ABSTRACT
BACKGROUND: Kawasaki disease (KD) is an acute febrile illness with systemic vasculitides, mostly affecting infants and young children. The etiology of KD is still unclear; however, altered gut microbiota have been recently implicated as a contributing factor for the development of vasculitis. METHODS: We conducted an age- and gender-matched case-control study on 50 patients and 200 control subjects to search for potential factors leading to intestinal dysbiosis associated with KD. Data were analyzed using conditional multivariable logistic regression. RESULTS: Previous antibiotic administration was associated with the patients who developed KD (odds ratio [OR] 11.7, 95% confidence interval [CI] 4.7-29.1, P < 0.0001), but not other variables, including breastfeeding and group nursery. In subgroup analyses, cesarean birth was indicated as an associated factor in addition to previous antibiotic administration in infants under 12 months of age (OR: 8.0, 95% CI: 1.8-34.4, P = 0.005), but not in older children. CONCLUSIONS: The association between previous antibiotic administration and the onset of KD was demonstrated. Antibiotics may contribute to the development of KD by affecting the intestinal microbiota in infants and young children.
Subject(s)
Anti-Bacterial Agents/adverse effects , Gastrointestinal Microbiome/drug effects , Mucocutaneous Lymph Node Syndrome/epidemiology , Antimicrobial Stewardship , Breast Feeding/statistics & numerical data , Case-Control Studies , Cesarean Section/statistics & numerical data , Child , Child, Preschool , Dysbiosis/epidemiology , Dysbiosis/etiology , Female , Humans , Infant , Logistic Models , Male , Mucocutaneous Lymph Node Syndrome/etiology , Odds Ratio , Risk Factors , Vasculitis/epidemiology , Vasculitis/etiologyABSTRACT
Intrauterine fetal growth restriction (IUGR) and death (IUFD) are both serious problems in the perinatal medicine. Fetal vasculopathy is currently considered to account for a pathogenic mechanism of IUGR and IUFD. We previously demonstrated that an innate immune receptor, the nucleotide-binding oligomerization domain-1 (Nod1), contributed to the development of vascular inflammations in mice at postnatal stages. However, little is known about the deleterious effects of activated Nod1 signaling on embryonic growth and development. We report that administration of FK565, one of the Nod1 ligands, to pregnant C57BL/6 mice induced IUGR and IUFD. Mass spectrometry analysis revealed that maternally injected FK565 was distributed to the fetal tissues across placenta. In addition, maternal injection of FK565 induced robust increases in the amounts of CCL2, IL-6, and TNF proteins as well as NO in maternal, placental and fetal tissues. Nod1 was highly expressed in fetal vascular tissues, where significantly higher levels of CCL2 and IL-6 mRNAs were induced with maternal injection of FK565 than those in other tissues. Using Nod1-knockout mice, we verified that both maternal and fetal tissues were involved in the development of IUGR and IUFD. Furthermore, FK565 induced upregulation of genes associated with immune response, inflammation, and apoptosis in fetal vascular tissues. Our data thus provided new evidence for the pathogenic role of Nod1 in the development of IUGR and IUFD at the maternal-fetal interface.
Subject(s)
Fetal Death/prevention & control , Fetal Growth Retardation/immunology , Nod1 Signaling Adaptor Protein/metabolism , Oligopeptides/administration & dosage , Vasculitis/immunology , Animals , Chemokine CCL2/metabolism , Female , Fetal Death/etiology , Fetal Growth Retardation/chemically induced , Humans , Interleukin-6/metabolism , Ligands , Maternal Exposure/adverse effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Nod1 Signaling Adaptor Protein/agonists , Nod1 Signaling Adaptor Protein/genetics , Pregnancy , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/metabolism , Vasculitis/chemically inducedABSTRACT
BACKGROUND: Streptococcus pyogenes is an uncommon pathogen of purpura fulminans, and the pathogenesis of S. pyogenes-purpura fulminans remains unclear because of paucity of cases. We reported a pediatric case of S. pyogenes-purpura fulminans with literature review of the disease. CASE PRESENTATION: A 3-year-old boy showed limping, lethargy and acral gangrene within 24 h. A diagnosis of S. pyogenes-purpura fulminans was made for bacterial isolation from throat and peripheral blood. Intensive therapy led to a survival with amputation of the left distal metatarsal bone, and normal development. The isolated M12 carried no mutation of csrS/R or rgg. Thrombophilia or immunodeficiency was excluded. DISCUSSION: Twelve-reported cases (9 pediatric and 3 elderly) of S. pyogenes-purpura fulminans started with shock and coagulopathy. Five patients age < 8 years had no underlying disease and survived. One youngest and two immunocompromised patients died. CONCLUSION: Streptococcus pyogenes-acute infectious purpura fulminans is a distinctive rare form of aggressive GAS infections.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Purpura Fulminans/pathology , Purpura Fulminans/therapy , Streptococcal Infections/drug therapy , Streptococcal Infections/pathology , Streptococcus pyogenes/drug effects , Streptococcus pyogenes/pathogenicity , Aged , Child , Child, Preschool , Fatal Outcome , Female , Humans , Infant , Male , Middle Aged , Treatment OutcomeABSTRACT
Atherosclerosis is essentially a vascular inflammatory process in the presence of an excess amount of lipid. We have recently reported that oral administration of a nucleotide-binding oligomerization domain (Nod)-1 ligand, FK565, induced vascular inflammation in vivo. No studies, however, have proven the association between Nod1 and atherosclerosis in vivo. To investigate a potential role of NOD1 in atherogenesis, we orally administered FK565 to apolipoprotein E knockout (Apoe(-/-)) mice for 4 wk intermittently and performed quantification of atherosclerotic lesions in aortic roots and aortas, immunohistochemical analyses, and microarray-based gene expression profiling of aortic roots. FK565 administration accelerated the development of atherosclerosis in Apoe(-/-) mice, and the effect was dependent on Nod1 in non-bone marrow origin cells by bone marrow transplantation experiments. Immunohistochemical studies revealed the increases in the accumulation of macrophages and CD3 T cells within the plaques in aortic roots. Gene expression analyses of aortic roots demonstrated a marked upregulation of the Ccl5 gene during early stage of atherogenesis, and the treatment with Ccl5 antagonist significantly inhibited the acceleration of atherosclerosis in FK565-administered Apoe(-/-) mice. Additionally, as compared with Apoe(-/-) mice, Apoe and Nod1 double-knockout mice showed reduced development of atherosclerotic lesions from the early stage as well as their delayed progression and a significant reduction in Ccl5 mRNA levels at 9 wk of age. Data in the present study show that the Nod1 signaling pathway in non-bone marrow-derived cells contributes to the development of atherosclerosis.
Subject(s)
Apolipoproteins E/deficiency , Atherosclerosis/immunology , Bone Marrow Cells/immunology , Macrophages/immunology , Nod1 Signaling Adaptor Protein/immunology , T-Lymphocytes/immunology , Adjuvants, Immunologic/pharmacology , Animals , Aorta/immunology , Aorta/pathology , Apolipoproteins E/genetics , Atherosclerosis/genetics , Atherosclerosis/pathology , Bone Marrow Cells/pathology , Macrophages/pathology , Mice , Mice, Knockout , Nod1 Signaling Adaptor Protein/genetics , Oligopeptides/pharmacology , T-Lymphocytes/pathologyABSTRACT
BACKGROUND: Botulism is a potentially fatal infection characterized by progressive muscle weakness, bulbar paralysis, constipation and other autonomic dysfunctions. A recent report suggested that cancer chemotherapy might increase the risk for the intestinal toxemia botulism in both adults and children. CASE PRESENTATION: We report a 5-year-old boy, who developed general muscle weakness, constipation, ptosis and mydriasis during the third induction therapy for relapsed acute myeloid leukemia. He had recent histories of multiple antibiotic therapy for bacteremia and intake of well water at home. Repeated bacterial cultures identified Clostridium botulinum producing botulinum neurotoxin A. Botulinum toxin A was isolated from his stools at 17, 21, and 23 days after the onset. Symptoms were self-limiting, and were fully recovered without anti-botulinum toxin globulin therapy. CONCLUSION: This is the second report of a pediatric case with cancer chemotherapy-associated intestinal toxemia botulism. Our case provides further evidence that the immunocompromised status due to anti-cancer treatments increases the risk for the development of botulism at all ages in childhood.
Subject(s)
Botulism/complications , Clostridium botulinum/pathogenicity , Intestines/microbiology , Leukemia/complications , Leukemia/drug therapy , Toxemia/complications , Anti-Bacterial Agents/pharmacology , Bacteremia/drug therapy , Bacterial Infections , Botulinum Toxins , Botulinum Toxins, Type A/isolation & purification , California , Child, Preschool , Clostridium botulinum/isolation & purification , Clostridium botulinum/metabolism , Drug Therapy , Feces/chemistry , Feces/microbiology , Humans , Male , Rare DiseasesABSTRACT
BACKGROUND: Febrile neutropenia (FN) is the main treatment-related cause of mortality among children with cancer, as the prolonged use of broad-spectrum antibiotics can lead to antibiotic resistance in these patients. Antibiotic cycling has been reported to limit the emergence of antibiotic-resistant bacteria among adult patients. However, no studies have evaluated pediatric patients with FN. METHODS: Between September 2011 and February 2014, 126 pediatric cancer patients were admitted to our center for chemotherapy and/or hematopoietic stem cell transplantation and were included in this study. Retrospective and prospective data collection were performed before and after antibiotic cycling, respectively. Between September 2011 and November 2012 (before antibiotic cycling was implemented), intravenous cefpirome was used as the empirical therapy for FN. Between December 2012 and February 2014 (after antibiotic cycling was implemented), the monthly antibiotic cycling involved intravenous piperacillin-tazobactam (PIPC/TAZ), intravenous meropenem or ciprofloxacin (CPFX), and intravenous cefepime in that order. For children aged ≥13 years, the monthly cycling involved intravenous PIPC/TAZ, and CPFX was administered. RESULTS: The detection rates for extended-spectrum ß-lactamase producers in blood and stool culture samples decreased significantly after the implementation of antibiotic cycling (0.33/1000 patient-days vs 0/1000 patient-days, p = 0.03; 1.00/1000 patient-days vs 0/1000 patient-days, p < 0.01; respectively). CONCLUSION: Antibiotic cycling was associated with a decreased emergence of multidrug-resistant microbes.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Febrile Neutropenia/drug therapy , Febrile Neutropenia/epidemiology , Neoplasms/complications , Adolescent , Adult , Anti-Bacterial Agents/administration & dosage , Bacteremia/complications , Bacteremia/drug therapy , Bacteremia/epidemiology , Bacteremia/microbiology , Child , Child, Preschool , Drug Resistance, Bacterial , Empirical Research , Febrile Neutropenia/complications , Febrile Neutropenia/microbiology , Feces/microbiology , Female , Humans , Infant , Infant, Newborn , Male , Nasal Cavity/microbiology , Prospective Studies , Retrospective Studies , Treatment Outcome , Young Adult , beta-LactamasesABSTRACT
BACKGROUND: The immune responses to pneumococcal conjugate vaccine (PCV) are low in immunocompromised hosts. The effect of memory B cells on the immune response to PCV remains elusive. METHODS: In this prospective study, 53 children who received 7-valent PCV were enrolled. Antipneumococcal immunoglobulin G (IgG) levels and opsonization index (OI) titers, along with lymphocyte subsets, were investigated in immunocompromised and immunocompetent hosts. Immunocompromised patients comprised 8 hematopoietic stem cell transplant recipients (group A) and 9 immunosuppressive therapy recipients (group B), and controls consisted of 14 children aged >1 year (group C) and 22 infants (group D). RESULTS: Serotype-specific IgG concentrations and OIs in group A were lower than those in group C. These did not differ among groups B, C, and D. The rates of achieving immunity (defined as an IgG level of 1.0 µg/mL and an OI of 8) in group A were also lower than in group C. Despite the sustained numbers of total T cells and B cells, CD27(+) B-cell and CD4(+) T-cell counts in group A were lower than those in group C. In group B, the immunoglobulin D-expressing CD27(-) B-cell count was only lower than that in group C. CONCLUSIONS: Circulating numbers of CD27(+) B cells, rather than CD4(+) T cells, may predict the effective PCV responses in immunocompromised children.
Subject(s)
B-Lymphocytes/physiology , Heptavalent Pneumococcal Conjugate Vaccine/immunology , Pneumococcal Infections/prevention & control , Adolescent , Antibodies, Bacterial/blood , CD4-Positive T-Lymphocytes , Child , Child, Preschool , Humans , Immunocompromised Host , Immunoglobulin G/blood , Infant , Tumor Necrosis Factor Receptor Superfamily, Member 7/metabolismABSTRACT
OBJECTIVE: Nod1 is an intracellular pattern recognition receptor for bacterial peptidoglycan fragments. We previously reported that a synthetic Nod1 ligand, FK565, induced acute coronary arteritis in mice similar to that of Kawasaki disease. However, the molecular mechanisms underlying this characteristic inflammation have remained elusive. APPROACH AND RESULTS: We found that CD11c(+)MHC class II(+) cells accumulated in the heart of FK565-treated mice before arteritis development. Morphological features and gene expression signatures of the cardiac CD11c(+)MHC class II(+) cells suggested that this population is closely related to macrophages, and thus, we designated them cardiac CD11c(+) macrophages. Nod1 in nonhematopoietic cells, rather than hematopoietic cells, was required for the increase of cardiac CD11c(+) macrophages and arteritis development. Among nonhematopoietic cells, cardiac endothelial cells produced a large amount of chemokines in response to FK565. Endothelial cell-specific blockade of Nod1 signaling suppressed FK565-induced expression of these chemokines, accumulation of cardiac CD11c(+) macrophages, and subsequent coronary arteritis development. We also found that CCR2(+)Ly6C(hi) inflammatory monocytes in peripheral blood supplied precursors of cardiac CD11c(+) macrophages. CCR2-deficient mice or pertussis toxin-treated mice exhibited decreased numbers of cardiac CD11c(+) macrophages and reduced arteritis. CONCLUSIONS: These results suggest that Ly6C(hi) monocytes are recruited to FK565-activated endothelial cells to generate cardiac CD11c(+) macrophages, which play a pivotal role in the pathogenesis of acute coronary arteritis.
Subject(s)
Arteritis/metabolism , Coronary Artery Disease/metabolism , Macrophages/metabolism , Nod1 Signaling Adaptor Protein/metabolism , Animals , Antigens, Ly , Arteritis/chemically induced , CD11c Antigen , Chemokines/metabolism , Coronary Artery Disease/chemically induced , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Macrophages/drug effects , Mice , Monocytes/metabolism , NF-kappa B/antagonists & inhibitors , Oligopeptides/pharmacology , Receptors, CCR2/metabolism , Receptors, CCR5/metabolism , Receptors, G-Protein-Coupled/antagonists & inhibitorsABSTRACT
Toxic shock syndrome (TSS) is a critical illness associated with toxin from Staphylococcus aureus. Despite recent advances in critical care, mortality remains high and additional effective therapy is required. We report an adolescent case of TSS successfully treated with direct hemoperfusion using polymyxin-B immobilized fiber (PMX-DHP). The patient with spina bifida also had ischial pressure ulcer, and developed TSS associated with methicillin-resistant S. aureus. Despite conventional treatment, the patient developed refractory shock, which was immediately improved with PMX-DHP. PMX-DHP has been widely used for the treatment of sepsis to remove circulating endotoxins produced by Gram-negative bacteria, but beneficial effects have also been reported for Gram-positive bacterial infection. To our knowledge, this is the first report on PMX-DHP for TSS in an adolescent patient, and we propose that PMX-DHP could be a new treatment strategy for severe TSS in children as well.
Subject(s)
Gram-Positive Bacterial Infections/therapy , Hemoperfusion/instrumentation , Polymyxin B , Shock, Septic/transmission , Adolescent , Equipment Design , Humans , Male , Treatment OutcomeABSTRACT
We investigated the utility of procalcitonin in early diagnosis of bacterial central nervous system (CNS) infection. Serum procalcitonin level was markedly elevated in the patients with systemic meningitis but not in the patients with brain abscess and subdural empyema. Procalcitonin may be useless to diagnose focal bacterial CNS infection.
Subject(s)
Brain Abscess/diagnosis , Calcitonin/blood , Empyema, Subdural/diagnosis , Haemophilus Infections/complications , Meningitis, Bacterial/diagnosis , Protein Precursors/blood , Staphylococcal Infections/complications , Streptococcal Infections/complications , Adolescent , Biomarkers/blood , Brain Abscess/blood , Brain Abscess/microbiology , C-Reactive Protein/metabolism , Calcitonin Gene-Related Peptide , Child , Child, Preschool , Empyema, Subdural/blood , Empyema, Subdural/microbiology , Female , Haemophilus influenzae , Humans , Infant , Infant, Newborn , Male , Meningitis, Bacterial/blood , Meningitis, Bacterial/microbiology , Retrospective Studies , Staphylococcus epidermidisABSTRACT
The aim of this study is to investigate the utility of several biomarkers in differentiating bacterial community-acquired lower respiratory tract infection (CA-LRTI) from non-bacterial CA-LRTI in children and the difference of their diagnostic performance between pneumonia and bronchitis. A retrospective cohort study composed of 108 pediatric patients hospitalized for CA-LRTI was performed during 2010-2013. Based on the findings of chest X-ray and sputum samples, patients were divided into 4 categories, group of bacterial pneumonia or bronchitis, and non-bacterial (viral or etiology-unknown) pneumonia or bronchitis. Peripheral white blood cell and neutrophil counts, and serum C-reactive protein (CRP) and procalcitonin (PCT) levels were compared among the 4 groups. Finally, 54 patients were the subject of this study. In the patients with pneumonia, serum CRP and PCT levels were significantly elevated in the group of bacterial pneumonia (CRP: p = 0.02, PCT: p = 0.0008). The area under the receiver operating characteristic curve for PCT for distinguishing between bacterial and non-bacterial pneumonia was the largest, and sensitivity, specificity, positive predictive value and negative predictive value of PCT were best among 4 markers. On the other hand, in the patients with bronchitis, neutrophil count was significantly decreased in non-bacterial bronchitis whereas no significant differences of WBC count, CRP level or PCT level were seen. In conclusion, PCT was the most useful marker to differentiate bacterial pneumonia whereas neutrophil count contributed most to the discrimination of bacterial bronchitis. The diagnostic performance of biomarkers may be different between pneumonia and bronchitis.
Subject(s)
Bronchitis/diagnosis , C-Reactive Protein/metabolism , Calcitonin/blood , Neutrophils , Pneumonia, Bacterial/diagnosis , Pneumonia, Viral/diagnosis , Protein Precursors/blood , Adolescent , Area Under Curve , Biomarkers/blood , Bronchitis/blood , Bronchitis/microbiology , Calcitonin Gene-Related Peptide , Child , Child, Preschool , Community-Acquired Infections/diagnosis , Community-Acquired Infections/microbiology , Diagnosis, Differential , Female , Hospitalization , Humans , Infant , Leukocyte Count , Male , Pneumonia, Bacterial/blood , Pneumonia, Viral/blood , Predictive Value of Tests , ROC Curve , Retrospective StudiesABSTRACT
A 12-year-old Japanese girl developed infective endocarditis and central nervous system disease. The previously healthy girl showed altered consciousness and abnormal behaviors along with the classical signs of septic emboli. Staphylococcus aureus was isolated from peripheral blood, but not, the pleocytotic cerebrospinal fluid. Diagnostic imaging studies revealed a vegetative structure in the morphologically normal heart, and multiple thromboembolisms in the brain and spleen. Low plasma activity of protein S (12%) and thrombophilic family history allowed the genetic study, demonstrating that she carried a heterozygous mutation of PROS1 (exon 13; 1689C > T, p.R474C). Surgical intervention of the thrombotic fibrous organization and subsequent anticoagulant therapy successfully managed the disease. There are no reports of infective endocarditis in childhood occurring as the first presentation of heritable thrombophilia. Protein S deficiency might be a risk factor for the development or exacerbation of infective endocarditis in children having no pre-existing heart disease.
Subject(s)
Endocarditis, Bacterial/microbiology , Protein S Deficiency/microbiology , Staphylococcal Infections/diagnosis , Child , Endocarditis, Bacterial/blood , Endocarditis, Bacterial/pathology , Female , Heart Ventricles/pathology , Humans , Pedigree , Protein S Deficiency/blood , Protein S Deficiency/pathology , Staphylococcal Infections/blood , Staphylococcal Infections/pathology , Staphylococcus aureus/isolation & purification , Thromboembolism/microbiologyABSTRACT
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by fever, cytopenias, hepatosplenomegaly, and coagulopathy with the background of hypercytokinemia. Early diagnosis and etoposide therapy are not established for affected newborns. An afebrile infant suffered from apnea 4 days after birth, showing leukocytosis, thrombocytopenia, coagulopathy, and cerebrospinal fluid pleocytosis. Serum levels of ferritin and sIL-2R were high. Bone marrow studies revealed activated/hemophagocytosing macrophages. Coxsackievirus B1 (CB1) was isolated from the throat and stool. Serum anti-CB1 antibody titers were elevated in the patient (4 â 16; 6 â 43 days after birth) and mother (128; 10 days after delivery). Normal expressions of perforin and CD107a precluded inherited HLH. The vertically transmitted CB1-HLH was successfully treated without administration of corticosteroid, cyclosporine, or etoposide. Serum cytokine levels showed dominant expression of monokines (IL-1ß/6/8, and TNF-α) but not IFN-γ, which is the central player of inherited HLH. The cytokine profile might represent a unique pathophysiology of enterovirus-driven neonatal HLH.
Subject(s)
Enterovirus B, Human/isolation & purification , Enterovirus Infections/transmission , Enterovirus Infections/virology , Infectious Disease Transmission, Vertical , Lymphohistiocytosis, Hemophagocytic/virology , Humans , Infant, Newborn , MaleABSTRACT
OBJECTIVE: The goal of this study was to investigate the effects of stimulants for a nucleotide-binding domain, leucine-rich repeat-containing (NLR) protein family on human artery endothelial cells and murine arteries. METHODS AND RESULTS: Human coronary artery endothelial cells were challenged in vitro with microbial components that stimulate NLRs or Toll-like receptors. We found stimulatory effects of NLR and Toll-like receptor ligands on the adhesion molecule expression and cytokine secretion by human coronary artery endothelial cells. On the basis of these results, we examined the in vivo effects of these ligands in mice. Among them, FK565, 1 of the nucleotide-binding oligomerization domain (Nod)-1 ligands induced strong site-specific inflammation in the aortic root. Furthermore, coronary arteritis/valvulitis developed after direct oral administration or ad libitum drinking of FK565. The degree of the respective vascular inflammation was associated with persistent high expression of proinflammatory chemokine/cytokine and matrix metallopeptidase (Mmp) genes in each tissue in vivo by microarray analysis. CONCLUSIONS: This is the first coronary arteritis animal model induced by oral administration of a pure synthetic Nod1 ligand. The present study has demonstrated an unexpected role of Nod1 in the development of site-specific vascular inflammation, especially coronary arteritis. These findings might lead to the clarification of the pathogenesis and pathophysiology of coronary artery disease in humans.
Subject(s)
Arteritis/immunology , Coronary Vessels/immunology , Endothelial Cells/immunology , Immunity, Innate , Nod1 Signaling Adaptor Protein/metabolism , Animals , Arteritis/chemically induced , Arteritis/genetics , Arteritis/metabolism , Arteritis/pathology , Cells, Cultured , Chemokines/genetics , Chemokines/metabolism , Coronary Vessels/drug effects , Coronary Vessels/metabolism , Coronary Vessels/pathology , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelial Cells/pathology , Female , Gene Expression Profiling/methods , Humans , Immunity, Innate/drug effects , Inflammation Mediators/metabolism , Intercellular Adhesion Molecule-1/metabolism , Ligands , Matrix Metalloproteinases/genetics , Matrix Metalloproteinases/metabolism , Mice , Mice, Inbred Strains , Nod1 Signaling Adaptor Protein/agonists , Oligonucleotide Array Sequence Analysis , Oligopeptides , Organ Culture Techniques , Toll-Like Receptors/metabolismABSTRACT
AIMS: Coronary arteritis is a life-threatening complication that may arise in the acute stage of Kawasaki disease (KD), the leading cause of systemic vasculitis in childhood. Various microorganisms and molecular pathogens have been reported to cause KD. However, little is known about the key molecules that contribute to the development of coronary arteritis in KD. METHODS AND RESULTS: To identify causative molecules for coronary arteritis in KD, we prospectively recruited 105 patients with KD and 65 disease controls in four different parts of Japan from 2015 to 2018. During this period, we conducted lipidomics analyses of their sera using liquid chromatography-mass spectrometry (LC-MS). The comprehensive LC-MS system detected a total of 27 776 molecules harbouring the unique retention time and m/z values. In the first cohort of 57 KD patients, we found that a fraction of these molecules showed enrichment patterns that varied with the sampling region and season. Among them, 28 molecules were recurrently identified in KD patients but not in controls. The second and third cohorts of 48 more patients with KD revealed that these molecules were correlated with inflammatory markers (leucocyte counts and C-reactive proteins) in the acute stage. Notably, two of these molecules (m/z values: 822.55 and 834.59) were significantly associated with the development of coronary arteritis in the acute stage of KD. Their fragmentation patterns in the tandem MS/MS analysis were consistent with those of oxidized phosphatidylcholines (PCs). Further LC-MS/MS analysis supported the concept that reactive oxygen species caused the non-selective oxidization of PCs in KD patients. In addition, the concentrations of LOX-1 ligand containing apolipoprotein B in the plasma of KD patients were significantly higher than in controls. CONCLUSION: These data suggest that inflammatory signals activated by oxidized phospholipids are involved in the pathogenesis of coronary arteritis in KD. Because the present study recruited only Japanese patients, further examinations are required to determine whether oxidized PCs might be useful biomarkers for the development of coronary arteritis in broad populations of KD.
Subject(s)
Arteritis/blood , Coronary Artery Disease/blood , Lipidomics , Mucocutaneous Lymph Node Syndrome/blood , Phosphatidylcholines/blood , Adaptor Proteins, Signal Transducing/blood , Arteritis/diagnosis , Arteritis/etiology , Biomarkers/blood , Case-Control Studies , Child , Child, Preschool , Chromatography, Liquid , Coronary Artery Disease/diagnosis , Coronary Artery Disease/etiology , Female , Humans , Japan , Lipoproteins, LDL/blood , Male , Mucocutaneous Lymph Node Syndrome/complications , Mucocutaneous Lymph Node Syndrome/diagnosis , Oxidation-Reduction , Phenylalanine/blood , Prospective Studies , Scavenger Receptors, Class E/blood , Tandem Mass SpectrometryABSTRACT
Background: Arthritis may occur after the diagnosis of Kawasaki disease (KD). Most cases are self-limiting; however, some patients require prolonged treatment. Method: To characterize KD-related arthritis, 14 patients who required arthritis treatment within 30 days after the diagnosis of KD were recruited from the 23rd KD survey in Japan. Twenty-six additional patients were included from our tertiary center and literature review cohorts. Results: The estimated prevalence of KD-related arthritis in Japan was 48 per 100,000 KD patients. Patients with KD-related arthritis had an older age at onset (52 vs. 28 months, P = 0.002) and higher rate of intravenous immunoglobulin (IVIG) resistance in comparison to those without arthritis (86 vs. 17%, P < 0.001). Among 40 patients, 18 had arthritis in the acute phase KD (continued fever-onset type) and 22 did in the convalescent phase (interval fever-onset type). Both showed a similar rate of complete KD or IVIG response. Interval-type patients required biologics for arthritis control less frequently (5 vs. 39%, P = 0.02) and had a higher 2-year off-treatment rate (100 vs. 43%, P = 0.009) than continued-type ones. Interval-types showed lower serum ferritin and interleukin-18 levels than continued-types. When continued-types were grouped according to whether or not they required biologics (n = 7 and n = 11, respectively), the former subgroup had higher ferritin and interleukin-18 levels (P = 0.01 and 0.02, respectively). A canonical discriminant analysis differentiated interval-type from continued-type with the combination of age, time to arthritis, and the ferritin and matrix metalloproteinase-3 levels. Conclusion: Arthritis requiring treatment is a rare complication of KD. KD-associated arthritis includes interval-type (KD-reactive) and continued-type (true systemic-onset juvenile idiopathic arthritis [JIA] requiring biologics), and overlapping arthritis, suggesting the pathophysiological continuity of autoinflammation between KD and JIA.
ABSTRACT
Recent linkage analyses of nondiabetic African-American patients with focal segmental glomerulosclerosis (FSGS) have identified MYH9, encoding nonmuscle myosin heavy chain IIA (NMMHC-IIA), as a gene having a critical role in this disease. Abnormalities of the MYH9 locus also underlie rare autosomal dominant diseases such as May-Hegglin anomaly, and Sebastian, Epstein (EPS), and Fechtner (FTNS) syndromes that are characterized by macrothrombocytopenia and cytoplasmic inclusion bodies in granulocytes. Among these diseases, patients with EPS or FTNS develop progressive nephritis and hearing disability. We analyzed clinical features and pathophysiological findings of nine EPS-FTNS patients with MYH9 mutations at the R702 codon hot spot. Most developed proteinuria and/or hematuria in early infancy and had a rapid progression of renal impairment during adolescence. Renal histopathological findings in one patient showed changes compatible with FSGS. The intensity of immunostaining for NMMHC-IIA in podocytes was decreased in this patient compared with control patients. Thus, MYH9 R702 mutations display a strict genotype-phenotype correlation, and lead to the rapid deterioration of podocyte structure. Our results highlight the critical role of NMMHC-IIA in the development of FSGS.
Subject(s)
Kidney Diseases/etiology , Molecular Motor Proteins/genetics , Mutation , Myosin Heavy Chains/genetics , Proteinuria/etiology , Adolescent , Adult , Child , Child, Preschool , Disease Progression , Female , Hearing Loss, Sensorineural/genetics , Humans , Male , Nephritis, Hereditary/genetics , Thrombocytopenia/genetics , Young AdultABSTRACT
BACKGROUND: This study evaluated whether the recommended teicoplanin loading dose (3 loading doses of 10 mg/kg every 12 hours) achieves a 15-30 µg/mL trough levels in 26 children (2-16 years). In addition, we examined the incidences of renal impairment and hepatic dysfunction in children treated with teicoplanin. METHODS: This retrospective study was conducted between October 2008 and March 2014. RESULTS: The percentage of patients with a trough level <10 and <15 µg/mL were 15.4% (4/26) and 46.2% (12/26), respectively. There were significant correlations between age and concentration/cumulative loading dose (C/D) ratio (P = 0.045), serum creatinine and C/D ratio (P < 0.001) and estimated glomerular filtration rate and C/D ratio (P = 0.005). Serum creatinine was significantly lower when trough levels were <15 µg/mL compared with ≥15 µg/mL. The incidences of renal impairment and hepatic dysfunction were 2.3% and 5.8%, respectively, with no significant difference between <20 and ≥20 µg/mL trough-level groups. CONCLUSIONS: The recommended loading dose may be insufficient to achieve 15-30 µg/mL in children with normal renal function. In addition, the target trough level ≥20 µg/mL for deep-seated infections seems to be safe in children.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacokinetics , Teicoplanin/administration & dosage , Teicoplanin/pharmacokinetics , Adolescent , Anti-Bacterial Agents/blood , Child , Child, Preschool , Drug Monitoring , Female , Humans , Male , Retrospective Studies , Teicoplanin/bloodABSTRACT
BACKGROUND: We previously reported that biofilms and innate immunity contribute to the pathogenesis of Kawasaki disease. Therefore, we aimed to assess the efficacy of clarithromycin, an antibiofilm agent, in patients with Kawasaki disease. METHODS AND RESULTS: We conducted an open-label, multicenter, randomized, phase 2 trial at 8 hospitals in Japan. Eligible patients included children aged between 4 months and 5 years who were enrolled between days 4 and 8 of illness. Participants were randomly allocated to receive either intravenous immunoglobulin (IVIG) or IVIG plus clarithromycin. The primary end point was the duration of fever after the initiation of IVIG treatment. Eighty-one eligible patients were randomized. The duration of the fever did not differ between the 2 groups (mean±SD, 34.3±32.4 and 31.1±31.1 hours in the IVIG plus clarithromycin group and the IVIG group, respectively [P=0.66]). The relapse rate of patients in the IVIG plus clarithromycin group was significantly lower than that in the IVIG group (12.5% versus 30.8%, P=0.046). No serious adverse events occurred during the study period. In a post hoc analysis, the patients in the IVIG plus clarithromycin group required significantly shorter mean lengths of hospital stays than those in the IVIG group (8.9 days versus 10.3 days, P=0.049). CONCLUSIONS: Although IVIG plus clarithromycin therapy failed to shorten the duration of fever, it reduced the relapse rate and shortened the duration of hospitalization in patients with Kawasaki disease. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: UMIN000015437.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Clarithromycin/therapeutic use , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/therapeutic use , Mucocutaneous Lymph Node Syndrome/drug therapy , Adolescent , Anti-Bacterial Agents/adverse effects , Bacteriological Techniques , Biofilms/drug effects , Biofilms/growth & development , Child , Child, Preschool , Clarithromycin/adverse effects , Drug Therapy, Combination , Female , Humans , Immunity, Innate/drug effects , Immunoglobulins, Intravenous/adverse effects , Immunologic Factors/adverse effects , Infant , Japan , Length of Stay , Male , Mucocutaneous Lymph Node Syndrome/diagnosis , Mucocutaneous Lymph Node Syndrome/immunology , Mucocutaneous Lymph Node Syndrome/microbiology , Multiplex Polymerase Chain Reaction , Recurrence , Time Factors , Treatment OutcomeABSTRACT
OBJECTIVES: Patients with primary immunodeficiency diseases (PID) are highly susceptible to various microorganisms. However, no population-based studies have been performed among common viral pathogens, such as respiratory syncytial virus (RSV), rotavirus (RV), varicella-zoster virus (VZV) and influenza virus (IV). The objective of this study was to reveal the clinical burden of these four infections among PID patients in Japan. METHODS: We conducted a nationwide survey by sending questionnaires to 898 hospitals with pediatric departments throughout Japan. RESULTS: Nine hundred ten PID patients from 621 hospitals were registered (response rate: 69.2%). Fifty-four of the patients were hospitalized due to these viral infections. The durations of hospitalization due to RSV and RV infections differed significantly in the PID patients with and without cellular immunodeficiency (12.0 vs 6.5 days, p = 0.041; and 14.0 vs 6.0 days, p = 0.031, respectively). There was no significant difference in the duration of hospitalization in PID patients with and without cellular immunodeficiency who were hospitalized with IV infections (7.3 vs 6.1 days, p = 0.53). CONCLUSIONS: Special attention should be paid to PID patients with compromised cellular immunity who present with RSV and RV infection due to their high risk for severe disease.