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      Editorial: Translational research in severe COVID-19 and long-term symptoms post-COVID-19

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          Abstract

          In addition to acute and severe symptoms of SARS-CoV-2 infection, many patients worldwide suffer persistent symptoms from post-COVID-19 syndrome (PCS). This Research Topic aims to publish original translational research and review articles contributing to developing additional knowledge of PCS, considering the acute infection that contributes to developing post-COVID symptoms and mortality and thus trying to identify target markers for managing the affected subjects. In this Editorial, we have summarized 13 manuscripts: 5 related to acute infection, seven concerning the role of molecular and clinical factors of PCS, and 1 in vitro research study about preventive therapy. Acute SARS-CoV-2 infection could severely compromise the subject's health. There is a decreasing trend of deaths, hospitalizations, and intensive care unit (ICU) admissions, principally due to vaccination, acquired post-infection immunity, and less aggressive virus variants. Concerning mortality, Martin-Conty et al. in a prospective, multicenter, ambulance-based ongoing study in Spain, observed long-term mortality as the primary outcome in acute patients treated by emergency medical services, and COVID-19 was observed as an independent risk factor for long-term mortality. They identified that patients who previously experienced an acute COVID-19 episode presented a mortality rate almost twice that of non-COVID-19 subjects, suggesting, with a final model adjustment, that COVID-19 was a risk factor for long-term mortality. Due to the elevated mortality in hospitalized COVID-19 patients, there is an increased interest in finding serum biomarkers predicting mortality to adopt beneficial measures and easy protocols during the post-COVID follow-up. From Mexico, Cortes-Tellez et al. analyzed serum levels of different parameters from a routine laboratory in a cohort of severe COVID-19 hospitalized patients. They observed in a multivariate analysis that leukocytes and neutrophils were the best biomarkers for predicting mortality risk independently of age, gender, or comorbidities. The authors concluded the importance of using them routinely. Likewise, Pavan Kumar et al. in a comparative research study from India, elucidated the role of matrix metalloproteinases (MMPs) in the pathogenesis of pediatric COVID-19, examining the MMPs plasma levels in children with Multisystem Inflammatory Syndrome (MIS-C) and acute COVID-19 and comparing them to convalescent COVID-19 and children with other common tropical diseases. Higher levels of MMPs were observed in children needing ICU admission. Lastly, MMP levels showed a significant correlation with laboratory parameters, comprising CRP, ferritin, lymphocytes, D-dimer, and sodium levels, and the authors proposed that MMPs play a crucial role in the MIS-C and COVID-19 pathogenesis in children and may help distinguish MIS-C from other conditions with an overlapping clinical phenotype. On the other hand, SARS-CoV-2 reinfection is also a topic because it impacts sequels and illness severity. Suljic et al. from Slovenia, showed in an observational case-control study that reinfections with the Delta variant generate fewer hospitalizations than first infection, suggesting the development of more robust immunity protection developed by infected individuals and also vaccinated individuals (hybrid immunity). This study provides additional insight into reinfection, which may allow appropriate public health measures to be taken. Concerning the imaging study of COVID-19 pneumonia evolution during hospitalization, lung ultrasound (LUS) has been extensively used during the COVID-19 pandemic. Blair et al. from the United States, prospectively studied 244 moderate (non-ICU) and severe (ICU) COVID-19 hospitalized adults in a longitudinal cohort to evaluate the association between LUS characteristics and clinical severity. The authors described that at baseline, B-lines (edema, fibrosis, inflammation) were more prevalent in severe patients than in moderate ones. However, no significant differences were found between severe and moderate illness over time. Thus, the authors do not support the use of serial LUS to monitor the progression of disease severity. Pulmonary fibrosis due to SARS-CoV-2 infection is a significant concern (1). A study performed on postmortem patients in Spain (Pérez-Mies et al.) documented the evolution of diffuse alveolar damage (DAD) to the fibrosing pattern and defined the transcriptional programs involved. The authors analyzed lung autopsy samples from five lobes of 33 patients with a severe and prolonged SARS-CoV-2 course. They found that progression to fibrosis in severe COVID-19 was associated with overexpression of fibrogenic pathways (PI3K-AKT) and significant expression of SPARC and CTHRC1 in exudative-fibrosing DAD compared with the control. Whereas downregulation of the Hippo pathway was observed (suggesting epithelial cell damage response), the authors did not observe any role in the epithelial–mesenchymal transition in the fibrosis process. They suggested a possible role of viral persistence in maintaining lung damage. Concerning PCS, we know that at least 65 million individuals around the world are suffering from this multisystemic condition comprising persistent and severe symptoms lasting at least 2 months, usually after 3 months of acute SARS-CoV-2 infection that is not explained by another diagnosis (2). Different terms such as long COVID, persistent post-COVID, and post-acute COVID-19 syndrome define the same condition. Several hypotheses have been proposed to explain this syndrome. Predicting which patients will develop PCS is a challenge. In this sense, Lai et al. from Massachusetts, addressed an interesting systematic review to determine potential prognostic serum biomarkers for long COVID. They concluded that the persistence of up-regulation of IL-6, CRP, and TNF-α might present potential diagnostic biomarkers of PCS. In patients with neurological symptoms, neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) in serum may serve as diagnostic biomarkers, and the authors proposed to evaluate IL-4, IFN-α, CCL2, ferritin, and hemoglobin too. They also suggested evaluating CXCL10, TGF-β, IFN-β, and IL-1α in patients with pulmonary symptoms. Another interesting topic in the follow-up is the sequelae in computed tomography (CT) and their association with risk factors. Rincon-Alvarez et al. reported in their Colombian cohort that older age, male sex, and ICU admission were related to typical patterns of admission CT and that a third of patients with moderate and severe COVID had abnormal lung computed tomography at 6-month follow-up. Concerning health-related quality of life (HRQoL) in patients with PCS, Ahmad et al. employing a multicenter cohort study in a Swedish population, explored the frequency of self-reported continued symptoms and diminished HRQoL in relation to functional exercise capacity 6 months after infection, and they also explored risk factors for COVID-19 sequelae. Hospitalization was a significant risk factor for developing persistent symptoms, reduced overall health, and post-acute COVID syndrome (PACS). They concluded that persistent symptoms and reduced HRQoL are frequent in COVID-19 survivors and that patients requiring hospitalization due to severe infection were more likely to develop PACS. Furthermore, Al-Husinat et al. looking for the prevalence of PCS after mild-to-moderate COVID-19 in the Jordanian population, applied the Newcastle PCS Follow-up Screening Questionnaire and found that mood disturbance followed by fatigue, anxiety, and myalgia were the most frequent PCS symptoms. Female sex substantially raised the risk for multiple PCS symptoms. They concluded that PCS is highly prevalent among COVID-19 survivors, especially in female patients and patients with comorbidities, and also recommended physical and mental rehabilitation. In contrast, Román-Montes et al. analyzed the prevalence, symptoms, and HRQoL of PCS in a retrospective cross-sectional study of 246 Mexican patients who required hospitalization because of severe infection. They determined a prevalence of 76% of PCS in patients with a median age of 55 years. It was associated with smoking, severe COVID-19, lower arterial blood oxygen saturation on admission, extensive lung involvement, and elevated fibrinogen levels. Moreover, the most frequent symptoms of PCS were difficulty concentrating (81%), dyspnea (75%), and arthralgia (71%). They suggested identifying diagnostic and therapeutic interventions to restore health and QoL in those patients. However, no successful treatment is currently offered for managing PCS symptoms, while only rehabilitation programs are promoted, and regular drugs are prescribed for supportive therapies (3). Concerning rehabilitation programs in PCS, Allendes et al. from Chile performed a systematic review on cardiovascular and autonomic dysfunction in PCS. They concluded that alterations in the autonomic nervous system partially mediate cardiovascular sequelae of COVID-19 infection. They hypothesized that applying new cardiovascular rehabilitation programs should allow healthcare personnel to manage the consequences of long-term COVID-19. Dissook et al. reported on a study testing the activity of phytochemical polyphenol compounds (rosmarinic acid and luteolin) from Perilla frutescens in an in vitro lung cell model of SARS-CoV-2-induced inflammation. They documented that these compounds inhibited SARS-CoV-2 spike S1-induced inflammatory responses in A549 cells in a dose-dependent manner, seemingly through the JAK1/STAT3-NLRP3 inflammasome axis, at both the gene transcription and protein levels. They concluded that luteolin and P. frutescens may be potential candidates in the preventive therapeutic strategy for inflammation-related post-acute sequelae of COVID-19. The present Research Topic contributes novel information toward a better understanding of the possible biomarkers and risk factors contributing to post-COVID symptoms, mortality, radiologic and histologic evolution, and potential preventive therapeutic plants and rehabilitation programs to improve the QoL of PCS patients. Author contributions VV-Z: Investigation, Methodology, Writing—original draft, Writing—review and editing. GP-R: Conceptualization, Investigation, Methodology, Validation, Writing—original draft, Writing—review and editing. LC-G: Investigation, Methodology, Writing—original draft, Writing—review and editing. IB-R: Conceptualization, Investigation, Methodology, Writing—original draft, Writing—review and editing. RF-V: Conceptualization, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing—original draft, Writing—review and editing.

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          Most cited references3

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          Long COVID: major findings, mechanisms and recommendations

          Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process. Long COVID is an often debilitating illness of severe symptoms that can develop during or following COVID-19. In this Review, Davis, McCorkell, Vogel and Topol explore our knowledge of long COVID and highlight key findings, including potential mechanisms, the overlap with other conditions and potential treatments. They also discuss challenges and recommendations for long COVID research and care.
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            Progression to Fibrosing Diffuse Alveolar Damage in a Series of 30 Minimally Invasive Autopsies with COVID-19 Pneumonia in Wuhan, China

            Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), infection has been deemed as a global pandemic by the World Health Organisation. While diffuse alveolar damage (DAD) is recognised to be the primary manifestation of COVID-19 pneumonia, there has been little emphasis on the progression to the fibrosing phase of DAD. This topic is of great interest, due to growing concerns regarding the potential long-term complications in prolonged survivors.
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              Non-pharmacological treatments for COVID-19: current status and consensus

              Purpose COVID-19 is a disease caused by SARS-CoV-2 (coronavirus type 2 of the severe acute respiratory syndrome), isolated in China, in December 2019. The strategy currently used by physicians is to control disease and to treat symptoms, including non-pharmacological treatments, as there is still no specific treatment for COVID-19. Thus, the aim of this article is to carry out a systematic review about non-pharmacological treatments used for COVID-19, addressing current status and consensus found in the literature. Methods Three databases were consulted for evidence referring to the drugs indicated for COVID-19 (Cochrane Central, MEDLINE and Embase). The following terms and combinations were used: ((“2019-nCoV” OR 2019nCoV OR nCoV2019 OR “nCoV-2019” OR “COVID-19” OR COVID19 OR “HCoV-19” OR HCoV19 OR CoV OR “2019 novel*” OR Ncov OR “n-cov” OR “SARS-CoV-2” OR “SARSCoV-2” OR “SARSCoV2” OR “SARSCoV2” OR SARSCov19 OR “SARS-Cov19” OR “SARS-Cov-19”) OR “severe acute respiratory syndrome*” OR ((corona* OR corono*) AND (virus* OR viral* OR virinae*)) AND ((“lung injury”) OR (“ventilation use”) OR (“respiratory injuries” OR prone)) AND (treatment)) NOT Drugs NOT medicines NOT antivirals. Results A total of 28 articles were selected. These articles adopted one or more treatment methods for patients with severe cases of COVID-19, i.e., oxygen therapy, prone position, inhaled nitric oxide, intravenous infusion, passive immunotherapy, mesenchymal stem cells (MSC). Conclusion There is still no specific treatment approved for patients with COVID-19. The available evidence is not able yet to indicate the benefits or harms of non-pharmacological treatments, but some studies show that some treatments can play an important role in relation to COVID-19. The current consensus among researchers is that several studies using a randomized clinical trial should be carried out to provide evidence of safety and efficacy of the proposed treatments.
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                Author and article information

                Contributors
                URI : http://loop.frontiersin.org/people/1360383/overviewRole: Role: Role: Role:
                URI : http://loop.frontiersin.org/people/607085/overviewRole: Role: Role: Role: Role: Role:
                URI : http://loop.frontiersin.org/people/206562/overviewRole: Role: Role: Role:
                URI : http://loop.frontiersin.org/people/1126734/overviewRole: Role: Role: Role: Role:
                URI : http://loop.frontiersin.org/people/566016/overviewRole: Role: Role: Role: Role: Role: Role: Role: Role: Role:
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                27 September 2023
                2023
                27 September 2023
                : 10
                : 1261211
                Affiliations
                [1] 1Interstitial Lung Disease Unit, Department of Respiratory, University Hospital of Bellvitge, CIBERES, University of Barcelona (UB)-IDIBELL , Barcelona, Spain
                [2] 2HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas , Mexico City, Mexico
                [3] 3Laboratory of Integrative Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas , Mexico City, Mexico
                [4] 4Translational Research Laboratory on Aging and Pulmonary Fibrosis, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas , Mexico City, Mexico
                [5] 5HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas , Mexico City, Mexico
                Author notes

                Edited and reviewed by: Marc Jean Struelens, Université libre de Bruxelles, Belgium

                *Correspondence: Ramcés Falfán-Valencia rfalfanv@ 123456iner.gob.mx
                Article
                10.3389/fmed.2023.1261211
                10565468
                37828951
                292fe0f5-7b98-47d1-9ec8-fe92171a20e0
                Copyright © 2023 Vicens-Zygmunt, Pérez-Rubio, Chavez-Galan, Buendia-Roldan and Falfán-Valencia.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 19 July 2023
                : 13 September 2023
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 3, Pages: 3, Words: 2023
                Categories
                Medicine
                Editorial
                Custom metadata
                Infectious Diseases: Pathogenesis and Therapy

                covid-19,long covid-19,post-covid-19,post-covid-19 syndrome,sars-cov-2

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