SARS-CoV-2 と COVID-19 に関する備忘録 Vol.37

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆New-onset gastrointestinal disorders in COVID-19 patients 3.5 years post-infection in the inner-city population in the Bronx【nature scientific reports　2024年12月30日】

Abstract

This study examined the incidence, characteristics, and risk factors of new gastrointestinal disorders (GID) associated with SARS-CoV-2 infection up to 3.5 years post-infection. This retrospective study included 35,102 COVID-19 patients and 682,594 contemporary non-COVID-19 patients without past medical history of GID (controls) from the Montefiore Health System in the Bronx (3/1/2020 to 7/31/2023). Comparisons were made with unmatched and propensity-matched (1:2) controls. The primary outcome was new GID which included peptic ulcer, inflammatory bowel disease, irritable bowel syndrome, diverticulosis, diverticulitis, and biliary disease. Multivariate Cox proportional hazards model analysis was performed with adjustment for covariates. There were 2,228 (6.34%) COVID-19 positive patients who developed new GID compared to 38,928 (5.70%) controls. COVID-19 patients had an elevated risk of developing new GID (adjusted HR = 1.18 (95% CI 1.12–1.25) compared to propensity-matched controls, after adjusting for confounders that included smoking, obesity, diabetes, hypertension. These findings underscore the need for additional research and follow-up of at-risk individuals for developing GID post infection.

◆Neurological post-COVID syndrome is associated with substantial impairment of verbal short-term and working memory【nature scientific reports　2025年1月11日】

Abstract

A substantial proportion of patients suffer from Post-COVID Syndrome (PCS) with fatigue and impairment of memory and concentration being the most important symptoms. We here set out to perform in-depth neuropsychological assessment of PCS patients referred to the Neurologic PCS clinic compared to patients without sequelae after COVID-19 (non-PCS) and healthy controls (HC) to decipher the most prevalent cognitive deficits. We included n = 60 PCS patients with neurologic symptoms, n = 15 non-PCS patients and n = 15 healthy controls. Basic socioeconomic data and subjective complaints were recorded. This was followed by a detailed neuropsychological test battery, including assessments of general orientation, motor and cognitive fatigue, screening of depressive and anxiety symptoms, information processing speed, concentration, visuomotor processing speed, attention, verbal short-term and working memory, cognitive flexibility, semantic and phonematic word fluency, as well as verbal and visual memory functions. Neurologic PCS patients had more complaints with significantly higher fatigue scores as well as higher levels of depressive and anxiety symptoms compared to Non-PCS and HC. Deep neuropsychological assessment showed that neurologic PCS patients performed worse in a general screening of cognitive deficits compared to HC. Neurologic PCS patients showed impaired mental flexibility as an executive subfunction, verbal short-term memory, working memory and general reactivity (prolonged reaction time). Multiple regression showed fatigue affected processing speed; depression did not. Self-reported cognitive deficits of patients with neurologic PCS including fatigue, concentration, and memory deficits, are well mirrored in impaired performance of cognitive domains of concentration and working memory. The present results should be considered to optimize treatment algorithms for therapy and rehabilitation programs of PCS patients with neurologic symptoms.

◆Chapter 26 – Pediatric neurological and neuropsychiatric manifestations of COVID-19【ScienceDirect　2025年1月9日】

Abstract

SARS2-CoV-2 represents a new trigger of the central nervous system (CNS) inflammatory diseases and neuropsychiatric manifestations in children and adolescents.
Studies report neurologic involvement incidence that range from 4.8% to 66%: 40% of children with acute SARS-CoV-2, 25% with Long-COVID, and 66% with multisystem inflammatory syndrome (MIS-C) presented at least one neurological symptom.
The most common neurological manifestations reported in children with acute COVID-19 were headache (16%), acute encephalopathy (15%), and seizures (8%).
The most common neuroimaging finding was leptomeningeal contrast enhancement, suggesting neuritis, myelitis, and/or encephalomyelitis.
Different hypotheses of mechanistic pathways have been described as causes of neurologic disease in COVID-19:

  • Direct viral invasion and replication in the CNS.
  • Vascular insufficiency (vasoconstriction, or clot occlusion).
  • Nonspecific effects of systemic viral illness or medication.
  • Immune system dysregulation.

Long-term follow-up is necessary to define the future incidence of neurological and neuropsychiatric morbidity after SARS-CoV-2 infection, especially in children and adolescents.

◆Choroid plexus volume is enlarged in long COVID and associated with cognitive and brain changes【nature molecular psychiatry　2025年1月15日】

Abstract

Patients with post-COVID condition (PCC) present with diverse symptoms which persist at long-term after SARS-CoV-2 infection. Among these symptoms, cognitive impairment is one of the most prevalent and has been related to brain structural and functional changes. The underlying mechanisms of these cognitive and brain alterations remain elusive but neuroinflammation and immune mechanisms have been majorly considered. In this sense, the choroid plexus (ChP) volume has been proposed as a marker of neuroinflammation in immune-mediated conditions and the ChP epithelium has been found particularly susceptible to the effects of SARS-CoV-2. The objective was to investigate the ChP in PCC and evaluate its relationships with cognition, brain, and immunological alterations. One-hundred and twenty-nine patients with PCC after a mean of 14.79 ± 7.17 months of evolution since the infection and 36 healthy controls were recruited. Participants underwent a neuropsychological, and neuroimaging assessment and immunological markers evaluation. Results revealed ChP volume enlargement in PCC compared to healthy controls. The ChP enlargement was associated with cognitive dysfunction, grey matter volume reduction in frontal and subcortical areas, white matter integrity and diffusivity changes and functional connectivity changes. These ChP changes were also related to intermediate monocytes levels. Findings suggest that the ChP integrity may play a relevant role in the pathophysiology of cognitive deficits and the observed brain changes in PCC. The previously documented function of the ChP in maintaining brain homeostasis and regulating the entry of immune cells into the brain supports the presence of neuroinflammatory mechanisms in this disorder.

◆Chapter 26 – Pediatric neurological and neuropsychiatric manifestations of COVID-19【ScienceDirect　2025年1月8日】

Summary

Background

After surviving Coronavirus Disease 2019 (COVID-19), some people develop symptoms known as post-acute sequelae of COVID-19 (PASC). PASC is an emerging phenomenon yet to be fully understood, and identifying risk factors has been challenging. This study investigated the association between the number of COVID-19 episodes and the incidence of PASC among essential workers.

Methods

We analyzed data from 2511 essential workers, mainly first responders, with confirmed polymerase chain reaction, antibody, or antigen-positive test results for SARS-CoV-2 infection from March 2020 to February 2024. Data were collected through in-person questionnaires and surveys sent via text and email, internal medical records, follow-up calls, and external medical records. Participants who reported continuation or the development of new symptoms three months after the initial SARS-CoV-2 infection, with symptoms lasting for at least two months, were categorized as having PASC, while those without any COVID-19 or whose symptoms resolved were classified as non-PASC. PASC was common in this cohort so we used a Poisson regression model to compute multivariable-adjusted Relative Risk (RR) for the association between risk of PASC and SARS-CoV-2 re-infection, severity, and vaccination status at first infection.

Findings

A total of 475 (prevalence = 18.9%, [95% confidence interval] = [17.4–20.5]) PASC patients were identified. The mean (standard deviation (SD)) age of participants who experienced PASC (54.8 (7.2) years) was similar to those who did not (54.2 (7.4) years). There were 403 (16.1% [14.6–17.5]) participants who experienced multiple instances of COVID-19. After adjusting for relevant demographic, lifestyle, and clinical variables, we found a significant association between the risk of experiencing PASC and multiple SARS-COV-2 infections (RR = 1.41 [1.14–1.74]), severe COVID-19 (RR = 3.17 [2.41–4.16]), and being unvaccinated at first infection (RR = 3.29 [2.46–4.41]).

Interpretation

Although the pathogenetic mechanism for PASC remains unclear, identifying risk factors such as lack of vaccination or re-infection can assist in better understanding and managing the condition.

Funding

National Institute on Aging (NIH/NIA R01 AG049953) and Centers for Disease Control and Prevention (CDC/NIOSH U01 OH011864) and (CDC/NIOSH U01 OH012275).

◆Global Prevalence of Long COVID, its Subtypes and Risk factors: An Updated Systematic Review and Meta-Analysis【medRxiv　2025年1月6日】

Abstract

Importance Updated knowledge regarding the global prevalence of long COVID (or post-COVID-19 condition), its subtypes, risk factors, and variations across different follow-up durations and geographical regions is necessary for informed public health recommendations and healthcare delivery.

Objective The primary objective of this systematic review is to evaluate the global prevalence of long COVID and its subtypes and symptoms in individuals with confirmed COVID-19 diagnosis, while the secondary objective is to assess risk factors for long COVID in the same population.

Data Sources Studies on long COVID published from July 5, 2021, to May 29, 2024, searched from PubMed, Embase, and Web of Science were used for this systematic review. Supplemental updates to the original search period were made.

Study Selection There were four inclusion criteria: (1) human study population with confirmed COVID-19 diagnosis; (2) appropriate index diagnosis date; (3) outcome must include either prevalence, risk factors, duration, or symptoms of long COVID; and (4) follow-up time of at least two months after the index date. The exclusion criteria were: (1) non-human study population; (1) case studies or reviews; (2) studies with imaging, molecular, and/or cellular testing as primary results; (3) studies with specific populations such as healthcare workers, residents of nursing homes, and/or those living in long-term care facilities; and (4) studies that did not meet the sample size threshold needed to estimate overall prevalence with margin of error of 0.05.

Data Extraction and Synthesis Two screeners independently performed screenings and data extraction, and decision conflicts were collectively resolved. The data were pooled using a random-effects meta-analysis framework with a DerSimonian-Laird inverse variance weighted estimator.

Main Outcomes and Measures The primary estimand (target population parameter of interest) was the prevalence of long COVID and its subtypes among individuals with confirmed COVID-19 diagnoses, and the secondary estimand was effect sizes corresponding to ten common risk factors of long COVID in the same population.

Results A total of 442 studies were included in this mega-systematic review, and 429 were meta-analyzed for various endpoints, avoiding duplicate estimates from the same study. Of the 442 studies, 17.9% of the studies have a high risk of bias. Heterogeneity is evident among meta-analyzed studies, where the I2 statistic is nearly 100% in studies that estimate overall prevalence. Global estimated pooled prevalence of long COVID was 36% among COVID-19 positive individuals (95% confidence interval [CI] 33%-40%) estimated from 144 studies. Geographical variation was observed in the estimated pooled prevalence of long COVID: Asia at 35% (95% CI 25%-46%), Europe at 39% (95% CI 31%-48%), North America at 30% (95% CI 24%-38%), and South America at 51% (95% CI 35%-66%). Stratifying by follow-up duration, the estimated pooled prevalence for individuals with longer follow-up periods of 1 to 2 years (47% [95% CI 37%-57%]) compared to those with follow-up times of less than 1 year (35% [95% CI 31%-39%]) had overlapping CI and were therefore not statistically distinguishable. Top five most prevalent long COVID subtypes among COVID-19 positive cases were respiratory at 20% (95% CI 14%-28%) estimated from 31 studies, general fatigue at 20% (95% CI 18%-23%) estimated from 121 studies, psychological at 18% (95% CI 11%-28%) estimated from 10 studies, neurological at 16% (95% CI 8%-30%) estimated from 23 studies, and dermatological at 12% (95% CI 8%-17%) estimated from 10 studies. The most common symptom based on estimated prevalence was memory problems estimated at 11% (95% CI 7%-19%) meta-analyzed from 12 studies. The three strongest risk factors for long COVID were being unvaccinated for COVID-19, pre-existing comorbidity, and female sex. Individuals with any of these risk factors had higher odds of having long COVID with pooled estimated odds ratios of 2.34 (95% CI 1.49-3.67) meta-analyzed from 6 studies, 1.59 (95% CI 1.28-1.97) from 13 studies, and 1.55 (95% CI 1.25-1.92) from 22 studies, respectively.

Conclusions and Relevance This study shows long COVID is globally prevalent in the COVID-19 positive population with highly varying estimates. The prevalence of long COVID persists over extended follow-up, with a high burden of symptoms 1 to 2 years post-infection. Our findings highlight long COVID and its subtypes as a continuing health challenge worldwide. The heterogeneity of the estimates across populations and geographical regions argues for the need for carefully designed follow-up with representative studies across the world.

Question What are the prevalence and patterns of long COVID and its subtypes, and what are the risk factors of long COVID?

Results Meta-analysis of 429 studies published from 2021-2024 estimated a pooled global long COVID prevalence of 36% in COVID-19 positive individuals. Variations in geographical regions showed that South America had the highest pooled prevalence of 51% (95% CI: 35%-66%), and the prevalence does not seem to diminish with extended follow-up (less than 1 year: 35%, 95% CI: 31%-39% vs. 1 to 2 years: 47%, 95% CI: 37%-57%). The estimated pooled prevalence of eight major long COVID subtypes in COVID-19 positive individuals were 20% (respiratory), 20% (general fatigue), 18% (psychological), 16% (neurological), 12% (dermatological), 10% (cardiovascular), 9% (musculoskeletal) and 5% (gastrointestinal).

Meaning Quantitative evidence shows a persistent prevalence of long COVID globally, with a significant burden of symptoms 1 to 2 years post-infection, underscoring the need for having accurate and standardized diagnostic tests and biomarkers for long COVID, a better understanding of the physiology of the condition, its treatment, and its potential effect on healthcare needs and workforce participation. The heterogeneity and wide range of the prevalence estimates call for representative samples in well-designed follow-up studies of long COVID across the world.

◆Long COVID and recovery from Long COVID: quality of life impairments and subjective cognitive decline at a median of 2 years after initial infection【OXFORD ACADEMIC : Occupational Medicine　2025年1月11日】

Abstract

Background

The symptoms of Long coronavirus disease 2019 (Covid-19) are heterogeneous, creating uncertainty for employers regarding the diagnosis. The prevalence of Long Covid-19 in the workforce is also unknown. Furthermore, workers affected by Long Covid-19 encounter considerable difficulties in ensuring work safety and returning to their jobs due to this condition.

Aims

This review is aimed to identify the prevalence of Long Covid-19 in the workplace and to determine the various symptoms of Long Covid-19 experienced by the workers.

Methods

A meta-analysis was conducted to calculate the pooled estimates for the prevalence of Long Covid-19. Heterogeneity among the estimates was evaluated using the I² statistic.

Results

The pooled prevalence of Long Covid-19 among workers across the 11 studies was 38% (95% CI 23–56). A total of 43 symptoms associated with Long Covid-19 were identified in the workplace, with the top five symptoms being dyspnoea at moderate activity (51%, 95% CI 39–62), mental symptoms (38%, 95% CI 6–87), dyspnoea at mild activity (35%, 95% CI 25–47), fatigue (26%, 95% CI 3–78) and effort intolerance (24%, 95% CI 15–35).

Conclusions

The review indicates a significant burden of long-lasting symptoms within the workforce. The top five reported symptoms of Long Covid-19 were dyspnoea during mild and moderate activities, mental symptoms, fatigue and effort intolerance.

◆Executive function deficit in patients with long COVID syndrome: A systematic review【Heliyon　2025年1月19日】

Abstract

Background

Post-COVID-19 condition (Long COVID) refers to a condition in which patients endure persistent symptoms for more than 12 weeks, typically occurring at least 3 months after the onset of Coronavirus disease 2019 (COVID-19) infection. It occurs when a constellation of symptoms persists following the initial illness, and this may obstruct a daily routine and impose difficulty in life. Therefore, this study aimed to systematically review published articles assessing the neurocognitive profile of long COVID patients, with a specific emphasis on executive function (EF), and to determine the correlation between EF deficits and brain alterations through the utilisation of neuroimaging modalities.

Methods

A thorough search was conducted using the PubMed/MEDLINE and Web of Science online databases following the PICOS and PRISMA 2020 guidelines. All included studies were deemed to be of high quality according to the Newcastle–Ottawa Scale (NOS).

Results

A total of 31 out of 3268 articles were included in the present study. The main outcome is the proportion of individuals with cognitive deficits, particularly in the EF domain, as detected by neuropsychological assessments. The present study also revealed that EF deficits in long COVID patients are correlated with disruptions in the frontal and cerebellar regions, affecting processes such as nonverbal reasoning, executive aspects of language, and recall. This consistent disturbance also emphasised the correlation between EF deficits and brain alterations in patients with long COVID.

Conclusion

The present study highlights the importance of evaluating EF deficits in long COVID patients. This insight has the potential to improve future treatments and interventions.

◆Infectivity of exhaled SARS-CoV-2 aerosols is sufficient to transmit covid-19 within minutes【nature scientific reports　2023年12月1日】

Abstract

Exhaled SARS-CoV-2-containing aerosols contributed significantly to the rapid and vast spread of covid-19. However, quantitative experimental data on the infectivity of such aerosols is missing. Here, we quantified emission rates of infectious viruses in exhaled aerosol from individuals within their first days after symptom onset from covid-19. Six aerosol samples from three individuals were culturable, of which five were successfully quantified using TCID50. The source strength of the three individuals was highest during singing, when they exhaled 4, 36, or 127 TCID50/s, respectively. Calculations with an indoor air transmission model showed that if an infected individual with this emission rate entered a room, a susceptible person would inhale an infectious dose within 6 to 37 min in a room with normal ventilation. Thus, our data show that exhaled aerosols from a single person can transmit covid-19 to others within minutes at normal indoor conditions.

◆Driving Under the Cognitive Influence of COVID-19: Exploring the Impact of Acute SARS-CoV-2 Infection on Road Safety【Neurology Journals　2024年12月8日】

Abstract

Objective

This study evaluated the association between acute COVID-19 cases and the number of car crashes with varying COVID-19 vaccination rates, Long COVID rates, and COVID-19 mitigation strategies.

Background

The ongoing SARS-CoV-2 pandemic has led to significant concern over long-term post-infection sequelae, especially in the Neurologic domain. Long COVID symptoms, including cognitive impairments, could potentially impact activities requiring high cognitive function, such as driving. Despite various potential impacts on driving skills and the general prevalence of Long COVID, the specific effects on driving capabilities remain understudied.

Design/Methods

This study utilized a Poisson regression model to analyze data from 2020-2022, comparing aggregate car crash records and COVID-19 statistics. This model adjusted for population and included binary variables for specific months to account for stay-at-home orders. The correlation between acute COVID-19 cases and car crashes was investigated across seven states, considering vaccination rates and COVID-19 mitigation measures as potential confounders.

Results

Findings indicate an association between acute COVID-19 rates and increased car crashes with an OR of 1.5 (1.23-1.26 95%CI). The analysis did not find a protective effect of vaccination against increased crash risks, contrary to previous assumptions. The OR of car crashes associated with COVID-19 was comparable to driving under the influence of alcohol at legal limits or driving with a seizure disorder.

Conclusions

The study suggests that acute COVID-19, regardless of Long COVID status, is linked to an increased risk of car crashes presumably due to neurologic changes caused by SARS-CoV-2. These findings underscore the need for further research into the neuropsychological impacts of COVID-19. Further studies are recommended to explore the causality and mechanisms behind these findings and to evaluate the implications for public safety in other critical operational tasks. Finally, neurologists dealing with post-COVID patients, should remember that they may have an obligation to report medically impaired drivers.

◆Strategic Inhibition of CHRM Autoantibodies: Molecular Insights and Therapeutic Potentials in Long COVID【ACS Publications　2025年1月21日】

Abstract

In addition to the conventional symptoms reported for COVID-19, it is becoming increasingly clear that patients with long COVID are exhibiting new symptoms due to the emergence of autoantibodies against G-protein-coupled receptors, among which human muscarinic cholinergic receptors (CHRMs) have been prominently reported. With a chronic condition such as long COVID, additional symptoms caused by anti-CHRM autoantibodies (AAbs) have proven to be an added burden on these patients. The origins of these AAbs, their interactions with, and effects on the function of neural and non-neural cells within the nervous system have remained unknown. Furthermore, the specific symptom complex to which they contribute has not been clearly understood. In this context, we address these issues here and suggest methods to combat the autoantibodies that contribute to neurological symptoms in long COVID.

◆Rate of postural orthostatic tachycardia syndrome increased after COVID-19 pandemic【Healio　2025年1月21日】

After the COVID-19 pandemic, the incidence rate of postural orthostatic tachycardia syndrome increased significantly, according to new data published in the European Heart Journal – Quality of Care and Clinical Outcomes.

“Postural orthostatic tachycardia syndrome (POTS) is a chronic condition characterized by an abnormal increase in heart rate upon standing, often accompanied by symptoms such as dizziness, lightheadedness, fatigue and syncope,” Dharmindra Dulal, medical student at the University of Toledo College of Medicine and Life Sciences, and colleagues wrote. “Viral illnesses, including influenza, Epstein-Barr virus and, more recently, COVID-19, have been identified as potential triggers for the onset of POTS in previously healthy individuals. … Given the increasing number of POTS cases reported after COVID-19, we sought to examine the baseline characteristics of POTS patients, as well as trends in the incidence and prevalence of POTS, both before and after the onset of the COVID-19 pandemic.”

Using data from the TriNetX database — a cohort of more than 65 million adult patients across 64 health care organizations — Dulal and colleagues analyze trends over time to assess changes in POTS rates before and after the pandemic.

Monthly data on incidence, cases and prevalence of POTS were collected from January 2018 to June 2024, with March 1, 2020, serving as the cutoff for pre- and post-pandemic eras.

The researchers identified 11,191 patients with POTS for the pre-pandemic cohort (mean age, 36 years; 86% women) and 51,601 (mean age, 35 years; 87% women) patients for the post-pandemic cohort.

There was no significant difference in comorbid conditions between the pre- and post-pandemic cohorts. However, the researchers noted the prevalence of autonomic nervous system disorders (18% vs. 15%), idiopathic peripheral autonomic neuropathy (3% vs. 1%), and epilepsy and recurrent seizures (7% vs. 6%) were higher (P < .001) in the pre-pandemic cohort compared with the post-pandemic cohort. The researchers reported an increase in the incidence rate of POTS in the post-pandemic group (P < .0001), with the rate increasing from 1.42 per 1,000,000 person-years in the pre-pandemic group to 20.3 per 1,000,000 person-years in the post-pandemic group, according to the study. Monthly incident cases of POTS showed a similar trend, with an average of 4.21 additional monthly cases in the pre-pandemic cohort to 22.66 cases in the post-pandemic cohort (P < .001), according to the study. The month-to-month prevalence rate of POTS initially declined from 220.45 to 205.64 cases after the pandemic, but was followed by a robust increase starting in January 2023 to 504.77 (P < .001). “This study demonstrates a significant increase in the incidence and prevalence of postural orthostatic tachycardia syndrome following the COVID-19 pandemic,” the researchers wrote. “Our analysis of a large cohort from the TriNetX database reveals that many patients with post-viral symptom may develop POTS, emphasizing the need for clinicians to screen for this condition in post-COVID patients. These findings highlight the importance of early identification and management of POTS to improve patient outcomes. Ongoing research is essential to explore the mechanisms linking COVID-19 to POTS and to assess the long-term implications of these trends in the context of evolving health care needs”

◆Sex Differences in Long COVID【JAMA Network　2025年1月22日】

Abstract

Importance A substantial number of individuals worldwide experience long COVID, or post-COVID condition. Other postviral and autoimmune conditions have a female predominance, but whether the same is true for long COVID, especially within different subgroups, is uncertain.

Objective To evaluate sex differences in the risk of developing long COVID among adults with SARS-CoV-2 infection.

Design, Setting, and Participants This cohort study used data from the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER)–Adult cohort, which consists of individuals enrolled in and prospectively followed up at 83 sites in 33 US states plus Washington, DC, and Puerto Rico. Data were examined from all participants enrolled between October 29, 2021, and July 5, 2024, who had a qualifying study visit 6 months or more after their initial SARS-CoV-2 infection.

Exposure Self-reported sex (male, female) assigned at birth.

Main Outcomes and Measures Development of long COVID, measured using a self-reported symptom-based questionnaire and scoring guideline at the first study visit that occurred at least 6 months after infection. Propensity score matching was used to estimate risk ratios (RRs) and risk differences (95% CIs). The full model included demographic and clinical characteristics and social determinants of health, and the reduced model included only age, race, and ethnicity.

Results Among 12 276 participants who had experienced SARS-CoV-2 infection (8969 [73%] female; mean [SD] age at infection, 46 [15] years), female sex was associated with higher risk of long COVID in the primary full (RR, 1.31; 95% CI, 1.06-1.62) and reduced (RR, 1.44; 95% CI, 1.17-1.77) models. This finding was observed across all age groups except 18 to 39 years (RR, 1.04; 95% CI, 0.72-1.49). Female sex was associated with significantly higher overall long COVID risk when the analysis was restricted to nonpregnant participants (RR, 1.50; 95%: CI, 1.27-1.77). Among participants aged 40 to 54 years, the risk ratio was 1.42 (95% CI, 0.99-2.03) in menopausal female participants and 1.45 (95% CI, 1.15-1.83) in nonmenopausal female participants compared with male participants.

Conclusions and Relevance In this prospective cohort study of the NIH RECOVER-Adult cohort, female sex was associated with an increased risk of long COVID compared with male sex, and this association was age, pregnancy, and menopausal status dependent. These findings highlight the need to identify biological mechanisms contributing to sex specificity to facilitate risk stratification, targeted drug development, and improved management of long COVID.

◆The Blood-Cerebrospinal Fluid Barrier as a Potential Entry Site for the SARS-CoV-2 Virus【WILEY Online Library　2025年1月21日】

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an RNA virus responsible for coronavirus disease 2019 (COVID-19). While SARS-CoV-2 primarily targets the lungs and airways, it can also infect other organs, including the central nervous system (CNS). The aim of this study was to investigate whether the choroid plexus could serve as a potential entry site for SARS-CoV-2 into the brain. Tissue samples from 24 deceased COVID-19-positive individuals were analyzed. Reverse transcription real-time PCR (RT-qPCR) was performed on selected brain regions, including the choroid plexus, to detect SARS-CoV-2 viral RNA. Additionally, immunofluorescence staining and confocal microscopy were used to detect and localize two characteristic proteins of SARS-CoV-2: the spike protein S1 and the nucleocapsid protein. RT-qPCR analysis confirmed the presence of SARS-CoV-2 viral RNA in the choroid plexus. Immunohistochemical staining revealed viral particles localized in the epithelial cells of the choroid plexus, with the spike protein S1 detected in the late endosomes. Our findings suggest that the blood-cerebrospinal fluid (B-CSF) barrier in the choroid plexus serves as a route of entry for SARS-CoV-2 into the CNS. This study contributes to the understanding of the mechanisms underlying CNS involvement in COVID-19 and highlights the importance of further research to explore potential therapeutic strategies targeting this entry pathway.

◆Persistent symptoms and clinical findings in adults with post-acute sequelae of COVID-19/post-COVID-19 syndrome in the second year after acute infection: A population-based, nested case-control study【PLOS Medicine　2025年1月23日】

Abstract

Background

Self-reported health problems following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are common and often include relatively non-specific complaints such as fatigue, exertional dyspnoea, concentration or memory disturbance and sleep problems. The long-term prognosis of such post-acute sequelae of COVID-19/post-COVID-19 syndrome (PCS) is unknown, and data finding and correlating organ dysfunction and pathology with self-reported symptoms in patients with non-recovery from PCS is scarce. We wanted to describe clinical characteristics and diagnostic findings among patients with PCS persisting for >1 year and assessed risk factors for PCS persistence versus improvement.

Methods and findings

This nested population-based case-control study included subjects with PCS aged 18–65 years with (n = 982) and age- and sex-matched control subjects without PCS (n = 576) according to an earlier population-based questionnaire study (6–12 months after acute infection, phase 1) consenting to provide follow-up information and to undergo comprehensive outpatient assessment, including neurocognitive, cardiopulmonary exercise, and laboratory testing in four university health centres in southwestern Germany (phase 2, another 8.5 months [median, range 3–14 months] after phase 1). The mean age of the participants was 48 years, and 65% were female. At phase 2, 67.6% of the patients with PCS at phase 1 developed persistent PCS, whereas 78.5% of the recovered participants remained free of health problems related to PCS. Improvement among patients with earlier PCS was associated with mild acute index infection, previous full-time employment, educational status, and no specialist consultation and not attending a rehabilitation programme. The development of new symptoms related to PCS among participants initially recovered was associated with an intercurrent secondary SARS-CoV-2 infection and educational status. Patients with persistent PCS were less frequently never smokers (61.2% versus 75.7%), more often obese (30.2% versus 12.4%) with higher mean values for body mass index (BMI) and body fat, and had lower educational status (university entrance qualification 38.7% versus 61.5%) than participants with continued recovery. Fatigue/exhaustion, neurocognitive disturbance, chest symptoms/breathlessness and anxiety/depression/sleep problems remained the predominant symptom clusters. Exercise intolerance with post-exertional malaise (PEM) for >14 h and symptoms compatible with myalgic encephalomyelitis/chronic fatigue syndrome were reported by 35.6% and 11.6% of participants with persistent PCS patients, respectively. In analyses adjusted for sex-age class combinations, study centre and university entrance qualification, significant differences between participants with persistent PCS versus those with continued recovery were observed for performance in three different neurocognitive tests, scores for perceived stress, subjective cognitive disturbances, dysautonomia, depression and anxiety, sleep quality, fatigue and quality of life. In persistent PCS, handgrip strength (40.2 [95% confidence interval (CI) [39.4, 41.1]] versus 42.5 [95% CI [41.5, 43.6]] kg), maximal oxygen consumption (27.9 [95% CI [27.3, 28.4]] versus 31.0 [95% CI [30.3, 31.6]] ml/min/kg body weight) and ventilatory efficiency (minute ventilation/carbon dioxide production slope, 28.8 [95% CI [28.3, 29.2]] versus 27.1 [95% CI [26.6, 27.7]]) were significantly reduced relative to the control group of participants with continued recovery after adjustment for sex-age class combinations, study centre, education, BMI, smoking status and use of beta blocking agents. There were no differences in measures of systolic and diastolic cardiac function at rest, in the level of N-terminal brain natriuretic peptide blood levels or other laboratory measurements (including complement activity, markers of Epstein–Barr virus [EBV] reactivation, inflammatory and coagulation markers, serum levels of cortisol, adrenocorticotropic hormone and dehydroepiandrosterone sulfate). Screening for viral persistence (PCR in stool samples and SARS-CoV-2 spike antigen levels in plasma) in a subgroup of the patients with persistent PCS was negative. Sensitivity analyses (pre-existing illness/comorbidity, obesity, medical care of the index acute infection) revealed similar findings. Patients with persistent PCS and PEM reported more pain symptoms and had worse results in almost all tests. A limitation was that we had no objective information on exercise capacity and cognition before acute infection. In addition, we did not include patients unable to attend the outpatient clinic for whatever reason including severe illness, immobility or social deprivation or exclusion.

Conclusions

In this study, we observed that the majority of working age patients with PCS did not recover in the second year of their illness. Patterns of reported symptoms remained essentially similar, non-specific and dominated by fatigue, exercise intolerance and cognitive complaints. Despite objective signs of cognitive deficits and reduced exercise capacity, there was no major pathology in laboratory investigations, and our findings do not support viral persistence, EBV reactivation, adrenal insufficiency or increased complement turnover as pathophysiologically relevant for persistent PCS. A history of PEM was associated with more severe symptoms and more objective signs of disease and might help stratify cases for disease severity.

◆Prion-like Domains in Spike Protein of SARS-CoV-2 Differ across Its Variants and Enable Changes in Affinity to ACE2【MDPI　2025年1月25日】

Abstract

Currently, the world is struggling with the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prions are proteins that possess a unique conformational conversion, with the ability to rapidly shift between multiple conformations due to residue hydrophobicity and net sequence charge, and viral prion-like proteins are known as potential regulators of viral infections. However, the prion-like domains (PrD) in the SARS-CoV-2 proteome have not been analyzed. In this in silico study, using the PLAAC algorithm, we identified the presence of prion-like domains in the SARS-CoV-2 spike protein. Compared with other viruses, a striking difference was observed in the distribution of prion-like domains in the spike protein since SARS-CoV-2 is the only coronavirus with a prion-like domain found in the receptor-binding domain of the S1 region of the spike protein. The presence and unique distribution of prion-like domains in the SARS-CoV-2 receptor-binding domains of the spike protein are particularly interesting since although the SARS-CoV-2 and SARS-CoV S proteins share the same host cell receptor, angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 demonstrates a 10- to 20-fold higher affinity for ACE2. We identified prion-like domains in the α1 helix of the ACE2 receptor that interact with the viral receptor-binding domain of SARS-CoV-2. Finally, we found substantial differences in the prion-like domain of the S1 region of the spike protein across emerging variants including Omicron (B.1.1.529). Taken together, the present findings indicate that the identified PrDs in the SARS-CoV-2 receptor-binding domain (RBD) and ACE2 region that interact with RBD play important functional roles in viral adhesion and entry.

◆VA study shows COVID more severe than RSV, flu【University of Minnesota CIDRAP　2025年1月29日】

A large study of Veterans Affairs (VA) patients in JAMA Internal Medicine shows that, during the 2022 to 2023 season, having COVID-19 was associated with more severe disease outcomes than flu or respiratory syncytial virus (RSV) infection. Differences became less pronounced, however, during the 2023 to 2024 season.

The study compared outcomes among nonhospitalized veterans who underwent same-day testing and were diagnosed as having either flu, COVID, or RSV from August 1, 2022, to March 31, 2023, or from August 1, 2023, to March 31, 2024. Previous studies on VA cohorts have focused on hospitalized patients and on patients who have not undergone simultaneous testing for all three respiratory viruses.

Primary outcomes included rates of 30-day hospitalization, intensive care unit admission, and death, as well as the secondary outcome of long-term death extending through 180 days.

Higher COVID death rate for both seasons

A total of 68,581 patients were seen in 2022 to 2023 and 72,939 in the 2023 to 2024 season. In the 2022-23 season 6,239 (9.1%) patients had RSV, 16,947 (24.7%) had influenza, and 4,395 (66.2%) had COVID-19. Those rates were 13.4%, 26.4%, and 60.3%, respectively, during the 2023-24 season.

The median age for patients was 66 (53 to 75) years, and 87.0% were male.

The 30-day risk of death during the 2022 to 2023 season was slightly higher for COVID-19 (1.0%) compared to influenza (0.7%) or RSV (0.7%), but similar during the 2023 to 2024 season (0.9%, 0.7%, and 0.7%, respectively). Mortality risk at 180 days was higher for COVID-19 during both seasons (2023-2024 risk difference [RD] for COVID-19 vs influenza, 0.8% [95% confidence interval [CI], 0.3%to 1.2%]; RD for COVID-19 vs RSV, 0.6% [95% CI, 0.1% to 1.1%]).

By 180 days, the COVID-19 death rate reached 3.1% in the 2022-23 season and 2.9% in the 2023-24 season. For both seasons, the cumulative incidence of death was highest for COVID-19 throughout follow-up.

In the 2022 to 2023 season, weighted 30-day hospitalizations occurred in 17.5%, 15.9%, and 14.4% of patients diagnosed as having COVID-19, influenza, and RSV, respectively, the authors said. During the 2023 to 2024 season, weighted 30-day hospitalizations occurred in 16.3% of persons diagnosed with influenza, 16.2% diagnosed with COVID-19, and 14.3% with RSV.

Differences in hospitalization and mortality outcomes were primarily found in persons 65 years and older, as well as those who were unvaccinated.

“Differences in hospitalization and mortality outcomes were primarily found in persons 65 years and older, as well as those who were unvaccinated,” the authors wrote.

Vaccination mitigated COVID risk

The authors found that vaccination against COVID-19, however, offset risks of serious disease outcomes.

“Among groups vaccinated for their respective infections during the 2022 to 2023 season, no difference in 30-day hospitalization risk was found between COVID-19 and influenza,” the authors wrote. “No mortality differences between COVID-19 and influenza were found among vaccinated subgroups at any time point through 180 days during either season.”

The authors included information only about COVID-19 vaccination, and not seasonal flu vaccination.

“The higher burden of short-term and long-term adverse outcomes observed with COVID-19 compared with the other RVIs [respiratory viral illnesses] appeared to be attenuated by vaccination, particularly in the 2022 to 2023 season,” they concluded.

◆SARS-CoV-2 S-protein expression drives syncytia formation in endothelial cells【nature scientific reports　2025年1月28日】

Abstract

SARS-CoV-2 is a viral infection, best studied in the context of epithelial cell infection. Epithelial cells, when infected with SARS-CoV-2 express the viral S-protein, which causes host cells to fuse together into large multi-nucleated cells known as syncytia. Because SARS-CoV-2 infections also frequently present with cardiovascular phenotypes, we sought to understand if S-protein expression would also result in syncytia formation in endothelial cells. S-protein expression in endothelial cells was sufficient to induce the formation of multi-nucleated cells, with an average of 10% of all cells forming syncytia with an average of 6 nuclei per syncytia after 72 h of S-protein expression. Formation of syncytia was associated with the formation of gaps between cells, suggesting the potential for syncytia formation to compromise barrier function. Inhibition of myosin light chain kinase (MLCK), but not Rho-associated protein kinase, inhibited the formation of syncytia, suggesting a role for MLCK in syncytia formation. Further supporting the role of cellular contractility in syncytia formation, we also observed a reduction in the occurrence of syncytia for endothelial cells grown on substrates with reduced stiffness. Because endothelial cells are exposed to physiological forces due to blood flow, we examined the effects of cyclic biaxial stretch and fluid shear stress. While biaxial stretch did not affect syncytia formation, endothelial cells exposed to fluid shear stress were more resistant to syncytia formation. Finally, we observed that endothelial cells are suitable host cells for SARS-CoV-2 viral infection and replication, and that viral infection also causes syncytia formation. Our studies indicate that endothelial cells, in addition to epithelial cells, should also be considered a target for SARS-CoV-2 infection and a driver of COVID-19-associated pathology.

◆COVID lung damage evident in up to 1/3 of cases 12 months after infection【Health Imaging : Hannah Murphy　2025年1月27日】

A significant number of patients who have recovered from mild COVID-19 infections show lung abnormalities on imaging for a year or longer after recovering from the virus.

Though effective protocols to treat and prevent acute COVID infections have been well established by now, there are still many unknowns about how the virus affects long-term health. Efforts to understand long COVID range from evaluating its impact on mental health and fatigue to brain fog and the onset of new autoimmune disorders and beyond. Now, new research is giving providers a more detailed view of the long-term respiratory ramifications of the virus, revealing that up to one-third of patients display obvious lung damage on imaging even a year after recovering from their initial infection.

What’s more, these findings are not exclusive to severe cases of the virus and have been observed in individuals who reported having more moderate infections, according to authors of a new paper detailing the research.

“Severe COVID-19 typically results in pulmonary sequelae. However, current research lacks clarity on the differences in these sequelae among various clinical subtypes,” Xiaohong Lyu, with the Radiology Department at the First Affiliated Hospital of Jinzhou Medical University in China, and colleagues note. “This study aimed to evaluate the changing lung imaging features and predictive factors in patients with COVID-19 pneumonia in northern China over a 12-month follow-up period after the relaxation of COVID-19 restrictions in 2022.”

The team analyzed the cases of 103 individuals who were diagnosed with COVID pneumonia in 2022. Participants were divided into three groups—moderate, severe and critical—based on the severity of their infections. Low-dose CT scans were completed on all participants at baseline and then again 3, 6, and 12 months after discharge. Imaging results were then compared alongside pulmonary function tests.

During the follow-up period, just under 70% showed lung abnormalities on imaging at some point, nearly 10% of which were described as fibrotic changes. Age (65 or older), longer hospital stays and consolidation volumes at the time of infection were all correlated with the presence of abnormalities after 12 months.

By the end of the study period, 34% continued to struggle with abnormal lung function and 9% had been diagnosed with pulmonary fibrosis and restrictive ventilatory dysfunction. These findings were present in both the moderate and severe cohorts.

“Even among moderate patients with mild symptoms, over a third had persistent abnormal lung changes after one year post-COVID-19 infection,” the authors note. “Fibrotic changes are primarily observed in severe and critical patients, with these fibrosis-like changes tending to stabilize after six months and remaining relatively unchanged over time.”

The group suggests that radiologists should take note of consolidation volumes on baseline imaging of patients who have tested positive for the virus, as this could help guide strategies to blunt the long-term impact of COVID.

The study abstract is available in Academic Radiology.

◆Longitudinal Assessment of Pulmonary Involvement and Prognosis in Different Subtypes of COVID-19 Patients After One Year Using Low-Dose CT: A Prospective Observational Study【ScienceDirect　2025年1月25日】

Rationale and Objectives

Severe COVID-19 typically results in pulmonary sequelae. However, current research lacks clarity on the differences in these sequelae among various clinical subtypes. This study aimed to evaluate the changing lung imaging features and predictive factors in patients with COVID-19 pneumonia in northern China over a 12-month follow-up period after the relaxation of COVID-19 restrictions in 2022.

Materials and Methods

Imaging and clinically relevant data from three groups (moderate, severe, and critical) of patients with varying severity were prospectively analyzed. Low-dose CT scans were conducted at 3, 6, and 12 months after discharge, with chest CT images evaluated at baseline and each follow-up using qualitative and quantitative analyses. Clinical symptoms and pulmonary function recovery at 12 months were documented. The correlation between lung function and CT results was analyzed. Univariate and multivariable logistic regression analyses were employed to examine factors influencing prognosis, while a post-hoc analysis model was utilized to investigate the relationships among different groups, time points, and chest CT findings.

Results

Among the 103 hospitalized patients with COVID-19 pneumonia, 64 completed the 12-month evaluation. The median age was 63.70 ± 12.15%, and 62.5% (40/64) were men. During the follow-up period, while 67.19% (43/64) showed abnormalities, including fibrotic changes in 9.38% (6/64). Multivariable logistic regression identified age ≥ 65 (OR: 8.66; 95% CI: 1.86, 40.34; P = 0.006), length of hospital stays (OR: 1.23; 95% CI: 1.03, 1.47; P = 0.022), and baseline consolidation volume as a percentage of the whole lung (OR: 56.95; 95% CI: 1.198, 2706.782; P = 0.04) as independent risk factors for persistent CT lung abnormalities at 1 year. After 1 year, 34.38% (22/64) of patients still had abnormal lung function, and 9.38% (6/64) had pulmonary fibrosis and restrictive ventilatory dysfunction. The relationship between lung function and CT findings is weak correlation. The mixed model analysis revealed significant differences between groups, particularly between the moderate and severe groups, and significant changes in CT values over time.

Conclusion

One year after infection, more than one third of even moderate patients with mild symptoms had persistent pulmonary abnormalities. In our study, fibrotic changes were seen in severe and critically ill patients and remained stable 6 months after discharge from hospital. Imaging parameters can predict the prognosis. The larger the extent of baseline consolidation, the worse the prognosis of elderly patients.

◆Plasma proteomic evidence for increased β-amyloid pathology after SARS-CoV-2 infection【nature medicine　2025年1月30日】

Abstract

Previous studies have suggested that systemic viral infections may increase risks of dementia. Whether this holds true for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infections is unknown. Determining this is important for anticipating the potential future incidence of dementia. To begin to do this, we measured plasma biomarkers linked to Alzheimer’s disease pathology in the UK Biobank before and after serology-confirmed SARS-CoV-2 infections. SARS-CoV-2 infection was associated with biomarkers associated with β-amyloid pathology: reduced plasma Aβ42:Aβ40 ratio and, in more vulnerable participants, lower plasma Aβ42 and higher plasma pTau-181. The plasma biomarker changes were greater in participants who had been hospitalized with COVID-19 or had reported hypertension previously. We showed that the changes in biomarkers were linked to brain structural imaging patterns associated with Alzheimer’s disease, lower cognitive test scores and poorer overall health evaluations. Our data from this post hoc case–control matched study thus provide observational biomarker evidence that SARS-CoV-2 infection can be associated with greater brain β-amyloid pathology in older adults. While these results do not establish causality, they suggest that SARS-CoV-2 (and possibly other systemic inflammatory diseases) may increase the risk of future Alzheimer’s disease.

◆Study: Air purifier use at daycare centres cut kids’ sick days by a third【yle　2023年11月28日】

Use of air purifiers at two daycare centres in Helsinki led to a reduction in illnesses and absences among children and staff, according to preliminary findings of a new study led by E3 Pandemic Response.

Air purifiers of various sizes and types were placed in two of the city’s daycare centres during cold and flu seasons.

The initial results from the first year of research are promising, according to researcher Enni Sanmark, from HUS Helsinki University Hospital.

“Children were clearly less sick in daycare centres where air purification devices were used — down by around 30 percent,” Sanmark explained.

The air purifiers were changed at two daycare centres serving as a control in the experiment, in order to rule out the effect that possible epidemic fluctuations could have on the results. The study’s next phase will continue until April.

“We will be able to analyse whether there were only decreases in flu-type illnesses or whether the use of air purification could also help reduce stomach ailments,” Sanmark said.

On average, daycare centre-aged children suffer 10-13 infectious illnesses every year, with each illness lasting from one to three weeks, according to the research.

Meanwhile, kids between the ages of 1-3 come down with flu-like symptoms between five to eight times a year — and children also often suffer stomach bugs, on top of that. Kids are particularly prone to catching colds after returning to daycare after their summer break.

Those illnesses are often shared by the kids’ parents and daycare staff, prompting absences from work.

Sanmark said that employers face costs of around 370 euros for one day of an employee’s sick leave.

“It would be a big savings if we could get rid of 30 percent of sick days spread by children, as well as the illnesses that go home to parents,” Sanmark said.

The research aims to help build an air purification scheme that could be used at other daycare centres — namely how to get the air cleaner at such facilities in ways that aren’t too noisy, expensive or take up too much space.

The final results of the study are expected next spring.

“At the moment, we are cautiously positive. Daycares and schools [here] have not done this before, but of course results from around the world show that air purification can reduce pathogens in the air, so our results are in line with these findings. We’re excited and will continue our research,” Sanmark said.

Prompted by the Covid-19 crisis, the E3 Pandemic Response project is a private and public effort that aims to “harness modern science and technology to create effective countermeasures to prevent the spreading of novel infectious diseases”.

◆Immune damage in Long Covid【Science　2024年6月18日】

Acute infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause a respiratory illness that can be associated with systemic immune cell activation and inflammation, widespread multiorgan dysfunction, and thrombosis. Not everyone fully recovers from COVID-19, leading to Long Covid, the treatment of which is a major unmet clinical need. Long Covid can affect people of all ages, follows severe as well as mild disease, and involves multiple organs. The persistence of lingering symptoms after acute disease creates a considerable challenge for understanding the specific pathophysiology and risk factors underlying Long Covid. On page 273 of this issue, Cervia-Hasler et al. report a multicenter, longitudinal study of 113 patients who either fully recovered from COVID-19 or developed Long Covid, identifying localized activation of the innate immune defense complement system as a likely culprit that induces thromboinflammation and prevents the restoration of fitness after acute COVID-19.

Patients with Long Covid display signs of immune dysfunction and exhaustion, persistent immune cell activation, and autoimmune antibody production, which are also pathological features of acute COVID-19. Cervia-Hasler et al. undertook a proteomic screen measuring serum levels of 6596 human proteins that are recognized by 7289 epitope-specific DNA oligonucleotide aptamer probes. The patients with severe or mild acute COVID-19 were analyzed during the acute infection and 6 months later. Comparison of the 40 Long Covid patients, 73 recovered patients, and 39 healthy controls revealed that most serum biomarkers that were elevated in patients with Long Covid at 6 months overlapped with those that were altered in the subgroup of the cohort with severe acute COVID-19.

In particular, the blood antimicrobial defense systems of complement and pentraxin 3 stood out as being significantly associated with Long Covid development. Complement components and pentraxins, which include serum amyloid proteins, serve humoral immunity by destroying and opsonizing pathogens for rapid clearance by innate immune cells. These proteins are up-regulated in hepatocytes as part of the inflammationinduced systemic acute phase response. However, the up-regulated markers of this response in Long Covid—pentraxin 3 and certain complement factors—are produced mainly by immune and other tissue-resident cells and not the liver, indicating that persistent inflammation in Long Covid patients is local rather than systemic.