key: cord-0831496-mem5fokx authors: Scholze, A. R.; Melo, E. C.; Major, C. B.; Cruz, C. F.; Alcantara, L. R.; Dalcol, C.; Seiva, F. R. F.; Mantovani, M. d. F.; Mattei, A.; Silveira, H. S.; Chuffa, L. G. d. A. title: Differences and similarities in diagnostic methods and treatments for Coronavirus disease 2019 (COVID-19): a scoping review date: 2020-11-03 journal: nan DOI: 10.1101/2020.10.30.20222950 sha: 881161f0eeaa210f4f439e0c050542d1f1b3ed23 doc_id: 831496 cord_uid: mem5fokx Aims: We investigate a range of studies related to COVID-19 with focus on scientific evidence reporting the main diagnosis and treatments of the disease. Main Methods: Scoping review conducted in the databases, MEDLINE, Cochrane, Embase, LILACS, Scopus, and Web of Science, and the gray Google Scholar literature, until May 2020. We follow PRISMA-SCR and the recommendations of the Joanna Briggs Institute. The identified studies were independently selected by peers. The qualitative data extracted were synthesized and organized into categories, and the quantitative data were generated through descriptive and inferential statistics. Key-findings: 6060 articles were identified, of which 30 were included in this review. The publications are predominantly from China (n=22, 73.3%), and with a type of cross-sectional study (n=12, 40.0%), followed by a cohort (n=7, 23.0%). Among them, 16 studies addressed the diagnosis, and computed tomography was considered as non-invasive complementary method for detecting and evaluating the progression of COVID-19. Laboratory tests have been used to detect enzymatic or viral activities, and to monitor the inflammation associated with COVID-19. 14 studies included different therapeutic associations, such as Lopinavir/Ritonavir (LPV/r) and Arbidol, Hydroxychloroquine, Azithromycin, Tocilizumab and Remdesivir, and Corticosteroids/Plasminogen. Significance: The evidence related to diagnostic methods are clear, and include tomography and laboratory tests. Medicinal or associated medications for the treatment of COVID-19, although showing a reduction in signs and COVID-19-related symptoms, can cause adverse effects of mild or severe intensity depending on viral load and inflammatory activity. Additional studies should be performed to identify the most reliable treatment for COVID-19. The current pandemic experienced globally, beginning in the city of Wuhan, China, at the end of 2019, is caused by a novel coronavirus called SARS-CoV-2, the disease being named COVID-19. Coronavirus is a family of viruses that cause respiratory diseases in humans, from the common cold to diseases such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), which resulted in high mortality rates in 2003y and 2012y, respectively [1] . To date, the disease has affected more than 27 million individuals in 216 countries, areas, or territories, culminating in more than 890 thousand confirmed deaths throughout the world. According to the number of cases, the most affected regions are the regions of the Americas, Southeast Asia, and Europe [1]. The main signs and symptoms of COVID-19 are multiple and include fever (83% -99%), cough (59% -82%), fatigue (44% -70%), decreased appetite (40% -84%), dyspnoea (31% -40%), myalgia (11% -35%), as well as other less specific symptoms involving the sore throat, nasal congestion, headache, diarrhea, nausea and vomiting, loss of olfactory sensitivity or taste [2] . In addition to the signs and symptoms, the diagnosis of COVID-19 are often performed by two methods: the molecular test and the serological test. The molecular test, known as RT-PCR, identifies the presence of the virus during the acute phase of the disease, and the serological test, also known as the rapid test, checks the antibody response of a given individual after days to weeks, indicating that the person has already been infected with SARS-CoV2. However, there are still uncertainties regarding the tests currently used with regard to sensitivity, specificity, and the ability to assess cross-reactivity with other types of coronavirus, such as SARS-CoV and MERS [1] . Regarding the available treatments, the agentes or compounds most often mentioned as "possible healing agents" are chloroquine, hydroxychloroquine, and azithromycin; however, the evidence is insufficient to indicate the use of a particular drug, alone or combined, during the treatment of COVID-19, and its use may be associated with more adverse effects than benefits. Following the incessant rush in searching for an effective treatment, several studies have adopted dubious measures in relation to the scientific robustness, in order to justify their clinical use [2] . This review followed the guidelines of the Preferred Reporting Items for Systematic reviews and Meta-Analyzes extension for Scoping Reviews (PRISMA-ScR), according to the stages of identification, screening, eligibility, and inclusion of studies [6] . The stage of identification of the studies was carried out by three researchers together (S-AR, C-AB, and BM-C), and resulted in 6,060 articles, of which 190 were duplicated. The identified studies were organized in the Software State of the Art through Systematic Review (StArt), which contributed to the selection, screening, and extraction of data, according to the inclusion and exclusion criteria. The inclusion and exclusion criteria were widely discussed among the researchers. Results of primary and secondary evidence, from the adult population over 18 years old, who presented methods of diagnosing COVID-19 and/or treating COVID- 19 were included. The studies involving partial results on COVID-19, technical notes, . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 preliminary reports, editorials, single case studies, approaches with a primary focus on pathophysiology, microbiology, or biochemistry were excluded. The articles were screened based on two stages. In the first stage, an independent review was carried out by six pairs of researchers to reduce the potential bias (S-AR and AL; C-AB and C-CFR; DC and BM-C; M-EC and S -FRF; C-LGA and S-HS; M-AT and M-MF). A form for selection, sorting, and data extraction was developed in the StArt software and pre-tested by the researchers. Each researcher individually evaluated 980 titles and articles abstracts, approximately, regarding the inclusion or exclusion criteria, with subsequent issuance of the "accepted" or "rejected" opinion. Those articles that had no abstract available, their full text was accessed for screening. In cases where there was disagreement between the researchers of the pair, the article was referred to a third reviewer. A total of 711 articles were eligible to read the full text. Kappa reliability, interobserver agreement was used. In the second stage of the screening, eleven The form developed in the StArt software helped to extract data, such as country and year of publication, study design (descriptive, cross-sectional, case-control, cohort, ecological, randomized, quasi-experimental trial, systematic review, integrative review, or scoping review), confirmation of COVID-19 by laboratory tests (PCR and/or rapid test) and/or diagnostic imaging (X-ray, ultrasound, tomography and/or resonance), type of treatment of convalescent plasma, anticoagulant, antibiotic, corticoid, antiretroviral and/or others) , drug name, dosage, efficacy (cure, death, clinical improvement, treatment change or ineffectiveness), results and outcomes, conclusions and/or recommendations. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 The extracted qualitative data were synthesized and organized into three categories, characterization of the included studies, diagnoses used for the detection of COVID-19, and associated treatments. Quantitative data regarding the geographic location of the literature and the type of approach, whether COVID-19 diagnosis and treatment or both, were georeferenced using ArcGIS Software version 10.6. The other data were analyzed using descriptive statistics, with the support of SPSS software version 20.0. According to the PRISMA statement, we initially selected 6.060 published articles. Among them, 190 articles were duplicated and finally excluded, resulting in 5.870 papers for the initial screening. After a careful screening and based on the scopus of the research, a total of 711 papers were included for full reading. Following the eligibility criteria, 30 papers were then adopted for the analysis (Figure 1 ). This study is presented in three categories as follows: characterization of the included studies, diagnoses used for the detection of COVID-19 and associated treatments. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 After analyzing the spatial distribution of publications associated with COVID-19 in the world, it was noted that, until the time of data collection, there were few countries that had developed studies on the treatment and diagnosis of COVID-19. In Figure 2 we can verify that, the stronger the color degradation, the greater the publications and, in those countries in which they were not painted, there was no study available in the databases. The Figure 3 shows the publications related to diagnosis (n= 16; 53.33%) and treatments (n = 14; 46.67%). Therefore, China was the country that developed the most studies focusing in both diagnosis and treatment (n = 22; 73.33%) followed by France (n = 2; 6.67%); the Japan, Switzerland, Italy, Qatar, and India had one study published. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 All articles were peer-reviewed and published in 2020 (from january to late may). Of note, four articles (13.3%) were published in the Journal of Medical Virology, two articles (6.6%) in the Journal of infection and in Radiology, respectively; the other articles were included in different journals. A number of important and specific types of studies were included in this review, and the most prevalent was the Cross-sectional (n = 12, 40.0%), followed by Cohort (n= 7, 23.0%), Systematic Review (n= 3, 10, 0%) and . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. Regarding the sampling of the included studies, the literature reviews included 10 to 13 articles, with an average of 11.33. Most notably, studies with human beings presented samples ranging from six to 4,880, with an average of 443.70 (Table 1) . Switzerland . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 19: initial assessment. [15] 16526 Clinical evaluation of a rapid colloidal gold immunochromatography assay for SARS-Cov-2 IgM/IgG. [16] Cohort China . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) China . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) To evaluate the diagnostic value of computed tomography (CT) and real-time reverse transcriptasepolymerase (rRT-PCR) chain reaction for COVID-19 pneumonia RRT-PCR can produce initial false-negative results. It is suggested that patients with typical computed tomography findings, but with negative rRT-PCR results should be isolated, and rRT-PCR should be repeated to avoid diagnostic errors 1980 Positive rate of RT-PCR detection of SARS-CoV-2 infection in 4880 cases from one hospital in Wuhan, China, from Jan to Feb 2020. [9] Retrospective analysis of Viral Nucleic Acid (NAT) tests of 4,880 cases from January 22 to February 14, 2020, at Renmin Hospital, Wuhan University The viral nucleic acid (NAT) test played an important role in identifying SARS-CoV-2 infection . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) To investigate the diagnostic value of serological testicles and dynamic variance of serum antibody in COVID-19 The serological test is effective for the diagnosis of SARS-CoV-2 infection. The positive rate and variance of the IgG titer are higher compared to IgM in COVID-19 16526 Clinical evaluation of a rapid colloidal gold immunochromatograph y assay for SARS-Cov-2 IgM/IgG. [16] To assess the potential to be used in screening patients with COVID-19 The colloidal gold immunochromatography assay for the SARS-Cov-2 specific IgM/IgG antibody has a sensitivity of 71.1% and specificity of 96.2% in this population, showing potential as a rapid diagnostic test . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) To evidence statistically relevant differences that may be useful in identifying positive and negative COVID-19 patients in plasma leukocyte (WBCs), platelets, Creactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ -glutamyl A combination of cutoff points for hematological parameters can help identify false positive/negative rRT-PCR testicles. A blood test analysis can be used as an alternative to rRT-PCR to identify patients positive for COVID-19 in countries that serve with a large shortage of reagents for rRT-PCR . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 8 COVID-19 or not (ID: 26301). There was a predictive capacity regarding the tomography resources. After analyzing the 1 st and 4 th days after admission, it is easy to predict early and non-invasively the progression to severe disease, providing a promising prognostic indicator for the clinical management of COVID -19 (ID: 27120). When analyzing the tomography images, most patients had peripheral lesion distribution (ID: 2045, 16332, 16386, 26301, 26904) , as well as ground glass density foci (ID: 2045, 16332, 16386, 26301, 26904, 42956) . There was also an association with advanced age, resulting in higher case number and in greater complexity of the pathology (ID: 16332, 26115 and 27120). We observed that the serological samples showed sensitivities to the IgM and to predict the result of the COVID-19 test, thus providing us a more precise detection method (ID: 42996). An interesting study sought to compare two groups of patients with positive rRT-PCR results (positive group) and 102 patients with negative rRT-PCR results (negative group), and it was indicated a strong association between COVID-19-positive patients with a low blood leukocytes (neutrophils, eosinophils, and basophils), lymphocytes and monocytes in the positive rRT-PCR group. Finally, elevation in activities of pyridoxal phosphate-dependent enzymes, AST and ALT were also observed in the positive group (ID: 26805). We registered and included 14 articles regarding the COVID-19 treatment as the main subject. The most common treatments included the Lopinavir/Ritonavir (LPV/r), Arbidol, Hydroxychloroquine, Azithromycin, Corticosteroids, and Plasminogen as therapeutic forms (Table 3) . Investigating whether lopinavir/ritonavir (LPV/r) in combination with other adjuvant drugs associated with pneumonia has a better therapeutic effect on COVID-19. Combined treatment of lopinavir/ritonavir compared to treatment with adjuvant drugs associated with pneumonia alone has a more evident therapeutic effect in reducing body temperature and restoring normal physiological mechanisms without evident toxic and side effects. Hospitalized with Severe Covid-19. [11] To evaluate the safety and efficacy of Lopinavir and Ritonavir against SARS-CoV-2 infections In patients with severe COVID-19 benefit, none were seen with treatment with lopinavir-ritonavir other than the standard treatment. Systematic review of the efficacy and safety of antiretroviral drugs against SARS, MERS or COVID-19: initial assessment. [15] This systematic review summarizes the clinical results of using antiretroviral drugs for the prevention and treatment of coronaviruses and the planned clinical trials. It is still uncertain whether LPV/r and other antiretrovirals improve clinical findings or prevent infection among patients at high risk of acquiring COVID-19. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101/2020.10.30.20222950 doi: medRxiv preprint 0 16533 Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study. [17] Comparison of treatment with arbidol and lopinavir/ritonavir (LPV/r) for patients with COVID- 19 with LPV/r only. In patients with COVID-19, there is an apparent favorable clinical response with an association of arbidol and LPV/r compared to LPV/r alone. Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients. [19] The result, especially approved in the ICU and/or mortality, was compared between patients with COVID-19 with TCZ and without TCZ. The TCZ added to the "standard treatment" reduces admissions to intensive care units and/or mortality in patients with COVID-19. TCZ may be decisive in the treatment of critically ill patients with COVID-19. Tocilizumab for the Treatment of Severe COVID-19. [20] Report an experience with tocilizumab in hospitalized patients with severe COVID-19 The possible role of tocilizumab in the treatment of patients with severe COVID-19 cannot be assure, since the decline in inflammatory markers, associated with radiological improvement and reduced ventilatory support requirements are encouraging, but the results needed to be confirmed in controlled and randomized studies. Plasminogen improves lung lesions and hypoxemia in patients with COVID-19. [21] To investigate whether plasminogen can improve lung injuries and hypoxemia caused by COVID-19 Although it is reported that plasminogen is dramatically increased in adults with Acute Respiratory Discomfort Syndrome, this study reinforces that additional plasminogen can be effective and efficient in the treatment of lung injuries and hypoxemia during loading by COVID-19. Although more studies are needed, this study highlights a possible hope of emergence to rapid epidemic 26112 Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an openlabel non-randomized clinical trial. [22] Assess the effect of hydroxychloroquine on respiratory viral loads. Hydroxychloroquine treatment is associated with the reduction/disappearance of viral load in patients with and its effect is reinforced by azithromycin. Corticosteroid treatment of patients with coronavirus disease 2019 . [25] To evaluate the effectiveness of corticosteroid treatment in patients with coronavirus 2019 Corticosteroids are widely used in the treatment of patients with COVID-19 but found no association between therapy and outcomes in patients without acute respiratory distress syndrome. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 1 26251 Tocilizumab treatment in COVID-19: A single center experience. [26] Discuss the response to treatment with tocilizumab therapy in patients infected with COVID-19. It showed a good response in patients with tocilizumab. The number of reported cases is still small and the use of laboratory parameters to define disease activity is still a challenge. The duration of treatment observed in our study may not be enough to make a final conclusion. Evaluation of Antiviral Therapies for Coronavirus Disease 2019 Pneumonia in Shanghai, China. [28] To evaluate the therapeutic effect of antiviral drugs on coronavirus pneumonia The inclusion of antiviral drugs in therapeutic regimens based on symptomatic treatment had no significant additional impact on improvement in patients with COVID-19. The results of chest tomography, clinical manifestations, and laboratory tests at hospital discharge were not consistent. Virological and Clinical Cure in Covid-19 Patients Treated with Hydroxychloroquine: A Systematic Review and Meta-Analysis. [29] To evaluate the efficacy and safety of Hydroxychloroquine in clinical settings. Treatment with hydroxychloroquine can result in benefits in fever cases, radiological progression, with a profile of adverse events when compared to control / conventional/standard treatment. Benefits in time for normalizing body temperature and days of coughing can be expected. However, no difference was seen for virological cure six to seven days after initiation of therapy and combined death or worsening of the disease. Treatment with the combination of hydroxychloroquine and azithromycin is uncertain at this time, with most data being reported by the same research group. 26717 Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19. [30] To evaluate the antiviral and safety effects of lopinavir/ritonavir and arbidol in patients with COVID-19. The results showed that Arbidol monotherapy are more effective than the combination of lopinavir / ritonavir in the treatment of COVID-19. 26988 Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebocontrolled, multicentre trial. [33] Evaluation of the effect of intravenous remdesivir in adults admitted to hospital with severe COVID-19. In this study of adult patients admitted to the hospital for severe COVID-19, remdesivir was not associated with statistically assessed clinical benefits. However, the numerical reduction in the time to clinical improvement in those treated previously required in larger studies. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 The studies that reported the effect of using Lopinavir / Ritonavir (LPV/r) pointed to several controversies and uncertainties about the effectiveness of the combination added to the standard treatment in people with Covid-19 (ID: 2099, 16445, 1897 and 26401) . Regarding the use of adjuvant drugs associated with pneumonia alone, the treatment with LPV/r showed a more evident therapeutic effect in reducing symptoms such as body temperature and in restoring normal physiological mechanisms. These therapeutic regimens showed no evident toxic/side effects and presented improvements in relation to laboratory results; they acted by reducing the abnormal proportion of white blood cells, lymphocytes, and C-reactive protein in COVID- 19infected patients (ID: 1897) . Considering the mortality rate in 28 days, both standard and combined treatment (LPV / r) were similar (19.2% vs. 25 .0%; 95% CI). In addition, some adverse effects such as nausea, vomiting and diarrhea were more common in patients treated with LPV / r (ID: 2099). A systematic review identified that administration of LPV/r compared to standard treatment did not show a significant difference in the time of clinical improvement (ID: 26401 and 16445), although the treated group showed the shorter time. Notably, the LPV/r-treated group displayed a lower mortality (ID: 16445) than that of standard treatment. The review highlights two studies describing a possible protective effect of LPV/r as profilaxis after viral exposure. In a cohort study, no differences were found between LPV/r-treated group and the standard treatment for the controlo of pneumonia and clinical results (ID: 26401). Other articles described the effect of Arbidol and LPV/r (ID: 16533, 26717), one of which evaluated the association of Arbidol and LPV/r compared to those treated with LPV / r only (ID: 16533) while other evaluated the combination of LPV/r with Arbidol monotherapy (ID: 26717). Both articles showed better results for the groups that either used Arbidol, in combination with LPV/r or even used as monotherapy. When comparing the use of Arbidol + LPV/r with isolated LPV/r, it was observed that chest CT images improved in 69.0% of patients who used the combination Arbidol + LPV. Furthermore, the detection rate of SARS-CoV-2 in nasopharyngeal samples after seven days of treatment was reduced in the group using the triple combination. By investigating these compounds affecting the viral loading, the authors demonstrated a 100.0% reduction in the detection of viral load after 14 days of . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 admission in patients treated with Arbidol (n = 16); otherwise, in the group treated with LPV/r (n = 34), the viral load was found in 44.1% of patients (ID: 26717). On the other hand, a cohort that evaluated the use of monotherapy with Arbidol found no clinical efficacy when compared with patients treated only for their symptoms (ID: 26401). This same study observed no improvements in pulmonary images or in the average length of hospital stay after combining with other antivirals (Arbidol + Ritonavir or Interferon + LPV/r or Interferon + Darunavir). Patients treated with Hydroxychloroquine (HCQ) (ID: 26402) demonstrated a reduction in radiological progression of the disease compared to conventional treatment (OR for radiological disease progression during treatment was 0.31; 95% CI, [0, 11-0.9] ). In addition to these results, there were signs of benefits of HCQ over time for normalizing body temperature while reducing the number of days of dry coughing. Through comparison of patients treated with HCQ and the controls (treated with conventional treatment), no expressive differences in virological cure (OR, 2.37, 95% CI, 0. 13-44.53) , death or clinical worsening of the disease (OR, 1.37, 95% CI, 1, 37-21.97 ) and safety (OR, 2.19, 95% CI, 0.59-8.18) was observed. Coversely, a clinical trial (ID: 26112) demonstrated a significant reduction or elimination of viral load; after six days of treatment inclusion, 70% of the patients were cured virologically compared to the control group (12.5%, p = 0.001). Regarding the adverse effects of HCQ, a total of seven events were identified in the systematic review and included nausea, diarrhea, abnormal liver function, skin rash and headache; however, when these results were combined and analyzed, no significant difference was observed between the two arms (OR, 2.19; 95% CI, [0.59- More importantly, the clinical trial showed that after five days of treatment with HCQ + Azithromycin, 100.0% of the patients presented with virological cure compared with 50.0% in those treated with HQC alone and 18.8% in the control group (p = 0.002) (ID: 26112). . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 Three articles reported the use of Tocilizumab in people with COVID-19 (ID: 25217; 25243 and 26251) and concluded that treatment with Tocilizumab significantly reduced the proportion of patients on invasive mechanical ventilation (ID: 25217 and 25243) and the number of death outcome and admissions to the Intensive Care Unit (ID: 25217). In addition, there was a significant reduction in C-reactive protein levels and benefits in decreasing inflammatory activity (ID: 26251). The adverse events associated with Tocilizumab were anemia, increased alanine aminotransferase and prolonged QT interval (ID: 25243). Regarding the use of Remdesivir, no time difference was observed until clinical improvement (risk ratio 1 23 [95% CI 0 87-1 75]). In addition, the adverse events were reported in 66% of treated patients, being the most described as constipation, hypoalbuminemia, hypokalemia, anemia, thrombocytopenia, and increased total bilirubin. Although not significant, the time to clinical improvement was faster for patients using Remdesivir (ID: 26988) By evaluating the efficacy of corticosteroids (Methylprednisolone) used in the treatment of COVID-19, it was not possible to verify an association between the treatment and the time of virus elimination, length of hospitalization or duration of symptoms. In fact, patients treated with corticosteroids had more clinical symptoms, a higher rate of inflammation and several abnormalities on chest tomography (ID: 26211). The inhalation of freeze-dried plasminogen was also evaluated in patients with COVID-19 and the main results for clinically moderate patients included improvements in lung injury conditions and reduction in the heart frequency; patients with more severe conditions tends to show better oxygen saturation (ID: 25876). This may be effective and efficient in the treatment of lung injuries and hypoxemia during infections by SARS-CoV-2. We conducted a scope review of COVID-19, thoroughly researching databases and other sources based on the geographic distribution of publications until May 2020, and, China was the country with the largest number of publications related to COVID-. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 19. Our scoping review consistently evaluated important studies that emerged during the first semester in an attempt to explore what is expected in terms of diagnosis and treatment. Facing this challenge, we incorporated several study types and research areas, with special attention to the randomised controlled trials and cohort studies, which were non-existent before early February. To date, the main diagnostic methods described included CT imaging and laboratory testing. It is assumed that imaging methods are effective to differentiate the degree and the involvement of the respiratory organs by the virus following patients stratification with various ages. In fact, the great majority of studies performed in hospitals and specialized clinics were dedicated to explore CT findings. Likewise, the laboratory tests using serum or nasopharyngeal samples of patients are widely used to detect produced antibodies, enzymatic activities or the viral counterparts. It seems true that the combination of CT images with RT-PCR provide a more realistic framework to detect the SARS-CoV-2 infection with disease aggravation. Other important parameters that should be taken into consideration after viral infection confirmation are the number of inflammatory and immune cells in association with the levels of PCR, LDH, AST, ALT, albumin, and urea. The research topics found in the articles/studies had both similarities and differences. Basic research was mostly settled on correlating the COVID-19 diagnosis with altered parameters and molecular signatures in a number of tissues and systems; for the current scoping, this was often filtered out so that we only adopt research on healthy patients to avoid sampling bias. It seems true that SARS-CoV-2 has also been detected in non-respiratory specimens, including blood, ocular fluids, stool, and semen; however, if these sites predispose to the transmission is still unclear [37] [38] [39] [40] [41] . Although the detection of SARS-CoV-2 RNA in blood has also been recently reported not all studies have tested it [42, 43] . Our review did not retrieve studies on detection of short-and long-term risks of reinfection. Despite the recent data on individuals tested for reinfection exists and follows a distinct paradigm [44, 45] , it is important to employ a combination of strategies, i.e., images and blood dosages, to map these immunological differences. This review may provide to other researchers identification of contradictory results and research gaps allowing future approaches to fill it. Notably, an integrative review matching the diagnostic methods with personal parameters throughout disease . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 evolution would be of great value. The reviews and short reports generally provide generic information of the virus, transmission, and treatments. A recent scoping review (from 01 december to 06 February) described in detail the evidence for the development of clinical practice guidelines and public health policies [46] ; in that time, the authors had few clinical research available. In this sense, our scoping review may add significant contribution to this study since it was centered in clinical practice advances and in medical management of hospitalized patients. On one hand, our scoping review has weakness regarding few studies and variability of methods and reported data. On the other hand, all studies have many strengths as they were well-conducted using large sample size and with high potential for reproducibility. The effectiveness of the treatments for COVID-19 are still controversial and open for tireless debate. Based on our scoping review, different drugs were tested, ones with better outcomes than others. During the period we evaluated the studies, there were no therapeutic regimen with specific dosage or duration that can be applied to every patient; so far, a vaccine is not available. We now summarize and discuss the main results about the treatments we have surveyed. Patients treated with the HIV combined therapy Lopinavir (PubChem CID: 92727) and Ritonavir (PubChem CID: 392622) had improved laboratory results, but the mortality rate did not differ between LPV/r and the standard protocol (ID: 26401 and 16445). Besides, the certainty of the evidence of randomized and observational studies were frequently low. Corroborating this issue, a randomized, controlled, open-label trial with 199 adult patients found no additional benefits with LPV/r treatment compared to standard supportive care alone, i.e., oxygen and vasopressor support, antibiotics, renalreplacement therapy and extracorporeal membrane oxygenation. Also, after 28 days of the combined treatment the viral RNA loads or duration of viral RNA detectability were similar between patients in the LPV/r and in the standard care group [11] . On the other hand, studies evaluating the combination of LPV/r with Arbidol (PubChem CID: 31411) or Arbidol monotherapy had distinct outcome (ID: 16533, 26717), making Arbidol, also known as Umifenovir, a promising repurposed candidate to treat COVID- 19 . In a small cohort with 67 patients admitted with abnormal chest CT findings, Arbidol treatment tended to increase the discharging rate and reduced mortality [47] . To confirm the efficacy of the treatment with Arbidol there is an ongoing randomized, open, multicenter clinical trial scheduled to publish its outcomes in December of the . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 current year (NCT04260594). Anyway, the findings of our review lead us to believe that the combination of Lopinavir, Ritonavir and Arabidol may help in delaying the progression of lung injuries while decreasing the likelihood of respiratory and gastrointestinal transmission, and avoiding long-standing hospitalization as well. However, we do not rule out the need for new randomized, multicenter research with larger samples. Although chloroquine (PubChem CID:3652) and its safer derivative, hydroxychloroquine (PubChem CID:3652) have already a well-documented history for coping malaria and inflammatory autoimmune disease, these drugs are under the spotlight of a heated debate about their safety, efficacy and cost benefit for the treatment of COVID-19. For the sake of contextualize hydroxychloroquine has a more potent in vitro activity, i.e., lower EC 50 , and is more effective than chloroquine for both prophylaxis and treatment [48] . The study by Sarma and colleagues demonstrated that HCQ improved the radiologic findings, shortened the periods of fever and dry coughing, however, it was not observed significantly difference in the viral clearance compared to the control group. A prospective randomized study of 30 patients in China showed that after seven days receiving HCQ plus standard cares, virologic clearance was similar to those who received the standard care alone [49] . On the other hand, Gautret et al. [50] demonstrated the efficiency of HCQ in clearing viral nasopharyngeal carriage and went farther showing that, within five days, the combination of HCQ with the antibiotic Azithromycin (PubChem CID:447043) negativized 6 of 6 patients infected with the SARS-CoV-2 versus 8 of 14 patients that received HCQ alone. Weighing up the pros and cons of the possible therapeutic regimens with chloroquine or HCQ, one may argue that these drugs are relatively well tolerated and no significant adverse effects have been reported at the doses and durations proposed for COVID-19 treatment [51] ; on the flip side, it should not be disregard the serious possible adverse effects that, though rare, include QTc prolongation, hypoglycemia, neuropsychiatric effects, and retinopathy [52] . Furthermore, there were few statistically robust results confirming the regimen efficacy. Together, these evidence lead us to suggest that before initiating the treatment for COVID-19, it is mandatory an individualized, detailed, independent and, above all, consensual assessment to make the best possible choice. When the therapy was conducted with Tocilizumab (PubChem SID: 135345962) the number of patients that were admitted to Intensive Care Unit and needed invasive . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 mechanical ventilation was reduced (ID: 25217; 25243 and 26251). From those patients who were already in ICU, 76% improved or remained stable after Tocilizumab treatment. Overall, from 100 patients admitted in one study, 77 of them benefited from the treatment. However, 23 patients had their respiratory condition worsened and 20 of them died [53] . Contrasting this study, a cohort conducted by Campochiaro et al. [54] verified no clinical improvement or reduced mortality between tocilizumab and standard treatment patients. The use of Remdesivir (PubChem CID: 121304016) did not improve clinical outcomes and was associated with some adverse effects. Therefore, we reinforce the need for more literature about the definitive efficacy of the humanized monoclonal antibody that targets the IL-6 receptor, and about the ATP analog. More recently, the solidary big trial by WHO, which enrolled approximately 11,000 individuals in 400 hospitals around the world, revealed that hydroxychloroquine, ritonavir/lopinavir, and remdesivir did not increase patients survival nor lowered mortality or delayed the urgent need for artificial ventilation [55] . Although there is enough evidence that inflammatory status plays a determinant role in the clinic evolution of patients with COVID-19, a study (ID: 26211) analyzing the use of methylprednisolone (PubChem CID: 6741) showed no benefit, but only adverse effects. Conversely, 26 patients treated with low-dose of corticosteroid for a few days had faster recovery and improvement of lung symptoms [47] . According to Saghazadeh et al. [56] , the use of corticosteroids may cause suppression of antiviral immune response, so the empiric use of this class of drug may be restricted until controlled clinical trials prove that this treatment modality ameliorates the inflammatory-related symptoms and reduces the COVID-19-related death. The inhalation of manipulated plasminogen was useful in treating lung lesions and hypoxemia, however this was demonstrated by only one study, and the heterogeneity of the patients (clinically moderate, severe or critical) reinforces the need for further trials. The main evidence related to diagnostic methods is clear, and includes tomography and laboratory tests. However, we felt a lack of rigorous studies focused on novel and more reliable diagnostics methods. The medications for the treatment of COVID-19, although showing some reduction of the signs and symptoms related to this disease, the viral load, inflammatory activity and mortality, may cause adverse effects . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 of mild, medium or severe intensity. More studies are encouraged to continuously review and update the literature on this subject to effectively uncover a feasible therapy to fight COVID-19 until the vaccine is released safely and affordable. This research did not receive any specific grant from funding agencies. Data and materials are fully available without restriction The authors declare no conflict of interest. All authors approved the final manuscript LGAC, HSS: design, critical analysis and draft the manuscript. The authors approved the final version of the manuscript. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org /10.1101 /10. /2020 The role of resveratrol and melatonin in the nitric oxide and its oxidation products mediated functional and structural modifications of two glycolytic enzymes: GAPDH and LDH PRISMA extension for scoping reviews (PRISMA-ScR): Checklist and explanation Diagnosis of the Coronavirus disease (COVID-19): rRT-PCR or CT? 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