[RECOMMENDATION FOR ITCH ASSESSMENT FROM THE ATOPIC ITCH CONSENSUS MEETING (AICOM)].

BACKGROUND: Itch is the most troublesome symptom of atopic dermatitis, and it is important to assess it appropriately for optimal treatment. We discussed issues regarding itch and the most appropriate methods of assessment at the Atopic Itch Consensus Meeting (AICOM), attended by physicians and researchers with expertise in itch treatment and research. METHODS: The AICOM participants prepared a draft consensus statement that addressed the most appropriate itch assessment methods for age groups <2 years, 2-6 years, 7-14 years, and ≥15 years. Consensus was defined as agreement by ≥80% of the participants. RESULTS: Votes were cast by 20 participants (8 dermatologists, 7 pediatricians, and 5 researchers), and a consensus on the best current methods of itch assessment was reached with 95% agreement. For infants and preschool children, because subjective evaluation is difficult, a checklist for itch assessment was developed for caregivers. CONCLUSION: For itch assessment, we recommend subjective evaluation by the patient using a rating scale. For infants and preschoolers, evaluation should be done by the caregiver using a checklist, combined with objective evaluation (of skin lesions, for example) by a physician. We anticipate that more objective itch assessment indices will be established in the future.

The dual aspects of IgD in the development of tolerance and the pathogenesis of allergic diseases.

The cell-surface form of IgD is co-expressed with IgM on mature, naïve B cells as B-cell receptors. The secreted IgD antibody (Ab) is found in relatively modest concentrations in the blood and other body fluids as it has a relatively short serum half-life. IgD Abs produced in the upper-respiratory mucosa presumably participate in host defense against pathogens. The allergen-mediated cross-linkage of basophil-bound IgD Ab enhances type 2 cytokine secretion; IgD Ab may also interfere with IgE-mediated basophil degranulation, suggesting dual and opposing roles of IgD Ab in allergen sensitization and the development of allergen immune tolerance. We recently demonstrated that children with egg allergies who avoided all forms of egg have lower ovomucoid-specific IgD and IgG4 Ab levels than those who only partially avoided egg products and that different mechanisms may regulate allergen-specific IgD Ab production compared to allergen-specific IgG4 Ab production. The relationship between antigen-specific IgD Ab levels and the clinical improvement of asthma and food allergies suggests that antigen-specific IgD Ab affects the process of outgrowing allergies. We discuss the possibility that allergen-specific IgD Ab production reflects low-affinity, allergen-specific IgE production as children outgrow a food allergy.

Severity estimation of very-long-chain acyl-CoA dehydrogenase deficiency via 13C-fatty acid loading test.

BACKGROUND: The clinical severity of very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is difficult to predict using conventional diagnostic methods. METHODS: Peripheral blood mononuclear cells obtained from 14 VLCAD deficiency patients and 23 healthy adults were loaded with carbon-13-universally labeled (U-13C-) fatty acids. Differences in acylcarnitine ratios between the patients and healthy groups and correlations between acylcarnitine ratios and a newly established clinical severity score (CSS) in the patient group were statistically examined. RESULTS: There was a significant decrease in the 13C-C2/13C-C18 and 13C-C12/13C-C14 ratios in the U-13C-stearic acid loading test and in the 13C-C2/13C-C18:1 and 13C-C12:1/13C-C14:1 ratios in the U-13C-oleic acid loading test in the patient group. The values of each ratio were significantly correlated with the CSS, suggesting that they could predict disease severity. Additionally, patients with a higher 13C-C16/13C-C18 ratio than the 13C-C14/13C-C18 ratio in the U-13C-stearic acid loading test had a significantly higher CSS and were presumed to have more severe disease. CONCLUSIONS: Our data indicated that this method could be used to predict the clinical severity of VLCAD deficiency, and identify patients at a risk of severe disease. IMPACT: We established a novel method to predict the severity of VLCAD deficiency by performing a loading test with carbon-13-labeled fatty acids on peripheral blood mononuclear cells. The U-13C-oleic acid loading test was useful for comparing the patient group with the control group in terms of disease severity. The U-13C-stearic acid loading test was useful for identifying the more severely affected patients. These methods are relatively less invasive and enable rapid evaluation of the clinical severity.

Mechanical stimulation is a risk factor for phlebitis associated with peripherally inserted central venous catheter in neonates.

BACKGROUND: Our peripherally inserted central venous catheter (PICC) management plan for neonates previously included routine inspection for swelling and induration of the insertion site of a PICC using palpation. However, we discontinued routine palpation from July 13, 2018, owing to a peculiarly high incidence of PICC-related phlebitis. The aim of this study was to prove that routine palpation was the cause of PICC-related phlebitis. METHODS: We retrospectively reviewed medical records of infants who were admitted to the neonatal intensive care unit and underwent PICC placement from January 2018 to January 2019. The infants were classified into palpating (before July 13, 2018) and non-palpating (after or on July 13, 2018) groups. We analyzed and compared the incidence of PICC-related phlebitis in the two groups. RESULTS: Phlebitis related to PICC was more frequently observed in the palpating group (10/29 infants, 34.5%) than in the non-palpating group (1/31, 3.2%) (P = 0.002). After discontinuation of routine palpating in PICC management, the frequency of non-scheduled removal of the PICC due to phlebitis decreased. The indwelling period was significantly longer in the non-palpating group than in the palpating group. CONCLUSIONS: Our results suggest that mechanical stimulation using palpation of the insertion site was the cause of PICC-related phlebitis, resulting in early non-scheduled removal.

Successful management of a Bacillus cereus catheter-related bloodstream infection outbreak in the pediatric ward of our facility.

Bacillus cereus can spread easily in various environments and can contaminate medical environments, such as ventilator equipment, intravascular catheters, and linen. B. cereus is known to infect immunocompromised patients. Although nosocomial B. cereus outbreaks are often reported, effective preventive measures are not clarified. We report an outbreak of B. cereus catheter-related bloodstream infection (CRBSI) in the pediatric ward and aim at identifying risk factors and effective infection control measures for the outbreak. The nurse station at the pediatric ward and blood cultures were assessed. Sterilization of devices has been ensured thereafter. We identified common risk factors including catheter placement for liquid nutrition, use of high-caloric amino-acid-containing infusion fluid, immunocompromised patients, and contact of the catheter route with the floor. Intervention by the Infection Control Team and educating the medical staff regarding methods of disinfection, including scrubbing the facility, helped terminate the outbreak. We discuss a pre-emptive intervention to terminate the outbreak of CRBSI.

National survey of Japanese patients with mevalonate kinase deficiency reveals distinctive genetic and clinical characteristics.

OBJECTIVES: Mevalonate kinase deficiency (MKD), a rare autosomal recessive autoinflammatory syndrome, is caused by disease-causing variants of the mevalonate kinase (MVK) gene. A national survey was undertaken to investigate clinical and genetic features of MKD patients in Japan. METHODS: The survey identified ten patients with MKD. Clinical information and laboratory data were collected from medical records and by direct interviews with patients, their families, and their attending physicians. Genetic analysis and measurement of MVK activity and urinary excretion of mevalonic acid were performed. RESULTS: None of the 10 patients harbored MVK disease-causing variants that are common in European patients. However, overall symptoms were in line with previous European reports. Continuous fever was observed in half of the patients. Elevated transaminase was observed in four of the 10 patients, two of whom fulfilled the diagnostic criteria for hemophagocytic lymphohistiocytosis. About half of the patients responded to temporary administration of glucocorticoids and NSAIDs; the others required biologics such as anti-IL-1 drugs. CONCLUSION: This is the first national survey of MKD patients in a non-European country. Although clinical symptoms were similar to those reported in Europe, the incidence of continuous fever and elevated transaminase was higher, probably due to differences in disease-causing variants.

Ph-like acute lymphoblastic leukemia with a novel PAX5-KIDINS220 fusion transcript.

Although "paired box 5" (PAX5)-related fusion genes are well documented in childhood B-cell precursor acute lymphoblastic leukemia (ALL), these types of fusion with the exception of PAX5-JAK2 are rarely seen in patients with gene expression profiles similar to those of BCR-ABL1 (Philadelphia)-positive ALL (Ph-like ALL). We report a novel fusion of the genes PAX5 and "kinase D-interacting substrate of 220 kDa" (KIDINS220, also known as ARMS) in a Ph-like ALL. As PAX5 is a master regulator of B-lymphocyte differentiation, PAX5 rearrangements induce a differentiation block in B lymphocytes. KIDINS220 is a mediator of multiple receptor signaling pathways, interacts with both T- and B-cell receptors, and is necessary for sustained extracellular signal-regulated kinase (ERK) signaling. Although functional studies are needed, the PAX5-KIDINS220 fusion protein might not only inhibit wild-type PAX5 function, but also promote sustained activation of the ERK signaling pathway through upregulation of KIDINS220. © 2016 Wiley Periodicals, Inc.

Nationwide questionnaire-based survey of oral immunotherapy in Japan.

BACKGROUND: Clinical trials on oral immunotherapy (OIT) have been increasing for nearly a decade; however, several national guidelines do not recommend OIT as a standardized procedure. The aim of this study was to obtain insights into the current use and practice of OIT in Japan. METHODS: A first questionnaire was mailed to 524 training and teaching facilities of the Japan Pediatric Society. The first survey requested information on the implementation of OIT, whereas the second survey aimed to gather more detailed information on OIT, such as its safety. RESULTS: In total, 360 facilities (69%) responded to the survey; among them, 102 (28%) provided OIT to 7973 patients [1544 received OIT while hospitalized (inpatient OIT), whereas 6429 received OIT without hospitalization (outpatient OIT)]. Approval for OIT was obtained from an ethics committee or institutional review board in 89% and 31% of facilities for inpatient and outpatient OIT, respectively. In inpatient OIT, immediate allergic reactions requiring treatment occurred in 68% of patients while hospitalized, and in another 56%, following discharge. In contrast, 11% of patients developed immediate allergic reactions in outpatient OIT. Adrenaline injections at home were required in 2%. Sixteen patients developed adverse reactions other than immediate allergic reactions, among which eosinophilic gastroenteritis was most common. CONCLUSIONS: OIT is widely provided not only as clinical research but also as general practice in Japan. However, because there is a high risk of developing anaphylaxis at home, OIT should be conducted carefully as in a clinical research setting taking safety into consideration.

Aicardi-Goutières syndrome is caused by IFIH1 mutations.

Aicardi-Goutières syndrome (AGS) is a rare, genetically determined early-onset progressive encephalopathy. To date, mutations in six genes have been identified as etiologic for AGS. Our Japanese nationwide AGS survey identified six AGS-affected individuals without a molecular diagnosis; we performed whole-exome sequencing on three of these individuals. After removal of the common polymorphisms found in SNP databases, we were able to identify IFIH1 heterozygous missense mutations in all three. In vitro functional analysis revealed that IFIH1 mutations increased type I interferon production, and the transcription of interferon-stimulated genes were elevated. IFIH1 encodes MDA5, and mutant MDA5 lacked ligand-specific responsiveness, similarly to the dominant Ifih1 mutation responsible for the SLE mouse model that results in type I interferon overproduction. This study suggests that the IFIH1 mutations are responsible for the AGS phenotype due to an excessive production of type I interferon.

Urinary podocalyxin as a possible novel marker of intrauterine nephrogenesis and extrauterine podocyte injury.

BACKGROUND: The number of nephrons at birth is determined during fetal development and is modulated thereafter by postnatal podocyte injury. Hyperfiltration, caused by a reduced number of nephrons, is a risk factor for chronic kidney disease. It is therefore important to monitor the formation of nephrons. METHODS: Urine samples were collected from infants within 1-2 days of birth, with follow-up sampling for preterm infants at 37-39 weeks of corrected age. Urinary levels of podocalyxin (PCX), ß2-microglobulin (ß2MG), N-acetyl-ß-D-glucosaminidase (NAG), total protein (TP), microalbumin (mAlb) and creatinine were measured and the relationship between these markers evaluated. RESULTS: Seventy-nine neonates were enrolled in this study. Urinary levels of PCX at birth were higher than normal adult reference values, with levels increasing up to a gestational age of 36 weeks (p = 0.0242). At 37-39 weeks corrected age, urinary levels of PCX decreased to adult levels. The levels of PCX in the urine at birth were not correlated to urinary levels of ß2MG, NAG, TP and mAlb. CONCLUSIONS: An increased urinary level of PCX may be a marker of both active nephron formation and podocyte injury sustained at birth. As such, changes in urinary levels of PCX are likely to reflect adaptation of renal function to the extra-uterine environment.

Treatment with Geranylgeranylacetone Induces Heat Shock Protein 70 and Attenuates Neonatal Hyperoxic Lung Injury in a Model of Bronchopulmonary Dysplasia.

PURPOSE: Bronchopulmonary dysplasia (BPD) is a respiratory complication characterized by abnormal alveolar development in premature infants. Geranylgeranylacetone (GGA) can induce heat shock protein (HSP) 70, which has cytoprotective effects against various stressors. Here, we investigated whether GGA protected neonatal lungs from hyperoxic stress in a murine BPD model, and measured the serum HSP70 levels in preterm humans treated with oxygen. METHODS: Newborn mice were exposed to >90% oxygen and administered GGA or vehicle alone orally on days 1, 2, and 3 of life. At 2 days of age, HSP70 expression in the lung was determined by western blotting. At 8 days of age, the lungs were processed for histological analysis. Radial alveolar count (RAC) and mean linear intercept (MLI) were measured as parameters of alveolarization. Apoptosis was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method and cleaved caspase-3 immunohistochemistry. Serum HSP70 levels in preterm humans treated with oxygen were measured by enzyme-linked immunosorbent assay. RESULTS: GGA administration enhanced the HSP70 expression to two-fold compared with normoxia-exposed and vehicle-treated mice. Hyperoxia reduced HSP70 expression, whereas GGA abrogated the effects. Hyperoxia-exposed mice exhibited more apoptotic cells in lung parenchyma and a more simplified alveolar structure with less RAC and larger MLI than normoxia-exposed mice. GGA suppressed the increase in apoptotic cells and the structural changes of the lungs induced by hyperoxia. Serum HSP70 levels of preterm human infants gradually decreased with age. CONCLUSIONS: GGA may attenuate hyperoxic injury in neonatal lungs and thereby may prevent the development of BPD.

ACTN1 rod domain mutation associated with congenital macrothrombocytopenia.

Mutations in ACTN1, the gene encoding the actin-crosslinking protein α-actinin-1, cause autosomal dominant macrothrombocytopenia. α-Actinin-1 exists as antiparallel dimers, composed of an N-terminal actin-binding domain (ABD), four spectrin-like repeats (SLRs), which form the spacer rod, and a C-terminal calmodulin-like (CaM) domain. All of the previously reported ACTN1 mutations associated with macrothrombocytopenia reside within the ABD and the CaM domain and not within the SLR domain. In this report, we describe a mutation in SLR2 of α-actinin-1 (p.Leu395Gln) associated with familial macrothrombocytopenia. A 3-year-old boy and his mother both had this mutation. They showed a mild form of thrombocytopenia without severe bleeding, accompanied by an elevated mean platelet volume. Consistent with the previous reports of mutations that reside in the ABD or the CaM domain, immunofluorescence examination revealed disorganization of the actin cytoskeleton in Gln395 mutant-transduced Chinese hamster ovary cells. Our findings suggest a novel mechanism for the pathogenesis of ACTN1-related macrothrombocytopenia that does not involve functional domain mutations.