SARS-CoV-2 と COVID-19 に関する備忘録 Vol.9――Long COVID、なぜ味覚が無くなるか？…etc.

投稿日投稿者しとらす

SARS-CoV-2 と COVID-19 に関するメモ・備忘録


◆Impact of COVID-19 on Physical Fitness in Central Indian Athletes Aged 20-30 Years: A Cross-Sectional Pilot Study【Cureus　2023年9月28日】

Abstract

Background

Physical fitness is of utmost importance to athletes as it ensures better performance in competitive sports. Athletes who contracted COVID-19 frequently experienced persistent symptoms for weeks or months afterward. Due to the direct effects of COVID-19 infection on pulmonary, cardiovascular, and neurological systems, combined with the negative effects of isolation and inactivity, it has been observed that physical fitness decreases in individuals. This study aimed to evaluate the physical fitness of young athletes in the age group of 20 to 30 years after mild-to-moderate COVID-19 infection and compare them with unaffected athletes of the same age group.

Methodology

A field-based, cross-sectional, comparative study was conducted from July 2022 to August 2022 in Nagpur, India. Physical fitness levels of 50 young athletes in the age group of 20-30 years who never got infected with COVID-19 were compared to 50 athletes with a recent history of mild-to-moderate COVID-19 infection using the Harvard step test, breath-holding test, and peak expiratory flow rate measurement. Participants were included based on COVID-19 diagnosis using standard procedures and confirmation of recovery through negative reverse transcriptase polymerase chain reaction tests.

Results

Overall physical fitness of athletes who suffered from mild-to-moderate COVID-19 infection was significantly less than those who were not infected. Compared to their non-COVID-19 counterparts, the COVID-19-recovered athletes showed reduced physical fitness index (p < 0.0001 for males and p = 0.0003 for females), reduced peak expiratory flow rate (p < 0.0001 for males and p < 0.0001 for females), and reduced breath-holding time (p < 0.0001 for males and p < 0.0001 for females). Conclusions

COVID-19 had a significant impact on various components of physical fitness which may potentially affect the athletic performance and overall well-being of young athletes.

Introduction

The COVID-19 pandemic has not only posed a threat to public health but has also disrupted various aspects of society, including sports and physical activities. Young athletes, who are essential contributors to the sporting world, have been affected by the virus and its associated consequences. There are now consistent reports of athletes reporting persistent and residual symptoms many weeks to months after COVID-19 infection.

The main site of COVID-19 infection is the lungs, as the virus gets into the body through the respiratory pathway. The infection starts spreading in one lung and progressively into another leading to impairment of the lungs to swap oxygen and carbon dioxide. Physical exercise is considered key for its general benefits as well as a method to help airway clearance. All body organs must function properly for good physical fitness; the effects of COVID-19 infection on the lungs may cause complications. As the body’s need for oxygen increases with higher levels of physical activity, a reduction in oxygen consumption may result in decreased physical strength, capability, and endurance. Good physical fitness is the foundation of sports; an athlete with good physical fitness not only improves the efficiency of learning sports abilities but also reduces the risk of injuries and mishaps.

The purpose of this pilot study was to investigate the effects of COVID-19 infection on the physical fitness of young athletes aged 20 to 30 years. By examining the various components of physical fitness, this study aimed to provide preliminary insights into the potential long-term impact of COVID-19 on the athletic performance and overall well-being of this population.

 


◆Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms【medRxiv　2023年10月4日】

Abstract

Background Autoimmune responses contribute to the pathophysiology of Long COVID, affective symptoms and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Objectives To examine whether Long COVID, and its accompanying affective symptoms and CFS are associated with immunoglobulin (Ig)A/IgM/IgG directed at neuronal proteins including myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), synapsin, α+β-tubulin, neurofilament protein (NFP), cerebellar protein-2 (CP2), and the blood-brain-barrier-brain-damage (BBD) proteins claudin-5 and S100B.

Methods IgA/IgM/IgG to the above neuronal proteins, human herpes virus-6 (HHV-6) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were measured in 90 Long COVID patients and 90 healthy controls, while C-reactive protein (CRP), and advanced oxidation protein products (AOPP) in association with affective and CFS ratings were additionally assessed in a subgroup thereof.

Results Long COVID is associated with significant increases in IgG directed at tubulin (IgG-tubulin), MBP, MOG and synapsin; IgM-MBP, MOG, CP2, synapsin and BBD; and IgA-CP2 and synapsin. IgM-SARS-CoV-2 and IgM-HHV-6 antibody titers were significantly correlated with IgA/IgG/IgM-tubulin and -CP2, IgG/IgM-BBD, IgM-MOG, IgA/IgM-NFP, and IgG/IgM-synapsin. Binary logistic regression analysis shows that IgM-MBP and IgG-MBP are the best predictors of Long COVID. Multiple regression analysis shows that IgG-MOG, CRP and AOPP explain together 41.7% of the variance in the severity of CFS. Neural network analysis shows that IgM-synapsin, IgA-MBP, IgG-MOG, IgA-synapsin, IgA-CP2, IgG-MBP and CRP are the most important predictors of affective symptoms due to Long COVID with a predictive accuracy of r=0.801.

Conclusions Brain-targeted autoimmunity contributes significantly to the pathogenesis of Long COVID and the severity of its physio-affective phenome.

Introduction

Ongoing neuro-psychiatric symptoms have been reported in a substantial percentage of coronavirus disease (COVID) survivors (Davis, McCorkell et al. 2023). These symptoms encompass chronic fatigue syndrome (CFS), depression, and anxiety persisting for up to 12 months post-recovery, commonly known as “Long COVID disease” (Groff, Sun et al. 2021, Lopez-Leon, Wegman-Ostrosky et al. 2021, Premraj, Kannapadi et al. 2022). Recent data reveal that globally, at least 65 million individuals suffer from Long COVID disease (Davis, McCorkell et al. 2023).

In a recent previous article co-authored by some of the present’s study collaborators, it was observed that CFS and affective symptoms due to Long COVID are predicted by elevated peak body temperature (PBT) and decreased oxygen saturation (SpO2) during the acute phase of illness (Al-Hadrawi, Al-Rubaye et al. 2022). Both PBT and lower SpO2 are indices of the severity of the immune-inflammatory response during acute infection (Al-Jassas, Al-Hakeim et al. 2022). In another article by some of this study’s authors, a validated latent vector could be extracted from the CFS, fibromyalgia, depressive and anxiety symptoms due to acute and Long COVID and this latent construct was named the “physio-affective phenome” of acute COVID-19 (Al-Jassas, Al-Hakeim et al. 2022) or Long COVID (Al-Hadrawi, Al-Rubaye et al. 2022, Al-Hakeim, Al-Rubaye et al. 2022, Al-Hakeim, Al-Rubaye et al. 2022, Maes, Al-Rubaye et al. 2022).

However, there is still much debate on what causes Long COVID disease and the severity of CFS, depression and anxiety symptoms due to Long COVID. In this context, in yet another study, some of the same authors have identified molecular pathways implicated in the onset of symptoms in individuals with Long COVID disease, including activation of immune-inflammatory processes with oxidative and nitrosative stress reactions (Al-Hakeim, Al-Rubaye et al. 2022, Al-Hakeim, Al-Rubaye et al. 2022), increased insulin resistance (Al-Hakeim, Al-Rubaye et al. 2023, Maes, Almulla et al. 2023), decreased tryptophan levels and increased tryptophan catabolites, such as kynurenine (Al-Hakeim, Abed et al. 2023, Al-Hakeim, Khairi Abed et al. 2023). Moreover, a recent meta-analysis reported that Long COVID disease is accompanied by increased C-reactive protein (CRP), D-dimer, lactate dehydrogenase, leukocytes, lymphocytes, and interleukin (IL)-6 (Yong, Halim et al. 2023).

Recently, Vojdani et al. discovered that Long COVID patients show elevated levels of immunoglobulins (Ig) IgG/IgM directed against Severe Acute Respiratory Syndrome Coronavirus 2 (IgG/IgM-SARS-CoV-2), human Herpesvirus type 6 (HHV-6) and its deoxyuridine 5′-triphosphate nucleotidohydrolase (HHV-6-duTPase) along with IgA/IgM at activin-A (a self-antigen) (Vojdani, Almulla et al. 2023). These findings confirmed previous studies which indicated that Long COVID disease is accompanied by persistence of SARS-CoV-2, reactivation of dormant viruses, and autoimmune reactions against self-proteins (Acosta-Ampudia, Monsalve et al. 2022, Rojas, Rodríguez et al. 2022, Su, Yuan et al. 2022, Vojdani, Vojdani et al. 2023). Importantly, Vojdani et al. were able to predict the Long COVID diagnosis with high sensitivity (78.9%) and specificity (81.8%) based on elevated levels of IgA-activin-A, IgG-HHV-6, IgM-HHV-6-duTPase, IgG-SARS-CoV-2, and IgM-HHV-6, and a factor extracted from all IgA levels to all viral antigens (Vojdani, Almulla et al. 2023).

Neurological disease, which involves both the central and peripheral nervous systems, is observed in more than one-third of patients with COVID-19 and long COVID (Stefanou, Palaiodimou et al. 2022). The entry of SARS-CoV-2 into central nervous system (CNS) cells is facilitated via the engagement of the virus with the angiotensin-converting enzyme (ACE) receptor on the surface of neurons, endothelial and smooth muscle cells of the cerebral blood vessels (Stefanou, Palaiodimou et al. 2022). This entry of the virus, and the entry of T helper (Th)-1 and Th-17 cells, as well M1 macrophage cytokines into the CNS may result in activation of microglia, resulting in neuronal cell damage, the release of neuronal cell antigens, and antibody production (Elizalde-Díaz, Miranda-Narváez et al. 2022, Stefanou, Palaiodimou et al. 2022).

Autoantibodies that are directed to endogenous proteins have been observed in several neuro-psychiatric illnesses which show clinical and pathophysiological features like Long COVID (Morris and Maes 2013, Apostolou, Rizwan et al. 2022, Komaroff and Lipkin 2023). For example, antibodies against synapsin in psychiatric patients are detected in association with increased agitation (Sæther, Vaaler et al. 2019). Increased neurofilament light and P-tau concentrations were established in patients with depression (Al-Hakeim, Al-Naqeeb et al. 2023). Increased levels of IgG directed at myelin basic protein (MBP, essential for the myelin sheath in brain oligodendrocytes) have been identified in bipolar patients (Kamaeva, Smirnova et al. 2022). CFS patients display increased antibodies against a multitude of neuronal proteins including microtubulin-related protein-2, a component of the cytoskeleton in eukaryotic cells (Vernon and Reeves 2005, Morris and Maes 2013).

Numerous studies reported that individuals recovered from COVID-19 (3-12 months after infection) show significant elevations of specific autoantibodies including those against calprotectin, nucleoprotein, whole spike, and spike subunits (Moody, Sonda et al. 2022), ACE2 (Arthur, Forrest et al. 2021), and apolipoprotein A-1 (Apo-A1) (L’Huillier, Pagano et al. 2022). Additionally IgG/IgM against cardiolipin and betaL2 glycoprotein I (Pisareva, Badiou et al. 2023), cyclic citrullinated peptide (CCP) and tissue transglutaminase (Lingel, Meltendorf et al. 2021) along with IgG against interferon (IgG-IFN), histone and centromere protein were also detected (Rojas, Rodríguez et al. 2022). There is also evidence that the blood-brain-barrier (BBB) is dysfunctional in Long COVID (Krasemann, Haferkamp et al. 2022, Hernández-Parra, Reyes-Hernández et al. 2023). Increased autoantibody titers to BBB proteins such as claudin are observed in Long COVID patients (Fonseca, Filgueiras et al. 2023). In the latter, the severity of illness is associated with increased serum levels of S100B, a danger-associated molecular pattern (DAMP) molecule, suggesting increased BBB permeability and brain damage (Aceti, Margarucci et al. 2020).

However, it is largely unknown whether autoimmune reactions directed against neuronal proteins are a feature of Long COVID disease. Hence, the aim of this study is to examine autoantibodies (IgA/IgM/IgG) directed at MBP, myelin oligodendrocyte glycoprotein (MOG), cerebellar-protein-2, synapsin, tubulin, neurofilament protein (NFP), and BBB-brain damage (BBD) proteins (claudin-5 and S100B) in Long COVID disease. In addition, we employ the precision medicine method (Maes 2022, Maes and Stoyanov 2022) to delineate whether these antibodies can predict CFS and affective symptoms due to Long COVID disease.

 


◆Ginger intake suppresses neutrophil extracellular trap formation in autoimmune mice and healthy humans【JCI insite　2023年9月22日】

Abstract

We previously reported that treatment of mice with 6-gingerol, the most abundant phytochemical in ginger root, leads to phosphodiesterase inhibition that counteracts neutrophil hyperactivity in models of antiphospholipid syndrome (APS) and lupus. Here, we explored the extent to which oral intake of a whole-ginger extract would similarly impact neutrophils in both autoimmune mice and healthy humans. In vitro, a solubilized ginger extract was able to attenuate neutrophil extracellular trap formation (NETosis) by human neutrophils through a mechanism that was dependent upon the cyclic AMP–dependent kinase, protein kinase A. When mice with features of either APS or lupus were administered a ginger extract orally, they demonstrated reduced circulating NETs, as well as the tempering of other disease outcomes, such as large-vein thrombosis (APS) and autoantibody production (lupus). In a pilot clinical trial, which was validated in a second cohort, daily intake of a ginger supplement for 7 days by healthy volunteers boosted neutrophil cAMP, inhibited NETosis in response to disease-relevant stimuli, and reduced circulating plasma NET levels. In summary, this work demonstrates that ginger intake restrains neutrophil hyperactivity in autoimmune mouse models and that ginger consumption by healthy individuals makes their neutrophils more resistant to NETosis.

Introduction

Chronic, incurable autoimmune diseases such as antiphospholipid syndrome (APS) and lupus are associated with significant morbidity, mortality, and health care costs. Lupus is the prototypical systemic autoimmune disease characterized by autoantibodies against nuclear components, which result in circulating immune complexes that deposit in and damage organs. APS, sometimes presenting in patients with lupus and sometimes as a standalone autoimmune disease, is associated with aberrant innate immune and vascular cell activation resulting in a markedly increased risk of thrombosis in vascular beds of all sizes. While these diseases demonstrate unique clinical phenotypes, there is convincing evidence that both are pathologically driven by a shared mechanism: dysfunctional and exaggerated neutrophil extracellular trap formation (termed NETosis). Through NETosis, neutrophils expel their nuclear chromatin in pro-inflammatory web-like structures that are decorated with potentially toxic granule-derived proteins. Excessive NETosis propels inflammatory and thrombotic cascades, contributing to end organ damage over time and to the pathophysiology of many autoimmune diseases, including APS and lupus.

Recent studies by our group and others have demonstrated that excessive NETosis has the potential to promote breaks in adaptive immune tolerance that result in durable autoantibody formation. At the same time, disease-associated autoantibodies drive further NETosis, thereby setting up a vicious cycle. Our work has further revealed a particularly important role for neutrophils and NETs in the thrombo-inflammatory disease manifestations that are relevant to not only APS and lupus but also other diseases, such as COVID-19. We have also found that targeting NETosis through various mechanisms (neutrophil depletion, deoxyribonuclease, adenosine receptor agonists) mitigates thrombosis in APS models. Safe agents that restrain NETosis in patients might therefore improve outcomes across various autoimmune and inflammatory diseases.

Natural herbs with antiinflammatory properties are potentially untapped resources in our search for agents that can combat pathogenic NETosis. We previously reported that a purified preparation of 6-gingerol, the most abundant bioactive phytochemical in ginger root, inhibited neutrophil phosphodiesterase (PDE) activity, boosting intracellular cyclic AMP (cAMP) levels and thereby counteracting neutrophil hyperactivity in mouse models of APS and lupus. In those experiments, purified 6-gingerol was delivered by intraperitoneal injection. To better understand the potential NET-inhibiting benefits of ginger in humans, studies using an orally administered ginger supplement are needed.

Here, we aimed to validate the effect of ginger on neutrophil activity, using an oral ginger extract and including healthy humans. Such a study can set the stage for the eventual clinical testing of ginger in patients with NET-driven autoimmune diseases, such as lupus, APS, rheumatoid arthritis, vasculitis, and even COVID-19.

 


◆Habitual short sleepers with pre-existing medical conditions are at higher risk of Long COVID【Journal Clinical Sleep Medicine　2023年10月3日】

Abstract

STUDY OBJECTIVES: Preliminary evidence suggests that the risk of Long COVID is higher among people with pre-existing medical conditions. Based on its proven adjuvant role in immunity, habitual sleep duration may alter the risk for developing Long COVID. The objective of this study was to determine whether the odds of Long COVID are higher amongst those with pre-existing medical conditions, and whether the strength of this association varies by habitual sleep duration.

METHODS: Using data from 13,461 respondents from 16 countries who participated in the 2021 survey based International COVID Sleep Study II (ICOSS II), we studied the associations between habitual sleep duration, pre-existing medical conditions, and Long COVID.

RESULTS: Of 2,508 individuals who had COVID-19, 61% reported at least one Long COVID symptom. Multivariable logistic regression analysis showed that the risk of having Long COVID was 1.8-fold higher for average-length sleepers (6-9h/night) with pre-existing medical conditions compared to those without pre-existing medical conditions [aOR 1.84 (1.18-2.90), P=0.008]. The risk of Long COVID was 3-fold higher for short sleepers with pre-existing medical conditions [aOR 2.95 (1.04-8.4), P=0.043] and not significantly higher for long sleepers with pre-existing conditions [aOR 2.11 (0.93-4.77), P=0.073] compared to average-length sleepers without pre-existing conditions.

CONCLUSIONS: Habitual short nighttime sleep duration exacerbated the risk of Long COVID in individuals with pre-existing conditions. Restoring nighttime sleep to average duration represents a potentially modifiable behavioral factor to lower the odds of Long COVID for at-risk patients.

 


◆Long-Term Dysfunction of Taste Papillae in SARS-CoV-2【NEJM Evidence　2023年7月20日】

Abstract

BACKGROUND

We sought to determine whether ongoing taste disturbance in the postacute sequelae of coronavirus disease 2019 period is associated with persistent virus in primary taste tissue.

METHODS

We performed fungiform papillae biopsies on 16 patients who reported taste disturbance lasting more than 6 weeks after molecularly determined severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Then, on multiple occasions, we rebiopsied 10 of those patients who still had taste complaints for at least 6 months postinfection. Fungiform papillae obtained from other patients before March 2020 served as negative controls. We performed hematoxylin and eosin staining to examine fungiform papillae morphology and immunofluorescence and fluorescence in situ hybridization to look for evidence of persistent viral infection and immune response.

RESULTS

In all patients, we found evidence of SARS-CoV-2, accompanying immune response and misshapen or absent taste buds with loss of intergemmal neurite fibers. Six patients reported normal taste perception by 6 months postinfection and were not further biopsied. In the remaining 10, the virus was eliminated in a seemingly random fashion from their fungiform papillae, but four patients still, by history, reported incomplete return to preinfection taste perception by the time we wrote this report.

CONCLUSIONS

Our data show a temporal association in patients between functional taste, taste papillae morphology, and the presence of SARS-CoV-2 and its associated immunological changes. (Funded by Intramural Research Program/National Institute on Aging/National Institute of Allergy and Infectious Diseases/National Institutes of Health; ClinicalTrials.gov numbers NCT03366168 and NCT04565067.)

Introduction

We have previously reported that angiotensin-converting enzyme 2, one of the known receptors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is present on type II taste receptor cells within taste buds embedded in taste papillae. SARS-CoV-2 is known to infect and replicate within these cells during the acute phase of coronavirus disease 2019 (Covid-19), likely accounting for complete loss of taste (ageusia), partial loss of taste (hypogeusia), and/or distorted sense of taste (dysgeusia) during the early stages of infection. However, symptoms of altered taste perception may be present in people for several months and in some patients for more than a year following SARS-CoV-2 infection. To study whether the pathology underlying persistent taste symptoms still resides in the primary taste organs, we performed fungiform papillae biopsies from patients who had both a positive polymerase chain reaction (PCR+) for SARS-CoV-2 and acute taste disturbance that was followed by lingering taste symptoms. None required hospitalization, and none were prescribed monoclonal antibodies to SARS-CoV-2 or antiviral treatment for their infection. In the biopsy samples, we looked for the presence of virus and hallmarks of pathology that might be linked to taste disturbance. In 10 patients with lingering taste symptoms, we obtained fungiform papillae on multiple occasions allowing us to investigate the pathophysiology underlying their altered taste perception and observe any changes occurring within the fungiform papillae that might correlate with taste alterations. Taste perception in 6 of those 10 patients returned to pre–SARS-CoV-2 levels by the time of their last biopsy.

 


◆Event Rate and Predictors of Post-Acute COVID-19 Sequalae and the Average Time to Diagnosis in General Population【medRxiv　2023年2月23日】

Abstract

Background Post- COVID-19 sequalae involves a variety of new, returning or ongoing symptoms that people experience more than four weeks after getting COVID-19. The aims of this meta-analysis were to assess the prevalence of Post-Acute COVID-19 sequalae and estimate the average time to its diagnosis; and meta-regress for possible moderators.

Methods A standard search strategy was used in PubMed, and then later modified according to each specific database. Search terms included “long COVID-19 or post-acute COVID-19 syndrome/sequalae”. The criteria for inclusion were published clinical articles reporting the long COVID-19, further, the average time to diagnosis of post-acute COVID-19 sequelae among primary infected patients with COVID-19. Random-effects model was used. Rank Correlation and Egger’s tests were used to ascertain publication bias. Sub-group, sensitivity and meta-regression analysis were conducted. A 95% confidence intervals were presented and a p-value < 0.05 was considered statistically significant. Review Manager 5.4 and comprehensive meta-analysis version 4 (CMA V4) were used for the analysis. The trial was PROSPERO registered (CRD42022328509). Results Prevalence of post-acute COVID-19 sequalae was 42.5% (95% confidence interval (CI) 36 % to 49.3%). The PACS event rates’ range was 25 % at four months and 66 % at two months and mostly, signs and symptoms of PASC were experienced at three (54.3%, P < 0.0001) to six months (57%, P < 0.0001), further increasing at 12 months (57.9%, P= 0.0148). At an average of two months, however with the highest event rate (66%), it was not significantly associated with PACS diagnosis (P=0.08). On meta-regression, comorbidities collectively contributed to 14% of PACS with a non-significant correlation (Q = 7.05, df = 8, p = 0.5313) (R2=0.14). A cardiovascular disorder especially hypertension as a stand-alone, showed an event rate of 32% and significantly associated with PACS, 0.322 (95% CI 0.166, 0.532) (P < 0.001). Chronic obstructive pulmonary disorder (COPD) and abnormal basal metabolic index (BMI) had higher event rates of PACS (59.8 % and 55.9 %) respectively, with a non-significant correlation (P > 0.05). With a significant association, hospital re-admission contributed to 17% (Q = 8.70, df = 1, p = 0.0032) (R2= 0.17) and the study design 26% (Q = 14.32, df = 3, p = 0.0025) (R2=0.26). All the covariates explained at least some of the variance in effect size on PACS at 53% (Q = 38.81, df = 19, p = 0.0047) (R2 analog = 0.53).

Conclusion The prevalence of PACS in general population was 42.5%, of which cardiovascular disorders were highly linked with it with COPD and abnormal BMI also being possible conditions found in patients with PACS. Hospital re-admission predicted highly, an experience of PACS as well as prospective study design. Clinical and methodological characteristics in a specific study contributed to over 50% of PACS events. The PACS event rates ranged between 25 % at four months and 66 % at two months with most signs and symptoms experienced between three to six months increasing at 12 months.

Introduction

Post-acute sequelae of COVID-19, also known as “long COVID,” is used to describe the long-term symptoms that might be experienced weeks to months after primary infection with SARS-CoV-2, the virus that causes COVID-19. Recent literature suggests that, the syndrome is described by a diverse set of symptoms that persist after a diagnosed COVID-19 infection. This post-acute infection represents a significant challenge for patients, physicians, and society because the causes, patient profile, and even symptom patterns remain difficult to characterize. It may include memory loss, gastrointestinal (GI) distress, fatigue, anosmia, shortness of breath, and other symptoms. PASC has been associated with acute disease severity, further, it is suspected to be related to autoimmune factors, as well as unresolved viral fragments. Post-COVID conditions are found more often in people who had severe COVID-19 illness, but anyone who has been infected with the virus that causes COVID-19 can experience post-COVID conditions, even people who had mild illness or no symptoms from COVID-19. There is no test to diagnose post-COVID conditions, and people may have a wide variety of symptoms that could come from other health problems. This can make it difficult for healthcare providers to recognize post-COVID conditions. Diagnosis is considered based on health history, including if you had a diagnosis of COVID-19 either by a positive test or by symptoms or exposure, as well as doing a health examination. Long COVID may be due to persistent immune disturbances.

Studies of patients who have recovered from SARS-CoV-2 infection but have persistent symptoms have ranged widely in size, quality, and methodology, leading to confusion about the prevalence and types of persistent symptoms. SARS-CoV-2 can produce short/long-term sequelae and reports describing post-acute COVID-19 syndrome (PACS) in the general population are increasing, however limited by lack of proper pooled average time estimation for diagnosis or occurrence. Therefore, this review aimed at assessing the prevalence and factors associated with PACS in our cohort of general population.

 


◆Retinal tissue and microvasculature loss in COVID-19 infection【nature：scientific reports　2023年3月29日】

Abstract

This cross-sectional study aimed to investigate the hypothesis that permanent capillary damage may underlie the long-term COVID-19 sequela by quantifying the retinal vessel integrity. Participants were divided into three subgroups; Normal controls who had not been affected by COVID-19, mild COVID-19 cases who received out-patient care, and severe COVID-19 cases requiring intensive care unit (ICU) admission and respiratory support. Patients with systemic conditions that may affect the retinal vasculature before the diagnosis of COVID-19 infection were excluded. Participants underwent comprehensive ophthalmologic examination and retinal imaging obtained from Spectral-Domain Optical Coherence Tomography (SD-OCT), and vessel density using OCT Angiography. Sixty-one eyes from 31 individuals were studied. Retinal volume was significantly decreased in the outer 3 mm of the macula in the severe COVID-19 group (p = 0.02). Total retinal vessel density was significantly lower in the severe COVID-19 group compared to the normal and mild COVID-19 groups (p = 0.004 and 0.0057, respectively). The intermediate and deep capillary plexuses in the severe COVID-19 group were significantly lower compared to other groups (p < 0.05). Retinal tissue and microvascular loss may be a biomarker of COVID-19 severity. Further monitoring of the retina in COVID-19-recovered patients may help further understand the COVID-19 sequela.

Introduction

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus two (SARS-CoV-2). In December 2019, an outbreak of this respiratory disease emerged in Wuhan, China which was declared a pandemic in March 2020 and has affected many lives since then. As of October 17, 2022, the total number of confirmed cases globally per the World Health Organization (WHO) is 621,797,133, with total deaths of 6,545,561.

The virus affects multiple organ systems aside from the respiratory system. The term “long COVID” was introduced only a few months after the outbreak, as patients reported various symptoms that persisted or developed even after recovery from the infection. Douaud, et al. investigated brain changes associated with the virus, and one of their notable findings was a greater reduction in the global brain size. A systematic review performed by Castanares-Zapatero, et al. found that persistent inflammatory processes result in brain microglia activation, as well as pulmonary microvascular damage that may potentially lead to pulmonary hypertension. At the vascular level, the virus promotes an inflammatory state in the vascular endothelium, causing endotheliitis, ultimately leading to a prothrombotic state in the microcirculation. López Reboiro, et al. suggested that von Willebrand factor (vWF) and lupus anticoagulant (LA), in addition to other molecules, play a crucial role in thrombogenesis induced by this virus. Obtaining serum measurements of vWF and LA may predict permanent endothelial damage, leading to long COVID sequelae such as neuropathic pain or neuropsychiatric issues.

In the eye, several works of literature reported various retinal findings after infection with the novel coronavirus. There is some evidence of vascular pathology associated with COVID-19 infection. The most commonly reported ocular manifestations were retinal hemorrhages and cotton wool spots, while the most common vision-threatening manifestation was retinal vein occlusion with macular edema, making this disease vasculopathic in nature. Several case reports have also diagnosed paracentral acute middle maculopathy, a vasculopathy associated with deep retinal microvascular circulation, after COVID-19 infection using optical coherence tomography (OCT). These are all anecdotal case reports, and many of these patients likely had comorbidities that are not described fully in the papers.

OCT Angiography (OCTA) is a non-invasive imaging technique that provides three-dimensional visualization of the retinal vasculature by moving particles, such as erythrocytes. Although OCTA has been used in assessing retinal vasculature in patients infected with COVID-19, some of these studies included patients with systemic confounders, including hypertension and diabetes mellitus, which are known to affect the retinal microvasculature.

The purpose of this study was to investigate the retinal thickness, volume, and vessel density of patients who were diagnosed and recovered from COVID-19 using Spectral Domain OCT (SD-OCT) and OCTA and to compare findings with a control group who had not been infected. We aim to understand the natural course of the ocular findings of this disease. The patients included in this study were carefully selected and had no prior systemic disease that might alter the retinal microvascular architecture.

 


◆The immunology of long COVID【nature reviews immunology　2023年7月11日】

Abstract

Long COVID is the patient-coined term for the disease entity whereby persistent symptoms ensue in a significant proportion of those who have had COVID-19, whether asymptomatic, mild or severe. Estimated numbers vary but the assumption is that, of all those who had COVID-19 globally, at least 10% have long COVID. The disease burden spans from mild symptoms to profound disability, the scale making this a huge, new health-care challenge. Long COVID will likely be stratified into several more or less discrete entities with potentially distinct pathogenic pathways. The evolving symptom list is extensive, multi-organ, multisystem and relapsing–remitting, including fatigue, breathlessness, neurocognitive effects and dysautonomia. A range of radiological abnormalities in the olfactory bulb, brain, heart, lung and other sites have been observed in individuals with long COVID. Some body sites indicate the presence of microclots; these and other blood markers of hypercoagulation implicate a likely role of endothelial activation and clotting abnormalities. Diverse auto-antibody (AAB) specificities have been found, as yet without a clear consensus or correlation with symptom clusters. There is support for a role of persistent SARS-CoV-2 reservoirs and/or an effect of Epstein–Barr virus reactivation, and evidence from immune subset changes for broad immune perturbation. Thus, the current picture is one of convergence towards a map of an immunopathogenic aetiology of long COVID, though as yet with insufficient data for a mechanistic synthesis or to fully inform therapeutic pathways.

 


◆Course of post COVID-19 disease symptoms over time in the ComPaRe long COVID prospective e-cohort【nature communications　2022年4月5日】

Abstract

About 10% of people infected by severe acute respiratory syndrome coronavirus 2 experience post COVID-19 disease. We analysed data from 968 adult patients (5350 person-months) with a confirmed infection enroled in the ComPaRe long COVID cohort, a disease prevalent prospective e-cohort of such patients in France. Day-by-day prevalence of post COVID-19 symptoms was determined from patients’ responses to the Long COVID Symptom Tool, a validated self-reported questionnaire assessing 53 symptoms. Among patients symptomatic after 2 months, 85% still reported symptoms one year after their symptom onset. Evolution of symptoms showed a decreasing prevalence over time for 27/53 symptoms (e.g., loss of taste/smell); a stable prevalence over time for 18/53 symptoms (e.g., dyspnoea), and an increasing prevalence over time for 8/53 symptoms (e.g., paraesthesia). The disease impact on patients’ lives began increasing 6 months after onset. Our results are of importance to understand the natural history of post COVID-19 disease.

 


◆Multimodal Molecular Imaging Reveals Tissue-Based T Cell Activation and Viral RNA Persistence for Up to 2 Years Following COVID-19【medRxiv　2023年7月27日】

Abstract

The etiologic mechanisms of post-acute medical morbidities and unexplained symptoms (Long COVID) following SARS-CoV-2 infection are incompletely understood. There is growing evidence that viral persistence and immune dysregulation may play a major role. We performed whole-body positron emission tomography (PET) imaging in a cohort of 24 participants at time points ranging from 27 to 910 days following acute SARS-CoV-2 infection using a novel radiopharmaceutical agent, [18F]F-AraG, a highly selective tracer that allows for anatomical quantitation of activated T lymphocytes. Tracer uptake in the post-acute COVID group, which included those with and without Long COVID symptoms, was significantly higher compared to pre-pandemic controls in many anatomical regions, including the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. Although T cell activation tended to be higher in participants imaged closer to the time of the acute illness, tracer uptake was increased in participants imaged up to 2.5 years following SARS-CoV-2 infection. We observed that T cell activation in spinal cord and gut wall was associated with the presence of Long COVID symptoms. In addition, tracer uptake in lung tissue was higher in those with persistent pulmonary symptoms. Notably, increased T cell activation in these tissues was also observed in many individuals without Long COVID. Given the high [18F]F-AraG uptake detected in the gut, we obtained colorectal tissue for in situ hybridization SARS-CoV-2 RNA and immunohistochemical studies in a subset of participants with Long COVID symptoms. We identified cellular SARS-CoV-2 RNA in rectosigmoid lamina propria tissue in all these participants, ranging from 158 to 676 days following initial COVID-19 illness, suggesting that tissue viral persistence could be associated with long-term immunological perturbations.

 


◆Influence of Prior SARS-CoV-2 Infection on COVID-19 Severity: Evidence from the National COVID Cohort Collaborative【medRxiv　2023年8月3日】

Abstract

Background As SARS-CoV-2 has transitioned from a pandemic to endemic disease, the majority of new infections have been among previously infected individuals. To manage the risks and benefits of ongoing COVID-19 policies, it is important to understand whether prior infection modifies the severity of subsequent infections.

Methods We used data from first and second COVID-19 episodes in the National COVID Cohort Collaborative (N3C), a collection of health systems who provide de-identified electronic health records for research purposes. Our analysis was a sequential series of nested trial emulations. In the first of two analytic stages, we created a month-specific model of the probability of prior infection for each individual. In the second stage, we used an ordinal logistic regression with inverse probability weights calculated in the first stage to simulate a series of monthly trials comparing severity between the cohorts of first and second infections. In addition to cohort-wide effect estimates, we also conducted analyses among race/ethnicity, sex, and age subgroups.

Results From an initial cohort of 7,446,481 combined first and second infections, we identified a cohort of 2,227,484 infections, among which 7.6% were second infections. Ninety-four percent of patients with two recorded infections experienced mild disease for both. The overall odds ratio (OR) for more severe disease with prior infection was 1.06 (95% confidence interval [CI]: 1.03 – 1.10). Monthly point estimates of the OR ranged from 0.56 (95% CI: 0.37 – 0.84) in October 2020 to 1.64 (95% CI: 1.33 – 2.00) in February 2023. In most subgroups, the effect of prior infection was significant. In 8 out of 10 subgroups, the maximum monthly OR occurred after the minimum monthly OR, suggesting that protection has waned throughout the pandemic.

Conclusion Overall, prior infection was associated with a significant slightly elevated risk of severe disease. This effect varied month to month. As the pandemic proceeded, the effect of prior infection tended to evolve from generally protective during the pre-Omicron era to unprotective during the Omicron era. This points to the need for continued strategies to avert and minimize the harms of COVID-19, rather than relying upon immunity acquired through previous infection.

Question Does prior infection with SARS-CoV-2 affect the severity of subsequent COVID-19 episodes?

Findings We observed a mild protective effect of prior infection during the early and mid-stages of the pandemic that waned after the rise of the Omicron variants, ultimately resulting in loss of protection or a tendency toward more severe second infections.

Meaning Prior infection alone is likely not enough to avert the worst public health harms of endemic SARS-CoV-2. Interventions to avoid infection and reduce the severity of COVID-19 will still be important in the post-pandemic era.

Introduction

The SARS-CoV-2 pandemic’s shift into an endemic disease has necessarily been accompanied by substantial adjustments to public health policy. Policies around recommendations for vaccine boosters, public investment in novel treatments for COVID-19, and reimbursement for telemedicine have already changed or begun to be debated. As of late 2022, an estimated 94% of Americans had experienced at least one episode of COVID-19. Since the majority of new cases have been among people with prior exposure to the SARS-CoV-2 virus, an understanding of how prior infection changes disease severity is vital to making policy decisions informed by reasonable risk-benefit calculations.

One of the hallmarks of an infectious disease’s transition from epidemic to endemic status is a reduction in disease severity due, in part, to an increasing number of the population with some immune protection against the disease. In many cases, this takes place through prior infections. It is therefore reasonable to hypothesize that prior infection with SARS-CoV-2 also confers some protective effect, although some evidence has suggested that the protective effect of natural antibodies against SARS-CoV-2 may decay relatively quickly compared to antibodies against other viruses. Published efforts to understand the severity of repeat COVID-19 episodes have been surprisingly rare. This may have been due in part to the notable challenges of studying repeat infection. Among other challenges, these have included the emergence of several new strains since the start of the pandemic, the introduction of vaccines, and the likely increase in the rate of self-management for COVID-19. Rigorously studying reinfection severity requires both large datasets of comprehensive health information and sophisticated analytic methods.

In this study, we used the National COVID Cohort Collaborative (N3C) dataset to conduct an analysis of reinfection severity. The N3C collected deidentified data from 76 health systems covering 18.9 million individuals and 7.5 million COVID-19 cases to provide comprehensive information on a large, diverse swath of patients throughout the United States. We used causal methods with these data to assess the relevance of reinfection to COVID-19 severity both at the population level and across subgroups defined by gender, race/ethnicity, and age.