key: cord-0713999-w456o5ee
authors: Kheirabadi, Dorna; Haddad, Fatemeh; Mousavi‐Roknabadi, Razieh S.; Rezaeisadrabadi, Mohammad; Dehghan, Hamidreza; Fazlzadeh, Aylar
title: A complementary critical appraisal on systematic reviews regarding the most efficient therapeutic strategies for the current COVID‐19 (SARS‐CoV‐2) pandemic
date: 2021-02-01
journal: J Med Virol
DOI: 10.1002/jmv.26811
sha: f71af3d7279ec8069335c47d7c62986bb735a631
doc_id: 713999
cord_uid: w456o5ee

BACKGROUND: This critical appraisal aims to clarify which systematic reviews on COVID‐19 treatment are based on high‐value evidence. Hereby, the most profitable medicines can be suggested. METHODS: The mesh terms of "COVID‐19 drug treatment" (Supplementary Concept) and "COVID‐19 drug treatment" were sequentially utilized as search strategies in Medline and Science direct on October 18, 2020. Searches were confined to systematic reviews/meta‐analyses. The Cochrane database was searched on November 1, 2020 with "COVID." With adding up four articles from other resources, 84 systematic reviews were considered for initial screening. Finally, 22 articles fulfilled the criteria and were assessed using PRISMA guidelines. RESULTS: Increasing number of clinical trials from the onset of the COVID‐19 pandemic has revealed that hydroxychloroquine and chloroquine are not only profitable but also deleterious. Lopinavir/ritonavir failed to maintain their initial efficacy in improving clinical symptoms and mortality rate. Steroids and tocilizumab were suggested in patients with intensely severe symptoms. Steroids reduced mechanical ventilation and death in severely ill patients. Plasma or immunoglobulins effects are absolutely controversial. Favorable impressions of remdesivir have been relied on for the early onset of this drug. Hypotension and abnormal liver function tests were realized as its side effects. Favipiravir has resulted in a higher viral clearance than remdesivir. However, this claim needs to be proved with subsequent clinical trials. CONCLUSIONS: Currently, remdesivir and favipiravir are advantageous drugs that should be administered in the early phases. Their side effects are not well known and need to be found in the following research projects. Steroids and tocilizumab have been considered beneficial in the cytokine storm phase.

with mortality. 12 This novel virus mortality rate is approximately 3.7% based on reports till March 12, 2020 , and caused many more deaths than its predecessors. 13 A large number of studies have reported various treatments for MERS, SARS, and COVID-19, whereas the major problem in this period of time is the lack of definite specific therapeutic drugs or vaccines for prevention. In spite of identifying various drug choices, scientific evidence is still incipient and of low methodological quality, and some previous systematic reviews and meta-analysis claimed the poor quality of the included studies. 4, 14, 15 Previous treatment strategies were explained and compared to find the most efficient drug regimen. The therapeutic protocols include supportive standard care, antivirals, antibiotics, vitamins, immunomodulators, antimalarial drugs, corticosteroids, antiretroviral drugs, convalescent plasma hemoperfusion, and extracorporeal membrane oxygenation (ECMO). 4, 15, 16 Owing to the lack of definite therapeutic protocol, this complementary critical appraisal on previous systematic reviews was carried out upon multiple databases to assess the current evidence regarding COVID-19 treatment strategies.

As a surprisingly large number of systematic reviews were published within a short time period, we decided to precisely assess the usefulness and quality of them. Considering the day-to-day increase in the population of infected people and its mortality rate, we came to this decision to compare the varieties of currently available treatments to determine the high-quality documented ones as well as knowledge gaps. This study assists to reveal whether the treatment strategies offered in previously published systematic reviews are based on strong evidence such as randomized clinical trials (RCTs) with large enough samples or weak ones such as case series and case reports. The most evidential systematic reviews are done including mostly RCTs, not case series and reports. In the second place, it can give a guide to the other researchers and inform them which treatments need to be proved with more clinical trials and which ones not properly assessed so far. Through this study and comparing the current evidence, it could offer treatments that are more evidently useful. and Aylar Fazlzadeh).

Then, the full texts of the studies were evaluated by two authors (MR and Razieh S. Mousavi-Roknabadi [RSM]); they decided whether these met the inclusion criteria, independently. Disagreements were resolved by discussion between all authors, and finally, the articles were selected based on consensus. Neither of the authors was blind to the journal titles or to the study authors or institutions. The following data were extracted from the included studies: Study authors, study designs, methods, treatment, main findings, complications, and conclusion. The report of this systematic review was made according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement 17 ( Figure 1) .

The methodological quality of the included studies was assessed by the authors (RSM and MR). The quality of the systematic reviews was assessed using PRISMA guidelines through an evidence-based set of items to report the quality of the systematic review. For each item in PRISMA guideline, "Yes" was given if any of the items were fully complied within the study, "Not Suitable" if any of the items were not suitable, and "No" if any of the items have not complied. If a study gets more than 80% of the items as "Yes," it was considered as high-quality, if it gets 50%-80%, it was considered as medium, and if it gets less than 50%, it was considered as low. The review protocol was not previously registered.

Totally, 84 (46 articles in Medline, 33 articles in Cochrane Database of Systematic Reviews, 1 article from Science Direct, and 4 articles from other resources) were achieved at the first step by searching.

After an initial assessment, no duplication was found. After the identification and the screening, 50 systematic reviews were selected as potential studies. No article from Science Direct fulfilled the inclusion criteria. After reading the full text of these articles, 22 articles formed the final sample (19 articles from Medline, 1 from Cochrane library, and 2 from other resources). 4, 14, [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] Inter-rater agreement following the first round of screening between the two investigators was 93.90% (Cohen's k = 0.842). Within the second round of screening, the inter-rater agreement was raised to 100%.

The results are shown in Table 1 . All studied were published in 2020.

Our investigation for previous studies illustrated that most of the available reported evidence (59.1%) did not have high quality (Table 2 ).

In a systematic review and meta-analysis, Yang et al. 18 

Note: PRISMA items: Title: (1) Identify the report as a systematic review, meta-analysis, or both. Abstract (2) Structured summary: Provide a structured summary including, as applicable: Background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. Introduction: (3) Describe the rationale for the review in the context of what is already known. (4) Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). Methods: (5) Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. (6) Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. (7) Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

(8) Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. (9) State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). (10) Describe the method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. (11) List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. (12) Describe methods used for assessing the risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. (13) State the principal summary measures (e.g., risk ratio, difference in means). corticosteroids in critical and noncritical patients. The effects of corticosteroids may be influenced by other therapeutic options, such as antiviral drugs. Critical patients were more likely to require corticosteroid therapy. Corticosteroid treatment was associated with higher mortality, longer length of stay, higher rate of bacterial infection, and hypokalemia, but not hyperglycemia or hypocalcemia.

The study limitations were that most of the studies were retrospective cohort and historical control studies, with a low level of evidence with a lack of RCTs with optimized design. There was no uniform standard for the time and dosage used in different studies.

In addition, publication bias due to the rapid evolution of the SARS-CoV-2 situation and some unpublished studies may influence the results. 18 In another meta-analysis, Li et al. 19 RCTs demonstrated. 16 The results of a meta-analysis by Patel et al. 24 showed that HCQ did not improve the mortality in patients with COVID-19. In treatment with HCQ plus azithromycin, the risk of mortality was higher than those who received neither of these drugs. Also, they Finally, they stated that although the use of CQ may be supported by expert opinion, the clinical use of this drug should be approved. 34 In another systematic review by Hernandez et al. 26 arrhythmias with a higher-dose therapy was found. There were no assessments of these drugs for prophylaxis against COVID-19. 26 Chowdhury et al. 27 stated that HCQ or CQ is efficacious compared to supportive care and to LPV/r in the treatment of patients with COVID-19 in their systematic review. But the potential risk of QTc prolongation in combination with HCQ plus azithromycin was

observed. The small sample size in assessed trials was the main limitation. Finally, it was reported that no sufficient data was available to support the route use of these drugs as therapies for these patients. 27 Andrade et al. 4 enrolled 36 studies in their systematic review.

Most of the studies were retrospective cohort. They reported there is no significant difference in the probability of negative viral load by In another systematic review, although they stated that remdesivir did not have a significant effect on the time to clinical improvement, they found that the benefit of remdesivir may significantly depend on the time of administration (2 h after infection). However, the available evidence was not high-quality and sufficient about the safety and efficacy of this drug. 30 In another systematic review on different types of drugs in the treatment of COVID-19, Lima et al. 31 found that antivirals, especially antiretrovirals, were the most frequently studied class of therapeutic agents (30%). After that, antitumor (16%), antimalarial (7%), antibacterial (5%), anticoagulant (3.5%), anti-inflammatory (3.5%), phosphodiesterase (PDE)-inhibiting (3.5%), anti-rheumatic (3.5%), sedativehypnotic (3.5%), and antivenous insufficiency agents (3.5%) were placed. They concluded that LPV/r had low effectiveness on COVID-19, but arbidol, remdesivir, and CQ/HCQ showed promising effects. 31 In a systematic review done by AminJafari and Ghasemi, 32 One of the reasons for this alteration in treatment strategies compared to the beginning of the pandemic has been related to the increased number of controlled clinical trial studies. Overall, the authors of this article, by summarizing the existing studies, conclude that the use of antimalarials cannot lead to a reduction in mortality rate, and due to serious cardiac complications, its harm can outweigh the profit. 4, 12, [21] [22] [23] [24] [25] [26] 33 Antiretroviral drugs, including LPV/r, have been shown to be less effective in improving clinical symptoms and mortality rates in various studies. Also, the use of these drugs in outpatients did not reduce their hospitalization rate. In general, as mentioned in the studies, the effects of this class of drugs are ambiguous. In some existing studies, the use of remdesivir has been preferred to LPV/r. 14, 20, 30, 33 As one of the approved mechanisms of this disease is the inflammatory cascade, the use of corticosteroids has been considered.

In early studies, steroids did not reduce death in the ICU and had no effect on clearing the virus. However, in more recent studies including more clinical trials and high-quality studies, corticosteroids have reduced the need for mechanical ventilation and death especially in patients with highly severe symptoms. We believe that the use of corticosteroids in severely ill patients can be effective and lead to a reduction in mortality. 16, 18 On the basis of this pathophysiological justification, the use of tocilizumab has also been considered, and in the present article, has recommended its use in very critically ill patients. 13 The results regarding the use of plasma or immunoglobulin have been quite contradictory. In some studies, it did not improve symptoms or mortality. In others, it has reduced respiratory symptoms and the severity of the disease. Interferon-α may decrease mortality based on the low and very low quality of evidence. [31] [32] [33] Remdesivir and favipiravir have come to the attention of researchers in recent months. In existing clinical trials, favipiravir has led to higher clearance of the virus and cough amelioration. 28 Promising results have been observed in patients using Remdesivir, but its side effects are still less known due to the novelty of the drug. The Finally, none of the above treatments has been approved as a definitive treatment of the Wuhan coronavirus disease.

The authors declare that there are no conflict of interests. 

The peer review history for this article is available at https://publons. com/publon/10.1002/jmv.26811ARDP202000455.

Research data are not shared.

Razieh S. Mousavi-Roknabadi http://orcid.org/0000-0001-

Mohammad Rezaeisadrabadi http://orcid.org/0000-0002-

Emerging coronaviruses: genome structure, replication, and pathogenesis

Oral ribavirin for the treatment of noninfluenza respiratory viral infections: a systematic review

Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study

Pharmacological therapies for patients with human coronavirus infections: a rapid systematic review

Therapeutic options for Middle East respiratory syndrome coronavirus (MERS-CoV)-possible lessons from a systematic review of SARS-CoV therapy

Potential rapid diagnostics, vaccine and therapeutics for 2019 novel coronavirus (2019-nCoV): a systematic review

Failure in initial stage containment of global COVID-19 epicenters

SARS: systematic review of treatment effects

Current meta-analysis does not support the possibility of COVID-19 reinfections

Coronavirus infections and immune responses

Epidemiological and clinical characteristics of 6635 COVID-19 patients: a pooled analysis

Risk factors for hospitalization, mechanical ventilation, or death among 10 131 US Veterans with SARS-CoV-2 infection

Antiviral therapy in management of COVID-19: a systematic review on current evidence

Perspectives on the early quality of evidence guiding the therapeutic management of SARS-CoV-2: a systematic literature review

Efficacy of tocilizumab treatment in severely ill COVID-19 patients

Systematic review of the efficacy and safety of antiretroviral drugs against SARS, MERS or COVID-19: initial assessment

Evaluations of the uptake and impact of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement and extensions: a scoping review

The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis

Impact of corticosteroid therapy on outcomes of persons with SARS-CoV-2, SARS-CoV, or MERS-CoV infection: a systematic review and meta-analysis

A systematic review of the prophylactic role of chloroquine and hydroxychloroquine in coronavirus disease-19 (COVID-19)

Lopinavir/ritonavir for COVID-19: a living systematic review

Hydroxychloroquine in patients with COVID-19: a systematic review and meta-analysis

Does adding of hydroxychloroquine to the standard care provide any benefit in reducing the mortality among COVID-19 patients?: a systematic review

Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: a systematic search and a narrative review with a special reference to India and other developing countries

Hydroxychloroquine or chloroquine for treatment or prophylaxis of COVID-19: a living systematic review

A rapid systematic review of clinical trials utilizing chloroquine and hydroxychloroquine as a treatment for COVID-19

Remdesivir for the treatment of COVID-19: a systematic review of the literature

Systematic review on repurposing use of favipiravir against SARS-CoV-2

Use of remdesivir in the management of COVID-19: a systematic review on current evidence

The potential of drug repositioning as a short-term strategy for the control and treatment of COVID-19 (SARS-CoV-2): a systematic review

The possible of immunotherapy for COVID-19: a systematic review

Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review

A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19

Efficacy and safety of antiviral treatment for COVID-19 from evidence in studies of SARS-CoV-2 and other acute viral infections: a systematic review and meta-analysis