Early hematopoietic cell transplantation for familial hemophagocytic lymphohistiocytosis in a regional treatment network in Japan.

Familial hemophagocytic lymphohistiocytosis (FHLH) is a fatal hyperinflammation syndrome arising from the genetic defect of perforin-mediated cytolysis. Curative hematopoietic cell transplantation (HCT) is needed before development of central nervous system (CNS) disease. We studied treatment outcomes of 13 patients (FHLH2 n = 11, FHLH3 n = 2) consecutively diagnosed from 2011 to 2022 by flow cytometric screening for non-myeloablative HCT in a regional treatment network in Kyushu, Japan. One patient with a novel PRF1 variant escaped screening, but all patients with FHLH2 reached diagnosis and 8 of them received HCT until 3 and 9 months of age, respectively. The earliest HCT was conducted 65 days after birth. Three pretransplant deaths occurred in newborns with liver failure at diagnosis. Ten posttransplant patients have remained disease-free, 7 of whom had no neurological involvement. Time from first etoposide infusion to HCT was shorter in patients without CNS disease or bleeding than in patients with those factors (median [range] days: 62 [50-81] vs. 122 [89-209], p = 0.016). Six of 9 unrelated patients had a PRF1 c.1090_1091delCT variant. These results suggest that the critical times to start etoposide and HCT are within 3 months after birth and during etoposide control, respectively. Newborn screening may increase the percentage of disease-free survivors without complications.

Survey of diversity awareness and environment among members of the Pediatric Rheumatology Association of Japan.

BACKGROUND: Diversity management has gained traction in Japan. The Pediatric Rheumatology Association of Japan (PRAJ) has an Advisory Committee for Diversity Promotion with a broader focus on promoting diversity. The objectives of this study were to better understand the problems faced by PRAJ members regarding the work environment, childcare and nursing care, and work-life balance. METHODS: A web-based questionnaire was administered to members of the PRAJ and 79 responses were evaluated. RESULTS: Of the respondents, 73% were male and 27% were female. A total of 14% worked for more than 12 h on weekdays, and 22% worked for more than 60 h per week and 38% had fewer than 4 days off per month. Regarding childcare, 54% of the respondents were raising preschool children and 83% had taken parental leave for less than 1 year. A total of 17% of participants had family members in need of care. For both childcare and caregiving, the burden was greater for women. Only 18% of the respondents reported a well-balanced work-life balance, and the most common reasons for a lack of balance were not having enough time, heavy workload, and heavy housework load. CONCLUSIONS: The working hours of the respondents were long, and female members had a greater burden of childcare and caregiving, which was considered a barrier to the career development of women. In the future, there will be a need to promote a sense of equality in diverse human resources, develop support for family life, and shorten working hours.

Three Signs to Help Detect Sjögren's Syndrome: Incidental Findings on Magnetic Resonance Imaging and Computed Tomography.

This study aimed to retrospectively investigate the prevalence of Sjögren's syndrome (SS) among patients with ranulas, parotid cysts, or parotid calcifications; identify the characteristic magnetic resonance imaging (MRI) or computed tomography (CT) findings of the lesions associated with SS; and compare the SS disease stages among SS patients with the three lesion types. A total of 228 patients with the lesions were classified into SS, possible SS, and non-SS groups. The prevalence of SS among patients with ranulas, parotid cysts, or parotid calcifications was 16%, 24%, and 40%, and the rates of either SS or possible SS were 25%, 41%, and 64%, respectively. SS was associated with (i) ranulas: ≤17 mm; (ii) parotid cysts: bilateral and multiple; and (iii) parotid calcifications: in females, bilateral, multiple, parenchymal, and no coexisting calcifications in other tissues. SS patients with ranulas were significantly younger and had lower submandibular gland stage scores on MRI/CT than those with other lesions. Additionally, in 58% and 15% of SS patients with ranulas and parotid calcifications, respectively, detection of the lesions led to the diagnosis of primary SS. Therefore, recognizing the prevalence of SS among patients with these lesions and the findings associated with SS can help detect undiagnosed SS.

Disseminated Mycobacterium genavense Infection Mimicking Sarcoidosis: A Case Report and Review of Literature on Japanese Patients.

Sarcoidosis is a systemic inflammatory disease characterized by noncaseating epithelioid cell granulomas. However, certain infections can exhibit similar histological findings. We present a case of a 69-year-old man who was initially diagnosed with sarcoidosis and later was confirmed, through 16S rRNA sequencing, to have disseminated Mycobacterium genavense infection. Acid-fast bacteria were detected in the bone marrow biopsy using Ziehl-Neelsen staining, but routine clinical tests did not provide a definitive diagnosis. The patient tested negative for HIV, anti-interferon-gamma antibodies, and genetic immunodeficiency disorders. He was treated with multiple drugs, including aminoglycosides and macrolides, but showed no improvement in fever and pancytopenia. However, these clinical signs responded favorably to steroid therapy. We reviewed 17 Japanese cases of M. genavense infection. All cases were in males; 7/17 (41%) were HIV-negative; and 12/17 (71%) had a decreased CD4 count. Genetic analysis confirmed M. genavense isolation, and macrolides were used universally. Mycobacterium genavense infection is challenging to identify and mimics other systemic inflammatory diseases such as sarcoidosis. There are no standard treatment protocols. Our case report and Japanese case review contribute to understanding this rare disease.

Serum leucine-rich alpha-2 glycoprotein and calprotectin in children with inflammatory bowel disease: A multicenter study in Japan.

BACKGROUND AND AIM: Serum leucine-rich alpha-2 glycoprotein (LRG) and calprotectin have been studied as disease activity markers in adults with inflammatory bowel disease (IBD). We evaluated them in pediatric IBD patients. METHODS: Subjects under 17 years old undergoing care at 11 Japanese pediatric centers were retrospectively assigned to 3 groups representing Crohn's disease (CD), ulcerative colitis (UC), and normal controls (NC) with irritable bowel syndrome or no illness. Serum LRG and calprotectin were measured using commercial enzyme-linked immunosorbent assay kits. RESULTS: We enrolled 173 subjects, including 74 with CD, 77 with UC, and 22 NC. Serum LRG concentrations in active CD (median, 200 µg/mL) were significantly greater than in remission (81 µg/mL; P < 0.001) or NC (69 µg/mL; P < 0.001). Serum calprotectin concentrations in active CD (2941 ng/mL) also were significantly greater than in remission (962 ng/mL; P < 0.05) or NC (872 ng/mL; P < 0.05). Serum LRG concentrations in active UC (134 µg/mL) were significantly greater than in remission (65 µg/mL; P < 0.01) but not significantly greater than in NC (69 µg/mL); serum calprotectin concentrations in active UC (1058 ng/mL) were not significantly different from those in remission (671 ng/mL) or NC (872 ng/mL). In receiver operating characteristic analyses of LRG, calprotectin, C-reactive protein, and erythrocyte sedimentation rate for ability to distinguish active IBD from remission, CD and UC showed areas under receiver operating characteristic curves for LRG (0.77 and 0.70, respectively), exceeding those for calprotectin, C-reactive protein, or erythrocyte sedimentation rate. CONCLUSIONS: In pediatric IBD, serum LRG may better reflect disease activity than serum calprotectin, particularly in CD.

Epidemiology conduction of paediatric rheumatic diseases based on the registry database of the Pediatric Rheumatology Association of Japan.

OBJECTIVES: Although epidemiological surveys of paediatric rheumatic diseases in Japan have been conducted, they were single surveys with no continuity. This is the first report of the Pediatric Rheumatology Association of Japan registry database, which was established to continuously collect data for paediatric rheumatic diseases. METHODS: Pediatric Rheumatology International Collaborate Unit Registry version 2 (PRICUREv2) is a registry database established by the Pediatric Rheumatology Association of Japan. The registry data were analysed for the age of onset, time to diagnosis, sex differences, seasonality, and other factors. RESULTS: Our data showed the same trend regarding rates of paediatric rheumatic diseases reported in Japan and other countries. The age of onset was lower in juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis and higher in systemic lupus erythematosus and Sjögren's syndrome. The time to diagnosis was relatively short in JIA and systemic lupus erythematosus but longer in juvenile dermatomyositis and Sjögren's syndrome. Rheumatoid factor-positive polyarticular JIA showed a seasonality cluster with regard to onset. CONCLUSION: PRICUREv2 aided the retrieval and evaluation of current epidemiological information on patients with paediatric rheumatic diseases. It is expected that the data collection will be continued and will be useful for expanding research in Japan.

Comparison of salivary gland MRI and ultrasonography findings among patients with Sjögren's syndrome over a wide age range.

OBJECTIVES: This retrospective study compared MRI and US findings among patients with SS over a wide age range. METHODS: Ninety patients with SS aged 8-84 years who had undergone both MRI and US examinations were divided into four groups according to age, as follows: <18 years (juvenile SS, JSS), 9 patients; 18-39 years, 12 patients; 40-69 years, 53 patients; >69 years, 16 patients. Imaging findings of parotid glands (PGs) and submandibular glands (SMGs) were compared among the four groups. Furthermore, the relationships within and between imaging findings and various clinical findings were examined. RESULTS: On MRI, patients with JSS commonly exhibited multiple high-intensity spots in the PGs on MR sialography and fat-suppressed T2-weighted imaging. With increasing SS group age, the frequencies and numbers of the high-intensity spots were lower. Fat areas on MRI and hyperechoic bands on US were rarely observed in the PGs and SMGs of patients with JSS, whereas they were more common in patients with adult SS. In addition, the presence of hyperechoic bands on US, the presence of fat areas on MRI, and decreased salivary flow were associated with one another. CONCLUSION: Salivary gland imaging findings in patients with JSS were characterized by punctate sialectasis, whereas those findings in patients with adult SS were characterized by fatty degeneration. Distinct findings in patients with JSS and adult SS are likely to reflect differences in glandular lesion stage. MRI and US are presumably useful for evaluation of glandular lesion severity during follow-up.

Serum Zinc and Selenium in Children with Inflammatory Bowel Disease: A Multicenter Study in Japan.

BACKGROUND: Reports of zinc and selenium deficiencies accompanying inflammatory bowel disease (IBD) mostly have originated from Western countries and concerned adult patients. Whether Japanese children with IBD have similar deficiencies remained unclear. AIM: We aimed to elucidate differences in serum zinc and selenium concentrations in Japanese children between types of IBD. METHODS: Children under 17 years old undergoing care at 12 Japanese pediatric centers were retrospectively enrolled between November 2016 and February 2018 to 3 groups representing Crohn's disease (CD), ulcerative colitis (UC), and normal controls (NC) with irritable bowel syndrome or no illnesses. Serum zinc and selenium were measured by atomic absorption spectrophotometry. Zinc and selenium deficiencies were defined by serum concentrations < 70 µg/dL and < 9.5 µg/dL, respectively. RESULTS: Subjects included 98 patients with CD (median age, 13 years), 118 with UC (11 years), and 43 NC (11 years). Serum zinc and selenium were significantly lower in CD (median, 64 and 12.6 µg/dL respectively) than in UC (69 and 14.6; P < 0.05 and P < 0.001) or NC (77 and 15.7; P < 0.01 and P < 0.001). Zinc deficiency was significantly more prevalent in CD (60.2%) than in NC (37.2%; P < 0.05), but not than in UC (51.7%; P = 0.22). Selenium deficiency was significantly more prevalent in CD (15.3%) than in UC (5.9%; P < 0.05) or NC (0%; P < 0.01). CONCLUSIONS: In Japanese children under 17 years old, serum zinc and selenium were significantly lower in CD than in UC or NC. Zinc and selenium should be monitored, and supplemented when deficient, in children with IBD, especially CD.

Respiratory function declines in children with asthma associated with chemical species of fine particulate matter (PM2.5) in Nagasaki, Japan.

BACKGROUND: The differential effects of PM2.5 fractions on children's lung function remain inconclusive. This study aimed to examine whether lung function in asthmatic children was associated with increased PM2.5 fractions in urban areas in Nagasaki prefecture, Japan, where the air pollution level is relatively low but influenced by transboundary air pollution. METHODS: We conducted a multiyear panel study of 73 asthmatic children (boys, 60.3%; mean age, 8.2 years) spanning spring 2014-2016 in two cities. We collected self-measured peak expiratory flow (PEF) twice a day and daily time-series data for PM2.5 total mass and its chemical species. We fitted a linear mixed effects model to examine short-term associations between PEF and PM2.5, adjusting for individual and time-varying confounders. A generalized linear mixed effects model was also used to estimate the association for worsening asthma defined by severe PEF decline. Back-trajectory and cluster analyses were used to investigate the long-range transboundary PM2.5 in the study areas. RESULTS: We found that morning PEFs were adversely associated with higher levels of sulfate (- 1.61 L/min; 95% CI: - 3.07, - 0.15) in Nagasaki city and organic carbon (OC) (- 1.02 L/min; 95% CI: - 1.94, - 0.09) in Isahaya city, per interquartile range (IQR) increase at lag1. In addition, we observed consistent findings for worsening asthma, with higher odds of severe PEF decline in the morning for sulfate (odds ratio (OR) = 2.31; 95% CI: 1.12, 4.77) and ammonium (OR = 1.73; 95% CI: 1.06, 2.84) in Nagasaki city and OC (OR = 1.51; 95% CI: 1.06, 2.15) in Isahaya city, per IQR increase at lag1. The significant chemical species were higher on days that could be largely attributed to the path of Northeast China origin (for sulfate and ammonium) or both the same path and local sources (for OC) than by other clusters. CONCLUSIONS: This study provides evidence of the differential effects of PM2.5 fractions on lung function among asthmatic children in urban areas, where the Japanese national standards of air quality have been nearly met. Continuous efforts to promote mitigation actions and public awareness of hazardous transboundary air pollution are needed to protect susceptible children with asthma.

Functional analysis of novel A20 variants in patients with atypical inflammatory diseases.

BACKGROUND: A20 haploinsufficiency (HA20) is an early-onset autoinflammatory disease caused by mutations in the TNFAIP3 gene, which encodes the protein A20. Numerous truncating mutations in the TNFAIP3 gene have been reported in HA20 patients, whereas fewer missense variants have had their pathogenicity confirmed. Here, we evaluated the pathogenic significance of three previously unreported missense variants of the TNFAIP3 gene in suspected cases of HA20. METHODS: We obtained the clinical features and immunological data of three patients with missense variants (Glu192Lys, Ile310Thr, and Gln709Arg) of unknown significance of TNFAIP3. We then performed in vitro functional assays including analysis of nuclear factor (NF)-κB reporter gene activity, detection of A20 expression and phosphorylation of A20 by IκB kinase ß (IKKß), and K63-deubiquitination assay using TNFAIP3-deficient HEK293 cells. Three known pathogenic missense mutations reported previously were also investigated. RESULTS: The inhibitory effect on NF-κB reporter gene activity was significantly disrupted by A20 Glu192Lys and the three known mutations. The variants Ile310Thr and Gln709Arg did not show a difference from the wild type in any of the assays performed in this study. CONCLUSIONS: Among the three variants in the TNFAIP3 gene, Glu192Lys was interpreted as being likely pathogenic, but Ile310Thr and Gln709Arg as being not pathogenic (uncertain significance and likely benign, respectively), based on the American College of Medical Genetics and Genomics standards and guidelines. Our study highlights the necessity of performing in vitro functional assays, notably, NF-κB reporter gene assay, to evaluate the pathogenicity of TNFAIP3 missense variants for the accurate diagnosis of HA20.

Childhood-onset of primary Sjögren's syndrome: phenotypic characterization at diagnosis of 158 children.

OBJECTIVES: To characterize the phenotypic presentation at diagnosis of childhood-onset primary SS. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry using worldwide data-sharing cooperative merging of pre-existing clinical SS databases from the five continents. For this study, we selected those patients in whom the disease was diagnosed below the age of 19 years according to the fulfilment of the 2002/2016 classification criteria. RESULTS: Among the 12 083 patients included in the Sjögren Big Data Registry, 158 (1.3%) patients had a childhood-onset diagnosis (136 girls, mean age of 14.2 years): 126 (80%) reported dry mouth, 111 (70%) dry eyes, 52 (33%) parotid enlargement, 118/122 (97%) positive minor salivary gland biopsy and 60/64 (94%) abnormal salivary US study, 140/155 (90%) positive ANA, 138/156 (89%) anti-Ro/La antibodies and 86/142 (68%) positive RF. The systemic EULAR Sjögren's syndrome disease activity index (ESSDAI) domains containing the highest frequencies of active patients included the glandular (47%), articular (26%) and lymphadenopathy (25%) domains. Patients with childhood-onset primary SS showed the highest mean ESSDAI score and the highest frequencies of systemic disease in 5 (constitutional, lymphadenopathy, glandular, cutaneous and haematological) of the 12 ESSDAI domains, and the lowest frequencies in 4 (articular, pulmonary, peripheral nerve and CNS) in comparison with patients with adult-onset disease. CONCLUSIONS: Childhood-onset primary SS involves around 1% of patients with primary SS, with a clinical phenotype dominated by sicca features, parotid enlargement and systemic disease. Age at diagnosis plays a key role in modulating the phenotypic expression of the disease.

Juvenile primary Sjögren's syndrome with ranula: is ranula a clinical sign that leads to early detection of Sjögren's syndrome?

Juvenile primary Sjögren's syndrome (pSS) is rare. Although recurrent parotitis is reported to be the most common symptom of juvenile pSS, the clinical symptoms and features of the syndrome are not well understood and are poorly defined. Here we report a rare case of juvenile pSS in a patient with plunging ranula. The patient had no symptoms other than swelling of the oral floor and had no symptoms of parotitis. Magnetic resonance imaging (MRI) revealed the diagnosis of plunging ranula. In addition, the findings of the bilateral parotid glands on MRI and subsequent ultrasonography (US) strongly suggested SS. On the basis of these imaging findings and laboratory data, a pediatric rheumatologist confirmed the diagnosis of juvenile pSS. The ranula may be one clinical sign of SS. However, this association remains generally unknown. Hypothesizing that SS might cause ranula development, we retrospectively investigated cases of patients with ranula who underwent MRI at our hospital. We found that many of these patients (> 20%) had characteristic findings strongly suggestive of SS. This result suggests that SS-induced changes in the sublingual glands are one cause of ranula formation. We think that ranula is a sign of early-stage SS. Therefore, patients with ranulae, whether adults or children, should undergo careful assessment of not only the sublingual glands but also the parotid and submandibular glands with MRI and/or US to investigate possible SS. This assessment may lead to early detection of SS.

Diagnostic accuracy of serum proteinase 3 antineutrophil cytoplasmic antibodies in children with ulcerative colitis.

BACKGROUND AND AIM: Serologic markers such as myeloperoxidase (MPO) antineutrophil cytoplasmic antibodies (ANCA) (MPO-ANCA) have been used to screen patients for ulcerative colitis (UC). However, MPO-ANCA shows limited accuracy in Asians. Proteinase 3 ANCA (PR3-ANCA) has performed better at UC diagnosis in Japanese adults than MPO-ANCA. The present study aimed to evaluate usefulness of PR3-ANCA for diagnosis of UC in Japanese pediatric practice. METHODS: Patients under 17 years old undergoing assessment at 12 Japanese pediatric centers between November 2016 and February 2018 were prospectively enrolled and divided into groups with UC, Crohn's disease (CD), intestinal disease control (IC), and healthy control (HC). Serum PR3-ANCA and MPO-ANCA were analyzed using chemiluminescence enzyme immunoassay kits. RESULTS: Sera from 367 patients (148 with UC at a median age of 12 years; 120 with CD, 13 years; 56 with IC, 10.5 years; and 43 with HC, 10 years) were examined. Median PR3-ANCA values in UC (1.6 U/mL) were greater than in CD (0.2; P < 0.001), IC (0.15; P < 0.001), and HC (0.1; P < 0.001). In receiver operating characteristic curve analyses, the area under the curve for PR3-ANCA was 0.79, significantly greater than for MPO-ANCA (0.58; P < 0.001). Using a cut-off value of 0.8 U/mL determined from the receiver operating characteristic analyses, PR3-ANCA showed significantly greater sensitivity (64.9%) than MPO-ANCA (cut-off, 0.2 U/mL; sensitivity, 19.6%; P < 0.001) and good specificity (83.6%). CONCLUSIONS: In Japanese children and adolescents, PR3-ANCA performed better as a serologic marker for diagnosis of UC than MPO-ANCA. To our knowledge, this is the first report of such a comparison.

A neonatal case of coxsackievirus B3 vertical infection with symptoms of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome of excessive immune activation that most commonly affects infants. We report the case of a term female neonate with HLH associated with coxsackievirus B3 Infection. Her mother was hospitalized due to high fever 4 days before the delivery. The patient was delivered by vaginal delivery after the induction of labor. She was admitted to the neonatal care unit due to continuous high fever and poor sucking on her 4th day of life. She developed apnea on her 5th day of life. Laboratory findings on the patient's 7th day of life indicated severe thrombocytopenia, liver dysfunction, coagulation abnormality and hyperferritinemia. Coxsackievirus B3 was isolated from all cultured specimens by the PCR method. She received intravenous transfusion of platelets and immunoglobulin. Her platelet count gradually increased to the normal range by her 14th day of life and she was discharged without any sequelae on her 25th day of life. To the best of our knowledge, this is the first case report of neonatal HLH associated with a vertical transmission of coxsackievirus B3. Coxsackievirus is an important virus that can cause HLH in neonates. An early diagnosis and timely treatment are crucial.

Association between Asian dust exposure and respiratory function in children with bronchial asthma in Nagasaki Prefecture, Japan.

BACKGROUND: Studies on the adverse effects of Asian dust (AD) on respiratory function in children are scarce. The objective of this study was to examine the association between AD and respiratory function by measuring peak expiratory flow rates (PEFRs) in asthmatic children. METHODS: The study was carried out from March to May from 2014 through 2016. One hundred ten children with bronchial asthma were recruited from four hospitals in the Goto Islands and south Nagasaki area in Nagasaki prefecture. The parents were asked to record their children's PEFRs every morning/evening and clinical symptoms in an asthma diary. AD was assessed from light detection and ranging data, and a linear mixed-effects model was used to estimate the effects of AD on daily PEFR. Time-stratified case-crossover analyses were performed to examine the association between AD and asthma attacks defined by reduction levels in PEFR. RESULTS: AD was detected on 11 days in the Goto Islands, and on 23 days in the south Nagasaki area. After adjusting for age, sex, temperature, and daily oxidants, we found a consistent association between AD and a 1.1% to 1.7% decrease in PEFR in the mornings and a 0.7% to 1.3% decrease in the evenings at a lag of 0 to 5 days. AD was not associated with the number of asthma attacks, respiratory symptoms, or other symptoms at any lag days examined. CONCLUSIONS: Exposure to AD was associated with reduced PEFR, although the effects were not large enough to induce clinically apparent symptoms, in clinically well-controlled asthmatic children.

Antibodies to Crohn's disease peptide 353 as a diagnostic marker for pediatric Crohn's disease: a prospective multicenter study in Japan.

BACKGROUND: Various serologic markers such as anti-glycoprotein 2 antibodies and anti-Saccharomyces cerevisiae antibodies have been reported to be diagnostically useful in Crohn's disease. Mitsuyama et al. reported that antibodies to Crohn's disease peptide 353, a newly proposed serologic marker, were more useful in Japanese adults than anti-Saccharomyces. We addressed the same issue in Japanese children and adolescents. METHODS: Prospectively enrolled subjects under 17 years old assessed and treated at 12 pediatric centers in Japan included groups with Crohn's disease, ulcerative colitis, other intestinal diseases, or good health. The 3 serum markers were analyzed by enzyme-linked immunosorbent assays. RESULTS: Enrolled subjects, numbering 367, included 120 with Crohn's disease, 148 with ulcerative colitis, 56 with other intestinal diseases, and 43 healthy subjects. In Crohn's disease, anti-Crohn's disease peptide 353, anti-glycoprotein 2, and anti-Saccharomyces concentrations (median, 2.25, 3.0, and 8.9 U/mL) were significantly greater than in ulcerative colitis (1.1, 1.9, and 3.4; all P < 0.001), other intestinal diseases (1.1, 1.85, and 2.95; all P < 0.001), and healthy controls (1.1, 1.7, and 2.8; all P < 0.001), respectively. At 95% specificity, sensitivity of anti-Crohn's disease peptide (45.0%) was significantly higher than for anti-glycoprotein 2 (30.8%; P < 0.05) or anti-Saccharomyces (26.7%; P < 0.01). CONCLUSIONS: Anti-Crohn's disease peptide 353 proved more useful for diagnosis of Crohn's disease in Japanese children than the other 2 markers. To our knowledge, this is the first pediatric report to that effect.

Anaphylaxis to Carboxymethylcellulose: Add Food Additives to the List of Elicitors.

A 14-year-old girl developed 4 episodes of anaphylaxis of unknown etiology, which required intramuscular adrenaline administration each time. She had eaten pizza and a cheeseburger immediately before the first 2 episodes, respectively, but had not eaten anything for several hours before the last 2 episodes. It turned out that she had eaten the same ice lolly 4 hours before the first 3 episodes and a Café au lait Swirkle (a half-frozen beverage) 4 hours before the last episode. We detected carboxymethylcellulose sodium as the only common ingredient in all anaphylactic episodes. Skin prick tests were positive for carboxymethylcellulose solution and carboxymethylcellulose-containing food products. We obtained a custom-made carboxymethylcellulose sodium-free ice lolly from the manufacturer and confirmed that it did not induce anaphylactic reactions by a challenge test. Carboxymethylcellulose, an anionic water-soluble polymer derived from native cellulose, is considered to be unabsorbable from the human gut and has been widely and increasingly used in pharmaceutical preparations, cosmetics, and food. This article is the first report of anaphylaxis caused by carboxymethylcellulose-containing foods, whereas anaphylaxis to carboxymethylcellulose has been rarely associated with carboxymethylcellulose-containing pharmaceuticals. Although the exact mechanisms underlying the induction of late-onset anaphylaxis by carboxymethylcellulose remain unclear, a small minority of cellulose-digesting microbial flora in the human colon and contamination of food products with carboxymethylcellulose of low molecular weight might be involved. The induction of recurrent anaphylaxis by various products should be a clue that prompts physicians to suspect food additives as a cause for anaphylaxis.

Early canakinumab therapy for the sensorineural deafness in a family with Muckle-Wells syndrome due to a novel mutation of NLRP3 gene.

Cryopyrin-associated periodic syndrome (CAPS) is one of the autoinflammatory disorders caused by mutations in NLRP3 gene. The over-production of interleukin (IL)-1ß induced by NLRP3 gene mutations plays an important role in the pathophysiology of CAPS. We diagnosed 3 patients with CAPS, who were lineal family members having a novel mutation of NLRP3 gene. The objective of this report is to compare the characteristics of symptoms and differences in the therapeutic responses of them, who had the same mutation. In addition, we aimed to examine the usefulness of cytokine measurement for diagnosis or determination of treatment effect of CAPS. A 5-year-old Japanese boy (proband) came to our hospital because of short stature, reached the diagnosis of Muckle-Wells syndrome (MWS) due to a mutation in NLRP3 gene, which had not been reported so far (p.G328E, c.G983A). His mother and grandmother harbored the same mutation of NLRP3. We measured serum concentrations of cytokines in the proband assessed by flow-cytometric bead array. All of them had episodic skin eruptions with conjunctivitis, hearing loss, and arthralgia, but not periodic fever, cold-triggered episodes, and chronic aseptic meningitis. Only the proband had short stature. Canakinumab therapy led to a prompt relief of symptoms and normalized laboratory data in all patients. Audiograms demonstrated an improved hearing level in the proband, but not two others despite of the same mutation. All cytokines did not show any characteristic findings. Sensorineural hearing loss and itchless rash but not serum cytokine profile deserved attention to the diagnosis and treatment start of CAPS. The early intervention of IL-1ß blockade may reduce the chance of complete deafness in patients with CAPS.

Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome.

Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency characterized by recurrent respiratory tract infections, lymphoproliferation, and defective IgG production. Heterozygous mutations in PIK3CD, PIK3R1, or PTEN, which are related to the hyperactive phosphoinositide 3-kinase (PI3K) signaling, were recently presented to cause APDS1 or APDS2 (APDSs), or APDS-like (APDS-L) disorder. In this study, we examined the AKT phosphorylation of peripheral blood lymphocytes and monocytes in patients with APDSs and APDS-L by using flow cytometry. CD19+ B cells of peripheral blood in APDS2 patients showed the enhanced phosphorylation of AKT at Ser473 (pAKT) without any specific stimulation. The enhanced pAKT in CD19+ B cells was normalized by the addition of a p110δ inhibitor. In contrast, CD3+ T cells and CD14+ monocytes did not show the enhanced pAKT in the absence of stimulation. These findings were similarly observed in patients with APDS1 and APDS-L. Among CD19+ B cells, enhanced pAKT was prominently detected in CD10+ immature B cells compared with CD10- mature B cells. Enhanced pAKT was not observed in B cells of healthy controls, patients with common variable immunodeficiency, and hyper IgM syndrome due to CD40L deficiency. These results suggest that the enhanced pAKT in circulating B cells may be useful for the discrimination of APDS1, APDS2, and APDS-L from other antibody deficiencies.