Colchicine for Early COVID-19? Trial May Support Oral Therapy at Home

But some find science-by-press-release troubling.

Anti-inflammatory oral drug colchicine improved COVID-19 outcomes for patients with relatively mild cases, according to certain topline results from the COLCORONA trial announced in a brief press release.

Overall, the drug used for gout and rheumatic diseases reduced risk of death or hospitalizations by 21% versus placebo, which “approached statistical significance.”

However, there was a significant effect among the 4,159 of 4,488 patients who had their diagnosis of COVID-19 confirmed by a positive PCR test:

  • 25% fewer hospitalizations
  • 50% less need for mechanical ventilation
  • 44% fewer deaths

If full data confirm the topline claims — the press release offered no other details, and did not mention plans for publication or conference presentation — colchicine would become the first oral drug proven to benefit non-hospitalized patients with COVID-19.

“Our research shows the efficacy of colchicine treatment in preventing the ‘cytokine storm’ phenomenon and reducing the complications associated with COVID-19,” principal investigator Jean-Claude Tardif, MD, of the Montreal Heart Institute, said in the press release. He predicted its use “could have a significant impact on public health and potentially prevent COVID-19 complications for millions of patients.”

Currently, the “tiny list of outpatient therapies that work” for COVID-19 includes convalescent plasma and monoclonal antibodies, which “are logistically challenging (require infusions, must be started very early after symptom onset),” tweeted Ilan Schwartz, MD, PhD, an infectious diseases researcher at the University of Alberta in Edmonton.

The COLCORONA findings were “very encouraging,” tweeted Martin Landray, MB ChB, PhD, of the Big Data Institute at the University of Oxford in England. His group’s RECOVERY trial has already randomized more than 6,500 hospitalized patients to colchicine versus usual care as one of the arms of the platform trial, though he did not offer any findings from that study.

“Different stage of disease so remains an important question,” he tweeted. “Maybe old drugs can learn new tricks!” Landray added, pointing to dexamethasone.

A small open-label, randomized trial from Greece had also shown less clinical status deterioration in hospitalized patients on colchicine.

“I think this is an exciting time. Many groups have been pursuing lots of different questions related to COVID and its complications,” commented Richard Kovacs, MD, immediate past-president of the American College of Cardiology. “We’re now beginning to see the fruit of those studies.”

The COLCORONA announcement came late Friday, following closely on the heels of the topline results from the ACTIVE-4a, REMAP-CAP, and ATTACC trials showing a significant morbidity and mortality advantage to therapeutic-dose anticoagulation in non-ICU patients in the hospital for COVID-19.

COLCORONA was conducted remotely, without in-person contact, with participants across Canada, the U.S., Europe, South America, and South Africa. It randomized participants double-blind to colchicine 0.5 mg or a matching placebo twice daily for the first 3 days and then once daily for the last 27 days.

Participants were ages 40 and older, not hospitalized at the time of enrollment, and had at least one risk factor for COVID-19 complications: age 70-plus, obesity, diabetes, uncontrolled hypertension, known asthma or chronic obstructive pulmonary disease, known heart failure, known coronary disease, fever of ≥38.4°C (101.12°F) within the last 48 hours, dyspnea at presentation, or certain blood cell abnormalities.

It had been planned as a 6,000-patient trial, but whether it was stopped for efficacy at a preplanned interim analysis or for some other reason was not spelled out in the press release. Whether the PCR-positive subgroup was preplanned also wasn’t clear. Key details such as confidence intervals, adverse effects, and subgroup results were omitted as well.

While a full manuscript is reportedly underway, “we don’t know enough to bring this into practice yet,” argued Kovacs.

The centuries-old drug has long been used for gout and arthritis and more recently for pericarditis along with showing promise in cardiovascular secondary prevention.

However, the drug isn’t as inexpensive in the U.S. as in Canada, Kovacs noted.

Some physicians also warned about the potential for misuse of the findings and attendant risks.

Dhruv Nayyar, MD, of the University of Toronto, tweeted that he has already had “patients inquiring why we are not starting colchicine for them. Science by press release puts us in a difficult position while providing care. I just want to see the data.”

Angela Rasmussen, MD, a virologist with the Georgetown Center for Global Health Science and Security’s Viral Emergence Research Initiative in Washington, agreed, tweeting: “When HCQ [hydroxychloroquine] was promoted without solid data, there was at least one death from an overdose. We don’t need people self-medicating with colchicine.”

As was the case with hydroxychloroquine before the papers proved little efficacy in COVID-19, Kovacs told MedPage Today: “We always get concerned when these drugs are repurposed that we might see an unintended run on the drug and lessen the supply.”

Citing the well-known diarrheal side effect of colchicine, infectious diseases specialist Edsel Salvana, MD, of the University of Pittsburgh and University of the Philippines in Manila, tweeted a plea for use only in the trial-proven patient population with confirmed COVID-19 — not prophylaxis.

The dose used was on par with that used in cardiovascular prevention and other indications, so the diarrhea incidence would probably follow the roughly 10% rate seen in the COLCOT trial, Kovacs suggested.

In the clinic, too, there are some cautions. As Elin Roddy, MD, a respiratory physician at Shrewsbury and Telford Hospital NHS Trust in England, tweeted: “Lots of drug interactions with colchicine potentially — statins, macrolides, diltiazem — we have literally been running up to the ward to cross off clarithromycin if RECOVERY randomises to colchicine.”

Blocking the deadly cytokine storm is a vital weapon for treating COVID-19

https://theconversation.com/blocking-the-deadly-cytokine-storm-is-a-vital-weapon-for-treating-covid-19-137690?utm_medium=email&utm_campaign=Latest%20from%20The%20Conversation%20for%20May%2022%202020%20-%201630015658&utm_content=Latest%20from%20The%20Conversation%20for%20May%2022%202020%20-%201630015658+Version+A+CID_f23e0e73a678178a59d0287ef452fe33&utm_source=campaign_monitor_us&utm_term=Blocking%20the%20deadly%20cytokine%20storm%20is%20a%20vital%20weapon%20for%20treating%20COVID-19

Blocking the deadly cytokine storm is a vital weapon for treating ...

The killer is not the virus but the immune response.

The current pandemic is unique not just because it is caused by a new virus that puts everyone at risk, but also because the range of innate immune responses is diverse and unpredictable. In some it is strong enough to kill. In others it is relatively mild.

My research relates to innate immunity. Innate immunity is a person’s inborn defense against pathogens that instruct the body’s adaptive immune system to produce antibodies against viruses. Those antibody responses can be later used for developing vaccination approaches. Working in the lab of Nobel laureate Bruce Beutler, I co-authored the paper that explained how the cells that make up the body’s innate immune system recognize pathogens, and how overreacting to them in general could be detrimental to the host. This is especially true in the COVID-19 patients who are overreacting to the virus.

Cell death – a chess game of sacrifice

I study inflammatory response and cell death, which are two principal components of the innate response. White blood cells called macrophages use a set of sensors to recognize the pathogen and produce proteins called cytokines, which trigger inflammation and recruit other cells of the innate immune system for help. In addition, macrophages instruct the adaptive immune system to learn about the pathogen and ultimately produce antibodies.

To survive within the host, successful pathogens silence the inflammatory response. They do this by blocking the ability of macrophages to release cytokines and alert the rest of the immune system. To counteract the virus’s silencing, infected cells commit suicide, or cell death. Although detrimental at the cellular level, cell death is beneficial at the level of the organism because it stops proliferation of the pathogen.

For example, the pathogen that caused the bubonic plague, which killed half of the human population in Europe between 1347 and 1351, was able to disable, or silence, people’s white blood cells and proliferate in them, ultimately causing the death of the individual. However, in rodents the infection played out differently. Just the infected macrophages of rodents died, thus limiting proliferation of the pathogen in the rodents’ bodies which enabled them to survive.

The “silent” response to plague is strikingly different from the violent response to SARS-CoV-2, the virus that causes COVID-19. This suggests that keeping the right balance of innate response is crucial for the survival of COVID-19 patients.

Vintage engraving of a dead cart collecting the bodies of plague victims during the last Great Plague of London, which extended from 1665 to 1666. duncan1890/ Getty Images

Path to a cytokine storm

Here’s how an overreaction from the immune system can endanger a person fighting off an infection.

Some of the proteins that trigger inflammation, named chemokines, alert other immune cells – like neutrophils, which are professional microbe eaters – to convene at the site of infections where they can arrive first and digest the pathogen.

Others cytokines – such as interleukin 1b, interleukin 6 and tumor necrosis factor – guide neutrophils from the blood vessels to the infected tissue. These cytokines can increase heartbeat, elevate body temperature, trigger blood clots that trap the pathogen and stimulate the neurons in the brain to modulate body temperature, fever, weight loss and other physiological responses that have evolved to kill the virus.

When the production of these same cytokines is uncontrolled, immunologists describe the situation as a “cytokine storm.” During a cytokine storm, the blood vessels widen further (vasolidation), leading to low blood pressure and widespread blood vessel injury. The storm triggers a flood of white blood cells to enter the lungs, which in turn summon more immune cells that target and kill virus-infected cells. The result of this battle is a stew of fluid and dead cells, and subsequent organ failure.

The cytokine storm is a centerpiece of the COVID-19 pathology with devastating consequences for the host.

When the cells fail to terminate the inflammatory response, production of the cytokines make macrophages hyperactive. The hyperactivated macrophages destroy the stem cells in the bone marrow, which leads to anemia. Heightened interleukin 1b results in fever and organ failure. The excessive tumor necrosis factor causes massive death of the cells lining the blood vessels, which become clotted. At some point, the storm becomes unstoppable and irreversible.

Drugs that break the cytokine storm

One strategy behind the treatments for COVID is, in part, based in part on breaking the vicious cycle of the “cytokine storm.” This can be done by using antibodies to block the primary mediators of the storm, like IL6, or its receptor, which is present on all cells of the body.

Inhibition of tumor necrosis factor can be achieved with FDA-approved antibody drugs like Remicade or Humira or with a soluble receptor such as Enbrel (originally developed by Bruce Beutler) which binds to tumor necrosis factor and prevents it from triggering inflammation. The global market for tumor necrosis factor inhibitors is US$22 billion.

Drugs that block various cytokines are now in clinical trials to test whether they are effective for stopping the deadly spiral in COVID-19.