Open Forum Infectious Diseases

REVIEW ARTICLE

Critical Review of the Scientific Evidence and

Recommendations in COVID-19 Management Guidelines
Jiaxing Xie,1,a Zhufeng Wang,2,a Jingyi Liang,2,a Huimin Lin,1,a Zhaowei Yang,1,a Yingzhi Wang,3,a Hanwen Liang,2 Hongkai Wu,2 Ruchong Chen,1

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Younger Ou,2 Fengyan Wang,2 Yuan Wang,2 Yan Wang,2 Weizhan Luo,2 Jianheng Zhang,2 Naijian Li,1 Zhengtu Li,2 Mei Jiang,2 Shiyue Li,2 and Jing Li1
1
Department of Allergy and Clinical Immunology, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, the First
Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China, 2National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou
Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China, and 3Department of Pulmonary and Critical Care Medicine, China State Key
Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

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.
Keywords.  COVID-19; evidence; guideline; management; recommendation.

INTRODUCTION must also be considered. To face the rapid global spreading

The coronavirus disease 2019 (COVID-19) pandemic has be- of severe acute respiratory syndrome coronavirus 2 (SARS-
come a global public health crisis. As of June 17, 2021, COVID- CoV-2) and the difficulty for overburdened front-line workers
19 has affected >176 million people in >200 countries or regions and policy-makers of staying up to date on the emerging litera-
and resulted in >3.8 million deaths [1]. The economic burden ture, many national and international organizations have issued
and health threat of COVID-19 are extremely dreadful and have rapid advice or interim guidelines for COVID-19 management.
become more severe as the number of global infections and These guidelines have integrated the best possible informa-
deaths increases [2,3]. tion in response to health and social care emergencies to help
The management of the disease relies largely on symptomatic frontline health care professionals improve clinical outcomes
and supportive treatments. For severe or critically ill patients [4]. However, little is known about the quality and variability of
with acute respiratory distress syndrome (ARDS) and sepsis, in the recommendations among different guidelines. Additionally,
addition to supplemental oxygen, mechanical ventilation, and substantial differences exist in clinical practices across countries
ARDS-specific therapies, antiviral and antibiotic treatments and hospitals. To provide the best care possible, clinicians need
to understand the discrepancy of recommendations among
 
guidelines and choose evidence-based recommendations de-
Received 27 April 2021; editorial decision 6 July 2021; accepted 13 July 2021.
a veloped by trustworthy methodologies [5].
Equal contribution, co-first authors
Correspondence: Mei Jiang, PhD, National Clinical Research Center for Respiratory Disease, Many issues related to the clinical management of acute
State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, the COVID-19 remain to be clarified, including the role of non-
First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou,
Guangdong, 510120, China (jiangme927@163.com). invasive ventilation (NIV), high-flow nasal cannula (HFNC),
Open Forum Infectious Diseases®2021 usage of corticosteroids or other supportive therapies, and
© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases various antiviral medications. In this study, we aimed to sys-
Society of America. This is an Open Access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/ tematically review and evaluate currently available guidelines
licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the for acute COVID-19 management and specifically compare
work, in any medium, provided the original work is not altered or transformed in any way, and that
the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com the available recommendations and the quality of supporting
https://doi.org/10.1093/ofid/ofab376 evidence.

Critical Review of COVID-19 Management Guidelines  •  ofid  • 1

METHODS user’s manual: (actual score – minimal possible score)/(max-
We registered this study protocol and reported the results ac- imal possible score – minimal possible score) [9]. The stand-
cording to the Preferred Reporting Items for Systematic Reviews ardized scores ranged from 0% to 100%. Guidelines with an
and Meta-Analyses guidelines (CRD42020180074) [6]. overall score >60% were classified as “recommended,” between
30% and 60% as “recommended with modifications,” and <30%
Data Sources and Searches as “not recommended” [10, 11].
We searched PubMed, Web of Science, and Cochrane Library
Data Synthesis and Analysis
for COVID-19 guidelines published through June 17, 2021,

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Eight clinicians independently extracted the general charac-
as well as websites of international organizations, government
teristics of the eligible guidelines and the recommendations
health institutions, relevant specialty societies, guideline-
concerning respiratory support, ARDS management, antiviral
specific databases, and Google Scholar. The bibliographies of
and immunomodulatory therapies, and other pharmacologic
included studies were further screened for additional poten-
treatments (corticosteroids, antibiotics, antipyretics, and neura-
tially relevant articles. The detailed search strategies and re-
minidase inhibitors). We developed recommendation matrices
sults are presented in the Supplementary Data (Supplementary
to assist with systematic comparison, categorization, and sum-
Methods 1 and 2). Our search was restricted to guidelines de-
marization, including comparison of the strength of the recom-
veloped by international or national health care organizations
mendation and quality of evidence.
and medical societies published in English.
The general characteristics, standardized score in each do-
Guideline Selection main, distribution of level of evidence, and strength of recom-
To be included, guidelines had to make specific recommenda- mendation of each eligible guideline were depicted using either
tions for the management of acute COVID-19 regarding NIV, median and range, mean and SD, or frequency and percentage.
HFNC, use of corticosteroids or other supportive therapies, and Subgroup analyses were performed according to country,
use of various antiviral medications. When several versions of target population, type of guideline, and development method.
the same document were available, only the latest version was Agreement among the 4 reviewers was measured by intraclass
retained. For each eligible guideline, we thoroughly searched correlation coefficient (ICC) with a 95% CI. All analyses were
for supplementary supporting documents to better inform our conducted using R software, version 3.6.1 (http://CRAN.R-
assessments. The following types of document were excluded: project.org; R Foundation, Vienna, Austria).
(i) guidelines regarding diagnosis, home care, or prevention and
control of infection; (ii) guidelines for special populations such RESULTS
as newborns, children, or pregnant women; (iii) guidelines de- Characteristics of the Included Guidelines
veloped by autonomous medical institutions or nonprofessional A total of 66 guidelines met the inclusion criteria (Figure 1). The
societies; (iv) documents such as systematic reviews, clinical general characteristics of these eligible guidelines are shown in
trials, commentaries, case series, letters, or chapters in books Figure 2 and Supplementary Table 1. Eleven (17%) were devel-
or booklets; (v) documents that were not published in English oped by international organizations [4, 12–21], and 13 (20%)
or not available in full-text format; (vi) specialty guidelines for originated from North America [22–34], 1 (2%) from South
triage, tracheotomy, complications, palliative treatment, and America [35], 31 (47%) from Europe [36–66], and 10 (15%)
rehabilitation. from the Asia-Pacific area region [67–76]. Only 25 (38%) guide-
lines provide an approximate update interval, with an average
Data Extraction and Quality Assessment of 2.2  months (min: 0.25  months; max: 6  months). Twenty-
Two reviewers (Z.W. and J.X.) independently screened and ex- four guidelines (36%) were developed using evidence-based
tracted all relevant information from included guidelines using methods, and 20 (30%) graded the strength of recommenda-
predesigned forms. Whenever discrepancies arose, resolution tions, of which only 9 (14%) appraised the quality of evidence
was achieved by consensus or by consulting the third expert (Supplementary Table 2). In order to compare the strength of
adjudicator (M.J.). The quality of eligible guidelines was in- the recommendations and quality of evidence obtained by dif-
dependently evaluated by 4 appraisers who had been trained ferent grading systems, a composite grading system applicable
in clinical practice guidelines appraisal using the Appraisal of to all recommendations was generated (Supplementary Table
Guidelines for Research and Evaluation II (AGREE II) instru- 3).
ment [7–9]. AGREE II contains 23 items within 6 domains.
Each item was scored on 7-point Likert scale that varies from Quality Assessment of the Guidelines
1 (strongly disagree) to 7 (strongly agree). A standardized score The standardized AGREE II scores obtained by all guide-
was calculated as the percentage of the maximal possible score lines for each domain and the overall assessment are shown
for each domain using the formula provided in the AGREE II in Supplementary Table 4. The guidelines scored moderately

2 • ofid  •  Xie et al

 Records identified through database Additional records identified through

Identification
searching other sources
(n = 6998) (n = 83)

Records after duplicates removed

(n = 3751)

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Screening

Titles/abstracts screened Titles/abstracts excluded

(n = 3751) (n = 3643)

Full-text articles excluded

Eligibility

Full-text articles assessed for

eligibility (n = 42)
(n = 108)
37 recommendations field
not of interesta
5 duplicate records

Guidelines selected for

Included

evaluation
(n = 66)

Figure 1.  Search and selection flowchart for the retrieval of COVID-19 management guidelines. aGuidelines for pregnant women, children, newborns, diagnosis, quaran-
tine, home care, protection, radiology, ultrasound, triage, tracheotomy, complications, palliative treatment, rehabilitation. Abbreviation: COVID-19, coronavirus disease 2019.

in the domains scope and purpose (mean, 68%; range, 31%– Recommendations Related to Respiratory Support
89%) and clarity and presentation (mean, 69%; range, 21%– Oxygen Therapy
85%) but scored highly variably in the other 4 domains Ten documents [12–14, 16, 26, 29, 47, 54, 69, 76] recom-
(Figure 3). Most guidelines (n  =  38, 70%) were categorized mended timely supplementation of oxygen for patients with
as “recommended with modifications” for use during the COVID-19 in the circumstance of severe acute respiratory
COVID-19 pandemic, 12 (22%) were “recommended,” and 4 infection (SARI), respiratory distress, hypoxemia, shock,
(7%) were “not recommended” (Supplementary Table 4). The or other severe symptoms (Supplementary Table 6). Seven
overall agreement of the 4 appraisers was considered good documents recommended the use of SpO2 as an indicator and
(ICC, 0.849; 95% CI, 0.833–0.864). Supplementary Table initiation of oxygen therapy under specific SpO2 threshold
5 shows the quality scores of the guidelines across the dif- levels as follows: <90% (Surviving Sepsis Campaign [SSC]
ferent subgroups. The quality of the guidelines issued during [4]: strong, moderate; American Association for Respiratory
2021, originating from North America, developed by evi- Care [AARC] [27] and World Health Organization [WHO]
dence-based methods or by >1 organization, was higher than [13]: strong, ungraded); <92% (SSC [4]: strong, low; French
the other guidelines. Society of Respiratory Diseases [FSRD] [60] and Australasian
Society for Infectious Diseases [ASID] [68]: ungraded; AARC
Recommendations [27]: weak, ungraded); or <93% (Chinese Thoracic Society
General recommendations relevant to COVID-19 manage- [CTS] & Chinese Association of Chest Physicians [CACP]
ment in adults are listed in Table 1. Two hundred eleven re- [70] and Pakistan Chest Society [PCS] [71]: ungraded);
commendations were extracted from 66 documents. Among or significantly below baseline [68]. Moreover, it was re-
these, only 62.6% (132 recommendations) and 56.4% (119 re- commended that the SpO2 target level not be maintained
commendations) were supported by, respectively, assessment of above 96% [4, 14, 16, 27, 54] (SSC [4] and Pan American
strength or quality of evidence. Health Organization [PAHO] [14]: strong, moderate; AARC

Critical Review of COVID-19 Management Guidelines  •  ofid • 3

 Category No. (%) Category No. (%)
Date of publication Development method

Year 2020 49 (74%) EB 24 (36%)

Non-EB 42 (64%)
Year 2021 17 (26%)
Strength of recommendations
Region
Yes 20 (30%)
Asia-Pacific 10 (15%)
No 46 (70%)
Europe 31 (47%) Quality of evidence

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International 11 (17%) Yes 9 (14%)

No 57 (86%)
North America 13 (20%)
Grading system
South America 1 (2%)
GRADE 15 (23%)
Target population
Not mentioned 51 (77%)
Critically ill patients 17 (26%) Version

General population 49 (74%) First 35 (53%)

Type of guidelines Updated 31 (47%)

Management 50 (76%) Developers

Medical society 44 (67%)
Not only management 16 (24%)
Nonmedical society 22 (33%)
Type of publication
No. developed organization
Guideline 12 (18%)
>1 17 (26%)

Othersa 54 (82%) 1 49 (74%)

0 20 40 60 80 100 0 20 40 60 80 100

% of general characteristics of % of general characteristics of

identified guidelines (n = 66) identified guidelines (n = 66)

Figure 2.  Proportion of the COVID-19 management guidelines according to general characteristics. aProtocol, interim guidance, recommendation, consensus. Abbreviations:
COVID-19, coronavirus disease 2019; EB, evidence-based; GRADE, Grading of Recommendations Assessment Development and Evaluation.

Scope and purpose

Stakeholder involvement

Rigor of development

Clarity of presentation

Applicability

Editorial independence

0 30 60 90
AGREE II domain scores for all included guidelines, %

Figure 3.  AGREE domain scores of all included guidelines. The vertical line at 60% represents the cutoff score at or above which a domain was considered “adequately ad-
dressed.” 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.

4 • ofid  •  Xie et al

[27]: strong, ungraded; Thomas et  al. [16] and Italian Recommendations for ARDS Management
Society of Anti-infective Therapy [SITA] & Italian Society of Endotracheal Intubation
Pulmonology [SIP] [54]: ungraded). It was consistently recommended that endotracheal intubation be
performed by the most trained and experienced operators in most
NIV/HFNC documents [4, 13, 14, 26, 37, 38, 45, 50, 52] (National Institutes
Multiple guidelines [4, 12, 13, 19, 23, 26, 41, 42, 50, 61, 67, of Health [NIH] [23]: strong, very low; SSC [4], CCCGWG [26],
69–71] recommended that NIV/HFNC be used (SSC [4] and and WHO [13]: strong, ungraded) (Supplementary Table 7). Upon
National COVID-19 Clinical Evidence Taskforce [NCCET] worsening of the patient condition, early endotracheal intubation

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[67]: weak, low; European Respiratory Society [ERS] [19]: in a controlled setting was recommended by most guidelines [4,
weak, very low; WHO [13], COVID-19 Clinical Care Guidance 12–16, 23, 26, 37, 41, 42, 50–52, 69] (SSC [4], CCCGWG [26],
Working Group [CCCGWG] [26], and AARC [27]: weak, un- WHO [13], and NIH [23]: strong).
graded) under close monitoring (within 1–4 hours) in cases of
worsening respiratory status and early intubation in a controlled ARDS Ventilation
setting. However, in some of the guidelines [16, 37, 43, 45, 68, Most documents consistently recommended using low tidal
75], NIV was not recommended (ungraded). Some guidelines volume (Vt), airway platform pressure <30 cmH2O, prone ven-
recommended against HFNC for adult patients with COVID- tilation, and neuromuscular blockade agents in ARDS. Most
19 (ungraded) [37, 43–45, 52]. guidelines [4, 13–15, 23, 26, 27, 44, 45, 67, 69] suggested using a

Table 1.  General Recommendations for Management of COVID-19

No. of Recommendations (%)

Supported
by an As- Supported
sessment of by Quality of
Topic Type of Intervention Guidelines That Provide Recommendations Extracted Strength Evidence

Respiratory support Timing of start of WHO-toolkit [12], CCCGWG [26], WHO [13], PAHO [14], 7 4 (57) 3 (43)
oxygen therapy Thomas et al. [16], SITA&SIP [54], CTS&CACP [70], PCS [71],
NHC&SATCM [69], Chinese experts [76], NICE (managing symp-
toms) [47], ASID [68], AARC [27], SSC [4], FSRD [60]
Target of oxygen WHO [13], Poland [59], WHO-toolkit [12], CCCGWG [26], Thomas 11 4 (36) 2 (18)
therapy 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]
HFNC and NIV WHO-toolkit [12], NHC&SATCM [69], SSC [4], CCCGWG [26], 9 PCS [71] 3 3 (33)
ITS&IRS [41], ARIR&AIFI [42], NHS (management) [50], WHO (33)
[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]
Management of Endotracheal intu- SSC [4], ICSI [38], SIAARTI&EAMS [45], CCCGWG [26], NHS (rapid 4 4 (100) 3 (75)
ARDS bation 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]
ARDS ventilation NIH [23], CCCGWG [26], NHS (critical care), SSC [4], WHO [13], 15 13 (87) 11 (73)
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 ex-
perts [76], Thomas et al. [16], SIAARTI&EAMS [45], ASAIO [29],
ICSI [38], ASAIO (ECMO) [30], INMI [44], GRS [58]
Hemodynamics WHO-toolkit [12], NHC&SATCM [69], WHO [13], PCS [71], NHS 8 8 (100) 8 (100)
(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 4 3 (75) 2 (50)
[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) [49]

Critical Review of COVID-19 Management Guidelines  •  ofid • 5

Table 1.  Continued

No. of Recommendations (%)

Supported
by an As- Supported
sessment of by Quality of
Topic Type of Intervention Guidelines That Provide Recommendations Extracted Strength Evidence
Antiviral or General recom- SIMIT [43], Korea [73], NHC&SATCM [69], HSE.ie (antiviral therapy), 8 4 (50) 5 (63)
immunomodulatory mendations ASID [68], PAHO [14], ATS [24], NIH [23], WHO-toolkit [12], INMI
therapy [44], ITS&IRS [41], NHS (rapid guideline), Kluge et al. [37], Chi-

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nese experts [76]
Chloroquine or NHC&SATCM [69], HSE.ie (antiviral therapy), INMI [44], SIMIT [43], 11 5 (45) 5 (45)
hydroxychloroquine 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 [4]
Hydroxychloroquine/ IDSA [25], HSE.ie (antiviral therapy), ACP [31], PCS [71], Brazil [35], 3 2 (67) 1 (33)
chloroquine plus PAHO [14], NIH [23], NCCET [67], ERS [19]
azithromycin
Lopinavir/ritonavir NHC&SATCM [69], SIAARTI&EAMS [45], INMI [44], Korea [73], 6 3 (50) 3 (50)
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]
Remdesivir INMI [44], IDSA [25], PCS [71], ACOEM [28], BMJ GDG panel [56], 10 9 (90) 7 (70)
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]
Interferon NHC&SATCM [69], CMAJ [72], NCCET [67], ACOEM [28], Korea 11 8 (73) 7 (64)
[73], NIH [23], ERS [19]
IL-6 inhibitors PCS [71], HSE.ie (tocilizumab) [39], NHC&SATCM [69], INMI [44], 5 3 (60) 2 (40)
SIMIT [43], ERS [19], Belgium Task Force [36], IDSA [25], NIH
[23], ASAIO (ECMO) [30], SSC [4], ACOEM [28]
IL-1 inhibitors NIH [23] 1 0 0
Convalescent plasma NHC&SATCM [69], PCS [71], Chinese experts [76], SIMTI&SIdEM 5 2 (40) 3 (60)
[53], CTS&CACP [70], Korea [73], ASAIO (ECMO) [30], ACOEM
[28], PAHO [14], NCCET [67], NIH [23], IDSA [25], SSC [4], CMAJ
[72]
IVIG NHC&SATCM [69], NIH [23], Korea [73], NCCET [67], Chinese ex- 5 2 (40) 3 (60)
perts [76]
Ribavirin NHC&SATCM [69], ACOEM [28], Korea [73], CMAJ [72] 3 1 (33) 2 (67)
Favipiravir NCCET [67], SITA&SIP [54], Korea [73], ACOEM [28] 2 1 (50) 2 (100)
HIV protease inhibi- NIH [23] 2 2 (100) 2 (100)
tors
JAK inhibitors ACOEM [28], NCCET [67], NIH [23] 3 3 (100) 3 (100)
Umifenovir SITA&SIP [54], NCCET [67] 1 1 (100) 1 (100)
Oseltamivir Chinese experts [76], Brazil [35], SITA&SIP [54] 2 1 (50) 1 (50)
Sarilumab NHS (sarilumab) [65], NCCET [67], NICE (critical care) [48], NIH [23] 2 1 (50) 1 (50)
Tocilizumab NHS (tocilizumab) [66], IDSA [25], Belgium Task Force [36], NHS 3 2 (67) 2 (67)
(rapid guideline) [52], NCCET [67], CTS&CACP [70], PAHO [14],
NICE (critical care) [48], SITA&SIP [54], ASAIO (ECMO) [30], NIH
[23], Brazil [35]
Ivermectin WHO (therapeutics) [21], ACOEM [28], NIH [23], NCCET [67], IDSA 3 2 (67) 3 (100)
[25]
Bamlanivimab or/plus NIH [23], IDSA [25], NCCE 2 2 (100) 2 (100)
etesevimab
Casirivimab or/plus ACOEM [28], IDSA [25], NCCET [67] 2 2 (100) 2 (100)
imdevimab
Other NCCET [67], NIH [23], PAHO [14], Chinese experts [76] 5 5 (100) 4 (80)

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Table 1.  Continued

No. of Recommendations (%)

Supported
by an As- Supported
sessment of by Quality of
Topic Type of Intervention Guidelines That Provide Recommendations Extracted Strength Evidence
Other pharmacologic Corticosteroids CTS&CACP [70], NHC&SATCM [69], SSC [4], CMAJ [72], NIH [23], 24 13 (54) 12 (50)
treatments PAHO [14], Kluge et al. [37], SIMIT [43], CCCGWG [26], IDSA
[25],WHO (corticosteroids) [17],WHO (therapeutics), ERS [19],

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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]
Antibiotics CTS&CACP [70], ASID [68], WHO-toolkit [12], ICSI [38], Brazil [35], 17 10 (59) 7 (41)
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]
Antipyretic WHO-toolkit [12], PCS [71], PAHO [14], WHO [13], NIH [23], SSC [4], 9 5 (56) 4 (44)
NICE (managing symptoms) [47]
Neuraminidase in- WHO-toolkit [12], CCCGWG [26], NHS (critical care), ASID [68], 8 4 (50) 3 (38)
hibitor Brazil [35], Korea [73], SITA&SIP [54], WHO [13]

The acronyms of guidelines and organizations are defined in Supplementary Table 1.

Other abbreviations: ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation; HFNC, high-flow nasal cannula; IL, interleukin; IVIG, intravenous immuno-
globulin, NIV, noninvasive ventilation.

higher positive end-expiratory pressure (PEEP) strategy (WHO ECMO

[13]: strong, ungraded; SSC [4], PAHO [14], and NIH [23]: In mechanically ventilated adults with refractory hypoxemia
weak, low; CCCGWG [26], WHO [13], and AARC [27]: weak, despite optimizing ventilation, the use of rescue therapies,
ungraded), whereas several documents (AARC [27]: strong, proning, and ECMO was suggested by most documents [4, 12–
ungraded; Intensive Care Society of Ireland [ICSI] [38], CTS 14, 23, 24, 26, 27, 37, 38, 48, 51, 52, 67–71] (ASAIO [ECMO]
& CACP [70] and PCS [71]: ungraded) recommended setting [30]: strong, ungraded; SSC [4], PAHO [14], and NIH [23]:
the PEEP appropriately, with PCS [71] and CTS & CACP [70] weak, low; CCCGWG [26], WHO [13], and AARC [27]: weak,
considering PEEP titration or low PEEP (ungraded). Inhaled ungraded). However, ASAIO (ECMO) [30] recommended
pulmonary vasodilator as rescue therapy for ARDS was recom- against the initiation of ECMO before maximizing conventional
mended in 6 documents (SSC [4]: weak, very low; AARC [27] therapies for ARDS, in particular prone positioning (strong,
and American Society for Artificial Internal Organs [ASAIO; ungraded).
extracorporeal membrane oxygenation {ECMO}] [30]: weak,
ungraded; NIH [23]: ungraded, very low; ICSI [38] and Kluge Recommendations for Antiviral Therapy
et al. [37]: ungraded). However, some guidelines (SSC [4] and Four guidelines (Lombardy Section of the Italian Society of
PAHO [14]: strong, low; NIH [23]: strong, moderate; AARC Infectious and Tropical Diseases [SIMIT] [43], Korea [73],
[27]: strong, ungraded; PCS [71]: ungraded) recommended National Health Commission [NHC] & State Administration of
against the routine use of inhaled nitric oxide. Traditional Chinese Medicine [SATCM] [69], Ireland’s Health
Services [HSE.ie; antiviral therapy] [40]) were in favor of trying
Hemodynamics antiviral therapy (Supplementary Table 8). However, currently,
Most documents [4, 12–14, 23, 26, 27, 37, 50–52, 69, 71, 76] re- most guidelines [12, 23, 24, 37, 41, 44, 52, 68, 76] do not recom-
commended a conservative fluid strategy and crystalloid fluid [4, mend any special drugs or therapies for COVID-19.
12–14, 23, 26] for patients in shock (CCCGWG [26] and WHO
[13]: strong, ungraded; PAHO [14]: strong, low; SSC [4] and NIH Chloroquine/Hydroxychloroquine
[23]: weak, low; AARC [27]: weak, ungraded). Regarding the Ten guidelines [24, 29, 40, 43–45, 54, 69, 73, 74] recom-
type of vasopressor, recommendations [4, 13, 14, 23, 26, 52] were mended chloroquine/hydroxychloroquine as antiviral therapy
generally consistent and indicated norepinephrine as the first- (American College of Occupational and Environmental
line vasoactive agent (NIH [23]: strong, low; SSC [4] and PAHO Medicine [ACOEM] [28]: weak, moderate; Korea [73]: un-
[14]: weak, low; CCCGWG [26] and WHO [13]: weak, ungraded; graded, very low), while 11 guidelines [4, 13, 14, 19, 21, 23, 25,
and Chinese experts [76]: weak, ungraded). 31, 35, 67, 72] recommended against its use (Infectious Diseases

Critical Review of COVID-19 Management Guidelines  •  ofid • 7

Society of America [IDSA] [25], ERS [19], PAHO [14], and SSC this treatment only in severe cases. Only ACOEM [28] (weak,
[4]: strong, moderate; WHO [13], WHO (therapeutics) [21], low) advised avoiding its routine use.
NCCET [67], and NIH [23]: strong, high; Brazil [35]: weak,
low; Canadian Medical Association Journal [CMAJ] [72]: weak, Interleukin-1 Inhibitors
ungraded). The NIH [23] acknowledged insufficient evidence to rec-
ommend either for or against the use of interleukin (IL)-1
Azithromycin Combined With Chloroquine/Hydroxychloroquine inhibitors.
This combination was no longer recommended in the updated

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guidelines from the PCS [71], IDSA [25], American College Convalescent Plasma
of Physicians (ACP) [31], Brazil [35], PAHO [14], NIH [23], NHC & SATCM [69], PCS [71], and Chinese experts [76] re-
NCCET [67], and ERS [19] (NIH [23]: strong, high; PAHO [14]: commended that convalescent plasma could be used for patients
strong, moderate; IDSA [25]: strong, low; Brazil [35]: weak, with rapid disease progression or in severe or critical states (un-
very low; NCCET [67]: strong, low; ERS [19]: weak, moderate). graded). Additionally, ASAIO (ECMO) [30] and ACOEM [28]
mentioned this therapy as a treatment option. However, SSC
Lopinavir/Ritonavir [4] (weak, low) and CMAJ [72] (weak, ungraded) suggested
Eight guidelines [40, 43–45, 54, 59, 69, 73] recommended the avoiding the routine use of convalescent plasma in critical cases.
use of lopinavir/ritonavir (Korea [73]: ungraded, very low).
However, SSC [4], Brazil [35], CMAJ [72], WHO [13], PAHO Intravenous Immunoglobulin
[14], NCCET [67], NIH [23], ERS [19], and IDSA [25] recom- Only NHC & SATCM [69] suggested the use of intravenous im-
mended against the routine use of this combination for severe munoglobulin (IVIG) in severe and critical cases (ungraded),
patients (NIH [23]: strong, very low; WHO [13]: strong, un- while Chinese experts [76] suggested using caution with IVIG.
graded; ERS [19]: strong, low; SSC [4]: weak, low; Brazil [35]:
weak, very low; CMAJ [72]: weak, ungraded; NCCET [67], Ribavirin
PAHO [14], and IDSA [25]: strong, moderate). Recent guidelines from Korea [73] and CMAJ [72] did not
recommend the use of this drug (Korea [73]: weak, very low;
Remdesivir CMAJ [72]: weak, ungraded).
Most guidelines [4, 20, 23–26, 29, 32, 36, 44, 56, 59, 64, 67, 71]
Recommendations of Other Pharmacologic Treatments
recommended the use of remdesivir as antiviral therapy (IDSA
Antibiotics
[25]: weak, moderate; ACOEM [28]: ungraded, low). The NIH
Indications for antibiotic use were different across guide-
[23] (ungraded, very low) recommended that patients who
lines (Supplementary Table 9). Seven documents (NHS [rapid
have not shown clinical improvement after 5  days of therapy
guideline] [52], NHS [management] [50], CTS & CACP [70],
have a treatment extension for up to 10 days. However, Korea
National Institute for Health and Care Excellence [NICE; anti-
[73], SITA & SIP [54], and the National Health Service (NHS;
biotics] [55]: ungraded; Korea [73]: strong, moderate; WHO
rapid guideline) [52] recommended the use of remdesivir only
[13]: strong, ungraded; and SIMIT [43]) recommended using
in clinical trials (Korea [73]: ungraded, very low; NHS (rapid
antibiotics in patients who presented with reasonable evidence
guideline) [52]: weak, ungraded).
of bacterial infections. Empirical use of antimicrobials/antibac-
terial agents was suggested for patients with sepsis [12, 13, 26,
Interferons
54, 70] (WHO [13]: strong, ungraded), mechanical ventilation,
Only NHC & SATCM [69] recommended that interferon-ɑ be
respiratory failure [4, 14] (SSC [4] and PAHO [14]: weak, low),
tried in hospitals (ungraded). CMAJ [72] recommended the
or possible secondary bacterial infection and in a critical state
use of interferon-ɑ only in the context of clinical trials (weak,
[35, 37, 38, 44, 52, 68] (ACOEM [28]: ungraded, low). Six docu-
ungraded). Interferon β-1a (NCCET [67]: weak, very low) and
ments [13, 35, 52, 55, 69] recommended against blind or inap-
interferon gamma (NCCET [67]: weak, very low) were only re-
propriate use of antibiotic drugs (WHO [13]: strong, ungraded;
commended in the context of clinical trials. However, CMAJ
Brazil [35]: weak, very low; Korea [73]: strong, moderate; NICE
[72] (weak, ungraded) and ERS [19] (weak, very low) advised
[antibiotics] [55]: strong, ungraded).
against the use of interferon-β.

Interleukin-6 Inhibitors Neuraminidase Inhibitor

HSE.ie (tocilizumab) [39], NHC & SATCM [69], IRCCS Five documents [12, 13, 26, 35, 52] (Brazil [35]: weak, very low)
National Institute for Infectious Diseases (INMI) [44], SIMIT recommended empirical neuraminidase therapy for suspected
[43], ERS [19], and the Belgium Task Force [36] recommended cases of influenza. However, Korea [73] (weak, moderate) and
the use of interleukin-6 inhibitors, while PCS [71] recommended Brazil [35] (strong, very low) recommended against its use.

8 • ofid  •  Xie et al

Antipyretic dexamethasone than among those receiving standard of care
Antipyretics were recommended for fever in mild [12, 13], mod- [78]. Consequently, the recommendations regarding dexa-
erate [71], severe [12, 71], and critically ill adults [4]. PAHO methasone in NIH and NCCET guidelines have changed. It is
[14] (weak, low) suggested that antipyretics should be used for crucial to evaluate temporal changes in guidelines’ quality and
temperature control and the choice of drug should be adapted help clinicians become aware of discrepancies and adjustments
to the patient’s comorbidities. Regarding drug selection, para- of the recommendations to guide clinical decision-making and
cetamol was recommended rather than nonsteroidal anti-in- improve patient outcomes.
flammatory drugs (NSAIDs) [47, 71]. The NIH [23] (strong, As COVID-19 was an emerging infectious disease, there was

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very low) recommended that clinicians use acetaminophen or no direct evidence available to develop evidence-based guide-
NSAIDs. lines on short notice. Most existing guidelines were interim
guidance or rapid guidelines that largely relied on experts’ ex-
Corticosteroids periences. The developers may not have had enough time to
A total of 30 guidelines [4, 13, 14, 17, 22–26, 28, 37, 38, 43, 49, compose the guidelines according to the standard methods and
50, 54, 59, 67–70, 72] provided recommendations regarding procedures such as conducting systematic reviews of the evi-
corticosteroids. Three documents (CMAJ [72]: weak, un- dence and literature. Yet, compared with the guidelines issued at
graded; and SIMIT [43]: ungraded) recommended using cor- early stages (in 2020), the quality of those issued in 2021 clearly
ticosteroids in patients with ARDS, and low-dose corticosteroid improved, owing to a deeper understanding of the disease and
therapy was preferred over no corticosteroid therapy in patients new emerging evidence. Currently, clinical information related
with refractory shock (SSC [4], PAHO [14], NIH [23]: weak, to the optimal management of acute COVID-19 is evolving
low). Moreover, the use of glucocorticoids was recommended quickly, and many clinical trials are ongoing, which will pro-
for patients with COVID-19 without hypoxemia requiring vide evidence of higher quality. Most guidelines are living docu-
supplemental oxygen (IDSA [25]: weak, low) and patients ments that are updated frequently as newly published data and
with severe COVID-19 (WHO [corticosteroids] [17], WHO other authoritative information become available. We believe
[therapeutics] [21]: strong, moderate), but not for patients with that it is reasonable to adopt current recommendations into
nonsevere COVID-19 (WHO [corticosteroids] [17]: weak, low; practice to improve management while waiting for new evi-
WHO [13]: strong ungraded; NHS [tocilizumab] [66]: un- dence to surface.
graded) or with severe COVID-19 without ARDS (CMAJ [72]: Guideline documents are generally consistent regarding
weak, ungraded). Six documents (ICSI [38], CDC [22], NHS the timing to start oxygen therapy in COVID-19 patients.
[rapid guideline] [52], NHS [management] [50], ASID [68], Considering the harmful potential of hyperoxia and depletion
and Korea [73]: ungraded, very low) recommended against the of oxygen resources, it is not appropriate to maintain SpO2 at
routine use of corticosteroids. a high level (>96%). Guidelines differ on NIV/HFNC recom-
mendations, mainly based on previous clinical experience in
the respective countries; NIV/HFNC for COVID-19 has been
DISCUSSION
associated with a high failure rate, worse outcomes, and a pos-
This study critically reviewed the scientific evidence and re- sible increase in the risks of aerosolization and delayed intu-
commendations from guidelines on acute COVID-19 manage- bation, especially for the use of NIV. Based on an unblinded
ment. Generally, the quality of the existing guidelines was low clinical trial [79] and a meta-analysis [80] performed before
and highly variable. The recommendations across guidelines the COVID-19 pandemic, some guidelines have suggested that
had considerable discrepancies and lacked clear links between HFNC is preferable over NIV in adults with COVID-19 and
recommendations and underlying evidence. acute respiratory failure. It remains uncertain whether NIV/
Some of our results were similar to those of a previous study HFNC should be used in adults with COVID-19. Therefore,
[5] that reviewed guidelines produced early during the pan- any patients receiving HFNC or NIPPV should be monitored
demic. However, with the progress of the pandemic, our un- closely and vigilantly to facilitate intubation in case of rapid
derstanding of COVID-19 has deepened gradually. As more deterioration. Early intubation may be particularly appro-
and more new evidence emerges, the recommendations also priate when patients have additional acute organ dysfunction
need to be updated in a timely manner. The RECOVERY trial or chronic comorbidities, or when HFNC and NIPPV are not
showed that the use of dexamethasone lowered the 28-day available [81, 82].
mortality rate among patients who were receiving either in- For critical COVID-19 with ARDS, the recommendations
vasive mechanical ventilation or oxygen alone at randomiza- were generally consistent. For septic shock, all documents con-
tion [77]. In another trial involving patients with ARDS who sistently recommended resuscitation and vasopressors, meas-
were undergoing mechanical ventilation, the 60-day mortality ures derived from the Surviving Sepsis Campaign “International
rate was 15 percentage points lower among patients receiving Guidelines for Management of Sepsis and Septic Shock” [83].

Critical Review of COVID-19 Management Guidelines  •  ofid • 9

The overall opinion on indication for ECMO was relatively con- 14, 23, 37, 69], whereas other guidelines [59, 72] recommended
sistent. Based on a preliminary report [84], HNS [49] proposes a total treatment duration of 7–10 days, with progressive dose
revised and strict ECMO inclusion criteria in response to the reduction. The Korean guidelines [73] recommended against
COVID-19 pandemic. In addition to the above conditions, it routine use of corticosteroids based on adverse effects such as
was also necessary to score and evaluate the potential benefits prolonged viral replication, which may result in mechanical
of the recommendations. Given the limited clinical resources, ventilation and higher mortality [22] or increased exposure to
ASAIO (ECMO) [30] recommended against the use of ECMO fungal pathogens [52]. Recent guidelines have consistently re-
before conventional therapies. However, NIH [19] recom- commended the use of corticosteroids at early stages of severe

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mended either for or against the routine use of ECMO for pa- illness.
tients with refractory hypoxemia because of the lack of available Our study has several strengths. We had a broad inclusion of
conclusive evidence [85, 86]. guidelines located in a broad range of geographical locations.
During the initial phase of the COVID-19 pandemic, there Furthermore, we evaluated the quality of the guidelines using
were no drugs or therapy proven to be effective. As China and AGREE II, which is an internationally validated instrument
Italy were the first countries to suffer from COVID-19 out- for guidelines assessment. Our team was composed of experts
breaks, most guidelines in these 2 countries recommended from different backgrounds, gathering front-line clinical ex-
various antiviral treatments. With the publication of additional perts and methodologists. A  significant degree of agreement
clinical research results related to the use of more remdesivir, among the 4 reviewers was achieved, which improved the re-
the guidelines published after April 2020 gave more detailed liability of our findings. However, some limitations could bias
suggestions in terms of subgroups of patients, dosage, and dura- our study and limit generalizability. First, the guidelines were
tion. A number of clinical studies on COVID-19 treatment with limited to publications in the English language. Second, it was
remdesivir, favipiravir, and tocilizumab have shown beneficial difficult to identify recommendations that were not developed
outcomes. Therefore, recent guidelines have recommended the by evidence-based methods. This limitation may be mitigated
use of antiviral drugs for patients with severe COVID-19. by the involvement of reviewers with clinical experience to cap-
Clinical trials testing baloxavir marboxil, darunavir- ture recommendations. Third, we could not always identify all
cobicistat, HIV protease inhibitors, mesenchymal stem cells the supplemental materials necessary for quality assessments
(MSCs), and umifenovir have been published. However, the use and might have underestimated guideline quality. Finally, the
of these treatments was only recommended for clinical trials, AGREE II instrument focuses on methods of guideline devel-
and these treatments should be cautiously used due to various opment and transparency of reporting, but does not assess the
potential adverse reactions. More clinical trials are ongoing potential impacts of the recommendations on patient outcomes
[87], and candidate drugs are under development [88]. [92].
The guidelines generally agree on the scope of application of
antibiotics and recommend their empirical use in severe or crit- CONCLUSIONS
ical cases with sepsis, but not for mild or uncomplicated cases
The quality of existing guidelines for COVID-19 management
[4, 14, 37, 44, 71]. Some documents [13, 23, 26] recommended
was generally low and highly variable. There were consider-
constant reassessment in order to de-escalate early or stop an-
able recommendation discrepancies between guidelines and a
tibiotic treatments, while others recommended against blind
general lack of evidence, especially for the recommendations
or inappropriate use of antibiotic drugs [13, 55, 73]. Disease
related to respiratory support and antiviral therapy.
severity and suspected co-infection are important indications
for antibiotic use. Fever is one of the most common symptoms
Acknowledgments
of COVID-19, and most guidelines agree that the administra-
Financial support.  This study was funded by the National Key R&D
tion of antipyretics should be based on fever symptoms, disease Program of China (2018YFC1311900), the National Science Foundation
severity, and comorbidities [4, 12–14, 71]. Regarding drug se- of China (81770017), the Clinical Innovation Research Program of
lection, because NSAIDs like ibuprofen have been reported to Guangzhou Regenerative Medicine and Health Guangdong Laboratory
(2018GZR0201002), and the Zhongnanshan Medical Foundation of
potentially increase ACE2 expression [89] and inhibit antibody Guangdong Province and Guangdong Province Science and Technology
production [90], paracetamol was recommended rather than Innovation Strategy Special Foundation (2020B111134019).
NSAIDs in the NICE (managing symptoms) [47] and the PCS Potential conflicts of interest.  The authors declare that they have
no competing interests. All authors have submitted the ICMJE Form for
guidelines [71]. However, the Food and Drug Administration
Disclosure of Potential Conflicts of Interest. Conflicts that the editors con-
rapidly stated that there was no evidence linking the use of sider relevant to the content of the manuscript have been disclosed.
NSAIDs to worsening COVID-19 [91]. Patient consent.  No patient consent statement or ethics approval was
Whether corticosteroids could be used in COVID-19 patients required.
Reproducible research statement.  Study protocol: available at www.
remained controversial until August 2020. Most guidelines re- crd.york.ac.uk/prospero (PROSPERO: CRD42020180074). Statistical code
commended the use of corticosteroids for certain conditions [4, and data set: available from Dr. Mei Jiang (jiangmei927@163.com).

10 • ofid  •  Xie et al

 Author contributions.  S.Y.L., J.L., and M.J.  had full access to all of 22. Centers for Disease Control and Prevention. Interim clinical guidance for man-
the data in the study and take responsibility for the integrity of the data agement of patients with confirmed coronavirus disease (COVID-19). Available
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23. National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment
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