SARS-CoV-2 と COVID-19 に関する備忘録 Vol.18――角膜神経異常、ACE2受容体があるところには片っ端から感染、甲状腺、神経細胞プラス心血管障害…etc.

SARS-CoV-2 と COVID-19 に関するメモ・備忘録

The long-term health outcomes, pathophysiological mechanisms and multidisciplinary management of long COVID【nature:Signal Transduction and Targeted Therapy 2023年11月1日】


There have been hundreds of millions of cases of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With the growing population of recovered patients, it is crucial to understand the long-term consequences of the disease and management strategies. Although COVID-19 was initially considered an acute respiratory illness, recent evidence suggests that manifestations including but not limited to those of the cardiovascular, respiratory, neuropsychiatric, gastrointestinal, reproductive, and musculoskeletal systems may persist long after the acute phase. These persistent manifestations, also referred to as long COVID, could impact all patients with COVID-19 across the full spectrum of illness severity. Herein, we comprehensively review the current literature on long COVID, highlighting its epidemiological understanding, the impact of vaccinations, organ-specific sequelae, pathophysiological mechanisms, and multidisciplinary management strategies. In addition, the impact of psychological and psychosomatic factors is also underscored. Despite these crucial findings on long COVID, the current diagnostic and therapeutic strategies based on previous experience and pilot studies remain inadequate, and well-designed clinical trials should be prioritized to validate existing hypotheses. Thus, we propose the primary challenges concerning biological knowledge gaps and efficient remedies as well as discuss the corresponding recommendations.


Neuroinflammatory Findings of Corneal Confocal Microscopy in Long COVID-19 Patients, 2 Years after Acute SARS-CoV-2 Infection【MDPI 2023年10月12日】


Objective: To describe corneal confocal microscopy findings in patients with long COVID-19 with persistent symptoms over 20 months after SARS-CoV-2 infection. Design: A descriptive cross-sectional study that included a total of 88 patients; 60 patients with Long COVID-19 and 28 controls. Long COVID-19 diagnosis was established according to the World Health Organization criteria. Corneal confocal microscopy using a Heidelberg Retina Tomograph II (Heidelberg Engineering, Heidelberg, Germany) was performed to evaluate sub-basal nerve plexus morphology (corneal nerve fiber density, nerve fiber length, nerve branch density, nerve fiber total branch density, nerve fiber area, and nerve fiber width). Dendritic cell density and area, along with microneuromas and other morphological changes of the nerve fibers were recorded. Results: Long COVID-19 patients presented with reduced corneal nerve density and branch density as well as shorter corneal nerves compared to the control group. Additionally, Long COVID-19 patients showed an increased density of dendritic cells also with a greater area than that found in the control group of patients without systemic diseases. Microneuromas were detected in 15% of Long COVID-19 patients. Conclusions: Long COVID-19 patients exhibited altered corneal nerve parameters and increased DC density over 20 months after acute SARS-CoV-2 infection. These findings are consistent with a neuroinflammatory condition hypothesized to be present in patients with Long COVID-19, highlighting the potential role of corneal confocal microscopy as a promising noninvasive technique for the study of patients with Long COVID-19.


SARS-CoV-2 Affects Thyroid and Adrenal Glands: An 18F-FDG PET/CT Study【MDPI 2023年10月26日】


Background: Since most endocrine glands express ACE-2 receptors and can be infected by SARS-CoV-2 virus, this retrospective multicentre observational study aims to assess the metabolic activity of thyroid and adrenal glands of COVID-19 patients by 18F-FDG PET/CT. Methods: We retrospectively evaluated the 18F-FDG PET/CT scans of COVID-19 patients admitted by three different centres, either in a low-intensity department or in the intensive care unit (ICU). A visual assessment and a semi-quantitative evaluation of areas of interest in thyroid and adrenal glands were performed by recording SUVmax and SUVmean. The 18F-FDG PET/CT uptake in COVID-19 patients was compared with those observed in normal age-matched controls. Results: Between March 2020 and March 2022, 33 patients from three different centres (twenty-eight patients in a low-intensity department and five patients in ICU), were studied by 18F-FDG PET/CT during active illness. Seven of them were also studied after clinical remission (3–6 months after disease onset). Thirty-six normal subjects were used as age-matched controls. In the thyroid gland, no statistically significant differences were observed between control subjects and COVID-19 patients at diagnosis. However, at the follow-up PET/CT study, we found a statistically higher SUVmax and SUVmean (p = 0.009 and p = 0.004, respectively) in the thyroid of COVID-19 patients. In adrenal glands, we observed lower SUVmax and SUVmean in COVID-19 patients at baseline compared to control subjects (p < 0.0001) and this finding did not normalize after clinical recovery (p = 0.0018 for SUVmax and p = 0.002 for SUV mean). Conclusions: In our series, we observed persistent low 18F-FDG uptake in adrenal glands of patients at diagnosis of COVID-19 and after recovery, suggesting a chronic hypofunction. By contrast, thyroid uptake was comparable to normal subjects at disease onset, but after recovery, a subgroup of patients showed an increased metabolism, thus possibly suggesting the onset of an inflammatory thyroiditis. Our results should alert clinicians to investigate the pituitary–adrenal axis and thyroid functionality at the time of infection and to monitor them after recovery.


Association of SARS-CoV-2 Infection during Early Weeks of Gestation with Situs Inversus【The NEW ENGLAND JOURNAL of MEDICINE 2023年11月2日】

Situs inversus, including situs inversus totalis (with dextrocardia) and partial situs inversus (with levocardia), is a rare congenital condition in which visceral organization is inverted as compared with normal organ development. We noted a striking increase in the number of cases of fetal situs inversus that were diagnosed by means of ultrasonography at our hospital several months after the “zero-Covid” policies in China were lifted.

We determined the incidence of fetal situs inversus from January 2014 through July 2023 using clinical data from two obstetrical centers in different regions of China. During the first 7 months of 2023, the incidence of situs inversus (diagnosed by means of routine ultrasonography at a gestational age of approximately 20 to 24 weeks, with no change having been made in the diagnostic protocol or physician training) at these centers was over four times as high as the mean annual incidence from 2014 through 2022 (Figure 1 and Fig. S1 and Table S1 in the Supplementary Appendix, available with the full text of this letter at; the incidence peaked in April 2023 and remained elevated through June 2023. Overall, 56 cases of situs inversus were identified from January 2023 through July 2023 (52 cases of situs inversus totalis and 4 cases of partial situs inversus). The increase followed the surge of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections that occurred after the zero-Covid policies were discontinued; this surge, which ultimately was estimated to affect approximately 82% of the population in China, began in early December 2022, peaked around December 20, 2022, and ended in early February 2023.1 Although no conclusions can be made regarding causality, our observations suggest a possible relationship between SARS-CoV-2 infection and fetal situs inversus that warrants further study.

Congenital situs inversus has been linked to aberrant morphogen distribution and cilia dysfunction of the left–right organizer in visceral lateralization during the early weeks of gestation.2 Although vertical transmission of SARS-CoV-2 is debated,3 fetal infection early in gestation could hypothetically affect visceral lateralization; alternatively, SARS-CoV-2–mediated maternal inflammatory responses4,5 might indirectly affect left–right organizer function and impair visceral lateralization. Further analysis is necessary to verify that genetic abnormalities in primary ciliary dyskinesia–related genes that may not have been detected during prenatal genetic screening did not contribute to the incidence of these cases and to assess the potential contribution of environmental factors. It is notable that situs inversus diagnoses remained extremely rare despite the increase in incidence at our centers after the SARS-CoV-2 surge.


How SARS-CoV-2 contributes to heart attacks and strokes【NIH 2023年10月24日】

At a Glance

  • SARS-CoV-2 infected coronary arteries and increased inflammation in atherosclerotic plaques.
  • The findings suggest how COVID-19 could increase the risk of heart attack and stroke.

COVID-19 is known to increase the risk of heart attack and stroke. The intense inflammation that occurs throughout the body in severe cases likely contributes to this increased risk. But it’s not clear whether SARS-CoV-2, the virus that causes COVID-19, also affects blood vessels directly.

To find out, an NIH-funded research team, led by Dr. Chiara Giannarelli at New York University School of Medicine, analyzed coronary artery tissue samples from eight people who died of COVID-19 between May 2020 and May 2021. Results appeared in Nature Cardiovascular Research on September 28, 2023.

The team found SARS-CoV-2 viral RNA in coronary artery tissue from all patients. They found more viral RNA in the arterial walls than in the surrounding fat tissue. Many of the infected cells were macrophages, a type of white blood cell that ingests pathogens. Samples with more macrophages had more viral RNA.

Macrophages also help remove cholesterol from blood vessels. When macrophages become laden with cholesterol, they are known as foam cells. Accumulation of foam cells within arteries forms plaques that are a hallmark of atherosclerosis. The team confirmed that SARS-CoV-2 could infect human macrophages and foam cells in a petri dish. The foam cells were much more susceptible to infection than the macrophages. This could explain why people with atherosclerosis are more vulnerable to COVID-19.

In both cell types, infection depended on a protein on the surface of the cells called neuropilin. Turning off the gene for neuropilin in these cells reduced infection. So did blocking the virus from binding to neuropilin.

Infection triggered several inflammatory pathways in macrophages and foam cells. The cells also released molecules that are known to contribute to heart attacks and strokes. In arterial plaques that had been surgically removed from patients, the researchers saw an inflammatory response to SARS-CoV-2 infection like that seen in the cultured cells.

The findings suggest that SARS-CoV-2 may increase the risk of heart attacks and stroke by infecting artery wall tissue, including associated macrophages. This provokes inflammation in atherosclerotic plaques, which could lead to heart attack or stroke.

“These results shed light onto a possible connection between preexisting heart issues and Long COVID symptoms,” Giannarelli says. “It appears that the immune cells most involved in atherosclerosis may serve as a reservoir for the virus, giving it the opportunity to persist in the body over time.”

“Since the early days of the pandemic, we have known that people who had COVID-19 have an increased risk for cardiovascular disease or stroke up to one year after infection,” says Dr. Michelle Olive of NIH’s National Heart, Lung, and Blood Institute. “We believe we have uncovered one of the reasons why.”

The authors plan to further investigate the potential link between infection of the arteries and Long COVID. They also aim to see if their results also hold true for newer SARS-CoV-2 variants.

—by Brian Doctrow, Ph.D.


Baroreflex sensitivity is impaired in survivors of mild COVID-19 at 3–6 months of clinical recovery; association with carotid artery stiffness【The Physiological Society 2023年10月31日】


The association between the stiffening of barosensitive regions of central arteries and the derangements in baroreflex functions remains unexplored in COVID-19 survivors. Fifty-seven survivors of mild COVID-19 (defined as presence of upper respiratory tract symptoms and/or fever without shortness of breath or hypoxia; SpO2 > 93%), with an age range of 22–66 years (27 females) participated at 3–6 months of recovering from the acute phase of RT-PCR positive COVID-19. Healthy volunteers whose baroreflex sensitivity (BRS) and arterial stiffness data were acquired prior to the onset of the pandemic constituted the control group. BRS was found to be significantly lower in the COVID survivor group for the systolic blood pressure-based sequences (BRSSBP) [9.78 (7.16–17.74) ms/mmHg vs 16.5 (11.25–23.78) ms/mmHg; p = 0.0253]. The COVID survivor group showed significantly higher carotid β stiffness index [7.16 (5.75–8.18) vs 5.64 (4.34–6.96); (p = 0.0004)], and pulse wave velocity β (PWVβ) [5.67 (4.96–6.32) m/s vs 5.12 (4.37–5.41) m/s; p = 0.0002]. BRS quantified by both the sequence and spectral methods showed an inverse correlation with PWVβ in the male survivors. Impairment of BRS in the male survivors of mild COVID-19 at 3–6 months of clinical recovery shows association with carotid artery stiffness.