An umbrella review on treatments and therapeutic options for COVID-19

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Abstract

Introduction. As the COVID-19 pandemic continues to pose a significant challenge to global health, effective therapeutic options for preventing and treating the disease have become increasingly important. We aimed to provide an update on current treatments and therapeutic options for COVID-19 patients. Materials and methods. The purpose of this umbrella review is to explore the current treatments and therapeutic options for COVID-19 patients. Keywords and their combinations were searched across online databases in Embase, PubMed/MEDLINE, Web of Science, and Scopus spanning from July 1, 2020, through March 3, 2023. Publications were selected for data extraction in two steps based on the study inclusion/exclusion criteria. The study adheres to the PRISMA checklist as well as NIH bias risk and quality assessment tool. Results. In this review, 28 relevant articles were selected for the final qualitative synthesis. The majority of included studies had reported on the efficacy of Lopinavir/Ritonavir (n = 4), Ivermectin (n = 3), Baricitinib (n = 2), Tocilizumab (n = 2), Remdesivir (n = 2), ACEI/ARB (n = 2), Vitamin D (n = 2), Molnupiravir (n = 2), Traditional Chinese medicine (TCM) (n = 2), Convalescent plasma transfusion (CPT) (n = 2) and hydroxychloroquine (n = 2) in treating COVID-19. It appeared that Baricitinib, Remdesivir, ACEI/ARB, TCM, and CPT may have beneficial effects on reducing mortality, hospitalization duration, and disease severity in COVID-19 patients. Other interventions, such as Lopinavir/Ritonavir, Ivermectin, Vitamin D, and Hydroxychloroquine did not show clear benefits or had inconclusive results. Conclusion. This umbrella review provides a comprehensive overview of the current evidence on the effectiveness and safety of various pharmacological and non-pharmacological interventions for COVID-19. These results provide an updated overview of the current landscape for COVID-19 treatments, highlighting potential avenues for further research and clinical practice. It is crucial to continue monitoring emerging evidence and conducting rigorous studies to guide the development and optimization of therapeutic strategies against COVID-19.

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Introduction

The COVID-19 pandemic has posed a significant challenge to global health, with millions of cases and deaths reported worldwide. The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 has become a global public health emergency [30, 40]. As the world continues to grapple with the pandemic, there has been a growing need for effective therapeutic options to prevent and treat COVID-19 [28, 34]. Several potential therapeutic opportunities have emerged, including antiviral drugs, monoclonal antibody therapies, anti-inflammatory drugs, convalescent plasma therapy, and vaccines [7]. In this context, ongoing research and development of treatments and prevention measures have become critical in managing the COVID-19 pandemic [13] and effective therapeutic options for preventing and treating the disease have become increasingly important [24, 25, 28].

The pandemic has highlighted the need to develop treatment guidelines based on current and reliable evidence, rather than relying solely on past experiences and theories. Although various potential therapeutic opportunities have emerged, including antiviral drugs, monoclonal antibody therapies, anti-inflammatory drugs, convalescent plasma therapy, and vaccines, it is essential to frequently review and revise these guidelines due to the rapid pace at which new evidence can emerge during a crisis [4]. The rapidly changing nature of information during a crisis means that guidelines can quickly become outdated, and it is important to stay up-to-date on the latest developments in order to provide the best possible care. By continually revising guidelines, healthcare professionals can ensure that they are providing the most effective and evidence-based treatments to their patients [14, 19].

Against this background, it is crucial to emphasize the importance of ongoing research to fully understand the effectiveness and safety of COVID-19 treatment and prevention options. This review provides a brief overview of some of the potential options for COVID-19, highlighting benefits and the need for ongoing research to fully understand their effectiveness and the safety of current therapeutic options.

Materials and methods

This review investigated currently available treatments and therapeutic options for COVID-19 patients and elaborate on the implications and potential adverse effects. This study adheres to items of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. The risk of bias for included studies was assessed by the National Institute of Health (NIH) quality and bias risk assessment tool.

Data sources. We performed a comprehensive search on the online database of Embase, PubMed/ MEDLINE, Web of Science, and Scopus. Combining the relevant keywords and search queries all the relevant articles published in the English language were browsed and retrieved from July 1st, 2020, to March 3rd, 2023. The comprehensive list of queries in different databases is provided in Supplementary Material 1. Here is an example of a search query in the PubMed/MEDLINE database: ((“COVID-19”[mesh] OR “SARS-CoV-2”[mesh] OR COVID-19[tiab] OR SARS-CoV-2[tiab] OR coronavirus disease 2019[tiab] OR severe acute respiratory syndrome coronavirus 2[tiab] OR 2019 nCoV [tiab] OR SARS Coronavirus 2[tiab]) AND (“Therapeutics”[mesh] OR Therapeutic [tiab] OR Therapy [tiab] OR Therapies[tiab] OR Treatment[tiab] OR Medicine [tiab] OR Drug[tiab] OR Medication[tiab]) NOT (Vaccine[ti] OR Vaccination[ti])).

Study selection. To ensure the selection of the most appropriate studies, we employed two distinct selection steps. Initially, three research staff screened titles and abstracts of the retrieved articles. In the next step, three other researchers conducted a thorough full-text review of the initially selected articles. Pertinent publications that met the inclusion/exclusion criteria were included for data extraction. The inclusion criteria were as follows: The study had to a systematic review, written in English, peer-reviewed prior to publication, and published in the allocated time period (July 1st 2020 — March 3rd 2023). Studies were excluded if they were original articles, duplicated, non-human research models, ongoing experiments and/or lacking published data, conference abstracts or abstracts without accessible full texts, preprint papers, editorial letters, case reports, or series.

Data extraction. Three researchers extracted the necessary data from the eligible articles. A preplanned spreadsheet was used to record the detailed information, which is presented in Table 2. Any potential duplicates were removed, and the accuracy of the extracted data was verified by other members of the research team.

 

Table 2. Description of the findings reported in the eligible studies

Reference

Country

Method (search date and searched databases)

Number of review studies

Current treatment/medicine

Therapeutic dose

Clinical considerations

Main findings

[1]

Brazil

Pubmed/EMBASE/Cochrane library/MedRxiv

October 7, 2020 — April 30, 2022

27 RCT

Baricitinib

Sarilumab

Tocilizumab

Not reported

Baricitinib has not been studied in severe renal failure and cannot be given in pregnancy

Baricitinib and Sarilumab are alternatives to Tocilizumab for reducing mortality in COVID-19 patients admitted to the hospital and undergoing corticosteroid treatment

[2]

Switzerland

Pubmed/EMBASE/Cochrane COVID-19 trial registry/ClinicalTrials.gov/International Clinical Trial Registry Platform/preprint servers

January 1, 2020 — April 11, 2022

9 RCT

Remdesivir

Not reported

Remdesivir has specific side effects (eg, severe bradycardia)

In non-ventilated hospitalized patients with COVID-19 who did not require ventilation, Remdesivir demonstrated a decrease in mortality

[6]

Pakistan

Pubmed/The Cochrane Library/EMBASE

Inception — October 5, 2022

6 RCT

Quercetin

Safe up to 500 mg per day

Quercetin is a cheap and easily accessible therapeutic option for COVID-19 patient

The administration of Quercetin, especially in its phytosome formulation can provide benefits for COVID-19 patients by improving its bioavailability

[8]

Germany

Medline/EMBASE/Clinicaltrial.org/MedRxiv/WHO International Clinical Trial Registry Platform/CCSR

Inception — December 13, 2021

5 RCT

Anakinra

Not reported

Anakinra might be beneficial in hospitalized patients with COVID-19 with low-flow/high-flow oxygen therapy and suPAR > 6 ng/ml

When compared to placebo or standard care alone, Anakinra does not exhibit any impact on mortality, clinical improvement, worsening or safety outcomes in adult hospitalized patients with COVID-19

[9]

Canada

Medline/EMBASE/Pubmed/Web of science/CENTRAL/CINAHL/International pharmaceutial abstracts

January 1, 2020 — December 17, 2022

6 RCT

3 Cohort study

1 Case-Control

1 Non-randomized clinical trial

SSRI (Fluvoxamine)

50–100 mg

Bid

100 mg bid is more effective than 50 mg bid

Fluvoxamine is a potential therapy in COVID-19 out-patients with medium doses showing more favorable results in comparison with low doses

[11]

Spain

PubMed, Web of Science, the Cochrane COVID-19 Study Register, ClinicalTrials.gov-COVID-19 subset, and the WHO International Clinical Trials Registry Platform (ICTRP)

Inception — May 2022

27 RCT

Vitamin D

Not reported

No adverse events were observed in the trials, indicating the safety of Vitamin D supplements within the examined doses

No adverse events were observed in the trials. It can be concluded that Vitamin D supplementation using the doses and preparations examined, is safe

[12]

Australia

Medline/EMBASE/Pubmed/PsycINFO

November 2021 — July 7, 2022

8 Retrospective cohort

2 Prospective cohort

3 Cross-sectional study

1 Case-Control

1 Case-Series

3 Retrospective chart review

Clozapine

Not reported

There was a reduction in neutrophil level in COVID-19 positive clozapine users

There is no evidence suggesting that the immune system of Clozapine users put them at risk of COVID-19. It is still crucial to closely monitor these patients

[15]

China

Pubmed/Embase/Cochrane Library

January 2000 — May 2022

26 Retrospective cohort

2 Prospective cohort

ACEI/ARB

Not reported

The effect of ACEI/ARB is more obvious in HTN population. The reduction of hospitalization in female is more than male

Use of ACE/ARB among EAST-Asian COVID-19 patients did not show any adverse outcomes and was associated with shorter hospitalization and reduced mortality rates

[16]

Germany

Medline/EMBASE/ClinicalTrials.gov/WHO International Clinical Trials Registry Platform/medRxiv/Cochrane Central Register of controlled trials/VA ESP/WHO COVID-19 Global Literature

Inception — February 2022

6 RCT

Janus Kinase Inhibitors:

Baricitinib

Tofacitinib

Ruxolitinib

Not reported

There is no evidence on the efficacy and safety of systemic JAK inhibitors for non-hospitalized individuals

Systemic JAK inhibitors reduce all-cause mortality in hospitalized individuals with moderate-severe COVID-19

[17]

Indonesia

Pubmed/Science direct

Inception — October 4, 2021

6 RCT

Anticoagulants in prophylactic vs intermediat/therapeutic doses

Not reported

The incidence of bleeding at the intermediate/therapeutic doses compared to the prophylactic dose

There was no significant differences in thromboembolic events or all-cause mortality

[18]

China

Campbell Library/Cochrane Library/EMBASE/PubMed/Web of Science/CBM/CNKI/CQVIP/WanFang Data

Inception — March 23, 2022

76 RCT

50 Systematic Review

TCMs

(Tradional Chinese Medicine)

Not reported

XBJ as a TCM was the most common intervention

In terms of treatment, rehabilitation and prevention TCM is a promising alternative

[20]

China

PubMed/the Cochrane Library/Ovid/Embase

December 1, 2019 — April 30, 2022

4 RCT

5 Retrospective cohort

1 Prospective cohort

1 Non-experimental comparative study

ACEI/ARB

Not reported

The effects of continuing ACE/ARB treatment may have been influenced by factors such as male sex and the presence of D.M.

Previous ACEI/ARB treatment was associated with lower hospital mortality, ICU admission, and IMV in patients with COVID-19

[21]

China

CBM/CNKI/Wanfang/PubMed/Cochrane Library/EMBASE/preprint platforms

Date of database creation — March 31, 2021

51 Systematic Reviews

CHM

(Chinese Herbal Medicine)

Not reported

Clinical evidence of the benefits of CHM for acute respiratory infections such as COVID-19, SARS, and H1N1 seems more sufficient than other acute infections

Chinese herbal medicine, used alone or in combination with conventional medicine has benefits in relieving symptoms of patients with acute respiratory infections

[22]

India

LitCOVID/Google Scholar/Science Direct/EBSCO/Scopus/Web of Science/EMBASE

Search date not reported

11 RCTs

4 Case reports

1 Case-series

4 Retrospective cohort

3 Non-randomized clinical trial

2 Pilot and prosspective comparative studies

Ayurvedic medicines and formulations:

Ayush-64

Guduchi Ghana vati

Chyawanprash

Not reported

500 mg BD

500 mg BD

12–24 g BD

Ayurvedic medicines have antiviral, antioxidant, anti-inflammatory, and immunomodulatory properties

Ayurvedic medicines can be combined with standard treatments to aid in early virus detection, accelerate recovery from COVID-19, expedite hospital discharge, and prevent further deterioration

[23]

India

PubMed/MedRxiv/BioRxiv/FDA/ClinicalTrials.Gov/ctri.nic.in/Google Scholar

January 2021 — March 2022

6 RCT:

4 Published

2 Unpublished

Molnupiravir

50–800 mg

Bid

Or single dose

Up to 1600 mg

The drug is well tolerated and safe with no significant adverse events on short-term use

Clinical studies provide evidence that Molnupiravir significantly reduces the risk of hospitalization or death in high-risk mild COVID-19 patients

[26]

Germany

Pubmed/Embase/Scopus/Google Scholar

No time constrain

9 RCTs

9 Retrospective cohorts

2 Prospective cohorts

2 Cross-sectional study

1 Case-control

Vitamin C and D

Supplementation

Not reported

Vitamin D modulates the innate immune response

Vitamin C has antioxidant, anti-inflammatory, antithrombotic, and immunomodulatory functions

Administration of vitamins C and D in COVID-19 patients doesn’t impact disease susceptibility, severity, and progression

[27]

Iran

PubMed/Scopus/Web of Sciences

Inception — January1, 2022

46 Reviews

Main intervention:

Favipiravir

Remdesivir Hydroxychloroqine

Ivermectin Lopinavir/Ritonavir

Tocilizumab

Not reported

Not reported

The main limitations observed in the included studies were heterogeneity, sample size, follow-up, treatment variations, study design, definitions, synthesis, quality, and search methodology

[29]

Iran

PubMed/Scopus/Web of Sciences/Embase

December 2019 — March 2021

266 in silico

34 in vitro

15 in vivo

Main intervention:

Saquinavir

Ritonavir

Lopinavir

Herbal medicine

Not reported

Discovering drugs that have multitarget antiviral and anti-inflammatory actions is crucial due to the nature of COVID-19 — Certain herbal medicine exhibit this potential

For antiviral development, the main focus has been on targeting the protease and spike glycoprotein

[31]

Greece

Pubmed/Medline and Embase

September 2022

3 RCTs

4 Retrospective cohorts

1 Prospective cohort

N-acetyl cysteine (NAC)

The studies by Mousapour, Taher, and de Alencar used 1 g/12 h, 40 mg/kg/day, and 21 g (divided into two doses) respectively

Due to the limited certainty of evidence presented in the studies, it is not possible to provide recommendations for clinical practices

In RCTs, the point estimates for hard clinical outcomes tend to be near the null effect line (lack of significant impact). Observational studies show heterogeneity, with certain studies suggesting positive outcomes

[32]

India

Google Scholar

January 2020 to May 2020

49 Studies

Hydroxychloroquine, Lopinavir and Ritonavir, Ultra-violet radiation therapy, Convalescent plasma transfusion (CPT) therapy

Not reported

New drugs are in the premature stage of this pandemic. Further research is needed to fully understand the life cycle of n.COV and expedite the development of drugs and vaccines

ICMR and NIH provide guidelines for Hydroxychloroquine and other antiviral drugs. Ongoing research includes natural products, herbs, combination therapy, UV radiation, MD simulations for vaccine development, and CPT

[33]

USA

Google Scholar and PubMed and medRxiv

Search date not reported

3 Cohort

1 Case-control

1 RCT

2 Comparative studies

Arbidol, Lopinavir/Ritonavir

Not reported

Adverse reactions were rarely reported including ECG changes, GI symptoms, bacterial infections, and hepatic and renal dysfunction

Antiviral regimens did not show clear benefits in terms of hospitalization duration and time to negative PCR in mild diseases

[36]

Germany

Cochrane COVID-19 Study Register, Scopus, and WHO COVID-19 Global literature on coronavirus disease database

Inception — July 2022

1 RCT

8 Ongoing studies

Nirmatrelvir combined with Ritonavir

Not reported

Ritonavir’s role as a CYP3A4 inhibitor, makes Nirmatrelvir/Ritonavir prone to drug interactions, especially in patients with comorbidities

Low certainty evidence suggests that Nirmatrelvir/Ritonavir reduces the risk of all-cause mortality, and hospital admission/death in high-risk, unvaccinated COVID-19 patients with symptom onset within 5 days. Low-moderate certainty evidence suggests the safety of Nirmatrelvir/Ritonavir in patients without prior-concomitant therapies that rely on CYP3A4

[38]

USA

EMBASE, PubMed, medRxiv, Scopus, Prospero, and Google Scholar

inception — February 2021

4 RCTs

2 Retrospective cohorts

2 Case-controls

Colchicine

Not reported

The use of Colchicine for treating COVID-19 is not recommended. Additional high-quality, multicenter RCTs are needed

3 observational studies showed a decrease in all-cause mortality. 1 observational study showed a decrease in the risk of mechanical ventilation. 2 RCTs showed a reduction in hospitalization

[39]

Germany

Cochrane COVID-19 Study Register, Web of Science, medRxiv, and Research Square

Inception — May 2021

11 RCTs

IverIvermectinectin

Not reported

The existing reliable evidence does not support the use of Ivermectin as an effective treatment or preventive measure for COVID-19

Evidence for the effectiveness of Ivermectin in treating COVID-19 is currently uncertain for both in-patients and out-patients with limited/no beneficial effects in different aspects such as viral clearance-clinical improvement and adverse events

[41]

China

PubMed, EMBASE, Cochrane Library, Web of Science databases

Inception — October 25, 2022

7 Retrospective cohorts

2 RCTs

Thymosin alpha1 (Ta1)

Not reported

This meta-analysis does not provide support for the utilization of Ta1 in hospitalized adult COVID-19 patients

The meta-analysis results suggest that Ta1 therapy does not have a statistically significant impact on mortality. Subgroup analyses show a beneficial effect on mortality in patients > 60 years with a proportion of females < 40% and with severe COVID-19

[42]

Australia

PubMed, Web of Science, ScienceDirect and Scopus

Inception — June 2022

5 Retrospective cohorts

12 Case reports

1 Case series

Convalescent plasma

Therapy (CPT)

Not reported

CPT is an effective supportive therapy for COVID-19 patients with hematological malignancies

CPT may lead to improved clinical outcomes, including higher survival rates, enhanced clearance of SARS-CoV-2, presence of anti-SARS-CoV-2 antibodies, shorter hospital discharge time, and better recovery after one month of CPT. The treatment was not associated with adverse events

[43]

India

PubMed, MedRxiv and Google Scholar

October 2021 — January 2022

1 RCT

13 Preclinical studies

Molnupiravir

Not reported

Molnupiravir may benefit non-pregnant, unvaccinated adults with COVID-19 who face an elevated risk of severity and hospitalization

Molnupiravir shows promise as a useful agent in reducing death and composite of hospitalization or death in high-risk adult patients with COVID-19. It offers the advantage of being cost-effective

[47]

China

Studies were not restricted by the year of publication, study site, drug dose, or control group

9 RCT

Ivermectin (IVM)

Not reported

In the absence of superior alternatives, clinicians should use IVM with caution in the clinical setting. Self-medication is not recommended for patients

IVM shows potential effectiveness in treating mild to moderately ill patients. Its role as an antiviral drug in COVID-19 is still in the early stages of clinical application

 

Quality and bias risk evaluation. The quality and precision of the studies and reported results were assured by adhering to the items outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Additionally, the National Institute of Health (NIH) quality and bias risk assessment tool was used to assess and minimize the potential risk of bias in the selected studies. Table 1 presents the results of the quality assessment. The questionnaire at the bottom of the table was used by two researchers to rate the included studies.

 

Table 1. Quality/Bias risk ratings of the included studies according to the NIH Quality Assessment Tool*

Reference

Questions

Rating by reviewers

1

2

3

4

5

6

7

8

#1

#2

[1]

Yes

Yes

Yes

Yes

NR

Yes

Yes

Yes

Good

Good

[2]

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Good

Good

[6]

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Good

Good

[8]

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Good

Good

[9]

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Good

Good

[11]

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Good

Fair

[12]

Yes

Yes

Yes

NR

Yes

Yes

Yes

NA

Fair

Good

[15]

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Good

Good

[16]

Yes

Yes

Yes

Yes

Yes

Yes

No

NA

Good

Fair

[17]

Yes

Yes

Yes

Yes

No

Yes

No

NA

Fair

Fair

[18]

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Good

Good

[20]

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Good

Good

[21]

Yes

Yes

Yes

Yes

Yes

Yes

No

NA

Fair

Good

[22]

Yes

Yes

Yes

No

No

Yes

No

NA

Fair

Fair

[23]

Yes

Yes

Yes

Yes

NR

Yes

No

NA

Good

Good

[26]

Yes

Yes

Yes

NR

Yes

Yes

No

NA

Fair

Fair

[27]

Yes

Yes

Yes

Yes

Yes

Yes

Yes

NA

Good

Good

[29]

Yes

Yes

Yes

Yes

Yes

Yes

No

NA

Good

Good

[31]

Yes

Yes

Yes

Yes

No

Yes

No

NA

Fair

Good

[32]

Yes

Yes

Yes

Yes

No

Yes

NR

No

Fair

Fair

[33]

Yes

Yes

Yes

Yes

No

Yes

NR

Yes

Fair

Fair

[36]

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Good

Good

[38]

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Good

Fair

[39]

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Good

Good

[41]

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Good

Fair

[42]

Yes

Yes

Yes

Yes

Yes

Yes

NR

No

Fair

Fair

[43]

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Good

Good

[47]

Yes

Yes

Yes

Yes

Yes

Yes

No

NA

Good

Fair

Note. NIH — National Institutes of Health; CD — cannot determine; NR — not reported; NA — not applicable. *The NIH Quality Assessment Tool for Systematic reviews and Meta-Analysis (https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools) contains 8 questions: 1 — Is the review based on a focused question?; 2 — Were eligibility criteria for included and excluded studies predefined and specified?; 3 — Did the literature search strategy use a comprehensive, systematic approach?; 4 — Were titles, abstracts and full-text articles dually and independently reviewed for inclusion and exclusion to minimize bias?; 5 — Was the quality of each included study rated independently by two or more reviewers using a standard method to appraise its internal validity?; 6 — Were the included studies listed along with important characteristics and results of each study?; 7 —Was publication bias assessed?; 8 — Was heterogeneity assessed?

 

Results

In this review, we identified a total of 4717 relevant sources. After an initial check, 805 duplicate articles were excluded, and the remaining 3912 articles were screened based on the relevancy of titles and abstracts through which 3561 resources were excluded. From the remaining 351 articles, 323 were excluded as they have not met the eligibility criteria. These excluded studies were non-English studies (n = 32), enduring studies (n = 53), systematic review protocols (n = 24), non-human studies (n = 85), studies unrelated to treatment and medicine (n = 113), and non-full-text studies (n = 16). Ultimately, 28 articles most relevant to the study objective were selected for the final review.

A total of 28 potential treatment regimens were identified for COVID-19 as shown in Table 2. The majority of included studies reported on the efficacy of Lopinavir/Ritonavir (n = 4), Ivermectin (n = 3), Baricitinib (n = 2), Tocilizumab (n = 2), Remdesivir (n = 2), ACEI/ARB (n = 2), Vitamin D (n = 2), Molnupiravir (n = 2), Traditional Chinese medicine (TCM) (n = 2), Convalescent plasma transfusion (CPT) (n = 2) and hydroxychloroquine (n = 2) in treating COVID-19.

Despite many studies on Lopinavir/Ritonavir, which have shown no specific adverse effects, current research still lacks strong evidence regarding its antiviral effects against COVID-19. Ivermectin shows potential effectiveness in mild-moderate COVID-19 patients. However, further studies are needed. One study indicated that in the absence of antiviral treatments, cautious administration of Ivermectin can be considered. Studies showed that Baricitinib (which is a type of JAK inhibitor) along with Sarilumab, served as a good alternative for COVID-19 treatment and it can lead to a reduction in mortality rate among hospitalized patients with moderate-severe COVID-19. It appeared that Molnupiravir, which is a prodrug for Hydroxycitidine, could reduce the hospitalization and mortality rates in high-risk COVID-19 patients. Some studies have demonstrated the potential of Chinese traditional and herbal medicine as an alternative for the prevention, treatment, and rehabilitation of COVID-19 patients. Furthermore, recent studies have indicated that certain drugs can be beneficial in specific subgroups of COVID-19 patients. For instance, ACE/ARB has shown potential effectiveness in reducing ICU admission and mortality rate among individuals with hypertension who were previously using ACE/ARB. Additionally, Convalescent Plasma Therapy (CPT) has demonstrated effectiveness in patients with hematological malignancies, while Remdesivir has shown positive outcomes in non-ventilated hospitalized patients. Nirmatrelvir/Ritonavir, sold under the name Paxlovid, a combination of the SARS-CoV-2 protease inhibitor nirmatrelvir, and ritonavir, a CYP3A4 inhibitor, is one of the best therapeutic choices for high-risk patients in reducing all-cause mortality and hospital admission. In people without prior or concomitant therapies low- to moderate-certainty evidence revealed that nirmatrelvir/ritonavir can be safe.

 

Рисунок. Блок-схема процесса поиска исследований в PRISMA 2020

Figure. PRISMA 2020 flow diagram of study retrieval process

 

Discussion

The main objective of this umbrella review was to evaluate and summarize the existing evidence on the potential treatments and therapeutic options for COVID-19 patients. The review provides a comprehensive overview of the current knowledge in this field. A total of 28 systematic reviews and meta-analyses were included in this review and encompassed a wide range of treatment modalities, including antiviral drugs, immunomodulators, JAK inhibitors, Convalescent plasma transfusion (CPT), Traditional Medicine and Supplementary medicine. The most frequently used therapies in selected studies were Lopinavir/Ritonavir (n = 4), Ivermectin (n = 3), Baricitinib (n = 2), Tocilizumab (n = 2), Remdesivir (n = 2), ACEI/ARB (n = 2), Vitamin D (n = 2), Molnupiravir (n = 2), Traditional Chinese Medicine (TCM) (n = 2), Convalescent plasma transfusion (CPT) (n = 2) and hydroxychloroquine (n = 2).

Lopinavir/Ritonavir is a combination of protease inhibitors that has been used to treat HIV infection and was also effective against SARS-CoV and MERS-CoV in vitro and in animal models [35]. Some previous studies reported that there is no significant difference between Lopinavir/Ritonavir and standard care in terms of mortality, viral clearance, or adverse events [37]. In our review, Lopinavir/Ritonavir did not show clear benefits in terms of hospitalization duration and time to negative PCR in mild diseases [27, 29, 32].

Ivermectin is an antiparasitic agent that inhibits the replication of viruses in vitro. The molecular hypothesis of Ivermectin’s antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the early stages of infection [36]. One of three studies that evaluated Ivermectin, indicated that it has potential effectiveness in treating mild to moderately ill patients. However, its role as an antiviral drug against COVID-19 in clinical setting is not clear yet as the other two studies were inconclusive [27, 36, 47].

Baricitinib is a Janus kinase (JAK1/JAK2) inhibitor developed to treat patients suffering from rheumatoid arthritis. JAK-STAT signaling is critical to multiple cellular processes, including survival, differentiation, and proliferation [45]. The conclusion of two studies that examined Baricitinib was in line, as they concluded Baricitinib is an alternative to Tocilizumab, which is a recombinant humanized anti-IL-6 receptor monoclonal antibody that has been approved for use in patients with rheumatologic disorders and chimeric antigen receptor T cell-induced cytokine release syndrome [46] for reducing mortality in COVID-19 patients admitted to the hospital and undergoing corticosteroid treatment. Systemic JAK inhibitors reduce all-cause mortality in hospitalized individuals with moderate-severe COVID-19 [1, 16].

Remdesivir is a nucleotide analog that inhibits viral RNA polymerase and has broad-spectrum antiviral activity against several RNA viruses, including SARS-CoV-2 [3]. Studies have shown that in non-ventilated hospitalized patients with COVID-19 who did not require ventilation, Remdesivir can decrease mortality. It is important to note that Remdesivir is associated with specific adverse effects, such as significant bradycardia, so rigorous attention is needed during the administration of this drug in COVID-19 patients [2, 27].

The ACEI/ARB drug class was analyzed in two studies included in this review. The findings of these studies were consistent. The first study examined the use of ACE/ARB among COVID-19 patients of East Asian descent and found no adverse outcomes. Additionally, ACEI/ARB use was associated with shorter hospitalization and reduced mortality rates. The beneficial effects of ACEI/ARB were more pronounced in individuals with hypertension, and the reduction in hospitalization was greater in females compared to males. In the second study, it was concluded that prior ACEI/ARB treatment was linked to lower hospital mortality, ICU admission, and the need for Intermittent Mandatory Ventilation (IMV) in COVID-19 patients [15, 20].

Two studies investigating the effects of vitamin D supplementation, with one study combining it with vitamin C, were included in this review. Vitamin D plays a role in modulating the innate immune response, while vitamin C possesses antioxidant, anti-inflammatory, antithrombotic, and immunomodulatory functions. Administration of vitamins C and D to COVID-19 patients did not demonstrate any influence on disease susceptibility, severity, or progression. Importantly, no adverse events were observed in the trials, indicating the safety of vitamin D supplements at the examined doses [11, 26].

Molnupiravir is an antiviral drug similar to Remdesivir, targeting the RNA-dependent RNA polymerase (RdRp) enzyme utilized by the coronavirus for transcription and replication of its viral RNA genome [44]. Two reviews encompassing a total of 7 randomized controlled trials (RCTs) provide evidence that Molnupiravir shows promise as a valuable agent, significantly reducing the risk of hospitalization or death in high-risk/mild COVID-19 patients. Additionally, it may benefit non-pregnant, unvaccinated adults with COVID-19 who face an elevated risk of severity and hospitalization. Another advantageous feature of Molnupiravir is its cost-effectiveness. The drug has demonstrated good tolerance and safety with no significant adverse events reported in short-term use at doses ranging from 50–800 mg BID or a single dose up to 1600 mg [23, 43, 44].

Traditional Chinese Medicine (TCM) is a holistic approach that uses herbal formulas, acupuncture, moxibustion, and other modalities to treat various diseases based on the principles of yin-yang balance, qi circulation, and organ function. TCM has been widely used in China to prevent and treat COVID-19 patients with different disease stages and syndromes. Two comprehensive reviews, comprising a total of 76 randomized controlled trials (RCTs) and 101 reviews, have reached a consensus that TCM shows promise as an alternative approach for treatment, rehabilitation, and prevention. Furthermore, when used alone or in conjunction with conventional medicine, TCM has demonstrated benefits in alleviating symptoms among patients with acute respiratory infections. Notably, one intervention that emerged as commonly utilized was Xuebijing (XBJ) injection [18, 21].

Convalescent plasma therapy (CPT) involves the use of plasma collected from individuals who have recovered from COVID-19. This plasma contains neutralizing antibodies against the SARS-CoV-2 virus. CPT has been utilized as a passive immunotherapy for COVID-19 patients, aiming to transfer immunity from donors to recipients [10]. One study has demonstrated that CPT can serve as an effective supportive therapy for COVID-19 patients with hematological malignancies. The findings indicate that CPT may lead to improved clinical outcomes, including higher survival rates, enhanced clearance of SARS-CoV-2, presence of anti-SARS-CoV-2 antibodies, shorter hospital discharge time, and better recovery after one month of CPT. Importantly, the treatment did not show any association with adverse events [31, 42]. Data on the effectiveness of Hydroxychloroquine as an antimalarial used for treating COVID-19 patients were inconclusive [27, 31]. While there has been an umbrella study on the effects of Hydroxychloroquine and chloroquine therapy in COVID-19 [5], no umbrella review has compared different classes of therapeutic options.

In addition to the above-mentioned treatments, this umbrella review discussed other therapeutic options for COVID-19 patients. These include Thymosin alpha1 (Ta1), anticoagulants, other antivirals (such as Nirmatrelvir, Saquinavir, Favipiravir), Ultra-violet radiation therapy, Colchicine, Arbidol, N-acetyl cysteine (NAC), Ayurvedic medicines, JAK inhibitors (such as Tofacitinib, Ruxolitinib, Sarilumab), SSRI (Fluvoxamine), Clozapine, Quercetin and Anakinra (immunomodulator). Among these treatment options, Ayurvedic medicines, JAK inhibitors (such as Tofacitinib, Ruxolitinib, Sarilumab), SSRI (Fluvoxamine), colchicine, and Quercetin have shown to be beneficial in treating COVID-19 [6, 9, 16, 22, 39]. On the other hand, NAC, anticoagulants, Clozapine, and Anakinra were non-beneficial [8, 12, 17, 33]. In the case of Thymosin alpha1 (Ta1), the findings suggest that Ta1 therapy does not have a statistically significant impact on mortality. However, subgroup analyses indicated a beneficial effect on mortality in patients over 60 years of age, with a proportion of females less than 40%, and with severe COVID-19 [41].

The main limitations of this systematic review are the heterogeneity of the included studies in terms of design, population, intervention, comparator, outcome, and quality; the lack of meta-analysis due to the scarcity and diversity of data; and the possibility of publication bias due to the rapid emergence and dissemination of COVID-19 literature. Therefore, the results of this review should be interpreted with caution and updated regularly. Despite the extensive research conducted on treatments for COVID-19, there are still gaps and areas of uncertainty in the existing evidence. For example, there is limited evidence on the effectiveness of certain antiviral drugs or immunomodulatory therapies. Additionally, the long-term effects of these treatments and their impact on specific patient populations, such as pregnant women or individuals with comorbidities, require further investigation. Therefore, more high-quality RCTs are needed to evaluate the efficacy and safety of these treatments and to identify the optimal dose, duration, timing, and combination of interventions for different subgroups of COVID-19 patients.

Conclusion

In conclusion, this umbrella review offers a comprehensive overview of the current evidence on the effectiveness and safety of various pharmacological and non-pharmacological interventions for COVID-19. Based on the included studies, we found that some interventions, such as Baricitinib, Remdesivir, ACEI/ARB, TCM, and CPT may have beneficial effects on reducing mortality, hospitalization duration, and disease severity in COVID-19 patients. However, the results should be interpreted with caution due to the heterogeneity and potential bias of the studies. Other interventions, such as Lopinavir/Ritonavir, Ivermectin, Vitamin D, and Hydroxychloroquine did not demonstrate clear benefits or provided inconclusive results. Therefore, additional high-quality randomized controlled trials are needed to confirm the efficacy and safety of these interventions, while also investigating optimal dosage, duration, and timing. Furthermore, future research should also consider the potential interactions, adverse events, and cost-effectiveness of the interventions, as well as the individual characteristics and preferences of the patients. The results of this study can be useful for clinicians and physicians who need evidence to choose the best treatment in a critical situation such as COVID-19.

Additional information

Ethics approval and consent to participate. Not applicable.

Consent to publication. Not applicable.

Availability of data and material. The authors stated that all information provided in this article could be shared.

Supplementary materials are available at: http://dx.doi.org/10.15789/2220-7619-AUR-15080.

Competing interests. The authors declare that there is no conflict of interest regarding the publication of this manuscript.

Funding. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors’ contributions:

The conception and design of the study: E. Mehraeen, S. SeyedAlinaghi.

Acquisition of data: R. Shahidi, A. Molla, A.M. Afsahi.

Analysis and interpretation of data: A.M. Afsahi.

Drafting the article: E. Mehraeen, P. Mirzapour, H. Siami, F.F. Rad, F. Abbaspour, N. Mozafari, K. Fakhredini.

Revising it critically for important intellectual content: S. SeyedAlinaghi, E. Mehraeen and O. Dadras.

Final approval of the version to be submitted: S. SeyedAlinaghi, E. Mehraeen.

Acknowledgments. The present study was conducted in collaboration with Khalkhal University of Medical Sciences, Iranian Research Center for HIV/AIDS, Tehran University of Medical Sciences.

×

About the authors

SeyedAhmad SeyedAlinaghi

Iranian Research Center for HIV/AIDS (IRCHA), Tehran University of Medical Sciences

Email: s_a_alinaghi@yahoo.com

MD, MPhil, PhD, Clinical Epidemiologist, Associate Professor, Research Deputy 

Иран, Tehran

Amir M. Afsahi

University of California

Email: amir.masoud.afsahi@gmail.com

MD, PhD, Department of Radiology, School of Medicine

США, San Diego

Ayoob Molla

Bushehr University of Medical Sciences

Email: Ayoob.dpt87@gmail.com

MD Student, School of Medicine

Иран, Bushehr

Pegah Mirzapour

Iranian Research Center for HIV/AIDS (IRCHA), Tehran University of Medical Sciences

Email: pegah.mirzapour@yahoo.com

Iranian Research Center for HIV/AIDS (IRCHA)

Иран, Tehran

Ramin Shahidi

Bushehr University of Medical Sciences

Email: dr.raminshahidi1@gmail.com

MD, School of Medicine

Иран, Bushehr

Haleh Siami

Islamic Azad University

Email: Haleh.siami@gmail.com

MD student, School of Medicine

Иран, Tehran

Farid F. Rad

Tehran University of Medical Sciences

Email: farid.f.rad@gmail.com

MD student, School of Medicine

Иран, Tehran

Faeze Abbaspour

Tehran University of Medical Sciences

Email: absprfaeze@gmail.com

School of Medicine

Иран, Tehran

Navid Mozafari

Bushehr University of Medical Sciences

Email: navidmozaffari97@gmail.com

School of Medicine

Иран, Bushehr

Kamal Fakhredini

Behavioral Diseases Research Center, Health Institute, Kermanshah University of Medical Sciences

Email: fakhredini1@gmail.com

PhD, MD student

Иран, Kermanshah

Esmaeil Mehraeen

Khalkhal University of Medical Sciences

Author for correspondence.
Email: es.mehraeen@gmail.com

PhD, Assistant Professor, Department of Health Information Technology

Иран, Khalkhal

Omid Dadras

University of Bergen

Email: omiddadras@yahoo.com

MD, Dr.PH, Bergen Addiction Research, Department of Addiction Medicine

Норвегия, Bergen

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