Decomposing mechanisms of COVID-19 mortality in empirical datasets: A modeling study.

Our objective was to decompose mortality mechanisms during the coronavirus disease 2019 (COVID-19) pandemic to estimate direct, indirect, and associated deaths from COVID-19. Given the confirmatory diagnosis of COVID-19, a death event that was not necessarily caused by respiratory complications but stemmed from other complications was categorized as an indirect death from COVID-19. Associated deaths occurred in patients who did not have COVID-19 but died during the surge in COVID-19 cases when overwhelming pressure was exerted on the healthcare system. Analyzing the sixth wave (i.e., the first epidemic wave of the Omicron B.1.1.529 variant from January to May 2022), decomposition was achieved using the binomial and Poisson sampling process models fitted to two pieces of data (i.e., COVID-19 death certificate and excess data by major cause of death). The total numbers of direct, indirect, and associated deaths during the sixth wave in Osaka were estimated at 1,071; 948; and 2,157; respectively. The number of associated deaths was greater than the sum of direct and indirect deaths. We further observed that the composition of indirect and associated deaths differed by major cause of death, and deaths caused by circulatory disease included a greater proportion of indirect deaths compared with deaths by other causes. The goals of healthcare services for endemic COVID-19 include the sustainable provision of services to avoid preventable deaths. Therefore, gaining an in-depth understanding of mechanisms that lead to excess death is vital for improving future pandemic response efforts.

Habitual Mask Wearing as Part of COVID-19 Control in Japan: An Assessment Using the Self-Report Habit Index.

Although the Japanese government removed mask-wearing requirements in 2023, relatively high rates of mask wearing have continued in Japan. We aimed to assess psychological reasons and the strength of habitual mask wearing in Japan. An Internet-based cross-sectional survey was conducted with non-random participant recruitment. We explored the frequency of mask usage, investigating psychological reasons for wearing masks. A regression analysis examined the association between psychological reasons and the frequency of mask wearing. The habitual use of masks was assessed in the participant's most frequently visited indoor space and public transport using the self-report habit index. The principal component analysis with varimax rotation revealed distinct habitual characteristics. Among the 2640 participants surveyed from 6 to 9 February 2023, only 4.9% reported not wearing masks at all. Conformity to social norms was the most important reason for masks. Participants exhibited a slightly higher degree of habituation towards mask wearing on public transport compared to indoor spaces. The mask-wearing rate was higher in females than in males, and no significant difference was identified by age group. Daily mask wearing in indoor spaces was characterized by two traits (automaticity and behavioral frequency). A high mask-wearing frequency has been maintained in Japan during the social reopening transition period. Mask wearing has become a part of daily habit, especially on public transport, largely driven by automatic and frequent practice.

Possible adaptation measures for climate change in preventing heatstroke among older adults in Japan.

Introduction: Heatstroke mortality is highest among older adults aged 65 years and older, and the risk is even doubled among those aged 75 years and older. The incidence of heatstroke is expected to increase in the future with elevated temperatures owing to climate change. In the context of a super-aged society, we examined possible adaptation measures in Japan that could prevent heatstroke among older people using an epidemiological survey combined with mathematical modeling. Methods: To identify possible interventions, we conducted a cross-sectional survey, collecting information on heatstroke episodes from 2018 to 2019 among people aged 75 years and older. Responses were analyzed from 576 participants, and propensity score matching was used to adjust for measurable confounders and used to estimate the effect sizes associated with variables that constitute possible interventions. Subsequently, a weather-driven statistical model was used to predict heatstroke-related ambulance transports. We projected the incidence of heatstroke-related transports until the year 2100, with and without adaptation measures. Results: The risk factor with the greatest odds ratio (OR) of heatstroke among older adults was living alone (OR 2.5, 95% confidence interval: 1.2-5.4). Other possible risk factors included an inability to drink water independently and the absence of air conditioning. Using three climate change scenarios, a more than 30% increase in the incidence of heatstroke-related ambulance transports was anticipated for representative concentration pathways (RCP) 4.5 and 8.5, as compared with a carbon-neutral scenario. Given 30% reduction in single living, a 15% reduction in the incidence of heatstroke is expected. Given 70% improvement in all three risk factors, a 40% reduction in the incidence can be expected. Conclusion: Possible adaptation measures include providing support for older adults living alone, for those who have an inability to drink water and for those without air conditioning. To be comparable to carbon neutrality, future climate change under RCP 2.6 requires achieving a 30% relative reduction in all three identified risks at least from 2060; under RCP 4.5, a 70% reduction from 2050 at the latest is needed. In the case of RCP 8.5, the goal of heatstroke-related transports approaching RCP 1.9 cannot be achieved.

Identifying High-Risk Events for COVID-19 Transmission: Estimating the Risk of Clustering Using Nationwide Data.

The transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to be overdispersed, meaning that only a fraction of infected cases contributes to super-spreading. While cluster interventions are an effective measure for controlling pandemics due to the viruses' overdispersed nature, a quantitative assessment of the risk of clustering has yet to be sufficiently presented. Using systematically collected cluster surveillance data for coronavirus disease 2019 (COVID-19) from June 2020 to June 2021 in Japan, we estimated the activity-dependent risk of clustering in 23 establishment types. The analysis indicated that elderly care facilities, welfare facilities for people with disabilities, and hospitals had the highest risk of clustering, with 4.65 (95% confidence interval [CI]: 4.43-4.87), 2.99 (2.59-3.46), and 2.00 (1.88-2.12) cluster reports per million event users, respectively. Risks in educational settings were higher overall among older age groups, potentially being affected by activities with close and uncontrollable contact during extracurricular hours. In dining settings, drinking and singing increased the risk by 10- to 70-fold compared with regular eating settings. The comprehensive analysis of the COVID-19 cluster records provides an additional scientific basis for the design of customized interventions.

Projecting the COVID-19 immune landscape in Japan in the presence of waning immunity and booster vaccination.

Coronavirus disease 2019 (COVID-19) booster vaccination has been implemented globally in the midst of surges in infection due to the Delta and Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The objective of the present study was to present a framework to estimate the proportion of the population that is immune to symptomatic SARS-CoV-2 infection with the Omicron variant (immune proportion) in Japan, considering the waning of immunity resulting from vaccination and naturally acquired infection. We quantified the decay rate of immunity against symptomatic infection with Omicron conferred by the second and third doses of COVID-19 vaccine. We estimated the current and future vaccination coverage for the second and third vaccine doses from February 17, 2021 to August 1, 2022 and used data on the confirmed COVID-19 incidence from February 17, 2021 to April 10, 2022. From this information, we estimated the age-specific immune proportion over the period from February 17, 2021 to August 1, 2022. Vaccine-induced immunity, conferred by the second vaccine dose in particular, was estimated to rapidly wane. There were substantial variations in the estimated immune proportion by age group because each age cohort experienced different vaccination rollout timing and speed as well as a different infection risk. Such variations collectively contributed to heterogeneous immune landscape trajectories over time and age. The resulting prediction of the proportion of the population that is immune to symptomatic SARS-CoV-2 infection could aid decision-making on when and for whom another round of booster vaccination should be considered. This manuscript was submitted as part of a theme issue on "Modelling COVID-19 and Preparedness for Future Pandemics".

Time-dependent risk of COVID-19 death with overwhelmed health-care capacity in Japan, 2020-2022.

BACKGROUND: It has been descriptively argued that the case fatality risk (CFR) of coronavirus disease (COVID-19) is elevated when medical services are overwhelmed. The relationship between CFR and pressure on health-care services should thus be epidemiologically explored to account for potential epidemiological biases. The purpose of the present study was to estimate the age-dependent CFR in Tokyo and Osaka over time, investigating the impact of caseload demand on the risk of death. METHODS: We estimated the time-dependent CFR, accounting for time delay from diagnosis to death. To this end, we first determined the time distribution from diagnosis to death, allowing variations in the delay over time. We then assessed the age-dependent CFR in Tokyo and Osaka. In Osaka, the risk of intensive care unit (ICU) admission was also estimated. RESULTS: The CFR was highest among individuals aged 80 years and older and during the first epidemic wave from February to June 2020, estimated as 25.4% (95% confidence interval [CI] 21.1 to 29.6) and 27.9% (95% CI 20.6 to 36.1) in Tokyo and Osaka, respectively. During the fourth wave of infection (caused by the Alpha variant) in Osaka the CFR among the 70s and ≥ 80s age groups was, respectively, 2.3 and 1.5 times greater than in Tokyo. Conversely, despite the surge in hospitalizations, the risk of ICU admission among those aged 80 and older in Osaka decreased. Such time-dependent variation in the CFR was not seen among younger patients < 70 years old. With the Omicron variant, the CFR among the 80s and older in Tokyo and Osaka was 3.2% (95% CI 3.0 to 3.5) and 2.9% (95% CI 2.7 to 3.1), respectively. CONCLUSION: We found that without substantial control, the CFR can increase when a surge in cases occurs with an identifiable elevation in risk-especially among older people. Because active treatment options including admission to ICU cannot be offered to the elderly with an overwhelmed medical service, the CFR value can potentially double compared with that in other areas of health care under less pressure.

Quantifying the future risk of dengue under climate change in Japan.

Background: In metropolitan Tokyo in 2014, Japan experienced its first domestic dengue outbreak since 1945. The objective of the present study was to quantitatively assess the future risk of dengue in Japan using climate change scenarios in a high-resolution geospatial environment by building on a solid theory as a baseline in consideration of future adaptation strategies. Methods: Using climate change scenarios of the Model for Interdisciplinary Research on Climate version 6 (MIROC6), representative concentration pathway (RCP) 2.6, 4.5, and 8.5, we computed the daily average temperature and embedded this in the effective reproduction number of dengue, R(T), to calculate the extinction probability and interepidemic period across Japan. Results: In June and October, the R(T) with daily average temperature T, was <1 as in 2022; however, an elevation in temperature increased the number of days with R(T) >1 during these months under RCP8.5. The time period with a risk of dengue transmission gradually extended to late spring (April-May) and autumn (October-November). Under the RCP8.5 scenario in 2100, the possibility of no dengue-free months was revealed in part of southernmost Okinawa Prefecture, and the epidemic risk extended to the entire part of northernmost Hokkaido Prefecture. Conclusion: Each locality in Japan must formulate action plans in response to the presented scenarios. Our geographic analysis can help local governments to develop adaptation policies that include mosquito breeding site elimination, distribution of adulticides and larvicides, and elevated situation awareness to prevent transmission via bites from Aedes vectors.

Assessing Public Health and Social Measures Against COVID-19 in Japan From March to June 2021.

Background: Public health and social measures (PHSM) against COVID-19 in Japan involve requesting the public to voluntarily reduce social contact; these measures are not legally binding. The effectiveness of such PHSM has been questioned with emergence of the SARS-CoV-2 Alpha variant (B.1.1.7), which exhibited elevated transmissibility. Materials and Methods: We investigated the epidemic dynamics during the fourth epidemic wave in Japan from March to June 2021 involving pre-emergency measures and declaration of a state of emergency (SoE). We estimated the effective reproduction number (R t ) before and after these interventions, and then analyzed the relationship between lower R t values and each PHSM. Results: With implementation of pre-emergency measures (PEM) in 16 prefectures, the R t was estimated to be < 1 in six prefectures; its average relative reduction ranged from 2 to 19%. During the SoE, 8 of 10 prefectures had an estimated R t < 1, and the average relative reduction was 26%-39%. No single intervention was identified that uniquely resulted in an R t value < 1. Conclusion: An SoE can substantially reduce the R t and may be required to curb a surge in cases caused by future SARS-CoV-2 variants of concern with elevated transmissibility. More customized interventions did not reduce the R t value to < 1 in this study, but that may be partly attributable to the greater transmissibility of the Alpha variant.

Response to COVID-19 during the Tokyo Olympic Games: Did we properly assess the risk?

BACKGROUND: The number of coronavirus disease 2019 (COVID-19) cases was expected to increase during the Tokyo Olympic Games because of the increased physical contact within and between the domestic population and international participants of the Games. The rapid rise of the Delta variant (B.1.617) in Japan meant that hosting the Olympic Games without any restrictions was likely to lead to an increase in cases. We aimed to quantitatively assess possible COVID-19 response strategies for the Olympic Games, comparing the prevalence of severe cases and the cumulative number of COVID-19 deaths via scenario analysis. METHODS: We used a discrete-time deterministic compartmental model structured by age group. Parameters were calibrated using the age-stratified COVID-19 incidence data in Osaka. Numerical simulations incorporated the planned Olympics Games and nationwide COVID-19 vaccination into the proposed model, alongside various subjects and types of countermeasures. RESULTS: Our model-informed approach suggested that having spectators at the Tokyo Olympic Games could lead to a surge in both cases and hospitalization. Projections for the scenario that explicitly incorporated the spread of the Delta variant (i.e., time-dependent increase in the relative transmissibility) showed that imposing stringent social distancing measures (Rt=0.7) for more than 8 weeks from the end of the Olympic Games might be required to suppress the prevalence of severe cases of COVID-19 to avoid overwhelming the intensive care unit capacity in Tokyo. CONCLUSIONS: Our modeling analyses guided an optimal choice of COVID-19 response during and after the Tokyo Olympic Games, allowing the epidemic to be brought under control despite such a large mass gathering.

Age-Dependent Risks of COVID-19 Putatively Caused by Variant Alpha in Japan.

Background: Osaka, the third largest prefecture in Japan, experienced a rapid replacement of preexisting strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by variant alpha during March-April 2021. Assessing the burden of variant alpha on health centers and medical institutions is vital to anticipating the surge of patients. The present study aimed to estimate the age-dependent risks of coronavirus disease (COVID-19) putatively caused by variant alpha in Japan, focusing on epidemiological dynamics in Osaka. Methods: Descriptive analyses were conducted using data on confirmed, severe and fatal cases of COVID-19 from 16 November 2020 to 22 May 2021. All cases were divided into 6-9 age groups to compare the risks of confirmed diagnosis, severe illness and death from COVID-19 with variant alpha to those caused by preexisting strains. Results: Individuals with COVID-19 aged under 30 years were more likely to be infected with variant alpha than those in their 40s. The incidence of severe illness and death among all age groups with COVID-19 due to variant alpha was higher than that due to preexisting strains. Patients older than 40 years experienced an increased risk of severe illness and death if infected with variant alpha. However, the proportion of severe cases was lower in the group aged 80 years and older infected with variant alpha than in those infected with preexisting strains. Conclusion: Our analysis suggests that the incidence of infection among young people aged below 30 years old increased relative to ordinary strains. Risks of severe illness and death in patients with variant alpha COVID-19 was higher than in those with preexisting strains in Osaka, Japan. However, a decrease in the risk of severe illness was observed in people aged ≥80 years, which is probably because medical facilities in Osaka were overwhelmed in April and May 2021. Continuous monitoring of COVID-19 cases with new variants is vital to secure sufficient medical resources for all patients who require medical care.

High population burden of Omicron variant (B.1.1.529) is associated with the emergence of severe hepatitis of unknown etiology in children.

OBJECTIVES: To explore a potential country-based ecological link between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.529) infection and an apparent current global outbreak of severe hepatitis of unknown etiology among children. METHODS: We examined country-level statistical associations between reported detection of one or more unexplained severe hepatitis cases in children and the cumulative number of Omicron (B.1.1.529) cases in 38 Organisation for Economic Co-operation and Development (OECD) member countries plus Romania. RESULTS: At least one focal hepatitis case was detected in 12 of the 39 countries included in our analysis. Numbers of confirmed Omicron cases reported in these 12 countries ranged from 4.4 to 11.9 million. Among the remaining 27 countries, this measure ranged from 0.5 to 5.5 million cases. Countries which reported focal hepatitis cases experienced higher precedent population burdens of Omicron cases relative to those which did not report any such hepatitis cases (p=0.013). CONCLUSION: Prior exposure to Omicron variant (B.1.1.529) may be associated with an increased risk for severe hepatitis among children, indicating a critical need to conduct cofactor studies.

Phenomenological and mechanistic models for predicting early transmission data of COVID-19.

Forecasting future epidemics helps inform policy decisions regarding interventions. During the early coronavirus disease 2019 epidemic period in January-February 2020, limited information was available, and it was too challenging to build detailed mechanistic models reflecting population behavior. This study compared the performance of phenomenological and mechanistic models for forecasting epidemics. For the former, we employed the Richards model and the approximate solution of the susceptible-infected-recovered (SIR) model. For the latter, we examined the exponential growth (with lockdown) model and SIR model with lockdown. The phenomenological models yielded higher root mean square error (RMSE) values than the mechanistic models. When using the numbers from reported data for February 1 and 5, the Richards model had the highest RMSE, whereas when using the February 9 data, the SIR approximation model was the highest. The exponential model with a lockdown effect had the lowest RMSE, except when using the February 9 data. Once interventions or other factors that influence transmission patterns are identified, they should be additionally taken into account to improve forecasting.

Case Report: Splenic Infarction in Infectious Mononucleosis due to Epstein-Barr Virus Infection.

Epstein-Barr virus (EBV) is the most common cause of infectious mononucleosis (IM) and IM is a clinical syndrome typically characterized by fever, pharyngitis, and cervical lymph node enlargement. We describe the case of a 19-year-old man with IM complicated by splenic infarction. The patient visited our hospital because of upper abdominal pain without a fever and sore throat. Abdominal computed tomography revealed a low-density area in the spleen, which indicated splenic infarction. The next day, he developed a fever. After diminishing abdominal pain and fever, he developed pharyngitis accompanied by fever. Acute EBV infection was confirmed by serological tests. The patient was successfully managed with no specific therapy. Splenic infarction is a rare complication of IM and this case showed that splenic infarction can precede a fever and pharyngitis.

Containment, Contact Tracing and Asymptomatic Transmission of Novel Coronavirus Disease (COVID-19): A Modelling Study.

When a novel infectious disease emerges, enhanced contact tracing and isolation are implemented to prevent a major epidemic, and indeed, they have been successful for the control of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which have been greatly reduced without causing a global pandemic. Considering that asymptomatic and pre-symptomatic infections are substantial for the novel coronavirus disease (COVID-19), the feasibility of preventing the major epidemic has been questioned. Using a two-type branching process model, the present study assesses the feasibility of containing COVID-19 by computing the probability of a major epidemic. We show that if there is a substantial number of asymptomatic transmissions, cutting chains of transmission by means of contact tracing and case isolation would be very challenging without additional interventions, and in particular, untraced cases contribute to lowering the feasibility of containment. Even if isolation of symptomatic cases is conducted swiftly after symptom onset, only secondary transmissions after the symptom onset can be prevented.

Hospital Caseload Demand in the Presence of Interventions during the COVID-19 Pandemic: A Modeling Study.

A surge in hospital admissions was observed in Japan in late March 2020, and the incidence of coronavirus disease (COVID-19) temporarily reduced from March to May as a result of the closure of host and hostess clubs, shortening the opening hours of bars and restaurants, and requesting a voluntary reduction of contact outside the household. To prepare for the second wave, it is vital to anticipate caseload demand, and thus, the number of required hospital beds for admitted cases and plan interventions through scenario analysis. In the present study, we analyzed the first wave data by age group so that the age-specific number of hospital admissions could be projected for the second wave. Because the age-specific patterns of the epidemic were different between urban and other areas, we analyzed datasets from two distinct cities: Osaka, where the cases were dominated by young adults, and Hokkaido, where the older adults accounted for the majority of hospitalized cases. By estimating the exponential growth rates of cases by age group and assuming probable reductions in those rates under interventions, we obtained projected epidemic curves of cases in addition to hospital admissions. We demonstrated that the longer our interventions were delayed, the higher the peak of hospital admissions. Although the approach relies on a simplistic model, the proposed framework can guide local government to secure the essential number of hospital beds for COVID-19 cases and formulate action plans.

Assessing the Impact of Reduced Travel on Exportation Dynamics of Novel Coronavirus Infection (COVID-19).

The impact of the drastic reduction in travel volume within mainland China in January and February 2020 was quantified with respect to reports of novel coronavirus (COVID-19) infections outside China. Data on confirmed cases diagnosed outside China were analyzed using statistical models to estimate the impact of travel reduction on three epidemiological outcome measures: (i) the number of exported cases, (ii) the probability of a major epidemic, and (iii) the time delay to a major epidemic. From 28 January to 7 February 2020, we estimated that 226 exported cases (95% confidence interval: 86,449) were prevented, corresponding to a 70.4% reduction in incidence compared to the counterfactual scenario. The reduced probability of a major epidemic ranged from 7% to 20% in Japan, which resulted in a median time delay to a major epidemic of two days. Depending on the scenario, the estimated delay may be less than one day. As the delay is small, the decision to control travel volume through restrictions on freedom of movement should be balanced between the resulting estimated epidemiological impact and predicted economic fallout.

Communicating the Risk of Death from Novel Coronavirus Disease (COVID-19).

To understand the severity of infection for a given disease, it is common epidemiological practice to estimate the case fatality risk, defined as the risk of death among cases. However, there are three technical obstacles that should be addressed to appropriately measure this risk. First, division of the cumulative number of deaths by that of cases tends to underestimate the actual risk because deaths that will occur have not yet observed, and so the delay in time from illness onset to death must be addressed. Second, the observed dataset of reported cases represents only a proportion of all infected individuals and there can be a substantial number of asymptomatic and mildly infected individuals who are never diagnosed. Third, ascertainment bias and risk of death among all those infected would be smaller when estimated using shorter virus detection windows and less sensitive diagnostic laboratory tests. In the ongoing COVID-19 epidemic, health authorities must cope with the uncertainty in the risk of death from COVID-19, and high-risk individuals should be identified using approaches that can address the abovementioned three problems. Although COVID-19 involves mostly mild infections among the majority of the general population, the risk of death among young adults is higher than that of seasonal influenza, and elderly with underlying comorbidities require additional care.

Real-Time Estimation of the Risk of Death from Novel Coronavirus (COVID-19) Infection: Inference Using Exported Cases.

The exported cases of 2019 novel coronavirus (COVID-19) infection that were confirmed outside China provide an opportunity to estimate the cumulative incidence and confirmed case fatality risk (cCFR) in mainland China. Knowledge of the cCFR is critical to characterize the severity and understand the pandemic potential of COVID-19 in the early stage of the epidemic. Using the exponential growth rate of the incidence, the present study statistically estimated the cCFR and the basic reproduction number-the average number of secondary cases generated by a single primary case in a naïve population. We modeled epidemic growth either from a single index case with illness onset on 8 December, 2019 (Scenario 1), or using the growth rate fitted along with the other parameters (Scenario 2) based on data from 20 exported cases reported by 24 January 2020. The cumulative incidence in China by 24 January was estimated at 6924 cases (95% confidence interval [CI]: 4885, 9211) and 19,289 cases (95% CI: 10,901, 30,158), respectively. The latest estimated values of the cCFR were 5.3% (95% CI: 3.5%, 7.5%) for Scenario 1 and 8.4% (95% CI: 5.3%, 12.3%) for Scenario 2. The basic reproduction number was estimated to be 2.1 (95% CI: 2.0, 2.2) and 3.2 (95% CI: 2.7, 3.7) for Scenarios 1 and 2, respectively. Based on these results, we argued that the current COVID-19 epidemic has a substantial potential for causing a pandemic. The proposed approach provides insights in early risk assessment using publicly available data.