key: cord-0920786-9okit7cz
authors: Xie, Jiaxing; Wang, Zhufeng; Liang, Jingyi; Lin, Huimin; Yang, Zhaowei; Wang, Yingzhi; Liang, Hanwen; Wu, Hongkai; Chen, Ruchong; Ou, Younger; Wang, Fengyan; Wang, Yuan; Wang, Yan; Luo, Weizhan; Zhang, Jianheng; Li, Naijian; Li, Zhengtu; Jiang, Mei; Li, Shiyue; Li, Jing
title: Critical Review of the Scientific Evidence and Recommendations in COVID-19 Management Guidelines
date: 2021-07-14
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab376
sha: d68364de5f9231dc73f5e41b1859e0dbb1c6b009
doc_id: 920786
cord_uid: 9okit7cz

BACKGROUND: Little is known about the quality and potential impacts of the guidelines for coronavirus disease 2019 (COVID-19) management. METHODS: We systematically searched PubMed, Web of Science, Cochrane Library, guideline databases, and specialty society websites to evaluate the quality of the retrieved guidelines using the Appraisal of Guidelines for Research and Evaluation II. RESULTS: A total of 66 guidelines were identified. Only 24% were categorized as “recommended” for clinical practice. The 211 identified recommendations for COVID-19 management were classified into 4 topics: respiratory support (27), acute respiratory distress syndrome management (31), antiviral or immunomodulatory therapy (95), or other medicines (58). Only 63% and 56% of recommendations were supported by, respectively, assessment of the strength of the recommendations or level of evidence. There were notable discrepancies between the different guidelines regarding the recommendations on COVID-19 management. CONCLUSIONS: The quality of the guidelines for COVID-19 management is heterogeneous, and the recommendations are rarely supported by evidence.

The coronavirus disease 2019 (COVID-19) pandemic has become a global public health crisis. As of June 17, 2021, COVID-19 has affected >176 million people in >200 countries or regions and resulted in >3.8 million deaths [1] . The economic burden and health threat of COVID-19 are extremely dreadful and have become more severe as the number of global infections and deaths increases [2, 3] .

The management of the disease relies largely on symptomatic and supportive treatments. For severe or critically ill patients with acute respiratory distress syndrome (ARDS) and sepsis, in addition to supplemental oxygen, mechanical ventilation, and ARDS-specific therapies, antiviral and antibiotic treatments must also be considered. To face the rapid global spreading of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the difficulty for overburdened front-line workers and policy-makers of staying up to date on the emerging literature, many national and international organizations have issued rapid advice or interim guidelines for COVID-19 management. These guidelines have integrated the best possible information in response to health and social care emergencies to help frontline health care professionals improve clinical outcomes [4] . However, little is known about the quality and variability of the recommendations among different guidelines. Additionally, substantial differences exist in clinical practices across countries and hospitals. To provide the best care possible, clinicians need to understand the discrepancy of recommendations among guidelines and choose evidence-based recommendations developed by trustworthy methodologies [5] .

Many issues related to the clinical management of acute COVID-19 remain to be clarified, including the role of noninvasive ventilation (NIV), high-flow nasal cannula (HFNC), usage of corticosteroids or other supportive therapies, and various antiviral medications. In this study, we aimed to systematically review and evaluate currently available guidelines for acute COVID-19 management and specifically compare the available recommendations and the quality of supporting evidence. METHODS We registered this study protocol and reported the results according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (CRD42020180074) [6] .

We searched PubMed, Web of Science, and Cochrane Library for COVID-19 guidelines published through June 17, 2021, as well as websites of international organizations, government health institutions, relevant specialty societies, guidelinespecific databases, and Google Scholar. The bibliographies of included studies were further screened for additional potentially relevant articles. The detailed search strategies and results are presented in the Supplementary Data (Supplementary Methods 1 and 2). Our search was restricted to guidelines developed by international or national health care organizations and medical societies published in English.

To be included, guidelines had to make specific recommendations for the management of acute COVID-19 regarding NIV, HFNC, use of corticosteroids or other supportive therapies, and use of various antiviral medications. When several versions of the same document were available, only the latest version was retained. For each eligible guideline, we thoroughly searched for supplementary supporting documents to better inform our assessments. The following types of document were excluded: (i) guidelines regarding diagnosis, home care, or prevention and control of infection; (ii) guidelines for special populations such as newborns, children, or pregnant women; (iii) guidelines developed by autonomous medical institutions or nonprofessional societies; (iv) documents such as systematic reviews, clinical trials, commentaries, case series, letters, or chapters in books or booklets; (v) documents that were not published in English or not available in full-text format; (vi) specialty guidelines for triage, tracheotomy, complications, palliative treatment, and rehabilitation.

Two reviewers (Z.W. and J.X.) independently screened and extracted all relevant information from included guidelines using predesigned forms. Whenever discrepancies arose, resolution was achieved by consensus or by consulting the third expert adjudicator (M.J.). The quality of eligible guidelines was independently evaluated by 4 appraisers who had been trained in clinical practice guidelines appraisal using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument [7] [8] [9] . AGREE II contains 23 items within 6 domains. Each item was scored on 7-point Likert scale that varies from 1 (strongly disagree) to 7 (strongly agree). A standardized score was calculated as the percentage of the maximal possible score for each domain using the formula provided in the AGREE II user's manual: (actual score -minimal possible score)/(maximal possible score -minimal possible score) [9] . The standardized scores ranged from 0% to 100%. Guidelines with an overall score >60% were classified as "recommended, " between 30% and 60% as "recommended with modifications, " and <30% as "not recommended" [10, 11] .

Eight clinicians independently extracted the general characteristics of the eligible guidelines and the recommendations concerning respiratory support, ARDS management, antiviral and immunomodulatory therapies, and other pharmacologic treatments (corticosteroids, antibiotics, antipyretics, and neuraminidase inhibitors). We developed recommendation matrices to assist with systematic comparison, categorization, and summarization, including comparison of the strength of the recommendation and quality of evidence.

The general characteristics, standardized score in each domain, distribution of level of evidence, and strength of recommendation of each eligible guideline were depicted using either median and range, mean and SD, or frequency and percentage. Subgroup analyses were performed according to country, target population, type of guideline, and development method. Agreement among the 4 reviewers was measured by intraclass correlation coefficient (ICC) with a 95% CI. All analyses were conducted using R software, version 3.6.1 (http://CRAN.Rproject.org; R Foundation, Vienna, Austria).

A total of 66 guidelines met the inclusion criteria ( Figure 1 ). The general characteristics of these eligible guidelines are shown in Figure 2 and Supplementary Table 1 . Eleven (17%) were developed by international organizations [4, [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] , and 13 (20%) originated from North America [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] , 1 (2%) from South America [35] , 31 (47%) from Europe , and 10 (15%) from the Asia-Pacific area region [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] . Only 25 (38%) guidelines provide an approximate update interval, with an average of 2.2 months (min: 0.25 months; max: 6 months). Twentyfour guidelines (36%) were developed using evidence-based methods, and 20 (30%) graded the strength of recommendations, of which only 9 (14%) appraised the quality of evidence (Supplementary Table 2 ). In order to compare the strength of the recommendations and quality of evidence obtained by different grading systems, a composite grading system applicable to all recommendations was generated (Supplementary Table  3 ).

The standardized AGREE II scores obtained by all guidelines for each domain and the overall assessment are shown in Supplementary Table 4 . The guidelines scored moderately in the domains scope and purpose (mean, 68%; range, 31%-89%) and clarity and presentation (mean, 69%; range, 21%-85%) but scored highly variably in the other 4 domains ( Figure 3 ). Most guidelines (n = 38, 70%) were categorized as "recommended with modifications" for use during the COVID-19 pandemic, 12 (22%) were "recommended," and 4 (7%) were "not recommended" (Supplementary Table 4 ). The overall agreement of the 4 appraisers was considered good (ICC, 0.849; 95% CI, 0.833-0.864). Supplementary Table  5 shows the quality scores of the guidelines across the different subgroups. The quality of the guidelines issued during 2021, originating from North America, developed by evidence-based methods or by >1 organization, was higher than the other guidelines.

General recommendations relevant to COVID-19 management in adults are listed in Table 1 . Two hundred eleven recommendations were extracted from 66 documents. Among these, only 62.6% (132 recommendations) and 56.4% (119 recommendations) were supported by, respectively, assessment of strength or quality of evidence.

Ten documents [12-14, 16, 26, 29, 47, 54, 69, 76] recommended timely supplementation of oxygen for patients with COVID-19 in the circumstance of severe acute respiratory infection (SARI), respiratory distress, hypoxemia, shock, or other severe symptoms (Supplementary Table 6 [71] : ungraded); or significantly below baseline [68] . Moreover, it was recommended that the SpO 2 target level not be maintained above 96% [4, 14, 16, 27, 54] The vertical line at 60% represents the cutoff score at or above which a domain was considered "adequately addressed." The vertical line at 30% represents the cutoff score at or below which a domain was considered "poorly addressed." Abbreviation: AGREE, Appraisal of Guidelines for Research and Evaluation II. [37, [43] [44] [45] 52] .

It was consistently recommended that endotracheal intubation be performed by the most trained and experienced operators in most documents [4, 13, 14, 26, 37, 38, 45, 50, 52] (National Institutes of Health [NIH] [23] : strong, very low; SSC [4] , CCCGWG [26] , and WHO [13] : strong, ungraded) (Supplementary Table 7 ). Upon worsening of the patient condition, early endotracheal intubation in a controlled setting was recommended by most guidelines [4, 12-16, 23, 26, 37, 41, 42, 50-52, 69] (SSC [4] , CCCGWG [26] , WHO [13] , and NIH [23] : strong).

Most documents consistently recommended using low tidal volume (Vt), airway platform pressure <30 cmH 2 O, prone ventilation, and neuromuscular blockade agents in ARDS. Most guidelines [4, 13-15, 23, 26, 27, 44, 45, 67, 69] suggested using a Respiratory support Timing of start of oxygen therapy WHO-toolkit [12] , CCCGWG [26] , WHO [13] , PAHO [14] , Thomas et al. [16] , SITA&SIP [54] , CTS&CACP [70] , PCS [71] , NHC&SATCM [69] , Chinese experts [76] , NICE (managing symptoms) [47] , ASID [68] , AARC [27] , SSC [4] , FSRD [60] 7 4 (57) 3 (43) Target of oxygen therapy WHO [13] , Poland [59] , WHO-toolkit [12] , CCCGWG [26] , Thomas et al. [16] , PAHO [14] , PCS [71] , Kluge et al. [37] , SITA&SIP [54] , INMI [44] , CTS&CACP [70] , NHS (rapid guideline) [52] , ITS&IRS [41] , NHS (critical care) [44] , ICM [57] , NHS (oxygen therapy) [51] , FSRD [60] , SSC [4] , AARC [27] 11 4 (36) 2 (18) HFNC and NIV WHO-toolkit [12] , NHC&SATCM [69] , SSC [4] , CCCGWG [26] , ITS&IRS [41] , ARIR&AIFI [42] , NHS (management) [50] , WHO [13] , CTS&CACP [70] , PCS [71] , AARC [27] , NCCET [67] , FSRD [60] , ERS [19] , BTS&ICS [61] , SIAARTI&EAMS [45] , Thomas et al. [16] , SIMIT [43] , ASID [68] , Kluge et al. [37] , NHS (critical care) [44] , INMI [44] , NHS (rapid guideline) [52] , SIMIT [43] , ICM [57] , ISCCM [75] , GRS [58] , NIH [23] , ASAIO [29] 9 PCS [71] 3 (33)

Endotracheal intubation SSC [4] , ICSI [38] , SIAARTI&EAMS [45] , CCCGWG [26] , NHS (rapid guideline) [52] , NHS (critical care), NHS (management) [50] , WHO [13] , PAHO [14] , Kluge et al. [37] , NIH [23] , PCS [71] , NCCET [67] , WHO-toolkit [12] , NHC&SATCM [69] , Thomas et al. [16] , ITS&IRS [41] , ARIR&AIFI [42] , CTS&CACP [70] , SAS&ANZICS [15] , ISCCM [75] 4 4 (100) 3 (75) ARDS ventilation NIH [23] , CCCGWG [26] , NHS (critical care), SSC [4] , WHO [13] , CTS&CACP [70] , PAHO [14] , PCS [71] , WHO-toolkit [12] , NHC&SATCM [69] , AARC [27] , NCCET [67] , NHS (oxygen therapy) [51] , SAS&ANZICS [15] , Kluge et al. [37] , Chinese experts [76] , Thomas et al. [16] , SIAARTI&EAMS [45] , ASAIO [29] , ICSI [38] , ASAIO (ECMO) [30] , INMI [44] , GRS [58] 15 13 (87) 11 (73) Hemodynamics WHO-toolkit [12] , NHC&SATCM [69] , WHO [13] , PCS [71] , NHS (oxygen therapy) [51] , Kluge et al. [37] , SSC [4] , CCCGWG [26] , NHS (critical care), NHS (management) [50] , PAHO [14] , NIH [23] , AARC [27] , Chinese experts [76] ECMO NIH [23] , ATS [24] , SSC [4] , WHO [13] , NCCET [67] , WHO-toolkit [12] , NHC&SATCM [69] , ICSI [38] , CCCGWG [26] , NICE (critical care) [48] , PCS [71] , NHS (critical care), NHS (oxygen therapy) [51] , CTS&CACP [70] , PAHO [14] , Kluge et al. [37] , AARC [27] , ASAIO (ECMO) [30] , NHS (ECMO) [ General recommendations SIMIT [43] , Korea [73] , NHC&SATCM [69] , HSE.ie (antiviral therapy), ASID [68] , PAHO [14] , ATS [24] , NIH [23] , WHO-toolkit [12] , INMI [44] , ITS&IRS [41] , NHS (rapid guideline), Kluge et al. [37] , Chinese experts [76] 8 4 (50) 5 (63) Chloroquine or hydroxychloroquine NHC&SATCM [69] , HSE.ie (antiviral therapy), INMI [44] , SIMIT [43] , ICMR [74] , SIAARTI&EAMS [45] , ASAIO [29] , SITA&SIP [54] , ACOEM [28] , Korea [73] , AST&ERS [20] , NIH [23] , ASAIO (ECMO) [30] , IDSA [25] , Brazil [35] , CMAJ [72] , ACP [31] , WHO [13] , PAHO [14] , NCCET [67] , ERS [19] , WHO (therapeutics) [21] , SSC [ Lopinavir/ritonavir NHC&SATCM [69] , SIAARTI&EAMS [45] , INMI [44] , Korea [73] , SIMIT [43] , HSE.ie (antiviral therapy), SITA&SIP [54] , Poland [59] , CCCGWG [26] , ASAIO (ECMO) [30] , WHO [13] , PAHO [14] , NCCET [67] , Brazil [35] , NIH [23] , ERS [19] , IDSA [25] , SSC [4] , CMAJ [72] 6 3 (50) 3 (50) Remdesivir INMI [44] , IDSA [25] , PCS [71] , ACOEM [28] , BMJ GDG panel [56] , NICN (critical care), NHS (tocilizumab) [66] , CCCGWG [26] , ASAIO [29] , NHS (remdesivir) [64] , ACP (remdesivir) [32] , Belgium Task Force [36] , Poland [59] , NCCET [67] , AST&ERS [20] , NIH [23] , ACP (remdesivir), SSC [4] , HSE.ie (antiviral therapy), SIMIT [43] , Kluge et al. [37] , Korea [73] , SITA&SIP [54] , NHS (rapid guideline), ATS [24] , ASAIO (ECMO) [30] , ERS [19] , WHO [13] , PAHO [14] , WHO (therapeutics) [13] 10 9 (90) 7 (70) Interferon NHC&SATCM [69] , CMAJ [72] , NCCET [67] , ACOEM [28] , Korea [73] , NIH [23] , ERS [ [70] , NHC&SATCM [69] , SSC [4] , CMAJ [72] , NIH [23] , PAHO [14] , Kluge et al. [37] , SIMIT [43] , CCCGWG [26] , IDSA [25] ,WHO (corticosteroids) [17] ,WHO (therapeutics), ERS [19] , NHS (management) [50] , ICSI [38] , CDC [22] , NHS (ECMO) [49] , ASID [68] , ATS [24] , NCCET [67] , AST&ERS [20] , NHS (rapid guideline) [52] , Brazil [35] , ICM [57] , Korea [73] , ACOEM [28] , WHO [13] , NHS (tocilizumab) [66] , Poland [59] , SITA&SIP [54] 24 13 (54) 12 (50) Antibiotics CTS&CACP [70] , ASID [68] , WHO-toolkit [12] , ICSI [38] , Brazil [35] , NICE (managing pneumonia), NHS (management) [50] , SSC [4] , Belgium Task Force [36] , NIH [23] , NHS (rapid guideline) [52] , NHC&SATCM [69] , ACOEM [28] , NICE (antibiotics) [55] , SIMIT [43] , CCCGWG [26] , WHO [13] , INMI [44] NICE (antibiotics) [55] , PAHO [14] , SITA&SIP [54] , Korea [73] , NHS (critical care), NHS (management) [50] , Kluge et al. [37] , CTS&CACP [70] 17 10 (59) 7 (41) Antipyretic WHO-toolkit [12] , PCS [71] , PAHO [14] , WHO [13] , NIH [23] , SSC [4] , NICE (managing symptoms) [ [25] , ERS [19] , PAHO [14] , and SSC [4] : strong, moderate; WHO [13] , WHO (therapeutics) [21] , NCCET [67] , and NIH [23] : strong, high; Brazil [35] : weak, low; Canadian Medical Association Journal [CMAJ] [72] : weak, ungraded).

This combination was no longer recommended in the updated guidelines from the PCS [71] , IDSA [25] , American College of Physicians (ACP) [31] , Brazil [35] , PAHO [14] , NIH [23] , NCCET [67] , and ERS [19] (NIH [23] : strong, high; PAHO [14] : strong, moderate; IDSA [25] : strong, low; Brazil [35] : weak, very low; NCCET [67] : strong, low; ERS [19] : weak, moderate).

Eight guidelines [40, 43-45, 54, 59, 69, 73] recommended the use of lopinavir/ritonavir (Korea [73] : ungraded, very low). However, SSC [4] , Brazil [35] , CMAJ [72] , WHO [13] , PAHO [14] , NCCET [67] , NIH [23] , ERS [19] , and IDSA [25] [14] , and IDSA [25] : strong, moderate).

Most guidelines [4, 20, 23-26, 29, 32, 36, 44, 56, 59, 64, 67, 71] recommended the use of remdesivir as antiviral therapy (IDSA [25] : weak, moderate; ACOEM [28] : ungraded, low). The NIH [23] (ungraded, very low) recommended that patients who have not shown clinical improvement after 5 days of therapy have a treatment extension for up to 10 days. However, Korea [73] , SITA & SIP [54] , and the National Health Service (NHS; rapid guideline) [52] recommended the use of remdesivir only in clinical trials (Korea [73] : ungraded, very low; NHS (rapid guideline) [52] : weak, ungraded).

Only NHC & SATCM [69] recommended that interferon-ɑ be tried in hospitals (ungraded). CMAJ [72] recommended the use of interferon-ɑ only in the context of clinical trials (weak, ungraded). Interferon β-1a (NCCET [67] : weak, very low) and interferon gamma (NCCET [67] : weak, very low) were only recommended in the context of clinical trials. However, CMAJ [72] (weak, ungraded) and ERS [19] (weak, very low) advised against the use of interferon-β.

HSE.ie (tocilizumab) [39] , NHC & SATCM [69] , IRCCS National Institute for Infectious Diseases (INMI) [44] , SIMIT [43] , ERS [19] , and the Belgium Task Force [36] recommended the use of interleukin-6 inhibitors, while PCS [71] recommended this treatment only in severe cases. Only ACOEM [28] (weak, low) advised avoiding its routine use.

The NIH [23] acknowledged insufficient evidence to recommend either for or against the use of interleukin (IL)-1 inhibitors.

NHC & SATCM [69] , PCS [71] , and Chinese experts [76] recommended that convalescent plasma could be used for patients with rapid disease progression or in severe or critical states (ungraded). Additionally, ASAIO (ECMO) [30] and ACOEM [28] mentioned this therapy as a treatment option. However, SSC [4] (weak, low) and CMAJ [72] (weak, ungraded) suggested avoiding the routine use of convalescent plasma in critical cases.

Only NHC & SATCM [69] suggested the use of intravenous immunoglobulin (IVIG) in severe and critical cases (ungraded), while Chinese experts [76] suggested using caution with IVIG.

Recent guidelines from Korea [73] and CMAJ [72] did not recommend the use of this drug (Korea [73] : weak, very low; CMAJ [72] : weak, ungraded).

Indications for antibiotic use were different across guidelines (Supplementary Table 9 

Five documents [12, 13, 26, 35, 52] (Brazil [35] : weak, very low) recommended empirical neuraminidase therapy for suspected cases of influenza. However, Korea [73] (weak, moderate) and Brazil [35] (strong, very low) recommended against its use.

Antipyretics were recommended for fever in mild [12, 13] , moderate [71] , severe [12, 71] , and critically ill adults [4] . PAHO [14] (weak, low) suggested that antipyretics should be used for temperature control and the choice of drug should be adapted to the patient's comorbidities. Regarding drug selection, paracetamol was recommended rather than nonsteroidal anti-inflammatory drugs (NSAIDs) [47, 71] . The NIH [23] (strong, very low) recommended that clinicians use acetaminophen or NSAIDs.

A total of 30 guidelines [4, 13, 14, 17, 22-26, 28, 37, 38, 43, 49, 50, 54, 59, 67-70, 72] provided recommendations regarding corticosteroids. Three documents (CMAJ [72] : weak, ungraded; and SIMIT [43] : ungraded) recommended using corticosteroids in patients with ARDS, and low-dose corticosteroid therapy was preferred over no corticosteroid therapy in patients with refractory shock (SSC [4] , PAHO [14] , NIH [23] : weak, low [50] , ASID [68] , and Korea [73] : ungraded, very low) recommended against the routine use of corticosteroids.

This study critically reviewed the scientific evidence and recommendations from guidelines on acute COVID-19 management. Generally, the quality of the existing guidelines was low and highly variable. The recommendations across guidelines had considerable discrepancies and lacked clear links between recommendations and underlying evidence. Some of our results were similar to those of a previous study [5] that reviewed guidelines produced early during the pandemic. However, with the progress of the pandemic, our understanding of COVID-19 has deepened gradually. As more and more new evidence emerges, the recommendations also need to be updated in a timely manner. The RECOVERY trial showed that the use of dexamethasone lowered the 28-day mortality rate among patients who were receiving either invasive mechanical ventilation or oxygen alone at randomization [77] . In another trial involving patients with ARDS who were undergoing mechanical ventilation, the 60-day mortality rate was 15 percentage points lower among patients receiving dexamethasone than among those receiving standard of care [78] . Consequently, the recommendations regarding dexamethasone in NIH and NCCET guidelines have changed. It is crucial to evaluate temporal changes in guidelines' quality and help clinicians become aware of discrepancies and adjustments of the recommendations to guide clinical decision-making and improve patient outcomes.

As COVID-19 was an emerging infectious disease, there was no direct evidence available to develop evidence-based guidelines on short notice. Most existing guidelines were interim guidance or rapid guidelines that largely relied on experts' experiences. The developers may not have had enough time to compose the guidelines according to the standard methods and procedures such as conducting systematic reviews of the evidence and literature. Yet, compared with the guidelines issued at early stages (in 2020), the quality of those issued in 2021 clearly improved, owing to a deeper understanding of the disease and new emerging evidence. Currently, clinical information related to the optimal management of acute COVID-19 is evolving quickly, and many clinical trials are ongoing, which will provide evidence of higher quality. Most guidelines are living documents that are updated frequently as newly published data and other authoritative information become available. We believe that it is reasonable to adopt current recommendations into practice to improve management while waiting for new evidence to surface.

Guideline documents are generally consistent regarding the timing to start oxygen therapy in COVID-19 patients. Considering the harmful potential of hyperoxia and depletion of oxygen resources, it is not appropriate to maintain SpO 2 at a high level (>96%). Guidelines differ on NIV/HFNC recommendations, mainly based on previous clinical experience in the respective countries; NIV/HFNC for COVID-19 has been associated with a high failure rate, worse outcomes, and a possible increase in the risks of aerosolization and delayed intubation, especially for the use of NIV. Based on an unblinded clinical trial [79] and a meta-analysis [80] performed before the COVID-19 pandemic, some guidelines have suggested that HFNC is preferable over NIV in adults with COVID-19 and acute respiratory failure. It remains uncertain whether NIV/ HFNC should be used in adults with COVID-19. Therefore, any patients receiving HFNC or NIPPV should be monitored closely and vigilantly to facilitate intubation in case of rapid deterioration. Early intubation may be particularly appropriate when patients have additional acute organ dysfunction or chronic comorbidities, or when HFNC and NIPPV are not available [81, 82] .

For critical COVID-19 with ARDS, the recommendations were generally consistent. For septic shock, all documents consistently recommended resuscitation and vasopressors, measures derived from the Surviving Sepsis Campaign "International Guidelines for Management of Sepsis and Septic Shock" [83] .

The overall opinion on indication for ECMO was relatively consistent. Based on a preliminary report [84] , HNS [49] proposes revised and strict ECMO inclusion criteria in response to the COVID-19 pandemic. In addition to the above conditions, it was also necessary to score and evaluate the potential benefits of the recommendations. Given the limited clinical resources, ASAIO (ECMO) [30] recommended against the use of ECMO before conventional therapies. However, NIH [19] recommended either for or against the routine use of ECMO for patients with refractory hypoxemia because of the lack of available conclusive evidence [85, 86] .

During the initial phase of the COVID-19 pandemic, there were no drugs or therapy proven to be effective. As China and Italy were the first countries to suffer from COVID-19 outbreaks, most guidelines in these 2 countries recommended various antiviral treatments. With the publication of additional clinical research results related to the use of more remdesivir, the guidelines published after April 2020 gave more detailed suggestions in terms of subgroups of patients, dosage, and duration. A number of clinical studies on COVID-19 treatment with remdesivir, favipiravir, and tocilizumab have shown beneficial outcomes. Therefore, recent guidelines have recommended the use of antiviral drugs for patients with severe COVID-19.

Clinical trials testing baloxavir marboxil, darunavircobicistat, HIV protease inhibitors, mesenchymal stem cells (MSCs), and umifenovir have been published. However, the use of these treatments was only recommended for clinical trials, and these treatments should be cautiously used due to various potential adverse reactions. More clinical trials are ongoing [87] , and candidate drugs are under development [88] .

The guidelines generally agree on the scope of application of antibiotics and recommend their empirical use in severe or critical cases with sepsis, but not for mild or uncomplicated cases [4, 14, 37, 44, 71] . Some documents [13, 23, 26] recommended constant reassessment in order to de-escalate early or stop antibiotic treatments, while others recommended against blind or inappropriate use of antibiotic drugs [13, 55, 73] . Disease severity and suspected co-infection are important indications for antibiotic use. Fever is one of the most common symptoms of COVID-19, and most guidelines agree that the administration of antipyretics should be based on fever symptoms, disease severity, and comorbidities [4, [12] [13] [14] 71] . Regarding drug selection, because NSAIDs like ibuprofen have been reported to potentially increase ACE2 expression [89] and inhibit antibody production [90] , paracetamol was recommended rather than NSAIDs in the NICE (managing symptoms) [47] and the PCS guidelines [71] . However, the Food and Drug Administration rapidly stated that there was no evidence linking the use of NSAIDs to worsening COVID-19 [91] .

Whether corticosteroids could be used in COVID-19 patients remained controversial until August 2020. Most guidelines recommended the use of corticosteroids for certain conditions [4, 14, 23, 37, 69] , whereas other guidelines [59, 72] recommended a total treatment duration of 7-10 days, with progressive dose reduction. The Korean guidelines [73] recommended against routine use of corticosteroids based on adverse effects such as prolonged viral replication, which may result in mechanical ventilation and higher mortality [22] or increased exposure to fungal pathogens [52] . Recent guidelines have consistently recommended the use of corticosteroids at early stages of severe illness.

Our study has several strengths. We had a broad inclusion of guidelines located in a broad range of geographical locations. Furthermore, we evaluated the quality of the guidelines using AGREE II, which is an internationally validated instrument for guidelines assessment. Our team was composed of experts from different backgrounds, gathering front-line clinical experts and methodologists. A significant degree of agreement among the 4 reviewers was achieved, which improved the reliability of our findings. However, some limitations could bias our study and limit generalizability. First, the guidelines were limited to publications in the English language. Second, it was difficult to identify recommendations that were not developed by evidence-based methods. This limitation may be mitigated by the involvement of reviewers with clinical experience to capture recommendations. Third, we could not always identify all the supplemental materials necessary for quality assessments and might have underestimated guideline quality. Finally, the AGREE II instrument focuses on methods of guideline development and transparency of reporting, but does not assess the potential impacts of the recommendations on patient outcomes [92] .

The quality of existing guidelines for COVID-19 management was generally low and highly variable. There were considerable recommendation discrepancies between guidelines and a general lack of evidence, especially for the recommendations related to respiratory support and antiviral therapy.

Disease and healthcare burden of COVID-19 in the United States

Estimating the burden of SARS-CoV-2 in France

Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19)

Scope, quality, and inclusivity of clinical guidelines produced early in the COVID-19 pandemic: rapid review

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Corticosteroids for COVID-19

Use of tracheostomy during the COVID-19 pandemic

Management of hospitalised adults with coronavirus disease 2019 (COVID-19): a European Respiratory Society living guideline

Updated guidance on the management of COVID-19: from an

Centers for Disease Control and Prevention. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19)

COVID-19) treatment guidelines

COVID-19: interim guidance on management pending empirical evidence. From an American Thoracic Society-led international task force

Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19 infection

Canadian Critical Care Society and Association of Medical Microbiology and Infectious Disease (AMMI) Canada. Clinical management of patients with moderate to severe COVID-19 -interim guidance

American Association for Respiratory Care

Coronavirus (COVID-19)

Advanced pulmonary and cardiac support of COVID-19 patients: emerging recommendations from ASAIO-A "living working document

Extracorporeal life support organization coronavirus disease 2019 interim guidelines: a consensus document from an international group of interdisciplinary extracorporeal membrane oxygenation providers

Scientific Medical Policy Committee of the American College of Physicians. Should clinicians use chloroquine or hydroxychloroquine alone or in combination with azithromycin for the prophylaxis or treatment of COVID-19? Living practice points from the American College of Physicians (version 1)

Should remdesivir be used for the treatment of patients with COVID-19? Rapid, living practice points from the American College of Physicians (version 2)

Critical Care and Acute Care Surgery Committees of the American Association for the Surgery of Trauma. Performing tracheostomy during the Covid-19 pandemic: guidance and recommendations from the Critical Care and Acute Care Surgery Committees of the American Association for the Surgery of Trauma

Tracheotomy recommendations during the COVID-19 pandemic

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

Interim clinical guidance for adults with suspected or confirmed Covid-19 in Belgium

German recommendations for critically ill patients with COVID-19

Guidance document for the intensive care management of the adult patient with confirmed or suspected COVID-19

drugs-management-programme/interim-recommendations-for-the-use-oftocilizumab-in-the-management-of-patients-who-have-severe-covid-19-withsuspected-hyperinflammation

Interim guidance for the use of antiviral therapy in the clinical management of acute respiratory infection with SARS-CoV-2 (COVID-19)

Managing the respiratory care of patients with COVID-19

Respiratory physiotherapy in patients with COVID-19 infection in acute setting: a position paper of the Italian Association of Respiratory Physiotherapists (ARIR)

Vademecum for the treatment of people with COVID-19

National Institute for the Infectious Diseases "L. Spallanzani", IRCCS. Recommendations for COVID-19 clinical management

The Italian coronavirus disease 2019 outbreak: recommendations from clinical practice

Swiss Society of Intensive Care Medicine. Recommendations for the admission of patients with COVID-19 to intensive care and intermediate care units (ICUs and IMCUs)

COVID-19 rapid guideline: managing symptoms (including at the end of life) in the community

National Institute for Health and Care Excellence

Clinical guide for extra corporeal membrane oxygenation (ECMO) for respiratory failure in adults during the coronavirus pandemic

Clinical management of persons admitted to hospital with suspected COVID-19 infection

Clinical guide for the optimal use of oxygen therapy during the coronavirus pandemic

COVID-19 rapid guideline: managing COVID-19

Position paper on the preparation of immune plasma to be used in the treatment of patients with COVID-19

Balancing evidence and frontline experience in the early phases of the COVID-19 pandemic: current position of the Italian Society of Anti-infective Therapy (SITA) and the Italian Society of Pulmonology (SIP)

COVID-19 rapid guideline: antibiotics for pneumonia in adults in hospital

Remdesivir for severe COVID-19: a clinical practice guideline

Critical care preparation and management in the COVID-19 pandemic

Position paper for the state-of-the-art application of respiratory support in patients with COVID-19

Management of SARS-CoV-2 infection: recommendations of the Polish Association of Epidemiologists and Infectiologists as of March 31

Respiratory Support Chronic Care Group AVO2 of the French Society of Respiratory Diseases SPLF; GAVO2 collaborators. Respiratory support in patients with COVID-19 (outside intensive care unit). A position paper of the Respiratory Support and Chronic Care Group of the French Society of Respiratory Diseases

BTS/ICS guidance: respiratory care in patients with acute hypoxaemic respiratory failure associated with COVID-19

ICS guidance for prone positioning of the conscious COVID patient

Acute use of non-steroidal anti-inflammatory drugs (NSAIDs) in people with or at risk of COVID-19

Interim clinical commissioning policy: remdesivir for patients hospitalised with COVID-19 (adults and children 12 years and older)

Interim clinical commissioning policy: sarilumab for critically ill patients with COVID-19 pneumonia (adults)

Interim clinical commissioning policy: tocilizumab for hospitalised patients with COVID-19 pneumonia (adults)

National COVID-19 Clinical Evidence Taskforce. Australian guidelines for the clinical care of people with COVID-19

Interim guidelines for the clinical management of COVID-19 in adults

Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7)

Chinese Association of Chest Physicians. Guidance for the management of adult patients with coronavirus disease 2019

COVID-19 management guidelines

Treatment of patients with nonsevere and severe coronavirus disease 2019: an evidence-based guideline

Interim guidelines on antiviral therapy for COVID-19

Ministry of Health and Family Welfare, Government of India. Revised advisory on the use of hydroxychloroquine (HCQ) as prophylaxis for SARS-CoV-2 infection

Airway management and related procedures in critically ill COVID-19 patients: position statement of the Indian Society of Critical Care Medicine

Chinese expert consensus on the diagnosis and treatment of severely and critically ill patients with coronavirus disease 2019

Dexamethasone in hospitalized patients with Covid-19 -preliminary report

Dexamethasone in ARDS network. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial

Highflow oxygen through nasal cannula in acute hypoxemic respiratory failure

The effect of high-flow nasal cannula in reducing the mortality and the rate of endotracheal intubation when used before mechanical ventilation compared with conventional oxygen therapy and noninvasive positive pressure ventilation. A systematic review and meta-analysis

International NIV Network. Noninvasive mechanical ventilation in high-risk pulmonary infections: a clinical review

Saudi Critical Care Trials Group. Noninvasive ventilation in critically ill patients with the Middle East respiratory syndrome

Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock

CESAR trial collaboration. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial

Venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review and metaanalysis

Extracorporeal membrane oxygenation for pandemic influenza A(H1N1)-induced acute respiratory distress syndrome: a cohort study and propensity-matched analysis

Potential drug development and therapeutic approaches for clinical intervention in COVID-19

Clinical management of COVID-19: a review of pharmacological treatment options

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells

FDA advises patients on use of non-steroidal antiinflammatory drugs (NSAIDs) for COVID-19

Conflict between guideline methodologic quality and recommendation validity: a potential problem for practitioners