Effect of vitamin D3 on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19

array:21 ["pii" => "S1807593224001510" "issn" => "18075932" "doi" => "10.1016/j.clinsp.2024.100474" "estado" => "S250" "fechaPublicacion" => "2024-01-01" "aid" => "100474" "copyrightAnyo" => "2024" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:17 [ "pii" => "S1807593224001509" "issn" => "18075932" "doi" => "10.1016/j.clinsp.2024.100473" "estado" => "S250" "fechaPublicacion" => "2024-01-01" "aid" => "100473" "copyright" => "HCFMUSP" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "Original articles" "titulo" => "COVID-19 and myocardial injury: Targeting elevated biomarkers for potential novel therapies" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "en" ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0001" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1173 "Ancho" => 2500 "Tamanyo" => 107143 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0001" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "An analysis of Veterans admitted through the Emergency Room at the Richmond VA Medical Center in 2021 shows that 10 % of the individuals with myocardial injury and a non-ACS diagnosis had COVID-19 as the primary diagnosis, with a poor outcome at a median of 6-months following hospital discharge. CHF, Other diagnoses included Congestive Heart Failure; COPD or Pneumonia, Pulmonary; GI, Gastrointestinal from bleeding, renal failure or other non-specific diagnoses." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Pengyang Li, Qun Chen, Ion S. Jovin, Anit Mankad, Jose F. Huizar, John D. Markley, Bradley Bart, Brack Hattler, Edward Lesnefsky, Edward O. McFalls" "autores" => array:10 [ 0 => array:2 [ "nombre" => "Pengyang" "apellidos" => "Li" ] 1 => array:2 [ "nombre" => "Qun" "apellidos" => "Chen" ] 2 => array:2 [ "nombre" => "Ion S." "apellidos" => "Jovin" ] 3 => array:2 [ "nombre" => "Anit" "apellidos" => "Mankad" ] 4 => array:2 [ "nombre" => "Jose F." "apellidos" => "Huizar" ] 5 => array:2 [ "nombre" => "John D." "apellidos" => "Markley" ] 6 => array:2 [ "nombre" => "Bradley" "apellidos" => "Bart" ] 7 => array:2 [ "nombre" => "Brack" "apellidos" => "Hattler" ] 8 => array:2 [ "nombre" => "Edward" "apellidos" => "Lesnefsky" ] 9 => array:2 [ "nombre" => "Edward O." "apellidos" => "McFalls" ] ] ] ] "resumen" => array:1 [ 0 => array:3 [ "titulo" => "Highlights" "clase" => "author-highlights" "resumen" => "<ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001">•During the COVID-19 pandemic, the prevalence of COVID-19 as the primary diagnosis for hospitalized patients with myocardial injury was 10 %.</li><li class="elsevierStyleListItem" id="celistitem0002">••The mortality at 6 months was more than 40 % and independent predictors of death included age, peak troponin, and peak C-reactive protein levels.</li><li class="elsevierStyleListItem" id="celistitem0003">•Future studies should focus on targeting elevated oxidant stress and inflammatory biomarkers among these patients.</li></ul>" ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593224001509?idApp=UINPBA00004N" "url" => "/18075932/000000790000000C/v115_202410170932/S1807593224001509/v115_202410170932/en/main.assets" ] "itemAnterior" => array:17 [ "pii" => "S1807593224001443" "issn" => "18075932" "doi" => "10.1016/j.clinsp.2024.100467" "estado" => "S250" "fechaPublicacion" => "2024-01-01" "aid" => "100467" "copyright" => "HCFMUSP" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "Original articles" "titulo" => "Clinical application of pulse-gated non-enhanced rapid magnetic resonance imaging in the definitive diagnosis of aortic dissection" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "en" ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0001" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1619 "Ancho" => 1433 "Tamanyo" => 176017 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0006" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "CNR image, SNR measurement." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "QinWen Yan, Gang Hu, Qin Wang, Lei Wu, Jun Zhang, Lan He, CiLai Jiao, Si Ma, MinChao Xiong" "autores" => array:9 [ 0 => array:2 [ "nombre" => "QinWen" "apellidos" => "Yan" ] 1 => array:2 [ "nombre" => "Gang" "apellidos" => "Hu" ] 2 => array:2 [ "nombre" => "Qin" "apellidos" => "Wang" ] 3 => array:2 [ "nombre" => "Lei" "apellidos" => "Wu" ] 4 => array:2 [ "nombre" => "Jun" "apellidos" => "Zhang" ] 5 => array:2 [ "nombre" => "Lan" "apellidos" => "He" ] 6 => array:2 [ "nombre" => "CiLai" "apellidos" => "Jiao" ] 7 => array:2 [ "nombre" => "Si" "apellidos" => "Ma" ] 8 => array:2 [ "nombre" => "MinChao" "apellidos" => "Xiong" ] ] ] ] "resumen" => array:1 [ 0 => array:3 [ "titulo" => "Highlights" "clase" => "author-highlights" "resumen" => "<ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001">•Free breathing pulse gated non-enhanced rapid MR imaging can obtain images with diagnostic value.</li><li class="elsevierStyleListItem" id="celistitem0002">•Multi-plane and multi-angle thin-layer scanning are favorable for the display of the rupture, while some complex tears and bidirectional tears are poorly displayed.</li><li class="elsevierStyleListItem" id="celistitem0003">•Free breathing pulse gated non-enhanced rapid MR imaging technique can be used for the exclusive and definitive diagnosis of aortic dissection.</li><li class="elsevierStyleListItem" id="celistitem0004">•Non-enhancement peripheral pulse-gating rapid magnetic resonance imaging can be used for deterministic diagnosis of aortic dissection.</li></ul>" ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593224001443?idApp=UINPBA00004N" "url" => "/18075932/000000790000000C/v115_202410170932/S1807593224001443/v115_202410170932/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original articles" "titulo" => "Effect of vitamin D3 on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19" "tieneTextoCompleto" => true "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Lucas P. Sales, Lucas V.B. Souza, Alan L. Fernandes, Igor H. Murai, Mayara D. Santos, Margarete B.G. Vendramini, Ricardo M. Oliveira, Camille P. Figueiredo, Valéria F. Caparbo, Bruno Gualano, Rosa M.R. Pereira" "autores" => array:12 [ 0 => array:3 [ "nombre" => "Lucas P." "apellidos" => "Sales" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0001" ] ] ] 1 => array:3 [ "nombre" => "Lucas V.B." "apellidos" => "Souza" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0001" ] ] ] 2 => array:3 [ "nombre" => "Alan L." "apellidos" => "Fernandes" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0001" ] ] ] 3 => array:3 [ "nombre" => "Igor H." "apellidos" => "Murai" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0001" ] ] ] 4 => array:3 [ "nombre" => "Mayara D." "apellidos" => "Santos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0001" ] ] ] 5 => array:3 [ "nombre" => "Margarete B.G." "apellidos" => "Vendramini" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0001" ] ] ] 6 => array:3 [ "nombre" => "Ricardo M." "apellidos" => "Oliveira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0002" ] ] ] 7 => array:3 [ "nombre" => "Camille P." "apellidos" => "Figueiredo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0001" ] ] ] 8 => array:3 [ "nombre" => "Valéria F." "apellidos" => "Caparbo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0001" ] ] ] 9 => array:4 [ "nombre" => "Bruno" "apellidos" => "Gualano" "email" => array:1 [ 0 => "gualano@usp.br" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0001" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0001" ] ] ] 10 => array:3 [ "nombre" => "Rosa M.R." "apellidos" => "Pereira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0001" ] ] ] 11 => array:1 [ "colaborador" => "in memoriam" ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil" "etiqueta" => "a" "identificador" => "aff0001" ] 1 => array:3 [ "entidad" => "RDO Diagnósticos Médicos, São Paulo, SP, Brazil" "etiqueta" => "b" "identificador" => "aff0002" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0001" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0001" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 4250 "Ancho" => 2818 "Tamanyo" => 683457 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0003" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Trial CONSORT diagram." ] ] ] "textoCompleto" => "IntroductionSince the beginning of the Coronavirus Disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a possible relationship between the infection and autoimmune reactions has been hypothesized.<a class="elsevierStyleCrossRef" href="#bib0001">1</a> In addition to the most common clinical manifestations (i.e., fever, cough, and dyspnea), the presence of myalgia, joint pain (arthralgia), and thrombotic events was recurrent in hospitalized patients.<a class="elsevierStyleCrossRefs" href="#bib0002">2-4</a> One of the explanations is the fact that SARS-CoV-2 infection affects regulatory T-cell levels, aggravating inflammatory processes that may lead to autoimmunity.<a class="elsevierStyleCrossRef" href="#bib0005">5</a>In this context, Zhang et al.<a class="elsevierStyleCrossRef" href="#bib0006">6</a> described three cases of thrombosis associated with both Antiphospholipid (aPL) antibodies, Anticardiolipin (aCL), and anti–β2-Glycoprotein-I (aβ2-GP). These antibodies target phospholipid-binding proteins and phospholipids in cell membranes, leading to a hypercoagulable state through interference with the coagulation cascade, activation of endothelial cells and platelets, and inhibition of natural anticoagulant pathways.<a class="elsevierStyleCrossRef" href="#bib0007">7</a>Pascolini et al.<a class="elsevierStyleCrossRef" href="#bib0008">8</a> showed that the frequency of autoantibody positivity in the COVID-19 group was significantly higher than in the control group (45 % vs. 12 %; p = 0.03). The subgroup of patients testing positive for autoantibodies exhibited higher lactate levels and a poorer prognosis compared to the subgroup testing negative. The mortality rate due to COVID-19 complications was significantly higher in the autoantibody-positive subgroup compared to the negative subgroup (40 % vs. 5.5 %; p = 0.03).The role of vitamin D3 supplementation in autoimmunity has been extensively investigated. In addition to influencing viral neutralization, recruitment of immune system cells and dendritic cell maturation,<a class="elsevierStyleCrossRef" href="#bib0009">9</a>,<a class="elsevierStyleCrossRef" href="#bib0010">10</a> vitamin D3 acts on lymphocytes T and B proliferation, immune cells that participate in antibody production.<a class="elsevierStyleCrossRef" href="#bib0011">11</a>,<a class="elsevierStyleCrossRef" href="#bib0012">12</a> For instance, Najafipoor et al.<a class="elsevierStyleCrossRef" href="#bib0013">13</a> demonstrated that patients who received 50,000 IU of vitamin D3 per week for 6 months, in addition to interferon therapy, presented lower increases in IgG levels against Epstein-Barr virus 1 and viral capsid antigen compared to the control group, who only received disease-modifying interferon therapy alone. These findings align with previous evidence on the importance of adequate serum levels of vitamin D to reduce disease activity and remission, and to enhance responsiveness to rheumatoid arthritis treatment.<a class="elsevierStyleCrossRef" href="#bib0014">14</a>Altogether, these findings suggest that vitamin D deficiency could act as an environmental trigger contributing to B-cell hyperactivation, which could culminate in increased autoantibody production.<a class="elsevierStyleCrossRef" href="#bib0010">10</a>,<a class="elsevierStyleCrossRefs" href="#bib0015">15-17</a> Although numerous clinical trials worldwide have investigated the impact of vitamin D3 on COVID-19 outcomes,<a class="elsevierStyleCrossRefs" href="#bib0017">17-21</a> the role of vitamin D3 on aPL antibodies remains poorly understood. To fill this gap, the present exploratory study aimed to assess the effect of a single oral dose of 200,000 IU of vitamin D3 on aPL antibodies in hospitalized patients with moderate to severe COVID-19.MethodsStudy designThis is a post-hoc, exploratory analysis from a double-blind, placebo-controlled, randomized clinical trial performed in two centers in Sao Paulo, Brazil, and registered in ClinicalTrials.gov, NCT04449718. This study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of both centers: Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo and Hospital de Campo do Ibirapuera (Ethics Committee Approval Number 30959620.4.1001.0068). Before being admitted to the study, all patients provided written informed consent. This manuscript was reported according to the CONSORT guidelines. Additional information about the trial concept and design, patient recruitment, supplementation protocol and blindness, procedures, and endpoints has been previously published.<a class="elsevierStyleCrossRef" href="#bib0022">22</a>ParticipantsPatients were recruited from both hospitals from June 2, 2020 to August 27, 2020. The end of follow-up was on October 7, 2020. Inclusion criteria were age ≥ 18 years; confirmed diagnosis of COVID-19 by polymerase chain reaction testing for SARS-CoV-2 from nasopharyngeal swabs, or computed tomography scan findings consistent with those found in COVID-19 (bilateral multifocal ground-glass opacities ≥ 50 %); and flu syndrome with institutional criteria for hospitalization on hospital admission (respiratory rate > 24 breaths/minute, oxygen saturation < 93 % on room air, or the presence of risk factors for complications (e.g., obesity, diabetes, systemic arterial hypertension, neoplasms, immunosuppression, heart disease, pulmonary tuberculosis), followed by COVID-19 confirmation. Patients who met these criteria were considered to have moderate to severe COVID-19 according to the criteria from the NIH-COVID-19 Treatment Guidelines.<a class="elsevierStyleCrossRef" href="#bib0023">23</a>Patients were excluded if they were unable to read and sign the written informed consent form; were already under invasive mechanical ventilation; received prior vitamin D3 supplementation (> 1000 IU/d or weekly equivalent); had kidney failure requiring dialysis or creatinine > 2.0 mg/dL or hypercalcemia (calcium > 10.5 mg/dL); were pregnant or lactating women; were expecting to be discharged within 24 h. Absence of fever in the previous 72 h, no need for supplemental oxygen in the previous 48 h, and oxygen saturation greater than 93 % on room air without respiratory distress were used as criteria for hospital discharge.Randomization and maskingPatients were allocated in a 1:1 ratio into the vitamin D3 or placebo groups as previously described.<a class="elsevierStyleCrossRef" href="#bib0022">22</a> Patients enrolled in the vitamin D3 group received a single oral dose of 200,000 IU of vitamin D3 diluted in vehicle (10 mL of a peanut oil solution) immediately after randomization, while those in the placebo group received only vehicle. Both solutions were prepared by the same unit (pharmacy of Hospital das Clínicas) and were identical in appearance, color, smell, and taste. This selected dose is within the recommended dose range for effectively promoting vitamin D sufficiency.<a class="elsevierStyleCrossRef" href="#bib0024">24</a>ProceduresBaseline demographic, self-reported anthropometric (weight and height), and clinical characteristics (coexisting chronic diseases, acute COVID-19 symptoms, patients’ medications throughout hospitalization, oxygen supplementation requirement, and imaging features) were collected upon hospital admission. Serum levels of 25-hydroxyvitamin D were assessed by chemiluminescent immunoassay (ARCHITECT 25-OH Vitamin D 5P02; Abbott Diagnostics). The frequency of thrombotic events during hospitalization was assessed through electronic medical records. The presence and titers of aCL antibodies (IgG, IgM and IgA) were analyzed through commercial fluoro immunoenzymatic assay (Thermo Scientific™/Phadia™ 250 Immunoassay Analyzers). The aβ2-GP antibodies (IgG, IgM and IgA) were detected by ELISA using a commercial kit (Quanta Lite®, Inova Diagnostics Ins., San Diego, CA, USA). Only patients who had blood samples collected on the day of randomization and on hospital discharge were included in this study. Patients who died throughout follow-up were not included due to the absence of blood samples.Outcome measuresHerein, it was reported on the following post hoc exploratory outcomes: presence and titers of aPL antibodies: aCL (IgG, IgM and IgA) and aβ2-GP (IgG, IgM and IgA).Statistical analysisThe sample size was chosen based on feasibility and resources, as previously described.<a class="elsevierStyleCrossRef" href="#bib0022">22</a> Independent t-test and Mann-Whitney U test were used for continuous variables. Proportions were analyzed by chi-square or Fisher's exact test. Generalized Estimating Equations (GEE) for repeated measures were used for testing possible differences in serum presence and titers of autoantibodies assuming group and time as fixed factors, with marginal and binomial distributions, and a first-order autoregressive correlation matrix to test the main and interaction effects. Bonferroni's adjustment was performed in GEE analyses to maintain a family-wise two-sided significance threshold of 0.05, considering 6 pairwise comparisons for all outcomes. All analyses were performed by a per-protocol approach with no imputation for missing, data using IBM-SPSS software, version 20.0. The significance level was set at a two-sided p-value ≤ 0.05.ResultsA total of 1240 patients were screened for eligibility; however, only 240 were randomized during the acute-phase of SARS-CoV-2 infection, with 120 being assigned to each group. Three patients withdrew their informed consent. Of the 119 patients who were randomized to the vitamin D3 group, 13 (11 %) were excluded due to insufficient blood samples, and 9 (7 %) died throughout the follow-up. From 118 patients who were randomized to the placebo group, 15 (13 %) were excluded due to insufficient blood samples, and 6 (5 %) died throughout the follow-up (<a class="elsevierStyleCrossRef" href="#fig0001">Fig. 1</a>).<elsevierMultimedia ident="fig0001"></elsevierMultimedia>The mean (SD) age was 55.3 (13.9) years, Body Mass Index (BMI) was 32.2 (7.1) kg/m2, 106 (54.6 %) patients were male, 108 (55.7 %) were white, and 175 (90.2 %) required respiratory support at baseline. No significant differences between groups were found at baseline (<a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>).<elsevierMultimedia ident="tbl0001"></elsevierMultimedia>In the vitamin D group, 84 patients (87 %) exhibited moderate disease, whereas 13 patients (13 %) had severe disease. In the placebo group, 86 patients (89 %) had moderate disease, while 11 patients (11 %) had severe disease.As expected, mean (SD) 25-hydroxyvitamin-D was significantly increased from baseline to discharge after a single oral dose of 200,000 UI of vitamin D3 [from 21.1 (9.9) ng/mL to 44.5 (15.0) ng/mL] compared to placebo [from 20.0 (8.2) ng/mL to 19.5 (10.6) ng/mL] [significant group by time interaction (p < 0.001)]. No significant difference between vitamin D3 [3 (3.1 %)] and placebo [4 (4.1 %)] groups was observed in the frequency of thrombotic events (p = 0.700).One hundred nine (66.5 %) patients tested positive for at least one type of aPL antibody. There was a significant group by time interaction (p = 0.046) for the frequency of aCL (IgG), with values increasing from baseline to discharge in the placebo group [from 13 (13.4 %) to 25 (25.8 %), p = 0.004], while frequency of aCL (IgG) in vitamin D3 group remained similar [from 25 (25.8 %) to 29 (29.9 %), p = 1.00], after Bonferroni's adjustment. However, the frequency of aCL (IgG) did not change between the groups on discharge. No significant differences between vitamin D3 and placebo groups were found for titers and frequency of aCL (IgM and IgA) and aβ2-GP (IgG, IgM and IgA) antibodies (<a class="elsevierStyleCrossRef" href="#tbl0002">Table 2</a>).<elsevierMultimedia ident="tbl0002"></elsevierMultimedia>DiscussionTo the best of our knowledge, this is the first double-blind, placebo-controlled, randomized clinical trial investigating the influence of 200,000 IU of vitamin D3 on aPL antibodies among hospitalized patients with moderate to severe COVID-19. Overall, no significant differences between vitamin D3 and placebo groups were found for any autoantibodies upon hospital discharge.Antiphospholipid antibodies, such as aCL, aβ2-GP, and lupus anticoagulant, belong to a heterogeneous group of antibodies associated with Antiphospholipid Antibodies Syndrome (APS), a thrombosis-related systemic autoimmune disease affecting arteries, veins, and small blood vessels.<a class="elsevierStyleCrossRef" href="#bib0025">25</a> It has been shown the presence of these antibodies in some viral infections,<a class="elsevierStyleCrossRefs" href="#bib0026">26-29</a> among which COVID-19<a class="elsevierStyleCrossRef" href="#bib0006">6</a> stands out, with a prevalence of aPL antibodies ranging from 3.7 % to 88.0 % in previous studies.<a class="elsevierStyleCrossRefs" href="#bib0030">30-33</a> Similarly, herein the authors found that 66.5 % (129/194) of the patients showed at least one type of aPL antibody.The immunomodulatory role of vitamin D appears to involve antigen-presenting cells, such as dendritic cells and macrophages, expressing a nuclear Vitamin D Receptor (VDR), a member of the nuclear receptor superfamily of transcriptional regulators involved in 1-alfa,25-dihidroxicolecalciferol signaling.<a class="elsevierStyleCrossRef" href="#bib0034">34</a> However, the mechanisms underlying the inhibitory effects of vitamin D on antibody production are not fully understood. In part, this event could be explained by the regulatory effect of vitamin D on B-cells related to immune tolerance. Vitamin D sufficiency would act in the proliferation and apoptosis of activated B-cells, which are closely related to antibody production,<a class="elsevierStyleCrossRefs" href="#bib0035">35-37</a> while vitamin D deficiency would play the opposite effect, increasing the production of autoantibodies through the activation of B-cells.<a class="elsevierStyleCrossRef" href="#bib0037">37</a>,<a class="elsevierStyleCrossRef" href="#bib0038">38</a>Riancho-Zarrabeitia et al.<a class="elsevierStyleCrossRef" href="#bib0039">39</a> demonstrated an association between circulating vitamin D insufficiency (between 10 and 30 ng/mL) and the presence of lupus anticoagulant, an aPL antibody. When evaluating only patients with aPL antibodies syndrome, they showed an association between vitamin D insufficiency and higher frequency of anti-β2-glycoprotein-I, but not aCL.<a class="elsevierStyleCrossRef" href="#bib0039">39</a>Another study assessed the effect of 50,000 IU of vitamin D in patients with Hashimoto's thyroiditis, a condition also characterized by autoimmune inflammation. Participants received the supplement weekly for three months and had a significant reduction in serum thyroid autoantibodies levels compared to baseline.<a class="elsevierStyleCrossRef" href="#bib0040">40</a> Accordingly, an in vitro study<a class="elsevierStyleCrossRef" href="#bib0041">41</a> showed that the 1,25-dihydroxyvitamin-D modestly reduced autoantibody production in peripheral blood mononuclear cells of disease-active systemic lupus erythematosus.In patients with COVID-19, the presence of aPL antibodies has been suggested as one of the physiopathologic mechanisms for the cause of hypercoagulation and thrombotic events.<a class="elsevierStyleCrossRef" href="#bib0006">6</a>,<a class="elsevierStyleCrossRef" href="#bib0042">42</a> In addition to promoting platelet aggregation and activation, aPL antibodies promote the upregulation of pro-inflammatory cytokines, cell adhesion molecules, and endothelial nitric oxide synthase that induce a pro-inflammatory and pro-coagulant endothelial phenotype.<a class="elsevierStyleCrossRef" href="#bib0043">43</a>Notwithstanding, controversial results exist. In a prospective single-center observational study, patients with positive aPL antibodies did not have an increased risk of thrombosis risk during intensive care unit hospitalization.<a class="elsevierStyleCrossRef" href="#bib0032">32</a> Additionally, Borghi et al.<a class="elsevierStyleCrossRef" href="#bib0044">44</a> did not observe a significant correlation between the presence of aβ2-GP IgG and thrombosis, suggesting that aPL antibodies in COVID-19 may be different from those detectable in APS.<a class="elsevierStyleCrossRef" href="#bib0044">44</a> Accordingly, the patients with aPL antibodies did not experience a high number of thrombotic events during hospitalization (4/133; p = 0.680), with no differences noted between the groups (p = 0.700). It is important to note that the presence of aCL in the present study was not significantly different between groups at discharge.These conflicting results might be due to the fact that most of aPL antibodies associated with the virus are thought to be transient in patients with critical illness,<a class="elsevierStyleCrossRef" href="#bib0045">45</a>,<a class="elsevierStyleCrossRef" href="#bib0046">46</a> so it is unclear whether either they represent a simple epiphenomenon or are actually involved in COVID-19-associated coagulopathy.<a class="elsevierStyleCrossRef" href="#bib0047">47</a> In a study in which aPL testing was repeated 1 month after COVID-19 aPL-positive patients were admitted to the intensive care, aPL antibodies were primarily a transient phenomenon that occurred during the acute phase.<a class="elsevierStyleCrossRef" href="#bib0048">48</a> Another confounded factor is that most patients were under anticoagulant medication, a drug that is related to the prevention of thrombotic events.This study has some strengths, such as the comprehensive assessment of antibodies related to autoimmune diseases, the randomized, controlled, double-blinded design, and the enrollment of hospitalized patients with moderate to severe COVID-19. Also, these findings increase the knowledge on the role of vitamin D3 on aPL antibodies and better inform health professionals on more efficient healthcare delivery and resource management.However, there are several limitations. First, the relatively small sample size could increase the chances of type 2 error. Second, the heterogeneity in pre-existing diseases and treatments of the patients, although no significant differences were observed between groups at baseline. Third, the results may have been influenced by the high rate of patients using anticoagulants (∼90 %). Finally, the authors were unable to measure other aPL antibodies, such as lupus anticoagulant antibodies.In conclusion, these findings do not support the use of a single oral dose of 200,000 IU of vitamin D3 to modulate autoantibodies in hospitalized patients with moderate to severe COVID-19.Data availabilityDeidentified participant data of this study must be requested from the corresponding author upon publication (sent to gualano@usp.br). The codebook of this study will be made available upon request by qualified clinical researchers for specified purposes dependent on the nature of the request and the intentional use of the data, with investigator support. The request must include a statistician. The lead author (BG) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as originally planned (and, if relevant, registered) have been explained.Authors’ contributionsBG and RMRP: Had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis; LPS, LCVS and RMRP: Conceived and designed the study; LPS, LVBS, VFC and RMRP: Drafted the manuscript; LPS, ALF, BG, and RMRP: Performed statistical analysis; BG and RMRP: Provided supervision; LPS, MBGV, RMO, CPF and VFC: Provided administrative, technical, or material support; and all authors performed data acquisition, analysis, interpretation and critically revised the manuscript for important intellectual content. All authors read and approve the manuscript as submitted." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres2273684" "titulo" => "Highlights" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abss0001" ] ] ] 1 => array:3 [ "identificador" => "xres2273685" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abss0002" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abss0003" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abss0004" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abss0005" "titulo" => "Conclusion" ] ] ] 2 => array:2 [ "identificador" => "xpalclavsec1894946" "titulo" => "Keywords" ] 3 => array:2 [ "identificador" => "sec0001" "titulo" => "Introduction" ] 4 => array:3 [ "identificador" => "sec0002" "titulo" => "Methods" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0003" "titulo" => "Study design" ] 1 => array:2 [ "identificador" => "sec0004" "titulo" => "Participants" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Randomization and masking" ] 3 => array:2 [ "identificador" => "sec0006" "titulo" => "Procedures" ] 4 => array:2 [ "identificador" => "sec0007" "titulo" => "Outcome measures" ] 5 => array:2 [ "identificador" => "sec0008" "titulo" => "Statistical analysis" ] ] ] 5 => array:2 [ "identificador" => "sec0009" "titulo" => "Results" ] 6 => array:2 [ "identificador" => "sec0010" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0011" "titulo" => "Data availability" ] 8 => array:2 [ "identificador" => "sec0012" "titulo" => "Authors’ contributions" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-08-15" "fechaAceptado" => "2024-07-21" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1894946" "palabras" => array:5 [ 0 => "COVID-19" 1 => "SARS-CoV-2 Infection" 2 => "Vitamin D" 3 => "Antiphospholipid Antibodies Syndrome" 4 => "Antiphospholipid Antibodies" ] ] ] ] "tieneResumen" => true "highlights" => array:2 [ "titulo" => "Highlights" "resumen" => "<ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001">•The impact of vitamin D3 supplementation on autoimmunity remains a subject of debate.</li><li class="elsevierStyleListItem" id="celistitem0002">•A single dose of 200,000 IU of vitamin D3 was not able to modulate autoantibodies in COVID-19 patients.</li><li class="elsevierStyleListItem" id="celistitem0003">•aPL antibody positivity was not associated with thrombotic events despite vitamin D3 supplementation.</li><li class="elsevierStyleListItem" id="celistitem0004">•aPL antibodies associated with the virus seem to be transient in critical patients.</li></ul>" ] "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectiveTo investigate the effect of a single oral dose of 200,000 IU of vitamin D3 on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19. MethodsThis is a post-hoc, exploratory analysis from a double-blind, placebo-controlled, randomized clinical trial performed in two centers in Sao Paulo, Brazil. Hospitalized patients with COVID-19 were randomly assigned to receive either vitamin D3 (n = 97) or placebo (n = 97). In this post-hoc analysis, the endpoints were titers and frequency of anti–β2-Glycoprotein-I (aβ2-GP) and Anticardiolipin (aCL) antibodies [Immunoglobulin G, M and A (IgG, IgM and IgA)]. ResultsOverall mean (SD) age was 55.3 (13.9) years, Body Mass Index (BMI) was 32.2 (7.1 kg/m2), and 106 participants (54.6 %) were male. There was a significant group by time interaction (p = 0.046) for frequency of aCL IgG, with increased values from baseline to discharge in the placebo group [n (%), from 13 (13.4) to 25 (25.8)] compared to the vitamin D3 [from 25 (25.8) to 29 (29.9)]. However, the frequency of aCL IgG did not change between the groups on discharge. No significant differences between vitamin D3 and placebo groups were found for any other autoantibodies. ConclusionThese findings do not support the use of a single oral dose of 200,000 IU of vitamin D3 to modulate autoantibodies in hospitalized patients with moderate to severe COVID-19." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abss0002" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abss0003" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abss0004" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abss0005" "titulo" => "Conclusion" ] ] ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "fig0001" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 4250 "Ancho" => 2818 "Tamanyo" => 683457 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0003" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Trial CONSORT diagram." ] ] 1 => array:8 [ "identificador" => "tbl0001" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0001" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "1Values are mean ± SD, median (IQR), or n (%). Continuous variables were analyzed by independent t-test. Percentages were analyzed by Chi-Square or Fisher's exact test.COVID-19, Coronavirus Disease 2019; BMI, Body Mass Index; ESR, Erythrocyte Sedimentation Rate." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0001"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristic \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0002"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Vitamin D3 group (n = 97) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0003"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Placebo group (n = 97) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0004"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Age, years \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0005"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">55.2 ± 13.8 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0006"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">55.4 ± 14.3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0007"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Sex, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0008"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0009"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0010"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0011"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">57 (58.8) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">49 (50.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0013"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0014"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">40 (41.2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0015"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">48 (49.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0016"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Race or ethnicity, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0017"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0018"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0019"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">White \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0020"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">49 (50.5) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0021"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">59 (60.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0022"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Pardo<a class="elsevierStyleCrossRef" href="#tb1fn1">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0023"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">31 (32.0) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0024"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">28 (28.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0025"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Black \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0026"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">16 (16.5) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0027"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">10 (10.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0028"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Asian \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0029"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">1 (1.0) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0030"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0031"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">BMI, kg/m2<a class="elsevierStyleCrossRef" href="#tb1fn2">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0032"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">32.3 ± 6.8 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0033"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">32.1 ± 7.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0034"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Time for hospital length of stay, days \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0035"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">6.0 (4.0-8.0) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0036"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">7.0 (6.0-10.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0037"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Concomitant medications, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0038"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0039"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0040"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Anticoagulant<a class="elsevierStyleCrossRef" href="#tb1fn3">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0041"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">90 (93.8) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0042"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">83 (85.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0043"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Antibiotic<a class="elsevierStyleCrossRef" href="#tb1fn3">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0044"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">81 (84.4) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0045"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">84 (86.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0046"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Glucocorticoid<a class="elsevierStyleCrossRef" href="#tb1fn3">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0047"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">65 (67.7) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0048"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">62 (63.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0049"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Antihypertensive<a class="elsevierStyleCrossRef" href="#tb1fn3">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0050"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">55 (57.3) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0051"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">43 (44.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0052"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Proton pump inhibitorc \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0053"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">40 (41.7) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0054"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">40 (41.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0055"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Antiemetic<a class="elsevierStyleCrossRef" href="#tb1fn3">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0056"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">38 (39.6) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0057"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">49 (50.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0058"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Analgesic<a class="elsevierStyleCrossRef" href="#tb1fn3">c</a>,<a class="elsevierStyleCrossRef" href="#tb1fn4">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0059"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">37 (38.5) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0060"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">45 (46.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0061"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Hypoglycemic<a class="elsevierStyleCrossRef" href="#tb1fn3">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0062"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">23 (24) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0063"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">20 (20.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0064"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Hypolipidemic<a class="elsevierStyleCrossRef" href="#tb1fn3">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0065"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">14 (14.6) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0066"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">14 (14.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0067"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Thyroid<a class="elsevierStyleCrossRef" href="#tb1fn3">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0068"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">8 (8.3) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0069"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">8 (8.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0070"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Antiviral<a class="elsevierStyleCrossRef" href="#tb1fn3">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0071"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">4 (4.2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0072"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">3 (3.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0073"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Acute COVID-19 symptoms, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0074"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0075"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0076"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Fever \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0077"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">70 (72.2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0078"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">68 (70.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0079"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Cough \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0080"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">83 (85.6) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0081"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">81 (83.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0082"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Fatigue \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0083"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">80 (82.5) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0084"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">84 (86.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0085"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Joint pain \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0086"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">40 (41.2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0087"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">33 (34) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0088"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Myalgia \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0089"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">60 (61.9) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0090"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">60 (61.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0091"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Nasal congestion \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0092"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">33 (34) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0093"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">33 (34) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0094"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Runny nose \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0095"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">34 (35.1) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0096"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">36 (37.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0097"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Sore throat \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0098"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">35 (36.1) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0099"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">23 (23.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0100"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Diarrhea \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0101"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">32 (33) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0102"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">40 (41.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0103"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Coexisting diseases, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0104"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0105"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0106"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Hypertension \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0107"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">53 (54.6) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0108"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">47 (48.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0109"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Cardiovascular disease \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0110"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">14 (14.4) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0111"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">12 (12.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0112"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Diabetes \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0113"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">39 (40.2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0114"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">28 (28.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0115"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Chronic obstructive pulmonary disease \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0116"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5 (5.2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0117"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5 (5.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0118"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Asthma \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0119"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">6 (6.2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0120"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">7 (7.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0121"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Obesity \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0122"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">56 (57.7) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0123"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">56 (58.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0124"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Rheumatic disease \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0125"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">10 (10.3) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0126"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">9 (9.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0127"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Chronic kidney disease \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0128"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">2 (2.1) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0129"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0130"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Respiratory support, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0131"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0132"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0133"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">No oxygen therapy \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0134"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">14 (14.4) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0135"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5 (5.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0136"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Oxygen therapy \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0137"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">70 (72.2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0138"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">81 (83.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0139"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Non-invasive ventilation \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0140"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">13 (13.4) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0141"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">11 (11.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0142"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Computed tomography findings, n (%)<a class="elsevierStyleCrossRef" href="#tb1fn5">e</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0143"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0144"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0145"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Ground-glass opacities < 50 % \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0146"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">38 (44.7) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0147"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">31 (38.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0148"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Ground-glass opacities ≥ 50 % \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0149"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">47 (55.3) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0150"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">50 (61.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0151"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Laboratory values<a class="elsevierStyleCrossRef" href="#tb1fn6">f</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0152"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0153"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0154"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Platelet, 103/µL \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0155"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">313 ± 114 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0156"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">299 ± 133 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0157"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Mean platelet volume, Fl \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0158"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">10.5 ± 0.4 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0159"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">10.7 ± 0.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0160"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">ESR, mm/h \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0161"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">56.0 (24.0‒86.0) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0162"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">61.0 (35.5‒88.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0163"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">C-reactive protein, mg/L \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0164"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">56.9 (22.3‒92.7) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0165"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">65.9 (28.8‒103.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0166"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">D-dimer, ng/mL \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0167"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">770.5 (558.0‒1497.0) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0168"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">840.0 (526.0‒1424.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3692415.png" ] ] ] "notaPie" => array:6 [ 0 => array:3 [ "identificador" => "tb1fn1" "etiqueta" => "a" "nota" => "Pardo is the exact term used in Brazilian Portuguese, meaning “mixed ethnicity”, according to the Brazilian Institute of Geography and Statistics." ] 1 => array:3 [ "identificador" => "tb1fn2" "etiqueta" => "b" "nota" => "BMI data was missing for 7.7 % of patients (n = 7 in the vitamin D3 group and n = 8 in the placebo group)." ] 2 => array:3 [ "identificador" => "tb1fn3" "etiqueta" => "c" "nota" => "Anticoagulant, antibiotic, glucocorticoid, antihypertensive, proton pump inhibitor, antiemetic, hypoglycemic, hypolipidemic, thyroid and antiviral data were missing for 0.5 % of patients (n = 1 in the vitamin D3 group)." ] 3 => array:3 [ "identificador" => "tb1fn4" "etiqueta" => "d" "nota" => "Analgesic data was missing for 1.0 % of patients (n = 1 in the vitamin D3 group and n = 1 in the placebo group)." ] 4 => array:3 [ "identificador" => "tb1fn5" "etiqueta" => "e" "nota" => "Computed tomography findings data were missing for 14.4 % of patients (n = 12 in the vitamin D3 group and n = 16 in the placebo group)." ] 5 => array:3 [ "identificador" => "tb1fn6" "etiqueta" => "f" "nota" => "Reference values: Platelet (150‒400/103/µL); Mean platelet volume (9.4‒12.4 Fl); ESR (≤ 15 mm/h); C-reactive protein (< 5 mg/L); D-dimer (< 500 ng/mL)." ] ] ] "descripcion" => array:1 [ "en" => "Baseline demographic and clinical characteristics." ] ] 2 => array:8 [ "identificador" => "tbl0002" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0002" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Data expressed as n (% within group) and median (IQR). Data were analyzed by Generalized Estimating Equations (GEE). aCL, Anticardiolipin; aβ2-GP, Anti-β2-Glycoprotein-I.No significant differences were observed between groups at baseline; p-value derives from unadjusted group by time interaction from F-test." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0169"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Outcomes</th><a name="en0170"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Vitamin D3 group (n = 97)</th><a name="en0171"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Placebo group (n = 97)</th><a name="en0172"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p</th></tr><tr title="table-row"><a name="en0174"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Baseline \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0175"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Discharge \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0176"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Baseline \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0177"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Discharge \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0179"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">aCL IgG, n (%)<a class="elsevierStyleCrossRef" href="#tb2fn1">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0180"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">25 (25.8) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0181"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">29 (29.9) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0182"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">13 (13.4)<a class="elsevierStyleCrossRef" href="#tb2fn2">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0183"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">25 (25.8) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0184"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.046 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0185"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">aCL IgG, U/mL<a class="elsevierStyleCrossRef" href="#tb2fn1">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0186"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">22.7 (11.4‒41.5) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0187"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">26.0 (16.1‒48.6) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0188"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">17.5 (11.5‒28.0) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0189"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">25.6 (13.7‒41.4) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0190"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.160 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0191"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">aCL IgM, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0192"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">14 (14.4) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0193"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">14 (14.4) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0194"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">14 (14.4) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0195"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">20 (20.6) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0196"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.139 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0197"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">aCL IgM, U/mL<a class="elsevierStyleCrossRef" href="#tb2fn1">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0198"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">17.3 (11.2‒30.0) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0199"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">22.0 (14.6‒34.2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0200"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">16.4 (10.3‒29.3) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0201"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">18.0 (13.3‒32.9) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0202"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.550 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0203"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">aCL IgA, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0204"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">6 (6.2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0205"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">7 (7.2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0206"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">9 (9.3) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0207"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">8 (8.2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0208"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.559 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0209"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">aCL IgA, U/mL \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0210"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">14.7 (10.2‒22.8) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0211"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">14.8 (11.1‒20.9) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0212"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">17.0 (11.9‒24.8) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0213"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">17.7 (11.2‒24.4) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0214"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.097 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0215"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">aβ2-GP IgG, n (%)<a class="elsevierStyleCrossRef" href="#tb2fn1">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0216"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">11 (11.3) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0217"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">19 (19.6) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0218"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">19 (19.6) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0219"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">21 (21.6) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0220"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.145 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0221"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">aβ2-GP IgG, U/mL \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0222"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">4.6 (2.8‒7.3) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0223"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">4.7 (3.1‒8.8) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0224"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5.0 (2.9‒8.4) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0225"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5.6 (3.8‒9.8) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0226"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.493 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0227"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">aβ2-GP IgM, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0228"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">31 (32.0) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0229"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">32 (33.0) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0230"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">28 (28.9) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0231"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">35 (36.1) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0232"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.300 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0233"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">aβ2-GP IgM, U/mL<a class="elsevierStyleCrossRef" href="#tb2fn1">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0234"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">7.1 (4.1‒10‒9) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0235"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">7.7 (4.5‒11.8) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0236"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">6.3 (3.8‒10.8) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0237"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">8.1 (4.6‒12.5) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0238"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.152 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0239"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">aβ2-GP IgA, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0240"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">41 (42.3) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0241"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">38 (39.2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0242"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">45 (46.4) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0243"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">46 (47.4) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0244"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.551 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0245"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">aβ2-GP IgA, U/mL \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0246"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">9.8 (6.9‒15.9) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0247"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">10.3 (6.7‒15.8) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0248"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">11.5 (7.3‒17.4) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0249"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">11.3 (6.6‒18.2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0250"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.772 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3692414.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tb2fn1" "etiqueta" => "a" "nota" => "p < 0.05 for main effect of time." ] 1 => array:3 [ "identificador" => "tb2fn2" "etiqueta" => "b" "nota" => "Significantly different (p < 0.05) from discharge in both groups." ] ] ] "descripcion" => array:1 [ "en" => "Effect of vitamin D3 on autoantibodies in patients with moderate to severe COVID-19." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "cebibsec1" "bibliografiaReferencia" => array:48 [ 0 => array:3 [ "identificador" => "bib0001" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "COVID-19 infection and rheumatoid arthritis: faraway, so close!" 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Original articles

Lucas P. Salesa, Lucas V.B. Souzaa, Alan L. Fernandesa, Igor H. Muraia, Mayara D. Santosa, Margarete B.G. Vendraminia, Ricardo M. Oliveirab, Camille P. Figueiredoa, Valéria F. Caparboa, Bruno Gualanoa,

Corresponding author

gualano@usp.br

Corresponding author.

, Rosa M.R. Pereiraa, in memoriam

a Rheumatology Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil

b RDO Diagnósticos Médicos, São Paulo, SP, Brazil

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0008">Introduction</span><p id="para0009" class="elsevierStylePara elsevierViewall">Since the beginning of the Coronavirus Disease 2019 &#40;COVID-19&#41; pandemic&#44; caused by Severe Acute Respiratory Syndrome Coronavirus 2 &#40;SARS-CoV-2&#41;&#44; a possible relationship between the infection and autoimmune reactions has been hypothesized&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> In addition to the most common clinical manifestations &#40;i&#46;e&#46;&#44; fever&#44; cough&#44; and dyspnea&#41;&#44; the presence of myalgia&#44; joint pain &#40;arthralgia&#41;&#44; and thrombotic events was recurrent in hospitalized patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0002"><span class="elsevierStyleSup">2-4</span></a> One of the explanations is the fact that SARS-CoV-2 infection affects regulatory T-cell levels&#44; aggravating inflammatory processes that may lead to autoimmunity&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a></p><p id="para0010" class="elsevierStylePara elsevierViewall">In this context&#44; Zhang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> described three cases of thrombosis associated with both Antiphospholipid &#40;aPL&#41; antibodies&#44; Anticardiolipin &#40;aCL&#41;&#44; and anti&#8211;&#946;2-Glycoprotein-I &#40;a&#946;2-GP&#41;&#46; These antibodies target phospholipid-binding proteins and phospholipids in cell membranes&#44; leading to a hypercoagulable state through interference with the coagulation cascade&#44; activation of endothelial cells and platelets&#44; and inhibition of natural anticoagulant pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a></p><p id="para0011" class="elsevierStylePara elsevierViewall">Pascolini et al&#46;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> showed that the frequency of autoantibody positivity in the COVID-19 group was significantly higher than in the control group &#40;45 &#37; vs&#46; 12 &#37;&#59; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;03&#41;&#46; The subgroup of patients testing positive for autoantibodies exhibited higher lactate levels and a poorer prognosis compared to the subgroup testing negative&#46; The mortality rate due to COVID-19 complications was significantly higher in the autoantibody-positive subgroup compared to the negative subgroup &#40;40 &#37; vs&#46; 5&#46;5 &#37;&#59; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;03&#41;&#46;</p><p id="para0012" class="elsevierStylePara elsevierViewall">The role of vitamin D<span class="elsevierStyleInf">3</span> supplementation in autoimmunity has been extensively investigated&#46; In addition to influencing viral neutralization&#44; recruitment of immune system cells and dendritic cell maturation&#44;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> vitamin D<span class="elsevierStyleInf">3</span> acts on lymphocytes T and B proliferation&#44; immune cells that participate in antibody production&#46;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> For instance&#44; Najafipoor et al&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> demonstrated that patients who received 50&#44;000 IU of vitamin D<span class="elsevierStyleInf">3</span> per week for 6 months&#44; in addition to interferon therapy&#44; presented lower increases in IgG levels against Epstein-Barr virus 1 and viral capsid antigen compared to the control group&#44; who only received disease-modifying interferon therapy alone&#46; These findings align with previous evidence on the importance of adequate serum levels of vitamin D to reduce disease activity and remission&#44; and to enhance responsiveness to rheumatoid arthritis treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a></p><p id="para0013" class="elsevierStylePara elsevierViewall">Altogether&#44; these findings suggest that vitamin D deficiency could act as an environmental trigger contributing to B-cell hyperactivation&#44; which could culminate in increased autoantibody production&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">15-17</span></a> Although numerous clinical trials worldwide have investigated the impact of vitamin D<span class="elsevierStyleInf">3</span> on COVID-19 outcomes&#44;<a class="elsevierStyleCrossRefs" href="#bib0017"><span class="elsevierStyleSup">17-21</span></a> the role of vitamin D<span class="elsevierStyleInf">3</span> on aPL antibodies remains poorly understood&#46; To fill this gap&#44; the present exploratory study aimed to assess the effect of a single oral dose of 200&#44;000 IU of vitamin D<span class="elsevierStyleInf">3</span> on aPL antibodies in hospitalized patients with moderate to severe COVID-19&#46;</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Methods</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Study design</span><p id="para0014" class="elsevierStylePara elsevierViewall">This is a <span class="elsevierStyleItalic">post-hoc</span>&#44; exploratory analysis from a double-blind&#44; placebo-controlled&#44; randomized clinical trial performed in two centers in Sao Paulo&#44; Brazil&#44; and registered in ClinicalTrials&#46;gov&#44; NCT04449718&#46; This study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of both centers&#58; Hospital das Clinicas da Faculdade de Medicina da Universidade de S&#227;o Paulo and Hospital de Campo do Ibirapuera &#40;Ethics Committee Approval Number 30959620&#46;4&#46;1001&#46;0068&#41;&#46; Before being admitted to the study&#44; all patients provided written informed consent&#46; This manuscript was reported according to the CONSORT guidelines&#46; Additional information about the trial concept and design&#44; patient recruitment&#44; supplementation protocol and blindness&#44; procedures&#44; and endpoints has been previously published&#46;<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Participants</span><p id="para0015" class="elsevierStylePara elsevierViewall">Patients were recruited from both hospitals from June 2&#44; 2020 to August 27&#44; 2020&#46; The end of follow-up was on October 7&#44; 2020&#46; Inclusion criteria were age &#8805; 18 years&#59; confirmed diagnosis of COVID-19 by polymerase chain reaction testing for SARS-CoV-2 from nasopharyngeal swabs&#44; or computed tomography scan findings consistent with those found in COVID-19 &#40;bilateral multifocal ground-glass opacities &#8805; 50 &#37;&#41;&#59; and flu syndrome with institutional criteria for hospitalization on hospital admission &#40;respiratory rate &#62; 24 breaths&#47;minute&#44; oxygen saturation &#60; 93 &#37; on room air&#44; or the presence of risk factors for complications &#40;e&#46;g&#46;&#44; obesity&#44; diabetes&#44; systemic arterial hypertension&#44; neoplasms&#44; immunosuppression&#44; heart disease&#44; pulmonary tuberculosis&#41;&#44; followed by COVID-19 confirmation&#46; Patients who met these criteria were considered to have moderate to severe COVID-19 according to the criteria from the NIH-COVID-19 Treatment Guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a></p><p id="para0016" class="elsevierStylePara elsevierViewall">Patients were excluded if they were unable to read and sign the written informed consent form&#59; were already under invasive mechanical ventilation&#59; received prior vitamin D<span class="elsevierStyleInf">3</span> supplementation &#40;&#62; 1000 IU&#47;d or weekly equivalent&#41;&#59; had kidney failure requiring dialysis or creatinine &#62; 2&#46;0 mg&#47;dL or hypercalcemia &#40;calcium &#62; 10&#46;5 mg&#47;dL&#41;&#59; were pregnant or lactating women&#59; were expecting to be discharged within 24 h&#46; Absence of fever in the previous 72 h&#44; no need for supplemental oxygen in the previous 48 h&#44; and oxygen saturation greater than 93 &#37; on room air without respiratory distress were used as criteria for hospital discharge&#46;</p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">Randomization and masking</span><p id="para0017" class="elsevierStylePara elsevierViewall">Patients were allocated in a 1&#58;1 ratio into the vitamin D<span class="elsevierStyleInf">3</span> or placebo groups as previously described&#46;<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> Patients enrolled in the vitamin D<span class="elsevierStyleInf">3</span> group received a single oral dose of 200&#44;000 IU of vitamin D<span class="elsevierStyleInf">3</span> diluted in vehicle &#40;10 mL of a peanut oil solution&#41; immediately after randomization&#44; while those in the placebo group received only vehicle&#46; Both solutions were prepared by the same unit &#40;pharmacy of Hospital das Cl&#237;nicas&#41; and were identical in appearance&#44; color&#44; smell&#44; and taste&#46; This selected dose is within the recommended dose range for effectively promoting vitamin D sufficiency&#46;<a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Procedures</span><p id="para0018" class="elsevierStylePara elsevierViewall">Baseline demographic&#44; self-reported anthropometric &#40;weight and height&#41;&#44; and clinical characteristics &#40;coexisting chronic diseases&#44; acute COVID-19 symptoms&#44; patients&#8217; medications throughout hospitalization&#44; oxygen supplementation requirement&#44; and imaging features&#41; were collected upon hospital admission&#46; Serum levels of 25-hydroxyvitamin D were assessed by chemiluminescent immunoassay &#40;ARCHITECT 25-OH Vitamin D 5P02&#59; Abbott Diagnostics&#41;&#46; The frequency of thrombotic events during hospitalization was assessed through electronic medical records&#46; The presence and titers of aCL antibodies &#40;IgG&#44; IgM and IgA&#41; were analyzed through commercial fluoro immunoenzymatic assay &#40;Thermo Scientific&#8482;&#47;Phadia&#8482; 250 Immunoassay Analyzers&#41;&#46; The a&#946;2-GP antibodies &#40;IgG&#44; IgM and IgA&#41; were detected by ELISA using a commercial kit &#40;Quanta Lite&#174;&#44; Inova Diagnostics Ins&#46;&#44; San Diego&#44; CA&#44; USA&#41;&#46; Only patients who had blood samples collected on the day of randomization and on hospital discharge were included in this study&#46; Patients who died throughout follow-up were not included due to the absence of blood samples&#46;</p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0014">Outcome measures</span><p id="para0019" class="elsevierStylePara elsevierViewall">Herein&#44; it was reported on the following <span class="elsevierStyleItalic">post hoc</span> exploratory outcomes&#58; presence and titers of aPL antibodies&#58; aCL &#40;IgG&#44; IgM and IgA&#41; and a&#946;2-GP &#40;IgG&#44; IgM and IgA&#41;&#46;</p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0015">Statistical analysis</span><p id="para0020" class="elsevierStylePara elsevierViewall">The sample size was chosen based on feasibility and resources&#44; as previously described&#46;<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> Independent <span class="elsevierStyleItalic">t</span>-test and Mann-Whitney <span class="elsevierStyleItalic">U</span> test were used for continuous variables&#46; Proportions were analyzed by chi-square or Fisher&#39;s exact test&#46; Generalized Estimating Equations &#40;GEE&#41; for repeated measures were used for testing possible differences in serum presence and titers of autoantibodies assuming group and time as fixed factors&#44; with marginal and binomial distributions&#44; and a first-order autoregressive correlation matrix to test the main and interaction effects&#46; Bonferroni&#39;s adjustment was performed in GEE analyses to maintain a family-wise two-sided significance threshold of 0&#46;05&#44; considering 6 pairwise comparisons for all outcomes&#46; All analyses were performed by a per-protocol approach with no imputation for missing&#44; data using IBM-SPSS software&#44; version 20&#46;0&#46; The significance level was set at a two-sided p-value &#8804; 0&#46;05&#46;</p></span></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0016">Results</span><p id="para0021" class="elsevierStylePara elsevierViewall">A total of 1240 patients were screened for eligibility&#59; however&#44; only 240 were randomized during the acute-phase of SARS-CoV-2 infection&#44; with 120 being assigned to each group&#46; Three patients withdrew their informed consent&#46; Of the 119 patients who were randomized to the vitamin D3 group&#44; 13 &#40;11 &#37;&#41; were excluded due to insufficient blood samples&#44; and 9 &#40;7 &#37;&#41; died throughout the follow-up&#46; From 118 patients who were randomized to the placebo group&#44; 15 &#40;13 &#37;&#41; were excluded due to insufficient blood samples&#44; and 6 &#40;5 &#37;&#41; died throughout the follow-up &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia><p id="para0022" class="elsevierStylePara elsevierViewall">The mean &#40;SD&#41; age was 55&#46;3 &#40;13&#46;9&#41; years&#44; Body Mass Index &#40;BMI&#41; was 32&#46;2 &#40;7&#46;1&#41; kg&#47;m<span class="elsevierStyleSup">2</span>&#44; 106 &#40;54&#46;6 &#37;&#41; patients were male&#44; 108 &#40;55&#46;7 &#37;&#41; were white&#44; and 175 &#40;90&#46;2 &#37;&#41; required respiratory support at baseline&#46; No significant differences between groups were found at baseline &#40;<a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia><p id="para0023" class="elsevierStylePara elsevierViewall">In the vitamin D group&#44; 84 patients &#40;87 &#37;&#41; exhibited moderate disease&#44; whereas 13 patients &#40;13 &#37;&#41; had severe disease&#46; In the placebo group&#44; 86 patients &#40;89 &#37;&#41; had moderate disease&#44; while 11 patients &#40;11 &#37;&#41; had severe disease&#46;</p><p id="para0024" class="elsevierStylePara elsevierViewall">As expected&#44; mean &#40;SD&#41; 25-hydroxyvitamin-D was significantly increased from baseline to discharge after a single oral dose of 200&#44;000 UI of vitamin D3 &#91;from 21&#46;1 &#40;9&#46;9&#41; ng&#47;mL to 44&#46;5 &#40;15&#46;0&#41; ng&#47;mL&#93; compared to placebo &#91;from 20&#46;0 &#40;8&#46;2&#41; ng&#47;mL to 19&#46;5 &#40;10&#46;6&#41; ng&#47;mL&#93; &#91;significant group by time interaction &#40;p &#60; 0&#46;001&#41;&#93;&#46; No significant difference between vitamin D3 &#91;3 &#40;3&#46;1 &#37;&#41;&#93; and placebo &#91;4 &#40;4&#46;1 &#37;&#41;&#93; groups was observed in the frequency of thrombotic events &#40;<span class="elsevierStyleItalic">p</span> &#61; 0&#46;700&#41;&#46;</p><p id="para0025" class="elsevierStylePara elsevierViewall">One hundred nine &#40;66&#46;5 &#37;&#41; patients tested positive for at least one type of aPL antibody&#46; There was a significant group by time interaction &#40;<span class="elsevierStyleItalic">p</span> &#61; 0&#46;046&#41; for the frequency of aCL &#40;IgG&#41;&#44; with values increasing from baseline to discharge in the placebo group &#91;from 13 &#40;13&#46;4 &#37;&#41; to 25 &#40;25&#46;8 &#37;&#41;&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;004&#93;&#44; while frequency of aCL &#40;IgG&#41; in vitamin D<span class="elsevierStyleInf">3</span> group remained similar &#91;from 25 &#40;25&#46;8 &#37;&#41; to 29 &#40;29&#46;9 &#37;&#41;&#44; <span class="elsevierStyleItalic">p</span> &#61; 1&#46;00&#93;&#44; after Bonferroni&#39;s adjustment&#46; However&#44; the frequency of aCL &#40;IgG&#41; did not change between the groups on discharge&#46; No significant differences between vitamin D<span class="elsevierStyleInf">3</span> and placebo groups were found for titers and frequency of aCL &#40;IgM and IgA&#41; and a&#946;2-GP &#40;IgG&#44; IgM and IgA&#41; antibodies &#40;<a class="elsevierStyleCrossRef" href="#tbl0002">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0002"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0017">Discussion</span><p id="para0026" class="elsevierStylePara elsevierViewall">To the best of our knowledge&#44; this is the first double-blind&#44; placebo-controlled&#44; randomized clinical trial investigating the influence of 200&#44;000 IU of vitamin D<span class="elsevierStyleInf">3</span> on aPL antibodies among hospitalized patients with moderate to severe COVID-19&#46; Overall&#44; no significant differences between vitamin D<span class="elsevierStyleInf">3</span> and placebo groups were found for any autoantibodies upon hospital discharge&#46;</p><p id="para0027" class="elsevierStylePara elsevierViewall">Antiphospholipid antibodies&#44; such as aCL&#44; a&#946;2-GP&#44; and lupus anticoagulant&#44; belong to a heterogeneous group of antibodies associated with Antiphospholipid Antibodies Syndrome &#40;APS&#41;&#44; a thrombosis-related systemic autoimmune disease affecting arteries&#44; veins&#44; and small blood vessels&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a> It has been shown the presence of these antibodies in some viral infections&#44;<a class="elsevierStyleCrossRefs" href="#bib0026"><span class="elsevierStyleSup">26-29</span></a> among which COVID-19<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> stands out&#44; with a prevalence of aPL antibodies ranging from 3&#46;7 &#37; to 88&#46;0 &#37; in previous studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">30-33</span></a> Similarly&#44; herein the authors found that 66&#46;5 &#37; &#40;129&#47;194&#41; of the patients showed at least one type of aPL antibody&#46;</p><p id="para0028" class="elsevierStylePara elsevierViewall">The immunomodulatory role of vitamin D appears to involve antigen-presenting cells&#44; such as dendritic cells and macrophages&#44; expressing a nuclear Vitamin D Receptor &#40;VDR&#41;&#44; a member of the nuclear receptor superfamily of transcriptional regulators involved in 1-alfa&#44;25-dihidroxicolecalciferol signaling&#46;<a class="elsevierStyleCrossRef" href="#bib0034"><span class="elsevierStyleSup">34</span></a> However&#44; the mechanisms underlying the inhibitory effects of vitamin D on antibody production are not fully understood&#46; In part&#44; this event could be explained by the regulatory effect of vitamin D on B-cells related to immune tolerance&#46; Vitamin D sufficiency would act in the proliferation and apoptosis of activated B-cells&#44; which are closely related to antibody production&#44;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">35-37</span></a> while vitamin D deficiency would play the opposite effect&#44; increasing the production of autoantibodies through the activation of B-cells&#46;<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0038"><span class="elsevierStyleSup">38</span></a></p><p id="para0029" class="elsevierStylePara elsevierViewall">Riancho-Zarrabeitia et al&#46;<a class="elsevierStyleCrossRef" href="#bib0039"><span class="elsevierStyleSup">39</span></a> demonstrated an association between circulating vitamin D insufficiency &#40;between 10 and 30 ng&#47;mL&#41; and the presence of lupus anticoagulant&#44; an aPL antibody&#46; When evaluating only patients with aPL antibodies syndrome&#44; they showed an association between vitamin D insufficiency and higher frequency of anti-&#946;2-glycoprotein-I&#44; but not aCL&#46;<a class="elsevierStyleCrossRef" href="#bib0039"><span class="elsevierStyleSup">39</span></a></p><p id="para0030" class="elsevierStylePara elsevierViewall">Another study assessed the effect of 50&#44;000 IU of vitamin D in patients with Hashimoto&#39;s thyroiditis&#44; a condition also characterized by autoimmune inflammation&#46; Participants received the supplement weekly for three months and had a significant reduction in serum thyroid autoantibodies levels compared to baseline&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">40</span></a> Accordingly&#44; an <span class="elsevierStyleItalic">in vitro</span> study<a class="elsevierStyleCrossRef" href="#bib0041"><span class="elsevierStyleSup">41</span></a> showed that the 1&#44;25-dihydroxyvitamin-D modestly reduced autoantibody production in peripheral blood mononuclear cells of disease-active systemic lupus erythematosus&#46;</p><p id="para0031" class="elsevierStylePara elsevierViewall">In patients with COVID-19&#44; the presence of aPL antibodies has been suggested as one of the physiopathologic mechanisms for the cause of hypercoagulation and thrombotic events&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0042"><span class="elsevierStyleSup">42</span></a> In addition to promoting platelet aggregation and activation&#44; aPL antibodies promote the upregulation of pro-inflammatory cytokines&#44; cell adhesion molecules&#44; and endothelial nitric oxide synthase that induce a pro-inflammatory and pro-coagulant endothelial phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib0043"><span class="elsevierStyleSup">43</span></a></p><p id="para0032" class="elsevierStylePara elsevierViewall">Notwithstanding&#44; controversial results exist&#46; In a prospective single-center observational study&#44; patients with positive aPL antibodies did not have an increased risk of thrombosis risk during intensive care unit hospitalization&#46;<a class="elsevierStyleCrossRef" href="#bib0032"><span class="elsevierStyleSup">32</span></a> Additionally&#44; Borghi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0044"><span class="elsevierStyleSup">44</span></a> did not observe a significant correlation between the presence of a&#946;2-GP IgG and thrombosis&#44; suggesting that aPL antibodies in COVID-19 may be different from those detectable in APS&#46;<a class="elsevierStyleCrossRef" href="#bib0044"><span class="elsevierStyleSup">44</span></a> Accordingly&#44; the patients with aPL antibodies did not experience a high number of thrombotic events during hospitalization &#40;4&#47;133&#59; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;680&#41;&#44; with no differences noted between the groups &#40;<span class="elsevierStyleItalic">p</span> &#61; 0&#46;700&#41;&#46; It is important to note that the presence of aCL in the present study was not significantly different between groups at discharge&#46;</p><p id="para0033" class="elsevierStylePara elsevierViewall">These conflicting results might be due to the fact that most of aPL antibodies associated with the virus are thought to be transient in patients with critical illness&#44;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">45</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0046"><span class="elsevierStyleSup">46</span></a> so it is unclear whether either they represent a simple epiphenomenon or are actually involved in COVID-19-associated coagulopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0047"><span class="elsevierStyleSup">47</span></a> In a study in which aPL testing was repeated 1 month after COVID-19 aPL-positive patients were admitted to the intensive care&#44; aPL antibodies were primarily a transient phenomenon that occurred during the acute phase&#46;<a class="elsevierStyleCrossRef" href="#bib0048"><span class="elsevierStyleSup">48</span></a> Another confounded factor is that most patients were under anticoagulant medication&#44; a drug that is related to the prevention of thrombotic events&#46;</p><p id="para0034" class="elsevierStylePara elsevierViewall">This study has some strengths&#44; such as the comprehensive assessment of antibodies related to autoimmune diseases&#44; the randomized&#44; controlled&#44; double-blinded design&#44; and the enrollment of hospitalized patients with moderate to severe COVID-19&#46; Also&#44; these findings increase the knowledge on the role of vitamin D<span class="elsevierStyleInf">3</span> on aPL antibodies and better inform health professionals on more efficient healthcare delivery and resource management&#46;</p><p id="para0035" class="elsevierStylePara elsevierViewall">However&#44; there are several limitations&#46; First&#44; the relatively small sample size could increase the chances of type 2 error&#46; Second&#44; the heterogeneity in pre-existing diseases and treatments of the patients&#44; although no significant differences were observed between groups at baseline&#46; Third&#44; the results may have been influenced by the high rate of patients using anticoagulants &#40;&#8764;90 &#37;&#41;&#46; Finally&#44; the authors were unable to measure other aPL antibodies&#44; such as lupus anticoagulant antibodies&#46;</p><p id="para0036" class="elsevierStylePara elsevierViewall">In conclusion&#44; these findings do not support the use of a single oral dose of 200&#44;000 IU of vitamin D<span class="elsevierStyleInf">3</span> to modulate autoantibodies in hospitalized patients with moderate to severe COVID-19&#46;</p></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0018">Data availability</span><p id="para0037" class="elsevierStylePara elsevierViewall">Deidentified participant data of this study must be requested from the corresponding author upon publication &#40;sent to gualano&#64;usp&#46;br&#41;&#46; The codebook of this study will be made available upon request by qualified clinical researchers for specified purposes dependent on the nature of the request and the intentional use of the data&#44; with investigator support&#46; The request must include a statistician&#46; The lead author &#40;BG&#41; affirms that the manuscript is an honest&#44; accurate&#44; and transparent account of the study being reported&#59; that no important aspects of the study have been omitted&#59; and that any discrepancies from the study as originally planned &#40;and&#44; if relevant&#44; registered&#41; have been explained&#46;</p></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0019">Authors&#8217; contributions</span><p id="para0038" class="elsevierStylePara elsevierViewall">BG and RMRP&#58; Had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis&#59; LPS&#44; LCVS and RMRP&#58; Conceived and designed the study&#59; LPS&#44; LVBS&#44; VFC and RMRP&#58; Drafted the manuscript&#59; LPS&#44; ALF&#44; BG&#44; and RMRP&#58; Performed statistical analysis&#59; BG and RMRP&#58; Provided supervision&#59; LPS&#44; MBGV&#44; RMO&#44; CPF and VFC&#58; Provided administrative&#44; technical&#44; or material support&#59; and all authors performed data acquisition&#44; analysis&#44; interpretation and critically revised the manuscript for important intellectual content&#46; All authors read and approve the manuscript as submitted&#46;</p></span></span>"
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          "titulo" => "Introduction"
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              "titulo" => "Randomization and masking"
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    "fechaRecibido" => "2023-08-15"
    "fechaAceptado" => "2024-07-21"
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          "clase" => "keyword"
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            0 => "COVID-19"
            1 => "SARS-CoV-2 Infection"
            2 => "Vitamin D"
            3 => "Antiphospholipid Antibodies Syndrome"
            4 => "Antiphospholipid Antibodies"
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    "tieneResumen" => true
    "highlights" => array:2 [
      "titulo" => "Highlights"
      "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara008" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001"><span class="elsevierStyleLabel">&#8226;</span><p id="para0001" class="elsevierStylePara elsevierViewall">The impact of vitamin D<span class="elsevierStyleInf">3</span> supplementation on autoimmunity remains a subject of debate&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0002"><span class="elsevierStyleLabel">&#8226;</span><p id="para0002" class="elsevierStylePara elsevierViewall">A single dose of 200&#44;000 IU of vitamin D<span class="elsevierStyleInf">3</span> was not able to modulate autoantibodies in COVID-19 patients&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0003"><span class="elsevierStyleLabel">&#8226;</span><p id="para0003" class="elsevierStylePara elsevierViewall">aPL antibody positivity was not associated with thrombotic events despite vitamin D3 supplementation&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0004"><span class="elsevierStyleLabel">&#8226;</span><p id="para0004" class="elsevierStylePara elsevierViewall">aPL antibodies associated with the virus seem to be transient in critical patients&#46;</p></li></ul></p></span>"
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abss0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Objective</span><p id="spara009" class="elsevierStyleSimplePara elsevierViewall">To investigate the effect of a single oral dose of 200&#44;000 IU of vitamin D<span class="elsevierStyleInf">3</span> on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19&#46;</p></span> <span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Methods</span><p id="spara010" class="elsevierStyleSimplePara elsevierViewall">This is a post-hoc&#44; exploratory analysis from a double-blind&#44; placebo-controlled&#44; randomized clinical trial performed in two centers in Sao Paulo&#44; Brazil&#46; Hospitalized patients with COVID-19 were randomly assigned to receive either vitamin D<span class="elsevierStyleInf">3</span> &#40;<span class="elsevierStyleItalic">n</span> &#61; 97&#41; or placebo &#40;<span class="elsevierStyleItalic">n</span> &#61; 97&#41;&#46; In this post-hoc analysis&#44; the endpoints were titers and frequency of anti&#8211;&#946;2-Glycoprotein-I &#40;a&#946;2-GP&#41; and Anticardiolipin &#40;aCL&#41; antibodies &#91;Immunoglobulin G&#44; M and A &#40;IgG&#44; IgM and IgA&#41;&#93;&#46;</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Results</span><p id="spara011" class="elsevierStyleSimplePara elsevierViewall">Overall mean &#40;SD&#41; age was 55&#46;3 &#40;13&#46;9&#41; years&#44; Body Mass Index &#40;BMI&#41; was 32&#46;2 &#40;7&#46;1 kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#44; and 106 participants &#40;54&#46;6 &#37;&#41; were male&#46; There was a significant group by time interaction &#40;<span class="elsevierStyleItalic">p</span> &#61; 0&#46;046&#41; for frequency of aCL IgG&#44; with increased values from baseline to discharge in the placebo group &#91;n &#40;&#37;&#41;&#44; from 13 &#40;13&#46;4&#41; to 25 &#40;25&#46;8&#41;&#93; compared to the vitamin D<span class="elsevierStyleInf">3</span> &#91;from 25 &#40;25&#46;8&#41; to 29 &#40;29&#46;9&#41;&#93;&#46; However&#44; the frequency of aCL IgG did not change between the groups on discharge&#46; No significant differences between vitamin D3 and placebo groups were found for any other autoantibodies&#46;</p></span> <span id="abss0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Conclusion</span><p id="spara012" class="elsevierStyleSimplePara elsevierViewall">These findings do not support the use of a single oral dose of 200&#44;000 IU of vitamin D<span class="elsevierStyleInf">3</span> to modulate autoantibodies in hospitalized patients with moderate to severe COVID-19&#46;</p></span>"
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          "leyenda" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">1</span>Values are mean &#177; SD&#44; median &#40;IQR&#41;&#44; or n &#40;&#37;&#41;&#46; Continuous variables were analyzed by independent <span class="elsevierStyleItalic">t</span>-test&#46; Percentages were analyzed by Chi-Square or Fisher&#39;s exact test&#46;</p><p id="spara004" class="elsevierStyleSimplePara elsevierViewall">COVID-19&#44; Coronavirus Disease 2019&#59; BMI&#44; Body Mass Index&#59; ESR&#44; Erythrocyte Sedimentation Rate&#46;</p>"
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                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Vitamin D3 group &#40;<span class="elsevierStyleItalic">n</span> &#61; 97&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Placebo group &#40;<span class="elsevierStyleItalic">n</span> &#61; 97&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Age&#44; years&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">55&#46;2 &#177; 13&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0006"></a><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="top">55&#46;4 &#177; 14&#46;3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">57 &#40;58&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="top">49 &#40;50&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0014"></a><td class="td" title="\n
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                  \t\t\t\t</td><a name="en0015"></a><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">49 &#40;50&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><a name="en0035"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">6&#46;0 &#40;4&#46;0-8&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0036"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">7&#46;0 &#40;6&#46;0-10&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0037"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Concomitant medications&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0038"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0039"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0040"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Anticoagulant<a class="elsevierStyleCrossRef" href="#tb1fn3"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0041"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">90 &#40;93&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0042"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">83 &#40;85&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0043"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Antibiotic<a class="elsevierStyleCrossRef" href="#tb1fn3"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0044"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">81 &#40;84&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0045"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">84 &#40;86&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0046"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Glucocorticoid<a class="elsevierStyleCrossRef" href="#tb1fn3"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0047"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">65 &#40;67&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0048"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">62 &#40;63&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0049"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Antihypertensive<a class="elsevierStyleCrossRef" href="#tb1fn3"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0050"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">55 &#40;57&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0051"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">43 &#40;44&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0052"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Proton pump inhibitorc&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0053"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">40 &#40;41&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0054"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">40 &#40;41&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0055"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Antiemetic<a class="elsevierStyleCrossRef" href="#tb1fn3"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0056"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">38 &#40;39&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0057"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">49 &#40;50&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0058"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Analgesic<a class="elsevierStyleCrossRef" href="#tb1fn3"><span class="elsevierStyleSup">c</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tb1fn4"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0059"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">37 &#40;38&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0060"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">45 &#40;46&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0061"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Hypoglycemic<a class="elsevierStyleCrossRef" href="#tb1fn3"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0062"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">23 &#40;24&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0063"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">20 &#40;20&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0064"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Hypolipidemic<a class="elsevierStyleCrossRef" href="#tb1fn3"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0065"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">14 &#40;14&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0066"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">14 &#40;14&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0067"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Thyroid<a class="elsevierStyleCrossRef" href="#tb1fn3"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0068"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">8 &#40;8&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0069"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">8 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0070"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Antiviral<a class="elsevierStyleCrossRef" href="#tb1fn3"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0071"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">4 &#40;4&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0072"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">3 &#40;3&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0073"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Acute COVID-19 symptoms&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0074"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0075"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0076"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Fever&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0077"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">70 &#40;72&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0078"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">68 &#40;70&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0079"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Cough&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0080"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">83 &#40;85&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0081"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">81 &#40;83&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0082"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Fatigue&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0083"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">80 &#40;82&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0084"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">84 &#40;86&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0085"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Joint pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0086"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">40 &#40;41&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0087"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">33 &#40;34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0088"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Myalgia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0089"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">60 &#40;61&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0090"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">60 &#40;61&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0091"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Nasal congestion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0092"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">33 &#40;34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0093"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">33 &#40;34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0094"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Runny nose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0095"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">34 &#40;35&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0096"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">36 &#40;37&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0097"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Sore throat&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0098"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">35 &#40;36&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0099"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">23 &#40;23&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0100"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Diarrhea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0101"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">32 &#40;33&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0102"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">40 &#40;41&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0103"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Coexisting diseases&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0104"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0105"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0106"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0107"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">53 &#40;54&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0108"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">47 &#40;48&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0109"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Cardiovascular disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0110"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">14 &#40;14&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0111"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">12 &#40;12&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0112"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Diabetes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0113"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">39 &#40;40&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0114"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">28 &#40;28&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0115"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Chronic obstructive pulmonary disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0116"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5 &#40;5&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0117"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5 &#40;5&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0118"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Asthma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0119"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">6 &#40;6&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0120"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">7 &#40;7&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0121"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Obesity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0122"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">56 &#40;57&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0123"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">56 &#40;58&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0124"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Rheumatic disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0125"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">10 &#40;10&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0126"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">9 &#40;9&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0127"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Chronic kidney disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0128"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">2 &#40;2&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0129"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0130"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Respiratory support&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0131"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0132"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0133"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>No oxygen therapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0134"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">14 &#40;14&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0135"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5 &#40;5&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0136"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Oxygen therapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0137"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">70 &#40;72&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0138"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">81 &#40;83&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0139"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Non-invasive ventilation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0140"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">13 &#40;13&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0141"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">11 &#40;11&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0142"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Computed tomography findings&#44; n &#40;&#37;&#41;<a class="elsevierStyleCrossRef" href="#tb1fn5"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0143"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0144"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0145"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Ground-glass opacities &#60; 50 &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0146"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">38 &#40;44&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0147"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">31 &#40;38&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0148"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Ground-glass opacities &#8805; 50 &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0149"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">47 &#40;55&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0150"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">50 &#40;61&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0151"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Laboratory values<a class="elsevierStyleCrossRef" href="#tb1fn6"><span class="elsevierStyleSup">f</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0152"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0153"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0154"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Platelet&#44; 10<span class="elsevierStyleSup">3</span>&#47;&#181;L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0155"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">313 &#177; 114&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0156"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">299 &#177; 133&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0157"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Mean platelet volume&#44; Fl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0158"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">10&#46;5 &#177; 0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0159"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">10&#46;7 &#177; 0&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0160"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>ESR&#44; mm&#47;h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0161"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">56&#46;0 &#40;24&#46;0&#8210;86&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0162"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">61&#46;0 &#40;35&#46;5&#8210;88&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0163"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>C-reactive protein&#44; mg&#47;L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0164"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">56&#46;9 &#40;22&#46;3&#8210;92&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0165"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">65&#46;9 &#40;28&#46;8&#8210;103&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0166"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>D-dimer&#44; ng&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0167"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">770&#46;5 &#40;558&#46;0&#8210;1497&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0168"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">840&#46;0 &#40;526&#46;0&#8210;1424&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab3692415.png"
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          "notaPie" => array:6 [
            0 => array:3 [
              "identificador" => "tb1fn1"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="notep0003">Pardo is the exact term used in Brazilian Portuguese&#44; meaning &#8220;mixed ethnicity&#8221;&#44; according to the Brazilian Institute of Geography and Statistics&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tb1fn2"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="notep0004">BMI data was missing for 7&#46;7 &#37; of patients &#40;<span class="elsevierStyleItalic">n</span> &#61; 7 in the vitamin D<span class="elsevierStyleInf">3</span> group and <span class="elsevierStyleItalic">n</span> &#61; 8 in the placebo group&#41;&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tb1fn3"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="notep0005">Anticoagulant&#44; antibiotic&#44; glucocorticoid&#44; antihypertensive&#44; proton pump inhibitor&#44; antiemetic&#44; hypoglycemic&#44; hypolipidemic&#44; thyroid and antiviral data were missing for 0&#46;5 &#37; of patients &#40;<span class="elsevierStyleItalic">n</span> &#61; 1 in the vitamin D<span class="elsevierStyleInf">3</span> group&#41;&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tb1fn4"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="notep0006">Analgesic data was missing for 1&#46;0 &#37; of patients &#40;<span class="elsevierStyleItalic">n</span> &#61; 1 in the vitamin D<span class="elsevierStyleInf">3</span> group and <span class="elsevierStyleItalic">n</span> &#61; 1 in the placebo group&#41;&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tb1fn5"
              "etiqueta" => "e"
              "nota" => "<p class="elsevierStyleNotepara" id="notep0007">Computed tomography findings data were missing for 14&#46;4 &#37; of patients &#40;<span class="elsevierStyleItalic">n</span> &#61; 12 in the vitamin D<span class="elsevierStyleInf">3</span> group and <span class="elsevierStyleItalic">n</span> &#61; 16 in the placebo group&#41;&#46;</p>"
            ]
            5 => array:3 [
              "identificador" => "tb1fn6"
              "etiqueta" => "f"
              "nota" => "<p class="elsevierStyleNotepara" id="notep0008">Reference values&#58; Platelet &#40;150&#8210;400&#47;10<span class="elsevierStyleSup">3</span>&#47;&#181;L&#41;&#59; Mean platelet volume &#40;9&#46;4&#8210;12&#46;4 Fl&#41;&#59; ESR &#40;&#8804; 15 mm&#47;h&#41;&#59; C-reactive protein &#40;&#60; 5 mg&#47;L&#41;&#59; D-dimer &#40;&#60; 500 ng&#47;mL&#41;&#46;</p>"
            ]
          ]
        ]
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          "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall">Baseline demographic and clinical characteristics&#46;</p>"
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        "identificador" => "tbl0002"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0002"
            "detalle" => "Table "
            "rol" => "short"
          ]
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        "tabla" => array:3 [
          "leyenda" => "<p id="spara006" class="elsevierStyleSimplePara elsevierViewall">Data expressed as n &#40;&#37; within group&#41; and median &#40;IQR&#41;&#46; Data were analyzed by Generalized Estimating Equations &#40;GEE&#41;&#46; aCL&#44; Anticardiolipin&#59; a&#946;2-GP&#44; Anti-&#946;2-Glycoprotein-I&#46;</p><p id="spara007" class="elsevierStyleSimplePara elsevierViewall">No significant differences were observed between groups at baseline&#59; p-value derives from unadjusted group by time interaction from F-test&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0169"></a><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Outcomes</th><a name="en0170"></a><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Vitamin D<span class="elsevierStyleInf">3</span> group &#40;<span class="elsevierStyleItalic">n</span> &#61; 97&#41;</th><a name="en0171"></a><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Placebo group &#40;<span class="elsevierStyleItalic">n</span> &#61; 97&#41;</th><a name="en0172"></a><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p</th></tr><tr title="table-row"><a name="en0174"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Baseline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0175"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Discharge&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0176"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Baseline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0177"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Discharge&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0179"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">aCL IgG&#44; n &#40;&#37;&#41;<a class="elsevierStyleCrossRef" href="#tb2fn1"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0180"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">25 &#40;25&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0181"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">29 &#40;29&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0182"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">13 &#40;13&#46;4&#41;<a class="elsevierStyleCrossRef" href="#tb2fn2"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0183"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">25 &#40;25&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0184"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;046&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0185"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">aCL IgG&#44; U&#47;mL<a class="elsevierStyleCrossRef" href="#tb2fn1"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0186"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">22&#46;7 &#40;11&#46;4&#8210;41&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0187"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">26&#46;0 &#40;16&#46;1&#8210;48&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0188"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">17&#46;5 &#40;11&#46;5&#8210;28&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0189"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">25&#46;6 &#40;13&#46;7&#8210;41&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0190"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;160&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0191"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">aCL IgM&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0192"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">14 &#40;14&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0193"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">14 &#40;14&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0194"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">14 &#40;14&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0195"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">20 &#40;20&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0196"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;139&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0197"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">aCL IgM&#44; U&#47;mL<a class="elsevierStyleCrossRef" href="#tb2fn1"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0198"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">17&#46;3 &#40;11&#46;2&#8210;30&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0199"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">22&#46;0 &#40;14&#46;6&#8210;34&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0200"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">16&#46;4 &#40;10&#46;3&#8210;29&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0201"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">18&#46;0 &#40;13&#46;3&#8210;32&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0202"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;550&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0203"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">aCL IgA&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0204"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">6 &#40;6&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0205"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">7 &#40;7&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0206"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">9 &#40;9&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0207"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">8 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0208"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;559&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0209"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">aCL IgA&#44; U&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0210"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">14&#46;7 &#40;10&#46;2&#8210;22&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0211"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">14&#46;8 &#40;11&#46;1&#8210;20&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0212"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">17&#46;0 &#40;11&#46;9&#8210;24&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0213"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">17&#46;7 &#40;11&#46;2&#8210;24&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0214"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;097&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0215"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">a&#946;2-GP IgG&#44; n &#40;&#37;&#41;<a class="elsevierStyleCrossRef" href="#tb2fn1"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0216"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">11 &#40;11&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0217"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">19 &#40;19&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0218"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">19 &#40;19&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0219"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">21 &#40;21&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0220"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;145&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0221"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">a&#946;2-GP IgG&#44; U&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0222"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">4&#46;6 &#40;2&#46;8&#8210;7&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0223"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">4&#46;7 &#40;3&#46;1&#8210;8&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0224"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#46;0 &#40;2&#46;9&#8210;8&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0225"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#46;6 &#40;3&#46;8&#8210;9&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0226"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;493&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0227"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">a&#946;2-GP IgM&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0228"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">31 &#40;32&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0229"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">32 &#40;33&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0230"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">28 &#40;28&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0231"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">35 &#40;36&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0232"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;300&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0233"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">a&#946;2-GP IgM&#44; U&#47;mL<a class="elsevierStyleCrossRef" href="#tb2fn1"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0234"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">7&#46;1 &#40;4&#46;1&#8210;10&#8210;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0235"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">7&#46;7 &#40;4&#46;5&#8210;11&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0236"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">6&#46;3 &#40;3&#46;8&#8210;10&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0237"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">8&#46;1 &#40;4&#46;6&#8210;12&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0238"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;152&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0239"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">a&#946;2-GP IgA&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0240"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">41 &#40;42&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0241"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">38 &#40;39&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0242"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">45 &#40;46&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0243"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">46 &#40;47&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0244"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;551&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0245"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">a&#946;2-GP IgA&#44; U&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0246"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">9&#46;8 &#40;6&#46;9&#8210;15&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0247"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">10&#46;3 &#40;6&#46;7&#8210;15&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0248"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">11&#46;5 &#40;7&#46;3&#8210;17&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0249"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">11&#46;3 &#40;6&#46;6&#8210;18&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0250"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#46;772&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spara005" class="elsevierStyleSimplePara elsevierViewall">Effect of vitamin D<span class="elsevierStyleInf">3</span> on autoantibodies in patients with moderate to severe COVID-19&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "cebibsec1"
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            0 => array:3 [
              "identificador" => "bib0001"
              "etiqueta" => "1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "COVID-19 infection and rheumatoid arthritis&#58; faraway&#44; so close&#33;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "EG Favalli"
                            1 => "F Ingegnoli"
                            2 => "O De Lucia"
                            3 => "G Cincinelli"
                            4 => "R Cimaz"
                            5 => "R Caporali"
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                        ]
                      ]
                    ]
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                    0 => array:1 [
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                        "tituloSerie" => "Autoimmun Rev"
                        "fecha" => "2020"
                        "volumen" => "19"
                        "numero" => "5"
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                    ]
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                    0 => array:2 [
                      "titulo" => "Arthralgia as an initial presentation of COVID-19&#58; observation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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Article information

ISSN: 18075932
Original language: English

DOI:10.1016/j.clinsp.2024.100474

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