key: cord-274481-k1dp1ilv
authors: Falavigna, Maicon; Colpani, Verônica; Stein, Cinara; Azevedo, Luciano Cesar Pontes; Bagattini, Angela Maria; de Brito, Gabriela Vilela; Chatkin, José Miguel; Cimerman, Sergio; Corradi, Mirian de Freitas Dal Ben; da Cunha, Clovis Arns; de Medeiros, Flávia Cordeiro; de Oliveira Junior, Haliton Alves; Fritscher, Leandro Genehr; Gazzana, Marcelo Basso; Gräf, Débora Dalmas; Marra, Lays Pires; Matuoka, Jessica Yumi; Nunes, Michelle Silva; Pachito, Daniela Vianna; Pagano, Cássia Garcia Moraes; Parreira, Patrícia do Carmo Silva; Riera, Rachel; Silva Júnior, Amilton; Tavares, Bruno de Melo; Zavascki, Alexandre Prehn; Rosa, Regis Goulart; Dal-Pizzol, Felipe
title: Guidelines for the pharmacological treatment of COVID-19. The task-force/consensus guideline of the Brazilian Association of Intensive Care Medicine, the Brazilian Society of Infectious Diseases and the Brazilian Society of Pulmonology and Tisiology
date: 2020
journal: Rev Bras Ter Intensiva
DOI: 10.5935/0103-507x.20200039
sha: 
doc_id: 274481
cord_uid: k1dp1ilv

INTRODUCTION: Different therapies are currently used, considered, or proposed for the treatment of COVID-19; for many of those therapies, no appropriate assessment of effectiveness and safety was performed. This document aims to provide scientifically available evidence-based information in a transparent interpretation, to subsidize decisions related to the pharmacological therapy of COVID-19 in Brazil. METHODS: A group of 27 experts and methodologists integrated a task-force formed by professionals from the Brazilian Association of Intensive Care Medicine (Associação de Medicina Intensiva Brasileira - AMIB), the Brazilian Society of Infectious Diseases (Sociedad Brasileira de Infectologia - SBI) and the Brazilian Society of Pulmonology and Tisiology (Sociedade Brasileira de Pneumologia e Tisiologia - SBPT). Rapid systematic reviews, updated on April 28, 2020, were conducted. The assessment of the quality of evidence and the development of recommendations followed the GRADE system. The recommendations were written on May 5, 8, and 13, 2020. RESULTS: Eleven recommendations were issued based on low or very-low level evidence. We do not recommend the routine use of hydroxychloroquine, chloroquine, azithromycin, lopinavir/ritonavir, corticosteroids, or tocilizumab for the treatment of COVID-19. Prophylactic heparin should be used in hospitalized patients, however, no anticoagulation should be provided for patients without a specific clinical indication. Antibiotics and oseltamivir should only be considered for patients with suspected bacterial or influenza coinfection, respectively. CONCLUSION: So far no pharmacological intervention was proven effective and safe to warrant its use in the routine treatment of COVID-19 patients; therefore such patients should ideally be treated in the context of clinical trials. The recommendations herein provided will be revised continuously aiming to capture newly generated evidence.

Early in December 2019, the first cases of novel pneumonia from unknown etiology were described in the city of Wuhan, China. Subsequent studies have

The recommendation panel was composed of 13 voting members, guideline methodologists (five members), and researchers responsible for the literature systematic review (nine members). The participants were indicated by the specialty societies or by the group methodologists, aiming to provide representativity and balance of technical competencies.

Potential conflicts of interest data were collected with the standard WHO formulary. Members with a direct financial conflict of interest related to a given intervention had no right to vote for the related questions. A list of participants, their role in the guideline, and statement of conflicts of interest are provided in appendix 1.

The questions were first proposed by the group of methodologists, and revised by the panel experts. The inclusion criteria were: a drug available for prescription in Brazil, and a clinical practice variability, or a clinically relevant doubt related to its use, being this last the prioritizing factor for clinical questions.

Eight questions were prepared according to the acronym PICO (population, intervention, comparator, and outcome), considering six drug classes (aminoquinolines, antivirals, antibiotics, corticosteroids, anticoagulants, and immunobiologicals). Each research question could generate one or more recommendations.

Remdesivir was not included in this document as, by the assessment time, it was not approved for prescription in Brazil. Were considered, but not prioritized, questions related to the use of nonsteroidal anti-inflammatory drugs and angiotensin receptor blockers (ARBs) or angiotensinconverting enzyme inhibitors. During the conduction of the recommendations panel, the question on the use of heparin was requested to be included, once it was not part of the initial scope.

The searches were conducted on MEDLINE (via Pub-Med®), the Cochrane CENTRAL, and Embase databases, and also in the grey-literature bases, between April 22 and 30, 2020. Additionally searches on prepublication articles sources, such as OpenGrey (http://www.opengrey.eu), meDrxiv (https://www.medrxiv.org), and Biorxiv (www. biorxiv.org) were conducted; these articles were considered during the analyses, even though not peer-reviewed.

The search strategies are shown in appendix 2. Additional evidence, emerging during the process and identified by members of the group, were considered during the discussions, although not included in the initial search results.

Literature search, data extraction, and synthesis were performed by one single investigator and checked by a second revisor in case of doubts or inconsistencies. (11, 12) The synthesis was conducted in a qualitative model. First, titles and abstracts of the identified manuscripts were identified by the search strategy, and potentially eligible studies preselected. Second, the full text of the selected papers was assessed, to confirm eligibility.

Considering the limited number of studies published so far, the following study designs were taken into consideration according to the evidence hierarchy: randomized clinical trials, quasi-randomized clinical trials, non-randomized clinical trials, cohort studies, casecontrol studies, series and case studies. The assessment of methodological quality and/or risk of bias of the included articles was conducted with tools appropriate for each study design: AMSTAR-2 for systematic reviews with and without metanalysis; (13) Cochrane's risk of bias table for randomized clinical trials; (14) ROBINS-I for non-randomized or quasi-randomized clinical trials; (15) ROBINS-I or Newcastle-Ottawa for longitudinal comparative observational studies (case-control and cohort); (15, 16) the Joanna Briggs Institute case-series tool for phase I or phase II trials without a direct comparator and case-series (17) and the Joanna Briggs Institute toll for cross-sectional studies. (18) 

The GRADE (9, 19) system was used for the assessment of the quality of the evidence and the development of recommendations. Previously to the recommendations meetings, the certainty of the evidence was rated either as high, moderate, low, or very low (Table 1) .

According to this methodology, recommendations may be either strong or weak (conditionals), favorable or against the intervention. The implication of the strength of the recommendation is shown in table 2.

The data from the systematic review for each PICO question were compiled into evidence profiles and presented to the experts' panel. (20) (21) (22) (23) (24) For the development of recommendations were considered: benefits, risks, quality of the evidence, costs, and variability of implementation. The recommendations were agreed upon by teleconferences held on May 5, May 8, and May 13, 2020. Whenever appropriate, the panel could provide recommendations according to subpopulations. A consensus was aimed for all the recommendations; if no consensus could be achieved, a voting procedure was conducted, and a simple majority required for approval of that specific recommendation.

The target population for the recommendations is constituted of patients either diagnosed or clinically suspected of SARS-CoV-2 infection. Clinical suspicion is when, based on epidemiological data, clinical history, signs, and symptoms, in addition to complementary tests, COVID-19 is the most likely diagnostic hypothesis. Information on diagnosis can be found elsewhere. (25) (26) (27) The disease severity was grouped into five categories, in line with the National Institutes of Health (NIH) guidelines for the treatment of COVID-19 (Table 3 ). (28) For the categorization of acute respiratory distress syndrome (ARDS) the Berlin's criteria were adopted as presented in table 4 .

Eleven recommendations were issued. These recommendations are summarized in table 5. Detailed information on the evidence is shown in appendix 3, as GRADE evidence profiles, with complete references. 

High Strong confidence that the true effect lies close to that of the effect estimate. It is unlikely that additional trials will change the confidence in the estimated effect.

Moderate Moderate confidence in the effect estimate. Future trials may modify the confidence in the effect estimate, and also can change the estimate.

Limited confidence in the effect estimate. Future trials are likely to importantly impact our confidence in the effect estimate.

Very Low Uncertain confidence in the effect estimate. Any effect estimate is uncertain.

Source: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach. Updated October 2013. Available from: https://gdt.gradepro.org/app/handbook/handbook.html. (19) 

The recommendation should be adopted as a healthcare policy in most of the situations.

Substantial debate required and the involvement of stakeholders.

Most of the individuals would want the intervention to be indicated, and only a small number would reject the recommendation.

A large portion of the individuals would want the intervention to be indicated; however, some individuals would reject the recommendation.

Most of the patients should receive the recommended intervention. The clinician should acknowledge that different choices are appropriate for each patient and choose consistently with his/her values and preferences. May 18] . Available from: https:// www.covid19treatmentguidelines.nih.gov/. (28) 

Recommendation 1 -we suggest against the routine use of hydroxychloroquine or chloroquine for treatment of COVID-19 patients (weak recommendation; Level of Evidence: low).

Summary of the evidence: the systematic review identified three comparative clinical trials with available data on the effects of hydroxychloroquine (HCQ) in COVID-19 patients: two open randomized clinical trials (29, 30) in a patient population with mild to moderate disease, and one cohort study. (31) No trials comparing chloroquine (CQ) to non-CQ therapy were found. The combined data from both clinical trials failed to show clinical-radiological improvement (relative risk -RR = 0.61; 95% confidence interval [95%CI] 0.26 -1.43), or improved viral negativation rates within seven days (RR = 2.00; 95%CI 0.02 -20.00), (29, 31) however, one of the studies prepublication version has shown on the raw data analysis an increased improvement rate with HCQ (80.6% versus 54.8%; p = 0.0476). (30) Mortality and mechanical ventilation requirements, considered to be clinically relevant outcomes, were assessed in an observational study with 364 patients, (32) showing an increased mortality rate with HCQ (HCQ: 27.8%; HCQ + azithromycin: 22.1%; standard therapy: 11.4%), with a significant association remaining after the propensity score-adjusted analysis comparing HCQ to the standard therapy (hazard ratio -HR = 2.61; 95%CI 1.10 -6.17). (32) After the review date, an additional cohort study was identified involving 1,376 moderate to severe COVID-19 hospitalized patients. In this study, no association was found with death or invasive mechanical ventilation requirement (HR = 1.04; CI95% 0.82 -1.32). (33) This trial was considered in the evidence analysis and because it was a well-designed observational study, with adjustment for confounders and appropriate sample size, the degree of confidence for the lack of benefit was increased from very low, to low.

The association between HCQ and arrhythmias is well-known. An observational study has shown that seven out of 37 (19%) patients receiving HCQ monotherapy developed a QT interval ≥ 500ms. (34) Additionally, in a randomized clinical trial that compared patients using high-dose (1,200mg CQ for 10 days; total dose 12g) versus a lower dose (900mg on the first day, followed by 450mg daily for four days; total dose 2.7g), a 13.5% (95%CI 6.9 -23.0%) overall mortality rate was found in association with the high-dose (in this trial both groups had a cointervention with ceftriaxone and azithromycin), suggesting a potential dose-response gradient. (35) Comments: the recommendations panel interpreted that the available evidence suggests no clinically significant benefit of HCQ or CQ therapy. There was an agreement that the risk of cardiovascular adverse events is moderate, particularly regarding arrhythmias. So far, the existing comparative trials have only assessed hospitalized patients, therefore providing no basis for considerations on using or not these drugs in outpatients. The prescription of these products may be considered on a shared clinicianpatient decision, only for severe or critically ill patients, hospitalized, under constant QTc interval monitoring, and avoiding concomitant QTc prolonging therapies. Its use should preferably be under clinical trial protocols.

Recommendation 2 -we suggest against the routine use the hydroxychloroquine or chloroquine plus azithromycin combination for treatment of COVID-19 patients (weak recommendation; Level of Evidence very low).

Summary of the evidence: no clinical trials were identified to assess azithromycin monotherapy. Azithromycin added to an HCQ regimen was assessed in one single trial, showing improved viral negativation in the group treated with the combination therapy (HQ + azithromycin 100%; n = 6/6 versus HQ 57%; n = 8/14; six-day negativation). (36) No randomized clinical trials were identified for the comparison of HCQ + azithromycin versus standard therapy. Viral negativation was assessed by four studies, three from the same research group, showing viral negativation above 90% after five to 10 days therapy; (36) (37) (38) in contrast, in one study treating ten patients with HCQ + azithromycin, negativation was found in only two patients (20%). (39) A total of six studies assessed mortality, with 35 deaths among 1,342 patients. (35, (37) (38) (39) (40) (41) Regarding adverse cardiovascular events, eight studies were identified. Five of them found a prolonged QT interval in some patients treated with HCQ/CQ plus azithromycin. (35, 39, 40, 42, 43) A retrospective analysis of 130 thousand rheumatoid arthritis patients showed an increased risk of cardiovascular death with HCQ + azithromycin as compared with HCA + amoxicillin (HR = 2.19; 95%CI 1.22 -3.94; 30-day outcome). (44) The same analysis has also shown an increased risk of angina (HR = 1.15; 95%CI 1.05 -1.26) and heart failure (HR = 1.22; 95%CI 1.02 -1.45). In a non-comparative trial with 1,061 patients with HCQ + azithromycin, no patient has shown to have heart toxicity. (38) Comments: the recommendations panel interpreted that the available evidence does not suggest a clinically significant benefit from the treatment with HCQ or CQ in combination with azithromycin. There was an understanding that there is an associated moderate increase of cardiovascular adverse events, especially arrhythmias, potentialized by the association of HCQ/ CQ with azithromycin, and additional care related to these adverse events is required. So far, the existing comparative trials have only assessed hospitalized patients, providing no basis for discussions on using or not this combination in outpatients. Its use may be considered in a shared clinician-patient decision, only in severe or critically ill patients, hospitalized, with frequent QTc interval monitoring and avoiding QTc prolonging concomitant therapy. Its use should be preferentially under clinical trial protocols.

Recommendation 3 -we recommend against the use of oseltamivir for the treatment of COVID-19 in patients with no suspected influenza coinfection (strong recommendation; Level of Evidence very low).

Recommendation 4 -We suggest the use of empirical oseltamivir treatment in patients with Severe Acute Respiratory Syndrome (SARS) or flu-like syndrome with risk factors for complications when a diagnosis of influenza cannot be ruled out (weak recommendation; Level of Evidence very low).

Summary of the evidence: no randomized clinical trial assessing the effectivity of oseltamivir in COVID-19 patients was identified. A cohort study with 504 COVID-19 hospitalized patients assessed the use of oseltamivir, lopinavir/ritonavir, and umifenovir. (45) The mortality rate in the oseltamivir group (n = 66) was 12.2% versus 16.2% in the non-oseltamivir group (odds ratio -OR = 0.71; 95%CI 0.28 -1.59). Also, no difference was found regarding lung injury improvement as assessed by a chest CT scan (41.2% versus 43.3%). The study has important methodological issues, such as lacking randomization, sample representativity, and control for confounders.

Comments: the recommendations panel interpreted that there is no evidence to support the use of oseltamivir for SARS-CoV-2 therapy; besides, there is no theoretical rationale to support this use.

However, oseltamivir may be considered in cases of suspected influenza infection in patients with ARDS or flu-like syndrome with risk-factors for influenza complications (chronic diseases, immunosuppression, age ≥ 65 years, and pregnant women). (46) The usual dose for adults with appropriate renal function is 75mg twice daily for five days. (25, 47) Suspected influenza should take into consideration the patient's symptoms, radiological findings, as well as local epidemiology. A suspect may remain even in individuals with a history of immunization, once the vaccine's effectiveness is rarely above 80%. (48, 49) If testing for influenza is possible, oseltamivir may be stopped upon negative results, given the available test has appropriate sensitiveness for seasonal A, B, and H1N1 influenza. The decision on oseltamivir use was made based on indications for its use out of the context of the COVID-19 pandemic, with no appropriate information on the behavior of influenza in the scenery of a SARS-CoV-2 epidemics. (46) If well-developed local protocols are in place, we suggest them to be adhered to.

Recommendation 5 -we suggest against the routine use lopinavir/ritonavir for treatment of COVID-19 (weak recommendation; Level of Evidence low).

Summary of the evidence -two randomized clinical trials assessed the use of lopinavir/ritonavir in COVID-19 patients. (50,51) One of them assessed 90 patients in the lopinavir/ritonavir group and 100 patients with standard therapy. Patients in the intervention group had lower but not statistically significant mortality rates (19.2% versus 25%; 28-day mortality rate), and no clinically significant improvement within 14 days (45.5% with the intervention versus 30% in the control group; p < 0.05); the time to clinical improvement was reduced in one day (median: 15 days versus 16 days; HR = 1.39; 95%CI 1.00 -1.91; modified intention-to-treat analysis, excluding three early mortality patients). (50) Another randomized clinical trial included 21 patients in the lopinavir/ritonavir group and seven in the control group, with no statistically significant difference between the groups for outcomes such as fever, coughing relief rate, clinical condition deterioration rate, and CT scan improvement. (51) In both trials, there was no viral negativation difference between the groups. The adverse effects observed included anorexia, nausea, abdominal discomfort or diarrhea, acute gastritis, and reduced appetite; the lopinavir/ritonavir discontinuation rate was 13.8%. (5l) Comments: the recommendations panel interpreted that the available evidence suggests no clinically significant benefit from the lopinavir/ritonavir therapy. This therapy could be considered promising, and the lack of observed benefits may result from the small number of assessed patients. Despite the high discontinuation rate due to adverse events and potential drug interactions, lopinavir/ ritonavir is a relatively safe therapy for short term courses. This drug may be considered upon a clinician-patient shared decision, in hospitalized severe and critically ill patients, in centers with professionals experienced with this therapy. It should be preferably used under clinical trial protocols.

Recommendation 6 -we suggest against the routine use corticosteroids for COVID-19 patients' treatment (weak recommendation; Level of Evidence very low).

Summary of the evidence: no clinical trials specifically assessing the use in COVID-19 patients were found. Four observational studies reported that the use of corticosteroids during hospitalization is associated with increased mortality; these studies combined hospitalized patients' populations, however, with heterogeneous clinical features. (52-55) One trial, however, suggests that the use of methylprednisolone reduced the risk of death in patients with ARDS (HR = 0.38; 95%CI 0.20 -0.72). (56) The outcomes for respiratory symptoms are variable in hospitalized patients. (57, 58) The studies' limitations include the lack of randomization and control groups, variable doses used, small samples, and retrospective analysis of the data.

Despite the systematic review conducted did not involve other coronaviruses infections, indirect information on SARS and Mid-East respiratory syndrome (MERS) show an absence of impact on mortality (RR = 1.07; 95%CI 0.81 -1.42) and a prolonged time to viral negativation (3.78 days; 95%CI 1.16 -6.41 days). (59) Comments: the recommendations panel interpreted that there is no evidence supporting the routine use of corticosteroids for COVID-19 patients. Corticosteroids should be avoided during the first seven to 10 days after the symptoms start, when the viral response is more relevant, as there is evidence that corticosteroids may delay viral negativation.

Some evidence points out to a potential benefit for moderate to severe ARDS patients out of the viral infection context. (60) Its use may be considered for selected cases with moderate to severe ARDS, without suspected uncontrolled bacterial infection, 10 to 14 days after the COVID-19 symptoms start. The doses used in the studies ranged between 10mg and 20mg dexamethasone or 40mg to 120mg methylprednisolone daily, for five to 10 days. Their use should preferentially be under clinical research protocols.

Patients with other indications for corticosteroids use (e.g.: asthma and exacerbated chronic obstructive pulmonary disease -COPD) should use these drugs according to the clinical indication, assessing other potential risks and benefits during COVID-19 infection.

Recommendation 7 -we suggest against the routine use tocilizumab for COVID-19 treatment (weak recommendation; Level of Evidence very low).

Summary of the evidence: no comparative trials evaluating tocilizumab effectiveness in COVID-19 patients were found; only two case series were identified. One of the series included 21 patients, all with chest CT changes, 20 on ventilatory support (45% with high-flow oxygen, 35% with a nasal cannula, 5% with an oxygen mask, 5% with non-invasive mechanic ventilation and 10% with invasive mechanical ventilation). Within five days, 75% of them had their ventilatory support requirements reduced; no deaths occurred during the follow-up period. (61) In another case series 15 patients were included, two moderately ill, six with severe disease, and seven in a very severe condition. Of the 15 patients, three died, two had increased severity, nine had clinical stabilization and one showed clinical improvement.

Serum interleukin-6 (IL-6) was reduced in 10 patients after tocilizumab; increased IL-6 was found in the five patients with treatment failure, all of them with an initially very severe condition. (62) Comments: the recommendation panel interpreted that no benefit and safety evidence was shown that would suggest the routine use of tocilizumab. Besides, this drug is costly, and especially during an epidemic, the use of resources should be rationalized, and the use of interventions with no benefit evidence avoided. This drug may be considered in a shared clinician-patient decision for severe and critically ill hospitalized patients, with a confirmed diagnosis of SARS-CoV-2 infection, and significantly increased markers or inflammation (e.g.: IL-6, D-dimer, C reactive protein, lactate dehydrogenase -LDH, and ferritin). The use of tocilizumab should be restricted to centers with professionals who are experienced in its use. Tocilizumab use should preferentially be under clinical trial protocols.

Recommendation 8 -we recommend the routine use of venous thromboembolism prophylaxis in COVID-19 hospitalized patients (strong recommendation; Level of Evidence very low).

Recommendation 9 -we suggest against the routine use therapeutic heparin doses for COVID-19 treatment (weak recommendation; Level of Evidence very low).

Summary of the evidence: two retrospective cohorts were identified. (63,64) One of them assessed 449 severe or critically ill hospitalized COVID-19 patients; 99 of them were given heparin for at least seven days (94 enoxaparin 40mg -60mg daily and five unfractionated heparin 10,000 -15,000IU/daily), and 350 control patients (without any anticoagulant or heparin, or less than seven days of use). In this study, the 28-day mortality rate was similar (heparin 30.3% versus controls 29.7%). In the subgroup with an International Society on Thrombosis and Hemostasis -Sepsis-Induced Coagulopathy score (ISTH SIC) ≥ 4 (from one of the following features: platelets < 100,000, International Normalized Ratio -INR > 1.4 or a Sequential Organ Failure Assessment -SOFA -score ≥ 2), the mortality in the heparin group was lower (40% versus 64.2%; p = 0.029; n = 97). Increased effectiveness was also seen in patients with increased D-dimer, with a significantly reduced mortality in a group with D-dimer values above or equal to six-times the upper limit of the normal (32.8% versus 52.4%; p = 0.017). (64) In a study that assessed 42 patients, all of them with an immunosuppressor or corticosteroids, and severe to moderate COVID-19, 21 patients were given low molecular weight heparin (13 enoxaparin 40mg daily, two enoxaparin 20mg daily, four nadroparin 4,100IU daily and two low molecular weight sodium heparin 5,000IU daily, median: 11 days) and 21 controls, D-dimer and IL-6 levels were significantly reduced, and lymphocytes counts were increased, with no hospital length of stay differences. (65) Comments: the recommendations panel interpreted that there is no indication for therapeutic dose heparins (e.g.: enoxaparin 1mg/kg subcutaneously -SC -every 12 hours) for the treatment of COVID-19. The rationale for other anticoagulants is analogous. Anticoagulation is associated with an increased risk of bleeding events and should be restricted to patients with a clear indication (e.g.: atrial fibrillation, pulmonary thromboembolism, deep venous thrombosis, among others), according to appropriate protocols.

COVID-19 patients apparently have an increased risk of thromboembolic events, and the assisting team should be aware of developing signs and symptoms. COVID-19 hospitalized patients should be given thromboembolism prophylaxis according to risk-stratification strategies, adhering to local hospital protocols. However, the use of prophylactic doses can be extended to all COVID-19 patients, as some SARS-CoV-2 patients appear to have a hypercoagulability state, with increased thromboembolic events rate as seen in observational clinical trials and post mortem examinations. (66,67) As an example, enoxaparin 40mg to 60mg SC oncedaily doses, or unfractionated heparin 5,000IU SC twice or three times a day, could be used. Although there is limited evidence for pharmacological prophylaxis in COVID-19 patients, this is a low-cost and well-tolerated intervention that may potentially prevent major clinical events. Heparin should not be used for cases with contraindications (e.g.: increased risk of bleeding, active bleeding, and severe thrombocytopenia); (68) low molecular weight heparin should be used carefully in renal dysfunction patients.

Recommendation 10 -we suggest against the use prophylactic antibiotics in patients with a suspected or confirmed COVID-19 diagnosis (weak recommendation; Level of Evidence very low).

Summary of the evidence: no randomized clinical trials were found to assess the empirical antibiotics therapy effectiveness in COVID-19 patients without evidence of bacterial infections. Therefore, so far there is no clinical data enough to show benefits or risks of antibiotics in COVID-19 patients with no signs of bacterial infection. We did not access the evidence for bacterial infections therapy.

Comments: the panel interpreted that considering the lack of evidence, there is no base for prophylactic antibiotic therapy in COVID-19 patients. In addition to the lack of benefit evidence, this could result in adverse events, increased antimicrobial resistance, and costs.

There is no appropriate data on bacterial coinfection in COVID-19 patients, however, one should bear in mind that overlapping infections may occur. It is understood that those patients should be given antibiotics, similarly to COVID-19 patients, taking into consideration the local epidemiology and adhering to local protocols and guidelines from infection control services. Table 6 shows a didactic summary of the recommendations according to the evaluated interventions, presenting their judgment regarding perceived benefits, risks, costs, availability, and evidence. Appendix 4 presents the most important drug interactions of potential COVID-19 therapies.

During epidemics, when consolidated effective therapies are not available, there is a trend to use therapies based on preclinical studies results, or based on observational studies with important limitations. (69) Experiences from other epidemics have shown that such interventions benefits may be far below the expected, as with oseltamivir during the influenza A (H1N1) epidemics in 2009. (60,70) During the Ebola virus epidemics in 2014, several interventions were tested, including CQ, HCQ, favipiravir, immunobiological agents, and convalescent plasma; none was proven effective. (71) By the time when this guideline is publicized, we face a scenario where no specific COVID-19 proposed intervention is proven effective. Regarding safety, drugs such as HCQ (especially when combined with azithromycin) at the doses proposed for COVID-19 have been shown relevantly associated with cardiovascular events. (34, 35, 40, 45) In the absence of effective therapies, treatment under clinical trial protocols should be encouraged. In this context, healthcare professionals should seek information on therapeutic clinical trials, especially randomized clinical trials, already approved by regulatory agencies and ethical committees possibly ongoing in their institutions.

Several other interventions are proposed, such as remdesivir, beta interferon, ivermectin, nitazoxandine, convalescent plasma, umifenovir, among others. (72) (73) (74) (75) (76) (77) This guideline chose to prioritize those interventions raising more clinical practice concerns in Brazil by the time of its development. Of note, the current speed of COVID-19 knowledge generation renders these recommendations prone to become outdated in a short frame of time. As most of the interventions are based on evidence from small observational or interventional trials, we understand that as new well-designed clinical trials, with appropriate sample sizes, are published, there is a huge potential that herein presented recommendations shall be changed. Therefore, it is of paramount importance that readers of this guideline keep this in mind as one of the most important limitations of this document.

Also, it is necessary to understand that a clinical guideline aims to guide the clinical practice not necessarily applicable to every patient. The scarcity of evidence with appropriate methodology renders impossible to provide more categorical recommendations; we stress that a significant portion of the studies we evaluated was preliminary published in Ahead of Print bases, with no editorial board and peer review evaluations. Therefore, in this document we present suggested actions, to be contextualized according to features such as the patient's clinical profile, existing comorbidities, and risk of developing adverse effects, in addition to the assisting team's experience with the proposed interventions, patient's preferences, service structure, as well as costs and available resources. Regarding costs, in the context of public health, it is important to emphasize that, in a scenario of an epidemic, resource allocation should be prioritized to interventions more likely to be beneficial, such as Personal Protective Equipment and interventions related to the patient's ventilatory support. Therefore, under the light of the current COVID-19 knowledge, some investments in pharmacological therapies are debatable. However, the treatment of patients under clinical trial protocols, with appropriate study design and the potential to provide an answer to the society, should be encouraged. With this document we hope to guide clinical practice in a national context, therefore reducing the therapeutic variability. In addition to the evidence available in the scientific literature, the recommendations took into consideration some Brazilian specific features, such as the availability of some drugs (either because of lack of regulatory clearance or due to difficult access), population and healthcare professionals acceptance, and costs associated with their use. Also, most of this document's recommendations are in line with WHO therapeutic recommendations. (27) This document consists of a joint positioning by three medical societies, taking into consideration the need for the development of encompassing recommendations and contextualization of different medical specialties regarding of the frailty of the available evidence, that may be an applicable tool both for physicians working in the public health system and the supplementary system.

The developing group is committed to strive for periodically bring updates to this document, in a context of living guidelines, (78) where recommendations are updated as new evidence becomes available. Additional interventions will be included as they become relevant doubts for COVID-19 therapy. ) OR "Bulbul coronavirus HKU11" OR "Thrush coronavirus HKU12" OR "novel coronavirus" OR "covid-19" OR "sarscov 2" OR "Betacoronavirus*"

#2 "Anti-Bacterial Agents" [mesh] OR "Anti-Bacterial Agents" OR "Agents, Anti-Bacterial" OR "Anti-Bacterial Agents" OR "Antibacterial Agents" OR "Agents, Antibacterial" OR "Anti-Bacterial Compounds" OR "Anti-Bacterial Compounds" OR "Compounds, Anti-Bacterial" OR "Bacteriocidal Agents" OR "Agents, Bacteriocidal" OR "Bacteriocides" OR "Anti-Mycobacterial Agents" OR "Agents, Anti-Mycobacterial" OR "Anti Mycobacterial Agents" OR "Antimycobacterial Agents" OR "Agents, Antimycobacterial" OR "Antibiotics" OR "Antibiotic" OR "antimicrobials" OR "antibacterials" OR "Azithromycin" [mesh] OR "Azythromycin" OR "Sumamed" OR "Toraseptol" OR "Vinzam" OR "CP-62993" OR "CP 62993" OR "CP62993" OR "Zithromax" OR "Azitrocin" OR "Azadose" OR "Ultreon" OR "Zitromax" OR "Azithromycin Dihydrate" OR "Dihydrate, Azithromycin" OR "Azithromycin Monohydrate" OR "Monohydrate, Azithromycin" OR "Goxal" OR "Zentavion" #5 "Enoxaparin"[Mesh] OR Enoxaparin OR Enoxaparine OR "PK-10,169" OR "PK 10,169" OR "PK10,169" OR "PK-10169" OR "PK 10169" OR "PK10169" OR "EMT-967" OR "EMT 967" OR "EMT967" OR Lovenox OR Clexane OR "EMT-966" OR "EMT 966" OR "EMT966" #6 "Nadroparin"[Mesh] OR Nadroparine OR "Nadroparin Calcium" OR "Calcium, Nadroparin" OR Fraxiparin OR Fraxiparine #7 "Dalteparin"[Mesh]" OR Tedelparin OR "Dalteparin Sodium" OR "Sodium, Dalteparin" OR Fragmin OR Fragmine #8 #2 OR #3 OR #4 OR #5 OR #6 OR #7 #9 #1 AND #8 OR "Bulbul coronavirus HKU11" OR "Thrush coronavirus HKU12" OR "novel coronavirus" OR "covid 19" OR "sarscov 2" OR "Betacoronavirus*" #2 "Anti-Bacterial Agents" [mesh] OR "Anti-Bacterial Agents" OR "Agents, Anti-Bacterial" OR "Anti-Bacterial Agents" OR "Antibacterial Agents" OR "Agents, Antibacterial" OR "Anti-Bacterial Compounds" OR "Anti-Bacterial Compounds" OR "Compounds, Anti-Bacterial" OR "Bacteriocidal Agents" OR "Agents, Bacteriocidal" OR "Bacteriocides" OR "Anti-Mycobacterial Agents" OR "Agents, Anti-Mycobacterial" OR "Anti Mycobacterial Agents" OR "Antimycobacterial Agents" OR "Agents, Antimycobacterial" OR "Antibiotics" OR "Antibiotic" OR "antimicrobials" OR "antibacterials" OR "Azithromycin"

[mesh] OR "Azythromycin" OR "Sumamed" OR "Toraseptol" OR "Vinzam" OR "CP-62993" OR "CP 62993" OR "CP62993" OR "Zithromax" OR "Azitrocin" OR "Azadose" OR "Ultreon" OR "Zitromax" OR "Azithromycin Dihydrate" OR "Dihydrate, Azithromycin" OR "Azithromycin Monohydrate" OR "Monohydrate, Azithromycin" OR "Goxal" OR "Zentavion" OR "Vancomycin" [mesh] OR "Vancomycin" OR "Ceftriaxone" [mesh] OR "Ceftriaxone" OR "Cefepime"

[mesh] OR "Cefepime" OR "Levofloxacin" [mesh] OR "Levofloxacin" OR "Fluoroquinolones" [mesh] OR "Fluoroquinolones" OR "Amoxicillin" [mesh] OR "Amoxicillin" OR "Ciprofloxacin" [mesh] OR "Ciprofloxacin" OR "Cephalexin" [mesh] OR "Cephalexin" OR " 

Bibliografia: Borba et al., 2020 (7) ; Million et al., 2020 (8) ; Lane et al., 2020 (9) ; Gautret et al., 2020 (10) ; Molina et al., 2020 (11) ; Chorin et al., 2020 (12) ; Columbia University Kidney Transplant Program, 2020 (13) ; Gabriels et al., 2020 (14) ; Ramireddy et al., 2020 (15) ; Chang et al., 2020 (16) ; Gautret et al., 2020 (4) Avaliação da certeza , Gautret et al., 2020 (10) , Molina et al., 2020 (11) , Chorin et al., 2020 (12) , Columbia

University Kidney Transplant Program, 2020 (13) , Borba et al., 2020 (7) ) mostrou (11) ); § Borba, et al, 2020 (7) avaliaram Pergunta 4 -Lopinavir associado a ritonavir comparado a cuidados padrão em paciente com infecção por COVID-19

Bibliografia: Cao et al., 2020 (18) ; Li et al., 2020 (19) ; Deng et al., 2020 (20) ; Ye et al., 2020 (21) ; Zhu et al., 2020 (22) ; Shi et al., 2020 (23) ; Liu et al., 2020 (17) ; Sun et al., 2020 (24) Avaliação da certeza (25) ; Wu et al., 2020 (26) ; Guan et al., 2020 (27) ; Shang et al., 2020 (28) ; Cao et al.,2020 (29) ; Li et al., 2020 (30) ; Xu et al. (31) , 2020; Zha et al., 2020 (32) ; Lu et al., 2020 (33) ; Wang et al., 2020 (34) 

Bibliografia: Luo et al., 2020 (35) ; Xu et al., 2020 (36) Avaliação da certeza 

Bibliografia: Shi et al., 2020 (37) ; Tang et al., 2020 (38) Avaliação da certeza 

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

China Novel Coronavirus Investigating and Research Team. A novel coronavirus from patients with pneumonia in China

Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region

Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area

Covid 19. Painel de casos de doença pelo coronavírus 2019 (COVID-19) no Brasil pelo Ministério da Saúde

Treating COVID-19-off-label drug use, compassionate use, and randomized clinical trials during pandemics

Chicken soup in the time of COVID

Covid-19 -a reminder to reason

GRADE: an emerging consensus on rating quality of evidence and strength of recommendations

Development of rapid guidelines: 3. GIN-McMaster Guideline Development Checklist extension for rapid recommendations

Reviews: Rapid! Rapid! Rapid! …and systematic

Alliance for Health Policy and Systems Research & World Health Organization. Rapid reviews to strengthen health policy and systems: a practical guide

AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both

Cochrane Handbook for Systematic Reviews of Interventions

ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions

The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses

The Joanna Briggs Institute Critical Appraisal tools for use in JBI Systematic Reviews. Checklist for Case Series

Joanna Briggs Institute Reviewer's Manual. The Joanna Briggs Institute

Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach

Corticoides para infecção por SARS-CoV-2 (Covid-19). Revisão sistemática rápida

Hidroxicloroquina e cloroquina para COVID-19. Revisão sistemática rápida

Heparinas para infecção por SARS-CoV-2 (COVID-19). Revisão sistemática rápida

Associação hidroxicloroquina/cloroquina e azitromicina para Covid-19. Revisão sistemática rápida

Antibioticoterapia para Covid-19 sem evidência de infecção bacteriana. Revisão sistemática rápida

Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19

Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde. Departamento de Gestão e Incorporação de Tecnologias e Inovações em Saúde. Coordenação-Geral de Gestão de Tecnologias em Saúde. Coordenação de Gestão de Protocolos Clínicos e Diretrizes Terapêuticas. Diretrizes para Diagnóstico e Tratamento da COVID-19

Clinical care for severe acute respiratory infection: toolkit. COVID-19 adaptation. Geneva: World Health Organization

National Institutes of Health. Treatment Guidelines Panel. Coronavirus Diseases 2019 (COVID-19). COVID-19 Treatment Guidelines

Zhejiang Da Xue Xue Bao Yi Xue Ban

Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: openlabel, randomized, controlled trial

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial

Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19

Observational study of hydroxychloroquine in hospitalized patients with Covid-19

Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19)

Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study

Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in Marseille, France

A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19. Zhejiang Da Xue Xue Bao Yi Xue Ban

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial

Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open-label, randomized, controlled trial

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19)

Observational study of hydroxychloroquine in hospitalized patients with Covid-19

Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial

Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in Marseille, France

Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study

Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study

No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection

The QT interval in patients with SARS-CoV-2 infection treated with hydroxychloroquine/ azithromycin

Early description of coronavirus 2019 disease in kidney transplant recipients in New York

Inpatient use of mobile continuous telemetry for COVID-19 patients treated with hydroxychloroquine and azithromycin. HeartRhythm Case Rep

Experience with hydroxychloroquine and azithromycin in the COVID-19 pandemic: implications for QT interval monitoring

Inpatient use of ambulatory telemetry monitors for COVID-19 patients treated with hydroxychloroquine and/or azithromycin

The effect of arbidol hydrochloride on reducing mortality of Covid-19 patients: a retrospective study of real world date from three hospitals in Wuhan

A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19

An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI)

Arbidol combined with LPV/r versus LPV/r alone against corona virus disease 2019: a retrospective cohort study

Clinical efficacy of lopinavir/ritonavir in the treatment of Coronavirus disease 2019

Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19

Evaluation of antiviral therapies for coronavirus disease 2019 (COVID-19) pneumonia in Shanghai

Incidence of Adverse Drug Reactions in COVID-19 Patients in China: An Active Monitoring Study by Hospital Pharmacovigilance System

Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia

Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China

Clinical characteristics of coronavirus disease 2019 in China

The treatment and outcomes of patients with COVID-19 in Hubei, China: a multi-centered, retrospective, observational study

Clinical features and short-term outcomes of 102 patients with corona virus disease 2019 in Wuhan, China

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

Factors associated with prolonged viral RNA shedding in patients with COVID-19

Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19)

Adjuvant corticosteroid therapy for critically ill patients with COVID-19

No clear benefit to the use of corticosteroid as treatment in adult patients with coronavirus disease 2019 : a retrospective cohort study

Tocilizumab treatment in COVID-19: A single center experience

Effective treatment of severe COVID-19 patients with tocilizumab

The potential of low molecular weight heparin to mitigate cytokine storm in severe COVID-19 patients: a retrospective clinical study

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy