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. 2020 Apr 17;2(3):100061. doi: 10.1016/j.infpip.2020.100061

Therapeutic management of patients with COVID-19: a systematic review

M Tobaiqy a,, M Qashqary b, S Al-Dahery c, A Mujallad d, AA Hershan e, MA Kamal f,g, N Helmi f,h
PMCID: PMC7162768  PMID: 34316558

Summary

Background

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which was declared a global pandemic by the World Health Organization on 11th March 2020. The treatment guidelines for COVID-19 vary between countries, yet there is no approved treatment to date.

Aim

To report any evidence of therapeutics used for the management of patients with COVID-19 in clinical practice since emergence of the virus.

Methods

A systematic review protocol was developed based on the PRISMA statement. Articles for review were selected from Embase, Medline and Google Scholar. Readily accessible peer-reviewed, full articles in English published from 1st December 2019 to 26th March 2020 were included. The search terms included combinations of: COVID, SARS-COV-2, glucocorticoids, convalescent plasma, antiviral and antibacterial. There were no restrictions on the types of study eligible for inclusion.

Results

Four hundred and forty-nine articles were identified in the literature search; of these, 41 studies were included in this review. These were clinical trials (N=3), case reports (N=7), case series (N=10), and retrospective (N=11) and prospective (N=10) observational studies. Thirty-six studies were conducted in China (88%). Corticosteroid treatment was reported most frequently (N=25), followed by lopinavir (N=21) and oseltamivir (N=16).

Conclusions

This is the first systematic review to date related to medication used to treat patients with COVID-19. Only 41 studies were eligible for inclusion, most of which were conducted in China. Corticosteroid treatment was reported most frequently in the literature.

Keywords: SARS-CoV-2, COVID-19, Hydroxychloroquine, Arbidol hydrochloride, Corticosteroids, Convalescent plasma therapy

Introduction

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which was declared a global pandemic by the World Health Organization (WHO) on 11th March 2020. SARS-CoV-2 was discovered in December 2019 in Wuhan City, Hubei Province, China. The origin of the virus is unknown, but initially, newly diagnosed cases were linked to the Huanan Seafood Wholesale Market where people can buy wild animals, such as bats [1]. SARS-CoV-2, a novel enveloped RNA betacoronavirus, has phylogenetic similarity to severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus [2].

One of the characteristics of COVID-19 is that it is highly contagious; China and 164 other countries have been affected in less than 3 months. Despite China reaching 81,151 confirmed cases with 3242 deaths, the country has reported only one new domestic case since 18th March 2020. As of that date, the total worldwide confirmed cases was 193,475 with 7864 deaths (WHO). Although protective measures have been implemented in China (e.g. isolation from confirmed and suspected cases) to reduce spread of the virus, the need for effective treatment is imperative to stop the outbreak and reduce the morbidity and mortality of COVID-19 [1].

Since the onset of the outbreak, many agents that could have efficacy against COVID-19 have been proposed. Various antiviral agents were included in the latest guidelines from the National Health Commission, including interferon, lopinavir/ritonavir, chloroquine phosphate, ribavirin and arbidol [3]. Angiotensin receptor blockers, such as losartan, have also been suggested for the treatment of COVID-19 [4].

The treatment guidelines for COVID-19 vary between countries. The WHO guidelines are very general, recommending management of symptoms, and advise caution with paediatric patients, pregnant women and patients with underlying co-morbidities. There is no approved treatment for COVID-19; the recommendation is to provide supportive management according to each patient's need (e.g. antipyretics for fever, oxygen therapy for respiratory distress). Moreover, WHO recommendations indicate that severe cases should be given empiric antimicrobial therapy, with mechanical ventilation implemented depending on the patient's clinical condition. Some of the Asian guidelines (e.g. the Japanese guidelines) were not easy to interpret as they have not yet been translated into English. However, the treatment protocols across countries are similar, and include hydroxychloroquine, chloroquine phosphate, remedesivir and lopinavir/ritonavir [[5], [6], [7]]. Treatment guidelines between countries differ slightly, as shown in Table I [[8], [9], [10], [11]].

Table I.

Comparison between the treatment guidelines for coronavirus disease 2019 in Saudi Arabia, the USA, Europe and Egypt [[8], [9], [10], [11]]

Saudi Arabia (Ministry of Health) USA (Massachusetts General Hospital) Europe (Ireland) Egypt
Mild-to-moderate Hydroxychloroquine
Chloroquine
Chloroquine phosphate
Clinical trial of remdesivir Chloroquine (oral)
Hydroxychloroquine (oral)
Lopinavir/ritonavir (oral)
Remdesivir (intravenous)
Oseltamivir
Hydroxychloroquine
Chloroquine phosphate
Severe Hydroxychloroquine
Chloroquine
Chloroquine phosphate
Combination therapy (lopinavir/ritonavir)
Hydroxychloroquine
Chloroquine
Lopinavir/ritonavir
Darunavir/cobicistat
Oseltamivir
Hydroxychloroquine
Chloroquine phosphate
Lopinavir/ritonavir
Serum ferritin, D-dimer
Critical Combination therapy (lopinavir/ritonavir)
Hydroxychloroquine
Remdesivir
With USA United States of America, interferon-β B1 (Betaseron) Antibiotics
Oseltamivir
Hydroxychloroquine (or chloroquine phosphate)
Azithromycin Hydrocortisone Therapeutic anticoagulants if D-Dimer Invasive

In light of limited evidence in the literature regarding medication used to treat COVID-19, this review aims to retrospectively evaluate the therapeutic management received by patients with COVID-19 since emergence of the virus.

Methods

A systematic review protocol was developed based on PRISMA-P and the PRISMA statement. Articles for review were selected from Embase, Medline and Google Scholar. Readily accessible peer-reviewed, full articles in English, published from 1st December 2019 to 26th March 2020, were included. The search terms included combinations of: COVID-19, SARS-COV-2, glucocorticoids, chloroquine, convalescent plasma, antiviral, antibacterial, oseltamivir, hydroxychloroquine, chloroquine phosphate and monoclonal antibodies. There were no restrictions on the types of study eligible for inclusion; however, these were likely to be quantitative studies and randomized clinical trials. The focus of this review was therapeutics for the management of patients with COVID-19.

The primary outcomes were: (1) evidence of therapeutics used for the management of patients with COVID-19 in clinical practice, irrespective of patient characteristics, setting and outcome measures, in order to discuss the most commonly reported medicines; and (2) clinical outcomes of therapeutic treatment (i.e. recovery, mortality) in patients with COVID-19. The secondary outcome of this review was adverse events associated with treatment.

Duplicate articles were removed. Titles and abstracts were screened independently by two reviewers, followed by review of full articles where any doubt remained. Inclusions and exclusions were recorded following PRISMA guidelines, and detailed reasons for exclusion were recorded. Critical appraisal checklists appropriate to each study design were applied and checked by a second team member. Any bias or quality issues identified were considered prior to a quantitative meta-analysis and meta-narrative. Critical Appraisal Skills Programme checklist tools were used for quality assessment. A data extraction tool was designed to capture focus of interest, population, geographical location, methodology, specific mention of therapeutic treatment and adverse events, key findings and further research. Ethical approval was not required for this review of existing peer-reviewed literature.

Results

Four hundred and forty-nine articles were identified in the literature search. Inclusions and exclusions are reported following PRISMA guidelines in Figure 1, with reasons for exclusion recorded (Table II). In total, 213 duplicate studies were excluded. In addition, 18 studies were excluded due to language (Chinese N=9, Dutch N=2, Vietnamese N=1, Spanish N=1, Italian N=1, Russian N=1, Portuguese N=1, Iranian N=1, German N=1), and 10 studies were excluded for other reasons, including incomplete and irrelevant articles.

Figure 1.

Figure 1

PRISMA flow diagram reporting search results. COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.

Table II.

Excluded papers and reasons for exclusion

No. Authors Title COVID-19
Yes/no
Reason for exclusion
1 Chughtai et al., 2020 Policies on the use of respiratory protection for hospital health workers to protect from coronavirus disease (COVID-19) Yes No details on therapeutics/commentary
2 Gurwitz, 2020 Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics Yes Commentary
3 Wang et al., 2020 Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Yes Commentary
4 Colson et al., 2020 Chloroquine and hydroxychloroquine as available weapons to fight COVID-19 Yes Commentary
5 Liu et al., 2020 Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy Yes No details on therapeutics/commentary
6 Baron et al., 2020 Teicoplanin: an alternative drug for the treatment of coronavirus COVID-19? Yes Commentary
7 Mitja and Clotet, 2020 Use of antiviral drugs to reduce COVID-19 transmission Yes Commentary
8 Colson et al., 2020 Chloroquine for the 2019 novel coronavirus SARS-CoV-2 Yes Commentary
9 Morse et al., 2020 Learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV Yes Commentary
10 Thevarajan et al., 2020 Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19 Yes Commentary
11 Elfiky, 2020 Anti-HCV, nucleotide inhibitors, repurposing against COVID-19 Yes Commentary
12 Ung, 2020 Community pharmacist in public health emergencies: quick to action against the coronavirus 2019-nCoV outbreak Yes Commentary
13 Gupta, 2020 Clinical considerations for patients with diabetes in times of COVID-19 epidemic Yes Commentary
14 Dong et al., 2020 Discovering drugs to treat coronavirus disease 2019 (COVID-19) Yes Commentary
15 Zhang et al., 2020 Liver injury in COVID-19: management and challenges Yes Commentary
16 Cunningham et al., 2020 Treatment of COVID-19: old tricks for new challenges Yes Commentary
17 Ko et al., 2020 Arguments in favour of remdesivir for treating SARS-CoV-2 infections Yes Commentary
18 Arabi et al., 2020 COVID-19: a novel coronavirus and a novel challenge for critical care Yes Commentary
19 Wang and Shi, 2020 Managing neonates with respiratory failure due to SARS-CoV-2 Yes Commentary
20 Stebbing et al., 2020 COVID-19: combining antiviral and anti-inflammatory treatments Yes Commentary
21 Touret and Lamballerie, 2020 Of chloroquine and COVID-19 Yes Commentary
22 Porcheddu et al., 2020 Similarity in case fatality rates (CFR) of COVID-19/SARS-COV-2 in Italy and China Yes No therapeutic data/commentary
23 Zhang et al., 2020 Therapeutic and triage strategies for 2019 novel coronavirus disease in fever clinics Yes Commentary
24 Baden and Rubin, 2020 COVID-19 – the search for effective therapy Yes Commentary
25 Baud et al., 2020 COVID-19 in pregnant women Yes No therapeutic data/commentary
26 Ortega et al., 2020 Unrevealing sequence and structural features of novel coronavirus using in silico approaches: the main protease as molecular target Yes No therapeutic data
27 Ma et al., 2020 2019 novel coronavirus disease in hemodialysis (HD) patients: report from one HD center in Wuhan, China Yes No therapeutic data
28 Columbus et al., 2020 2019 novel coronavirus: an emerging global threat Yes Commentary
29 Barry et al., 2020 COVID-19 in the shadows of MERS-CoV in the Kingdom of Saudi Arabia Yes Commentary
30 Wang et al., 2020 A precision medicine approach to managing 2019 novel coronavirus pneumonia Yes No therapeutic data/commentary
31 Singhal, 2020 A Review of coronavirus disease-2019 (COVID-19) Yes Review article
32 Li et al., 2020 A simple laboratory parameter facilitates early identification of COVID-19 patients Yes Retrospective case-negative control study
33 Guo et al., 2020 A survey for COVID-19 among HIV/AIDS patients in two districts of Wuhan, China Yes No therapeutic data
34 Gao et al., 2020 Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies Yes Commentary
35 Deng et al., 2020 Arbidol combined with LPV/r versus LPV/r alone against corona virus disease 2019: a retrospective cohort study Yes Retrospective control study
36 Murthy et al., 2020 Care for critically ill patients with COVID-19 Yes Commentary
37 Deng and Peng, 2020 Characteristics of and public health responses to the coronavirus disease 2019 outbreak in China Yes Review
38 Wang et al., 2020 Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China Yes No therapeutic data
39 Xiong et al., 2020 Clinical and high-resolution CT features of the COVID-19 infection: comparison of the initial and follow-up changes Yes No therapeutic data
40 Chen et al., 2020 Clinical and immunologic features in severe and moderate forms of coronavirus disease 2019 Yes No therapeutic data
41 Chen et al., 2020 Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records Yes No therapeutic data
42 Hong et al., 2020 Clinical characteristics of novel coronavirus disease 2019 (COVID-19) in newborns, infants and children Yes Perspectives/no therapeutic data
43 Ye et al., 2020 Clinical characteristics of severe acute respiratory syndrome coronavirus 2 reactivation Yes No therapeutic data
44 Anderson et al., 2020 Clinical management of suspected or confirmed COVID-19 disease Yes Review
45 Zhang et al., 2020 Clinical trials for the treatment of coronavirus disease 2019 (COVID-19): a rapid response to urgent need Yes Commentary
46 Chen et al., 2020 Convalescent plasma as a potential therapy for COVID-19 Yes Commentary
47 Yang et al., 2020 Corona virus disease 2019: a growing threat to children? Yes Commentary/no therapeutic data
48 Kooraki et al., 2020 Coronavirus (COVID-19) outbreak: what the department of radiology should know Yes Commentary/no therapeutic data
49 Rasmussen et al., 2020 Coronavirus disease 2019 (COVID-19) and pregnancy: what obstetricians need to know Yes Commentary/no therapeutic data
50 Liu et al., 2020 Coronavirus disease 2019 (COVID-19) during pregnancy: a case series Yes No therapeutic data
51 Mclntosh et al., 2020 Coronavirus disease 2019 (COVID-19) Yes Review
52 He and Li, 2020 Coronavirus disease 2019 (COVID-19): what we know? Yes Review
53 Xiong et al., 2020 Coronaviruses and the cardiovascular system: acute and long-term implications Yes Commentary
54 Gong et al., 2020 Correlation analysis between disease severity and inflammation-related parameters in patients with COVID-19 pneumonia Yes No therapeutic data
55 Dong et al., 2020 Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China Yes No therapeutic data
56 Shereen et al., 2020 COVID-19 infection: origin, transmission, and characteristics of human coronaviruses Yes Review
57 Rio and Malani, 2020 COVID-19 – new insights on a rapidly changing epidemic Yes Review
58 Yi et al., 2020 COVID-19: what has been learned and to be learned about the novel coronavirus disease Yes Review
59 Rezaeetalab et al., 2020 COVID-19: a new virus as a potential rapidly spreading in the worldwide Yes Review
60 Shaker et al., 2020 COVID-19: pandemic contingency planning for the allergy and immunology clinic Yes No therapeutic data
61 Aslam and Mehra, 2020 COVID-19: yet another coronavirus challenge in transplantation Yes Commentary
62 Padmanabhan, 2020 Potential dual therapeutic approach against SARS-CoV-2/COVID-19 with nitazoxanide and hydroxychloroquine Yes Commentary
63 Hick et al., 2020 Duty to plan: health care, crisis standards of care, and novel coronavirus SARS-CoV-2 Yes Discussion
64 Yang et al., 2020 Epidemiological and clinical features of COVID-19 patients with and without pneumonia in Beijing, China Yes No therapeutic data
65 Khan, 2020 Epidemiology of corona virus in the world and its effects on the China economy Yes Review
66 Hoehl et al., 2020 Evidence of SARS-CoV-2 infection in returning travelers from Wuhan, China Yes Commentary
67 Yang et al., 2020 Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome Yes Review
68 Cascella et al., 2020 Features, evaluation and treatment of coronavirus (COVID-19) Yes Review
69 Erol, 2020 High-dose intravenous vitamin C treatment for COVID-19 (a mechanistic approach) Yes Review
70 Liu et al., 2020 Highly ACE2 expression in pancreas may cause pancreas damage after SARS-CoV-2 infection Yes Commentary
71 Zhang et al., 2020 Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19 Yes No therapeutic data
72 Mao et al., 2020 Implications of COVID-19 for patients with pre-existing digestive diseases Yes Commentary
73 Ferguson et al., 2020 Impact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand Yes No therapeutic data
74 Qiu et al., 2020 Intensive care during the coronavirus epidemic Yes Commentary
75 Poon et al., 2020 ISUOG interim guidance on 2019 novel coronavirus infection during pregnancy and puerperium: information for healthcare professionals Yes Review
76 Khan et al., 2020 The emergence of a novel coronavirus (SARS-CoV-2), their biology and therapeutic options Yes Discussion
77 Sun et al., 2020 Lower mortality of COVID-19 by early recognition and intervention: experience from Jiangsu Province Yes Commentary
78 Guzzi et al., 2020 Master regulator analysis of the SARS-CoV-2/human interactome Yes No therapeutic data
79 Memish et al., 2020 Middle East respiratory syndrome No Review
80 Nicastri, 2020 Recommendations for COVID-19 clinical management Yes Commentary
81 Li et al., 2020 Network bioinformatics analysis provides insight into drug repurposing for COVID-2019 Yes No therapeutic data
82 Xiong et al., 2020 Novel and potent inhibitors targeting DHODH, a rate-limiting enzymein de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2 Yes No therapeutic data
83 Rezabakhsh et al., 2020 Novel coronavirus (COVID-19): a new emerging pandemic threat Yes Survey/no therapeutic data
84 Ai et al., 2020 Optimizing diagnostic strategy for novel coronavirus pneumonia, a multi-center study in Eastern China Yes No therapeutic data
85 Qiu et al., 2020 Outcome reporting from protocols of clinical trials of coronavirus disease 2019 (COVID-19): a review Yes No therapeutic data
86 Bajema et al., 2020 Persons evaluated for 2019 novel coronavirus – United States, January 2020 Yes Commentary
87 Shanmugaraj et al., 2020 Perspectives on monoclonal antibody therapy as potential therapeutic intervention for coronavirus disease-19 (COVID-19) Yes Review
88 Zhou and Zhao, 2020 Perspectives on therapeutic neutralizing antibodies against the novel coronavirus SARS-CoV-2 Yes Review
89 Hoffmann et al., 2020 SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Yes No therapeutic data
90 Zhang and Liu, 2020 Potential interventions for novel coronavirus in China: a systematic review Yes Review
91 Vasylyeva, 2020 Pregnancy and COVID-19: a brief review Yes Review
92 Alamri et al., 2020 Pharmacoinformatics and molecular dynamic simulation studies reveal potential inhibitors of SARS-CoV-2 main protease 3CLpro Yes No therapeutic data
93 Fisher and Heymann, 2020 Q&A: The novel coronavirus outbreak causing COVID-19 Yes Commentary
94 Goh et al., 2020 Rapid progression to acute respiratory distress syndrome: review of current understanding of critical illness from COVID-19 infection Yes No therapeutic data
95 Chen et al., 2020 Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients Yes No therapeutic data
96 Bouadma et al., 2020 Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists Yes Review
97 Zhu et al., 2020 Systematic review of the registered clinical trials of coronavirus disease2019 (COVID-19) Yes Review
98 Yang et al., 2020 The deadly coronaviruses: the 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China Yes Review
99 Li et al., 2020 The neuroinvasive potential of SARS CoV2 may play a role in the respiratory failure of COVID 19 patients Yes Review
100 Naicker et al., 2020 The novel coronavirus 2019 epidemic and kidneys Yes Review
101 Fang et al., 2020 Transmission dynamics of the COVID 19 outbreak and effectiveness of government interventions: a data driven analysis Yes No therapeutic data
102 Sun et al., 2020 Understanding of COVID 19 based on current evidence Yes Review
103 Wang et al., 2020 Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures Yes Review
104 Maoujoud et al., 2020 What nephrologist should know about COVID-19 outbreak? Yes Commentary
105 Cortegiani et al., 2020 A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19 Yes Review
106 Ryu et al., 2020 An interim review of the epidemiological characteristics of 2019 novel coronavirus Yes Review
107 Yang and Shen, 2020 Targeting the endocytic pathway and autophagy process as a novel therapeutic strategy in COVID-19 Yes Review
108 Fan et al., 2020 Bat coronaviruses in China Yes Review
109 Russell et al., 2020 Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury Yes Commentary
110 Liang et al., 2020 Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells Yes No therapeutic data/commentary
111 Wu et al., 2020 Co-infection with SARS-CoV-2 and influenza A virus in patient with pneumonia, China Yes Commentary
112 Martinez et al., 2020 Compounds with therapeutic potential against novel respiratory 2019 coronavirus Yes Commentary
113 Tang et al., 2020 Coronavirus disease 2019 (COVID-19) pneumonia in a hemodialysis patient Yes No therapeutic data
114 Chang et al., 2020 Coronavirus disease 2019: coronaviruses and blood safety Yes Review
115 Walker, 2020 COVID-19, Australia: Epidemiology Report 2 Yes Commentary
116 Lu, 2020 Drug treatment options for the 2019-new coronavirus (2019-nCoV) Yes Commentary
117 Hellewell et al., 2020 Feasibility of controlling COVID-19 outbreaks by isolation of cases and contacts Yes No therapeutic data
118 Prompetchara et al., 2020 Immune responses in COVID-19 and potential vaccines: lessons learned from SARS and MERS epidemic Yes Review
119 Ashour et al., 2020 Insights into the recent 2019 novel coronavirus (SARS-CoV-2) in light of past human coronavirus outbreaks Yes Review
120 Zhou et al., 2020 Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2 Yes No therapeutic data
121 Devaux et al., 2020 New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Yes Review
122 Cauchi and Locht, 2020 Non-specific effects of live attenuated pertussis vaccine against heterologous infectious and inflammatory diseases Yes Review
123 Chang et al., 2020 Potential therapeutic agents for COVID-19 based on the analysis of protease and RNA polymerase docking Yes No therapeutic data
124 Pang et al., 2020 Potential rapid diagnostics, vaccine and therapeutics for 2019 novel coronavirus (2019-nCoV): a systematic review Yes Review
125 Chen et al., 2020 Recurrence of positive SARS-CoV-2 RNA in COVID-19: a case report Yes Commentary
126 Liu et al., 2020 Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases Yes Review
127 Gralinski and Menachery, 2020 Return of the coronavirus: 2019-nCoV Yes Commentary
128 Cao et al., 2020 SARS-CoV-2 infection in children: transmission dynamics and clinical characteristics Yes Commentary
129 Walls et al., 2020 Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein Yes Commentary
130 Xu et al., 2020 Systematic comparison of two animal-to-human transmitted human coronaviruses: SARS-CoV-2 and SARS- Yes Review
131 Garrett, 2020 The art of medicine COVID-19: the medium is the message Yes Commentary
132 Habibzadeh and Stoneman, 2020 The novel coronavirus: a bird's eye view Yes Review
133 Wu et al., 2020 The SARS-CoV-2 outbreak: what we know Yes Review
134 Nezhad et al., 2020 Therapeutic approaches for COVID-19 based on the dynamics of interferon-mediated immune responses Yes No therapeutic data
135 Lu, 2020 Timely development of vaccines against SARS-CoV-2 Yes Commentary
136 Kim et al., 2020 Viral load kinetics of SARS-CoV-2 infection in first two patients in Korea Yes Commentary
137 Sekhar, 2020 Virtual screening based prediction of potential drugs for COVID-19 Yes No therapeutic data
138 Park et al., 2020 Virus isolation from the first patient with SARS-CoV-2 in Korea Yes Commentary
139 Lake, 2020 What we know so far: COVID-19 current clinical knowledge and research Yes Review
140 Ralph et al., 2020 2019-nCoV (Wuhan virus), a novel coronavirus: human-to-human transmission, travel-related cases, and vaccine readiness Yes Review
141 Jin, 2020 A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version) Yes Review
142 Liu et al., 2020 Association of cardiovascular manifestations with in-hospital outcomes in patients with COVID-19: a hospital staff data Yes No therapeutic data
143 Lai et al., 2020 Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): facts and myths Yes Review
144 Bordi et al., 2020 Differential diagnosis of illness in patients under investigation for the novel coronavirus (SARS-CoV-2), Italy, February 2020 Yes Commentary
145 Li, 2020 Diagnosis and clinical management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: an operational recommendation of Peking Union Medical College Hospital (V2.0) Yes Review
146 Song and Karako, 2020 COVID-19: real-time dissemination of scientific information to fight a public health emergency of international concern Yes Commentary
147 Vankadari and Wilce, 2020 Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26 Yes Review
148 Hsih et al., 2020 Featuring COVID-19 cases via screening symptomatic patients with epidemiologic link during flu season in a medical center of central Taiwan Yes No therapeutic data
149 Stoecklin et al., 2020 First cases of coronavirus disease 2019 (COVID-19) in France: surveillance, investigations and control measures, January 2020 Yes No therapeutic data
150 Chan et al., 2020 Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan Yes No therapeutic data
151 Boulos and Geraghty, 2020 Geographical tracking and mapping of coronavirus disease COVID-19/severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic and associated events around the world: how 21st century GIS technologies are supporting the global fight against outbreaks and epidemics Yes No therapeutic data
152 Zeng et al., 2020 Mortality of COVID-19 is associated with cellular immune function compared to immune function in Chinese Han population Yes No therapeutic data
153 Ahmed et al., 2020 Preliminary identification of potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-2) based on SARS-CoV immunological studies Yes No therapeutic data
154 Lai et al., 2020 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges Yes Review
155 Alhazzani et al., 2020 Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19) Yes No therapeutic data
156 Guo et al., 2020 The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status Yes Review
157 Yang et al., 2020 Traditional Chinese medicine in the treatment of patients infected with 2019-new coronavirus (SARS-CoV-2): a review and perspective Yes Review
158 Liu et al., 2020 Therapeutic effects of dipyridamole on COVID-19 patients with coagulation dysfunction Yes No therapeutic data
159 World Health Organization, 2020 Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected Yes Guidelines
160 Li et al., 2020 Development and clinical application of a rapid IgM-IgG combined antibody test for SARS-CoV-2 infection diagnosis Yes No therapeutic data
161 Mao et al., 2020 Clinical and pathological characteristics of 2019 novel coronavirus disease (COVID-19): a systematic reviews Yes Review
162 Cui et al., 2020 Clinical features and sexual transmission potential of SARS-CoV-2 infected female patients: a descriptive study in Wuhan, China Yes No therapeutic data
163 Saw Swee Hock School of Public Health, 2020 COVID-19 science report: therapeutics Yes Report
164 Yao, 2020 In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Yes Commentary
165 Pongpirul et al., 2020 Journey of a Thai taxi driver and novel coronavirus Yes No therapeutic data
166 Liu et al., 2020 A locally transmitted case of SARS-CoV-2 infection in Taiwan Yes No therapeutic data
167 Velavan and Meyer, 2020 The COVID-19 epidemic Yes Commentary

Consensus on final inclusion of studies (N=41) (negotiated without the need for a third reviewer) is presented in Table III.

Table III.

Data extracted from included papers

Author/title/DOI Sample size Mean age (years) Gender Type of study Therapeutic treatment Type: N (%) Outcomes (recovery/mortality) Adverse events Quality assessment (applicable/inapplicable)
1 Cao et al. A trial of lopinavir–ritonavir in adults hospitalized with severe COVID-19. N Engl J Med 2020. https://doi.org/10.1056/NEJMoa2001282 199 58 120 M
79 F
Randomized clinical trial Lopinavir and ritonavir Lopinavir and ritonavir: 50%Standard care: 50% In hospitalized adult patients with severe COVID-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard careNineteen deaths among patients who received the intervention 14% of patients who received lopinavir–ritonavir developed gastrointestinal adverse events, including anorexia, nausea, abdominal discomfort or diarrhoea, as well as two serious adverse events (both acute gastritis)Two recipients had self-limited skin eruptions The study addressed a focused issue
Randomization with intention-to-treat analysis
The population who entered the study were accounted for properly in the conclusion
Not blinded
The two groups who entered the study were similar and treated equally
The primary outcome was specified clearly
2 Cao et al. Clinical features and short-term outcomes of 18 patients with coronavirus disease 2019 in intensive care unit. Intensive Care Med 2020.https://doi.org/10.1007/s00134-020-05987-7 41 49 30 M
11 F
Prospective Antibiotics and oseltamivir (orally 75 mg twice daily)Corticosteroid was given as a combined regimen if severe community-acquired pneumonia was diagnosed by physicians at the designated hospital All patients received empirical antibiotic treatmentAntiviral (oseltamivir): 38 (93%)Systemic corticosteroid: 9 (22%) Antiviral: 12 ICU admissions (92%)
Antibiotic: 13 ICU admissions (100%)
Corticosteroid: six ICU admissions (46%)
Not reported Adverse events not reported
Treatment given not specified
Types of antibiotics given not mentioned
3 Chen et al. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. medRxiv 2020. https://doi.org/10.1101/2020.03.17.200 236 56 (25–86) Favipiravir group:59 M
57 FArbidol group:51 M
69 F
Randomized controlled trial Favipiravir
Arbidol
Antiviral: 116
Antiviral: 120
71 patients recovered Abnormal liver function tests, raised serum uric acid, psychiatric symptom reactions and digestive tract reactions No effective antiviral drug was reported, and the drugs mentioned were based on the sixth edition of the guidelines of Chinese diagnosis and treatment plan of COVID-19 patients
4 Chen et al. Thalidomide combined with low-dose glucocorticoid in the treatment of COVID-19 pneumonia 2020. Preprints 2020; 2020020395. https://www.preprints.org/manuscript/202002.0395/v1 1 45 F Case report Thalidomide and low-dose glucocorticoid. The patient was first treated with oral ofloxacin and oseltamivir, but her condition deteriorated. The patient was subsequently treated with lopinavir/ritonavir Thalidomide inhibits the cytokine surge and regulates immune functions. In addition, it can be used to calm patients down in order to reduce oxygen consumption and relieve digestive symptoms Not reported Randomized controlled trials are needed
5 Chen et al. Clinical study of mesenchymal stem cell treating acute respiratory distress syndrome induced by epidemic influenza A (H7N9) infection, a hint for COVID-19 treatment. Engineering 2020. https://doi.org/10.1016/j.eng.2020.02.006 61 62 Not mentioned Open labelled clinical trial Oseltamivir or peramivir (according to standard therapy) and antibiotics were given based on positive blood test results Not mentioned 17.6% of patients in the experimental group and 54.5% of patients in the control group died Not reported With only 17 patients using mesenchymal stem cells, it cannot be guaranteed that every step was perfect during the phase with a single clinical trialSome patients refused to attend and some did not complete follow-up. Thus, there is still concern about the long-term safety of mesenchymal stem cell transplantation for the treatment of H7N9-induced ARDS, despite the lack of side-effects observed in this clinical trial This study was undertaken on patients with H7N9 not COVID-19
6 Chen et al. Retrospective analysis of clinical features in 101 death cases with COVID-19. medRxiv 2020. https://doi.org/10.1101/2020.03.09.20033068 101 65.46 64 M
37 F
Single centre and observational study (retrospective) Antiviral drugs, including oseltamivir, ribavirin, lopinavir, ritonavir, ganciclovir and interferon
Glucocorticoids, IV immunoglobulins and thymosin preparations

Antibiotic treatment, including cephalosporins, quinolones, carbapenems, linezolid and tigecycline
Antiviral: 61 (60.4%) Glucocorticoid: 59 (58.42%)IV immunoglobulin: 63.37%
Thymosin: 44.55%Antibiotic: 101 (100%)Restricted antibiotic: 63 (62.38%)Antifungal: 23 (22.78%)
101 patients died Not reported Only the critical death patients are included No comparison was made between the improvement groups
7 Chen et al. Clinical progression of patients with COVID-19 in Shanghai, China. J Infect 2020. https://doi.org/10.1016/j.jinf.2020.03.004 249 51 126 M
123 F
Retrospective, single-centre study Antiviral drugs (e.g. lopinavir/ritonavir, arbidol) were used in a small proportion of patients Corticosteroids were not used unless considered necessary by an expert panel (e.g. ARDS) Not mentioned Two patients died (0.8%)
22 patients were admitted to ICU (8.8%)
Eight patients developed ARDS (3.2%)
215 patients were discharged (86.3%)
Not reported A small proportion the patients were still hospitalized at the time of manuscript submission. Therefore, clinical outcomes in these patients were not available and continued observations are needed SARS-CoV-2 was not tested daily for all patients. Hence, the actual time to viral clearance should be shorter than the estimated value
8 Chen et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395:507–13. 99 55.5 67 M
32 F
Retrospective, single-centre descriptive study Antibiotic: cephalo-sporins, quinolones, carbapenems, tigecycline against meticillin-resistant Staphylococcus aureus, linezolid
Antifungal
Antiviral: oseltamivir, ganciclovir and lopinavir/ritonavir
Glucocorticoid: methylprednisolone sodium succinate, methylprednisolone and dexamethasone-
Immunoglobulin
Antibiotic: 70 (71%)
Antifungal: 15 (15%)
Antiviral: 75 (76%), including oseltamivir (75 mg every 12 h, orally), ganciclovir (0.25 g every 12 h, intravenously), and lopinavir/ritonavir (500 mg twice daily, orally). The duration of antiviral treatment was 3–14 days
Glucocorticoid: 19 (19%)

IV immunoglobulin: 27 (27%)
11 (11%) patients died Not reported or NA Suspected but undiagnosed cases were ruled out in the analyses More detailed patient information, particularly regarding clinical outcomes, was unavailable at the time of analysis
9 Chen et al. Epidemiological and clinical features of 291 cases with coronavirus disease 2019 in areas adjacent to Hubei, China: a double-center observational study. medRxiv 2020. https://doi.org/10.1101/2020.03.03.20030353 291 46 145 M
146 F
Double-centre observational study Antiviral including lopinavir and ritonavir Recombinant human interferon-α2b Recombinant cytokine gene-derived protein Arbidol hydrochloride Chinese medicine Antiviral: 285 (97.9%)Lopinavir/ritonavir: 75.9% Recombinant human interferon-α2b: 45.4% Recombinant cytokine gene-derived protein: 18.9%

Arbidol hydrochloride: 17.2%

Chinese medicine: 281 (96.6%)
Two (0.7%) patients died Not reported Due to limitations of the retrospective study, laboratory examinations were performed according to the clinical care needs of the patients; as such, some laboratory examinations were not completed Given the short observation period, nearly half of the patients were still receiving treatment in hospital at the end of the follow-up period, and it was not possible to determine mortality and prognosis of the whole case series
10 Cui et al. A 55-day-old female infant infected with COVID 19: presenting with pneumonia, liver injury, and heart damage. J Infect Dis 2020. https://doi.org/10.1093/infdis/jiaa113 1 55 days F Case report Inhaled interferon-α1b (15 μg, bid); amoxicillin potassium clavulanate (30 mg/kg, Q8H, ivgtt) NA NA NA Case report for infant patient
Adverse events and outcomes not reported
11 Du et al. Clinical features of 85 fatal cases of COVID-19 from Wuhan: a retrospective observational study. SSRN 2020. https://ssrn.com/abstract=3546088 191 56 119 M
72 F
Retrospective, multi-centre cohort study Antibiotic
Antiviral (lopinavir and ritonavir)
Corticosteroid


IV immunoglobulin
Antibiotic: 181 (95%)
Antiviral (lopinavir and ritonavir): 41 (21%)
Corticosteroid: 57 (30%)


IV immunoglobulin: 46 (24%)
181 (95%) patients received antibiotics: 53 (98%) died, 128 (93%) survived (P=0.15)
41 (21%) patients received antivirals: 12 (22%) died, 29 (21%) survived (P=0.87)
57 (30%) patients received corticosteroid: 26 (48%) died, 31 (23%) survived (P=0.0005)
46 (24%) patients received IV immunoglobulin: 36 (67%) died, 10 (7%) survived (P<0.0001)
54 patients died in hospital
Not reported Lack of effective antivirals, inadequate adherence to standard supportive therapy, and high-dose corticosteroid use may also have contributed to the poor clinical outcomes in some patients
12 Gautret et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020:105949. https://doi.org/10.1016/j.ijantimicag.2020.105949 Treated: 20
Control: 16
Total: 36
45.1 15 M
21 other
Open label non- randomized clinical trial Hydroxychloroquine and azithromycin Hydroxychloroquine sulfate 200 mg, three times per day for 10 days On day 6 post inclusion, 100% of patients treated with a combination of hydroxychloroquine and azithromycin were virologicaly cured, compared with 57.1% of patients treated with hydroxychloroquine alone and 12.5% of patients in the control group One patient stopped treatment on day 3 post inclusion due to nausea Clinical follow-up and occurrence of side-effects were not discussed
13 Guan et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020. https://doi.org/10.1056/NEJMoa2002032 1099 47.9 41.1% F Retrospective observational study IV antibiotic
Oseltamivir
Antifungal
Systemic glucocorticoid
Antibiotic: 637 (58%)
Oseltamivir: 393 (35.8%)
Antifungal: 31 (2.8%)
Glucocorticoid: 204 (18.6%)
5.0% of patients were admitted to the ICU, 2.3% underwent invasive mechanical ventilation and 1.4% died among the 173 patients with severe disease Not reported Drug dose, frequency and duration were not included
14 Holshue et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020. https://doi.org/10.1056/NEJMoa2001191 1 35 M Case report Antipyretic consisting of guaifenesin 650 mg
600 mg
Discharged with no symptoms Not reported This was only a single case study and does not represent the whole population
As this was a case report, it is not certain that the positive impact on the patient's health was due to the medication taken
Randomized controlled trials are needed
15 Huang et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395:497–506. 41 49 30 M (73%)
11 F (27%)
Prospective collection and analysed data for patients with pneumonia Antiviral: 38 (93%)
Antibiotic: 41 (100%)
Corticosteroid: 9 (22%)
Not mentioned One patient was admitted to ICU
Six patients died
Not reported As the causative pathogen has just been identified, kinetics of viral load and antibody titres were not available at the time of the study
16 Huang et al. Early and critical care in severe patients with COVID-19 in Jiangsu Province, China: a descriptive study. 2020. https://doi.org/10.21203/rs.3.rs-17397/v1 60 57 58.3% M
42.8% other
Multi-centre retrospective cohort study was conducted to extract and analyse epidemiological, clinical and laboratory data and treatment of 60 severe cases Antiviral: 60 (100%)
Abidor: 50 (83.3)
Lopinavir/ritonavir: 41 (68.3)
Interferon: 12 (20.0)
Ribavirin: 7 (11.7)
Oseltamivir: 2 (3.3)
Fluoroquinolone: (61.7%)
34 patients (56.7%) received IV glucocorticoids at doses ranging from 40 to 80 mg/day
28 patients (46.7%) received immunoglobulin (IgG enriched) injections for 5–9 days of immunoregulation
50 patients improved significantly
Two patients were discharged
Eight patients remained in a serious condition
Four patients who developed secondary infections received glucocorticoids Most drug doses, frequencies and durations were not included
The effect of glucocorticoids was not significant
17 Huang et al. Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China. medRxiv 2020. https://doi.org/10.1101/2020.02.27.20029009 36 69.22 25 M (69.44%)
11 F (30.56%)
Retrospective, single-centre study Antibiotic: 36 (100%)
Antiviral: 35 (97.22%)
Glucocorticoid: 25 (69.44%)
Not mentioned All patients died All patients died Drug dose, frequency and duration were not included
18 Jian-ya G. Clinical characteristics of 51 patients discharged from hospital with COVID-19 in Chongqing, China. medRxiv 2020. https://doi.org/10.1101/2020.02.20.20025536 51 45 32 M (62.7%)
19 F (37.3%)
Retrospective, single-centre case series Oseltamivir (oral): 7 (13.7%)
Interferon (oral): 51 (100%)
Kaletra (oral): 51 (100%)
Thymopentin (IM): 48 (94.1%)
Traditional Chinese medicine decoction (oral): 28 (54.9%)
Reduling (IV): 30 (58.8%)
Xuebijing (IV): 2 (3.9%)
Not mentioned One patient died with shock complications Six patients had an obvious decline in appetite
.
Drug dose, frequency and duration were not included
19 Liang et al. Clinical characteristics of 457 cases with coronavirus disease 2019. Available at SSRN. 2020. https://doi.org/10.2139/ssrn.3543581 457 Varies 267 M (58%)
9 pregnant women (2%)
Systematic review Antiviral: 352 (77%)
Antibacterial:
258 (56%)
Glucocorticoid:
130 (28%)
Not mentioned 195 patients improved and were discharged 35 patients died Drug dose, frequency and duration were not included
20 Liao et al. Epidemiological and clinical characteristics of COVID-19 in adolescents and young adults. medRxiv 2020. https://doi.org/10.1101/2020.03.10.20032136 46 Not mentioned because they were two groups 17 M (53.1)
15 F (46.9)
Retrospective case series data Antiviral: 46 (100.0%)
Antifungal: 5 (10.9%)
Glucocorticoid
Not mentioned 78.3% of patients were discharged Three patients developed acute kidney injury during treatment At the end of this study, nearly 20% of the patients were still hospitalized
21 Lim et al. Case of the index patient who caused tertiary transmission of coronavirus disease 2019 in Korea: the application of lopinavir/ritonavir for the treatment of COVID-19 pneumonia monitored by quantitative RT-PCR. J Korean Med Sci 2020; 35. https://doi.org/10.3346/jkms.2020.35.e79 1 54 M Case report Lopinavir/ritonavir 200 mg
50 mg
(two tablets bid)
Reduced viral load and improved clinical symptoms The patient also complained of psychiatric symptoms such as depression, insomnia and suicidal thoughts after isolation This was a single case and does not represent the whole population
Randomized controlled trials are needed
22 Liu et al. Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression. Int J Infect Dis 2020. https://doi.org/10.1016/j.ijid.2020.03.013 10 42 6 F
4 other
Retrospective observational single-centre study Lopinavir,
Interferon-α2b atomization inhalation
400 mg every
twelve hours
Oeosinophil counts presented potential as predictor of the development of COVID-19
Seven patients were discharged
Three patients stopped lopinavir: two deteriorated and one was hospitalized for longer than other patients who continued taking lopinavir
Digestive adverse effect and hypokalaemia Small sample size
23 Liu et al. Epidemiological, clinical characteristics and outcome of medical staff infected with COVID-19 in Wuhan, China: a retrospective case series analysis. medRxiv 2020. https://doi.org/10.1101/2020.03.09.20033118 64 35 (29–43) 23 M
41 F
Single centre- retrospective-observational study Immunoglobulin Thymosin Corticosteroid Antibody: 23 Hormone: 33 Steroid hormone: 7 34 patients were discharged
30 patients were still hospitalized
Not reported Preliminary insight into epidemiological features and clinical outcomes Single centre
24 Liu et al. Detection of COVID-19 in children in early January 2020 in Wuhan, China. N Engl J Med 2020. https://doi.org/10.1056/NEJMc2003717 Six 3 (1–7) 2 M
4 F
Retrospective case series analysis Ribavirin
Oseltamivir
Glucocorticoid
IV immunoglobulin
Antiviral: 2
Antiviral: 6
Steroid hormone: 4
Antibody: 1
Six patients recovered Not reported Small sample size
25 Liu et al. Clinical features and progression of acute respiratory distress syndrome in coronavirus disease 2019. medRxiv 2020. https://doi.org/10.1101/2020.02.17.20024166 109 55 59 M
50 F
Retrospective case series analysis Glucocorticoid IV immunoglobulin Steroid hormone: 43

Antibody: 32
Antibiotic: 105
Antiviral: 105
31 patients died Not reported This study did not mention the names of the therapeutic treatment used among patients with ARDS
26 Lo et al. Evaluation of SARS-CoV-2 RNA shedding in clinical specimens and clinical characteristics of 10 patients with COVID-19 in Macau. Int J Biol Sci 2020; 16:1698–707. https://doi.org/10.7150/ijbs.45357 10 54 (27–64) 3 M
1 teenager
6 other
Retrospective case series analysis Lopinavir
Ritonavir
Antiviral: 10 Five patients were discharged
Five patients were still hospitalized
Not reported Small sample size, so difficult to draw a definite conclusion Single centre Half of the enrolled patients were still hospitalized at the time of submission of this paper. Therefore, there may have been bias regarding the prognosis of the patients
27 Mo et al. Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China. Clin Infect Dis 2020. https://doi.org/10.1093/cid/ciaa270 155 54 (42–66) 86 M
69 other
Single-centre, retrospective case series analysis Arbidol
Lopinavir and ritonavir
Interferon inhalation
Immune enhancer
Antiviral: 31
Antiviral: 27


Antiviral: 30

Immune enhancer: 14
22 patients died Not reported Selection bias may have occurred, and a large-scale nationwide study is needed
28 Wang et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020. https://doi.org/10.1001/jama.2020.1585 138 56 (42–68) 75 M
63 F
Retrospective, single-centre case series Oseltamivir
Moxifloxcain
Ceftriaxone
Azithromycin
Glucocorticoid
Antiviral: 124
Antibacterial: 89
Antibacterial: 34
Antibacterial: 25
Glucocorticoid: 62
47 patients were discharged
Six patients died
85 patients were still hospitalized
Not reported Most patients were still hospitalized at the time of manuscript submission. Therefore, there may have been bias regarding the prognosis of the patients.
29 Wang et al. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China. Clin Infect Dis 2020. https://doi.org/10.1093/cid/ciaa272 69 42 (35–62) 32 M
37 F
Retrospective case series - Antiviral: 66
Antibiotic: 66
Antifungal: 8
Corticosteroid: 10
Arbidol: 36
44 patients were still hospitalized
18 patients were discharged
Five patients died
Not reported Drug dose, frequency and duration were not included
30 Wu et al. Heart injury signs are associated with higher and earlier mortality in coronavirus disease 2019 (COVID-19). medRxiv 2020. https://doi.org/10.1101/2020.02.26.20028589 188 52 119 M
69 other
Retrospective cohort study - Antibiotic: 185
Antiviral: 158
Corticosteroid: 59
43 patients died
145 patients were discharged
12 patients were still hospitalized
Not reported Drug dose, frequency and duration were not included
31 Wu F et al. A new coronavirus associated with human respiratory disease in China. Nature 2020; 579:265–9. 1 41 M Epidemiological investigations Antiviral
Antibiotic
Glucocorticoid
Oxygen
Oseltamivir
Cefoselis
Not mentioned
Mechanical ventilation
Recovered Not reported Applicable
32 Xu et al. Clinical characteristics of SARS-CoV-2 pneumonia compared to controls in Chinese Han population. medRxiv 2020. https://doi.org/10.1101/2020.03.08.20031658 Patients: 69
Controls: 14,117
57 50.7% M
49.3% F
Retrospective, multi-centre case series Antiviral
Antibiotic
Oxygen
Oseltamivir: 38 (55.1%)
Moxifloxacin, ceftriaxone, azithromycin, tigecycline or linezolid:
31 (44.9%)
Mechanical ventilation: 2
Invasive ventilator: 2
Three patients were discharged
One patient recovered
One patient died
Six patients with a significant increase in IL6 were also treated with methylprednisolone Applicable
33 Xu et al. Clinical findings in critical ill patients infected with SARS-CoV-2 in Guangdong Province, China: a multi-center, retrospective, observational study. medRxiv 2020. https://doi.org/10.1101/2020.03.03.20030668 45 56.7 29 M (64.4%)
16 F (35.6%)
Multi-centre, retrospective, observational study Antiviral: 45 (100) patients
Antibacterial: 45 (100)
Antifungal: 19 (42.2)
Convalescent plasma: 6 (13.3)
Glucocorticoid: 21 (46.7)
Immunoglobulin: 28 (62.2)
Albumin: 35 (77.8)
Osehamivir ribavirin
Not mentioned
Not mentioned
Not mentioned
Not mentioned
Not mentioned
Not mentioned
23 (51.1%) patients were discharged from the ICU
11 (24.2%) patients were discharged
One (2.2%) patient died
37 (82.2%) patients developed ARDS and 13 (28.9%) patients developed septic shock
20 (44.4%) patients required intubation and nine (20%) patients required extracorporeal membrane oxygenation
At the time of study submission, half of the patients had not been discharged from the ICU; as such, it was difficult to estimate ICU stay, ventilation-free days, case fatality rate and the predictors of fatality
Drug dose, frequency and duration were not included
34 Xu et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ 2020; 368:m606. 62 41 35 M (56%)
27 F (44%)
Retrospective study Antiviral: 55 (89%)
Antibiotic
Corticosteroid and gamma globulin
Interferon-α inhalation: 8 (13%)
Lopinavir/ritonavir: 4 (6%)
Arbidol + interferon-α inhalation: 1 (2%)
Lopinavir/ritonavir + interferon-α inhalation: 21 (34%)
Arbidol + lopinavir/ritonavir: 17 (28%)
Arbidol + lopinavir/ritonavir + interferon-α inhalation: 4 (6%)
28 (45%)
16 (26%)
No deaths Not reported At the time of study submission, most patients had not been discharged, so it was difficult to estimate the case fatality rate or the predictors of fatality
35 Xu et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020. https://doi.org/10.1016/S2213-2600(20)30076-X 1 50 M Postmortem biopsies Antiviral
Antibiotic
Corticosteroid
Interferon-α2b atomization
Lopinavir + ritonavir
Moxifloxacin
Methylprednisolone
Died due to cardiac arrest Chest x-ray showed progressive infiltrate and diffuse gridding shadow in both lungs. Hypoxaemia and shortness of breath worsened and patient had sudden cardiac arrest This was a single case study and does not represent the whole population
The patient refused ventilator support in the ICU repeatedly because he suffered from claustrophobia; therefore, he received high-flow nasal cannula
There is a need for randomized controlled trials
36 Yang et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020. https://doi.org/10.1016/S2213-2600(20)30079-5 52 59.7 35 M (67%)
17 F (33%)
Single-centre retrospective, observational study Vasoconstrictor
Antiviral:
23 (44%)

Antibacterial
Glucocorticoid
Immunoglobulin
18 (35%)
Oseltamivir: 18 (35%)
Ganciclovir: 14 (27%)
Lopinavir: 7 (13.5%).
49 (94%)
30 (58%)
28 (54%)
32 (61.5%) patients died Not reported Due to the exploratory nature of the study, which was not driven by formal hypotheses, the sample size calculation was waived
The researchers acknowledged that some specific information from the ICU was missing, such as mechanical ventilation settings
Drug dose, frequency and duration were not included
37 Young et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA 2020. https://doi.org/10.1001/jama.2020.3204 18 47 9 M (50%)
9 F (50%)
Descriptive case series Antiretroviral
Antiviral
Antibiotic
Lopinavir/ritonavir
Oseltamivir
Not reported
No deaths Not reported Small sample size
Drug dose, frequency and duration were not included
38 Zhang et al. Clinical characteristics of 82 death cases with COVID-19. medRxiv 2020. https://doi.org/10.1101/2020.02.26.20028191 82 72.5 65.9% M Death cases Antiviral
Antibiotic
Corticosteroid
82 (100%)
82 (100%)
29 (35.3%)
Not reported The study was performed in one setting. No information was given about the hospital's capabilities in terms of personnel or equipment because the mortality rate from this centre was a little higher than other centres
Traditional Chinese medicine was given
Drug dose, frequency and duration were not included
39 Zhang et al. Clinical features and outcomes of 221 patients with COVID-19 in Wuhan, China. medRxiv 2020. https://doi.org/10.1101/2020.03.02.20030452 221 55 108 M (48.9%)
113 F (51.1%)
Retrospective case study Antiviral:
196 (88.7%)
Antibiotic
Corticosteroid: 115 (52.0%)
Oseltamivir
Arbidol hydrochloride
Interferon-α atomization inhalation
Lopinavir/ritonavir
Moxifloxacin hydrochloride
Piperacillin sodium tazobactam sodium
Cefoperazone sulbactam
Glucocorticoid: 64 (49.6%)
12 (5.4%) patients died Not reported The dose and duration of IV glucocorticoid treatment showed no difference in symptomatic relief and death
Drug dose, frequency and duration were not included
40 Zhang et al. The potential role of IL-6 in monitoring coronavirus disease 2019. https://doi.org/10.1101/2020.03.01.20029769 80 53 46 F (57.5%)
34 M (42.5%)
Data collection (clinical data from patients with COVID-19 diagnosed by laboratory test in study institution)
Observation of clinical manifestation
Antibiotic: 73 (91.25%)
Oseltamivir: 20 (25%)
Ribavirin, ganciclovir or peramivir: 47 (58.75%)
Arbidol: 49 (61.25%)
Antifungal: 10 (12.5%)
IV immunoglobin: 36 (45%)
Corticosteroid: 29 (36·25%)
Not mentioned IL-6 may be used as a biomarker for disease monitoring in severe cases of COVID-19 Not reported Drug dose, frequency and duration were not included
IL-6 and the pathogenesis of COVID-19 remains elusive
41 Zhou et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020. https://doi.org/10.1016/S0140-6736(20)30566-3 191 56 119 M (62%)
72 F (38%)
Retrospective cohort study Antibiotic: 181 (95%)
Antiviral:
41 (21%)
Corticosteroid: 57 (30%)
IV immunoglobin:
46 (24%)
Lopinavir/ritonavir 137 patients were discharged
54 patients died
191 patients There was no observation of a shortening of the duration of viral shedding after lopinavir/ritonavir treatment
Drug dose, frequency and duration were not included

COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; ICU, intensive care unit; ARDS, acute respiratory distress syndrome; IL-6, interleukin-6; NA, not applicable; IV, intravenous; IM, intramuscular.

Forty-one studies were included in this review. These were clinical trials (N=3), case reports (N=7), case series (N=10), and retrospective (N=11) and prospective (N=10) observational studies. Thirty-six studies were conducted in China, and one in each of Korea, the USA, France, Singapore and Macau.

Patient characteristics

In total, 8806 patients were reported in the 41 studies included in this review. The mean age of patients was 50.8 years based on 39 studies; age was not specified in two studies.

Reported therapeutics

Corticosteroids, an anti-inflammatory medication, were reported most commonly in this systematic review (N=25), using different names and product characteristics (corticosteroid N=21, methylprednisolone N=3, dexamethasone N=1). Use of lopinavir, an antiviral HIV medication (N=21) – in combination with ritonavir (N=18) or alone (N=3) – oseltamivir (N=16) and arbidol hydrochloride (N=8) was also reported.

In terms of antibacterial agents, moxifloxacin (N=4) and tigecycline were reported most frequently.

Convalescent plasma therapy was reported in one multi-centre retrospective observational study of six patients.

Treatment outcome

The outcome measures recorded were patient discharge and recovery, ongoing hospitalization and mortality (Table III).

Discussion

To the authors' knowledge, this is the first systematic review related to medication used to treat patients with COVID-19. Only 41 eligible research articles were identified and included in this review [2,5,[12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49]]. Of these, three studies were clinical trials; the rest were case reports, case series, or prospective or retrospective observational studies. Systemic corticosteroids with different names and formulations were reported most frequently, followed by the antivirals lopinavir, oseltamivir and arbidol hydrochloride. Convalescent plasma therapy was reported in one multi-centre retrospective observational study and was administered to six patients.

Although quality assessment was applied to the research articles included in this review, there was insufficient evidence to conduct a meta-analysis, and it was not possible to conduct subgroup analysis (adults and children; different formulations, dosages and durations).

Most studies included in this review were of low quality, with incomplete or inconsistent information on study design and outcome. As such, it was difficult to analyse the medication in terms of efficacy and safety.

Despite these limitations, this is the first systematic review on medication used to treat patients with COVID-19, and provides up-to-date insight on the current therapeutic guidelines for management of these patients. Most of the medications reported in this review are available in the USA, Saudi Arabia, Europe and Egypt (Table I).

Corticosteroids were the most commonly reported medication in this review; however, they are not recommended in any guidelines. In the absence of conclusive scientific evidence, WHO and the US Centers for Disease Control and Prevention (CDC) have recommended that corticosteroids should not be used routinely in patients with COVID-19 for treatment of viral pneumonia or acute respiratory distress syndrome (ARDS) unless indicated for other conditions, such as asthma or chronic obstructive pulmonary disease exacerbation, or septic shock [5,50,51]. Careful use of low-to-moderate doses of corticosteroids as a short course is advised. Hyperglycaemia, hypernatraemia and hypokalaemia are the most common adverse effects associated with the use of corticosteroids and should be monitored routinely [5,51].

Lopinavir/ritonavir (Kaletra) was the second most commonly reported medication in this review. A randomized clinical trial reported that this HIV treatment had negative outcomes for patients with COVID-19 (Table II) [30,[52], [53], [54]]. No benefit of lopinavir/ritonavir treatment compared with standard care was observed in this study, and 19 patients who received the intervention died. However, some study limitations were observed, including lack of blinding. RCT NCT04252885 and the SOLIDARITY trial are ongoing to determine the efficacy of lopinavir/ritonavir in patients with COVID-19 [52].

Oseltamivir (Tamiflu), used to treat influenza A and influenza B, was the third most commonly reported medication in this review. Oseltamivir has been recommended by WHO for people at high risk of infection for prevention of pandemic influenza. A retrospective observational study reported the use of oseltamivir in 1099 patients with COVID-19; however, the study was not able to provide any solid data on the effectiveness of oseltamivir in the prevention or treatment of COVID-19. Study limitations included incomplete documentation of patient data and recall bias [55,56].

Arbidol hydrochloride was the fourth most commonly reported medication in this review. It is a broad-spectrum inhibitor of influenza A and B virus, parainfluenza virus and other viruses, including hepatitis C virus. Arbidol hydrochloride is used in Russia and China, but has not yet been approved for use in other countries [52]. However, no conclusive evidence of its efficacy in patients with COVID-19 was reported. In this review, it was reported together with favipiravir, which was approved for the treatment of novel influenza on 15th February 2020 in China [52].

Chloroquine phosphate and hydroxychloroquine were reported in this review and showed favourable outcomes in the recovery of patients with COVID-19 [6,7,[57], [58], [59], [60]]. These two medications are likely to share the same mechanism of action. Chloroquine, an antimalarial, has shown positive outcomes in patients with COVID-19. Furthermore, hydroxychloroquine has shown significant effectiveness against intracellular pathogens such as Coxiella burnetii, the agent of Q fever [22]. This French open label, non- randomized clinical trial was promising and the first clinical trial of these medications in patients with COVID-19. The effect of hydroxychloroquine was significant because it showed a reduction in the viral load compared with the control group [22]. Moreover, the effect of hydroxychloroquine was significantly more potent when given in conjunction with azithromycin. However, clinical follow-up and the occurrence of adverse effects were not discussed in the study, and further work is needed to reduce the morbidity and mortality of COVID-19 [[57], [58], [59]]. Although chloroquine and hydroxychloroquine have shown promising activity against SARSCoV-2, there is a risk of arrhythmia associated with their administration. Therefore, caution is required for use at higher cumulative dosages. It is recommended that their use in cases of suspected/confirmed COVID-19 should be restricted to hospitalized patients. On 30th March 2020, the US Food and Drug Administration (FDA) issued an emergency use authorization for chloroquine and hydroxychloroquine to treat patients hospitalized with COVID-19 [60].

Convalescent plasma therapy was reported in a multi-centre cohort research trial of 45 critically ill patients with COVID-19 admitted to an intensive care unit in Wuhan. The findings showed that convalescent plasma therapy was administered to six patients and no transfusion reactions occurred; however, the study did not provide adequate information about the efficacy of convalescent plasma therapy due to the limited sample size and lack of a randomized control group [61,62].

Convalescent plasma therapy could be a promising treatment method for patients with COVID-19. A recent case series from China showed that five critically ill patients with laboratory-confirmed COVID-19 (who had ARDS) improved. After receiving plasma transfusion, their body temperature normalized within 3 days (in four of the five patients), their viral loads became undetectable within 12 days, and three of the five patients were discharged from hospital and were in a stable condition at 37 days post transfusion [63]. On 24th March 2020, the US FDA approved convalescent plasma therapy for investigational use under the traditional Investigational New Drug Applications regulatory pathway, and for eligible patients who have confirmed COVID-19 and severe or immediately life-threatening conditions such as respiratory failure, septic shock, and/or multiple organ dysfunction or failure [64,65]. Notably there are potential risks and ethical issues associated with convalescent plasma therapy, including increased risk of a thrombotic event (from 0.04% to 14.9%), lack of high-quality research in this particular area, and the selection of donors with high neutralizing antibody titres [65].

In conclusion, this is the first systematic review of medication used to treat patients with COVID-19. Only 41 research articles were eligible for inclusion in this review, mainly conducted in China, of which only three were clinical trials.

The use of corticosteroids to treat patients with COVID-19 was reported most frequently in this review, despite safety alerts issued by WHO and CDC, followed by lopinavir, oseltamivir and arbidol hydrochloride.

Although further research is warranted as the amount of the evidence increases, this review presents the current picture of treatment modalities used for COVID-19. Efficacy and safety profiles of treatments for COVID-19 will need to be characterized in future studies.

Conflict of interest statement

None declared.

Funding sources

None.

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