SARS-CoV-2 と COVID-19 に関する備忘録 Vol.26

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

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◆Virological characteristics of the SARS-CoV-2 XEC variant【bioRxiv　2024年10月17日】

Abstract

The SARS-CoV-2 JN.1 variant (BA.2.86.1.1), arising from BA.2.86.1 with spike protein (S) substitution S:L455S, outcompeted the previously predominant XBB lineages by the beginning of 2024. Subsequently, JN.1 subvariants including KP.2 (JN.1.11.1.2) and KP.3 (JN.1.11.1.3), which acquired additional S substitutions (e.g., S:R346T, S:F456L, and S:Q493E), have emerged concurrently. As of October 2024, KP.3.1.1 (JN.1.11.1.3.1.1), which acquired S:31del, outcompeted other JN.1 subvariants including KP.2 and KP.3 and is the most predominant SARS-CoV-2 variant in the world. Thereafter, XEC, a recombinant lineage of KS.1.1 (JN.13.1.1.1) and KP.3.3 (JN.1.11.1.3.3), was first identified in Germany on August 7, 2024. XEC acquired two S substitutions, S:T22N and S:F59S, compared with KP.3 through recombination, with a breakpoint at genomic position 21,738–22,599. We estimated the relative effective reproduction number (Re) of XEC using a Bayesian multinomial logistic model based on genome surveillance data from the USA, the United Kingdom, France, Canada, and Germany, where this variant has spread as of August 2024. In the USA, the Re of XEC is 1.13-fold higher than that of KP.3.1.1. Additionally, the other countries under investigation herein showed higher Re for XEC. These results suggest that XEC has the potential to outcompete the other major lineage including KP.3.1.1. We then assessed the virological properties of XEC using pseudoviruses. Pseudovirus infection assay showed that the infectivity of KP.3.1.1 and XEC was significantly higher than that of KP.3. Although S:T22N did not affect the infectivity of the pseudovirus based on KP.3, S:F59S significantly increased it. Neutralization assay was performed using three types of human sera: convalescent sera after breakthrough infection (BTI) with XBB.1.5 or KP.3.3, and convalescent sera after JN.1 infection. In all serum groups, XEC as well as KP.3.1.1 showed immune resistance when compared to KP.3 with statistically significant differences. In the cases of XBB.1.5 BTI sera and JN.1 infection sera, the 50% neutralization titers (NT50s) of XEC and KP.3.1.1 were comparable. However, we revealed that the NT50 of XEC was significantly (1.3-fold) lower than that of KP.3.1.1. Moreover, both S:T22N and S:F59S significantly (1.5-fold and 1.6-fold) increased the resistance to KP.3.3 BTI sera. Here we showed that XEC exhibited higher pseudovirus infectivity and higher immune evasion than KP.3. Particularly, XEC exhibited more robust immune resistance to KP.3.3 BTI sera than KP.3.1.1. Our data suggest that the higher Re of XEC than KP.3.1.1 is attributed to this property and XEC will be a predominant SARS-CoV-2 variant in the world in the near future.

◆DNA Damage in Moderate and Severe COVID-19 Cases: Relation to Demographic, Clinical, and Laboratory Parameters【MDPI　2024年9月24日】

Abstract

The ability of the SARS-CoV-2 virus to cause DNA damage in infected humans requires its study as a potential indicator of COVID-19 progression. DNA damage was studied in leukocytes of 65 COVID-19 patients stratified by sex, age, and disease severity in relation to demographic, clinical, and laboratory parameters. In a combined group of COVID-19 patients, DNA damage was shown to be elevated compared to controls (12.44% vs. 5.09%, p < 0.05). Severe cases showed higher DNA damage than moderate cases (14.66% vs. 10.65%, p < 0.05), and males displayed more damage than females (13.45% vs. 8.15%, p < 0.05). DNA damage is also correlated with international normalized ratio (INR) (r = 0.471, p < 0.001) and creatinine (r = 0.326, p < 0.05). In addition to DNA damage, severe COVID-19 is associated with age, C-reactive protein (CRP), and creatinine. Receiver operating characteristic analysis identified age, INR, creatinine, DNA damage, and CRP as significant predictors of disease severity, with cut-off values of 72.50 years, 1.46 s, 78.0 µmol/L, 9.72%, and 50.0 mg/L, respectively. The results show that DNA damage correlates with commonly accepted COVID-19 risk factors. These findings underscore the potential of DNA damage as a biomarker for COVID-19 severity, suggesting its inclusion in prognostic assessments to facilitate early intervention and improve patient outcomes.

◆Evaluating Long-Term Autonomic Dysfunction and Functional Impacts of Long COVID: A Follow-Up Study【medRxiv　2024年10月16日】

Abstract

Background The longitudinal prevalence and autonomic symptom burden in Long COVID patients is not well-established.

Objective Assess the duration and severity of autonomic dysfunction in adults with Long COVID and evaluate its impact on function and quality of life.

Design A follow-up survey of a subset of participants from a cross-sectional online survey of adults with Long COVID. Multivariable logistic regression identified predictors of moderate to severe autonomic dysfunction.

Participants 526 adults (ages 20-65) with a history of Long COVID

Main measures The Composite Autonomic Symptom 31 (COMPASS-31) score, the RAND 36-Item Health Survey, the prevalence of new postural orthostatic tachycardia syndrome (POTS), and predictors of autonomic dysfunction, including POTS

Key results 71.9% of Long COVID patients had a COMPASS-31 score >20, suggestive of moderate to severe autonomic dysfunction. The median symptom duration was 36 [30-40] months, reaching up to 3.5 years after SARS-CoV-2 infection. 37.5% of Long COVID patients could no longer work or had to drop out of school due to their Long COVID illness. 40.5% were newly diagnosed with POTS following SARS-CoV-2 infection.

Conclusions Evidence of persistent moderate to severe autonomic dysfunction was seen in 71.9% of Long COVID patients in our study, with a 36-month median symptom duration, suggesting that enduring autonomic dysfunction is highly prevalent in the Long COVID population. Moderate to severe autonomic dysfunction was significantly correlated with impaired function and capacity, highlighting the need to address POTS and other manifestations of autonomic dysfunction as a key component of Long COVID management.

◆Catching COVID-19 during childhood could increase risk of type 2 diabetes later in life【Diabetes.co.uk　2024年10月22日】

Children and young people who have contracted COVID-19 are more at risk of developing type 2 diabetes in the future compared to those never infected with the disease, a study has indicated.

Recent research has found that children and young people who have been infected with COVID-19 are nearly 60% more at risk of developing type 2 diabetes compared to those affected by different respiratory diseases.

COVID-19 can trigger the development of type 2 diabetes because the virus can cause cells in the pancreas to not produce enough insulin by disrupting an individual’s metabolism.

Type 2 diabetes is associated with a higher risk of having a stroke or heart attack, previous studies have revealed.

The authors said: “Some of these cases could have been lurking before the participants became sick with COVID-19, and diabetes was discovered while they were treated for COVID-19. However, a substantial portion of the cases follow the infection.”

Roughly 34 million people living in the US have type 2 diabetes, with 5,000 of them younger than the age of 19, data from the CDC has shown.

In this trial, academics from Case Western Reserve University in Ohio examined the health data of 613,602 children and adolescents between 2020 and 2022.

Approximately 50% of the people involved in the study had contracted COVID-19 at some point and the other half had been diagnosed with either bronchitis, pneumonia or asthma.

One in 200 of the participants were classed as obese or overweight. The research team assessed the participant’s health after one, three, and six months of being diagnosed with either COVID-19 or another respiratory illness.

They discovered that the participants who had contracted COVID-19 were 55% more at risk of developing type 2 diabetes one month after infection compared to those with other respiratory conditions.

According to the study, the risk decreased to 48% after three months and increased to 58% after six months.

In addition, the children who are overweight or obese were at double the risk of developing type 2 diabetes compared to those at a normal weight, the findings have reported.

The results have also shown that the participants who had been admitted to hospital within a month after being infected with COVID-19 were three times more at risk of going on to develop type 2 diabetes compared to those hospitalised with other illnesses.

The authors said: “COVID-19 could disrupt metabolism, leading to nutrient imbalances and weight gain, which have been associated with type 2 diabetes risk.

“Infection may increase the development of antibodies that attack cells in the pancreas, which produce insulin.”

They concluded: “If the body can’t produce enough insulin, glucose builds up in the blood, increasing the risk of diabetes. Further studies are needed to see how likely the diabetes is to persist or reverse later in life.”

◆Post-Acute COVID-19 Syndrome: Prevalence of Peripheral Microvascular Endothelial Dysfunction and Associations With NT-ProBNP Dynamics【The American Journal of Medicine　2024年10月16日】

Abstract

Background

Post-acute COVID-19 syndrome (PACS) has been linked to microvascular endothelial dysfunction as a potential underlying pathomechanism and can manifest even following a mild course of the initial infection. Prevalence of microvascular endothelial dysfunction and circulating natriuretic peptides in such PACS patients remains unknown.

Methods

This prospective, cross-sectional cohort study enrolled 92 patients (82% females, median age 48 years) with PACS. Reactive hyperemia index (RHI) was evaluated with peripheral arterial tonometry, where <1.67 was defined as microvascular endothelial dysfunction, 1.67-2.0 as impaired function, and >2 normal endothelial function, on average 31 months after the acute infection. N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were collected at 2 different time points within over a 1-year span.

Results

In total, 41% of PACS subjects had microvascular endothelial dysfunction and 20% had impaired RHI. No major differences in clinical characteristics, routine chemistry laboratory testing, or symptom burden were observed across the groups. Only subjects with microvascular endothelial dysfunction and impaired endothelial function had a significant increase in NT-proBNP levels over time, and those with larger increase in NT-proBNP had significantly lower RHI. There was a significant correlation between relative or absolute increase in NT-proBNP and RHI, which remained significant in a multivariable adjusted linear regression.

Conclusions

Peripheral microvascular endothelial dysfunction was prevalent in a symptomatic PACS population long after recovery from a mild acute infection. Increases in NT-proBNP levels were associated with microvascular endothelial dysfunction, suggesting a link between, and providing a foundation for, future studies on post viral microvascular endothelial dysfunction in PACS.

Graphical abstract

Ninety-two subjects with post-acute COVID-19 were enrolled in this prospective cohort study. Subjects contracted acute COVID-19 during the first wave. N-terminal pro-B-type natriuretic peptide (NT-proBNP) 1 and symptom evaluation were performed around 10 months after the acute infection. Around 2-3 years after the acute infection, an additional NT-proBNP was collected and evaluation of microvascular endothelial function with reactive hyperemia index (RHI) as readout was performed. Forty-one percent of the subjects had microvascular endothelial dysfunction microvascular endothelial dysfunction (MVD) and 20% had impaired RHI. These 2 groups had increase in NT-proBNP levels, whereas no change in NT-proBNP levels was observed in the group with normal RHI. A significant correlation between microvascular function in all patients and delta or relative change in NT-proBNP levels was observed. No major differences were observered in clinical characteristics.

◆Altered amyloid plasma profile in patients with disabling headaches after SARS-CoV-2 infection and vaccination【medRxiv　2024年10月22日】

Abstract

Background and objectives New onset persistent headache has been reported following acute COVID-19 disease and to some degree also after SARS-CoV-2 vaccination. Still, the mechanisms for these headache types are unclear. The purpose of this study was to assess levels of amyloid related biomarkers in patients with persistent headache after COVID-19 and SARS-CoV-2 vaccine.

Methods In this prospective observational cohort, patients with severe headache as the dominating symptom after COVID-19 disease (n=29) and SARS-CoV-2 vaccination (n=31), had neurological assessments with reassessments after 6 months. Plasma levels of amyloid precursor protein (APP), pregnancy zone protein (PZP), cathepsin L1 (CTSL) and serum Amyloid A (SAA1) were measured by ELISA in relation to levels in healthy controls (n=16).

Results We found a strong and persistent upregulation of APP in patients with headache after COVID-19 as compared to the two other groups. At both inclusion and after 6 months APP levels were also increased in those with accompanying cognitive symptoms. In contrast, plasma levels of PZP were elevated in both headache groups as compared to healthy controls at inclusion and after 6 months follow-up, but with no relation to cognitive symptoms. CTSL was only elevated in those with COVID-19 associated headache at baseline, whereas SAA1 showed levels comparable in all groups.

Conclusion Altered plasma levels of soluble markers potentially reflecting changes in amyloid processing was found in patients with persistent headache after SARS-CoV-2 vaccine and particular in those with persistent headache after COVID-19 disease where we also found some association with cognitive symptoms.

◆SARS-CoV-2 Infection and the Neuroendocrine System【Karger　2024年10月21日】

Abstract

Background: The novel coronavirus strain SARS-CoV-2 triggered the COVID-19 pandemic with severe economic and social ramifications. As the pathophysiology of SARS-CoV-2 infection in the respiratory system becomes more understood, growing evidence suggests that the virus also impacts the homeostasis-regulating neuroendocrine system, potentially affecting other organ systems. Summary: This review explores the interactions between SARS-CoV-2 and the neuroendocrine system, highlighting the effect of this virus on various endocrine glands, including the brain, hypothalamus, pituitary, pineal, thyroid, parathyroid, adrenal glands, pancreatic islets, gonads, and adipose tissue. The viral invasion disrupts normal hormonal pathways, leading to a range of endocrine disorders, immune dysregulation, and metabolic disturbances. Key Messages: There is potential for SARS-CoV-2 to induce autoimmune responses, exacerbate existing endocrine conditions, and trigger new-onset disorders. Understanding these interactions is crucial for developing treatment strategies that address not only the respiratory symptoms of COVID-19 but also its endocrine complications. The review emphasizes the need for further research to elucidate the long-term effects of SARS-CoV-2 on endocrine health.

◆COVID survivors may develop dementia【nature india　2024年10月21日】

COVID-19 survivors show signs of significant cognitive deficits which could become dementia even a year after having the virus1. They also have an increased risk of depression, anxiety and disrupted sleep.

People who have had COVID-19 should be subjected to close monitoring and regular check-ups to ensure early detection of cognitive impairment and timely therapeutic interventions, says a team of researchers at the Bangur Institute of Neurosciences in Kolkata.

Previous research has suggested that the coronavirus may enter the brain through the olfactory system but little is known about how the virus affects the brain.

To find out, the scientists, led by Atanu Biswas and Madhushree Chakrabarty, did brain scans and assessed the mental health of COVID survivors using phone and in-person interviews. They then matched these with a control group of people who had not contracted COVID.

The team, which included researchers at the Indian Statistical Institute in Kolkata and the Burdwan Medical College in Purba Bardhaman, found that more than 80% of people tested reported at least one of four symptoms – depression, anxiety, stress and insomnia – ranging from mild to severe.

Patients with higher socioeconomic status experienced less anxiety. At least 6.1% of the patients were diagnosed with mild cognitive impairment and 4% developed dementia.

More than 60% of the patients experienced a loss of taste and smell during the active phase of the infection. This could alter the function of brain areas linked to cognitive ability and emotional well-being, the researchers say.

◆Research reveals new clues to the mysteries of long COVID【University of Alberta Folio　2024年10月28日】

Researchers at the University of Alberta have pinpointed two proteins that could serve as markers for identifying patients with long COVID — a discovery that may lead to treatments that will bring better quality of life for the millions of people suffering from the debilitating condition.

“We wanted to find out more about what is going on with long COVID to bring relief to sufferers — especially those patients with the most debilitating symptoms, a condition called chronic fatigue syndrome, which leads to extreme tiredness and other disabling symptoms,” says immunologist Shokrollah Elahi, a professor in the U of A’s Mike Petryk School of Dentistry, who led three groundbreaking studies aimed at improving our understanding of how long COVID develops and who may be susceptible.

Most people who get the SARS-CoV-2 infection feel sick for a week or two and then recover. But about 10 per cent end up with long-term complications that can linger for months or even years. Those complications can be wide-ranging and affect all kinds of organs, with symptoms including chronic fatigue, intense pain, trouble breathing, difficulty sleeping, cardiovascular issues and cognitive problems commonly called “brain fog.”

In the first two studies, recently published in the Journal of Autoimmunity and Frontiers in Immunology, the researchers looked at two sets of subjects: 78 patients with severe long COVID symptoms and 58 people who were infected with SARS-CoV-2 but fully recovered without any complications.

Telltale signs

Elahi and his team looked at various immune cells and proteins in the blood of the study participants. They discovered that the long COVID group had higher levels of immune cells called neutrophils and monocytes that cause inflammation, and fewer protective lymphocytes. They also had more worn-out or exhausted killer T cells, which are a key part of the immune system’s defence against infections.

In the blood of the long COVID patients, the team also found higher levels of various proteins related to systemic inflammation — especially galectin-9 and artemin. These two proteins could help solve the mysteries of long COVID, Elahi says, because higher levels of galectin-9 in patients are associated with increased inflammation and brain fog. In the case of artemin, higher levels are associated with widespread pain, more severe pain and cognitive impairment.

The researchers observed that galectin-9 is shed by stressed neutrophils — the most abundant white blood cells — in long COVID patients. This released galectin-9 can promote chronic inflammation by affecting various immune cells, as Elahi’s group reported in a previous study on HIV infection.

They also found that long COVID dysregulates the production of red blood cells, which results in an abundance of immature red blood cells in the blood of these patients. Normally, immature red blood cells are present in the bone marrow but not in the blood of healthy people. It is these immature red blood cells in the blood that suppress the immune system and contribute to the elevation of artemin in the plasma of long COVID patients.

Severe infection doesn’t necessarily lead to long COVID

Elahi notes that the seriousness of the initial infection does not affect the likelihood of developing long COVID. In fact, most people who end up with long COVID initially had only a mild infection that did not require intensive care or hospitalization.

The research team also found that women are disproportionately affected by long COVID and are three times more likely than men to develop the condition.

In the third study, published last week in The Lancet Microbe, Elahi’s team showed there are no signs of systemic SARS-CoV-2 present in the blood of long COVID patients who were examined 12 months after infection — challenging previous assertions that the virus remains present in the blood of long COVID sufferers.

So if it’s not the virus itself, what could be causing long COVID? Thanks to the information provided by galectin-9 and artemin, Elahi says he has an idea as to what is happening.

“I think that chronic inflammation in long COVID patients results in the elevation of these two proteins. At the earliest stage of disease, we know that some patients have gastrointestinal symptoms like diarrhea — but not everybody,” he points out. “I think those individuals who have gastrointestinal involvement are more likely to develop long COVID.”

The gastrointestinal problems result in damage to the intestinal tissues, along with gut leakiness. It means that if even small traces of microbes from the gut get into the bloodstream, it could result in chronic inflammation in long COVID patients. The team found elevated levels of protein markers associated with gut leakiness in these patients.

Elahi says that is actually good news, because these gut problems can be treated. “There are medications available that can be used for gut leakiness. So I think that might be a solution for long COVID patients.”

Elahi adds that in a previous study, his team discovered that some long COVID patients had a deficiency in two amino acids, sarcosine and serine, that have anti-inflammatory functions and neuroprotective effects. Both are available as food supplements that can be purchased at health-food stores or online.

“Some patients who have taken them have claimed signs of improvement.”

Elahi says the U of A, with its recognized excellence in research related to health and well-being, is a great environment in which to do his work.

“The most important thing when you want to do human studies is having resources in place, having infrastructure so you can recruit patients. In particular, Dr. Mo Osman and his team with the University of Alberta Hospital have been instrumental for clinical assessment and patient recruitment.”

Elahi is also grateful to the long COVID community on Facebook, who were helpful in identifying and getting access to patients for the studies.

“Basically, as scientists, whatever we do, we have to bring it from the bench to the bedside, to see if we can benefit patients. This is our goal,” says Elahi, who is a member of the Women and Children’s Health Research Institute.

The research was funded mainly by a grant from the Canadian Institutes of Health Research. Funding was also provided by the Li Ka Shing Institute of Virology. The researchers also thank the study volunteers who provided samples and supported the work.

◆Post-acute sequelae of SARS-CoV-2 cardiovascular symptoms are associated with trace-level cytokines that affect cardiomyocyte function【nature microbiology　2024年10月30日】

Abstract

An estimated 65 million people globally suffer from post-acute sequelae of COVID-19 (PASC), with many experiencing cardiovascular symptoms (PASC-CVS) like chest pain and heart palpitations. This study examines the role of chronic inflammation in PASC-CVS, particularly in individuals with symptoms persisting over a year after infection. Blood samples from three groups—recovered individuals, those with prolonged PASC-CVS and SARS-CoV-2-negative individuals—revealed that those with PASC-CVS had a blood signature linked to inflammation. Trace-level pro-inflammatory cytokines were detected in the plasma from donors with PASC-CVS 18 months post infection using nanotechnology. Importantly, these trace-level cytokines affected the function of primary human cardiomyocytes. Plasma proteomics also demonstrated higher levels of complement and coagulation proteins in the plasma from patients with PASC-CVS. This study highlights chronic inflammation’s role in the symptoms of PASC-CVS.