Response In Pediatric Patients Research Articles

Longitudinal evaluation of the Abbott ARCHITECT SARS-CoV-2 IgM and IgG assays in a pediatric population

BackgroundClinical laboratory testing has been an essential part of COVID-19 management. Serology can provide valuable information regarding a patient’s exposure to virus, and may have a larger role to play as vaccines becomes available. Limited data is available on the serological response in pediatric patients. Here we investigate the use of one manufacturer’s commercial assays for detecting IgM and IgG in an exclusively pediatric population. MethodsAbbott SARS-CoV-2 IgM and IgG assays were performed on an Abbott ARCHITECT i1000. For specificity studies, we tested 78 patient specimens collected before the COVID-19 pandemic, and 66 specimens from patients who tested negative for SARS-CoV-2 nucleic acid amplification test (NAAT) during the COVID-19 pandemic. For sensitivity we tested 181 specimens from 41 patients with a positive NAAT result. Precision data was acquired for 20 days. ResultsFor IgM, the highest qualitative positive agreement with molecular results was observed to be 15–30 days after a positive NAAT result or after symptom onset. For IgG, the highest positive agreement was 31–60 days after a positive NAAT result or 61–90 days after the start of symptoms. IgM started to decline 30 days after NAAT results and faded by 90 days. IgG started to decrease 60 days after a positive NAAT result. ConclusionThe Abbott IgM and IgG assays have negative agreements of 98.7–100% relative to NAAT results. The IgM and IgG levels assayed by these methods start to decline months after positive molecular results and onset of symptoms in a pediatric population.

Comparison of intraocular pressure and hemodynamic responses to insertion of laryngeal mask airway or endotracheal tube in elective paediatric ophthalmic procedures

Introduction: The main objective of the study was to assess the benefits of using laryngeal mask airway in place of endotracheal intubation in reducing the intraocular pressure and hemodynamic response in paediatric patients posted for elective ophthalmic procedures. This prospective randomized study was conducted over a period of six months in the Regional institute of Ophthalmology. Materials and Methods: Sixty paediatric patients aged between 2-12 years, belonging to ASA grade 1 & 2 and posted for elective ophthalmic procedures were allocated into two groups, each of 30 patients, by a closed envelope method. Laryngeal mask airway (LMA) insertion for group I and Endotracheal intubation (ETI) for group II were performed. Intraocular pressure measurements at Baseline, pre-insertion, at 30th second and at 2nd minutes between the groups were compared. Corresponding responses in heart rate (HR), and mean arterial pressure (MAP) were also compared. Results: Statistically significant differences were seen at 30th second of intubation between group I and group II in HR [107.8±13.417in group I and 126.2±10.996 in group II], MAP [84.8±4.637 in group I and 98.4±8.6 in group II] and IOP (11.07+1.9 mmHg in group I and 15.76+2.7 mmHg in group II; P = 0.0001)]. Similarly, significant differences were also observed at 2nd minute of intubation. Conclusion: We found that LMA insertion has less influence on intraocular pressure and hemodynamic response and it is associated with less postoperative complications in children undergoing elective ophthalmic procedures under general anaesthesia. Keywords: Laryngeal mask airway, Intubation, Pressor response, Ophthalmic, Intraocular.

Venetoclax Alone or in Combination with Chemotherapy: Responses in Pediatric Patients with Relapsed/Refractory Acute Myeloid Leukemia with Heterogeneous Genomic Profiles

Venetoclax Alone or in Combination with Chemotherapy: Responses in Pediatric Patients with Relapsed/Refractory Acute Myeloid Leukemia with Heterogeneous Genomic Profiles

CD28 Expression Distinguishes Plasma Cell Fate in Pediatric Patients Suffering from COVID-19/Kawasaki's Disease Vs MIS-C

The COVID-19 pandemic has ravaged the global community and highlighted the importance of antibody-mediated antiviral immune responses. The SARS-CoV-2 virus is highly pathogenic, but is unique from other viral infections in that pediatric patients are largely spared from severe symptoms. However, a small number of pediatric patients present autoimmune-like symptoms after COVID-19 infection, termed Multisystem Inflammatory Syndrome in Children, or MIS-C. Symptomatically, it shares some similarity to that of Kawasaki's Disease (KD), an autoimmune disorder linked to coronavirus infection thought to be driven by autoantibody production. Understanding the immunological mechanisms that facilitate clearance of SARS-CoV-2 or drive the development of life-threatening autoimmune symptoms in MIS-C or KD is critical for our ability to design successful vaccines that do not elicit autoimmunity in children.Antibodies are produced by terminally differentiated B lymphocytes known as Plasma Cells (PC). Because successful immune responses/vaccination strategies against SARS-CoV-2 are dependent upon effective PC production, the dysregulation of which may lead to the development of Kawasaki's Disease or MIS-C, it is critical to understand the immunological mechanisms that define the pediatric PC response leading to these individual outcomes.We therefore sought to characterize the B cell-PC immune response in pediatric patients that have successfully cleared SARS-CoV-2 and compare the B cell immunological landscape to children who develop either KD or MIS-C. We used the 10X Genomics Platform to interrogate at a single cell level the CD19+ B/PC populations in the peripheral blood of pediatric patients at the transcriptional level as well as with VDJ deep sequencing.We began by clustering the CD19+ populations based on transcriptional similarity and found that both COVID-19 and KD exhibited 12 distinct clusters, but that MIS-C only had 6 clusters. Intriguingly, in evaluating clonal diversity, KD presented a broad spectrum of clonotypes while the COVID-19 and MISC patients were much more limited. This suggested that although KD and MIS-C both present with similar autoimmune-like symptoms, the mechanistic basis for their respective etiology may be distinct. We therefore sought to more deeply probe the subset of cells responsible for antibody production by evaluating the PC subsets.High BLIMP1 expression (PC lineage-defining transcription factor) was present in 2 distinct clusters in COVID-19/KD patients, but was broadly distributed at lower levels in MIS-C. We then looked at genes which were significantly upregulated in the most terminally differentiated cells from each patient. 50 genes were significantly higher in the COVID-19 and KD populations, and 54 in MIS-C. Using gene ontology analysis in COVID-19 and KD, we saw increased expression of transcripts involved in protein trafficking, redox responses, and respiratory metabolism. In comparison, the MIS-C patient demonstrated significance for programs involved in immature B cell development and inflammation. Taken together, this suggests that in COVID-19 and KD there is a program of terminal PC differentiation which is absent in MIS-C. To understand the mechanistic basis for the terminal differentiation in COVID-19 and KD, we sought to probe possible regulators of PC fate.We have recently published that CD28, the canonical T cell costimulatory molecule, is expressed by PC, and CD28 signaling through the adaptor protein SLP-76 leads to increased BLIMP1 expression and an IRF4-mediated metabolic program necessary for PC survival. Interestingly, SLP-76 was expressed at high levels in COVID-19 and KD patients, but was low in MIS-C. Similarly, CD28 was expressed in both COVID-19 and KD patients and correlated with higher IRF4 levels and metabolic genes, but was entirely absent in MIS-C.Taken together, these findings suggest that CD28 signaling may facilitate PC fate in COVID-19 pediatric patients and the development of KD arises from broad antibody specificity, possibly explaining how vascular antigens become targets. Furthermore, MIS-C, although similar in symptomatic presentation to KD, has an etiology driven by antigen-independent inflammation arising from immature B cells due to a lack of CD28-mediated PC differentiation and survival, which can be evaluated diagnostically by simple flow cytometry in a vaccination setting.DisclosuresNo relevant conflicts of interest to declare.

Extrapolating Pharmacodynamic Effects From Adults to Pediatrics: A Case Study of Ustekinumab in Pediatric Patients With Moderate to Severe Plaque Psoriasis.

Ustekinumab (STELARA) is a human monoclonal antibody against interleukins-12 and -23 for the treatment of adult and adolescent (≥12 to <18years of age) patients with moderate-to-severe plaque psoriasis. A phase III study was recently completed in pediatric patients (≥6 to <12years of age) with psoriasis. The objectives of the current analysis were to develop a population pharmacokinetic (PK) model and a joint longitudinal exposure-response model using ordered categorial end points derived from Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA) scores (namely a joint PASI response criteria (PRC) and PGA model) to characterize the PK and exposure-response relationship of ustekinumab in pediatric patients with psoriasis. The developed pediatric models reasonably predicted the PK of ustekinumab, as well as the PRC and PGA clinical response in pediatric patients with psoriasis. In addition, the joint PRC and PGA modeling framework was able to adequately extrapolate clinical response in pediatric patients using data collected from clinical studies in adult patients with psoriasis.

Phase I/II Study of Stereotactic Body Radiation Therapy for Pulmonary Metastases in Pediatric Patients

PurposePulmonary metastases are common in many pediatric solid tumors; however, little is known about safety and efficacy of lung stereotactic body radiation therapy (SBRT) for pediatric patients. We conducted a phase I/II study to investigate the minimum effective dose level of SBRT with an acceptable safety profile in pediatric patients. Methods and MaterialsPatients with sarcoma and metastatic pulmonary lesions ≤3 cm in diameter and ≤21 years of age were enrolled. Dose levels 1, 2, and 3 were 24, 30, and 36 Gy in 3 fractions, respectively. Enrolled patients with metastases from primary renal tumors and sarcoma histologies were to begin at dose level 1 and 2, respectively. Exclusion criteria included receipt of whole-lung/hemi-thorax irradiation >12 Gy within 6 months of consent. Primary endpoints were tolerability and safety per Common Terminology Criteria for Adverse Events grading and disease response at 6 weeks post-SBRT per response evaluation criteria in solid tumors (RECIST) 1.1 criteria. Secondary endpoints included rates of local control and distant failure within the lung, but outside of the treatment volume. ResultsFive patients with median age of 13 years (range, 7-21) received SBRT at dose level 2. Primary tumor histologies included Ewing sarcoma (n = 3), anaplastic chordoma (n = 1), and osteosarcoma (n = 1). No grade ≥3 adverse events were observed. At 6 weeks after SBRT, 7/8 (87.5%) lesions achieved partial response. With median follow-up of 2.1 years (range, 1.4-2.5), 2-year local control and distant failure-free survival were 60% (n = 8) and 40% (n = 5), respectively. One patient developed widespread metastases and succumbed to disease 1.4 years after SBRT. ConclusionsSBRT for pulmonary metastases produces responses in pediatric patients with sarcoma at 6 weeks with acceptable toxicity; however, patients remain at risk of local and distant failure within the lung. Future prospective studies are needed to investigate whether higher doses of SBRT, possibly in combination with other therapies, are safe and provide more durable response.

Efficacy of Helicobacter pylori Eradication Therapy on Platelet Recovery in Pediatric Immune Thrombocytopenic Purpura-Case Series and a Systematic Review.

Evidence relating to the efficacy of Helicobacter pylori eradication therapy for chronic immune thrombocytopenic purpura (cITP) in childhood is inadequate. The aim of this retrospective study was to determine the efficacy of H. pylori eradication therapy for platelet response in pediatric patients with cITP in our hospital, and to perform a systematic review of previous reports about pediatric patients with cITP who were positive for H. pylori infection and were treated with H. pylori eradication therapy. Analysis of the data of pediatric patients with cITP in our hospital and a systematic review of digital literature databases of studies in pediatric patients with cITP were performed. Data of 33 pediatric patients with cITP from our hospital records showed that the prevalence of H. pylori infection and the rate of response to platelet therapy were 15% and 33.3%, respectively. Data of 706 pediatric patients from 18 previous reports showed that the prevalence of H. pylori infection and rate of platelet response were 23% and 43.8%, respectively. Eradication therapy for H. pylori infection in pediatric cITP patients can be expected to result in a response equivalent to that in the adult population, with fewer adverse effects than other treatments for cITP.

Kinetics of Viral Clearance and Antibody Production Across Age Groups in Children with Severe Acute Respiratory Syndrome Coronavirus 2 Infection

ObjectivesTo improve understanding of transition from viral infection to viral clearance, and antibody response in pediatric patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.Study designThis retrospective analysis of children tested for SARS-CoV-2 by reverse transcription (RT) polymerase chain reaction (PCR) and immunoglobulin G antibody at a quaternary-care, free-standing pediatric hospital between March 13, 2020, and June 21, 2020, included 6369 patients who underwent PCR testing and 215 patients who underwent antibody testing. During the initial study period, testing focused primarily on symptomatic children; the later study period included asymptomatic patients who underwent testing as preadmission or preprocedural screening. We report the proportion of positive and negative tests, time to viral clearance, and time to seropositivity.ResultsThe rate of positivity varied over time due to viral circulation in the community and transition from targeted testing of symptomatic patients to more universal screening of hospitalized patients. Median duration of viral shedding (RT-PCR positivity) was 19.5 days and time from RT-PCR positivity to negativity was 25 days. Of note, patients aged 6 through 15 years demonstrated a longer time of RT-PCR positivity to negativity, compared with patients aged 16 through 22 years (median 32 vs 18 days, P = .015). Median time to seropositivity, by chemiluminescent testing, from RT-PCR positivity was 18 days, whereas median time to reach adequate levels of neutralizing antibodies (defined as comparable with 160 titer by plaque reduction neutralization testing) was 36 days.ConclusionsThe majority of patients demonstrated a prolonged period of viral shedding after infection with SARS CoV-2. It is unknown whether this correlates with persistent infectivity. Only 17 of 33 patients demonstrated adequate neutralizing antibodies during the time frame of specimen collection. It remains unknown whether immunoglobulin G antibody against spike structured proteins correlates with immunity, and how long antibodies and potential protection persist.

Revaccination management of a large cohort of pediatric patients following a potential lapse in cold storage

IntroductionIn a pediatric clinic in California (US), 3823 patients were vaccinated with potentially-compromised vaccines following lapses in cold storage chain management between February 2014 and April 2015. A revaccination program was initiated in May 2015. Families were contacted by mail and encouraged to discuss follow-up options with their care team, namely: revaccination, serological testing and/or revaccination, or no further action. This study aimed: to understand which families were more likely to respond to the outreach, and to engage in any testing and/or revaccination; to determine whether or not vaccination with these potentially-compromised vaccines elicited sufficient immune response in pediatric patients; and to estimate the program cost. MethodsPatients who had received potentially-compromised vaccines were identified, and relevant data were extracted from their electronic health records. Logistic regression analyses were performed to identify factors associated with response to outreach, serological testing and/or revaccination. Results3823 patients between 0 and 21 years received an average of 3.1 potentially-compromised vaccines. 2547 revaccinations were performed (1515 patients) and 544 patients had serological testing results. Non-immune titer levels were only reported for 3–4% and 8% of the tested patients who had received potentially-compromised tetanus and hepatitis B vaccines, respectively, and only for children two years old and younger. Three years after the revaccination program started, 77% of all cases were considered resolved and 62.5% of patients (1970/3152) who were administered potentially-compromised vaccines were either revaccinated or had seroprotective titers. Response to outreach and decision to choose serological testing and/or revaccinate were affected by patient age, race/ethnicity and zip code median income (p < 0.05). ConclusionWe observed race/ethnicity, patient age and income differences in response to the outreach and decision-making. For patients vaccinated with potentially-compromised vaccines, serological testing should be considered prior to revaccination. Revaccination may not be the most appropriate course of action for all patients.

Effect of temperature maintenance by forced-air warming blankets of different temperatures on changes in inflammatory factors in children undergoing congenital hip dislocation surgery.

BackgroundHypothermia is associated with many adverse clinical outcomes in pediatric patients, and thus, it is important to find an effective and safe method for preventing peri-operative hypothermia and its associated adverse outcomes in pediatric patients. This study aimed to investigate the effect of forced-air warming blankets with different temperatures on changes in the transforming growth factor-β (TGF-β), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-10 levels in children undergoing surgical treatment for developmental displacement of the hip (DDH).MethodsThe study included 123 children undergoing surgery for DDH under general anesthesia. The patients were randomly assigned to three groups, using a random number table: the 32, 38, and 43°C groups according to the temperature setting of the forced-air warming blankets. For each patient, body temperature was recorded immediately after anesthesia induction and intubation (T0), at initial incision (T1), at 1 h after incision (T2), at 2 h after incision (T3), at the end of surgery (T4), immediately upon return to the ward after surgery (T5), and then at 12 h (T6), 24 h (T7), 36 h (T8), and 48 h (T9) after the surgery. The serum levels of TGF-β, TNF-α, IL-1β, and IL-10 were measured at T0 and T4 for all groups.ResultsThe number of patients with fever in the 38°C group was significantly less than those in the 32 and 43°C groups (χ2 = 6.630, P = 0.036). At T0, the body temperatures in the 38 and 43°C groups were significantly higher than that in the 32°C group (F = 17.992, P < 0.001). At T2, the body temperature was significantly higher in the 43°C group than those in the 32 and 38°C groups (F = 12.776, P < 0.001). Moreover, at T4, the serum levels of TGF-β (F = 3286.548, P < 0.001) and IL-10 (F = 4628.983, P < 0.001) were significantly increased in the 38°C group, and the serum levels of TNF-α (F = 911.415, P < 0.001) and IL-1β (F = 322.191, P < 0.001) were significantly decreased in the 38°C group, compared with the levels in the 32 and 43°C groups.ConclusionForce-air warming blankets set at 38°C maintained stable body temperature with less adverse outcome and effectively inhibited the inflammatory response in pediatric patients undergoing surgery for DDH.Clinical trial registrationChiCTR1800014820; http://www.chictr.org.cn/showproj.aspx?proj=25240.

Therapeutic Plasma Exchange Application in Children Requires Individual Decision.

Therapeutic plasma exchange (TPE) is a treatment administered with the aim of removing a pathogenic material or compound causing morbidity in a variety of neurologic, hematologic, renal, and autoimmune diseases. In this study, we aimed to assess the indications, efficacy, reliability, complications, and treatment response of pediatric patients for TPE. This retrospective study analyzed data from 39 patients aged from 0 to 18 years who underwent a total of 172 TPE sessions from January 2015 to April 2018 in a tertiary pediatric intensive care unit. Indications for TPE were, in order of frequency, macrophage activation syndrome (28.2%, n = 11), renal transplantation rejection (15.4%, n = 6), liver failure (15.4%, n = 6), Guillain-Barre's syndrome (15%, n = 6), hemolytic uremic syndrome (7.7%, n = 3), acute demyelinating disease (7.7%, n = 3), septic shock (5.1%, n = 2), and intoxication (5.1%, n = 2). No patient had any adverse event related to the TPE during the procedure. The TPE session was ended prematurely in one patient due to insufficient vascular access and lack of blood flow (2.6%). In the long term, thrombosis due to the indwelling central catheter occurred (5.1%, n = 2). TPE appears to be an effective first-stage or supplementary treatment in a variety of diseases, may be safely used in pediatric patients, and there are significant findings that its area of use will increase. In experienced hands and when assessed carefully, it appears that the rate of adverse reactions and vascular access problems may be low enough to be negligible.

Serum neurofilament light chain is a useful biomarker in pediatric multiple sclerosis.

ObjectiveTo investigate serum neurofilament light chain (sNfL) as a potential biomarker for disease activity and treatment response in pediatric patients with multiple sclerosis (MS).MethodsIn this retrospective cohort study, sNfL levels were measured in a pediatric MS cohort (n = 55, follow-up 12–105 months) and in a non-neurologic pediatric control cohort (n = 301) using a high-sensitivity single-molecule array assay. Association of sNfL levels and treatment and clinical and MRI parameters were calculated.ResultsUntreated patients had higher sNfL levels than controls (median 19.0 vs 4.6 pg/mL; CI [4.732, 6.911]), p < 0.001). sNfL levels were significantly associated with MRI activity (+9.1% per contrast-enhancing lesion, CI [1.045, 1.138], p < 0.001; +0.6% per T2-weighted lesion, CI [1.001, 1.010], p = 0.015). Higher values were associated with a relapse <90 days ago (+51.1%; CI [1.184, 1.929], p < 0.001) and a higher Expanded Disability Status Scale score (CI [1.001, 1.240], p = 0.048). In patients treated with interferon beta-1a/b (n = 27), sNfL levels declined from 14.7 to 7.9 pg/mL after 6 ± 2 months (CI [0.339, 0.603], p < 0.001). Patients with insufficient control of clinical or MRI disease activity under treatment with interferon beta-1a/b or glatiramer acetate who switched to fingolimod (n = 18) showed a reduction of sNfL levels from 16.5 to 10.0 pg/mL 6 ± 2 months after switch (CI [0.481, 0.701], p < 0.001).ConclusionssNfL is a useful biomarker for monitoring disease activity and treatment response in pediatric MS. It is most likely helpful to predict disease severity and to guide treatment decisions in patients with pediatric MS. This study provides Class III evidence that sNfL levels are associated with disease activity in pediatric MS.

Balanced Steady-State Free Precession Techniques Improve Detection of Residual Germ Cell Tumor for Treatment Planning.

Identification of a partial/complete chemotherapy response in pediatric patients with intracranial germ cell tumors is clinically important for radiation treatment and management. Partial/complete response is conventionally determined on postcontrast MR imaging sequences. The purpose of this study was to assess the diagnostic utility of a balanced steady-state free precession sequence as an adjunct to standard MR imaging sequences for the detection of residual tumor in pediatric patients on postchemoreduction pre-radiation planning MR imaging. This was a retrospective study of pediatric patients with intracranial germ cell tumors undergoing postchemotherapy, preradiotherapy MR imaging. Patients underwent 1.5T or 3T MR imaging with pre- and postcontrast T1WIs, T2WIs, and a balanced steady-state free precession sequence. Two neuroradiologists independently reviewed standard MR imaging sequences without the balanced steady-state free precession sequence, then with the balanced steady-state free precession sequence 1 week later. Assessment for partial/complete response was determined using Response Assessment in Neuro-Oncology criteria. A 5-point Likert scale scored the diagnostic confidence of the neuroradiologist rating each study without/with the balanced steady-state free precession sequence. Rates of residual disease concordance and diagnostic confidence levels without/with the balanced steady-state free precession sequence were calculated. Thirty-nine patients were included with 31 males and 8 females (mean age, 14.15 ± 4.26 years). Thirty-one patients had single-site disease; 8 patients had multisynchronous disease (47 sites in total). Compared to review of the standard MR sequences alone, the addition of the balanced steady state free precession sequence resulted in higher rates of tumor partial response categorization and greater diagnostic confidence levels (P < .001, P < .001). The balanced steady-state free precession sequence improves detection of residual chemotherapy-reduced intracranial germ cell tumors and increases diagnostic confidence of the neuroradiologist. The balanced steady-state free precession sequence may be an important adjunct to the standard MR imaging protocol for radiation planning.

Inflammatory Responses in Pediatric Patients with Suspected Myocarditis

Myocarditis is one major cause for the development of acute or chronic heart failure where immunosuppressive therapies are still divergently discussed. The aim of this study was to analyze cytokines in children with suspected myocarditis to describe their immunologic patterns and to reveal potential therapeutic targets. Sera of children hospitalized with suspected myocarditis and sera from a pediatric control cohort collected during April 2017 and July 2019 were analyzed. Sera were taken after admission and before further intensive care treatment. The cytokines Interleukin (IL)-1 beta, IL-2, IL-6, IL-10 and IL-1 receptor antagonist (IL-1RA) were analyzed by enzyme-linked immunosorbent assay (ELISA) kits of Meso Scale Discovery Inc. and R&D Systems™. A subcohort of patients with a severe disease course needing mechanical circulatory support, heart transplantation or death was defined. Thirty-nine children with suspected myocarditis, median age (IQR) 12.3 (2.1-16.4) years, 55% male and 33 controls 5.3 (3.4-9.3) years, 31% male were included in the analyses. IL-1RA was significantly higher in patients (671.2 pg/ml) than in controls (379.0 pg/ml; p<0.001). Also IL-6 was significantly higher in patients compared to controls (3.4 pg/ml vs. 0.5 pg/ml; p<0.001). Within the patient cohort IL-1RA correlated positively with leucocytes (rs=0.432, p=0.017). IL-6 correlated with leucocytes (rs=0.393, p=0.032), CRP (rs=0.356, p=0.050), Troponin (rs=0.502, p=0.015). IL-2 and IL-10 correlated with BNP (IL-2: rs=0.481, p=0.011, IL-10: rs=0.387, p=0.046) and the Z-Score of the left ventricular enddiastolic diameter in echocardiography (IL-2: rs=0.625, p<0.001, IL-10: rs=0.394, p=0.028). Within the subcohort with severe disease courses (n=9), IL-1ß was not significantly reduced compared to the other patients and the controls (p=0.387) with a corresponding significantly elevated IL1-RA and IL-6 (p<0.001, respectively). In children with suspected myocarditis cytokines as IL-2, IL-6 and IL-10 correlate with myocardial damage and dysfunction as potential markers for heart failure. The higher levels of IL-1RA in children with severe disease course may represent the immunologic reaction of a more fulminant myocarditis pointing towards potential therapeutic targets in children with an inappropriate elevation of IL-1RA.

Assessment of antiplatelet therapy response in pediatric patients following cardiac surgery by microfluidic assay

IntroductionAnti-platelet therapies, like aspirin, are routinely used following many surgical repairs for congenital heart disease to prevent life-threatening thrombotic complications. Optimal dosing is not well studied and determination of real-time dose response to prophylactic aspirin is not routinely performed due to blood volume requirements and poor predictive value of existing platelet function assays (PFAs). Our objective was to study platelet function and thrombosis in post-operative cardiac patients under physiologic shear conditions using a novel collagen-coated microfluidic thrombosis assay (MTA) compared to a standard whole blood aggregometry (WBA) assay before and after clinically and experimentally administered aspirin therapy. MethodsWe recruited congenital heart surgical patients with post-operative indications for aspirin therapy at the Children's Hospital of Michigan. Samples of 1.8 mL blood were drawn within 24 h of initiating aspirin (D0) and 24 to 48 h after initiating aspirin (D1). Blood samples were split for use in the MTA and the WBA. The MTA sample was run through collagen coated microfluidic channels at shear stress of 10 dyne/cm2 and pulse frequency of 1.67 Hz to simulate physiologic flow conditions. Each sample was run under untreated conditions (reflects the study subject's endogenous platelet function, D0, D1) and following exogenous aspirin administration (reflects maximum theoretical platelet response to aspirin, +eASA). The kinetics of thrombus formation was assessed as area percent of signal intensity (total fluorescent intensity, TFI) of thrombosis at 6 &10 min and as area under curve (AUC) for MTA and as AUC and impedance at 6 min for WBA. ResultsResults from MTA and WBA on pre- and post-aspirin blood samples collected from 18 subjects, with and without exogenously added aspirin, were analyzed in this study. Fold changes for AUC were calculated for each test and were compared using Wilcoxon signed rank test; this showed no statistically significant difference. Three of the patients were found to have no response to endogenous or exogenous aspirin. ConclusionsWe observed that measured platelet function is variable and potential sources of variability could be sample source, timing of sample from bypass, platelet count, transfusions and others. Standard aspirin doses might not be adequate for patients who are at high risk of thrombosis. In this study, we demonstrate the feasibility of employing microfluidic thrombosis assay to assess real time clinical platelet function in the cardiac ICU setting. Microfluidic assays provide real time assessment of platelet function under physiologic flow conditions and might be helpful with optimizing aspirin doses. Further studies on larger cohorts are required to validate this possibility.

The predictive value of pre-treatment paroxysmal nocturnal hemoglobinuria clone on response to immunosuppressive therapy in patients with aplastic anemia: a meta-analysis

ABSTRACT Background Although pre-treatment paroxysmal nocturnal hemoglobinuria (PNH) clone has been reported in a fraction of aplastic anemia (AA) for a long time, its predictive value on response to immunosuppressive therapy (IST) remained debatable. Therefore, we conducted a meta-analysis to elaborate this issue. Methods The identified articles were retrieved from five English databases PubMed, EMBASE, Web of Science, Medline, the Cochrane Library, and four Chinese databases Weipu, Wangfang, China National Knowledge Infrastructure (CNKI), and SinoMed. We extracted odds ratios (ORs) and the corresponding 95% confidential intervals (CIs) for response to IST in AA patients with pre-treatment PNH clone versus those without from the available studies. Results Twelve studies covering 1787 patients were included this meta-analysis. The pooled ORs indicated that the pre-treatment PNH clone had no impact on 3-month response (pooled OR: 1.323, 95% CI: 0.260–6.735, p = 0.736), 6-month response (OR: 1.668, 95% CI: 0.802–3.470, p = 0.171), and overall response (OR: 2.220, 95% CI: 0.870–5.665, p = 0.095), including overall response in pediatric patients (OR: 1.919, 95% CI: 0.378–9.738, p = 0.432). However, pre-treatment PNH clone had a favorable impact on 12-month response (OR: 2.725, 95% CI: 1.525–4.870, p = 0.001). Conclusion Pre-treatment PNH clone is associated with favorable 12-month response to IST in AA, the underlying mechanism needs further exploring.

Impact of stress-induced hyperglycemia on the outcome of children with trauma: A cross-sectional analysis based on propensity score-matched population

This was a retrospective study of pediatric trauma patients and were hospitalized in a level-1 trauma center from January 1, 2009 to December 31, 2016. Stress-induced hyperglycemia (SIH) was defined as a hyperglycemia level ≥200 mg/dL upon arrival at the emergency department without any history of diabetes or a hemoglobin A1c level ≥6.5% upon arrival or during the first month of admission. The results demonstrated that the patients with SIH (n = 36) had a significantly longer length of stay (LOS) in hospital (16.4 vs. 7.8 days, p = 0.002), higher rates of intensive care unit (ICU) admission (55.6% vs. 20.9%, p < 0.001), and higher in-hospital mortality rates (5.6% vs. 0.6%, p = 0.028) compared with those with non-diabetic normoglycemia (NDN). However, in the 24-pair well-balanced propensity score-matched patient populations, in which significant difference in sex, age, and injury severity score were eliminated, patient outcomes in terms of LOS in hospital, rate of ICU admission, and in-hospital mortality rate were not significantly different between the patients with SIH and NDN. The different baseline characteristics of the patients, particularly injury severity, may be associated with poorer outcomes in pediatric trauma patients with SIH compared with those with NDN. This study also indicated that, upon major trauma, the response of pediatric patients with SIH is different from that of adult patients.

Survivals of the Intraoperative Motor-evoked Potentials Response in Pediatric Patients Undergoing Spinal Deformity Correction Surgery: What Are the Neurologic Outcomes of Surgery?

This is a retrospective cases study from a prospective patient register. To clarify the clinical implication regard to the survivals of motor-evoked potential (MEP) response. Intraoperative neurophysiological monitoring has become an essential component for decreasing the incidence of neurological deficits during spine surgeries. Significant motor-evoked potential (MEP) loss but does not vanish completely is common especially in some high-risk and complicated pediatric spine deformity surgeries. A total of 1820 young patients (mean age = 12.2 years) underwent spinal deformity correction were mainly analyzed. Intraoperative monitoring (somatosensory-evoked potential, MEP, free-run electromyography, free-run electromyography) and postoperative neurologic outcomes were mainly analyzed in this study. All patients with monitoring alerts were divided into two groups: group 1, intraoperative MEP recovery group; and group 2, no obvious MEP recovery group. Moreover, the patients would be followed up strictly if he/she showed IOM alerting. The surviving MEP response was identified as significant monitoring alerts (80%-95% MEP Amp. loss) associated with high-risk surgical maneuvers. The results showed that there were 32 pediatric patients (group 1, 21 cases and group 2, 11 cases) presenting significant MEP monitoring alerts (80%-95% loss) relative to baseline. The patients in group 1 presented the partial/entire signal recovery from MEP alerts and they did not show spinal cord deficits postoperation. The patients in group 2 without obvious intraoperative MEP recovery showed different levels of new spinal deficits, no patient showed postoperative complete paraplegia or permanent spinal cord/nerve root deficits. When the intraoperative MEP changes significant and persistent but without totally disappeared, the rate of postoperative neural complication is relatively low. The chance of recovery of these neurological deficits is very high. Therefore, this phenomenon may be used to predictive of nonpermanent paraplegia. 3.

Abstract 2891: Landscape of infiltrating immune repertoire in pediatric solid tumors

Abstract Introduction: Immune repertoire is a highly diverse pool of B and T cell receptors (B/TCR) that determine boundaries of immune surveillance. Pre-existing immune clones within Tumor MicroEnvironment (TME) suggest existence of a functional antigen presenting machinery and recognizing T cells, which fail to eliminate tumor, likely due to immunosuppressive environment. Shifts in composition of immune repertoire upon immune checkpoint blockade have been reported in adult cancers and shown to be associated with clinical response. As immunotherapy is being introduced to pediatric oncology, there is a need to better understand immunogenomic aspects of TME in childhood cancers. Objective: We hypothesize that characteristics of TCRs in conjunction with gene expression profile of immune cells are key determinants of immune response in pediatric patients. Methods: We compiled a pan-pediatric cohort and associated RNAseq datasets through multiple research initiatives. Participating programs include NCI TARGET (n ~ 270), International Cancer Genome Consortium (ICGC, n ~ 250) and Children’s Brain Tumor Tissue Consortium (CBTTC, n ~ 790). As comparator, we analyzed 7 adult cancer types as well as data from constitutive mismatch repair deficiency (CMMRD) consortium. We devised a simple and reliable index to estimate immune diversity. We used CIBERSORT tool to infer immune fraction of TME and investigated immune-related gene expression. In partnership with Gabriela Miller’s Kids First Data Resource Centre, analyses were performed on CAVATICA computational platform. Results: While median number of RNAseq reads were comparable across TARGET, CBTTC and TCGA datasets (~ 67-90 million reads), ICGC dataset contained a median of ~ 208 million reads. However, number of reads mapped to immune loci were comparable across all datasets and appeared to be confounded by infiltration extent rather than technical discordance. Our preliminary results indicate Neuroblastoma harbored the highest median of inferred diversity across pediatric cancers (TRβ=59.38). Inferred immune content indicated a range of infiltration from 0.59 in Teratoma/Germinoma to 0.15 in Medulloblastoma. Immune checkpoint gene expression across pediatric cancers show overall downward trend compared to adult counterparts. Conclusions: Our comprehensive study will serve as a common ground for researchers to delineate immune component of pediatric tumor microenvironment. Covered in this study are common solid tumors as well as rare malignancies, characterization of which will aid rational design of immunotherapy-related clinical trials of pediatric cancers. Note: This abstract was not presented at the meeting. Citation Format: Arash Nabbi, Natalie Jäger, Sumedha Sudhaman, Pengbo Sun, S. Y. Cindy Yang, Kelsey Zhu, Marcel Kool, Komal Rathi, Karthik Kalletla, Pichai Raman, Yuankun Zhu, Joseph N. Paulson, David T. Jones, Uri Tabori, Adam C. Resnick, Stefan M. Pfister, Trevor J. Pugh. Landscape of infiltrating immune repertoire in pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2891.

Methotrexate Disposition in Pediatric Patients with Acute Lymphoblastic Leukemia: What Have We Learnt From the Genetic Variants of Drug Transporters.

Methotrexate (MTX) is one of the leading chemotherapeutic agents with the bestdemonstrated efficacies against childhood acute lymphoblastic leukemia (ALL). Due to the narrow therapeutic range, significant inter- and intra-patient variabilities of MTX, non-effectiveness and/or toxicity occur abruptly to cause chemotherapeutic interruption or discontinuation. The relationship between clinical outcome and the systemic concentration of MTX has been well established, making the monitoring of plasma MTX levels critical in the treatment of ALL. Besides metabolizing enzymes, multiple transporters are also involved in determining the intracellular drug levels. In this mini-review, we focused on the genetic polymorphisms of MTX-disposition related transporters and the potential association between the discussed genetic variants and MTX pharmacokinetics, efficacy, and toxicity in the context of MTX treatment. We searched PubMed for citations published in English using the terms "methotrexate", "transporter", "acute lymphoblastic leukemia", "polymorphisms", and "therapeutic drug monitoring". The retrieval papers were critically reviewed and summarized according to the aims of this mini-review. Solute carrier (SLC) transporters (SLC19A1, SLCO1A2, SLCO1B1, and SLC22A8) and ATP-binding cassette (ABC) transporters (ABCB1, ABCC2, ABCC3, ABCC4, ABCC5, and ABCG2) mediate MTX disposition. Of note, the influences of polymorphisms of SLC19A1, SLCO1B1 and ABCB1 genes on the clinical outcome of MTX have been extensively studied. Overall, the data critically reviewed in this mini-review article confirmed that polymorphisms in the genes encoding SLC and ABC transporters confer higher sensitivity to altered plasma levels, MTX-induced toxicity, and therapeutic response in pediatric patients with ALL. Pre-emptive determination may be helpful in individualizing treatment.