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BACKGROUND: Cytokine release syndrome (CRS) is an acute systemic inflammatory syndrome characterized by fever and multiple organ failure, which is triggered by immunotherapy or certain infections. Immune checkpoint inhibitors rarely cause immune-related adverse event- cytokine release syndrome (irAE-CRS). This article presents a case report of irAE-CRS triggered by coronavirus disease 2019 (COVID-19). CASE PRESENTATION: A 60-year-old man with type 2 diabetes received nivolumab treatment for esophagogastric junction carcinoma and experienced two immune-related adverse events: hypothyroidism and skin disorder. Eleven days before his visit to our hospital, he had a fever and was diagnosed with COVID-19. Five days before his visit, he developed a fever again, along with general malaise, water soluble diarrhea, and myalgia of the extremities. On admission, the patient was in a state of multiple organ failure, and although the source of infection was unknown, a tentative diagnosis of septic shock was made. The patient's condition was unstable despite systemic management with antimicrobial agents, high-dose vasopressors, and intravenous fluids. We suspected CRS due to irAE (irAE-CRS) based on his history of nivolumab use. Steroid pulse therapy (methylprednisolone 1 g/day) was started, and the patient temporarily recovered. However, his respiratory condition worsened; consequently, he was placed on a ventilator and tocilizumab was added to the treatment. His muscle strength recovered to the point where he could live at home, and was subsequently discharged. CONCLUSION: In patients previously treated with immune checkpoint inhibitors, irAE-CRS should be considered as a differential diagnosis when multiple organ damage is observed in addition to inflammatory findings. It is recommended to start treatment with steroids; if the disease is refractory, other immunosuppressive therapies such as tocilizumab should be introduced as early as possible.
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OBJECTIVES: To update evidence on the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) and provide information to the taskforce for the 2024 update of the Japan College of Rheumatology (JCR) clinical practice guidelines (CPG) for the management of rheumatoid arthritis (RA). METHODS: We searched various databases for randomised controlled trials on RA published until June 2022, with no language restriction. For each of the 15 clinical questions, 2 independent reviewers screened the articles, evaluated the core outcomes, and performed meta-analyses. RESULTS: Subcutaneous injection of methotrexate (MTX) showed similar efficacy to oral MTX in MTX-naïve RA patients. Ozoralizumab combined with MTX improved drug efficacy compared to the placebo in RA patients with inadequate response (IR) to csDMARD. Rituximab with and without concomitant csDMARDs showed similar efficacy to other bDMARDs in bDMARD-IR RA patients. Combined Janus kinase inhibitors and MTX achieved similar clinical responses and equal safety during a 4-year period compared to tumour necrosis factor inhibitors in MTX-IR RA patients. Biosimilars showed efficacy equivalent to that of the original bDMARDs in csDMARD-IR and bDMARD-IR RA patients. CONCLUSION: This systematic review provides latest evidence for the 2024 update of the JCR CPG for RA management.
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Leprosy is a global health issue, causing long-term functional morbidity and stigma. Rapid diagnosis and appropriate treatment are important; however, early diagnosis is often challenging, especially in nonendemic areas. Here, we report a case of borderline lepromatous leprosy accompanied by dapsone-induced (neutropenia, anemia, and methemoglobinemia) and clofazimine-induced (skin discoloration and ichthyosis) side effects and type 1 leprosy reactions during administration of the multidrug therapy. The patient completely recovered without developing any deformities or visual impairment. To ensure early diagnosis and a favorable outcome, clinicians should be aware of the diminished sensation of skin lesions as a key physical finding and manage the drug toxicities and leprosy reactions appropriately in patients on multidrug therapy.
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Hipersensibilidad , Lepra Dimorfa , Lepra Lepromatosa , Lepra Multibacilar , Lepra , Enfermedades del Sistema Nervioso Periférico , Enfermedades Cutáneas Bacterianas , Humanos , Clofazimina/efectos adversos , Dapsona/efectos adversos , Quimioterapia Combinada , Leprostáticos/efectos adversos , Lepra/patología , Lepra Dimorfa/diagnóstico , Lepra Dimorfa/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Lepra Multibacilar/tratamiento farmacológico , Lepra Lepromatosa/diagnóstico , Lepra Lepromatosa/tratamiento farmacológico , Lepra Lepromatosa/patologíaRESUMEN
Anadromous salmonids exhibit partial migration, where some individuals within a population migrate down to the ocean through complex interactions between body size and photoperiod. This study aimed to integrate the ontogenetic and seasonal patterns of smoltification, a series of changes for future marine life, in a strain of masu salmon (Oncorhynchus masou). Spring smoltification, as evidenced by the activation of gill Na+,K+-ATPase (NKA), was induced during winter under an advanced photoperiod. In addition, juveniles showed an additional peak in gill NKA activity in August regardless of the photoperiod. When juvenile masu salmon were subjected to feeding manipulations during the first spring/summer, only fish exceeding a fork length of 12 cm exhibited an increased gill NKA activity. We tested whether size-driven smoltification required a long-day period by exposing juveniles to a constant short-day length (9-h light and 15-h dark) from January to November. Juveniles under short-day conditions exceeded 12 cm in June but showed no signs of smoltification. Thus, masu salmon undergo photoperiod-limited, size-driven smoltification during the first summer and size-limited, photoperiod-driven smoltification the following spring. The findings of the present study provide a framework for further elucidation of the physiological mechanisms underlying partial migration in salmonids.
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Oncorhynchus , Salmonidae , Animales , Oncorhynchus/fisiología , Fotoperiodo , Tamaño Corporal , Hormona del Crecimiento , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Branquias/metabolismo , Salmonidae/metabolismoRESUMEN
Candida auris is a health hazard because of its antifungal resistance and the potential to cause healthcare-associated outbreaks. To our knowledge, no previous cases of candidemia caused by C. auris have been reported in Japan. Herein, we report the first known case of clade I C. auris candidemia in a Japanese man with coronavirus disease 2019 (COVID-19) infection who was medically evacuated from the Philippines. A 71-year-old Japanese man traveled to Cebu Island in the Philippines 5 months before admission to our hospital. He contracted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the Philippines and was admitted to the intensive care unit (ICU) in a local hospital. During his medical evacuation, we implemented precautions given his history of COVID-19 and pneumonia caused by multi-drug-resistant Acinetobacter baumannii complex. His blood culture revealed that C. auris infection was treated with antifungal agents but he did not survive. No evidence of nosocomial transmission was found among other patients in the ICU. This case study determines that accurate detection of C. auris, appropriate antifungal agent selection, precautions, and patient isolation are crucial to prevent nosocomial outbreaks, especially in patients with a history of multidrug-resistant organism (MDRO) colonization or international hospitalization. Medical professionals should recognize the risk of MDROs in international medical evacuation settings, considering the recent resumption of cross-border travel after the COVID-19 pandemic.
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COVID-19 , Candidemia , Infección Hospitalaria , Masculino , Humanos , Anciano , Candidemia/microbiología , Candida auris , Candida , COVID-19/epidemiología , Pandemias , Japón , SARS-CoV-2 , Pruebas de Sensibilidad Microbiana , Filipinas , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Infección Hospitalaria/microbiologíaRESUMEN
Adult-onset immunodeficiency due to interferon-γ-neutralizing autoantibodies (nIFNγ-autoAbs) can remain underdiagnosed. We present a case of severe Mycobacterium colombiense infection with nIFNγ-autoAbs. To ensure early diagnosis, clinicians should have a high index of suspicion in patients of Asian descent with opportunistic infections and perform QuantiFERON-TB assay for disease screening.
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Presently, coronavirus disease-19 (COVID-19) is spreading worldwide without an effective treatment method. For COVID-19, which is often asymptomatic, it is essential to adopt a method that does not cause aggravation, as well as a method to prevent infection. Whether aggravation can be predicted by analyzing the extent of lung damage on chest computed tomography (CT) scans was examined. The extent of lung damage on pre-intubation chest CT scans of 277 patients with COVID-19 was assessed. It was observed that aggravation occurred when the CT scan showed extensive damage associated with ground-glass opacification and/or consolidation (p < 0.0001). The extent of lung damage was similar across the upper, middle, and lower fields. Furthermore, upon comparing the extent of lung damage based on the number of days after onset, a significant difference was found between the severe pneumonia group (SPG) with intubation or those who died and non-severe pneumonia group (NSPG) ≥3 days after onset, with aggravation observed when ≥14.5% of the lungs exhibited damage at 3-5 days (sensitivity: 88.2%, specificity: 72.4%) and when ≥20.1% of the lungs exhibited damage at 6-8 days (sensitivity: 88.2%, specificity: 69.4%). Patients with aggravation suddenly developed hypoxemia after 7 days from the onset; however, chest CT scans obtained in the paucisymptomatic phase without hypoxemia indicated that subsequent aggravation could be predicted based on the degree of lung damage. Furthermore, in subjects aged ≥65 years, a significant difference between the SPG and NSPG was observed in the extent of lung damage early beginning from 3 days after onset, and it was found that the degree of lung damage could serve as a predictor of aggravation. Therefore, to predict and improve prognosis through rapid and appropriate management, evaluating patients with factors indicating poor prognosis using chest CT is essential.
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COVID-19 , Humanos , COVID-19/diagnóstico por imagen , SARS-CoV-2 , Tomografía Computarizada por Rayos X/métodos , Pulmón/diagnóstico por imagen , Hipoxia , Estudios RetrospectivosRESUMEN
BACKGROUND: The role of programmed cell death, especially pyroptosis and apoptosis, in unfavorable immune responses in COVID-19 remains to be elucidated. METHODS: We conducted a cross-sectional analysis to investigate the association between the serum gasdermin D (GSDMD) levels, a pyroptotic marker, and caspase-cleaved cytokeratin 18 fragment (M30), an apoptotic marker, and the clinical status and abnormal chest computed tomography (CT) findings in patients with COVID-19. RESULTS: In this study, 46 patients diagnosed with COVID-19 were divided into the following three groups according to the disease severity: mild to moderate group (n = 10), severe group (n = 14), and critical group (n = 22). The serum GSDMD levels were higher in the critical group than in the mild to moderate group (P = 0.016). In contrast, serum M30 levels were lower in the critical group than in the severe group (P = 0.048). Patients who required mechanical ventilation or died had higher serum GSDMD levels than those who did not (P = 0.007). Area of consolidation only and of ground glass opacity plus consolidation positively correlated with serum GSDMD levels (r = 0.56, P < 0.001 and r = 0.53, P < 0.001, respectively). CONCLUSION: Higher serum GSDMD levels are associated with critical respiratory status and the consolidation area on chest CT in patients with COVID-19, suggesting that excessive activation of pyroptosis may affect the clinical manifestations in patients with COVID-19.
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COVID-19 , Humanos , Proteínas de Unión a Fosfato/metabolismo , COVID-19/diagnóstico por imagen , Estudios Transversales , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de Neoplasias/metabolismo , Tomografía , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: The mechanism of allergic reactions to COVID-19 mRNA vaccines has not been clarified. Polyethylene glycol (PEG) is a potential antigen in the components of vaccines. However, there is little evidence that allergy after COVID-19 mRNA vaccination is related to PEG. Furthermore, the role of polysorbate (PS) as an antigen has also not been clarified. The objective of this study was to investigate whether PEG and PS allergies are reasonable causes of allergic symptoms after vaccination by detecting PEG-specific and PS-specific antibodies. METHODS: Fourteen patients who developed immediate allergic reactions to BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccines and nineteen healthy controls who did not present allergic symptoms were recruited. Serum PEG-specific immunoglobulin E (IgE) and immunoglobulin G (IgG) and PS-specific IgE and IgG were measured by enzyme-linked immunosorbent assay. Skin tests using PEG-2000 and PS-80 were applied to five patients and three controls. RESULTS: Serum levels of PEG-specific IgE and IgG in patients with immediate allergic reactions to the COVID-19 mRNA vaccine were higher than those in the control group. Serum levels of PS-specific IgE in patients with allergy to the vaccine were higher than those in patients of the control group. Intradermal tests using PEG verified the results for PEG-specific IgE and IgG. CONCLUSIONS: The results suggest that PEG is one of the antigens in the allergy to COVID-19 mRNA vaccines. Cross-reactivity between PEG and PS might be crucial for allergy to the vaccines. PEG-specific IgE and IgG may be useful in diagnosing allergy to COVID-19 mRNA vaccines.
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Vacuna BNT162/efectos adversos , COVID-19 , Hipersensibilidad , COVID-19/diagnóstico , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Humanos , Hipersensibilidad/diagnóstico , Hipersensibilidad Inmediata , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Polietilenglicoles , Polisorbatos , ARN Mensajero , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
Recently, immune response to coronavirus disease (COVID-19) has attracted attention where an association between higher antibody titer and worsening disease severity has been reported. However, our experiences with severe COVID-19 patients with low antibody titers led to hypothesizing that suppressed humoral immune response may be associated with poorer prognosis in severe COVID19. In this study, antibody titers in severe COVID19 patients were measured at 7, 10, 12, and 14 days after onset. Patients were divided into survivors and non-survivors. SARS-CoV-2 IgM in survivors and non-survivors were 0.06 AU and 0.02 AU (P = 0.048) at 10 days, 0.1 AU and 0.03 AU (P = 0.02) at 12 days, and 0.17 AU and 0.06 AU (P = 0.02) at 14 days. IgG in survivors and non-survivors were 0.01 AU and 0.01 AU (P = 0.04) at 7 days, 0.42 AU and 0.01 AU (P = 0.04) at 12 days, and 0.42 AU and 0.01 AU (P = 0.02) at 14 days. Multivariate analysis showed better survival among patients with IgM positivity at 12 days (P = 0.04), IgG positivity at 12 days (P = 0.04), IgM positivity at 14 days (P = 0.008), and IgG positivity at 14 days (P = 0.005). In severe COVID-19, low antibody titers on days 12 and 14 after onset were associated with poorer prognosis.
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COVID-19 , Anticuerpos Antivirales , Humanos , Inmunoglobulina G , Inmunoglobulina M , SARS-CoV-2RESUMEN
Optic perineuritis (OPN) is an intraorbital inflammatory disease that targets the optic nerve sheath, which can cause severe vision loss. OPN has been recently reported to be sometimes caused by myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). MOGAD is rarely reported to be complicated with other autoimmune diseases. We report the first rare case of MOG-associated OPN complicated with granulomatous with polyangiitis (GPA). The vision loss, in this case, was initially considered to be caused by cavernous sinusitis in GPA. However, she was diagnosed with MOGAD with serial MRI findings and positive MOG antibody and had been successfully treated with glucocorticoid and tocilizumab for one and half years. This case emphasized the importance of evaluating the MOG antibody in a patient with recurrent OPN, complicated with vasculitis.
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Large amounts of radiocesium were released into marine environments following the Fukushima Daiichi Nuclear Power Plant accident in March 2011. Released radiocesium influenced not only marine environment but also marine biota in Fukushima. Since marine biota as fisheries products is important for Japanese market, it is important to assess the distribution of radiocesium in coastal environment off Fukushima for safety concerns of radioactive contamination. Radiocesium concentrations in sediments are important for understanding fishing ground conditions and for proving the safety of fisheries products in Fukushima. In this study, monthly monitoring data collected from May 2011 to March 2020 were analyzed to describe the temporal variability of 137Cs concentrations in coastal sediments off Fukushima (total of 3647 samples from eight lines at depths of 7-125 m off Fukushima, and three sites in Matsukawa-ura Lagoon). The 137Cs concentration in sediment showed a decreasing trend, but our nonlinear model fitting suggested that this rate of decrease had slowed down. Additionally, 137Cs concentrations were up to 4.08 times greater in shallow sampling sites (7, 10, 20 m depth) following heavy rainfall events (before five months vs. after five months), such as typhoons. These observations were consistent with increasing input from particulate 137Cs fluxes from rivers and increasing dissolved 137Cs concentrations in seawater. Finally, our numerical modeling suggested that riverine 137Cs input could maintain 137Cs concentrations in coastal sediment. These results indicate that riverine 137Cs input following heavy rainfall events is the main factor for maintaining 137Cs concentrations in coastal sediments near the Fukushima Daiichi Nuclear Power Plant.
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Accidente Nuclear de Fukushima , Monitoreo de Radiación , Contaminantes Radiactivos del Agua , Radioisótopos de Cesio/análisis , Sedimentos Geológicos , Japón , Contaminantes Radiactivos del Agua/análisisRESUMEN
The coronavirus disease (COVID-19) is known to cause hyperferritinemia and haemophagocytic lymphohistiocytosis. Including this laboratory parameter, symptoms similar to COVID-19 have been observed in adult-onset Still's disease (AOSD), catastrophic antiphospholipid syndrome, macrophage activation syndrome, and septic shock, which has led to the proposal of a concept called 'hyperferritinemic syndromes'. High levels of some clinical markers in both COVID-19 and AOSD make them difficult to differentiate. While the efficacy of ciclesonide had been expected for mild pneumonia with COVID-19, the efficacy of tocilizumab (TCZ), which is a known treatment for AOSD, was not established. We report the first known occurrence of COVID-19 diagnosed in March 2020, preceded by the diagnosis of AOSD in April 2019. The patient was given prednisolone and TCZ, which led to remission. With the dyspnea and ground-glass appearance on chest computed tomography, PCR test revealed COVID-19 infection. Ciclesonide was started on Day 7 of the disease onset, which led to improved inflammatory markers. We infer that while TCZ is theoretically useful for COVID-19 due to its inhibition of interleukin 6. AOSD and COVID-19 may be differentiated by levels of ferritin, and appropriate treatment must be allocated.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Síndrome de Activación Macrofágica , Enfermedad de Still del Adulto , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , COVID-19/diagnóstico , Ferritinas , Humanos , Síndrome de Activación Macrofágica/diagnóstico , Síndrome de Activación Macrofágica/tratamiento farmacológico , Prednisolona/uso terapéutico , Enfermedad de Still del Adulto/diagnóstico , Enfermedad de Still del Adulto/tratamiento farmacológicoRESUMEN
The distributions of dissolved 137Cs in river, nearshore, and offshore waters on the east and west coasts of the Japanese island of Honshu were studied in 2018-2021, 7-10 years after the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident. On the east side along the north western North Pacific (Fukushima Prefecture), estuarine processes, including desorption from riverine particles and dissolution into pore water from riverine particles that had settled to the seafloor, contributed to the maintenance of high dissolved 137Cs activities in nearshore and offshore waters. A survey and mass-balance calculation in a semi-enclosed estuarine area, the Matsukawa-ura, in the northern part of Fukushima, provided convincing evidence that rivers contributed to the influx of 137Cs to coastal waters. In contrast, the extremely low activities of dissolved and particulate 137Cs in the Tedori River of Ishikawa Prefecture on the western side of Japan along the Japan Sea suggested that inputs of riverine 137Cs made a negligible contribution to the increase of dissolved 137Cs activities in the nearshore and offshore waters. The relatively high dissolved 137Cs activities observed in the offshore waters of the Japan Sea were due to movement of FDNPP-derived 137Cs into the Japan Sea via the Tsushima Warm Current. Mechanisms controlling the distributions of 137Cs activities in coastal waters of the eastern and western sides of Japan therefore differ.
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Accidente Nuclear de Fukushima , Monitoreo de Radiación , Contaminantes Radiactivos del Agua , Radioisótopos de Cesio/análisis , Japón , Contaminantes Radiactivos del Agua/análisisAsunto(s)
Hematopoyesis Extramedular , Mielofibrosis Primaria/patología , Anciano , Femenino , Hematopoyesis Extramedular/efectos de los fármacos , Humanos , Quinasas Janus/antagonistas & inhibidores , Hígado/efectos de los fármacos , Hígado/patología , Nitrilos/uso terapéutico , Mielofibrosis Primaria/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéuticoRESUMEN
Revertant mosaicism, or "natural gene therapy," refers to the spontaneous in vivo reversion of an inherited mutation in a somatic cell. Only approximately 50 human genetic disorders exhibit revertant mosaicism, implicating a distinctive role played by mutant proteins in somatic correction of a pathogenic germline mutation. However, the process by which mutant proteins induce somatic genetic reversion in these diseases remains unknown. Here we show that heterozygous pathogenic CARD14 mutations causing autoinflammatory skin diseases, including psoriasis and pityriasis rubra pilaris, are repaired mainly via homologous recombination. Rather than altering the DNA damage response to exogenous stimuli, such as X-irradiation or etoposide treatment, mutant CARD14 increased DNA double-strand breaks under conditions of replication stress. Furthermore, mutant CARD14 suppressed new origin firings without promoting crossover events in the replication stress state. Together, these results suggest that mutant CARD14 alters the replication stress response and preferentially drives break-induced replication (BIR), which is generally suppressed in eukaryotes. Our results highlight the involvement of BIR in reversion events, thus revealing a previously undescribed role of BIR that could potentially be exploited to develop therapeutics for currently intractable genetic diseases.