Quercetin reduces COVID-19 risk: real-time meta analysis of 12 studies
Control
Abstract
Significantly lower risk is seen for ICU admission, hospitalization, recovery, cases, and viral clearance. 11 studies from 9 independent teams in 7 countries show significant
benefit.
Meta analysis using the most serious outcome reported shows
46% [20‑64%] lower risk. Results are similar for Randomized Controlled Trials, higher quality studies, and after excluding studies using combined treatment and slightly worse for peer-reviewed studies.
Results are very robust — in exclusion sensitivity analysis 9 of
12 studies must be excluded to avoid finding statistically significant
efficacy in pooled analysis.
Studies typically use advanced formulations for greatly improved bioavailability.
No treatment is 100%
effective. Protocols combine safe and effective options with individual
risk/benefit analysis and monitoring.
Dietary sources may be preferred. The quality of non-prescription supplements varies widely1-3.
All data and sources to reproduce this analysis are in the appendix.
Quercetin for COVID-19 — Highlights
Quercetin reduces risk with very high confidence for ICU admission, recovery, cases, viral clearance, and in pooled analysis, high confidence for hospitalization, and very low confidence for mortality and ventilation.
Studies typically use advanced formulations for greatly improved bioavailability.
26th treatment shown effective in July 2021, now with p = 0.002 from 12 studies.
Real-time updates and corrections with a consistent protocol for 169 treatments. Outcome specific analysis and combined evidence from all studies including treatment delay, a primary confounding factor.
Figure 1.
A. Random effects
meta-analysis. This plot shows pooled effects,
see the specific outcome analyses for individual outcomes.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Effect extraction is pre-specified, using the most serious outcome reported.
For details see the appendix.
B. Timeline of results in quercetin studies. The marked dates indicate the time when efficacy was known with a statistically significant improvement of ≥10% from ≥3 studies for pooled outcomes, one or more specific outcome, pooled outcomes in RCTs, and one or more specific outcome in RCTs. Efficacy based on RCTs only was delayed by 6.0 months, compared to using all studies. Efficacy based on specific outcomes was delayed by 6.0 months, compared to using pooled outcomes. Efficacy based on specific outcomes in RCTs was delayed by 17.5 months, compared to using pooled outcomes in RCTs.
SARS-CoV-2 infection primarily begins in the upper respiratory
tract and may progress to the lower respiratory tract, other tissues, and the
nervous and cardiovascular systems, which may lead to cytokine storm,
pneumonia, ARDS, neurological injury6-18 and
cognitive deficits9,14, cardiovascular
complications19-23, organ failure, and death.
Minimizing replication as early as possible is recommended.
SARS-CoV-2 infection and replication involves the complex interplay of 100+
host and viral proteins and other factorsA,24-31, providing many
therapeutic targets for which many existing compounds have known activity.
Scientists have predicted that over 9,000 compounds may
reduce COVID-19 risk32, either by
directly minimizing infection or replication, by supporting immune system
function, or by minimizing secondary complications.
In Silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spikeB,33-46, MproC,36-39,41,42,45-61, RNA-dependent RNA polymeraseD,42,45,46,62,63 , PLproE,45,49,55, ACE2F,35,41,43,49,50,64 , TMPRSS2G,35, nucleocapsidH,45, helicaseI,45,48,65, endoribonucleaseJ,33, NSP16/10K,66, cathepsin LL,67, Wnt-3M,35, FZDN,35, LRP6O,35, ezrinP,68, ADRPQ,39, NRP1R,43, EP300S,69, PTGS2T,50, HSP90AA1U,50,69, matrix metalloproteinase 9V,70, IL-6W,71,72, IL-10X,71, VEGFAY,72, and RELAZ,72 proteins, and inhibition of spike-ACE2 interactionAA,73.
In Vitro studies demonstrate inhibition of the MproC,57,74-76 protein, and inhibition of spike-ACE2 interactionAA,77.
In Vitro studies demonstrate efficacy in Calu-3AB,78, A549AC,71, HEK293-ACE2+AD,79, Huh-7AE,40, Caco-2AF,80, Vero E6AG,36,80,81, mTECAH,82, RAW264.7AI,82, and HLMECAJ,73 cells.
Animal studies demonstrate efficacy in K18-hACE2 miceAK,83, db/db miceAL,82,84, BALB/c miceAM,85, and rats81.
Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice85, inhibits LPS-induced cytokine storm by modulating key inflammatory and antioxidant pathways in macrophages86, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity87.
We analyze all significant
controlled studies of
quercetin
for COVID-19.
Search methods, inclusion criteria, effect extraction criteria (more serious
outcomes have priority), all individual study data, PRISMA answers, and
statistical methods are detailed in Appendix 1. We present random
effects meta-analysis results for all studies, studies within each treatment stage, individual outcomes, peer-reviewed studies, Randomized Controlled Trials (RCTs), and higher quality studies.
Figure 2 shows stages of possible treatment for
COVID-19. Prophylaxis refers to regularly taking medication before
becoming sick, in order to prevent or minimize infection. Early
Treatment refers to treatment immediately or soon after symptoms appear,
while Late Treatment refers to more delayed treatment.
Figure 2. Treatment stages.
In Silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spikeB,33-46, MproC,36-39,41,42,45-61, RNA-dependent RNA polymeraseD,42,45,46,62,63 , PLproE,45,49,55, ACE2F,35,41,43,49,50,64 , TMPRSS2G,35, nucleocapsidH,45, helicaseI,45,48,65, endoribonucleaseJ,33, NSP16/10K,66, cathepsin LL,67, Wnt-3M,35, FZDN,35, LRP6O,35, ezrinP,68, ADRPQ,39, NRP1R,43, EP300S,69, PTGS2T,50, HSP90AA1U,50,69, matrix metalloproteinase 9V,70, IL-6W,71,72, IL-10X,71, VEGFAY,72, and RELAZ,72 proteins, and inhibition of spike-ACE2 interactionAA,73.
In Vitro studies demonstrate inhibition of the MproC,57,74-76 protein, and inhibition of spike-ACE2 interactionAA,77.
In Vitro studies demonstrate efficacy in Calu-3AB,78, A549AC,71, HEK293-ACE2+AD,79, Huh-7AE,40, Caco-2AF,80, Vero E6AG,36,80,81, mTECAH,82, RAW264.7AI,82, and HLMECAJ,73 cells.
Animal studies demonstrate efficacy in K18-hACE2 miceAK,83, db/db miceAL,82,84, BALB/c miceAM,85, and rats81.
Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice85, inhibits LPS-induced cytokine storm by modulating key inflammatory and antioxidant pathways in macrophages86, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity87.
Preclinical research is an important part of the development of
treatments, however results may be very different in clinical trials.
Preclinical results are not used in this paper.
SARS-CoV-2 infection and replication involves multiple steps as
shown in Table 1. Each step can be disrupted by therapeutics. The
timing of each step may vary significantly, and the cycle is continuous, with
released virions attaching to new host cells.
The efficacy of treatments depends on the delay from infection and the steps
targeted. Preclinical research suggests that quercetin is most likely to interfere with early steps in the viral lifecycle, suggesting greater benefit for prophylaxis and very early treatment.
| Step | Details | Approximate timing | Predicted benefit of quercetin |
|---|---|---|---|
| Viral attachment | Viral binding to specific receptors on host cell surface | Initial step | High: spike and ACE2 binding |
| Viral entry | Uptake of viral particle into host cell via mechanisms like endocytosis or membrane fusion | Within minutes to 1 hour | Moderate: spike binding |
| Viral uncoating and release | Disassembly of virion to release viral genome into host cell | 1-2 hours | - |
| Genome replication and transcription | Production of viral mRNAs from the genome template and genome copies | 2-4 hours | Moderate: RdRp binding |
| Translation and protein processing | Production of new viral proteins from the viral transcripts | 4-8 hours | Moderate: Mpro and PLpro binding |
| Viral assembly and budding | Self-assembly of viral components and encapsidation of viral genome to form new viral particles, often utilizing host cell membrane | 8-12 hours | - |
| Viral release | Escape of newly formed virions from the host cell to spread infection | 12-24 hours | - |
Table 2 summarizes the results for all stages combined, for Randomized Controlled Trials, for peer-reviewed studies, with different exclusions, and for specific outcomes.
Table 3 shows results by treatment stage.
Figure 3 plots individual results by treatment stage.
Figure 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13
show forest plots for random effects meta-analysis of
all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, recovery, cases, viral clearance, peer reviewed studies, and all studies excluding combined treatment studies.
| Improvement | Studies | Patients | Authors | |
|---|---|---|---|---|
| All studies | 46% [20‑64%] ** | 12 | 1,496 | 116 |
| After exclusions | 38% [14‑56%] ** | 10 | 1,283 | 96 |
| Peer-reviewed studiesPeer-reviewed | 36% [16‑52%] ** | 11 | 1,383 | 109 |
| Excluding combined treatmentExc. combined | 55% [12‑77%] * | 6 | 692 | 73 |
| Randomized Controlled TrialsRCTs | 40% [17‑57%] ** | 11 | 1,383 | 111 |
| Mortality | 61% [-35‑89%] | 5 | 790 | 58 |
| ICU admissionICU | 74% [29‑90%] ** | 5 | 790 | 58 |
| HospitalizationHosp. | 36% [5‑56%] * | 4 | 361 | 47 |
| Recovery | 35% [21‑45%] **** | 8 | 998 | 73 |
| Cases | 93% [73‑98%] **** | 3 | 346 | 24 |
| Viral | 56% [38‑68%] **** | 3 | 200 | 26 |
| RCT mortality | 61% [-35‑89%] | 5 | 790 | 58 |
| RCT hospitalizationRCT hosp. | 36% [5‑56%] * | 4 | 361 | 47 |
| Early treatment | Late treatment | Prophylaxis | |
|---|---|---|---|
| All studies | 32% [7‑50%] * | 35% [-21‑65%] | 93% [73‑98%] **** |
| After exclusions | 31% [7‑49%] * | 35% [-21‑65%] | 94% [64‑99%] ** |
| Peer-reviewed studiesPeer-reviewed | 32% [7‑50%] * | 35% [-21‑65%] | 94% [64‑99%] ** |
| Excluding combined treatmentExc. combined | 79% [-83‑98%] | 38% [-22‑68%] | 93% [9‑99%] * |
| Randomized Controlled TrialsRCTs | 32% [7‑50%] * | 35% [-21‑65%] | 92% [66‑98%] *** |
| Mortality | 79% [-83‑98%] | 47% [-138‑88%] | |
| ICU admissionICU | 87% [-5‑98%] | 75% [-10‑94%] | |
| HospitalizationHosp. | 68% [31‑85%] ** | 23% [-3‑43%] | |
| Recovery | 33% [16‑47%] *** | 37% [14‑54%] ** | |
| Cases | 93% [73‑98%] **** |
||
| Viral | 56% [38‑68%] **** | ||
| RCT mortality | 79% [-83‑98%] | 47% [-138‑88%] | |
| RCT hospitalizationRCT hosp. | 68% [31‑85%] ** | 23% [-3‑43%] |
Figure 3. Scatter plot showing the most serious outcome in all studies, and for studies within each stage. Diamonds shows the results of random effects meta-analysis.
Figure 4. Random effects meta-analysis for all studies.
This plot shows pooled effects,
see the specific outcome analyses for individual outcomes.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Effect extraction is pre-specified, using the most serious outcome reported.
For details see the appendix.
Figure 5. Random effects meta-analysis for mortality results.
Figure 6. Random effects meta-analysis for ventilation.
Figure 7. Random effects meta-analysis for ICU admission.
Figure 8. Random effects meta-analysis for hospitalization.
Figure 9. Random effects meta-analysis for recovery.
Figure 10. Random effects meta-analysis for cases.
Figure 11. Random effects meta-analysis for viral clearance.
Figure 12. Random effects meta-analysis for peer reviewed studies.
Effect extraction is pre-specified, using the most serious outcome reported,
see the appendix for details.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Zeraatkar et al. analyze 356 COVID-19 trials, finding no significant
evidence that preprint results are inconsistent with peer-reviewed studies.
They also show extremely long peer-review delays, with a median of 6 months to
journal publication. A six month delay was equivalent to around 1.5 million
deaths during the first two years of the pandemic. Authors recommend using
preprint evidence, with appropriate checks for potential falsified data, which
provides higher certainty much earlier. Davidson et al. also showed no
important difference between meta analysis results of preprints and
peer-reviewed publications for COVID-19, based on 37 meta analyses including
114 trials.
Figure 13. Random effects meta-analysis for all studies excluding combined treatment studies.
Effect extraction is pre-specified, using the most serious outcome reported,
see the appendix for details.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Figure 14 shows a comparison of results for RCTs and non-RCT studies.
Figure 15, 16, and 17
show forest plots for random effects meta-analysis of
all Randomized Controlled Trials, RCT mortality results, and RCT hospitalization results.
RCT results are included in Table 2 and Table 3.
Figure 14. Results for RCTs and non-RCT studies.
Figure 15. Random effects meta-analysis for all Randomized Controlled Trials.
This plot shows pooled effects,
see the specific outcome analyses for individual outcomes.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Effect extraction is pre-specified, using the most serious outcome reported.
For details see the appendix.
Figure 16. Random effects meta-analysis for RCT mortality results.
Figure 17. Random effects meta-analysis for RCT hospitalization results.
RCTs help to make study groups more similar and can provide a higher level of
evidence, however they are subject to many biases102, and
analysis of double-blind RCTs has identified extreme levels of bias103.
For COVID-19, the overhead may delay treatment, dramatically compromising
efficacy; they may encourage monotherapy for simplicity at the cost of
efficacy which may rely on combined or synergistic effects; the participants
that sign up may not reflect real world usage or the population that benefits
most in terms of age, comorbidities, severity of illness, or other factors;
standard of care may be compromised and unable to evolve quickly based on
emerging research for new diseases; errors may be made in randomization and
medication delivery; and investigators may have hidden agendas or vested
interests influencing design, operation, analysis, reporting, and the
potential for fraud. All of these biases have been observed with COVID-19
RCTs. There is no guarantee that a specific RCT provides a higher level of
evidence.
RCTs are expensive and many RCTs are funded
by pharmaceutical companies or interests closely aligned with pharmaceutical
companies. For COVID-19, this creates an incentive to show efficacy for
patented commercial products, and an incentive to show a lack of efficacy for
inexpensive treatments. The bias is expected to be significant, for example
Als-Nielsen et al. analyzed 370 RCTs from Cochrane reviews, showing that
trials funded by for-profit organizations were 5 times more likely to
recommend the experimental drug compared with those funded by nonprofit
organizations. For COVID-19, some major philanthropic organizations are
largely funded by investments with extreme conflicts of interest for and
against specific COVID-19 interventions.
High quality RCTs for novel acute diseases are more challenging, with
increased ethical issues due to the urgency of treatment, increased risk due
to enrollment delays, and more difficult design with a rapidly evolving
evidence base. For COVID-19, the most common site of initial infection is the
upper respiratory tract. Immediate treatment is likely to be most successful
and may prevent or slow progression to other parts of the body. For a
non-prophylaxis RCT, it makes sense to provide treatment in advance and
instruct patients to use it immediately on symptoms, just as some governments
have done by providing medication kits in advance. Unfortunately, no RCTs have
been done in this way. Every treatment RCT to date involves delayed treatment.
Among the 169 treatments we have analyzed,
67% of RCTs involve very late treatment 5+ days after
onset. No non-prophylaxis COVID-19 RCTs match the potential real-world use of
early treatments. They may more accurately represent results for treatments
that require visiting a medical facility, e.g., those requiring intravenous
administration.
RCTs have a bias against finding an effect for interventions
that are widely available — patients that believe they need the
intervention are more likely to decline participation and take the
intervention. RCTs for quercetin are more likely to enroll low-risk
participants that do not need treatment to recover, making the results less
applicable to clinical practice. This bias is likely to be greater for widely
known treatments, and may be greater when the risk of a serious outcome is
overstated. This bias does not apply to the typical pharmaceutical trial of a
new drug that is otherwise unavailable.
Figure 18.
For COVID-19, observational study results do not systematically
differ from RCTs, RR 0.99 [0.93‑1.06]
across 169 treatments105.
Evidence shows that observational studies
can also provide reliable results. Concato et al. found that well-designed
observational studies do not systematically overestimate the magnitude of the
effects of treatment compared to RCTs. Anglemyer et al. analyzed reviews
comparing RCTs to observational studies and found little evidence for
significant differences in effect estimates.
We performed a similar analysis across the 169 treatments
we cover, showing no significant difference in the results of RCTs compared to
observational studies, RR 0.99 [0.93‑1.06]108. Similar results are found for all low-cost treatments, RR
1.01 [0.92‑1.11]. High-cost treatments
show a non-significant trend towards RCTs showing greater efficacy,
RR 0.92 [0.83‑1.03].
Details can be found in the
supplementary data.
Lee et al. showed that only 14% of the guidelines of the Infectious
Diseases Society of America were based on RCTs. Evaluation of studies relies
on an understanding of the study and potential biases. Limitations in an RCT
can outweigh the benefits, for example excessive dosages, excessive treatment
delays, or remote survey bias may have a greater effect on results. Ethical
issues may also prevent running RCTs for known effective treatments. For more
on issues with RCTs see110,111.
Currently, 53 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. Of these, 58% have been confirmed in RCTs, with a mean delay of 7.8 months (66% with 8.9 months delay for low-cost treatments). The remaining treatments either have no RCTs, or the point estimate is consistent.
We need to evaluate each trial on its own merits. RCTs for a
given medication and disease may be more reliable, however they may also be
less reliable. For off-patent medications, very high conflict of interest
trials may be more likely to be RCTs, and more likely to be large trials that
dominate meta analyses.
To avoid bias in the selection of studies, we analyze all
non-retracted studies. Here we show the results after excluding
studies with major issues likely to alter results, non-standard studies, and
studies where very minimal detail is currently available. Our bias evaluation
is based on analysis of each study and identifying when there is a significant
chance that limitations will substantially change the outcome of the study. We
believe this can be more valuable than checklist-based approaches such as
Cochrane GRADE, which can be easily influenced by potential bias, may ignore
or underemphasize serious issues not captured in the checklists, and may
overemphasize issues unlikely to alter outcomes in specific cases (for example
certain specifics of randomization with a very large effect size and
well-matched baseline characteristics).
The studies excluded are as below.
Figure 19 shows a forest plot for random
effects meta-analysis of all studies after exclusions.
Arslan, paper no longer available at the source, and the contact does not reply to queries.
Di Pierro, randomization resulted in significant baseline differences that were not adjusted for.
Figure 19. Random effects meta-analysis for all studies after exclusions.
This plot shows pooled effects,
see the specific outcome analyses for individual outcomes.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Effect extraction is pre-specified, using the most serious outcome reported.
For details see the appendix.
Heterogeneity in COVID-19 studies arises from many factors including:
The time between infection or the onset of symptoms and
treatment may critically affect how well a treatment works. For example an
antiviral may be very effective when used early but may not be effective in
late stage disease, and may even be harmful. Oseltamivir, for example, is
generally only considered effective for influenza when used within 0-36 or
0-48 hours114,115. Baloxavir marboxil studies for influenza
also show that treatment delay is critical — Ikematsu et al. report
an 86% reduction in cases for post-exposure prophylaxis, Hayden et al.
show a 33 hour reduction in the time to alleviation of symptoms for treatment
within 24 hours and a reduction of 13 hours for treatment within 24-48 hours,
and Kumar et al. report only 2.5 hours improvement for inpatient
treatment.
| Treatment delay | Result |
| Post-exposure prophylaxis | 86% fewer cases116 |
| <24 hours | -33 hours symptoms117 |
| 24-48 hours | -13 hours symptoms117 |
| Inpatients | -2.5 hours to improvement118 |
Figure 20 shows a mixed-effects meta-regression for efficacy
as a function of treatment delay in COVID-19 studies from 169 treatments, showing
that efficacy declines rapidly with treatment delay. Early treatment is
critical for COVID-19.
Figure 20. Early treatment is more effective. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 169 treatments.
Details of the patient population including age and comorbidities may
critically affect how well a treatment works. For example, many COVID-19
studies with relatively young low-comorbidity patients show all patients
recovering quickly with or without treatment. In such cases, there is little
room for an effective treatment to improve results, for example as in
López-Medina et al.
Efficacy may depend critically on the distribution of
SARS-CoV-2 variants encountered by patients. Risk varies significantly across
variants120, for example the Gamma variant shows significantly
different characteristics121-124. Different
mechanisms of action may be more or less effective depending on variants, for
example the degree to which TMPRSS2 contributes to viral entry can differ
across variants125,126.
Effectiveness may depend strongly on the dosage and treatment regimen.
The quality of medications may vary significantly between
manufacturers and production batches, which may significantly affect efficacy
and safety. Williams et al. analyze ivermectin from 11 different sources,
showing highly variable antiparasitic efficacy across different manufacturers.
Xu (C) et al. analyze a treatment from two different manufacturers, showing 9
different impurities, with significantly different concentrations for each
manufacturer.
Non-prescription supplements may show very wide variations in quality1,2.
Across all
studies there is a strong association between different outcomes, for example
improved recovery is strongly associated with lower mortality. However,
efficacy may differ depending on the effect measured, for example a treatment
may be more effective against secondary complications and have minimal effect
on viral clearance.
The
distribution of studies will alter the outcome of a meta analysis. Consider a
simplified example where everything is equal except for the treatment delay,
and effectiveness decreases to zero or below with increasing delay. If there
are many studies using very late treatment, the outcome may be negative, even
though early treatment is very effective.
All meta analyses combine heterogeneous studies, varying in population,
variants, and potentially all factors above, and therefore may obscure
efficacy by including studies where treatment is less effective. Generally, we
expect the estimated effect size from meta analysis to be less than that for
the optimal case.
Looking at all studies is valuable for providing an overview of all research,
important to avoid cherry-picking, and informative when a positive result is
found despite combining less-optimal situations. However, the resulting
estimate does not apply to specific cases such as
early treatment in high-risk populations.
While we present results for all studies, we also present treatment time and
individual outcome analyses, which may be more informative for specific use
cases.
This section validates the use of pooled effects for COVID-19, which enables
earlier detection of efficacy, however pooled effects are no longer required
for quercetin as of January 2022. Efficacy is now known based on specific outcomes for all studies and when restricted to RCTs. Efficacy based on specific outcomes was delayed by 6.0 months compared to using pooled outcomes. Efficacy based on specific outcomes in RCTs was delayed by 17.5 months compared to using pooled outcomes in RCTs.
For COVID-19, delay in clinical results translates into
additional death and morbidity, as well as additional economic and societal
damage. Combining the results of studies reporting different outcomes is
required.
There may be no mortality in a trial with low-risk patients,
however a reduction in severity or improved viral clearance may translate
into lower mortality in a high-risk population.
Different studies may report lower severity, improved recovery, and lower mortality,
and the significance may be very high when combining the results.
"The studies reported different outcomes" is not a good reason for
disregarding results.
Pooling the results of studies reporting different outcomes allows us to use
more of the available information. Logically we should, and do, use additional
information when evaluating treatments—for example dose-response and
treatment delay-response relationships provide additional evidence of efficacy
that is considered when reviewing the evidence for a treatment.
We present both specific outcome and pooled analyses.
In order to combine the results of studies reporting different outcomes we use
the most serious outcome reported in each study, based on the thesis that
improvement in the most serious outcome provides comparable measures of
efficacy for a treatment. A critical advantage of this approach is
simplicity and transparency.
There are many other ways to combine evidence for different outcomes, along
with additional evidence such as dose-response relationships, however these
increase complexity.
Trials with high-risk patients may be restricted due to ethics for treatments
that are known or expected to be effective, and they increase difficulty for
recruiting. Using less severe outcomes as a proxy for more serious outcomes
allows faster and safer collection of evidence.
For many COVID-19 treatments, a reduction in mortality logically
follows from a reduction in hospitalization, which follows from a reduction in
symptomatic cases, which follows from a reduction in PCR positivity. We can
directly test this for COVID-19.
Analysis of the the association between different outcomes across studies from
all 169
treatments we cover confirms the validity of pooled outcome analysis for COVID-19.
Figure 21 shows that lower hospitalization is very strongly associated
with lower mortality (p < 0.000000000001).
Similarly, Figure 22 shows that improved recovery is very strongly associated
with lower mortality (p < 0.000000000001).
Considering the extremes, Singh (D) et al. show an association between viral clearance and
hospitalization or death, with p = 0.003 after excluding one large
outlier from a mutagenic treatment, and based on 44 RCTs including 52,384
patients.
Figure 23 shows that improved viral clearance is strongly associated
with fewer serious outcomes. The association is very similar to
Singh (D) et al., with higher confidence due to the larger number of
studies. As with Singh (D) et al., the confidence increases
when excluding the outlier treatment, from p = 0.00000011 to p = 0.0000000048.
Figure 21. Lower hospitalization is associated with lower mortality, supporting pooled outcome analysis.
Figure 22. Improved recovery is associated with lower mortality, supporting pooled outcome analysis.
Figure 21. Improved viral clearance is associated with fewer serious outcomes, supporting pooled outcome analysis.
Currently, 53 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. 90% of these have been confirmed with one or more specific outcomes, with a mean delay of 4.9 months. When restricting to RCTs only, 55% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 7.3 months.
Figure 24 shows when treatments were found effective during the
pandemic. Pooled outcomes often resulted in earlier detection of efficacy.
Figure 24. The time when studies showed that
treatments were effective, defined as statistically significant improvement of
≥10% from ≥3 studies.
Pooled results typically show efficacy earlier than specific
outcome results. Results from all studies often shows efficacy much earlier
than when restricting to RCTs.
Results reflect conditions as used in trials to date, these depend on the
population treated, treatment delay, and treatment regimen.
Pooled analysis could hide efficacy, for example a treatment that is
beneficial for late stage patients but has no effect on viral clearance may
show no efficacy if most studies only examine viral clearance. In practice, it
is rare for a non-antiviral treatment to report viral clearance and to not
report clinical outcomes; and in practice other sources of heterogeneity such
as difference in treatment delay is more likely to hide efficacy.
Analysis validates the use of pooled effects and shows significantly faster
detection of efficacy on average.
However, as with all meta analyses, it is important to review the different
studies included. We also present individual outcome analyses, which may be
more informative for specific use cases.
Publishing is often biased
towards positive results, however evidence suggests that there may be a negative bias for
inexpensive treatments for COVID-19. Both negative and positive results are
very important for COVID-19, media in many countries prioritizes negative
results for inexpensive treatments (inverting the typical incentive for
scientists that value media recognition), and there are many reports of
difficulty publishing positive results147-150.
For quercetin, there is currently not
enough data to evaluate publication bias with high confidence.
One method to evaluate bias is to compare prospective vs.
retrospective studies. Prospective studies are more likely to be published
regardless of the result, while retrospective studies are more likely to
exhibit bias. For example, researchers may perform preliminary analysis with
minimal effort and the results may influence their decision to continue.
Retrospective studies also provide more opportunities for the specifics of
data extraction and adjustments to influence results.
Figure 25 shows a scatter plot of
results for prospective and retrospective studies.
100% of retrospective studies
report a statistically significant positive effect for
one or more outcomes, compared to
91% of prospective studies, consistent with a bias toward publishing positive results.
The median effect size for
retrospective studies is 94% improvement,
compared to 67% for prospective
studies, suggesting a potential bias towards publishing results showing higher efficacy.
Figure 25. Prospective vs. retrospective studies.
The diamonds show the results of random effects meta-analysis.
Funnel
plots have traditionally been used for analyzing publication bias. This is
invalid for COVID-19 acute treatment trials — the underlying assumptions
are invalid, which we can demonstrate with a simple example. Consider a set of
hypothetical perfect trials with no bias. Figure 26 plot A
shows a funnel plot for a simulation of 80 perfect trials, with random group
sizes, and each patient's outcome randomly sampled (10% control event
probability, and a 30% effect size for treatment). Analysis shows no asymmetry
(p > 0.05). In plot B, we add a single typical variation in COVID-19 treatment
trials — treatment delay. Consider that efficacy varies from 90% for
treatment within 24 hours, reducing to 10% when treatment is delayed 3 days.
In plot B, each trial's treatment delay is randomly selected. Analysis now
shows highly significant asymmetry, p < 0.0001, with six variants of
Egger's test all showing p < 0.05151-158.
Note that these tests fail even though treatment delay is uniformly
distributed. In reality treatment delay is more complex — each trial has
a different distribution of delays across patients, and the distribution
across trials may be biased (e.g., late treatment trials may be more common).
Similarly, many other variations in trials may produce asymmetry, including
dose, administration, duration of treatment, differences in SOC,
comorbidities, age, variants, and bias in design, implementation, analysis,
and reporting.
Figure 26. Example funnel plot analysis for simulated perfect trials.
Pharmaceutical drug
trials often have conflicts of interest whereby sponsors or trial staff have a
financial interest in the outcome being positive. Quercetin for COVID-19
lacks this because it is an inexpensive and widely available supplement.
In contrast, most COVID-19 quercetin trials have been run by
physicians on the front lines with the primary goal of finding the best
methods to save human lives and minimize the collateral damage caused by
COVID-19. While pharmaceutical companies are careful to run trials under
optimal conditions (for example, restricting patients to those most likely to
benefit, only including patients that can be treated soon after onset when
necessary, and ensuring accurate dosing), not all quercetin trials
represent the optimal conditions for efficacy.
Summary statistics from
meta analysis necessarily lose information. As with all meta analyses, studies
are heterogeneous, with differences
in treatment delay, treatment regimen, patient demographics, variants,
conflicts of interest, standard of care, and other factors. We provide analyses for specific
outcomes and by treatment delay, and we aim to identify key characteristics in
the forest plots and summaries. Results should be viewed in the context of
study characteristics.
Some analyses classify treatment based on early or late
administration, as done here, while others distinguish between mild, moderate,
and severe cases. Viral load does not indicate degree of symptoms — for
example patients may have a high viral load while being asymptomatic. With
regard to treatments that have antiviral properties, timing of treatment is
critical — late administration may be less helpful regardless of
severity.
Details of treatment delay per patient is often not available.
For example, a study may treat 90% of patients relatively early, but the
events driving the outcome may come from 10% of patients treated very late.
Our 5 day cutoff for early treatment may be too conservative, 5 days may be too late in many cases.
Comparison across treatments is confounded by differences in
the studies performed, for example dose, variants, and conflicts of interest.
Trials with conflicts of interest may use designs better suited to the
preferred outcome.
In some cases, the most serious outcome has very few events,
resulting in lower confidence results being used in pooled analysis, however
the method is simpler and more transparent. This is less critical as the
number of studies increases. Restriction to outcomes with sufficient power may
be beneficial in pooled analysis and improve accuracy when there are few
studies, however we maintain our pre-specified method to avoid any
retrospective changes.
Studies show that combinations of treatments can be highly
synergistic and may result in many times greater efficacy than individual
treatments alone129-145.
Therefore standard of care may be critical and benefits may diminish or
disappear if standard of care does not include certain treatments.
This real-time analysis is constantly updated based on
submissions. Accuracy benefits from widespread review and submission of
updates and corrections from reviewers. Less popular treatments may receive
fewer reviews.
No treatment or intervention is 100% available and
effective for all current and future variants. Efficacy may vary significantly
with different variants and within different populations. All treatments have
potential side effects. Propensity to experience side effects may be predicted
in advance by qualified physicians. We do not provide medical advice. Before
taking any medication, consult a qualified physician who can compare all
options, provide personalized advice, and provide details of risks and
benefits based on individual medical history and situations.
SARS-CoV-2 infection and replication involves a complex
interplay of 100+ host and viral proteins and other
factors24-31, providing many therapeutic
targets.
Over 9,000 compounds have been predicted to reduce COVID-19
risk32, either by directly
minimizing infection or replication, by supporting immune system function, or
by minimizing secondary complications.
Figure 27 shows an overview of the results for quercetin
in the context of multiple COVID-19 treatments, and Figure 28 shows a plot
of efficacy vs. cost for COVID-19 treatments.
Figure 27.
Scatter plot showing results within the context of multiple COVID-19 treatments.
Diamonds shows the results of random effects meta-analysis.
0.6% of 9,000+ proposed treatments show efficacy315.
Figure 28. Efficacy vs. cost for COVID-19 treatments.
Studies to date show that quercetin is
an effective treatment for COVID-19.
Significantly lower risk is seen for ICU admission, hospitalization, recovery, cases, and viral clearance. 11 studies from 9 independent teams in 7 countries show significant
benefit.
Meta analysis using the most serious outcome reported shows
46% [20‑64%] lower risk. Results are similar for Randomized Controlled Trials, higher quality studies, and after excluding studies using combined treatment and slightly worse for peer-reviewed studies.
Results are very robust — in exclusion sensitivity analysis 9 of
12 studies must be excluded to avoid finding statistically significant
efficacy in pooled analysis.
Studies typically use advanced formulations for greatly improved bioavailability.
Small prophylaxis RCT with 113 patients showing fewer cases with quercetin + vitamin C + bromelain prophylaxis. Note that this paper disappeared from SSRN without explanation.
RCT 100 outpatients in Pakistan, 50 treated with quercetin phytosome, showing faster viral clearance and improved recovery with treatment. Patients in the treatment group were significantly younger (41 vs. 54).
RCT 152 outpatients in Pakistan, 76 treated with quercetin phytosome, showing lower mortality, ICU admission, and hospitalization with treatment.
Small RCT with 50 outpatients, 25 treated with curcumin, quercetin, and vitamin D, showing improved recovery and viral clearance with treatment. 168mg curcumin, 260mg, 360IU vitamin D3 daily for 14 days.
RCT 49 hospitalized COVID-19 patients, 25 treated with curcumin and quercetin, shower lower mortality/ICU admission and improved recovery with treatment. All patients received vitamin D.
336mg curcumin, 520mg quercetin, and 18μg vitamin D3 daily for 14 days. The control arm received 20μg vitamin D3 daily. Baseline fever favored treatment while vaccination favored control.
336mg curcumin, 520mg quercetin, and 18μg vitamin D3 daily for 14 days. The control arm received 20μg vitamin D3 daily. Baseline fever favored treatment while vaccination favored control.
RCT 50 COVID+ outpatients in Pakistan, 25 treated with curcumin, quercetin, and vitamin D, showing significantly faster viral clearance, significantly improved CRP, and faster resolution of acute symptoms (p=0.154). 168mg curcumin, 260mg quercetin and 360IU cholecalciferol.
Retrospective 113 outpatients, 53 (patient choice) treated with zinc, quercetin, vitamin C/D/E, l-lysine, and quina, showing lower cases with treatment. Results are subject to selection bias and limited information on the groups is provided. See316.
RCT 447 moderate-to-severe hospitalized patients in Turkey, 52 treated with quercetin, bromelain, and vitamin C, showing no statistically significant difference in clinical outcomes.
RCT 120 healthcare workers, 60 treated with quercetin phytosome, showing lower risk of cases with treatment. Quercetin phytosome 250mg twice a day.
Small RCT with 60 severe hospitalized patients in Iran, 30 treated with quercetin, showing shorter time until discharge. All patients received remdesivir or favipiravir, and vitamin C, vitamin D, famotidine, zinc, dexamethasone, and magnesium (depending on serum levels). Quercetin 1000mg daily for 7 days. IRCT20200419047128N2.
RCT 60 hospitalized COVID-19 patients with type 2 diabetes showing quercetin treatment decreased levels of inflammatory markers (interleukin-6, CRP, ferritin), reduced length of hospital stay, and improved capillaroscopy measures compared to standard care. Quercetin was administered at 0.5g intravenously once daily for 10 days. The authors hypothesize the benefits may be due to the anti-inflammatory, antioxidant and endothelium-protective effects of quercetin,
RCT 200 patients in Ukraine, 99 treated with IV quercetin/polyvinylirolidone followed by oral quercetin/pectin, showing improved recovery with treatment.
We perform ongoing searches of PubMed, medRxiv, Europe PMC,
ClinicalTrials.gov, The Cochrane Library, Google Scholar, Research
Square, ScienceDirect, Oxford University Press, the reference lists of other
studies and meta-analyses, and submissions to the site c19early.org.
Search terms are quercetin and COVID-19 or SARS-CoV-2. Automated searches are performed twice daily, with all matches reviewed for inclusion.
All studies regarding the use of quercetin for COVID-19 that report
a comparison with a control group are included in the main analysis.
Sensitivity analysis is performed, excluding studies with major issues,
epidemiological studies, and studies with minimal available information.
Studies with major unexplained data issues, for example major outcome data that
is impossible to be correct with no response from the authors, are excluded.
This is a living analysis and is updated regularly.
We extracted effect sizes and associated data from all studies.
If studies report multiple kinds of effects then the most serious
outcome is used in pooled analysis, while other outcomes are included in the
outcome specific analyses. For example, if effects for mortality and cases are
both reported, the effect for mortality is used, this may be different to the
effect that a study focused on.
If symptomatic
results are reported at multiple times, we used the latest time, for example
if mortality results are provided at 14 days and 28 days, the results at 28
days have preference. Mortality alone is preferred over combined outcomes.
Outcomes with zero events in both arms are not used, the next most serious
outcome with one or more events is used. For example, in low-risk populations
with no mortality, a reduction in mortality with treatment is not possible,
however a reduction in hospitalization, for example, is still valuable.
Clinical outcomes are considered more important than viral test status. When
basically all patients recover in both treatment and control groups,
preference for viral clearance and recovery is given to results mid-recovery
where available. After most or all patients have recovered there is little or
no room for an effective treatment to do better, however faster recovery is
valuable.
If only individual symptom data is available, the most serious symptom has
priority, for example difficulty breathing or low SpO2 is more
important than cough.
When results provide an odds ratio, we compute the relative risk when
possible, or convert to a relative risk according to317.
Reported confidence intervals and p-values were used when available,
using adjusted values when provided. If multiple types of adjustments are
reported propensity score matching and multivariable regression has preference
over propensity score matching or weighting, which has preference over
multivariable regression. Adjusted results have preference over unadjusted
results for a more serious outcome when the adjustments significantly alter
results. When needed, conversion between reported p-values and
confidence intervals followed Altman, Altman (B), and Fisher's exact
test was used to calculate p-values for event data. If continuity
correction for zero values is required, we use the reciprocal of the opposite
arm with the sum of the correction factors equal to 1320.
Results are expressed with RR < 1.0 favoring treatment, and using the risk of
a negative outcome when applicable (for example, the risk of death rather than
the risk of survival). If studies only report relative continuous values such
as relative times, the ratio of the time for the treatment group versus the
time for the control group is used. Calculations are done in Python
(3.13.3) with
scipy (1.15.3), pythonmeta (1.26), numpy (2.2.6), statsmodels (0.14.4), and plotly (6.0.1).
Forest plots are computed using PythonMeta321
with the DerSimonian and Laird random effects model (the fixed effect
assumption is not plausible in this case) and inverse variance weighting.
Results are presented with 95% confidence intervals. Heterogeneity among studies was
assessed using the I2 statistic.
Mixed-effects meta-regression results are computed with R (4.4.0) using the metafor
(4.6-0) and rms (6.8-0) packages, and using the most serious sufficiently powered outcome.
For all statistical tests, a p-value less than 0.05 was considered statistically significant.
Grobid 0.8.2 is used to parse PDF documents.
We have classified studies as early treatment if most patients
are not already at a severe stage at the time of treatment (for example based
on oxygen status or lung involvement), and treatment started within 5 days of
the onset of symptoms. If studies contain a mix of early treatment and late
treatment patients, we consider the treatment time of patients contributing
most to the events (for example, consider a study where most patients are
treated early but late treatment patients are included, and all mortality
events were observed with late treatment patients).
We note that a shorter time may be preferable. Antivirals are typically only
considered effective when used within a shorter timeframe, for example 0-36 or
0-48 hours for oseltamivir, with longer delays not being effective114,115.
We received no funding, this research is done in our spare
time. We have no affiliations with any pharmaceutical companies or political
parties.
A summary of study results is below. Please submit
updates and corrections at https://c19early.org/qmeta.html.
Effect extraction follows pre-specified rules as detailed above
and gives priority to more serious outcomes.
For pooled analyses, the first (most serious) outcome is used, which may
differ from the effect a paper focuses on.
Other outcomes are used in outcome specific analyses.
| Di Pierro, 1/13/2023, Randomized Controlled Trial, Pakistan, peer-reviewed, mean age 47.6, 13 authors, study period December 2020 - September 2021, trial NCT04861298 (history), excluded in exclusion analyses: randomization resulted in significant baseline differences that were not adjusted for. | risk of death, 66.7% lower, RR 0.33, p = 1.00, treatment 0 of 50 (0.0%), control 1 of 50 (2.0%), NNT 50, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm). |
| risk of ICU admission, 66.7% lower, RR 0.33, p = 1.00, treatment 0 of 50 (0.0%), control 1 of 50 (2.0%), NNT 50, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm). | |
| risk of hospitalization, 66.7% lower, RR 0.33, p = 1.00, treatment 0 of 50 (0.0%), control 1 of 50 (2.0%), NNT 50, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm). | |
| risk of no recovery, 36.8% lower, RR 0.63, p = 0.007, treatment 24 of 50 (48.0%), control 38 of 50 (76.0%), NNT 3.6, day 7. | |
| risk of no viral clearance, 57.9% lower, RR 0.42, p < 0.001, treatment 16 of 50 (32.0%), control 38 of 50 (76.0%), NNT 2.3, mid-recovery, day 7. | |
| risk of no viral clearance, 50.0% higher, RR 1.50, p = 1.00, treatment 3 of 50 (6.0%), control 2 of 50 (4.0%), day 14. | |
| risk of no viral clearance, 66.7% lower, RR 0.33, p = 1.00, treatment 0 of 50 (0.0%), control 1 of 50 (2.0%), NNT 50, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 21. | |
| Di Pierro (C), 6/8/2021, Randomized Controlled Trial, Pakistan, peer-reviewed, 19 authors, study period September 2020 - March 2021, trial NCT04578158 (history). | risk of death, 85.7% lower, RR 0.14, p = 0.25, treatment 0 of 76 (0.0%), control 3 of 76 (3.9%), NNT 25, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm). |
| risk of ICU admission, 94.1% lower, RR 0.06, p = 0.006, treatment 0 of 76 (0.0%), control 8 of 76 (10.5%), NNT 9.5, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm). | |
| risk of hospitalization, 68.2% lower, RR 0.32, p = 0.003, treatment 7 of 76 (9.2%), control 22 of 76 (28.9%), NNT 5.1. | |
| Din Ujjan, 1/18/2023, Randomized Controlled Trial, Pakistan, peer-reviewed, 6 authors, study period 21 September, 2021 - 21 January, 2022, this trial uses multiple treatments in the treatment arm (combined with curcumin and vitamin D) - results of individual treatments may vary, trial NCT04603690 (history). | risk of no recovery, 28.6% lower, RR 0.71, p = 0.11, treatment 15 of 25 (60.0%), control 21 of 25 (84.0%), NNT 4.2, no symptoms, day 7. |
| risk of no recovery, 71.4% lower, RR 0.29, p < 0.001, treatment 6 of 25 (24.0%), control 21 of 25 (84.0%), NNT 1.7, <= 1 symptom, day 7. | |
| risk of no recovery, 76.9% lower, RR 0.23, p = 0.005, treatment 3 of 25 (12.0%), control 13 of 25 (52.0%), NNT 2.5, <= 2 symptoms, day 7. | |
| risk of no recovery, 85.7% lower, RR 0.14, p = 0.23, treatment 0 of 25 (0.0%), control 3 of 25 (12.0%), NNT 8.3, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), <= 3 symptoms, day 7. | |
| risk of no viral clearance, 90.9% lower, RR 0.09, p = 0.05, treatment 0 of 25 (0.0%), control 5 of 25 (20.0%), NNT 5.0, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 14. | |
| risk of no viral clearance, 73.7% lower, RR 0.26, p < 0.001, treatment 5 of 25 (20.0%), control 19 of 25 (76.0%), NNT 1.8, day 7. | |
| Khan, 5/1/2022, Randomized Controlled Trial, Pakistan, peer-reviewed, 7 authors, study period 2 September, 2021 - 28 November, 2021, this trial uses multiple treatments in the treatment arm (combined with curcumin and vitamin D) - results of individual treatments may vary, trial NCT05130671 (history). | risk of no recovery, 33.3% lower, RR 0.67, p = 0.15, treatment 10 of 25 (40.0%), control 15 of 25 (60.0%), NNT 5.0. |
| relative CRP reduction, 39.1% better, RR 0.61, p = 0.006, treatment 25, control 25. | |
| risk of no viral clearance, 50.0% lower, RR 0.50, p = 0.009, treatment 10 of 25 (40.0%), control 20 of 25 (80.0%), NNT 2.5. |
Effect extraction follows pre-specified rules as detailed above
and gives priority to more serious outcomes.
For pooled analyses, the first (most serious) outcome is used, which may
differ from the effect a paper focuses on.
Other outcomes are used in outcome specific analyses.
| Gérain, 6/22/2023, Randomized Controlled Trial, Belgium, peer-reviewed, 8 authors, study period 1 April, 2021 - 29 October, 2021, this trial uses multiple treatments in the treatment arm (combined with curcumin) - results of individual treatments may vary, trial NCT04844658 (history). | risk of death, 67.1% lower, RR 0.33, p = 0.49, treatment 0 of 25 (0.0%), control 1 of 24 (4.2%), NNT 24, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 7. |
| risk of death/ICU, 91.1% lower, RR 0.09, p = 0.02, treatment 0 of 25 (0.0%), control 5 of 24 (20.8%), NNT 4.8, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 7. | |
| risk of mechanical ventilation, 89.1% lower, RR 0.11, p = 0.05, treatment 0 of 25 (0.0%), control 4 of 24 (16.7%), NNT 6.0, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 7. | |
| risk of ICU admission, 89.1% lower, RR 0.11, p = 0.05, treatment 0 of 25 (0.0%), control 4 of 24 (16.7%), NNT 6.0, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 7. | |
| risk of no hospital discharge, 72.6% lower, RR 0.27, p = 0.07, treatment 2 of 25 (8.0%), control 7 of 24 (29.2%), NNT 4.7, day 14. | |
| risk of no hospital discharge, 58.9% lower, RR 0.41, p = 0.02, treatment 6 of 25 (24.0%), control 14 of 24 (58.3%), NNT 2.9, day 7. | |
| hospitalization time, 37.5% lower, relative time 0.62, p = 0.008, treatment median 5.0 IQR 4.0 n=25, control median 8.0 IQR 6.0 n=24. | |
| relative WHO score, 50.0% better, RR 0.50, p = 0.04, treatment 22, control 24, day 7. | |
| Onal, 1/19/2021, Randomized Controlled Trial, Turkey, peer-reviewed, 10 authors, study period 7 May, 2020 - 8 July, 2020, this trial uses multiple treatments in the treatment arm (combined with bromelain and vitamin C) - results of individual treatments may vary. | risk of death, 29.3% higher, RR 1.29, p = 0.57, treatment 1 of 49 (2.0%), control 6 of 380 (1.6%). |
| risk of ICU admission, 94.0% lower, RR 0.06, p = 0.39, treatment 0 of 49 (0.0%), control 14 of 380 (3.7%), NNT 27, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm). | |
| risk of no hospital discharge, 77.8% lower, RR 0.22, p = 0.10, treatment 1 of 49 (2.0%), control 35 of 380 (9.2%), NNT 14. | |
| Shohan, 12/2/2021, Randomized Controlled Trial, Iran, peer-reviewed, mean age 50.9 (treatment) 52.7 (control), 8 authors, study period December 2020 - January 2021, average treatment delay 7.8 days. | risk of death, 85.7% lower, RR 0.14, p = 0.24, treatment 0 of 30 (0.0%), control 3 of 30 (10.0%), NNT 10.0, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm). |
| risk of ICU admission, 40.0% lower, RR 0.60, p = 0.71, treatment 3 of 30 (10.0%), control 5 of 30 (16.7%), NNT 15. | |
| time to discharge from end of intervention, 32.4% lower, relative time 0.68, p = 0.04, treatment 30, control 30. | |
| Tylishchak, 12/6/2024, Randomized Controlled Trial, Ukraine, peer-reviewed, 7 authors. | risk of no recovery, 40.0% lower, RR 0.60, p = 0.71, treatment 3 of 30 (10.0%), control 5 of 30 (16.7%), NNT 15, SpO2<90. |
| hospitalization time, 14.6% lower, relative time 0.85, p < 0.001, treatment mean 13.77 (±0.75) n=30, control mean 16.13 (±0.79) n=30. | |
| Zupanets, 9/1/2021, Randomized Controlled Trial, Ukraine, peer-reviewed, 14 authors. | risk of no recovery, 29.4% lower, RR 0.71, p = 0.50, treatment 9 of 99 (9.1%), control 13 of 101 (12.9%), NNT 26. |
| recovery time, 18.2% lower, relative time 0.82, p = 0.03, treatment 99, control 101. |
Effect extraction follows pre-specified rules as detailed above
and gives priority to more serious outcomes.
For pooled analyses, the first (most serious) outcome is used, which may
differ from the effect a paper focuses on.
Other outcomes are used in outcome specific analyses.
| Arslan, 11/16/2020, Randomized Controlled Trial, Turkey, preprint, 7 authors, study period 20 March, 2020 - 31 August, 2020, this trial uses multiple treatments in the treatment arm (combined with vitamin C and bromelain) - results of individual treatments may vary, trial NCT04377789 (history), excluded in exclusion analyses: paper no longer available at the source, and the contact does not reply to queries. | risk of case, 91.7% lower, RR 0.08, p = 0.03, treatment 1 of 71 (1.4%), control 9 of 42 (21.4%), NNT 5.0, adjusted per study, inverted to make RR<1 favor treatment. |
| Margolin, 7/6/2021, retrospective, USA, peer-reviewed, 5 authors, this trial uses multiple treatments in the treatment arm (combined with zinc, vitamin C/D/E, l-lysine, and quina) - results of individual treatments may vary. | risk of case, 94.4% lower, RR 0.06, p = 0.003, treatment 0 of 53 (0.0%), control 9 of 60 (15.0%), NNT 6.7, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm). |
| risk of COVID-19 or flu-like illness, 81.1% lower, RR 0.19, p = 0.01, treatment 2 of 53 (3.8%), control 12 of 60 (20.0%), NNT 6.2. | |
| Rondanelli, 1/4/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Italy, peer-reviewed, 12 authors, study period 12 January, 2021 - 25 May, 2021, trial NCT05037240 (history). | risk of symptomatic case, 92.9% lower, HR 0.07, p = 0.04, treatment 1 of 60 (1.7%), control 4 of 60 (6.7%), adjusted per study, inverted to make HR<1 favor treatment, Cox proportional risk. |
Viral infection and replication involves attachment, entry, uncoating and release, genome replication and transcription, translation and protein processing, assembly and budding, and release. Each step can be disrupted by therapeutics.
The trimeric spike (S) protein is a glycoprotein that mediates viral entry by binding to the host ACE2 receptor, is critical for SARS-CoV-2's ability to infect host cells, and is a target of neutralizing antibodies. Inhibition of the spike protein prevents viral attachment, halting infection at the earliest stage.
The main protease or Mpro, also known as 3CLpro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting Mpro disrupts the SARS-CoV-2 lifecycle within the host cell, preventing the creation of new copies.
RNA-dependent RNA polymerase (RdRp), also called nsp12, is the core enzyme of the viral replicase-transcriptase complex that copies the positive-sense viral RNA genome into negative-sense templates for progeny RNA synthesis. Inhibiting RdRp blocks viral genome replication and transcription.
The papain-like protease (PLpro) has multiple functions including cleaving viral polyproteins and suppressing the host immune response by deubiquitination and deISGylation of host proteins. Inhibiting PLpro may block viral replication and help restore normal immune responses.
The angiotensin converting enzyme 2 (ACE2) protein is a host cell transmembrane protein that serves as the cellular receptor for the SARS-CoV-2 spike protein. ACE2 is expressed on many cell types, including epithelial cells in the lungs, and allows the virus to enter and infect host cells. Inhibition may affect ACE2's physiological function in blood pressure control.
Transmembrane protease serine 2 (TMPRSS2) is a host cell protease that primes the spike protein, facilitating cellular entry. TMPRSS2 activity helps enable cleavage of the spike protein required for membrane fusion and virus entry. Inhibition may especially protect respiratory epithelial cells, buy may have physiological effects.
The nucleocapsid (N) protein binds and encapsulates the viral genome by coating the viral RNA. N enables formation and release of infectious virions and plays additional roles in viral replication and pathogenesis. N is also an immunodominant antigen used in diagnostic assays.
The helicase, or nsp13, protein unwinds the double-stranded viral RNA, a crucial step in replication and transcription. Inhibition may prevent viral genome replication and the creation of new virus components.
The endoribonuclease, also known as NendoU or nsp15, cleaves specific sequences in viral RNA which may help the virus evade detection by the host immune system. Inhibition may hinder the virus's ability to mask itself from the immune system, facilitating a stronger immune response.
The NSP16/10 complex consists of non-structural proteins 16 and 10, forming a 2'-O-methyltransferase that modifies the viral RNA cap structure. This modification helps the virus evade host immune detection by mimicking host mRNA, making NSP16/10 a promising antiviral target.
Cathepsin L is a host lysosomal cysteine protease that can prime the spike protein through an alternative pathway when TMPRSS2 is unavailable. Dual targeting of cathepsin L and TMPRSS2 may maximize disruption of alternative pathways for virus entry.
Wingless-related integration site (Wnt) ligand 3 is a host signaling molecule that activates the Wnt signaling pathway, which is important in development, cell growth, and tissue repair. Some studies suggest that SARS-CoV-2 infection may interfere with the Wnt signaling pathway, and that Wnt3a is involved in SARS-CoV-2 entry.
The frizzled (FZD) receptor is a host transmembrane receptor that binds Wnt ligands, initiating the Wnt signaling cascade. FZD serves as a co-receptor, along with ACE2, in some proposed mechanisms of SARS-CoV-2 infection. The virus may take advantage of this pathway as an alternative entry route.
Low-density lipoprotein receptor-related protein 6 is a cell surface co-receptor essential for Wnt signaling. LRP6 acts in tandem with FZD for signal transduction and has been discussed as a potential co-receptor for SARS-CoV-2 entry.
The ezrin protein links the cell membrane to the cytoskeleton (the cell's internal support structure) and plays a role in cell shape, movement, adhesion, and signaling. Drugs that occupy the same spot on ezrin where the viral spike protein would bind may hindering viral attachment, and drug binding could further stabilize ezrin, strengthening its potential natural capacity to impede viral fusion and entry.
The Adipocyte Differentiation-Related Protein (ADRP, also known as Perilipin 2 or PLIN2) is a lipid droplet protein regulating the storage and breakdown of fats in cells. SARS-CoV-2 may hijack the lipid handling machinery of host cells and ADRP may play a role in this process. Disrupting ADRP's interaction with the virus may hinder the virus's ability to use lipids for replication and assembly.
Neuropilin-1 (NRP1) is a cell surface receptor with roles in blood vessel development, nerve cell guidance, and immune responses. NRP1 may function as a co-receptor for SARS-CoV-2, facilitating viral entry into cells. Blocking NRP1 may disrupt an alternative route of viral entry.
EP300 (E1A Binding Protein P300) is a transcriptional coactivator involved in several cellular processes, including growth, differentiation, and apoptosis, through its acetyltransferase activity that modifies histones and non-histone proteins. EP300 facilitates viral entry into cells and upregulates inflammatory cytokine production.
Prostaglandin G/H synthase 2 (PTGS2, also known as COX-2) is an enzyme crucial for the production of inflammatory molecules called prostaglandins. PTGS2 plays a role in the inflammatory response that can become severe in COVID-19 and inhibitors (like some NSAIDs) may have benefits in dampening harmful inflammation, but note that prostaglandins have diverse physiological functions.
Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90AA1) is a chaperone protein that helps other proteins fold correctly and maintains their stability. HSP90AA1 plays roles in cell signaling, survival, and immune responses. HSP90AA1 may interact with numerous viral proteins, but note that it has diverse physiological functions.
Matrix metalloproteinase 9 (MMP9), also called gelatinase B, is a zinc-dependent enzyme that breaks down collagen and other components of the extracellular matrix. MMP9 levels increase in severe COVID-19. Overactive MMP9 can damage lung tissue and worsen inflammation. Inhibition of MMP9 may prevent excessive tissue damage and help regulate the inflammatory response.
The interleukin-6 (IL-6) pro-inflammatory cytokine (signaling molecule) has a complex role in the immune response and may trigger and perpetuate inflammation. Elevated IL-6 levels are associated with severe COVID-19 cases and cytokine storm. Anti-IL-6 therapies may be beneficial in reducing excessive inflammation in severe COVID-19 cases.
The interleukin-10 (IL-10) anti-inflammatory cytokine helps regulate and dampen immune responses, preventing excessive inflammation. IL-10 levels can also be elevated in severe COVID-19. IL-10 could either help control harmful inflammation or potentially contribute to immune suppression.
Vascular Endothelial Growth Factor A (VEGFA) promotes the growth of new blood vessels (angiogenesis) and has roles in inflammation and immune responses. VEGFA may contribute to blood vessel leakiness and excessive inflammation associated with severe COVID-19.
RELA is a transcription factor subunit of NF-kB and is a key regulator of inflammation, driving pro-inflammatory gene expression. SARS-CoV-2 may hijack and modulate NF-kB pathways.
The interaction between the SARS-CoV-2 spike protein and the human ACE2 receptor is a primary method of viral entry, inhibiting this interaction can prevent the virus from attaching to and entering host cells, halting infection at an early stage.
Calu-3 is a human lung adenocarcinoma cell line with moderate ACE2 and TMPRSS2 expression and SARS-CoV-2 susceptibility. It provides a model of the human respiratory epithelium, but many not be ideal for modeling early stages of infection due to the moderate expression levels of ACE2 and TMPRSS2.
A549 is a human lung carcinoma cell line with low ACE2 expression and SARS-CoV-2 susceptibility. Viral entry/replication can be studied but the cells may not replicate all aspects of lung infection.
HEK293-ACE2+ is a human embryonic kidney cell line engineered for high ACE2 expression and SARS-CoV-2 susceptibility.
Huh-7 cells were derived from a liver tumor (hepatoma).
Caco-2 cells come from a colorectal adenocarcinoma (cancer). They are valued for their ability to form a polarized cell layer with properties similar to the intestinal lining.
Vero E6 is an African green monkey kidney cell line with low/no ACE2 expression and high SARS-CoV-2 susceptibility. The cell line is easy to maintain and supports robust viral replication, however the monkey origin may not accurately represent human responses.
mTEC is a mouse tubular epithelial cell line.
RAW264.7 is a mouse macrophage cell line.
HLMEC (Human Lung Microvascular Endothelial Cells) are primary endothelial cells derived from the lung microvasculature. They are used to study endothelial function, inflammation, and viral interactions, particularly in the context of lung infections such as SARS-CoV-2. HLMEC express ACE2 and are susceptible to SARS-CoV-2 infection, making them a relevant model for studying viral entry and endothelial responses in the lung.
A mouse model expressing the human ACE2 receptor under the control of the K18 promoter.
A mouse model of obesity and severe insulin resistance leading to type 2 diabetes due to a mutation in the leptin receptor gene that impairs satiety signaling.
A mouse model commonly used in infectious disease and cancer research due to higher immune response and susceptibility to infection.
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