74.5 m) than in the control group (398.7 ± 92.9 m) (p = 0.016). PROs scores for all participants were within the limits of the normal range. The estimated cost per participant of carrying out this intervention was USD $126.57. Our 12-week behavioral PA intervention, based on the COM-B framework, was found to be acceptable, feasible and safe in childhood cancer survivors. This study is an important step in the right direction to make exercise standard practice in pediatric oncology.

Inflammatory and tissue injury marker dynamics in pediatric acute respiratory distress syndrome.

BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS).METHODSIn a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models.RESULTSIn 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality.CONCLUSIONSPediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.FUNDINGNIH (K23HL-136688, R01-HL148054).

Assessment on the use of allopurinol to improve safety and efficacy of mercaptopurine in pediatric patients with Acute Lymphoblastic Leukemia and Lymphoma during maintenance therapy.

BACKGROUND: Mercaptopurine is an important component of acute lymphoblastic leukemia (ALL) and lymphoma (LLy) maintenance therapy. The 6-thioguanine nucleosides (6-TGN) are believed to be the primary contributor to myelosuppression and immunosuppressive effects, while 6-methylmercaptopurine (6-MMPN) is believed to be responsible for several toxicities including hepatotoxicity, pancreatitis, and hypoglycemia. Previous reports suggest the addition of allopurinol may reduce these toxicities. AIMS: To assess the use of allopurinol to improve both safety and efficacy of mercaptopurine in pediatric patients with ALL and LLy during maintenance therapy. Secondary objectives included evaluating patient tolerability and skewed metabolism. In addition, we also analyzed mercaptopurine daily dose reduction upon allopurinol initiation. METHODS AND RESULTS: The primary endpoint was time within goal ANC prior to and after initiation of allopurinol. Secondary endpoints included; improvement in selective toxicities (hepatotoxicity, pancreatitis, and hypoglycemia) and 6-MMPN to 6-TGN ratio prior to and after allopurinol initiation. In addition, an exploratory endpoint assessing mercaptopurine daily dose reduction prior to and after allopurinol initiation was included. Sixteen patients met inclusion criteria and 15 (94%) of which were included in this study. Median percent of maintenance days within goal ANC prior to and after initiation of allopurinol was 27.8 (IQR 22.6-44.9) and 41.6 (IQR 20.2-58.2) respectively. All patients experienced selective toxicities; 15 (100%) hepatotoxicity, 1 (7%) pancreatitis, and 3 (20%) hypoglycemia. Improvement of toxicities was seen in 13/15 (87%), 1/1 (100%), and 2/3 (67%) respectively. Average 6-MMPN:6-TGN ratio prior to allopurinol initiation was 304:1 and after, allopurinol initiation improved to 15:1, resulting in a 95% reduction. Average mercaptopurine dose prior to and after allopurinol initiation decreased by about 56% (63 to 28 mg/m2 /day). CONCLUSION: Results suggest that the use of allopurinol in pediatric patients with ALL and LLy receiving mercaptopurine during maintenance therapy is both safe and effective.

Identification of molecular subphenotypes in two cohorts of paediatric ARDS.

BACKGROUND: Two subphenotypes of acute respiratory distress syndrome (ARDS), hypoinflammatory and hyperinflammatory, have been reported in adults and in a single paediatric cohort. The relevance of these subphenotypes in paediatrics requires further investigation. We aimed to identify subphenotypes in two large observational cohorts of paediatric ARDS and assess their congruence with prior descriptions. METHODS: We performed latent class analysis (LCA) separately on two cohorts using biomarkers as inputs. Subphenotypes were compared on clinical characteristics and outcomes. Finally, we assessed overlap with adult cohorts using parsimonious classifiers. FINDINGS: In two cohorts from the Children's Hospital of Philadelphia (n=333) and from a multicentre study based at the University of California San Francisco (n=293), LCA identified two subphenotypes defined by differential elevation of biomarkers reflecting inflammation and endotheliopathy. In both cohorts, hyperinflammatory subjects had greater illness severity, more sepsis and higher mortality (41% and 28% in hyperinflammatory vs 11% and 7% in hypoinflammatory). Both cohorts demonstrated overlap with adult subphenotypes when assessed using parsimonious classifiers. INTERPRETATION: We identified hypoinflammatory and hyperinflammatory subphenotypes of paediatric ARDS from two separate cohorts with utility for prognostic and potentially predictive, enrichment. Future paediatric ARDS trials should identify and leverage biomarker-defined subphenotypes in their analysis.

Comparison of whole blood cytokine immunoassays for rapid, functional immune phenotyping in critically ill patients with sepsis.

BACKGROUND: Sepsis is characterized by highly heterogeneous immune responses associated with a spectrum of disease severity. Methods that rapidly and sensitively profile these immune responses can potentially personalize immune-adjuvant therapies for sepsis. We hypothesized that the ELLA microfluidic approach to measure cytokine production from the whole blood of septic and critically ill patients would deliver faster, more precise results than the existing optic-driven ELISpot quantification. We tested our hypothesis by measuring ex vivo-stimulated production of TNF and IFNγ in critically ill and septic patients (n = 22), critically ill and non-septic patients (n = 10), and healthy volunteers (n = 10) through both ELLA and ELISpot immunoassays. Blood samples were subjected to one of three stimulants for 4 h or 18 h durations during days 1, 7-10, and 14 of critical illness. Stimulants for lymphocytes included anti-CD3/anti-CD28 and phorbol 12-myristate 13-acetate (PMA), whereas LPS was used for monocytes. Stimulated TNF and IFNγ concentrations were then associated with 30-day mortality. RESULTS: Both ELISpot and ELLA immunoassays showed substantial agreement in TNF concentrations post 4 h and 18 h LPS stimulation, with concordance correlation coefficients at 0.62 and 0.60, respectively. ELLA had a broad dynamic measurement range and provided accurate TNF and IFNγ readings at both minimal and elevated cytokine concentrations (with mean coefficients of variation between triplicate readings at 2.1 ± 1.4% and 4.9 ± 7.2%, respectively). However, there was no association between the ELLA-determined cytokine concentrations on the first day of critical illness and 30-day mortality rate. In contrast, using the ELISpot for cytokine quantification revealed that non-survivors had reduced baseline TNF levels at 18 h, decreased LPS-induced TNF levels at 18 h, and diminished TNF levels post 4 h/18 h anti-CD3/28 stimulation. CONCLUSIONS: Our study affirms the feasibility of obtaining dependable immune phenotyping data within 6 h of blood collection from critically ill patients, both septic and non-septic, using the ELLA immunoassay. Both ELLA and ELISpot can offer valuable insights into prognosis, therapeutic strategies, and the underlying mechanisms of sepsis development.

The Association between Infant Colic and the Multi-Omic Composition of Human Milk.

Infant colic is a common condition with unclear biologic underpinnings and limited treatment options. We hypothesized that complex molecular networks within human milk (i.e., microbes, micro-ribonucleic acids (miRNAs), cytokines) would contribute to colic risk, while controlling for medical, social, and nutritional variables. This hypothesis was tested in a cohort of 182 breastfed infants, assessed with a modified Infant Colic Scale at 1 month. RNA sequencing was used to interrogate microbial and miRNA features. Luminex assays were used to measure growth factors and cytokines. Milk from mothers of infants with colic (n = 28) displayed higher levels of Staphylococcus (adj. p = 0.038, d = 0.30), miR-224-3p (adj. p = 0.023, d = 0.33), miR-125b-5p (adj. p = 0.028, d = 0.29), let-7a-5p (adj. p = 0.028, d = 0.27), and miR-205-5p (adj. p = 0.029, d = 0.26) compared to milk from non-colic mother-infant dyads (n = 154). Colic symptom severity was directly associated with milk hepatocyte growth factor levels (R = 0.21, p = 0.025). A regression model involving let-7a-5p, miR-29a-3p, and Lactobacillus accurately modeled colic risk (X2 = 16.7, p = 0.001). Molecular factors within human milk may impact colic risk, and provide support for a dysbiotic/inflammatory model of colic pathophysiology.

Chronic pain in children and adolescents diagnosed with cancer: the challenge of mitigating the pain and the potential of integrating exercise into pain management.

BACKGROUND: Pain is one of the most common and distressing symptoms experienced by children and adolescents diagnosed with cancer. It is vital that children and adolescents receive adequate pain management early on in their cancer treatments to mitigate pain and cancer-related symptoms. Exercise training shows particular promise in the management of acute and chronic pain among children and adolescents diagnosed with cancer. METHODS: This position paper comes to outline the challenge of mitigating pain in children and adolescents diagnosed with cancer, and the potential benefits of integrating exercise training to the management of chronic pain in this population in need. RESULTS: Integrating exercise training into the care and pain management of children and adolescents diagnosed with cancer who have chronic pain would have the advantage of addressing several shortcomings of pain medication. Pain medication aims to temporarily manage or reduce pain; it does not have the potential to directly improve a patient's physical condition in the way that exercise training can. The current paucity of data available on the use of exercise training as a complementary treatment to pain medications to reduce chronic pain in children and adolescents diagnosed with cancer allows only for hypotheses on the effectiveness of this pain management modality. CONCLUSION: More research on this important topic is necessary and mitigating pain effectively while also reducing the use of opioid pain medication is an important goal shared by patients, their families, clinicians, and researchers alike. Future research in this area has great potential to inform clinical care, clinical care guidelines, and policy-making decisions for pain management in children and adolescents diagnosed with cancer who experience chronic pain.

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.

Multi-omic factors associated with future wheezing in infants.

BACKGROUND: The pathophysiology of wheezing is multifactorial, impacted by medical, demographic, environmental, and immunologic factors. We hypothesized that multi-omic analyses of host and microbial factors in saliva would enhance the ability to identify infants at risk for wheezing. METHODS: This longitudinal cohort study included 161 term infants. Infants who developed wheezing (n = 27) within 24 months of delivery were identified using the International Study of Asthma and Allergies in Childhood Written Questionnaire and review of the medical record. Standardized surveys were used to assess infant traits and environmental exposures. Saliva was collected for multi-omic assessment of cytokines, microRNAs, mRNAs, and microbiome/virome RNAs. RESULTS: Two infant factors (daycare attendance, family history of asthma) and three salivary "omic" features (miR-26a-5p, Elusimicrobia, Streptococcus phage phiARI0131-1) differed between the two groups (adjusted p < 0.05). miR-26a-5p levels were correlated with Elusimicrobia (R = -0.87, p = 3.7 × 10-31). A model employing the three omic features plus daycare attendance and family asthma history yielded the highest predictive accuracy for future wheezing episodes (AUC = 0.74, 95% CI: 0.703-0.772, 77% sensitivity, 62% specificity). CONCLUSIONS: Host-microbiome interactions in saliva may yield pathophysiologic clues about the origins of wheezing and aid identification of infants at risk of future wheezing episodes. IMPACT: Wheezing is multi-factorial, but the relative contributions of infant traits, environment, and underlying biology are poorly understood. This multi-omic study identifies three molecular factors, including salivary microRNAs, microbes, and viral phages associated with increased risk of infant wheezing. Measurement of these molecular factors enhanced predictive accuracy for future wheezing when combined with family asthma history and daycare attendance. Validation of this approach could be used to identify infants at risk for wheezing and guide personalized medical management.

Case Report: Successful avoidance of etoposide for primary hemophagocytic lymphohistiocytosis-induced multiple organ dysfunction syndrome using emapalumab.

We describe the case of an infant who presented with simple rhinovirus/enterovirus bronchiolitis whose condition worsened with rapid progression to multiple organ dysfunction syndrome (MODS). The patient was presumed to have either primary or secondary hemophagocytic lymphohistiocytosis (HLH), and treatment was initiated using dexamethasone, anakinra, and intravenous immunoglobulin to modulate the immune system. Due to the organ dysfunction, the use of etoposide was avoided and instead, emapalumab, an interferon gamma antagonist, was administered at a dose of 6 mg/kg. The patient's organ failure improved, and the levels of inflammatory markers decreased. The flow cytometry analysis revealed that cytotoxic cells lacked perforin expression, and subsequent genetic analysis confirmed homozygous pathogenic mutations in the perforin gene. This case highlights the potential avoidance of etoposide in cases of primary HLH, the possible benefit of an elevated initial dose of emapalumab, and the contribution offered by a multi-specialty team approach to complex diagnosis.

Understanding immunological origins of atopic dermatitis through multi-omic analysis.

BACKGROUND: The pathophysiology of atopic dermatitis (AD) is multifactorial, impacted by individual medical, demographic, environmental, and immunologic factors. This study used multi-omic analyses to assess how host and microbial factors could contribute to infant AD development. METHODS: This longitudinal cohort study included 129 term infants, identified as AD (n = 37) or non-AD (n = 92) using the Infant Feeding Practices-II survey and review of medical records. Standardized surveys were used to assess medical and demographic traits (gestational age, sex, race, maternal AD, and atopy family history), and environmental exposures (delivery method, maternal tobacco use, pets, breastfeeding duration, and timing of solid food introduction). Saliva was collected at 6 months for multi-omic assessment of cytokines, microRNAs, mRNAs, and the microbiome. The contribution of each factor to AD status was assessed with logistic regression. RESULTS: Medical, demographic, and environmental factors did not differ between AD and non-AD infants. Five "omic" factors (IL-8/IL-6, miR-375-3p, miR-21-5p, bacterial diversity, and Proteobacteria) differed between groups (p < .05). The severity of AD was positively associated with levels of miR-375-3p (R = .17, p = .049) and Proteobacteria (R = .22, p = .011), and negatively associated with levels of miR-21-5p (R = .20, p = .022). Multi-omic features accounted for 17% of variance between groups, significantly improving an AD risk model employing medical, demographic, and environmental factors (X2  = 32.47, p = .006). CONCLUSION: Interactions between the microbiome and host signaling may predispose certain infants to AD by promoting a pro-inflammatory environment.

Hematopoietic Cell Transplantation for Congenital Dyserythropoietic Anemia: A Report from the Pediatric Transplant and Cellular Therapy Consortium.

Hematopoietic cell transplantation (HCT) is the sole curative option for congenital dyserythropoietic anemia (CDA), a rare type of hemolytic anemia characterized by anemia, ineffective erythropoiesis, and secondary hemochromatosis. In this retrospective multicenter study, we report the outcomes of children with CDA who underwent HCT at participating Pediatric Transplantation and Cellular Therapy Consortium centers. Clinical information on HCT and associated outcomes was collected retrospectively using a common questionnaire. Data were analyzed using descriptive statistics and appropriate analysis. Eighteen patients with CDA who underwent allogeneic HCT between 2002 and 2020 were identified. The majority of patients (n = 13) had CDA type II, and the remainder had either CDA type I (n = 2) or CDA of unknown type (n = 3). Mutations were identified in 7 patients (39%), including SEC23B in 5, GATA1 in 1, and abnormality of chromosome 20 in 1. Thirteen patients had evidence of iron overload pre-HCT and received chelation therapy for a median duration of 10 months (range, 2 months to 17 years) pre-HCT. The median age at the time of HCT was 5.5 years (range, 0.7 to 26 years). Donors were HLA-matched (sibling, 4; unrelated, 10) and mismatched (haploidentical, 1; unrelated, 3). Graft sources were bone marrow in 15 patients, umbilical cord blood in 2 patients, or both in 1 patient. Conditioning included busulfan-based myeloablative (67%), fludarabine-based reduced-intensity (27%), or nonmyeloablative (6%) regimens. Five patients developed veno-occlusive disease, and 4 had viral reactivation. The cumulative incidence of acute graft-versus-host disease (GVHD) was 33%, and that of chronic GVHD was 22%. Four patients (22%) experienced graft failure; all engrafted following either a second HCT (n = 2) or third HCT (n = 2) but sustained considerable morbidities (3 GVHD, 1 death, 2 viral reactivation). With a median follow-up of 3.2 years (range, 0.6 to 14 years)), the 2-year overall survival, event-free survival (EFS), and GVHD-free EFS were 88% (95% confidence interval [CI], 73% to 100%), 65% (95% CI, 45% to 92%), and 60% (95% CI, 40% to 88%), respectively. Univariate analysis did not identify any patient- or transplantation-related variables impacting outcomes. Our study indicates that HCT can be curative for patients with CDA. Strategies such as aggressive chelation, use of preconditioning therapy, and early HCT in the presence of a suitable donor before comorbidities occur are needed to improve engraftment without increasing the risk for toxicity and mortality.

Biomarkers associated with mortality in pediatric patients with cardiac arrest and acute respiratory distress syndrome.

AIMS: To identify plasma biomarkers associated with cardiac arrest in a cohort of children with acute respiratory distress syndrome (ARDS), and to assess the association of these biomarkers with mortality in children with cardiac arrest and ARDS (ARDS + CA). METHODS: This was a secondary analysis of a single-center prospective cohort study of children with ARDS from 2014-2019 with 17 biomarkers measured. Clinical characteristics and biomarkers were compared between subjects with ARDS + CA and ARDS with univariate analysis. In a sub-cohort of ARDS + CA subjects, the association between biomarker levels and mortality was tested using univariate and bivariate logistic regression. RESULTS: Biomarkers were measured in 333 subjects: 301 with ARDS (median age 5.3 years, 55.5% male) and 32 ARDS + CA (median age 8 years, 53.1% male). More arrests (69%) occurred out-of-hospital with a median CPR duration of 11 (IQR 5.5, 25) minutes. ARDS severity, PRISM III score, vasoactive-ionotropic score and extrapulmonary organ failures were worse in the ARDS + CA versus ARDS group. Eight biomarkers were elevated in the ARDS + CA versus ARDS cohort: sRAGE, nucleosomes, SP-D, CCL22, IL-6, HSP70, IL-8, and MIP-1b. sRAGE, SP-D, and CCL22 remained elevated when the cohorts were matched for illness severity. When controlling for severity of ARDS and cardiac arrest characteristics, sRAGE, IL-6 and granzyme B were associated with mortality in the ARDS + CA group. CONCLUSION: sRAGE, IL-6 and granzyme B were associated with cardiac arrest mortality when controlling for illness severity. sRAGE was consistently higher in the ARDS + CA cohort compared to ARDS and retained independent association with mortality.

Case Report: Rapid Recognition and Immune Modulation of Secondary HLH Due to Disseminated HSV Infection.

We describe the case of a newborn who presented with multiple organ dysfunction syndrome (MODS) and hyperferritinemia, who eventually met criteria for hemophagocytic lymphohistiocytosis (HLH) due to disseminated herpes simplex virus 1 (HSV-1). While the cytokine storm abated after administration of multiple immune modulatory therapies including dexamethasone, etoposide, intravenous immune globulin, anakinra, as well as the interferon gamma antagonist emapalumab, multiple organ dysfunction syndrome progressed. Care was withdrawn after 5 days. Subsequent genetic testing did not reveal any mutations associated with familial HLH. This case highlights that even with appropriate antiviral treatment and immune suppression, disseminated HSV is often fatal. Further study is warranted to determine whether early immune modulatory therapy including interferon gamma blockade can interrupt the HLH inflammatory cascade and prevent progression of MODS.

PICU Passport: Pilot study of a handheld resident curriculum.

BACKGROUND: To explore the impact of an educational tool designed to streamline resident learning during their pediatric intensive care (PICU) rotations. METHODS: Topics and procedures were chosen for inclusion based on national requirements for pediatric residents. Residents received a PICU Passport at the beginning of their rotations. PICU faculty were provided learning objectives for each topic. Residents and faculty were surveyed before and after starting use of the Passport. RESULTS: Twenty-two residents pre-Passport and 38 residents post-Passport were compared. Residents were more satisfied with their educational experiences (27 % vs. 79 %; P < 0.001), more likely to report faculty targeted teaching towards knowledge gaps (5 % vs. 63 %; P < 0.001) and felt more empowered to ask faculty to discuss specific topics (27 % vs. 76 %; P = 0.002). The median number of teaching sessions increased from 3 to 10 (Z = 4.2; P < 0.001). Most residents (73 %) felt the Passport helped them keep track of their learning and identify gaps in their knowledge. CONCLUSIONS: The PICU Passport helps residents keep track of their learning and identify gaps in their knowledge. Passport use increases resident satisfaction with education during their PICU rotation and empowers residents to ask PICU faculty to address specific knowledge gaps.

Cytokine Panels and Pediatric Acute Respiratory Distress Syndrome: A Translational Investigation.

OBJECTIVES: To identify and compare serum and lower respiratory tract fluid biomarkers of lung injury using well-characterized mouse models of lung injury. To explore the relationship between these preclinical biomarkers and clinical outcomes in a discovery cohort of pediatric patients with acute respiratory failure from pneumonia. DESIGN: Prospective, observational cohort study. SETTING: A basic science laboratory and the PICU of a tertiary-care children's hospital. PATIENTS: PICU patients intubated for respiratory failure from a suspected respiratory infection. INTERVENTIONS: Prospective enrollment and collection of lower respiratory tract fluid samples. MEASUREMENTS AND MAIN RESULTS: C57BL6/J mice were intranasally inoculated with escalating doses of influenza A virus or toll-like receptor agonists to simulate varying degrees of lung injury. Serum and bronchoalveolar lavage fluid were measured for the presence of cytokines using commercially available multiplex cytokine assays. Elevated levels of C-C motif chemokine ligand 7 at the peak of inflammation in both bronchoalveolar lavage fluid and serum correlated with lethality, with the bronchoalveolar lavage fluid ratio of C-C motif chemokine ligand 7:C-C motif chemokine ligand 22 providing the best prediction in the mouse models. These preclinical biomarkers were examined in the plasma and lower respiratory tract fluid of a discovery cohort of pediatric patients with acute respiratory failure from pneumonia. The primary clinical outcome measure was ventilator-free days, with secondary outcomes of pediatric acute respiratory distress syndrome severity and mortality. Elevation in peak lower respiratory tract fluid C-C motif chemokine ligand 7:C-C motif chemokine ligand 22 ratios demonstrated a significant negative correlation with ventilator-free days (r = -0.805; p < 0.02). CONCLUSIONS: This study provides evidence that lung immune profiling via lower respiratory tract fluid cytokine analysis is feasible and may provide insight into clinical outcomes. Further validation of markers, including the C-C motif chemokine ligand 7:C-C motif chemokine ligand 22 ratio in this limited study, in a larger cohort of patients is necessary.

A Novel Mutation in Chronic Granulomatous Disease: Treating the Family, Not Just the Patient.

Chronic Granulomatous Disease (CGD) is caused by genetic defects in the phagocyte NADPH oxidase leading to potentially severe infections with catalase positive micro-organisms. With the innate immune system being affected this disease usually presents before the age of 5 years with infections involving the skin, lung, liver or lymphnodes. Infections with specific catalase positive organisms, especially Burkholderia cepacia, Serratia, Nocardia and Chromobacterium violaceum prompt a workup for CGD in affected patients. In addition, a family history of CGD also warrants testing. The pattern of inheritance of CGD varies across geographic regions of the world and societies, with X-linked inheritance being most prevalent in the United States and Europe. Affected patients require life-long therapy with prophylactic antibiotics, antifungals, and possibly interferon-gamma. Hematopoietic Stem Cell Transplantation is the only curative therapy known to date. Identification, diagnosis and management of patients with CGD usually involves a multi-specialty team including Pediatrics, Immunology, Infectious Diseases, Hematology/Oncology and often also Pulmonology and GI/Hepatology. Frequent follow up is paramount for good outcomes; infections have to be recognized and treated promptly and often preemptively. This is challenging for most patients and their families but presents a significant barrier for patients with limited access to care, limited resources or other challenging social situations. This case report describes the difficulties of managing a family with a novel mutation and multiple affected family members in different custody arrangements. It highlights the importance of close contact and communication with the family in deciding on management and treatment options. Educating the family and patient is critical to avoid complications of the disease and allow shared decision making that ultimately leads to better outcomes.

Murine erythroid short-term radioprotection requires a BMP4-dependent, self-renewing population of stress erythroid progenitors.

Acute anemic stress induces a systemic response designed to increase oxygen delivery to hypoxic tissues. Increased erythropoiesis is a key component of this response. Recovery from acute anemia relies on stress erythropoiesis, which is distinct from steady-state erythropoiesis. In this study we found that the bone morphogenetic protein 4-dependent (BMP4-dependent) stress erythropoiesis pathway was required and specific for erythroid short-term radioprotection following bone marrow transplantation. BMP4 signaling promoted the development of three populations of stress erythroid progenitors, which expanded in the spleen subsequent to bone marrow transplantation in mice. These progenitors did not correspond to previously identified bone marrow steady-state progenitors. The most immature population of stress progenitors was capable of self renewal while maintaining erythropoiesis without contribution to other lineages when serially transplanted into irradiated secondary and tertiary recipients. These data suggest that during the immediate post-transplant period, the microenvironment of the spleen is altered, which allows donor bone marrow cells to adopt a stress erythropoietic fate and promotes the rapid expansion and differentiation of stress erythroid progenitors. Our results also suggest that stress erythropoiesis may be manipulated through targeting the BMP4 signaling pathway to improve survival after injury.