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OBJECTIVE: While the aetiology of idiopathic multicentric Castleman disease (iMCD) remains unclear, the involvement of autoinflammatory mechanisms has been suggested. Herein we report a Japanese patient with iMCD with a novel heterozygous Ile729Met mutation in exon 10 of the Mediterranean fever (MEFV) gene. METHODS: We performed genetic analysis via targeted next-generation sequencing analysis and Sanger sequencing and conducted molecular dynamics simulations to investigate the hydrophobic interactions around the 729th amino acid in human pyrin. RESULTS: In February 2011, a 59-year-old man was diagnosed with IgG4-related disease at our department based on the findings of cervical and hilar lymphadenopathies, typical lung lesions and cervical lymph node biopsy. The patient was followed up without treatment, as he was asymptomatic. However, he had been experiencing prolonged fatigue and fever with high levels of CRP since June 2017. Axillary lymph node biopsy findings led to the diagnosis of iMCD. He was successfully treated with an IL-6 inhibitor and has been in remission for 12 months. Genetic analyses for hereditary autoinflammatory disease-related genes were performed, revealing a novel heterozygous Ile729Met mutation in exon 10 of the MEFV gene. We identified that this novel mutation significantly altered the local interaction of the human pyrin B30.2 domain by molecular dynamics simulation analysis and experimentally had the potential for inflammasome activation with increased inflammatory cytokines. CONCLUSION: The abnormal function of pyrin due to a mutation in the MEFV gene in this patient may have contributed to the development of MCD by inducing IL-6 production via inflammasome signalling.
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Enfermedad de Castleman/genética , Mutación , Pirina/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Simulación de Dinámica MolecularRESUMEN
The SARS-CoV-2 mRNA vaccine BNT162b2 (Pfizer-BioNTech) has become a game-changer in the COVID-19 crisis. Faster and wider coverage of vaccine supply is urgently needed, although vaccine supply is far from abundant in many countries and regions. There is no denying that Japan is vaccinating at a slower pace than in many other countries. At the end of April 2021, it had administered less than 2% of the population, according to the statistics website Our World in Data.1 Single-dose vaccination may be considered to induce an adequate antibody response in individuals with prior infection,2-5 which can lead to more effective vaccine distribution to people in serious need. However, multiple antibody responses in populations with various backgrounds, including prior COVID-19 infection, underlying diseases, and age, have not been investigated sufficiently. Due to the lack of antibody measurement data, antibody follow-up measurement recommendations have yet to be suggested. Accumulation of available data regarding quantitative antibody titer will lead to the establishment of personally customized schedules, including antibody follow-up, and will balance both faster delivery of vaccines and confirmation of effective vaccination.
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IntroductionThe coronavirus disease 2019 (COVID-19) pandemic has been a major concern worldwide; however, easily accessible treatment options for patients with mild COVID-19 remains limited. Since oral intake of Lactococcus lactis strain Plasma (LC-Plasma) enhances both the innate and acquired immune systems through activation of plasmacytoid dendritic cells (pDCs), we hypothesized that the oral intake of LC-Plasma could aid the relief or prevention of symptoms in patients with asymptomatic or mild COVID-19. Methods and analysisThis is an exploratory, multicenter, double-blind, randomized, placebo-controlled trial. This study was initiated in December 2021 and concludes in April 2023. The planned number of enrolled subjects is 100 (50 patients x 2 groups); subject enrolment will be conducted until October 2022. Patients with asymptomatic or mild COVID-19 will be enrolled and randomly assigned in a 1:1 ratio to Group A (oral intake of LC-Plasma-containing capsule, 200 mg/day, for 14 days) or Group B (oral intake of placebo capsule, for 14 days). The primary endpoint is the change in subjective symptoms measured by the severity score. Secondary endpoints include SARS-CoV-2 viral loads, biomarkers for pDC activation, serum SARS-CoV-2-specific antibodies, serum cytokines, interferon and interferon-inducible antiviral effectors, and the proportion of subjects with emergency room visits to medical institutions or who are hospitalized. Ethics and disseminationThe study protocol was approved by the Clinical Research Review Board of Nagasaki University, in accordance with the Clinical Trials Act of Japan. The study will be conducted in accordance with the Declaration of Helsinki, Clinical Trials Act, and other current legal regulations in Japan. Written informed consent will be obtained from all participants. The results of this study will be reported in journal publications. RegistrationThis study was registered in the Japan Registry of Clinical Trials (registration number: jRCTs071210097). ARTICLE SUMMARYO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIThis is the first randomized controlled trial to assess the efficacy of Lactococcus lactis strain Plasma (LC-Plasma) in preventing the onset and attenuation of symptoms in patients with asymptomatic or mild COVID-19. C_LIO_LIThis study is also the first to evaluate the significance of pDC-related immune responses, including interferon production, clearance of symptoms, and prevention of COVID-19 progression. C_LIO_LIThe results of this study may contribute to the development of novel treatment options for asymptomatic or mild COVID-19 patients. C_LIO_LIThis is an exploratory study, due to the lack of previous clinical evidence that evaluated the effect of LC-Plasma intake in patients with COVID-19. C_LIO_LIOther limitations include the subjective endpoint as the primary endpoint and generalizability, since this study will be conducted only in Japan in Japanese patients. C_LI
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IntroductionThe coronavirus disease 2019 (COVID-19) epidemic has been emerged worldwide. Although several medications have been approved for treating moderate-to-severe COVID-19, no treatment strategy has been established for mild COVID-19 patients who do not require oxygen administration. The spread of SARS -CoV-2 has been mostly through patients with mild COVID-19; therefore, treating patients with mild COVID-19 is critical in society. Clarithromycin is a macrolide antimicrobial agent that has been widely used for bacterial respiratory infectious diseases. Clarithromycin also acts an immunomodulating drug and suppresses cytokine storms in viral respiratory diseases, including influenza infection. In this study, we aimed to evaluate the efficacy of clarithromycin in patients with mild COVID-19. Methods and analysisThis is a multicenter, open-label, randomized controlled, 3-armed parallel group comparison, exploratory trial. Subjects with mild COVID-19 pneumonia who did not require oxygen administration were enrolled and randomly assigned in a 1:1:1 ratio to Group A (administration of clarithromycin 800 mg/day), Group B (administration of clarithromycin 400 mg/day), or Group C (standard treatment without clarithromycin). The primary endpoint was the number of days required to improve clinical symptoms as measured by the severity score. Secondary endpoints included days to recover the body temperature, proportion of subjects with oxygen administration, inflammatory cytokines, viral load, serum immunoglobulins, peripheral blood lymphocytes, blood biomarkers, and pneumonia infiltrations. Ethics and disseminationThe study protocol was approved by the Clinical Research Review Board of Nagasaki University in accordance with the Clinical Trials Act in Japan. The study will be conducted in accordance with the Declaration of Helsinki, the Clinical Trials Act, and other current legal regulations in Japan. Written informed consent will be obtained from all participants. The results of this study will be reported as journal publications. RegistrationThis study was registered at the Japan Registry of Clinical Trials (registration number: jRCTs071210011). Strengths and limitations of this studyO_LIThis is the first randomized controlled trial to evaluate the efficacy of clarithromycin against COVID-19 pneumonia, especially in patients with mild COVID-19 pneumonia who do not require oxygen administration. C_LIO_LITo date, no treatment strategy has been established for mild COVID-19 pneumonia. C_LIO_LIThe major limitations of this study are its exploratory nature and relatively small sample size. C_LIO_LIAnother limitation is the open-label study design and generalizability because this study was conducted only in Japan with Japanese patients. C_LI
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BackgroundA few studies on antibody testing have focused on asymptomatic or mild coronavirus disease 2019 (COVID-19) patients with low initial anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody responses. Anti-SARS-CoV-2 antibody-testing performance was evaluated using blood samples from asymptomatic or mild COVID-19 patients. MethodsBlood samples were collected from 143 COVID-19 patients during an outbreak on a cruise ship 3 weeks after diagnosis. Simultaneously, a second SARS-CoV-2 genetic test was performed. Samples stored before the COVID-19 pandemic were also used to evaluate the lateral flow immunochromatographic assay (LFA) and electrochemiluminescence immunoassay (ECLIA). Titers of anti-SARS-CoV-2 IgM and IgG antibodies against the nucleocapsid and spike proteins were measured using the enzyme-linked immunosorbent assay to compare false-negative-with positive-result samples. ResultsSensitivity, specificity, positive-predictive, and negative-predictive values of LFA-detected IgM antibodies were 0.231, 1.000, 1.000, and 0.613, respectively; those of LFA-detected IgG antibodies were 0.483, 0.989, 0.972, and 0.601, respectively; and those of ECLIA-detected total antibodies were 0.783, 1.000, 1.000, and 0.848, respectively. IgM-, IgG-, and total-antibody positivity rates in the patients with negative results from the second genetic testing were 22.9%, 47.6%, and 72.4%, respectively. All antibody titers, especially those of the IgG antibody against nucleocapsid protein, were significantly lower in blood samples with false-negative results than in those with positive results. ConclusionsThese findings suggest that anti-SARS-CoV-2 antibody testing has lower performance in asymptomatic or mild COVID-19 patients than required in the guidelines, and situations in which it is useful are limited.
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Background and objectiveLimited evidence exists regarding the outcomes of patients with coronavirus disease 2019 (COVID-19) who are not hospitalized. This study aimed to assess the outcomes for mild COVID-19 patients in terms of emergency department (ED) visits and hospital admission given initial outpatient triage evaluation and to identify the triage factors affecting these outcomes. MethodsThis retrospective cohort study investigated adult COVID-19 Japanese patients who were triaged at Nagasaki University Hospital between April 1, 2021, and May 31, 2021. A triage checklist with 30 factors was used to identify patients requiring hospitalization. Patients recommended for isolation were followed up for later ED visit or hospital admission. ResultsOverall, 338 COVID-19 patients (mean age, 44.7; 45% women) visited the clinic at an average of 5.4 days after symptom onset. Thirty-six patients (10.6%) were hospitalized from triage, and the rest were recommended for isolation. Seventy-two non-hospitalized patients (23.8%) visited ED during their isolation period, and 30 (9.9%) were hospitalized after ED evaluation. The mean duration to ED visit and hospitalization after symptom onset were 8.8 and 9.7 days, respectively. Checklist factors associated with hospitalization during the isolation period were age > 50 years, obesity with BMI > 25, underlying hypertension, tachycardia with HR > 100/min or blood pressure >135 mmHg at triage, and >{square}3-day delay in hospital visit after symptom onset. ConclusionClinicians should be wary of COVID-19 patients with above risk factors and prompt them to seek follow-up assessment by a medical professional. SUMMARY AT A GLANCEOverall, 338 patients with mild COVID-19 were retrospectively followed up. Factors such as age >{square}50 years, BMI{square}> {square}25, underlying hypertension, high blood pressure and tachycardia at triage, and delayed visit after symptom onset were associated with emergency department visit and hospitalization during the isolation period.