中等症～重症CoVIDに対するコルヒチンのRCT

コルヒチンは昔からある安価で比較的安全な痛風発作抑制剤ですが、その作用は、

細胞微小管機能の(移動・再配置による)抑制、NLRP3インフラマソーム阻害作用、シアリダーゼ（ニューロアミニダーゼ）抑制が主な機序として知られており、決して尿酸値自体を下げるものではありません。

広汎性「マクロファージ活性化抑制剤」とも呼べるものです。

昨年、ギリシャから出た報告を紹介しましたが、今回はブラジルからの小規模RCTで、やはり有効性が示されました。

（※　2021/02/11管理者記載）

******************************************

ブラジル·University of Sao PauloのMaria Isabel Lopes氏らは、中等症～重症の新型コロナウイルス感染症（COVID-19）患者75例を対象に、標準治療に上乗せしたコルヒチンの効果を検証する二重盲検プラセボ対照ランダム化比較試験（RCT）を実施。

その結果、コルヒチンはプラセボに比べ酸素投与および入院の必要性の2点を有意に抑制したとRMD Open（2021年2月4日オンライン版）に発表した。

＜炎症時に活性化するNLRP3インフラマソームを阻害＞

Lopes氏らは、さまざまな知見から「COVID-19入院患者に見られる過剰な炎症の基礎をなすのは、蛋白質複合体NLRP3インフラマソームの異常な活性化である」と考察。NLRP3インフラマソーム阻害作用が示されているコルヒチン投与により、COVID-19患者の転帰が改善するかどうかを検討した。

　対象は、中等症～重症COVID-19と確定診断された入院患者75例。

アジスロマイシン、ヒドロキシクロロキン、ヘパリン、メチルプレドニゾロンによる治療に上乗せして、

コルヒチンを1～5日目は0.5mg 1日3回投与、6～10日目は0.5mg 1日2回投与するコルヒチン群とプラセボ群に1:1でランダムに割り付けた。

　主要評価項目は、安静時の酸素飽和度が92％以下で酸素投与が必要な期間、入院期間、死亡率などとした。

＜安価で安全、入院短縮で病床確保にも貢献＞

　試験を完了したコルヒチン群36例〔年齢中央値54.5歳、四分位範囲（IQR）42.5～64.5歳、男性53％〕とプラセボ群36例（同55.0歳、42.0～67.0歳、39％）の計72例を解析に組み入れた。

　その結果、酸素投与が必要な期間の中央値は、プラセボ群の6.5日（IQR 4.0～9.0日）に比べコルヒチン群では4.0日（同2.0～6.0日）と有意に短かった（P＜0.001）。治療7日目に酸素投与が必要だった患者の割合も、それぞれ42％、9％とコルヒチン群で有意に少なかった（P＝0.001、log rank test）。

　同様に、入院期間の中央値はプラセボ群の9.0日（IQR 7.0～12.0日）に比べコルヒチン群では7.0日（同5.0～9.0日）と有意に短かった（P＝0.003）。治療10日目に入院していた患者の割合も、それぞれ39％、9％とコルヒチン群で有意に少なかった（P＝0.002、log rank test）。

　死亡はプラセボ群の男性2例で、死因はいずれも人工呼吸器関連肺炎だった。

　最も発現頻度が高かった有害事象は下痢で、有意ではないもののコルヒチン群で多かった（17％ vs. 6％、P＝0.26）。

　以上を踏まえ、Lopes氏らは「中等症～重症COVID-19患者において、標準治療へのコルヒチン上乗せは安全性と忍容性が高く、酸素投与が必要な期間および入院期間をプラセボに比べ有意に短縮した」と結論。「入院期間の短縮は費用削減と病床確保につながり、COVID-19パンデミック下の日常診療において重要な意味を持つ。加えて、コルヒチンは医療経済的にも有益である」と付言している。

Beneficial effects of colchicine for moderate to severe COVID-19:

a randomised, double-blinded, placebo-controlled clinical trial

• Maria Isabel Lopes, Leticia P Bonjorno, Marcela C Giannini1, Natalia B Amaral, Pamella Indira Menezes, Saulo Musse Dib, Samara Libich Gigante, Maira N Benatti, Uebe C Rezek, Laerte L Emrich-Filho, Betania A A Sousa, Sergio C L Almeida, Rodrigo Luppino Assad, Flavio P Veras, Ayda Schneider, Tamara S Rodrigues, Luiz O S Leiria, Larissa D Cunha, Jose C Alves-Filho, Thiago M Cunha, Eurico Arruda, Carlos H Miranda, Antonio Pazin-Filho, Maria Auxiliadora-Martins, Marcos C Borges, Benedito A L Fonseca, Valdes R Bollela, Cristina M Del-Ben, Fernando Q Cunha, Dario S Zamboni, Rodrigo C Santana, Fernando C Vilar, Paulo Louzada-Junior and Rene D R Oliveira

https://rmdopen.bmj.com/content/7/1/e001455

Abstract

Objective To evaluate whether the addition of colchicine to standard treatment for COVID-19 results in better outcomes.

Design We present the results of a randomised, double-blinded, placebo-controlled clinical trial of colchicine for the treatment of moderate to severe COVID-19, with 75 patients allocated 1:1 from 11 April to 30 August 2020. Colchicine regimen was 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days. The primary endpoints were the need for supplemental oxygen, time of hospitalisation, need for admission and length of stay in intensive care unit and death rate.

Results Seventy-two patients (36 for placebo and 36 for colchicine) completed the study. Median (and IQR) time of need for supplemental oxygen was 4.0 (2.0–6.0) days for the colchicine group and 6.5 (4.0–9.0) days for the placebo group (p<0.001). Median (IQR) time of hospitalisation was 7.0 (5.0–9.0) days for the colchicine group and 9.0 (7.0–12.0) days for the placebo group (p=0.003). At day 2, 67% versus 86% of patients maintained the need for supplemental oxygen, while at day 7, the values were 9% versus 42%, in the colchicine and the placebo groups, respectively (log rank; p=0.001). Two patients died, both in placebo group. Diarrhoea was more frequent in the colchicine group (p=0.26).

Conclusion Colchicine reduced the length of both, supplemental oxygen therapy and hospitalisation. The drug was safe and well tolerated. Once death was an uncommon event, it is not possible to ensure that colchicine reduced mortality of COVID-19.

Introduction

Systemic inflammation is the hallmark of moderate to severe cases of COVID-19.¹ Its outbreak has already sent millions to infirmaries and intensive care units (ICUs) throughout the world, mainly due to pulmonary infiltrates resulting in the severe acute respiratory syndrome (SARS).² High levels of interleukin (IL)-1β, IL-6, IL-18 and tumour necrosis factor (TNF) are some of the many immunological disturbances in the pathophysiology of the high inflammatory status of COVID-19,³ which counts, moreover, with markedly elevation of serum C reactive protein (CRP) and uncommon neutrophilia and lymphopaenia.^{4 5} Neutrophils release neutrophil extracellular traps (NETs), which were found to be toxic to lung epithelial cells in vitro. Furthermore, high levels of NETs were present in the plasma of patients with COVID-19 compared with healthy controls, and the presence of these cellular components was at least 10 times higher in tracheal aspirates than in plasma of the same patients, raising the question whether they have a role in the lung lesions.⁶

The inflammasome of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) may be important in certain antiviral responses.⁷ After viral activation of the protein complex, mainly in monocytes and antigen-presenting tissue cells, its constituent pro-caspase-1 suffers autocleavage and, by its turn, cleaves pro-IL-1β and pro-IL-18 to their active form: IL-1β and IL-18.⁸ Both products activate B, T and NK cells in addition to stimulating the release of other inflammatory cytokines.⁹It seems appropriate to infer that an aberrant activation of inflammasome underlies the ‘hyper’ inflammation found in hospitalised patients with COVID-19.

For decades, colchicine has been successfully used for the treatment and prevention of crystal-induced arthritis, for example, gout. Systemic autoinflammatory diseases such as familial Mediterranean fever and Behçet’s disease are conditions in which colchicine use may be necessary continuously.¹⁰ Much of this success comes from its direct effect on phagocytes residing or migrating into the synovial joints, vessel walls or other tissues, leading to inflammasome inhibition and impaired production and release of IL-1β¹¹ and NETs.¹² In all of these situations, the drug is well tolerated, and its adverse effects are broadly recognised.

Piantoni et al¹³ discussed the rationale of its use for the treatment of COVID-19, with focus on the control of the systemic inflammation caused by SARS-CoV-2 infection. A case–control study¹⁴ and an open-label clinical trial¹⁵ of colchicine for COVID-19 have results published hitherto.

Methods

Trial design

We conducted a randomised, double-blinded, placebo-controlled clinical trial to evaluate the use of colchicine for the treatment of hospitalised patients with moderate to severe COVID-19. The randomisation was performed 1:1 for placebo or colchicine by using the online tool at https://www.randomizer.org/.

To estimate the sample size, we took into account the parallelism of the groups and the 1:1 randomisation, with a minimal difference of effect of 0.30 attributed to the intervention on the primary endpoints. Alpha and beta errors of, respectively, 0.05 and 0.10, were predetermined, which resulted in a minimal number of 27 participants per group. Considering the prominent need of efficient therapies for COVID-19, besides limitations to conduct a clinical trial in a single centre, a minimal number of 60 patients seemed to be appropriate whether randomised into two groups of 30 patients.

The trial is registered on the National Registry under the alphanumeric code RBR-8jyhxh (http://www.ensaiosclinicos.gov.br/rg/RBR-8jyhxh/). All patients signed the consent form.

Intervention

Patients of the intervention arm received colchicine 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days; if body weight ≥80 kg, the first dose was 1.0 mg. Whether a patient had chronic kidney disease, with glomerular filtration rate under 30 mL/min/1.73 m2, colchicine dose was reduced to 0.25 mg thrice daily for 5 days, then 0.25 mg twice daily for 5 days, no matter the body weight.

All participants received the institutional treatment for COVID-19 with azithromycin 500 mg once daily for up to 7 days, hydroxychloroquine 400 mg twice daily for 2 days, then 400 mg once daily for up to 8 days and unfractionated heparin 5000 UI thrice daily until the end of hospitalisation. During the study conduction, the first results of the RECOVERY Collaborative Group were launched,¹⁶ showing the benefits of adding a glucocorticoid to the treatment of COVID-19. Then, methylprednisolone 0.5 mg/kg/day for 5 days was added to the institutional protocol, for use if the patient’s need for supplemental oxygen was equal to 6 L/min or more. Study and institutional protocol drugs were suspended when participants reached good clinical and laboratory parameters and could be discharged.

Study population

For a matter of selection criteria, we classified patients according to the severity of COVID-19: the mild form of the disease was defined in patients with flu-like symptoms without dyspnoea and imaging findings of pneumonia; the moderate form was defined in patients with fever, dyspnoea and imaging findings of pneumonia; the severe form in those with the same findings of moderate form plus respiratory rate ≥30 times per minute or oxygen saturation (SatO2) ≤92%; and the critical form was defined when patients presented respiratory failure or shock.^{17 18} The inclusion criteria were: individuals hospitalised with moderate or severe forms of COVID-19 diagnosed by RT-PCR in nasopharyngeal swab specimens and lung CT scan involvement compatible with COVID-19 pneumonia; older than 18 years; body weight >50 kg; normal levels of serum Ca2+ and K+; QT interval <450 ms at 12 derivations ECG (according to the Bazett formula) and negative serum or urinary β-HCG if woman under 50 years. The exclusion criteria were defined as: mild form of COVID-19 or in need for ICU admission; diarrhoea resulting in dehydration; known allergy to colchicine; diagnosis of porphyria, myasthenia gravis or uncontrolled arrhythmia at enrolment; pregnancy or lactation; metastatic cancer or immunosuppressive chemotherapy; regular use of digoxin, amiodarone, verapamil or protease inhibitors; chronic liver disease with hepatic failure; and inability to understand the consent Form.

Setting

Patients were evaluated daily, and blood collection for general laboratory tests were performed at days 0, 2, 4 and 7 if discharge did not happen before. Twelve derivations ECG were performed each 24–48 hours. The definition of requirement of oxygen supply was a measure of SatO2 ≤92% at rest. The criteria for discharging patients from the hospital were the absence of dyspnoea and SatO2 >92%, both for at least 48 consecutive hours.

Main endpoints

The primary endpoints were clinical parameters, such as the time of need for supplemental oxygen; time of hospitalisation; need for admission and length of stay in ICU; and death rate and causes of mortality. As secondary endpoints, we assessed clinical and laboratory parameters: measures of serum CRP, serum lactate dehydrogenase (LDH) and relation neutrophil to lymphocyte of peripheral blood samples from day 0 to day 7; the number, type and severity of adverse events; frequency of interruption of the study protocol due to adverse events; and frequency of QT interval above 450 ms.

Statistical analysis

We present descriptive statistics as absolute numbers and percentage or median and IQR. Absolute numbers and percentage were compared with Fisher’s exact test. Comparisons of clinical and laboratory parameters expressed in median and IQR were done through Mann-Whitney test. Additionally, Kaplan-Meier survival curves were performed, with analysis by Mantel-Haenszel log rank test, to compare the time to abandon supplemental oxygen and time to discharge between the groups. Kruskall-Wallis test was used for comparisons of laboratory exams at the four blood collection times, followed by Dunn’s Multiple Comparison test. For all tests, p<0.05 was considered for statistical significance.

Results

Participants

The enrolment started on 11 April and stopped on 31 August 2020. We assessed 131 patients and included 75 for randomisation as shown in figure 1.The baseline laboratory and clinical characteristics of the 72 patients who completed the study are presented in table 1. All patients received the institutional protocol treatment with hydroxychloroquine, azithromycin and heparin. Twenty-five and 24 patients, respectively, for colchicine and placebo groups received methylprednisolone. No treatment, institutional or interventional, was interrupted due to adverse events. The groups were similar in terms of demographic characteristics, clinical status and laboratory evaluation at baseline. There was a slight predominance of men in the colchicine group. Moreover, 35 out of 36 patients in the colchicine group had body mass index (BMI) above 25.0 kg/m2 (data not shown) and the group median arterial oxygen partial pressure (PaO2)/fractional inspired oxygen (FiO2) was 50.0 lower, for both parameters with no statistical difference.

Outcomes

At least half of the patients receiving colchicine stopped using supplemental oxygen for the fourth day (median 4.0; IQR 2.0–6.0 days) of intervention, while the same happened to the patients receiving placebo on the seventh day (median 6.5; IQR 4.0–9.0 days; p<0.001). Significant difference (p=0.003) between the groups was found for the time of hospitalisation, in detriment of the placebo group (median 7.0; IQR 5.0–9.0 days vs median 9.0; IQR 7.0–12.0 days).

Two and four patients, respectively, for colchicine and placebo groups needed admission to ICU. The ICU assistant team preferred to stop the study intervention for one patient per group. For this reason, these two patients were taken off the final analysis. Although the interventions were stopped, both patients were followed for some main outcomes: the time of treatment before ICU admission was 2 and 3 days, the length of stay in ICU was 12 and 11 days and the time of hospitalisation was 23 and 26 days, respectively, for colchicine and placebo groups. Two patients of the placebo group died (two male; death rate of 6%) and none of the colchicine group. The cause of death was ventilator-associated pneumonia in both cases. No statistical analysis was performed for the need for admission in ICU and the death rate due to the small number of events for each group.

Kaplan-Meier survival curves for the need for supplemental oxygen and the maintenance of hospitalisation are depicted in figures 2 and 3, respectively. At day 2, 67% versus 86% of patients maintained the need for supplemental oxygen, while at day 7, these values were 9% versus 42%, in the colchicine and placebo groups, respectively (log rank test, 10.6; p=0.001). Hospitalisation was maintained for 42% versus 72% of patients at day 7 and 9% versus 39% at day 10, in the colchicine and placebo groups, respectively (log rank test, 9.2; p=0.002). Both outcomes presented similar behaviour, once the last is at large extension a consequence of the first one.

＜Figure2＞

＜Figure3＞

We evaluated some laboratory parameters as secondary endpoints. Figure 4 and online supplemental figures 1 and 2 show the temporal variations of serum CRP and LDH and peripheral blood relation neutrophil to lymphocyte, respectively, from day 0 to day 7. Starting both groups at similar levels of serum CRP, at day 4, patients of the colchicine group presented significant reduction compared with themselves and with patients of the placebo group at day 0 (p<0.001). It is possible to observe that serum levels of CRP became different between the groups in the interval between days 2 and 4, with values near normal range (median=1.3 mg/dL) for the colchicine group at day 4. For the placebo group, statistical difference compared with the baseline occurred at day 7 (p<0.001), but no return to normal range of median CRP was observed at that time. The post-test for LDH showed a difference between day zero and days 4 and 7 for the colchicine group. No difference inter and intragroup for the relation neutrophil to lymphocyte was obtained.

＜Figure4＞

The majority of adverse events (table 2) was mild (exception for pneumonia) and, to some extent, attributable to the viral infection itself or its complications, not entailing patients withdrawal. It seems to be the case of aspartate aminotransferase and alanine aminotransferase transient elevations, under 3× the upper limit of normal, with no difference between the groups (data not shown). New or worsened diarrhoea was more frequent in the intervention group (17% vs 6%). None of the patients suffered dehydration, and the diarrhoea was controlled with the prescription of an antisecretory agent (eg, racecadotril). Cardiac adverse events, undoubtedly the main issue on the use of hydroxychloroquine and/or azithromycin for COVID-19, did not have an augmented frequency by adding colchicine. No participant had QT interval above 450 ms during the observational period (data not shown). No difference between the groups on QT interval variation was observed from the value of day 0 to the highest value.

Discussion

We presented the results of a randomised, double-blinded, placebo-controlled clinical trial of colchicine for COVID-19. Patients receiving colchicine abandoned oxygen supplementation earlier than those receiving placebo (median: 4.0 vs 6.5 days) and the time until discharge followed a similar tendency. These two primary endpoints have relevance for daily practice in the COVID-19 pandemic, by reducing the length of hospitalisation, consequently diminishing costs and the need for hospital beds. Besides that, the treatment with colchicine is not expensive.

Mainly obese women represented the study population (39 women and 33 men). Although the susceptibility to SARS-CoV-2 infection seems not related to gender, the clinical presentation of COVID-19 was proved worse in men, with higher rates of mortality.¹⁹ We also could not evaluate mortality rate by gender, but the two patients who died were men. The higher frequency of women in our study population comes from the fact that 19 out of 29 patients that met exclusion criteria were men with critical forms of the disease due to respiratory failure at the baseline evaluation.

A wide variation of the magnitude of systemic inflammation, reflected in the broad ranges of serum CRP (2.3–28.2 mg/dL) and SatO2/FiO2 (65–400), assures that this sample of patients is widely representative of the hospitalisations due to COVID-19 pneumonia. Taking into account the effect on both, the CRP curve and the need for supplemental oxygen, colchicine use seems promising if we consider that the systemic inflammation was safely halted in a shorter period compared with the standard treatment.

Six patients needed ICU admission and all of them had SatO2/FiO2 <100 at enrolment. It is certain that the effect of colchicine in reducing systemic inflammation is not enough for every patient and that for some of them no intervention would prevent respiratory failure. These six patients received methylprednisolone. Worthy of mention, the concomitant use of a glucocorticoid should not be considered to have influence on the more favourable evolution of the intervention group, once both groups had similar number of randomised patients receiving the drug.

The study protocol used the maximum safe daily dose of colchicine²⁰ considering a body weight of 50 kg, that is, 0.030 mg/kg. Body weight of the participants ranged from 62 to 145 kg, which results, for some patients, in a daily dose under 0.015 mg/kg, the minimal dose for chronic use of colchicine. This range was maintained, even for the first 24 hours, aiming to avoid the occurrence or worsening of diarrhoea, a frequent manifestation of COVID-19.

Only 5 out of 72 analysed patients had normal values of BMI, four of them randomised to the placebo group. Systemic inflammation is a common characteristic linking obesity, metabolic syndrome and elevated cardiovascular risk,^{21 22} with highlighted role for IL-1β and NLRP3 inflammasome. The adipose tissue of obese has macrophage type 1 as the main resident phagocytic cell. This subgroup of macrophages is primed to secrete proinflammatory cytokines, such as IL-1β, IL-6 and TNF.²³ Some groups found obesity a risk factor for severity of COVID-19, as reported in a systematic review with meta-analysis.²⁴ Because of the small number of non-obese in our study population, we cannot simply extrapolate our findings to non-obese individuals of the general population, once the action of colchicine may be limited to those in which the association of obesity and inflammation has a pivotal pathophysiological effect.

Colchicine was already tested as protective against ischaemic events postmyocardial infarction with some success,²⁵ and it was found to ameliorate endothelial function in a subgroup of patients with coronary disease and augmented peripheral blood leucocyte count.²⁶

Recently, our group reported two possible mechanisms involved on lung inflammation in COVID-19. First, we reported the possible role for neutrophil extracellular traps on lung inflammation in COVID-19.⁶ Second, we found that the activation of NLRP3 inflammasome was associated with the severity of COVID-19 and poor clinical outcome.²⁷ One of the actions of colchicine is to reduce migration of leucocytes, mainly neutrophils, to inflamed tissues.⁹ Whatever the mechanism of action—inhibiting inflammasome, reducing neutrophil migration and activation or preventing endothelial damage–colchicine seems to be beneficial for the treatment of hospitalised patients with COVID-19. The markedly reduction of serum CRP levels between second and fourth days coincides with clinical recovery of the majority of patients. Most of the participants were in the second week of symptoms, a phase in which systemic inflammation becomes striking. It is very unlikely that colchicine has some antiviral effect.

Worthy of note is the fact that the drug did not contribute to hepatic or cardiac adverse events nor caused immunosuppression. Diarrhoea was not a limiting adverse event, and an antisecretory drug may be added when necessary.

The GReek Study in the Effects of Colchicine in Covid-19 Complications Prevention (GRECCO-19), an open-label randomised clinical trial, had some results recently published.¹⁵ The authors found that patients receiving colchicine were less prone to clinical deterioration, despite the fact that their serum levels of CRP showed no significant difference compared with those of patients not receiving the drug. For a matter of comparison, when analysing patients with body weight >60 kg in use of azithromycin (approximately 92%), patients of GRECCO-19 study received a total dose of 5.0 mg of colchicine in the first 5 days, while in our study, patients received 7.5 or 8.0 mg in the same period. This difference of dosage of ≥50% for the first 5 days may explain the evident reduction of serum CRP in the present study and justify the better evolution of the intervention group. Scarsi et al¹⁴ showed an association between treatment with colchicine and improved survival in a single-centre cohort of adult hospitalised patients with COVID-19 pneumonia and SARS. They conclude that their results may support the rationale of colchicine use for the treatment of COVID-19 and that the efficacy and safety must be determined in controlled clinical trials. Authors used the dose of 1.0 mg/day for all patients with reduction to 0.5 mg if diarrhoea occurred.

Our clinical trial has some limitations. The most evident is the reduced number of patients and the impossibility to evaluate the capacity of colchicine to avoid admission to ICU and reduce mortality. To balance this, the blinding and the control by a placebo arm strengthen our finds. The absence of mechanistic investigations, for example, measures of the plasmatic levels of cytokines, is another limitation. Our exclusion criteria were some kind of restrictive, such as the prohibition of some cardiovascular drugs. Much of this concern was related to drugs that could impair colchicine metabolism or excretion, but some concern was also due to the potential hazardous effect of hydroxychloroquine and azithromycin combined use for myocardial fibres. Finally, as patients were discharged, the number of blood samples reduced through the first week of observation and beyond, once it would not be appropriate to summon up the patients for new blood collections due to SARS-CoV-2 transmission possibility.

Conclusions

Patients who received colchicine in this randomised, double-blinded, placebo-controlled clinical trial presented better evolution in terms of the need for supplemental oxygen and the length of hospitalisation. Serum CRP was a laboratory marker of clinical improvement. Colchicine was safe and well tolerated. Clinical trials with larger numbers of patients should be conducted to further evaluate the efficacy and safety of colchicine as an adjunctive therapy for hospitalised patients with moderate to severe COVID-19.

References

1. 1 ↵Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020;46:846–8.doi:10.1007/s00134-020-05991-xpmid:http://www.ncbi.nlm.nih.gov/pubmed/32125452CrossRefPubMedGoogle Scholar

2. 1 ↵Guan W-J, Ni Z-Y, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708–20.doi:10.1056/NEJMoa2002032pmid:http://www.ncbi.nlm.nih.gov/pubmed/32109013CrossRefPubMedGoogle Scholar

3. 1 ↵Mandel M, Harari G, Gurevich M, et al. Cytokine prediction of mortality in COVID19 patients. Cytokine 2020;134:155190. doi:10.1016/j.cyto.2020.155190pmid:http://www.ncbi.nlm.nih.gov/pubmed/32673995PubMedGoogle Scholar

4. 1 ↵Wu Y, Huang X, Sun J, et al. Clinical characteristics and immune injury mechanisms in 71 patients with COVID-19. mSphere 2020;5:e00362–20.doi:10.1128/mSphere.00362-20pmid:http://www.ncbi.nlm.nih.gov/pubmed/32669467PubMedGoogle Scholar

5. 1 ↵Rodriguez-Morales J, Cardona-Ospina A, Gutiérrez-Ocampo E. Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis. Travel Med Infect Dis. 2020.Google Scholar

6. 1 ↵Veras FP, Pontelli MC, Silva CM, et al. SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology. J Exp Med 2020;217:e20201129. doi:10.1084/jem.20201129pmid:http://www.ncbi.nlm.nih.gov/pubmed/32926098CrossRefPubMedGoogle Scholar

7. 1 ↵Zhao C, Zhao W. Nlrp3 Inflammasome-A key player in antiviral responses. Front Immunol 2020;11:211. doi:10.3389/fimmu.2020.00211pmid:http://www.ncbi.nlm.nih.gov/pubmed/32133002CrossRefPubMedGoogle Scholar

8. 1 ↵Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol 2016;16:407–20.doi:10.1038/nri.2016.58pmid:http://www.ncbi.nlm.nih.gov/pubmed/27291964CrossRefPubMedGoogle Scholar

9. 1 ↵Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol 2015;16:343–53.doi:10.1038/ni.3123pmid:http://www.ncbi.nlm.nih.gov/pubmed/25789684CrossRefPubMedGoogle Scholar

10. 1 ↵Liantinioti G, Argyris AA, Protogerou AD, et al. The role of colchicine in the treatment of autoinflammatory diseases. Curr Pharm Des 2018;24:690–4.doi:10.2174/1381612824666180116095658pmid:http://www.ncbi.nlm.nih.gov/pubmed/29336247PubMedGoogle Scholar

11. 1 ↵Nuki G. Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr Rheumatol Rep 2008;10:218–27.doi:10.1007/s11926-008-0036-3pmid:http://www.ncbi.nlm.nih.gov/pubmed/18638431CrossRefPubMedGoogle Scholar

12. 1 ↵Safi R, Kallas R, Bardawil T, et al. Neutrophils contribute to vasculitis by increased release of neutrophil extracellular traps in Behçet's disease. J Dermatol Sci 2018;92:143–50.doi:10.1016/j.jdermsci.2018.08.010pmid:http://www.ncbi.nlm.nih.gov/pubmed/30237006PubMedGoogle Scholar

13. 1 ↵Piantoni S, Colombo E, Airò P, et al. The rationale for the use of colchicine in COVID-19: comments on the letter by Cumhur Cure M et al. Clin Rheumatol 2020;39:2489–90.doi:10.1007/s10067-020-05232-ypmid:http://www.ncbi.nlm.nih.gov/pubmed/32564213PubMedGoogle Scholar

14. 1 ↵Scarsi M, Piantoni S, Colombo E, et al. Association between treatment with colchicine and improved survival in a single-centre cohort of adult hospitalised patients with COVID-19 pneumonia and acute respiratory distress syndrome. Ann Rheum Dis 2020;79:1286–9.doi:10.1136/annrheumdis-2020-217712pmid:http://www.ncbi.nlm.nih.gov/pubmed/32732245Abstract/FREE Full TextGoogle Scholar

15. 1 ↵Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial. JAMA Netw Open 2020;3:e2013136. doi:10.1001/jamanetworkopen.2020.13136pmid:http://www.ncbi.nlm.nih.gov/pubmed/32579195PubMedGoogle Scholar

16. 1 ↵RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med 2020. doi:doi:10.1056/NEJMoa2021436. [Epub ahead of print: 17 Jul 2020].pmid:http://www.ncbi.nlm.nih.gov/pubmed/32678530Google Scholar

17. 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;323:1239–42.doi:10.1001/jama.2020.2648pmid:http://www.ncbi.nlm.nih.gov/pubmed/32091533CrossRefPubMedGoogle Scholar

18. 1 ↵Jin Y-H, Cai L, Cheng Z-S, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res 2020;7:4.doi:10.1186/s40779-020-0233-6pmid:http://www.ncbi.nlm.nih.gov/pubmed/32029004CrossRefPubMedGoogle Scholar

19. 1 ↵Mi J, Zhong W, Huang C, et al. Gender, age and comorbidities as the main prognostic factors in patients with COVID-19 pneumonia. Am J Transl Res 2020;12:6537–48.pmid:http://www.ncbi.nlm.nih.gov/pubmed/33194050PubMedGoogle Scholar

20. 1 ↵Niel E, Scherrmann J-M. Colchicine today. Joint Bone Spine 2006;73:672–8.doi:10.1016/j.jbspin.2006.03.006pmid:http://www.ncbi.nlm.nih.gov/pubmed/17067838CrossRefPubMedWeb of ScienceGoogle Scholar

21. 1 ↵Esser N, Legrand-Poels S, Piette J, et al. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract 2014;105:141–50.doi:10.1016/j.diabres.2014.04.006pmid:http://www.ncbi.nlm.nih.gov/pubmed/24798950CrossRefPubMedGoogle Scholar

22. 1 ↵Rocha VZ, Libby P. Obesity, inflammation, and atherosclerosis. Nat Rev Cardiol 2009;6:399–409.doi:10.1038/nrcardio.2009.55pmid:http://www.ncbi.nlm.nih.gov/pubmed/19399028CrossRefPubMedWeb of ScienceGoogle Scholar

23. 1 ↵Chawla A, Nguyen KD, Goh YPS. Macrophage-Mediated inflammation in metabolic disease. Nat Rev Immunol 2011;11:738–49.doi:10.1038/nri3071pmid:http://www.ncbi.nlm.nih.gov/pubmed/21984069CrossRefPubMedGoogle Scholar

24. 1 ↵Yang J, Hu J, Zhu C. Obesity aggravates COVID-19: a systematic review and meta-analysis. J Med Virol 2020;30.Google Scholar

25. 1 ↵Tardif J-C, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381:2497–505.doi:10.1056/NEJMoa1912388pmid:http://www.ncbi.nlm.nih.gov/pubmed/31733140CrossRefPubMedGoogle Scholar

26. 1 ↵Kajikawa M, Higashi Y, Tomiyama H, et al. Effect of short-term colchicine treatment on endothelial function in patients with coronary artery disease. Int J Cardiol 2019;281:35–9.doi:10.1016/j.ijcard.2019.01.054pmid:http://www.ncbi.nlm.nih.gov/pubmed/30683457PubMedGoogle Scholar

27. 1 ↵Rodrigues TS, de Sá KSG, Ishimoto AY, 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:e20201707. doi:10.1084/jem.20201707pmid:http://www.ncbi.nlm.nih.gov/pubmed/33231615PubMedGoogle Scholar