Assessment of type I interferon signatures in undifferentiated inflammatory diseases: A Japanese multicenter experience.

Purpose: Upregulation of type I interferon (IFN) signaling has been increasingly detected in inflammatory diseases. Recently, upregulation of the IFN signature has been suggested as a potential biomarker of IFN-driven inflammatory diseases. Yet, it remains unclear to what extent type I IFN is involved in the pathogenesis of undifferentiated inflammatory diseases. This study aimed to quantify the type I IFN signature in clinically undiagnosed patients and assess clinical characteristics in those with a high IFN signature. Methods: The type I IFN signature was measured in patients' whole blood cells. Clinical and biological data were collected retrospectively, and an intensive genetic analysis was performed in undiagnosed patients with a high IFN signature. Results: A total of 117 samples from 94 patients with inflammatory diseases, including 37 undiagnosed cases, were analyzed. Increased IFN signaling was observed in 19 undiagnosed patients, with 10 exhibiting clinical features commonly found in type I interferonopathies. Skin manifestations, observed in eight patients, were macroscopically and histologically similar to those found in proteasome-associated autoinflammatory syndrome. Genetic analysis identified novel mutations in the PSMB8 gene of one patient, and rare variants of unknown significance in genes linked to type I IFN signaling in four patients. A JAK inhibitor effectively treated the patient with the PSMB8 mutations. Patients with clinically quiescent idiopathic pulmonary hemosiderosis and A20 haploinsufficiency showed enhanced IFN signaling. Conclusions: Half of the patients examined in this study, with undifferentiated inflammatory diseases, clinically quiescent A20 haploinsufficiency, or idiopathic pulmonary hemosiderosis, had an elevated type I IFN signature.

Nationwide surveillance of bacterial pathogens isolated from children conducted by the surveillance committee of Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2017: General overview of pathogenic antimicrobial susceptibility.

A nationwide surveillance of the antimicrobial susceptibility of pediatric patients to bacterial pathogens was conducted by Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in Japan in 2017. The isolates were collected from 18 medical facilities between March 2017 and May 2018 by the three societies. Antimicrobial susceptibility testing was conducted at the central laboratory (Infection Control Research Center, Kitasato University, Tokyo) according to the methods recommended by the Clinical Laboratory Standards Institute. Susceptibility testing was evaluated in 926 strains (331 Streptococcus pneumoniae, 360 Haemophilus influenzae, 216 Moraxella catarrhalis, 5 Streptococcus agalactiae, and 14 Escherichia coli). The ratio of penicillin-resistant S. pneumoniae was 0% based on CLSI M100-ED29 criteria. However, three meropenem or tosufloxacin resistant S. pneumoniae isolates were obtained. Among H. influenzae, 13.1% of them were found to be ß-lactamase-producing ampicillin resistant strains, while 20.8% were ß-lactamase non-producing ampicillin-resistant strains. No capsular type b strains were detected. In M. catarrhalis, 99.5% of the isolates were ß-lactamase-producing strains. All S. agalactiae and E. coli strains were isolated from sterile body sites (blood or cerebrospinal fluid). The ratio of penicillin-resistant S. agalactiae was 0%, while that of extended spectrum ß-lactamase-producing E. coli was 14.3%.

Dominant mutations in ORAI1 cause tubular aggregate myopathy with hypocalcemia via constitutive activation of store-operated Ca²âº channels.

The store-operated Ca(2+) release-activated Ca(2+) (CRAC) channel is activated by diminished luminal Ca(2+) levels in the endoplasmic reticulum and sarcoplasmic reticulum (SR), and constitutes one of the major Ca(2+) entry pathways in various tissues. Tubular aggregates (TAs) are abnormal structures in the skeletal muscle, and although their mechanism of formation has not been clarified, altered Ca(2+) homeostasis related to a disordered SR is suggested to be one of the main contributing factors. TA myopathy is a hereditary muscle disorder that is pathologically characterized by the presence of TAs. Recently, dominant mutations in the STIM1 gene, encoding a Ca(2+) sensor that controls CRAC channels, have been identified to cause tubular aggregate myopathy (TAM). Here, we identified heterozygous missense mutations in the ORAI1 gene, encoding the CRAC channel itself, in three families affected by dominantly inherited TAM with hypocalcemia. Skeletal myotubes from an affected individual and HEK293 cells expressing mutated ORAI1 proteins displayed spontaneous extracellular Ca(2+) entry into cells without diminishment of luminal Ca(2+) or the association with STIM1. Our results indicate that STIM1-independent activation of CRAC channels induced by dominant mutations in ORAI1 cause altered Ca(2+) homeostasis, resulting in TAM with hypocalcemia.

Comparison between virus shedding and fever duration after treating children with pandemic A H1N1/09 and children with A H3N2 with a neuraminidase inhibitor.

BACKGROUND: Shedding of the pandemic virus during an influenza pandemic is thought to persist longer than shedding of influenza viruses during annual influenza seasons, because people have much less immunity against a pandemic influenza. A correlation is thought to exist between the length of virus shedding and the clinical severity of influenza illness. METHODS: We compared the virus isolation rates of children with pandemic A H1N1/09 influenza infection and children with A H3N2 influenza infection after the patients had been treated with one of three neuraminidase inhibitors (NAI) such as peramivir, laninamivir and oseltamivir. The clinical effectiveness of each NAI was assessed on the basis of the duration of the febrile period after the start of treatment. RESULTS: Influenza viruses were isolated from 15 of the 34 patients in the A H3N2 group (mean age 6.2 years) and from 4 of the 25 patients in the A H1N1/09 (mean age 5.6 years) virus group (44.1% versus 16.0%; P<0.05). However, the differences between the duration of fever in the patients in the A H3N2 group and A H1N1/09 group after treatment with the NAIs were not significant. CONCLUSIONS: The virus isolation rates after treatment with each of the NAIs were significantly lower in the A H1N1/09 group, suggesting that the pandemic A H1N1/09 virus was more sensitive to the NAIs than the seasonal A H3N2 virus was. Clinically, there were no significant differences in the effectiveness of the NAIs between the H1N1/09 infected group and H3N2 infected group.

Primary ciliary dyskinesia diagnosed on nasal mucosal biopsy in two newborns.

Primary ciliary dyskinesia (PCD) is a genetic disease that causes abnormalities in ciliary structure and/or function. Ciliated cells line the upper and lower respiratory tracts and the Eustachian tube. Impairment of mucus clearance at these sites leads to sinusitis, repeated pulmonary infections, bronchiectasis, and chronic otitis media. Situs inversus occurs randomly in approximately 50% of subjects with PCD. The triad of situs inversus, bronchiectasis and sinusitis is known as Kartagener syndrome. PCD is usually an autosomal recessive disease, but occasional instances of X-linked transmission have been reported. Specific diagnosis requires examination of ciliary function or structure on light and electron microscopy. Early diagnosis and respiratory management are important in order to prevent the development of bronchiectasis and deterioration in lung function. We report early diagnosis of PCD on nasal mucosal biopsy in two newborns who presented with prolonged respiratory distress and rhinorrhea.

[Efficacy and safety of faropenem in pediatric patients with bacterial infectious diseases].

The only oral penem antibiotic, faropenem (FRPM: Farom Dry Syrup for pediatrics), is one of the few antibiotics that exerts potent antibacterial activity against penicillin-resistant Streptococcus pneumoniae (PRSP), and the dosage and administration schedule has been established for children. We studied the efficacy and safety of the drug in 113 pediatric patients with mild-to-moderate bacterial infectious diseases: upper respiratory tract infection (pharyngitis or tonsillitis), acute bronchitis, otitis media and urinary tract infection (UTI). The patients were administered oral FRPM at the dose of 15-30 mg/kg/day three times a day for 3 to 8 days (or 5 to 14 days for group A streptococcal infection). The study drug was found to be clinically effective in 63/70 cases (90.0%) of upper respiratory tract infection, 6/7 cases of acute bronchitis, 16/17 cases (94.1%) of otitis media and 6/6 cases of UTI. FRPM was demonstrated to have very potent antibacterial activity against S. pneumoniae, with a high bacteriological eradication rate. No serious adverse drug reactions were observed. The only side effect was diarrhea in 12.5% of the patients (14/112 cases). There was little difference in the incidence of diarrhea between FRPM and other oral beta-lactam antibiotics. Compliance with FRPM was found to be very good in this study. These findings suggest that FRPM is as useful for the treatment of bacterial infectious diseases in children as oral penicillin and cephem antibiotics.

Prospective surveillance for atypical pathogens in children with community-acquired pneumonia in Japan.

A total of 141 children with community-acquired pneumonia (CAP) were studied prospectively to determine the causative microorganisms. Microbial investigations included examination of postnasal swabs, cultures, polymerase chain reaction (PCR), and serology. The atypical pathogens occurring most frequently were Mycoplasma pneumoniae (58 patients [41.1%]), Chlamydia pneumoniae (4 patients [2.8%]), and concurrent occurrence of both pathogens (1 patient [0.7%]). Patients aged under 4 years showed a relatively lower rate of atypical bacterial etiology compared with those aged 4 years or older. Major bacterial pathogens were detected in 89 patients (atypical pathogens were detected in 28 patients simultaneously), including Streptococcus pneumoniae in 34 patients, Haemophilus influenzae in 60, Moraxella catarrhalis in 48, and multiple pathogens in 42. In patients suspected of having atypical pneumonia, macrolides are recommended.