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KSR Number: KSRA127095

Potential interventions for novel coronavirus in China: a systematic review

Risk of Bias Assessment

Overall summary: High risk of bias in the review

Bottom Line

The review aimed to summarise therapeutic options available for the treatment of novel coronavirus (COVID-19 or 2019-CoV). It identified a number of options, including nutritional interventions, immunoenhancers, coronavirus-specific treatments, antiviral treatments and other compounds with potential therapeutic use in the treatment of COVID-19. Nutritional interventions could have a positive effect on the host immune response against viral infections. Other treatment options have more direct effects on COVID-19 and were shown to be beneficial when used against other coronaviruses (severe acute respiratory syndrome, SARS; Middle East respiratory syndrome, MERS). While the review is useful in identifying potential treatment options, there are a number of limitations. It is likely that potentially relevant studies have been missed by the searches. Interpretation of included studies is hampered by the lack of reporting of study characteristics and the risk of bias was not assessed. It is unclear whether all relevant results have been presented. It should be noted that a number of the included studies were conducted in-vitro or in animal models, i.e. not in humans. Nevertheless, published a few weeks after the COVID-19 outbreak, the review gives an overview of available treatment options. This might guide clinicians treating patients with COVID-19 as well as researchers considering potential treatment options that should be studied in further detail.

Risk of Bias Assessment

Overall summary High risk of bias in the review

High

It is likely that potentially relevant studies have been missed. Not enough details are given on the included studies, e.g. regarding study characteristics and the risk of bias. It is unclear whether all relevant results have been presented.

A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4? No
B. Was the relevance of identified studies to the review's research question appropriately considered? Probably yes
C. Did the reviewers avoid emphasizing results on the basis of their statistical significance? Probably yes
Risk of bias in the review High

Details of Review

Number of studies NR
Number of participants NR
Last search date NR
Review type Intervention
Objective To summarise therapeutic options available for the treatment of novel coronavirus (COVID-19 or 2019-CoV)
Population Not defined
Interventions 34 interventions (9 nutritional interventions, 7 immunoenhancers, 8 coronavirus-specific treatments, 6 antiviral treatments, 3 other compounds)
Comparator Not defined
Outcome Not defined
Study design Not defined

Results

The review aimed to identify available therapeutic options for the treatment of novel coronavirus (COVID-19 or 2019-CoV). A total of 33 interventions (9 nutritional interventions, 7 immunoenhancers, 8 coronavirus-specific treatments, 6 antiviral treatments, 3 other compounds) were identified. Each intervention is briefly discussed by the authors of the review and its suitably for the treatment of COVID-19 or 2019-CoV assessed.

The authors identified a number of nutritional interventions as potentially useful interventions to improve host immune response against viral infections, namely vitamins A, B C and D as well as Omega-3 including protectin D1, selenium supplement and zinc supplement. In addition, vitamin E could be considered as an additional treatment due to reducing oxidative stress through binding to free radical as an antioxidant while iron could also be considered as iron deficiency has been reported as a risk factor for the development of recurrent acute respiratory tract infections.

Immunoenhancers such as interferons, levamisole and cyclosporine A could be used for treatment of novel coronavirus. According to the authors, non-immunosuppressive derivatives of cyclosporine A might serve as broad-range coronavirus inhibitors applicable against the emerging novel virus like COVID-19. Other options include intravenous gammaglobulin (IVIg), thymosin, thymopentin and Chinese Medicine. The authors noted that about a third of critically ill patients with severe acute respiratory syndrome (SARS) receiving IVIg developed venous thrombo-embolism including pulmonary embolism despite use of low molecular weight heparin. Thymosin alpha 1 should be used before the administration of methylprednisolone while thymopentin and Chinese medicine could enhance antibody response and host immunity, respectively.

Three coronaviral protease inhibitors, targeting chymotrypsin-like (3C-like; cinanserin, flavonoids) or papain-like protease (PLP; diarylheptanoids) coronavirus encoded proteins, respectively, were identified. According to the authors, cinanserin might be a good choice for the treatment of COVID-19 infection. Flavonoids might have a similar effect due to the inhibition of 3C-like protease (3CLpro) and have been used in SARS and Middle East respiratory syndrome (MERS). The authors noted that diarylheptanoids have been found to be able to inhibit papain-like protease of SARS-CoV.

Five spike (S) protein-angiotensin-converting enzyme 2 (ACE2) blockers were identified. Recombinant human monoclonal antibody (mAb), chloroquine, emodin, and promazine could be used as alternative choices for the treatment of COVID-19 while nicotianamine is another potential treatment option.

Regarding antiviral treatments, the authors suggested that due to adverse reactions and the lack of in-vitro efficacy, the use of ribavarin should be carefully considered. Better potential options should be considered, including 1) lopinavir (LPV)/ritonavir (RTV), especially when used in combination with ribavirin, and IFN-alpha 2a, 2) remdesivir (RDV), 3) nelfinavir, 4) arbidol, and 5) nitric oxide (NO) inhalation. This is partly based on positive effects in the treatment of SARS-CoV.

Other compounds discussed by the authors are alpha-lipoic acid (ALA), estradiol and phytoestrogen, and mucroporin-M1. The authors consider all of these compounds to be potential therapeutic options in the treatment of COVID-19.

Full Risk of Bias Assessment

No clear eligibility criteria were defined and it is unclear whether any restrictions were applied to included studies. However, not defining clear eligibility criteria was considered appropriate as the review aimed to summarise therapeutic options available for the treatment of novel coronavirus (COVID-19 or 2019-CoV)

1.1 Did the review adhere to pre-defined objectives and eligibility criteria? Probably yes
1.2 Were the eligibility criteria appropriate for the review question? Probably yes
1.3 Were eligibility criteria unambiguous? Probably no
1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)? No information
1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)? No information
Concerns regarding specification of study eligibility criteria Low

According to the review, "an online search on PubMed and Web of Science with the key words of SARS, MERS, and coronaviruses" was conducted. No methods additional to database searching were used to identify relevant reports. It is unclear whether there were restrictions based on date, publication format, or language. Furthermore, the number of reviewers involved in the selection was not reported. It is likely that potentially relevant studies might have been missed due to the limited range of databases searched as well as the limited numbers of search terms.

2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports? No
2.2 Were methods additional to database searching used to identify relevant reports? No
2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible? Probably no
2.4 Were restrictions based on date, publication format, or language appropriate? No information
2.5 Were efforts made to minimise error in selection of studies? No information
Concerns regarding methods used to identify and/or select studies High

It is unclear how many reviewers were involved in the data extraction. Details such as the characteristics of included studies were not reported, which limits the interpretation of the study results. It should be noted that a number of the included studies were conducted in-vitro or in animal models, i.e. not in humans. It is unclear whether all relevant study results were presented. The risk of bias of included studies was not assessed.

3.1 Were efforts made to minimise error in data collection? No
3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results? No
3.3 Were all relevant study results collected for use in the synthesis? Probably no
3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria? No
3.5 Were efforts made to minimise error in risk of bias assessment? No
Concerns regarding methods used to collect data and appraise studies High

Results were summarised narratively, i.e. no formal analyses were done. The authors acknowledged that findings were partly based on other coronaviruses. No risk of bias assessment was conducted, as noted in domain 3.

4.1 Did the synthesis include all studies that it should? Probably yes
4.2 Were all pre-defined analyses reported or departures explained? Probably yes
4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies? Probably yes
4.4 Was between-study variation minimal or addressed in the synthesis? Probably yes
4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses? Probably yes
4.6 Were biases in primary studies minimal or addressed in the synthesis? No
Concerns regarding synthesis and findings Low

Abstract

An outbreak of a novel coronavirus (COVID-19 or 2019-CoV) infection has posed significant threats to international health and the economy. In the absence of treatment for this virus, there is an urgent need to find alternative methods to control the spread of disease. Here, we have conducted an online search for all treatment options related to coronavirus infections as well as some RNA virus infection and we have found that general treatments, coronavirus-specific treatments, and antiviral treatments should be useful in fighting COVID-19. We suggest that the nutritional status of each infected patient should be evaluated before the administration of general treatments and the current children's RNA virus vaccines including influenza vaccine should be immunized for uninfected people and health care workers. In addition, convalescent plasma should be given to COVID-19 patients if it is available. In conclusion, we suggest that all the potential interventions be implemented to control the emerging COVID-19 if the infection is uncontrollable. This article is protected by copyright. All rights reserved.