Prevalence and trends in persistent symptoms following COVID-19 in Japan: A nationwide cross-sectional survey.

INTRODUCTION: Even during the endemic phase of the COVID-19 pandemic, the impact of persistent symptoms on patients and healthcare systems remains significant. Thus, a more comprehensive understanding of these symptoms is essential. METHODS: Using data from the Japan Society and New Tobacco Internet Survey conducted in February 2023, this cross-sectional study investigated the prevalence of, and changes in, persistent COVID-19 symptoms. RESULTS: In total, 21,108 individuals responded to the survey. Of these, 29.1 % (6143) had a history of COVID-19. Our analysis found that arm/leg/joint pain (adjusted odds ratio [aOR]: 1.17; 95 % confidence interval [95 % CI]: 1.03-1.33), back pain (aOR: 1.13; 95 % CI: 1.01-1.27), chest pain (aOR: 1.53; 95 % CI: 1.20-1.96), malaise (aOR: 1.14; 95 % CI: 1.02-1.28), loss of taste (aOR: 2.55; 95 % CI: 1.75-3.72), loss of smell (aOR: 2.33; 95 % CI: 1.67-3.26), memory impairment (aOR: 1.27; 95 % CI: 1.04-1.56), and cough (aOR: 1.72; 95 % CI: 1.38-2.13) were independently associated with a history of COVID-19 contracted more than two months but less than six months previously. Further, back pain (aOR: 1.24; 95 % CI: 1.04-1.47) and loss of taste (aOR: 2.28; 95 % CI: 1.24-4.21) showed independent association with COVID-19 contracted more than 12 months previously. CONCLUSIONS: Various symptoms were independently associated with a history of COVID-19. While most patients tend to recover within a year after contracting COVID-19, certain symptoms, such as back pain and loss of taste, persist longer than a year, underscoring public health concerns and emphasizing the need for health care services to support patients suffering from persistent symptoms.

Sotos syndrome with marked overgrowth in three Japanese patients with heterozygous likely pathogenic NSD1 variants: case reports with review of literature.

We report three Japanese patients with Sotos syndrome accompanied by marked overgrowth, i.e., a 2 8/12-year-old boy with a height of 105.2 cm (+4.4 SD) (patient 1), the mother of patient 1 with a height of 180.8 cm (+4.1 SD) (patient 2), and a 12 10/12-year-old girl with a height of 189.4 cm (+6.3 SD) (patient 3). In addition to the marked overgrowth (tall stature), patients 1-3 exhibited Sotos syndrome-compatible macrocephaly and characteristic features, whereas intellectual and developmental disabilities remained at a borderline level in patient 1 and were apparently absent from patients 2 and 3. Thus, whole exome sequencing was performed to confirm the diagnosis, revealing a likely pathogenic c.6356A>G:p.(Asp2119Gly) variant in NSD1 of patients 1 and 2, and a likely pathogenic c.6599dupT:p.(Ser2201Valfs*4) variant in NSD1 of patient 3 (NM_022455.5). The results, in conjunction with the previously reported data in nine patients with marked overgrowth (≥4.0 SD), imply that several patients with Sotos syndrome have extreme tall stature even in adulthood. Thus, it is recommended to examine NSD1 in patients with marked overgrowth as the salient feature.

Intravenous methylprednisolone pulse therapy and the risk of in-hospital mortality among acute COVID-19 patients: Nationwide clinical cohort study.

BACKGROUND: Steroids are widely used to modulate the inflammatory reactions associated with coronavirus disease 2019 (COVID-19); however, the optimal upper limit dose of steroid use for acute COVID-19 care remains unclear and currently available data may suffer from a time-dependent bias of no effectiveness or reversed causation given the desperate situation of treatment during this pandemic. Accordingly, the aim of this study was to elucidate the impact of intravenous pulse therapy with methylprednisolone (500 mg or greater per day) on the risk of in-hospital mortality among patients with COVID-19 by controlling for time-dependent bias. METHODS: We performed a prospective cohort study with 67,348 hospitalised acute COVID-19 patients at 438 hospitals during 2020-2021 in Japan. The impact of intravenous methylprednisolone pulse therapy on the risk of in-hospital mortality was examined based on hazard ratios (HRs) and 95% confidence intervals (95% CIs), with stratification according to the status of invasive mechanical ventilation (iMV). Time-dependent bias was controlled for in a marginal structural model analysis, with reference to patients without methylprednisolone therapy. RESULTS: During the study period, 2400 patients died. In-hospital mortality rates of iMV-free patients without or with methylprednisolone pulse therapy were 2.3% and 19.5%, and the corresponding values for iMV-receiving patients were 24.7% and 28.6%, respectively. The marginal structural model analysis showed that intravenous pulse therapy with methylprednisolone was associated with a lower risk of in-hospital mortality among patients receiving-iMV (HR 0.59; 95% CI 0.52-0.68). In contrast, pulse therapy with methylprednisolone increased the risk of in-hospital mortality among iMV-free patients (HR 3.38; 95% CI 3.02-3.79). The benefits of pulse therapy for iMV-receiving patients were greater than in those treated with intermediate/higher doses (40-250 mg intravenously) of methylprednisolone (HR 0.80; 95% CI 0.71-0.89). CONCLUSION: The results of our study suggest that intravenous methylprednisolone showed dose-response efficiencies, and pulse therapy may benefit critically ill patients with acute COVID-19, such as those requiring iMV.

Association between hospital internal medicine physician workforce and patient admissions during the COVID-19 pandemic in Japan.

BACKGROUND: Hospital physician workforce in Japan is the lowest among developed countries. Many patients with novel coronavirus disease 2019 (COVID-19) with high risk of mortality could not be hospitalized during case surges in Japan and only about 5% of total acute care beds were used as COVID-19 beds nationwide. However, the relationship between the number of hospital physicians and patient admissions remains unclear. Thus, we aimed to evaluate this relationship in areas with the highest incidences during the surges. METHODS: Data collection was performed for teaching hospitals accredited with the specialty of internal medicine in three prefectures which experienced the highest COVID-19 incidences in Japan (Tokyo, Osaka, Okinawa). Association was examined between the number of full-time physicians (internal medicine staff physicians and residents) and admissions of internal medicine patients through ambulance transport from April 2020 to March 2021. Analysis was conducted separately for community hospitals and university hospitals because the latter have roles as research institutions in Japan. Community hospitals included private, public, and semi-public hospitals. RESULTS: Of 117 teaching hospitals in three prefectures, data from 108 teaching hospitals (83 community hospitals and 25 university hospitals) were available. A total of 102,400 internal medicine patients were admitted to these hospitals during the one-year period. Private hospitals received the greatest mean number of patient admissions (290 per 100 beds), followed by public hospitals (227) and semi-public hospitals (201), and university hospitals (94). Among community hospitals, a higher number of resident physicians per 100 beds was significantly associated with a greater number of patient admissions per 100 beds with beta coefficient of 11.6 (95% CI, 1.5 to 21.2, p = 0.025) admissions by one physician increase per 100 beds. There was no such association among university hospitals. CONCLUSIONS: Community hospitals with many resident physicians accepted more internal medicine admissions through ambulance transport during the COVID-19 pandemic. An effective policy to counter physician shortage in hospitals in Japan may be to increase internal medicine resident physicians among community hospitals to save more lives.

Estimating nationwide cases of sexually transmitted diseases in 2015 from sentinel surveillance data in Japan.

BACKGROUND: The rates of newly diagnosed cases of sexually transmitted diseases, including genital chlamydial infection and gonorrhea, are important for prevention and control of these diseases. However, nationwide rates are not reported in Japan. METHODS: We used the number of cases of sexually transmitted diseases reported by nationwide sentinel surveillance in 2015, together with the number of all disease outpatients in September 2014 at all medical institutions, drawn from the Survey of Medical Institutions of Japan. The number of cases of sexually transmitted diseases in the total population was estimated using the ratio estimation method with the number of all disease outpatients as auxiliary information. This method is currently used for estimating influenza cases from sentinel surveillance data in Japan. RESULTS: The estimated number of newly diagnosed cases per 100,000 population in 2015 in Japan was 244 (95% confidence interval 211-277) for genital chlamydial infection, 87 (95% confidence interval 74-100) for genital herpes, 61 (95% confidence interval 29-93) for condyloma acuminatum, and 89 (95% confidence interval 64-113) for gonorrhea. CONCLUSION: We estimated the nationwide number of newly diagnosed cases of sexually transmitted diseases in Japan from sentinel surveillance data. This provides useful information for public health policy-making.

Association of severe abnormal behavior and acetaminophen with/without neuraminidase inhibitors.

BACKGROUND: Even though abnormal behavior related with influenza and neuraminidase inhibitors (NI) has been discussed, the risks of acetaminophen and co-administration of NI and acetaminophen have not been examined. This study assesses those risks. MATERIALS AND METHODS: All cases of patients with influenza who present with severe abnormal behavior are reported by physicians of all clinics and hospitals throughout Japan. The numbers of people diagnosed as having influenza, whether prescribed NI and acetaminophen or not, were extracted from the National Database of Electronic Medical Claims (NDBEMC). The study period was from September 2009 to March 2016. RESULTS: We found two consistent results among four combinations of age class and severity. The one was that patients who did not use NI or acetaminophen showed significantly higher incidence of abnormal behavior than zanamivir with acetaminophen, another one was that patients with oseltamivir only has higher incidence than zanamivir with acetaminophen. Concerning about acetaminophen, the use of it significantly decrease risk for severe and the most severe instances in 5-9-year-old patients with laninamivir and the severe instances in 10-19-year-old patients with zanamivir. DISCUSSION: We also demonstrated that acetaminophen alone or co-administered with NI does not seem to raise the risk of abnormal behavior in influenza patients.

Species differences in circulation and inflammatory responses in children with common respiratory adenovirus infections.

Human adenoviruses (HAdVs) cause severe inflammatory respiratory infections, but previous epidemiological studies lacked analysis of the characteristics of the inflammation. Consecutive patients <13 years old with acute febrile illness during a 2-year period were tested. HAdV strains were isolated from nasopharyngeal swabs, and molecular identification was performed by hexon, fiber, and species-specific PCR methods. Blood inflammatory markers, including the white blood cell (WBC) count, CRP, and 29 cytokines, were measured. A total of 187 patients were enrolled, and HAdV types were identified from 175 patients (93.5%). Species C (types 2, 1, 5, and 6, in order of frequency) was most common at 37.1%, followed by B (type 3) at 30.9% and E (type 4) at 26.9%. Species C was detected predominantly in 1-year-old, whereas B and E were in older ages. Species C and B had seasonal circulation patterns, but E was found in only one season during the 2-year study period. The WBC count was highest in patients with species C. Eleven of the 29 tested serum cytokines were detected. Seven kinds, including G-CSF, IL-6, and TNF-α, were elevated in species C infections, whereas IL-10 was lowest in species C. Species differences in inflammatory responses, especially regarding serum cytokines were described in common pediatric HAdV infections. Species C causes the strongest inflammatory responses in young children.

Severe abnormal behavior incidence after administration of neuraminidase inhibitors using the national database of medical claims.

An earlier study using the number of abnormal behaviors reported to the study group as the numerator and the number of influenza patient prescribed each neuraminidase inhibitor (NI) estimated by respective pharmaceutical companies found no significant difference among incidence rates of the most severe abnormal behaviors by type of NI throughout Japan. However, the dataset for the denominator used in that earlier study was the estimated number of prescriptions. In the present study, to compare the incidence rates of abnormal behavior more precisely among influenza patients administered several sorts of NI or administered no NI, we used data obtained from the National Database of Electronic Medical Claims (NDBEMC) as the denominator to reach a definitive conclusion. Results show that patients not administered any NI (hereinafter un-administered) or those administered peramivir sometimes showed higher risk of abnormal behavior than those administered oseltamivir, zanamivir, or laninamivir. However, the un-administered or peramivir patients were fewer than those taking other NI. Therefore, accumulation of data through continued research is expected to be necessary to reach a definitive conclusion about the relation between abnormal behavior and NI in influenza patients. Since severe abnormal behaviors with all types of NI or of un-administered patients have been reported, there are some risks in the administration of NI or even in un-administered cases. Therefore, we infer that the policy mandating package inserts in all types of NI.

Number of sentinel medical institutions needed for estimating prefectural incidence in influenza surveillance in Japan.

BACKGROUND: The sentinel surveillance system in Japan provides estimates of nationwide influenza incidence. Although prefectural influenza incidences can be estimated using data from the current surveillance system, such estimates may be imprecise. METHODS: We calculated the numbers of sentinel medical institutions (SMIs) needed in the surveillance system to estimate influenza incidences in prefectures, under the assumption that the standard error rates in 75% of influenza epidemic cases are less than 10%. Epidemic cases observed in 47 prefectures during the 2007/2008, 2008/2009, and 2009/2010 seasons, respectively, were used. RESULTS: The present total number of SMIs was 6669. With respect to current standards, the increases required in prefectures ranged from 0 to 59, and the total increase required in the number of SMIs was 1668. CONCLUSIONS: We used sentinel surveillance data for Japan to calculate the number of SMIs required to estimate influenza incidence in each prefecture.

Abnormal behavior during influenza in Japan during the last seven seasons: 2006-2007 to 2012-2013.

A few mortalities and cases of severe abnormal behavior have been reported after oseltamivir administration for influenza, thus increasing medical and public concerns regarding the drug's safety. We investigated the association between oseltamivir and abnormal behavior for seven years. All outpatient clinics and hospitals all over the country were requested to report severe abnormal behavior that could have resulted in a fatality if nobody intervened, such as abrupt running outside the home or intention of jumping off a building. The survey was performed prospectively between the 2007-2008 and 2012-2013 seasons, and retrospectively for the 2006-2007 season. As the result of the investigation, eight-hundred fifty-eight cases were reported and among of them 95.7% were positive by the influenza rapid diagnosis test. The epidemic curve of severe abnormal behavior showed a pattern similar to influenza-like illness. The same pattern was observed regardless of age group, gender, or timing of the incidents after waking. Consequently, specific association between the types of medications used or the types of antiviral and abnormal behavior was not observed clearly. The reported abnormal behaviors include fatal cases that would have died if nobody had stopped. This suggested that patients with influenza should be observed with caution for possible abnormal behavior whether taking oseltamivir or other neuraminidase inhibitor anti-influenza drugs.

Usefulness of a pluralistic approach in sentinel surveillance: seasonal influenza activity based on case counts per sentinel site in the National Epidemiological Surveillance of Infectious Diseases Program and test counts, case counts, and test positivity from the National Hospital Organization.

In Japan, based on the National Epidemiological Surveillance of Infectious Diseases (NESID) Program, influenza cases from ~5,000 sentinel sites are monitored weekly as part of influenza surveillance (as number of influenza cases/sentinel site). One limitation is that the number of influenza tests conducted is not reported. Separately, the National Hospital Organization (NHO), with ~140 hospitals, routinely publishes three indicators: number of influenza tests, influenza-positive case counts, and test positivity. We used NESID and NHO data from April 2011 to June 2022 to assess the usefulness of multiple indicators to monitor influenza activity. Temporal trends of the NHO and NESID indicators were similar, and NHO indicator levels well-correlated with those of the NESID indicator. Influenza positivity in the NHO data, however, showed an earlier rise and peak time compared to the NESID indicator. Importantly, through the non-epidemic summer periods and the coronavirus disease 2019 pandemic, a sizable number of influenza tests continued to be done at NHO hospitals, with results showing considerably low case counts and test positivity. These data show that a relatively small number of sentinel sites is sufficient to monitor influenza activity nationally, and, that utilizing multiple indicators can increase our confidence in situational awareness and data interpretations.

Association of Individual Behaviors With Infection Prevention Measures and COVID-19 Development: A Japanese Cross-Sectional Study.

During the COVID-19 pandemic, people often modified their behaviors and performed individual infection control practices despite the uncertain effectiveness of these in preventing COVID-19. A cross-sectional study using a nationwide internet survey (Japan COVID-19 Society Internet Survey) was conducted from September 2022 through October 2022. The questionnaire consisted of individual-level social distancing behaviors and infection prevention measures, and COVID-19 vaccination status. A multivariate logistic regression was performed to determine factors associated with the diagnosis of COVID-19 in the last two months of the survey date. In total, 19,296 respondents were selected for the primary analysis. Of 19,296 respondents, those with COVID-19 diagnosed in the last two months were 1,909 (9.9%). Factors independently associated with a recent history of COVID-19 were meeting colleagues in person ≧ 1 per week (adjusted odds ratio [aOR] 1.72). The response of "never or rarely" to the question of taking out (i.e., dining in) foods was marginally associated with a recent history of COVID-19 (aOR 1.27). Most individual, infection prevention practices and behavioral modifications during the omicron variant phase of the pandemic did not substantially impact COVID-19 prevention in the community.

Risk of Underlying Diseases and Effectiveness of Drugs on COVID-19 Inpatients Assessed Using Medical Claims in Japan: Retrospective Observational Study.

Background: Results of earlier studies have demonstrated underlying diseases such as cancer, diabetes mellitus, immunodeficiency, hypertension and heart failure to be risk factors for severe outcomes and mortality. Furthermore, clinical trials have shown that drugs such as antiviral drugs, antibody cocktails, steroids and anti-inflammatory drugs can be expected to prevent severe COVID-19 outcomes and death. Methods: This study, using inpatient records from the Medical Information Analysis Databank covering national hospital organizations in Japan, was conducted to evaluate the effects of underlying diseases and/or administered drugs on mortality. Subjects were all inpatients receiving oxygen administration and inpatients using respiratory ventilators, categorized by three age classes: all ages, patients 65 years old or older, and patients younger than 65 years old. We used logistic regression to analyze outcomes for underlying diseases, administered drugs, age, sex, the proportion of the mutated strains, and vaccine coverage. Results: Patients with hypertension, except for younger inpatients, have a lower risk of mortality (estimated coefficient 0.67 among all inpatients (p < 0.01): 0.77 among inpatients with oxygen therapy (p = 0.02) and 0.57 among inpatients with respiratory ventilation w (p = 0.01)). Except for younger inpatients, antibody cocktail (casirivimab/imdevimab or sotrovimab) administration was associated with a higher probability of survival (estimated coefficient 0.27 among all inpatients (p < 0.01)). It raised the survival probability consistently, although other drugs might have reduced the probability of survival. Conclusion: These findings suggest that antiviral drugs (remdesivir, estimated coefficient 1.44 (p < 0.01)), steroids (dexamethasone, estimated coefficient 1.85 (p < 0.01)), and anti-inflammatory drugs (baricitinib, estimated coefficient 1.62 (p < 0.01), and tocilizumab, estimated coefficient 2.73 (p < 0.01)) might not contribute to survival. These results have not been reported from earlier studies. More sophisticated estimation procedures, such as treatment effect models, are necessary to obtain conclusive results.

Drug effectiveness for COVID-19 inpatients inferred from Japanese medical claim data using propensity score matching.

Background: Earlier studies and clinical trials of Coronavirus 2019 (COVID-19) showed that drugs such as antiviral drugs, antibody cocktails, and steroids and anti-inflammatory drugs can prevent severe outcomes and death. Methods: Observational data in Japan assess drug effectiveness against COVID-19. We applied the average treatment effect model, particularly propensity scoring, which can treat the choice of administered drug as if administration were randomly assigned to inpatients. Data of the Medical Information Analysis Databank, operated by National Hospital Organization in Japan, were used. The outcome was defined as mortality. Subjects were all inpatients, inpatients with oxygen administration, and inpatients using respiratory ventilation, classified by three age classes: all ages, 65 years old or older, and younger than 65 years old. Information about demographic characteristics, underlying disease, administered drug, the proportions of Alpha, Beta and Omicron variant strains, and vaccine coverage were used as explanatory variables for logistic regression. Results: Estimated results indicated that only one antibody cocktail (sotrovimab, casirivimab and imdevimab) was associated with raising the probability of survival consistently and significantly. By contrast, other drugs, an antiviral drug (remdesivir), a steroid (dexamethasone), and an anti-inflammatory drug (baricitinib and tocilizumab) were related to reduce the probability of survival. However, propensity score matching method might engender biased results because of a lack of data such as detailed information related to intervention and potential confounders. Therefore, the effectiveness of some drugs might not be evaluated properly in this study. Conclusions: Results indicate high likelihood that antibody cocktails were consistently associated with high probability of survival, although low likelihood was found for other drugs for older patients with mild to severe severity and all age patients with moderate severity. Further study is necessary in light of the lack of available data.

Comparing clinical outcomes of ARB and ACEi in patients hospitalized for acute COVID-19.

Continued receipt of Renin-Angiotensin-Aldosterone inhibitors in patients with COVID-19 has shown potential in producing better clinical outcomes. However, superiority between ACEi (angiotensin-converting enzyme inhibitors) and ARB (angiotensin II receptor blockers) regarding clinical outcomes in this setting remains unknown. We retrospectively collected data on patients hospitalized for acute COVID-19 using the nationwide administrative database (Diagnosis and Procedure Combinations, DPC). The DPC data covered around 25% of all acute care hospitals in Japan. Patient outcomes, with focus on inpatient mortality, were compared between patients previously prescribed ACEi and those prescribed ARB. Comparisons based on crude, multivariate and propensity-score adjusted analysis were conducted. We examined a total of 7613 patients (ARB group, 6903; ACEi group 710). The ARB group showed lower crude in-hospital mortality, compared to the ACEi group (5% vs 8%; odds ratio, 0.65; 95% CI 0.48-0.87), however not in the multivariate-adjusted model (odds ratio, 0.95; 95% CI 0.69-1.3) or propensity-score adjusted models (odds ratio, 0.86; 95% CI 0.63-1.2). ARB shows potential in reducing hospital stay duration over ACEi in patients admitted for COVID-19, but does not significantly reduce in-hospital mortality. Further prospective studies are needed to draw a definitive conclusion, but continuation of either of these medications is warranted to improve clinical outcomes.

Analysis of hydroxychloroquine prescriptions for COVID-19 in Japan.

Number of hydroxychloroquine prescriptions per month for patients with coronavirus disease 2019 (COVID-19) in Japan from January 2020 to November 2021. The blue bars show the monthly number of chloroquine prescriptions for COVID-19 among patients in the Medical Data Vision database, which includes data on approximately 20% of acute care hospitals in Japan. The gray line shows the national number of COVID-19 notifications in Japan by month over the same period.

Prolonged Symptoms after COVID-19 in Japan: A Nationwide Survey of the Symptoms and Their Impact on Patients' Quality of Life.

BACKGROUND: Clinical details of long COVID are still not well understood because of potential confounding with a wide range of pre-existing comorbidities. METHODS: The present study used datasets from a nationwide, cross-sectional, online survey. We determined which prolonged symptoms were more likely to be associated with post-COVID condition after adjusting for a wide range of comorbidities and baseline characteristics. This study also used the EuroQol 5 Dimension 5 Level (EQ-5D-5L) and Somatic Symptom Scale-8 to assess health-related quality of life (QOL) and somatic symptoms in individuals with a previous history of COVID-19, defined as the diagnosis of COVID-19 made at least 2 months prior to the online survey. RESULTS: In total, 19,784 respondents were included for analysis; of these, 2397 (12.1%) had a previous history of COVID-19. The absolute difference of adjusted prevalence of symptoms attributed to prolonged symptoms after COVID-19 ranged from -0.4% to +2.0%. Headache (adjusted odds ratio [aOR]: 1.22; 95% confidence interval [95% CI]:1.07-1.39), chest discomfort (aOR:1.34, 95% CI:1.01-1.77), dysgeusia (aOR: 2.05, 95% CI: 1.39-3.04), and dysosmia (aOR: 1.96, 95% CI: 1.35-2.84) were independently associated with a previous history of COVID-19. Individuals with a previous history of COVID-19 had lower health-related QOL scores. CONCLUSIONS: After adjusting for potential comorbidities and confounders, clinical symptoms, such as headache, chest discomfort, dysgeusia, and dysosmia, were found to be independently associated with a previous history of COVID-19, which was diagnosed 2 or more months previously. These protracted symptoms might have impacted QOL and the overall somatic symptom burden in subjects with a previous history of COVID-19.