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.

Results from a preclinical study in rodents and a Phase 1/2, randomized, double-blind, placebo-controlled, parallel-group study of COVID-19 vaccine S-268019-a in Japanese adults.

BACKGROUND: In early 2020, developing vaccines was an urgent need for preventing COVID-19 from a contingency perspective. METHODS: S-268019-a is a recombinant protein-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comprising a modified recombinant spike protein antigen adjuvanted with agatolimod sodium, a Toll-like receptor-9 agonist. In the preclinical phase, it was administered intramuscularly twice at a 2-week interval in 7-week-old mice. Immunogenicity was assessed, and the mice were challenged intranasally with mouse-adapted SARS-CoV-2 at 2 and 8 weeks, respectively, after the second immunization. After confirming the preclinical effect, a Phase 1/2, randomized, parallel-group clinical study was conducted in healthy adults (aged 20-64 years). All participants received 2 intramuscular injections at various combinations of the antigen and the adjuvant (S-910823/agatolimod sodium, in µg: 12.5/250, 25/250, 50/250, 25/500, 50/500, 100/500, 10/500, 100/100, 200/1000) or placebo (saline) in an equivalent volume at a 3-week interval and were followed up until Day 50 in this interim analysis. RESULTS: In the preclinical studies, S-268019-a was safe and elicited robust immunoglobulin G (IgG) and neutralizing antibody responses in mice. When challenged with SARS-CoV-2, all S-268019-a-treated mice survived and maintained weight until 10 days, whereas all placebo- or adjuvant-treated (without antigen) mice died within 6 days. In the Phase 1/2 trial, although S-268019-a was well tolerated in adult participants, was safe up to Day 50, and elicited robust anti-spike protein IgG antibodies, it did not elicit sufficient neutralizing antibody levels. CONCLUSIONS: The S-268019-a vaccine was not sufficiently immunogenic in Japanese adults despite robust immunogenicity and efficacy in mice. Our results exemplify the innate challenges in translating preclinical data in animals to clinical trials, and highlight the need for continued research to overcome such barriers. (jRCT2051200092).

Real-world Data on the Incidence of Coronavirus Disease (COVID-19) in Patients With Advanced Thoracic Cancer During the Early Phase of the Pandemic in Japan.

BACKGROUND/AIM: The severity and associated mortality of coronavirus disease 2019 (COVID-19) are higher in patients with thoracic cancer than in healthy populations and those with other cancer types. Here, we investigated real-world data on the incidence of COVID-19 and false-negative cases using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) real-time reverse-transcription polymerase chain reaction (rRT-PCR) testing in patients with thoracic cancer. PATIENTS AND METHODS: We retrospectively reviewed patients with advanced thoracic cancer at the National Cancer Center Hospital between March 2020-May 2021. Blood samples were collected and evaluated for IgM and IgG antibodies specific for nucleocapsid (N) and spike (S) protein SARS-CoV-2 before and after rRT-PCR testing. False-negative cases were assessed based on anti-SARS-CoV-2 antibody levels before and after rRT-PCR testing. RESULTS: A total of 2,107 patients with thoracic cancer were identified between March 2020 and May 2021, 7 (0.3%) of whom developed COVID-19. Among the 218 patients who underwent at least one rRT-PCR test because of suspected COVID-19 symptoms or as a screening test at our institute, the most common diagnosis was non-COVID-19 pneumonia (34.4%), followed by tumor fever (30.7%). Furthermore, of the 218 patients, 120 paired serum samples before and after rRT-PCR testing were available. Seroconversion was identified in all three patients with positive SARS-CoV-2 rRT-PCR results but was only observed in 1 out of the 117 patients who tested negative; the rate of false-negative cases was low (0.9%). CONCLUSION: COVID-19 incidence among patients with advanced thoracic cancer was low during the early phase of the pandemic in Japan.

Phase 1/2 clinical trial of COVID-19 vaccine in Japanese participants: A report of interim findings.

We initiated a randomized, placebo-controlled, phase 1/2 trial to evaluate the safety and immunogenicity of the S-268019-b recombinant protein vaccine, scheduled as 2 intramuscular injections given 21 days apart, in 60 randomized healthy Japanese adults. We evaluated 2 regimens of the S-910823 antigen (5 µg [n = 24] and 10 µg [n = 24]) with an oil-in-water emulsion formulation and compared against placebo (n = 12). Reactogenicity was mild in most participants. No serious adverse events were noted. For both regimens, vaccination resulted in robust IgG and neutralizing antibody production at days 36 and 50 and predominant T-helper 1-mediated immune reaction, as evident through antigen-specific polyfunctional CD4+ T-cell responses with IFN-γ, IL-2, and IL-4 production on spike protein peptides stimulation. Based on the interim analysis, the S-268019-b vaccine is safe, produces neutralizing antibodies titer comparable with that in convalescent serum from COVID-19-recovered patients. However, further evaluation of the vaccine in a large clinical trial is warranted.

Efficacy and Safety of Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is an enveloped, single-stranded RNA virus. Favipiravir is an orally administrable antiviral drug whose mechanism of action is to selectively inhibit RNA-dependent RNA polymerase. A preliminary trial in COVID-19 patients reported significant improvements across a multitude of clinical parameters, but these findings have not been confirmed in an adequate well-controlled trial. We conducted a randomized, single-blind, placebo-controlled Phase III trial assessing the efficacy and safety of favipiravir in patients with moderate pneumonia not requiring oxygen therapy. METHODS: COVID-19 patients with moderate pneumonia (SpO2 ≥ 94%) within 10 days of onset of fever (temperature ≥ 37.5 °C) were assigned to receive either placebo or favipiravir (1800 mg twice a day on Day 1, followed by 800 mg twice a day for up to 13 days) in a ratio of 1:2. An adaptive design was used to re-estimate the sample size. The primary endpoint was a composite outcome defined as the time to improvement in temperature, oxygen saturation levels (SpO2), and findings on chest imaging, and recovery to SARS-CoV-2-negative. This endpoint was re-examined by the Central Committee under blinded conditions. RESULTS: A total of 156 patients were randomized. The median time of the primary endpoint was 11.9 days in the favipiravir group and 14.7 days in the placebo group, with a significant difference (p = 0.0136). Favipiravir-treated patients with known risk factors such as obesity or coexisting conditions provided better effects. Furthermore, patients with early-onset in the favipiravir group showed higher odds ratio. No deaths were documented. Although adverse events in the favipiravir group were predominantly transient, the incidence was significantly higher. CONCLUSIONS: The results suggested favipiravir may be one of options for moderate COVID-19 pneumonia treatment. However, the risk of adverse events, including hyperuricemia, should be carefully considered. TRIAL REGISTRATION: Clinicaltrials.jp number: JapicCTI-205238.

The background occurrence of selected clinical conditions prior to the start of an extensive national vaccination program in Japan.

INTRODUCTION: The COVID-19 pandemic caused by SARS-CoV-2 has now affected tens of millions of people globally. It is the hope that vaccines against SARS-CoV-2 will deliver a comprehensive solution to this global pandemic; however, this will require extensive national vaccination programs. Ultimately, clinical conditions and even sudden unexplained death will occur around the time of vaccination, thus a distinction needs to be made between events that are causally related to the vaccine or temporally related to vaccination. This study aimed to estimate the background occurrence of 43 clinical conditions in the Japanese population. METHODS: A retrospective cohort study was conducted from 2013 to 2019 using data from two large healthcare claims databases (MDV and JMDC) in Japan. The estimated number of new cases and incidence were calculated based on the actual number of new cases identified in the databases. The PubMed and Ichushi-web databases, as well as grey literature such as guidelines and government statistics, were also searched to identify any publications related to incidence of these conditions in Japan. RESULTS AND CONCLUSION: The estimates of the number of total cases and incidence were similar for the MDV and JMDC databases for some diseases. In addition, some estimates were similar to those in the scientific literature. For example, from the MDV and JMDC databases, estimates of incidence of confirmed Bell's palsy in 2019 were 41.7 and 47.9 cases per 100,000 population per year, respectively. These estimates were of the same order from the scientific publication. Determining whether clinical conditions occurring around the time of vaccination are causally or only temporally related to vaccination will be critical for public health decision makers as well as for the general public. Comparison of background occurrence at the population level may provide some additional objective evidence for the evaluation of temporality or causality.

The clinical characteristics of pediatric coronavirus disease 2019 in 2020 in Japan.

BACKGROUND: The COVID-19 pandemic has affected the lives of people of all ages. Most reports on pediatric cases suggest that children experience fewer and milder symptoms than do adults. This is the first nationwide study in Japan focusing on pediatric cases reported by pediatricians, including cases with no or mild symptoms. METHODS: We analyzed the epidemiological and clinical characteristics and transmission patterns of 840 pediatric (<16 years old) COVID-19 cases reported between February and December 2020 in Japan, using a dedicated database which was maintained voluntarily by members of the Japan Pediatric Society. RESULTS: Almost half of the patients (47.7%) were asymptomatic, while most of the others presented mild symptoms. At the time of admission or first outpatient clinic visit, 84.0% of the cases were afebrile (<37.5°C). In total, 609 cases (72.5%) were exposed to COVID-19-positive household members. We analyzed the influence of nationwide school closures that were introduced in March 2020 on COVID-19 transmission routes among children in Japan. Transmission within households occurred most frequently, with no significant difference between the periods before and after declaring nationwide school closures (70.9% and 74.5%, respectively). CONCLUSIONS: COVID-19 symptoms in children are less severe than those in adults. School closure appeared to have a limited effect on transmission. Controlling household transmission from adult family members is the most important measure for prevention of COVID-19 among children.

Difference in SARS-CoV-2 Antibody Status Between Patients With Cancer and Health Care Workers During the COVID-19 Pandemic in Japan.

Importance: Patients with cancer and health care workers (HCWs) are at high risk of SARS-CoV-2 infection. Assessing the antibody status of patients with cancer and HCWs can help understand the spread of COVID-19 in cancer care. Objective: To evaluate serum SARS-CoV-2 antibody status in patients with cancer and HCWs during the COVID-19 pandemic in Japan. Design, Setting, and Participants: Participants were enrolled for this prospective cross-sectional study between August 3 and October 30, 2020, from 2 comprehensive cancer centers in the epidemic area around Tokyo, Japan. Patients with cancer aged 16 years or older and employees were enrolled. Participants with suspected COVID-19 infection at the time of enrollment were excluded. Exposures: Cancer of any type and cancer treatment, including chemotherapy, surgery, immune checkpoint inhibitors, radiotherapy, and targeted molecular therapy. Main Outcomes and Measures: Seroprevalence and antibody levels in patients with cancer and HCWs. Seropositivity was defined as positivity to nucleocapsid IgG (N-IgG) and/or spike IgG (S-IgG). Serum levels of SARS-CoV-2 IgM and IgG antibodies against the nucleocapsid and spike proteins were measured by chemiluminescent enzyme immunoassay. Results: A total of 500 patients with cancer (median age, 62.5 years [range, 21-88 years]; 265 men [55.4%]) and 1190 HCWs (median age, 40 years [range, 20-70 years]; 382 men [25.4%]) were enrolled. In patients with cancer, 489 (97.8%) had solid tumors, and 355 (71.0%) had received anticancer treatment within 1 month. Among HCWs, 385 (32.3%) were nurses or assistant nurses, 266 (22.4%) were administrative officers, 197 (16.6%) were researchers, 179 (15.0%) were physicians, 113 (9.5%) were technicians, and 50 (4.2%) were pharmacists. The seroprevalence was 1.0% (95% CI, 0.33%-2.32%) in patients and 0.67% (95% CI, 0.29%-1.32%) in HCWs (P = .48). However, the N-IgG and S-IgG antibody levels were significantly lower in patients than in HCWs (N-IgG: ß, -0.38; 95% CI, -0.55 to -0.21; P < .001; and S-IgG: ß, -0.39; 95% CI, -0.54 to -0.23; P < .001). Additionally, among patients, N-IgG levels were significantly lower in those who received chemotherapy than in those who did not (median N-IgG levels, 0.1 [interquartile range (IQR), 0-0.3] vs 0.1 [IQR, 0-0.4], P = .04). In contrast, N-IgG and S-IgG levels were significantly higher in patients who received immune checkpoint inhibitors than in those who did not (median N-IgG levels: 0.2 [IQR, 0.1-0.5] vs 0.1 [IQR, 0-0.3], P = .02; S-IgG levels: 0.15 [IQR, 0-0.3] vs 0.1[IQR, 0-0.2], P = .02). Conclusions and Relevance: In this cross-sectional study of Japanese patients with cancer and HCWs, the seroprevalence of SARS-CoV-2 antibodies did not differ between the 2 groups; however, findings suggest that comorbid cancer and treatment with systemic therapy, including chemotherapy and immune checkpoint inhibitors, may influence the immune response to SARS-CoV-2.

The Impact of COVID-19 on Cancer Care in the Post Pandemic World: Five Major Lessons Learnt from Challenges and Countermeasures of Major Asian Cancer Centres.

OBJECTIVE: The COVID-19 pandemic has dramatically affected healthcare services around Asia. The Asian National Cancer Centres Alliance and the Asia-Pacific Organisation for Cancer Prevention collaborated to assess the mid- and long- term impact of COVID-19 to cancer care in Asia. METHODS: The two entities organised a combined symposium and post-meeting interactions among representatives of major cancer centres from seventeen Asian countries to outlining major challenges and countermeasures. RESULTS: Participating stakeholders distilled five big questions. 1) "Will there be an explosion of late-stage cancers after the pandemic?" To address and recover from perceived delayed prevention, screening, treatment and care challenges, collaboration of key stakeholders in the region and alignment in cancer care management, policy intervention and cancer registry initiatives would be of essential value. 2) "Operations and Finance" The pandemic has resulted in significant material and financial casualties. Flagged acute challenges (shortages of supplies, imposition of lockdown) as well as longer-standing reduction of financial revenue, manpower, international collaboration, and training should also be addressed. 3) "Will telemedicine and technological innovations revolutionize cancer care?" Deploying and implementing telemedicine such as teleconsultation and virtual tumour boards were considered invaluable. These innovations could become a new regular practice, leading to expansion of tele-collaboration through collaboration of institutions in the region. 4) "Will virtual conferences continue after the pandemic?" Virtual conferences during the pandemic have opened new doors for knowledge sharing, especially for representatives of low- and middle-income countries in the region, while saving time and costs of travel. 5) "How do we prepare for the next pandemic or international emergency?" Roadmaps for action to improve access to appropriate patient care and research were identified and scrutinised. CONCLUSION: Through addressing these five big questions, focused collaboration among members and with international organisations such as City Cancer Challenge will allow enhanced preparedness for future international emergencies.
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A novel highly quantitative and reproducible assay for the detection of anti-SARS-CoV-2 IgG and IgM antibodies.

The quantitative range and reproducibility of current serological tests for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are not optimized. Herein, we developed a diagnostic test that detects SARS-CoV-2 IgG and IgM with high quantitativeness and reproducibility and low interference. The system was based on the high-sensitivity chemiluminescence enzyme immunoassay (HISCL) platform and detects IgG and IgM specific to SARS-CoV-2 spike and nucleocapsid proteins. Quantification accuracy and reproducibility were evaluated using serially diluted samples from 60 SARS-CoV-2-infected patients. Assay performance was evaluated using serum samples from the SARS-CoV-2-infected patients and 500 SARS-CoV-2-negative serum samples collected before the emergence of SARS-CoV-2. The system showed high quantification accuracy (range, 102), high reproducibility (within 5%), and no cross-reaction between SARS1- and MERS-S proteins. Detection accuracy was 98.3% and 93.3% for IgG and IgM against spike proteins and 100% and 71.7% for IgG and IgM against nucleocapsid proteins, respectively. Mean antibody levels were > 10 times that in negative samples upon admission and > 100 times that at convalescent periods. Clinical severity upon admission was not correlated with IgG or IgM levels. This highly quantitative, reproducible assay system with high clinical performance may help analyze temporal serological/immunological profiles of SARS-CoV-2 infection and SARS-CoV-2 vaccine effectiveness.

Uniform infection screening allowed safe head and neck surgery during the coronavirus disease 2019 pandemic in Japan.

BACKGROUND: The purpose of this study was to determine whether a uniform infection screening protocol could be used to safely perform head and neck cancer surgery during the coronavirus disease 2019 pandemic and clarify how surgical treatment changed compared with the pre-pandemic period. MATERIALS AND METHODS: During the unprecedented coronavirus disease 2019 pandemic in Tokyo, we continued providing head and neck cancer care, guided by our own uniform screening protocol. In this study, medical records of 208 patients with head and neck malignancy, who underwent surgical treatment at our hospital during the first and second wave of pandemic for each 2-month period (first wave: 30 March 2020-30 May 2020, second wave: 14 July 2020-14 September 2020) and the 2-month pre-pandemic period (30 October 2019-30 December 2020), were analysed. RESULTS: A total of 133 patients were admitted for surgical treatment and all, except six patients with emergency tracheostomy, were screened according to the protocol. As a result, all 127 patients received surgical treatment as planned, and all 1247 medical staff members involved in the surgeries were uninfected by severe acute respiratory syndrome coronavirus 2. During the first wave of pandemic, 20% reduction of head and neck surgery was requited; however, restrictions of surgery were not necessary during the second wave. Surgical procedure, length of hospitalization, postoperative complications and number of medical staff were unchanged compared with pre-pandemic period. CONCLUSION: Our data indicate that continuation of head and neck anticancer surgical treatment in an epidemic area during the coronavirus disease 2019 pandemic were safe and feasible, if adequate and strict preventive measures are vigorously and successfully carried out.

COVID-19 pneumonia in a patient with adult T-cell leukemia-lymphoma.

Although some patients with COVID-19 develop only mild symptoms, fatal complications have been observed among those with comorbidities. As patients with cancer are immunocompromised, they are thought to have a high risk of severe illness associated with COVID-19. We report a COVID-19 patient with adult T-cell leukemia-lymphoma (ATL) who was treated using favipiravir. A 69-year-old woman with lymphoma-type ATL was treated using cyclophosphamide, doxorubicin, vincristine, prednisolone and mogamulizumab (M-CHOP) with substantial efficacy. However, in cycle 4 of M-CHOP therapy, she developed fever with mild cough. The patient was admitted to the hospital and CT revealed bilateral ground-glass opacities. SARS-CoV-2 was detected by RT-PCR and the patient was diagnosed with COVID-19. Considering severe immunosuppression caused by ATL, we initiated favipiravir therapy. Subsequently, the fever improved without antipyretics and her C-reactive protein level decreased rapidly. SARS-CoV-2 PCR tests were negative on days 17 and 18 of favipiravir therapy, and the patient was discharged without residual disease on the final CT. This is the first documented case of COVID-19 in a patient with ATL. Although severe immunosuppression caused by ATL was present, severe COVID-19 pneumonia did not develop. The immunosuppressed condition caused by hematological malignancy may not always be a risk factor for severe illness associated with COVID-19. Further accumulation of data regarding COVID-19 in patients with hematological malignancies is warranted to clarify the risk factors for severe illness, the best-in-class antiviral agent, and the optimal treatment strategy in this population.