Covid Analysis, September 29, 2022, DRAFT
https://c19quercetin.com/meta.html
•Statistically significant improvements are seen for ICU admission, hospitalization, recovery, cases, and viral clearance. 8 studies from 7 independent teams in 6 different countries show statistically significant
improvements in isolation (3 for the most serious outcome).
•Meta analysis using the most serious outcome reported shows
63% [27‑81%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, similar for peer-reviewed studies, and similar after excluding studies using combined treatment.
•Studies typically use advanced formulations for greatly improved bioavailability.
•No treatment, vaccine, or
intervention is 100% effective and available. All practical, effective, and
safe means should be used based on risk/benefit analysis.
Multiple treatments are typically used
in combination, and other treatments
may be more effective.
Only 44% of quercetin
studies show zero events with treatment.
The quality of non-prescription supplements can vary widely [Crawford, Crighton].
•All data to reproduce this paper and
sources are in the appendix.
Highlights
Quercetin reduces
risk for COVID-19 with very high confidence for recovery, cases, and in pooled analysis, high confidence for ICU admission, low confidence for hospitalization and viral clearance, and very low confidence for mortality.
Studies typically use advanced formulations for greatly improved bioavailability.
We show traditional outcome specific analyses and combined
evidence from all studies, incorporating treatment delay, a primary
confounding factor in COVID-19 studies.
Real-time updates and corrections,
transparent analysis with all results in the same format, consistent protocol
for 47
treatments.
Figure 1. A. Random effects
meta-analysis. This plot shows pooled effects, discussion can be found in the heterogeneity section,
and results for specific outcomes can be found in the individual outcome analyses.
Effect extraction is pre-specified, using the most serious outcome reported.
For details of effect extraction see the appendix.
B. Scatter plot showing the
distribution of effects reported in studies. C. History of all reported
effects (chronological within treatment stages).
Introduction
We analyze all significant studies
concerning the use 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, for studies within each treatment stage, for individual outcomes, for
peer-reviewed studies, for Randomized Controlled Trials (RCTs), and after
exclusions.
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.
Preclinical Research
4 In Silico studies support the efficacy of quercetin [Chellasamy, Kandeil, Sekiou, Şimşek].
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.
Results
Figure 3 shows a visual overview of the results, with details in
Table 1 and Table 2.
Figure 4, 5, 6, 7, 8, 9, 10, 11, and 12
show forest plots for a random effects meta-analysis of
all studies with pooled effects, mortality results, ICU admission, hospitalization, recovery, cases, viral clearance, peer reviewed studies, and all studies excluding combined treatment studies.
Figure 3. Overview of results.
| Treatment time | Number of studies reporting positive effects | Total number of studies | Percentage of studies reporting positive effects | Random effects meta-analysis results |
| Early treatment | 3 | 3 | 100% |
38% improvement RR 0.62 [0.35‑1.08] p = 0.09 |
| Late treatment | 2 | 3 | 66.7% |
31% improvement RR 0.69 [0.33‑1.42] p = 0.32 |
| Prophylaxis | 3 | 3 | 100% |
93% improvement RR 0.07 [0.02‑0.27] p < 0.0001 |
| All studies | 8 | 9 | 88.9% |
63% improvement RR 0.37 [0.19‑0.73] p = 0.0042 |
Table 1. Results by treatment stage.
| Studies | Early treatment | Late treatment | Prophylaxis | Patients | Authors | |
| All studies | 9 | 38% [-8‑65%] | 31% [-42‑67%] | 93% [73‑98%] | 1,279 | 94 |
| With exclusions | 7 | 38% [-15‑66%] | 31% [-42‑67%] | 94% [64‑99%] | 1,124 | 75 |
| Peer-reviewed | 8 | 38% [-8‑65%] | 31% [-42‑67%] | 94% [64‑99%] | 1,166 | 87 |
| Randomized Controlled TrialsRCTs | 8 | 38% [-8‑65%] | 31% [-42‑67%] | 92% [66‑98%] | 1,166 | 89 |
Table 2. Results by treatment stage for all studies and with different exclusions.
Figure 4. Random effects meta-analysis for all studies with pooled effects.
This plot shows pooled effects, discussion can be found in the heterogeneity section,
and results for specific outcomes can be found in the individual outcome analyses.
Effect extraction is pre-specified, using the most serious outcome reported.
For details of effect extraction see the appendix.
Figure 5. Random effects meta-analysis for mortality results.
Figure 6. Random effects meta-analysis for ICU admission.
Figure 7. Random effects meta-analysis for hospitalization.
Figure 8. Random effects meta-analysis for recovery.
Figure 9. Random effects meta-analysis for cases.
Figure 10. Random effects meta-analysis for viral clearance.
Figure 11. Random effects meta-analysis for peer reviewed studies.
[Zeraatkar] analyze 356 COVID-19 trials, finding no
significant evidence that peer-reviewed studies are more trustworthy.
They also show extremely slow review times during a pandemic. Authors
recommend using preprint evidence, with appropriate checks for potential
falsified data, which provides higher certainty much earlier.
Effect extraction is pre-specified, using the most serious outcome reported,
see the appendix for details.
Figure 12. 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.
Exclusions
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 may underemphasize serious issues not captured in the checklists,
overemphasize issues unlikely to alter outcomes in specific cases (for
example, lack of blinding for an objective mortality outcome, or certain
specifics of randomization with a very large effect size), or be easily
influenced by potential bias. However, they can also be very high
quality.
The studies excluded are as below.
Figure 13 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 13. Random effects meta-analysis for all studies after exclusions.
This plot shows pooled effects, discussion can be found in the heterogeneity section,
and results for specific outcomes can be found in the individual outcome analyses.
Effect extraction is pre-specified, using the most serious outcome reported.
For details of effect extraction see the appendix.
Randomized Controlled Trials (RCTs)
Figure 14 shows the distribution of results for Randomized Controlled Trials and other studies, and
a chronological history of results.
Figure 15 and 16
show forest plots for a random effects meta-analysis of
all Randomized Controlled Trials and RCT mortality results.
Table 3 summarizes the results.
Figure 14. The distribution of results for Randomized Controlled Trials and other studies, and
a chronological history of results.
Figure 15. Random effects meta-analysis for all Randomized Controlled Trials.
This plot shows pooled effects, discussion can be found in the heterogeneity section,
and results for specific outcomes can be found in the individual outcome analyses.
Effect extraction is pre-specified, using the most serious outcome reported.
For details of effect extraction see the appendix.
Figure 16. Random effects meta-analysis for RCT mortality results.
| Treatment time | Number of studies reporting positive effects | Total number of studies | Percentage of studies reporting positive effects | Random effects meta-analysis results |
| Randomized Controlled Trials | 7 | 8 | 87.5% |
57% improvement RR 0.43 [0.23‑0.82] p = 0.01 |
| RCT mortality results | 3 | 4 | 75.0% |
59% improvement RR 0.41 [0.11‑1.55] p = 0.19 |
Table 3. Randomized Controlled Trial results.
Heterogeneity
Heterogeneity in COVID-19 studies arises from many factors including:
Treatment delay.
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 hours [McLean, Treanor].
Figure 17 shows a mixed-effects meta-regression for efficacy
as a function of treatment delay in COVID-19 studies from 47 treatments, showing
that efficacy declines rapidly with treatment delay. Early treatment is
critical for COVID-19.
Figure 17. Meta-regression
showing efficacy as a function of treatment delay in COVID-19 studies from 47 treatments. Early
treatment is critical.
Patient demographics.
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 (as in [López-Medina]).Effect measured.
Efficacy may differ
significantly depending on the effect measured, for example a treatment may be
very effective at reducing mortality, but less effective at minimizing cases
or hospitalization. Or a treatment may have no effect on viral clearance while
still being effective at reducing mortality.Variants.
There are many different
variants of SARS-CoV-2 and efficacy may depend critically on the distribution
of variants encountered by the patients in a study. For example, the Gamma
variant shows significantly different characteristics
[Faria, Karita, Nonaka, Zavascki]. Different mechanisms of action may be
more or less effective depending on variants, for example the viral entry
process for the omicron variant has moved towards TMPRSS2-independent fusion,
suggesting that TMPRSS2 inhibitors may be less effective
[Peacock, Willett].Regimen.
Effectiveness may depend strongly on the dosage and treatment regimen.
Other treatments.
The use of other
treatments may significantly affect outcomes, including anything from
supplements, other medications, or other kinds of treatment such as prone
positioning.Medication quality.
The
quality of medications may vary significantly between manufacturers and
production batches, which may significantly affect efficacy and safety.
[Williams] analyze ivermectin from 11 different sources, showing
highly variable antiparasitic efficacy across different manufacturers.
[Xu] 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 quality
[Crawford, Crighton].
Meta analysis.
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 the treatment may be very effective when used earlier.In general, by combining heterogeneous studies, as all meta
analyses do, we run the risk of obscuring an effect by including studies where
the treatment is less effective, not effective, or harmful.
When including studies where a treatment is less effective we
expect the estimated effect size to be lower than that for the optimal case.
We do not a priori expect that pooling all studies will create a
positive result for an effective treatment. 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 pooled results for all studies, we also present individual
outcome and treatment time analyses, which are more relevant for specific use
cases.
Discussion
Publication bias.
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 results
[Boulware, Meeus, Meneguesso].
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.
100% of retrospective studies
report a statistically significant positive effect for
one or more outcomes, compared to
88% of prospective studies, consistent with a bias toward publishing positive results.
The median effect size for
retrospective studies is 94% improvement,
compared to 76% for prospective
studies, suggesting a potential bias towards publishing results showing higher efficacy.
Figure 18 shows a scatter plot of
results for prospective and retrospective studies.
Figure 18. Prospective vs. retrospective studies.
Funnel plot 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 19 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 < 0.05
[Egger, Harbord, Macaskill, Moreno, Peters, Rothstein, Rücker, Stanley].
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 19. Example funnel plot analysis for
simulated perfect trials.
Conflicts of interest.
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.
Early/late vs. mild/moderate/severe.
Some analyses classify treatment based on early/late administration (as we do
here), while others distinguish between mild/moderate/severe cases. We note
that 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.Notes.
4 of 9 studies
combine treatments. The results of
quercetin
alone may differ.
3 of 8 RCTs use combined treatment.
Conclusion
Quercetin is
an effective treatment for COVID-19.
Statistically significant improvements are seen for ICU admission, hospitalization, recovery, cases, and viral clearance. 8 studies from 7 independent teams in 6 different countries show statistically significant
improvements in isolation (3 for the most serious outcome).
Meta analysis using the most serious outcome reported shows
63% [27‑81%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, similar for peer-reviewed studies, and similar after excluding studies using combined treatment.
Studies typically use advanced formulations for greatly improved bioavailability.
Study Notes
[Arslan]
Small prophylaxis RCT with 113 patients showing fewer cases with quercetin + vitamin C + bromelain prophylaxis. NCT04377789. Note that this paper disappeared from SSRN without explanation.
