BENEFICIAL EFFECTS ON COLCHICINE FOR MODERATE TO SEVERE COVID 19 : a randomised,

double blinded, placebo controlled clinical trial

Maria Isabel Lopes

2 possible mechanism involved in lung inflammation of COVID :

- Neutrophil extracellular trap (NET) on lung inflammation COVID (due neutrophils release NET which is toxic to
lung epithelial cells)
- Activation of NRLP3 inflammasome was associated with severity and poor clinical outcome

Mechanism of colchicine in COVID :

- Reduce migration of leukocytes mainly neutrophils to inflamed tissue
- Inhibiting NRLP3 inflammasome
- Activation/preventing endothelial damage

Drug didn’t contribute to hepatic/cardiac adverse events nor caused immunosupression

Research :
- The need of oxygen supplementation (colchicine vs control)
o At day 2 : 67% vs 86%
o At day 7 : 9% vs 42%
- Length of hospitalisation
o Day 7 : 42% vs 72%
o Day 10 : 9% vs 39%
- Serum CRP
o Starting with similar amount of CRP  at day 4 there is significant reduction compared to placebo
(p<0.001)

Another research (GRECCO-19) :

- Colchicine group were less prone to clinical deterioration despite the fact that their serum CRP showed no
significant difference compared to placebo
- GRECCO use 5mg colchicine in 5 days, than this research use 7.5-8mg  then there is a reduction in serum CRP
in this research  means that by increasing the dosage up to 50% may decrease the serum CRP

COLCHICINE REDUCES LUNG INJURY IN EXPERIMENTAL ARDS

Jocelyn Dupuis

Colchicine Mechanism in ARDS

Colchicine didn’t reduce the circulating neutrophilia, but nevertheless markedly reduced lung recruitment of
neutrophils. Release of neutrophils elastase, myeloperoxidase and NETs contribute to ALI leading to pulmo edema,
alveolar wall thickening, and altered gas exchanges with reduced of PaO2 and increased PaCO2.
 Following the reduction of lung neutrophils recruitment, all of these parameters were improved by colchicine
therapy
 The lack of effect of colchicine on increased circulating neutrophils suggests that treatment didn’t interfere with
early signalling events responsible for bone marrow release neutrophils

Benefit of colchicine was related to a reduction in a lung recruitment and activation of neutrophils

Experimental using oleic acid to induce ARDS in rats

Injection of high concentration of oleic acid  induce rapid high permeability lung edema with inflammation & impaired
gas exchanges and mechanics  causing lung injury with neutrophils infiltration & production of cytokines and
chemokines
 - Acute lung damage caused by oleic acid is characterized by important neutrophils accumulation & activation
leading to intense inflammation, concordant (sesuai) to pathophysiology of human ARDS
- Similarities happen to covid related ARDS  among the potential inflammatory pathways shared by oleic acid
toxicity and covid is the NRLP3 inflammasome pathway, which acts as a mechanism triggering the inflammation
response to covid infection (which colchicine inhibits the NRLP3 inflammasome pathway)

Inflammatory cytokine storm & a state of hypercoagulability are 2 main important pathophysiological mechanism in
COVID
- Cytokine storm  responsible for the ALI in COVID
o Increases level of TNF a, IL-1, IL-6, and IL-10 are found  particularly IL-6 is associated with poor
outcomes in COVID

Colchicine
- Anti mitotic drug  it binds to unpolymerized tubulin to form tubulin colchicine complexes  thereby inhibiting
their polymerization  as a result, it blocks the cell division during the metaphase mitosis
- Also inhibits NRLP3 inflammasome  leading to decrease levels of IL-1b, IL-18, IL-6, CRP, and reduction of
mortality from major cardiovascular events

Research
- Inflammatory markers
o Significant reduction from the baseline of ferritin, CRP, and d dimer in colchicine group
- Primary outcomes (colchicine vs control)
o Lower rate intubation 47.1% vs 87.2%
o Lower mortality 47.1% vs 80.8%
o Higher discharge rate 52.9% vs 19.2%
o But the mortality in all intubated patients and duration of hospitalization was not statistically
different between 2 groups
- Hypothesize that patients with progressing/established ARDS may have crossed the point where colchicine
would no longer be effective in controlling the inflammatory cascade. This may explain the equally high
mortality in intubated patients for both colchicine and control groups (93.8% vs 88.2%).
o Early administration of colchicine may be paramount in the timely prevention of an acute
hyperinflammatory state leading to deterioration
- Both colchicine and control groups showed an overall decrease in LDH levels
o But only in colchicine group showed an overall decrease in CRP and ferritin levels
o D dimer also had a significant decrease in colchicine
 Direct endothelial injury caused by inflammatory cytokines has been shown to cause a state of
hypercoagulability, which can lead to an increase in D dimer levels  colchicine may be
responsible for the lower rise of D dimer levels, which could function as an adjunctive to
anticoagulants