A significant outbreak of respiratory human adenovirus infections among children aged 3-6 years in Hokkaido, Japan, in 2023.

Human adenovirus (HAdV) infections present diverse clinical manifestations upon infecting individuals, with respiratory infections predominating in children. We surveyed pediatric hospitalizations due to respiratory HAdV infections across 18 hospitals in Hokkaido Prefecture, Japan, from July 2019 to March 2024, recording 473 admissions. While hospitalizations remained below five cases per week from July 2019 to September 2023, a notable surge occurred in late October 2023, with weekly admissions peaking at 15-20 cases from November to December. There were dramatic shifts in the age distribution of hospitalized patients: during 2019-2021, 1-year-old infants and children aged 3-6 years represented 51.4%-54.8% and 4.1%-13.3%, respectively; however, in 2023-2024, while 1-year-old infants represented 19.0%-20.1%, the proportion of children aged 3-6 years increased to 46.2%-50.0%. Understanding the emergence of significant outbreaks of respiratory HAdV infections and the substantial changes in the age distribution of hospitalized cases necessitates further investigation into the circulating types of HAdV in Hokkaido Prefecture and changes in children's neutralizing antibody titers against HAdV.

Clinical Characteristics of Pediatric Parainfluenza Virus Infections: A Comparative Analysis of Parainfluenza Virus Serotypes 1-4 From April 2021 to October 2023 in Hokkaido, Japan.

BACKGROUND: Parainfluenza virus (PIV) is widely known as a causative virus of acute respiratory tract infections in children, and 4 serotypes (PIV-1-PIV-4) have been identified. The purpose of the present study was to clarify the clinical characteristics of the PIV serotypes in pediatric PIV infections in Japan. METHODS: Between April 2021 and October 2023, 8821 children aged <16 years who presented with respiratory symptoms underwent multiplex polymerase chain reaction analyses at the Department of Pediatrics, NTT Medical Center Sapporo. All 1490 cases in which PIV was detected were analyzed for their clinical characteristics by PIV serotypes. RESULTS: Of the 1490 cases, 608 were positive for a single PIV serotype: 91 (13.5%) for PIV-1, 54 (4.8%) for PIV-2, 361 (62.1%) for PIV-3 and 102 (19.6%) for PIV-4. The median ages were 3.5 years for PIV-1, 5.4 years for PIV-2, 1.9 years for PIV-3 and 2.2 years for PIV-4, with a significantly older age for PIV-2. Compared with the other serotypes, croup was significantly more common in PIV-1 and lower respiratory tract infection was significantly more common in PIV-4. Of the 608 cases with a single PIV serotype, 114 were hospitalized. The proportion of hospitalized patients was higher for PIV-4 than for the other PIV serotypes, but the difference was not significant. CONCLUSIONS: Lower respiratory tract infection was more frequent in PIV-4 than in the other PIV serotypes, and PIV-4 infection may increase the risk of hospitalization.

Resurgence of human metapneumovirus infection and influenza after three seasons of inactivity in the post-COVID-19 era in Hokkaido, Japan, 2022-2023.

Following the coronavirus disease 2019 (COVID-19) outbreak in February 2020, incidences of various infectious diseases decreased notably in Hokkaido Prefecture, Japan. However, Japan began gradually easing COVID-19 infection control measures in 2022. Here, we conducted a survey of children hospitalized with human metapneumovirus (hMPV), influenza A and B, and respiratory syncytial virus infections in 18 hospitals across Hokkaido Prefecture, Japan, spanning from July 2019 to June 2023. From March 2020 to June 2022 (28 months), only 13 patients were hospitalized with hMPV, and two patients had influenza A. However, in October to November 2022, there was a re-emergence of hMPV infections, with a maximum of 27 hospitalizations per week. From July 2022 to June 2023 (12 months), the number of hMPV-related hospitalizations dramatically increased to 317 patients, with the majority aged 3-6 years (38.2%, [121/317]). Influenza A also showed an increase from December 2022, with a peak of 13 hospitalizations per week in March 2023, considerably fewer than the pre-COVID-19 outbreak in December 2019, when rates reached 45 hospitalizations per week. These findings suggest the possibility of observing more resurgences in infectious diseases in Japan after 2023 if infection control measures continue to be relaxed. Caution is needed in managing potential outbreaks.

Acute osteomyelitis/septic pulmonary embolism associated with familial infections caused by PVL-positive ST6562 MRSA-IVa, a presumptive variant of USA300 clone.

Panton-Valentine leukocidin (PVL)-positive methicillin-resistant Staphylococcus aureus (MRSA) occasionally causes severe invasive infections. A 10-year-old immunocompetent boy in Hokkaido, the northern main island of Japan, was admitted with acute osteomyelitis of the right ilium, complicated by septic thrombophlebitis of the right common iliac vein and septic pulmonary embolism. As MRSA was isolated from blood and sputum samples of the patient, linezolid and vancomycin were initially used for treatment, and later clindamycin was added based on PCR-positive results for PVL genes. During his hospitalization, the patient was complicated by abscesses around the right ilium and septic arthritis of the right hip, which required surgical drainage. Prior to his admission, his youngest sister had developed a right breast abscess, and another sister and his mother developed contagious impetigo and hordeolum, respectively, during his hospitalization. These infections in the patient and his family members were caused by an identical PVL-positive MRSA strain belonging to ST6562, a single-locus variant of ST8. Due to the genetically close characteristics, this ST6562 MRSA was considered a genetic variant of the USA300 CA-MRSA clone (ST8-MRSA-IVa) predominating in the United States. The ST6562 MRSA-IVa is suggested to have occurred in Japan, associated with potential spread of the USA300 clone.

Changing Patterns of Infectious Diseases Among Hospitalized Children in Hokkaido, Japan, in the Post-COVID-19 Era, July 2019 to June 2022.

BACKGROUND: Many reports have reported a reduction in respiratory infectious diseases and infectious gastroenteritis immediately after the coronavirus disease 2019 (COVID-19) pandemic, but data continuing into 2022 are very limited. We sought to understand the current situation of various infectious diseases among children in Japan as of July 2022 to improve public health in the post-COVID-19 era. METHODS: We collected data on children hospitalized with infectious diseases in 18 hospitals in Japan from July 2019 to June 2022. RESULTS: In total, 3417 patients were hospitalized during the study period. Respiratory syncytial virus decreased drastically after COVID-19 spread in early 2020, and few patients were hospitalized for it from April 2020 to March 2021. However, an unexpected out-of-season re-emergence of respiratory syncytial virus was observed in August 2021 (50 patients per week), particularly prominent among older children 3-6 years old. A large epidemic of delayed norovirus gastroenteritis was observed in April 2021, suggesting that the nonpharmaceutical interventions for COVID-19 are less effective against norovirus. However, influenza, human metapneumovirus, Mycoplasma pneumoniae , and rotavirus gastroenteritis were rarely seen for more than 2 years. CONCLUSIONS: The incidence patterns of various infectious diseases in Japan have changed markedly since the beginning of the COVID-19 pandemic to the present. The epidemic pattern in the post-COVID-19 era is unpredictable and will require continued careful surveillance.

Evaluation of peripheral basophil activation during exercise provocation test for desensitized patients.

Some food allergic patients who have undergone oral immunotherapy develop exercise-induced allergic reactions on desensitization (EIARDs). This study investigated basophil activation status during the exercise provocation test (EPT) performed to diagnose EIARD. EPT was performed on 20 participants, and in vivo basophil activation status was analyzed using activation markers CD203c and CD63. The results showed that there was no significant difference between EPT-positive and negative subjects for basophil activation status throughout EPT. Consequently, in vivo basophil activation after ingestion of the causative food may not be associated with EIARDs. New tests are desired for predicting EIARDs.

Surveillance in hospitalized children with infectious diseases in Japan: Pre- and post-coronavirus disease 2019.

INTRODUCTION: The epidemic of coronavirus disease 2019 (COVID-19) rapidly spread worldwide, and the various infection control measures have a significant influence on the spread of many infectious diseases. However, there have been no multicenter studies on how the number of hospitalized children with various infectious diseases changed before and after the outbreak of COVID-19 in Japan. METHODS: We conducted a multicenter, prospective survey for hospitalized pediatric patients in 18 hospitals in Hokkaido Prefecture, Japan, from July 2019 to February 2021. We defined July 2019 to February 2020 as pre-COVID-19, and July 2020 to February 2021 as post-COVID-19. We surveyed various infectious diseases by sex and age. RESULTS: In total, 5300 patients were hospitalized during the study period. The number of patients decreased from 4266 in the pre-COVID-19 period to 701 (16.4%) post-COVID-19. Patients with influenza and RSV decreased from 308 to 795 pre-COVID-19 to zero and three (0.4%) post-COVID-19. However, patients with adenovirus (respiratory infection) only decreased to 60.9% (46-28) of pre-COVID levels. Patients with rotavirus, norovirus, and adenovirus gastroenteritis decreased markedly post-COVID-19 to 2.6% (38-1), 27.8% (97-27) and 13.5% (37-5). The number of patients with UTIs was similar across the two periods (109 and 90). KD patients decreased to 31.7% (161-51) post-COVID-19. CONCLUSIONS: We suggest that current infection control measures for COVID-19 such as wearing masks, washing hands, and disinfecting hands with alcohol are effective against various infectious diseases. However, these effects vary by disease.

Calcium [¹³C]carbonate breath test for quantitative measurement of total gastric acid in rats.

OBJECTIVE: A traditional measurement of gastric acid, involving nasogastric intubation of stomach and acid suction, has been suggested as a gold standard. However, this causes the patient discomfort and cost increase, and is 'time-consuming'. MATERIAL AND METHODS: A calcium [(13)C]carbonate (Ca(13)CO(3)) breath test was carried out in rats without or with concomitant drugs omeprazole (OMP) and pentagastrin (PG) known as an inhibitor and an inducer of acid, respectively. This test was aimed at evaluating a correlation between the breath response and the total amount of gastric acid. To search for an absorption pathway of (13)CO(2) gas produced by the reaction of Ca(13)CO(3) with hydrochloric acid in the stomach of rats, we compared the breath responses after intra-gastric administration of (13)CO(2) gas and sodium [(13)C]bicarbonate (NaH(13)CO(3)). RESULTS: A linear relationship of the breath parameter (breath-C(max)) with the dose of Ca(13)CO(3) was obtained in the range of 4-200 µmol/kg. However, theses parameters were saturated at >200 µmol/kg. The direct correlation between the breath-C(max) and the total amount of gastric acid in rats with or without OMPs or PG (r = 0.994) demonstrated that the change in breath response is an accurate or sensitive indicator of the total amount of gastric acid. (13)CO(2) gas generated in the rat stomach was likely to diffuse across the stomach wall as (13)CO(2) gas directly into the blood plasma. CONCLUSIONS: The present study showed that Ca(13)CO(3) breath test is a good tool to accurately predict the total amount of gastric acid.

Desirable pharmacokinetic properties of (13)C-uracil as a breath test probe of gastric emptying in comparison with (13)C-acetate and (13)C-octanoate in rats.

OBJECTIVE: To investigate the possible use of a (13)C-uracil breath test for gastric emptying by evaluating the pharmacokinetic properties of (13)C-uracil in a breath test in rats, in comparison with (13)C-acetate and (13)C-octanoate, traditional (13)C-probes for gastric emptying. MATERIAL AND METHODS: Absorption of the (13)C-probes from different parts of the gastrointestinal tract was evaluated in fasted rats. (13)C-Uracil breath tests for gastric emptying were carried out in conditions where delayed gastric emptying was induced by clonidine, quinpirole, and propantheline, and in a postoperative ileus model. Following oral administration, we measured residual (13)C-uracil in the stomach and correlated the amount with the breath response. RESULTS: All the (13)C-probes employed were well absorbed from the intestine after intraduodenal administration. After intragastric administration, (13)C-uracil was not absorbed from the stomach, but (13)C-acetate and (13)C-octanoate were partly absorbed from the stomach. The cumulative (14)C-uracil recovery (%) at 168 h was 92.3, 6.3, or 0.5%, from expired gases, urine, and feces, respectively. Delta(13)C values in (13)C-uracil breath tests were decreased in conditions characterized by delayed gastric emptying. A highly negative correlation was observed between the breath response and the residual ratio of (13)C-uracil in the stomach after oral administration of (13)C-uracil, indicating that (13)C-uracil can be used as an in vivo probe for evaluating gastric emptying in a quantitative manner. CONCLUSIONS: This study showed that (13)C-uracil has desirable pharmacokinetic properties as an in vivo probe of gastric emptying. It is thus suggested that the (13)C-uracil breath test may be useful for the measurement of gastric emptying in humans.

Physiologically based pharmacokinetic modelling of the three-step metabolism of pyrimidine using C-uracil as an in vivo probe.

AIMS: Approximately 80% of uracil is excreted as beta-alanine, ammonia and CO2 via three sequential reactions. The activity of the first enzyme in this scheme, dihydropyrimidine dehydrogenase (DPD), is reported to be the key determinant of the cytotoxicity and side-effects of 5-fluorouracil. The aim of the present study was to re-evaluate the pharmacokinetics of uracil and its metabolites using a sensitive assay and based on a newly developed, physiologically based pharmacokinetic (PBPK) model. METHODS: [2-(13)C]Uracil was orally administrated to 12 healthy males at escalating doses of 50, 100 and 200 mg, and the concentrations of [2-(13)C]uracil, [2-(13)C]5,6-dihydrouracil and beta-ureidopropionic acid (ureido-(13)C) in plasma and urine and (13)CO2 in breath were measured by liquid chromatography-tandem mass spectrometry and gas chromatograph-isotope ratio mass spectrometry, respectively. RESULTS: The pharmacokinetics of [2-(13)C]uracil were nonlinear. The elimination half-life of [2-(13)C]5,6-dihydrouracil was 0.9-1.4 h, whereas that of [2-(13)C]uracil was 0.2-0.3 h. The AUC of [2-(13)C]5,6-dihydrouracil was 1.9-3.1 times greater than that of [2-(13)C]uracil, whereas that of ureido-(13)C was 0.13-0.23 times smaller. The pharmacokinetics of (13)CO2 in expired air were linear and the recovery of (13)CO2 was approximately 80% of the dose. The renal clearance of [2-(13)C]uracil was negligible. CONCLUSION: A PBPK model to describe (13)CO2 exhalation after orally administered [2-(13)C]uracil was successfully developed. Using [2-(13)C]uracil as a probe, this model could be useful in identifying DPD-deficient patients at risk of 5-fluorouracil toxicity.

Relationships among plasma [2-(13)C]uracil concentrations, breath (13)CO(2) expiration, and dihydropyrimidine dehydrogenase (DPD) activity in the liver in normal and dpd-deficient dogs.

Dihydropyrimidine dehydrogenase (DPD), the first enzyme in the sequential metabolism of pyrimidine, regulates blood concentrations of 5-fluorouracil and is deeply involved in its toxicity. This study was designed to examine the effects of a DPD inhibitor on blood concentrations of [2-(13)C]uracil ([(13)C]uracil) and (13)CO(2) concentration (Delta(13)C) expired in breath after oral or intravenous administration of [(13)C]uracil to DPD-suppressed dogs prepared by pretreatment with 5-(trans-2-bromovinyl)uracil (BVU), a DPD inhibitor. Area under the curve (AUC(t)) of [(13) C]uracil after oral administration at 20 micromol/kg to dogs pretreated with BVU at 2, 5, and 40 mmol/kg were 37-, 88- and 120-fold higher than those of the control dogs, respectively. In contrast, breath AUC(t) values of Delta(13)C were reduced to 0.88-, 0.47- and 0.13-fold the control values, respectively. Upon intravenous administration of [(13)C]uracil at 20 micromol/kg to dogs pretreated with BVU at 0.5, 2, and 40 micromol/kg, blood AUC(t) values of [(13)C]uracil were 1.4-, 4.2-, and 13-fold higher than those of the control group, respectively, whereas breath AUC(t) values were reduced to 1.0-, 0.83-, and 0.07-fold the respective control values. DPD activities in the liver cytosol of dogs pretreated with BVU at 0.5, 2, 5, and 40 micromol/kg were decreased to 0.71-, 0.12-, 0.06-, and 0.04-fold those of the control dogs, respectively. These findings demonstrate that breath output (Delta(13)C) is a good marker of hepatic DPD activity in vivo.