Serum pepsinogen cut-off values in Helicobacter pylori-infected children.

BACKGROUND: The aim of this study was to evaluate the standard values for gender- and age-stratified serum pepsinogen (sPG) in Helicobacter pylori (H. pylori) non-infected children and to determine the optimal cut-off values of sPG for predicting H. pylori-infected gastritis in children. METHODS: A prospective study for determination of sPG levels was performed in children with epigastric pain who underwent esophagogastroduodenoscopy over the past 16 years. After excluding subjects diagnosed with inflammatory bowel diseases, eosinophilic gastrointestinal disorders, or immunoglobulin A vasculitis, the diagnosis of H. pylori infection was defined by positive tissue culture or concordant-positive results for histology and the rapid urease test. RESULTS: A total of 405 subjects were diagnosed as being H. pylori-infected (79) or non-infected (326). In the H. pylori non-infected group, there were no significant differences in sPG levels among age groups; males had higher sPG I and sPG II levels than females. In the H. pylori-infected group, sPG I and sPG II levels were significantly higher and the sPG I/II ratio was lower than those in the non-infected group. In receiver operating characteristics analyses in diagnosing H. pylori infection, the areas under the curves for sPG I, sPG II and sPG I/II ratio were 0.896, 0.980, and 0.946, respectively. The optimal cut-off value of sPG II of ≥9.0 ng/mL was considered positive for H. pylori infection (sensitivity: 92.4%, specificity: 93.9%). CONCLUSIONS: The optimal cut-off value of sPG II of ≥9.0 ng/mL may be a good predictor of H. pylori-infected gastritis in children.

Absent X-linked inhibitor of apoptosis protein expression in T cell blasts and causal mutations including non-coding deletion.

BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) deficiency is one of inborn errors of immunity characterized by recurrent hemophagocytic lymphohistiocytosis and refractory inflammatory bowel disease (IBD), mimicking Crohn's disease. The aim of this study is to make an accurate diagnosis of XIAP deficiency based on genetic and XIAP expression studies and to investigate endoscopic findings shared by patients with this disease. METHODS: Four male patients with recurrent hemophagocytic lymphohistiocytosis and long-term refractory IBD were studied for the diagnosis of XIAP deficiency. Endoscopic findings of the four patients were also studied in parallel. RESULTS: These four patients were diagnosed with XIAP deficiency based on the absent XIAP expression in cultured T-cell blasts. Sequence analysis of the responsible gene, XIAP, demonstrated two novel nonsense mutations of p.Gln114X and p.Glu25X, and a previously reported nonsense mutation of p.Arg381X. Although no mutations in the coding region were detected in the fourth patient, further studies demonstrated a novel 2,199 bp deletion encompassing non-coding exon 1, presumably affecting transcription and stability of XIAP mRNA. All of the patients eventually underwent hematopoietic stem cell transplantation, leading to a complete or partial remission of IBD. These four patients shared an endoscopic finding of multiple wide and longitudinal ulcers with straight and non-raised edge in the colon. CONCLUSIONS: X-linked inhibitor of apoptosis protein expression in T-cell blasts could facilitate the diagnosis of this disease, especially with causal mutations in non-coding regions.

The updated JSPGHAN guidelines for the management of Helicobacter pylori infection in childhood.

The Japan Pediatric Helicobacter pylori Study Group published the first guidelines on childhood H. pylori infection in 1997. They were later revised by the Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition (JSPGHAN). The H. pylori eradication rates, when employing triple therapy with amoxicillin and clarithromycin, currently recommended as the first-line therapy of H. pylori infection in Japan, have substantially decreased, creating an important clinical problem worldwide. In Japanese adults, the "test-and-treat" strategy for H. pylori infection is under consideration as an approach for gastric cancer prevention. However, the combined North American and European pediatric guidelines have rejected such a strategy for asymptomatic children. As risk for gastric cancer development is high in Japan, determining whether the "test-and-treat" strategy can be recommended in children has become an urgent matter. Accordingly, the JSPGHAN has produced a second revision of the H. pylori guidelines, which includes discussion about the issues mentioned above. They consist of 19 clinical questions and 34 statements. An H. pylori culture from gastric biopsies is recommended, not only as a diagnostic test for active infection but for antimicrobial susceptibility testing to optimize eradication therapy. Based upon antimicrobial susceptibility testing of H. pylori strains (especially involving clarithromycin), an eradication regimen including use of the antibiotics to which H. pylori is susceptible is recommended as the first-line therapy against H. pylori-associated diseases. The guidelines recommend against a "test-and-treat" strategy for H. pylori infection for asymptomatic children to protect against the development of gastric cancer because there has been no evidence supporting this strategy.

Clinical effectiveness of four neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir) for children with influenza A and B in the 2014-2015 to 2016-2017 influenza seasons in Japan.

The clinical effectiveness of four neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir, and peramivir) for children aged 0 months to 18 years with influenza A and B were investigated in the 2014-2015 to 2016-2017 influenza seasons in Japan. A total of 1207 patients (747 with influenza A and 460 with influenza B) were enrolled. The Cox proportional-hazards model using all of the patients showed that the duration of fever after administration of the first dose of the NAI was shorter in older patients (hazard ratio = 1.06 per 1 year of age, p < 0.001) and that the duration of fever after administration of the first dose of the NAI was shorter in patients with influenza A infection than in patients with influenza B infection (hazard ratio = 2.21, p < 0.001). A logistic regression model showed that the number of biphasic fever episodes was 2.99-times greater for influenza B-infected patients than for influenza A-infected patients (p < 0.001). The number of biphasic fever episodes in influenza A- or B-infected patients aged 0-4 years was 2.89-times greater than that in patients aged 10-18 years (p = 0.010), and the number of episodes in influenza A- or B-infected patients aged 5-9 years was 2.13-times greater than that in patients aged 10-18 years (p = 0.012).

Intrafamilial, Preferentially Mother-to-Child and Intraspousal, Helicobacter pylori Infection in Japan Determined by Mutilocus Sequence Typing and Random Amplified Polymorphic DNA Fingerprinting.

BACKGROUND: The infection route of Helicobacter pylori has been recognized to be mainly intrafamilial, preferentially mother-to-child, especially in developed countries. To determine the transmission route, we examined whether multilocus sequence typing (MLST) was useful for analysis of intrafamilial infection. The possibility of intraspousal infection was also evaluated. MATERIALS AND METHODS: Clonal relationships between strains derived from 35 index Japanese pediatric patients, and their family members were analyzed by two genetic typing procedures, MLST and random amplified polymorphic DNA (RAPD) fingerprinting. RESULTS: Mostly coincident results were obtained by MLST and RAPD. By MLST, the allele of loci in the isolates mostly matched between the index child and both the father and mother for 9 (25.7%) of the 35 patients, between the index child and the mother for 25 (60.0%) of the 35 patients. CONCLUSIONS: MLST is useful for analyzing the infection route of H. pylori as a highly reproducible method. Intrafamilial, especially mother-to-children and sibling, infection is the dominant transmission route. Intraspousal infection is also thought to occur in about a quarter in the Japanese families.

Long-term therapeutic effectiveness of maintenance enteral nutrition for Crohn's disease.

BACKGROUND: Long-term effectiveness of enteral nutrition for maintaining remission in pediatric Crohn's disease (CD) is poorly documented. The aim of this study was therefore to examine the long-term effectiveness of enteral nutrition with aminosalicylates as maintenance therapy for those in whom remission was primarily induced by total parenteral nutrition or exclusive enteral nutrition with aminosalicylates. METHODS: We retrospectively analyzed data for 58 pediatric patients with newly diagnosed CD during a median follow-up period of 50 months (range, 12-216 months). Data for remission-induced patients in whom enteral nutrition with aminosalicylates was used as maintenance therapy were analyzed with particular reference to time to first relapse and time to first intestinal surgery. RESULTS: Twenty-five (43.1%) of the patients relapsed with a median duration of remission of 32.4 months (range, 6-73.2 months). The cumulative rates of continuous remission were 0.88 (95%CI: 0.79-0.96) at 1 year, 0.73 (95%CI: 0.61-0.85) at 2 years, and 0.52 (95%CI: 0.35-0.68) at 5 years. None of the patients received corticosteroids, immunomodulators or anti-tumor necrosis factor agents until relapse. Disease location had no impact on timing of relapse, but with regard to disease behavior there was a trend towards earlier relapse in patients with penetrating type. Only six of the 58 patients (10.3%) needed intestinal surgery. There was a trend towards need for surgery in patients with ileal disease and with stricturing type. CONCLUSIONS: Enteral nutrition therapy with aminosalicylates is effective for maintaining remission and decreasing the rate of intestinal surgery in pediatric CD.

Positive relationship between a polymorphism in Helicobacter pylori neutrophil-activating protein a gene and iron-deficiency anemia.

BACKGROUND: Numerous studies have suggested a link between iron-deficiency anemia (IDA) and Helicobacter pylori infection. Previously, we found that strains isolated from IDA patients showed higher levels of Fe ion uptake and Fe-ion-dependent rapid proliferation than those of strains derived from patients without IDA. MATERIALS AND METHODS: Twenty-four H. pylori strains from IDA patients (IDA strains) and 25 strains from patients who had H. pylori gastritis without anemia (non-IDA strains) were examined. Their nucleotide sequences of napA, fur, and feoB, which contribute to Fe ion uptake, were determined. RESULTS: Numerous polymorphisms of the three genes were found in both strains. Frequency of neutrophil-activating protein A (NapA), which encoded by napA, with threonine at amino acid residue No. 70 (Thr70-type NapA) was significantly higher in IDA strains than in non-IDA strains. Strains with Thr70-type NapA showed significantly higher levels of Fe(3+) and Fe(2+) uptake than did strains with other types, Ser70-type of NapA, which is found in standard strains. Other significantly different occurrences of polymorphisms between IDA and non-IDA groups were not observed in these genes. CONCLUSION: The results suggest that H. pylori strains with Thr70-type NapA have enhanced Fe ion uptake ability and are associated with the pathogenesis of IDA.

[Iron-deficiency anemia].

Numerous studies have suggested a link between iron-deficiency anemia(IDA) and Helicobacter pylori infection. Previously, we found that strains isolated from IDA patients showed higher levels of Fe ion uptake and Fe-iron-dependent rapid proliferation than those of strains derived from patients without IDA. Recently we examined the nucleotide sequences of nap A, fur, and feo B of H. pylori strains from 24 IDA patients and those from 25 non-IDA patients. Frequency of neutrophil-activating protein A(Nap A), which encoded by nap A, with threonine at amino acid residue No. 70 (Thr70-type Nap A) was significantly higher in IDA strains than non-IDA strains. Strains with Thr70-type Nap A showed significantly higher levels of Fe3+ and Fe2+ uptake than strains with other type, Ser70-type Nap A, which is found in standard strains.

Detection of human bocaviruses 1 to 4 from nasopharyngeal swab samples collected from patients with respiratory tract infections.

Human bocaviruses (HBoV) 1, 2, 3, and 4 (HBoV1-4) were detected in 132 (15.5%), 5 (0.6%), 3 (0.4%), and 5 (0.6%) of 850 nasopharyngeal swab samples collected from children with respiratory tract infections, respectively. Out of the 145 HBoV1-4-positive samples, 62 (42.8%) were codetected with other respiratory viruses.

Leukocytapheresis in pediatric patients with ulcerative colitis.

OBJECTIVE: Leukocytapheresis (LCAP) is a nonpharmacologic therapy that has recently been used to treat ulcerative colitis (UC). This multicenter open-label study prospectively assessed the efficacy and safety of LCAP in pediatric patients with UC. PATIENTS AND METHODS: Twenty-three patients ages 8 to 16 years with moderate (n = 19) to severe (n = 4) steroid-resistant UC were enrolled. One of 2 LCAP columns with different volumes (model EX and the half-volume model EI) was selected, according to body weight. LCAP was performed once per week for 5 consecutive weeks. Clinical and laboratory data were collected at predetermined time points. The primary endpoint was decreased stool frequency/hematochezia score, and secondary endpoints were clinical, laboratory, and endoscopic improvements. RESULTS: The stool frequency/hematochezia score decreased significantly from 4.5 ± 1.2 before treatment to 1.6 ± 1.9 after the fifth treatment. Clinical parameters, including stool frequency, presence of visible blood, abdominal pain, and body temperature, were significantly improved. Fecal calprotectin decreased significantly. Endoscopic findings evaluated using Matts score also improved (P < 0.01). The steroid dose decreased from 1.1 ± 0.4 mg/kg before treatment to 0.8 ± 0.5 mg/kg after treatment. There were no significant differences in changes between the EX and EI columns. The incidence of adverse effects was 61%, although none was serious. The most common adverse effects were decreased hematocrit and hemoglobin concentration. CONCLUSIONS: The present study showed that LCAP was well tolerated in children with UC, mostly moderate, and was as effective as in adults. The types of pediatric patients best suited to LCAP remain to be determined.

P1 gene of Mycoplasma pneumoniae isolated from 2016 to 2019 and relationship between genotyping and macrolide resistance in Hokkaido, Japan.

We characterized 515 Mycoplasma pneumoniae specimens in Hokkaido. In 2013 and 2014, the p1 gene type 1 strain, mostly macrolide-resistant, was dominant and the prevalence of macrolide resistance was over 50 %. After 2017, the p1 gene type 2 lineage, mostly macrolide-sensitive, increased and the prevalence of macrolide resistance became 31.0 % in 2017, 5.3 % in 2018 and 16.3 % in 2019.

Patients with Epstein-Fechtner syndromes owing to MYH9 R702 mutations develop progressive proteinuric renal disease.

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.

Success and limitations of plasma treatment in pregnant women with congenital thrombotic thrombocytopenic purpura.

BACKGROUND: Congenital thrombotic thrombocytopenic purpura (cTTP), otherwise known as Upshaw-Schulman syndrome, is an extremely rare hereditary disease. Pregnancy is identified as a trigger for TTP episodes in patients with cTTP. OBJECTIVES: To investigate the ideal management of pregnant patients with cTTP. PATIENTS/METHODS: We identified 21 patients with a reproductive history (38 pregnancies) in a Japanese cTTP registry. Fetal outcomes were compared between two groups: group 1 (n = 12), pregnancy after diagnosis of confirmed cTTP by ADAMTS13 gene analysis; and group 2 (n = 26), pregnancy before diagnosis of confirmed cTTP. RESULTS: In group 1, ADAMTS13 activity was closely monitored until delivery in most cases. Among 10 pregnancies in group 1, prophylactic fresh frozen plasma (FFP) infusions during pregnancy were performed to replenish ADAMTS13. In group 2, prophylactic FFP infusions were not administrated in 23 pregnancies and FFP test infusions were performed in only three pregnancies. The live birth rate of group 1 was significantly higher than that of group 2 (91.7% vs 50.0%, respectively, P = .027). The fetal survival rates of women without FFP infusions were dramatically decreased after 20 weeks of gestation. The FFP infusion dosage in group 1 was generally higher than 5 mL/kg/wk by 20 weeks of gestation. CONCLUSIONS: Our results indicate that FFP infusions of more than 5 mL/kg/wk should be initiated as soon as patients become pregnant. However, even with these infusions, patients with repeated TTP episodes before pregnancy might have difficulty giving birth successfully. Recombinant ADAMTS13 products might be new treatment options for pregnant patients with cTTP.

[Iron-deficiency anemia in children].

Recent studies including case reports, case series, observational epidemiologic studies and intervention trials have suggested an association of Helicobacter pylori (H. pylori) and iron-deficiency anemia (IDA). Resolution of IDA was reported to be achieved among the patients who had a suboptimal response to iron therapy despite adequate iron supplementation or who had frequent relapses after stopping iron supplementation in children, especially in puberty. The biologic mechanism by which H. pylori induces the iron stores is not fully understood, but we recently reported that strains of H. pylori derived from pediatric patients with IDA showed enhanced Fe ion uptake and Fe ion-dependent rapid growth compared with those from patients with non-IDA.

Enhanced infectivity of strains of Helicobacter pylori isolated from children compared with parental strains.

PURPOSE: Intra-familial infection, mother-to-child infection, is considered to be one of the main routes of transmission for Helicobacter pylori, in developed countries such as Japan. A major role for intra-familial spread in the pathogenicity of H. pylori is now beyond controversy, although the major route of transmission remains poorly understood. We performed this study to clarify the factors determining intra-familial transmission. METHODOLOGY: We used several H. pylori strains isolated from family members to compare infectivity. H. pylori K21 and K22 strains were isolated from the father and mother, and the K25 strain was isolated from the third child of the family. Mongolian gerbils were inoculated with H. pylori strains and the infectivity of three strains was compared in each experiment. In addition, the whole genome sequence, adhesion to gastric epithelial cells and the growth of static condition or continuous flow culture among three strains of H. pylori were analysed.Results/Key findings. Most of the colonies were determined as the same molecular type K25 in all of the four grouped animals and H. pylori K25 was observed as the dominant strain. The stronger adhesion capacity of the K25 strain was observed in comparison with the other two strains through in vitro analysis. By assessing the genomic profiles of H. pylori isolates from three strains, identified TnPZ regions were detected only in the K25 strain. CONCLUSION: The infectivity of H. pylori isolates intra-familial infection and animal infection were prescribed by the adhesion capacity and molecular type of each strain.

Enhanced Fe ion-uptake activity in Helicobacter pylori strains isolated from patients with iron-deficiency anemia.

Recent studies have suggested a link between iron-deficiency anemia and Helicobacter pylori infection. In the current study, strains of H. pylori derived from patients with iron-deficiency anemia showed enhanced Fe ion uptake and Fe ion-dependent rapid growth compared with those from patients with non-iron-deficiency anemia. H. pylori with enhanced Fe ion-uptake ability may be a causative factor for iron-deficiency anemia.

Comparison of a lateral-flow immunochromatography assay with real-time reverse transcription-PCR for detection of human metapneumovirus.

A lateral-flow immunochromatography (IC) assay for the detection of human metapneumovirus (hMPV) has been developed by using two mouse monoclonal antibodies to the nucleocapsid protein of hMPV. The purpose of this study was to compare the virus detection rate in nasopharyngeal secretions by the IC assay with that by real-time reverse transcription-PCR (RT-PCR). We collected nasopharyngeal swab samples from 247 children with respiratory symptoms in Sapporo, Japan, during the period from April to July 2007. Sixty-eight of the 247 children were positive for hMPV by real-time RT-PCR. When the real-time RT-PCR was used as the reference standard, the IC assay results were positive for 48 of the 68 real-time RT-PCR-positive children (70.6% sensitivity) and 8 of the 179 real-time RT-PCR-negative children (95.5% specificity). Although the sensitivity of the IC assay is lower than that of real-time RT-PCR, the IC assay is a rapid and useful test for the diagnosis of hMPV infections in children.

Predominance of mother-to-child transmission of Helicobacter pylori infection detected by random amplified polymorphic DNA fingerprinting analysis in Japanese families.

BACKGROUND: Helicobacter pylori (H. pylori) is one of the most common bacterial pathogens in humans but the route of transmission remains unclear. We investigated transmission by DNA fingerprinting analysis of cultured H. pylori from pediatric patients and their family members. METHODS: Forty-two index patients with a mean age of 11.7 years (range, 4-19) were diagnosed as having H. pylori gastritis with or without duodenal/gastric ulcer disease. A total of 66 family members for whom the results of the H. pylori stool antigen test and/or serum H. pylori IgG test were positive underwent endoscopic examination and biopsy or aspiration of gastric juice for H. pylori culture. The extraction of H. pylori genomic DNA and PCR-based RAPD analysis were performed. RESULTS: Thirty-two (76%) of the 42 patients showed DNA fingerprint patterns identical to those of at least one of the respective family members. The patterns of 29 (69%) of the analyses of the H. pylori infected patients were identical to those of their mothers. The patterns for 7 patients were identical to those of their fathers, and those for 6 of the latter patients were also identical to those of their mothers. The rate of fingerprint patterns identical to those of the index patients was significantly higher in those of mothers compared with those of fathers (P < 0.01). CONCLUSIONS: Mother-to-child transmission is the predominant route of H. pylori infection in Japan.

Efficacy and safety of azathioprine and 6-mercaptopurine in Japanese pediatric patients with ulcerative colitis: a survey of the Japanese Society for Pediatric Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Azathioprine (AZA) and 6-mercaptopurine (6-MP) have recently been used in Japanese pediatric patients with ulcerative colitis. The aims of this study were to evaluate both the therapeutic efficacy and safety of AZA/6-MP in this group of patients. METHODS: Fourteen members of the Japanese Society for Pediatric Inflammatory Bowel Disease reported 35 retrospective cases that received AZA/6-MP and were evaluated for adverse drug effects. In those who tolerated AZA/6-MP, disease activity and corticosteroid doses before and during the first 6 months of therapy were assessed. RESULTS: AZA or 6-MP was safely used in 21 of 35 patients (60%) without adverse drug effects. The disease activity began to decrease from the first month of therapy and the maximum effect was achieved after 3 months. The mean daily prednisolone dose was decreased from 26.9 to 11.6 mg and dose reduction was achieved in 58% of patients after 6 months of therapy. Fourteen of the 35 patients (40%) experienced adverse drug effects, including leukopenia (n = 11), aplastic anemia (n = 1), pancreatitis (n = 1) and liver dysfunction (n = 1). CONCLUSIONS: The majority of Japanese children with ulcerative colitis tolerated AZA/6-MP and experienced favorable effects. However, 40% experienced adverse drug effects, mainly myelosuppression.