Peripheral White Blood Cell Count Research Articles

The Febrile Infant: Where Art Meets Science to Prevent Harm.

1. Mobeen H. Rathore, MD, CPE* 1. *Editorial Board Member, Pediatrics in Review > With a nod (tongue in cheek) to the author’s previously published title (1) > One consistent thought continues to hold true when it comes to assessing the febrile infant. Be suspicious. > > —JZ, HDA Perhaps Dr Arnold Smith put it most eloquently: “Sorting out the child at risk, from those with illness that is not a threat to their health, is a fundamental goal of pediatrics” (Fig 1). (2) What Dr Smith wrote 40 years ago is true even today. Fever continues to be one of the most common ailments in children. Although fever is a friend of the patient, infection is a foe. Identifying the foe is a complicated task for the evaluating physician. This is even more challenging in infants and especially neonates because of less-than-optimal history, mostly unreliable examination, and more specific signs of infection in the neonates often appearing later in the disease course. Even a thorough laboratory evaluation is not always helpful. Ultimately it is the selection of optimum broad spectrum empirical antibiotic drug therapy that is really the most important decision to protect neonates from the serious morbidity and mortality of neonatal sepsis. Fortunately, most infections in children, including in neonates, are viral and self-limited, causing no serious morbidity. Unfortunately, rarely, bacterial infections can be serious and sometimes life-threatening. Herein lies the challenge even for the most experienced and knowledgeable …

Association between serum ferritin and the severity of drug eruptions.

BackgroundEarly recognition and treatment for severe drug eruption are important in improving clinical outcomes. A few studies have reported laboratory parameters to evaluate the severity of drug eruptions. This study aimed to determine the association between serum ferritin and the severity of drug eruptions.MethodsWe retrospectively reviewed patients diagnosed with drug eruptions in our hospital from 2013 to 2018.ResultsWe identified 85 patients (mean age 53.4 years), 20 in the severe cutaneous adverse drug reactions (SCADRs) group and 65 in the non‐SCADRs group. Serum ferritin level was higher in the SCADRs group compared with that in the CADRs group (P<.001). Serum ferritin was positively associated with peripheral white blood cell count, aspartate aminotransferase level, alanine aminotransferase level, blood glucose level, blood creatinine level, and body temperature. Receiver operating characteristic (ROC) analysis revealed a good diagnostic value of ferritin (area under the curve [AUC]:0.87, 95% confidence interval [CI]:0.78‐0.96) with a sensitivity of 80% and a specificity of 87.7% at a cutoff value of 416.15 ng/mL.ConclusionsSerum ferritin is significantly associated with the severity of CADRs and hence might be potentially used to evaluate the severity of CADRs.

Peripheral white blood cell count as a screening tool for ventriculostomy-related infections

One of the most common complications following external ventricular drain (EVD) placement is infection. Routine cultures of cerebrospinal fluid (CSF) are often used to screen for infection, however several days may pass before infection is discovered. In this study, we compared the predictive value of daily recorded vital sign parameters and peripheral white blood count (WBC) in identifying ventriculostomy-related infections. Patients with EVDs who had CSF cultures for microorganisms performed between January 2011 and July 2017 were assigned to either an infected and/or uninfected study group. Clinical parameters were then compared using t-test, chi squared and multiple logistic regression analyses. Patients of any age and gender were included. One hundred seventy uninfected and 10 infected subjects were included in the study. Nine of the 10 infected patients had an elevated WBC (>10.4 × 103/μL), with a significantly greater WBC (15.9 × 103/μL) than the uninfected group (10.4 × 103/μL) (p-value ≤ 0.0001). Using logistic regression, we found no association between patient vital signs and CSF infection except for WBC (p = .003). As a diagnostic marker for CSF infection, the sensitivity and specificity of WBC elevation greater than 15 × 103/μL was 70% (7/10) and 90.2% (147/163), respectively. This study serves as a ‘proof of concept’ that WBC could be useful as potential screening tool for early detection of CSF infection post-EVD placement. Future investigation using a large, multicenter prospective study is needed to further assess the applicability of this parameter.

Prognostic significance of the PANK family expression in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a highly heterogenous hematological malignancy and its prognostication depends on the genetic mutation and expression profile of each patient. Pantothenate kinase (PANK) is a regulatory enzyme that controls coenzyme A (CoA) biosynthesis. It has four isoforms encoded by PANK1-4, respectively. Whether the expression of the PANK family has prognostic significance in AML remains unclear. We screened The Cancer Genome Atlas database for AML patients with complete PANK1-4 expression data. Eighty-four AML patients met the criteria and were included in this study. Clinical characteristics at diagnosis, including peripheral blood (PB) white blood cell counts (WBC), blast percentages in PB and bone marrow (BM), French-American-British (FAB) subtypes and the frequencies of common genetic mutations were described. Survival was estimated using the Kaplan-Meier method and the log-rank test. Multivariate Cox proportional hazard models were constructed for event-free survival (EFS) and overall survival (OS), using a limited backward elimination procedure. Patients with high PANK2 expression had significantly longer event-free survival (EFS) and overall survival (OS) than patients with low PANK2 expression (P=0.007, P=0.016, respectively), whereas patients with high PANK4 expression had shorter EFS and OS than patients with low PANK4 expression (P=0.022, P=0.015, respectively). Multivariate analysis confirmed that high PANK4 expression was an independent risk factor for EFS and OS (both P<0.05). Our study suggested that high PANK2 expression might have favorable effects on AML, while high PANK4 expression was indicative of poor prognosis.

A Mixture of Functional Complex Extracts from Lycium barbarum and Grape Seed Enhances Immunity Synergistically In Vitro and In Vivo

A mixture of multiple ingredients is often more effective than the individual ingredients. The functions of Lycium barbarum polysaccharide (LBP) glycoconjugate and grape seed procyanidins (GSP) are widely known. Here, we investigated the synergistic immune-enhancing activity of LBP and GSP. Atomic force microscopy results suggested that the mixture of LBP and GSP exhibited circular structure unlike LBP alone, and the addition of polyphenols may change the spatial conformation of the sugar chain. The changes in the structure were related to the synergistic effect of the two functional agents on immune recovery. In vitro, the proliferation rate of splenocytes was higher in LBP + GSP group (64.16%), rather than the sum of LBP group (13.01%) and GSP group (43.61%) individually used. This synergistical proliferation of splenocytes may be correlated to the increasing intracellular free calcium levels. Furthermore, the mixture significantly enhanced the immunity in vivo, as evident from the recovery of peripheral white blood cell counts in LBP + GSP group (18.535 × 109 /L) to normal group levels (18.115 × 109 /L) and higher B cell proliferation than normal group (P < 0.05). These results highlight the immune-enhancing activity of the combination of LBP and GSP associated with the structural changes, which may facilitate the development of functional foods with fewer resources but enhanced activities. PRACTICAL APPLICATION: The synergistic effects of LBP and GSP on immunomodulatory were better than the sum of the effects of the individual agents both in vitro and in vivo. Our results may provide a research-based support for the development of related functional products and an insight into the production of food resources with a fewer but more effective functional agents for better results.

A multicentric clinical study on clinical characteristics and drug sensitivity of children with pneumococcal meningitis in China

Objective: To understand clinical characteristics of children with pneumococcal meningitis (PM) in China and to analyze the drug sensitivity of Streptococcus pneumoniae isolates and associated impacts on death and sequelae. Methods: The clinical data, follow-up results and antimicrobial sensitivity of isolated strains of 155 children (including 98 males and 57 females, age ranged from 2 months to 15 years) with PM in 10 tertiary-grade A class hospitals of Infectious Diseases Surveillance of Pediatrics (ISPED) from 2013 to 2017 were collected and analyzed retrospectively. Patients were divided into different groups according to the following standards: ≤1 year old group,>1-3 years old group and >3 years old group according to age; death group and non-death group according to the death within 30 days after PM diagnosis; complication group and non-complication group according to the abnormal cranial imaging diagnosis; sequelae group and no-sequelae group according to the follow-up results. Bonfereoni chi-square segmentation and Kruskal-Wallis H test were used for statistical analysis. Results: There were 64 cases (41.3%) in the ≤1 year old group, 39 cases in the >1-3 years old group (25.2%), and 52 cases (33.5%) in the >3 years old group. The most common clinical manifestation was fever (151 cases, 97.4%). The mortality was 16.8% (26/155) during hospitalization. The neurological complication rate was 49.7% (77/155) during hospitalization, including the most common complication, subdural effusion and (or) empyema in 50 cases (32.3%) and hearing impairment in 6 cases. During follow-up after discharge, no death was found and focal neurological deficits were found in 47 cases (30.3%), including the frequent neurological sequelae: cognitive and mental retardation of different degree in 22 cases and hearing impairment in 14 cases (9.0%). The rate of cure and improvement on discharge was 74.8% (116/155) and the lost to follow-up rate was 8.4% (13/155). The proportions of died cases, neurological complications during hospitalization and proportions of peripheral white blood cell count <12 × 10(9)/L before admission in ≤1 year old group were significantly higher than those in >3 years old group (25.0% (16/64) vs. 5.8% (3/52), 75.0% (48/64) vs. 25.0% (13/52), 48.4% (31/64) vs. 15.4% (8/52), χ(2)=7.747, 28.767, 14.044; P=0.005, 0.000, 0.000). The proportions of headache, vomiting, neck resistance and high risk factors of purulent meningitis in >3 years old group were significantly higher than those in ≤ 1 year old group (67.3%(35/52) vs. 1.6%(1/64), 80.8% (42/52) vs. 48.4% (31/64), 69.2% (36/52) vs. 37.5% (24/64), 55.8% (29/52) vs. 14.1%(9/64), χ(2)=57.940, 12.856, 11.568, 22.656; P=0.000, 0.000, 0.001, 0.000). Streptococcus pneumoniae isolates were completely sensitive to vancomycin (100.0%, 152/152), linezolid (100.0%, 126/126), moxifloxacin (100.0%, 93/93) and ofloxacin (100.0%,41/41); highly sensitive to levofloxacin (99.3%, 142/143) and ertapenem (84.6%, 66/78); moderately sensitive to ceftriaxone (48.4%, 45/93), cefotaxime (40.0%, 44/110) and meropenem (38.0%, 38/100); less sensitive to penicillin (19.6%, 27/138) and erythromycin (4.2%, 5/120). The proportions of non-sensitive strains of penicillin (21/21) and meropenem (17/18) in the death group were significantly higher than those (90/117, 45/82) in the survived group(χ(2)=4.648 and 9.808, P=0.031 and 0.002). Conclusions: The children's PM is mainly found in infants under 3 years old in China. Death and neurological complications are more common in PM children under 1 year old. The clinical manifestations and peripheral blood inflammatory markers of PM patients under 1 year old are not typical. Fever is the most common clinical manifestation and subdural effusion and (or) empyema is the most common complication. Long-term hearing impairment is common in PM and the follow-up time must be prolonged. The dead PM cases had high in sensitive rates to penicillin and meropenem.

High Concentration of C-Reactive Protein Is Associated With Serious Bacterial Infection in Previously Healthy Children Aged 3 to 36 Months With Fever and Extreme Leukocytosis

The aim of the study was to investigate the diagnostic efficacy of C-reactive protein (CRP) in predicting serious bacterial infection (SBI) in febrile children aged 3 to 36 months with extreme leukocytosis (EL), defined as a peripheral white blood cell count of 25,000 to 49,999/mm. The presence of SBI was reviewed in previously healthy children aged 3 to 36 months with a fever of 39°C or higher and EL, who visited a tertiary care hospital emergency department between September 2010 and August 2015. We measured cutoff values of CRP with corresponding likelihood ratios (LRs) and posttest probabilities (PPs). Of 9989 febrile children, 4252 (42.6%) underwent assays for white blood cell and CRP. Of 233 (5.5%) children with EL, 133 (3.1%) were enrolled, of whom 43 (32.3%; 95% confidence interval [CI], 25.0%-40.7%) had SBI, including 33 pyelonephritis, 5 deep abscesses, 3 lobar pneumonia, and 2 soft tissue infections. With the cutoff of 7.8 mg/dL, the sensitivity of CRP in predicting SBI was 81.4% (95% CI, 67.4%-90.3%); the specificity, 80.0% (95% CI, 70.6%-87.0%); the positive predictive value, 66.0% (95% CI, 52.6%-77.3%); the negative predictive value, 90.0% (95% CI, 81.5%-94.9%); the positive LR, 4.1; and the PP, 66.0% (95% CI, 55.6%-75.0%). A CRP concentration of 16.1 mg/dL or higher yielded an LR of 11.2 and a PP of 84.2% (95% CI, 62.1%-94.5%). A CRP concentration of lower than 3.4 mg/dL yielded an LR of 0.05 and a PP of 2.4% (95% CI, 0.3%-14.6%). High concentration of CRP is strongly associated with the presence of SBI in febrile children with EL.

Sépsis neonatal tardia a streptococcus do Grupo A: um agente improvável

Neonatal sepsis due to group A Streptococcus is rare and has a high associated mortality. The case of a 14-day-old female neonate who presented to the Emergency Department with feed refusal and hyporeactivity is reported. The girl was born at 36 weeks of gestation and had an unremarkable pregnancy and birth. Peripheral white blood cell count was 18.100/mm3 with 81% neutrophils, and C-reactive protein was 13.6 mg/dL. Urinalysis, cerebrospinal fluid cytochemical examination, and chest X-ray were normal. A multisensitive group A Streptococcus was isolated in the blood culture and ten-day course of ampicillin was completed. Urine and cerebrospinal fluid cultures were negative. All co-inhabitants were tested for the presence of group A Streptococcus antigen in the oropharynx, which was positive in a two-year-old cousin. Group A Streptococcus is an uncommon neonatal sepsis agent. Transmission in the community through a carrier should be considered. This case highlights the importance of infection preventive measures for the newborn at home.

Platelet and peripheral white blood cell counts at diagnosis predict the response of adult immune thrombocytopenia to recombinant human interleukin-11: A retrospective, single-center, case-control study.

This study evaluated the effectiveness of recombinant human interleukin-11 (rhIL-11) in the treatment of immune thrombocytopenia (ITP) and determined whether clinical and laboratory findings predicted the treatment response.This retrospective, single-center, case–control study included 103 adult patients with ITP treated between July 2010 and April 2014 at Jiangxi Province People's Hospital. About 49 patients in the pred+IL group received prednisone (conventional dose) combined with an rhIL-11 regimen, and 54 patients in the pred alone group received prednisone (conventional dose) alone. Demographic data, initial and follow-up platelet counts, proportions of patients achieving platelet counts ≥30 × 109/L (response) and ≥100 × 109/L (complete response) at different time points, and adverse reactions were compared between groups.Complete response rates were similar between groups overall but higher in the pred+IL group than in the pred alone group for newly diagnosed patients and those with severe ITP (P < .05). Proportions of patients achieving response or complete response at different time points were similar between groups overall but higher in the pred+IL group than in the pred alone group for newly diagnosed patients and those with severe ITP (P < .05). Posttreatment platelet count correlated negatively with platelet count at diagnosis and white blood cell (WBC) count at diagnosis in patients with newly diagnosed ITP (r = −0.337, P = .073 and r = −0.367, P = .050, respectively) or ITP with bleeding-related episodes (r = −0.357, P = .020 and r = −0.434, P = .004, respectively). No immediate or postinfusion severe adverse reactions were observed.rhIL-11 increased CR and improved hemostasis in patients with newly diagnosed or severe ITP. Platelet and WBC counts at diagnosis can predict the response to rhIL-11.

Infectious causes and outcomes in patients presenting with cerebral spinal fluid pleocytosis.

To evaluate the infectious etiologies, clinical features, and outcomes of patients with CNS infections at a tertiary care center. Patients that present with a pleocytosis in the cerebral spinal fluid (CSF), defined as a CSF WBC count > 5cells/mm3, from July 2015 to June 2016 at a tertiary care hospital were analyzed for this report. Data from patients with confirmed (n = 43) and presumed (n = 51) CNS infections were analyzed. CNS infection was the leading known cause of CSF pleocytosis (n = 43, 18% of all patients with a pleocytosis in the CSF), and HSV-2 was identified as the leading causative pathogen (n = 10) followed by varicella zoster virus (n = 5). Fifty-three percent of patients with a pleocytosis in the CSF did not receive a diagnosis. In the patients that did not receive a diagnosis, CNS infection was presumed to be the cause in 51 patients (21% of patients with CSF pleocytosis). The mean time to diagnosis for patients with confirmed CNS infection was 16days, but time to diagnosis was highly variable depending on the causative pathogen. There was a significant overlap in CSF parameters and peripheral white blood cell counts in patients diagnosed with a viral, bacterial, or fungal infection. Neuroimaging changes were present in only 44% of CNS infections. The overall mortality was 7% for CNS infections, and 17% of patients with a CNS infection had a severe neurologic deficit at presentation while only 3% had a severe deficit at the last neurologic assessment. This study provides new insights into the infectious causes of disease in a cohort of patients with pleocytosis in the CSF. The study provides new insights into the time to diagnosis and outcomes in patients that present with pleocytosis in the CSF.

A Clinical Prediction Algorithm to Stratify Pediatric Musculoskeletal Infection by Severity.

There are currently no algorithms for early stratification of pediatric musculoskeletal infection (MSKI) severity that are applicable to all types of tissue involvement. In this study, the authors sought to develop a clinical prediction algorithm that accurately stratifies infection severity based on clinical and laboratory data at presentation to the emergency department. An IRB-approved retrospective review was conducted to identify patients aged 0 to 18 who presented to the pediatric emergency department at a tertiary care children's hospital with concern for acute MSKI over a 5-year period (2008 to 2013). Qualifying records were reviewed to obtain clinical and laboratory data and to classify in-hospital outcomes using a 3-tiered severity stratification system. Ordinal regression was used to estimate risk for each outcome. Candidate predictors included age, temperature, respiratory rate, heart rate, C-reactive protein (CRP), and peripheral white blood cell count. We fit fully specified (all predictors) and reduced models (retaining predictors with a P-value ≤0.2). Discriminatory power of the models was assessed using the concordance (c)-index. Of the 273 identified children, 191 (70%) met inclusion criteria. Median age was 5.8 years. Outcomes included 47 (25%) children with inflammation only, 41 (21%) with local infection, and 103 (54%) with disseminated infection. Both the full and reduced models accurately demonstrated excellent performance (full model c-index 0.83; 95% confidence interval, 0.79-0.88; reduced model 0.83; 95% confidence interval, 0.78-0.87). Model fit was also similar, indicating preference for the reduced model. Variables in this model included CRP, pulse, temperature, and an interaction term for pulse and temperature. The odds of a more severe outcome increased by 30% for every 10 U increase in CRP. Clinical and laboratory data obtained in the emergency department may be used to accurately differentiate pediatric MSKI severity. The predictive algorithm in this study stratifies pediatric MSKI severity at presentation irrespective of tissue involvement and anatomic diagnosis. Prospective studies are needed to validate model performance and clinical utility. Level II-prognostic study.

Influence of a whole yeast product (Pichia guilliermondii) fed throughout gestation and lactation on performance and immune parameters of the sow and litter.

A study was conducted using 3 groups of gestating gilts and sows (n = 98) to determine the effects of Pichia guilliermondii (Pg), a whole cell-inactivated yeast product (CitriStim; ADM Alliance Nutrition), on performance and immune parameters of dams and litters. Within 24 h of breeding, gilts and sows were allotted to 1 of 3 treatments consisting of a control (SC) diet or SC diet supplemented with 0.1 (S1) or 0.2% (S2) Pg. Dietary treatments were maintained through lactation. Colostrum and milk (day 14) samples were collected for IgA, IgG, and IgM analysis. Blood samples were collected from sows on day 110 of gestation (group 3 only), while at weaning for all 3 groups, and from piglets at 14 d of age for peripheral white blood cell counts and serum IgA, IgG, and IgM analysis. Inclusion of Pg resulted in an increase in number born alive as the level of Pg increased (12.49, 13.33, and 13.43 born alive per litter for SC, S1, and S2, respectively; linear effect [LS], P = 0.003). Additionally, the percentage of piglets weighing less than 0.9 kg at birth was reduced in sows provided Pg at 0.1% or 0.2% compared with control (LS, P = 0.006). Sows receiving Pg during gestation and lactation also weaned a greater number of piglets (10.31, 10.55, and 10.60 weaned per litter in control, 0.1% and 0.2% Pg, respectively; LS, P = 0.02). However, percent preweaning mortality was 17.58%, 19.38%, and 19.61% for control, 0.1%, and 0.2% Pg, respectively (LS, P = 0.02). There were no differences in gestation BW gain, farrowing (days 110 to 48 h postfarrowing) or lactation (day 110 to weaning) BW loss, number of mummies or stillborn, or piglets' individual birth or weaning weight. On day 110 of gestation, the neutrophil concentration (quadratic effect [QS], P = 0.03) and neutrophil:lymphocyte ratio (QS, P = 0.04) in peripheral blood were greater in S1 than SC, with S2 being intermediate. At weaning there was a linear increase in neutrophil concentration (P = 0.03), neutrophil:lymphocyte ratio (P = 0.01), and percentage of neutrophils in the leukocyte population (P = 0.01) as level of Pg increased in sow diets. In conclusion, Pg inclusion in sow diets linearly increased total number born alive and weaned, with no change in average birth or weaning weight, and decreased the number of lightweight pigs at birth. However, inclusion of Pg had no effect on immune parameters measured in milk, colostrum, or day 14 piglet serum, but increased the peripheral blood neutrophil concentration of gilts and sows.

Benzene-induced mouse hematotoxicity is regulated by a protein phosphatase 2A complex that stimulates transcription of cytochrome P4502E1

Chronic benzene exposure is associated with hematotoxicity and the development of aplastic anemia and leukemia. However, the signaling pathways underlying benzene-induced hematotoxicity remain to be defined. Here, we investigated the role of protein phosphatase 2A (PP2A) in the regulation of benzene-induced hematotoxicity in a murine model. Male mice with a hepatocyte-specific homozygous deletion of the Ppp2r1a gene (encoding PP2A Aα subunit) (HO) and matched wildtype (WT) mice were exposed to benzene via inhalation at doses of 1, 10, and 100 ppm for 28 days. Peripheral white blood cell counts and activation of bone marrow progenitors were attenuated in the HO mice, indicating that Ppp2r1a deletion protects against benzene-induced hematotoxicity. Moreover, elevation of urinary S-phenyl mercapturic acid, a benzene metabolite, was much greater in WT mice than in HO mice. Real-time exhalation analysis revealed more exhaled benzene but fewer benzene metabolites in HO mice than in WT mice, possibly because of the down-regulation of Cyp2e1, encoding cytochrome P4502E1, in hepatocytes of the HO mice. Loss-of-function screening disclosed that PP2A complexes containing the B56α subunit participate in regulating Cyp2e1 expression. Notably, PP2A-B56α suppression in HepG2 cells resulted in persistent β-catenin phosphorylation at Ser33-Ser37-Thr41 in response to CYP2E1 agonists. In parallel, nuclear translocation of β-catenin was inhibited, concomitant with a remarkable decrease of Cyp2e1 expression. These findings support the notion that a regulatory cascade comprising PP2A-B56α, β-catenin, and Cyp2e1 is involved in benzene-induced hematotoxicity, providing critical insight into the role of PP2A in responses to the environmental chemicals.

Abstract WP147: Influence of White Blood Cell Count on Outcome for Thrombolysis-Treated Acute Ischemic Stroke ENCHANTED Post HocAnalysis

Background: Increased inflammatory reaction can aggravate brain injury after acute ischemic stroke, but the clinical effect of such response is not fully understood. The aim of this study was to determine associations of peripheral white blood cell (WBC) count on clinical outcome among participants of the ENCHANTED study. Methods: Data are from the Enhanced Control of Hypertension for &lt; and &amp;gt; for &gt; Thrombolysis Stroke Study (ENCHANTED), aninternational, multicenter, randomized controlled trial where patients with acute ischemic stroke were randomized to low-dose (0.6 mg/ kg) or standard-dose (0.9 mg/kg) IV alteplase.Blood samples were collected on admission &amp;lt; for &lt; and &amp;gt; for &gt; WBC count was measured at local laboratories. The primary outcome was death or disability, defined by scores 3–6 on the modified Rankin Scale at 90 days.Secondary outcomes included ordinal mRS shift,fatal intracerebral hemorrhage(ICH) by various standard criteria.Associations of baseline WBC count &amp;lt; for &lt; and &amp;gt; for &gt; outcomes were evaluated in logistic regression models. Results: There were 3179 participants with relevant data who were classified into quartiles of WBC counts (≤ 6.30, 6.31–7.82, 7.83–9.80, &amp;lt; for &lt; and &amp;gt; for &gt; ≥ 9.81х109/L, respectively).Increased WBC count was associated with younger age,elevated NIHSS scores, less antithrombotic used,elevated heart rate,elevated fever treated,stroke severity. Risks of death or major disability at 90 days increased progressively with higher WBC count: frequencies of 30.4%, 34.7%,39.1% &amp;lt; for &lt; and &amp;gt; for &gt; 44.8% for quartile groups, respectively (P &lt;.0001 for trend). After adjustment for baseline clinical &amp;lt; for &lt; and &amp;gt; for &gt; imaging variables including age, sex, body temperature, systolic BP, heart rate, high NIHSS scores, &amp;lt; for &lt; and &amp;gt; for &gt; randomized treatment, the association between WBC count &amp;lt; for &lt; and &amp;gt; for &gt; primary outcome was still significant (P &lt;.0001 for trend). Conclusions: Elevated WBC count on admission may be an independent prognostic predicator in patients with Acute Ischemic Stroke, but this requires further evaluation in a prospective cohort study.

CSF inflammatory markers differ in gram-positive versus gram-negative shunt infections

BackgroundCerebrospinal fluid (CSF) shunt placement is frequently complicated by bacterial infection. Shunt infection diagnosis relies on bacterial culture of CSF which can often produce false-negative results. Negative cultures present a conundrum for physicians as they are left to rely on other CSF indices, which can be unremarkable. New methods are needed to swiftly and accurately diagnose shunt infections. CSF chemokines and cytokines may prove useful as diagnostic biomarkers. The objective of this study was to evaluate the potential of systemic and CSF biomarkers for identification of CSF shunt infection.MethodsWe conducted a retrospective chart review of children with culture-confirmed CSF shunt infection at Children’s Hospital and Medical Center from July 2013 to December 2015. CSF cytokine analysis was performed for those patients with CSF in frozen storage from the same sample that was used for diagnostic culture.ResultsA total of 12 infections were included in this study. Patients with shunt infection had a median C-reactive protein (CRP) of 18.25 mg/dL. Median peripheral white blood cell count was 15.53 × 103 cells/mL. Those with shunt infection had a median CSF WBC of 332 cells/mL, median CSF protein level of 406 mg/dL, and median CSF glucose of 35.5 mg/dL. An interesting trend was observed with gram-positive infections having higher levels of the anti-inflammatory cytokine interleukin (IL)-10 as well as IL-17A and vascular endothelial growth factor (VEGF) compared to gram-negative infections, although these differences did not reach statistical significance. Conversely, gram-negative infections displayed higher levels of the pro-inflammatory cytokines IL-1β, fractalkine (CX3CL1), chemokine ligand 2 (CCL2), and chemokine ligand 3 (CCL3), although again these were not significantly different. CSF from gram-positive and gram-negative shunt infections had similar levels of interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α), IL-6, and IL-8.ConclusionsThis pilot study is the first to characterize the CSF cytokine profile in patients with CSF shunt infection and supports the distinction of chemokine and cytokine profiles between gram-negative and gram-positive infections. Additionally, it demonstrates the potential of CSF chemokines and cytokines as biomarkers for the diagnosis of shunt infection.

Myeloid neoplasms with eosinophilia and abnormal PDGFRA/B: report of three cases and review of literature

Objective To investigate clinical and hematological features of myeloid neoplasms with eosinophilia and abnormal PDGFRA/B and the effect of imatinib. Methods The data of three eosinophilia patients with abnormal PDGFRA/B fusion gene in Changhai Hospital, the Second Military Medical University and 22 Chinese cases reported in Chinese medical journals were analyzed. Thirty-one cases of idiopathic hypereosinophilic syndrome from Changhai Hospital, the Second Military Medical University were used as the controls. Results Compared with idiopathic hypereosinophilic syndrome, no differences were found in age, percentage of bone marrow eosinophils and counts of platelets in peripheral blood in myeloid neoplasms with eosinophilia and abnormal PDGFRA/B (all P > 0.05), but statistical differences were found in gender (χ 2= 5.080, P= 0.016), peripheral blood white blood cell count (t= 4.908, P= 0.001), eosinophilic granulocyte absolute value (χ 2= 17.230, P= 0.001) and hemoglobin concentration (t= 2.770, P= 0.013). The median follow-up time was 17 months (3-108 months) in 24 myeloid neoplasms patients with eosinophilia and abnormal PDGFRA/B from Chinese report. Complete hematopoietic remission (CHR) rate was 91.7% (22/24) after the treatment of imatinib. The total complete molecular remission (CMR) rate was 75.0% (18/24). The median time of remission was 3 months (1-8 months). CMR in patients with PDGFRA and with PDGFRB was 76.5% (13/17) and 85.7% (6/7), respectively. Only one patient (4.2%) died of disease relapse. Conclusion Imatinib has a favorable effect on myeloid neoplasms with eosinophilia and abnormal PDGFRA/B featured by distinct hematologic and clinical manifestations. Key words: Eosinophilia; Gene fusion; Myeloid neoplasms; Remission

Comparision of the Clinical and Prognostic Characteristic in Adult and Pediatric AML1/ETO-Positive Acute Myeloid Leukemia

AML1/ETO-positive acute myeloid leukemia (AML) is a heterogeneous malignancy. Up until now, the difference between adult (>14-year old) and pediatric (≤14-year old) AML1/ETO+ AML remains unclear. In this retrospective multi-center study we analyzed 173 AML1/ETO+ AML patients including 98 adults and 75 kids, and found that AML-M2 phenotype was the most common morphology, especially higher in adult patients with an incidence of 92.9%, as compared with 82.7% (P=0.005) in pediatric patients. Furthermore, higher incidence of extramedulary leukemia (29.6% vs. 13.3%, P=0.001) and C-KIT mutation (21/67, 31.3% vs. 12/66, 18.2%, P=0.079) were observed in adult patients than pediatric patients. No significant difference in gender ratio, peripheral white blood cells count, immunology and cytogenetic abnormality including affiliated cytogenetic abnormalities and lose of sex chromosmoe between the two age groups. Among adult patients, idarubicin combined with cytarabine (IA) or daunorubicin combined with cytarabine (DA) was the major induction regimens, while FLAG (fludalabin,cytarabine and G-CSF) combined with idarubicin or DA combined with etoposid (DAE) was the main regimens in pediatric patients for one to two cycles. Not only the first-cycle complete remission (CR) rate (69/74, 93.2% vs. 56/95, 58.9%, P <0.001), but also the second-course cumulative CR rate (73/74, 98.6% vs. 82/95, 86.3%, P=0.004) in pediatric patients was much better than that in adult patients. After obtaining CR, standard dose cytarabine (SDAC)-based or medium dose cytarabine (MDAC)-based regimens were given to the adult patients as the major consolidation regimens, while pediatric patients received MDAC or homoharringtonine combined with cytarabine and etoposid (HAE). With a median of 23.5(2-126) months follow-up, cumulatively 35/87(40.2%) patients relapsed and 39/98(39.8%) cases died in adult group, which were much higher than that in pediatric patients, with the cumulative incidence of recurrence of 18/74(24.3%) (P=0.032) and cumulative death rate of 13/75(17.3%) (P=0.001). Survival analysis showed that EML [RFS: HR 3.20(1.63-6.28), P=0.001; OS: HR 2.92(1.55-5.51), P=0.001] and C-KIT mutation [RFS: HR 3.17(1.47-6.93), P=0.003; OS: HR 2.24(1.03-4.86), P=0.041] were the adverse factors for relapse free survival (RFS) and overall survival (OS). Nevertheless, neither these two factor were negative for the survival of pediatric patients. Taking together, significant difference in bone marrow morphology, incidence of EML and C-KIT mutation, also prognostic factors were observed between the adult and pediatric AML1/ETO+ AML patients. Intensive induction might be a main reason for higher CR rate and better survival in pediatric patients. DisclosuresNo relevant conflicts of interest to declare.

Augmentation of the Acute Myeloid Leukemia-Composite Model (AML-CM) with Performance Status and Secondary Leukemia

Background:To help optimize decision-making for acute myeloid leukemia (AML) treatment in the clinic, risk models comprising different variables were developed. A Treatment-Related Mortality (TRM) model was developed to predict 28-day mortality. The TRM model includes age, performance status, platelet count, albumin, secondary AML, peripheral white blood cell count, peripheral blood blast percentage, and creatinine (Walter et al, 2011 Nov 20; 29(33): 4417-4424). More recently, an AML-specific composite model (AML-CM) introduced the combination of cytogenetic/molecular risks per European Leukemia Network (ELN) classification with burdens of increasing age and comorbidities. The AML-CM can predict both early and late mortality after diagnosis of AML (Sorror et al, 2017; 3(12):1675-1682). All factors within the TRM model were tested during the development of the AML-CM, except for the impacts of Karnofsky Performance Status (KPS), and presence of secondary AML. To this end, we explored the possibility of augmenting the AML-CM by testing the prognostic value added by including KPS and presence of secondary AML.Methods:The study comprises two cohorts from two different institutions: 311 patients (pts) to be used for development of new scores and 187 pts to be used for independent validation. Both cohorts were seen for initial therapy for AML between 2008 and 2017. We collected patients' demographics and comorbidity information through patient charts. We defined secondary AML as an occurrence of AML after a previous malignancy or after hematological abnormalities for at least one month. Afterwards, Cox regression models were designed to test whether KPS and secondary AML have independent prognostic impacts that could be added to the AML-CM. Prediction of eight-week and one-year mortality were compared between the original versus augmented AML-CM using c-statistics and area under the curve (AUC) of the receiver-operator characteristic curve (ROC) in the independent validation cohort from the different institution.Results:In a multivariate model, after adjusting for AML-CM variables, both secondary AML (hazard ratio [HR] =2.19, p=0.0001) and worse KPS percentages (KPS 80-75%: HR=1.53, p=0.06; KPS ≤70%: HR=2.60, p=0.0001) were significantly associated with one-year mortality. Using the same equation used in the development of the AML-CM, we assigned 1 point to KPS 80-75%, 2 points to KPS ≤70% and 2 points to secondary AML. These points were added to those of age, comorbidities and ELN risks in order to calculate the augmented AML-CM scores.In the validation set, the augmented AML-CM had a c-statistic estimate of 0.71 vs. 0.69 for the original AML-CM. The true AUC for prediction of 1-year mortality was 0.75 vs. 0.72 while the AUC for prediction of 8-week mortality was 0.83 vs. 0.79 for the augmented AML-CM and original AML-CM, respectively.Figure 1 shows the discrimination of four risk groups per the new augmented AML-CM scores. Patients with scores of 1-3, 4-6, 7-9, and ≥10 had 1-year survival rates of 91%, 76%, 46% and 37%, respectively.Conclusions:In this study we found that worse KPS percentages add prognostic value to those of age and comorbidities, while secondary AML adds prognostic value to that of ELN cytogenetic/molecular risks for prediction of early (8-week) and late (1-year) mortality after diagnosis of AML. This suggests that KPS provides prognostic information above what is provided by age and comorbidities alone. Similarly, the classification of a patient's AML as secondary AML provides prognostic information beyond what is understood about the patient's disease risk as indicated by the ELN cytogenetic/molecular risk category.Combining these five factors: age, comorbidity burden, performance status, disease risk, and presence of secondary AML results in an augmented AML-CM that can be used in the clinic for improved risk-assessment before treatment decisions. [Display omitted] DisclosuresBecker:GlycoMimetics: Research Funding.

Zoledronic Acid Reduces Osteonecrosis and Anti-Leukemic Efficacy in Murine Models of Acute Lymphoblastic Leukemia Therapy

Background: Osteonecrosis and osteopenia frequently complicate acute lymphoblastic leukemia (ALL) therapy. Interventions which reduce these bony toxicities without impairing the anti-leukemic efficacy of therapy are lacking. Case reports suggest that bisphosphonates may reduce the pain associated with osteonecrosis; however, it is unclear if they are effective in preventing or reducing the progression of osteonecrosis or modifying bone density loss during therapy. Their impact on the anti-leukemic efficacy of therapy is also unknown.Methods: We tested the efficacy of the bisphosphonate zoledronic acid (ZA) in the murine model of osteonecrosis. Four-week-old Balb/c mice were treated with dexamethasone (2mg/L in drinking water) and PEGylated-asparaginase [1200IU/kg intraperitoneal (IP) weekly] for 6 weeks. To test whether ZA could prevent osteonecrosis, mice received ZA 100ug/kg IP weekly starting with therapy initiation (early zoledronic acid group, receiving 6 total doses). To test whether ZA could prevent the progression of osteonecrosis, ZA administration was delayed until the fourth week of therapy (late zoledronic acid group, receiving 2 total doses) after osteonecrosis processes have already begun. All mice were humanly euthanized at 10 weeks post-natal. At the end of the 6 week therapy, osteonecrosis was assessed histologically at the distal femur, while bone density and quality measurements were obtained from the proximal tibia using the Siemeons Inveon uCT system.To test the impact of zoledronic acid on the anti-leukemic efficacy of therapy, nine-week-old B6 mice were injected with 2000 Arf-/- Bcr/Abl+ syngeneic acute lymphoblastic leukemia cells. Mice received three weeks of therapy identical to the osteonecrosis studies (including zoledronic acid randomization), except dexamethasone was increased to 4mg/L in the drinking water. Mice were sacrificed when moribund and leukemia as cause of death was confirmed by peripheral white blood cell count and spleen weight.Results: Osteonecrosis was reduced in the early zoledronic acid group compared to the control group (12/69 limbs vs. 25/72 limbs, p=0.03). The incidence of osteonecrosis in the late zoledronic acid group (19/56 limbs) was identical to that in the control group (p=1). Both zoledronic acid interventions increased the cortical thickness of the tibia [median 0.12mm in therapy treated controls; 0.18mm in early zoledronic acid group (p=<0.001 vs. control); 0.15mm in late zoledronic acid group (p=<0.001 vs. control)]. Thinner cortical wall thickness was associated with an increased risk of osteonecrosis in univariate analysis (p=0.03) but not in multivariate analysis including treatment arm (p=0.32). Epiphyseal arteriopathy, the preceding vascular lesion in osteonecrosis, was less common in early zoledronic acid mice vs. controls (15/60 vs. 28/51, p=0.002). Late zoledronic acid administration resulted in a similar rate of arteriopathy (22/47) compared to controls (p=0.55). There was no difference in the incidence of asparaginase plasma concentrations <1u/mL (p=0.25) or in plasma dexamethasone levels (p=0.67) in mice receiving ZA vs. control treated mice.Because early zoledronic acid administration reduced the rate of osteonecrosis and improved bone density, we tested its effect on the anti-leukemic efficacy of therapy. Mice that received zoledronic acid and chemotherapy had a shorter survival than mice receiving chemotherapy alone (mean 36 vs. 41.6 days, log-rank p=0.046, Figure 1).Conclusion: Zoledronic acid administration early in acute lymphoblastic leukemia therapy reduces osteonecrosis and osteopenia. Zoledronic acid is ineffective in reducing osteonecrosis when given later in therapy. However, the use of zoledronic acid impairs the combined anti-leukemic efficacy of dexamethasone and asparaginase. Further studies are underway to understand this relationship. [Display omitted] DisclosuresRelling:Shire Pharmaceuticals: Research Funding.

KMT2D Is a Haploinsufficient Tumor Suppressor in Acute Leukemia

Introduction: Epigenetic dysregulation plays a critical role in hematologic tumorigenesis and cancer progression. Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 (mixed-lineage leukemia 4), belongs to a family of mammalian histone H3 lysine 4 (H3K4) methyltransferases, which is amongst the most frequently mutated epigenetic genes in human cancers. It was reported that deletion of KMT2D inhibits MLL1-fusion-induced acute myeloid leukemia (Santos et al. 2014). However, in human cancers, the vast majority of the mutations in KMT2D is heterozygous deletion. Recent studies have revealed the role of KMT2D in lymphomagenesis, but the potential tumor suppressor function of KMT2D in leukemogenesis remains largely unclear. In addition, KMT2D was found to exist within a macromolecular complex named COMPASS (complex of proteins associated with Set1). KMT2C is another component of the complex, and was validated as another haploinsufficient tumor suppressor gene in acute myeloid leukemia (Chen et al. 2014). Mutations in KMT2D and KMT2C frequently co-occur in hematologic malignancies. Thus, we sought to first examine the role and molecular mechanism of KMT2D in acute leukemia, and then investigate whether co-mutated gene KMT2D and KMT2C have cooperative function in malignancies initiation and progression.Methods: Here we utilized RNAi approach to knockdown the expression of Kmt2d, and an approximate 50% reduction in gene dosage was validated by quantitative RT-PCR. We introduced two independent short-hairpin RNAs (shRNAs) targeting Kmt2d and a shRNA targeting Nf1 into p53 null hematopoietic stem and progenitor cells (hereafter referred to as shKmt2d;shNf1;p53-/- cells), and transplanted them into sublethally irradiated mice to model the impact of haploinsufficient tumor suppressors. The recipient mice were then monitored for the emergence of diseases by complete blood count as well as overall survival. Bone marrow was harvested and analyzed by flow cytometry after sacrifice. Histological analyses of blood smear, liver, spleen and bone marrow were conducted to accurately diagnose the disease. Besides, we established Kmt2d heterozygous and homozygous conditional knockout mouse models (Kmt2d fl/+; Mx1-Cre, Kmt2d fl/fl; Mx1-Cre) to further investigate the respective role of haploinsufficiency and deletion of KMT2D in acute leukemia. To study the cooperative function of KMT2D and KMT2C in leukemogenesis, two genes were co-suppressed by shRNAs in the same aforementioned genetic background (shNf1; p53-/-). Transplantation-based mouse modeling approach was used and the recipient mice were monitored for evidence of hematologic diseases.Results: A significant increase in peripheral white blood cell counts, anemia and thrombocytopenia were noticed in recipients of shKmt2d;shNf1;p53-/- cells over the same period after 4 weeks post-transplantation. Massive hepatomegaly and splenomegaly were displayed in those mice and a dramatic reduction in survival was observed (shKmt2d-1: median survival = 47 days, p = 0.0004 versus shRen; and shKmt2d-2: median survival = 74 days, p = 0.0127 versus shRen). Flow cytometry of cells from bone marrow of sacrificed mice showed a substantial enrichment of doule-positve cells (shRNAs targeting Kmt2d were linked to GFP and those targeting Nf1 were linked to mCherry) as compared to pre-injected, which were filled with leukemic cells that expressed myeloid/lymphoid lineage markers. Pathological analyses demonstrated the onset of acute myeloid/lymphoid leukemia. In Kmt2d and Kmt2c double-knockdown animal assay, the onset of acute myeloid leukemia was promoted compared with single-knockdown groups. (shKmt2d;shKmt2c: median survival = 48.5 days, p < 0.0001 versus shKmt2d; p = 0.0013 versus shKmt2c).Conclusions: KMT2D is a haploinsufficient tumor suppressor in acute leukemia. KMT2D deficiency cooperates with KMT2C to promote the development and progress of acute leukemia. Further understandings of the molecular mechanism of KMT2D as a haploinsufficient tumor suppressor in acute leukemia and the cooperative function of KMT2D and KMT2C in leukemogenesis are demanded, which can provide insights into developing novel therapeutic targets. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.