Febrile Controls Research Articles

Suppressed plasmablast responses in febrile infants, including children with Kawasaki disease.

Abstract Kawasaki disease (KD), the leading cause of acquired heart disease in children, primarily affects infants and toddlers. Future studies on KD immune responses are hampered by a limited understanding of normal immune responses in these ages. Plasmablasts are a transitional form of B cells that lead to long-term plasma cells, and their levels rise in the peripheral blood after exposure to a foreign antigen. In adults, these responses are both temporally and functionally well characterized. To date, there have been few studies on plasmablasts in the predominant age range of KD. This study is focused on characterizing the normal plasmablast responses in the predominant age range of KD presentation. Children presenting to an urban pediatric emergency room who had fever and symptoms overlapping those of KD, were recruited. Peripheral blood mononuclear cells were isolated and evaluated utilizing flow cytometry with specific B cell markers from 18 KD subjects and 69 febrile controls. Plasmablast numbers and timing of response are similar between infectious disease control and KD subjects. In both groups, infants have diminished plasmablast responses compared to older children. Using deep sequencing, immunoglobluin variable gene usage and sequences will be compared between infants and older children. In this single-time point survey, we demonstrate that infants have a blunted peripheral plasmablast response. Overall, similar plasmablast responses in KD and controls support an infectious disease relationship to KD. Future time-course studies of plasmablasts in infants are warranted as this phenomenon may contribute to observed poor serum immune responses and maintenance of such responses in this age group.

English

The aim of the present study was to assess the antipyretic activity of the macrolide antibiotic, tilmicosin, at dose levels of 20 and 40 mg/kg of body weight, subcutaneously, in Brewer's yeast-induced fever model in mice. Pyrexia was induced by subcutaneous injection of 20 mL/kg of 20% (w/v) Brewer’s yeast suspension into the animal’s scruff region. Eighteen hours later, feverish animals were treated with either tilmicosin or acetylsalicylic acid (200 mg/kg injectable solution, subcutaneously) or vehicle; and rectal temperatures were evaluated at 1, 2, 3, 4 and 5 h post-treatment using digital thermometers. Tilmicosin showed dose-dependent significant decrease in the elevated body temperature of mice that remained sustained throughout the tested time points from 1 to 5 h in the used model. Both small and large dose levels showed a significant inhibition of elevated body temperature when compared with the corresponding febrile controls (37.65 ± 0.04 vs. 38.41 ± 0.08°C and 37.44 ± 0.04 vs. 38.44 ± 0.04, after 1 h; 37.19 ± 0.04 vs. 38.41 ± 0.08°C and 36.80 ± 0.03 vs. 38.44 ± 0.04°C after 5 h, respectively). These activities were standardized as 38.0 and 51.59% and 47.9 and 66.43% after 5 h, respectively, compared to that of the standard antipyretic and acetylsalicylic acid (200 mg/kg of body weight, subcutaneously). These results may indicate that tilmicosin, in addition to its well established antibacterial activity, possesses significant antipyretic activity that may be beneficial in symptomatic relief when it is used in therapy of infectious disease conditions and inflammatory disorders.   Key words: Antipyretic, tilmicosin, macrolides.

Quantitative N-glycoproteomics reveals altered glycosylation levels of various plasma proteins in bloodstream infected patients.

Bloodstream infections are associated with high morbidity and mortality with rates varying from 10–25% and higher. Appropriate and timely onset of antibiotic therapy influences the prognosis of these patients. It requires the diagnostic accuracy which is not afforded by current gold standards such as blood culture. Moreover, the time from blood sampling to blood culture results is a key determinant of reducing mortality. No established biomarkers exist which can differentiate bloodstream infections from other systemic inflammatory conditions. This calls for studies on biomarkers potential of molecular profiling of plasma as it is affected most by the molecular changes accompanying bloodstream infections. N-glycosylation is a post-translational modification which is very sensitive to changes in physiology. Here we have performed targeted quantitative N-glycoproteomics from plasma samples of patients with confirmed positive blood culture together with age and sex matched febrile controls with negative blood culture reports. Three hundred and sixty eight potential N-glycopeptides were quantified by mass spectrometry and 149 were further selected for identification. Twenty four N-glycopeptides were identified with high confidence together with elucidation of the peptide sequence, N-glycosylation site, glycan composition and proposed glycan structures. Principal component analysis, orthogonal projections to latent structures-discriminant analysis (S-Plot) and self-organizing maps clustering among other statistical methods were employed to analyze the data. These methods gave us clear separation of the two patient classes. We propose high-confidence N-glycopeptides which have the power to separate the bloodstream infections from blood culture negative febrile patients and shed light on host response during bacteremia. Data are available via ProteomeXchange with identifier PXD009048.

HAMP promoter hypomethylation and increased hepcidin levels as biomarkers for Kawasaki disease

Kawasaki disease (KD) is the most common coronary vasculitis to appear in children with anemia and has been associated with elevated plasma hepcidin levels. We recruited a total of 241 cases, including 18 KD patients, who were tested both prior to receiving intravenous immunoglobulin (IVIG) and at least 3 weeks after IVIG treatment, and 18 febrile controls, who were observed in the Illumina HumanMethylation450 BeadChip study for their CpG markers. The remaining cases consisted of another 92 KD patients and 113 controls that were used for validation by pyrosequencing. We performed a genetic functional study using Luciferase assays. A support vector machine (SVM) classification model was adopted to identify KD patients and control subjects. In this study, KD patients clearly demonstrated a significantly epigenetic hypomethylation of HAMP promoter compared to controls. After receiving IVIG treatment, the hypomethylation status in KD patients was restored, and we observed a significant opposite tendency between the DNA methylation of target CpG sites (cg23677000 and cg04085447) and the hepcidin level. Furthermore, reporter gene assays were used to detect target CpG sites, the methylation of which displayed decreased levels of HAMP gene expression. Of particular note, we developed a SVM classification model with a 90.9% sensitivity, a 91.9% specificity, and 0.94 auROC in the training set. An independent blind cohort also had good performance (96.1% sensitivity and 89.7% specificity). In this study, we demonstrate HAMP promoter hypomethylation, which upregulates hepcidin expression in KD patients. Furthermore, the reliability and robustness of our SVM classification model can accurately serve as KD biomarkers.

Serum Interleukin-6 Levels in Children with Febrile Seizures

To compare levels of Interleukin-6 (IL-6) in children with febrile seizures and febrile controls. Study conducted in a tertiary-care hospital in Northern India from November 2013 to April 2015, enrolling 160 children (80 each with febrile seizures and febrile controls), aged 6 - 60 months. Serum IL-6 estimated by ELISA method. Iron study done as per standard technique. All the cases of febrile seizure were followed up at 1 week, 3 months and 6 months for recurrence of seizures. The mean serum IL-6 levels in children with febrile seizures was 62.0 (63.9) pg/mL and febrile controls was 86.9 (70.6) pg/mL (P=0.025). Serum IL-6 levels were significantly lower in children with febrile seizures as compared to febrile controls.

Laboratory Markers in Incomplete Kawasaki Disease according to Coronary Artery Outcome.

Background and ObjectivesWe defined laboratory marker profiles typical of incomplete Kawasaki disease (iKD) during illness, especially with respect to the presence of a coronary artery abnormality such as coronary artery dilation or aneurysm.MethodsThis retrospective study examined the clinical and laboratory markers of patients with iKD over time, along with those of patients with complete KD (cKD) and febrile controls.ResultsOf 795 patients, 178 had iKD, 504 had cKD and 113 were febrile controls. During the transition from the acute to subacute phase, the age-adjusted hemoglobin levels and platelet counts were significantly lower and higher, respectively, in the subacute phase than in the acute phase in both iKD and cKD patients, which differed from those of febrile controls. Lower levels of acute and subacute age-adjusted hemoglobin levels in iKD patients (odds ratio [OR], 0.538 and 0.583; p=0.006 and 0.018, respectively) and higher subacute platelet counts in cKD patients (OR, 1.004; p=0.014) were correlated with the risk of coronary dilation. A higher acute neutrophil-to-lymphocyte ratio was associated with aneurysm only in cKD patients (OR, 1.059; p=0.044).ConclusionsThe iKD patients share KD-specific laboratory marker profiles in terms of complete blood cell counts and acute phase reactant levels with cKD patients. However, the factors predicting coronary dilation differ according to the phenotype; lower acute and subacute age-adjusted hemoglobin levels predict coronary dilation only in iKD patients.

Applicability of volume conductivity and scatter parameters for early prediction of dengue virus infection

Introduction: Dengue virus infection is an acute febrile illness endemic in several countries including India. Although the management is empirical, early diagnosis is crucial for timely intervention to reduce the morbidity and mortality. The diagnosis of dengue virus infection mainly depends on serological testing and virus isolation which are costly and time-consuming. A simple blood test like complete blood count (CBC) run on five-part differential cell counter with volume conductivity, and scatter (VCS) data can help in predicting dengue infection without additional cost. Methods: In the present study, we analyzed VCS parameters of 337 febrile patients over the period of 1 year (January 2016 to December 2016). Out of these, 255 cases were positive for dengue serology and 82 were febrile controls. Comparative analysis of utility of previously published dengue factor, lymph index, and monocyte factor along with the “New Dengue Factor” introduced in the present study. Results: The “New Dengue Factor” proposed by us gave highest “positive likelihood ratio” for the diagnosis of dengue virus infection. Dengue factor proposed by Sharma et al. was the most “sensitive,” and “lymph index” proposed by Hawaldar et al. was the most specific followed by the “New dengue factor” introduced in the present study. Conclusion: Factors derived from VCS parameters are useful for early prediction of dengue virus infection without incurring additional cost and thus would contribute to better patient care.

Urine neutrophil gelatinase-associated lipocalin and other biomarkers in infants with urinary tract infection and in febrile controls.

Urine biomarkers are commonly used in the evaluation of acute kidney injury, and are gaining attention as tools for studying urinary tract infections (UTIs). We analyzed neutrophil gelatinase-associated lipocalin (NGAL) and seven other urine biomarkers to evaluate their usefulness in the diagnosis of UTI in infants. Eight urine biomarkers were analyzed in 108 infants with UTI. Controls were 64 febrile children without UTI and 13 healthy children. Logistic regression and construction of receiver operating characteristic (ROC) curves were performed for UTI patients versus febrile controls for all biomarkers. The best biomarkers to differentiate between UTI and febrile controls were NGAL and interleukin 8 (IL8). Urine NGAL in absolute concentration and adjusted for creatinine had a sensitivity of 93% and 96% and a specificity of 95% and 100% for diagnosing UTI, with a cut-off concentration of 38ng/mL and 233ng/mg respectively. Urine biomarkers, particularly NGAL, can aid in the diagnosis of UTI among febrile infants. The results suggest that in infants with fever and high NGAL, UTI is most likely, whereas in infants with fever and low NGAL, other causes of fever should be looked for.

Epigenetic hypomethylation and upregulation of matrix metalloproteinase 9 in Kawasaki disease.

BackgroundKawasaki disease (KD) is a type of febrile coronary vasculitis occurring in children. Some researchers have suggested that changes in genetic signatures, such as matrix metalloproteinases (MMPs), are critical markers for cardiovascular diseases. This study aims to provide a comprehensive survey of global DNA methylation levels and MMP transcripts of KD patients compared to control subjects.Materials and MethodsFor chips studies, we recruited a total of 18 KD patients, prior to receiving intravenous immunoglobulin (IVIG) and at least 3 weeks after IVIG treatment, as well as 18 healthy and 18 febrile control subjects. We applied Illumina HumanMethylation450 BeadChip and Affymetrix GeneChip® Human Transcriptome Array 2.0 to evaluate their CpG markers and expression levels, respectively. Then we used a separate cohort to carry out real-time quantitative PCR validations of mRNA levels.ResultsThe expressions of mRNA levels of MMP-8, -9, and -25 were significantly upregulated in KD patients compared to the healthy and febrile controls. Once KD patients underwent IVIG treatment, these MMPs considerably decreased. In particular, the methylation status of CpG sites of MMP-9 indicated a significant opposite tendency between both stages of not only the KD samples but also the controls. We also observed the mRNA level of MMP-9 to be higher in KD patients with coronary arterial lesion formation.ConclusionThis study is the first to report epigenetic hypomethylation, an increased MMP-9 transcript, and the upregulation of MMP-9 in KD patients who had formed coronary arterial lesions.

Relationship between IL-27 and coronary arterial lesions in children with Kawasaki disease.

Kawasaki disease (KD) arises due to the disorder of the inflammation response and faulty immune regulation. Interleukin-27 (IL-27) is a novel cytokine with both pro-inflammatory and anti-inflammatory effects. This study investigated the relationship between serum levels of IL-27, Interleukin-17A (IL-17A), Interleukin-10 (IL-10), Interleukin-6 (IL-6), Interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and coronary artery lesions (CALs) in patients with KD. We obtained blood samples from 81 children with KD before intravenous immunoglobulin (IVIG) therapy. Levels of IL-27, IL-17A, IL-10, IL-6, IL-1β and TNF-α were measured in 251 cases, including 4 groups: the normal control group, NC (n=90), febrile control, FC (n=80), KD without coronary arteries (n=41) and KD with coronary arterial lesions (n=40). White blood cells counts (WBC), red blood cells counts (RBC), hemoglobin, C-reactive protein (CRP), erythrocyte sedimentation rate and procalcitonin (PCT) were tested in all subjects. Levels of IL-27, IL-10, IL-17A, IL-6, IL-1β and TNF-α were significantly elevated, and RBC and hemoglobin significantly decreased in the group of KD group compared with febrile and control groups. IL-27, IL-6, IL-1β and TNF-α serum levels are even higher in KD children with CALs. There was positive relationship between serum levels of IL-27 and WBC, CRP, PCT, IL-10, IL-17A, IL-6 and TNF-α in children with KD. The up-regulation of IL-27 may be closely linked to up-regulation of systemic pro-inflammatory markers in acute KD. Morover, IL-27 may be involved in the development of CALs in acute KD.

Identifying genetic hypomethylation and upregulation of Toll-like receptors in Kawasaki disease.

Kawasaki disease (KD) is an acute febrile systemic vasculitis that occurs in children and is characterized by elevated levels of proinflammatory cytokines. Toll-like receptors (TLRs) serve as the sensor arm of the innate immune system and induce proinflammatory cytokine expressions.We recruited a total of 18 paired KD patients, before intravenous immunoglobulin (IVIG) and at least 3 weeks after IVIG treatment, 18 healthy controls, and 18 febrile controls. For TLR genes and their cytosine-phosphate-guanine (CpG) markers, we used Affymetrix GeneChip® Human Transcriptome Array 2.0 and Illumina HumanMethylation450 BeadChip to evaluate gene expression levels and methylation patterns, respectively.KD patients demonstrated a significantly differential expression of TLR mRNA levels compared to both the healthy and febrile controls, with only TLR 3 and 7 not differing between the KD patients and the controls. After patients underwent IVIG treatment, the TLR mRNA levels, except for TLR3, decreased significantly in KD patients. In contrast, the methylation status of the CpG sites of TLR1, 2, 4, 6, 8, and 9 demonstrated an opposite tendency between the two stages of both the KD samples and the controls.TLRs, particularly TLR1, 2, 4, 6, 8, and 9, may stimulate the immunopathogenesis of KD. These results are among the first to use TLRs to prove that a bacterial inflammatory response may trigger KD.

Association of Toll-like receptor 2-positive monocytes with coronary artery lesions and treatment nonresponse in Kawasaki disease.

PurposeActivation of Toll-like receptor 2 (TLR2) present on circulating monocytes in patients with Kawasaki disease (KD) can lead to the production of proinflammatory cytokines and interleukin-10 (IL-10). We aimed to determine the association of the frequency of circulating TLR2+/CD14+ monocytes (FTLR2%) with the outcomes of KD, as well as to compare FTLR2% to the usefulness of sIL-10.MethodsThe FTLR2% in patients with KD was measured by flow cytometry. Serum levels of IL-10 (sIL-10) were determined in 31 patients with KD before the initial treatment with intravenous immunoglobulin (IVIG) and in 21 febrile controls by using enzyme-linked immunosorbent assay. Patients were classified as having coronary artery lesions (CALs) based on the maximal internal diameters of the proximal right coronary artery and proximal left anterior descending coronary artery one month after the initial diagnosis.ResultsWe found that FTLR2% greater than 92.62% predicted CALs with 80% sensitivity and 68.4% specificity, whereas FTLR2% more than 94.61% predicted IVIG resistance with 66.7% sensitivity and 71.4% specificity. Moreover, sIL-10 more than 15.52 pg/mL predicted CALs and IVIG resistance with 40% and 66.7% sensitivity, respectively, and 73.7% and 76.2% specificity, respectively.ConclusionWe showed that measuring FTLR2% before the initial treatment could be useful in predicting CAL development with better sensitivity than sIL-10 and with results comparable to sIL-10 results for the prediction of IVIG resistance in patients with KD. However, further studies are necessary to validate FTLR2% as a marker of prognosis and severity of KD.

Quantitative Evaluation of Medial Temporal Lobe Morphology in Children with Febrile Status Epilepticus: Results of the FEBSTAT Study.

The pathogenesis of febrile status epilepticus is poorly understood, but prior studies have suggested an association with temporal lobe abnormalities, including hippocampal malrotation. We used a quantitative morphometric method to assess the association between temporal lobe morphology and febrile status epilepticus. Brain MR imaging was performed in children presenting with febrile status epilepticus and control subjects as part of the Consequences of Prolonged Febrile Seizures in Childhood study. Medial temporal lobe morphologic parameters were measured manually, including the distance of the hippocampus from the midline, hippocampal height:width ratio, hippocampal angle, collateral sulcus angle, and width of the temporal horn. Temporal lobe morphologic parameters were correlated with the presence of visual hippocampal malrotation; the strongest association was with left temporal horn width (P < .001; adjusted OR, 10.59). Multiple morphologic parameters correlated with febrile status epilepticus, encompassing both the right and left sides. This association was statistically strongest in the right temporal lobe, whereas hippocampal malrotation was almost exclusively left-sided in this cohort. The association between temporal lobe measurements and febrile status epilepticus persisted when the analysis was restricted to cases with visually normal imaging findings without hippocampal malrotation or other visually apparent abnormalities. Several component morphologic features of hippocampal malrotation are independently associated with febrile status epilepticus, even when complete hippocampal malrotation is absent. Unexpectedly, this association predominantly involves the right temporal lobe. These findings suggest that a spectrum of bilateral temporal lobe anomalies are associated with febrile status epilepticus in children. Hippocampal malrotation may represent a visually apparent subset of this spectrum.

Candidemia in Patients with Body Temperature Below 37°C and Admitted to Internal Medicine Wards: Assessment of Risk Factors

BackgroundAn increasing number of candidemia episodes has been reported in patients cared for in internal medicine wards. These usually older and frail patients may not be suspected as having candidemia because they lack fever at the onset of the episode. To identify the risk factors associated with the lack of fever at the onset of candidemia (ie, the collection of the first positive blood culture for Candida spp.) in patients cared for in internal medicine wards, we compared 2 group of patients with or without fever. MethodsWe retrospectively review data charts from 3 tertiary care, university hospitals in Italy, comparing patients with or without fever at onset of candidemia. Consecutive candidemic episodes in afebrile patients and matched febrile controls were identified during the 3-year study period. Patient baseline characteristics and several infection-related variables were examined. Random forest analysis was used, given the number of predictors to be considered and the potential complexity of their relations with the onset of fever. ResultsWe identified 147 candidemic episodes without fever at onset and 147 febrile candidemia episodes. Factors associated with the lack of fever at onset of candidemia were diabetes, Clostridium difficile infection, and a shorter delta time from internal medicine wards admission to the onset of candidemia. The only variable associated with fever was the use of intravascular devices. Quite unexpectedly, antifungal therapy was administered more frequently to patients without fever, and no differences on 30-day mortality rate were documented in the 2 study groups. ConclusionsClinicians should be aware that an increasing number of patients with invasive candidiasis cared for in internal medicine wards may lack fever at onset, especially those with diabetes and C. difficile infection. Candidemia should be suspected in patients with afebrile systemic inflammatory response syndrome or in worsening clinical condition: blood cultures should be taken, and a timely and appropriate antifungal therapy should be considered.

A Classification Tool for Differentiation of Kawasaki Disease from Other Febrile Illnesses

To develop and validate a novel decision tree-based clinical algorithm to differentiate Kawasaki disease (KD) from other pediatric febrile illnesses that share common clinical characteristics. Using clinical and laboratory data from 801 subjects with acute KD (533 for development, and 268 for validation) and 479 febrile control subjects (318 for development, and 161 for validation), we developed a stepwise KD diagnostic algorithm combining our previously developed linear discriminant analysis (LDA)-based model with a newly developed tree-based algorithm. The primary model (LDA) stratified the 1280 subjects into febrile controls (n=276), indeterminate (n=247), and KD (n=757) subgroups. The subsequent model (decision trees) further classified the indeterminate group into febrile controls (n=103) and KD (n=58) subgroups, leaving only 29 of 801 KD (3.6%) and 57 of 479 febrile control (11.9%) subjects indeterminate. The 2-step algorithm had a sensitivity of 96.0% and a specificity of 78.5%, and correctly classified all subjects with KD who later developed coronary artery aneurysms. The addition of a decision tree step increased sensitivity and specificity in the classification of subject with KD and febrile controls over our previously described LDA model. A multicenter trial is needed to prospectively determine its utility as a point of care diagnostic test for KD.

A Novel Truncated Form of Serum Amyloid A in Kawasaki Disease.

BackgroundKawasaki disease (KD) is an acute vasculitis in children that can cause coronary artery abnormalities. Its diagnosis is challenging, and many cytokines, chemokines, acute phase reactants, and growth factors have failed evaluation as specific biomarkers to distinguish KD from other febrile illnesses. We performed protein profiling, comparing plasma from children with KD with febrile control (FC) subjects to determine if there were specific proteins or peptides that could distinguish the two clinical states.Materials and MethodsPlasma from three independent cohorts from the blood of 68 KD and 61 FC subjects was fractionated by anion exchange chromatography, followed by surface-enhanced laser desorption ionization (SELDI) mass spectrometry of the fractions. The mass spectra of KD and FC plasma samples were analyzed for peaks that were statistically significantly different.ResultsA mass spectrometry peak with a mass of 7,860 Da had high intensity in acute KD subjects compared to subacute KD (p = 0.0003) and FC (p = 7.9 x 10−10) subjects. We identified this peak as a novel truncated form of serum amyloid A with N-terminal at Lys-34 of the circulating form and validated its identity using a hybrid mass spectrum immunoassay technique. The truncated form of serum amyloid A was present in plasma of KD subjects when blood was collected in tubes containing protease inhibitors. This peak disappeared when the patients were examined after their symptoms resolved. Intensities of this peptide did not correlate with KD-associated laboratory values or with other mass spectrum peaks from the plasma of these KD subjects.ConclusionsUsing SELDI mass spectrometry, we have discovered a novel truncated form of serum amyloid A that is elevated in the plasma of KD when compared with FC subjects. Future studies will evaluate its relevance as a diagnostic biomarker and its potential role in the pathophysiology of KD.

Pediatric Kawasaki Disease and Adult Human Immunodeficiency Virus Kawasaki-Like Syndrome Are Likely the Same Malady.

Background. Pediatric Kawasaki disease (KD) and human immunodeficiency virus (HIV)+ adult Kawasaki-like syndrome (KLS) are dramatic vasculitides with similar physical findings. Both syndromes include unusual arterial histopathology with immunoglobulin (Ig)A+ plasma cells, and both impressively respond to pooled Ig therapy. Their distinctive presentations, histopathology, and therapeutic response suggest a common etiology. Because blood is in immediate contact with inflamed arteries, we investigated whether KD and KLS share an inflammatory signature in serum.Methods. A custom multiplex enzyme-linked immunosorbent assay (ELISA) defined the serum cytokine milieu in 2 adults with KLS during acute and convalescent phases, with asymptomatic HIV+ subjects not taking antiretroviral therapy serving as controls. We then prospectively collected serum and plasma samples from children hospitalized with KD, unrelated febrile illnesses, and noninfectious conditions, analyzing them with a custom multiplex ELISA based on the KLS data.Results. Patients with KLS and KD subjects shared an inflammatory signature including acute-phase reactants reflecting tumor necrosis factor (TNF)-α biologic activity (soluble TNF receptor I/II) and endothelial/smooth muscle chemokines Ccl1 (Th2), Ccl2 (vascular inflammation), and Cxcl11 (plasma cell recruitment). Ccl1 was specifically elevated in KD versus febrile controls, suggesting a unique relationship between Ccl1 and KD/KLS pathogenesis.Conclusions. This study defines a KD/KLS inflammatory signature mirroring a dysfunctional response likely to a common etiologic agent. The KD/KLS inflammatory signature based on elevated acute-phase reactants and specific endothelial/smooth muscle chemokines was able to identify KD subjects versus febrile controls, and it may serve as a practicable diagnostic test for KD.

Serum and CSF adiponectin, leptin, and interleukin 6 levels as adipocytokines in Egyptian children with febrile seizures: a cross-sectional study.

BackgroundA febrile seizure (FS) is the most common convulsive disorder in children. Activation of cytokine network is involved in FS pathogenesis. Adiponectin, leptin and IL-6 are the major adipocytokines secreted by fat cells. To date, only a few studies concerned the association of adipocytokines with febrile seizures. In this study, we tried to investigate serum and CSF levels of adiponectin, leptin, and interleukin-6 (IL-6); as adipocytokines, for the first time in Egyptian children with febrile seizures.MethodsThis was a prospective cross-sectional study included one hundred patients with febrile seizure, and matched with age, gender, 100 children with febrile illness without seizures (febrile control, FC) and 100 healthy control group (HC). Serum and cerebrospinal fluid (CSF) levels of adiponectin, leptin, and (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA) method.ResultsSerum adiponectin was significantly higher in children with FS (16.8 ± 3.7 ug/ml) and the FC group (18.3 ± 4.3 ug/ml) compared to the HC group (9.5 ± 2.2 ug/ml); P < 0.05, respectively. Serum leptin was significantly lower in children with FS (0.9 ± 0.3 ng/ml) compared to both the FC group (4.7 ± 1.2 ng/ml) and the HC group (1.8 ± 0.4 ng/ml); P < 0.01, respectively. Children with FS had significantly higher serum IL-6 levels (43.7 ± 11.7 ng/ml) than the FC group (21.9 ± 4.5 ng/ml) and the HC group (6.5 ± 1.8 ng/ml); P < 0.01, respectively. Patients with simple febrile seizures (SFS) had serum and CSF adiponectin levels similar to those with complex febrile seizures (CFS); (P > 0.05). Serum and CSF leptin levels were significantly lower in patients with CFS compared to the SFS group (P < 0.05). Serum and CSF IL-6 levels were significantly higher in patients with CFS compared to the SFS group (P < 0.01). On multivariate logistic regression analysis, the high serum IL-6 levels was the most significant risk factor associated with febrile seizures among studied children (OR: 6.2; 95 % CI: 3.58 –10.57; P = 0.0001).ConclusionOur data brought a novel observation that some adipocytokines like leptin and IL-6 could be, at least in part, an aetiopathogenetic factor in the manifestation of febrile seizures in susceptible Egyptian children. Moreover, we observed a significant association between high CSF IL-6 levels and susceptibility to complex febrile seizures as did the low CSF leptin levels.

Urinary Colorimetric Sensor Array and Algorithm to Distinguish Kawasaki Disease from Other Febrile Illnesses.

ObjectivesKawasaki disease (KD) is an acute pediatric vasculitis of infants and young children with unknown etiology and no specific laboratory-based test to identify. A specific molecular diagnostic test is urgently needed to support the clinical decision of proper medical intervention, preventing subsequent complications of coronary artery aneurysms. We used a simple and low-cost colorimetric sensor array to address the lack of a specific diagnostic test to differentiate KD from febrile control (FC) patients with similar rash/fever illnesses.Study DesignDemographic and clinical data were prospectively collected for subjects with KD and FCs under standard protocol. After screening using a genetic algorithm, eleven compounds including metalloporphyrins, pH indicators, redox indicators and solvatochromic dye categories, were selected from our chromatic compound library (n = 190) to construct a colorimetric sensor array for diagnosing KD. Quantitative color difference analysis led to a decision-tree-based KD diagnostic algorithm.ResultsThis KD sensing array allowed the identification of 94% of KD subjects (receiver operating characteristic [ROC] area under the curve [AUC] 0.981) in the training set (33 KD, 33 FC) and 94% of KD subjects (ROC AUC: 0.873) in the testing set (16 KD, 17 FC). Color difference maps reconstructed from the digital images of the sensing compounds demonstrated distinctive patterns differentiating KD from FC patients.ConclusionsThe colorimetric sensor array, composed of common used chemical compounds, is an easily accessible, low-cost method to realize the discrimination of subjects with KD from other febrile illness.

Pro-brain natriuretic peptide (ProBNP) levels in North Indian children with Kawasaki disease.

The diagnosis of Kawasaki disease (KD), a common pediatric vasculitis, is based solely on clinical criteria. There is a need for a robust laboratory marker that can help differentiate KD from other acute, febrile, childhood illnesses and also to predict cardiac involvement. We conducted a cross-sectional study of 25 consecutive patients admitted with diagnosis of KD from January 2013 to April 2014 and compared them with age- and sex-matched febrile controls. We studied the serum pro-brain natriuretic peptide (ProBNP) [ProBNP and N-terminal pro-B-type natriuretic peptide (NT-ProBNP) levels], a marker of myocardial dysfunction, in children with KD in acute and convalescent phases of disease. These levels were also estimated in febrile controls for comparison. The ProBNP (ProBNP and NT-ProBNP) levels were much higher in the acute phase of the KD patients compared to levels in the convalescent phase of KD (p=0.000014). Similarly, the levels in the acute phase were higher when compared to the age- and sex-matched febrile controls (p=0.000126). The receiver operating curve (ROC) analysis for the ProBNP levels in the acute phase of KD yielded an area under the curve of 0.954±0.034 (p<0.000, 95% CI 0.886-1.0). Based on ROC analysis, a cutoff of 1025pg/mL for ProBNP levels in the acute phase of KD had 88% sensitivity and 96% specificity for the diagnosis of KD. A lower cut-off of 514pg/mL yielded a 100% sensitivity and 80% specificity for the diagnosis of KD. The ProBNP levels were higher in those with coronary artery abnormalities (CAA) compared to those without CAA in both acute (p=0.013) and convalescent (p=0.045) phases. ProBNP levels may be used as a surrogate marker for the differentiation of KD from other febrile, infectious illnesses and may also predict the involvement of coronary arteries.