Acute Flaccid Myelitis With Human Rhinovirus A19 Detection: Case Report and Literature Review.

Human rhinovirus (HRV) has been sporadically detected in patients with acute flaccid myelitis (AFM). We report a case of AFM in a 2-year-old boy with severe neurologic sequelae, whose nasopharyngeal and stool samples tested positive for HRV-A19. Clinical information related to AFM with HRV is limited. Further study of the association of AFM with HRV is warranted.

Detection of enterovirus D68 among children with severe acute respiratory infection in Myanmar.

BACKGROUND: Enterovirus D68 (EV-D68) is an important reemerging pathogen that causes severe acute respiratory infection and acute flaccid paralysis, mainly in children. Since 2014, EV-D68 outbreaks have been reported in the United States, Europe, and east Asia; however, no outbreaks have been reported in southeast Asian countries, including Myanmar, during the previous 10 years. METHODS: EV-D68 was detected in nasopharyngeal swabs from children with acute lower respiratory infections in Myanmar. The samples were previously collected from children aged 1 month to 12 years who had been admitted to the Yankin Children Hospital in Yangon, Myanmar, between May 2017 and January 2019. EV-D68 was detected with a newly developed EV-D68-specific real-time PCR assay. The clade was identified by using a phylogenetic tree created with the Bayesian Markov chain Monte Carlo method. RESULTS: During the study period, nasopharyngeal samples were collected from 570 patients. EV-D68 was detected in 42 samples (7.4 %)-11 samples from 2017 to 31 samples from 2018. The phylogenetic tree revealed that all strains belonged to clade B3, which has been the dominant clade worldwide since 2014. We estimate that ancestors of currently circulating genotypes emerged during the period 1980-2004. CONCLUSIONS: To our knowledge, this is the first report of EV-D68 detection in children with acute lower respiratory infections in Yangon, Myanmar, in 2017-2018. Detection and detailed virologic analyses of EV-D68 in southeast Asia is an important aspect of worldwide surveillance and will likely be useful in better understanding the worldwide epidemiologic profile of EV-D68 infection.

An outbreak investigation of parechovirus-A3 in a newborn nursery.

OBJECTIVE: To investigate parechovirus-A3 (PeV-A3) transmission in a newborn nursery, after encountering 3 neonates with fever and rash. DESIGN: An observational study. SETTING: At a newborn nursery at the general hospital in Hyogo, Japan. PARTICIPANTS: Symptomatic neonates and their family members, and asymptomatic neonates born during the same period. METHODS: PCR assays for PeV-A and genotyping were used for the investigation of PeV-A3. Preserved umbilical cords were used to identify the route of transmission. RESULTS: PeV-A3 infection was confirmed in the three symptomatic neonates. The index case had fever and rash, and the 2 neonates treated later became symptomatic and had serum, cerebrospinal fluid, and stool specimens that were positive for PeV-A3 on PCR. The umbilical cord of the index case was positive for PeV-A3 on PCR. The family members of the index case, including the mother, were asymptomatic before delivery. The older sister and cousin of the PeV-A3-infected neonate had positive PCR results. The sequence analysis suggested 2 possible transmission routes: vertical and horizontal transmission in a newborn nursery and/or a family outside the hospital. The incubation period of PeV-A3 infection was estimated to be 1-3 days (maximum, 7 days). CONCLUSION: Horizontal transmission of PeV-A3 was confirmed in a newborn nursery. Vertical transmission was suggested by the detection of RNA in an umbilical cord sample from the index case. These observations indicate that PeV-A3 can be horizontally transmitted in a newborn nursery and that special caution is required to prevent healthcare-associated transmission of PeV-A3.

Incidence of Omicron Variant Reinfection and Reduction of Reinfection Risk After Coronavirus Disease 2019 Vaccination in Children.

Data are limited on the incidence of coronavirus disease 2019 (COVID-19) reinfection in children. This population-based cohort study in Niigata, Japan from January to November 2022 demonstrated the incidence of reinfection was 1337/48 099 (2.8%), and the hazard ratio for reinfection in vaccinated children was 0.29 (95% confidence interval, 0.20-0.40).

Human Rhinovirus as a Cause of Fever in Neonates and Young Infants During the COVID-19 Pandemic, 2020-2022.

BACKGROUND: Human rhinovirus (HRV) was predominant and persistent during the coronavirus disease 2019 (COVID-19) pandemic despite nonpharmaceutical interventions. The data whether HRV persistence also occurred in neonates and young infants were very limited. METHODS: This prospective observational study was conducted in Niigata, Japan, between January 2020 and September 2022. The participants were hospitalized neonates and infants aged less than 4 months with fever. We excluded patients with evidence of bacterial infection or obvious sick contact with influenza or respiratory syncytial virus infection, as confirmed by rapid antigen detection tests. COVID-19 diagnosed by polymerase chain reaction (PCR) or rapid antigen detection tests were also excluded. Parechovirus and enterovirus were examined by PCR using serum and/or cerebrospinal fluid. FilmArray Respiratory Panel v1.7 was conducted on nasopharyngeal swabs. If HRV was positive, the genotype was identified. RESULTS: We included 72 patients (median age, 54 days; interquartile range, 28.5-79 days), and sepsis was diagnosed in 31 (43.1%) patients. In total, 27 (37.5%) patients had had positive multiplex PCR tests. These patients were more likely to have rhinorrhea (P = 0.004), cough (P = 0.01), and sick contact (P < 0.001) than those who with negative multiplex PCR. HRV was the most frequently detected virus (n = 23, 85.2%), and species A (n = 15, 71.4%) and C (n = 6, 28.6%) were genotyped. No seasonality or monthly predominance of the specific HRV types was observed. CONCLUSIONS: HRV was an important cause of fever in neonates and young infants during the COVID-19 pandemic, 2020 to 2022.

Purulent nasal discharge due to gonococcal nasopharyngitis in a neonate.

Neonatal gonorrhea, caused by Neisseria gonorrhoeae, is an uncommon but important disease to prevent because its complications, such as gonococcal ophthalmia neonatorum causes blindness if untreated. Neonatal gonococcal nasopharyngitis is a rare, but important clinical manifestation to suspect gonococcal infection in a neonate. Herein we report a case of neonatal gonococcal nasopharyngitis, presented with purulent nasal discharge. A full-term male neonate without perinatal complications developed purulent eye discharge on the 7th day of life. N. gonorrhoeae was isolated from the eye discharge culture; however, he did not receive the standard regimen. Subsequently, he presented to our hospital with fever and nasal discharge on the 20th day of life. N. gonorrhoeae was also isolated from nasal discharge and nasopharyngeal swabs without any evidence of chlamydia or syphilis. He received intravenous cefotaxime until disseminated gonococcal infection was ruled out and was discharged without any sequelae. Rhinorrhea in newborns requires consideration of mother-to-child transmission of various microorganisms, not only common respiratory viruses, but also rare, serious preventable infections such as gonorrhea or syphilis. Along with the recent syphilis patients on the rise in Japan, gonorrhea is an important disease to recognize, and the incidence could increase. Clinical manifestations of neonatal gonococcal infections, including nasopharyngitis, need to be recognized to suspect the diagnosis and initiate appropriate treatment to prevent serious complications.

Detection of parechovirus-A in hospitalized children with acute lower respiratory infection in Myanmar, 2017-2018.

Parechovirus-A (PeV-A) causes emerging infection in children, and clinical presentation depends on genotype. The virus has been investigated mainly in developed countries; however, data from developing countries, especially in Asia, are sparse. This study investigated whether PeV-A circulated in children in Myanmar. This retrospective study evaluated PeV-A in nasopharyngeal samples from children aged 1 month to 12 years who were hospitalized with acute lower respiratory infection at Yankin Children Hospital, Yangon, Myanmar, during the period from May 2017 to April 2019. Real-time polymerase chain reaction (PCR) was used to detect PeV-A, and PCR-positive samples were used for genotyping and phylogenetic analysis. In total, 11/570 (1.9%) of samples were positive for PeV-A; 7 were successfully genotyped by sequencing the VP3/VP1 region, as follows: PeV-A1 (n = 4), PeV-A5 (n = 1), PeV-A6 (n = 1), and PeV-A14 (n = 1). Median age was 10.0 months (interquartile range 4.0-12.0 months), and other respiratory viruses were detected in all cases. Phylogenetic analysis showed that all detected PeV-A1 strains were in clade 1 A, which was a minor clade worldwide. Four PeV-A genotypes were detected in Myanmar. The clinical impact of PeV-A in children should be evaluated in future studies.

Outcomes of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplantation for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase 1/2 clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral vector expressing the human WAS complementary DNA under the control of a 1.6-kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All patients were alive and well with sustained multilineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections, and bleeding diathesis was universal. Immune function was consistently improved despite subphysiologic levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity after GT, despite similar percentages of WAS protein-expressing cells and gene marking to those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), interleukin-10-producing regulatory B cells (Bregs), and transitional B cells. Thus, recovery of the Breg compartment, along with Tregs appears to be protective against development of autoimmunity after GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered at clinicaltrials.gov as #NCT01410825.

Comparison of Clinical Characteristics of Children Infected With Coronavirus Disease 2019 Between Omicron Variant BA.5 and BA.1/BA.2 in Japan.

BACKGROUND: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has dramatically altered the clinical profile of pediatric coronavirus disease 2019 (COVID-19). In Japan, we experienced a pandemic of omicron subvariant BA.1/BA.2 from January through June 2022. However, after the emergence of BA.5 in early July 2022, the number of children hospitalized with COVID-19 increased dramatically in Japan. METHODS: We collected data on monthly numbers of cases and clinical characteristics of hospitalized children with COVID-19 in 13 hospitals, the total number of pediatric COVID-19 cases, and COVID-19 vaccination rates in Niigata, Japan, for the period from January 2020 through August 2022. We compared clinical presentation during the periods of BA.1/BA.2 predominance (January-June 2022) and BA.5 predominance (July-August 2022) and estimated vaccine effectiveness (VE) against hospitalization during the BA.5-predominant period. RESULTS: Between January 1, 2020, and August 31, 2022, 49,387 children (19,085 children/100,000 population) were newly diagnosed as having COVID-19, and 393 were hospitalized for COVID-19. Hospitalization for febrile seizure, especially complex seizure, was significantly higher during BA.5 predominance than during BA.1/BA.2 predominance (27.9% vs. 7.0%, P < 0.01). VE against hospitalization during BA.5 predominance was estimated to be 75% (95% confidence interval, 48%-88%, P < 0.01). CONCLUSIONS: The emergence of BA.5 significantly affected children in Japan; the number with complex febrile seizure who required hospitalization was higher than during BA.1/BA.2 predominance. The COVID-19 vaccination rate in children must be increased to prevent hospitalization for COVID-19 and to prepare for current and future variant outbreaks.

Acute and Postacute Clinical Characteristics of Coronavirus Disease 2019 in Children in Japan.

BACKGROUND: The clinical features of coronavirus disease 2019 (COVID-19) in children have been changing because of the emergence and rapid spread of variants of concern (VOC). The increase in cases infected with VOC has brought concern with persistent symptoms after COVID-19 in children. This survey aimed to analyze the clinical manifestations and persistent symptoms of pediatric COVID-19 cases in Japan. METHODS: We analyzed the clinical manifestations of pediatric COVID-19 cases reported between February 2020 and April 2022 in Japan, using a dedicated database updated voluntarily by the members of the Japan Pediatric Society. Using the same database, we also analyzed persistent symptoms after COVID-19 in children who were diagnosed between February 2020 and November 2021. RESULTS: A total of 5411 and 1697 pediatric COVID-19 cases were included for analyzing clinical manifestations and persistent symptoms, respectively. During the Omicron variant predominant period, the percentage of patients with seizures increased to 13.4% and 7.4% in patient groups 1-4 and 5-11 years of age, respectively, compared with the pre-Delta (1.3%, 0.4%) or Delta period (3.1%, 0.0%). Persistent and present symptoms after 28 days of COVID-19 onset were reported in 55 (3.2%). CONCLUSIONS: Our survey showed that the rate of symptomatic pediatric COVID-19 cases increased gradually, especially during the Omicron variant predominant period, and a certain percentage of pediatric cases had persistent symptoms. Certain percentages of pediatric COVID-19 patients had severe complications or prolonged symptoms. Further studies are needed to follow such patients.

Multiple pneumatoceles and lung abscesses caused by early-onset E. coli sepsis in a preterm neonate.

Early-onset sepsis (EOS) is a serious and fatal illness in neonates, Group B Streptococcus and Escherichia coli are major causative pathogens. We report a case of EOS and pneumonia caused by E. coli in a preterm neonate with multiple pneumatoceles and lung abscesses. A male neonate weighing 1670g was delivered at 33 6/7 weeks' gestation by a mother with clinical chorioamnionitis. He showed respiratory distress soon after birth and developed septic shock. He was intubated and mechanical ventilation was started. E.coli was detected in blood culture obtained from both the patient and his mother. He developed multiple pneumatoceles and lung abscesses. Surgical drainage was complicated, cefotaxime was thus continued until day 74. Pneumatoceles and lung abscesses are complications of neonatal pneumonia, rarely reported by E. coli. Multiple lung abscesses in our patient are distinct from single abscesses in previous case studies of neonatal lung abscesses. We speculate that bacteremia along with pneumatoceles led to multiple lung abscesses in our patient. These complications require long-term antibiotic therapy, to minimize morbidity and mortality, and should thus be considered when managing EOS caused by E. coli.

Molecular Evolution and Epidemiology of Parechovirus-A3 in Japan, 1997-2019.

Parechovirus-A3 (PeV-A3), first reported in 2004 in Japan, is an emerging pathogen that causes sepsis and meningoencephalitis in neonates and young infants. Although PeV-A3 has been identified worldwide, its epidemiological characteristics differ by region. To investigate the molecular evolution and epidemiology of PeV-A3, we performed genetic analyses of 131 PeV-A3 strains from the years 1997-2019 in Niigata, Japan. During 2016-2019, annual numbers remained steady, in contrast to the PeV-A3 epidemic interval of every 2-3 years that was observed in Japan from 2006. Bayesian evolutionary analysis of the complete viral protein 1 region revealed alternate dominant clusters during years of PeV-A3 epidemics. The branch including the oldest and first isolated PeV-A3 strains in Japan has been disrupted since 2001. The year of PeV-A3 emergence was estimated to be 1991. Continuous surveillance with genetic analyses of different regions will improve understanding of PeV-A3 epidemiology worldwide.

Decline in pediatric admission on an isolated island in the COVID-19 pandemic.

BACKGROUND: A decrease in pediatric hospitalizations during the COVID-19 pandemic has been reported worldwide; however, few studies have examined areas with a limited number of COVID-19 cases, where influenced by viral interference by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is minimum. METHODS: We conducted an epidemiological study of pediatric hospitalizations on Sado, an isolated island in Niigata, Japan, that was unique environment with few COVID-19 cases and reliable pediatric admissions monitoring. We compared numbers of monthly hospitalizations and associated diagnoses for the periods April 2016 to March 2020 (pre-pandemic period) and April 2020 to March 2021 (pandemic period). RESULTS: Data were analyzed for 1,144 and 128 patients in the pre-pandemic and pandemic periods, respectively. We observed only three adults and no pediatric COVID-19 cases during the pandemic period. The number of monthly admissions was significantly lower in the pandemic period (median [interquartile ranges (IQR)]: 11.0 [7.0-14.0]) than in the pre-pandemic period (23.0 [20.8-28.3]; P < 0.001). Similar decreases were observed for hospitalizations due to respiratory tract infection (P < 0.01), but not for asthma exacerbation (P = 0.15), and gastrointestinal tract infection (P = 0.33). CONCLUSIONS: Pediatric hospitalizations during the pandemic significantly decreased on an isolated Japanese island where COVID-19 was not endemic and all pediatric admissions were ascertainable. This observation highlights the impact of decreased travel and increased awareness of infection control measures on pediatric hospitalizations due to infectious diseases, not by the SARS-CoV-2 viral interference.

Performance of Nanopore and Illumina Metagenomic Sequencing for Pathogen Detection and Transcriptome Analysis in Infantile Central Nervous System Infections.

Background: Infantile central nervous system infections (CNSIs) can be life-threatening and cause severe sequelae. However, the causative microorganism remains unknown in >40% of patients with aseptic infections. This study aimed to analyze the metagenome for detection of pathogens and the transcriptome for host immune responses during infection in a single cerebrospinal fluid (CSF) sample using 2 different next-generation sequencing (NGS) platforms, Nanopore and Illumina. Methods: Twenty-eight CNSIs patients (<12 months) were enrolled, and 49 clinical samples (28 CSF and 21 blood) were collected. The DNA extracted from all 49 samples was sequenced using the Illumina sequencer for the detection of pathogens. Extracted RNA was obtained in sufficient quantities from 23 CSF samples and subjected to sequencing on both Nanopore and Illumina platforms. Human-derived reads subtracted during pathogen detection were used for host transcriptomic analysis from both Nanopore and Illumina sequencing. Results: RNA metagenomic sequencing using both sequencing platforms revealed putative viral pathogens in 10 cases. DNA sequencing using the Illumina sequencer detected 2 pathogens. The results of Nanopore and Illumina RNA sequencing were consistent; however, the mapping coverage and depth to the detected pathogen genome of Nanopore RNA sequencing were greater than those of Illumina. Host transcriptomic analysis of Nanopore sequencing revealed highly expressed genes related to the antiviral roles of innate immunity from pathogen-identified cases. Conclusions: The use of Nanopore RNA sequencing for metagenomic diagnostics of CSF samples should help to elucidate both pathogens and host immune responses of CNSI and could shed light on the pathogenesis of these infections.

Updates on Coronavirus Disease 2019 in Children in Japan.

This review provides updates on coronavirus disease 2019 (COVID-19) in children in Japan by summarizing published data. By the end of March 2022, Japan had experienced 6 waves of COVID-19 outbreaks. Over this time, the clinical features presented among children have changed in the context of the predominant variants. Although the COVID-19 pandemic affected children in terms of medical, physical and psychosocial aspects, the clinical outcomes have been favorable in Japan compared with those in some European countries and the United States, which may be partly due to a lower incidence of multisystem inflammatory syndromes in children and obesity. The COVID-19 vaccine has been available for children; however, the vaccination rate in children 5-11 years of age is lower than that in older children due to the government's lack of an active approach in this specific population. Further action is needed to improve the overall vaccination rates in children.

Household Secondary Transmission of the Severe Acute Respiratory Syndrome Coronavirus 2 Alpha Variant From a Community Cluster in a Nursery in Japan.

BACKGROUND: Spread of variants of concerns (VOCs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an increase in children with coronavirus disease 2019 (COVID-19). In February 2021, clusters of the Alpha variant of SARS-CoV-2 started to be reported in Niigata, Japan, including a large nursery cluster. We investigated the transmission routes and household secondary attack rates (SARs) in this cluster. METHODS: Epidemiologic data related to a nursery cluster in Niigata, Japan, particularly child-origin and adult-origin SARs, were analyzed. VOCs were confirmed by whole-genome sequencing of virus from patients. RESULTS: In total, 42 persons (22 children and 20 adults) in the cluster were infected with the Alpha variant. In the nursery, 13 of 81 children (16.0%) and 4 of 24 teachers (16.7%) were infected. SARS-CoV-2 later spread to 25 persons (10 children and 15 adults) outside the nursery. Child-origin and adult-origin household SARs were 27.7% (13/47) and 47.0% (8/17) ( P = 0.11), respectively, which were higher than rates attributable to non-VOCs in previous studies. CONCLUSIONS: As compared with non-VOCs, the Alpha variant of SARS-CoV-2 exhibited high transmissibility among children and adults and may pose a high risk for household secondary transmission from SARS-CoV-2-infected children. Increased transmissibility of current or future VOCs could lead to greater transmission from children to adults or other children.

Clinical manifestations and outcome of viral acute lower respiratory infection in hospitalised children in Myanmar.

BACKGROUND: Acute lower respiratory infection (ALRI) remains the leading cause of death in children worldwide, and viruses have been the major cause of ALRI. In Myanmar, ALRI is associated with high morbidity and mortality in children, and detailed information on ALRI is currently lacking. METHODS: This prospective study investigated the viral aetiologies, clinical manifestations, and outcomes of ALRI in hospitalised children aged 1 month to 12 years at the Yankin Children Hospital, Yangon, Myanmar from May 2017 to April 2019. The sample size was set to 300 patients for each year. Two nasopharyngeal swabs were obtained for the patients with suspected viral ALRI; one for rapid tests for influenza and respiratory syncytial virus (RSV), and the other for real-time PCR for the 16 ALRI-causing viruses. Pneumococcal colonization rates were also investigated using real-time PCR. Clinical information was extracted from the medical records, and enrolled patients were categorised by age and severity for comparison. RESULTS: Among the 5463 patients admitted with a diagnosis of ALRI, 570 (10.4%) were enrolled in this study. The median age of the patients was 8 months (interquartile range, 4-15 months). The most common symptoms were cough (93%) and difficulty in breathing (73%), while the most common signs of ALRI were tachypnoea (78%) and chest indrawing (67%). A total of 16 viruses were detected in 502 of 570 patients' samples (88%), with RSV B (36%) and rhinovirus (28%) being the most commonly detected. Multiple viruses were detected in 221 of 570 samples (37%) collected from 570 patients. Severe ALRI was diagnosed in 107 of 570 patients (19%), and RSV B and human rhinovirus were commonly detected. The mortality rate was 5%; influenza virus A (29%) and RSV B (21%) were commonly detected, and stunting and lack of immunization were frequently observed in such cases. Additionally, 45% (259/570) of the patients had pneumococcal colonization. CONCLUSIONS: Viral ALRI in hospitalised children with a median of 8 months has significant morbidity and mortality rates in Myanmar. RSV and rhinovirus were the most commonly detected from nasopharyngeal swabs, while influenza virus and RSV were the most frequently associated with fatal cases.

An atypical case of Kawasaki disease with severe pneumonia in a neonate.

BACKGROUND: Kawasaki disease (KD) is an acute, febrile, systemic vasculitis of unknown etiology that primarily affects the coronary arteries and generally occurs at around 1 year of age. Although the diagnosis of KD is generally not difficult, it is challenging in cases of incomplete KD lacking characteristic clinical manifestations. The incidence of incomplete KD is higher in infants younger than 6 months of age. Pneumonia is an extremely rare complication of KD and can be misinterpreted as atypical pneumonia rather than KD. Herein, we report a neonate with atypical KD and severe pneumonia who required mechanical ventilation. CASE PRESENTATION: Japanese one-month-old infant had only fever and rash on admission (day 1), and he was transferred to the intensive care unit for severe pneumonia on day 2. Although pneumonia improved following intensive care, he was diagnosed with KD on day 14 because of emerging typical clinical manifestations such as fever, bulbar nonexudative conjunctival injection, desquamation of the fingers, and coronary artery aneurysm. KD symptoms improved after three doses of intravenous immunoglobulin plus cyclosporine. However, small coronary aneurysms were present at the time of discharge. In a retrospective analysis, no pathogens were detected by multiplex real-time PCR in samples collected at admission, and the serum cytokine profile demonstrated prominent elevation of IL-6 as well as elevation of neopterin, sTNF-RI, and sTNF-RII, which suggested KD. CONCLUSIONS: The patient's entire clinical course, including the severe pneumonia, was caused by KD. As in this case, neonatal KD may exhibit atypical manifestations such as severe pneumonia requiring mechanical ventilation.