SARS-CoV-2 と COVID-19 に関する備忘録 Vol.44

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Acute Onset Neuropsychiatric Conditions in Children and Adolescents following SARS-CoV-2 Infection: A Case Series【Karger　2025年3月24日】

Abstract

Introduction: Neuropsychiatric symptoms following SARS-CoV-2 infection have been described in a substantial proportion of patients, acute, subacute, and chronic. Understanding of the neurological and neuropsychiatric sequelae of this virus is an emerging field of study with rapidly evolving descriptions of its impact on the central and peripheral nervous system.
Case Presentation: Here, we report a series of 8 pediatric patients presenting with acute onset neuropsychiatric symptoms following SARS-CoV-2 infection who received comprehensive medical and psychiatric evaluation and treatment in our research-based Neuroimmune Psychiatric Disorders Program. We provide a review of the research available to date regarding potential mechanisms underlying neuroinflammatory consequences of this endemic infection. Opportunities for further investigations of mechanisms, evaluations and impactful treatments following SARS-CoV-2 infection are described.
Conclusion: The pediatric cases presented share acute onset of obsessive-compulsive disorder, psychosis, tics, neurobehavioral and physiological symptoms, with significant response to treatments targeting inflammation in combination with psychiatric and psychological interventions. Ongoing study and identification of this phenomenon of abrupt neuropsychiatric changes following SARS-CoV-2 infection may lead to more effective treatments with potential application to broader populations.

◆Association between COVID-19 and the development of chronic kidney disease in patients without initial acute kidney injury【nature : scientific reports　2025年3月29日】

Abstract

While the association between COVID-19 and acute kidney injury (AKI) is well documented, the impact of COVID-19 on the development of advanced chronic kidney disease (CKD) remains unclear, particularly in patients without initial AKI. Using the TriNetX healthcare database, we conducted a matched cohort study comparing 141,587 COVID-19 and 141,587 influenza patients. We excluded patients with AKI within one month of infection and matched groups on demographics, comorbidities, and baseline laboratory values. The primary outcome was the incidence of advanced CKD (stages 3–5) at the 12-month follow-up. COVID-19 patients showed higher 12-month risks of advanced CKD (hazard ratio [HR]:2.02, 95% confidence interval [CI]:1.69–2.42, p < 0.0001), AKI (HR 3.04, 95%CI:2.61–3.55, p < 0.0001), and estimated glomerular filtration rate < 60 mL/min/1.73 m2 (HR:3.01, 95%CI:2.74–3.30, p < 0.0001) compared to influenza patients. Subgroup analyses showed consistently elevated risks across sexes and in patients over 45 years, while younger patients did not demonstrate an increased risk of advanced CKD at the 12-month follow-up. Diabetes mellitus and hypertension have emerged as the strongest predictors of advanced CKD development. In conclusion, COVID-19 is associated with an increased risk of long-term renal dysfunction compared with influenza, suggesting the need for extended monitoring of kidney function in high-risk populations.

◆The Impact of Long COVID on Language Proficiency Across Different School Levels in Hong Kong【MDPI　2025年3月28日】

Abstract

Long COVID, where symptoms persist after recovering from COVID-19, can affect cognitive functions like language. However, little is known about its impact on children’s language skills, especially across different school levels. This study investigated the impact of long COVID on language proficiency among 1244 children (Asian; 53.5% boys) from kindergartens (N = 408, Mage = 4.42 ± 1.26 years), primary schools (N = 547, Mage = 9.69 ± 1.96 years), and secondary schools (N = 289, Mage = 14.97 ± 1.85 years) in Hong Kong. Language proficiency was assessed using the Language Experience and Proficiency Questionnaire (LEAP-Q), which measured speaking, listening, reading, and writing in both Chinese and English. Participants were categorized into three groups: long COVID, recovered from COVID-19, and no history of COVID-19. One-way and two-way ANOVAs were used to analyze the differences in language proficiency across these groups and school levels. Children with long COVID symptoms exhibited significantly lower overall language proficiency, particularly in speaking and listening, compared to those in the recovered and no-COVID groups. The effect was more pronounced among primary and secondary students, with secondary school students showing the most substantial deficits. No significant differences were found between the recovered and no-COVID groups. The results suggest that long COVID might have detrimental effects on children’s linguistic proficiency. The language development of older students who suffered from long COVID could benefit from receiving targeted educational and therapeutic interventions.

◆Rates of infection with other pathogens after a positive COVID-19 test versus a negative test in US veterans (November, 2021, to December, 2023): a retrospective cohort study【THE LANCET Infectious Diseases　2025年4月1日】

Summary

Background

SARS-CoV-2 infection leads to post-acute sequelae that can affect nearly every organ system, including the immune system. However, whether an infection with SARS-CoV-2 is associated with increased risk of future infections with other pathogens is not yet fully characterised. In this study, we aimed to test the association between a positive test for COVID-19, compared with a negative test, and rates of future infections with other pathogens.

Methods

We used the US Department of Veterans Affairs health-care databases to build a spatiotemporally aligned cohort of 231 899 people with a positive COVID-19 test and 605 014 with a negative COVID-19 test (test-negative control group) between Nov 1, 2021, and Dec 31, 2023. We first did a discovery approach to map the associations between those with a positive COVID-19 test versus a negative test and laboratory-based outcomes of infectious illnesses. We then compared rates of a prespecified set of infectious disease outcomes between those with and without a positive COVID-19 test. To evaluate the specificity of the findings to COVID-19, we compared the rates of a prespecified set of infectious disease outcomes in a spatiotemporally aligned cohort of people admitted to hospital for COVID-19 (n=12 450) versus those admitted for seasonal influenza (n=3293). Outcomes were ascertained 30 days after the date of the first test until the end of follow-up (365 days after the first test plus 30 days, death, or July 18, 2024, whichever came first). An inverse probability weighting approach was used to balance demographic and health characteristics across cohorts. Log-binomial regression models were used to estimate risk ratios (RRs) and 95% CIs.

Findings

In the 12 months of follow-up, compared with participants who had a negative test for COVID-19, people with COVID-19 who did not require admission to hospital during the acute phase of infection had increased test positivity rates for bacterial infections (in blood, urine, and respiratory cultures) and viral diseases (including Epstein–Barr virus, herpes simplex virus reactivation, and respiratory viral infections). People who were positive for COVID-19 and admitted to hospital also had increased rates of bacterial infections in blood, respiratory, and urine biospecimens, and viral infections in blood and respiratory biospecimens. Analyses of prespecified outcomes showed that, compared with the test-negative control group, participants with a positive COVID-19 test who were not admitted to hospital had significantly increased rates of outpatient diagnosis of infectious illnesses (RR 1·17 [95% CI 1·15–1·19]), including bacterial, fungal, and viral infections; outpatient respiratory infections (1·46 [1·43–1·50]); and admission to hospital for infectious illnesses (1·41 [1·37–1·45]), including for sepsis and respiratory infections; the rates of prespecified outcomes were generally higher among those who were admitted to hospital for COVID-19 during the acute phase. Compared with people admitted to hospital for seasonal influenza, those admitted for COVID-19 had higher rates of admission to hospital for infectious illnesses (1·24 [1·10–1·40]), admission to hospital for sepsis (RR 1·35 [1·11–1·63]), and in-hospital use of antimicrobials (1·23 [1·10–1·37]).

Interpretation

Our results suggest that a positive test for COVID-19 (vs a negative test) was associated with increased rates of diagnosis of various infections in the 12 months following an acute SARS-CoV-2 infection. The putative long-term effects of COVID-19 on the immune system and the propensity for infection with other pathogens should be further evaluated in future studies.

◆Spike Protein–Fibrinogen Interaction: A Novel Immune Evasion Strategy of SARS-CoV-2?【ACS Publications　2025年3月19日】

Abstract

The host protein fibrinogen has been found to interact with the N-terminal domain (NTD) of the spike protein in SARS-CoV-2. However, the evolutionary benefit of this binding to the virus still remains unclear. Herein, we put forward with rationale and supporting evidence that the binding of fibrinogen to its more conserved NTD is an immune evasion strategy adopted by the virus to outsmart the NTD targeted neutralizing antibodies.

◆Cognitive Sequelae of COVID-19: Mechanistic Insights and Therapeutic Approaches【WILEY Online Library　2025年3月28日】

Abstract

Background

The COVID-19 pandemic has left an indelible mark on the world, with mounting evidence suggesting that it not only posed acute challenges to global healthcare systems but has also unveiled a complex array of long-term consequences, particularly cognitive impairment (CI). As the persistence of post-COVID-19 neurological syndrome could evolve into the next public health crisis, it is imperative to gain a better understanding of the intricate pathophysiology of CI in COVID-19 patients and viable treatment strategies.

Methods

This comprehensive review explores the pathophysiology and management of cognitive impairment across the phases of COVID-19, from acute infection to Long-COVID, by synthesizing findings from clinical, preclinical, and mechanistic studies to identify key contributors to CI, as well as current therapeutic approaches.

Results

Key mechanisms contributing to CI include persistent neuroinflammation, cerebrovascular complications, direct neuronal injury, activation of the kynurenine pathway, and psychological distress. Both pharmacological interventions, such as anti-inflammatory therapies and agents targeting neuroinflammatory pathways, and non-pharmacological strategies, including cognitive rehabilitation, show promise in addressing these challenges. Although much of the current evidence is derived from preclinical and animal studies, these findings provide foundational insights into potential treatment approaches.

Conclusion

By synthesizing current knowledge, this review highlights the importance of addressing COVID-19-related cognitive impairment and offers actionable insights for mitigation and recovery as the global community continues to grapple with the pandemic’s long-term impact.

◆Updates on the neurological manifestations of SARS-CoV-2 infection【Wolters Kluwer Health　2025年4月1日】

Abstract

Purpose of review

Since its emergence in 2020, the COVID-19 pandemic has created a global surge of survivors experiencing neurologic effects from SARS-CoV-2 infection. This review aims to provide an updated synthesis of the acute and chronic neurological manifestations of COVID-19, and to outline the current therapeutic strategies for these conditions.

Recent findings

Epidemiological studies have shown that COVID-19 patients with neurological symptoms during acute infection tend to have poorer hospital and functional outcomes. While the risk of adverse neurologic symptoms including cognitive dysfunction, headache, autonomic dysfunction, and chronic fatigue are thought to be greatest following infection with the original SARS-CoV-2 strain and its alpha variant, they remain prevalent after infection with subsequent less virulent strains as well. Some recent work has also found a link between SARS-CoV-2 and structural brain changes. However, ongoing trials show promising results for pharmacologic and nonpharmacologic treatments targeting the postacute neurological sequelae of COVID-19.

Summary

Lingering neurological manifestations after COVID-19 still pose considerable individual, healthcare system, and socioeconomic repercussions. Both preventive and multimodal treatment approaches are necessary to address these conditions. Further research is required to assess the lasting impacts of SARS-CoV-2 on the nervous system, particularly its potential contribution to the development of neurodegenerative diseases.

◆Reinfection with SARS-CoV-2 in the Omicron Era is Associated with Increased Risk of Post-Acute Sequelae of SARS-CoV-2 Infection: A RECOVER-EHR Cohort Study【medRxiv　2025年3月30日】

Abstract

IMPORTANCE Post-acute sequelae of SARS-CoV-2 infection (PASC) remains a major public health challenge. While previous studies have focused on characterizing PASC and identifying its subphenotypes in children and adolescents following an initial SARS-CoV-2 infection, the risks of PASC with Omicron-variant reinfections remain unclear. Using a real-world data approach, this study investigates the risks of PASC following reinfections during the Omicron phase in the pediatric population.

OBJECTIVE To investigate the risks of PASC diagnosis and 24 PASC symptoms and conditions after reinfection of SARS-CoV-2 during Omicron period in the pediatric population.

DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study used data from the RECOVER consortium comprising 40 children’s hospitals and health institutions in U.S. between January 2022 and October 2023.

EXPOSURES A second SARS-CoV-2 infection, confirmed by a positive polymerase-chain-reaction (PCR) or antigen tests, or a diagnose of COVID-19, occurring at least 60 days after the initial infection, compared to the initial infection.

MAIN OUTCOMES AND MEASURES PASC was identified using two approaches: (1) the ICD-10- CM diagnosis code U09.9 and (2) a symptom-based definition including 24 physician-identified symptoms and conditions. Absolute risks of incident PASC were reported, and relative risks (RRs) were calculated by comparing the second infection episode with the first infection episode groups using a modified Poisson regression model, adjusting for demographic, clinical, and healthcare utilization factors through exact matching and propensity scoring matching.

RESULTS A total of 465,717 individuals under 21 years old (mean [SD] age 8.17 [6.58] years; 52% male) were included. Compared to the first infection, a second infection was associated with significantly increased risk of an overall PASC diagnosis (RR, 2.08; 95% confidence interval [CI], 1.68-2.59), and with many specific conditions including: myocarditis (RR, 3.60; 95% CI, 1.46-8.86); changes in taste and smell (RR, 2.83; 95% CI, 1.41-5.67); thrombophlebitis and thromboembolism (RR, 2.28; 95% CI, 1.71-3.04); heart disease (RR, 1.96; 95% CI, 1.69 to 2.28); acute kidney injury (RR, 1.90; 95% CI, 1.38 to 2.61); fluid and electrolyte (RR, 1.89; 95% CI, 1.62 to 2.20); generalized pain (RR, 1.70; 95% CI, 1.48 to 1.95); arrhythmias (RR, 1.59; 95% CI, 1.45-1.74); abnormal liver enzyme (RR, 1.56; 95% CI, 1.24 to 1.96); fatigue and malaise (RR, 1.50; 95% CI, 1.38 to 1.64); musculoskeletal pain (RR, 1.45; 95% CI, 1.37 to 1.54); abdominal pain (RR, 1.42; 95% CI, 1.34 to 1.50); postural orthostatic tachycardia syndromes (POTS)/dysautonomia (RR, 1.35; 95% CI, 1.20 to 1.51); cognitive functions (RR, 1.32; 95% CI, 1.15 to 1.50); and respiratory signs and symptoms (RR, 1.29; 95% CI, 1.25 to 1.33). The risks were consistent across various organ systems, including cardiovascular, respiratory, gastrointestinal, neurological, and musculoskeletal systems.

CONCLUSIONS AND RELEVANCE Children and adolescents face significantly higher risk of various PASC outcomes after reinfection with SARS-CoV-2. These findings suggest a cumulative risk of PASC and highlight the urgent need for targeted prevention strategies to reduce reinfections, which includes an increased emphasis on initial or re-vaccination of children.

◆Gut barrier integrity biomarkers are associated with increased inflammation and predict disease status in hospitalized COVID-19 patients【bioRxiv　2025年3月31日】

Abstract

The COVID-19 global pandemic persists as an endemic disease with frequent case spikes and a significant continued burden on public health. Although most COVID-19 cases are asymptomatic or mild, severe infections requiring hospitalization have resulted in likely more than 14 million cumulative deaths to date. One hallmark of severe COVID-19 is a dysregulated immune response that leads to systemic inflammation and contributes to disease severity and mortality but is not explained by viral replication alone. Severe COVID-19 has been shown to disrupt the gut microbiome and increase intestinal permeability which may contribute to immune dysregulation and systemic inflammation. In this study, we investigated the differences in plasma biomarkers for microbial translocation and gut barrier damage as well as circulating cytokines between healthy volunteers and patients hospitalized with COVID-19. We then performed a correlation analysis to understand how the relationships between these plasma biomarkers differed and used a random forest model to assess their accuracy in distinguishing between these two groups. Our results demonstrated that hospitalized COVID-19 patients have elevated concentrations of pro-inflammatory cytokines and markers of microbial translocation, and that the relationships between these biomarkers were significantly altered compared to healthy volunteers, especially those related to the mucosal associated homeostatic cytokines IL-17A and IL-23. Furthermore, IL-6 and LBP were the top biomarkers for prediction accuracy in our random forest model, highlighting the importance of managing microbial translocation in COVID-19 and its potential utility as a biomarker for disease severity.

◆Gut barrier integrity biomarkers are associated with increased inflammation and predict disease status in hospitalized COVID-19 patients【THE LANCET Infectious Diseases　2025年4月3日】

Summary

Background

The substantial burden of post-COVID-19 condition (also known as long COVID) underscores the need for effective pharmacological interventions. Given that viral persistence has been hypothesised as a potential cause of long COVID, antiviral therapy might offer a promising approach to alleviating long COVID symptoms. We therefore investigated the efficacy, safety, and tolerability of nirmatrelvir–ritonavir for treating long COVID.

Methods

In this phase 2, decentralised, double-blind, randomised controlled trial, adults (aged ≥18 years) from the 48 states across the contiguous USA, with previous documented SARS-CoV-2 infection and long COVID symptoms starting within 4 weeks of initial infection and persisting for at least 12 weeks, were eligible for inclusion. Key exclusion criteria were use of nirmatrelvir–ritonavir within the previous 2 months, CYP3A4-dependent medications, or strong CYP3A4 inducers; acute medical illness such as SARS-CoV-2 infection within the past 2 weeks; active liver disease; renal impairment; and immunocompromise. Using software for 1:1 stratified block random assignment, participants were randomly allocated to receive either two tablets of nirmatrelvir (150 mg each) and one tablet of ritonavir (100 mg), or placebo and one tablet of ritonavir (100 mg), orally administered twice daily for 15 days, stratified by age, sex at birth, and COVID-19 vaccination status. Participants, clinicians, and the study team were masked to treatment allocation. The primary efficacy endpoint was the change in the Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Physical Health Summary Score (PHSS) from baseline to day 28, analysed by intention to treat. Safety endpoints were reported from baseline to week 6 in all participants who were exposed to the study treatment. This trial is registered with ClinicalTrials.gov (NCT05668091) and is now closed to new participants.

Findings

Between April 14, 2023, and Feb 26, 2024, 119 participants were screened. 100 were enrolled (66 [66%] female participants and 34 [34%] male participants), with 49 assigned to the nirmatrelvir–ritonavir group and 51 to the placebo–ritonavir group (intention-to-treat population). Three participants in the nirmatrelvir–ritonavir group and two in the placebo–ritonavir group withdrew before starting treatment and were excluded from the safety population. The mean PROMIS-29 PHSS at baseline was 39·6 (95% CI 37·4 to 41·9) in the nirmatrelvir–ritonavir group and 36·3 (34·4 to 38·2) in the placebo–ritonavir group. The adjusted change from baseline to day 28 was 0·45 (–0·93 to 1·83) in the nirmatrelvir–ritonavir group and 1·01 (–0·30 to 2·31) in the placebo–ritonavir group (adjusted mean difference –0·55 [95% CI –2·32 to 1·21; p=0·54]). No deaths or serious adverse events were recorded between baseline and week 6. Study drug-related treatment-emergent adverse events were reported in more participants in the nirmatrelvir–ritonavir group (35 [76%] of 46) compared with the placebo–ritonavir group (27 [55%] of 49), mostly driven by dysgeusia. Early treatment termination due to an adverse event occurred in two participants in the nirmatrelvir–ritonavir group and one in the placebo–ritonavir group.

Interpretation

Nirmatrelvir–ritonavir administered for 15 days did not significantly improve health outcomes in participants with long COVID compared with placebo–ritonavir at day 28. However, the study showed the feasibility of large-scale, decentralised trials in long COVID.

◆Gut barrier integrity biomarkers are associated with increased inflammation and predict disease status in hospitalized COVID-19 patients【THE LANCET Infectious Diseases　2025年4月3日】

Novel SARS-CoV-2 variants continue to emerge, driving waves of COVID-19. The evolution of SARS-CoV-2 took a surprising turn in 2023 with the emergence of BA.2.86, a BA.2-descendant harbouring multiple spike (S) protein mutations, enhancing antibody evasion. Subsequently, several BA.2.86-derived lineages emerged, with JN.1 dominating early and the JN.1-derived variants KP.3.1.1 and XEC dominating late in 2024. Currently, LP.8.1 is on the verge of becoming dominant. This study provides a preliminary virological characterisation of LP.8.1 and its sublineage LP.8.1.1.
The number of LP.8.1 infections is rapidly increasing in Asia and North America, and this lineage is also on the rise in Europe. Furthermore, LP.8.1.1 is spreading rapidly in Asia and North America. Both LP.8.1 and LP.8.1.1 harbour unique mutations in spike that may alter epitopes recognised by neutralising antibodies, including R346T and H445R. Interestingly, the two variants are distinguished by a single mutation, K679R, which generates a new furin consensus motif in the LP.8.1.1 S protein, overlapping the original furin motif located at the border between the S1 and S2 subunits.
We assessed how the mutations in LP.8.1 and LP.8.1.1 impact S protein interactions with the cellular receptor ACE2, S protein-driven cell–cell and virus–cell fusion, and inhibition of S protein-driven cell entry by antibodies. For this, we used S protein-expressing cells and S protein-bearing pseudotypes, a model that faithfully reflects SARS-CoV-2 cell entry and its inhibition.8 The S proteins of KP.3.1.1 and XEC served as controls. All S proteins were robustly expressed and comparably cleaved. Soluble ACE2 bound to cells expressing KP.3.1.1, XEC, LP.8.1, and LP.8.1.1 S proteins with similar efficiency. However, soluble ACE2 inhibited cell entry of particles pseudotyped with LP.8.1 or LP.8.1.1 S proteins (LP.8.1pp and LP.8.1.1pp) with higher efficiency than XECpp and KP.3.1.1pp, suggesting increased ACE2 affinity that remained undetected in the binding assay. Additionally, all S proteins drove cell–cell fusion with comparable efficiency. By contrast, LP.8.1pp and LP.8.1.1pp entry into human Calu-3 lung cells and LP.8.1.1pp entry into other well-characterised cell lines was reduced. Finally, we examined antibody-mediated neutralisation, focusing on LP.8.1pp, since K679R, the signature mutation of LP.8.1.1, is not expected to alter neutralisation. XECpp evaded neutralising antibodies present after vaccination with the JN.1-derived booster vaccine with 1·2-fold higher efficiency than KP.3.1.1pp (geometric mean titre 587 vs 506), as expected, while LP.8.1pp evaded neutralisation with 1·4-fold higher efficiency (geometric mean titre 587 vs 413).
Collectively, augmented ACE2 interaction and antibody evasion may promote the spread of LP.8.1 and LP.8.1.1 while the biological significance of the second furin motif in the LP.8.1.1 S protein remains unclear. The JN.1-derived booster vaccine increases neutralising antibody levels against JN.1-descendants and these antibodies potently neutralise LP.8.1, indicating that vaccination should augment protection against hospitalisation and post-COVID-19 sequelae caused by the emerging LP.8.1 lineage.

◆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.

◆Crosstalk Between Disrupted Blood-Brain Barrier, Neuroinflammation, and Coagulopathy in AC70 hACE2 Tg Mice with Prolonged Neurological Manifestations Induced by the Omicron BA.1 Variant of SARS-CoV-2【bioRxiv　2025年4月4日】

Abstract

Long COVID, or post-acute sequela of COVID (PASC), has emerged as a major post-pandemic challenge, with lasting neurological effects in a substantial number of patients. The underlying pathophysiological mechanisms of PASC remains elusive, largely due to the lack of suitable animal models that replicate key clinical and pathological features, especially in survivors of acute infection. Here, we employed the Omicron BA.1-infected AC70 hACE2 Tg mice to explore the pathogenesis of COVID-19. Our findings in the AC70/BA.1 model demonstrated that surviving mice developed lasting neurological sequelae of COVID-19, making it a promising platform for studying the pathogenesis of neuro- or long-COVID. Histopathological examinations revealed a transient pulmonary inflammatory response that correlated with the levels of live virus, whereas neuroinflammation within the brains persisted and progressed beyond the acute phase, without a clear linkage to direct virus effects. We showed that the severity of neurological sequelae directly correlated with the degree of blood-brain-barrier (BBB) disruption, alterations in tight junctions (TJs) and fibrinogen extravasation into the brain parenchyma. Additionally, BA.1-infected mice elicited a sustained systemic prothrombotic state, with dysregulated coagulation and fibrinolytic pathways in an organ-specific manner, as evidenced by distinct pattern of intracellular fibrin(ogen) depositions, elevated d-dimers, and tissue-plasminogen activator (t-PA) expression in the lungs and brains. We also found a positive correlation between progressive neuroinflammation and t-PA expression, which was closely co-localized with Iba-1-positive cells, indicating that activated microglia may serve as an additional source of t-PA in the CNS. Lastly, we showed that BA.1 variant triggered prolonged anti-Annexin A2 (ANXA2) autoantibody production. ANXA2 is essential for the neurovascular system, coordinating multiply dynamic processes within the endothelium, including cell surface fibrinolysis and TJ assembly. Our analysis revealed that impaired TJ structures coexisted with diminished ANXA2 levels around the brain vessels, suggesting its involvement in BBB dysfunction and neuroinflammation.

◆CD147-high classical monocytes: a cellular biomarker for COVID-19 disease severity and treatment response【BMC Inflammation and Regeneration　2025年4月7日】

Abstract

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to severe coronavirus disease 2019 (COVID-19), which is characterized by cytokine storm and organ dysfunction. The spike S1 subunit induces inflammatory cytokine production, but the immune cell subsets that respond to S1 stimulation and contribute to disease severity remain unclear.

Methods

We analyzed serum samples and peripheral blood mononuclear cells (PBMCs) from patients with COVID-19 (moderate: n = 7; severe: n = 25) and healthy controls (n = 38). Using mass cytometry (cytometry by time-of-flight; CyTOF), we analyzed immune cell responses to S1 subunit stimulation in PBMCs from healthy donors and patients with COVID-19. We examined correlations among identified cell populations, serum cytokine levels, and clinical parameters.

Results

Serum S1 subunit levels correlated with disease severity and inflammatory cytokine concentrations. S1 subunit stimulation induced dose-dependent cytokine production from PBMCs, predominantly from myeloid cells. CyTOF analysis identified classical monocytes with high CD147 expression (CD147hi cMono) as the primary source of S1-induced cytokines. The proportion of CD147hi cMono increased significantly in severe COVID-19 and decreased with clinical improvement. The frequency of CD147hi cMono showed a stronger positive correlation with clinical severity markers in younger patients compared to older patients.

Conclusions

CD147hi cMono are the primary cellular source of S1-induced inflammatory cytokines and may serve as potential biomarkers for monitoring COVID-19 severity and treatment response.

◆Brainstem Reduction and Deformation in the 4th Ventricle Cerebellar Peduncles in Long COVID Patients: Insights into Neuroinflammatory Sequelae and “Broken Bridge Syndrome”【medRxiv　2025年4月8日】

Abstract

Post-COVID Syndrome (PCS), also known as Long COVID, is characterized by persistent and often debilitating neurological sequelae, including fatigue, cognitive dysfunction, motor deficits, and autonomic dysregulation (Dani et al., 2021). This study investigates structural and functional alterations in the brainstem and cerebellar peduncles of individuals with PCS using diffusion tensor imaging (DTI) and volumetric analysis. Forty-four PCS patients (15 bedridden) and 14 healthy controls underwent neuroimaging. Volumetric analysis focused on 22 brainstem regions, including the superior cerebellar peduncle (SCP), middle cerebellar peduncle (MCP), periaqueductal gray (PAG), and midbrain reticular formation (mRt).

Significant volume reductions were observed in the SCP (p < .001, Hedges’ g = 3.31) and MCP (p < .001, Hedges’ g = 1.77), alongside decreased fractional anisotropy (FA) in the MCP, indicative of impaired white matter integrity. FA_Avg fractional anisotropy average tested by FreeSurfer Tracula, is an index of white matter integrity, reflecting axonal fiber density, axonal diameter and myelination. These neuroimaging findings correlated with clinical manifestations of motor incoordination, proprioceptive deficits, and autonomic instability. Furthermore, volume loss in the dorsal raphe (DR) and midbrain reticular formation suggests disruption of pain modulation and sleep-wake cycles, consistent with patient-reported symptoms. Post-mortem studies provide supporting evidence for brainstem involvement in COVID-19. Radtke et al. (2024) reported activation of intracellular signaling pathways and release of immune mediators in brainstem regions of deceased COVID-19 patients, suggesting an attempt to inhibit viral spread. While viral genetic material was detectable, infected neurons were not observed. Matschke et al. (2020) found that microglial activation and cytotoxic T lymphocyte infiltration were predominantly localized to the brainstem and cerebellum, with limited involvement of the frontal lobe. This aligns with clinical observations implicating the brainstem in PCS pathophysiology. Cell-specific expression analysis of genes contributing to viral entry (ACE2, TMPRSS2, TPCN2, TMPRSS4, NRP1, CTSL) in the cerebral cortex showed their presence in neurons, glial cells, and endothelial cells, indicating the potential for SARS-CoV-2 infection of these cell types. Associations with autoimmune diseases with specific autoantibodies, including beta-2 and M-2 against G-protein coupled alpha-1, beta-1, beta-2 adrenoceptors against angiotensin II type 1 receptor or M1,2,3-mAChR, among others, voltage-gated calcium channels (VGCC) are known (Blitshteyn et al. 2015 and Wallukat and Schminke et al. 2014). These findings support the “Broken Bridge Syndrome” hypothesis, positing that structural disconnections between the brainstem and cerebellum contribute to PCS symptomatology. Furthermore, we propose that chronic activation of the Extended Autonomic System (EAS), encompassing the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system, may perpetuate these symptoms (Goldstein, 2020). Perturbations in this system may relate to the elevation of toxic autoantibodies AABs (Beta-2 and M-2), specific epitopes of the COVID virus’s SPIKE protein and Cytokine storm of IL-1, IL-6, and IL-8 in their increased numbers (1,000->10,000)

Further research is warranted to elucidate the underlying neuroinflammatory mechanisms, EAS dysregulation, and potential therapeutic interventions for PCS.

◆Characteristic immune cell interactions in livers of children with acute hepatitis revealed by spatial single-cell analysis identify a possible postacute sequel of COVID-19【BMJ Journals　2025年4月5日】

Abstract

Background A rise in paediatric cases of acute hepatitis of unknown origin (AHUO) was observed in 2022, some requiring liver transplantation. A link to adeno-associated virus 2 infection and CD4+T-cell mediated disease was reported in cohorts in the UK and USA but does not explain all cases.

Objective To determine the intrahepatic immune cell interactions in the inflamed liver and a possible contribution of SARS-CoV-2 infection.

Design Patients with acute non-A non-E hepatitis (10/12 AHUO, 2/12 subacute) during February 2022–December 2022 undergoing liver biopsy were recruited in a European patient cohort. Hepatological, virological, histopathological and highly multiplexed spatial and single-cell analyses of liver biopsies were performed.

Results Patients were negative for adenoviral and SARS-CoV-2 PCR. Three patients had a positive adenoviral serology and 10/12 patients had a history or serological evidence of SARS-CoV-2 infection. Imaging mass cytometry identified significant intrahepatic immune infiltration with an enrichment of CD8+T-cells. The highest CD8 infiltration and concomitant peripheral immune activation were observed in patients with the most severe hepatitis. CD8+T-cell infiltration was connected to histomorphological interface hepatitis and bridging necrosis. Cellular neighbourhood analysis indicated disease-associated microanatomic interactions between CX3CR1+ endothelial and myeloid cell populations, interacting with effector CD8+T-cells suggesting a pathogenic cellular triad. Of note, we detected intrahepatic SARS-CoV-2 antigens in ACE2-expressing cells in the areas with significant pathology in 11/12 samples using several different detection methods. 10/12 patients were treated with corticosteroid therapy and no liver transplantation was required.

Conclusions We identified a possible manifestation of an immune-mediated postacute sequel to COVID-19 associated with a characteristic immune infiltrate in children with AHUO. COVID-19 testing should be considered in paediatric AHUO.

◆A nationwide study of risk factors for long COVID and its economic and mental health consequences in the United States【nature communications medicine　2025年4月8日】

Abstract

Background

In the United States, concerns have been increasingly raised over the future public health and economic burden of long COVID including disability and declines in labor force participation. However, only a handful of U.S. studies have explored sociodemographic or socioeconomic characteristics that put people at risk of long COVID or have investigated its economic and mental health sequelae.

Methods

Using repeated cross-sectional data on over 375,000 adults including nearly 50,000 adults with long COVID pooled from U.S. nationally-representative Household Pulse Survey data collected between September and November 2022 and between August and October 2023, I fit age- and gender-adjusted and multivariable modified Poisson regression models to examine multiple sociodemographic and socioeconomic factors as predictors of long COVID. I further estimate the risks of unemployment, financial hardship, and anxiety and depression among working-aged adults and adults with current long COVID symptoms, and estimate the economic burden of lost wages due to long COVID.

Results

Nearly one in seven adults (~35 million) and working-aged adults (~30 million) reported having a history of long COVID by late 2022 and late 2023. In age- and gender-adjusted models and fully-adjusted multivariable models, I find several factors predict long COVID including lower household income, and being Hispanic, female, gay/lesbian or bisexual. I also find having long COVID is linked to higher risks of recent unemployment, financial hardship, and anxiety and depressive symptomatology, with evidence of dose-response relationships.

Conclusions

Overall, an estimated 24 million working-aged adults with long COVID had been or may still be at risk of adverse socioeconomic and mental health outcomes. The lost earnings due to long COVID among working-aged adults are estimated to total $211 billion in 2022 and $218 billion in 2023. These findings highlight the substantial public health and economic implications of long COVID among Americans.

◆To test or not to test? A new behavioral epidemiology framework for COVID-19【PLOS One　2024年12月17日】

Abstract

Evidence from clinical research suggests that in the first two waves of COVID-19, the virus spread rapidly through a large number of undocumented asymptomatic infections. These ‘silent’ infections camouflaged the actual incidence of the disease, leading to downward biases in the rates of transmission, disease prevalence, and fatality. These, in turn, had implications for how people and policymakers responded to changing infection prevalence. This paper posits that in the early stages of the COVID-19 pandemic, a considerable number of SARS-CoV-2 infections spread through asymptomatic infected individuals who lacked economic incentives to test and isolate adequately. The decision to undertake testing and the subsequent possibility of isolation entails a calculus of benefits and costs for an individual. Given that the perceived net benefit of such actions is correlated with the observed risk of infection, the likelihood of an asymptomatic individual choosing to undergo testing increases with the existing infection prevalence rate. This behavior, in turn, influenced disease transmission and mortality dynamics. This study presents an analytical framework that integrates prevalence-dependent testing behavior into a traditional epidemiological model. The model’s predictions provide critical policy insights. It reveals that failing to account for testing and isolation behavior results in underestimation of the infection propagation and fatality rates when reported disease prevalence is low, thereby, skewing the containment strategies in the initial and late stages of a pandemic. The findings underscore the necessity of enhancing testing capacity as a crucial countermeasure for future contagions like COVID-19.

◆Geospatial and demographic patterns of SARS-CoV-2 spread in Massachusetts from over 130,000 genomes【medRxiv　2025年4月6日】

Abstract

Despite intensive study, gaps remain in our understanding of SARS-CoV-2 transmission patterns during the COVID-19 pandemic, in part due to limited contextual metadata accompanying most large genomic surveillance datasets. We analyzed over 130,000 SARS-CoV-2 genomes, over 85,000 with matched epidemiological data, collected in Massachusetts from November 2021 to January 2023, to investigate viral transmission dynamics at high resolution. The data were drawn from diagnostic testing at >600 facilities representing schools, workplaces, public testing, and other sectors, and encompass the emergence of six major viral lineages, each representing a new outbreak. We found urban areas as key hubs for new lineage introduction and interurban transmission as facilitating spread throughout the state. Young adults, especially those on college campuses, served as early indicators of emerging lineage dominance. Resident-aged populations in college campuses and nursing homes exhibited a higher likelihood of being linked to within-facility transmission, while staff-aged at those facilities were more linked to their surrounding community. Individuals with recent vaccine doses, including boosters, had a lower likelihood of initiating transmission. This dataset shows the value of linking genomic and epidemiologic data at scale for higher resolution insights into viral dynamics and their implication for public health strategy.

◆“SARS-CoV-2 airborne detection within different departments of a COVID-19 hospital building and evaluation of air cleaners in air viral load reduction”【ScienceDirect　2025年4月9日】

Abstract

The pandemic of COVID-19 has brought in light the necessity for the development of novel detection methods for airborne transmitted pathogens, and the importance of effective clean air measures in hospital departments. In this study, airborne SARS-CoV-2 and particle matter (PM1, PM2.5) detection was performed in different areas of the COVID-19 building at the Ippokrateio University Hospital in Thessaloniki, Greece. More specifically, Sioutas cascade impactors were placed in the ICU (Intensive Care Unit) and HDU (High-Dependency Unit) on the first floor, and at the corridor and rooms at the COVID-19 clinic on the second floor. Furthermore, TECORA air pumps were placed at the building entrance to measure for PM1 and PM2.5. Afterwards, in a COVID room with confirmed air viral load an air cleaner was placed to examine the effect on viral load reduction. Results showed that no viral copies were detected in the air of ICU and HDU departments, in which negative pressure air filtration with HEPA filters is applied. On the contrary, viral load was effectively detected in rooms and corridors of the COVID floor and ranged from 25,9 to 1123,7 copies/m3. PM1 filters showed 77.8 % viral positivity, and PM2.5 filters were 38.5 % virus positive. Moreover, air viral load in the COVID room with an air cleaner showed a reduction of up to 98.1 %. In conclusion, SARS-CoV-2 was effectively detected in the air of different areas in the COVID building after continuous sampling ranging between 24 h and 7 days, and it was shown how important and effective air cleaners are as first-line measures against pathogen airborne transmission in hospital environments.

◆Associations of epigenetic aging and COVID- 19: A 3-year longitudinal study【SPRINGER NATURE　2025年4月10日】

Abstract

Aging and COVID- 19 are known to influence DNA methylation, potentially affecting the rate of aging and the risk of disease. The physiological functions of 54 volunteers—including maximal oxygen uptake (VO₂ max), grip strength, and vertical jump—were assessed just before the COVID- 19 pandemic and again 3 years later. Of these volunteers, 27 had contracted COVID- 19. Eight epigenetic clocks were used to assess the rate of aging during the 3-year period: DNAmAge showed accelerated aging, and five clocks showed slowed aging (DNAmAgeSkinBlood, DNAmAgeHannum, DNAmFitAge, PhenoAge, and DNAmTL). When we considered only females, we observed a stronger effect in the increase of DNAmAge acceleration, while we observed slowed aging in the case of SkinBloodClock, and DNAmTL. The methylation of the promoter region of the H1 FNT genes, which encodes testis-specific histone H1 family member N (H1fnt) and plays a crucial role in spermatogenesis decreased the most significantly. In contrast, the promoter of CSTL1, which encodes Cystatin-like 1, showed the most significant increase. We found that having COVID- 19 during the 3-year study period significantly increased the progress of aging assessed by DNAmGrimAge, DNAmGrimAge2, and DNAmFitAge (p = 0.024, 0.047, 0.032, respectively, after we adjusted the analysis for baseline variables). The data suggest that COVID- 19 may have a mild long-term effect on epigenetic aging.

◆Cardiac symptoms in patients 3–6 months after contracting COVID-19– data from the polish STOP-COVID registry【BMC Infectious Diseases　2025年4月9日】

Abstract

Background

Common complaints of long COVID patients are cardiac symptoms such as fatigue, weakness, and a feeling of palpitations. The study aimed to investigate the clinical features of patients with persistent cardiological symptoms occurring within 3 to 6 months after COVID-19. Differences in ambulatory blood pressure monitoring (ABPM), Holter ECG (electrocardiogram) and Echocardiography between people with and without persistent cardiological symptoms were evaluated. We also assessed whether the symptoms of anxiety and depression may be implicated in the clinical outcomes.

Materials and methods

This was a retrospective study of patients affiliated with the STOP-COVID registry who attended a follow-up visit 3–6 months after undergoing COVID-19. The visit assessed the clinical symptoms present and performed tests: ABPM, Holter ECG and Echocardiography. 504 patients additionally had GAD-2 (Generalized Anxiety Disorder 2-item) and PHQ-2 (Patient Health Questionnaire-2) tests performed.

Results

The analysis included 1080 patients. At least 1 of the analyzed symptoms was present in 586 patients (54.3%). The most common symptom was fatigue (38.9%). Comparing patients with or without palpitations showed that the mean value of ventricular extrasystole was higher in the former group (p = 0.011). Comparing patients with and without cardiac symptoms, there were differences in the mean values of the PHQ-2 (p = 0.022) and GAD-2 (p < 0.001) scales, as well as in the percentage of responses related to the risk of anxiety or depression. Conclusion

Cardiological symptoms are common among health issues that patients must face after contracting COVID-19. People with palpitations had more excessive ventricular extrasystoles than patients without these symptoms.

◆SARS-CoV-2 Infection of Salivary Glands Compromises Oral Antifungal Innate Immunity and Predisposes to Oral Candidiasis【bioRxiv　2024年6月11日】

Abstract

Saliva contains antimicrobial peptides considered integral components of host innate immunity, and crucial for protection against colonizing microbial species. Most notable is histatin-5 which is exclusively produced in salivary glands with uniquely potent antifungal activity against the opportunistic pathogen Candida albicans. Recently, SARS-CoV-2 was shown to replicate in salivary gland acinar cells eliciting local immune cell activation. In this study, we performed mechanistic and clinical studies to investigate the implications of SARS-CoV-2 infection on salivary histatin-5 production and Candida colonization. Bulk RNA-sequencing of parotid salivary glands from COVID-19 autopsies demonstrated statistically significant decreased expression of histatin genes. In situ hybridization, coupled with immunofluorescence for co-localization of SARS-CoV-2 spike and histatin in salivary gland cells, showed that histatin was absent or minimally present in acinar cells with replicating viruses. To investigate the clinical implications of these findings, salivary histatin-5 levels and oral Candida burden in saliva samples from three independent cohorts of mild and severe COVID-19 patients and matched healthy controls were evaluated. Results revealed significantly reduced histatin-5 in SARS-CoV-2 infected subjects, concomitant with enhanced prevalence of C. albicans. Analysis of prospectively recovered samples indicated that the decrease in histatin-5 is likely reversible in mild-moderate disease as concentrations tended to increase during the post-acute phase. Importantly, salivary cytokine profiling demonstrated correlations between activation of the Th17 inflammatory pathway, changes in histatin-5 concentrations, and subsequent clearance of C. albicans in a heavily colonized subject. The importance of salivary histatin-5 in controlling the proliferation of C. albicans was demonstrated using an ex vivo assay where C. albicans was able to proliferate in COVID-19 saliva with low histatin-5, but not with high histatin-5. Taken together, the findings from this study provide direct evidence implicating SARS-CoV-2 infection of salivary glands with compromised oral innate immunity, and potential predisposition to oral candidiasis.

◆Cardiovascular post-acute sequelae of SARS-CoV-2 in children and adolescents: cohort study using electronic health records【nature communications　2025年4月11日】

Abstract

The risk of cardiovascular outcomes following SARS-CoV-2 infection has been reported in adults, but evidence in children and adolescents is limited. This paper assessed the risk of a multitude of cardiac signs, symptoms, and conditions 28-179 days after infection, with outcomes stratified by the presence of congenital heart defects (CHDs), using electronic health records (EHR) data from 19 children’s hospitals and health institutions from the United States within the RECOVER consortium between March 2020 and September 2023. The cohort included 297,920 SARS-CoV-2-positive individuals and 915,402 SARS-CoV-2-negative controls. Every individual had at least a six-month follow-up after cohort entry. Here we show that children and adolescents with prior SARS-CoV-2 infection are at a statistically significant increased risk of various cardiovascular outcomes, including hypertension, ventricular arrhythmias, myocarditis, heart failure, cardiomyopathy, cardiac arrest, thromboembolism, chest pain, and palpitations, compared to uninfected controls. These findings were consistent among patients with and without CHDs. Awareness of the heightened risk of cardiovascular disorders after SARS-CoV-2 infection can lead to timely referrals, diagnostic evaluations, and management to mitigate long-term cardiovascular complications in children and adolescents.

◆Development and Validation of POCOKIDS-Q—A Questionnaire to Assess Post COVID-19 Symptoms in Children【WILEY Online Library　2025年4月13日】

Abstract

Aim

To identify the symptom burden in children and adolescents with post COVID-19, a validated and reliable instrument is needed, particularly to assess symptoms and their impact on the child. The aim of this study was to describe the development, validation, and reliability of the Post COVID-19 in Kids Questionnaire (POCOKIDS-Q), which was designed to assess post COVID-19 symptoms in children and adolescents.

Methods

The POCOKIDS-Q was developed based on literature, clinical experience, and questionnaires for adults with post COVID-19. The linguistic validation involved 9- to 17-year-old children. Children and adolescents with the onset of post COVID-19 symptoms were asked to complete the final version through a web link. Exploratory and confirmatory factor analyses were performed to identify a factor structure that explains the covariances between the variables.

Results

The link to the POCOKIDS-Q was opened 324 times and fully completed by 213 (66%) children and young adults (median age 14 years) with post COVID-19 symptoms. Confirmatory factor analyses revealed four significant and correlated factors: brain fatigue, cognitive impact, physical impact, and emotional impact. The explanatory power of the factor model is high.

Conclusion

The POCOKIDS-Q is applicable for assessing post COVID-19 symptoms in children and young adults.