SARS-CoV-2 と COVID-19 に関する備忘録 Vol.39

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Reproducibility of Genetic Risk Factors Identified for Long COVID using Combinatorial Analysis Across US and UK Patient Cohorts with Diverse Ancestries【medRxiv　2025年2月6日】

Abstract

Background Long COVID is a major public health burden causing a diverse array of debilitating symptoms in tens of millions of patients globally. In spite of this overwhelming disease prevalence and staggering cost, its severe impact on patients’ lives and intense global research efforts, study of the disease has proved challenging due to its complexity. Genome-wide association studies (GWAS) have identified only four loci potentially associated with the disease, although these results did not statistically replicate between studies. A previous combinatorial analysis study identified a total of 73 genes that were highly associated with two long COVID cohorts in the predominantly (>91%) white European ancestry Sano GOLD population, and we sought to reproduce these findings in the independent and ancestrally more diverse All of Us (AoU) population.

Methods We assessed the reproducibility of the 5,343 long COVID disease signatures from the original study in the AoU population. Because the very small population sizes provide very limited power to replicate findings, we initially tested whether we observed a statistically significant enrichment of the Sano GOLD disease signatures that are also positively correlated with long COVID in the AoU cohort after controlling for population substructure.

Results For the Sano GOLD disease signatures that have a case frequency greater than 5% in AoU, we consistently observed a significant enrichment (77% – 83%, p < 0.01) of signatures that are also positively associated with long COVID in the AoU cohort. These encompassed 92% of the genes identified in the original study. At least five of the disease signatures found in Sano GOLD were also shown to be individually significantly associated with increased long COVID prevalence in the AoU population. Rates of signature reproducibility are strongest among self-identified white patients, but we also observe significant enrichment of reproducing disease associations in self-identified black/African-American and Hispanic/Latino cohorts. Signatures associated with 11 out of the 13 drug repurposing candidates identified in the original Sano GOLD study were reproduced in this study. Conclusion These results demonstrate the reproducibility of long COVID disease signal found by combinatorial analysis, broadly validating the results of the original analysis. They provide compelling evidence for a much broader array of genetic associations with long COVID than previously identified through traditional GWAS studies. This strongly supports the hypothesis that genetic factors play a critical role in determining an individual’s susceptibility to long COVID following recovery from acute SARS-CoV-2 infection. It also lends weight to the drug repurposing candidates identified in the original analysis. Together these results may help to stimulate much needed new precision medicine approaches to more effectively diagnose and treat the disease.

This is also the first reproduction of long COVID genetic associations across multiple populations with substantially different ancestry distributions. Given the high reproducibility rate across diverse populations, these findings may have broader clinical application and promote better health equity. We hope that this will provide confidence to explore some of these mechanisms and drug targets and help advance research into novel ways to diagnose the disease and accelerate the discovery and selection of better therapeutic options, both in the form of newly discovered drugs and/or the immediate prioritization of coordinated investigations into the efficacy of repurposed drug candidates.

◆Pediatric Gastrointestinal Tract Outcomes During the Postacute Phase of COVID-19【JAMA Network　2025年2月7日】

Abstract

Importance The profile of gastrointestinal (GI) tract outcomes associated with the postacute and chronic phases of COVID-19 in children and adolescents remains unclear.

Objective To investigate the risks of GI tract symptoms and disorders during the postacute (28-179 days after documented SARS-CoV-2 infection) and the chronic (180-729 days after documented SARS-CoV-2 infection) phases of COVID-19 in the pediatric population.

Design, Setting, and Participants This retrospective cohort study was performed from March 1, 2020, to September 1, 2023, at 29 US health care institutions. Participants included pediatric patients 18 years or younger with at least 6 months of follow-up. Data analysis was conducted from November 1, 2023, to February 29, 2024.

Exposures Presence or absence of documented SARS-CoV-2 infection. Documented SARS-CoV-2 infection included positive results of polymerase chain reaction analysis, serological tests, or antigen tests for SARS-CoV-2 or diagnosis codes for COVID-19 and postacute sequelae of SARS-CoV-2.

Main Outcomes and Measures GI tract symptoms and disorders were identified by diagnostic codes in the postacute and chronic phases following documented SARS-CoV-2 infection. The adjusted risk ratios (ARRs) and 95% CI were determined using a stratified Poisson regression model, with strata computed based on the propensity score.

Results The cohort consisted of 1 576 933 pediatric patients (mean [SD] age, 7.3 [5.7] years; 820 315 [52.0%] male). Of these, 413 455 patients had documented SARS-CoV-2 infection and 1 163 478 did not; 157 800 (13.6%) of those without documented SARS-CoV-2 infection had a complex chronic condition per the Pediatric Medical Complexity Algorithm. Patients with a documented SARS-CoV-2 infection had an increased risk of developing at least 1 GI tract symptom or disorder in both the postacute (8.64% vs 6.85%; ARR, 1.25; 95% CI, 1.24-1.27) and chronic (12.60% vs 9.47%; ARR, 1.28; 95% CI, 1.26-1.30) phases compared with patients without a documented infection. Specifically, the risk of abdominal pain was higher in COVID-19–positive patients during the postacute (2.54% vs 2.06%; ARR, 1.14; 95% CI, 1.11-1.17) and chronic (4.57% vs 3.40%; ARR, 1.24; 95% CI, 1.22-1.27) phases.

Conclusions and Relevance In this cohort study, the increased risk of GI tract symptoms and disorders was associated with the documented SARS-CoV-2 infection in children or adolescents during the postacute or chronic phase. Clinicians should note that lingering GI tract symptoms may be more common in children after documented SARS-CoV-2 infection than in those without documented infection.

◆Correlation of interferons and autoimmune aspects in long COVID-19 patients【OXFORD ACADEMIC international immunology　2025年2月8日】

Abstract

Long COVID, or post-acute sequelae of COVID-19 (PASC), represents a major global health challenge, with its underlying mechanisms remaining poorly understood despite substantial research and clinical trials. This study investigates the role of the interferon (IFN) axis in the pathogenesis of PASC, drawing parallels to systemic lupus erythematosus (SLE). The potential pathogenic role of IFNs was detected by meta-analyses of mRNA sequencing data comparing PASC patients to healthy controls. We analyzed serum samples from 39 PASC patients and found significant correlations among multiple IFN sub types, including IFN alpha-2, beta, gamma, lambda-1, and lambda-2/3. The biological activity of IFNs in the serum was positively correlated with levels of both total and type III IFNs. Notably, we detected the widespread presence of anti-double-stranded DNA (anti-dsDNA) and anti-Smith (anti-Sm) antibodies in these patients, with anti-dsDNA levels showing a strong correlation with IFN activity. On the basis of these findings, we propose a hypothetical autoimmune pathogenesis for PASC highlighting the crucial role of IFN signaling.

◆Reply: Muscle abnormalities in Long COVID【nature communications　2025年2月11日】

We thank Ranque et al. for their interest in our recent work and alternative interpretation of our data. We refute that our findings are due to deconditioning, as Long COVID-related skeletal muscle differ fundamentally from those caused by deconditioning. We demonstrated significant physiological differences in Long COVID patients with post-exertional malaise (PEM) compared to healthy controls, even at matched physical activity levels. PEM encompasses a variety of symptoms and not only muscle soreness. Our study did not address the efficacy of exercise training, and we reject misinterpretations that all forms of exercise cause PEM. We advocate further research to define safe exercise thresholds and improve the understanding of PEM.

◆Targeting the SARS-CoV-2 reservoir in long COVID【ScienceDirect　2025年2月10日】

Summary

There are no approved treatments for post-COVID-19 condition (also known as long COVID), a debilitating disease state following SARS-CoV-2 infection that is estimated to affect tens of millions of people. A growing body of evidence shows that SARS-CoV-2 can persist for months or years following COVID-19 in a subset of individuals, with this reservoir potentially driving long-COVID symptoms or sequelae. There is, therefore, an urgent need for clinical trials targeting persistent SARS-CoV-2, and several trials of antivirals or monoclonal antibodies for long COVID are underway. However, because mechanisms of SARS-CoV-2 persistence are not yet fully understood, such studies require important considerations related to the mechanism of action of candidate therapeutics, participant selection, duration of treatment, standardisation of reservoir-associated biomarkers and measurables, optimal outcome assessments, and potential combination approaches. In addition, patient subgroups might respond to some interventions or combinations of interventions, making post-hoc analyses crucial. Here, we outline these and other key considerations, with the goal of informing the design, implementation, and interpretation of trials in this rapidly growing field. Our recommendations are informed by knowledge gained from trials targeting the HIV reservoir, hepatitis C, and other RNA viruses, as well as precision oncology, which share many of the same hurdles facing long-COVID trials.

◆Post-COVID-19 Small Fiber Neuropathy as a New Emerging Quality of Life-Threatening Disease: A Systematic Review【MDPI　2025年2月2日】

Abstract

Post-acute sequelae of COVID-19 (PASC) syndrome is considered an emergent and diffuse multidisciplinary problem. Compelling evidence suggests that COVID-19 increases symptoms of pre-existent small fiber neuropathy (SFN) and might trigger de novo onset of SFN. In this systematic review, for the first time, we provide a comprehensive overview of the clinical and diagnostic features of PASC-SFN, including the accompanying disorders, disease evolution, and possible treatments, described in the recent literature. Following infection, many patients reported a wide range of symptoms and complications, not self-limiting and independent from previous infection severity. SFN begins more frequently with distal limb burning pain and numbness, which accompany other dysautonomia, cognitive, visual, and osteoarticular disorders involving multiple organ systems. In an initial diagnostic suspicion, some tests might be useful as complementary examinations, such as nerve quantitative sensory testing, electromyography, and optic nerve tomography. Otherwise, definite diagnosis is reached with skin biopsy as the gold standard, along with corneal in vivo microscopy when ocular discomfort is present. Being a long-term condition, multiple and dissimilar symptomatic and disease-modifying drugs were employed for the treatment of this condition with the achievement of partial results, including steroids, pregabalin, gabapentin, duloxetine, vitamins, homotaurine and phosphatidylserine, alpha lipoic acid, immunosuppressants, and intravenous immunoglobulin therapy. PASC-SFN is a complex emerging disease and extremely challenging for physicians. At present, the only feasible management of PASC-SFN is represented by a multidisciplinary tailored approach, with future definitive protocols for diagnosis and treatment deemed essential.

◆Recent advances in nutritional metabolism studies on SARS-CoV-2 infection【ScienceDirect　2025年1月27日】

Abstract

In the context of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), metabolic research has become crucial for in-depth exploration of viral infection mechanisms and in searching for therapeutic strategies. This paper summarizes the interrelationships between carbohydrate, lipid, and amino acid metabolism and COVID-19 infection, discussing their roles in infection progression. SARS-CoV-2 infection leads to insulin resistance and increased glycolysis, reducing glucose utilization and shifting metabolism to use fat as an energy source. Fat is crucial for viral replication, and imbalances in amino acid metabolism may interfere with immune regulation. Consequently, metabolic changes such as hyperglycemia, hypolipidemia, and deficiency of certain amino acids following SARS-CoV-2 infection can contribute to progression toward severe conditions. These metabolic pathways not only have potential value in prediction and diagnosis but also provide new perspectives for the development of therapeutic strategies. By monitoring metabolic changes, infection severity can be predicted early, and modulating these metabolic pathways may help reduce inflammatory responses, improve immune responses, and reduce the risk of thrombosis. Research on the relationship between metabolism and SARS-CoV-2 infection provides an important scientific basis for addressing the global challenge posed by COVID-19, however, further studies are needed to validate these findings and provide more effective strategies for disease control.

◆ACE-2-like Enzymatic Activity in COVID-19 Convalescent Patients with Persistent Pulmonary Symptoms Associated with Immunoglobulin【ScienceDirect　2025年2月13日】

Abstract

Many difficult to understand clinical features characterize COVID-19 and Post-Acute Sequelae of COVID-19 (PASC or Long COVID, LC). These can include blood pressure instability, hyperinflammation, coagulopathies, and neuropsychiatric complaints. The pathogenesis of these features remains unclear. The SARS-CoV-2 Spike protein Receptor Binding Domain (RBD) binds Angiotensin Converting Enzyme 2 (ACE2) on the surface of host cells to initiate infection. We hypothesized that some patients may produce anti-RBD antibodies that resemble ACE2 sufficiently to have ACE2-like catalytic activity, that is they are ACE2-like proteolytic abzymes that may help mediate the pathogenesis of COVID-19 and LC. In previous work, we showed that some acute COVID-19 patients had immunoglobulin-associated ACE2-like proteolytic activity, suggesting that some COVID-19 patients indeed produced ACE2-like abzymes. However, it remained unknown whether ACE2-like abzymes were seen only in acute COVID-19 patients or whether ACE2-like abzymes could also be identified in convalescent COVID-19 patients. Here we show that some convalescent COVID-19 patients attending a clinic for patients with persistent pulmonary symptoms also have ACE2-like abzymes and that the presence of ACE2-like catalytic activity correlates with alterations in blood pressure in an exercise test.

◆SARS-CoV-2 enhances complement-mediated endothelial injury via the suppression of membrane complement regulatory proteins【Taylor & Francis Online　2025年2月11日】

Abstract

Complement hyperactivation and thrombotic microangiopathy are closely associated with severe COVID-19. Endothelial dysfunction is a key mechanism underlying thrombotic microangiopathy. To address the relationship between endothelial injury, complement activation and thrombotic microangiopathy of severe COVID-19, we wonder whether, and if so, what and how SARS-CoV-2 factors make endothelial cells (ECs) sensitive to complement-mediated cytotoxicity. We revealed that multiple SARS-CoV-2 proteins enhanced complement-mediated cytotoxicity to ECs by inhibiting membrane complement regulatory proteins (CRPs) and enhancing the deposition of complement-recognizing component FCN1. By screening with CRISPR/Cas9-gRNA libraries, we identified that ADAMTS9, SYAP1, and HIGD1A as intrinsic regulators of CD59 on ECs, which were inhibited by the SARS-CoV-2 M, NSP16, and ORF9b proteins. IFN-γ, GM-CSF, and IFN-α upregulated CD55 and CD59, while IFN-γ antagonized the inhibition of CD59 by the three SARS-CoV-2 proteins. So, the deficiency of IFN-γ weakened the protection of ECs by CRPs against complement-mediated injury which may be enhanced during infection. Our findings illustrated the regulation of protection against complement-mediated attack on self-cells by SARS-CoV-2 infection and immune responses, providing insights into endothelial injury, thrombotic microangiopathy, and potential targets for treating severe COVID-19.

◆Prevalence of phalangeal bone marrow edema on MRI before and during the COVID-19 pandemic and correlation with chilblain skin lesions【National Library of Medicine　2023年4月11日】

Abstract

Objective

The purpose of this study is to establish the prevalence bone marrow edema of the phalanges of the feet and hands before and during the COVID-19 pandemic on MRI studies and correlate with clinically chilblain skin lesions and epidemiological data.

Methods

This observational retrospective study. In patients with confirmed bone marrow edema of the phalanges, epidemiological data and clinical findings were collected, including the history of current or remote COVID-19 infection and vaccination status. The two-proportion test was used to compare the frequency of bone marrow edema in the phalanges before and during the pandemic, and the comparison between the categories variables was performed using the one-proportion test.

Results

Of the total of 7215 patients, only 20 presented isolated bone marrow edema of the digits in MRI studies; 2 (0.05%) were found two years before the pandemic’s beginning, and 18 (0.64%) after the pandemic’s onset, demonstrating an increase of 13-fold in this period. 16 were women with a mean age of 40.3 years and 4 were men with a mean age of 53.5 years. The most frequently reported clinical symptoms by the patients were pain (85.0%), and erythema of the skin (45.0%). Of the 18 patients found after the pandemic’s onset, only 27.8% had COVID-19 infections confirmed by RT-PCR before the imaging study, and all cases were mild.

Conclusion

This study demonstrated a significant increase in the prevalence of bone marrow edema of the phalanges after the onset of the COVID-19 pandemic, particularly in middle-aged and younger women.

◆Non-Hospitalized Long COVID Patients Exhibit Reduced Retinal Capillary Perfusion: A Prospective Cohort Study【MDPI　2025年2月17日】

Abstract

The mechanism of post-acute sequelae of SARS-CoV-2 (PASC) is unknown. Using optical coherence tomography angiography (OCT-A), we compared retinal foveal avascular zone (FAZ), vessel density (VD), and vessel length density (VLD) in non-hospitalized Neuro-PASC patients with those in healthy controls in an effort to elucidate the mechanism underlying this debilitating condition. Neuro-PASC patients with a positive SARS-CoV-2 test and neurological symptoms lasting ≥6 weeks were included. Those with prior COVID-19 hospitalization were excluded. Subjects underwent OCT-A with segmentation of the full retinal slab into the superficial (SCP) and deep (DCP) capillary plexus. The FAZ was manually delineated on the full slab in ImageJ. An ImageJ macro was used to measure VD and VLD. OCT-A variables were analyzed using linear mixed-effects models with fixed effects for Neuro-PASC, age, and sex, and a random effect for patient to account for measurements from both eyes. The coefficient of Neuro-PASC status was used to determine statistical significance; p-values were adjusted using the Benjamani–Hochberg procedure. Neuro-PASC patients (N = 30; 60 eyes) exhibited a statistically significant (p = 0.005) reduction in DCP VLD compared to healthy controls (N = 44; 80 eyes). The sole reduction in DCP VLD in Neuro-PASC may suggest preferential involvement of the smallest blood vessels.

◆Unraveling the Co-Morbidity between COVID-19 and Neurodegenerative Diseases Through Multi-scale Graph Analysis: A Systematic Investigation of Biological Databases and Text Mining【bioRxiv　2025年2月14日】

Abstract

The COVID-19 pandemic has produced an overwhelming volume of research, yet much of it remains focused on individual diseases, largely ignoring the complex relationships between comorbidities. Although extensive literature exists on both neurodegenerative diseases (NDDs), namely Alzheimer’s and Parkinson’s, and COVID-19, their intersection remains underexplored. Co-morbidity modeling is essential, as patients, particularly those hospitalized, often present with multiple conditions. This study addresses this gap by investigating the crosstalk between COVID-19 and NDDs using a combination of knowledge graphs built from curated biomedical datasets and text mining tools. We conducted comprehensive graph analyses, including path analysis, phenotype coverage assessment, and mapping of cellular and genetic factors, to examine how various Knowledge Graphs (KGs)—such as PrimeKG, DrugBank, OpenTargets, and those generated from natural language processing (NLP) methodologies—illuminate molecular and phenotypic relationships between these diseases. Our findings reveal significant variability in graph density and connectivity across datasets, each offering unique insights into the landscape of COVID-19 and NDD co-morbidities. By integrating structured biological data with unstructured textual data, this study aimed to optimize co-morbidity modeling, maximize recall for identifying potential co-morbidity mechanisms, and consolidate this information in a dedicated co-morbidity hypothesis database. Key genetic and inflammatory markers, particularly immune response genes, emerged as consistent features across multiple KGs, reinforcing their potential role in COVID-19–NDD interactions. This integrative approach advances our understanding of the underlying mechanisms linking these diseases and facilitates the identification of potential therapeutic targets.