SARS-CoV-2 と COVID-19 に関する備忘録 Vol.38

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Long COVID impacting more than 1 million children: CDC study suggests【abc NEWS　2025年2月4日】

More than 1 million children may have been affected by long COVID as of 2023, new federal data published Monday suggests.

Long COVID, a condition that occurs when patients still have symptoms at least three months after clearing infection, has been well-documented in adults, but its impact on children has been less clear.

Researchers from two divisions within the Centers for Disease Control and Prevention looked at results from the 2023 National Health Interview Survey, a nationwide survey that monitors the health of the U.S. population.

One child aged 17 or under was randomly selected from each sample household within the survey, and parents responded to questions about whether their child had previous COVID-19 illness, if the child had symptoms lasting three months or longer and if the child still had those symptoms at the time of interview.

Results of the analysis, published in the journal JAMA Pediatrics, showed approximately 1.01 million children, or 1.4%, are believed to have ever experienced long COVID as of 2023 and about 293,000, or 0.4%, were experiencing the condition when the survey was being conducted.

This is similar to the 1.3%, or about 1 million, of children ever estimated to have had long COVID as of 2022, according to the authors.

Children between ages 12 and 17 were most likely to have ever experienced long COVID or to still have the condition. Long COVID prevalence was also higher among Hispanic and non-Hispanic white children compared to non-Hispanic Black and Asian children.

Long COVID was also most common among children with a family income of under $100,000 and of parents with an education level of an associate’s degree or less.

Among children currently experiencing long COVID at the time of interview, 80% reported to have some level of activity limitation compared with before they had COVID-19.

“The large proportion of children experiencing [long COVID] with any activity limitation highlights the need to examine the severity of activity limitation, functional outcomes, and days lost from school,” the authors wrote.

The authors said there may be an under-reporting of long COVID in younger children due to difficulty with the verbalization of their symptoms.

Long COVID most often occurs in people who had severe illness, but anyone can develop the condition, according to the CDC. People who are not vaccinated against COVID-19 are at higher risk of developing long COVID, the agency says.

Scientists are not sure what causes long COVID but have identified risk factors including having underlying conditions.

Research has also found that patients with long COVID tend to have lower cortisol levels and lower testosterone levels. Another theory is that virus particles may be persistently active, causing people to suffer long-term symptoms.

◆Co-infection of SARS‐CoV‐2 and influenza A/B among patients with COVID-19: a systematic review and meta-analysis【BMC Infectious Diseases　2025年1月31日】

Abstract

Background

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) is a public health problem and may result in co-infection with other pathogens such as influenza virus. This review investigates the co-infection of SARS-CoV-2 and influenza A/B among patients with COVID-19.

Methods

This meta- analysis included 38 primary studies investigating co-infection of SARS-CoV-2 with influenza in confirmed cases of COVID-19. The global online databases were used to identify relevant studies published between December 2019 and July 2024. Data analysis was performed using STATA Ver. 17 software, and standard errors of prevalence were calculated using the binomial distribution formula. Heterogeneity of study results was evaluated using the I-square and Q index, and publication bias was examined using the Begg’s and Egger’s tests, as well as funnel plot. A random effects model was used to determine prevalence rates, and a forest plot diagram was used to present results with 95% confidence intervals. In addition, sensitivity analyses were performed to check the impact of each primary study on the overall estimate.

Result

The analysis found that the prevalence of influenza in co-infected patients at 95% confidence interval using a random effect model was 14% (95% CI: 8–20%). Significant heterogeneity was observed in the random-effects model for influenza A, 11% (95% CI: 5-18%) and B, 4% (95% CI: 2-7%) in co-infected patients. The highest prevalence of influenza A/B (21%), influenza A (17%) and influenza B (20%) was shown in Asia and Europe respectively. Subgroup analysis by study year showed that the co-prevalence of COVID-19 and influenza A/B was similar in the pre-2021 and post-2021 time periods, at 14% (95% CI: 5-23%) for pre-2021 and 6-22% for 2021 and post-2021. Also, the overall prevalence of influenza A and B in COVID-19 patients is 11% and 4%, and there was no significant difference between the time periods before and after 2021. Meta-regression with a random-effects model showed that the variables location, year group, and total patients showed only 2.71% of very high heterogeneity (I² = 99.92%), and none of these variables had a significant effect on the co-prevalence of COVID-19 and influenza A/B (p > 0.05). Also, meta-regression results showed that these variables had no significant effect on influenza A and B prevalence (p > 0.05) and showed only a small proportion of the very high heterogeneity (I² = 99.72%), (I² = 68.78%). In our study, Egger’s test indicated that there was publication bias or small study effects in this meta-analysis (p = 0.0000).

Conclusion

The combination of SARS-CoV-2 with influenza and other respiratory viruses requires the best treatment protocols to reduce the severity of the disease. In this approach, high vaccination coverage against seasonal influenza and SARS-CoV-2 could reduce the risk of co-infection in the recent pandemic.

◆Cerebral Blood Flow in Orthostatic Intolerance【AHA Journals　2025年2月3日】

Abstract

Cerebral blood flow (CBF) is vital for delivering oxygen and nutrients to the brain. Many forms of orthostatic intolerance (OI) involve impaired regulation of CBF in the upright posture, which results in disabling symptoms that decrease quality of life. Because CBF is not easy to measure, rises in heart rate or drops in blood pressure are used as proxies for abnormal CBF. These result in diagnoses such as postural orthostatic tachycardia syndrome and orthostatic hypotension. However, in many other OI syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and long COVID, heart rate and blood pressure are frequently normal despite significant drops in CBF. This often leads to the incorrect conclusion that there is nothing hemodynamically abnormal in these patients and thus no explanation or treatment is needed. There is a need to measure CBF, as orthostatic hypoperfusion is the shared pathophysiology for all forms of OI. In this review, we examine the literature studying CBF dysfunction in various syndromes with OI and evaluate methods of measuring CBF including transcranial Doppler ultrasound, extracranial cerebral blood flow ultrasound, near infrared spectroscopy, and wearable devices.

◆SARS-CoV-2 Infection Association with Atherosclerotic Plaque Progression at Coronary CT Angiography and Adverse Cardiovascular Events【RSNA Radiology　2025年2月4日】

Abstract

Background

Patients with acute SARS-CoV-2 infection are reportedly at increased risk for future cardiovascular events; the mechanism underlying this risk remains unclear.

Purpose

To evaluate the impact of SARS-CoV-2 infection on coronary inflammation and plaques by using coronary CT angiography (CCTA) and the impact on clinical outcomes.

Materials and Methods

This retrospective analysis of a prospective study included consecutive patients who underwent serial CCTA between September 2018 and October 2023. The quantitative total and compositional percent atheroma volume (PAV) and annualized PAV change, presence of high-risk plaque, and attenuation of lesion-specific pericoronary adipose tissue (PCAT) at baseline and follow-up were compared between lesions in patients with and without SARS-CoV-2 infection. Relationships between SARS-CoV-2 infection and target lesion failure, which is a composite of cardiac death, target lesion myocardial infarction, and clinically driven target lesion revascularizations, were assessed with Cox models and log-rank tests.

Results

In 803 patients (mean age, 63.9 years ± 10.1 [SD]; 543 [67.6%] male patients), 2108 coronary artery lesions were evaluated in patients with SARS-CoV-2 infection (n = 690) and 480 coronary artery lesions were evaluated in patients without SARS-CoV-2 infection (n = 113). Compared with lesions in patients without SARS-CoV-2 infection, lesions in patients with SARS-CoV-2 infection demonstrated more rapid progression of overall PAV (0.90% per year ± 0.91 vs 0.62% per year ± 0.68, respectively; P < .001) and noncalcified PAV (0.78% per year ± 0.79 vs 0.42% per year ± 0.45, respectively; P < .001). The incidence of becoming high-risk plaque (21.0% [442 of 2108] vs 15.8% [76 of 480]; P = .03) and PCAT attenuation of −70.1 HU or higher (27.1% [571 of 2108] vs 19.8% [95 of 480]; P < .001) at follow-up was also greater in lesions in patients with SARS-CoV-2 infection (P < .001), despite similar prevalence at baseline. Lesions in patients with COVID-19 had a higher risk of target lesion failure (10.4% vs 3.1%, respectively; adjusted hazard ratio, 2.90; 95% CI: 1.68, 5.02; P < .001). Conclusion

SARS-CoV-2 infection was associated with a more rapid progression of lesion-based plaque volume and an increase in incidence of becoming high-risk plaque. Coronary plaques among patients who experienced COVID-19 were more prone to having an elevated risk of target lesion failure.

◆Exploring DNA methylation, telomere length, mitochondrial DNA, and immune function in patients with Long-COVID【BMC Medicine　2025年2月4日】

Abstract

Background

Long-COVID is defined as the persistency or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation. Common persistent symptoms are fatigue, sleep disturbances, post-exertional malaise (PEM), pain, and cognitive problems. Long-COVID is estimated to be present in about 65 million people. We aimed to explore clinical and biological factors that might contribute to Long-COVID.

Methods

Prospective longitudinal cohort study including patients infected with SARS-CoV-2 between March 2020 and March 2022. Patients were assessed between 4 and 12 months after infection at the COVID follow-up clinic at UZ Leuven. We performed a comprehensive clinical assessment (including questionnaires and the 6-min walking test) and biological measures (global DNA methylation, telomere length, mitochondrial DNA copy number, inflammatory cytokines, and serological markers such as C-reactive protein, D-dimer, troponin T).

Results

Of the 358 participants, 328 were hospitalised, of which 130 had severe symptoms requiring intensive care admission; 30 patients were ambulatory referrals. Based on their clinical presentation, we could identify 6 main clusters. One-hundred and twenty-seven patients (35.4%) belonged to at least one cluster. The bigger cluster included PEM, fatigue, sleep disturbances, and pain (n = 57). Troponin T and telomere shortening were the two main markers predicting Long-COVID and PEM-fatigue symptoms.

Conclusions

Long-COVID is not just one entity. Different clinical presentations can be identified. Cardiac involvement (as measured by troponin T levels) and telomere shortening might be a relevant risk factor for developing PEM-fatigue symptoms and deserve further exploring.

◆Exploring DNA methylation, telomere length, mitochondrial DNA, and immune function in patients with Long-COVID【Science Signaling　2025年1月21日】

Abstract

Activation of the stimulator of interferon genes (STING) pathway by cytosolic DNA leads to the activation of the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB). Although many viruses produce proteins that inhibit IRF3-dependent antiviral responses, some viruses produce proteins that inhibit STING-induced NF-κB activation without blocking IRF3 activation. Here, we found that STING-activated, NF-κB–dependent, and IRF3-independent innate immunity inhibited the replication of the DNA virus herpes simplex virus type 1 (HSV-1), the RNA virus coxsackievirus A16 (CV-A16), and the retrovirus HIV-1. The HIV-1 nonstructural protein Vpu bound to STING and prevented it from interacting with the upstream NF-κB pathway kinase inhibitor of NF-κB subunit β (IKKβ), thus blocking NF-κB signaling. This function of Vpu was conserved among Vpu proteins from diverse HIV-1 and simian immunodeficiency virus strains and was distinct from its action in disrupting other host antiviral pathways. Furthermore, the ORF3a protein from the coronavirus SARS-CoV-2 also promoted viral replication by interacting with STING and blocking STING-induced activity of NF-κB but not of IRF3. These findings demonstrate that diverse viral proteins have convergently evolved to selectively inhibit NF-κB–mediated innate immunity downstream of STING activation, suggesting that targeting this pathway may represent a promising antiviral strategy.

◆Thyroid function during COVID-19 and post-COVID complications in adults: a systematic review【Frontiers in Endocrinology　2025年2月4日】

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has presented multifaceted health challenges. COVID-19 primarily targets the respiratory system but also affects multiple organ systems, including the endocrine system. Emerging evidence suggests interactions between thyroid function, the acute phase of COVID-19, and the prolonged symptoms known as post-COVID sequalae or long COVID. Several studies have reported that COVID-19 can induce thyroid dysfunction, leading to conditions such as thyroiditis and alterations in thyroid hormone levels. The mechanisms through which SARS-CoV-2 affects the thyroid include direct viral infection of thyroid cells, leading to viral thyroiditis, which causes inflammation and transient or sustained thyroid dysfunction, as well as an excessive systemic immune response (cytokine storm). This is associated with elevated levels of cytokines, such as IL-6, that disrupt thyroid function and lead to nonthyroidal illness syndrome (NTIS). Medications administered during the acute illness phase, such as corticosteroids and antiviral drugs, can also impact thyroid hormone actions. The involvement of the thyroid gland in long COVID, or postacute sequelae of SARS-CoV-2 infection, is an area not well defined, with potential implications for understanding and managing this condition. Persistent low-grade inflammation affecting thyroid function over time can lead to ongoing thyroiditis or exacerbate pre-existing thyroid conditions. Viral infections, including SARS-CoV-2, can trigger or worsen autoimmune thyroid diseases, such as Hashimoto’s thyroiditis and Graves’ disease. Long COVID may disrupt the hypothalamic–pituitary–adrenal (HPA) axis, which can, in turn, affect the hypothalamic-pituitary-thyroid (HPT) axis, leading to abnormal thyroid function. This review was designed to systematically capture recent literature on COVID-19-related thyroid dysfunction in the adult population, the prognostic consequences of thyroid dysfunction during COVID-19, and the effects of thyroid dysfunction on patients with long COVID. A comprehensive search of PubMed and EMBASE databases was conducted. The systematic review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Study quality was assessed using the Critical Appraisal Skills Programme (CASP). A total of 53 studies met the inclusion criteria. The review summarises recent findings and provides an update of the current understanding of thyroid dysfunction in COVID-19-related spectrum of disorders, underscoring the complex nature of SARS-CoV-2 infection and its far-reaching impacts on human health.

◆Chronic autonomic symptom burden in long-COVID: a follow-up cohort study【SPRINGER NATURE　2025年2月5日】

Abstract

Purpose

Autonomic dysfunction is a common and often debilitating feature of long-COVID (LC), however, studies evaluating frequency and severity of chronic autonomic dysfunction in LC are limited. We utilized an established online cohort of participants with LC to assess duration and severity of autonomic dysfunction, impact on quality of life, risk factors of autonomic diagnoses including postural tachycardia syndrome (POTS), and efficacy of common treatments.

Methods

Our international cohort included 526 adults with LC aged 20–65 years who previously completed baseline evaluations of LC symptoms, autonomic symptom burden, and quality of life. Participants repeated survey instruments and completed new instruments assessing risk factors and symptom mitigation strategies. A subset of individuals completed a 10-min active stand test. Multivariable logistic regression identified predictors of autonomic symptom burden and incident autonomic diagnoses including POTS.

Results

A total of 71.9% of participants with LC had a Composite Autonomic Symptom Score-31 (COMPASS-31) score ≥ 20, suggestive of moderate-to-severe autonomic dysfunction. The median symptom duration was 36 [30–40] months, and 37.5% of participants could no longer work or had to drop out of school due to their illness. In addition, 40.5% of individuals with autonomic dysfunction were newly diagnosed with POTS, representing 33% of the total LC cohort. Female sex and joint hypermobility were associated with an increased risk of autonomic dysfunction.

Conclusions

Evidence of chronic moderate-to-severe autonomic dysfunction was seen in most participants with LC in our cohort and was significantly associated with reduced quality of life and functional disability. POTS was the most common post-COVID autonomic diagnosis.

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

Abstract

Background

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

Methods

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

Results

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

Conclusions

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

◆Long COVID Incidence Proportion in Adults and Children Between 2020 and 2024: An Electronic Health Record-Based Study From the RECOVER Initiative【THE LANCET eClinicalMedicine　2023年2月27日】

Summary

Background

We aimed to characterise the long-term health outcomes of survivors of severe acute respiratory syndrome (SARS) and determine their recovery status and possible immunological basis.

Methods

We performed a clinical observational study on 14 health workers who survived SARS coronavirus infection between Apr 20, 2003 and Jun 6, 2003 in Haihe Hospital (Tianjin, China). Eighteen years after discharge, SARS survivors were interviewed using questionnaires on symptoms and quality of life, and received physical examination, laboratory tests, pulmonary function tests, arterial blood gas analysis, and chest imaging. Plasma samples were collected for metabolomic, proteomic, and single-cell transcriptomic analyses. The health outcomes were compared 18 and 12 years after discharge. Control individuals were also health workers from the same hospital but did not infect with SARS coronavirus.

Findings

Fatigue was the most common symptom in SARS survivors 18 years after discharge, with osteoporosis and necrosis of the femoral head being the main sequelae. The respiratory function and hip function scores of the SARS survivors were significantly lower than those of the controls. Physical and social functioning at 18 years was improved compared to that after 12 years but still worse than the controls. Emotional and mental health were fully recovered. Lung lesions on CT scans remained consistent at 18 years, especially in the right upper lobe and left lower lobe lesions. Plasma multiomics analysis indicated an abnormal metabolism of amino acids and lipids, promoted host defense immune responses to bacteria and external stimuli, B-cell activation, and enhanced cytotoxicity of CD8+ T cells but impaired antigen presentation capacity of CD4+ T cells.

Interpretation

Although health outcomes continued to improve, our study suggested that SARS survivors still suffered from physical fatigue, osteoporosis, and necrosis of the femoral head 18 years after discharge, possibly related to plasma metabolic disorders and immunological alterations.

Funding

This study was funded by the Tianjin Haihe Hospital Science and Technology Fund (HHYY-202012) and Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-063B, TJYXZDXK-067C).

◆Prevalence of cardiovascular symptoms in post-acute COVID-19 syndrome: a meta-analysis【BMC Medicine　2025年2月6日】

Abstract

Background

Since its emergence in 2019, COVID-19 has continued to pose significant threats to both the physical and mental health of the global population, as well as to healthcare systems worldwide (Raman et al., Eur Heart J 43:1157–1172, 2022). Emerging evidence indicates that COVID-19 may lead to post-acute COVID-19 syndrome (PACS) with cardiovascular implications, potentially driven by factors such as ACE2 interaction with viruses, systemic inflammation, and endothelial dysfunction. However, there remains a limited amount of research on the cardiovascular manifestations of PACS, which may delay the development of optimal treatment strategies for affected patients. Therefore, it is crucial to investigate the prevalence of cardiovascular sequelae in COVID-19 patients and to determine whether COVID-19 infection acts as an independent risk factor for these outcomes.

Methods

This meta-analysis adhered to PRISMA guidelines and was registered in PROSPERO (CRD42024524290). A systematic search of PubMed, Embase, and the Cochrane Library was conducted up to March 17, 2024. The primary outcomes included hypertension, palpitations, and chest pain, with pooled effect estimate reported as proportions and odds ratios (ORs) with 95% confidence intervals (CIs). Sensitivity and subgroup analysis were performed to assess the robustness of the results and to identify sources of heterogeneity.

Results

A total of 37 studies, encompassing 2,965,467 patients, were included in the analysis. Pooled results from case–control studies revealed that, compared to the control group, the ORs of chest pain in the COVID-19 group was 4.0 (95% CI: 1.6, 10.0). The ORs for palpitation and hypertension were 3.4 (95% CI: 1.1, 10.2) and 1.7 (95% CI: 1.6, 1.8), respectively. The proportions of PACS patients experiencing chest pain, palpitation, and hypertension as sequelae were 22% (95% CI: 14%, 33%), 18% (95% CI: 13%, 24%), and 19% (95% CI: 12%, 31%), respectively.

Conclusions

Our findings indicate that 15% of COVID-19 patients experience cardiovascular sequelae. Furthermore, COVID-19 infection significantly increases the likelihood of developing these sequelae compared to uninfected individuals. Future research should prioritize investigating the underlying pathological mechanisms and developing targeted preventive and management strategies.

◆Prevalence of cardiovascular symptoms in post-acute COVID-19 syndrome: a meta-analysis【nature　2025年2月5日】

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly evolved over short timescales, leading to the emergence of more transmissible variants such as Alpha and Delta1. The arrival of the Omicron variant marked a major shift, introducing numerous extra mutations in the spike gene compared with earlier variants. These evolutionary changes have raised concerns regarding their potential impact on immune evasion, disease severity and the effectiveness of vaccines and treatments. In this epidemiological study, we identified two distinct patterns in the protective effect of natural infection against reinfection in the Omicron versus pre-Omicron eras. Before Omicron, natural infection provided strong and durable protection against reinfection, with minimal waning over time. However, during the Omicron era, protection was robust only for those recently infected, declining rapidly over time and diminishing within a year. These results demonstrate that SARS-CoV-2 immune protection is shaped by a dynamic interaction between host immunity and viral evolution, leading to contrasting reinfection patterns before and after Omicron’s first wave. This shift in patterns suggests a change in evolutionary pressures, with intrinsic transmissibility driving adaptation pre-Omicron and immune escape becoming dominant post-Omicron, underscoring the need for periodic vaccine updates to sustain immunity.