SARS-CoV-2 と COVID-19 に関する備忘録 Vol.21――COVID-19感染により10.6年分の加齢に相当する認知機能低下、持続性注意力と認知的迅速性を要するタスクで反応速度が遅くなる…etc.

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

一般向けメディアが東大の佐藤佳教授にインタビューした記事↓3部構成


 


◆Allergic diseases as risk factors for Long-COVID symptoms: Systematic review of prospective cohort studies【WILEY Online Library　2023年11月8日】

Abstract

Objective

The role of allergy as a risk factor for Long-COVID (LC) is unclear and has not been thoroughly examined yet. We aimed to systematically review and appraise the epidemiological evidence on allergic diseases as risk factors for LC.

Design

This is an initial systematic review. Two reviewers independently performed the study selection and data extraction using Covidence. Risk of bias (RoB) and certainty of evidence (GRADE) were assessed. Random effects meta-analyses were used to pool unadjusted ORs within homogeneous data subsets.

Data Sources

We retrieved articles published between January 1st, 2020 and January 19th, 2023 from MEDLINE via PubMed, Scopus, the WHO-COVID-19 database and the LOVE platform (Epistemonikos Foundation). In addition, citations and reference lists were searched.

Eligibility Criteria

We included prospective cohort studies recruiting individuals of all ages with confirmed SARS-CoV-2 infection that were followed up for at least 12 months for LC symptoms where information on pre-existing allergic diseases was available. We excluded all study designs that were not prospective cohort studies and all publication types that were not original articles.

Results

We identified 13 studies (9967 participants, range 39–1950 per study), all assessed as high RoB, due to population selection and methods used to ascertain the exposures and the outcome. Four studies did not provide sufficient data to calculate Odds Ratios. The evidence supported a possible relationship between LC and allergy, but was very uncertain. For example, pre-existing asthma measured in hospital-based populations (6 studies, 4019 participants) may be associated with increased risk of LC (Odds Ratio 1.94, 95% CI 1.08, 3.50) and findings were similar for pre-existing rhinitis (3 studies, 1141 participants; Odds Ratio 1.96, 95% CI 1.61, 2.39), both very low certainty evidence.

Conclusions

Pre-existing asthma or rhinitis may increase the risk of LC.

Graphical Abstract

We systematically reviewed and appraised the epidemiological evidence on allergic diseases as risk factors for Long-COVID. Meta-analysis revealed that pre-existing asthma measured in hospital-based populations and pre-existing rhinitis were significantly associated with increased Long-COVID incidences. Asthma and rhinitis may increase the risk of Long-COVID but the certainty of evidence is very low. CI, confidence interval; OR, odds ratio

 


◆ASSESSMENT AND CHARACTERIZATION OF COVID-19 RELATED COGNITIVE DECLINE: RESULTS FROM A NATURAL EXPERIMENT【medRxiv　2023年11月7日】

Abstract

Background Cognitive impairment is the most common and disabling manifestation of post-acute sequelae of SARS-CoV-2. There is an urgent need for the application of more stringent methods for evaluating cognitive outcomes in research studies.

Objective To determine whether cognitive decline emerges with the onset of COVID-19 and whether it is more pronounced in patients with Post-Acute Sequelae of SARS-CoV-2 or severe COVID-19.

Methods This longitudinal cohort study compared the cognitive performance of 276 patients with COVID-19 to that of 217 controls across four neuroinflammation or vascular disease-sensitive domains of cognition using data collected both before and after the pandemic starting in 2015.

Results The mean age of the COVID-19 group was 56.04±6.6 years, while that of the control group was 58.1±7.3 years. Longitudinal models indicated a significant decline in cognitive throughput ((β=-0.168, P=.001) following COVID-19, after adjustment for pre-COVID-19 functioning, demographics, and medical factors. The effect sizes were large; the observed changes in throughput were equivalent to 10.6 years of normal aging and a 59.8% increase in the burden of mild cognitive impairment. Cognitive decline worsened with coronavirus disease 2019 severity and was concentrated in participants reporting post-acute sequelae of SARS-CoV-2.

Conclusion COVID-19 was most likely associated with the observed cognitive decline, which was worse among patients with PASC or severe COVID-19. Monitoring patients with post-acute sequelae of SARS-CoV-2 for declines in the domains of processing speed and visual working memory and determining the long-term prognosis of this decline are therefore warranted.

Introduction

The World Health Organization and the Centers for Disease Control and Prevention use different criteria to define PASC as a condition characterized by persistent Coronavirus Disease 2019 (COVID-19) symptoms: the former requires symptoms to appear three months after the SARS-CoV-2 infection (COVID-19) onset and last for at least two months, while the latter requires at least four weeks of symptom persistence with no other explanation.

Cardiopulmonary such as dyspnea and chest pain, and neuropsychiatric symptoms such as brain fog, fatigue, headache, and depression were reported to be the most frequent complaints of PASC patients. Survivors of COVID-19 were found to seek more frequent medical care for respiratory, diabetes, and neuropsychiatric disorders at 6 months after the onset of SARS-CoV-2 infection compared to their pre-COVID-19 baseline.

Cognitive impairment has been reported as a prevalent and incapacitating condition among patients reporting the presence of post-acute sequelae of SARS-CoV-2 (PASC) that can persist for more than 12 weeks after COVID-19 symptom onset. Reported risk factors for COVID-19-related cognitive decline (CRCD) include common risk factors for age-related dementia including older age, more severe acute COVID-19 severity, female gender, educational attainment, angiotensin-converting enzyme 2 receptor overexpression, social isolation-related psychiatric symptoms, gut dysbiosis and dementia risk factors such as obesity, diabetes, cardiovascular disease, and hypertension. Intriguingly, COVID-19 vaccination can reduce the risk of CRCD both before and after contracting COVID-19, potentially via the removal of latent infections and the restoration of normal function of the immune and inflammatory systems.

Executive dysfunction is commonly reported following many infections including but not limited to West Nile virus, Human Immunodeficiency, Hepatitis C, and Chikungunya viruses. CRCD also appears to manifest as executive dysfunction and can include changes to working memory, verbal fluency, attention, and processing speed. Consistent with a view that COVID-19 might cause CRCD, executive dysfunction is associated with COVID-19 severity, and is evident in both mild and moderate COVID-19, irrespective of age at infection and may continue up to two years after COVID-19. Additionally, acute and subacute infarctions are the most common brain MRI findings in studies of neurological PASC, followed by olfactory bulb abnormalities, white matter abnormalities, cerebral microbleeds, and gray matter abnormalities. However, CRCD might manifest predominantly as subjective impairments, with difficulties in inattention, forgetfulness, and brain fog being frequently reported alongside other commonly presenting neurological symptoms such as headaches, fatigue, dizziness, sleep-related symptoms, and ageusia/anosmia. Yet, while subjective cognitive symptoms are important to functional limitations, they only mildly concur with changes to cognitive performance.

Despite growing concerns that PASC may cause cognitive impairment, existing research lacks control groups or pre-COVID-19 cognitive assessments. As cognitive impairment is a common comorbidity of PASC and may qualify people for accommodations and disability payments under the Americans with Disabilities Act, a recent viewpoint suggests more thorough studies of cognitive outcomes. Additionally, it remains unclear whether cognitive abnormalities result from SARS-CoV-2 infection or instead reflect pre-COVID-19 functioning that enhances susceptibility to severe COVID-19. In this study, we used a natural experiment that occurred when some essential workers were exposed to COVID-19 while others were not. We hypothesized that cognitive decline would correspond to SARS-CoV-2 infection and would be more severe in patients with more severe acute COVID-19 or PASC.

 


◆2-thiouridine is a broad-spectrum antiviral nucleoside analogue against positive-strand RNA viruses【PNAS　2023年10月13日】

Significance

Positive-sense single-stranded RNA (ssRNA+) viruses, such as dengue virus (DENV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have RNA-dependent RNA polymerase which is a promising target for broad-spectrum antivirals. We identified 2-thiouridine (s2U) as a broad-spectrum antiviral ribonucleoside analogue that exhibited antiviral activity against DENV. Furthermore, s2U inhibited SARS-CoV-2 infection including the currently circulating Omicron subvariants. In DENV2- or SARS-CoV-2-infected mice, s2U treatment significantly decreased viral load and improved survival rates. Since the efficacy of s2U against other ssRNA+ viruses including Zika virus, yellow fever virus, Japanese encephalitis virus, West Nile virus, Chikungunya virus, and other human coronaviruses was also identified, we demonstrated the potential clinical utility of s2U for Dengue, COVID-19, and other diseases caused by ssRNA+ viruses.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are causing significant morbidity and mortality worldwide. Furthermore, over 1 million cases of newly emerging or re-emerging viral infections, specifically dengue virus (DENV), are known to occur annually. Because no virus-specific and fully effective treatments against these or many other viruses have been approved, there is an urgent need for novel, effective therapeutic agents. Here, we identified 2-thiouridine (s2U) as a broad-spectrum antiviral ribonucleoside analogue that exhibited antiviral activity against several positive-sense single-stranded RNA (ssRNA+) viruses, such as DENV, SARS-CoV-2, and its variants of concern, including the currently circulating Omicron subvariants. s2U inhibits RNA synthesis catalyzed by viral RNA-dependent RNA polymerase, thereby reducing viral RNA replication, which improved the survival rate of mice infected with DENV2 or SARS-CoV-2 in our animal models. Our findings demonstrate that s2U is a potential broad-spectrum antiviral agent not only against DENV and SARS-CoV-2 but other ssRNA+ viruses.

 


◆SARS-CoV-2 infection correlates with male benign prostatic hyperplasia deterioration【WILEY Online Library　2023年10月18日】

Abstract

Introduction

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) affects extra-respiratory systems, with small-scale studies showing worsened male lower urinary tract symptoms (LUTS) after coronavirus disease 2019 (COVID-19). This study explores the correlation between SARS-CoV-2 infection and male benign prostatic hyperplasia (BPH) complications using large-scale real world data.

Materials and methods

All male patients attending the public healthcare system in Hong Kong receiving alpha-blocker monotherapy for LUTS from 2021 to 2022 were included in this study. Patients with and without positive polymerase chain reaction (PCR) test for SARS-CoV-2 are selected as the exposure group and control group, respectively. Baseline characteristics are retrieved, with propensity score matching performed to ensure balance of covariates between the two groups. BPH complications were then compared and subgroup analyses were performed.

Results

After propensity score matching, 17,986 patients were included for analysis, among which half had PCR-confirmed SARS-CoV-2 infection (n = 8993). When compared to controls, the SARS-CoV-2 group demonstrated statistically significant higher incidence of retention of urine (4.55% vs. 0.86%, p < 0.001), haematuria (1.36% vs. 0.41%, p < 0.001), clinical urinary tract infection (UTI) (4.31% vs. 1.49%, p < 0.001), culture-proven bacteriuria (9.02% vs. 1.97%, p < 0.001) and addition of 5ARI (0.50% vs. 0.02%, p < 0.001). Subgroup analysis demonstrated similar differences across different age groups. There are no statistically significance differences in incidence of retention, haematuria, or addition of 5ARI across different COVID-19 severities. Conclusions

SARS-CoV-2 infection is associated with increased incidence of urinary retention, haematuria, UTI and the addition of combination therapy in the short term, regardless of COVID-19 severity. This is the largest study demonstrating the detrimental urological effects of SARS-CoV-2 infection.

 


◆Rapid resistance profiling of SARS-CoV-2 protease inhibitors【bioRxiv　2023年2月27日】

Abstract

Resistance to nirmatrelvir (Paxlovid) has been shown by multiple groups and may already exist in clinical SARS-CoV-2 isolates. Here a panel of SARS-CoV-2 main protease (Mpro) variants and a robust cell-based assay are used to compare the resistance profiles of nirmatrelvir, ensitrelvir, and FB2001. The results reveal distinct resistance mechanisms (“fingerprints”) and indicate that these next-generation drugs have the potential to be effective against nirmatrelvir-resistant variants and vice versa.

Antiviral drugs are necessary to combat SARS-CoV-2/COVID-19, particularly with waning interest in the repeated vaccination boosts necessary to keep-up with virus evolution. The main protease (Mpro) of SARS-CoV-2 is essential for virus replication and, accordingly, a proven therapeutic target as evidenced by Paxlovid (active component: nirmatrelvir). However, as for drugs developed to treat other viruses and for first-generation SARS-CoV-2 vaccines, there is a high probability that variants will emerge that resist nirmatrelvir. Indeed, a flurry of recent studies has described a variety of candidate nirmatrelvir-resistance mutations. Thus, considerable urgency exists to develop next-generation Mpro inhibitors with different resistance mechanisms and, in parallel, robust systems to rapidly assess the potential impact of candidate resistance mutations.

 


◆Treatment of 95 post-Covid patients with SSRIs【nature：scientific reports　2023年11月2日】

Abstract

After Covid-19 infection, 12.5% develops post-Covid-syndrome (PCS). Symptoms indicate numerous affected organ systems. After a year, chronic fatigue, dysautonomia and neurological and neuropsychiatric complaints predominate. In this study, 95 PCS patients were treated with selective serotonin reuptake inhibitors (SSRIs). This study used an exploratory questionnaire and found that two-thirds of patients had a reasonably good to strong response on SSRIs, over a quarter of patients had moderate response, while 10% reported no response. Overall, patients experienced substantial improved well-being. Brainfog and sensory overload decreased most, followed by chronic fatigue and dysautonomia. Outcomes were measured with three different measures that correlated strongly with each other. The response to SSRIs in PCS conditions was explained by seven possible neurobiological mechanisms based on recent literature on PCS integrated with already existing knowledge. Important for understanding these mechanisms is the underlying biochemical interaction between various neurotransmitter systems and parts of the immune system, and their dysregulation in PCS. The main link appears to be with the metabolic kynurenine pathway (KP) which interacts extensively with the immune system. The KP uses the same precursor as serotonin: tryptophan. The KP is overactive in PCS which maintains inflammation and which causes a lack of tryptophan. Finally, potential avenues for future research to advance this line of clinical research are discussed.

 


◆A comparative characterization of SARS-CoV-2-specific T cells induced by mRNA or inactive virus COVID-19 vaccines【ScienceDirect　2022年11月15日】

Highlights

  • Inactivated SARS-CoV-2 vaccine induces a multi-protein-specific T cell response
  • The total T cell response is quantitatively similar to that induced by mRNA vaccine
  • Inactivated vaccine-induced multi-protein-specific T cells are primarily CD4+
  • The induced T cell responses tolerate the mutations of the Omicron viral lineage

Summary

Unlike mRNA vaccines based only on the spike protein, inactivated severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines should induce a diversified T cell response recognizing distinct structural proteins. Here, we perform a comparative analysis of SARS-CoV-2-specific T cells in healthy individuals following vaccination with inactivated SARS-CoV-2 or mRNA vaccines. Relative to spike mRNA vaccination, inactivated vaccines elicit a lower magnitude of spike-specific T cells, but the combination of membrane, nucleoprotein, and spike-specific T cell response is quantitatively comparable with the sole spike T cell response induced by mRNA vaccine, and they efficiently tolerate the mutations characterizing the Omicron lineage. However, this multi-protein-specific T cell response is not mediated by a coordinated CD4 and CD8 T cell expansion but by selective priming of CD4 T cells. These findings can help in understanding the role of CD4 and CD8 T cells in the efficacy of the different vaccines to control severe COVID-19 after Omicron infection.

Graphical abstract

 


◆Early Omicron infection is associated with increased reinfection risk in older adults in long-term care and retirement facilities【THE LANCET　2023年8月21日】

Summary

Background

Older adults are at increased risk of SARS-CoV-2 Omicron infection and severe disease, especially those in congregate living settings, despite high SARS-CoV-2 vaccine coverage. It is unclear whether hybrid immunity (combined vaccination and infection) after one Omicron infection provides increased protection against subsequent Omicron reinfection in older adults.

Methods

Incidence of SARS-CoV-2 Omicron infection was examined in 750 vaccinated residents of long-term care and retirement homes in the observational cohort COVID in Long-Term Care Study in Ontario, Canada, within a 75-day period (July to September 2022). Risk of infection was assessed by Cox proportional hazards regression. Serum anti-spike and anti-RBD SARS-CoV-2 IgG and IgA antibodies, microneutralization titres, and spike-specific T cell memory responses, were examined in a subset of 318 residents within the preceding three months.

Findings

133 of 750 participants (17.7%) had a PCR-confirmed Omicron infection during the observation period. Increased infection risk was associated with prior Omicron infection (at 9–29 days: 47.67 [23.73–95.76]), and this was not attributed to days since fourth vaccination (1.00 [1.00–1.01]) or residence outbreaks (>6 compared to ≤6: 0.95 [0.37–2.41]). Instead, reinfected participants had lower serum neutralizing antibodies to ancestral and Omicron BA.1 SARS-CoV-2, and lower anti-RBD IgG and IgA antibodies, after their initial Omicron infection.

Interpretation

Counterintuitively, SARS-CoV-2 Omicron infection was associated with increased risk of Omicron reinfection in residents of long-term care and retirement homes. Less robust humoral hybrid immune responses in older adults may contribute to risk of Omicron reinfection.

 


◆Prior COVID-19 infection is associated with persistent and higher thrombus burden in acute coronary syndromes【European Heart Journal　2023年11月9日】

Abstract

Background/Introduction

The COVID-19 pandemic challenged global healthcare systems by causing a multi-organ syndrome with a high mortality rate. COVID-19 infection is associated with a profound inflammatory response and hypercoagulability in the acute phase, however little is known on the persistence of endothelial dysfunction and hypercoagulability beyond this phase and its impact on acute coronary syndrome (ACS). 

Purpose

The purpose of this study was to investigate the effects of COVID-19 infection on the presentation and outcomes of coronary artery disease in patients with ACS.

Methods

A single centre prospective observational study was conducted from 10th of June 2020 to 6th of May 2021. Patients aged 18 or over presenting with ACS were included. Participants were excluded if they had active COVID-19 infection or if they did not undergo coronary angiography on admission.

Study participants were tested one presentation for SARS-CoV-2 nucleoprotein (N) antibody and SARS-CoV-2 spike protein receptor binding domain (RBD) antibody to determine whether the participants had prior COVID-19 infection, COVID-19 vaccination, or neither at the time of their presentation. Data was collected on their baseline demographics, angiographic findings, and treatments. Patients were followed up via telephone call and electronic case record review to assess outcomes at one year.

The primary end-point was all-cause mortality. Pre-specified secondary endpoints were cerebral infarction, repeat myocardial infarction or unplanned revascularisation and death (MACE) at one year, coronary artery ectasia, presence of thrombus, and thrombectomy requirement.

Results

280 patients were approached for the study. 5 refused participation, 8 were lost to follow-up, 2 did not undergo coronary angiography, and 98 had uninterpretable/insufficient blood samples for antibody analysis.

The remaining study population had 167 patients (median age 64 [43-85], 69.5% male). 22 (13.1%) had prior infection, 76 (45.5%) were antibody negative and 69 (41.3%) had a post COVID-19 immunisation response. 31.7% had diabetes mellitus, and 49.7% were smokers.

There was no difference in the primary endpoint between the groups. Patients with prior COVID-19 infection were more likely to have coronary ectasia/aneurysm compared to vaccinated and antibody negative patients (57.1% vs 27.5% and 30.3%, respectively p = 0.034). They were also more likely to have thrombosis (61.9% vs 33.3% and 52.6%, p = 0.019), and undergo thrombectomy (19.0% vs 4.3% and 3.9%, p=0.027).

Conclusions and Relevance

Our findings suggest that COVID-19 infection may lead to persistent endothelial dysfunction and hypercoagulability, portending increased severity of coronary artery ectasia and coronary thrombosis even after recovery from the initial infection.

 


◆Persistent cognitive slowing in post-COVID patients: longitudinal study over 6 months【SPRINGER LINK　2023年11月7日】

Abstract

Background

Fatigue is a frequent and one of the most debilitating symptoms in post-COVID syndrome (PCS). Recently, we proposed that fatigue is caused by hypoactivity of the brain’s arousal network and reflected by a reduction of cognitive processing speed. However, it is unclear whether cognitive slowing is revealed by standard neuropsychological tests, represents a selective deficit, and how it develops over time.

Objectives

This prospective study assesses whether PCS patients show deficits particularly in tests relying on processing speed and provides the first longitudinal assessment focusing on processing speed in PCS patients.

Methods

Eighty-eight PCS patients with cognitive complaints and 50 matched healthy controls underwent neuropsychological assessment. Seventy-seven patients were subsequently assessed at 6-month follow-up. The Test for Attentional Performance measured tonic alertness as primary study outcome and additional attentional functions. The Neuropsychological Assessment Battery evaluated all key cognitive domains.

Results

Patients showed cognitive slowing indicated by longer reaction times compared to control participants (r = 0.51, p < 0.001) in a simple-response tonic alertness task and in all more complex tasks requiring speeded performance. Reduced alertness correlated with higher fatigue (r =  − 0.408, p < 0.001). Alertness dysfunction remained unchanged at 6-month follow-up (p = 0.240) and the same was true for most attention tasks and cognitive domains. Conclusion

Hypoarousal is a core deficit in PCS which becomes evident as a selective decrease of processing speed observed in standard neuropsychological tests. This core deficit persists without any signs of amelioration over a 6-month period of time.

Introduction

It is now well established that post-COVID syndrome (PCS) represents a serious complication in a substantial number of patients following SARS-CoV-2 infection. PCS is diagnosed when COVID-19-related symptoms persist for more than 3 months. It can occur even after an initially mild to moderate course of infection, and comprise a large variety of symptoms. Around 30% of PCS patients show neurological and neuropsychiatric sequelae, such as fatigue, depressive symptoms, and cognitive dysfunction. These are experienced as particularly debilitating, as they have detrimental effects on daily functioning in PCS patients and hamper a successful return to their jobs.

Recently, we proposed that fatigue is caused by hypoactivity within the brain’s arousal network, reflected by a fundamental slowing of processing speed in PCS patients. In particular, the variance of (visual) processing speed in a laboratory task was explained by a neurophysiological measure of central nervous arousal, i.e., pupillary unrest, and the level of subjective mental fatigue. Thus, based on our data, processing speed not only seems to represent a reliable measure of the brain’s activation level, but it can also provide an objective proof of the subjective feeling of mental fatigue.

Although these results may represent an important step towards a better understanding of the neurocognitive deficits in PCS patients, a number of questions arise from this preceding study: first, it remains unclear whether a reduction of processing speed can be evidenced in standard neuropsychological assessment procedures as well. Given the high prevalence of PCS, the suitability of conventional, clinically established tests for disclosing processing speed deficits would be of great practical significance. Second, in our preceding study, we were not able to assess whether cognitive domains other than processing speed are also affected by the underlying arousal deficit. A demonstration that processing speed is selectively impaired in PCS patients would bear strong support for our hypoarousal model. Finally, it remains unknown whether hypoarousal is a temporary and transient, or a persisting problem in PCS patients. This is an important question for estimating the probability whether PCS patients are able to re-uptake their job in the near future. However, while subjective complaints of fatigue are known to prevail even after 2 years, follow-up observations including an objective measure of fatigue are still lacking. Hence, longitudinal assessment of processing speed is urgently required.

Thus, the first aim of the present study was to analyze whether a reduction of processing speed in PCS patients is evidenced in conventional neuropsychological tests as applied in a standard clinical setting. We compared PCS patients with cognitive complaints to sociodemographically matched healthy control participants and used tonic alertness, measured in a clinically established simple-response task, as our primary outcome. The second aim was to assess whether reduced processing speed is a selective deficit in PCS patients. We employed a computerized reaction time-based neuropsychological assessment procedure and a comprehensive test battery to explore whether the overall cognitive profile across different relevant cognitive domains would be indicative of particular deficits in tasks reliant on fast information processing speed. As secondary outcomes, we explored whether speed-dependent measures in general, such as reaction times and test scores relying on task completion times, were compromised in PCS patients. Additionally, we investigated whether test scores less dependent on processing speed were less affected. Third, to corroborate the relationship between hypoarousal and fatigue, we investigated whether performance in the primary outcome tonic alertness simple-response measure and the other measures that tapped processing speed was related to the degree of experienced fatigue. As a fourth aim of our study, we included a follow-up assessment after 6 months to evaluate whether processing speed deficits persist or ameliorate over time. To our knowledge, this is the first longitudinal study that particularly addresses processing speed, i.e., alertness dysfunction in PCS patients with cognitive complaints.