SARS-CoV-2 と COVID-19 に関する備忘録 Vol.55

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Central nervous system and systemic inflammatory networks associated with acute neurological outcomes in COVID-19【nature : scientific reports　2025年7月6日】

Abstract

COVID-19 is associated with a wide spectrum of neurological alterations, ranging from headache and dizziness to severe encephalopathy and inflammatory neurological diseases (IND), and neuropathological findings suggest immune-mediated processes. Therefore, we sought to characterize profiles of cytokines, chemokines, growth factors, and markers of central nervous system (CNS) homeostasis in COVID-19 patients with neurological alterations to identify key factors and mechanisms underlying CNS disturbances in COVID-19. The study included a case series of 52 COVID-19 patients with neurological manifestations, which were categorized into three groups: isolated refractory headache (n = 14), encephalopathy (n = 24), and IND (n = 14). Individuals with non-inflammatory, non-infectious neurological conditions (n = 9) were included as negative controls. Paired CSF and serum samples were assessed for 56 biomarkers. Regardless of the neurological condition, COVID-19 patients exhibited elevated CSF levels of proinflammatory mediators, including IL-2, IL-3, IL-6, IL-15, IL-25, IFN-α2, CCL7, CCL11, and GM-CSF. Patients with encephalopathy and IND also showed increased IL-1β, IL-18, TNF-α, neopterin, IL-7, CXCL8, CXCL9, TGF-α, EGF, sTREM-2, and HMGB1, consistent with a CNS cytokine storm. In contrast, individuals with isolated refractory headache showed a modest inflammatory profile, compatible with the limited CNS involvement. COVID-19 patients showed elevated serum IL-13, IL-18, TNF-α, VILIP-1, TGF-α, and VEGF levels, indicating systemic inflammation and potential blood–brain barrier (BBB) disruption. β-NGF was increased in the CSF of patients with encephalopathy and IND, suggesting the activation of neuroprotective responses during patient recovery. Functional protein network analysis showed a significant enrichment of interactions between factors altered in the CSF of patients with encephalopathy and IND, many of them related to processes of neuroinflammation and microglial functions, and leukocyte chemotaxis, activation and proliferation. These findings support a model in which both systemic immune activation and localized neuroinflammation contribute to the diversity of neurological outcomes observed in COVID-19, and dysregulated cytokine production, glial activation, inflammasome activity and BBB disturbances represent key factors in neuro-COVID-19 pathogenesis.

◆Cognitive impairment 2 years after mild to severe SARS-CoV-2 infection in a population-based study with matched-comparison groups【nature : scientific reports　2025年7月8日】

Abstract

COVID-19 may have long lasting cognitive consequences. Studies with a follow-up longer than 1 year after infection are lacking. This study presents the prevalence of cognitive impairment 2 years after SARS-CoV-2 infection in survivors of the first year of the pandemic and comparison groups matched 1:1 for sex, age, and level of care. Users of the Local Health Unit of Matosinhos (comprising almost all citizens of the municipality) were retrospectively selected according to hospitalization and SARS-CoV-2 infection between March 2020 and February 2021: group #1, hospitalized for COVID-19 (n = 101); group #2, hospitalized, uninfected (n = 87); group #3, non-hospitalized, infected (n = 252); group #4, non-hospitalized, uninfected (n = 258). Between July 2022 and October 2023, all participants completed the Montreal Cognitive Assessment. Those with a score below 1.5 SD of age- and education-specific norms (n = 279) were invited for a comprehensive neuropsychological assessment to identify cognitive impairment. The prevalence of cognitive impairment was higher in group #1 than #2 (19.1% vs. 6.8%; adjusted OR 5.41, 95% CI 1.54, 19.03) and in group #3 than #4 (10.7% vs. 3.2%; adjusted OR 3.27, 95% CI 1.23, 8.67). These results suggest that specific care to timely diagnose and treat cognitive impairment is needed for COVID-19 survivors of the first year of the pandemic.

◆Long COVID Syndrome Prevalence in 2025 in an Integral Healthcare Consortium: Persistent and Transient Symptoms【Preprints.org　2025年7月4日】

Abstract

BACKGROUND: Long COVID can persist for years, but little is known about its prevalence in relation to the number of infections. This study examines the prevalence of Long COVID in association with the number of infections and vaccination status. METHODS: We analyzed anonymized data on Long COVID cases and thrombotic events from March 2020, provided by the Data Analysis Control Department for the population assigned to the CST (192,651 at March 2025). Additionally, we evaluated responses from a specific Long COVID symptom survey distributed to the entire CST population (n=1871 respondents). Symptomatic patients suspected of having Long COVID underwent blood tests to exclude alternative diagnoses. RESULTS: The overall detected prevalence of Long COVID was 2.4‰, with higher frequency among women aged 30–59 years. The survey, combined with blood test, improved detection rates by 26.3%. Long COVID prevalence was 3-10 times higher in individuals with three or more infections than in those with only one recorded infection (based on survey/CST data, respectively). The absolute number of thrombotic events doubled from 2020 to 2024 (p<0.0000001), occurring in both vaccinated and unvaccinated individuals, as well as in those with prior COVID-19 infection. CONCLUSION: Our findings demonstrate a link between SARS-CoV-2 reinfection and Long COVID prevalence. Furthermore, we observed a significant post-pandemic increase in thrombotic events across all populations, regardless of vaccination status or documented prior COVID-19 infection. Results suggest that COVID diagnosis should continue in suspected cases and that healthcare workers attending respiratory patients should continue wearing protective masks.

◆Mycophenolic acid treatment drives the emergence of novel SARS-CoV-2 variants【PNAS　2025年7月9日】

Significance

Mycophenolic acid (MPA), an immunosuppressant widely used in posttransplant regimens, exhibits antiviral activity by depleting cellular guanosine triphosphate, thereby inhibiting viral replication. However, prolonged exposure to MPA can drive the emergence of novel viral variants with enhanced replication capabilities. Here, we identified specific mutations in severe respiratory syndrome coronavirus 2 that conferred altered viral fitness, allowing for faster replication and increased viral titers despite MPA treatment. Importantly, these mutations have been observed in vivo, suggesting a real-world risk of variant evolution under immunosuppressive treatment. However, these mutations have not yet been identified together in a single infected individual. These findings underscore the importance of vigilant monitoring in immunosuppressed patients, as treatment may inadvertently foster viral variants with a competitive advantage.

Abstract

Mycophenolic acid (MPA) is commonly used in immunosuppressive regimens following solid organ transplantation. We demonstrate that MPA treatment reproducibly inhibits the replication of a range of viruses, including severe respiratory syndrome coronavirus 2 (SARS-CoV-2). Mechanistically, we identified cellular guanosine triphosphate pool depletion as a key mediator of this antiviral effect. Strikingly, this inhibition can be overcome which was correlated with the emergence of three breakthrough mutations in the SARS-CoV-2 genome (S P812R, ORF3 Q185H, and E S6L). Subsequent analyses confirmed that the combination of these mutations conferred accelerated replication kinetics, higher viral titers, and more rapid onset of cytopathic effects, but not MPA resistance. Comparison of global transcriptional responses to infection highlighted dysregulation of specific cellular gene programs under MPA treatment prior to breakthrough mutation emergence. Together, these findings identify viral and host drivers of variant emergence under immunosuppression. They also advocate for close monitoring of immunosuppressed patients, where emergence of novel viral variants with a fitness advantage may arise.

◆Health economic outcomes and national economic impacts associated with Long COVID in England and Scotland【SPRINGER NATURE　2025年7月9日】

Abstract

Background

Two million people in the UK suffer from Long COVID (LC), imposing substantial health economic impacts. This study aimed to: 1) assess longitudinal changes in health utility scores and economic costs of LC, and number of services received at LC specialist clinics and clinic region to capture care intensity; 2) assess whether volume of services received responded to health needs; and 3) estimate the national economic impact of LC.

Methods

LC patients from 10 specialist clinics participated in the LOCOMOTION study. Patient-reported outcomes measures (EQ-5D-5L, C19-YRS and Health Economics Questionnaire) were completed on a digital platform. Associations were assessed between changes in economic outcomes (EQ-5D-3L utility, health economic costs) and number/type of LC specialist services received and region. Per-person values of quality-adjusted life-year losses, public sector costs, productivity losses and informal care costs were multiplied by LC prevalence to estimate national economic impacts.

Results

There was a statistically significant reduction in public sector costs over time. There was no significant association between the number of specialist services received and change in health utility scores. LC specialist clinic and outpatient service utilisation corresponded to health need and had significant regional variation after controlling for health need. LC is associated with a substantial economic impact nationally, estimated at £8.1 billion annually and £24.2 billion since its emergence, comparable to the annual cost of £9.4 billion for stroke.

Conclusion

The effectiveness of LC specialist clinic services warrants further research. The substantial national economic impact of LC warrants a nationwide LC care strategy.

◆The Global and Local Distribution of RNA Structure throughout the SARS-CoV-2 Genome【ASM Journals　2021年2月10日】

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19, the disease at the center of the current global pandemic. While knowledge of highly structured regions is integral for mechanistic insights into the viral infection cycle, very little is known about the location and folding stability of functional elements within the massive (∼30-kb) SARS-CoV-2 RNA genome. In this study, we analyzed the folding stability of this RNA genome relative to the structural landscape of other well-known viral RNAs. We present an in silico pipeline to predict regions of high-base-pair content across long genomes and to pinpoint hot spots of well-defined RNA structures, a method that allows for direct comparisons of RNA structural complexity within the several domains in SARS-CoV-2 genome. We report that the SARS-CoV-2 genomic propensity for stable RNA folding is exceptional among RNA viruses, superseding even that of hepatitis C virus (HCV), one of the most structured viral RNAs in nature. Furthermore, our analysis suggests various levels of RNA structure across genomic functional regions, with accessory and structural open reading frames (ORFs) containing the highest structural density in the viral genome. Finally, we took a step further to examine how individual RNA structures formed by these ORFs are affected by the differences in genomic and subgenomic contexts, which, given the technical difficulty of experimentally separating cellular mixtures of subgenomic RNA (sgRNA) from genomic RNA (gRNA), is a unique advantage of our in silico pipeline. The resulting findings provide a useful roadmap for planning focused empirical studies of SARS-CoV-2 RNA biology and a preliminary guide for exploring potential SARS-CoV-2 RNA drug targets.

◆Targeting sgRNA N secondary structure as a way of inhibiting SARS-CoV-2 replication【National Library of Medicine　2024年7月24日】

Abstract

SARS-CoV-2 is a betacoronavirus that causes COVID-19, a global pandemic that has resulted in many infections, deaths, and socio-economic challenges. The virus has a large positive-sense, single-stranded RNA genome of ∼30 kb, which produces subgenomic RNAs (sgRNAs) through discontinuous transcription. The most abundant sgRNA is sgRNA N, which encodes the nucleocapsid (N) protein. In this study, we probed the secondary structure of sgRNA N and a shorter model without a 3′ UTR in vitro, using the SHAPE (selective 2′-hydroxyl acylation analyzed by a primer extension) method and chemical mapping with dimethyl sulfate and 1-cyclohexyl-(2-morpholinoethyl) carbodiimide metho-p-toluene sulfonate. We revealed the secondary structure of sgRNA N and its shorter variant for the first time and compared them with the genomic RNA N structure. Based on the structural information, we designed gapmers, siRNAs and antisense oligonucleotides (ASOs) to target the N protein coding region of sgRNA N. We also generated eukaryotic expression vectors containing the complete sequence of sgRNA N and used them to screen for new SARS-CoV-2 gene N expression inhibitors. Our study provides novel insights into the structure and function of sgRNA N and potential therapeutic tools against SARS-CoV-2.

◆sgRNAs: A SARS-CoV-2 emerging issue【National Library of Medicine　2023年4月16日】

Abstract

Like for other coronaviruses, SARS-CoV-2 gene expression strategy is based on the synthesis of a nested set of subgenomic mRNA species (sgRNAs). These sgRNA are synthesized using a “discontinuous transcription” mechanism that relies on template switching at Transcription Regulatory Sequences (TRS). Both canonical (c-sgRNA) and non-canonical (nc-sgRNA, less numerous) subgenomic RNA species can be produced. Currently, sgRNAs are investigated on the basis of sequence data obtained through next generation sequencing (NGS), and bioinformatic tools are crucial for their identification, characterization and quantification. To date, few software have been developed to this aim, whose reliability and applicability to all the available NGS platforms need to be established, to build confidence on the information resulting from such tools. In fact, these information may be crucial for the in depth elucidation of viral expression strategy, particularly in respect of the significance of nc-sgRNAs, and for the possible use of sgRNAs as potential markers of virus replicative activity in infected patients.

◆COVID-19 still biggest respiratory killer, GP expert warns【RACGP　2025年7月9日】

When it comes to winter viruses, influenza and RSV vaccinations are now top of the list of concerns for many patients, particularly with COVID-19 vaccine boosters no longer recommended for most healthy people.

However, one expert warns that, while the pandemic may be over, COVID-19 remains the deadliest of the three viruses.

Head of General Practice at UNSW Sydney and RACGP Specific Interests Cancer and Palliative Care Chair Associate Professor Joel Rhee says it’s a fact that even many of his own medical students are unaware of.

‘When I ask [them], “what do you think is more serious – influenza or COVID-19?”, almost 100% say influenza,’ says Associate Professor Rhee.

‘But the statistics say otherwise. COVID-19 is still causing more deaths than flu.’

The Australian Bureau of Statistics (ABS) reports that from 2023–25, COVID-19 was the leading cause of deaths from acute respiratory infection.

By the end of March, the ABS recorded 516 deaths in 2025 from COVID-19, compared to 84 from influenza, and 36 from RSV.

While influenza affects people from all age groups, from infancy to elderly, COVID-19 ‘doesn’t seem to be a serious disease in young children’ said Associate Professor Rhee.

He said although the COVID-19 pandemic is over, the virus itself remains and still poses a danger to older Australians and those with underlying health conditions.

‘COVID-19 is still a significant cause of death in aged care,’ he said.

‘We’re no longer recommending an annual booster for most healthy people, but those over 65 or with underlying health conditions may need annual or more frequent boosters.’

Associate Professor Rhee said healthy people caring for vulnerable relatives or who are travelling should also consider a booster.

Wastewater surveillance shows a new COVID-19 variant is also emerging and causing a spike in infections.

‘There’s no reason to believe our current vaccines won’t work against it, but it’s all the more reason to practise good hygiene and test if you have symptoms,’ Associate Professor Rhee said.

‘If we can all take simple steps – getting vaccinated, washing hands after coming home or before eating or drinking, staying home when we’re sick, wearing a mask in crowded spaces – we can reduce the virus circulating in the community.’

◆Neuroimaging insights into the psychosocial impact of the COVID-19 pandemic: a systematic review【nature : translational psychiatry　2025年7月10日】

Abstract

The COVID-19 pandemic has posed an unprecedented threat to global health. However, neural substrates underlying mental health vulnerabilities brought by the pandemic remain elusive. We conducted a systematic review relating structural and functional brain abnormalities to mental health issues associated with COVID-19 at brain regional and network levels. A literature search on neuroimaging studies of mental health problems derived by COVID-19 was conducted in the PubMed, Web of Science and MEDLINE databases. We identified 46 studies across various imaging techniques and found that COVID-19-related mental health problems were principally associated with brain structural and functional alterations in the prefrontal cortex, insula, cingulate, hippocampus, and amygdala, as well as the affective cortical network. This review may facilitate the targeted development of therapies tailored to the pandemic context and provide insights for proactive prevention against future collective stressors and traumas.

◆Health outcomes up to 3 years and post-exertional malaise in patients after hospitalization for COVID-19: a multicentre prospective cohort study (CO-FLOW)【THE LANCET : Regional Health Europe　2025年4月6日】

Summary

Background

Many patients experience long-lasting health problems after COVID-19. The study aimed to assess 3-year trajectories of a comprehensive set of patient-reported outcome measures (PROMs) in patients hospitalized for COVID-19, particularly focusing on the 2- to 3-year trajectory. Additionally, we evaluated prevalence of post-exertional malaise (PEM) at 3 years, its risk factors, co-occurring health problems, and the 3-year trajectories of patients with and without PEM.

Methods

The CO-FLOW multicentre prospective cohort study followed up adults hospitalized for COVID-19 in 7 hospitals, located in the Netherlands. Study assessments were performed at 3, 6, 12, 24, and 36 months post-discharge, conducted between July 1, 2020, and May 22, 2024. PROMs on recovery, symptoms, fatigue, mental health, cognition, participation, sleep quality, work status, health-related quality of life (HRQoL), and PEM were collected. Generalized estimating equations were used to assess health trajectories and multivariable logistic regression to identify risk factors for PEM.

Findings

In total, 299/344 (87%) patients completed the 3-year follow-up and were included in the analysis. Complete recovery rates increased (p < 0.001), from 12% at 3 months to 24% at 3 years. Symptoms of impaired fitness, fatigue, and muscle weakness (all p < 0.0019) and PROMs for fatigue score, participation, return to work, and HRQoL (all p < 0.005) improved significantly over time, while PROMs for cognitive failures worsened (p < 0.001). Between the 2- and 3-year visits, memory problems (OR 1.4 [1.1–1.7], p < 0.001), and scores of fatigue (MD +1.0 [0.4–1.6], p = 0.002), cognitive failures (MD +2.2 [0.9–3.4], p < 0.001), and SF-36 mental component summary (−2.2 [−3.1 to −1.3], p < 0.001) significantly worsened. At 3 years, 66% of patients experienced fatigue, 63% impaired fitness, 59% memory problems, and 53% concentration problems. PROMs showed that 62% reported poor sleep quality, 55% fatigue, and 28% cognitive failures. PEM was reported by 105/292 (36%) patients at 3 years; risk factors were female sex (OR 3.4 [95% CI 1.9–6.0], p < 0.001), pre-existing pulmonary disease (3.0 [1.7–5.6], p < 0.001), physical inactivity pre-COVID-19 (2.3 [1.2–4.1], p = 0.008), and ICU treatment for COVID-19 (1.8 [1.02–3.0], p = 0.04). Concurrent fatigue, cognitive failures, and dyspnea were more common in patients with (42%) than without (6%) PEM. Patients with PEM showed poor health outcomes throughout the entire follow-up period, including worsening fatigue and HRQoL during the third year. Interpretation

Many health problems persisted up to 3 years post-discharge, with self-reported fatigue and cognitive problems worsening in the third year. PEM was common, and linked to a more severe phenotype of long COVID. These findings highlight the urgent need to optimize treatment options and investigate underlying pathological mechanisms of COVID-19.