SARS-CoV-2 と COVID-19 に関する備忘録 Vol.66

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Varying Levels of Inflammatory Activity in Brain and Body of Patients with Persistent Fatigue and Difficulty Concentrating After COVID-19: A TSPO PET Study【The Journal of Nuclear Medicine　2025年9月11日】

Abstract

A significant number of patients report persistent fatigue and difficulty concentrating after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a condition known as post–coronavirus disease 2019 (post-COVID) syndrome. The underlying mechanisms for these complaints remain poorly understood. Dysregulated immune and neurologic systems may play a role in the pathophysiology of post-COVID syndrome. A target providing direct information on immune activation is the 18-kDa translocator protein (TSPO), which is upregulated in activated microglia. The PET tracer N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)5,7dimethylpyrazolo[1,5a]pyrimidin-3-yl)acetamide ([18F]DPA-714) binds with high affinity to TSPO and serves as a biomarker for neuroinflammation. We aimed to assess whole-body inflammatory activity with TSPO PET in individuals with and without persistent severe fatigue and difficulty concentrating 2 y after infection with SARS-CoV-2 as well as its association with complaint severity. Methods: In this cross-sectional cohort study, we evaluated 47 post-COVID individuals, 33 of whom had severe fatigue and difficulty concentrating (age, 50 ± 8 y; 27 ± 9 mo after initial infection) and 14 who did not have these complaints (age, 47 ± 9 y; 25 ± 10 mo after initial infection). All individuals were high-affinity binders according to their TSPO genotype and completed whole-body 60-min dynamic [18F]DPA-714 PET with arterial sampling, MRI, genotyping, and questionnaires. Tracer binding was quantified using binding potential for cerebral regions and inhibitory constant or total distribution volume for extracerebral regions. Parameters were compared between 33 individuals with persistent complaints (severe fatigue and difficulty concentrating) and 14 without, and associations between parameters were assessed. Results: We found globally increased cerebral [18F]DPA-714 binding in some individuals reporting persistent complaints when compared with individuals without these complaints. No group-level differences were found in extracerebral binding. Large variability in cerebral and extracerebral binding was observed among individuals. Cerebral and extracerebral binding levels were not correlated with each other or with complaint severity. Conclusion: Increased specific [18F]DPA-714 binding was found in some individuals with post-COVID syndrome, indicating the presence of an inflammatory subtype and further supporting the role of neuroinflammation in subtypes of post-COVID syndrome.

◆Persistence of Cognitive Difficulties in Adults Three Years After COVID-19 Infection【MDPI　2025年9月11日】

Abstract

The COVID-19 pandemic has left millions worldwide with persistent cognitive difficulties, making long-term studies essential to understand their trajectory and inform rehabilitation strategies. This research is presented within the context of Long COVID, emphasizing that cognitive symptoms (including deficits in attention, memory, and executive functions) are reported even in non-hospitalized individuals, yet longitudinal evidence beyond two years remains scarce. An observational, cross-sectional, and retrospective design was applied to a sample of 297 adults with their cognition assessed, divided into mild, moderate, and severe COVID-19 groups, and evaluated using standardized cognitive tests. Findings showed that cognitive performance declined with increasing severity of COVID-19 symptoms, particularly in divided attention, working memory, executive control, verbal fluency, recognition memory, and general intelligence. Age consistently predicted lower scores across cognitive domains, especially in moderate and severe groups, whereas education level did not exert a significant protective effect. The study shows that cognitive deficits can persist at least three years after infection, affecting older adults and those with the more severe symptoms. These results highlight the need for long-term neuropsychological monitoring and individualized rehabilitation strategies to mitigate impacts on autonomy and quality of life.

◆Soluble tissue factor generated by necroptosis-triggered shedding is responsible for thrombosis【nature：cell research　2025年9月12日】

Abstract

Tissue factor (TF) is a cell surface protein critical for normal hemostasis and pathological thrombosis. Necroptosis is a form of regulated necrosis associated with different diseases. Here, we reported the identification of the first functional soluble tissue factor (sTF) in mediating blood coagulation, shed from the membrane full-length TF (flTF) by proteases, ADAMs, during necroptosis. By generating sTF-specific antibody and transgenic mice carrying knockin mutations at the ADAM cleavage site of TF (T211V212 mutated to E211E212), we demonstrated that this sTF is responsible for necroptosis-related thrombosis in inflammation and viral infection mouse models. Importantly, we showed that eliminating necroptosis or the cleavage of the flTF blocked the production of sTF and prevented thrombosis in mice. We also detected sTF in the plasma of human COVID-19 patients and showed that SARS-CoV-2 pseudovirus induced sTF production. Our findings demonstrated that the sTF plays a major role in thrombosis under necroptosis-related pathological conditions and provided a diagnostic marker and potential therapies for treating thrombosis without affecting hemostasis.

◆Studies show mostly poor long-COVID protection for Paxlovid【University of Minnesota：CIDRAP　2025年9月17日】

Two new studies find limited evidence of the usefulness of Paxlovid (nirmatrelvir-ritonavir) to prevent the development of long COVID—but with a small reduction for older COVID-19 patients.

Paxlovid is an antiviral drug approved for use in US patients 12 years an older who are at risk of developing severe complications from COVID-19 infections.

Several observation studies have shown a small protective effect of Paxlovid on long COVID, but the two new studies look at the protective factor in the wake of Omicron and subvariants in the United States.

Small effect seen on oldest patients

In the first study, published yesterday in PLOS Medicine, an analysis of a large cohort of people in the RECOVER trial who had COVID-19 since April 1, 2022, found that Paxlovid had no protective effect overall on the development of long COVID.

Data on 445,738 patients from the US National COVID Cohort Collaborative’s electronic health record database was used for this study. Of those patients, 151,180 (33.92%) had a Paxlovid prescription within the treatment period, and 18,663 (4.20%) had been diagnosed as having long COVID.

The adjusted cumulative incidence of long-COVID estimates were 4.53% (95% confidence interval [CI], 4.40 to 4.66) for treated patients and 4.60% (95% CI, 4.51 to 4.68) for untreated patients.

There was a small protective effects among patients aged 65 years or more, the authors said. There was no effect for other ages, and no effect seen between unvaccinated and fully vaccinated patients.

“Although it may have a small protective effect among higher-risk patients and on certain symptoms, the effect sizes are negligible,” the authors said. “For example, an absolute risk reduction of 0.43% among patients aged 65 years or more means that 233 people would need to be treated with Paxlovid to prevent one case of PASC [postacute sequelae of COVID-19].”

They concluded, “Although some prior observational studies suggested that Paxlovid held promise as a PASC preventive, this study—with a large, nationally sampled cohort; a contemporary study period; and causal inference methodology—found that Paxlovid treatment during acute COVID-19 had no effect on subsequent PASC incidence.”

Small risk reduction in adults

In the second study, published today in Open Forum Infectious Diseases, researchers from the Centers for Disease Control and Prevention (CDC) found that Paxlovid offered some protection against long COVID in a retrospective cohort study where 291,433 treated patients were matched to 582,866 untreated patients.

The effect was only seen, however, in older adults. A minimal effect was noted in adults ages 18 to 49, but no effect was found in adolescents.

Study participants were diagnosed with COVID-19 in the spring and summer of 2022 (April 1 to August 31) and had a higher risk of severe COVID-19 based on age (50 years and older) or underlying risk factors. Of 291,433 treated patients, 98,084 (33.7%) had one or more long-COVID symptoms and 40,147 (13.8%) had two or more symptoms.

Among participants 65 and older, Paxlovid was associated with a 12% reduced risk of at least one long-COVID symptom (adjusted hazard ratio (aHR), 0.88; 95% CI, 0.87 to 0.90).

Younger adults aged 18 to 49 years had a smaller 7% reduction in overall risk of long COVID (aHR, 0.93; 95% CI, 0.92 to 0.95) and a reduced risk of some but not all individual conditions, the authors said.

“Recent studies have found that nirmatrelvir-ritonavir is underutilized among older patients who are at risk of severe disease, despite the evidence of its benefits,” the authors concluded. “Clinicians may consider treatment of persons with mild to moderate acute COVID-19 who are at high risk of severe disease, particularly those aged ≥50 years, not only to prevent hospitalization and death but also to mitigate possible long-term consequences.”

◆Long-term Physical Capacity Following COVID-19: A Prospective, Three-Year Study【JOURNAL OF INFECTION　2025年9月12日】

Abstract

Objectives

COVID-19 impacts physical and respiratory health, and the clinical presentation ranges from asymptomatic cases to severe infections requiring hospitalisation. While the long-term effects on lung function and physical capacity are well-documented in moderate to severe cases, the long-term outcome for individuals with mild COVID-19 remains poorly understood. This study investigates the long-term recovery of physical capacity and breathlessness among both hospitalised and non-hospitalised individuals.

Methods

This prospective cohort study enrolled individuals with confirmed SARS-CoV-2 infection between April 2020 and May 2021 through the CoVUm-study. Participants underwent assessments of lung function at 3–6 months after infection and attended follow-ups up to three years post-infection. Physical capacity was evaluated at follow-ups, using the one-minute sit-to-stand test and the modified Medical Research Council scale to assess breathlessness.

Results

The cohort included 291 participants, 35% of whom were hospitalised during SARS-CoV-2 infection. At the 3-year follow-up, 191 participants completed the physical capacity test and 179 had an assessment of breathlessness. Physical capacity improved significantly in the total cohort up to two years post-infection where improvement plateaued. Hospitalisation and impaired diffusing capacity were significantly associated with reduced physical capacity (beta –6.4, p < 0.001; beta –8.9, p < 0.001, respectively) and breathlessness (beta 3.9, p < 0.001; beta 1.6, p = 0.012, respectively). While non-hospitalised participants demonstrated improvements in physical capacity for up to two years, improvement for hospitalised individuals plateaued by six months. Conclusion

Hospitalisation and impaired diffusing capacity are strong independent predictors of reduced physical capacity and persistent breathlessness up to three years post-infection. Non-hospitalised individuals also experience long-term reductions in physical capacity, underscoring the need for targeted rehabilitation strategies.

◆Women With Long COVID May Have Heavier Menstrual Bleeding — Study uncovers a potential bidirectional relationship between long COVID and menstruation【MEDPAGE TODAY　2025年9月16日】

Long COVID was associated with abnormal uterine bleeding but not impaired ovarian function, a study of U.K. women found.

Survey respondents with long COVID reported increased menstrual volume, duration, and intermenstrual bleeding without differences in regularity and frequency of their period compared with those who never had COVID. And women who recovered from acute COVID reported minimal menstrual disruption, reported Jacqueline Maybin, MBChB, PhD, of the Centre for Reproductive Health at the University of Edinburgh in Scotland, and colleagues in Nature Communications.

Since early in the pandemic, some women have reported changes to their menstrual cycle during or after SARS-CoV-2 infection, and then later with COVID vaccination. Long COVID is also more prevalent among women.

“Reassuringly, ovarian function appears to be maintained in this group of regularly cycling women with long COVID,” the researchers noted.

Maybin and team conducted a set of three complementary studies to assess whether COVID is linked to abnormal uterine bleeding or if long COVID symptoms vary within the menstrual cycle, as well as any potential underlying mechanisms.

One arm of the study was a survey of 12,187 menstruating people in the U.K. Most (77%) had never been diagnosed with COVID before (the study was conducted in January 2021), while 14% reported a previous acute COVID infection and 9% reported long COVID. About 40% had been vaccinated with at least one dose of the COVID shot. At baseline, 57% reported one or more abnormal menstrual symptoms and 20% had a diagnosis known to affect reproductive function.

In the second arm, researchers prospectively followed 54 women with long COVID using an app, asking about menstrual and long COVID symptoms. The median number of once-daily entries was 33, and the median number of cycles contributed per participant was three. They found that long COVID symptom severity was highest during the perimenstrual and proliferative phases.

“This may be explained by increased cytokine production during the menstrual phase, which was greater in those with long COVID than in controls,” authors wrote.

Lastly, to investigate potential mechanisms underpinning these associations, authors collected and analyzed serum and endometrium samples during proliferative, secretory, and menstrual phases from 10 women with long COVID who were not using exogenous hormones and from a subset of the control cohort. These samples showed that serum 5α-dihydrotestosterone, the most active androgen, was higher in the secretory phase for women with long COVID versus no COVID (P=0.0138). Those with long COVID also had lower endometrial androgen receptors, but otherwise there were no significant differences in ovarian hormones between groups.

“Collectively, these findings indicate a bidirectional relationship between long COVID and abnormal uterine bleeding, potentially mediated by disruptions in androgen regulation and the inflammatory response within the endometrium,” Maybin’s group concluded.

Future research should look into specific treatments for abnormal uterine bleeding among those with long COVID, as well as focusing on female-specific long COVID treatments and consideration of the menstrual cycle in the development of future long COVID biomarkers, they noted.

The online survey portion was disseminated through a Facebook advertising campaign featuring images of diverse menstruators. To be eligible, participants had to have menstruated before, live in the U.K., be older than 18, and give permission to use the data. The survey was live from Aug. 3, 2021, to Jan. 6, 2021, when it was closed because there were no new entries for a week. In total, 695,543 people viewed the survey, of whom 26,710 were eligible.

The survey incorporated feedback from women suffering from long COVID. It was a maximum of 105 questions and took an average of 24 minutes to complete. Answers could be saved and returned to for up to 14 days.

Participants were asked questions about their menstrual cycle’s frequency, regularity duration, and volume, as well as intermenstrual bleeding. The survey also asked socio-demographic information, health proxies like body mass index, and any relevant diagnoses, like polycystic ovary syndrome or endometriosis.

At the time of the survey, widespread COVID testing was not available in the U.K., so COVID exposure was operationalized based on whether people thought they had COVID or had ever tested positive, and was categorized as no COVID (referent group; median age 32), acute COVID (symptoms lasting less than 28 days; median age 31), or long COVID (symptoms lasting more than 28 days; median age 36).

People who had acute COVID infections in the past 30 days and those who didn’t have a menstrual bleed in the previous 12 months were excluded, as were persons who were post-menopausal, perimenopausal, breastfeeding, pregnant, enrolled in a clinical trial, with unknown vaccine status, or living outside the U.K.

Eligible participants completed 80% of the survey on average, while 61% answered everything. Nearly all respondents were white women, which the authors noted as a limitation.

◆Long COVID Incidence Proportion in Adults and Children Between 2020 and 2024: An Electronic Health Record-Based Study From the RECOVER Initiative【OXFORD ACADEMIC　2025年2月5日】

Abstract

Background

Incidence estimates of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, also known as long COVID, have varied across studies and changed over time. We estimated long COVID incidence among adult and pediatric populations in 3 nationwide research networks of electronic health records (EHRs) participating in the RECOVER (Researching COVID to Enhance Recovery) Initiative using different classification algorithms (computable phenotypes).

Methods

This EHR-based retrospective cohort study included adult and pediatric patients with documented acute SARS-CoV-2 infection and 2 control groups: contemporary coronavirus disease 2019 (COVID-19)–negative and historical patients (2019). We examined the proportion of individuals identified as having symptoms or conditions consistent with probable long COVID within 30–180 days after COVID-19 infection (incidence proportion). Each network (the National COVID Cohort Collaborative [N3C], National Patient-Centered Clinical Research Network [PCORnet], and PEDSnet) implemented its own long COVID definition. We introduced a harmonized definition for adults in a supplementary analysis.

Results

Overall, 4% of children and 10%–26% of adults developed long COVID, depending on computable phenotype used. Excess incidence among SARS-CoV-2 patients was 1.5% in children and ranged from 5% to 6% among adults, representing a lower-bound incidence estimation based on our control groups. Temporal patterns were consistent across networks, with peaks associated with introduction of new viral variants.

Conclusions

Our findings indicate that preventing and mitigating long COVID remains a public health priority. Examining temporal patterns and risk factors for long COVID incidence informs our understanding of etiology and can improve prevention and management.

◆Metabolic neuroimaging of myalgic encephalomyelitis/chronic fatigue syndrome and Long-COVID【Immunometabolism　2025年9月12日】

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID are complex, disabling conditions that have emerged as significant public health challenges, affecting millions worldwide. Despite their growing prevalence, effective diagnostics and treatments remain limited, largely due to an incomplete understanding of their underlying pathophysiology. Both conditions share hallmark symptoms of chronic fatigue, cognitive dysfunction, and postexertional malaise, but their biological underpinnings remain to be elucidated. Neuroimaging offers a promising, noninvasive window into the brain’s metabolic landscape and has the potential to uncover objective biomarkers for these conditions. In this mini review, we highlight recent advancements in metabolic neuroimaging, particularly positron emission tomography and magnetic resonance imaging/magnetic resonance spectroscopy, that reveal alterations in glucose and oxygen metabolism, neurotransmitter balance, and oxidative stress. These insights point toward shared disruptions in brain energy metabolism and neuroinflammatory processes, which may underlie the persistent symptoms in both ME/CFS and Long-COVID. Importantly, while some findings overlap, inconsistencies in metabolite profiles between ME/CFS and Long-COVID underscore the need for further stratification and longitudinal research. Standardizing definitions, such as identifying Long-COVID patients who meet ME/CFS diagnostic criteria, could help improve study comparability. By summarizing current imaging evidence, this review underscores the potential of neuroimaging to identify imaging biomarkers to advance the clinical diagnosis of Long-COVID and identify therapeutic targets for treatment development. As we continue to face the growing burden of Long-COVID and ME/CFS, metabolic imaging may serve as a powerful tool to bridge gaps in knowledge and accelerate progress toward effective care.

◆Cognitive sequelae in post-COVID-syndrome: a Danish-Swedish case-control study【Taylor & Francis Online　2025年9月13日】

Abstract

Background

While patients with post-COVID syndrome (PCS) suffer from cognitive deficits few studies directly compare patients with PCS to subjects recovered after an infection with the ‘Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)’.

Objectives

To investigate cognitive performance adjusting for age, increasing body-mass-index (BMI), smoking, years of education, gender and hospitalisation while infected in patients with PCS compared to controls fully recovered. Secondly, to stratify cognitive performance based on the SARS-CoV-2 virus strain (variant of concern ‘VOC’) causing the infection. Thirdly, to assess whether patients with PCS have increased levels of psychological distress and affected hand grip strength as both are associated with cognitive performance.

Methods

A Danish-Swedish case-control study we recruited adult patients (18–75 years) with PCS from long-COVID outpatient clinics in Region Zealand Denmark and Skåne County Sweden. Participants had confirmed SARS-CoV-2 infection >12 weeks prior to inclusion and healthy control subjects had recovered completely. All study participants were exposed to cognitive tests, Kessler’s psychological distress scale (K10) and tested with a hand-dynamometer.

Results

Recruiting 181 cases and 155 control subjects, patients with PCS had reduced cognitive performance scores on all domains though hardly clinically significant. Reduced processing speed was impacted the most with patients infected early in the pandemic exhibiting greater deficits.

Conclusion

PCS was associated with reduced cognitive processing speed compared to fully recovered controls with those infected early in the pandemic having greater deficits. Psychological distress and hand grip strength were affected in patients with PCS, but not decisively associated with cognitive performance.