Immunologic Dysregulation and Hypercoagulability as a Pathophysiologic Background in COVID-19 Infection and the Immunomodulating Role of Colchicine
Abstract
:1. Introduction: Coronavirus Disease 19 (COVID-19) Pandemic
2. COVID-19 Clinical and Pathophysiological Aspects
2.1. COVID-19 Infection: Clinical Course
2.2. COVID-19 Pathophysiology: Immunologic Dysregulation and Hypercoagulability
3. Colchicine and COVID-19 Infection
3.1. Brief History, Pharmacology and COVID-19 Hypothesis
3.2. Clinical Results with Colchicine in COVID-19 Patients
3.2.1. Studies Evaluating Colchicine as Prevention against COVID-19
3.2.2. Colchicine for the Treatment or Prevention of COVID-19 Complications
3.2.3. Meta-Analyses
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Therapeutic Strategy | Agent/Approach Tested |
---|---|
Immunization | active immunity: vaccines passive immunity: plasma, immunoglobulins |
Antiviral Agents | fusion inhibitors RNA polymerase inhibitors protease inhibitors endosome acidification inhibitors |
Supportive Care | ECMO artificial liver system (ALS) cytokine filters thromboprophylaxis |
Immunomodulation | Interferons Steroids Colchicine Macrolides JAK inhibitors BTK inhibitors IL-6 inhibitors IL-1 inhibitors Anti-GM-CSF Abs Thalidomide Cell therapies |
Author Country Year | Design | n | Age | ♀ (%) | BMI (kg/m2) | DM (%) | Colchicine Dosage | SoC | Findings | Outcome |
---|---|---|---|---|---|---|---|---|---|---|
Randomized Controlled Trials | ||||||||||
Deftereos SG [87] Greece April 2020 | prospective, open-label, RCT | 105 | 64 | 41.9 | 27.5 | 10.5 | L:2 mg M: 0.5 mg BD up to 21 days | HCQ ± AZM ± LPV/r ± tocilizumab | WHO-OSCD: 1.8% vs. 14% OR 0.11; 95% CI: 0.01–0.96; p: 0.02 | Positive |
Tardif JC et al. [90] Multinational March 2020–January 2021 | double-blinded RCT non-hospitalized patients | 4488 | 54 | 53.9 | 30 | 19.9 | 0.5 mg BD 3d 0.5 mg OD 27d | HCQ OACs Anti-platelets | Composite of death or hospitalization 4.7% vs. 5.8% OR:0.79; 95% CI: 0.61–1.03; p: 0.081 Secondary endpoint, Mechanical ventilation OR: 0.53; 95% CI: 0.25–1.09 secondary analysis PCR-confirmed COVID-19 Composite of death or hospitalization 4.6% vs. 6% OR: 0.75; 95% CI: 0.57–0.99; p: 0.042 Any hospital admission (not pre-specified) OR: 0.76; 95% CI: 0.58–0.99; p: 0.04 | Neutral |
Lopes M. et al. [93] Brazil April–August 2020 | double blinded RCT | 72 | 55 | 54 | 31.6 | 39 | 0.5 mg q 8 h 5 days 0.5 mg BD 5 days | AZM 500mg OD up to 7 days HCQ 400 mg BD daily for 2 days, then 400 mg OD up to 8 days | Need for supplemental oxygen 4.0 days vs. 6.5 days; p < 0.001 Time of hospitalization 7.0 days vs. 9.0 days; p: 0.003 | Positive |
Mareev VY et al. [94] (COLORIT study) Russia | prospective comparative RCT | 43 | 61 | 30 | 30.4 | 11.6 | 1 mg/day for 3 days 0.5 mg/day for 14 days | NA | Primary endpoint SHOCS-COVID score change day 12 8 to 2 vs. 7 to 7 (p: 0.002) Secondary outcomes Hospital stay: 13 vs. 17.5; p: 0.079 Any oxygen support: decreased from 50% to 9.5%; p: 0.011 Deaths: 0 vs. 2; p: 0.467 | Positive |
Horby PW et al. [91] Pre-print RECOVERY NCT04381936 Multinational November 2020–March 2021 | open-label, RCT | 11340 | 63.4 | 30.5 | NA | 25.5 | L: 1 mg + 0.5 mg 12 h later M: 0.5 mg BD up to 10 days | corticosteroids remdesivir tocilizumab convalescent plasma baricitinib aspirin | Primary outcome 28-day all-cause mortality RR: 1.01; 95% CI: 0.93–1.0; p: 0.77 Secondary outcomes time to discharge 10 vs. 10 d invasive mechanical ventilation 11 vs. 11% | Neutral |
Observational Studies | ||||||||||
Brunetti L et al. [95] USA March–May 2020 | propensity matched retrospective observational cohort | 66 | 62.9 | 34.8 | 30.7 | 21.2 | L: 1.2 mg M: 0.6 mg BD | AZM, HCQ ± remdesivir or tocilizumab | 28-days mortality OR:0.20; 95% Cl:0.05–0.80; p: 0.023 WHO-OSCI days 14 and 28 57.6% vs. 51.5%; p: 0.621 Not requiring supplemental oxygen on days 14 and 28 54.5% vs. 54.5%, p: 1.0 Hospital discharge by day 28 OR: 5.0; 95% CI: 1.25–20.1; p: 0.023 | Positive |
Scarsi M et al. [96] Italy March–April 2020 | retrospective, case-control observational study | 262 | 70 | 36.5 | NA | NA | M: 1 mg/day | HCQ ± dexamethasone ± LPV/r | 21 days survival rate: 84.2% vs. 63.6%, p: 0.001 adj HR: 0.151; 95% CI: 0.062–0.368; p < 0.0001 | Positive |
Sandhu T et al. [97] USA March–May 2020 | prospective comparative cohort study | 112 | 67 | 43 | 27.5 | 42 | 0.6 mg BD 3 days 0.6 mg OD for 9 days | HCQ, steroids, oseltmamivir Excluded if on: lamivudine dolutegravir, tocilizumab convalescent plasma | Mortality: 49.1% vs. 72.9%; p: 0.002 Intubations: 52.8% vs. 73.6%; p: 0.006 Discharge rate: 50.9% vs. 27.1%; p: 0.002 | Positive |
Kevorkian JP et al. [98] (COCAA-COLA study) France January–November 2020 | observational cohort study | 68 | 66 | 22 | 27 | 44 | Prednisone 1 mg/kg/day Furosemide 80 mg/day Salicylate 75 mg/day Colchicine L: 1.5 mg M: 0.5 mg q 8 h Rivaroxaban or Apixaban | dexamethasone (6 mg OD for up to 10 days) LMWH | Primary composite endpoint OR: 0.097; 95% CI: 0.001–0.48; p: 0.0009
| Positive |
Manenti L et al. [99] Italy February–April 2020 | retrospective cohort study age & sex matched | 141 | 61.5 | 29 | 27.5 | 17 | M: 1 mg/day up to 21 days | ABX, antivirals, HCQ, i.v steroids, tocilizumab | 21 days mortality adj HR: 0.24; 95% CI: 0.09–0.67; p: 0.006 WHO-OSCI: adj relative improvement rate 1.80 95% CI: 1.00–3.22; p: 0.048 | Positive |
García-Posada M et al. [100] Colombia May–August 2020 | descriptive observational study | 209 | 60 | 39 | NA | 25.3 | L:2 mg M: 0.5 mg BD up to 20 days | varying combinations of ABX corticosteroids LMWH or tocilizumab | All-cause mortality: (combination of ABX, LMWH, colchicine, corticosteroids) OR: 0.26; 95% CI: 0.08−0.71; p < 0.05 | positive |
Meta-Analysis | Journal | n | Studies Included | Mortality Effect |
---|---|---|---|---|
Vrachatis et al., 2021 [102] | Hell J Cardiol | 881 | 6 studies 3 cohorts 2 RCTs 1 case-control | OR 0.35 (95% CI: 0.24–0.52; p < 0.05) |
Salah et al., 2021 [103] | Am J Cardiol | 5259 | 8 studies 4 cohorts 3 RCTs 1 case-control | RR 0.62 (95% CI: 0.48–0.81; p = 0.0005) |
Hariyanto et al., 2021 [104] | Clin Exp Pharmacol Physiol | 5778 | 8 studies 4 cohorts 3 RCTs 1 case-control | OR 0.43 (95% CI: 0.32–0.58; p = n/R) |
Chiu et al., 2021 [105] | medRxiv (pre-print) | 5033 | 6 studies 3 cohorts 3 RCTs | OR 0.36 (95% CI: 0.17–0.76; p = n/R) |
Golpour et al., 2021 [106] | Int J Immunopathol Pharmacol | 5678 | 10 studies 5 cohorts 4 RCTs 1 case-control | RR 0.365 (95% CI: 0.555–0.748; p < 0.05) |
Elshafei et al., 2021 [107] | Eur J Clin Invest | 5522 | 9 studies 4 cohorts 4 RCTs 1 case-control | OR 0.35 (95% CI: 0.25–0.48; p = n/R) |
Nawangsih et al., 2021 [108] | Int Immunopharmacol | 5530 | 8 studies 5 cohorts 3 RCTs | OR 0.47 (95% CI: 0.31–0.72; p = 0.001) |
Lien et al., 2021 [109] | Life (Basel) | 17,205 | 11 studies 7 cohorts 4 RCTs | OR 0.57 (95% CI: 0.38–0.87; p < 0.01) |
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Vrachatis, D.A.; Papathanasiou, K.A.; Giotaki, S.G.; Raisakis, K.; Kossyvakis, C.; Kaoukis, A.; Kolokathis, F.; Deftereos, G.; Iliodromitis, K.E.; Avramides, D.; 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, 5128. https://doi.org/10.3390/jcm10215128
Vrachatis DA, Papathanasiou KA, Giotaki SG, Raisakis K, Kossyvakis C, Kaoukis A, Kolokathis F, Deftereos G, Iliodromitis KE, Avramides D, et al. Immunologic Dysregulation and Hypercoagulability as a Pathophysiologic Background in COVID-19 Infection and the Immunomodulating Role of Colchicine. Journal of Clinical Medicine. 2021; 10(21):5128. https://doi.org/10.3390/jcm10215128
Chicago/Turabian StyleVrachatis, Dimitrios A., Konstantinos A. Papathanasiou, Sotiria G. Giotaki, Konstantinos Raisakis, Charalampos Kossyvakis, Andreas Kaoukis, Fotis Kolokathis, Gerasimos Deftereos, Konstantinos E. Iliodromitis, Dimitrios Avramides, and et al. 2021. "Immunologic Dysregulation and Hypercoagulability as a Pathophysiologic Background in COVID-19 Infection and the Immunomodulating Role of Colchicine" Journal of Clinical Medicine 10, no. 21: 5128. https://doi.org/10.3390/jcm10215128