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BACKGROUND & AIMS: We investigate interrelationships between gut microbes, metabolites, and cytokines that characterize COVID-19 and its complications, and we validate the results with follow-up, the Japanese 4D (Disease, Drug, Diet, Daily Life) microbiome cohort, and non-Japanese data sets. METHODS: We performed shotgun metagenomic sequencing and metabolomics on stools and cytokine measurements on plasma from 112 hospitalized patients with SARS-CoV-2 infection and 112 non-COVID-19 control individuals matched by important confounders. RESULTS: Multiple correlations were found between COVID-19-related microbes (eg, oral microbes and short-chain fatty acid producers) and gut metabolites (eg, branched-chain and aromatic amino acids, short-chain fatty acids, carbohydrates, neurotransmitters, and vitamin B6). Both were also linked to inflammatory cytokine dynamics (eg, interferon γ, interferon λ3, interleukin 6, CXCL-9, and CXCL-10). Such interrelationships were detected highly in severe disease and pneumonia; moderately in the high D-dimer level, kidney dysfunction, and liver dysfunction groups; but rarely in the diarrhea group. We confirmed concordances of altered metabolites (eg, branched-chain amino acids, spermidine, putrescine, and vitamin B6) in COVID-19 with their corresponding microbial functional genes. Results in microbial and metabolomic alterations with severe disease from the cross-sectional data set were partly concordant with those from the follow-up data set. Microbial signatures for COVID-19 were distinct from diabetes, inflammatory bowel disease, and proton-pump inhibitors but overlapping for rheumatoid arthritis. Random forest classifier models using microbiomes can highly predict COVID-19 and severe disease. The microbial signatures for COVID-19 showed moderate concordance between Hong Kong and Japan. CONCLUSIONS: Multiomics analysis revealed multiple gut microbe-metabolite-cytokine interrelationships in COVID-19 and COVID-19related complications but few in gastrointestinal complications, suggesting microbiota-mediated immune responses distinct between the organ sites. Our results underscore the existence of a gut-lung axis in COVID-19.
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COVID-19 , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/genética , Estudos Transversais , SARS-CoV-2 , Fezes/química , Imunidade , Citocinas , Vitamina B 6/análiseRESUMO
BACKGROUND: While the prevalence of severe cases and mortality rate of coronavirus disease 2019 (COVID-19) appear to be reducing, the clinical characteristics and severity of hospitalized patients with asthma and COVID-19 remain largely unknown. This study aimed to examine the association of asthma with COVID-19 severity and mortality risk. METHODS: Data from the Japanese COVID-19 Registry Database were used to investigate the association between COVID-19 and asthma. This study focused on patients hospitalized for COVID-19 in 690 facilities from January 31, 2020, to December 31, 2022. Multivariate analysis using logistic regression was conducted to assess whether asthma, compared with other conditions, represents a risk factor for mortality and invasive mechanical ventilation after COVID-19. RESULTS: In total, 72,582 patients with COVID-19 were included in the analysis, of whom, 3731 were diagnosed with asthma. From January 2020 to June 2021, asthma showed no significant association with an increase in mortality (OR 0.837, 95% CI 0.639-1.080, p = 0.184) or invasive mechanical ventilation events (OR 1.084, 95% CI 0.878-1.326, p = 0.440). An analysis conducted after July 2021 yielded similar results. For patients with asthma, factors such as age, body-mass index, sex, and chronic kidney disease increased the risk of mechanical ventilation. However, non-vaccination status and high blood pressure increased the risk of mechanical ventilation during the second half of the study. CONCLUSION: Patients with asthma did not have an increased risk of mortality or mechanical ventilation due to COVID-19. However, patients with asthma had a higher risk of more severe COVID-19 due to factors such as advancing age, elevated body-mass index, chronic kidney disease, and non-vaccination.
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Asma , COVID-19 , Insuficiência Renal Crônica , Humanos , COVID-19/epidemiologia , COVID-19/complicações , Asma/epidemiologia , Asma/terapia , Asma/complicações , Respiração Artificial , Fatores de Risco , Insuficiência Renal Crônica/complicaçõesRESUMO
BACKGROUND: We evaluated the effectiveness of the BNT162b2 vaccine against infection, symptomatic infection, and hospitalization in older people during the Delta-predominant period (July 1 to September 30, 2021). METHODS: We performed a population-based cohort study in an older adult population aged ≥65 years using data from the Vaccine Effectiveness, Networking, and Universal Safety Study conducted from January 1, 2019, to September 30, 2021, in Japan. We matched BNT162b2 vaccinated and unvaccinated individuals in a 1:1 ratio on the date of vaccination of the vaccinated individual. We evaluated the effectiveness of the vaccine against infection, symptomatic infection, and COVID-19-related hospitalization by comparing the vaccinated and unvaccinated groups. We estimated the risk ratio and risk difference using the Kaplan-Meier method with inverse probability weighting. The vaccine effectiveness was calculated as (1 - risk ratio) × 100%. RESULTS: The study included 203,574 matched pairs aged ≥65 years. At 7 days after the second dose, the vaccine effectiveness (95% confidence interval) of BNT162b2 against infection, symptomatic infection, and hospitalization was 78.1% (65.2 to 87.8%), 79.1% (64.6 to 88.9%), and 93.5% (83.7 to 100%), respectively. CONCLUSIONS: BNT162b2 was highly effective against infection, symptomatic infection, and hospitalization in Japan's older adult population aged ≥65 years during the Delta-predominant period.
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BACKGROUND: There is limited understanding of the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan. METHODS: This study included 2638 cases enrolled from 227 healthcare facilities that participated in the COVID-19 Registry Japan (COVIREGI-JP). The inclusion criteria for enrollment of a case in COVIREGI-JP are both (1) a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test and (2) inpatient treatment at a healthcare facility. RESULTS: The median age of hospitalized patients with COVID-19 was 56 years (interquartile range [IQR], 40-71 years). More than half of cases were male (58.9%, 1542/2619). Nearly 60% of the cases had close contact to confirmed or suspected cases of COVID-19. The median duration of symptoms before admission was 7 days (IQR, 4-10 days). The most common comorbidities were hypertension (15%, 396/2638) and diabetes without complications (14.2%, 374/2638). The number of nonsevere cases (68.2%, nâ =â 1798) was twice the number of severe cases (31.8%, nâ =â 840) at admission. The respiratory support during hospitalization includes those who received no oxygen support (61.6%, 1623/2636) followed by those who received supplemental oxygen (29.9%, 788/2636) and invasive mechanical ventilation/extracorporeal membrane oxygenation (8.5%, 225/2636). Overall, 66.9% (1762/2634) of patients were discharged home, while 7.5% (197/2634) died. CONCLUSIONS: We identified the clinical epidemiological features of COVID-19 in hospitalized patients in Japan. When compared with existing inpatient studies in other countries, these results demonstrated fewer comorbidities and a trend towards lower mortality.
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COVID-19 , Adulto , Idoso , Hospitalização , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Sistema de Registros , SARS-CoV-2RESUMO
The salmeterol/fluticasone combination (SFC) inhaler is currently the most widely used maintenance drug for asthmatics worldwide. Although the effectiveness of SFC as either a dry powder inhaler (DPI) or a pressurized metered dose inhaler (pMDI) is well documented, there is limited data comparing the clinical efficacies of the two devices. To address this issue, we carried out a randomized crossover trial in which asthmatic patients (n = 47; mean age, 62.5 ± 16.5 years old) received a 12-week treatment of SFC DPI (50/250 µg twice daily) or SFC pMDI (four puffs of 25/125 µg daily). After a 4-week washout period, patients received another crossover treatment for 12 weeks. Respiratory resistance and reactance were measured by forced oscillation technique (MostGraph-01), spirometry, fractional exhaled nitric oxide (FeNO), and an asthma control test (ACT) every 4 weeks. The mean forced expiratory volume1.0 at the baseline was 2.16 ± 0.86 (L). Respiratory system resistance at 5 Hz (R5), the difference between R5 and R at 20 Hz (R5 - R20), and FeNO improved in both treatment groups, while reactance at 5 Hz (X5) and ACT score improved only in the pMDI group. In patients >70 years old (n = 21), R5, R5 - R20, ΔX5, and FeNO improved only in the pMDI group. These results suggest that SFC by pMDI produces a stronger anti-inflammatory and bronchodilatory effect even in patients whose asthma is well controlled by SFC delivered by DPI.
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Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Broncodilatadores/administração & dosagem , Combinação Fluticasona-Salmeterol/administração & dosagem , Administração por Inalação , Adulto , Idoso , Antiasmáticos/uso terapêutico , Broncodilatadores/uso terapêutico , Estudos Cross-Over , Inaladores de Pó Seco , Feminino , Combinação Fluticasona-Salmeterol/uso terapêutico , Volume Expiratório Forçado , Humanos , Masculino , Inaladores Dosimetrados , Pessoa de Meia-Idade , Estudos Prospectivos , Espirometria , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: Intravenous magnesium sulfate is used as adjunctive therapy for severe asthma exacerbations. However, previous randomized controlled trials of the administration of intravenous magnesium sulfate for asthma exacerbations have shown mixed results, and no study has evaluated its effect on mortality in patients with life-threatening asthma. The objective of this study was to investigate the association between intravenous magnesium sulfate administration and mortality in patients with severe asthma. METHODS: Patients with severe asthma requiring intravenous corticosteroids and oxygenation were selected using the Japanese Diagnosis Procedure Combination inpatient database. One-to-one propensity score matching was performed between patients having received or not intravenous magnesium sulfate. Primary outcomes were 7-, 14- and 28-day mortalities. Secondary outcomes were total dose of intravenous corticosteroids during hospitalization, duration of mechanical ventilation and length of stay. RESULTS: Among 14,122 eligible patients, 619 received intravenous magnesium sulfate. Propensity score matching created a matched cohort of 599 pairs with and without intravenous magnesium sulfate. There were no significant differences between patients with and without intravenous magnesium sulfate in terms of 28-day mortality (1.3% vs 1.8%, P = 0.488), median total dose of intravenous corticosteroids (2400 mg vs 2400 mg, P = 0.580), median duration of mechanical ventilation (1 day vs 1 day, P = 0.118) and median length of stay (16 days vs 13 days, P = 0.640). CONCLUSION: This study found no significant benefit of intravenous magnesium sulfate use in terms of mortality in patients with severe acute asthma.
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Corticosteroides/administração & dosagem , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Terapia Combinada/mortalidade , Sulfato de Magnésio/administração & dosagem , Doença Aguda , Administração por Inalação , Asma/mortalidade , Asma/fisiopatologia , Progressão da Doença , Quimioterapia Combinada , Feminino , Hospitalização , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração ArtificialRESUMO
BACKGROUND: Seasonal Allergic Rhinitis Caused by Japanese Cedar Pollinosis (SAR-JCP) is a most common allergic rhinitis, affecting about 40% in Japan, but the influence from SAR-JCP upon asthma is controversial. The purpose of this study is to investigate the effect of coexistence of SAR-JCP upon control status of asthma using SACRA (Self-Assessment of Allergic Rhinitis and Asthma Questionnaire). METHODS: The design was prospective, single-center, observational study. Asthmatic patients were classified into 3 groups, patients without rhinitis, those with perennial rhinitis or those with SAR-JCP from the results of SACRA. The control status of asthma were evaluated by Visual Analog Scale (VAS) in SACRA and Asthma Control Test (ACT) score. They were evaluated twice, from September to January (nonpollen-season) and February to April (pollen-season) and compared. RESULTS: 451 patients were enrolled and 325 cases (72%) were diagnosed as having comorbidity of rhinitis, among which 173 with only perennial rhinitis, while 152 with SAR-JCP. There was no significant difference in asthma control level measured by VAS and ACT score among 3 groups during nonpollen-season. The asthma control level measured by VAS (1.91-2.95) and ACT score (22.7-21.6) got worse during pollen-season among patients with SAR-JCP, even though 84% received treatment for rhinitis. Although it differed according to criteria, asthma control during pollen-season was impaired in 18-38% asthmatic patients with SAR-JCP. CONCLUSION: It is possible to minimize the influence of AR on asthma control by obtaining an accurate diagnosis and providing sufficient treatment for rhinitis.
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Asma , Rinite Alérgica Sazonal , Adulto , Idoso , Alérgenos/imunologia , Asma/tratamento farmacológico , Asma/epidemiologia , Asma/fisiopatologia , Comorbidade , Cryptomeria/imunologia , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Japão/epidemiologia , Antagonistas de Leucotrienos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pólen/imunologia , Prevalência , Rinite Alérgica Sazonal/epidemiologia , Rinite Alérgica Sazonal/fisiopatologiaRESUMO
BACKGROUND: The clinical usefulness of fixed-dose maintenance therapy with salmeterol/fluticasone (SFC) and budesonide/formoterol combination inhaler (BUD/FM) has been established, though evidence of the long-term anti-inflammatory effects of these 2 inhalers are limited. METHODS: Patients with moderate persistent adult asthma who had received SFC 50/250µg bid with well-control status were recruited. After switching to 8-week therapy with fixed-dose BUD/FM 4 puffs (640/18µg) (phase-1), patients chose either SFC or BUD/FM. FeNO and ACT score were evaluated every 8 weeks until the end of the 52-week treatment period for both treatment groups (phase-2). RESULTS: In total, 103 patients were examined: BUD/FM was chosen by 34 patients (BUD/FM group), while SFC was chosen by 23 (SFC group). Thirty-six received SFC consistently from the beginning of the study (control). Patients in the BUD/FM and SFC groups showed significant improvements in ACT scores and FeNO levels in phase-1; these beneficial effects persisted for 52 weeks in the BUD/FM group. On the other hand, in the SFC group, although the FeNO level decreased from 54.3 ± 26.4 ppb to 41.9 ± 18.3 ppb in phase-1, it increased to 54.5 ± 26.2 ppb, a level similar to the baseline prior to the beginning of BUD/FM therapy, at 8 weeks in phase-2, and remained at 50-odd ppb thereafter. CONCLUSIONS: These results suggest that maintenance therapy with fixed-dose BUD/FM is a useful treatment option exerting an airway anti-inflammatory effect for a period as long as 1 year, even for asthmatics who could not accomplish total control with SFC.
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Corticosteroides/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Asma/tratamento farmacológico , Corticosteroides/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Adulto , Idoso , Albuterol/administração & dosagem , Albuterol/análogos & derivados , Androstadienos/administração & dosagem , Asma/fisiopatologia , Budesonida/administração & dosagem , Estudos de Casos e Controles , Combinação de Medicamentos , Etanolaminas/administração & dosagem , Expiração , Feminino , Combinação Fluticasona-Salmeterol , Fumarato de Formoterol , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Óxido Nítrico , Adulto JovemRESUMO
Delays in clearance and rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported in immunocompromised patients. We encountered a case of recurrent, multi-mutational SARS-CoV-2 infection in a 40-year-old man with severe immunodeficiency due to Good syndrome. The patient had not received the SARS-CoV-2 vaccination. In August 2021, he was first admitted to the hospital owing to coronavirus disease 2019 (COVID-19) pneumonia and was administered dexamethasone, remdesivir, and baricitinib. Although his fever and respiratory condition improved once, chest computed tomography (CT) revealed extensive diffuse consolidation and ground-glass opacities (GGOs), and both methylprednisolone pulse therapy and tocilizumab yielded a limited effect. After a third course of remdesivir without immunosuppressants or steroids, the patient recovered, and he tested negative for SARS-CoV-2. On day 272 since the clinical onset, he was readmitted with dyspnea and mild fever due to a COVID-19 recurrence. He was infected with the Delta variant (AY.29), despite the Omicron (BA.2) variant being predominant at that time. During this admission, additional remdesivir and casirivimab/imdevimab yielded marked effects, and the SARS-CoV-2 quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) tests rapidly returned negative. Phylogenetic analysis demonstrated the accumulation of mutations, including those yielding remdesivir resistance, throughout the SARS-CoV-2 genome. Appropriate use of antivirals and monoclonal antibodies may aid in the recovery of patients with COVID-19 and immunodeficiency and in preventing the emergence of multi-mutational SARS-CoV-2 variants.
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Extracorporeal blood purification with polymyxin B immobilized fiber column direct hemoperfusion (PMX-DHP), is reported to be effective in treating COVID-19 pneumonitis with oxygen demand. This multicenter prospective study evaluated the efficacy and safety of PMX-DHP in oxygen-requiring patients with COVID-19 admitted between September 28, 2020, and March 31, 2022. The primary endpoint was the percentage of clinical improvement 15 days after treatment. The secondary endpoint was the percentage of worsened disease status. Data from the COVID-19 patient registry were used for the synthetic control group. The improvement rate on Day 15 did not differ between PMX-treated patients and controls; however, the deterioration rate was 0.38 times lower in the PMX-treated group, and the death rates on Day 29 were 0 and 11.1% in the PMX-treated and control groups, respectively. The PMX group showed a 0.73 times higher likelihood for reduced intensive care demand, as 16.7% of PMX-treated patients and 22.8% of controls worsened. After treatment blood oxygenation improved, urinary ß2-microglobulin and liver-type fatty acid-binding protein showed significant decreases, and IL-6 decreased once during treatment but did not persist. In this study, PMX treatment effectively prevented the worsening of COVID-19 pathology, accompanied by improved oxygenation. PMX treatment to remove activated cells may effectively improve patient outcomes.
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COVID-19 , Hemoperfusão , Polimixina B , Humanos , COVID-19/terapia , Polimixina B/administração & dosagem , Polimixina B/uso terapêutico , Masculino , Feminino , Hemoperfusão/métodos , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , SARS-CoV-2/isolamento & purificação , Resultado do Tratamento , Oxigênio , Oxigenoterapia/métodos , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagemRESUMO
This study aimed to evaluate diagnostic accuracy of SARS-CoV-2 RNA detection in saliva samples treated with a guanidine-based or guanidine-free inactivator, using nasopharyngeal swab samples (NPS) as referents. Based on the NPS reverse transcription-polymerase chain reaction (RT-PCR) results, participants were classified as with or without COVID-19. Fifty sets of samples comprising NPS, self-collected raw saliva, and saliva with a guanidine-based, and guanidine-free inactivator were collected from each group. In patients with COVID-19, the sensitivity of direct RT-PCR using raw saliva and saliva treated with a guanidine-based and guanidine-free inactivator was 100.0%, 65.9%, and 82.9%, respectively, with corresponding concordance rates of 94.3% (κ=88.5), 82.8% (κ=64.8), and 92.0% (κ=83.7). Among patients with a PCR Ct value of <30 in the NPS sample, the positive predictive value for the three samples was 100.0%, 80.0%, and 96.0%, respectively. The sensitivity of SARS-CoV-2 RNA detection was lower in inactivated saliva than in raw saliva and lower in samples treated with a guanidine-based than with a guanidine-free inactivator. However, in individuals contributing to infection spread, inactivated saliva showed adequate accuracy regardless of the inactivator used. Inactivators can be added to saliva samples collected for RT-PCR to reduce viral transmission risk while maintaining adequate diagnostic accuracy.
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COVID-19 , SARS-CoV-2 , Humanos , Guanidina , SARS-CoV-2/genética , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Reversa , Saliva , COVID-19/diagnóstico , Guanidinas , Nasofaringe , Manejo de Espécimes , Teste para COVID-19RESUMO
BACKGROUND AND OBJECTIVE: Allergic rhinitis (AR) is common in asthmatic patients and may impair asthma control. However, this comorbidity is frequently missed. A simple test is needed to enable physicians to diagnose and evaluate the severity of both diseases. The Self Assessment of Allergic Rhinitis and Asthma (SACRA) questionnaire, which GINA and ARIA Japan committees developed in 2011, consist of questionnaires based on GINA and ARIA guidelines for the diagnosis and severity of AR and asthma, and a visual analogue scale (VAS) to evaluate the severity of both diseases. Our objective was to investigate the clinical usefulness of SACRA as a patient-based screening tool for identifying asthmatic patients with AR. METHODS: SACRA, ACT (Asthma Control Test) and serum IgE RAST were performed in asthmatic patients. The correlation between SACRA and other parameters were analyzed. RESULTS: Four hundred twenty asthmatic patients were enrolled. Among 168 subjects who self-reported no concomitant AR, 76 asthmatics scored one or more symptoms on SACRA. Eventually, 32 of these 76 subjects were diagnosed with AR by physicians based on laboratory data or physical examinations by ear, nose and throat specialists. The sensitivity and specificity of SACRA for the diagnosis of AR were 92% and 66%, respectively. The estimated prevalence of AR among asthmatics was 66%, almost identical to that of the previous nationwide study in Japan. The level of asthma control assessed by the VAS on SACRA and the ACT score showed a strong correlation (r = -0.700, P < 0.001). CONCLUSIONS: SACRA may be a clinically useful tool for identifying bronchial asthma patients with AR.
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Asma/epidemiologia , Programas de Rastreamento/métodos , Guias de Prática Clínica como Assunto , Rinite Alérgica Perene/diagnóstico , Rinite Alérgica Perene/epidemiologia , Autorrelato , Inquéritos e Questionários , Adulto , Idoso , Comorbidade , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Prevalência , Reprodutibilidade dos Testes , Rinite Alérgica , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Escala Visual AnalógicaRESUMO
The National Center for Global Health and Medicine plays a central role in the treatment and research of infectious diseases in Japan. It has conducted various research and development activities on drugs to treat coronavirus disease 2019 (COVID-19) with clinical questions as starting points. Clinical trials are essential in developing new treatment modalities, but we have noticed some characteristic difficulties in clinical trials on emerging and re-emerging infectious diseases. For example, since there is no standard of care when an emerging infectious disease starts to spread, establishing an appropriate control group is complicated, and many things are hurried at the start of trials. This means there is little time to arrange a placebo, and conducting blinded, randomized, controlled trials has been difficult. Another issue characteristic of infectious disease has been that progress in enrolling subjects is affected by the spread of the disease. It was also a struggle to select institutions that provide medical care on the front lines of infectious disease and conduct clinical trials regularly. To start multicenter clinical trials expeditiously, a regulated and structured network is thus considered necessary. From the perspective of implementation, it is preferable to conduct decentralized clinical trials (DCTs) that do not depend on people coming to the medical institution, while from the perspective of preventing infections during the spread of COVID-19, wide adoption of eConsent is desirable. Based on the experience of COVID-19, new measures must be taken to prepare for emerging and re-emerging infectious diseases in the future.
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BACKGROUND: Pre-exposure prophylaxis (PrEP) against HIV infection is a new approach that involves the prophylactic use of the anti-HIV drug Truvada (tenofovir disoproxil fumarate [TDF] and emtricitabine [FTC]) by people not infected with HIV. OBJECTIVE: The objective of this investigator-initiated clinical study of PrEP was to evaluate the incidence of HIV and sexually transmitted infection (STI), safety and efficacy of PrEP in PrEP users, and their compliance with PrEP medication. The social, medical, and economic benefits of PrEP in Japan was assessed. METHODS: This single-center feasibility study of PrEP was conducted at the National Center for Global Health and Medicine, Tokyo, Japan, where a cohort of men who have sex with men without HIV was established in January 2017. This single-arm interventional study compared the efficacy and safety of PrEP in a single group of men who have sex with men who participated in PrEP cohort studies. For reference, the cohort study participants who did not participate in the PrEP study were included for comparison. Blood samples were collected for storage at baseline and clinic visits at 1, 3, and 6 months after starting PrEP and every 3 months thereafter. The participants were administered with 1 tablet of Truvada once daily as PrEP. They underwent blood and anal swab tests 1 and 3 months after starting PrEP and then HIV and STI infection assessments at 3-month intervals. Blood samples were centrifuged at the AIDS Clinical Center Laboratory. PrEP safety was evaluated by monitoring serum creatinine levels for symptoms of renal function disorders. The primary end point was the incidence of HIV in PrEP users (100 person-years). The secondary end points were the incidence of STI in PrEP users (100 person-years), incidence of adverse events caused by Truvada, frequency of high-risk sexual activity, and adherence to periodic visits and medication. RESULTS: The study protocol was reviewed and approved by the certified review board of the National Center for Global Health and Medicine (NCGM-C-003129-03) on April 20, 2020. Changes to the study plan were submitted for review by the certified review board and approved before implementation. Recruitment was completed on March 28, 2019, and the study was completed (last adult participant and last time point) on March 31, 2021. The data were analyzed, and the main results of the study have been published in a peer-reviewed journal. CONCLUSIONS: The findings indicated that PrEP is a highly effective and feasible strategy against HIV infection in terms of prophylactic response, retention, and compliance. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000031040; https://tinyurl.com/3msdkeb8 and Japan Registry of Clinical Trials jRCTs031180134; https://tinyurl.com/2p88mhyr. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/50919.
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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.5 became prevalent in July 2022 in Japan. Bivalent messenger RNA (mRNA) vaccines were approved as booster doses for individuals who received the primary series or booster dose by monovalent vaccines. We aimed to assess the effectiveness of bivalent vaccines in Japanese adults aged ≥65 years. Methods: We conducted a population-based cohort study using data collected from January 2019 to February 2023 in Japan. We included individuals aged ≥65 years in a municipality who received the first or second booster dose of monovalent mRNA vaccines. We estimated the effectiveness of the second or third booster dose of bivalent mRNA vaccines during the Omicron BA.5-predominant period (July-December 2022), compared with ≥90 days after the booster dose of monovalent vaccines. We used a Cox proportional hazard regression model with vaccination status as a time-dependent covariate. Results: A total of 81 977 individuals aged ≥65 years (mean [standard deviation] age, 78.3 [7.4] years; 33 487 male [40.8%]) were included in the study cohort. Among them, 57 396 were vaccinated with the second or third dose of bivalent vaccines (BA.1 or BA.4/5). The effectiveness against coronavirus disease 2019 (COVID-19) was estimated to be 57.9% (95% confidence interval, 52.7%-62.5%) for ≥14 days after the second or third bivalent booster dose, compared with 90 days after the first or second monovalent booster dose. Conclusions: The study showed that the bivalent mRNA vaccines as the second and third doses would provide protection against COVID-19 among adults ≥65 years in Japan.
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The reverse transcription polymerase chain reaction (RT-PCR) offers high sensitivity, but has some drawbacks, such as the time required for the RNA extraction. Transcription reverse-transcription concerted reaction (TRC) Ready® SARS-CoV-2 i is easy to use and can be performed in about 40 minutes. TRC Ready® SARS-CoV-2 i and real-time one-step RT-PCR using the TaqMan probe tests of cryopreserved nasopharyngeal swab samples from patients diagnosed with COVID-19 were compared. The primary objective was to examine the positive and negative concordance rates. A total of 69 samples cryopreserved at -80° C were examined. Of the 37 frozen samples that were expected to be RT-PCR positive, 35 were positive by the RT-PCR method. TRC Ready® SARS-CoV-2 i detected 33 positive cases and 2 negative cases. One frozen sample that was expected to be RT-PCR positive was negative on both TRC Ready® SARS-CoV-2 i and RT-PCR. In addition, one frozen sample that was expected to be RT-PCR positive was positive by the RT-PCR method and negative by TRC Ready® SARS-CoV-2 i. Of the 32 frozen samples that were expected to be RT-PCR negative, both the RT-PCR method and TRC Ready® SARS-CoV-2 i yielded negative results for all 32 samples. Compared with RT-PCR, TRC Ready® SARS-CoV-2 i had a positive concordance rate of 94.3% and a negative concordance rate of 97.1%. TRC Ready® SARS-CoV-2 i can be utilized in a wide range of medical sites such as clinics and community hospitals due to its ease of operability, and is expected to be useful in infection control.
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COVID-19 , Humanos , COVID-19/diagnóstico , SARS-CoV-2/genética , Teste para COVID-19 , Reação em Cadeia da Polimerase em Tempo Real/métodos , Nasofaringe , Sensibilidade e EspecificidadeRESUMO
During an earlier multicenter, open-label, randomized controlled trial designed to evaluate the effectiveness of high-dose inhaled ciclesonide in patients with asymptomatic or mild coronavirus disease 2019 (COVID-19), we observed that worsening of shadows on CT without worsening of clinical symptoms was more common with ciclesonide. The present study sought to determine if an association exists between worsening CT shadows and impaired antibody production in patients treated with inhaled ciclesonide. Eighty-nine of the 90 patients in the original study were prospectively enrolled. After exclusions, there were 36 patients each in the ciclesonide and control groups. We analyzed antibody titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein at various time points. Changes in viral load during treatment were compared. There was no significant difference in age, sex, body mass index, background clinical characteristics, or symptoms between the two groups. Although evaluation on day 8 suggested a greater tendency for worsening shadows on CT in the ciclesonide group (p = 0.072), there was no significant difference between them in the ability to produce antibodies (p = 0.379) or the maximum antibody titer during the clinical course. In both groups, worsening CT shadows and higher viral loads were observed on days 1-8, suggesting ciclesonide does not affect clearance of the virus (p = 0.134). High-dose inhaled ciclesonide did not impair production of antibodies against SARS-CoV-2 or affect elimination of the virus, suggesting that this treatment can be used safely in patients with COVID-19 patients who use inhaled steroids for asthma and other diseases.
Assuntos
Asma , COVID-19 , Pregnenodionas , Humanos , SARS-CoV-2 , Pregnenodionas/uso terapêuticoRESUMO
Although vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) induce effective immune responses, vaccination with booster doses is necessary because of waning immunity. We conducted an open-label, non-randomized, single-arm study in adults in Japan to assess the immunogenicity and safety of a single booster dose of the KD-414 purified whole-SARS-CoV-2-virion inactivated vaccine candidate after vaccination with a primary series of BNT162b2. The primary endpoint was serum neutralizing activity at 7 days after booster injection compared with the primary series of BNT162b2. The SARS-CoV-2-structural protein-binding antibody level and T cell response against SARS-CoV-2-Spike (S) peptides were also examined as secondary endpoints, and safety profile assessments were conducted. Twenty subjects who participated in a previous study declined an injection of KD-414 (non-KD-414 group) and received a booster dose of BNT162b2 instead. The non-KD-414 group was compared to the KD-414 group as a secondary outcome. A single dose of KD-414 induced lower serum neutralizing activity against the wild-type virus within 7 days compared to after the primary series of BNT162b2 but significantly induced anti-SARS-CoV-2-S1-receptor-binding domain-binding immunoglobulin G (IgG) antibodies and SARS-CoV-2-S peptide-specific CD4+ and CD8+ T cell responses. Local or systemic symptoms were significantly lower in the participants who received KD-414 than in those who received BNT162b2 as the third COVID-19 vaccine dose. The present data indicate that a single booster dose of KD-414 induces a substantial immune response in BNT162b2-primed individuals and has a good safety profile, thereby supporting further clinical trials to identify rational targets.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Adulto , Humanos , Vacinas contra COVID-19/efeitos adversos , Vacina BNT162 , Japão , COVID-19/prevenção & controle , SARS-CoV-2 , Anticorpos Antivirais , Imunogenicidade da Vacina , Anticorpos NeutralizantesRESUMO
BACKGROUND: In May 2022, a case of monkeypox (currently known as "mpox") with no history of overseas travel was reported in the United Kingdom, followed by reports of infections reported in Europe, the United States, and other countries worldwide. Due to the significant overlap in immune responses among viruses of the genus Orthopoxvirus (including smallpox virus, mpox virus, and vaccinia virus), it is believed that cross-immunity can be achieved by administering the smallpox virus vaccine. In Japan, a smallpox vaccine (LC16m8 strain vaccine) has been approved; however, there was no regulatory approval for the mpox vaccine during the design of this study. Although it is believed that individuals exposed to the mpox virus may receive smallpox vaccination as mpox prophylaxis, the existing evidence is not clear. OBJECTIVE: The primary objective was to evaluate the efficacy of the LC16m8 strain vaccine, approved for smallpox in Japan, for postexposure prophylaxis against mpox when administered to close contacts of individuals with mpox. The secondary objective was to investigate the safety of the vaccine for postexposure prophylaxis against mpox. METHODS: The study aimed to enroll 100 vaccinated participants who had been identified as close contacts of individuals with mpox. Consent was obtained, and the participants are inoculated with the vaccine. Daily recordings of symptoms (body temperature, headache, rash, and side effects) were made until day 21 and then again on day 28. Furthermore, additional evaluations of adverse events were performed by the investigators on days 7, 14, 21, and 28. Considering that the maximum incubation period for mpox is 21 days, the primary end point is the presence or absence of the disease 21 days after close contact. The primary analysis focused on cases within 4 days of intense contact as it has been reported that vaccination within this timeframe can reduce the incidence of the disease. RESULTS: The first trial participant was enrolled on July 28, 2022, and the research period concluded in March 2023. The study results will be published in a peer-reviewed scientific journal. CONCLUSIONS: This study allowed us to investigate the efficacy and safety of the LC16m8 strain vaccine in postexposure prophylaxis against mpox. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs031220137; https://jrct.niph.go.jp/en-latest-detail/jRCTs031220137. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46955.
RESUMO
Mpox is an acute exanthematous disease caused by the monkeypox virus. Since May 2022, it has spread as a community-acquired infection, mainly in Europe and the United States, and urgent measures to prevent this infection were also required in Japan. In this study, we investigated the post-exposure prophylaxis of mpox and safety after inoculating the smallpox vaccine. Participants in close contact with patients with mpox were inoculated with "Freeze-dried cell culture Smallpox Vaccine LC16," within 14 days after close contact. Six cases were registered, and all the participants were inoculated. No mpox symptoms or related complications were observed in the participants for 21 days after the close contact. Adverse events due to inoculation, such as rash, fever, lymphadenopathy, and local reaction at the inoculation site (comprising erythema, swelling, induration, and pain) were observed in the participants; however, all inoculation-related events were non-severe and non-serious, and the participants recovered during the 28-day observation period. The findings of this study suggest that inoculation with LC16 is an effective post-exposure prophylaxis in individuals who had close contact with patients with mpox. Further large-scale studies are warranted to validate these findings.