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<!doctype html> <html data-n-head-ssr lang="en" data-n-head="%7B%22lang%22:%7B%22ssr%22:%22en%22%7D%7D"> <head > <link data-n-head="ssr" rel="icon" type="image/png" sizes="16x16" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_16-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="icon" type="image/png" sizes="32x32" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_32-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="apple-touch-icon" type="image/png" sizes="180x180" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_180-tenantFavicon-Frontiers.png"> <title>Frontiers | Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology</title><meta data-n-head="ssr" charset="utf-8"><meta data-n-head="ssr" name="viewport" content="width=device-width, initial-scale=1"><meta data-n-head="ssr" data-hid="charset" charset="utf-8"><meta data-n-head="ssr" data-hid="mobile-web-app-capable" name="mobile-web-app-capable" content="yes"><meta data-n-head="ssr" data-hid="apple-mobile-web-app-title" name="apple-mobile-web-app-title" content="Frontiers | Articles"><meta data-n-head="ssr" data-hid="theme-color" name="theme-color" content="#0C4DED"><meta data-n-head="ssr" data-hid="description" property="description" name="description" content="BackgroundEmerging evidence indicates a potential role for monocytes in COVID-19 immunopathology. We investigated two soluble markers of monocyte activation,..."><meta data-n-head="ssr" data-hid="og:title" property="og:title" name="title" content="Frontiers | Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology"><meta data-n-head="ssr" data-hid="og:description" property="og:description" name="description" content="BackgroundEmerging evidence indicates a potential role for monocytes in COVID-19 immunopathology. We investigated two soluble markers of monocyte activation,..."><meta data-n-head="ssr" data-hid="keywords" name="keywords" content="COVID- 19,monocyte,sCD14,sCD163,immunopahtology"><meta data-n-head="ssr" data-hid="og:site_name" property="og:site_name" name="site_name" content="Frontiers"><meta data-n-head="ssr" data-hid="og:image" property="og:image" name="image" content="https://images-provider.frontiersin.org/api/ipx/w=1200&f=png/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g001.jpg"><meta data-n-head="ssr" data-hid="og:type" property="og:type" name="type" content="article"><meta data-n-head="ssr" data-hid="og:url" property="og:url" name="url" content="https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.560381/full"><meta data-n-head="ssr" data-hid="twitter:card" name="twitter:card" content="summary_large_image"><meta data-n-head="ssr" data-hid="citation_volume" name="citation_volume" content="11"><meta data-n-head="ssr" data-hid="citation_journal_title" name="citation_journal_title" content="Frontiers in Immunology"><meta data-n-head="ssr" data-hid="citation_publisher" name="citation_publisher" content="Frontiers"><meta data-n-head="ssr" data-hid="citation_journal_abbrev" name="citation_journal_abbrev" content="Front. Immunol."><meta data-n-head="ssr" data-hid="citation_issn" name="citation_issn" content="1664-3224"><meta data-n-head="ssr" data-hid="citation_doi" name="citation_doi" content="10.3389/fimmu.2020.560381"><meta data-n-head="ssr" data-hid="citation_firstpage" name="citation_firstpage" content="560381"><meta data-n-head="ssr" data-hid="citation_language" name="citation_language" content="English"><meta data-n-head="ssr" data-hid="citation_title" name="citation_title" content="Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology"><meta data-n-head="ssr" data-hid="citation_keywords" name="citation_keywords" content="COVID- 19; monocyte; sCD14; sCD163; immunopahtology"><meta data-n-head="ssr" data-hid="citation_abstract" name="citation_abstract" content="<sec><title>Background</title><p>Emerging evidence indicates a potential role for monocytes in COVID-19 immunopathology. We investigated two soluble markers of monocyte activation, sCD14 and sCD163, in COVID-19 patients, with the aim of characterizing their potential role in monocyte-macrophage disease immunopathology. To the best of our knowledge, this is the first study of its kind.</p></sec><sec><title>Methods</title><p>Fifty-nine SARS-Cov-2 positive hospitalized patients, classified according to ICU or non-ICU admission requirement, were prospectively recruited and analyzed by ELISA for levels of sCD14 and sCD163, along with other laboratory parameters, and compared to a healthy control group.</p></sec><sec><title>Results</title><p>sCD14 and sCD163 levels were significantly higher among COVID-19 patients, independently of ICU admission requirement, compared to the control group. We found a significant correlation between sCD14 levels and other inflammatory markers, particularly Interleukin-6, in the non-ICU patients group. sCD163 showed a moderate positive correlation with the time lapsed from admission to sampling, independently of severity group. Treatment with corticoids showed an interference with sCD14 levels, whereas hydroxychloroquine and tocilizumab did not.</p></sec><sec><title>Conclusions</title><p>Monocyte-macrophage activation markers are increased and correlate with other inflammatory markers in SARS-Cov-2 infection, in association to hospital admission. These data suggest a preponderant role for monocyte-macrophage activation in the development of immunopathology of COVID-19 patients.</p></sec>"><meta data-n-head="ssr" data-hid="citation_pdf_url" name="citation_pdf_url" content="https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.560381/pdf"><meta data-n-head="ssr" data-hid="citation_online_date" name="citation_online_date" content="2020/09/02"><meta data-n-head="ssr" data-hid="citation_publication_date" name="citation_publication_date" content="2020/09/23"><meta data-n-head="ssr" data-hid="citation_author_0" name="citation_author" content="G贸mez-Rial, Jose"><meta data-n-head="ssr" data-hid="citation_author_institution_0" name="citation_author_institution" content="Grupo de Investigaci贸n en Gen茅tica, Vacunas, Infecciones y Pediatr铆a, Instituto de Investigaci贸n Sanitaria de Santiago, Hospital Clinico Universitario and Universidade de Santiago de Compostela, Servizo Galego de Sa煤de, Spain"><meta data-n-head="ssr" data-hid="citation_author_1" name="citation_author" content="Curr谩s-Tuala, Maria Jos茅"><meta data-n-head="ssr" data-hid="citation_author_institution_1" name="citation_author_institution" content="Grupo de Investigaci贸n en Gen茅tica, Vacunas, Infecciones y Pediatr铆a, Instituto de Investigaci贸n Sanitaria de Santiago, Hospital Clinico Universitario and Universidade de Santiago de Compostela, Servizo Galego de Sa煤de, Spain"><meta data-n-head="ssr" data-hid="citation_author_2" name="citation_author" content="Rivero-Calle, Irene"><meta data-n-head="ssr" data-hid="citation_author_institution_2" name="citation_author_institution" content="Grupo de Investigaci贸n en Gen茅tica, Vacunas, Infecciones y Pediatr铆a, Instituto de Investigaci贸n Sanitaria de Santiago, Hospital Clinico Universitario and Universidade de Santiago de Compostela, Servizo Galego de Sa煤de, Spain"><meta data-n-head="ssr" data-hid="citation_author_3" name="citation_author" content="G贸mez-Carballa, Alberto"><meta data-n-head="ssr" data-hid="citation_author_institution_3" name="citation_author_institution" content="Grupo de Investigaci贸n en Gen茅tica, Vacunas, Infecciones y Pediatr铆a, Instituto de Investigaci贸n Sanitaria de Santiago, Hospital Clinico Universitario and Universidade de Santiago de Compostela, Servizo Galego de Sa煤de, Spain"><meta data-n-head="ssr" data-hid="citation_author_4" name="citation_author" content="Cebey-L贸pez, Miriam"><meta data-n-head="ssr" data-hid="citation_author_institution_4" name="citation_author_institution" content="Grupo de Investigaci贸n en Gen茅tica, Vacunas, Infecciones y Pediatr铆a, Instituto de Investigaci贸n Sanitaria de Santiago, Hospital Clinico Universitario and Universidade de Santiago de Compostela, Servizo Galego de Sa煤de, Spain"><meta data-n-head="ssr" data-hid="citation_author_5" name="citation_author" content="Rodr铆guez-Tenreiro, Carmen"><meta data-n-head="ssr" data-hid="citation_author_institution_5" name="citation_author_institution" content="Grupo de Investigaci贸n en Gen茅tica, Vacunas, Infecciones y Pediatr铆a, Instituto de Investigaci贸n Sanitaria de Santiago, Hospital Clinico Universitario and Universidade de Santiago de Compostela, Servizo Galego de Sa煤de, Spain"><meta data-n-head="ssr" data-hid="citation_author_6" name="citation_author" content="Dacosta-Urbieta, Ana"><meta data-n-head="ssr" data-hid="citation_author_institution_6" name="citation_author_institution" content="Grupo de Investigaci贸n en Gen茅tica, Vacunas, Infecciones y Pediatr铆a, Instituto de Investigaci贸n Sanitaria de Santiago, Hospital Clinico Universitario and Universidade de Santiago de Compostela, Servizo Galego de Sa煤de, Spain"><meta data-n-head="ssr" data-hid="citation_author_7" name="citation_author" content="Rivero-Velasco, Carmen"><meta data-n-head="ssr" data-hid="citation_author_institution_7" name="citation_author_institution" content="Intensive Medicine Department, Hospital Cl矛nico Universitario de Santiago de Compostela, Spain"><meta data-n-head="ssr" data-hid="citation_author_8" name="citation_author" content="Rodr铆guez-N煤帽ez, Nuria"><meta data-n-head="ssr" data-hid="citation_author_institution_8" name="citation_author_institution" content="Pneumology Department, Hospital Cl矛nico Universitario de Santiago de Compostela, Spain"><meta data-n-head="ssr" data-hid="citation_author_9" name="citation_author" content="Trastoy-Pena, Rocio"><meta data-n-head="ssr" data-hid="citation_author_institution_9" name="citation_author_institution" content="Microbiology Department, Hospital Cl矛nico Universitario de Santiago de Compostela, Spain"><meta data-n-head="ssr" data-hid="citation_author_10" name="citation_author" content="Rodr铆guez-Garc铆a, Javier"><meta data-n-head="ssr" data-hid="citation_author_institution_10" name="citation_author_institution" content="Clinical Biochemistry Laboratory, Hospital Cl矛nico Universitario de Santiago de Compostela, Spain"><meta data-n-head="ssr" data-hid="citation_author_11" name="citation_author" content="Salas, Antonio"><meta data-n-head="ssr" data-hid="citation_author_institution_11" name="citation_author_institution" content="Grupo de Investigaci贸n en Gen茅tica, Vacunas, Infecciones y Pediatr铆a, Instituto de Investigaci贸n Sanitaria de Santiago, Hospital Clinico Universitario and Universidade de Santiago de Compostela, Servizo Galego de Sa煤de, Spain"><meta data-n-head="ssr" data-hid="citation_author_12" name="citation_author" content="Martin贸n-Torres, Federico"><meta data-n-head="ssr" data-hid="citation_author_institution_12" name="citation_author_institution" content="Grupo de Investigaci贸n en Gen茅tica, Vacunas, Infecciones y Pediatr铆a, Instituto de Investigaci贸n Sanitaria de Santiago, Hospital Clinico Universitario and Universidade de Santiago de Compostela, Servizo Galego de Sa煤de, Spain"><meta data-n-head="ssr" data-hid="dc.identifier" name="dc.identifier" content="doi:10.3389/fimmu.2020.560381"><link data-n-head="ssr" rel="manifest" href="/article-pages/_nuxt/manifest.c499fc0a.json" 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Immunol.</span> <span>, 23 September 2020</span></p> <p class="ArticleLayoutHeader__info__journalDate"> Sec. Cytokines and Soluble Mediators in Immunity </p> <p class="ArticleLayoutHeader__info__doiVolume"><span> Volume 11 - 2020 | </span> <a href="https://doi.org/10.3389/fimmu.2020.560381" class="ArticleLayoutHeader__info__doi"> https://doi.org/10.3389/fimmu.2020.560381 </a></p> </div>  <p class="ArticleLayoutHeader__isPartOfRT"><span class="ArticleLayoutHeader__isPartOfRT__label">This article is part of the Research Topic</span> <span class="ArticleLayoutHeader__isPartOfRT__title">Coronavirus Disease (COVID-19): Pathophysiology, Epidemiology, Clinical Management and Public Health Response</span> <span class="Link__wrapper"><a aria-label="View all 400 articles" href="https://www.frontiersin.org/research-topics/13377/coronavirus-disease-covid-19-pathophysiology-epidemiology-clinical-management-and-public-health-response/magazine" target="_self" data-event="customLink-link-a_viewAll400Articles" class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right"><span>View all 400 articles</span></a></span></p></div> <div class="ArticleDetails__main__content"><div class="ArticleDetails__main__content__main ArticleDetails__main__content__main--fullArticle"><div class="JournalAbstract"><div class="JournalAbstract__titleWrapper"><h1>Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology</h1> </div> </div> <div class="JournalFullText"><div class="JournalAbstract"> <a id="h1" name="h1"></a> <div class="authors"><span class="author-wrapper notranslate"> <a href="https://loop.frontiersin.org/people/971915" class="user-id-971915"><img class="pr5" src="https://loop.frontiersin.org/images/profile/971915/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="\r\nJose Gmez-Rial,*&#x;">Jose Gómez-Rial</a><sup>1,2*†</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Maria Jos Currs-Tuala&#x;" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Maria José Currás-Tuala<sup>1†</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Irene Rivero-Calle," onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Irene Rivero-Calle<sup>1,3</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Alberto Gmez-Carballa," onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Alberto Gómez-Carballa<sup>1,4</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Miriam Cebey-Lpez" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Miriam Cebey-López<sup>1</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Carmen Rodríguez-Tenreiro" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Carmen Rodríguez-Tenreiro<sup>1</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Ana Dacosta-Urbieta," onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Ana Dacosta-Urbieta<sup>1,3</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Carmen Rivero-Velasco" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Carmen Rivero-Velasco<sup>5</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Nuria Rodríguez-Núez" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Nuria Rodríguez-Núñez<sup>6</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Rocio Trastoy-Pena" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Rocio Trastoy-Pena<sup>7</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Javier Rodríguez-García" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Javier Rodríguez-García<sup>8</sup></span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/1021428" class="user-id-1021428"><img class="pr5" src="https://loop.frontiersin.org/images/profile/1021428/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Antonio Salas,">Antonio Salas</a><sup>1,4</sup></span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/58621" class="user-id-58621"><img class="pr5" src="https://loop.frontiersin.org/images/profile/58621/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Federico Martinn-Torres,*">Federico Martinón-Torres</a><sup>1,3*</sup></span></div> <ul class="notes"> <li><span><sup>1</sup></span>Grupo de Investigación en Genética, Vacunas, Infecciones y Pediatría, Instituto de Investigación Sanitaria de Santiago, Hospital Clinico Universitario and Universidade de Santiago de Compostela, Servizo Galego de Saúde, Galicia, Spain</li> <li><span><sup>2</sup></span>Laboratorio de Inmunologìa, Servicio de Análisis Clìnicos, Hospital Clìnico Universitario Santiago de Compostela, Servizo Galego de Saúde, Galicia, Spain</li> <li><span><sup>3</sup></span>Translational Pediatrics and Infectious Diseases Section, Department of Pediatrics, Hospital Clìnico Universitario de Santiago de Compostela, Galicia, Spain</li> <li><span><sup>4</sup></span>Unidade de Xenética, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, and GenPoB Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clìnico Universitario de Santiago, Servizo Galego de Saúde, Galicia, Spain</li> <li><span><sup>5</sup></span>Intensive Medicine Department, Hospital Clìnico Universitario de Santiago de Compostela, Galicia, Spain</li> <li><span><sup>6</sup></span>Pneumology Department, Hospital Clìnico Universitario de Santiago de Compostela, Galicia, Spain</li> <li><span><sup>7</sup></span>Microbiology Department, Hospital Clìnico Universitario de Santiago de Compostela, Galicia, Spain</li> <li><span><sup>8</sup></span>Clinical Biochemistry Laboratory, Hospital Clìnico Universitario de Santiago de Compostela, Galicia, Spain</li> </ul> <p class="mb0"><b>Background:</b> Emerging evidence indicates a potential role for monocytes in COVID-19 immunopathology. We investigated two soluble markers of monocyte activation, sCD14 and sCD163, in COVID-19 patients, with the aim of characterizing their potential role in monocyte-macrophage disease immunopathology. To the best of our knowledge, this is the first study of its kind.</p> <p class="mb15"><b>Methods:</b> Fifty-nine SARS-Cov-2 positive hospitalized patients, classified according to ICU or non-ICU admission requirement, were prospectively recruited and analyzed by ELISA for levels of sCD14 and sCD163, along with other laboratory parameters, and compared to a healthy control group.</p> <p class="mb15"><b>Results:</b> sCD14 and sCD163 levels were significantly higher among COVID-19 patients, independently of ICU admission requirement, compared to the control group. We found a significant correlation between sCD14 levels and other inflammatory markers, particularly Interleukin-6, in the non-ICU patients group. sCD163 showed a moderate positive correlation with the time lapsed from admission to sampling, independently of severity group. Treatment with corticoids showed an interference with sCD14 levels, whereas hydroxychloroquine and tocilizumab did not.</p> <p class="mb15"><b>Conclusions</b> Monocyte-macrophage activation markers are increased and correlate with other inflammatory markers in SARS-Cov-2 infection, in association to hospital admission. These data suggest a preponderant role for monocyte-macrophage activation in the development of immunopathology of COVID-19 patients.</p> <div class="clear"></div> </div> <div class="JournalFullText"> <a id="h2" name="h2"></a><h2>Introduction</h2> <p class="mb15">Emerging evidence from SARS-Cov-2 infected patients suggests a key role for monocyte-macrophage in the immunopathology of COVID-19 infection, with a predominant monocyte-derived macrophage infiltration observed in severely damaged lungs (<a href="#B1">1</a>), and morphological and inflammation-related changes in peripheral blood monocytes that correlate with the patients’ outcome (<a href="#B2">2</a>). An overexuberant inflammatory immune response with production of a cytokine storm and T-cell immunosuppression are the main hallmarks of severity in these patients (<a href="#B3">3</a>). This clinical course resembles viral-associated hemophagocytic syndrome (VAHS), a rare severe complication of various viral infections mediated by proinflammatory cytokines, resulting in multiorgan failure and death (<a href="#B4">4</a>). A chronic expansion of inflammatory monocytes and over-activation of macrophages have been extensively described in this syndrome (<a href="#B5">5</a>–<a href="#B7">7</a>). Viral-associated hemophagocytic syndrome has been identified as a major contributor to death of patients in past pandemics caused by coronaviruses (<a href="#B8">8</a>), including previous SARS and MERS outbreaks (<a href="#B9">9</a>), and currently suggested for SARS-Cov-2 outbreak (<a href="#B10">10</a>).</p> <p class="mb15">CD14 and CD163 are both myeloid differentiation markers found primarily on monocytes and macrophages, and detection of soluble release of both in plasma is considered a good biomarker of monocyte-macrophage activation (<a href="#B11">11</a>, <a href="#B12">12</a>). Elevated plasma levels of soluble CD14 (sCD14) are associated to poor prognosis in VIH-infected patients, are a strong predictor of morbidity and mortality (<a href="#B13">13</a>, <a href="#B14">14</a>), and associated with diminished CD4+-T cell restoration (<a href="#B15">15</a>). In addition, soluble CD163 (sCD163) plasma levels are a good proxy for monocyte expansion and disease progression during HIV infection (<a href="#B16">16</a>). In measles infection, a leading cause of death associated with increased susceptibility to secondary infections and immunosuppression, sCD14 and sCD163 levels have been found to be significantly higher, indicating an important and persistent monocyte-macrophage activation (<a href="#B17">17</a>).</p> <p class="mb0">We hypothesized that monocytes/macrophages may be an important component of immunopathology associated to SARS-Cov-2 infection. In this paper, we analyze serum levels of soluble monocyte activation markers in COVID-19 patients and their correlation with severity and other inflammatory markers.</p> <a id="h3" name="h3"></a><h2>Materials and Methods</h2> <h3 class="pt0">Subjects</h3> <p class="mb0">We recruited 59 patients with confirmed PCR-positive diagnosis of SARS-Cov-2 infection, classified according to ICU admission requirement (<i>n</i> = 22 patients), or non-ICU requirement (<i>n</i> = 37), and age-matched healthy individuals (<i>n</i> = 20) as a control group. Demographic data, main medication treatment and routine lab clinical parameters including inflammatory biomarkers were collected for all infected patients. Leftover sera samples from routine analytical controls were employed for the analysis, after obtaining the corresponding informed consent. Time elapsed from hospital admission to sample extraction was also recorded.</p> <h3>Measurement of sCD14 and sCD163 Serum Levels</h3> <p class="mb0">To determine levels of soluble monocyte activation markers in serum specimens, appropriate sandwich ELISA (Quantikine, R&D systems, United Kingdom) were used following manufacturer indications. Briefly, diluted sera samples were incubated for 3 h at room temperature in the corresponding microplate strips coated with capture antibody. After incubation, strips were washed and incubated with the corresponding Human Antibody conjugate for 1 h. After washing, reactions were revealed and optical density at 450 nm was determined in a microplate reader. Concentration levels were interpolated from the standard curve using a four-parameter logistic (4-PL) curve-fit in Prism8 GraphPad software. Final values were corrected applying the corresponding dilution factor employed.</p> <h3>Statistical Analysis</h3> <p class="mb0">Data are expressed as median and interquartile range. All statistical analyses were performed using the statistical package R. Mann–Whitney tests were used for comparison between ICU and non-ICU groups <i>versus</i> healthy controls. Pearson’s correlation coefficients were used to quantify the association between sCD14 and sCD163 concentration and other lab parameters in non-ICU patients. Data outliers, falling outside the 1.5 interquartile range, were excluded from the statistical analysis. The nominal significance level considered was 0.05. Bonferroni adjustment was used to account for multiple testing.</p> <a id="h4" name="h4"></a><h2>Results</h2> <h3 class="pt0">Demographic and Clinical Laboratory Parameters</h3> <p class="mb0">Patients in the ICU group showed significant differences when compared to non-ICU group in several clinical laboratory parameters: lymphocytes, ferritin, <small>D</small>-dimer, Lactate dehydrogenase (LDH), procalcitonin (PCT), and Interleukin-6 (IL-6). The absolute value for circulating monocytes did not show significant differences between groups. However, these values may have been distorted by the use of tocilizumab, an IL-6 blocking drug extensively employed in the ICU group which interferes with monocyte function. Age and time elapsed from admission to sample extraction did not show differences between groups. Values are summarized in <a href="#T1">Table 1</a>.</p> <div class="DottedLine"></div> <div class="Imageheaders">TABLE 1</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-t001.jpg" name="table1" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-t001.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-t001.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-t001.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-t001.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-t001.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-t001.jpg" alt="www.frontiersin.org" id="T1" loading="lazy"> </picture> </a> <p><strong>Table 1.</strong> Demographic and clinical laboratory parameters of patients recruited.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <h3>Serum Levels for sCD14 and sCD163</h3> <p class="mb0">Median levels for sCD14 in sera from ICU patients were 2444.0 (95%CI: 1914.0–3251.0) ng/ml, compared to 2613.0 (95%CI: 2266.0–2991.0) ng/ml in non-ICU patients. The healthy control group median value was 1788.0 (95%CI: 1615.0–1917.0) ng/ml. We observed significant statistical differences when comparing infected patients against controls (<i>P</i>-value < 0.0001), however no significant differences were observed between ICU and non-ICU groups. Median levels for sCD163 in sera from ICU patients were 911.5 (95%CI: 624.7–1167.0) ng/ml, and 910.4 (95%CI: 733.1–1088.0) ng/ml in non-ICU patients. The healthy control group value was 495.6 (95%CI: 332.5–600.7) ng/ml. As with sCD14, we observed significant differences for values from infected patients compared to control group (<i>P</i>-value < 00001), but no differences between ICU and non-ICU infected patients. Values are summarized in <a href="#T2">Table 2</a> and <a href="#F1">Figure 1</a>.</p> <div class="DottedLine"></div> <div class="Imageheaders">TABLE 2</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-t002.jpg" name="table2" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-t002.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-t002.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-t002.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-t002.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-t002.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-t002.jpg" alt="www.frontiersin.org" id="T2" loading="lazy"> </picture> </a> <p><strong>Table 2.</strong> Concentration (ng/ml) of serum levels of sCD14 and sCD163 in patients from ICU and non-ICU groups, and healthy controls.</p> </div> <div class="clear"></div> <div class="DottedLine mb15"></div> <div class="Imageheaders">FIGURE 1</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g001.jpg" name="figure1" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g001.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g001.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g001.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g001.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g001.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g001.jpg" alt="www.frontiersin.org" id="F1" loading="lazy"> </picture> </a> <p><strong>Figure 1.</strong> Values of sCD14 <b>(A)</b> and sCD163 <b>(B)</b> in sera samples from patients in ICU, non-ICU, and healthy controls. Results are presented as median and interquartile range levels in ng/ml. Non-parametric Mann–Whitney tests were used for comparison between groups, and <i>P</i>-values for the different comparisons are displayed.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <h3>Correlation Between sCD14 and sCD163 Levels and Time Elapsed From Hospital Admission</h3> <p class="mb0">We assessed the correlation between sCD14 and sCD163 levels and time elapsed from hospital admission to sample extraction (<a href="#F2">Figure 2</a>). We found a significant positive correlation between sCD163 levels and time elapsed (<i>r</i><sup>2</sup> = 0.3246, <i>P</i>-value = 0.0156) We did not observe a significant correlation between sCD14 levels and time elapsed from hospital admission to sample extraction.</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 2</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g002.jpg" name="figure2" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g002.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g002.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g002.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g002.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g002.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g002.jpg" alt="www.frontiersin.org" id="F2" loading="lazy"> </picture> </a> <p><strong>Figure 2.</strong> Correlation between serum levels of sCD14 and sCD163 and time elapsed from admission to sample extraction (in days) for all infected patients. Pearson’s correlation coefficient (<i>r</i><sup>2</sup>) and <i>P</i>-value are shown.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <h3>Correlation Between sCD14 and sCD163 Levels and Clinical Laboratory Parameters</h3> <p class="mb0">We found significant correlations between sCD14 and sCD163 levels and several clinical laboratory parameters in infected patients (in these analysis, adjusted significance under Bonferrori correction is 0.01), but only in the non-ICU group, possibly reflecting an interference of the use of tocilizumab or corticoids in the ICU group. Levels of sCD14 showed a negative correlation with the absolute value of lymphocytes (<i>r</i><sup>2</sup> = −0.5501, <i>P</i>-value = 0.0005) and a positive correlation with levels of LDH (<i>r</i><sup>2</sup> = 0.5906, <i>P</i>-value = 0.0001), CRP (<i>r</i><sup>2</sup> = 0.6275, <i>P</i>-value < 0.0001); PCT (<i>r</i><sup>2</sup> = 0.4608, <i>P</i>-value = 0.0091), and Ferritin (<i>r</i><sup>2</sup> = 0.4414, <i>P</i>-value = 0.0090) (<a href="#F3">Figure 3</a>). No other significative associations were found with other lab parameters. Levels of sCD163 did not show significant correlation with clinical laboratory parameters (<a href="#F3">Figure 3</a>). Particularly, IL-6 also showed significant positive correlation with sCD14 (<i>r</i><sup>2</sup> = 0.6034, <i>P</i>-value = 0.0003) (<a href="#F4">Figure 4</a>).</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 3</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g003.jpg" name="figure3" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g003.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g003.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g003.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g003.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g003.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g003.jpg" alt="www.frontiersin.org" id="F3" loading="lazy"> </picture> </a> <p><strong>Figure 3.</strong> Association between serum levels of sCD14 and sCD163, and several laboratory parameters including Absolute Valor Lymphocytes <b>(A,B)</b>, LDH <b>(C,D)</b>, CRP <b>(E,F)</b>, PCT <b>(G,H)</b>, and Ferritin <b>(I,J)</b> in the non-ICU patient group. Pearson’s correlation coefficient (<i>r</i><sup>2</sup>) and <i>P</i>-value are shown. LDH, lactate dehydrogenase; CRP, C-reactive protein; PCT, procalcitonin.</p> </div> <div class="clear"></div> <div class="DottedLine mb15"></div> <div class="Imageheaders">FIGURE 4</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g004.jpg" name="figure4" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g004.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g004.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g004.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g004.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g004.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g004.jpg" alt="www.frontiersin.org" id="F4" loading="lazy"> </picture> </a> <p><strong>Figure 4.</strong> Association between serum levels of sCD14 and IL-6 levels in the non-ICU patient group. Pearson’s correlation coefficient (<i>r</i><sup>2</sup>) and <i>P</i>-value are presented.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <h3>Effect of Treatment on sCD14 and sCD163 Levels</h3> <p class="mb0">We analyzed possible interference of different treatments on sCD14 and sCD163 serum levels for all patients. We found an interference of corticoid treatment on sCD14, levels with median values of 2034 (95%CI: 1319–3159) ng/ml for treated group, and values of 2613 (95%CI: 2466–2913) ng/ml for non-treated group. Values were significantly lower in corticoid-treated group (<i>P</i>-value = 0.0069) (<a href="#F5">Figure 5</a>). No impact was found for corticoids on sCD163 levels. Likewise, hydroxychloroquine and/or tocilizumab were not found to have an impact on sCD14 and sCD163 serum levels.</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 5</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g005.jpg" name="figure5" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g005.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g005.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g005.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g005.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g005.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/560381/fimmu-11-560381-HTML/image_m/fimmu-11-560381-g005.jpg" alt="www.frontiersin.org" id="F5" loading="lazy"> </picture> </a> <p><strong>Figure 5.</strong> Effects of corticoid, hydroxychloroquine, and tocilizumab treatment on sCD14 and sCD163 levels. Results are presented as median and interquartile range levels in ng/ml. Non-parametric Mann–Whitney tests were used for comparison between groups, and <i>P</i>-values for the different comparisons are displayed.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <h3>Correlation Between sCD14 and sCD163 Levels and Hospital Stay</h3> <p class="mb0">Levels of sCD14 and sCD163 did not show association with length of hospital stay in both groups. Also, these biomarkers did not show association with the number of days of onset of symptoms.</p> <h3>Age-Dependence of sCD14 and sCD163 Levels</h3> <p class="mb0">We analyzed for possible age-dependence of sCD14 and sCD163 levels. Values did not show association between these biomarker levels and the age of patients.</p> <a id="h5" name="h5"></a><h2>Discussion</h2> <p class="mb15">Our results show, for the first time, increased levels of sCD14 and sCD163 in sera from SARS-Cov-2 infected patients admitted to hospital. We did not observe statistical differences when comparing ICU versus non-ICU patients. This is probably due to the interference on monocyte function and sCD14 levels produced by the use of corticoid treatment in ICU patients, as shown here and previously by others (<a href="#B18">18</a>, <a href="#B19">19</a>). However, levels of sCD14 showed a strong correlation with clinical laboratory parameters, including acute phase reactants (ferritin, LDH, C-reactive protein, procalcitonin) and a strong correlation with IL-6 levels in the non-ICU patient group, where no corticoids treatments were used. Hydroxychloroquine and tocilizumab treatment did not show interferences on sCD14 and sCD163 levels. Furthermore, sCD163 levels showed a correlation with the time elapsed from hospital admission to sample extraction, suggesting a potential indicator of disease progression.</p> <p class="mb15">Monocytes and macrophages constitute a key component of immune responses against viruses, acting as bridge between innate and adaptive immunity (<a href="#B20">20</a>). Activation of macrophages has been demonstrated to be pivotal in the pathogenesis of the immunosuppression associated to several viral infections (such as VIH, measles), where expansion of specific subsets of monocytes and macrophages in peripheral blood are observed, and considered to be drivers of immunopathogenesis (<a href="#B21">21</a>). Our results support the hypothesis of a preponderant role for monocytes in SARS-Cov-2 immunopathology, associated to an overexuberant immune response. Increased levels of monocyte-macrophage activation markers, and their correlation with other inflammatory biomarkers (particularly IL-6), indicate a close relationship between monocyte activation and immunopathology in these patients. Inflammatory markers are closely related to severity in COVID-19 pathology (<a href="#B22">22</a>) and selective blockade of IL-6 has been demonstrated to be a good therapeutic strategy in COVID-19 pathology (<a href="#B23">23</a>). Our results thus suggest that monocyte-macrophage activation can act as driver cells of the cytokine storm and immunopathology associated to severe clinical course of COVID-19 patients. Further, monitorization of monocyte activity trough these soluble activation markers and/or follow-up of circulating inflammatory monocytes in peripheral blood, could be useful to assess disease progression in the same way as in other viral infections (<a href="#B16">16</a>).</p> <p class="mb15">In addition, our results identify monocyte-macrophage as a good target for the design of therapeutic intervention using drugs that inhibit monocyte-macrophage activation and differentiation. In this sense, anti-GM CSF inhibitor drugs, currently under clinical trials for rheumatic and other auto-inflammatory diseases, might provide satisfactory results in COVID-19 patients. Other drugs targeting monocyte and/or macrophage could also be useful in COVID-19, as in other inflammatory diseases (<a href="#B24">24</a>). The strategy of inhibiting monocyte differentiation has proved useful in avoiding cytokine storm syndrome after CAR-T cell immunotherapy (<a href="#B25">25</a>), suggesting a possible therapeutic application to COVID-19 immunopathology (<a href="#B26">26</a>, <a href="#B27">27</a>).</p> <p class="mb15">The present study has several limitations, including a relatively low sample size and the interference of corticoids in ICU patients’ results. However, these preliminary results are strongly suggestive of an important implication of monocyte-macrophage in COVID-19 immunopathology, as highlighted by the correlations found between these biomarker levels and inflammatory parameters. Further studies using broader series are needed to confirm our findings.</p> <p class="mb0">In summary, our data underscore the preponderant role of monocyte and macrophage immune response in COVID-19 immunopathology and provide pointers for future interventions in drug strategies and monitoring plans for these patients.</p> <a id="h6" name="h6"></a><h2>Data Availability Statement</h2> <p class="mb0">The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.</p> <a id="h7" name="h7"></a><h2>Ethics Statement</h2> <p class="mb0">The studies involving human participants were reviewed and approved by Comité de Ética de la Investigación con Medicamentos de Galicia (fast-track approval 18-march-2020). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.</p> <a id="h8" name="h8"></a><h2>Author Contributions</h2> <p class="mb0">JG-R, FM-T, and AS designed and conceptualized the study and made the first draft. MC-T, IR-C, AG-C, MC-L, CR-T, AD-U, CR-V, NR-N, RT-P, and JR-G collected the samples and did the analysis, reviewed the draft and approved the final version. All authors contributed to the article and approved the submitted version.</p> <a id="fun1" name="fun1"></a><h2>Funding</h2> <p class="mb0">This study received support from the Instituto de Salud Carlos III: project GePEM (Instituto de Salud Carlos III(ISCIII)/PI16/01478/Cofinanciado FEDER), DIAVIR (Instituto de Salud Carlos III(ISCIII)/DTS19/00049/Cofinanciado FEDER; Proyecto de Desarrollo Tecnológico en Salud) and Resvi-Omics (Instituto de Salud Carlos III(ISCIII)/PI19/01039/Cofinanciado FEDER) and project BI-BACVIR (PRIS-3; Agencia de Conocimiento en Salud (ACIS)—Servicio Gallego de Salud (SERGAS)—Xunta de Galicia; Spain) given to AS; and projects ReSVinext (Instituto de Salud Carlos III(ISCIII)/PI16/01569/Cofinanciado FEDER), and Enterogen (Instituto de Salud Carlos III(ISCIII)/PI19/01090/Cofinanciado FEDER) given to FM-T.</p> <a id="conf1" name="conf1"></a><h2>Conflict of Interest</h2> <p class="mb0">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.</p> <a id="ack1" name="ack1"></a><h2>Acknowledgments</h2> <p class="mb0">This work was developed with support from the GEN-COVID Study Group (<a href="http://www.gencovid.eu/">www.gencovid.eu</a>) from the Hospital Clínico Universitario de Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago and Universidad de Santiago de Compostela, whose members are: Aguilera Guirao, Antonio; Álvarez Escudero, Julián; Antela López, Antonio; Barbeito Castiñeiras, Gema; Bello Paderne, Xabier; Ben García, Miriam; Carral García, María Victoria; Cebey López, Miriam; Coira Nieto, Amparo; Conde Pájaro, Mónica; Costa Alcalde, José Javier; Currás Tuala, María José; Dacosta Urbieta, Ana Isabel; Díaz Esteban, Blanca; Domínguez Santalla, María Jesús; Fernández Villaverde, Juan; Galbán Rodríguez, Cristóbal; García Allut, José Luis; García Vicente, Luisa; Giráldez Vázquez, Elena; Gómez Carballa, Alberto<sup>1</sup>; Gómez Rial, José; González Barcala, Francisco Javier; Guerra Liñares, Beatriz; Leboráns Iglesias, Pilar; Lence Massa, Beatriz; Lendoiro Fuentes, Marta; López Franco, Montserrat; López Lago, Ana; Navarro De la Cruz, Daniel; Núñez Masid, Eloína; Ortolá Devesa, Juan Bautista; Pardo Seco, Jacobo; Pazo Núñez, María; Pérez del Molino Bernal, Marisa; Pérez Freixo, Hugo; Piñeiro Rodríguez, Lidia; Pischedda, Sara; Portela Romero, Manuel; Pose Reino, Antonio; Prada Hervella, Gloria María; Queiro Verdes, Teresa; Redondo Collazo, Lorenzo; Regueiro Casuso, Patricia; Rey García, Susana; Rey Vázquez, Sara; Riveiro Blanco, Vanessa; Rivero Calle, Irene; Rivero Velasco, Carmen; Rodríguez Núñez, Nuria; Rodríguez-Tenreiro Sánchez, Carmen; Saborido Paz, Eva; Sadiki Orayyou, José Miguel; Saito Villanueva, Carla; Serén Fernández, Sonia; Souto Sanmartín, Pablo; Taboada Muñiz, Manuel; Trastoy Pena, Rocío; Treviño Castellano, Mercedes; Valdés Cuadrado, Luis; Varela García, Pablo; Vilas Iglesias, María Soledad; Viz Lasheras, Sandra. 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Immunol.</i> 11:560381. doi: 10.3389/fimmu.2020.560381</p> <p id="timestamps"> <span>Received:</span> 08 May 2020; <span>Accepted:</span> 02 September 2020;<br><span>Published:</span> 23 September 2020.</p> <div> <p>Edited by:</p> <a href="https://loop.frontiersin.org/people/83435/overview">Annalisa Del Prete</a>, University of Brescia, Italy</div> <div> <p>Reviewed by:</p> <a href="https://loop.frontiersin.org/people/405495/overview">Angela Ceribelli</a>, Humanitas Research Hospital, Italy<br> <a href="https://loop.frontiersin.org/people/1030452/overview">Kenneth Williams</a>, Boston College, United States</div> <p><span>Copyright</span> © 2020 Gómez-Rial, Currás-Tuala, Rivero-Calle, Gómez-Carballa, Cebey-López, Rodríguez-Tenreiro, Dacosta-Urbieta, Rivero-Velasco, Rodríguez-Núñez, Trastoy-Pena, Rodríguez-García, Salas and Martinón-Torres. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>. 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.</p> <p><span>*Correspondence:</span> Jose Gómez-Rial, <a id="encmail">am9zZS5nb21lei5yaWFsQHNlcmdhcy5lcw==</a>; Federico Martinón-Torres, <a id="encmail">ZmVkZXJpY28ubWFydGlub24udG9ycmVzQHNlcmdhcy5lcw==</a></p> <p><sup>†</sup>These authors have contributed equally to this work</p> <div class="clear"></div> </div></div></div> <p class="AbstractSummary__disclaimer"><span>Disclaimer: </span> All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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src="https://loop.frontiersin.org/images/profile/83435/32" alt="ANNALISA DEL PRETE" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> ANNALISA DEL PRETE </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> University of Brescia, Italy </div></div></a></div></div> <div class="ArticleDetailsEditors"><div class="ArticleDetailsEditors__editors"><div class="ArticleDetailsEditors__title">Reviewed by</div> <a href="https://loop.frontiersin.org/people/405495/overview" data-event="editorInfo-a-angelaCeribelli" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/405495/32" alt="Angela Ceribelli" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Angela Ceribelli </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> Humanitas Research Hospital, Italy </div></div></a><a href="https://loop.frontiersin.org/people/1030452/overview" data-event="editorInfo-a-kennethWilliams" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/1030452/32" alt="Kenneth Williams" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Kenneth Williams </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> Boston College, United States </div></div></a></div></div> <div class="ArticleDetailsGlossary ArticleDetailsGlossary--open"><button class="ArticleDetailsGlossary__header"><div class="ArticleDetailsGlossary__header__title">Table of contents</div> <div class="ArticleDetailsGlossary__header__arrow"></div></button> <div 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The journal aims to showcase advances and novel approaches to diagnosing and treating immune disorders in both animal and cellular models, as well as in humans. Indexed in MEDLINE, PubMed Central, Scopus and the SCIE Frontiers in Immunology is the official Journal of the \u003Ca href=\"http:\u002F\u002Fwww.iuisonline.org\u002F\" target=\"_blank\" rel=\"noopener\"\u003EInternational Union of Immunological Societies (IUIS)\u003C\u002Fa\u003E.\u003C\u002Fp\u003E\n\n\u003Cp\u003ELed by Field Chief Editor Pietro Ghezzi (Emeritus Professor at Brighton and Sussex Medical School), Frontiers in Immunology welcomes contributions that investigate the basic mechanisms of immune system development and function, with a particular emphasis on describing the clinical and immunological phenotype of human immune disorders and defining their molecular basis. Topics include:\u003C\u002Fp\u003E\n\u003Cul\u003E\n \u003Cli\u003Eadvances in biological drugs\u003C\u002Fli\u003E\n \u003Cli\u003Eimmune system development and function\u003C\u002Fli\u003E\n \u003Cli\u003Emolecular basis of human immune disorders\u003C\u002Fli\u003E\n \u003Cli\u003Enovel approaches to diagnosis and treatment of immune disorders\u003C\u002Fli\u003E\n \u003Cli\u003Eprecision medicine for immunological disorders\u003C\u002Fli\u003E\n \u003Cli\u003Estudies on animal and cellular models and in humans\u003C\u002Fli\u003E\n \u003Cli\u003Estudies on systems immunology with relevant experimental validation.\u003C\u002Fli\u003E\n\u003C\u002Ful\u003E\n\n\u003Cp\u003EFrontiers in Immunology particularly welcomes news ideas and approaches which supports and advances the UN鈥檚 Sustainable Development Goal (SDGs), specifically SDG 3: good health and well-being. The research published in this journal could lead to the development of new treatments and therapies for various immunological disorders, thereby promoting well-being for all.\u003C\u002Fp\u003E\n\n\u003Cp\u003EManuscripts that focus on clinical studies, medical treatments, or human diseases without a clear connection to immunology are not suitable for publication in this journal. Additionally, studies that use analytical molecular biology techniques without a clear immunological context or contribution to the field of immunology are also not within the scope of this journal.\u003C\u002Fp\u003E\n\n\u003Cp\u003EFrontiers in Immunology is dedicated to propelling advancements in the field of Immunology by providing unrestricted access to articles and disseminating scientific knowledge to researchers and the public. This enables future scientific breakthroughs.\u003C\u002Fp\u003E\n\n\u003Cp\u003EEthics Statement\u003C\u002Fp\u003E\n\n\u003Cp\u003EAll manuscripts submitted to鈥疐rontiers in Immunology that have been conducted in human subjects must conform with current regulations and the Declaration of Helsinki. Ethics committee approval and informed patient consent are required for studies involving human subjects. Institutional animal care and use committee (IACUC) approval is needed for studies involving animals. Phase I - Phase IV clinical trials submitted for publication in鈥疐rontiers in Immunology鈥痬ust have been registered with an appropriate public trials registry at the time or before the first patient enrolment. The information on the clinical trial registration (Unique Identifier and URL) must be included in the abstract. Authors are required to disclose all apparent or potential conflicts of interest according to the ICMJE guidelines and those of Frontiers.\u003C\u002Fp\u003E",palette:"red",impactFactor:"7.3",citeScore:"9.4",citations:"824000",showTagline:f,twitter:"@FrontImmunol",__typename:"Journal"},currentFrontiersJournal:{id:w,name:t,slug:x,printISSN:f,shortName:K,electronicISSN:L,abbreviation:$,specialtyId:f,publicationDate:f,isOnline:h,isOpenForSubmissions:h,spaceId:c,field:{id:aa,domainId:s,__typename:ab},__typename:a},articleHubSlug:e,articleHubPage:M,currentArticle:{id:560381,doi:ac,title:N,acceptanceDate:new Date(1599044015000),receptionDate:new Date(1588961230000),publicationDate:new Date(1600819200000),isPublished:h,abstract:ad,researchTopic:{id:13377,title:"Coronavirus Disease (COVID-19): Pathophysiology, Epidemiology, Clinical Management and Public Health Response",articlesCount:400,isMagazinePage:h,slug:"coronavirus-disease-covid-19-pathophysiology-epidemiology-clinical-management-and-public-health-response",isOpenForSubmission:i},articleType:{id:24,name:"Original Research"},stage:{id:O,name:e},keywords:["COVID- 19","monocyte","sCD14","sCD163","immunopahtology"],authors:[{id:ae,firstName:af,lastName:"G贸mez-Rial",givenNames:af,isCorresponding:i,isProfilePublic:h,userId:ae,affiliations:[{organizationName:q,countryName:m,cityName:e,stateName:e,zipCode:e},{organizationName:"Laboratorio de Inmunolog矛a, Servicio de An谩lisis Cl矛nicos, Hospital Cl矛nico Universitario Santiago de Compostela, Servizo Galego de Sa煤de",countryName:m,cityName:e,stateName:e,zipCode:e}]},{id:j,firstName:ag,lastName:"Curr谩s-Tuala",givenNames:ag,isCorresponding:i,isProfilePublic:i,userId:j,affiliations:[{organizationName:q,countryName:m,cityName:e,stateName:e,zipCode:e}]},{id:j,firstName:ah,lastName:"Rivero-Calle",givenNames:ah,isCorresponding:i,isProfilePublic:i,userId:j,affiliations:[{organizationName:q,countryName:m,cityName:e,stateName:e,zipCode:e},{organizationName:P,countryName:m,cityName:e,stateName:e,zipCode:e}]},{id:j,firstName:ai,lastName:"G贸mez-Carballa",givenNames:ai,isCorresponding:i,isProfilePublic:i,userId:j,affiliations:[{organizationName:q,countryName:m,cityName:e,stateName:e,zipCode:e},{organizationName:aj,countryName:m,cityName:e,stateName:e,zipCode:e}]},{id:j,firstName:ak,lastName:"Cebey-L贸pez",givenNames:ak,isCorresponding:i,isProfilePublic:i,userId:j,affiliations:[{organizationName:q,countryName:m,cityName:e,stateName:e,zipCode:e}]},{id:j,firstName:A,lastName:"Rodr铆guez-Tenreiro",givenNames:A,isCorresponding:i,isProfilePublic:i,userId:j,affiliations:[{organizationName:q,countryName:m,cityName:e,stateName:e,zipCode:e}]},{id:j,firstName:al,lastName:"Dacosta-Urbieta",givenNames:al,isCorresponding:i,isProfilePublic:i,userId:j,affiliations:[{organizationName:q,countryName:m,cityName:e,stateName:e,zipCode:e},{organizationName:P,countryName:m,cityName:e,stateName:e,zipCode:e}]},{id:j,firstName:A,lastName:"Rivero-Velasco",givenNames:A,isCorresponding:i,isProfilePublic:i,userId:j,affiliations:[{organizationName:"Intensive Medicine Department, Hospital Cl矛nico Universitario de Santiago de Compostela",countryName:m,cityName:e,stateName:e,zipCode:e}]},{id:j,firstName:am,lastName:"Rodr铆guez-N煤帽ez",givenNames:am,isCorresponding:i,isProfilePublic:i,userId:j,affiliations:[{organizationName:"Pneumology Department, Hospital Cl矛nico Universitario de Santiago de Compostela",countryName:m,cityName:e,stateName:e,zipCode:e}]},{id:j,firstName:an,lastName:"Trastoy-Pena",givenNames:an,isCorresponding:i,isProfilePublic:i,userId:j,affiliations:[{organizationName:"Microbiology Department, Hospital Cl矛nico Universitario de Santiago de Compostela",countryName:m,cityName:e,stateName:e,zipCode:e}]},{id:j,firstName:ao,lastName:"Rodr铆guez-Garc铆a",givenNames:ao,isCorresponding:i,isProfilePublic:i,userId:j,affiliations:[{organizationName:"Clinical Biochemistry Laboratory, Hospital Cl矛nico Universitario de Santiago de Compostela",countryName:m,cityName:e,stateName:e,zipCode:e}]},{id:ap,firstName:aq,lastName:"Salas",givenNames:aq,isCorresponding:i,isProfilePublic:h,userId:ap,affiliations:[{organizationName:q,countryName:m,cityName:e,stateName:e,zipCode:e},{organizationName:aj,countryName:m,cityName:e,stateName:e,zipCode:e}]},{id:ar,firstName:as,lastName:"Martin贸n-Torres",givenNames:as,isCorresponding:i,isProfilePublic:h,userId:ar,affiliations:[{organizationName:q,countryName:m,cityName:e,stateName:e,zipCode:e},{organizationName:P,countryName:m,cityName:e,stateName:e,zipCode:e}]}],editors:[{id:at,firstName:au,lastName:"DEL PRETE",givenNames:au,isCorresponding:i,isProfilePublic:h,userId:at,affiliations:[{organizationName:"University of Brescia",countryName:av,cityName:e,stateName:e,zipCode:e}]}],reviewers:[{id:aw,firstName:ax,lastName:"Ceribelli",givenNames:ax,isCorresponding:i,isProfilePublic:h,userId:aw,affiliations:[{organizationName:"Humanitas Research Hospital",countryName:av,cityName:e,stateName:e,zipCode:e}]},{id:ay,firstName:az,lastName:"Williams",givenNames:az,isCorresponding:i,isProfilePublic:h,userId:ay,affiliations:[{organizationName:"Boston College",countryName:"United States",cityName:e,stateName:e,zipCode:e}]}],journal:{id:w,slug:x,name:t,shortName:K,electronicISSN:L,field:{id:aa,domainId:s,__typename:ab},specialtyId:f,journalSectionPaths:[{section:aA,__typename:"journal_journalSectionPath"}],__typename:a},section:aA,impactMetrics:{views:8315,downloads:2138,citations:73},volume:Q,articleVolume:"Volume 11 - 2020",relatedArticles:[],isPublishedV2:i,contents:{titleHtml:N,fullTextHtml:"\u003Cdiv class=\"JournalAbstract\"\u003E\r\n\u003Ca id=\"h1\" name=\"h1\"\u003E\u003C\u002Fa\u003E\r\n\u003Cdiv class=\"authors\"\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F971915\" class=\"user-id-971915\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F971915\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"\\r\\nJose Gmez-Rial,*&#x;\"\u003EJose Gómez-Rial\u003C\u002Fa\u003E\u003Csup\u003E1,2*†\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Maria Jos Currs-Tuala&#x;\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EMaria José Currás-Tuala\u003Csup\u003E1†\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Irene Rivero-Calle,\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EIrene Rivero-Calle\u003Csup\u003E1,3\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Alberto Gmez-Carballa,\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EAlberto Gómez-Carballa\u003Csup\u003E1,4\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Miriam Cebey-Lpez\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EMiriam Cebey-López\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Carmen Rodríguez-Tenreiro\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003ECarmen Rodríguez-Tenreiro\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Ana Dacosta-Urbieta,\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EAna Dacosta-Urbieta\u003Csup\u003E1,3\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Carmen Rivero-Velasco\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003ECarmen Rivero-Velasco\u003Csup\u003E5\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Nuria Rodríguez-Núez\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003ENuria Rodríguez-Núñez\u003Csup\u003E6\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Rocio Trastoy-Pena\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003ERocio Trastoy-Pena\u003Csup\u003E7\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Javier Rodríguez-García\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EJavier Rodríguez-García\u003Csup\u003E8\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F1021428\" class=\"user-id-1021428\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F1021428\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Antonio Salas,\"\u003EAntonio Salas\u003C\u002Fa\u003E\u003Csup\u003E1,4\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F58621\" class=\"user-id-58621\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F58621\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Federico Martinn-Torres,*\"\u003EFederico Martinón-Torres\u003C\u002Fa\u003E\u003Csup\u003E1,3*\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003C\u002Fdiv\u003E\r\n\u003Cul class=\"notes\"\u003E\r\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EGrupo de Investigación en Genética, Vacunas, Infecciones y Pediatría, Instituto de Investigación Sanitaria de Santiago, Hospital Clinico Universitario and Universidade de Santiago de Compostela, Servizo Galego de Saúde, Galicia, Spain\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E\u003C\u002Fspan\u003ELaboratorio de Inmunologìa, Servicio de Análisis Clìnicos, Hospital Clìnico Universitario Santiago de Compostela, Servizo Galego de Saúde, Galicia, Spain\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E3\u003C\u002Fsup\u003E\u003C\u002Fspan\u003ETranslational Pediatrics and Infectious Diseases Section, Department of Pediatrics, Hospital Clìnico Universitario de Santiago de Compostela, Galicia, Spain\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E4\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EUnidade de Xenética, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, and GenPoB Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clìnico Universitario de Santiago, Servizo Galego de Saúde, Galicia, Spain\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E5\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EIntensive Medicine Department, Hospital Clìnico Universitario de Santiago de Compostela, Galicia, Spain\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E6\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EPneumology Department, Hospital Clìnico Universitario de Santiago de Compostela, Galicia, Spain\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E7\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EMicrobiology Department, Hospital Clìnico Universitario de Santiago de Compostela, Galicia, Spain\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E8\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EClinical Biochemistry Laboratory, Hospital Clìnico Universitario de Santiago de Compostela, Galicia, Spain\u003C\u002Fli\u003E\r\n\u003C\u002Ful\u003E\r\n\u003Cp class=\"mb0\"\u003E\u003Cb\u003EBackground:\u003C\u002Fb\u003E Emerging evidence indicates a potential role for monocytes in COVID-19 immunopathology. We investigated two soluble markers of monocyte activation, sCD14 and sCD163, in COVID-19 patients, with the aim of characterizing their potential role in monocyte-macrophage disease immunopathology. To the best of our knowledge, this is the first study of its kind.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003E\u003Cb\u003EMethods:\u003C\u002Fb\u003E Fifty-nine SARS-Cov-2 positive hospitalized patients, classified according to ICU or non-ICU admission requirement, were prospectively recruited and analyzed by ELISA for levels of sCD14 and sCD163, along with other laboratory parameters, and compared to a healthy control group.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003E\u003Cb\u003EResults:\u003C\u002Fb\u003E sCD14 and sCD163 levels were significantly higher among COVID-19 patients, independently of ICU admission requirement, compared to the control group. We found a significant correlation between sCD14 levels and other inflammatory markers, particularly Interleukin-6, in the non-ICU patients group. sCD163 showed a moderate positive correlation with the time lapsed from admission to sampling, independently of severity group. Treatment with corticoids showed an interference with sCD14 levels, whereas hydroxychloroquine and tocilizumab did not.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003E\u003Cb\u003EConclusions\u003C\u002Fb\u003E Monocyte-macrophage activation markers are increased and correlate with other inflammatory markers in SARS-Cov-2 infection, in association to hospital admission. These data suggest a preponderant role for monocyte-macrophage activation in the development of immunopathology of COVID-19 patients.\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"JournalFullText\"\u003E\r\n\u003Ca id=\"h2\" name=\"h2\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EIntroduction\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb15\"\u003EEmerging evidence from SARS-Cov-2 infected patients suggests a key role for monocyte-macrophage in the immunopathology of COVID-19 infection, with a predominant monocyte-derived macrophage infiltration observed in severely damaged lungs (\u003Ca href=\"#B1\"\u003E1\u003C\u002Fa\u003E), and morphological and inflammation-related changes in peripheral blood monocytes that correlate with the patients’ outcome (\u003Ca href=\"#B2\"\u003E2\u003C\u002Fa\u003E). An overexuberant inflammatory immune response with production of a cytokine storm and T-cell immunosuppression are the main hallmarks of severity in these patients (\u003Ca href=\"#B3\"\u003E3\u003C\u002Fa\u003E). This clinical course resembles viral-associated hemophagocytic syndrome (VAHS), a rare severe complication of various viral infections mediated by proinflammatory cytokines, resulting in multiorgan failure and death (\u003Ca href=\"#B4\"\u003E4\u003C\u002Fa\u003E). A chronic expansion of inflammatory monocytes and over-activation of macrophages have been extensively described in this syndrome (\u003Ca href=\"#B5\"\u003E5\u003C\u002Fa\u003E–\u003Ca href=\"#B7\"\u003E7\u003C\u002Fa\u003E). Viral-associated hemophagocytic syndrome has been identified as a major contributor to death of patients in past pandemics caused by coronaviruses (\u003Ca href=\"#B8\"\u003E8\u003C\u002Fa\u003E), including previous SARS and MERS outbreaks (\u003Ca href=\"#B9\"\u003E9\u003C\u002Fa\u003E), and currently suggested for SARS-Cov-2 outbreak (\u003Ca href=\"#B10\"\u003E10\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003ECD14 and CD163 are both myeloid differentiation markers found primarily on monocytes and macrophages, and detection of soluble release of both in plasma is considered a good biomarker of monocyte-macrophage activation (\u003Ca href=\"#B11\"\u003E11\u003C\u002Fa\u003E, \u003Ca href=\"#B12\"\u003E12\u003C\u002Fa\u003E). Elevated plasma levels of soluble CD14 (sCD14) are associated to poor prognosis in VIH-infected patients, are a strong predictor of morbidity and mortality (\u003Ca href=\"#B13\"\u003E13\u003C\u002Fa\u003E, \u003Ca href=\"#B14\"\u003E14\u003C\u002Fa\u003E), and associated with diminished CD4+-T cell restoration (\u003Ca href=\"#B15\"\u003E15\u003C\u002Fa\u003E). In addition, soluble CD163 (sCD163) plasma levels are a good proxy for monocyte expansion and disease progression during HIV infection (\u003Ca href=\"#B16\"\u003E16\u003C\u002Fa\u003E). In measles infection, a leading cause of death associated with increased susceptibility to secondary infections and immunosuppression, sCD14 and sCD163 levels have been found to be significantly higher, indicating an important and persistent monocyte-macrophage activation (\u003Ca href=\"#B17\"\u003E17\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EWe hypothesized that monocytes\u002Fmacrophages may be an important component of immunopathology associated to SARS-Cov-2 infection. In this paper, we analyze serum levels of soluble monocyte activation markers in COVID-19 patients and their correlation with severity and other inflammatory markers.\u003C\u002Fp\u003E\r\n\u003Ca id=\"h3\" name=\"h3\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EMaterials and Methods\u003C\u002Fh2\u003E\r\n\u003Ch3 class=\"pt0\"\u003ESubjects\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003EWe recruited 59 patients with confirmed PCR-positive diagnosis of SARS-Cov-2 infection, classified according to ICU admission requirement (\u003Ci\u003En\u003C\u002Fi\u003E = 22 patients), or non-ICU requirement (\u003Ci\u003En\u003C\u002Fi\u003E = 37), and age-matched healthy individuals (\u003Ci\u003En\u003C\u002Fi\u003E = 20) as a control group. Demographic data, main medication treatment and routine lab clinical parameters including inflammatory biomarkers were collected for all infected patients. Leftover sera samples from routine analytical controls were employed for the analysis, after obtaining the corresponding informed consent. Time elapsed from hospital admission to sample extraction was also recorded.\u003C\u002Fp\u003E\r\n\u003Ch3\u003EMeasurement of sCD14 and sCD163 Serum Levels\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003ETo determine levels of soluble monocyte activation markers in serum specimens, appropriate sandwich ELISA (Quantikine, R&D systems, United Kingdom) were used following manufacturer indications. Briefly, diluted sera samples were incubated for 3 h at room temperature in the corresponding microplate strips coated with capture antibody. After incubation, strips were washed and incubated with the corresponding Human Antibody conjugate for 1 h. After washing, reactions were revealed and optical density at 450 nm was determined in a microplate reader. Concentration levels were interpolated from the standard curve using a four-parameter logistic (4-PL) curve-fit in Prism8 GraphPad software. Final values were corrected applying the corresponding dilution factor employed.\u003C\u002Fp\u003E\r\n\u003Ch3\u003EStatistical Analysis\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003EData are expressed as median and interquartile range. All statistical analyses were performed using the statistical package R. Mann–Whitney tests were used for comparison between ICU and non-ICU groups \u003Ci\u003Eversus\u003C\u002Fi\u003E healthy controls. Pearson’s correlation coefficients were used to quantify the association between sCD14 and sCD163 concentration and other lab parameters in non-ICU patients. Data outliers, falling outside the 1.5 interquartile range, were excluded from the statistical analysis. The nominal significance level considered was 0.05. Bonferroni adjustment was used to account for multiple testing.\u003C\u002Fp\u003E\r\n\u003Ca id=\"h4\" name=\"h4\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EResults\u003C\u002Fh2\u003E\r\n\u003Ch3 class=\"pt0\"\u003EDemographic and Clinical Laboratory Parameters\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003EPatients in the ICU group showed significant differences when compared to non-ICU group in several clinical laboratory parameters: lymphocytes, ferritin, \u003Csmall\u003ED\u003C\u002Fsmall\u003E-dimer, Lactate dehydrogenase (LDH), procalcitonin (PCT), and Interleukin-6 (IL-6). The absolute value for circulating monocytes did not show significant differences between groups. However, these values may have been distorted by the use of tocilizumab, an IL-6 blocking drug extensively employed in the ICU group which interferes with monocyte function. Age and time elapsed from admission to sample extraction did not show differences between groups. Values are summarized in \u003Ca href=\"#T1\"\u003ETable 1\u003C\u002Fa\u003E.\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"Imageheaders\"\u003ETABLE 1\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"FigureDesc\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-t001.jpg\" name=\"table1\" target=\"_blank\"\u003E\r\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-t001.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-t001.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-t001.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-t001.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-t001.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-t001.jpg\" alt=\"www.frontiersin.org\" id=\"T1\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\r\n\u003Cp\u003E\u003Cstrong\u003ETable 1.\u003C\u002Fstrong\u003E Demographic and clinical laboratory parameters of patients recruited.\u003C\u002Fp\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Ch3\u003ESerum Levels for sCD14 and sCD163\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003EMedian levels for sCD14 in sera from ICU patients were 2444.0 (95%CI: 1914.0–3251.0) ng\u002Fml, compared to 2613.0 (95%CI: 2266.0–2991.0) ng\u002Fml in non-ICU patients. The healthy control group median value was 1788.0 (95%CI: 1615.0–1917.0) ng\u002Fml. We observed significant statistical differences when comparing infected patients against controls (\u003Ci\u003EP\u003C\u002Fi\u003E-value < 0.0001), however no significant differences were observed between ICU and non-ICU groups. Median levels for sCD163 in sera from ICU patients were 911.5 (95%CI: 624.7–1167.0) ng\u002Fml, and 910.4 (95%CI: 733.1–1088.0) ng\u002Fml in non-ICU patients. The healthy control group value was 495.6 (95%CI: 332.5–600.7) ng\u002Fml. As with sCD14, we observed significant differences for values from infected patients compared to control group (\u003Ci\u003EP\u003C\u002Fi\u003E-value < 00001), but no differences between ICU and non-ICU infected patients. Values are summarized in \u003Ca href=\"#T2\"\u003ETable 2\u003C\u002Fa\u003E and \u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E.\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"Imageheaders\"\u003ETABLE 2\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"FigureDesc\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-t002.jpg\" name=\"table2\" target=\"_blank\"\u003E\r\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-t002.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-t002.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-t002.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-t002.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-t002.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-t002.jpg\" alt=\"www.frontiersin.org\" id=\"T2\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\r\n\u003Cp\u003E\u003Cstrong\u003ETable 2.\u003C\u002Fstrong\u003E Concentration (ng\u002Fml) of serum levels of sCD14 and sCD163 in patients from ICU and non-ICU groups, and healthy controls.\u003C\u002Fp\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"DottedLine mb15\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 1\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"FigureDesc\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g001.jpg\" name=\"figure1\" target=\"_blank\"\u003E\r\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g001.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g001.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g001.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g001.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g001.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g001.jpg\" alt=\"www.frontiersin.org\" id=\"F1\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\r\n\u003Cp\u003E\u003Cstrong\u003EFigure 1.\u003C\u002Fstrong\u003E Values of sCD14 \u003Cb\u003E(A)\u003C\u002Fb\u003E and sCD163 \u003Cb\u003E(B)\u003C\u002Fb\u003E in sera samples from patients in ICU, non-ICU, and healthy controls. Results are presented as median and interquartile range levels in ng\u002Fml. Non-parametric Mann–Whitney tests were used for comparison between groups, and \u003Ci\u003EP\u003C\u002Fi\u003E-values for the different comparisons are displayed.\u003C\u002Fp\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Ch3\u003ECorrelation Between sCD14 and sCD163 Levels and Time Elapsed From Hospital Admission\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003EWe assessed the correlation between sCD14 and sCD163 levels and time elapsed from hospital admission to sample extraction (\u003Ca href=\"#F2\"\u003EFigure 2\u003C\u002Fa\u003E). We found a significant positive correlation between sCD163 levels and time elapsed (\u003Ci\u003Er\u003C\u002Fi\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E = 0.3246, \u003Ci\u003EP\u003C\u002Fi\u003E-value = 0.0156) We did not observe a significant correlation between sCD14 levels and time elapsed from hospital admission to sample extraction.\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 2\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"FigureDesc\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g002.jpg\" name=\"figure2\" target=\"_blank\"\u003E\r\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g002.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g002.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g002.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g002.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g002.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g002.jpg\" alt=\"www.frontiersin.org\" id=\"F2\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\r\n\u003Cp\u003E\u003Cstrong\u003EFigure 2.\u003C\u002Fstrong\u003E Correlation between serum levels of sCD14 and sCD163 and time elapsed from admission to sample extraction (in days) for all infected patients. Pearson’s correlation coefficient (\u003Ci\u003Er\u003C\u002Fi\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E) and \u003Ci\u003EP\u003C\u002Fi\u003E-value are shown.\u003C\u002Fp\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Ch3\u003ECorrelation Between sCD14 and sCD163 Levels and Clinical Laboratory Parameters\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003EWe found significant correlations between sCD14 and sCD163 levels and several clinical laboratory parameters in infected patients (in these analysis, adjusted significance under Bonferrori correction is 0.01), but only in the non-ICU group, possibly reflecting an interference of the use of tocilizumab or corticoids in the ICU group. Levels of sCD14 showed a negative correlation with the absolute value of lymphocytes (\u003Ci\u003Er\u003C\u002Fi\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E = −0.5501, \u003Ci\u003EP\u003C\u002Fi\u003E-value = 0.0005) and a positive correlation with levels of LDH (\u003Ci\u003Er\u003C\u002Fi\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E = 0.5906, \u003Ci\u003EP\u003C\u002Fi\u003E-value = 0.0001), CRP (\u003Ci\u003Er\u003C\u002Fi\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E = 0.6275, \u003Ci\u003EP\u003C\u002Fi\u003E-value < 0.0001); PCT (\u003Ci\u003Er\u003C\u002Fi\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E = 0.4608, \u003Ci\u003EP\u003C\u002Fi\u003E-value = 0.0091), and Ferritin (\u003Ci\u003Er\u003C\u002Fi\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E = 0.4414, \u003Ci\u003EP\u003C\u002Fi\u003E-value = 0.0090) (\u003Ca href=\"#F3\"\u003EFigure 3\u003C\u002Fa\u003E). No other significative associations were found with other lab parameters. Levels of sCD163 did not show significant correlation with clinical laboratory parameters (\u003Ca href=\"#F3\"\u003EFigure 3\u003C\u002Fa\u003E). Particularly, IL-6 also showed significant positive correlation with sCD14 (\u003Ci\u003Er\u003C\u002Fi\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E = 0.6034, \u003Ci\u003EP\u003C\u002Fi\u003E-value = 0.0003) (\u003Ca href=\"#F4\"\u003EFigure 4\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 3\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"FigureDesc\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g003.jpg\" name=\"figure3\" target=\"_blank\"\u003E\r\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g003.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g003.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g003.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g003.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g003.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g003.jpg\" alt=\"www.frontiersin.org\" id=\"F3\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\r\n\u003Cp\u003E\u003Cstrong\u003EFigure 3.\u003C\u002Fstrong\u003E Association between serum levels of sCD14 and sCD163, and several laboratory parameters including Absolute Valor Lymphocytes \u003Cb\u003E(A,B)\u003C\u002Fb\u003E, LDH \u003Cb\u003E(C,D)\u003C\u002Fb\u003E, CRP \u003Cb\u003E(E,F)\u003C\u002Fb\u003E, PCT \u003Cb\u003E(G,H)\u003C\u002Fb\u003E, and Ferritin \u003Cb\u003E(I,J)\u003C\u002Fb\u003E in the non-ICU patient group. Pearson’s correlation coefficient (\u003Ci\u003Er\u003C\u002Fi\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E) and \u003Ci\u003EP\u003C\u002Fi\u003E-value are shown. LDH, lactate dehydrogenase; CRP, C-reactive protein; PCT, procalcitonin.\u003C\u002Fp\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"DottedLine mb15\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 4\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"FigureDesc\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g004.jpg\" name=\"figure4\" target=\"_blank\"\u003E\r\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g004.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g004.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g004.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g004.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g004.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g004.jpg\" alt=\"www.frontiersin.org\" id=\"F4\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\r\n\u003Cp\u003E\u003Cstrong\u003EFigure 4.\u003C\u002Fstrong\u003E Association between serum levels of sCD14 and IL-6 levels in the non-ICU patient group. Pearson’s correlation coefficient (\u003Ci\u003Er\u003C\u002Fi\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E) and \u003Ci\u003EP\u003C\u002Fi\u003E-value are presented.\u003C\u002Fp\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Ch3\u003EEffect of Treatment on sCD14 and sCD163 Levels\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003EWe analyzed possible interference of different treatments on sCD14 and sCD163 serum levels for all patients. We found an interference of corticoid treatment on sCD14, levels with median values of 2034 (95%CI: 1319–3159) ng\u002Fml for treated group, and values of 2613 (95%CI: 2466–2913) ng\u002Fml for non-treated group. Values were significantly lower in corticoid-treated group (\u003Ci\u003EP\u003C\u002Fi\u003E-value = 0.0069) (\u003Ca href=\"#F5\"\u003EFigure 5\u003C\u002Fa\u003E). No impact was found for corticoids on sCD163 levels. Likewise, hydroxychloroquine and\u002For tocilizumab were not found to have an impact on sCD14 and sCD163 serum levels.\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 5\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"FigureDesc\"\u003E\r\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g005.jpg\" name=\"figure5\" target=\"_blank\"\u003E\r\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g005.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g005.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g005.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g005.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g005.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F560381\u002Ffimmu-11-560381-HTML\u002Fimage_m\u002Ffimmu-11-560381-g005.jpg\" alt=\"www.frontiersin.org\" id=\"F5\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\r\n\u003Cp\u003E\u003Cstrong\u003EFigure 5.\u003C\u002Fstrong\u003E Effects of corticoid, hydroxychloroquine, and tocilizumab treatment on sCD14 and sCD163 levels. Results are presented as median and interquartile range levels in ng\u002Fml. Non-parametric Mann–Whitney tests were used for comparison between groups, and \u003Ci\u003EP\u003C\u002Fi\u003E-values for the different comparisons are displayed.\u003C\u002Fp\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Ch3\u003ECorrelation Between sCD14 and sCD163 Levels and Hospital Stay\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003ELevels of sCD14 and sCD163 did not show association with length of hospital stay in both groups. Also, these biomarkers did not show association with the number of days of onset of symptoms.\u003C\u002Fp\u003E\r\n\u003Ch3\u003EAge-Dependence of sCD14 and sCD163 Levels\u003C\u002Fh3\u003E\r\n\u003Cp class=\"mb0\"\u003EWe analyzed for possible age-dependence of sCD14 and sCD163 levels. Values did not show association between these biomarker levels and the age of patients.\u003C\u002Fp\u003E\r\n\u003Ca id=\"h5\" name=\"h5\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EDiscussion\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb15\"\u003EOur results show, for the first time, increased levels of sCD14 and sCD163 in sera from SARS-Cov-2 infected patients admitted to hospital. We did not observe statistical differences when comparing ICU versus non-ICU patients. This is probably due to the interference on monocyte function and sCD14 levels produced by the use of corticoid treatment in ICU patients, as shown here and previously by others (\u003Ca href=\"#B18\"\u003E18\u003C\u002Fa\u003E, \u003Ca href=\"#B19\"\u003E19\u003C\u002Fa\u003E). However, levels of sCD14 showed a strong correlation with clinical laboratory parameters, including acute phase reactants (ferritin, LDH, C-reactive protein, procalcitonin) and a strong correlation with IL-6 levels in the non-ICU patient group, where no corticoids treatments were used. Hydroxychloroquine and tocilizumab treatment did not show interferences on sCD14 and sCD163 levels. Furthermore, sCD163 levels showed a correlation with the time elapsed from hospital admission to sample extraction, suggesting a potential indicator of disease progression.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EMonocytes and macrophages constitute a key component of immune responses against viruses, acting as bridge between innate and adaptive immunity (\u003Ca href=\"#B20\"\u003E20\u003C\u002Fa\u003E). Activation of macrophages has been demonstrated to be pivotal in the pathogenesis of the immunosuppression associated to several viral infections (such as VIH, measles), where expansion of specific subsets of monocytes and macrophages in peripheral blood are observed, and considered to be drivers of immunopathogenesis (\u003Ca href=\"#B21\"\u003E21\u003C\u002Fa\u003E). Our results support the hypothesis of a preponderant role for monocytes in SARS-Cov-2 immunopathology, associated to an overexuberant immune response. Increased levels of monocyte-macrophage activation markers, and their correlation with other inflammatory biomarkers (particularly IL-6), indicate a close relationship between monocyte activation and immunopathology in these patients. Inflammatory markers are closely related to severity in COVID-19 pathology (\u003Ca href=\"#B22\"\u003E22\u003C\u002Fa\u003E) and selective blockade of IL-6 has been demonstrated to be a good therapeutic strategy in COVID-19 pathology (\u003Ca href=\"#B23\"\u003E23\u003C\u002Fa\u003E). Our results thus suggest that monocyte-macrophage activation can act as driver cells of the cytokine storm and immunopathology associated to severe clinical course of COVID-19 patients. Further, monitorization of monocyte activity trough these soluble activation markers and\u002For follow-up of circulating inflammatory monocytes in peripheral blood, could be useful to assess disease progression in the same way as in other viral infections (\u003Ca href=\"#B16\"\u003E16\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EIn addition, our results identify monocyte-macrophage as a good target for the design of therapeutic intervention using drugs that inhibit monocyte-macrophage activation and differentiation. In this sense, anti-GM CSF inhibitor drugs, currently under clinical trials for rheumatic and other auto-inflammatory diseases, might provide satisfactory results in COVID-19 patients. Other drugs targeting monocyte and\u002For macrophage could also be useful in COVID-19, as in other inflammatory diseases (\u003Ca href=\"#B24\"\u003E24\u003C\u002Fa\u003E). The strategy of inhibiting monocyte differentiation has proved useful in avoiding cytokine storm syndrome after CAR-T cell immunotherapy (\u003Ca href=\"#B25\"\u003E25\u003C\u002Fa\u003E), suggesting a possible therapeutic application to COVID-19 immunopathology (\u003Ca href=\"#B26\"\u003E26\u003C\u002Fa\u003E, \u003Ca href=\"#B27\"\u003E27\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb15\"\u003EThe present study has several limitations, including a relatively low sample size and the interference of corticoids in ICU patients’ results. However, these preliminary results are strongly suggestive of an important implication of monocyte-macrophage in COVID-19 immunopathology, as highlighted by the correlations found between these biomarker levels and inflammatory parameters. Further studies using broader series are needed to confirm our findings.\u003C\u002Fp\u003E\r\n\u003Cp class=\"mb0\"\u003EIn summary, our data underscore the preponderant role of monocyte and macrophage immune response in COVID-19 immunopathology and provide pointers for future interventions in drug strategies and monitoring plans for these patients.\u003C\u002Fp\u003E\r\n\u003Ca id=\"h6\" name=\"h6\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EData Availability Statement\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb0\"\u003EThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\u003C\u002Fp\u003E\r\n\u003Ca id=\"h7\" name=\"h7\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EEthics Statement\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb0\"\u003EThe studies involving human participants were reviewed and approved by Comité de Ética de la Investigación con Medicamentos de Galicia (fast-track approval 18-march-2020). Written informed consent to participate in this study was provided by the participants’ legal guardian\u002Fnext of kin.\u003C\u002Fp\u003E\r\n\u003Ca id=\"h8\" name=\"h8\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAuthor Contributions\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb0\"\u003EJG-R, FM-T, and AS designed and conceptualized the study and made the first draft. MC-T, IR-C, AG-C, MC-L, CR-T, AD-U, CR-V, NR-N, RT-P, and JR-G collected the samples and did the analysis, reviewed the draft and approved the final version. All authors contributed to the article and approved the submitted version.\u003C\u002Fp\u003E\r\n\u003Ca id=\"fun1\" name=\"fun1\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EFunding\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb0\"\u003EThis study received support from the Instituto de Salud Carlos III: project GePEM (Instituto de Salud Carlos III(ISCIII)\u002FPI16\u002F01478\u002FCofinanciado FEDER), DIAVIR (Instituto de Salud Carlos III(ISCIII)\u002FDTS19\u002F00049\u002FCofinanciado FEDER; Proyecto de Desarrollo Tecnológico en Salud) and Resvi-Omics (Instituto de Salud Carlos III(ISCIII)\u002FPI19\u002F01039\u002FCofinanciado FEDER) and project BI-BACVIR (PRIS-3; Agencia de Conocimiento en Salud (ACIS)—Servicio Gallego de Salud (SERGAS)—Xunta de Galicia; Spain) given to AS; and projects ReSVinext (Instituto de Salud Carlos III(ISCIII)\u002FPI16\u002F01569\u002FCofinanciado FEDER), and Enterogen (Instituto de Salud Carlos III(ISCIII)\u002FPI19\u002F01090\u002FCofinanciado FEDER) given to FM-T.\u003C\u002Fp\u003E\r\n\u003Ca id=\"conf1\" name=\"conf1\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EConflict of Interest\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb0\"\u003EThe 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.\u003C\u002Fp\u003E\r\n\u003Ca id=\"ack1\" name=\"ack1\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAcknowledgments\u003C\u002Fh2\u003E\r\n\u003Cp class=\"mb0\"\u003EThis work was developed with support from the GEN-COVID Study Group (\u003Ca href=\"http:\u002F\u002Fwww.gencovid.eu\u002F\"\u003Ewww.gencovid.eu\u003C\u002Fa\u003E) from the Hospital Clínico Universitario de Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago and Universidad de Santiago de Compostela, whose members are: Aguilera Guirao, Antonio; Álvarez Escudero, Julián; Antela López, Antonio; Barbeito Castiñeiras, Gema; Bello Paderne, Xabier; Ben García, Miriam; Carral García, María Victoria; Cebey López, Miriam; Coira Nieto, Amparo; Conde Pájaro, Mónica; Costa Alcalde, José Javier; Currás Tuala, María José; Dacosta Urbieta, Ana Isabel; Díaz Esteban, Blanca; Domínguez Santalla, María Jesús; Fernández Villaverde, Juan; Galbán Rodríguez, Cristóbal; García Allut, José Luis; García Vicente, Luisa; Giráldez Vázquez, Elena; Gómez Carballa, Alberto\u003Csup\u003E1\u003C\u002Fsup\u003E; Gómez Rial, José; González Barcala, Francisco Javier; Guerra Liñares, Beatriz; Leboráns Iglesias, Pilar; Lence Massa, Beatriz; Lendoiro Fuentes, Marta; López Franco, Montserrat; López Lago, Ana; Navarro De la Cruz, Daniel; Núñez Masid, Eloína; Ortolá Devesa, Juan Bautista; Pardo Seco, Jacobo; Pazo Núñez, María; Pérez del Molino Bernal, Marisa; Pérez Freixo, Hugo; Piñeiro Rodríguez, Lidia; Pischedda, Sara; Portela Romero, Manuel; Pose Reino, Antonio; Prada Hervella, Gloria María; Queiro Verdes, Teresa; Redondo Collazo, Lorenzo; Regueiro Casuso, Patricia; Rey García, Susana; Rey Vázquez, Sara; Riveiro Blanco, Vanessa; Rivero Calle, Irene; Rivero Velasco, Carmen; Rodríguez Núñez, Nuria; Rodríguez-Tenreiro Sánchez, Carmen; Saborido Paz, Eva; Sadiki Orayyou, José Miguel; Saito Villanueva, Carla; Serén Fernández, Sonia; Souto Sanmartín, Pablo; Taboada Muñiz, Manuel; Trastoy Pena, Rocío; Treviño Castellano, Mercedes; Valdés Cuadrado, Luis; Varela García, Pablo; Vilas Iglesias, María Soledad; Viz Lasheras, Sandra. We would like to acknowledge the effort of all first-line healthcare workers supporting the patients included in this study.\u003C\u002Fp\u003E\r\n\u003Ca id=\"refer1\" name=\"refer1\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EReferences\u003C\u002Fh2\u003E\r\n\u003Cdiv class=\"References\" style=\"margin-bottom:0.5em;\"\u003E\r\n\u003Cp class=\"ReferencesCopy1\"\u003E\u003Ca name=\"B1\" id=\"B1\"\u003E\u003C\u002Fa\u003E1. Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J, et al. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing. \u003Ci\u003EmedRxiv.\u003C\u002Fi\u003E (2020). 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Gomez-Rial J, Rivero-Calle I, Salas A, Martinon-Torres F. Role of monocytes\u002Fmacrophages in covid-19 pathogenesis: implications for therapy. \u003Ci\u003EInfect. Drug Resist.\u003C\u002Fi\u003E (2020) 13:2485–2493. doi: 10.2147\u002FIDR.S258639\u003C\u002Fp\u003E\r\n\u003Cp class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F32801787\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.2147\u002FIDR.S258639\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?&title=Role+of+monocytes%2Fmacrophages+in+covid-19+pathogenesis%3A+implications+for+therapy%2E&journal=Infect%2E+Drug+Resist%2E&author=Gomez-Rial+J&author=Rivero-Calle+I&author=Salas+A&author=Martinon-Torres+F.&publication_year=2020&volume=13&pages=2485–2493\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"thinLineM20\"\u003E\u003C\u002Fdiv\u003E\r\n\u003Cdiv class=\"AbstractSummary\"\u003E\r\n\u003Cp\u003E\u003Cspan\u003EKeywords\u003C\u002Fspan\u003E: COVID-19, monocyte, sCD14, sCD163, immunopathology\u003C\u002Fp\u003E\r\n\u003Cp\u003E\u003Cspan\u003ECitation:\u003C\u002Fspan\u003E Gómez-Rial J, Currás-Tuala MJ, Rivero-Calle I, Gómez-Carballa A, Cebey-López M, Rodríguez-Tenreiro C, Dacosta-Urbieta A, Rivero-Velasco C, Rodríguez-Núñez N, Trastoy-Pena R, Rodríguez-García J, Salas A and Martinón-Torres F (2020) Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology. \u003Ci\u003EFront. Immunol.\u003C\u002Fi\u003E 11:560381. doi: 10.3389\u002Ffimmu.2020.560381\u003C\u002Fp\u003E\r\n\u003Cp id=\"timestamps\"\u003E\r\n\u003Cspan\u003EReceived:\u003C\u002Fspan\u003E 08 May 2020; \u003Cspan\u003EAccepted:\u003C\u002Fspan\u003E 02 September 2020;\u003Cbr\u003E\u003Cspan\u003EPublished:\u003C\u002Fspan\u003E 23 September 2020.\u003C\u002Fp\u003E\r\n\u003Cdiv\u003E\r\n\u003Cp\u003EEdited by:\u003C\u002Fp\u003E\r\n\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F83435\u002Foverview\"\u003EAnnalisa Del Prete\u003C\u002Fa\u003E, University of Brescia, Italy\u003C\u002Fdiv\u003E\r\n\u003Cdiv\u003E\r\n\u003Cp\u003EReviewed by:\u003C\u002Fp\u003E\r\n\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F405495\u002Foverview\"\u003EAngela Ceribelli\u003C\u002Fa\u003E, Humanitas Research Hospital, Italy\u003Cbr\u003E\r\n\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F1030452\u002Foverview\"\u003EKenneth Williams\u003C\u002Fa\u003E, Boston College, United States\u003C\u002Fdiv\u003E\r\n\u003Cp\u003E\u003Cspan\u003ECopyright\u003C\u002Fspan\u003E © 2020 Gómez-Rial, Currás-Tuala, Rivero-Calle, Gómez-Carballa, Cebey-López, Rodríguez-Tenreiro, Dacosta-Urbieta, Rivero-Velasco, Rodríguez-Núñez, Trastoy-Pena, Rodríguez-García, Salas and Martinón-Torres. This is an open-access article distributed under the terms of the \u003Ca rel=\"license\" href=\"http:\u002F\u002Fcreativecommons.org\u002Flicenses\u002Fby\u002F4.0\u002F\" target=\"_blank\"\u003ECreative Commons Attribution License (CC BY)\u003C\u002Fa\u003E. 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.\u003C\u002Fp\u003E\r\n\u003Cp\u003E\u003Cspan\u003E*Correspondence:\u003C\u002Fspan\u003E Jose Gómez-Rial, \u003Ca id=\"encmail\"\u003Eam9zZS5nb21lei5yaWFsQHNlcmdhcy5lcw==\u003C\u002Fa\u003E; Federico Martinón-Torres, \u003Ca id=\"encmail\"\u003EZmVkZXJpY28ubWFydGlub24udG9ycmVzQHNlcmdhcy5lcw==\u003C\u002Fa\u003E\u003C\u002Fp\u003E\r\n\u003Cp\u003E\u003Csup\u003E†\u003C\u002Fsup\u003EThese authors have contributed equally to this work\u003C\u002Fp\u003E\r\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\r\n\u003C\u002Fdiv\u003E",menuHtml:"\u003Cul class=\"flyoutJournal\"\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h1\"\u003EAbstract\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h2\"\u003EIntroduction\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h3\"\u003EMaterials and Methods\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h4\"\u003EResults\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h5\"\u003EDiscussion\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h6\"\u003EData Availability Statement\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h7\"\u003EEthics Statement\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h8\"\u003EAuthor Contributions\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#fun1\"\u003EFunding\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#conf1\"\u003EConflict of Interest\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#ack1\"\u003EAcknowledgments\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#refer1\"\u003EReferences\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003C\u002Ful\u003E\r\n"},files:[{name:"EPUB.epub",fileServerPackageEntryId:e,type:{code:aE,name:aE}},{name:aF,fileServerPackageEntryId:"fimmu-11-560381\u002Ffimmu-11-560381.pdf",type:{code:u,name:u}},{name:aF,fileServerPackageEntryId:e,type:{code:u,name:u}},{name:"fimmu-11-560381.xml",fileServerPackageEntryId:"fimmu-11-560381\u002Ffimmu-11-560381.xml",type:{code:"NLM_XML",name:"XML"}},{name:"Provisional PDF.pdf",fileServerPackageEntryId:e,type:{code:u,name:u}}]},currentArticlePageMetaInfo:{title:aG,link:[{rel:"canonical",href:aH}],meta:[{hid:B,property:B,name:B,content:aI},{hid:aJ,property:aJ,name:"title",content:aG},{hid:aK,property:aK,name:B,content:aI},{hid:aL,name:aL,content:"COVID- 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Immunol.","1664-3224",void 0,"Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology",18,"Translational Pediatrics and Infectious Diseases Section, Department of Pediatrics, Hospital Cl矛nico Universitario de Santiago de Compostela",11,1920,"por-journal.com",7,"escubed.org",1918,"fipp","https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002FB8A9338D-D05F-42BE-A5B9BE8019A37824\u002Fwebimage-78EBA97D-B178-435E-B00557EE47446315.png","22C10171-81B3-4DA6-99342F272A32E8BB","jpg","2022-06-27T09:59:56Z","fimmu",35,"journal_field","10.3389\u002Ffimmu.2020.560381","\u003Csec\u003E\u003Ctitle\u003EBackground\u003C\u002Ftitle\u003E\u003Cp\u003EEmerging evidence indicates a potential role for monocytes in COVID-19 immunopathology. We investigated two soluble markers of monocyte activation, sCD14 and sCD163, in COVID-19 patients, with the aim of characterizing their potential role in monocyte-macrophage disease immunopathology. To the best of our knowledge, this is the first study of its kind.\u003C\u002Fp\u003E\u003C\u002Fsec\u003E\u003Csec\u003E\u003Ctitle\u003EMethods\u003C\u002Ftitle\u003E\u003Cp\u003EFifty-nine SARS-Cov-2 positive hospitalized patients, classified according to ICU or non-ICU admission requirement, were prospectively recruited and analyzed by ELISA for levels of sCD14 and sCD163, along with other laboratory parameters, and compared to a healthy control group.\u003C\u002Fp\u003E\u003C\u002Fsec\u003E\u003Csec\u003E\u003Ctitle\u003EResults\u003C\u002Ftitle\u003E\u003Cp\u003EsCD14 and sCD163 levels were significantly higher among COVID-19 patients, independently of ICU admission requirement, compared to the control group. We found a significant correlation between sCD14 levels and other inflammatory markers, particularly Interleukin-6, in the non-ICU patients group. sCD163 showed a moderate positive correlation with the time lapsed from admission to sampling, independently of severity group. Treatment with corticoids showed an interference with sCD14 levels, whereas hydroxychloroquine and tocilizumab did not.\u003C\u002Fp\u003E\u003C\u002Fsec\u003E\u003Csec\u003E\u003Ctitle\u003EConclusions\u003C\u002Ftitle\u003E\u003Cp\u003EMonocyte-macrophage activation markers are increased and correlate with other inflammatory markers in SARS-Cov-2 infection, in association to hospital admission. These data suggest a preponderant role for monocyte-macrophage activation in the development of immunopathology of COVID-19 patients.\u003C\u002Fp\u003E\u003C\u002Fsec\u003E",971915,"Jose","Maria Jos茅","Irene","Alberto","Unidade de Xen茅tica, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, and GenPoB Research Group, Instituto de Investigaci贸n Sanitaria (IDIS), Hospital Cl矛nico Universitario de Santiago, Servizo Galego de Sa煤de","Miriam","Ana","Nuria","Rocio","Javier",1021428,"Antonio",58621,"Federico",83435,"ANNALISA","Italy",405495,"Angela",1030452,"Kenneth",{},531,"Cytokines and Soluble Mediators in Immunity","cytokines-and-soluble-mediators-in-immunity","EPUB","fimmu-11-560381.pdf","Frontiers | Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology","https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fimmunology\u002Farticles\u002F10.3389\u002Ffimmu.2020.560381\u002Ffull","BackgroundEmerging evidence indicates a potential role for monocytes in COVID-19 immunopathology. We investigated two soluble markers of monocyte activation,...","og:title","og:description","keywords","og:site_name","og:image","og:type","og:url","twitter:card","citation_volume","citation_journal_title","citation_publisher","citation_journal_abbrev","citation_issn","citation_doi","citation_firstpage","citation_language","citation_title","citation_keywords","citation_abstract","citation_pdf_url","citation_online_date","citation_publication_date","dc.identifier","articles","editors","research-topics","https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F0B4B1380-42EB-4FD5-9D7E2DBC603E79F8\u002Fwebimage-C4875379-1478-416F-B03DF68FE3D8DBB5.png","Man ultramarathon runner in the mountains he trains at sunset","How we publish","https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fhow-we-publish","Fee policy","https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Ffee-policy","Research Topics","https:\u002F\u002Fforum.frontiersin.org\u002F","Career opportunities","https:\u002F\u002Fcareers.frontiersin.org\u002F","https:\u002F\u002Fwww.frontiersin.org\u002Fabout\u002Fcontact","inflammation","Author guidelines","Editor guidelines","https:\u002F\u002Fwww.frontiersin.org\u002Fjournals","https:\u002F\u002Fwww.frontiersin.org\u002Farticles","Articles","https:\u002F\u002Fhelpcenter.frontiersin.org","Frontiers for Young Minds","Frontiers Facebook",9,"Transplant International","transplant-international","ti",1921,"Spanish Journal of Soil Science","spanish-journal-of-soil-science","sjss","ebm-journal.org","Public Health Reviews","public-health-reviews","phrs","Pathology and Oncology Research","pathology-and-oncology-research","pore",21,"Pastoralism: Research, Policy and Practice","pastoralism-research-policy-and-practice","past","Oncology Reviews","oncology-reviews","or","Journal of Pharmacy & Pharmaceutical Sciences","journal-of-pharmacy-pharmaceutical-sciences","jpps","Journal of Cutaneous Immunology and Allergy","journal-of-cutaneous-immunology-and-allergy","JCIA","Journal of Abdominal Wall Surgery","journal-of-abdominal-wall-surgery","jaws",1919,"International Journal of Public Health","international-journal-of-public-health","ijph","Frontiers in Pathology","pathology","fpath",13,12,17,6,"Experimental Biology and Medicine","experimental-biology-and-medicine","EBM","European Journal of Cultural Management and Policy","european-journal-of-cultural-management-and-policy","ejcmp","Earth Science, Systems and Society","earth-science-systems-and-society","esss","Dystonia","dystonia","dyst","British Journal of Biomedical Science","british-journal-of-biomedical-science","bjbs","Aerospace Research Communications","aerospace-research-communications","arc","Advances in Drug and Alcohol Research","advances-in-drug-and-alcohol-research","adar","Acta Virologica","acta-virologica","av","Acta Biochimica Polonica","acta-biochimica-polonica"));</script><script src="/article-pages/_nuxt/75f1046.js" defer></script><script src="/article-pages/_nuxt/a5e7651.js" defer></script><script src="/article-pages/_nuxt/f548f7f.js" defer></script><script src="/article-pages/_nuxt/e3c5a8f.js" defer></script><script src="/article-pages/_nuxt/d89174d.js" defer></script><script src="/article-pages/_nuxt/ed7fc59.js" defer></script><script src="/article-pages/_nuxt/2abb6c5.js" defer></script><script src="/article-pages/_nuxt/701e3a3.js" defer></script><script src="/article-pages/_nuxt/c9b2266.js" defer></script><script data-n-head="ssr" src="https://cdnjs.cloudflare.com/polyfill/v3/polyfill.min.js?features=es6" data-body="true" async></script><script data-n-head="ssr" src="https://cdnjs.cloudflare.com/ajax/libs/mathjax/2.7.1/MathJax.js?config=TeX-MML-AM_CHTML" data-body="true" async></script><script data-n-head="ssr" src="https://d1bxh8uas1mnw7.cloudfront.net/assets/altmetric_badges-f0bc9b243ff5677d05460c1eb71834ca998946d764eb3bc244ab4b18ba50d21e.js" data-body="true" async></script><script data-n-head="ssr" src="https://api.altmetric.com/v1/doi/10.3389/fimmu.2020.560381?callback=_altmetric.embed_callback&domain=www.frontiersin.org&key=3c130976ca2b8f2e88f8377633751ba1&cache_until=14-15" data-body="true" async></script><script data-n-head="ssr" src="https://crossmark-cdn.crossref.org/widget/v2.0/widget.js" data-body="true" async></script> </body> </html>