SARS-CoV-2 と COVID-19 に関する備忘録 Vol.27

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆A six-year study in a real-world population reveals an increased incidence of dyslipidemia during COVID-19【The Journal of Clinical Investigation　2024年9月12日】

Abstract

BACKGROUND. Recent studies conducted in individuals who survived COVID-19 suggest that SARS-CoV-2 infection is associated with an increased risk of dyslipidemia. However, it remains unclear whether this augmented risk is confirmed in the general population and how this phenomenon is affecting the overall burden of cardiometabolic diseases.

METHODS. To address these aspects, we conducted a 6-year longitudinal study to examine the broader effects of COVID-19 on dyslipidemia incidence in a real-world population (228,266 individuals) residing in Naples in southern Italy. The pre–COVID-19 and COVID-19 groups were balanced for demographic and clinical factors using propensity score matching.

RESULTS. Our analysis spans a period of 3 years during the COVID-19 pandemic (2020–2022), comparing dyslipidemia incidence with pre-pandemic data (2017–2019), with a follow-up of at least 1,095 days corresponding to 21,349,215 person-years. During the COVID-19 period, we detected an increased risk of developing any dyslipidemia when compared with the pre–COVID-19 triennium (OR = 1.29; 95% CI, 1.19–1.39). Importantly, these estimates were adjusted for comorbidities by a multivariate analysis.

CONCLUSIONS. Taken together, our data reveal a notable rise in dyslipidemia incidence during the COVID-19 pandemic, suggesting the utility of establishing specialized clinical monitoring protocols for patients who survive COVID-19 to mitigate the risk of developing dyslipidemia.

Introduction

Recent reports suggest that SARS-CoV-2 infection could be associated with an increased risk of dyslipidemia (1–5). A large observational study conducted by FAIR Health in people with COVID-19, with no control group, reported that approximately 3% developed dyslipidemia after the first 30 days of infection (2). Similarly, Xu et al. (1) used the national health care databases of the US Department of Veterans Affairs to build (a) a cohort of participants who had a positive COVID-19 test and survived the first 30 days of infection between March 2020 and January 2021, (b) a noninfected contemporary control group that included individuals enrolled between March 2020 and January 2021, and (c) a historical control group with individuals enrolled between March 2018 and January 2019 (1). Compared with the noninfected contemporary control group, those in the COVID-19 cohort had higher risks and burdens of dyslipidemia in the post-acute phase of the SARS-CoV-2 infection. However, these data do not clarify whether and to what extent such an increased risk could influence the global burden of cardiometabolic disease and how it may affect health systems and health care costs. In fact, the data currently available in the literature merely refer to comparisons between groups of patients who had a clinically confirmed positive SARS-CoV-2 test versus individuals with similar demographic characteristics who did not have COVID-19 (6), thus assessing the effect of the long-term individual COVID-19 infection (post-acute sequelae) on the incidence of dyslipidemia. Yet, it should be emphasized that the attenuation of the severity of COVID-19 symptoms and the use of less sensitive self-tests have made the less reliable evaluation of this complex phenomenon and its consequences for public health organizations in different countries (7).

Therefore, the present study was designed to examine the broader effects of the pandemic on dyslipidemia incidence in a real-world population residing in Naples, southern Italy. This analysis spans a period of 3 years during the pandemic (2020–2022), tracking individuals under the care of primary care physicians (8). We juxtaposed these findings with data from a pre–COVID-19 era population obtained from the same database, covering the period from 2017 to 2019.

◆Vitamin D levels in children and adolescents are associated with coronavirus disease-2019 outcomes: A systematic review and meta-analysis【Medicine LWW　2024年11月1日】

Abstract

Background:
To explore the relationship between vitamin D levels and risk of SARS-CoV-2 infection and its severity in children and adolescents, and provide a theoretical basis for clinical practice.

Methods:
The PubMed, Web of Science, Embase, MEDLINE, and Cochrane Library databases were searched for comprehensive cohort and case–control studies on the association between childhood vitamin D deficiency and the risk and prognosis of coronavirus disease-2019 (COVID-19). The search period was set from December 1, 2019, to December 31, 2023.

Results:
The vitamin D insufficiency rate in children with COVID-19 was 80.78% (95% CI, 62.6% to 93.89%), with a deficiency rate of 32% (95% CI: 19.01% to 46.61%). Vitamin D insufficiency was more common in children with COVID-19 than in healthy children (OR, 4.86; 95% CI: 2.56–9.26). The incidence of severe illness was higher (OR, 4.73; 95% CI: 1.39–16.11) whereas that of asymptomatic illness was lower (OR, 0.38; 95% CI: 0.38–0.81) in children with COVID-19 who had vitamin D insufficiency than in those who did not.

Conclusions:
Vitamin D insufficiency in children may increase the risk of COVID-19 infection and is associated with poor prognostic outcomes. Further research is required to confirm the optimal Vitamin D dose to prevent insufficiency in various sections of the population.

◆Utilizing blood single-cell transcriptomics to integrate intrinsic and systemic immune aging【bioRxiv　2024年11月3日】

Abstract

Biomarkers of aging provide insight into the biological effects of interventions and diseases. However, most biomarkers today are based on measurements derived from bulk cell measurements, making it challenging to interpret whether an effect is due to changes in cell type composition (systemic factors) or a cell intrinsic effect. Single-cell RNA sequencing provides a unique platform to simultaneously compare aging-associated changes on both a cellular and bulk level. We first generated a single-cell combined automated human blood cell type and age predictor (clock) for six distinct human T cell subsets. We applied these tools to find acute COVID is associated with a shift in CD8+ cytotoxic cell proportions, while cell type proportions are stable in patients with HIV on long-term ART treatment (HIV+ART). Both COVID and HIV+ART were associated with an increase in naive CD8 T cell transcriptomic age. We further found our single-cell aging biomarker is linked to ribosomal gene expression and has a link to mean cellular transcript length. This study highlights the potential of single cell transcriptomic biomarkers for understanding how the human immune system is impacted by age-associated systemic changes in cell type composition and intrinsic cellular aging.

◆SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation【nature : Signal Transduction and Targeted Therapy　2024年5月11日】

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a ‘highly transmissible respiratory pathogen, leading to severe multi-organ damage. However, knowledge regarding SARS-CoV-2-induced cellular alterations is limited. In this study, we report that SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics and activates the EGFR-mediated cell survival signal cascade during the early stage of viral infection. SARS-CoV-2 causes an increase in mitochondrial transmembrane potential via the SARS-CoV-2 RNA-nucleocapsid cluster, thereby abnormally promoting mitochondrial elongation and the OXPHOS process, followed by enhancing ATP production. Furthermore, SARS-CoV-2 activates the EGFR signal cascade and subsequently induces mitochondrial EGFR trafficking, contributing to abnormal OXPHOS process and viral propagation. Approved EGFR inhibitors remarkably reduce SARS-CoV-2 propagation, among which vandetanib exhibits the highest antiviral efficacy. Treatment of SARS-CoV-2-infected cells with vandetanib decreases SARS-CoV-2-induced EGFR trafficking to the mitochondria and restores SARS-CoV-2-induced aberrant elevation in OXPHOS process and ATP generation, thereby resulting in the reduction of SARS-CoV-2 propagation. Furthermore, oral administration of vandetanib to SARS-CoV-2-infected hACE2 transgenic mice reduces SARS-CoV-2 propagation in lung tissue and mitigates SARS-CoV-2-induced lung inflammation. Vandetanib also exhibits potent antiviral activity against various SARS-CoV-2 variants of concern, including alpha, beta, delta and omicron, in in vitro cell culture experiments. Taken together, our findings provide novel insight into SARS-CoV-2-induced alterations in mitochondrial dynamics and EGFR trafficking during the early stage of viral infection and their roles in robust SARS-CoV-2 propagation, suggesting that EGFR is an attractive host target for combating COVID-19.

◆Long-Term Risk of Autoimmune and Autoinflammatory Connective Tissue Disorders Following COVID-19【JAMA Network　2024年11月6日】

Abstract

Importance Few studies have investigated the association between COVID-19 and autoimmune and autoinflammatory connective tissue disorders; however, research with long-term observation remains insufficient.

Objective To investigate the long-term risk of autoimmune and autoinflammatory diseases after COVID-19 over an extended observation period.

Design, Setting, and Participants This retrospective nationwide population-based study investigated the Korea Disease Control and Prevention Agency–COVID-19–National Health Insurance Service (K-COV-N) cohort. Individuals with confirmed COVID-19 from October 8, 2020, to December 31, 2022, and controls identified among individuals who participated in the general health examination in 2018 were included in the analysis.

Exposures Confirmed COVID-19.

Main Outcomes and Measures Incidence and risk of autoimmune and autoinflammatory connective tissue disorders in patients after COVID-19. Various covariates, such as demographic characteristics, general health data, socioeconomic status, and comorbidity profiles, were balanced using inverse probability weighting.

Results A total of 6 912 427 participants (53.6% male; mean [SD] age, 53.39 [20.13] years) consisting of 3 145 388 with COVID-19 and 3 767 039 controls with an observational period of more than 180 days were included. Alopecia areata (adjusted hazard ratio [AHR], 1.11 [95% CI, 1.07-1.15]), alopecia totalis (AHR, 1.24 [95% CI, 1.09-1.42]), vitiligo (AHR, 1.11 [95% CI, 1.04-1.19]), Behçet disease (AHR, 1.45 [95% CI, 1.20-1.74]), Crohn disease (AHR, 1.35 [95% CI, 1.14-1.60]), ulcerative colitis (AHR, 1.15 [95% CI, 1.04-1.28]), rheumatoid arthritis (AHR, 1.09 [95% CI, 1.06-1.12]), systemic lupus erythematosus (AHR, 1.14 [95% CI, 1.01-1.28]), Sjögren syndrome (AHR, 1.13 [95% CI, 1.03-1.25]), ankylosing spondylitis (AHR, 1.11 [95% CI, 1.02-1.20]), and bullous pemphigoid (AHR, 1.62 [95% CI, 1.07-2.45]) were associated with higher risk in the COVID-19 group. Subgroup analyses revealed that demographic factors, including male and female sex, age younger than 40 years, and age 40 years and older, exhibited diverse associations with the risk of autoimmune and autoinflammatory outcomes. In addition, severe COVID-19 infection requiring intensive care unit admission, the Delta period, and not being vaccinated were associated with higher risk.

Conclusions and Relevance This retrospective cohort study with an extended follow-up period found associations between COVID-19 and the long-term risk of various autoimmune and autoinflammatory connective tissue disorders. Long-term monitoring and care of patients is crucial after COVID-19, considering demographic factors, disease severity, and vaccination status, to mitigate these risks.

◆The immune response to SARS-CoV-2 as a recall response susceptible to immune imprinting: a prospective cohort study【medRxiv　2024年11月6日】

Abstract

Background The antibody response to SARS-CoV-2 does not follow the immunoglobulin isotype pattern expected in a primary response and is inconsistent with the current interpretation of COVID-19 immunopathology as the result of a primary infection. To better understand the immune response to SARS-CoV-2, it is essential to determine whether it is primary or secondary (or recall). The analysis of highly granular immunological variable trajectories of a homogeneous cohort of patients receiving standardised medical care should discern between primary and secondary responses.

Methods This is a prospective cohort study of 191 SARS-CoV-2 infection cases and 44 healthy controls from the second wave of COVID-19 in the Barcelona area. The study stratified patients by severity and analysed the trajectories of SARS-CoV-2 antibodies and multiple immune variables for features associated with primary and recall immune responses.

Findings Isotype-specific antibody trajectories to SARS-CoV-2 proteins revealed a pattern of recall response in 94·2% of cases. In these cases, the detailed trajectories of plasmablasts, B cells, cTfh high-resolution subsets, and cytokines were consistent with a secondary response. The transcriptomic data indicated that this cohort is strictly comparable to contemporary cohorts.

Conclusions In most cases, the immune response to SARS-CoV-2 is a recall response. This opens the possibility that most COVID-19 cases are subjected to immune imprinting by endemic coronavirus, which, in turn, can contribute to severity by interfering with the immune response to SARS-CoV-2 and by antibody-dependent enhancement. Considering the immune responses to SARS-CoV-2 secondary provides a better perspective to interpret COVID-19 pathology.

Funding Grants COV20/00416, Cov20/00654, and COV20/00388 from Instituto de Salud Carlos III (ISCIII), Madrid, Spain, co-financed by the European Regional Development Fund (ERDF).

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study was funded by Instituto de Salud Carlos III, Madrid, Spain, grants COV20/00416, Cov20/00654, and COV20/00388 to RP-B, AT-S, and JB-M respectively, and co-financed by the European Regional Development Fund (ERDF). D.A-S is the recipient of a doctoral fellowship from the Vall Hebron Research Institute, Barcelona, Spain (up to 2022 and a postdoctoral fellowship Sara Borrell, CD23/00114 (from 2024). A.S-M was supported by a postdoctoral grant, Juan Rodes (JR18/00022), from Instituto de Salud Carlos III through the Ministry of Economy and Competitiveness, Spain. A.S.P was financially supported by the Spanish Ministerio de Ciencia e Innovacion, grant PID2019-104830RB-I00, and by the Departament Economia i Coneixement de la Generalitat de Catalunya, grant 2017SGR622 (GRBIO). Bioinformatics analysis has been conducted in the Statistics and Bioinformatics Unit (UEB) at Vall Hebron Research Institute (VHIR).

◆Clinical and functional assessment of SARS-CoV-2 sequelae among young marines – a panel study【THE LANCET Regional Health Americas　2024年10月23日】

Summary

Background

Long-term SARS-CoV-2 adverse health outcomes are of significant concern, especially among young adults with the potential for the greatest long-term morbidity. We sought to assess and characterize these outcomes in a cohort of Marines.

Methods

We used a cohort of US Marines from a previous longitudinal, prospective observational study of acute SARS-CoV-2, most of whom were enrolled prior to infection. A panel study was established to assess for post-acute sequelae of COVID-19 (PASC), defined as symptoms at least 4 weeks after symptom onset or diagnosis. Symptoms were assessed through questionnaires and validated quality of health metrics. Periodic US Marine Corps fitness testing metrics provided an additional standardized functional assessment and were compared to a pre-pandemic cohort.

Findings

Globally dispersed Marine participants (n = 899) seen an average of 330 days following initial enrollment were predominately male (n = 825, 91.7%), White (n = 613, 71.6%) or Black (n = 149, 17.4%) with a median age of 18 years (interquartile range: 18–19). Among 798 SARS-CoV-2 infected participants, 197 (24.7%) developed PASC. The most prevalent symptoms were loss of taste and/or smell (n = 82; 41.6%), shortness of breath (n = 74; 37.6%), and cough (n = 45; 22.8%). Those with PASC had higher rates and severity of somatic (p < 0.0001), general depressive (p < 0.0001), and anxiety (p = 0.005) symptoms. Compared to a historic cohort of Marines, participants with PASC scored worse on their physical fitness assessments due to slower run times (p = 0.002). Those with PASC continued to have decreased physical performance one year after completing initial training. Interpretation

In this population of healthy young adult US Marines with mostly either asymptomatic or mild acute COVID-19, one fourth reported physical, cognitive, or psychiatric long-term sequelae of infection. The Marines affected with PASC showed evidence of long-term decrease in functional performance suggesting that SARS-CoV-2 infection may negatively affect health for a significant proportion of young adults.

◆Long COVID facts and findings: a large-scale online survey in 74,075 Chinese participants【THE LANCET Regional Health Western Pacific　2024年10月10日】

Summary

Background

Research on long COVID in China is limited, particularly in terms of large-sample epidemiological data and the effects of recent SARS-CoV-2 sub-variants. China provides an ideal study environment owing to its large infection base, high vaccine coverage, and stringent pre-pandemic measures.

Methods

This retrospective study used an online questionnaire to investigate SARS-CoV-2 infection status and long COVID symptoms among 74,075 Chinese residents over one year. The relationships between baseline characteristics, vaccination status, pathogenic infection, and long COVID were analyzed using multinomial logistic regression, and propensity matching.

Findings

Analysis of 68,200 valid responses revealed that the most frequent long COVID symptoms include fatigue (30.53%), memory decline (27.93%), decreased exercise ability (18.29%), and brain fog (16.87%). These symptoms were less prevalent among those infected only once: fatigue (24.85%), memory decline (18.11%), and decreased exercise ability (12.52%), etc. Women were more likely to experience long COVID, with symptoms varying by age group, except for sleep disorders and muscle/joint pain, which were more common in older individuals. Northern China exhibits a higher prevalence of long COVID, potentially linked to temperature gradients. Risk factors included underlying diseases, alcohol consumption, smoking, and the severity of acute infection (OR > 1, FDR < 0.05). Reinfection was associated with milder symptoms but led to a higher incidence and severity of long COVID (OR > 1, FDR < 0.05). Vaccination, particularly multiple boosters, significantly reduced long-term symptoms by 30%–70% (OR < 1, FDR < 0.05). COVID-19 participants also self-reported more bacterial, influenza and mycoplasma infections, and 8%–10% of patients felt SARS-CoV-2-induced chronic diseases. Interpretation

This survey provides valuable insights into long COVID situation among Chinese residents, with 10%–30% (including repeated infection) reporting symptoms. Monitoring at-risk individuals based on identified risk factors is essential for public health efforts.

◆COVID-19 can cause inflammation that results in bone loss, higher fracture risk【UCDAVIS HEALTH　2023年7月21日】

Study involving mice suggests that coronavirus is linked to higher risk of bone loss-related diseases

A UC Davis Health study that looked at acute bone loss in mice who had COVID-19 showed that SARS‐CoV‐2 infection can cause significant changes in bone structure. The study is the first to suggest that people with COVID‐19 may experience long‐term orthopedic issues, such as decreased bone mass, increased fracture risk and other musculoskeletal complications.

“Our study provides direct evidence that SARS‐CoV‐2 infection leads to acute bone loss, an increased number of osteoclast bone cells, and thinner growth plates,” said senior author of the study, Dominik Haudenschild, professor emeritus in the Department of Orthopaedic Surgery at UC Davis Health.

In the study, mice who had COVID-19 showed significant bone loss. This loss decreased the bone mechanical strength and increased the risk of fractures. If similar bone loss occurs in human patients following their COVID‐19 recovery, it could leave them with a long‐term — even permanent — increased risk of fractures due to fragile bones. This is especially true in elderly patients.

Fragility fractures are breaks that happen due to minor trauma, such as when a person falls from standing height or less. The study suggested that the higher risk of fragility fractures may be one of the underreported long-haul symptoms of COVID-19.

“This study has profound clinical implications,” said R. Lor Randall, professor and chair of the Department of Orthopaedic Surgery. “Musculoskeletal ramifications of COVID may not be the first medical issue that comes to mind when one thinks about the pandemic. Nevertheless, many people suffer from fragile bones and COVID can put them at an even greater risk for fracture.”

◆Maternal COVID-19 infection associated with offspring neurodevelopmental disorders【nature : Modecular Psychiatry　2024年11月9日】

Abstract

Maternal COVID-19 infection increases the incidence of neurodevelopmental disorders (NDDs) in offspring, although the underlying mechanisms have not been elucidated. This study demonstrated that COVID-19 infection during pregnancy disrupted the balance of maternal and fetal immune environments, driving alterations in astrocytes, endothelial cells, and excitatory neurons. A risk score was established using 47 unique genes in the single-cell transcriptome of gestational mothers. The high risk score in CD4 proliferating T cell level served as an indicator for increased risk of offspring NDDs. Summary-based Mendelian randomization and phenome-wide association study analyses were conducted to identify the causal association of the transcriptional changes with the increased risk of offspring NDDs. Additionally, 10 drugs were identified as potential therapeutic candidates. Our findings support a model where the maternal COVID-19 infection changed the levels of CD4 proliferating T cells, leading to the alterations of astrocytes, endothelial cells, and excitatory neurons in offspring, contributing to the increased risk of NDDs in these individuals.