Characterization of human respiratory syncytial virus in children with severe acute respiratory infection before and during the COVID-19 pandemic.

Objectives: Annual outbreaks of human respiratory syncytial virus (HRSV) are caused by newly introduced and locally persistent strains. During the COVID-19 pandemic, global and local circulation of HRSV significantly decreased. This study was conducted to characterize HRSV in 2018-2022 and to analyze the impact of COVID-19 on the evolution of HRSV. Design/methods: Combined oropharyngeal and nasopharyngeal swabs were collected from children hospitalized with severe acute respiratory infection at two hospitals in Zambia. The second hypervariable region of the attachment gene G was targeted for phylogenetic analysis. Results: Of 3113 specimens, 504 (16.2%) were positive for HRSV, of which 131 (26.0%) and 66 (13.1%) were identified as HRSVA and HRSVB, respectively. In early 2021, an increase in HRSV was detected, caused by multiple distinct clades of HRSVA and HRSVB. Some were newly introduced, whereas others resulted from local persistence. Conclusions: This study provides insights into the evolution of HRSV, driven by global and local circulation. The COVID-19 pandemic had a temporal impact on the evolution pattern of HRSV. Understanding the evolution of HRSV is vital for developing strategies for its control.

Patient Admission and Mechanical Ventilator Allocation Decision-Making Processes by Frontline Medical Professionals in a Japanese ICU During the COVID-19 Pandemic: A Qualitative Study.

During the COVID-19 pandemic, the need to triage COVID-19 patients in ICUs emerged globally. Triage guidelines were established in many countries; however, the actual triage decision-making processes and decisions themselves made by frontline medical providers may not have exactly reflected those guidelines. Despite the need to understand decisions and processes in practice regarding patient ICU admission and mechanical ventilator usage to identify areas of improvement for medical care provision, such research is limited. This qualitative study was conducted to identify the decision-making processes regarding COVID-19 patient ICU admissions and mechanical ventilator allocation by frontline medical providers and issues associated with those processes in an ICU during the COVID-19 pandemic. Semi-structured, in-depth interviews were conducted with ICU physicians and nurses working at an urban tertiary referral hospital in Japan between February and April 2022. Patient characteristics that influenced triage decisions made by physicians and the interaction between physicians, nurses, and senior management staff upon making such decisions are discussed in this article. An implicated issue was the lack of legal support for Japanese physicians to practice withdrawal of life-sustaining treatments even during emergencies. Another issue was the impact of non-clinical forces-likely specific to health emergencies-on physicians' decisions regarding mechanical ventilator allocation, where such forces imposed a significant mental burden on the medical providers. We consider public policy and legal implications for future pandemics.

Epidemiological and molecular characterization of Coxsackievirus A6 causing hand, foot, and mouth disease in the Philippines, 2012-2017.

Coxsackievirus A6 (CVA6) is emerging as the dominant serotype among enteroviruses (EVs) responsible for hand, foot, and mouth disease (HFMD) outbreaks in multiple countries. However, details regarding this serotype in the Philippines are limited. In this study, we investigated the epidemiological and molecular characteristics of laboratory-confirmed CVA6 HFMD cases in the Philippines between 2012 and 2017. Data collected from case report forms submitted to the National Reference Laboratory for Poliovirus and other Enteroviruses were used to determine the distribution and clinical findings of laboratory-confirmed CVA6 HFMD. Phylogenetic analyses of the complete viral protein 1 (VP1) and partial 3D polymerase (3Dpol) gene sequences were performed to determine the genotype and recombinant (RF) form of the selected samples. An increase in the detection rate of CVA6 among enterovirus-positive HFMD cases was observed from 61.9% (140/226) in 2012 to 88.1% (482/587) in 2017, with most cases coming from the Luzon island group. Among the detected cases, the majority were children, with a median age of 2 years old (interquartile range: 1.17-3.40). Respiratory-related morbidities were the commonly reported complications (7.9%; 72/907). Based on the VP1 and 3Dpol gene sequence analysis, the CVA6 strains in this study were classified as genotype D3b and RF-A group, respectively. This study elucidated that CVA6 was the most prevalent enterovirus serotype causing HFMD in the Philippines in 2012-2017, with genotype D3b/RF-A circulating within this period. This study highlights the importance of viral surveillance and molecular epidemiological analysis to broaden our understanding of HFMD in the Philippines.

Time-varying overdispersion of SARS-CoV-2 transmission during the periods when different variants of concern were circulating in Japan.

Japan has implemented a cluster-based approach for coronavirus disease 2019 (COVID-19) from the pandemic's beginning based on the transmission heterogeneity (overdispersion) of severe acute respiratory coronavirus 2 (SARS-CoV-2). However, studies analyzing overdispersion of transmission among new variants of concerns (VOCs), especially for Omicron, were limited. Thus, we aimed to clarify how the transmission heterogeneity has changed with the emergence of VOCs (Alpha, Delta, and Omicron) using detailed contact tracing data in Yamagata Prefecture, Japan. We estimated the time-varying dispersion parameter ([Formula: see text]) by fitting a negative binomial distribution for each transmission generation. Our results showed that even after the emergence of VOCs, there was transmission heterogeneity of SARS-CoV-2, with changes in [Formula: see text] during each wave. Continuous monitoring of transmission dynamics is vital for implementing appropriate measures. However, a feasible and sustainable epidemiological analysis system should be established to make this possible.

Rapid Detection of SARS-CoV-2 RNA Using Reverse Transcription Recombinase Polymerase Amplification (RT-RPA) with Lateral Flow for N-Protein Gene and Variant-Specific Deletion-Insertion Mutation in S-Protein Gene.

Rapid molecular testing for severe acute respiratory coronavirus 2 (SARS-CoV-2) variants may contribute to the development of public health measures, particularly in resource-limited areas. Reverse transcription recombinase polymerase amplification using a lateral flow assay (RT-RPA-LF) allows rapid RNA detection without thermal cyclers. In this study, we developed two assays to detect SARS-CoV-2 nucleocapsid (N) gene and Omicron BA.1 spike (S) gene-specific deletion-insertion mutations (del211/ins214). Both tests had a detection limit of 10 copies/µL in vitro and the detection time was approximately 35 min from incubation to detection. The sensitivities of SARS-CoV-2 (N) RT-RPA-LF by viral load categories were 100% for clinical samples with high (>9015.7 copies/µL, cycle quantification (Cq): < 25) and moderate (385.5-9015.7 copies/µL, Cq: 25-29.9) viral load, 83.3% for low (16.5-385.5 copies/µL, Cq: 30-34.9), and 14.3% for very low (<16.5 copies/µL, Cq: 35-40). The sensitivities of the Omicron BA.1 (S) RT-RPA-LF were 94.9%, 78%, 23.8%, and 0%, respectively, and the specificity against non-BA.1 SARS-CoV-2-positive samples was 96%. The assays seemed more sensitive than rapid antigen detection in moderate viral load samples. Although implementation in resource-limited settings requires additional improvements, deletion-insertion mutations were successfully detected by the RT-RPA-LF technique.

Seroprevalence of four endemic human coronaviruses and, reactivity and neutralization capability against SARS-CoV-2 among children in the Philippines.

Four endemic human coronaviruses (HCoV), HCoV-229E, HCoV-NL63, HCoV-HKU1, and HCoV-OC43, are closely related to SARS-CoV-2. These coronaviruses are known to infect humans living in temperate areas, including children under 5 years old; however, the seroprevalence of four HCoVs among children in tropical areas, including the Philippines, remains unclear. This study aimed to assess the prevalence of antibodies against four HCoVs and to determine the reactivity and neutralization of these antibodies against SARS-CoV-2 among children in the Philippines. A total of 315 serum samples collected from 2015 to 2018, before the emergence of SARS-CoV-2, in Biliran island, Philippines, were tested for the presence of antibodies against four HCoVs and SARS-CoV-2 using recombinant spike ectodomain proteins by IgG-enzyme-linked immunosorbent assay (ELISA). Reactivity to and neutralization of SARS-CoV-2 were also investigated. The seroprevalence of the four HCoVs was 63.8% for HCoV-229E, 71.4% for HCoV-NL63, 76.5% for HCoV-HKU1, and 83.5% for HCoV-OC43 by ELISA. Age group analysis indicated that seropositivity to all HCoVs reached 80% by 2-3 years of age. While 69/315 (21.9%) of the samples showed reactive to SARS-CoV-2, almost no neutralization against SARS-CoV-2 was detected using neutralization assay. Reactivity of antibodies against SARS-CoV-2 spike protein obtained by ELISA may not correlate with neutralization capability.

Transmission of COVID-19 in Nightlife, Household, and Health Care Settings in Tokyo, Japan, in 2020.

Importance: There have been few studies on the heterogeneous interconnection of COVID-19 outbreaks occurring in different social settings using robust, surveillance epidemiological data. Objectives: To describe the characteristics of COVID-19 transmission within different social settings and to evaluate settings associated with onward transmission to other settings. Design, Setting, and Participants: This is a case series study of laboratory-confirmed COVID-19 cases in Tokyo between January 23 and December 5, 2020, when vaccination was not yet implemented. Using epidemiological investigation data collected by public health centers, epidemiological links were identified and classified into 7 transmission settings: imported, nightlife, dining, workplace, household, health care, and other. Main Outcomes and Measures: The number of cases per setting and the likelihood of generating onward transmissions were compared between different transmission settings. Results: Of the 44 054 confirmed COVID-19 cases in this study, 25 241 (57.3%) were among male patients, and the median (IQR) age of patients was 36 (26-52) years. Transmission settings were identified in 13 122 cases, including 6768 household, 2733 health care, and 1174 nightlife cases. More than 6600 transmission settings were detected, and nightlife (72 of 380 [18.9%]; P < .001) and health care (119 [36.2%]; P < .001) settings were more likely to involve 5 or more cases than dining, workplace, household, and other settings. Nightlife cases appeared in the earlier phase of the epidemic, while household and health care cases appeared later. After adjustment for transmission setting, sex, age group, presence of symptoms, and wave, household and health care cases were less likely to generate onward transmission compared with nightlife cases (household: adjusted odds ratio, 0.03; 95% CI, 0.02-0.05; health care: adjusted odds ratio, 0.57; 95% CI, 0.41-0.79). Household settings were associated with intergenerational transmission, while nonhousehold settings mainly comprised transmission between the same age group. Among 30 932 cases without identified transmission settings, cases with a history of visiting nightlife establishments were more likely to generate onward transmission to nonhousehold settings (adjusted odds ratio, 5.30 [95% CI, 4.64-6.05]; P < .001) than those without such history. Conclusions and Relevance: In this case series study, COVID-19 cases identified in nightlife settings were associated with a higher likelihood of spreading COVID-19 than household and health care cases. Surveillance and interventions targeting nightlife settings should be prioritized to disrupt COVID-19 transmission, especially in the early stage of an epidemic.

Comparison of Rhinovirus A-, B-, and C-Associated Respiratory Tract Illness Severity Based on the 5'-Untranslated Region Among Children Younger Than 5 Years.

Background: Rhinoviruses (RVs) are among the most frequently detected viruses from hospitalized children with severe acute respiratory infections, being classified into RV-A, RV-B, and RV-C (4 clades: C, GAC1, GAC2, and A2). This study aimed to compare the clinical characteristics and respiratory tract illness severity between the RV species and RV-C clades in children in primary care and hospital settings in rural communities in the Philippines. Methods: Clinical samples and information of children <5 years old in the Philippines were collected from 2014 to 2016. The samples were tested by reverse-transcription polymerase chain reaction (RT-PCR) targeting the 5'-untranslated region. PCR-positive samples were sequenced, and RV species were identified by phylogenetic analysis. Results: Overall, 3680 respiratory tract illness episodes in 1688 cohort children were documented; 713 of those were RV positive and identified as RV-A (n = 271), RV-B (n = 47), and RV-C (n = 395: C [n = 76], GAG1 [n = 172], GAG2 [n = 8], A2 [n = 138], and unidentified [n = 1]). Severe illnesses, low oxygen saturation, cough, and wheezing were more common in patients with RV-C, especially with GAC1, than in those with RV-A or RV-B. Furthermore, severe illness was significantly more common in RV-C (GAC1)-positive cases than in RV-A-positive cases (odds ratio, 2.61 [95% CI, 1.17-4.13]). Conclusions: Children infected with RV-C had more severe illnesses than children infected with RV-A and RV-B. Moreover, emerging clades of RV-C were associated with increased severity.

Japanese encephalitis virus genotype III from mosquitoes in Tarlac, Philippines.

Objectives: The aim of this study was to investigate the presence of Japanese encephalitis virus (JEV) in a rice-farming community in the Philippines and to determine its implications regarding the epidemiology of viral encephalitides in the Asia-Pacific Region. Methods: Mosquitoes were collected monthly from animal-baited traps close to flooded rice fields in two barangays (villages) in the Municipality of San Jose, Tarlac Province in Luzon, from May 2009 to July 2010. Virus was detected by nested reverse transcription PCR. Phylogenetic analysis of the amplified virus envelope gene was done using the maximum-likelihood method. Results: A total of 28 700 known vector mosquitoes were collected, namely Culex vishnui, Culex fuscocephala, Culex tritaeniorhynchus, and Culex gelidus. JEV genotype III was detected in C. tritaeniorhynchus, belonging to the same genotype but form a different clade from those reported in the 1980s and in 2020 in this country. Conclusions: Japanese encephalitis is associated with rice cultivation and the presence of infected mosquitoes in Tarlac, Philippines. It remains to be seen whether the observed genetic shift of genotype III to genotype I in Asia will in time have an impact on the epidemiology of Japanese encephalitis in the Philippines. For long-term disease control, regular surveillance and Japanese encephalitis immunization in children and travelers in high risk areas are recommended.

Incidence and length of outbreak period of COVID-19 and population density in comparison with seasonal influenza in Japan.

Objectives: There is no consensus regarding the impact of population density on the transmission of respiratory viral infections such as COVID-19 and seasonal influenza. Our study aimed to determine the correlation between population density and the incidence and duration of COVID-19 transmission. Methods: Publicly available data for confirmed COVID-19 cases in Japan, from January 2020 through November 2021, were retrospectively collected. The average numbers of seasonal influenza cases reported in the national database from 2013-2014 through 2019-2020 were identified. Using data for COVID-19 and seasonal influenza population density and incidence rates (age-adjusted), the Pearson's correlation coefficient was determined. Results: A significant positive correlation between log population density and length of outbreak period was observed for COVID-19 (r = 0.734; p < 0.001) but not for seasonal influenza. Additionally, a significant linear correlation was observed between population density and age-adjusted incidence rate for COVID-19 (r = 0.692; p < 0.001) but not for seasonal influenza. Conclusions: In Japan, areas with high population density experienced a prolonged and more intense COVID-19 outbreak compared with areas with low population density. This was not observed with seasonal influenza, suggesting that public health measures against COVID-19 should be tailored according to population density.

Integration of publicly available case-based data for real-time coronavirus disease 2019 risk assessment, Japan.

In response to the outbreak of coronavirus disease 2019 (COVID-19) in Japan, a national COVID-19 cluster taskforce (comprising governmental and nongovernmental experts) was established to support the country's Ministry of Health, Labour and Welfare in conducting daily risk assessment. The assessment was carried out using established infectious disease surveillance systems; however, in the initial stages of the pandemic these were not sufficient for real-time risk assessment owing to limited accessibility, delay in data entry and inadequate case information. Also, local governments were publishing anonymized data on confirmed COVID-19 cases on their official web sites as daily press releases. We developed a unique database for nationwide real-time risk assessment that included these case lists from local government web sites and integrated all case data into a standardized format. The database was updated daily and checked systematically to ensure comprehensiveness and quality. Between 15 January 2020 and 15 June 2021, 776 459 cases were logged in the database, allowing for analysis of real-time risk from the pandemic. This semi-automated database was used in daily risk assessments, and to evaluate and update control measures to prevent community transmission of COVID-19 in Japan. The data were reported almost every week to the Japanese Government Advisory Panel on COVID-19 for public health responses.

Prolonged shedding of infectious viruses with haplotype switches of SARS-CoV-2 in an immunocompromised patient.

A concern has been raised that the persistent COVID-19 infection in an immunocompromised host can be the source of the SARS-CoV-2 variants. This is the case of a 61-year-old man in complete remission of a follicular lymphoma after six cycles of rituximab and bendamustine with additional two cycles of rituximab completed eight months prior to the episode of COVID-19 pneumonia. The patient's respiratory failure was long-lasting, and required mechanical ventilation until day 75. Acquired immunity tested negative throughout the observational period. The viral RNA was detectable until day 100 while the infectious virus was isolated until day 79. Seven haplotypes were identified and the non-synonymous mutations accumulated in the spike gene which included E484Q and S494P. In the management of COVID-19 cases with suppressed immune statuses, initial evaluation of existing immunity and monitoring for infectiousness throughout the clinical course including the convalescent stage may be necessary.

Incidence of lower respiratory tract infection and associated viruses in a birth cohort in the Philippines.

BACKGROUND: Lower respiratory tract infection (LRTI) is an important cause of morbidity and mortality in infants and young children. However, the etiological role of viruses and the timing of developing LRTI are not well defined. METHODS: We analyzed the data of a prospective cohort study in the Philippines as a birth cohort. We detected LRTI among children who visited healthcare facilities with respiratory symptom, and collected nasopharyngeal swabs for virus detection. We analyzed the incidence rates (IRs) and cumulative proportion of LRTI and severe LRTI by age group and each virus detected. RESULTS: A total of 350 LRTI episodes were observed from 473 child-years yielded from 419 children. The IRs of LRTI were 70.8, 70.7, and 80.8 per 100 child-years for 0-5, 6-11, and 12-23 months of age, respectively. By 12 months of age, 45% of children developed LRTI at least once. Rhinovirus and respiratory syncytial virus were the most frequently detected viruses in all age groups. However, the IRs of influenza virus were low especially at 0-5 months of age. CONCLUSIONS: We identified various patterns of age-specific IRs of LRTI and severe LRTI for different viruses, which should be considered to establish more effective interventions including vaccinations.

Serotype Identification of Human Adenoviruses Associated with Influenza-Like Illnesses in the Philippines from 2006-2012 by Microneutralization and Molecular Techniques.

OBJECTIVES: Human adenoviruses (HAdV) are known to cause a wide range of diseases including acute respiratory infections, conjunctivitis, and acute gastroenteritis. In this study, we aimed to determine the serotypes of HAdV in patients with influenza-like illness (ILI) in the Philippines from 2006-2012 and to describe the demographic and epidemiological characteristics of patients who tested positive for HAdV. METHODS: Between 2006 and 2012, the Philippine National Influenza Centre detected HAdV in 1294 samples of patients with ILI. Serotype determination was done in select samples using microneutralization, polymerase chain reaction (PCR), and sequencing methods. RESULTS: A total of 8 serotypes were identified (HAdV 1-7 and 11), with HAdV-2 (27.8%), and HAdV-3 (27.8%) being the most prevalent. The majority of HAdV infections were found in children below 5 years of age (79.9%). CONCLUSIONS: The identification of HAdV circulating serotypes may serve as guide for designing disease intervention and control strategies and will provide important information regarding the contribution of this virus to respiratory infections, particularly in children, which remain a public health burden in the Philippines.

Secondary transmission of SARS-CoV-2 during the first two waves in Japan: Demographic characteristics and overdispersion.

OBJECTIVES: Super-spreading events caused by overdispersed secondary transmission are crucial in the transmission of COVID-19. However, the exact level of overdispersion, demographics, and other factors associated with secondary transmission remain elusive. In this study, we aimed to elucidate the frequency and patterns of secondary transmission of SARS-CoV-2 in Japan. METHODS: We analyzed 16,471 cases between January 2020 and August 2020. We generated the number of secondary cases distribution and estimated the dispersion parameter (k) by fitting the negative binomial distribution in each phase. The frequencies of the secondary transmission were compared by demographic and clinical characteristics, calculating the odds ratio using logistic regression models. RESULTS: We observed that 76.7% of the primary cases did not generate secondary cases with an estimated dispersion parameter k of 0.23. The demographic patterns of primary-secondary cases differed between phases, with 20-69 years being the predominant age group. There were higher proportions of secondary transmissions among older individuals, symptomatic patients, and patients with 2 days or more between onset and confirmation. CONCLUSIONS: The study showed the estimation of the frequency of secondary transmission of SARS-CoV-2 and the characteristics of people who generated the secondary transmission.

Epidemiological Factors Associated with COVID-19 Clusters in Medical and Social Welfare Facilities.

The characteristics of coronavirus disease 2019 (COVID-19) clusters in medical and social welfare facilities and the factors associated with cluster size are still not yet fully understood. We reviewed COVID-19 cases in Japan identified from January 15 to April 30, 2020 and analyzed the factors associated with cluster size in medical and social welfare facilities. In this study, COVID-19 clusters were identified in 56 medical and 34 social welfare facilities. The number of cases in those facilities peaked after the peak of the general population. The duration of occurrence of new cases in clusters was positively correlated with the number of cases in both types of facilities (rho = 0.44, P < 0.001; and rho = 0.69, P < 0.001, respectively). However, the number of days between the first case in a prefecture and the onset of clusters was negatively correlated with the number of cases only in clusters in social welfare facilities (rho = - 0.4, P = 0.004). Our results suggest that COVID-19 cases in those facilities were prevalent in the latter phase of the disease's community transmission, although the underlying mechanisms for such a trend could differ between medical and social welfare facilities.