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Background: The long-term sequelae of coronavirus disease 2019 (COVID-19) and its recovery have becoming significant public health concerns. Therefore, this study aimed to enhance the limited evidence regarding the relationship between sleep quality on long COVID among the older population aged 60 years or old., Methods: Our study included 4,781 COVID-19 patients enrolled from April to May 2023, based on the Peking University Health Cohort. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) scale. Long COVID was evaluated by well-trained health professionals through patients' self-reported symptoms. Binary logistic regression models were employed to calculate odds ratios (OR) and 95% confidence intervals (95% CI)., Results: The prevalence of long COVID among older adults was 57.4% (2,743/4,781). Specifically, the prevalence of general symptoms, cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, and neurological and psychiatric symptoms was 47.7% (2,282/4,781), 3.4% (163/4,781), 35.2% (1683/4,781), 8.7% (416/4,781) and 5.8% (279/4,781), respectively. For each one-point increase in PSQI scores, the risk of long COVID, general symptoms, cardiovascular symptoms, gastrointestinal symptoms, and neurological and psychiatric symptoms increased by 3% (95% CI: 1.01, 1.06), 3% (95% CI: 1.01, 1.06), 7% (95% CI: 1.01, 1.13), 11% (95% CI: 1.07, 1.15), and 20% (95% CI: 1.15, 1.25), respectively. In multivariate models, compared with good sleepers, COVID-19 patients with poor sleep quality exhibited an increased risk of general symptoms (aOR = 1.17; 95% CI: 1.03, 1.33), cardiovascular symptoms (aOR = 1.50; 95% CI: 1.06, 2.14), gastrointestinal symptoms (aOR = 2.03; 95% CI: 1.61, 2.54), and neurological and psychiatric symptoms (aOR = 2.57; 95% CI = 1.96, 3.37)., Conclusions: Our findings indicate that poor sleep quality is related to various manifestations of long COVID in older populations. A comprehensive assessment and multidisciplinary management of sleep health and long COVID may be essential to ensure healthy aging in the future., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the institutional review boards at Peking University (IRB00001052-21126). All participants had oral informed consent at the time of participation. The research has been performed in accordance with the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered an unprecedented public health crisis known as the coronavirus disease 2019 (COVID-19) pandemic. Gastrointestinal (GI) symptoms develop in patients during acute infection and persist after recovery from airway distress in a chronic form of the disease (long COVID). A high incidence of irritable bowel syndrome (IBS) manifested by severe abdominal pain and defecation pattern changes is reported in COVID patients. Although COVID is primarily considered a respiratory disease, fecal shedding of SARS-CoV-2 antigens positively correlates with bowel symptoms. Active viral infection in the GI tract was identified by human intestinal organoid studies showing SARS-CoV-2 replication in gut epithelial cells. In this review, we highlight the key findings in post-COVID bowel symptoms and explore possible mechanisms underlying the pathophysiology of the illness. These mechanisms include mucosal inflammation, gut barrier dysfunction, and microbiota dysbiosis during viral infection. Viral shedding through the GI route may be the primary factor causing the alteration of the microbiome ecosystem, particularly the virome. Recent evidence in experimental models suggested that microbiome dysbiosis could be further aggravated by epithelial barrier damage and immune activation. Moreover, altered microbiota composition has been associated with dysregulated serotonin pathways, resulting in intestinal nerve hypersensitivity. These mechanisms may explain the development of post-infectious IBS-like symptoms in long COVID. Understanding how coronavirus infection affects gut pathophysiology, including microbiome changes, would benefit the therapeutic advancement for managing post-infectious bowel symptoms., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Author. Published by Elsevier Inc. All rights reserved.)

Chest CT provides a way to quantify pulmonary airway and vascular tree measurements. In patients with COPD, CT airway measurement differences in females are concomitant with worse quality-of-life and other outcomes. CT total airway count (TAC), airway lumen area (LA), and wall thickness (WT) also differ in females with long-COVID. Our objective was to evaluate CT airway and pulmonary vascular and quality-of-life measurements in females with COPD as compared to ex-smokers and patients with long-COVID. Chest CT was acquired 3-months post-COVID-19 infection in females with long-COVID for comparison with the same inspiratory CT in female ex-smokers and COPD patients. TAC, LA, WT, and pulmonary vascular measurements were quantified. Linear regression models were adjusted for confounders including age, height, body-mass-index, lung volume, pack-years and asthma diagnosis. Twenty-one females (53 ± 14 years) with long-COVID, 17 female ex-smokers (69 ± 9 years) and 13 female COPD (67 ± 6 years) patients were evaluated. In the absence of differences in quality-of-life scores, females with long-COVID reported significantly different LA ( p  = 0.006) compared to ex-smokers but not COPD ( p  = 0.7); WT% was also different compared to COPD ( p  = 0.009) but not ex-smokers ( p  = 0.5). In addition, there was significantly greater pulmonary small vessel volume (BV 5 ) in long-COVID as compared to female ex-smokers ( p  = 0.045) and COPD ( p  = 0.003) patients and different large (BV 10 ) vessel volume as compared to COPD ( p  = 0.03). In females with long-COVID and highly abnormal quality-of-life scores, there was CT evidence of airway remodelling, similar to ex-smokers and patients with COPD, but there was no evidence of pulmonary vascular remodelling. Clinical Trial Registration: www.clinicaltrials.gov NCT05014516 and NCT02279329.

Objectives: Long COVID-19 (LC) patients experience a number of chronic idiopathic symptoms that are highly similar to those of post-viral myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We have therefore performed a systematic review and meta-analysis to determine the proportion of LC patients that satisfy ME/CFS diagnostic criteria., Methods: Clinical studies published between January 2020 and May 2023 were identified using the PubMed, Web of Science, Embase and CINAHL databases. Publication inclusion/exclusion criteria were formulated using the global CoCoPop framework. Data were pooled using a random-effects model with a restricted maximum-likelihood estimator. Study quality was assessed using the Joanna Briggs Institute critical assessment tool., Results: We identified 13 eligible studies that reported a total of 1973 LC patients. Our meta-analysis indicated that 51% (95% CI, 42%-60%) of LC patients satisfied ME/CFS diagnostic criteria, with fatigue, sleep disruption, and muscle/joint pain being the most common symptoms. Importantly, LC patients also experienced the ME/CFS hallmark symptom, post-exertional malaise., Conclusions: Our study not only demonstrates that LC patients exhibit similar symptom clusters to ME/CFS, but that approximately half of LC patients satisfy a diagnosis of ME/CFS. Our findings suggest that current ME/CFS criteria could be adapted to the identification of a subset of LC patients that may facilitate the standardised diagnosis, management and the recruitment for clinical studies in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background & Aims: Post-COVID-19 Syndrome (PCS) is characterized by symptoms including fatigue, reduced physical performance, dyspnea, cognitive impairment, and psychological distress. The mechanisms underlying the onset and severity of PCS point to mitochondrial dysfunction as significant contributor. This study examined fat oxidation as a function of mitochondrial capacity during exercise., Methods: Single-center prospective cohort study during inpatient rehabilitation. Cardiopulmonary exercise testing and assessment of fatigue using questionnaires were performed at admission and discharge. Detailed spirometric breath-by-breath data were used to calculate substrate oxidation rates., Results: Patients (N = 187; 38 % women; 49.7 ± 11.4 years) were referred to rehabilitation 253.4 ± 130.6 days after infection. Lead symptoms included fatigue/exercise intolerance (79.9 %), shortness of breath (77.0 %), and cognitive dysfunction (55.1 %). Fat oxidation capacity was disturbed in PCS patients overall (AUC: 11.3 [10.7-11.9]) compared to healthy controls (p < 0.0001), with hospitalization during acute infection predicting the level of disturbance (p < 0.0001). Low exercise capacity and high fatigue scores resulted in reduced fat oxidation (both p < 0.0001). In particular, younger males were affected by significantly reduced fat oxidation capacity (sex: p = 0.002; age: p < 0.001). Metabolic disturbance was significantly improved during exercise-based rehabilitation (AUC: 14.9 [14.4-15.4]; p < 0.0001), even for the group of younger impaired males (+44.2 %; p < 0.0001). Carbohydrate oxidation was not impaired., Conclusions: PCS-specific restrictions in fat oxidation may indicate persistent mitochondrial dysfunction. Clinical assessment of PCS patients should include detailed breath-by-breath analysis during exercise to identify metabolic alterations especially in the group of younger males identified in this report. Exercise-based rehabilitation results in improved exercise capacity and fat oxidation and thus likely mitochondrial function., Clinical Trials: NCT06468722., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Following the Omicron wave in early 2022, an estimated 60-70% of the French population was infected with the SARS-CoV-2 virus. One out of ten infected subjects could have persistent symptoms three months after infection, representing a public health challenge., Current State of Knowledge: The persistent symptoms may be secondary to diverse entities with distinct mechanisms. While organic infection sequelae occur mainly after severe COVID-19, some symptoms appear to be essentially psychological in origin; in addition, many subjects present stereotyped symptoms of fluctuating intensity with no identified anatomical or psychic substratum, often in the aftermath of a benign infection. The most frequent complaints are fatigue, pain, dyspnea and difficulty concentrating., Perspectives: The hypotheses explored to explain these symptoms include: persistent immune dysfunction, inducted autoimmunity, and microbiome disturbances. Persistent viral antigens may lie at the crossroads of these mechanisms. To date, these different etiological avenues have yet to lead to the development of diagnostic tests or specific therapeutic strategies., Conclusion: Prolonged symptoms after COVID-19 correspond to heterogeneous nosological entities with poorly understood mechanisms., (Copyright © 2024 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: Recent studies provide strong evidence for a key role of skeletal muscle pathophysiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In a 2021 review article on the pathophysiology of ME/CFS, we postulated that hypoperfusion and ischemia can result in excessive sodium and calcium overload in skeletal muscles of ME/CFS patients to cause mitochondrial damage. Since then, experimental evidence has been provided that supports this concept., Methods: We collect, summarize and discuss the current state of knowledge for the key role of skeletal muscle pathophysiology. We try to explain which risk factors and mechanisms are responsible for a subgroup of patients with post COVID syndrome (PCS) to develop ME/CFS (PC-ME/CFS)., Results: Mitochondrial dysfunction is a long-held assumption to explain cardinal symptoms of ME/CFS. However, mitochondrial dysfunction could not be convincingly shown in leukocytes. By contrast, recent studies provide strong evidence for mitochondrial dysfunction in skeletal muscle tissue in ME/CFS. An electron microscopy study could directly show damage of mitochondria in skeletal muscle of ME/CFS patients with a preferential subsarcolemmal localization but not in PCS. Another study shows signs of skeletal muscle damage and regeneration in biopsies taken one day after exercise in PC-ME/CFS. The simultaneous presence of necroses and signs of regeneration supports the concept of repeated damage. Other studies correlated diminished hand grip strength (HGS) with symptom severity and prognosis. A MRI study showed that intracellular sodium in muscles of ME/CFS patients is elevated and that levels correlate inversely with HGS. This finding corroborates our concept of sodium and consecutive calcium overload as cause of muscular and mitochondrial damage caused by enhanced proton-sodium exchange due to anaerobic metabolism and diminished activity of the sodium-potassium-ATPase. The histological investigations in ME/CFS exclude ischemia by microvascular obstruction, viral presence or immune myositis. The only known exercise-induced mechanism of damage left is sodium induced calcium overload. If ionic disturbance and mitochondrial dysfunction is severe enough the patient may be captured in a vicious circle. This energy deficit is the most likely cause of exertional intolerance and post exertional malaise and is further aggravated by exertion., Conclusion: Based on this pathomechanism, future treatment approaches should focus on normalizing the cause of ionic disbalance. Current treatment strategies targeting hypoperfusion have the potential to improve the dysfunction of ion transporters., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

The long-term physiological consequences of respiratory viral infections, particularly in the aftermath of the COVID-19 pandemic-termed post-acute sequelae of SARS-CoV-2 (PASC)-are rapidly evolving into a major public health concern 1-3 . While the cellular and molecular aetiologies of these sequelae are poorly defined, increasing evidence implicates abnormal immune responses 3-6 and/or impaired organ recovery 7-9 after infection. However, the precise mechanisms that link these processes in the context of PASC remain unclear. Here, with insights from three cohorts of patients with respiratory PASC, we established a mouse model of post-viral lung disease and identified an aberrant immune-epithelial progenitor niche unique to fibroproliferation in respiratory PASC. Using spatial transcriptomics and imaging, we found a central role for lung-resident CD8 + T cell-macrophage interactions in impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Specifically, IFNγ and TNF derived from CD8 + T cells stimulated local macrophages to chronically release IL-1β, resulting in the long-term maintenance of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFNγ + TNF or IL-1β markedly improved alveolar regeneration and pulmonary function. In contrast to other approaches, which require early intervention 10 , we highlight therapeutic strategies to rescue fibrotic disease after the resolution of acute disease, addressing a current unmet need in the clinical management of PASC and post-viral disease., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Post-COVID-19 condition (also known as long COVID) is generally defined as symptoms persisting for 3 months or more after acute COVID-19. Long COVID can affect multiple organ systems and lead to severe and protracted impairment of function as a result of organ damage. The burden of this disease, both on the individual and on health systems and national economies, is high. In this interdisciplinary Review, with a coauthor with lived experience of severe long COVID, we sought to bring together multiple streams of literature on the epidemiology, pathophysiology (including the hypothesised mechanisms of organ damage), lived experience and clinical manifestations, and clinical investigation and management of long COVID. Although current approaches to long COVID care are largely symptomatic and supportive, recent advances in clinical phenotyping, deep molecular profiling, and biomarker identification might herald a more mechanism-informed and personally tailored approach to clinical care. We also cover the organisation of services for long COVID, approaches to preventing long COVID, and suggestions for future research., Competing Interests: Declaration of interests In the past 36 months, TG has held research grants from UK National Institute for Health and Care Research, Balvi, Medical Research Council, Health Data Research UK, and Research Council of Norway. She is a Governing Body Fellow at Green Templeton College and a Visitor at the Pitt Rivers Museum, University of Oxford, and was until 2022, a trustee of the Hilda Martindale Charitable Trust (an educational hardship fund). MS has held research grants from National Institute for Health and Care Research, Research England Policy Support Fund, and the Engineering and Physical Sciences Research Council. He is the Editor-in-Chief of the Oxford Handbook of Rehabilitation Medicine. AP has received consulting fees and grants from the US National Institutes of Health and is Chief Medical Officer of Blooming Magnolia (a 501[c]3 non-profit organisation). JŽN acknowledges institutional support from the endowed Bowman Professorship in Medical Science that he holds at the University of Arizona. He holds or has held research grants from the US National Institutes of Health. He holds US patent number 11119103 (serological assays for SARS-CoV-2). TG and MS were funded by the UK National Institute for Health and Care Research (LOCOMOTION study), and JŽN by the US National Institutes of Health. The funders had no role in any aspect of the writing of this Review. The authors were not precluded from accessing any data in the study (which, being a Review, came from publicly available published papers), and they accept responsibility to submit this Review for publication., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Understanding the pathophysiology of long COVID is one of the most intriguing challenges confronting contemporary medicine. Despite observations recently made in the relevant molecular, cellular, and physiological domains, it is still difficult to say whether the post-acute sequelae of COVID-19 directly correspond to the consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This work hypothesizes that neutrophils and neutrophil extracellular traps (NETs) production are at the interconnection of three positive feedback loops which are initiated in the acute phase of SARS-CoV-2 infection, and which involve inflammation, immunothrombosis, and autoimmunity. This phenomenon could be favored by the fact that SARS-CoV-2 may directly bind and penetrate neutrophils. The ensuing strong neutrophil stimulation leads to a progressive amplification of an exacerbated and uncontrolled NETs production, potentially persisting for months beyond the acute phase of infection. This continuous self-stimulation of neutrophils leads, in turn, to systemic inflammation, micro-thromboses, and the production of autoantibodies, whose significant consequences include the persistence of endothelial and multiorgan damage, and vascular complications., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

The severe acute respiratory syndrome coronavirus 2 virus has, up to the time of this article, resulted in >770 million cases of COVID-19 illness worldwide, and approximately 7 million deaths, including >1.1 million in the United States. Although defined as a respiratory virus, early in the pandemic, it became apparent that considerable numbers of people recovering from COVID-19 illness experienced persistence or new onset of multi-system health problems, including neurologic and cognitive and behavioral health concerns. Persistent multi-system health problems are defined as Post-COVID-19 Condition (PCC), Post-Acute Sequelae of COVID-19, or Long COVID. A significant number of those with PCC report cognitive problems. This paper reviews the current state of scientific knowledge on persisting cognitive symptoms in adults following COVID-19 illness. A brief history is provided of the emergence of concerns about persisting cognitive problems following COVID-19 illness and the definition of PCC. Methodologic factors that complicate clear understanding of PCC are reviewed. The review then examines research on patterns of cognitive impairment that have been found, factors that may contribute to increased risk, behavioral health variables, and interventions being used to ameliorate persisting symptoms. Finally, recommendations are made about ways neuropsychologists can improve the quality of existing research., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Understanding the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is critical for advancing treatment options. This review explores the novel hypothesis that a herpesvirus infection of endothelial cells (ECs) may underlie ME/CFS symptomatology. We review evidence linking herpesviruses to persistent EC infection and the implications for endothelial dysfunction, encompassing blood flow regulation, coagulation, and cognitive impairment-symptoms consistent with ME/CFS and Long COVID. This paper provides a synthesis of current research on herpesvirus latency and reactivation, detailing the impact on ECs and subsequent systemic complications, including latent modulation and long-term maladaptation. We suggest that the chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be partly attributable to herpesvirus-induced endothelial maladaptation. Our conclusions underscore the necessity for further investigation into the prevalence and load of herpesvirus infection within the ECs of ME/CFS patients. This review offers conceptual advances by proposing an endothelial infection model as a systemic mechanism contributing to ME/CFS, steering future research toward potentially unexplored avenues in understanding and treating this complex syndrome.

For neurotypical adults, a single bout of low-to-moderate intensity physical activity usually transiently improves feelings of energy. Similar bouts of exercise have the opposite effect of increased feelings of fatigue when performed by samples with chronic multisymptom illnesses (CMIs) such as Long-COVID, Gulf War Illness (GWI), or Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The short-term adoption of regular moderate intensity physical activity (typical experiments are 1 to 6 months) among neurotypical adults results in small-to-moderate improvements in self-reported feelings of fatigue, energy, and vitality. Small improvements in these feelings, or no change at all, occur for CMIs, but limited data precludes strong conclusions. The mechanisms of exercise effects on fatigue, whether acute or chronic, are poorly understood but likely involve multiple neural circuits and associated transmitters. For CMIs, the mechanisms of acute worsening of fatigue with exercise may be driven by the yet unknown pathophysiological mechanisms of the disease (perhaps involving brain, immune and autonomic system dysfunction, and their interactions). Likewise, fatigue improvements may depend on whether chronic physical activity is a disease-modifying treatment., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The chapter explores the role of neuropsychology in understanding brain fog as a subjective complaint in the context of COVID-19. It discusses the historical and medical significance of the term "brain fog" and its psychological and neurological aspects. The chapter identifies the cognitive domains commonly affected by brain fog, such as attention, executive function, memory, and language. Additionally, it emphasizes the impact of societal changes during the COVID-19 pandemic on the general population as a crucial backdrop for understanding the issue. The chapter also highlights the important role of clinical and research neuropsychologists in gaining clarity on grouped data and individual patients' cognitive and emotional difficulties after COVID-19 infection. It discusses indications for neuropsychological rehabilitation and therapy and describes typical therapy phases and methods, including new approaches like telemedicine, virtual reality, and mobile app-based rehabilitation and self-tracking. The chapter underscores that experiences of brain fog can vary among COVID-19 patients and may change over time. It provides clinicians and interested parties with an in-depth understanding of brain fog and its manifestations, concomitant subtypes, and concrete strategies for addressing it. The chapter emphasizes the critical role of neuropsychology in scientifically examining brain fog and advocating for personalized approaches to cognitive rehabilitation., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Post-acute infection syndromes may develop after acute viral disease 1 . Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions 2-4 . However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein-Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers., (© 2023. The Author(s).)

Patients with post-acute sequelae of COVID-19 (PASC) present with a decrease in physical fitness. The aim of this paper is to reveal the relations between the remaining symptoms, blood volume distribution, exercise tolerance, static and dynamic lung volumes, and overall functioning. Patients with PASC were retrospectively studied. Pulmonary function tests (PFT), 6-minute walk test (6MWT), and cardiopulmonary exercise test were performed. Chest CT was taken and quantified. Patients were divided into two groups: minor functional limitations (MFL) and severe functional limitations (SFL) based on the completed Post-COVID-19 Functional Status scale (PCFS). Twenty one patients (3 M; 18 FM), mean age 44 (IQR 21) were studied. Eighteen completed the PCFS (8 MFL; 10 SFL). VO 2 max was suboptimal in both groups (not significant). 6MWT was significantly higher in MFL-group (p = 0.043). Subjects with SFL, had significant lower TLC (p = 0.029). The MFL-group had more air trapping (p = 0.036). Throughout the sample, air trapping correlated significantly with residual volume (RV) in L (p < 0.001). An increase in air trapping was related to an increase in BV5 (p < 0.001). Mean BV5 was 65% (IQR 5%). BV5% in patients with PASC was higher than in patients with acute COVID-19 infection. This increase in BV5% in patients with PASC is thought to be driven by the air trapping in the lobes. This study reveals that symptoms are more driven by occlusion of the small airways. Patients with more physical complaints have significantly lower TLC. All subjects encounter physical limitations as indicated by suboptimal VO 2 max. Treatment should focus on opening or re-opening of small airways by recruiting alveoli., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

2019 coronavirus disease (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to respiratory illness, COVID-19 patients exhibit neurological symptoms lasting from weeks to months (long COVID). It is unclear whether these neurological manifestations are due to an infection of brain cells. We found that a small fraction of human induced pluripotent stem cell (iPSC)-derived neurons, but not astrocytes, were naturally susceptible to SARS-CoV-2. Based on the inhibitory effect of blocking antibodies, the infection seemed to depend on the receptor angiotensin-converting enzyme 2 (ACE2), despite very low levels of its expression in neurons. The presence of double-stranded RNA in the cytoplasm (the hallmark of viral replication), abundant synthesis of viral late genes localized throughout infected cells, and an increase in the level of viral RNA in the culture medium (viral release) within the first 48 h of infection suggested that the infection was productive. Productive entry of SARS-CoV-2 requires the fusion of the viral and cellular membranes, which results in the delivery of the viral genome into the cytoplasm of the target cell. The fusion is triggered by proteolytic cleavage of the viral surface spike protein, which can occur at the plasma membrane or from endosomes or lysosomes. We found that SARS-CoV-2 infection of human neurons was insensitive to nafamostat and camostat, which inhibit cellular serine proteases, including transmembrane serine protease 2 (TMPRSS2). Inhibition of cathepsin L also did not significantly block infection. In contrast, the neuronal infection was blocked by apilimod, an inhibitor of phosphatidyl-inositol 5 kinase (PIK5K), which regulates early to late endosome maturation. IMPORTANCE COVID-19 is a disease caused by the coronavirus SARS-CoV-2. Millions of patients display neurological symptoms, including headache, impairment of memory, seizures, and encephalopathy, as well as anatomical abnormalities, such as changes in brain morphology. SARS-CoV-2 infection of the human brain has been documented, but it is unclear whether the observed neurological symptoms are linked to direct brain infection. The mechanism of virus entry into neurons has also not been characterized. Here, we investigated SARS-CoV-2 infection by using a human iPSC-derived neural cell model and found that a small fraction of cortical-like neurons was naturally susceptible to infection. The productive infection was ACE2 dependent and TMPRSS2 independent. We also found that the virus used the late endosomal and lysosomal pathway for cell entry and that the infection could be blocked by apilimod, an inhibitor of cellular PIK5K.

Introduction: COVID19 associated headaches are highly common and there is currently an unmet need to better understand their association with SARSCoV2 variants. Headaches are a prevalent symptom in the acute phase of COVID19 and are associated with a better prognosis and better immune response. They are also a relevant post-COVID symptom., Areas Covered: This article analyses the differences in the prevalence of headache as an onset symptom and in post-COVID headache among the different SARS-CoV-2 variants: the historical strain, Alpha, Delta and Omicron. The different pathophysiological mechanisms by which SARS-CoV-2 infection may cause headache are also discussed., Expert Opinion: The presence of headache at the acute phase is a risk factor for post-COVID headache, whereas a history of primary headache does not appear to be associated with post-COVID headache. The prevalence of headache as an onset symptom appears to be variable for the different SARS-CoV-2 variants, but current data are inconclusive. However, the current evidence also suggests that headache represents a prevalent symptom in the acute and post-infection COVID-19 phase, regardless of SARS-CoV-2 variant.

In the past two years, the world has faced the pandemic caused by the severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2), which by August of 2022 has infected around 619 million people and caused the death of 6.55 million individuals globally. Although SARS-CoV-2 mainly affects the respiratory tract level, there are several reports, indicating that other organs such as the heart, kidney, pancreas, and brain can also be damaged. A characteristic observed in blood serum samples of patients suffering COVID-19 disease in moderate and severe stages, is a significant increase in proinflammatory cytokines such as interferon-α (IFN-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6) and interleukin-18 (IL-18), as well as the presence of autoantibodies against interferon-α (IFN-α), interferon-λ (IFN-λ), C-C motif chemokine ligand 26 (CCL26), CXC motif chemokine ligand 12 (CXCL12), family with sequence similarity 19 (chemokine (C-C motif)-like) member A4 (FAM19A4), and C-C motif chemokine ligand 1 (CCL1). Interestingly, it has been described that the chronic cytokinemia is related to alterations of blood-brain barrier (BBB) permeability and induction of neurotoxicity. Furthermore, the generation of autoantibodies affects processes such as neurogenesis, neuronal repair, chemotaxis and the optimal microglia function. These observations support the notion that COVID-19 patients who survived the disease present neurological sequelae and neuropsychiatric disorders. The goal of this review is to explore the relationship between inflammatory and humoral immune markers and the major neurological damage manifested in post-COVID-19 patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elizalde-Díaz, Miranda-Narváez, Martínez-Lazcano and Martínez-Martínez.)