SARS-CoV-2 と COVID-19 に関する備忘録 Vol.28

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Long-term serum spike protein persistence but no correlation with post-COVID syndrome【medRxiv　2024年11月11日】

Abstract

According to the World Health Organization (WHO) and the Centers for Diseases Control and Prevention (CDC), currently an estimated 3 – 6 % of people suffer from post-COVID condition or syndrome (PCS). A subset meets diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Several studies have reported persistence of SARS-CoV-2 proteins or RNA in serum or tissues of both recovered individuals and PCS patients.

In this exploratory study, we investigated whether serum spike protein is associated with PCS and whether it correlates with symptom severity and laboratory biomarkers. We analyzed serum spike protein levels in 121 PCS patients following mild-to-moderate COVID-19, 72 of whom met diagnostic criteria for ME/CFS (post-COVID ME/CFS, pcMECFS). Pre-pandemic seronegative healthy controls (ppHC, n = 32) and post-COVID recovered healthy controls (pcHC, n = 37) after SARS-CoV-2 infection were also included in the study.

We found persistent serum SARS-CoV-2 spike protein in a subset of pcHC (11 %), PCS non-ME/CFS patients (2 %), and pcMECFS patients (14 %). There was no significant association with disease severity, symptoms, or laboratory markers. The spike protein concentration was independent of the time since last spike exposure (infection or vaccination). In five spike-positive out of a total of 22 patients who underwent immunoglobulin depletion via immunoadsorption (IA), spike protein was reduced or completely removed after treatment, indicating binding to immunoglobulins.

In summary, our study identified serum spike protein in a subset of patients after SARS-CoV-2 infection without evidence for a role in the pathogenesis of PCS.

◆Precision Phenotyping for Curating Research Cohorts of Patients with Post-Acute Sequelae of COVID-19 (PASC) as a Diagnosis of Exclusion【medRxiv　2024年4月16日】

Abstract

Scalable identification of patients with the post-acute sequelae of COVID-19 (PASC) is challenging due to a lack of reproducible precision phenotyping algorithms and the suboptimal accuracy, demographic biases, and underestimation of the PASC diagnosis code (ICD-10 U09.9). In a retrospective case-control study, we developed a precision phenotyping algorithm for identifying research cohorts of PASC patients, defined as a diagnosis of exclusion. We used longitudinal electronic health records (EHR) data from over 295 thousand patients from 14 hospitals and 20 community health centers in Massachusetts. The algorithm employs an attention mechanism to exclude sequelae that prior conditions can explain. We performed independent chart reviews to tune and validate our precision phenotyping algorithm. Our PASC phenotyping algorithm improves precision and prevalence estimation and reduces bias in identifying Long COVID patients compared to the U09.9 diagnosis code. Our algorithm identified a PASC research cohort of over 24 thousand patients (compared to about 6 thousand when using the U09.9 diagnosis code), with a 79.9 percent precision (compared to 77.8 percent from the U09.9 diagnosis code). Our estimated prevalence of PASC was 22.8 percent, which is close to the national estimates for the region. We also provide an in-depth analysis outlining the clinical attributes, encompassing identified lingering effects by organ, comorbidity profiles, and temporal differences in the risk of PASC. The PASC phenotyping method presented in this study boasts superior precision, accurately gauges the prevalence of PASC without underestimating it, and exhibits less bias in pinpointing Long COVID patients. The PASC cohort derived from our algorithm will serve as a springboard for delving into Long COVID’s genetic, metabolomic, and clinical intricacies, surmounting the constraints of recent PASC cohort studies, which were hampered by their limited size and available outcome data.

◆Investigating DNA damage caused by COVID-19 and influenza in post COVID-19【SPRINGER NATURE　2024年11月14日】

Abstract

The SARS-CoV-2 virus (termed COVID-19) was responsible for over 34 million global deaths. Although the COVID-19 pandemic has subsided, infection by emerging mutant variants of SARS-CoV-2 poses a continuing threat to public health. COVID-19 infection has been associated with the development of cytokine storm syndrome, hypercoagulability, immunological dysregulation and direct viral invasion of organs, and the long-term consequences for the health of COVID-19 survivors are currently unknown. Our research focuses on the possible mutagenic aspects of infection by COVID-19 and measures their harmful effects on DNA composition. DNA damage was investigated, using the comet assay method, during two periods: in the epidemic peak of COVID-19 and during the post-COVID-19 period, both in patients infected with COVID-19 and in those with influenza. During the epidemic peak, the levels of DNA damage ranged from the highest to the lowest levels in the following groups, respectively: intubated-ICU, non-intubated-ICU, non-ICU, and influenza, with a discernible increase in DNA damage in ICU-treated patients. The levels of DNA damage in the post-COVID-19 period were significantly lower compared to those in the epidemic peak period but there was still a discernible increase in DNA damage in the ICU group. Our results indicate that levels of DNA damage may be an effective indicator in prognostic decision-making and may therefore help to reduce mortality. Given that DNA damage and impaired repair processes can contribute to chronic diseases like diabetes, cancer, and neurodegenerative conditions, it will be crucial to investigate potential similar effects in patients with COVID-19.

◆Sex differences in postacute infection syndromes【Science Translational Medicine　2024年11月13日】

Abstract

Postacute infection syndromes like Long Covid disproportionately affect females, differing in prevalence, symptoms, and potential causes from males. This Viewpoint highlights these sex differences, gaps in current understanding, and the critical need for sex-based research.

◆Sex differences in postacute infection syndromes【BMJ journals　2024年10月17日】

Abstract

Objectives To examine trajectories of functional limitations, fatigue, health-related quality of life (HRQL) and societal costs of patients referred to long COVID clinics.

Design A population-based longitudinal cohort study using real-time user data.

Setting 35 specialised long COVID clinics in the UK.

Participants 4087 adults diagnosed with long COVID in primary or secondary care deemed suitable for rehabilitation and registered in the Living With Covid Recovery (LWCR) programme between 4 August 2020 and 5 August 2022.

Main outcome measures Generalised linear mixed models were fitted to estimate trajectories of functional limitations, using the Work and Social Adjustment Scale (WSAS); scores of ≥20 indicate moderately severe limitations. Other outcomes included fatigue using the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) reversed score (scores of ≥22 indicate impairment), HRQL using the EQ-5D-5L, and long COVID-related societal costs, encompassing healthcare costs and productivity losses.

Results The mean WSAS score at 6 months after registration in the LWCR was 19.1 (95% CI 18.6, 19.6), with 46% of the participants (95% CI 40.3%, 52.4%) reporting a WSAS score above 20 (moderately severe or worse impairment). The mean change in the WSAS score over the 6-month period was −0.86 (95% CI −1.32, –0.41). The mean reversed FACIT-F score at 6 months was 29.1 (95% CI 22.7, 35.5) compared with 32.0 (95% CI 31.7, 32.3) at baseline. The mean EQ-5D-5L score remained relatively constant between baseline (0.63, 95% CI 0.62, 0.64) and 6 months (0.64, 95% CI 0.59, 0.69). The monthly societal cost per patient related to long COVID at 6 months was £931, mostly driven by the costs associated with working days lost.

Conclusions Individuals referred to long COVID clinics in the UK reported small improvements in functional limitations, fatigue, HRQL and ability to work within 6 months of registering in the LWCR programme.

◆Dysrupted microbial tryptophan metabolism associates with SARS-CoV-2 acute inflammatory responses and long COVID【Taylor & Francis Online　2024年11月17日】

Abstract

Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and risk of long COVID has been associated with the depletion or over-abundance of specific taxa within the gut microbiome. However, the microbial mechanisms mediating these effects are not yet known. We hypothesized that altered microbial production of tryptophan and its downstream derivatives might contribute to inappropriate immune responses to viral infection. In patients hospitalized with COVID-19 (n = 172), serum levels of tryptophan and indole-3-propionate (IPA) negatively correlated with serum levels of many proinflammatory mediators (including C-reactive protein and Serum amyloid A), while C-glycosyltryptophan (C-Trp), indole-3-lactic acid (ILA) and indole-3-acetic acid (IAA) levels were positively correlated with levels of acute phase proteins, proinflammatory cytokines, alarmins and chemokines. A similar pattern was observed in long COVID patients (n = 20) where tryptophan and IPA were negatively associated with a large number of serum cytokines, while C-Trp and IAA were positively associated with circulating cytokine levels. Metagenomic analysis of the fecal microbiota showed the relative abundance of genes encoding the microbial enzymes required for tryptophan production (e.g. anthranilate synthase) and microbial tryptophan metabolism was significantly lower in patients hospitalized with COVID-19 (n = 380) compared to healthy controls (n = 270). Microbial tryptophan metabolites reduced innate cell proinflammatory responses to cytosolic DNA sensor Stimulator of interferon genes (STING), toll-like receptor (TLR)-3 and TLR-4 stimulation in vitro, while IL-10 secretion was enhanced. Microbial tryptophan metabolites also modified ex vivo human lymphocyte responses by limiting the production of TH1 and TH17 associated cytokines, while enhancing secretion of IL-22. These data suggest that lower levels of tryptophan production and tryptophan metabolism by gut microbes may increase the risk of severe and chronic outcomes to SARS-CoV-2 infection due to impaired innate and adaptive responses to infection. Screening patients for lower-level microbiome capacity for tryptophan metabolism may help identify at-risk individuals.

◆SARS-CoV-2 can cause lasting damage to cells’ energy production【National Institutes of Health : Sharon Reynolds　2023年8月22日】

At the beginning of the COVID-19 pandemic, the virus responsible for the disease, SARS-CoV-2, was feared for its devastating damage to the lungs. But it quickly became apparent that the virus can infect organs and tissues throughout the body, including the heart, brain, kidneys, and blood vessels.

Much of the resulting dysfunction was thought to be the result of inflammation, the immune system’s response to infection. But research has suggested that effects on mitochondria may also play a role in organ damage from SARS-CoV-2 infection. Mitochondria are the powerhouses of cells, producing most of the energy they need.

It’s been known that parts of SARS-CoV-2 bind to proteins in the mitochondria. But how this affects mitochondrial function hasn’t been clear. Dr. Afshin Beheshti, president of the nonprofit COVID-19 International Research Team and visiting researcher at Broad Institute, and Dr. Douglas Wallace from Children’s Hospital of Philadelphia led an international team, including NIH researchers, to look more closely at the phenomenon.

The researchers compared mitochondrial gene expression€”when genes were activated€”in tissue samples taken from the nasopharynx of 216 people with COVID-19 and 519 uninfected people. They also looked at mitochondrial function in autopsy samples from the hearts, kidneys, livers, lungs, and lymph nodes of 35 people who died from COVID-19 compared with that from 5 people who died from other causes. The results were published on August 9, 2023, in Science Translational Medicine.

The team found that the expression of mitochondrial genes involved in energy production was suppressed in the nasopharynx during acute infection. This shifted cells into a state where they produced more of the substances the virus needs for replication. The researchers did not find this suppression in lung tissue samples taken after the virus had been cleared from the body.

Tissue samples taken during autopsies from the heart, kidney, liver, and lymph nodes continued to show suppression of these mitochondrial genes long after the virus had been cleared from the body. The reason for this continued suppression is unclear. In tandem with reduced mitochondrial function in these tissues, the researchers saw an upregulation of genes related to cellular stress.

“The continued dysfunction we observed in organs other than the lungs suggests that mitochondrial dysfunction could be causing long-term damage to the internal organs of these patients,” Wallace says.

The team next used hamsters and mice to track mitochondrial function over the entire course of infection with SARS-CoV-2. They saw similar results in these animal models. Mitochondrial energy production was suppressed in the lungs during early SARS-CoV-2 infection, then bounced back once the immune system brought the virus under control. During early infection, mitochondrial gene expression was altered in the brain even though no SARS-CoV-2 was detected there, consistent with a systemic response to the virus.

The researchers also found a potential new target for treatment. They found that SARS-CoV-2 boosted expression of a regulatory molecule called miR-2392. This, in turn, lowered expression of mitochondrial genes involved in energy production.

“Neutralizing this microRNA might be able to impede the replication of the virus, providing an additional therapeutic option for patients who are at risk for more serious complications related to the disease,” Beheshti says.

◆Examining Brain Structures and Cognitive Functions in Patients with Recovered COVID-19 Infection: A Multicenter Study Using 7T MRI【medRxiv　2024年11月15日】

Abstract

Importance Emerging evidence suggests that severe acute respiratory syndrome, COVID-19, negatively impacts brain health, with clinical magnetic resonance imaging (MRI) showing a wide range of neurologic manifestations but no consistent pattern. Compared with 3 Tesla (3T) MRI, 7 Tesla (7T) MRI can detect more subtle injuries, including hippocampal subfield volume differences and additional standard biomarkers such as white matter lesions. 7T MRI could help with the interpretation of the various persistent post-acute and distal onset sequelae of COVID-19 infection.

Objective To investigate the differences in white matter hyperintensity (WMH), hippocampal subfields volumes, and cognition between patients hospitalized with COVID-19 and non-hospitalized participants in a multi-site/multi-national cohort.

Design Original investigation of patients hospitalized with COVID-19 between 5/2020 and 10/2022 in 3 USA and 1 UK medical centers with follow-up at hospital discharge.

Participants A total of 179 participants without a history of dementia completed cognitive, mood and other assessments and MRI scans.

Exposure COVID-19 severity, as measured by hospitalization vs no hospitalization

Main Outcomes and Measures 7T MRI scans were acquired. All WMH and hippocampal subfield volumes were corrected for intracranial volumes to account for subject variability. Cognition was assessed using a comprehensive battery of tests. Pearson correlations and unpaired t-tests were performed to assess correlations and differences between hospitalized and non-hospitalized groups.

Results We found similar WMH volume (4112 vs 3144mm³, p=0.2131), smaller hippocampal volume (11856 vs 12227mm³, p=0.0497) and lower cognitive and memory performance, especially the MoCA score (24.9 vs 26.4 pts, p=0.0084), duration completing trail making test B (97.6 vs 79.4 seconds, p=0.0285), Craft immediate recall (12.6 vs 16.4 pts, p<0.0001), Craft delay recall (12.0 vs 15.6 pts, p=0.0001), and Benson figure copy (15.2 vs 16.1 pts, p=0.0078) in 52 patients hospitalized for COVID-19 (19[37%] female; mean[SD] age, 61.1[7.4] years) compared with 111 age-matched non-hospitalized participants (66[59%] female; mean[SD] age, 61.5[8.4] years). Conclusions and Relevance Our results indicate that hospitalized COVID-19 cases show lower hippocampal volume when compared to non-hospitalized participants. We also show that WMH and hippocampal volumes correlate with worse cognitive scores in hospitalized patients compared with non-hospitalized participants, potentially indicating recent lesions and atrophy.

Key Points Question: Do white matter hyperintensity burden, hippocampal whole and subfield volumes, and cognition differ between patients hospitalized with COVID-19 versus participants without hospitalization?

Findings: We found no significant difference in white matter hyperintensity volume, but hippocampal volume was reduced, and cognitive and memory performance were worse in those hospitalized for COVID-19 compared with age-matched non-hospitalized group (either mild COVID-19 or no COVID-19 reported). In the hospitalized group, increased white matter hyperintensity and reduced hippocampal volumes are significantly higher correlated with worse cognitive and memory scores.

Meaning: Adults hospitalized for COVID-19 had lower hippocampal volumes and worse cognitive performance than adults with COVID-19 that did not lead to hospitalization or without reported COVID-19 infection.

◆EVagal nerve stimulation for the management of long COVID symptoms【ScienceDirect　2024年11月8日】

Abstract

This review investigates the therapeutic potential of vagal nerve stimulation (VNS) in managing long COVID, a condition marked by persistent symptoms following acute SARS-CoV-2 infection. Long COVID manifests as ongoing fatigue, cognitive impairment, and autonomic dysfunction, hypothesized to arise from sustained inflammatory and neurological dysregulation. The vagus nerve, central to modulating systemic inflammation and autonomic homeostasis, represents a promising therapeutic target for symptom alleviation through VNS. A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science to identify studies evaluating VNS in the context of long COVID. Preliminary evidence from small-scale pilot studies suggests VNS may attenuate systemic inflammation through activation of the cholinergic anti-inflammatory pathway (CAP), thus restoring autonomic balance and ameliorating symptoms such as fatigue, cognitive dysfunction, and anxiety. In targeting the inflammatory cascade that underlies both acute COVID-19 pathophysiology and its prolonged sequelae, VNS holds potential as an innovative intervention for persistent post-viral symptoms. While these initial findings indicate promise, current data remain limited in scope and robustness, underscoring the need for larger, controlled trials to validate the efficacy and mechanisms of VNS in long COVID management. Establishing a clearer understanding of VNS’s impact on inflammation and autonomic regulation in this context is crucial to inform clinical guidelines and therapeutic strategies for long COVID, potentially offering a targeted approach for mitigating this disabling condition.

◆Red Blood Cell Morphology Is Associated with Altered Hemorheological Properties and Fatigue in Patients with Long COVID【MDPI　2024年11月19日】

Simple Summary

SARS-CoV-2 alters the properties of oxygen-carrying red blood cells (RBCs) through a possible deterioration of hemorheological properties, such as aggregation and deformability. However, long-term changes in these properties and a possible association with morphological abnormalities remain unknown. Therefore, this study aims to investigate changes in the above-mentioned RBC properties in Long-COVID (LC). Venous blood was collected from n = 30 diagnosed LC and n = 30 non-Long-COVID controls (non-LC). Hematological parameters were measured, as well as the aggregation, deformability, and morphology of the RBCs and the mechanical sensitivity index (MS), which reflects the functional capacity of RBCs to deform. The results indicate that hematological parameters were not altered in LC. However, LC showed higher overall aggregation parameters. RBC deformability was higher in LC compared to non-LC; however, MS was limited in this group. LC showed a higher percentage of RBCs with abnormal shapes, which was related to MS and to fatigue, which is considered the leading symptom of LC. It is concluded that the symptoms of LC and changes in the blood flow determining the properties of RBCs are related to the morphological changes in RBCs. Future studies should investigate the underlying causes in order to develop appropriate therapies for this relatively new disease.

Abstract

Background: SARS-CoV-2 infection adversely affects rheological parameters, particularly red blood cell (RBC) aggregation and deformability, but whether these changes persist in patients suffering from Long-COVID (LC) and whether these changes are related to RBC morphology remain unknown. Methods: Venous blood was collected from n = 30 diagnosed LC patients and n = 30 non-LC controls and RBC deformability, RBC aggregation, and hematological parameters were measured. In addition, RBCs were examined microscopically for morphological abnormalities. The mechanical sensitivity index (MS) was assessed in n = 15 LC and n = 15 non-LC samples. Results: Hematological parameters did not differ between the groups. However, LC showed higher aggregation-related parameters. Although RBC deformability was higher in LC, MS, reflecting the functional capacity to deform, was limited in this group. RBCs from LC showed significantly more morphological abnormalities. The extent of morphological abnormalities correlated with MS and the FACIT-Fatigue score of the LC patients. Conclusion: RBCs from LC show a high degree of morphological abnormalities, which might limit the blood flow determining RBC properties and also be related to fatigue symptomatology in LC. Approaches are now needed to understand the underlying cause of these alterations and to ameliorate these permanent changes.

◆Hypopituitarism and COVID-19【SPRINGER NATURE　2024年11月19日】

Abstract

Purpose

This review aims to collect and examine recent research findings regarding hypopituitarism and COVID-19, focusing on the virus’s impact on the pituitary gland and the outcomes for infected patients with hormonal deficiencies.

Methods

Literature review using PubMed (pubmed.ncbi.nlm.nih.gov). The search included the following terms: “COVID19” in combination with “Pituitary” and “Hypopituitarism”.

Results

Many studies have aimed to evaluate the function of the pituitary gland in infected patients, revealing variable degrees of deficiencies. The results are very heterogenous mostly because many different tests and hormonal cut-off have been adopted. It is unclear whether primary virus damage or the inflammatory response is responsible for these hormonal alterations. Interestingly, pituitary defects may persist long after the initial infection, possibly contributing to the “Long COVID syndrome”. However, data on the recovery of pituitary function and long-term follow-up are not yet available. On the other hand, although findings are not consistent, patients with hypopituitarism may be at a higher risk for COVID-19 infection rate, complications, and mortality.

Conclusion

The COVID-19 pandemic presented challenges for endocrinologists. The endocrine system appears to be involved in both the acute phase of infection and the recovery period. Hypopituitarism can be a consequence of SARS-COV-2 infection, and patients with existing hypopituitarism may face higher risks of complications. It is advisable to educate these patients on how to adjust their replacement therapies. Long-term follow-up data on pituitary function after recovery from COVID-19 are needed.

◆Maternal COVID-19 infection and risk of respiratory distress syndrome among newborns: a systematic review and meta-analysis【BMC Infectious Diseases　2024年11月19日】

Abstract

Background

The COVID-19 pandemic has significantly impacted public health, with emerging evidence suggesting substantial effects on maternal and neonatal health. This systematic review and meta-analysis aimed to quantify the prevalence and risk of respiratory distress syndrome (RDS) in newborns born to mothers infected with SARS-CoV-2, the virus responsible for COVID-19.

Methods

We conducted a literature search in Embase, PubMed, and Web of Science up to April 20, without language or date restrictions. Observational studies reporting on the prevalence or risk of RDS among newborns from mothers with confirmed SARS-CoV-2 infection were included. Quality assessment was performed using the JBI tool. Statistical analysis was performed by using R software version 4.3.

Results

Twenty-two studies met the inclusion criteria. The pooled prevalence of RDS among newborns born to COVID-19-infected mothers was 11.5% (95% CI: 7.4–17.3%), with significant heterogeneity (I² = 93%). Newborns from infected mothers had a significantly higher risk of developing RDS, with a pooled risk ratio (RR) of 2.69 (95% CI: 1.77 to 4.17).

Conclusion

Newborns born to mothers with COVID-19 have a substantially increased risk of developing RDS. These findings emphasize the need for vigilant monitoring and appropriate management of pregnant women with COVID-19 to mitigate adverse neonatal outcomes.