SARS-CoV-2 と COVID-19 に関する備忘録 Vol.25――オミクロン感染により脳の一部が縮小した、COVID-19持続感染が心不全を起こしやすくする…etc.

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Gray Matter Thickness and Subcortical Nuclear Volume in Men After SARS-CoV-2 Omicron Infection【JAMA Network　2023年11月30日】

Key Points

Question What are the clinical manifestations and brain microstructural changes associated with the SARS-CoV-2 Omicron variant in the acute phase after infection?

Findings In this cohort study of 61 male patients with Omicron infection, the gray matter thickness in the left precuneus and right lateral occipital region and the ratio of the right hippocampus volume to the total intracranial volume were significantly reduced in the acute phase. Gray matter thickness and subcortical nuclear volume injury were significantly associated with anxiety and cognitive function.

Meaning These findings may provide new insights into the emotional and cognitive mechanisms affected by an Omicron infection, demonstrate its association with nervous system symptoms, and provide an imaging basis for early detection and intervention for neurological sequelae.

Abstract

Importance The clinical manifestations and effects on the brain of the SARS-CoV-2 Omicron variant in the acute postinfection phase remain unclear.

Objective To investigate the pathophysiological mechanisms underlying clinical symptoms and changes to gray matter and subcortical nuclei among male patients after Omicron infection and to provide an imaging basis for early detection and intervention.

Design, Setting, and Participants In this cohort study, a total of 207 men underwent health screening magnetic resonance imaging scans between August 28 and September 18, 2022; among them, 98 provided complete imaging and neuropsychiatric data. Sixty-one participants with Omicron infection were reevaluated after infection (January 6 to 14, 2023). Neuropsychiatric data, clinical symptoms, and magnetic resonance imaging data were collected in the acute post-Omicron period, and their clinical symptoms were followed up after 3 months. Gray matter indexes and subcortical nuclear volumes were analyzed. Associations between changes in gray matter and neuropsychiatric data were evaluated with correlation analyses.

Exposures Gray matter thickness and subcortical nuclear volume change data were compared before and after Omicron infection.

Main Outcomes and Measures The gray matter indexes and subcutaneous nuclear volume were generated from the 3-dimensional magnetization-prepared rapid acquisition gradient echo and were calculated with imaging software.

Results Ninety-eight men underwent complete baseline data collection; of these, 61 (mean [SD] age, 43.1 [9.9] years) voluntarily enrolled in post-Omicron follow-up and 17 (mean [SD] age, 43.5 [10.0] years) voluntarily enrolled in 3-month follow-up. Compared with pre-Omicron measures, Beck Anxiety Inventory scores were significantly increased (median, 4.50 [IQR, 1.00-7.00] to 4.00 [IQR, 2.00-9.75]; P = .006) and depressive distress scores were significantly decreased (median, 18.00 [IQR, 16.00-20.22] to 16.00 [IQR, 15.00-19.00]; P = .003) at the acute post-Omicron follow-up. Fever, headache, fatigue, myalgia, cough, and dyspnea were the main symptoms during the post-Omicron follow-up; among the participants in the 3-month follow-up, fever (11 [64.7%] vs 2 [11.8%]; P = .01), myalgia (10 [58.8%] vs 3 (17.6%]; P = .04), and cough (12 [70.6%] vs 4 [23.5%]; P = .02) were significantly improved. The gray matter thickness in the left precuneus (mean [SD], 2.7 [0.3] to 2.6 [0.2] mm; P < .001) and right lateral occipital region (mean [SD], 2.8 [0.2] to 2.7 [0.2] and 2.5 [0.2] to 2.5 [0.2] mm; P < .001 for both) and the ratio of the right hippocampus volume to the total intracranial volume (mean [SD]. 0.003 [0.0003] to 0.003 [0.0002]; P = .04) were significantly reduced in the post-Omicron follow-up. The febrile group had reduced sulcus depth of the right inferior parietal region compared with the nonfebrile group (mean [SD], 3.9 [2.3] to 4.8 [1.1]; P = .048. In the post-Omicron period, the thickness of the left precuneus was negatively correlated with the Beck Anxiety Inventory scores (r = −0.39; P = .002; false discovery rate P = .02), and the ratio of the right hippocampus to the total intracranial volume was positively correlated with the Word Fluency Test scores (r = 0.34; P = .007). Conclusions and Relevance In this cohort study of male patients infected with the Omicron variant, the duration of symptoms in multiple systems after infection was short. Changes in gray matter thickness and subcortical nuclear volume injury were observed in the post-Omicron period. These findings provide new insights into the emotional and cognitive mechanisms of an Omicron infection, demonstrate its association with alterations to the nervous system, and verify an imaging basis for early detection and intervention of neurological sequelae.

Introduction

According to a report by the Global Initiative on Sharing Avian Influenza Data, genomic surveillance and preliminary phylogenetic analysis of data from China since the abolition of the zero COVID-19 policy (in December 2022) have shown that the patterns of introduced variation and risks in China were similar to those seen globally, and the strains infecting China were dominated by the SARS-CoV-2 Omicron variant. During the Omicron variant phase of the pandemic in China, from December 1, 2022, through March 1, 2023, we collected alveolar lavage fluid from 157 hospitalized patients, of whom 40 were diagnosed with COVID-19. Subsequently, 6 cases underwent genetic sequencing of the Omicron variant, and the results were Omicron BA.5.2. Several follow-up studies have shown that, similar to infections of the SARS-CoV-2 Delta variant, Omicron infection has multiple systemic symptoms, including respiratory, neurological, and digestive symptoms, and neurological sequelae are becoming the focus of attention.

Long-term COVID-19 neurological sequelae (≥90 days) are diverse and include clinical symptoms (dizziness, headache, olfactory and taste disturbances, and motor delay), neuropsychiatric symptoms (insomnia, depression, anxiety, and reduced cognitive function), and structural and functional changes in the brain. In addition, severe neurological symptoms such as acute ischemic stroke, encephalitis, and acute necrotizing encephalopathy in the acute phase of SARS-CoV-2 infection (14-29 days) in individual cases have also been reported in the literature. However, few individuals with mild neurological symptoms in the acute phase receive comprehensive neuropsychiatric assessment and magnetic resonance imaging (MRI) examinations, and few studies have focused on neuropsychiatric changes and brain microstructural damage after infection with the Omicron variant. Therefore, we aimed to explore clinical symptoms and brain structural changes in the acute phase of SARS-CoV-2 Omicron infection (hereinafter referred to as the post-Omicron phase) for early detection of and intervention for possible neurological sequelae to alleviate the burden on society and the health care system.

We prospectively collected clinical symptom data, neuropsychiatric findings, and MRI examination results of the same group of participants, with the aim of exploring the changes in brain structure between the pre-Omicron and post-Omicron phases and the changes in symptoms across systems in the post-Omicron phase and 3 months after infection. The changes in gray matter and subcortical nucleus volume were investigated in a data-driven manner. Finally, correlation analysis was performed to explore whether brain microstructure alterations were associated with neuropsychiatric scale scores.

 

◆Infectivity of exhaled SARS-CoV-2 aerosols is sufficient to transmit covid-19 within minutes【nature : scientific reports　2023年12月1日】

Abstract

Exhaled SARS-CoV-2-containing aerosols contributed significantly to the rapid and vast spread of covid-19. However, quantitative experimental data on the infectivity of such aerosols is missing. Here, we quantified emission rates of infectious viruses in exhaled aerosol from individuals within their first days after symptom onset from covid-19. Six aerosol samples from three individuals were culturable, of which five were successfully quantified using TCID50. The source strength of the three individuals was highest during singing, when they exhaled 4, 36, or 127 TCID50/s, respectively. Calculations with an indoor air transmission model showed that if an infected individual with this emission rate entered a room, a susceptible person would inhale an infectious dose within 6 to 37 min in a room with normal ventilation. Thus, our data show that exhaled aerosols from a single person can transmit covid-19 to others within minutes at normal indoor conditions.

Introduction

The transmission routes that enabled the efficient spread of covid-19 have been debated, but it has become evident that short-range aerosol transmission has contributed significantly. However, as the infectivity peaks at or even before symptom onset it has been challenging to collect experimental data on the quantified infectivity of exhaled SARS-CoV-2 aerosols.

Three previous studies have reported attempts to cultivate exhaled aerosol samples from patients with covid-19. In one of these, no aerosol samples were positive when cultured, but the other two studies reported qualitative results of culture-positive virus in exhaled air. Two additional studies successfully quantified SARS-CoV-2 infectivity of aerosol samples. However, these were from room or car air, and collected over hours which made it difficult to derive emission rates. Moreover, Kitagawa et al. recently measured the 50% tissue culture infectious dose (TCID50) in air samples from a hospital patient room, but did not calculate individual emission rates. To our knowledge, no quantification has been done on virus isolated from exhaled aerosols of infected individuals. Nevertheless, this data is crucial for exposure assessments. Thus, critical information on emissions of infectious SARS-CoV-2 from exhaled air is still missing.

Source emission rates are crucial for modelling airborne transmission, which is key to estimate the risk for infection in different settings. Previously, we described an indoor air model for calculating the inhaled dose rate for SARS-CoV-2. However, calculation of exposure time to acquire an infection was uncertain as information was missing about infectious dose, size of the virus-containing aerosol particles and emission rates of SARS-CoV-2. These missing pieces of information are now available. Recently, a human challenge study instilled virus in the nose of human test subjects and presented a quantitative value of TCID50 representing one infectious dose, ID50, for SARS-CoV-2. There is also new information available on the particle size of virus containing aerosols. Thus, the quantified infectivity of exhaled SARS-CoV-2 is the remaining key to estimating the exposure time needed to acquire infection for people in contact with someone who exhales infectious SARS-CoV-2.

The aim of this study was to measure the emission rate of infectious exhaled SARS-CoV-2 and thereafter estimate the time needed to inhale an infectious dose. We isolated SARS-CoV-2 from exhaled aerosol samples collected in a previous study and quantified their infectivity. Finally, we calculated the inhaled deposited dose based on a previously described indoor air transmission model.

 

◆Long-term outcomes following hospital admission for COVID-19 versus seasonal influenza: a cohort study【THE LANCET　2023年12月14日】

Summary

Background

Previous comparative analyses of people admitted to hospital for COVID-19 versus influenza evaluated the risk of death, hospital readmission, and a narrow set of health outcomes up to 6 months following infection. We aimed to do a comparative evaluation of both acute and long-term risks and burdens of a comprehensive set of health outcomes following hospital admission for COVID-19 or seasonal influenza.

Methods

For this cohort study we used the health-care databases of the US Department of Veterans Affairs to analyse data from 81 280 participants admitted to hospital for COVID-19 between March 1, 2020, and June 30, 2022, and 10 985 participants admitted to hospital for seasonal influenza between Oct 1, 2015, and Feb 28, 2019. Participants were followed up for up to 18 months to comparatively evaluate risks and burdens of death, a prespecified set of 94 individual health outcomes, ten organ systems, overall burden across all organ systems, readmission, and admission to intensive care. Inverse probability weighting was used to balance the baseline characteristics. Cox and Poisson models were used to generate estimates of risk on both the relative scale and absolute scale as the event rate and disability-adjusted life-years (DALYs) per 100 persons.

Findings

Over 18 months of follow-up, compared to seasonal influenza, the COVID-19 group had an increased risk of death (hazard ratio [HR] 1·51 [95% CI 1·45–1·58]), corresponding to an excess death rate of 8·62 (95% CI 7·55–9·44) per 100 persons in the COVID-19 group versus the influenza group. Comparative analyses of 94 prespecified health outcomes showed that COVID-19 had an increased risk of 68·1% (64 of 94) pre-specified health outcomes; seasonal influenza was associated with an increased risk of 6·4% (six of 94) pre-specified health outcomes, including three out of four pre-specified pulmonary outcomes. Analyses of organ systems showed that COVID-19 had a higher risk across all organ systems except for the pulmonary system, the risk of which was higher in seasonal influenza. The cumulative rates of adverse health outcomes across all organ systems were 615·18 (95% CI 605·17–624·88) per 100 persons in COVID-19 and 536·90 (527·38–544·90) per 100 persons in seasonal influenza, corresponding to an excess rate of 78·72 (95% CI 66·15–91·24) per 100 persons in COVID-19. The total number of DALYs across all organ systems were 287·43 (95% CI 281·10–293·59) per 100 persons in the COVID-19 group and 242·66 (236·75, 247·67) per 100 persons in the seasonal influenza group, corresponding to 45·03 (95% CI 37·15–52·90) higher DALYs per 100 persons in COVID-19. Decomposition analyses showed that in both COVID-19 and seasonal influenza, there was a higher burden of health loss in the post-acute than the acute phase; and comparatively, except for the pulmonary system, COVID-19 had a higher burden of health loss across all other organ systems than seasonal influenza in both the acute and post-acute phase. Compared to seasonal influenza, COVID-19 also had an increased risk of hospital readmission (excess rate 20·50 [95% CI 16·10–24·86] per 100 persons) and admission to intensive care (excess rate 9·23 [6·68–11·82] per 100 persons). The findings were consistent in analyses comparatively evaluating risks in seasonal influenza versus COVID-19 by individuals’ respective vaccination status and in those admitted to hospital during the pre-delta, delta, and omicron eras.

Interpretation

Although rates of death and adverse health outcomes following hospital admission for either seasonal influenza or COVID-19 are high, this comparative analysis shows that hospital admission for COVID-19 was associated with higher long-term risks of death and adverse health outcomes in nearly every organ system (except for the pulmonary system) and significant cumulative excess DALYs than hospital admission for seasonal influenza. The substantial cumulative burden of health loss in both groups calls for greater prevention of hospital admission for these two viruses and for greater attention to the care needs of people with long-term health effects due to either seasonal influenza or SARS-CoV-2 infection.

 

◆Mechanisms of long COVID: An updated review【ScienceDirect　2023年12月6日】

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has been ongoing for more than 3 years, with an enormous impact on global health and economies. In some patients, symptoms and signs may remain after recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which cannot be explained by an alternate diagnosis; this condition has been defined as long COVID. Long COVID may exist in patients with both mild and severe disease and is prevalent after infection with different SARS-CoV-2 variants. The most common symptoms include fatigue, dyspnea, and other symptoms involving multiple organs. Vaccination results in lower rates of long COVID. To date, the mechanisms of long COVID remain unclear. In this narrative review, we summarized the clinical presentations and current evidence regarding the pathogenesis of long COVID.

 

◆SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells【nature immunology　2023年11月2日】

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA generally becomes undetectable in upper airways after a few days or weeks postinfection. Here we used a model of viral infection in macaques to address whether SARS-CoV-2 persists in the body and which mechanisms regulate its persistence. Replication-competent virus was detected in bronchioalveolar lavage (BAL) macrophages beyond 6 months postinfection. Viral propagation in BAL macrophages occurred from cell to cell and was inhibited by interferon-γ (IFN-γ). IFN-γ production was strongest in BAL NKG2r+CD8+ T cells and NKG2Alo natural killer (NK) cells and was further increased in NKG2Alo NK cells after spike protein stimulation. However, IFN-γ production was impaired in NK cells from macaques with persisting virus. Moreover, IFN-γ also enhanced the expression of major histocompatibility complex (MHC)-E on BAL macrophages, possibly inhibiting NK cell-mediated killing. Macaques with less persisting virus mounted adaptive NK cells that escaped the MHC-E-dependent inhibition. Our findings reveal an interplay between NK cells and macrophages that regulated SARS-CoV-2 persistence in macrophages and was mediated by IFN-γ.

Main

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates in both upper and lower airways, with viral RNA detectable days before symptoms, peaking within the first week, and gradually declining due to host antiviral responses. However, cellular and humoral immune responses, as well as the activation of neural pathways, can collectively contribute to distant inflammatory effects. Furthermore, in some SARS-CoV-2-infected individuals, complete clearance of the virus does not appear to occur over extended periods.

Macrophages (Mac) and natural killer (NK) cells are frontline innate effector cells against pathogens. Mac responds to microbial threats by producing inflammatory molecules, phagocytosing pathogens and promoting tissue repair. Dysregulated Macs, as observed during SARS-CoV-2 infection, can harm the host, such as in the infection-induced Mac activation syndrome. Mac comprises about 70% of the total leukocyte population in the lung and can be exploited by various viruses, including respiratory syncytial virus, for dissemination, long-term tissue persistence and virus replication. SARS-CoV-2 can infect monocytes and Macs through different pathways, but whether the virus can complete its lifecycle in these cells is still debated.

NK cells are crucial innate immune responders responsible for viral clearance and can modulate adaptive T and B cell responses. However, their contribution to SARS-CoV-2 immunity remains unclear. High NK cell levels in blood correlate with a rapid viral load decline, but NK cell frequency often decreases in the blood during early SARS-CoV-2 infection, and NK cells display an exhaustion phenotype. While NK cells from healthy individuals can directly kill SARS-CoV-2-infected cells in vitro, those from moderate or severe cases exhibit impaired cytotoxic activity.

Nonhuman primate (NHP) models are vital tools for understanding immune cell functioning and responses in tissues, particularly when studying human infectious diseases. We used an NHP model (cynomolgus macaques) to investigate lung-resident Mac and NK cell responses to SARS-CoV-2 (wild-type or Omicron strains) infection. We detected replication-competent SARS-CoV-2 in bronchoalveolar fluid (BALF) Mac for up to 18 months after infection. Interferon-γ (IFN-γ) inhibited SARS-CoV-2 replication in these BALF Mac. However, IFN-γ production was reduced in NK cells from some macaques. IFN-γ facilitated the resistance to NK cell-mediated killing through upregulation of major histocompatibility complex (MHC)-E on the cell surface of bronchioalveolar lavage (BAL) Mac, which promoted the persistence of the infected cells.

 

◆SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells【cell iScience　2023年12月22日】

Highlights

  • Persistent SARS-CoV-2 infection model of human cardiac tissue was established
  • Hypoxic stress to the persistent infection model led to cardiac dysfunction
  • ACE2 and SARS-CoV-2 S protein expression were elevated after the hypoxic stress
  • This research may predict a “heart failure pandemic” in the post COVID-19 era

Summary

Patients with chronic cardiomyopathy may have persistent viral infections in their hearts, particularly with SARS-CoV-2, which targets the ACE2 receptor highly expressed in human hearts. This raises concerns about a potential global heart failure pandemic stemming from COVID-19, an SARS-CoV-2 pandemic in near future. Although faced with this healthcare caveat, there is limited research on persistent viral heart infections, and no models have been established. In this study, we created an SARS-CoV-2 persistent infection model using human iPS cell-derived cardiac microtissues (CMTs). Mild infections sustained viral presence without significant dysfunction for a month, indicating persistent infection. However, when exposed to hypoxic conditions mimicking ischemic heart diseases, cardiac function deteriorated alongside intracellular SARS-CoV-2 reactivation in cardiomyocytes and disrupted vascular network formation. This study demonstrates that SARS-CoV-2 persistently infects the heart opportunistically causing cardiac dysfunction triggered by detrimental stimuli such as ischemia, potentially predicting a post COVID-19 era heart failure pandemic.

◆The role of COVID-19 vaccines in preventing post COVID-19 thromboembolic and cardiovascular complications: a multinational cohort study【medRxiv　2023年6月29日】

Abstract

Importance The overall effects of vaccination on the risk of cardiac, and venous and arterial thromboembolic complications following COVID-19 remain unclear.

Objective We studied the association between COVID-19 vaccination and the risk of acute and subacute COVID-19 cardiac and thromboembolic complications.

Design Multinational staggered cohort study, based on national vaccination campaign rollouts.

Setting Network study using electronic health records from primary care records from the UK, primary care data linked to hospital data from Spain, and national insurance claims from Estonia.

Participants All adults with a prior medical history of ≥180 days, with no history of COVID-19 or previous COVID-19 vaccination at the beginning of vaccine rollout were eligible.

Exposure Vaccination status was used as a time-varying exposure. Vaccinated individuals were classified by vaccine brand according to the first dose received.

Main Outcomes Post COVID-19 complications including myocarditis, pericarditis, arrhythmia, heart failure (HF), venous (VTE) and arterial thromboembolism (ATE) up to 1 year after SARS-CoV-2 infection.

Measures Propensity Score overlap weighting and empirical calibration based on negative control outcomes were used to minimise bias due to observed and unobserved confounding, respectively. Fine-Gray models were fitted to estimate sub-distribution Hazard Ratios (sHR) for each outcome according to vaccination status. Random effect meta-analyses were conducted across staggered cohorts and databases.

Results Overall, 10.17 million vaccinated and 10.39 million unvaccinated people were included. Vaccination was consistently associated with reduced risks of acute (30-day) and subacute post COVID-19 VTE and HF: e.g., meta-analytic sHR 0.34 (95%CI, 0.27-0.44) and 0.59 (0.50-0.70) respectively for 0-30 days, sHR 0.58 (0.48 – 0.69) and 0.71 (0.59 – 0.85) respectively for 90-180 days post COVID-19. Additionally, reduced risks of ATE, myocarditis/pericarditis and arrhythmia were seen, but mostly in the acute phase (0-30 days post COVID-19).

Conclusions COVID-19 vaccination reduced the risk of post COVID-19 complications, including cardiac and thromboembolic outcomes. These effects were more pronounced for acute (1-month) post COVID-19 outcomes, consistent with known reductions in disease severity following breakthrough vs unvaccinated SARS-CoV-2 infection.

Relevance These findings highlight the importance of COVID-19 vaccination to prevent cardiovascular outcomes after COVID-19, beyond respiratory disease.

Question What is the impact of COVID-19 vaccination to prevent cardiac complications and thromboembolic events following a SARS-CoV-2 infection?

Findings Results from this multinational cohort study showed that COVID-19 vaccination reduced risk for acute and subacute COVID-19 heart failure, as well as venous and arterial thromboembolic events following SARS-CoV-2 infection.

Meaning These findings highlight yet another benefit of vaccination against COVID-19, and support the recommendations for COVID-19 vaccination even in people at high cardiovascular risk.