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Pang Z, Tang A, He Y, Fan J, Yang Q, Tong Y, Fan H. Neurological complications caused by SARS-CoV-2. Clin Microbiol Rev 2024; 37:e0013124. [PMID: 39291997 PMCID: PMC11629622 DOI: 10.1128/cmr.00131-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/19/2024] Open
Abstract
SUMMARYSARS-CoV-2 can not only cause respiratory symptoms but also lead to neurological complications. Research has shown that more than 30% of SARS-CoV-2 patients present neurologic symptoms during COVID-19 (A. Pezzini and A. Padovani, Nat Rev Neurol 16:636-644, 2020, https://doi.org/10.1038/s41582-020-0398-3). Increasing evidence suggests that SARS-CoV-2 can invade both the central nervous system (CNS) (M.S. Xydakis, M.W. Albers, E.H. Holbrook, et al. Lancet Neurol 20: 753-761, 2021 https://doi.org/10.1016/S1474-4422(21)00182-4 ) and the peripheral nervous system (PNS) (M.N. Soares, M. Eggelbusch, E. Naddaf, et al. J Cachexia Sarcopenia Muscle 13:11-22, 2022, https://doi.org/10.1002/jcsm.12896), resulting in a variety of neurological disorders. This review summarized the CNS complications caused by SARS-CoV-2 infection, including encephalopathy, neurodegenerative diseases, and delirium. Additionally, some PNS disorders such as skeletal muscle damage and inflammation, anosmia, smell or taste impairment, myasthenia gravis, Guillain-Barré syndrome, ICU-acquired weakness, and post-acute sequelae of COVID-19 were described. Furthermore, the mechanisms underlying SARS-CoV-2-induced neurological disorders were also discussed, including entering the brain through retrograde neuronal or hematogenous routes, disrupting the normal function of the CNS through cytokine storms, inducing cerebral ischemia or hypoxia, thus leading to neurological complications. Moreover, an overview of long-COVID-19 symptoms is provided, along with some recommendations for care and therapeutic approaches of COVID-19 patients experiencing neurological complications.
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Affiliation(s)
- Zehan Pang
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Ao Tang
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Yujie He
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Junfen Fan
- Department of Neurology, Institute of Cerebrovascular Diseases Research, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Qingmao Yang
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Yigang Tong
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Huahao Fan
- School of Life Sciences, Tianjin University, Tianjin, China
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2
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Finsterer J, Scorza FA. COVID-19 reduces immune competence and precipitates superinfections. J Family Med Prim Care 2024; 13:2787-2788. [PMID: 39071013 PMCID: PMC11272030 DOI: 10.4103/jfmpc.jfmpc_1432_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 01/03/2024] [Accepted: 01/09/2024] [Indexed: 07/30/2024] Open
Abstract
Objectives Whether infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be complicated by immune suppression is under debate, but the following case suggests decreased immune competence during and after a SARS-CoV-2 infection. Case Report The patient is a 50-year-old woman with a previous history of transient hyperthyroidism, allergy against ambrosia, and burn-out syndrome, who experienced a mild infection with SARS-CoV-2 during which she developed candida pharyngitis, which was successfully treated with miconazole. Twenty-eight days after clinical recovery from the SARS-CoV-2 infection, she developed right-sided zoster oticus with vestibular neuronitis and was successfully treated with acyclovir. Conclusions The case suggests that infection with SARS-CoV-2 can weaken immune competence and precipitate the development of candidiasis and focal infection with the zoster virus. Even mild infections with SARS-CoV-2 may be complicated by immune-compromise and immune-concomitant superinfections, which is why coronavirus disease 2019 (COVID-19) patients should strengthen their immune system not only during but also after the infection.
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Affiliation(s)
- Josef Finsterer
- Department of Neurology, Neurology and Neurophysiology Center, Vienna, Austria
| | - Fulvio A. Scorza
- Disciplina de Neurociência, Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM), São Paulo, Brasil
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3
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Rieder AS, Wyse ATS. Regulation of Inflammation by IRAK-M Pathway Can Be Associated with nAchRalpha7 Activation and COVID-19. Mol Neurobiol 2024; 61:581-592. [PMID: 37640915 DOI: 10.1007/s12035-023-03567-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 08/07/2023] [Indexed: 08/31/2023]
Abstract
In spite of the vaccine development and its importance, the SARS-CoV-2 pandemic is still impacting the world. It is known that the COVID-19 severity is related to the cytokine storm phenomenon, being inflammation a common disease feature. The nicotinic cholinergic system has been widely associated with COVID-19 since it plays a protective role in inflammation via nicotinic receptor alpha 7 (nAchRalpha7). In addition, SARS-CoV-2 spike protein (Spro) subunits can interact with nAchRalpha7. Moreover, Spro causes toll-like receptor (TLR) activation, leading to pro- and anti-inflammatory pathways. The increase and maturation of the IL-1 receptor-associated kinase (IRAK) family are mediated by activation of membrane receptors, such as TLRs. IRAK-M, a member of this family, is responsible for negatively regulating the activity of other active IRAKs. In addition, IRAK-M can regulate microglia phenotype by specific protein expression. Furthermore, there exists an antagonist influence of SARS-CoV-2 Spro and the cholinergic system action on the IRAK-M pathway and microglia phenotype. We discuss the overexpression and suppression of IRAK-M in inflammatory cell response to inflammation in SARS-CoV-2 infection when the cholinergic system is constantly activated via nAchRalpha7.
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Affiliation(s)
- Alessanda S Rieder
- Laboratory of Neuroprotection and Neurometabolic Diseases (Wyse's Lab), Department of Biochemistry, ICBS, Universidade Federal Do Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre RS, 90035-003, Brazil
| | - Angela T S Wyse
- Laboratory of Neuroprotection and Neurometabolic Diseases (Wyse's Lab), Department of Biochemistry, ICBS, Universidade Federal Do Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre RS, 90035-003, Brazil.
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Chavda V, Yadav D, Parmar H, Brahmbhatt R, Patel B, Madhwani K, Jain M, Song M, Patel S. A Narrative Overview of Coronavirus Infection: Clinical Signs and Symptoms, Viral Entry and Replication, Treatment Modalities, and Management. Curr Top Med Chem 2024; 24:1883-1916. [PMID: 38859776 DOI: 10.2174/0115680266296095240529114058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 04/18/2024] [Accepted: 04/26/2024] [Indexed: 06/12/2024]
Abstract
The global pandemic known as coronavirus disease (COVID-19) is causing morbidity and mortality on a daily basis. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV- -2) virus has been around since December 2019 and has infected a high number of patients due to its idiopathic pathophysiology and rapid transmission. COVID-19 is now deemed a newly identified "syndrome" condition since it causes a variety of unpleasant symptoms and systemic side effects following the pandemic. Simultaneously, it always becomes potentially hazardous when new variants develop during evolution. Its random viral etiology prevents accurate and suitable therapy. Despite the fact that multiple preclinical and research studies have been conducted to combat this lethal virus, and various therapeutic targets have been identified, the precise course of therapy remains uncertain. However, just a few drugs have shown efficacy in treating this viral infection in its early stages. Currently, several medicines and vaccinations have been licensed following clinical trial research, and many countries are competing to find the most potent and effective immunizations against this highly transmissible illness. For this narrative review, we used PubMed, Google Scholar, and Scopus to obtain epidemiological data, pre-clinical and clinical trial outcomes, and recent therapeutic alternatives for treating COVID-19 viral infection. In this study, we discussed the disease's origin, etiology, transmission, current advances in clinical diagnostic technologies, different new therapeutic targets, pathophysiology, and future therapy options for this devastating virus. Finally, this review delves further into the hype surrounding the SARS-CoV-2 illness, as well as present and potential COVID-19 therapies.
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Affiliation(s)
- Vishal Chavda
- Department of Pathology, Stanford School of Medicine, Stanford University Medical Center, Palo Alto94305, CA, USA
- Department of Medicine, Multispeciality, Trauma and ICCU Center, Sardar Hospital, Ahmedabad, 382352, Gujarat, India
| | - Dhananjay Yadav
- Department of Life Science, Yeungnam University, South Korea
| | - Harisinh Parmar
- Department of Neurosurgery, Krishna institute of medical sciences, Karad, Maharashtra, India
| | - Raxit Brahmbhatt
- Department of Medicine, Multispeciality, Trauma and ICCU Center, Sardar Hospital, Ahmedabad, 382352, Gujarat, India
| | - Bipin Patel
- Department of Medicine, Multispeciality, Trauma and ICCU Center, Sardar Hospital, Ahmedabad, 382352, Gujarat, India
| | - Kajal Madhwani
- Department of Life Science, University of Westminster, London, W1B 2HW, United Kingdom
| | - Meenu Jain
- Gajra Raja Medical College, Gwalior, 474009, Madhya Pradesh, India
| | - Minseok Song
- Department of Life Science, Yeungnam University, South Korea
| | - Snehal Patel
- Department of Pharmacology, Nirma University, Ahmedabad, 382481, Gujarat, India
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Ludhiadch A, Paul SR, Khan R, Munshi A. COVID-19 induced ischemic stroke and mechanisms of viral entry in brain and clot formation: a systematic review and current update. Int J Neurosci 2023; 133:1153-1166. [PMID: 35412938 DOI: 10.1080/00207454.2022.2056460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 03/16/2022] [Indexed: 10/18/2022]
Abstract
Background: Coronavirus disease 2019, caused by SARS-CoV-2 (SCV-2) was stated as a pandemic on March 11 2020 by World Health Organization (WHO), and since then, it has become a major health issue worldwide. It mainly attacks the respiratory system with various accompanying complications, including cardiac injury, renal failure, encephalitis and Stroke.Materials and Methods: The current systematic review has been compiled to summarize the available literature on SCV-2 induced ischemic Stroke and its subtypes. Further, the mechanisms by which the virus crosses the blood-brain barrier (BBB) to enter the brain have also been explored. The role of CRP and D-dimer as potent prognostic markers was also explored. The literature search was carried out comprehensively on Google scholar, PubMed, SCOP US, Embase and Cochrane databases by following guidelines.Results: All the studies were reviewed thoroughly by authors and disagreements were resolved by consensus and help of the senior authors. The most common subtype of the IS was found to be large artery atherosclerosis in SCV-2 induced IS. Hypertension emerged as the most significant risk factor. The mechanism resulting in elevated levels of CRP and D-dimer have also been discussed. However, there is a scarcity of definitive evidence on how SCV-2 enters the human brain. The available literature based on various studies demonstrated that SCV-2 enters through the nasopharyngeal tract via olfactory cells to olfactory neurons, astrocytes and via choroid plexus through endothelial cells. Further, disruption of gut-brain axis has been also discussed.Conclusion: Data available in the literature is not adequate to come to a conclusion. Therefore, there is a need to carry out further studies to delineate the possible association between SCV-2 induced IS.
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Affiliation(s)
- Abhilash Ludhiadch
- Department of Human Genetics and Molecular Medicine Central, University of Punjab Bathinda, Bathinda, Punjab, India
| | - Swaraj Ranjan Paul
- Department of Human Genetics and Molecular Medicine Central, University of Punjab Bathinda, Bathinda, Punjab, India
| | - Rahul Khan
- Department of Human Genetics and Molecular Medicine Central, University of Punjab Bathinda, Bathinda, Punjab, India
| | - Anjana Munshi
- Department of Human Genetics and Molecular Medicine Central, University of Punjab Bathinda, Bathinda, Punjab, India
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Li Y, Chen Q, Wang L, Chen X, Wang B, Zhong W. The mechanisms of nerve injury caused by viral infection in the occurrence of gastrointestinal motility disorder-related diseases. Virol J 2023; 20:251. [PMID: 37915051 PMCID: PMC10621196 DOI: 10.1186/s12985-023-02185-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 09/14/2023] [Indexed: 11/03/2023] Open
Abstract
Gastrointestinal motility refers to the peristalsis and contractility of gastrointestinal muscles, including the force and frequency of gastrointestinal muscle contraction. Gastrointestinal motility maintains the normal digestive function of the human body and is a critical component of the physiological function of the digestive tract. At present, gastrointestinal motility disorder-related diseases are gradually affecting human production and life. In recent years, it has been consistently reported that the enteric nervous system has a coordinating and controlling role in gastrointestinal motility. Motility disorders are closely related to functional or anatomical changes in the gastrointestinal nervous system. At the same time, some viral infections, such as herpes simplex virus and varicella-zoster virus infections, can cause damage to the gastrointestinal nervous system. Therefore, this paper describes the mechanisms of viral infection in the gastrointestinal nervous system and the associated clinical manifestations. Studies have indicated that the means by which viruses can cause the infection of the enteric nervous system are various, including retrograde transport, hematogenous transmission and centrifugal transmission from the central nervous system. When viruses infect the enteric nervous system, they can cause clinical symptoms, such as abdominal pain, abdominal distension, early satiation, belching, diarrhea, and constipation, by recruiting macrophages, lymphocytes and neutrophils and regulating intestinal microbes. The findings of several case‒control studies suggest that viruses are the cause of some gastrointestinal motility disorders. It is concluded that one of the causes of gastrointestinal motility disorders is viral infection of the enteric nervous system. In such disorders, the relationships between viruses and nerves remain to be studied more deeply. Further studies are necessary to evaluate whether prophylactic antiviral therapy is feasible in gastrointestinal motility disorders.
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Affiliation(s)
- Yaqian Li
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Qiuyu Chen
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Department of Gastroenterology, Tianjin First Central Hospital, Tianjin, 300110, China
| | - Liwei Wang
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Xin Chen
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin, 300052, China.
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin, 300052, China.
| | - Weilong Zhong
- Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin, 300052, China.
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Vakili K, Fathi M, Yaghoobpoor S, Sayehmiri F, Nazerian Y, Nazerian A, Mohamadkhani A, Khodabakhsh P, Réus GZ, Hajibeygi R, Rezaei-Tavirani M. The contribution of gut-brain axis to development of neurological symptoms in COVID-19 recovered patients: A hypothesis and review of literature. Front Cell Infect Microbiol 2022; 12:983089. [PMID: 36619768 PMCID: PMC9815719 DOI: 10.3389/fcimb.2022.983089] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/25/2022] [Indexed: 12/24/2022] Open
Abstract
The gut microbiota undergoes significant alterations in response to viral infections, particularly the novel SARS-CoV-2. As impaired gut microbiota can trigger numerous neurological disorders, we suggest that the long-term neurological symptoms of COVID-19 may be related to intestinal microbiota disorders in these patients. Thus, we have gathered available information on how the virus can affect the microbiota of gastrointestinal systems, both in the acute and the recovery phase of the disease, and described several mechanisms through which this gut dysbiosis can lead to long-term neurological disorders, such as Guillain-Barre syndrome, chronic fatigue, psychiatric disorders such as depression and anxiety, and even neurodegenerative diseases such as Alzheimer's and Parkinson's disease. These mechanisms may be mediated by inflammatory cytokines, as well as certain chemicals such as gastrointestinal hormones (e.g., CCK), neurotransmitters (e.g., 5-HT), etc. (e.g., short-chain fatty acids), and the autonomic nervous system. In addition to the direct influences of the virus, repurposed medications used for COVID-19 patients can also play a role in gut dysbiosis. In conclusion, although there are many dark spots in our current knowledge of the mechanism of COVID-19-related gut-brain axis disturbance, based on available evidence, we can hypothesize that these two phenomena are more than just a coincidence and highly recommend large-scale epidemiologic studies in the future.
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Affiliation(s)
- Kimia Vakili
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Fathi
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shirin Yaghoobpoor
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Sayehmiri
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Nazerian
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Ashraf Mohamadkhani
- Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Pariya Khodabakhsh
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Gislaine Z. Réus
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Ramtin Hajibeygi
- Department of Cardiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mostafa Rezaei-Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Menezes Junior ADS, Schröder AA, Botelho SM, Resende AL. Cardiac Autonomic Function in Long COVID-19 Using Heart Rate Variability: An Observational Cross-Sectional Study. J Clin Med 2022; 12:jcm12010100. [PMID: 36614901 PMCID: PMC9821736 DOI: 10.3390/jcm12010100] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/12/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Heart rate variability is a non-invasive, measurable, and established autonomic nervous system test. Long-term COVID-19 sequelae are unclear; however, acute symptoms have been studied. OBJECTIVES To determine autonomic cardiac differences between long COVID-19 patients and healthy controls and evaluate associations among symptoms, comorbidities, and laboratory findings. METHODS This single-center study included long COVID-19 patients and healthy controls. The heart rate variability (HRV), a quantitative marker of autonomic activity, was monitored for 24 h using an ambulatory electrocardiogram system. HRV indices were compared between case and control groups. Symptom frequency and inflammatory markers were evaluated. A significant statistical level of 5% (p-value 0.05) was adopted. RESULTS A total of 47 long COVID-19 patients were compared to 42 healthy controls. Patients averaged 43.8 (SD14.8) years old, and 60.3% were female. In total, 52.5% of patients had moderate illness. Post-exercise dyspnea was most common (71.6%), and 53.2% lacked comorbidities. CNP, D-dimer, and CRP levels were elevated (p-values of 0.0098, 0.0023, and 0.0015, respectively). The control group had greater SDNN24 and SDANNI (OR = 0.98 (0.97 to 0.99; p = 0.01)). Increased low-frequency (LF) indices in COVID-19 patients (OR = 1.002 (1.0001 to 1.004; p = 0.030)) and high-frequency (HF) indices in the control group (OR = 0.987 (0.98 to 0.995; p = 0.001)) were also associated. CONCLUSIONS Patients with long COVID-19 had lower HF values than healthy individuals. These variations are associated with increased parasympathetic activity, which may be related to long COVID-19 symptoms and inflammatory laboratory findings.
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Affiliation(s)
- Antonio da Silva Menezes Junior
- Internal Medicine Department, Medicine School, Federal University of Goiás, Goiânia 74175-120, Brazil
- Medical and Life Sciences School, Medicine School, Pontifical Catholic University of Goiás, Goiânia 74000-000, Brazil
- Correspondence: or ; Tel.: +55-62982711177
| | - Aline Andressa Schröder
- Medical and Life Sciences School, Medicine School, Pontifical Catholic University of Goiás, Goiânia 74000-000, Brazil
| | - Silvia Marçal Botelho
- Internal Medicine Department, Medicine School, Federal University of Goiás, Goiânia 74175-120, Brazil
- Medical and Life Sciences School, Medicine School, Pontifical Catholic University of Goiás, Goiânia 74000-000, Brazil
| | - Aline Lazara Resende
- Internal Medicine Department, Medicine School, Federal University of Goiás, Goiânia 74175-120, Brazil
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Pelle MC, Zaffina I, Lucà S, Forte V, Trapanese V, Melina M, Giofrè F, Arturi F. Endothelial Dysfunction in COVID-19: Potential Mechanisms and Possible Therapeutic Options. Life (Basel) 2022; 12:1605. [PMID: 36295042 PMCID: PMC9604693 DOI: 10.3390/life12101605] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/29/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022] Open
Abstract
SARS-CoV-2, a novel coronavirus found in Wuhan (China) at the end of 2019, is the etiological agent of the current pandemic that is a heterogeneous disease, named coronavirus disease 2019 (COVID-19). SARS-CoV-2 affects primarily the lungs, but it can induce multi-organ involvement such as acute myocardial injury, myocarditis, thromboembolic eventsandrenal failure. Hypertension, chronic kidney disease, diabetes mellitus and obesity increase the risk of severe complications of COVID-19. There is no certain explanation for this systemic COVID-19 involvement, but it could be related to endothelial dysfunction, due to direct (endothelial cells are infected by the virus) and indirect damage (systemic inflammation) factors. Angiotensin-converting enzyme 2 (ACE2), expressed in human endothelium, has a fundamental role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In fact, ACE2 is used as a receptor by SARS-CoV-2, leading to the downregulation of these receptors on endothelial cells; once inside, this virus reduces the integrity of endothelial tissue, with exposure of prothrombotic molecules, platelet adhesion, activation of coagulation cascades and, consequently, vascular damage. Systemic microangiopathy and thromboembolism can lead to multi-organ failure with an elevated risk of death. Considering the crucial role of the immunological response and endothelial damage in developing the severe form of COVID-19, in this review, we will attempt to clarify the underlying pathophysiological mechanisms.
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Affiliation(s)
- Maria Chiara Pelle
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Isabella Zaffina
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Stefania Lucà
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Valentina Forte
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Vincenzo Trapanese
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Melania Melina
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Federica Giofrè
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Franco Arturi
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
- Research Centre for the Prevention and Treatment of Metabolic Diseases (CR METDIS), University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
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10
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Wais T, Hasan M, Rai V, Agrawal DK. Gut-brain communication in COVID-19: molecular mechanisms, mediators, biomarkers, and therapeutics. Expert Rev Clin Immunol 2022; 18:947-960. [PMID: 35868344 PMCID: PMC9388545 DOI: 10.1080/1744666x.2022.2105697] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 07/21/2022] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Infection with COVID-19 results in acute respiratory symptoms followed by long COVID multi-organ effects presenting with neurological, cardiovascular, musculoskeletal, and gastrointestinal (GI) manifestations. Temporal relationship between gastrointestinal and neurological symptoms is unclear but warranted for exploring better clinical care for COVID-19 patients. AREAS COVERED We critically reviewed the temporal relationship between gut-brain axis after SARS-CoV-2 infection and the molecular mechanisms involved in neuroinvasion following GI infection. Mediators are identified that could serve as biomarkers and therapeutic targets in SARS-CoV-2. We discussed the potential therapeutic approaches to mitigate the effects of GI infection with SARS-CoV-2. EXPERT OPINION Altered gut microbiota cause increased expression of various mediators, including zonulin causing disruption of tight junction. This stimulates enteric nervous system and signals to CNS precipitating neurological sequalae. Published reports suggest potential role of cytokines, immune cells, B(0)AT1 (SLC6A19), ACE2, TMRSS2, TMPRSS4, IFN-γ, IL-17A, zonulin, and altered gut microbiome in gut-brain axis and associated neurological sequalae. Targeting these mediators and gut microbiome to improve immunity will be of therapeutic significance. In-depth research and well-designed large-scale population-based clinical trials with multidisciplinary and collaborative approaches are warranted. Investigating the temporal relationship between organs involved in long-term sequalae is critical due to evolving variants of SARS-CoV-2.
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Affiliation(s)
- Tameena Wais
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
| | - Mehde Hasan
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
| | - Vikrant Rai
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
| | - Devendra K. Agrawal
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
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Progress Report: Antimicrobial Drug Discovery in the Resistance Era. Pharmaceuticals (Basel) 2022; 15:ph15040413. [PMID: 35455410 PMCID: PMC9030565 DOI: 10.3390/ph15040413] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 02/05/2023] Open
Abstract
Antibiotic resistance continues to be a most serious threat to public health. This situation demands that the scientific community increase their efforts for the discovery of alternative strategies to circumvent the problems associated with conventional small molecule therapeutics. The Global Antimicrobial Resistance and Use Surveillance System (GLASS) Report (published in June 2021) discloses the rapidly increasing number of bacterial infections that are mainly caused by antimicrobial-resistant bacteria. These concerns have initiated various government agencies and other organizations to educate the public regarding the appropriate use of antibiotics. This review discusses a brief highlight on the timeline of antimicrobial drug discovery with a special emphasis on the historical development of antimicrobial resistance. In addition, new antimicrobial targets and approaches, recent developments in drug screening, design, and delivery were covered. This review also discusses the emergence and roles of various antibiotic adjuvants and combination therapies while shedding light on current challenges and future perspectives. Overall, the emergence of resistant microbial strains has challenged drug discovery but their efforts to develop alternative technologies such as nanomaterials seem to be promising for the future.
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Elrobaa IH, New KJ. COVID-19: Pulmonary and Extra Pulmonary Manifestations. Front Public Health 2021; 9:711616. [PMID: 34650947 PMCID: PMC8505777 DOI: 10.3389/fpubh.2021.711616] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 07/30/2021] [Indexed: 01/08/2023] Open
Abstract
Introduction: The coronavirus disease-2019 (COVID-19) pandemic has been the most significant event in 2020, with ~86.8 million cases and 1.88 million deaths worldwide. It is a highly infectious disease, wherein the virus (severe acute respiratory syndrome coronavirus 2) rapidly multiplies and spreads to all parts of the body. Therefore, COVID-19 is not only respiratory disease but also a multisystem disease. Many people, including physicians, incorrectly believe that the disease affects only the respiratory tract. In this study, we aimed to describe COVID-19 manifestations and the underlying pathophysiology to provide the readers with a better understanding of this disease to achieve good management and to control the spread of this disease. Methods: Secondary data were obtained from PubMed, Google Scholar, and Scopus databases. The keywords used for the search were as follows: COVID-19, COVID-19 pulmonary manifestations, COVID-19 extra pulmonary manifestations, and pathophysiology of COVID-19. We collected secondary data from systemic reviews, metaanalyses, case series, and case reports in the form of public data that was published on websites of the government, medical corporations, medical peer-reviewed journals, and medical academies, all of which were indexed in PubMed, Google Scholar, or Scopus. Our questions were as follows: Is COVID-19 a respiratory disease only? and What are the extrapulmonary manifestations of COVID-19? Results: From our data, we found that a patient with COVID-19 may be either asymptomatic or symptomatic. Symptomatic cases may have either pulmonary or extrapulmonary manifestations. Pulmonary manifestations occur as mild, moderate, or severe cases. In mild and moderate cases, extrapulmonary manifestations such as gastroenteritis, fever, or vomiting may present alone. Some of these cases may be missed for diagnosis, and the patient may receive symptomatic treatment without a COVID-19 diagnosis, leading to increased spread of the infection. Extrapulmonary manifestations may occur in severe and critical cases as complications of severe infections (high viral overload) or the cytokine storm, such as in acute kidney injury (AKI), heart failure (HF), and venous thromboembolic (VTE) manifestation. Conclusion: COVID-19 is not a respiratory disease alone; rather, it is a multisystem disease. Pulmonary and extrapulmonary manifestations should be considered for early diagnosis and to control the spread of the infection.
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Affiliation(s)
- Islam H. Elrobaa
- Emergency Medicine Specialist in Hamad Medical Corporation, Qatar and Lecturer in Clinical Education Department, College of Medicine, Qatar University, Doha, Qatar
| | - Karl J. New
- Clinical Physiology, School of Health, Sport, and Professional Practice, Faculty of Life Science and Education, University of South Wales, Treforest, United Kingdom
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Yao XH, Luo T, Shi Y, He ZC, Tang R, Zhang PP, Cai J, Zhou XD, Jiang DP, Fei XC, Huang XQ, Zhao L, Zhang H, Wu HB, Ren Y, Liu ZH, Zhang HR, Chen C, Fu WJ, Li H, Xia XY, Chen R, Wang Y, Liu XD, Yin CL, Yan ZX, Wang J, Jing R, Li TS, Li WQ, Wang CF, Ding YQ, Mao Q, Zhang DY, Zhang SY, Ping YF, Bian XW. A cohort autopsy study defines COVID-19 systemic pathogenesis. Cell Res 2021; 31:836-846. [PMID: 34135479 PMCID: PMC8208380 DOI: 10.1038/s41422-021-00523-8] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 05/21/2021] [Indexed: 12/15/2022] Open
Abstract
Severe COVID-19 disease caused by SARS-CoV-2 is frequently accompanied by dysfunction of the lungs and extrapulmonary organs. However, the organotropism of SARS-CoV-2 and the port of virus entry for systemic dissemination remain largely unknown. We profiled 26 COVID-19 autopsy cases from four cohorts in Wuhan, China, and determined the systemic distribution of SARS-CoV-2. SARS-CoV-2 was detected in the lungs and multiple extrapulmonary organs of critically ill COVID-19 patients up to 67 days after symptom onset. Based on organotropism and pathological features of the patients, COVID-19 was divided into viral intrapulmonary and systemic subtypes. In patients with systemic viral distribution, SARS-CoV-2 was detected in monocytes, macrophages, and vascular endothelia at blood-air barrier, blood-testis barrier, and filtration barrier. Critically ill patients with long disease duration showed decreased pulmonary cell proliferation, reduced viral RNA, and marked fibrosis in the lungs. Permanent SARS-CoV-2 presence and tissue injuries in the lungs and extrapulmonary organs suggest direct viral invasion as a mechanism of pathogenicity in critically ill patients. SARS-CoV-2 may hijack monocytes, macrophages, and vascular endothelia at physiological barriers as the ports of entry for systemic dissemination. Our study thus delineates systemic pathological features of SARS-CoV-2 infection, which sheds light on the development of novel COVID-19 treatment.
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Affiliation(s)
- Xiao-Hong Yao
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Tao Luo
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Yu Shi
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Zhi-Cheng He
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Rui Tang
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Pei-Pei Zhang
- Department of Pathology, the First Hospital Affiliated to University of Science & Technology of China, Hefei, Anhui, China
- Department of Pathology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jun Cai
- Department of Pathology, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Xiang-Dong Zhou
- Department of Pulmonary & Critical Care Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Dong-Po Jiang
- Wound Trauma Medical Center, State Key Laboratory of Trauma, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Xiao-Chun Fei
- Department of Pathology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Xue-Quan Huang
- Department of Vascular Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Lei Zhao
- Department of Pathology, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Heng Zhang
- Department of Pathology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Hai-Bo Wu
- Department of Pathology, the First Hospital Affiliated to University of Science & Technology of China, Hefei, Anhui, China
| | - Yong Ren
- Department of Pathology, General Hospital of Central Theater Command of PLA, Wuhan, Hubei, China
| | - Zhen-Hua Liu
- Department of Ultrasound, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Hua-Rong Zhang
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Cong Chen
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Wen-Juan Fu
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Heng Li
- Department of Pathology, the First Hospital Affiliated to University of Science & Technology of China, Hefei, Anhui, China
| | - Xin-Yi Xia
- Institute of Laboratory Medicine, Jinling Hospital, School of Medicine, Nanjing University, the First School of Clinical Medicine, Southern Medical University, Nanjing, Jiangsu, China
| | - Rong Chen
- Wuhan Jinyintan Hospital (Wuhan Hospital for Infectious Diseases), Wuhan, Hubei, China
| | - Yan Wang
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Xin-Dong Liu
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Chang-Lin Yin
- Department of Critical Care Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Ze-Xuan Yan
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Juan Wang
- Emergency Department and Clinical Skills Training Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Rui Jing
- Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Tai-Sheng Li
- Department of Infectious Diseases, Peking Union Medical College Hospital, Beijing, China
| | - Wei-Qin Li
- Department of Critical Care Medicine, PLA Key Laboratory of Emergency and Critical Care Research, Jinling Hospital, Nanjing University, Nanjing, Jiangsu, China
| | - Chao-Fu Wang
- Department of Pathology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yan-Qing Ding
- Department of Pathology, Nan Fang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qing Mao
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Ding-Yu Zhang
- Wuhan Jinyintan Hospital (Wuhan Hospital for Infectious Diseases), Wuhan, Hubei, China
| | | | - Yi-Fang Ping
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China.
| | - Xiu-Wu Bian
- Institute of Pathology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China.
- Department of Pathology, the First Hospital Affiliated to University of Science & Technology of China, Hefei, Anhui, China.
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Barizien N, Le Guen M, Russel S, Touche P, Huang F, Vallée A. Clinical characterization of dysautonomia in long COVID-19 patients. Sci Rep 2021; 11:14042. [PMID: 34234251 DOI: 10.1038/s41598-021-93546-5.pdf] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 06/28/2021] [Indexed: 05/22/2023] Open
Abstract
Increasing numbers of COVID-19 patients, continue to experience symptoms months after recovering from mild cases of COVID-19. Amongst these symptoms, several are related to neurological manifestations, including fatigue, anosmia, hypogeusia, headaches and hypoxia. However, the involvement of the autonomic nervous system, expressed by a dysautonomia, which can aggregate all these neurological symptoms has not been prominently reported. Here, we hypothesize that dysautonomia, could occur in secondary COVID-19 infection, also referred to as "long COVID" infection. 39 participants were included from December 2020 to January 2021 for assessment by the Department of physical medicine to enhance their physical capabilities: 12 participants with COVID-19 diagnosis and fatigue, 15 participants with COVID-19 diagnosis without fatigue and 12 control participants without COVID-19 diagnosis and without fatigue. Heart rate variability (HRV) during a change in position is commonly measured to diagnose autonomic dysregulation. In this cohort, to reflect HRV, parasympathetic/sympathetic balance was estimated using the NOL index, a multiparameter artificial intelligence-driven index calculated from extracted physiological signals by the PMD-200 pain monitoring system. Repeated-measures mixed-models testing group effect were performed to analyze NOL index changes over time between groups. A significant NOL index dissociation over time between long COVID-19 participants with fatigue and control participants was observed (p = 0.046). A trend towards significant NOL index dissociation over time was observed between long COVID-19 participants without fatigue and control participants (p = 0.109). No difference over time was observed between the two groups of long COVID-19 participants (p = 0.904). Long COVID-19 participants with fatigue may exhibit a dysautonomia characterized by dysregulation of the HRV, that is reflected by the NOL index measurements, compared to control participants. Dysautonomia may explain the persistent symptoms observed in long COVID-19 patients, such as fatigue and hypoxia. Trial registration: The study was approved by the Foch IRB: IRB00012437 (Approval Number: 20-12-02) on December 16, 2020.
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Affiliation(s)
- Nicolas Barizien
- Department of Physical Medicine and Rehabilitation, Foch Hospital, Suresnes, France
| | - Morgan Le Guen
- Department of Anesthesiology, Foch Hospital, Suresnes, France
| | | | - Pauline Touche
- Department of Clinical Research and Innovation, Foch Hospital, 40 rue Worth, 92150, Suresnes, France
| | - Florent Huang
- Department of Cardiology, Foch Hospital, Suresnes, France
| | - Alexandre Vallée
- Department of Clinical Research and Innovation, Foch Hospital, 40 rue Worth, 92150, Suresnes, France.
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15
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Clinical characterization of dysautonomia in long COVID-19 patients. Sci Rep 2021; 11:14042. [PMID: 34234251 PMCID: PMC8263555 DOI: 10.1038/s41598-021-93546-5] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 06/28/2021] [Indexed: 01/07/2023] Open
Abstract
Increasing numbers of COVID-19 patients, continue to experience symptoms months after recovering from mild cases of COVID-19. Amongst these symptoms, several are related to neurological manifestations, including fatigue, anosmia, hypogeusia, headaches and hypoxia. However, the involvement of the autonomic nervous system, expressed by a dysautonomia, which can aggregate all these neurological symptoms has not been prominently reported. Here, we hypothesize that dysautonomia, could occur in secondary COVID-19 infection, also referred to as “long COVID” infection. 39 participants were included from December 2020 to January 2021 for assessment by the Department of physical medicine to enhance their physical capabilities: 12 participants with COVID-19 diagnosis and fatigue, 15 participants with COVID-19 diagnosis without fatigue and 12 control participants without COVID-19 diagnosis and without fatigue. Heart rate variability (HRV) during a change in position is commonly measured to diagnose autonomic dysregulation. In this cohort, to reflect HRV, parasympathetic/sympathetic balance was estimated using the NOL index, a multiparameter artificial intelligence-driven index calculated from extracted physiological signals by the PMD-200 pain monitoring system. Repeated-measures mixed-models testing group effect were performed to analyze NOL index changes over time between groups. A significant NOL index dissociation over time between long COVID-19 participants with fatigue and control participants was observed (p = 0.046). A trend towards significant NOL index dissociation over time was observed between long COVID-19 participants without fatigue and control participants (p = 0.109). No difference over time was observed between the two groups of long COVID-19 participants (p = 0.904). Long COVID-19 participants with fatigue may exhibit a dysautonomia characterized by dysregulation of the HRV, that is reflected by the NOL index measurements, compared to control participants. Dysautonomia may explain the persistent symptoms observed in long COVID-19 patients, such as fatigue and hypoxia.
Trial registration: The study was approved by the Foch IRB: IRB00012437 (Approval Number: 20-12-02) on December 16, 2020.
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16
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Xu J, Wu Z, Zhang M, Liu S, Zhou L, Yang C, Liu C. The Role of the Gastrointestinal System in Neuroinvasion by SARS-CoV-2. Front Neurosci 2021; 15:694446. [PMID: 34276298 PMCID: PMC8283125 DOI: 10.3389/fnins.2021.694446] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 06/14/2021] [Indexed: 12/15/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is one of the most devastating pandemics in history. SARS-CoV-2 has infected more than 100 million people worldwide, leading to more than 3.5 million deaths. Initially, the clinical symptoms of SARS-CoV-2 infection were thought to be restricted to the respiratory system. However, further studies have revealed that SARS-CoV-2 can also afflict multiple other organs, including the gastrointestinal tract and central nervous system. The number of gastrointestinal and neurological manifestations after SARS-CoV-2 infection has been rapidly increasing. Most importantly, patients infected with SARS-CoV-2 often exhibit comorbid symptoms in the gastrointestinal and neurological systems. This review aims to explore the pathophysiological mechanisms of neuroinvasion by SARS-CoV-2. SARS-CoV-2 may affect the nervous system by invading the gastrointestinal system. We hope that this review can provide novel ideas for the clinical treatment of the neurological symptoms of SARS-CoV-2 infection and references for developing prevention and treatment strategies.
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Affiliation(s)
- Jiali Xu
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zifeng Wu
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mi Zhang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shijiang Liu
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ling Zhou
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chun Yang
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Cunming Liu
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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17
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Wang MK, Yue HY, Cai J, Zhai YJ, Peng JH, Hui JF, Hou DY, Li WP, Yang JS. COVID-19 and the digestive system: A comprehensive review. World J Clin Cases 2021; 9:3796-3813. [PMID: 34141737 PMCID: PMC8180220 DOI: 10.12998/wjcc.v9.i16.3796] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 02/10/2021] [Accepted: 03/24/2021] [Indexed: 02/06/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is spreading at an alarming rate, and it has created an unprecedented health emergency threatening tens of millions of people worldwide. Previous studies have indicated that SARS-CoV-2 ribonucleic acid could be detected in the feces of patients even after smear-negative respiratory samples. However, demonstration of confirmed fecal-oral transmission has been difficult. Clinical studies have shown an incidence rate of gastrointestinal (GI) symptoms ranging from 2% to 79.1% in patients with COVID-19. They may precede or accompany respiratory symptoms. The most common GI symptoms included nausea, diarrhea, and abdominal pain. In addition, some patients also had liver injury, pancreatic damage, and even acute mesenteric ischemia/thrombosis. Although the incidence rates reported in different centers were quite different, the digestive system was the clinical component of the COVID-19 section. Studies have shown that angiotensin-converting enzyme 2, the receptor of SARS-CoV-2, was not only expressed in the lungs, but also in the upper esophagus, small intestine, liver, and colon. The possible mechanism of GI symptoms in COVID-19 patients may include direct viral invasion into target cells, dysregulation of angiotensin-converting enzyme 2, immune-mediated tissue injury, and gut dysbiosis caused by microbiota. Additionally, numerous experiences, guidelines, recommendations, and position statements were published or released by different organizations and societies worldwide to optimize the management practice of outpatients, inpatients, and endoscopy in the era of COVID-19. In this review, based on our previous work and relevant literature, we mainly discuss potential fecal-oral transmission, GI manifestations, abdominal imaging findings, relevant pathophysiological mechanisms, and infection control and prevention measures in the time of COVID-19.
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Affiliation(s)
- Ming-Ke Wang
- Department of Disease Control and Prevention, Naval Medical Center of PLA, Naval Medical University, Shanghai 200052, China
| | - Hai-Yan Yue
- Department of Digestive Diseases, Naval Medical Center of PLA, Naval Medical University, Shanghai 200052, China
| | - Jin Cai
- Department of Geriatrics, Naval Medical Center of PLA, Naval Medical University, Shanghai 200052, China
- Department of Infectious Diseases, Naval Medical Center of PLA, Naval Medical University, Shanghai 200052, China
| | - Yu-Jia Zhai
- Department of Outpatient Services, Naval Medical Center of PLA, Naval Medical University, Shanghai 200052, China
| | - Jian-Hui Peng
- Department of Quality Management, Guangdong Second Provincial General Hospital (Pazhou Campus), Guangzhou 510317, Guangdong Province, China
| | - Ju-Fen Hui
- Department of Disease Control and Prevention, Naval Medical Center of PLA, Naval Medical University, Shanghai 200052, China
| | - Deng-Yong Hou
- Department of Disease Control and Prevention, Naval Medical Center of PLA, Naval Medical University, Shanghai 200052, China
| | - Wei-Peng Li
- Department of Disease Control and Prevention, Naval Medical Center of PLA, Naval Medical University, Shanghai 200052, China
| | - Ji-Shun Yang
- Medical Care Center, Naval Medical Center of PLA, Naval Medical University, Shanghai 200052, China
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Tavčar P, Potokar M, Kolenc M, Korva M, Avšič-Županc T, Zorec R, Jorgačevski J. Neurotropic Viruses, Astrocytes, and COVID-19. Front Cell Neurosci 2021; 15:662578. [PMID: 33897376 PMCID: PMC8062881 DOI: 10.3389/fncel.2021.662578] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 03/22/2021] [Indexed: 12/13/2022] Open
Abstract
At the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was discovered in China, causing a new coronavirus disease, termed COVID-19 by the WHO on February 11, 2020. At the time of this paper (January 31, 2021), more than 100 million cases have been recorded, which have claimed over 2 million lives worldwide. The most important clinical presentation of COVID-19 is severe pneumonia; however, many patients present various neurological symptoms, ranging from loss of olfaction, nausea, dizziness, and headache to encephalopathy and stroke, with a high prevalence of inflammatory central nervous system (CNS) syndromes. SARS-CoV-2 may also target the respiratory center in the brainstem and cause silent hypoxemia. However, the neurotropic mechanism(s) by which SARS-CoV-2 affects the CNS remain(s) unclear. In this paper, we first address the involvement of astrocytes in COVID-19 and then elucidate the present knowledge on SARS-CoV-2 as a neurotropic virus as well as several other neurotropic flaviviruses (with a particular emphasis on the West Nile virus, tick-borne encephalitis virus, and Zika virus) to highlight the neurotropic mechanisms that target astroglial cells in the CNS. These key homeostasis-providing cells in the CNS exhibit many functions that act as a favorable milieu for virus replication and possibly a favorable environment for SARS-CoV-2 as well. The role of astrocytes in COVID-19 pathology, related to aging and neurodegenerative disorders, and environmental factors, is discussed. Understanding these mechanisms is key to better understanding the pathophysiology of COVID-19 and for developing new strategies to mitigate the neurotropic manifestations of COVID-19.
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Affiliation(s)
- Petra Tavčar
- Laboratory of Neuroendocrinology–Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Maja Potokar
- Laboratory of Neuroendocrinology–Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Celica Biomedical, Ljubljana, Slovenia
| | - Marko Kolenc
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Miša Korva
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tatjana Avšič-Županc
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Robert Zorec
- Laboratory of Neuroendocrinology–Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Celica Biomedical, Ljubljana, Slovenia
| | - Jernej Jorgačevski
- Laboratory of Neuroendocrinology–Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Celica Biomedical, Ljubljana, Slovenia
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Borah P, Deb PK, Al-Shar’i NA, Dahabiyeh LA, Venugopala KN, Singh V, Shinu P, Hussain S, Deka S, Chandrasekaran B, Jaradat DMM. Perspectives on RNA Vaccine Candidates for COVID-19. Front Mol Biosci 2021; 8:635245. [PMID: 33869282 PMCID: PMC8044912 DOI: 10.3389/fmolb.2021.635245] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/13/2021] [Indexed: 01/08/2023] Open
Abstract
With the current outbreak caused by SARS-CoV-2, vaccination is acclaimed as a public health care priority. Rapid genetic sequencing of SARS-CoV-2 has triggered the scientific community to search for effective vaccines. Collaborative approaches from research institutes and biotech companies have acknowledged the use of viral proteins as potential vaccine candidates against COVID-19. Nucleic acid (DNA or RNA) vaccines are considered the next generation vaccines as they can be rapidly designed to encode any desirable viral sequence including the highly conserved antigen sequences. RNA vaccines being less prone to host genome integration (cons of DNA vaccines) and anti-vector immunity (a compromising factor of viral vectors) offer great potential as front-runners for universal COVID-19 vaccine. The proof of concept for RNA-based vaccines has already been proven in humans, and the prospects for commercialization are very encouraging as well. With the emergence of COVID-19, mRNA-1273, an mRNA vaccine developed by Moderna, Inc. was the first to enter human trials, with the first volunteer receiving the dose within 10 weeks after SARS-CoV-2 genetic sequencing. The recent interest in mRNA vaccines has been fueled by the state of the art technologies that enhance mRNA stability and improve vaccine delivery. Interestingly, as per the "Draft landscape of COVID-19 candidate vaccines" published by the World Health Organization (WHO) on December 29, 2020, seven potential RNA based COVID-19 vaccines are in different stages of clinical trials; of them, two candidates already received emergency use authorization, and another 22 potential candidates are undergoing pre-clinical investigations. This review will shed light on the rationality of RNA as a platform for vaccine development against COVID-19, highlighting the possible pros and cons, lessons learned from the past, and the future prospects.
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Affiliation(s)
- Pobitra Borah
- School of Pharmacy, Graphic Era Hill University, Dehradun, India
- Pratiksha Institute of Pharmaceutical Sciences, Assam, India
| | - Pran Kishore Deb
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, Amman, Jordan
| | - Nizar A. Al-Shar’i
- Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Lina A. Dahabiyeh
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman, Jordan
| | - Katharigatta N. Venugopala
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
- Department of Biotechnology and Food Technology, Durban University of Technology, Durban, South Africa
| | - Vinayak Singh
- Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, South Africa
- South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa
| | - Pottathil Shinu
- Department of Biomedical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Snawar Hussain
- Department of Biomedical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Satyendra Deka
- Pratiksha Institute of Pharmaceutical Sciences, Assam, India
| | - Balakumar Chandrasekaran
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, Amman, Jordan
| | - Da’san M. M. Jaradat
- Department of Chemistry, Faculty of Science, Al-Balqa Applied University, Al-Salt, Jordan
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Borah P, Deb PK, Chandrasekaran B, Goyal M, Bansal M, Hussain S, Shinu P, Venugopala KN, Al-Shar’i NA, Deka S, Singh V. Neurological Consequences of SARS-CoV-2 Infection and Concurrence of Treatment-Induced Neuropsychiatric Adverse Events in COVID-19 Patients: Navigating the Uncharted. Front Mol Biosci 2021; 8:627723. [PMID: 33681293 PMCID: PMC7930836 DOI: 10.3389/fmolb.2021.627723] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 01/12/2021] [Indexed: 01/08/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme 2 (ACE2) receptor and invade the human cells to cause COVID-19-related pneumonia. Despite an emphasis on respiratory complications, the evidence of neurological manifestations of SARS-CoV-2 infection is rapidly growing, which is substantially contributing to morbidity and mortality. The neurological disorders associated with COVID-19 may have several pathophysiological underpinnings, which are yet to be explored. Hypothetically, SARS-CoV-2 may affect the central nervous system (CNS) either by direct mechanisms like neuronal retrograde dissemination and hematogenous dissemination, or via indirect pathways. CNS complications associated with COVID-19 include encephalitis, acute necrotizing encephalopathy, diffuse leukoencephalopathy, stroke (both ischemic and hemorrhagic), venous sinus thrombosis, meningitis, and neuroleptic malignant syndrome. These may result from different mechanisms, including direct virus infection of the CNS, virus-induced hyper-inflammatory states, and post-infection immune responses. On the other hand, the Guillain-Barre syndrome, hyposmia, hypogeusia, and myopathy are the outcomes of peripheral nervous system injury. Although the therapeutic potential of certain repurposed drugs has led to their off-label use against COVID-19, such as anti-retroviral drugs (remdesivir, favipiravir, and lopinavir-ritonavir combination), biologics (tocilizumab), antibiotics (azithromycin), antiparasitics (chloroquine and hydroxychloroquine), and corticosteroids (dexamethasone), unfortunately, the associated clinical neuropsychiatric adverse events remains a critical issue. Therefore, COVID-19 represents a major threat to the field of neuropsychiatry, as both the virus and the potential therapies may induce neurologic as well as psychiatric disorders. Notably, potential COVID-19 medications may also interact with the medications of pre-existing neuropsychiatric diseases, thereby further complicating the condition. From this perspective, this review will discuss the possible neurological manifestations and sequelae of SARS-CoV-2 infection with emphasis on the probable underlying neurotropic mechanisms. Additionally, we will highlight the concurrence of COVID-19 treatment-associated neuropsychiatric events and possible clinically relevant drug interactions, to provide a useful framework and help researchers, especially the neurologists in understanding the neurologic facets of the ongoing pandemic to control the morbidity and mortality.
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Affiliation(s)
- Pobitra Borah
- School of Pharmacy, Graphic Era Hill University, Dehradun, India
| | - Pran Kishore Deb
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, Amman, Jordan
| | - Balakumar Chandrasekaran
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, Amman, Jordan
| | - Manoj Goyal
- Department of Anesthesia Technology, College of Applied Medical Sciences in Jubail, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia
| | - Monika Bansal
- Department of Neuroscience Technology College of Applied Medical Sciences in Jubail, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia
| | - Snawar Hussain
- Department of Biomedical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Pottathil Shinu
- Department of Biomedical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Katharigatta N. Venugopala
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Kingdom of Saudi Arabia
- Department of Biotechnology and Food Technology, Durban University of Technology, Durban, South Africa
| | - Nizar A. Al-Shar’i
- Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Satyendra Deka
- Pratiksha Institute of Pharmaceutical Sciences, Chandrapur Road, Panikhaiti, Guwahati, India
| | - Vinayak Singh
- Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, South Africa
- South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa
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