Prerpints.org logo
Preprint
Article

This version is not peer-reviewed.

High Colchicine Doses Are More Effective in COVID-19 Outpatients than Nirmatrelvir/Ritonavir, Remdesivir, and Molnupiravir

A peer-reviewed article of this preprint also exists.

Submitted:

20 December 2024

Posted:

23 December 2024

You are already at the latest version

Preprints on COVID-19 and SARS-CoV-2
Abstract

Colchicine has an excellent basis for being effective against COVID-19 due to its anti-inflammatory, immunomodulatory, cardioprotective effects, and prevention of microvascular thrombosis. In addition colchicine has also antiviral effect, extremely favorable safety profile and since it does not exert any overt immunosuppressive activity, does not interfere with the effective viral clearing nor is associated with the occurrence of secondary infections.However, all studies to date on the effects of colchicine with low doses for COVID-19 treatment are conflicting and rather disappointing.As colchicine has the remarkable ability to accumulate intensively in leukocytes, where the cytokine storm is generated, we started high, but save doses colchicine for COVID-19 patient treatment. Our assumption was that a safe increase in colchicine doses to reach micromolar concentrations in leukocytes will result in NLRP3 inflammasome/cytokine storm inhibition and will enhance its antiviral effect by inducing microtubule dissociation.Outpatients’ high-dose colchicine treatment practically prevents hospitalizations. The total colchicine uptake analysis demonstrates reverse relationship with hospitalization. The period of colchicine uptake analysis demonstrates reverse relationship with hospitalization and post-COVID-19 symptomatics. Unlike the WHO-recommended antiviral preparations molnupiravir, remdesivir and paxlovid, colchicine, in addition to its antiviral effect, prevents the cytokine storm, and therefore has a strong effect not only in outpatients, but also in inpatients. Unlike antivirals, colchicine significantly reduces post-COVID-19 symptoms. The side effects of colchicine are similar to those of paxlovide. Colchicine price is incomparably lower and it is also easily available.

Keywords: 
COVID-19
;  
colchicine
;  
colchicine doses
;  
colchicine side effects
;  
antiviral drugs
;  
cytokine storm
Subject: 
Medicine and Pharmacology  -   Medicine and Pharmacology

Introduction

Successful treatment of COVID-19 outpatients is the biggest challenge. Around 80% of patients with COVID-19 were classified as mild (non-or mild pneumonia) and recover without specific treatment. However, about 15% of patients deteriorated (severe COVID-19) and 5% were critical [1]. These 20% of patients, who require hospitalization. The criterion for successful outpatient treatment is a reduction in hospitalizations. After millions of publications and tens of thousands of preclinical and/or clinical studies, more than 700 agents that have been reported with anti-SARS-CoV-2 effect [2], the World Health Organization (WHO) recommends only 3 antiviral drugs for outpatient use – molnupiravir (lagevrio), remdesivir (veklury) and ritonavir-boosted nirmatrelvir (paxlovid). All these drugs that inhibit viral replication, have serious side effects, their effectiveness varies widely and are very expensive [3,4,5].
In theory, colchicine has an excellent basis for being effective against COVID-19 due to its antiviral effects, anti-inflammatory effects, immunomodulatory effects, prevention of microvascular thrombosis and cardioprotective effects [4,6,7,8,9]. However, all studies to date on the effects of colchicine have been conducted with low doses of colchicine and the results are conflicting and rather disappointing, when evaluating its efficacy in inpatients [4,10,11,12,13].
In previous publications we demonstrated an excellent effect of high-dose colchicine in 785 inpatients, whose mortality decreased in a dose-dependent manner between 2- and 7-fold [14,15,16,17]. We are now demonstrating the effect of colchicine in the treatment of outpatients, while also monitoring their post-COVID-19 symptoms.

Materials and Methods

The therapy with high doses colchicine for COVID-19 patients was approved by the Medical Control Comission of UMBAL "Aleksandrovska" EAD, Sofia, Bulgaria (Protocol No. LKK-17-3-54-2020). All the patients were particularly questioned about liver and kidney chronic diseases and possible drug-drug interactions, informed about the side effects of high doses of colchicine and their consent was acquired.
We prepared a questioner for the outpatients treated with high colchicine doses for the period of October 2020 – May 2021. This period includes the two major COVID-19 waves in Bulgaria and all then existing SARS-CoV-2 variants, including delta (https://ncpha.government.bg/uploads/pages/103/AnalyticalReport_COVID_19.pdf). The collected data was analyzed statistically.

Statistical Analysis

Statistical analysis included the following:
(a)
Summary statistic tables of baseline characteristics: age, BMI and number of comorbidities, smoking status alongside disease specific information such as previous COVID-19 infections, subsequent COVID-19 infections despite therapy, days of prophylaxis, total number of tablets taken, total milligrams (mg) taken.
(b)
Chi-square analysis of proportions: proportion experiencing reinfection, proportion of patients requiring hospitalization
(c)
Student t-test for mean comparisons
(d)
Relative risk calculations
(e)
Sample size estimation
All statistics calculations were conducted in MedCalc Statistical Software Version 22.0014 (© 2023 MedCalc Software Ltd.)

Results

Sample size Estimation

Age-adjusted mortality in Bulgaria is around 15.5%, with the estimated mortality during peak COVID-19 contagion reaching 20.2%. Thus, we aimed to capture a sufficient sample size that would capture this 4.7% difference, meaning colchicine reduced mortality to pre-COVID levels within a 5% (∆) margin of error and 95% confidence (type I error probability α = 0.05, type II error β = 0.20) which resulted in a minimum sample size of 540 patients

Baseline Characteristics

A total of 547 responses were collected Baseline characteristics of questioned patients are summarized in Table 1 and Table 2 with the respective number of patients with available data, as well as missing data. Majority of patients filled in the sections on demographics and duration of Colchicine use. As well as post-COVID-19 symptoms. Majority of patients were elderly, with slightly elevated BMI, however low number of comorbidities. Mean duration of prophylactic intake of colchicine was 46 days. Vaccination coverage was reported at 29.07% which seems consistent with other official data from Bulgaria, as well as the percentage share of smokers (40.32%). Age distribution histogram of responders (Figure 1) indicates a heterogeneous mix of interviewees, which is a potential bias-minimization indicator.
Preprints 143607 g001
Figure 1. Age distribution histogram of responders.
Figure 1. Age distribution histogram of responders.
Preprints 143607 g001
Table 1. Baseline characteristics of included patients.
Table 1. Baseline characteristics of included patients.
Parameter (n) Min. 1st Qu.
25%		 Median
50%		 Mean 3rd Qu.
75%		 Max. 95% CI Stand. Dev Variance
Age (years) (534) 20 57 65 64.57 72 95 62.83 66.31 12.49 259.9109
BMI (kg/m2) (390) 14.53 22.49 25.25 25.56 27.76 65.74 25.06 to 26.05 4.956 24.5662
Days of C. intake (493) 1 7 10 13.36 20 45 12.65 to 14.06 7.98 63.7474
Number of tablets (492) 3 25 40 46.51 62 172 43.91 to 49.13 29.47 868.5608
Total mg of intake (492) 1.5 12.5 20 23.29 31 86 21.95 to 24.56 14.73 217.1402
Number of Comorbidities (375) 0 0 1 1.02 1 5 0.93 to 1.17 0.92 0.8524
Number of Post-COVID-19 symptoms Colchicine group(496) 0 0 3 3.274 5 12 3.016 – 3.532 2.9235 8.5469
Number of post-COVID-19 symptoms NO Colchicine group (112) 0 1 6 5.326 9 12 4.751-6.321 3.193 15.1142
Number of Cigarettes per day (224) 0 10 15 13.83 20 40 12.65 to 15.01 8.93 79.8425
The analysis shows decrease by 2.052 of the post-COVID-19 symptoms/patient (p<0.001).
Table 2. Percent share distribution of responses to yes and no questions.
Table 2. Percent share distribution of responses to yes and no questions.
Colchicine Intake N=547
Yes 496 (91.91%)
No 51 (7.59%)
unknown 0 (0.0%)
Vaccination Status N = 547
Yes 159 (29.07%)
No 382 (69.84%)
Unknown 6 (1.09%)
Have you had COVID-19 More than once? N = 547
Yes 135 (24.68%)
No 377 (68.92%)
Unknown 35 (6.04%)
Smoking Status N = 547
Yes 219 (40.32%)
No 321 (58.48%)
Not specified 7 (1.2%)
Hospitalizations due to COVID-19 prior to Colchicine N = 531
Yes 145 (26.51%)
No 402 (73.49%)
Hospitalizations due to COVID-19 after Colchicine N = 496
Yes 32 (6.05%)
No 464 (93.95%)
Not specified 0 (00.00%)
Diarrhoea related to colchicine use N = 496
Yes 426 (86.06%)
No 70 (13.94%)
Bromhexine Inhalations during treatment N = 442
Yes 349 (78.96%)
No 93 (21.04%)
Unknown N = 114
Bromhexine table form intake N = 468
Yes 149 (31.84%)
No 319 (68.16%)
Unknown n = 79
Highlighted is the number of hospitalized patients prior and after colchicine treatment.
Relative risk calculations show that there is a significant reduction in hospitalizations. The relative risk reduction in the treatment group was 76.38% lower from the control with an Absolute risk reduction of 20.86% in the entire population.
Relative risk - 0.2434
95% CI 0.1693 to 0.3499
z statistic 7.630
Significance level P < 0.0001
Odds ratio calculations show similar significant reductions in the hospitalization rate of 80.88%, conclusively showing that the subsequent hospitalization rate is reduced in the active treatment group.
Odds ratio 0.1912
95% CI 0.1275 to 0.2868
z statistic 7.998
Significance level P < 0.0001
Analysis shows a significant (about 4-fold) decrease of hospitalization due to the administration of high colchicine doses in outpatients. The decrease could be even bigger because part of the patients admitted to have been hospitalized not because they needed to, but as a preventive measure in the beginning of the pandemics.

Effect on Colchicine on Re-Infection Likelihood

As mentioned in the introduction section and in previous publications, the main effect of Colchicine is inhibition of the NLRP3 inflammasome after infection, which is why re-infection rates should not be affected by colchicine use. The purpose of this analysis was to confirm that no bias indicators were present and that groups were heterogeneous and randomly selected. Table 3 shows that there is no mean difference in the proportion of re-infected individuals. Because of the lack of colchicine on the re-infection rate we do not advise prophylactic colchicine administration.

Effect of Vaccine status on Re-Infection Likelihood

524 responders provided information regarding re-infection rate (Table 4), corresponding to n=23 missing data (4.2%). According to their reported outcomes, we confirm that colchicine does not reduce the likelihood of reinfection. However, Chi-Square analysis revealed that a significantly higher percentage share of vaccinated individuals have been re-infected (33.3% vs 22.6%) p= 0.0126.

Effect of Colchicine on Hospitalizations

The hospitalization rate among responders was 25.5% for the No colchicine group, and 6.05% for the entire colchicine group. The lowest hospitalization rate was observed in the group with 30 consecutive days of colchicine use. There was no significant observed difference in mean hospitalization rates within the colchicine prophylaxis group. However, hospitalization rates of each group showed a significant difference from the control group with the respective P-values shown right (Table 5). No patients died.
All colchicine users were analyzed in regard to their vaccination status and its effect on hospitalizations (Table 6). No significant difference was observed in vaccine effectiveness on hospitalization. From all 496 ambulatory patients, 31 total hospitalizations were observed with 5.9% of those being unvaccinated and 6.6% vaccinated. Among hospitalized patients the higher percentage share was of unvaccinated (70% vs 30%). Both Table 5 and Table 6 indicated that for one colchicine lowers hospitalization rates significantly with the benefit being more pronounced in vaccinated individuals.

Relative Risk Calculations

To estimate the impact and risk reduction of colchicine 3 separate risk ratio analyses were conducted (Table 7, Table 8 and Table 9). The last group consisted of both patients taking colchicine no more than 30 days and more than 30 days which increased the sample size from 52 to 62. According to calculations, relative risks were respectively 0.2283, 0.2714, and 0.1898 for the groups no more than 10 days, no more than 20 days and 30 days or more of colchicine intake. The highest relative risk reduction (1 – RR) was observed in the 3rd group – 91.02%.
Despite the variability of sample sizes, all confidence intervals show a Relative Risk Ratio lower than 1, showing that outpatient treatment with colchicine reduces hospitalization risk.

Colchicine safety

Of 496 patients 426 confirmed the presence of diarrhea related to colchicine use (86.06%), with n=50 (10%) missing data (Figure 2). Light diarrhea consisting of 3 bowel movements per day for the duration of treatment was reported in 242 individuals (48.79%), moderate up to 5 bowels movements per day was reported in 123 individuals (24.8%) and severe diarrhea consisting of more than 5 movements in only 11 (2.22%).

Discussion

Our results demonstrate an 87% reduction in hospitalizations, which is consistent with the most optimistic data from the manufacturers of paxlovid and remdesivir. Table 10 clearly shows the advantages of high-dose colchicine compared to the antiviral drugs recommended by the WHO: simultaneous inhibition of viral replication and protection from hyperactivation of the NLRP3 inflammasome,
  • strong effect not only in outpatients, but also in inpatients, side effects similar to paxlovid, and incomparably low cost and availability.
Table 10. Comparison between colchicine and WHO – recommended antiviral drugs: Molnupiravir, Remdesevir, Ritonavir/ Nirmatrelvir.
Table 10. Comparison between colchicine and WHO – recommended antiviral drugs: Molnupiravir, Remdesevir, Ritonavir/ Nirmatrelvir.
Inhibition
of NLRP3
inflammasome		 Reduced
Hospitalization		 Reduced
Inpatient
mortality		 Side effects *Cost
of One course of
treatment USD 		Rerferences
Molnupiravir
(Lagevrio)		 No 30% No Mutagenically questionalle rejected by EMA 712 https://www.ema.europa.eu/en/medicines/human/withdrawn applications/lagevrio).
Remdesevir
(Veklury)		 No 59%-87% Conflicting results Anaphylaxis acute liver failure 2613 19-25
Ritonavir
boosted
Nirmatrelvir
(Paxlocid)		 No 26%-88,9% No Contraindicated with drugs that are highly dependent on CYP3A 1158 26-29
Colchicine Yes 76.38% up to 7 fold Contraindicated with drugs (Clarithromycin) that are highly dependent on CYP3A diarrhoea 14 4,11,14,16,17,70,71,81-85
*Prices in Bulgaria.
We have always recommended that bromhexine be inhaled for COVID-19 disease [11,14]. Our results demonstrate the lowest rate of hospitalization precisely with the combination of high doses of colchicine plus inhaled BRH, compared to colchicine plus BRH tablets or colchicine alone.
In addition, outpatients treated under our regimen have 2 post-COVID-19 symptoms less.
In our sample, significantly more vaccinated individuals had a secondary encounter and subsequent infection with COVID-19. Recently, Smart et al. reported that vaccinated individuals are more likely to engage in “high-risk” activities, such as avoiding social distancing, engaging in more-frequent public activities [18]. Although our questionnaire did not include a specific section on frequency of outdoor or public activities, we suspect the results from the Chi-square analysis confirm this observation, since a significantly higher proportion had a secondary COVID-19 infection. This result highlights that better strategies of patient education are needed, particularly in the country. Although healthcare specialists are aware of the benefits of vaccines in regards to hospitalization rates, this information does not seem to translate to patients. Despite the abundance of information by institutions such as the CDC and WHO [https://www.cdc.gov/covid/vaccines/benefits.html], patients continue to engage in risky behaviour in the face of multiple COVID mutations.

WHO Recommendations for COVID-19 Outpatient Treatment

All three antiviral drugs recommended by the WHO were reported to be quite optimistic. Subsequent research, however, cooled the initial enthusiasm of the manufacturing companies.
The European Medicines Agency (EMA) rejected the low-potency (30% reduction in hospitalizations) and mutagenically questionable molnupinavir (lagevrio) from Merck&Co Inc. (https://www.ema.europa.eu/en/medicines/human/withdrawn applications/lagevrio).
The effectiveness of remdesivir in reducing hospitalizations ranged from 87% to 59% [19,20]. Remdesivir has a number of serious side effects, including anaphylaxis, acute liver failure and death [3] and “this medicine is to be given only by or under the immediate supervision of your doctor” (https://www.mayoclinic.org/drugs-supplements/remdesivir-intravenous-route/side-effects/drg20503608).
Data on the effect of remdesivir in inpatients are highly contradictory, from no positive impact on the COVID-19 mortality to some minor effect [21,22,23,24,25].
It is not logical to expect a reduction in mortality in inpatients from antiviral agents, such as remdesivir, when COVID-19 has entered its immunological phase (usually after the 7th day) were the viral load is lower or not detectable.
The WHO’s favorite remains to be ritonavir-boosted nirmatrelvir (рaxlovid), which is “strongly recommended in favor” [11].
However, paxlovid has recently suffered a real meltdown [4]. The EPIC-SR RCT demonstrated no benefit from Paxlovid in a vaccinated population, and in unvaccinated patients without risk factors. Now the guidelines recommend paxlovid only for persons who are at high risk for disease progression [26].
It was originally announced an 88.9% reduction in risk of hospitalization in paxlovid-treated outpatients (26) but these percentages varied widely from 88.9% to 26% [27]. In addition, paxlovide was not effective in hospitalized patients [28], did not reduce the risk of developing long COVID [29] and caused rebounds, or just didn’t prevent them [5].
The failure of antivirals to prevent the COVID-19 complications is due to the fact that there is no direct link between viral replication and the hyperresponsiveness of the NLRP3 inflammasome [11,30,31].
It is now clear that the hyperactivation of the NLRP3 inflammasome, leading to CS and tissue injury is related with lower or non-detectable viral load [11,32,33,34], suggesting that SARS-CoV-2 per see may not be required for continuous inflammasome activation. Disease progression in fatal cases of COVID-19 is related with increasing inflammasome activation and decreasing viral load [35].
However, some patients with higher viral loads died faster, with reduced inflammatory process, and increased disseminated intravascular coagulation [35]. Inflammation and coagulation/thrombosis are closely intertwined and are key features of severe COVID-19. The aberrant activation of the NLRP3 inflammasome may also promote hyperactivation of immunothrombosis programmes [36,37].
It is worth noting that SARS-CoV-2 S protein triggered the priming and activation of the NLRP3 inflammasome resulting in hypercoagulability - mature IL-1β formation, which enhanced production of coagulation factors such as von Willebrand factor (vWF), factor VIII or tissue factor and enhanced levels of inflammatory markers including C-reactive protein, ferritin and cytokines, associated with hyper-coagulation state [9,38,39].

Why Colchicine Is So Effective for Outpatient and Inpatient Treatment?

Similarly, to the antiviral drugs recommended by the WHO, colchicine has also antiviral effect, but in addition it can inhibit the NLRP3 inflammasome, preventing the hyper-coagulation state and the CS. Moreover, colchicine has an extremely favorable safety profile and since it does not exert any overt immunosuppressive activity, it does not interfere with the effective viral clearing nor is associated with the occurrence of secondary infections [40].

Antiviral Effects of Colchicine

Microtubules are long polymers of tubulin, that are polarized both in their intrinsic structure. They form part of the cytoskeleton, provide structure, shape to eukaryotic cells and tracks for fast transport of cargoes, including viruses, among others [41]. An intact microtubule system is essential for for the process of virion formation. Two key factors determine the efficiency of the virus assembly process: intracellular transport (microtubules function as tracks) and molecular interactions [42].
At higher concentrations colchicine may induce microtubule dissociation [43]. Whereas plasma concentration after single dosing of 0.6-mg colchicine is approximately 3 nmol/L, it has been shown to accumulate in neutrophils to 40 to 200 nmol/L, well above its Ki of 24 nmol/L for microtubule polymerization [44,45]. Disrupting the microtubular network by colchicine binding to free tubulin dimers, may inhibit the SARS-CoV-2 cell entry/endocytosis, the assembly and the exocytosis/spreed of the new virions. All this can affect the replication machinery within the cell, similarly to other viruses as IAVs (Influenza A viruses), flaviviruses like Zika and Dengue, RSV (respiratory syncytial virus) [46,47]. Colchicine has been demonstrated to decrease Dengue and Zika replication by inhibiting tubulin polymerization [48]. Colchicine has a proven antiviral effect in RSV were the virus replication was inhibited significantly, the level of IL-6 and TNF-α and the phosphorylation of Stat3, COX-2, and p38 were decreased also significantly [47].
In addition, Molecular Docking Analysis of colchicine demonstrated that it targets the main SARS-CoV-2 protease (Mpro) and to a lesser extent the RNA-dependent RNA Polymerase (RdRp), thus preventing viral replication [49,50].
In leukocytes, colchicine prevents microtubule polymerization, microtubule-based inflammatory cell chemotaxis, reduces their adhesion, recruitment and activation, leading to inhibition of vesicle transport, cytokine secretion and generation of leukotrienes, phagocytosis, migration and division. All these data show the great potential of colchicine against viral infections and that its antiviral effect is greatly underestimated.

Colchicine Inhibits the NLRP3 Inflammasome in Higher Concentrations

NLRs (nucleotide-binding domain, leucine-rich repeat-containing), a family of receptors form multiprotein complex (inflammasome), together with the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro–caspase-1. As a component of the innate immune system, the inflammasome plays an important role in the recognition of danger-associated signals and induces pro-inflammatory cytokines, most notably IL-1β and IL-18 [7].
NLRP3 (formerly NALP3) inflammasome is by far the most thoroughly studied NLR [49]. The NLRP3 inflammasome is vital part of the innate immune system for antiviral host defense, and has been detected in various cell types including myeloid cells, lung epithelial cells and cardiac cells [52].
The most serious complication of COVID-19 is the CS, due to aberrant activation of the NLRP3 inflammasome, with subsequent vascular inflammation, endothelial dysfunction, coagulopathy and multi-organ damage [9,53,54,55]. SARS-CoV-2 can activates the NLRP3 inflammasome directly (through ORF8b, S and N proteins) or indirectly (via diverse cellular signaling mechanisms) [9,11]
Rodrigues et al. also investigated whether NLRP3 inflammasome activation correlated with disease severity and clinical outcomes. They showed positive associations of caspase-1 and/or IL-18 levels with C-reactive protein (CRP), LDH, IL-6, and ferritin [56], that in turn correlated with COVID-19 severity [57,58,59,60,61,62]
This is the rationale where colchicine, a well known NLRP3 inflammasome inhibitor at micromolar concentrations, has been repurposed for the treatment of COVID-19 [63].
Colchicine has a great potential to prevent the CS and the hyper-coagulation state by inhibiting the aberrant activation of NLRP3 inflammasome. Microtubules mediate assembly of the NLRP3 inflammasome [64], therefore inhibiting the microtubule assembly, colchicine disrupts NLRP3 inflammasome activation [65].
Thus, colchicine reduces the viral load because it has an antiviral effect, and by inhibiting the NLRP3 inflammasome it prevents the CS and thrombus formation.

Dosing Strategies

The Collapse of Low-Doses Colchicine Against COVID-19

A wide variety of scientific research, including clinical trials, on the effect of colchicine as a treatment against COVID-19 continue to this day to report conflicting results [4,8,12,13,66].
The WHO does not recommend the use of colchicine, but “forgets” to specify that this applies to low doses. And why does he not recommend the application of high doses of colchicine? The explanation is simple - no clinical studies have been conducted with high doses.
Of all clinical trials with colchicine, only one gave two different doses – low (1.6 mg) and high (4.8 for 6 hours), but this was for the treatment of a gout attack. Since it is concluded that there is no difference in the effects between low and high dose colchicine, it is appropriate to use the low dose. Thus the incidence of diarrhea will drop from 76.9% to 23 % [67]. Low-dose colchicine is automatically used to fight COVID-19, even though it is a different disease. It is incredible and inexplicable that despite the fact that colchicine accumulates in white blood cells, where the CS is generated, and has the capacity to inhibit the NLRP3 inflammasome, no one has repeated the 2010 year low- and high-dose colchicine clinical trial [4,11].
Moreover, the high dose of 4.8 mg in 6 hours is even higher than our maximum loading dose of 5 mg in 24 hours. Most importantly, however, aside from the increased incidence of diarrhea, these colchicine concentrations are absolutely safe. In a number of cases, high loading doses of colchicine have been used (4 mg - 6.7 mg) [67,68,69,70]. No life-threatening side effects are described, with the most common being diarrhea. Patients treated with our regimen suffered diarrhea with frequency comparable to that in the literature [67,68]

Our Dosage Strategy

Our dosage strategy is detailed in our other publications [4,11,16,17,70,71]. In short, the NLRP3 inflammasome inhibition has been assessed at colchicine concentrations 10-to 100-fold higher than those achieved in serum [72]. However, colchicine has the remarkable ability to accumulate intensively in leukocytes, where the CS is generated [67,73,74]. Our assumption was that a safe increase in colchicine doses to reach micromolar concentrations in leukocytes will result in NLRP3 inflammasome/CS inhibition [4].

Does Colchicine Have an Immunosuppressive Effect?

There is no conclusive opinion about the immunosuppressive effect of colchicine in the literature. Most of the publications imply that used at standard doses, colchicine shows no immunosuppressive effect [75] and does not cause any significant risk of infection. This is a serious advantage of colchicine over glucocorticoids such as dexamethasone [76]. This is very important for the treatment of the first (viral) phase of COVID-19 infection, because the non-administration of immunosuppressants or glucocorticoids (which are well-known to increase the risk of infections) may be useful to avoid a decrease of the immune system [77].
According to others, colchicine as an immunosuppressive drug [78], weakens the immune system, rendering the patient prone to pneumonia infection [79,80].
Our data strongly support the opinion that colchicine does not have an immunosuppressive effect, since all unvaccinated patients treated with colchicine according to our scheme produce anti-SARS-CoV-2 antibodies.

Why Didn’t We Try to Do a Randomized Clinical Trial - Ethical Considerations

Randomized clinical trials (RCTs) are the gold standard of clinical trial design. This randomization is normally performed by a computer. We firmly decided not to conduct such during the COVID-19 epidemics for the following reasons: In the spring of 2020, we were convinced of the amazing effect of high doses of colchicine in the treatment of outpatients and inpatients. We have published some of the most characteristic and severe cases [71,81,82,83,84]. Particularly interesting are the four cases of accidental overdoses of colchicine, which led to rapid recovery of the COVID-19 patients [84,85].
All of us, our families, friends, and patients with COVID-19 have been treated with the high-dose colchicine regimen. Our ethics do not allow us to put every person randomly assigned to either a treatment arm or a control arm (RCT); or the patient not knowing which group he is in (blint RCT) or neither the participant nor the researcher to know which group the participant is in (double blint RCT). How do we let the computer "to decide" whether your mother or father, sister or brother will live, deteriorate or die to make the results look more scientific?
As we have already commented [4] the large-scale, randomized, controlled RECOVERY trial, pretending to be “an exceptional study that is leading the global fight against COVID-19” analysed 2178 reported deaths among 11162 randomized patients treated with low dose colchicine [10]. The WHO automatically complies with the conclusions of these clinical trials and gives “Strong recommendation against” the use of colchicine for COVID-19 treatment [86]. The conclusion “overall result is negative”, applies only for low-dose colchicine. If high doses of colchicine had been tested, the deaths in this RCT would have been about 5 times less. Because of this fundamental omission, in our view, the opportunity to save millions of human lives was missed [4].

Conclusion:

Our experience with a number of severe cases of COVID-19, high-dose colchicine led us to the following conclusions:
  • Already at the beginning of COVID-19, high doses of colchicine should be administered because of its antiviral effect, and inhibition of the NLRP3 inflammasome leading to prevention of the CS and thrombus formation.
  • Outpatients’ high-dose colchicine treatment practically prevents hospitalizations.
  • Total colchicine uptake analysis demonstrates reverse relationship with hospitalization.
  • The period of colchicine uptake analysis demonstrates reverse relationship with hospitalization and post-COVID-19 symptomatics.

Acknowledgements

The work was funded by Project BG-RRP-2.004-0004-C01 financed by Bulgarian National Science Fund. The research is financed by the Bulgarian National Plan for Recovery and Resilience.

References

  1. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239–1242. [CrossRef]
  2. Li G, Hilgenfeld R, Whitley R, et al. Therapeutic strategies for COVID-19: progress and lessons learned. Nat Rev Drug Discov. 2023;22:449–475. [CrossRef]
  3. Ahmed-Khan M, Matar G, Coombes K, Moin K, Joseph B, Funk C. Remdesivir-associated acute liver failure in a COVID-19 patient: A case report and literature review. Cureus. 2023;15,e34221. [CrossRef]
  4. Mitev V. Colchicine—The Divine Medicine against COVID-19. J Pers Med. 2024;14:756. [CrossRef]
  5. Sax P. The Rise and Fall of Paxlovid-HIV and ID Observations. NEJM Journal Watch. 2024. Available online: https://blogs.jwatch.org (accessed on 3 June 2024; https://www.ema.europa.eu/en/medicines/human/withdrawnapplications/lagevrio, accessed on 10 June 2024.
  6. Reyes AZ, Hu KA, Teperman J, Muskardin TLW, Tardif JC, Shah B., et al. Anti-inflammatory therapy for COVID-19 infection: the case for colchicine. Ann Rheum Dis. 2021;80(5):550-557.
  7. Bonaventura A, Vecchié A, Dagna L, Tangianu F, Abbate A, Dentali F. Colchicine for COVID-19: targeting NLRP3 inflammasome to blunt hyperinflammation. Inflamm Res. 2022;71(3):293-307. [CrossRef]
  8. Rabbani AB, Oshaughnessy M, Tabrizi R, Rafique A, Parikh RV, Ardehali R. Colchicine and COVID-19: A Look Backward and a Look Ahead. Med Res Arch. 2024;12(9). [CrossRef]
  9. Villacampa A, Alfaro E, Morales C et al. SARS-CoV-2 S protein activates NLRP3 inflammasome and deregulates coagulation factors in endothelial and immune cells. CCS. 2024;22(1):38. [CrossRef]
  10. RECOVERY Collaborative Group. Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial. Lancet Respir Med. 2021;9:1419–1426.
  11. Mitev V. Comparison of treatment of Covid-19 with inhaled bromhexine, higher doses of colchicine and hymecromone with WHO-recommended paxlovide, mornupiravir, remdesivir, anti-IL-6 receptor antibodies and baricitinib. Pharmacia. 2023;70(4):1177-1193. [CrossRef]
  12. Elshiwy K, Amin GEE, Farres MN, Samir R, Allam MF. The role of colchicine in the management of COVID-19: a Meta-analysis. BMC Pulm Med. 2024;24(1):190. [CrossRef]
  13. Cheema HA, Jafar U, Shahid A, et al. Colchicine for the treatment of patients with COVID-19: an updated systematic review and meta-analysis of randomised controlled trials. BMJ. Open 2024;14:e074373. [CrossRef]
  14. Mitev V, Mondeshki T, Marinov K, Bilukov R: Colchicine, bromhexine, and hymecromone as part of COVID19 treatment - cold, warm, hot. Curr. Infect. Dis. Rep. 2023;10:106-114.
  15. Khan BA (ed): BP International, London, UK; 2023;10:106-13. 10.9734/bpi/codhr/v10/5310A 10.
  16. Tiholov R, Lilov AI, Georgieva G, Palaveev KR, Tashkov K, Mitev V. Effect of increasing doses of colchicine on thetreatment of 333 COVID-19 inpatients. Immun Inflamm Dis. 2024;12(5).e1273. [CrossRef]
  17. Mitev V. High colchicine doses are really silver bullets against COVID-19. AMB. 2024;51(4):95-96. [CrossRef]
  18. Smart SJ, Polachek SW. COVID-19 vaccine and risk-taking. J Risk Uncertain.2024;68:25–49. [CrossRef]
  19. Gottlieb RL, Vaca CE, Paredes R, Mera J, Webb BJ, Perez G, Oguchi G, Ryan P et al. Investigators. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med. 2022;386(4):305-315. [CrossRef]
  20. Molina KC, Webb BJ, Kennerley V, Beaty LE, Bennett TD, Carlson NE, et al. Real-world evaluation of early remdesivir in high-risk COVID-19 outpatients during Omicron including BQ.1/BQ.1.1/XBB.1.5. BMC Infect Dis.2024;24(1):802. [CrossRef]
  21. Amirizadeh M, Kharazmkia A, Abdoli SK, Abbarik AH, Azimi G. The effect of remdesivir on mortality and the outcome of patients with COVID-19 in intensive care unit: A case-control study. Health Sci Rep.2023;6(11):e1676. [CrossRef]
  22. Chokkalingam AP, Hayden J, Goldman JD, Li H, Asubonteng J, Mozaffari E, et al. Association of remdesivir treatment with mortality among hospitalized adults with COVID-19 in the United States. JAMA Network. Open 2022;5(12). [CrossRef]
  23. Gupte V, Hegde R, Sawant S, Kalathingal K, Jadhav S, Malabade R, et al. Safety and clinical outcomes of remdesivir in hospitalised COVID-19 patients: a retrospective analysis of active surveillance database. BMC Infect Dis. 2022;22(1). [CrossRef]
  24. Pan, Hongchao et al. Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet. 2022;399(10339):1941 – 1953.
  25. Mozaffari E, Chandak A, Chima-Melton C, Kalil AC, Jiang H, Lee E, Der-Torossian C, et al. Remdesivir is ssociated with Reduced Mortality in Patients Hospitalized for COVID-19 Not Requiring Supplemental Oxygen. Open Forum Infect Dis. 2024;11(6):ofae202. [CrossRef]
  26. Hammond J, Fountaine R, Yunis C, Fleishaker D, Almas M, Bao W, et al. Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19. N Engl J Med. 2024;390:1186-1195. [CrossRef]
  27. Paltra S, Conrad T. Clinical Effectiveness of Ritonavir-Boosted Nirmatrelvir-A Literature Review. Adv. Respir Med. 2024;92;66-76. [CrossRef]
  28. Liu J, Pan X, Zhang S, Li M, Ma K, Fan C, et al. Efficacy and safety of Paxlovid in severe adult patients with SARS-Cov-2 infection: a multicenter randomized controlled study. Lancet Reg Health West. 2023;33:100694. [CrossRef]
  29. Durstenfeld MS, Peluso MJ, Lin F, Peyser ND, Isasi C, Carton TW, et al. Association of nirmatrelvir for acute SARS-CoV-2 infection with subsequent Long COVID symptoms in an observational cohort study. J Med Virol. 2024;96:e29333. [CrossRef]
  30. Walsh KA, Jordan K, Clyne B, Rohde D, Drummond L, Byrne P, et al. SARS-CoV-2 detection, viral load and infectivity over the course of an infection. J. Infect. Res. 2020;81(3):357-371.
  31. Kelleni MT. SARS CoV-2 viral load might not be the right predictor of COVID-19 mortality. J Infect. 2021;82(2):e35. [CrossRef]
  32. Jamilloux Y, Henry T, Belot A, Viel S, Fauter M, El Jammal T, Walzer T, François B, et al. Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmunity Reviews. 2020;19:102567. [CrossRef]
  33. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033–1034. [CrossRef]
  34. Freeman TL, Swartz TH. Targeting the NLRP3 inflammasome in severe COVID-19. Frontiers in Immunology. 2020;11:1518. [CrossRef]
  35. de Sá KSG, Amaral LA, Rodrigues TS, Caetano CCS, Becerra A, Batah SS, et al. Pulmonary inflammation and viral replication define distinct clinical outcomes in fatal cases of COVID-19. PLoS Pathog. 2024;20(6): e1012222. [CrossRef]
  36. Stark K, & Massberg S. Interplay between inflammation and thrombosis in cardiovascular pathology. Nat Rev Cardiol. 2021;18(9):666-682.
  37. Potere N, Garrad E, Kanthi Y, Di Nisio M, Kaplanski G, Bonaventura A, et al. NLRP3 inflammasome and interleukin-1 contributions to COVID-19-associated coagulopathy and immunothrombosis. Cardiovasc Res. 2023;119(11):2046-2060. [CrossRef]
  38. Vrachatis DA, Papathanasiou KA, Giotaki SG, Raisakis K, Kossyvakis C, Kaoukis A, et al. Immunologic Dysregulation and Hypercoagulability as a Pathophysiologic Background in COVID-19 Infection and the Immunomodulating Role of Colchicine. J Clin Med. 2021;10(21):5128. [CrossRef]
  39. Potere N, Garrad E, Kanthi Y, Di Nisio M, Kaplanski G, Bonaventura A, Connors JM, De Caterina R, Abbate A. NLRP3 inflammasome and interleukin-1 contributions to COVID-19-associated coagulopathy and immunothrombosis. Cardiovasc Res. 2023;119(11):2046-2060. [CrossRef]
  40. Reyes AZ, Hu KA, Teperman J, Muskardin TLW, Tardif JC, Shah B, et al. Anti-inflammatory therapy for COVID-19 infection: the case for colchicine. ARD. 2021;80(5):550-557.
  41. Barlan K, Gelfand VI. Microtubule-Based Transport and the Distribution, Tethering, and Organization of Organelles. Cold Spring Harb Perspect Biol. 2017;9(5):a025817. [CrossRef]
  42. de Haan CA, Rottier PJ. Molecular interactions in the assembly of coronaviruses. Adv Virus Res.2005;64:165-230. [CrossRef]
  43. Taylor EW.The mechanism of colchicine inhibition of mitosis: I. Kinetics of inhibition and the binding of h3-colchicine. JCB.1965;25:145–160. [CrossRef]
  44. Sherline P, Leung JT, Kipnis DM. Binding of colchicine to purified microtubule protein. JBC.1975;250:5481–5486. [CrossRef]
  45. Chappey O, Niel E, Dervichian M, Wautier JL, Scherrmann JM, Cattan D. Colchicine concentration in leukocytes of patients with familial Mediterranean fever. B J Clin Pharmacol.1994;38:87–89. [CrossRef]
  46. Hegazy A., Soltane R., Alasiri A. et al. Anti-rheumatic colchicine phytochemical exhibits potent antiviral activities against avian and seasonal Influenza A viruses (IAVs) via targeting different stages of IAV replication cycle. BMC Complement Med Ther 24, 49 (2024). [CrossRef]
  47. Lu N, Yang Y, Liu H, et al. Inhibition of respiratory syncytial virus replication and suppression of RSV-induced airway inflammation in neonatal rats by colchicine. 3 Biotech. 2019;9:392. [CrossRef]
  48. Richter M, Boldescu V, Graf D, Streicher F, Dimoglo A, Bartenschlager R, et al. Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1-Activated Prodrugs as Antiviral Agents. Chem Med Chem. 2019;14(4):469-483. [CrossRef]
  49. Kamel NA, Ismail NSM, Yahia IS, Aboshanab KM. Potential Role of Colchicine in Combating COVID-19 Cytokine Storm and Its Ability to Inhibit Protease Enzyme of SARS-CoV-2 as Conferred by Molecular Docking Analysis. Medicina (Kaunas). 2021;58(1):20. [CrossRef]
  50. Rabbani AB, Oshaughnessy M, Tabrizi R, et al. Colchicine and COVID-19: A Look Backward and a Look Ahead Medical Research Archives. 2024;12:(9):2375-1924. [CrossRef]
  51. de Zoete MR, Palm NW, Zhu S, Flavell RA. Inflammasomes. Cold Spring Harb Perspect Biol. 2014;6(12):a016287. [CrossRef]
  52. Place DE, & Kanneganti TD. Recent advances in inflammasome biology. Current opinion in immunology. 2018;50:32-38.
  53. Bai B, Yang Y, Wang QI, Li M, Tian C, Liu Y, et al. NLRP3 inflammasome in endothelial dysfunction. Cell death & disease. 2020;11(9):776.
  54. Wang M, Yu F, Chang W, Zhang Y, Zhang L, Li P. Inflammasomes: a rising star on the horizon of COVID-19 pathophysiology. Front Immunol. 2023;12(14):1185233. [CrossRef]
  55. Rodrigues TS, Zamboni DS. Inflammasome activation by SARS-CoV-2 and its participation in COVID-19 exacerbation. Curr Opin Immunol. 2023;84:102-387. [CrossRef]
  56. Rodrigues TS, de Sá KS, Ishimoto AY, Becerra A, Oliveira S, Almeida L, et al. Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients. J Exp Med. 2021;218(3):e20201707. [CrossRef]
  57. Velavan TP, & Meyer CG. Mild versus severe COVID-19: Laboratory markers. IJID. 2020;95:304-307.
  58. Lin Z, Long F, Yang Y, Chen X, Xu L, & Yang M. Serum ferritin as an independent risk factor for severity in COVID-19 patients. J. Infect. Res. 2020;81(4): 647-679.
  59. Henry BM, Aggarwal G, Wong J, Benoit S., Vikse J, Plebani M, et al. Lactate dehydrogenase levels predict coronavirus disease 2019 (COVID-19) severity and mortality: A pooled analysis. Am. J. Emerg. Med.2020;38(9):1722-1726.
  60. Szarpak L, Ruetzler K, Safiejko K, Hampel M, Pruc M, Kanczuga-Koda L, et al. Lactate dehydrogenase level as a COVID-19 severity marker. Am J Emerg Med. 2020;45:638.
  61. Gorham J, Moreau A, Corazza F, Peluso L, Ponthieux F, Talamonti M, et al . Interleukine-6 in critically ill COVID-19 patients: A retrospective analysis. PLoS One, 2020;15(12), e0244628.
  62. Mojtabavi H, Saghazadeh A, & Rezaei N. Interleukin-6 and severe COVID-19: a systematic review and meta-analysis. Eur Cytokine Netw. 2020;31:44-49.
  63. Kow CS, Ramachandram DS, Hasan SS. Colchicine for COVID-19: Hype or hope? Eur J Intern Med. 2022;97:106-107. [CrossRef]
  64. Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, et. al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat. Immunol. 2013;14(5):454-460. [CrossRef]
  65. Vitiello A, Ferrara F. Colchicine and SARS-CoV-2: Management of the hyperinflammatory state. Respir Med. 2021;178:106322. [CrossRef]
  66. Casey A, Quinn S, McAdam B, et al. Colchicine—regeneration of an old drug. Ir J Med Sci.2023;192:115–123. [CrossRef]
  67. Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum. 2010;62(4):1060-8. PMID: 20131255. [CrossRef]
  68. Ahern MJ, Reid C, Gordon TP, et al. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med. 1987;17(3):301–304. [CrossRef]
  69. Pascart T, Lancrenon S, Lanz S, et al. GOSPEL 2 - colchicine for the treatment of gout flares in France - a GOSPEL survey subgroup analysis. Doses used in common practices regardless of renal impairment and age. Joint Bone Spine. 2016;83(6):687–693. [CrossRef]
  70. Mitev V. What is the lowest lethal dose of colchicine? Biotechnol. Biotechnol. Equip. 2023;37:1 10.1080/13102818.2023.2288240.
  71. Mondeshki T, Bilyukov R, Tomov T, Mihaylov M, Mitev V: Complete, rapid resolution of severe bilateral pneumonia and acute respiratory distress syndrome in a COVID-19 patient: role for a unique therapeutic combination of inhalations with bromhexine, higher doses of colchicine, and hymecromone. Cureus. 2022;14:e30269. 10.7759/cureus.30269;
  72. Cronstein BN, Sunkureddi P. Mechanistic aspects of inflammation and clinical management of inflammation in acute gouty arthritis. J Clin Rheumatol. 2013;19(1):19-29. [CrossRef]
  73. Leung YY, Hui, LLY, Kraus VB. Colchicine—update on mechanisms of action and therapeutic uses. In Seminars in arthritis and rheumatism. 2015;45(3):341-350. [CrossRef]
  74. Dupuis J, Sirois MG, Rhéaume E, Nguyen QT, Clavet-Lanthier MÉ, Brand G, et al. Colchicine reduces lung injury in experimental acute respiratory distress syndrome. PLoS One. 2020;15(12):e0242318. [CrossRef]
  75. American Society of Health-System Pharmacists. Colchicine Monograph for Professionals. Drugs Com Retrieved 27 March 2019.
  76. Vitiello A, Ferrara F. Colchicine and SARS-CoV-2: Management of the hyperinflammatory state. Respir Med. 2021;178:106322. [CrossRef]
  77. Conti P, Ronconi G, Caraffa AL, Gallenga CE, Ross R, Frydas I, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020;34(2):327-331.
  78. Dalbeth N, Lauterio TJ, Wolfe HR. Mechanism of action of colchicine in the treatment of gout. Clin Ther.2014;36(10):1465–1479. [CrossRef]
  79. Spaetgens B., de Vries F., Driessen JHM, et al. Risk of infections in patients with gout: a population-based cohort study. Sci Rep 7, 1429 (2017). [CrossRef]
  80. Tsai T-L, Wei JC-C, Wu Y-T, Ku Y-H, Lu K-L, Wang Y-H. The Association Between Usage of Colchicine and Pneumonia: A Nationwide, Population-Based Cohort Study. Front. Pharmacol.2019;10:908. [CrossRef]
  81. Lilov A, Palaveev K, Mitev V. High Doses of Colchicine Act as “Silver Bullets” Against Severe COVID-19. Cureus. 2024:16(2): e54441. [CrossRef]
  82. Mondeshki T, Mitev V. High-Dose Colchicine: Key Factor in the Treatment of Morbidly Obese COVID-19 Patients. Cureus. 2024;16(4): e58164. [CrossRef]
  83. Bulanov D, Yonkov A, Arabadzhieva E, Mitev V. Successful Treatment with High-Dose Colchicine of a 101-Year-Old Patient Diagnosed with COVID-19 After an Emergency Cholecystectomy. Cureus. 2024;16(6): e63201. [CrossRef]
  84. Marinov K, Mondeshki T, Georgiev H, Dimitrova V, Mitev V. Effects of long-term prophylaxis with bromhexine hydrochloride and treatment with high colchicine doses of COVID-19. Preprints 2024;2024102410. [CrossRef]
  85. Mondeshki T, Bilyukov R, Mitev V. Effect of an Accidental Colchicine Overdose in a COVID-19 Inpatient With Bilateral Pneumonia and Pericardial Effusion. Cureus. 2023;15(3) 2023: e35909. [CrossRef]
  86. https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-therapeutics-2022.4/, accessed on 10 June 2024.
Preprints 143607 g002
Figure 2. Distribution of Diarrhea and its severity among colchicine ambulatory patients.
Figure 2. Distribution of Diarrhea and its severity among colchicine ambulatory patients.
Preprints 143607 g002
Table 3. Mean re-infection rates as reported by participants and respective mean difference.
Table 3. Mean re-infection rates as reported by participants and respective mean difference.
Sample size Mean Std. Dev. Variance 95% CI Difference from No colchicine P-value from no colchicine
No colchicine 51 34.09% 47.95 22.99 19.51 – 48.67 -
Up to 10 days of colchicine Intake 276 25.00% 43.38 18.82 19.86 -30.14 14.09% P = 0.2043
Up to 20 days of colchicine Intake 153 26.80% 44.44 19.75 19.7 – 33.89 7.29% P = 0.3471
Up to 30 days of colchicine Intake 55 23.64% 42.88 18.38 12.05 – 35.23 10.45% P = 0.2556
Over 30 days of colchicine Intake 10 10% 31.62 10 1.01 – 32.62 24.09 P = 0.2043
Total with colchicine 496 25.05% 43.38 18.81 21.19 – 28.91 9.045 P = 0.1901
The table shows no effect of colchicine of the re-infection rates.
Table 4. Chi-square 2x2 table of vaccinated vs unvaccinated individuals treated with colchicine and re-infection likelihood.
Table 4. Chi-square 2x2 table of vaccinated vs unvaccinated individuals treated with colchicine and re-infection likelihood.
Have you had COVID-19 more than once since treatment start
Have you been vaccinated? No Yes Total
No 288 (77.4%) 84 (22.6%) 372 (71.00%)
Yes 101 (66.7%) 51 (33.3%) 152 (29.4%)
Total 389 (74.2%) 135 (25.8%) 524
Chi-Squared 6.231 Significance P = 0.0126
Table 5. Mean hospitalization rates reported by responders after colchicine treatment initiation.
Table 5. Mean hospitalization rates reported by responders after colchicine treatment initiation.
Hospitalizations due to COVID-19 after consultation Sample size Mean Std. Dev. Variance 95% CI Difference from No colchicine P-value
No colchicine 51 25.5% 45.07 19.37 13.1 – 37.9 -
Any intake of colchicine 496 6.05% 23.86 5.69 3.94 – 8.15 19.45% P < 0.0001
Up to 10 days of colchicine 275 5.82% 23.45 5.5 3.03 – 8.6 19.68% P < 0.0001
Up to 20 days of colchicine 159 6.92% 25.46 6.48 2.93 – 10. 9 18.58% P = 0.0007
Up to 30 days of colchicine 52 3.85% 19.42 37.71 1.56 – 9.25 21.65% P = 0.0046
Table 6. Chi-square analysis of hospitalization rates among vaccinated and unvaccinated individuals post colchicine intake.
Table 6. Chi-square analysis of hospitalization rates among vaccinated and unvaccinated individuals post colchicine intake.
Have you been hospitalized due to COVID-19?
Have you been vaccinated? No Yes Total
No 336
94.1% RT
72.4% CT
68.0% GT		 22
5.9% RT
70.0% CT
4.3% GT		 358 (72.2%)
Yes 128
93.4% RT
27.6% CT
25.95% GT		 9
6.6% RT
30.0% CT
1.75% GT		 139 (27.8%)
Total 465
(93.95%)		 31
(6.05%)		 496
Chi-Squared = 0.005 DF = 1 Significance P = 0.9453 Contingency = 0.003
RT: % of Row Total; CT: % of Column Total; GT: % of Grand Total.
Table 7. Relative risk calculations for 2 subgroups - no colchicine vs up to 10 days of intake.
Table 7. Relative risk calculations for 2 subgroups - no colchicine vs up to 10 days of intake.
Have you been hospitalized due to COVID-19?
Colchicine dose No Yes Total
No colchicine 38 13 51
Up to 10 days of colchicine 259 16 275
Total 297 29 326
Relative Risk = 0.2283 95 % CI = 0.1170 to 0.4452 Significance p < 0.0001
Table 8. Relative risk calculations for 2 subgroups - no colchicine vs up to 20 days of intake.
Table 8. Relative risk calculations for 2 subgroups - no colchicine vs up to 20 days of intake.
Have you been hospitalized due to COVID-19?
Colchicine dose No Yes Total
No colchicine 38 13 51
Up to 20 days of colchicine 148 11 159
Total 186 24 210
Relative Risk 0.2714 95% CI – 0.1297 to 0.5680 Significance p = 0.0007
Table 9. Relative risk calculations for 2 subgroups - no colchicine vs up to 30 days or more of Colchicine.
Table 9. Relative risk calculations for 2 subgroups - no colchicine vs up to 30 days or more of Colchicine.
Have you been hospitalized due to COVID-19?
Colchicine dose No Yes Total
No colchicine 38 13 51
Up to 30 days of colchicine 59 3 49
Total 97 16 155
Relative Risk 0.1898 95% CI – 0.05720 to 0.6299 Significance p = P = 0.0066
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
Prerpints.org logo

Preprints.org is a free preprint server supported by MDPI in Basel, Switzerland.

facebook logotwitter logolinkedin logo
bsky
MDPI Initiatives
Important Links
Subscribe

Disclaimer

Terms of Use

Privacy Policy

Privacy Settings

© 2025 MDPI (Basel, Switzerland) unless otherwise stated