SARS-CoV-2 と COVID-19 に関する備忘録 Vol.42

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Five years later, COVID-19 continues to leave its mark on Albertans【CBC : Jennifer Lee　2025年3月5日】

Five years after the province identified its first COVID-19 case, Albertans are being urged not to lose sight of those still struggling with its devastating impacts.

In a moment few Albertans will forget, Dr. Deena Hinshaw — Alberta’s then chief medical officer of health — took to the podium on March 5, 2020, to announce that a woman in her 50s had tested positive after returning from a cruise.

It was the province’s first presumptive COVID-19 case.

Since then, 6,691 Albertans have died due to the illness. And while deaths and hospitalizations have dropped significantly, COVID-19 continues to kill hundreds of Albertans every year.

“This is not a disease that has come and gone. It’s unfortunately something that’s left its mark on Alberta,” said Craig Jenne, professor in the department of microbiology, immunology and infectious diseases at the University of Calgary.

“The pandemic has ended but, unfortunately, the endemic stage has now begun. And this is a virus that we’re going to have to deal with basically every year moving forward.”

And while many expected SARS-CoV-2 would eventually become a seasonal virus, similar to influenza, that hasn’t truly happened.

“It’s not like the flu,” said Sarah Otto, a professor at the University of British Columbia who specializes in mathematical modelling.

“It’s so transmissible and so easy to get that people are getting it … multiple times a year.”

Otto, an evolutionary biologist, is one of several Canadian scientists tracking COVID-19 variants.

“We’re not seeing it go away in the summer. It goes through these little undulations as new variants evolve and we see a little uptick. But then people’s immunity builds and it goes down again. And that’s happening year after year.”

Prior to the pandemic, the leading cause of death due to infectious diseases in Canada was influenza, according to Jenne.

That has changed.

“Last year alone, COVID killed more than four times as many Albertans as flu,” said Jenne, who is also the deputy director of the Snyder Institute for Chronic Diseases.

“[It] continues to be a significant threat to people that have underlying health conditions, older and — to a certain extent — younger Albertans.”

Long COVID continues

And the pandemic has left another mark: long COVID.

Estimates about its prevalence vary, but according to a national survey involving Statistics Canada and the Public Health Agency of Canada, 19 per cent of Canadians infected with SARS-CoV-2 reported experiencing long-term symptoms (for three or more months) in 2023.

“As of June 2023, about 100,000 Canadian adults have been unable to return to work or school because of their symptoms,” the report said.

The most common symptoms reported are fatigue, brain fog and shortness of breath.

But other problems can occur as well, according to doctors, including uncontrolled and rapid increases in heart rate, known as tachycardia. It can be triggered by activities as simple as standing up and walking into another room.

Prior to the pandemic, Dr. Satish Raj, a Calgary-based cardiologist, was already treating patients with similar problems after viral infections. The condition is known as POTS.

“What was different about COVID wasn’t that this type of thing had never happened before, but that it had never happened before on the scale, societally, as it happened with COVID,” said Raj, a University of Calgary professor and medical director of the Calgary autonomic investigation and management clinic.

He estimates five to 10 per cent of Albertans have ongoing symptoms after a COVID infection, and up to two per cent are so debilitated they can’t go to work or school.

His waitlist has grown since COVID-19 hit and is now close to two years.

“In our desire to move on and get past it, I think we’re forgetting some of the people who have been wounded by it,” said Raj.

“We’re not necessarily showing a commitment to providing the resources to help them to continue to be part of society.”

Last year, Alberta Health Services shuttered its long COVID outpatient program, which provided multi-disciplinary specialized care.

Care is less co-ordinated now, said Raj.

“I think there’s a major domino effect by getting rid of those clinics — not just for the patients for whom they’re caring — but as an information resource for physician and providers.”

In a statement, Alberta Health Services said most people can manage symptoms at home and people should start by contacting their primary care provider or Health Link for support.

Meanwhile, with testing no longer easily accessible to the public, confirming a diagnosis of long COVID is increasingly difficult, according to Dr. Grace Lam, a University of Alberta respirologist.

“It makes it really quite challenging to pin down how many Albertans are still suffering with this or are newly developing this at this point.”

Lam, who also treats long COVID patients, worries about people being infected multiple times.

“With repeated infections, your risk of long COVID does increase,” she said.

But there is hope, according to Lam, who said clinical trials are exploring treatment options.

Meanwhile, reflecting on the past five years, Jenne pointed to what he sees as key achievements, including global surveillance and co-operation that led to the rapid development and deployment of vaccines.

“We were able to dramatically impact the number of lives lost,” he said.

“There’s a lot of lessons in there as we move forward knowing that, unfortunately, it’s only a matter of time before another virus shows up and creates a significant public health threat.”

◆Structural brain changes in post-COVID condition and its relationship with cognitive impairment【ABC 7 NewYork　2025年3月14日】

NEW YORK (WABC) — March marks five years since the COVID-19 virus took hold in the New York City metropolitan area, leading to a lockdown and tens of thousands of deaths.

While the world might not be in a global pandemic anymore, Sean Clarke, a professor of nursing leadership at New York University, said COVID is still a constant presence.

“The virus is still persistent and still moving. It’s still not a trivial thing,” Clarke told ABC News. “It hasn’t vanished, it’s just at a different point.”

Since 2020, over 7 million lives have been lost to the virus, according to the World Health Organization. And lives continue to be lost.

There have been more than 3,000 COVID-19 deaths over the last 28 days, with U.S. accounting for 2,700 of those deaths, according to WHO.

While COVID-19 vaccines are available for adults and children, vaccination rates are low. As of February 22, fewer than 25% of adults were vaccinated with the updated 2024-25 COVID-19 vaccine, according to the Centers for Disease Control and Prevention.

In addition to active COVID-19 cases, many patients have reported experiencing long COVID-19, where symptoms continue for years after the initial infection. According to the Mayo Clinic, some researchers have estimated that 10% to 35% of people who have had COVID-19 went on to have long COVID.

Symptoms of COVID

The following list from the Centers for Disease Control and Prevention does not include all possible symptoms. Symptoms may change with new COVID-19 variants and can vary depending on vaccination status. Possible symptoms include:

Fever or chills
Cough
Shortness of breath or difficulty breathing
Sore throat
Congestion or runny nose
New loss of taste or smell
Fatigue
Muscle or body aches
Headache
Nausea or vomiting
Diarrhea

COVID isolation guidelines

COVID-19’s health impacts are now similar to other respiratory viruses, like flu, which are also important causes of illness and death, especially for people at higher risk. As a result, the CDC has shifted to unified Respiratory Virus Guidance, rather than additional guidance for each specific virus.

The updated Respiratory Virus Guidance recommends that people stay home and away from others until at least 24 hours after both their symptoms are getting better overall, and they have not had a fever (and are not using fever-reducing medication).

Frequently Asked Questions about COVID

Here are answers to what doctors say are some of the most common questions they still get about COVID-19 – and a few questions they wish they were hearing more often.

Do I really need another vaccination?

It’s the most common question Lee gets from patients and families, and one Dr. Susan Fuchs, an attending physician in the emergency department at the Ann and Robert H. Lurie Children’s Hospital, hears variations of.

Some people ask her, “Is a vaccine worth it?” The answer is yes, said Fuchs, who also is a professor of pediatrics at the Feinberg School of Medicine at Northwestern University in Chicago.

Fuchs acknowledged that the vaccines don’t stop every case – she’s been vaccinated and had COVID-19 twice herself. But vaccines protect against severe illness, hospitalization and death, according to the Centers for Disease Control and Prevention, which recommends vaccination for everybody 6 months or older.

Are COVID-19 vaccines safe?

Fuchs wishes more people would come to her with their worries about vaccine safety and side effects. Most people, she said, endure little more than a sore arm or a low-grade fever. Other common side effects include muscle pain, joint pain, fatigue, headache or chills.

“There are minor side effects with most vaccines,” Fuchs said. “But it’s better than getting the actual illness.”

The approved vaccines are still being monitored, she said. And “right now, we’re saying it’s a safe vaccine – no matter which one you get from whichever company.”

Who has the answers about boosters or other concerns?

Fuchs said that while people don’t ask about the emergence of different COVID-19 variants the way they once did, people can easily become confused about how often they need their vaccination updated.

Her advice: “Go to your family doctor.”

Lee said it’s easy for people to feel overwhelmed when there are “so many different sources coming at you all at once.” She regularly hears from patients or family members who have a concern they’ve heard from friends or at church or read online that they want to check with her. “I absolutely love and welcome those conversations,” she said.

Will I ever get better?

Most of the patients Hsu interacts with have long COVID, an assortment of symptoms that continue four weeks or more after the initial infection. People who have it ask him, “Is this going to shorten my life? Do people get better?”

Researchers don’t have all the answers to that, Hsu said. But large numbers of people – many of them previously young, active and healthy – “are now effectively disabled because of long COVID.”

Some people with long COVID – maybe a third – have gotten better, he said, but “I think the majority of people are still dealing with ongoing symptoms and are nowhere near back toward their baseline.”

Researchers are learning how the virus can persist in the body for years, Hsu said, and they’ve seen hints that abnormal blood clotting may be at the root of some problems.

He’s hopeful that treatments will be found, but at the moment, the answers about long COVID remind him of how doctors felt at the start of the pandemic. “We want to help, but we don’t have effective therapies to help just yet.”

He wishes more people were asking questions about how to limit the spread of the virus. People who have had a mild case of COVID-19 might not be as afraid of getting reinfected, Hsu said.

But risks of heart disease, stroke, high blood pressure and other conditions increase after an infection, he said. And each infection could become severe or lead to long COVID.

He emphasized how serious long COVID can be. Some of his patients are formerly high-energy, highly accomplished people who now are so drained that they can’t get out of bed to come to his clinic. “I can only see them virtually, and it’s just devastating.”

How can I protect myself and the people around me?

Like Hsu, Lee said she wished she heard this question more often.

“Even before COVID, this would come up with the flu shot,” Lee said. “Young, healthy people would say, ‘Well, you know, I don’t really get too sick from the flu. I don’t really have to worry about it.’ And my plea was always, ‘Well, think about your grandmother or your neighbor, or the person who you work with,'” or someone who cares for a child with a disability at home.

According to the CDC, age is the strongest risk factor for severe COVID-19, and the risk grows higher the older someone gets. Other high-risk groups include people with underlying conditions such as heart disease, people on dialysis and those with suppressed immune systems.

Staying up to date with vaccinations is one important way to protect them, Hsu said.

“I’m not one who just blindly says everyone should get a vaccine,” he said. “I do understand everyone has their own approach to weighing the risks and benefits of the vaccine. My concern is that the risks of the vaccine are real but have been overstated by influential voices on social media.”

Beyond vaccines, Lee said that advice from the pandemic’s peak on limiting the spread of the virus holds up. “If you’re sick, stay home. If somebody is sick, don’t let them come visit you.”

She acknowledged the importance of staying socially connected, especially for older people. “I do want people to visit their older adults in their lives and spend time with them and pick up the phone and talk with them, because I think the flip side to people being too cautious or too scared about getting someone sick is the social isolation.”

But, she added, “I want them to do it safely, when everyone’s feeling good.”

COVID-19 and the flu are similar in that some people might dismiss them if they’ve had only mild cases in the past, Lee said. But both can be deadly. And even when they aren’t fatal, a case of either that requires hospitalization can have many unintended consequences, especially for older adults, sometimes leading to lasting disability.

“That’s something a lot of people don’t consider,” Lee said, “and it’s not something most people want to face.”

Fuchs said parents should not send their children back to school until they have been fever-free for 24 hours without medication. And she still wears a mask at work because she doesn’t want to spread COVID-19 from patient to patient.

Hsu’s recommendation is “if it’s clear that cases are rising, then it may be a good time to be more mindful about wearing a mask in public” and to make sure large gatherings are held either outdoors or in a well-ventilated area.

“I also think it’s really important to take care of ourselves and our bodies better,” Hsu said, with a healthy diet, regular exercise and medical checkups. “I do think that these measures can make us more resilient to an infection.”

Lee seconded Hsu’s advice for getting up to date with any routine health screenings that might have been delayed during the pandemic. That can be a good time to raise whatever COVID-19 concerns someone might have, she said.

“It’s stressful to try to make sense of all the things that you hear or read,” Lee said, but there’s an easy way to avoid that stress over health concerns. “Pick up the phone and make an appointment.”

◆Analysis of risk factors for long COVID after mild COVID-19 during the Omicron wave in Japan【ScienceDirect　2025年3月5日】

Abstract

Background

Post-COVID-19 syndrome, referred to as “long COVID,” is characterized by persistent symptoms that develop during or after SRAS-CoV-2 infection lasting for ≥12 weeks, which cannot be explained by factors other than COVID-19. Previous studies before the Omicron pandemic have identified female sex, older age (≥50 years), severity of illness, obesity, diabetes, and smoking as risk factors for long COVID. However, data on long COVID following the emergence of the Omicron variants are limited.

Methods

An online survey was conducted among outpatients diagnosed with mild COVID-19 at 14 participating institutions in Japan between July 30, 2022, and December 31, 2023.

Results

Of the included 246 cases, 76 (35.5%) experienced at least one long COVID symptom 12 weeks after onset. Logistic regression analysis revealed that age ≥40 years was significantly associated with an increased risk of respiratory (odds ratio [OR]: 3.80, 95% confidence interval [CI]: 1.67–8.65) and neurologic symptoms (OR: 4.53, 95% CI: 1.84–11.13). Conversely, antiviral drug use was associated with a decreased risk of respiratory symptoms (OR: 0.31, 95% CI: 0.11–0.93).

Conclusion

Caution is warranted when treating patients over 40 years of age with mild COVID-19 due to their higher susceptibility to developing long COVID. Antiviral drugs may be beneficial in managing respiratory symptoms and mitigating disease severity.

◆mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS【BMC Journal of Translational Medicine　2025年3月10日】

Abstract

Post-acute SarS-Cov2 (PASC), Myalgia encephalomyelitis/Chronic fatigue syndrome (ME/CFS) and Post-acute infection syndrome (PAIS) consist of chronic post–acute infectious syndromes, sharing exhaustive fatigue, post exertional malaise, intermittent pain, postural tachycardia and neuro-cognitive-psychiatric dysfunction. However, the concerned shared pathophysiology is still unresolved in terms of upstream drivers and transducers. Also, risk factors which may determine vulnerability/progression to the chronic phase still remain to be defined. In lack of drivers and a cohesive pathophysiology, the concerned syndromes still remain unmet therapeutic needs. ‘mTORC1 Syndrome’ (TorS) implies an exhaustive disease entity driven by sustained hyper-activation of the mammalian target of rapamycin C1 (mTORC1), and resulting in a variety of disease aspects of the Metabolic Syndrome (MetS), non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, some cancers, neurodegeneration and other [Bar-Tana in Trends Endocrinol Metab 34:135–145, 2023]. TorS may offer a cohesive insight of PASC, ME/CFS and PAIS drivers, pathophysiology, vulnerability and treatment options.

◆mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS【nature : acta pharmacologica sinica　2025年3月11日】

Abstract

SARS-CoV-2 can encode circular RNAs (circRNAs); however, the potential effects of exogenous SARS-CoV-2 circRNAs on cardiovascular sequelae remain unknown. Three circRNAs derived from the nucleocapsid (N) gene of SARS-CoV-2, namely, circSARS-CV2-Ns, were identified for functional studies. In particular, circSARS-CV2-N1368 was shown to enhance platelet adhesiveness to endothelial cells (ECs) and inhibit EC-dependent vascular relaxation. Moreover, exogenous expression of circSARS-CV2-N1368 suppressed EC proliferation and migration and decreased angiogenesis and cardiac organoid beating. Mechanistically, we elucidated that circSARS-CV2-N1368 sponged the microRNA miR-103a-3p, which could reverse circSARS-CV2-N1368-induced EC damage. Additionally, activating transcription factor 7 (ATF7) was identified as a target gene of miR-103a-3p, and Toll-like receptor 4 (TLR4) was verified as a downstream gene of ATF7 that mediates circARS-CV2-N1368-induced activation of nuclear factor kappa B (NF-κB) signaling and ROS production in ECs. Importantly, the reactive oxygen species (ROS) scavenger NAC mitigated the circSARS-CV2-N1368-promoted EC impairment. Our findings reveal that the TLR4/NF-κB/ROS signal pathway is critical for mediating circSARS-CV2-N1368-promoted oxidative damage in ECs, providing insights into the endothelial impairment caused by circSARS-CV2-Ns.

◆SARS-CoV-2 Infects Peripheral Sensory Neurons and Promotes Axonal Degeneration via TRPV1 Activation【bioRxiv　2025年3月10日】

Summary

Common neurological symptoms of COVID-19, such as anosmia, headaches, and cognitive dysfunction, depend on interactions between the peripheral and central nervous systems. However, the molecular mechanisms by which SARS-CoV-2 affects the peripheral nervous system remain poorly understood, with ongoing debate about whether sensory neurons can be directly infected by the virus. In this study, human iPSC-derived sensory neurons were exposed to the SARS-CoV-2 BA.5 variant, a mutant virus, or viral S1 proteins. Under control conditions, sensory neurons exhibited low expression of ACE2. However, exposure to BA.5 or S1 proteins significantly upregulated ACE2 expression in peripherin-positive sensory neurons. Virological analysis confirmed that SARS-CoV-2 directly infects TRPV1-expressing sensory neurons, including olfactory neurons. Moreover, exposure to the live virus or S1 proteins induced TRPV1 upregulation and translocation from the nucleus to the cytosol, resulting in axonal destruction. Single-nucleus transcriptomic analysis revealed that viral exposure enhanced cAMP signaling, virus receptor and transmembrane transporter activities, and inflammatory regulation of TRP channels, which collectively contributed to synaptic and axonal damage. Importantly, treatment with a TRPV1 antagonist demonstrated neuroprotective effects. These findings underscore the need for further research into the interaction between SARS-CoV-2 and TRPV1, as well as its downstream signaling pathways, to develop therapeutic strategies for preventing sensory neuron loss during viral infections.

◆Spatial transcriptomics of the epipharynx in long COVID identifies SARS-CoV-2 signalling pathways and the therapeutic potential of epipharyngeal abrasive therapy【nature scientific reports　2025年3月12日】

Abstract

In this study, the critical role of the epipharynx in managing long-term coronavirus disease 2019 (COVID-19), and in particular, how residual SARS-CoV-2 RNA affects signalling pathways in the epipharynx were investigated via spatial gene expression analysis (Visium HD). Moreover, we hypothesize that epipharyngeal abrasive therapy (EAT) targeting the epipharynx could improve long COVID symptoms by modulating local inflammation and gene expression. We conducted a comparative analysis of the gene expression profiles of three patients with long COVID and two control individuals without COVID-19. Residual SARS-CoV-2 RNA was detected in the epipharynx of patients with long COVID, along with the activation of signalling pathways in epithelial and immune cells. After EAT, the viral RNA was either completely cleared or significantly reduced. T-cell receptor signalling pathways were suppressed; the levels of proinflammatory cytokines, such as interleukin-6 and tumour necrosis factor-α, were reduced; and excessive antibody production was mitigated. Histology showed that EAT effectively eliminated the inflamed, dysfunctional ciliated epithelium. This study clarifies that SARS-CoV-2 has long-term effects on the immune response in the epipharynx, emphasizing the need to focus on chronic epipharyngitis as a potential cause of long COVID. Furthermore, EAT may offer a promising approach to alleviating persistent long COVID symptoms.

◆Neuroimaging findings in children with COVID-19 infection: a systematic review and meta-analysis【nature scientific reports　2025年2月27日】

Abstract

The COVID-19 pandemic has impacted individuals differently, and there’s been a growing body of evidence pointing to neurological complications caused by the virus. However, our understanding of the range of neurological issues linked to SARS-CoV-2 infection in children is limited. This systematic review and meta-analysis aimed to assess the abnormal neuroimaging findings in pediatric COVID-19 patients, shedding light on this crucial aspect of the disease’s impact on children. We conducted an extensive search in the PubMed, Medline, and ScienceDirect databases for observational studies reporting neuroimaging findings of the brain and spinal cord in children with COVID-19 between December 1, 2019, and October 30, 2021. Grey literature sources, including medRxiv and Google Scholar, were also explored. Pooled proportions of abnormal neuroimaging findings, categorized into neurovascular findings, ADEM-like lesions, encephalitic pattern, myelitis, transient splenial lesions, and other anomalies, were calculated using a random-effects model. Between-study heterogeneity was assessed using the χ2 statistic for pooled proportions and the inconsistency index I2. The Quality of the studies was evaluated using the NIH Quality Assessment Tool and the adapted Newcastle–Ottawa Scale. Our search yielded 9,605 articles, with 96 studies (involving 327 pediatric patients) included in the qualitative analysis. Of these, five reports (encompassing 111 patients) underwent quantitative analysis. The pooled proportion of pediatric COVID-19 patients with neurological symptoms and exhibiting abnormal neuroimaging findings was 43.74%. These findings were further categorized into neurovascular findings (8.22%), ADEM-like lesions (7.69%), encephalitic pattern (13.95%), myelitis (4.60%), transient splenial lesions (16.26%), and other abnormalities (12.03%). Insignificant between-study heterogeneity was observed in all categories, and our analysis did not reveal significant publication bias. In conclusion, a substantial proportion of pediatric COVID-19 patients with neurological symptoms have abnormal neuroimaging findings, underscoring the need for vigilant monitoring of neurological complications in this vulnerable population. Standardized reporting and long-term follow-up studies are essential to fully understand the implications of these findings. Collaborative research efforts will deepen our understanding of COVID-19’s neurological dimensions in children and enhance clinical care for this population.

◆Post-Acute SARS-CoV-2 Antigenemia Is Associated With Some but Not All Long COVID Symptoms【CROI　2025年3月12日】

Abstract

Background

SARS-CoV-2 (SCV2) RNA and antigens can be found in several tissues many months after infection, but whether SCV2 persistence causes Long COVID (LC) is unproven. The scant data in favor of causation has related persistent SCV2 to non-specific LC definitions. It is unknown whether persistent SCV2 is associated with all, or only some, of the different symptoms of this heterogenous condition.

Methods

Sampling from UCSF’s LIINC cohort, we defined 5 LC case groups and 1 non-LC control group. Consistent with the NASEM definition, LC groups had ≥1 symptom in a given grouping that was rated “very bothersome” at ≥2 visits 3-14 months after the first confirmed SCV2 infection. LC case groups were: a) neurologic (headache, brain fog or dizziness); b) cardiopulmonary (cough, dyspnea, chest pain or palpitations); c) gastrointestinal (GI; nausea, vomiting, diarrhea, constipation, belly pain or appetite loss); d) musculoskeletal (back, joint or muscle pain); and e) fatigue. The non-LC group was those whose acute symptoms resolved within 30 days of infection and who had no symptoms 3-14 months post-infection. SCV2 spike, S1, and nucleocapsid (N) antigens were measured in plasma by single molecule array (Simoa) assay. Odds ratios (OR) were used to relate antigenemia at any visit 3-14 months post-infection to concurrent symptoms.

Results

Spike antigenemia was found in 7.5% (3/40) of the non-LC group. In unadjusted analyses, spike antigenemia was associated with neurologic, cardiopulmonary, and musculoskeletal symptoms but not GI or fatigue (Table). After adjustment for confounding, associations endured for neurologic (OR 4.5, p=0.037), cardiopulmonary (OR 4.8, p=0.08), and musculoskeletal (OR 5.5, p=0.049) symptoms. After exclusion of timepoints within 1 month of known SCV2 vaccination or reinfection, point estimates were similar but confidence intervals widened slightly. No significant associations were seen with S1 or N antigens.

Conclusions

Among adults with prior SCV2 infection, we found evidence for an association between SCV2 spike antigenemia 3-14 months post-infection and some but not all LC symptoms. This work highlights the need for well-characterized participants, with and without a variety of symptoms, to yield associations, and it suggests that different mechanisms might contribute to the variable presentation of LC. Nonetheless, given the novelty of the system, more work is needed (including intervention studies) to confirm the findings and exclude confounding before causation is inferred.

◆Exploring the Molecular Pathways of Long COVID With Post-Exertional Fatigue: A Multiomic Approach【CROI　2025年3月12日】

Abstract

Background

Post-exertional malaise (PEM) is a disabling condition characterized by worsened symptoms after mental or physical exertion, commonly seen in Long-COVID (LC). While its underlying pathophysiology is unclear, potential mechanisms include oxidative stress, and metabolic derangements. We conducted a multiomic analysis to identify changes in energy metabolism, immune function and cellular stress responses in patients with LC affected by PEM (LC-PEM).

Methods

We included 25 LC-PEM and 25 COVID-19 survivors without persistent symptoms (Recovered) matched by sex, age and COVID-19 severity. We detected the levels in plasma of 6 short-chain fatty acids (SCFA) by GC-MS/MS, 95 metabolites by GC-qTOF and 795 proteins in the proteomic analysis by nanoLC-MS/MS. Statistical analyses included t-tests, partial-least square discriminant analysis (PLS-DA), Random Forest, Joint-Pathway analyses (KEGG database) and ROC Curve.

Results

Acetic acid was the only SCFA with lower levels in the LC-PEM group (p=0.001). Metabolomics revealed 29 differentially expressed metabolites (23 increased, 6 decreased in LC-PEM, all p<0.04), while proteomics showed 51 differentially expressed proteins between groups (39 increased and 11 decreased, p<0.01 in all cases). In a multiomic analysis, the PLS-DA of the identified 81 significant compounds demonstrated clear separation between groups (Fig1A). The enrichment pathway analysis identified 25 affected pathways, including complement and coagulation cascades, glucagon signalling pathway, TCA cycle, pyruvate metabolism, fatty acid biosynthesis, different amino acid metabolisms, glycolysis/gluconeogenesis, HIF-1 signalling pathway, butanoate metabolism and glyoxylate and dicarboxylate metabolism. Random Forest highlighted glyceraldehyde-3-phosphate dehydrogenase, Protein S100-A9, Fumaric acid and Galectin-3-binding protein as most associated with LC-PEM. The ROC curve analysis of the combination of 4 compounds yielded an AUC of 0.978 (95% CI: 0.942–1.013, p<0.001, Fig1B), indicating an excellent discriminatory ability between the LC-PEM and recovered groups. Conclusions

Coagulation and inflammatory problems linked to metabolic changes, such as upregulated glycolysis and fatty acid synthesis, are associated with LC-PEM. These findings highlight the need for a multifaceted approach addressing both metabolic and immunological factors. Future research should validate these biomarkers in larger cohorts and explore targeted treatments to address these imbalances.

◆Novel Plasma Biomarkers for the Detection of Long COVID Defined by Multiapproach Analysis【CROI　2025年3月12日】

Abstract

Background

Long COVID (LC) is a newly defined syndrome linking COVID infection with an umbrella of long-lasting symptoms. Due to this variety of presentation and lack of understanding of the mechanism involved, no reliable biomarkers have been found so far, and diagnostic uncertainty remains high. In the prospect of personalized medicine, there is a dire need for diagnostic and prognostic markers. To address this issue, we designed a multi-approach exploratory study on a well characterized cohort of LC patients using Resolved COVID infections (RC) and Uninfected Controls (UC).

Methods

Plasma samples from 100 LC, 60 RC and 60 UC were analyzed by using state-of-the-art IVDr NMR allowing to harvest detailed lipidomic and metabolomic data and immune and mitochondrial stress markers explored by several multiplex ELISAs and electrochemiluminescent assays. On these data, we performed multivariate dimensionality reduction models (PCA, OPLS-DA) to visualize data distribution and discriminant variables between groups. Candidate biomarkers were validated with univariate analysis and ROC curve analysis, and then used to construct a machine deep learning model able to sort patients into diagnostic groups. Finally, LC symptoms were correlated with the most significant variables.

Results

We identified several potential biomarkers related to platelet and neutrophil activation, inflammation, TCA cycle, vascularization, lipoproteins. Models fed by those biomarkers alone were sufficient to cluster the LC group from the two other groups. We also found that both previously infected groups (RC and LC) had a specific signature distinguishing them from UC. SARS-CoV-2 infection induced host immuno-metabolic signatures that persisted after full recovery (RC group). However, this signature was different in the LC group and was associated with LC pathophysiology. We created several machine learning models to test whether these biomarkers along with the other variables are enough to predict LC patients. Our model was able to correctly predict 99% of LC patients and had about 70% accuracy in distinguishing RC from UC patients.

Conclusions

In this study, we identified potential biomarkers sufficient to diagnose LC with 99% accuracy. These biomarkers were associated with immune and metabolic dysregulation, as well as content symptoms, providing clues to future therapeutic targets. We are now testing these markers in a prospective setting to validate their use in clinical practice.

◆Diffusion tensor imaging after COVID-19 infection: A systematic review【ScienceDirect　2025年3月15日】

Abstract

Background

Most COVID-19 neuroimaging research focuses on clinically evident lesions occurring during the acute period after infection. Chronic effects on brain structure, especially at a microstructural level, are less well defined. Existing advanced neuroimaging studies report inconsistent differences in white matter integrity after COVID-19 infection. Our aim was to systematically evaluate the advanced neuroimaging literature with a specific focus on examining diffusion MRI (dMRI) abnormalities observable after the resolution of the acute phase of COVID-19 illness.

Methods

A search of the literature was conducted on PubMed, Embase, and Scopus on May 27th, 2023, and an updated search was performed September 20th, 2024. Inclusion criteria were a quantitative comparison of dMRI metrics between COVID-19 patients and non-COVID-19 volunteers with MRI acquired >6 weeks after COVID-19. Studies that included only subgroups of COVID-19 patients with specific symptoms, case reports, and post-mortem studies were excluded. Forwards and backwards citation chasing were performed.

Results

The initial search identified 1709 unique records, and 11 met inclusion criteria. Most studies included hospitalized COVID-19 patients, with brain MRI acquired between 2 and 6 months after COVID-19 infection. The majority of studies reported lower fractional anisotropy and higher mean diffusivity in the post-COVID-19 cohort, compared to non-COVID-19 controls. However, there were inconsistent findings, with one study reporting higher fractional anisotropy after COVID-19 infection. Cohorts with a more severe acute COVID-19 illness tended to have lower fractional anisotropy and higher mean diffusivity than cohorts with a milder illness course. Compared to shorter follow-up periods, a longer time between COVID-19 and MRI was associated with fewer differences between COVID-19 patients and non-COVID-19 volunteers.

Conclusion

A review of the literature indicates that the heterogeneity of findings regarding dMRI metrics after the resolution of the acute phase of COVID-19 illness may be due in part to the severity of COVID-19 illness and the time between COVID-19 and MRI. Future studies should also consider how different SARS-CoV-2 variants differentially affect the structural brain differences after COVID-19.

◆SARS-CoV-2 Placentitis: A Review of Pathologic Findings and Discussion of Differential Diagnosis【ARCHIVES of Pathology & Laboratory Medicine　2025年3月17日】

Abstract

Context.—

Maternal SARS-CoV-2 infection has been associated with increased adverse events in the mother, as well as increased stillbirths (11.5 per 1000), spontaneous abortions, and premature delivery. Clinical symptomatology, or the lack thereof, does not appear to be directly related to fetal or neonatal complications. SARS-CoV-2 placentitis is now recognized as the culprit, and the presence of the virus in the syncytiotrophoblasts of the placenta has emerged as a significant predictor of fetal compromise.

Objective.—

To provide a review of the clinical presentation and outcomes, morphologic characteristics, detection methods, and differential diagnosis of SARS-CoV-2 placentitis.

Data Sources.—

A case of placental pathology in a patient with COVID-19 infection at the University of Michigan, as well as a review of the available literature through a search of PubMed and Google Scholar.

Conclusions.—

SARS-CoV-2 placentitis is a well-documented outcome of symptomatic and asymptomatic COVID-19 infection during pregnancy. It can disrupt placental function and lead to severe outcomes in the neonate, including growth restriction and stillbirths. Chronic histiocytic intervillositis, perivillous fibrin deposition, and trophoblast necrosis, when present together, may act as a morphologic signature of SARS-CoV-2 placentitis. The histologic differential diagnosis includes massive perivillous fibrin deposition (MPFD)/maternal floor infarction (MFI), chronic villitis of unknown origin, or other infectious villitides. Immunohistochemistry and RNA in situ hybridization are specific to the viral antibodies and RNA, respectively, and are essential for classification.

◆Long COVID and New Onset Disability Nearly 2 Years After Initial Infection【ScienceDirect　2025年3月17日】

Abstract

Introduction

The objective of this study was to determine the prevalence of ongoing long COVID symptoms and related disability in a population-based cohort nearly 2 years after SARS-CoV-2 infection.

Methods

Six domains of age-standardized disability (i.e., mobility, cognition, independent living, vision, hearing, self-care) were assessed by ongoing long COVID status using cohort data from a population-based survey of adults with COVID-19 onset from March–December 2020 in Michigan. Baseline data were collected June 2020–October 2021 and follow-up data were collected January–November 2022. Associations between ongoing long COVID and each domain of disability were also examined using adjusted modified Poisson regression models. Analyses were conducted 2024–2025.

Results

Nearly 2 years after initial infection, 24.0% of 1,547 respondents reported ongoing long COVID symptoms. When comparing disability status 4 weeks prior to COVID-19 illness to the time of the follow-up survey, respondents with ongoing long COVID symptoms had large increases in the prevalence of cognition (8.8% to 45.3%), mobility (12.7% to 40.0%), independent living (4.7% to 20.7%), and self-care (2.1% to 10.9%) disability, and more modest increases in the prevalence of vision and hearing disability. Respondents without ongoing long COVID symptoms experienced smaller increases in disability prevalence. In regression models, ongoing long COVID was associated with higher prevalence of all 6 disability domains.

Conclusions

The ongoing burden of long COVID and related disability is substantial and warrants increased attention by the public health and medical communities.

◆Altered auditory brainstem responses are post-acute sequela of SARS-CoV-2 (PASC)【nature scientific reports　2025年3月18日】

Abstract

The Post-acute Sequela of SARS-CoV-2 (PASC) syndrome, also known as Long-COVID, often presents with subjective symptoms such as brain fog and cognitive fatigue. Increased tinnitus, and decreased hearing in noise ability also occur with PASC, yet whether auditory manifestations of PASC are linked with the cognitive symptoms is not known. Electrophysiology, specifically the Auditory Brainstem Response (ABR), provides objective measures of auditory processing. We hypothesized that ABR findings would be linked to PASC and with subjective feelings of cognitive fatigue. Eighty-two individuals, 37 with PASC (mean age: 47.5, Female: 83%) and 45 healthy controls (mean age: 38.5, Female: 76%), were studied with an auditory test battery that included audiometry and ABR measures. Peripheral hearing thresholds did not differ between groups. The PASC group had a higher prevalence of tinnitus, anxiety, depression, and hearing handicap in addition to increased subjective cognitive fatigue. ABR latency findings showed a significantly greater increase in the wave V latency for PASC subjects when a fast (61.1 clicks/sec) compared to a slow click (21.1 clicks/sec) was used. The increase in latency correlated with cognitive fatigue scores and predicted PASC status. The ABR V/I amplitude ratio was examined as a measure of central gain. Although these ratios were not significantly elevated in the full PASC group, to minimize the cofounding effect of age, the cohort was median split on age. Elevated V/I amplitude ratios were significant predictors of both predicted PASC group classification and cognitive fatigue scores in the younger PASC subjects compared to age-matched controls providing evidence of elevated central gain in younger individuals with PASC. More frequent tinnitus also significantly predicted higher subjective cognitive fatigue scores. Our findings suggest that PASC may alter the central auditory pathway and lead to slower conduction and elevated auditory neurophysiology responses at the midbrain, a pattern associated with the typical aging process. This study marks a significant stride toward establishing an objective measure of subjective cognitive fatigue through assessment of the central auditory system.

◆Now we know how COVID attacks your heart【NATIONAL GEOGRAPHIC　2023年11月7日】

Scientists have noticed that COVID-19 can trigger serious cardiovascular problems, especially among older people who have a buildup of fatty material in their blood vessels. But now a new study has revealed why and shown that SARS-CoV-2, the virus that causes COVID-19, directly infects the arteries of the heart.

The study also found that the virus can survive and grow inside the cells that form plaque—the buildup of fat-filled cells that narrow and stiffen the arteries leading to atherosclerosis. If the plaque breaks, it can block blood flow and cause a heart attack or a stroke. The SARS-CoV-2 infection makes the situation worse by inflaming the plaque and increasing the chance that it breaks free.

This can explain long-term cardiovascular effects seen in some, if not all, COVID-19 patients.

SARS-CoV-2 virus has already been found to infect many organs outside the respiratory system. But until now it hadn’t been shown to attack the arteries.

“No one was really looking if there was a direct effect of the virus on the arterial wall,” says Chiara Giannarelli, a cardiologist at NYU Langone Health, in New York, who led the study. Giannarelli noted that her team detected viral RNA—the genetic material in the virus—in the coronary arteries. “You would not expect to see [this] several months after recovering from COVID.”

Mounting evidence now shows that SARS-CoV-2 is not only a respiratory virus, but it can also affect the heart and many other organ systems, says Ziyad Al-Aly, a clinical epidemiologist at Washington University in St. Louis. Al-Aly’s research has shown that the risk of developing heart and cardiovascular diseases, including heart failure, stroke, irregular heart rhythms, cardiac arrest, and blood clots increases two to five times within a year of COVID-19, even when the person wasn’t hospitalized.

“This important study links, for the first time, directly the SARS-CoV-2 virus with atherosclerotic plaque inflammation,” says Charalambos Antoniades, chair of cardiovascular medicine at the University of Oxford, United Kingdom.

Virus triggers the inflammation in plaque

A recent study of more than 800,000 people led by Fabio Angeli, a cardiologist at University of Insubria in Varese, Italy, has shown that COVID-19 patients develop high blood pressure twice as often as others. More worrying is that the risk of cardiac diseases can also rise for patients who suffered only mild COVID symptoms.

“I saw a patient who now has a defibrillator, and she didn’t even have a severe [COVID] illness,” says Bernard Gersh, a cardiologist at Mayo Clinic, Rochester, Minnesota.

Wondering whether the cardiovascular damage during COVID was due to the virus directly attacking the blood vessels, the NYU team analyzed autopsied tissue from the coronary arteries and plaque of older people who had died from COVID-19. They found the virus was present in the arteries regardless of whether the fatty plaques were big or small.

“The original finding in this study is that the virus was convincingly found in the plaque in the coronary artery,” says Juan Carlos Kaski, a cardiovascular specialist at St George’s, University of London, who was not involved in the study.

The NYU team found that in the arteries, the virus predominantly colonized the white blood cells called macrophages. Macrophages are immune cells that are mobilized to fight off an infection, but these same cells also absorb excess fats—including cholesterol from blood. When microphages load too much fat, they change into foam cells, which can increase plaque formation.

To confirm that the virus was indeed infecting and growing in the cells of the blood vessels, scientists obtained arterial and plaque cells—including macrophages and foam cells—from healthy volunteers. Then they grew these cells in the lab in petri dishes and infected them with SARS-CoV-2.

Giannarelli found that although virus infected macrophages at a higher rate than other arterial cells, it did not replicate in them to form new infectious particles. But when the macrophages had become loaded with cholesterol and transformed into foam cells, the virus could grow, replicate, and survive longer.

“We found that the virus tended to persist longer in foam cells,” says Giannarelli. That suggests that foam cells might act as a reservoir of SARS-CoV-2. Since more fatty buildup would mean a greater number of foam cells, plaque can increase the persistence of the virus or the severity of COVID-19.

Scientists found that when macrophages and foam cells were infected with SARS-CoV-2 they released a surge of small proteins known as cytokines, which signal the immune system to mount a response against a bacterial or viral infection. In arteries, however, cytokines boost inflammation and formation of even more plaque.

“We saw that there was a degree of inflammation [caused] by the virus that could aggravate atherosclerosis and cardiovascular events,” says Giannarelli.

These findings also confirm previous reports that measuring inflammation in the blood vessel wall can diagnose the extent of long-term cardiovascular complications after COVID-19, says Antoniades.

“What this study has found is that plaque rupture can be accelerated and magnified by the presence of the virus,” says Kaski.

Understanding heart diseases after COVID

While this new research clearly shows that SARS-CoV-2 can infect, grow, and persist in the macrophages of plaques and arterial cells, more studies are needed to fully understand the many ways COVID-19 can alter cardiac health.

“The NYU study identifies one potential mechanism, especially the viral reservoir, to explain the possible effects” says Gersh. “But It’s not going to be the only mechanism.”

This study only analyzed 27 samples from eight elderly deceased patients, all of whom already had coronary artery disease and were infected with the original strains of virus. So, the results of this study do not necessarily apply to younger people without coronary artery disease; or to new variants of the virus, which cause somewhat milder disease, says Angeli.

“We do not know if this will happen in people who have been vaccinated,” says Kaski. “There are lots of unknowns.”

It is also not clear whether and to what extent the high inflammatory reaction observed in the arteries of patients within six months after the infection, as shown in the new study, will last long-enough to trigger new plaque formation. “New studies are needed to show the time-course of the resolution of vascular inflammation after the infection,” says Antoniades.

COVID patients should watch for any new incidence of shortness of breath with exertion, chest discomfort, usually with exertion, palpitations, loss of consciousness; and talk to their physician about possible heart disease.