Kalil and Stebbing published their data in The Lancet Respiratory Medicine on 1st September.
Antibacterial, antifungal, antiviral, and antiparasitic treatments developed in the past century have improved survival outcomes, even in high-mortality conditions such as sepsis. This is a condition that is mostly caused by bacteria but can also be due to other infections.
In the 21st century, of all therapies that have improved the outcomes of patients with sepsis, appropriate and early administration of antibiotics has been shown to be the most effective therapy to save lives.
However, despite highly effective antibiotics that can kill microorganisms causing sepsis, and cultures showing eradication of these organisms, overall mortality from the condition remains high.
In part, this high mortality might be explained by dysregulated immune responses arising from redundant pathways in the human immune system, which have developed – along with the array of defence mechanisms involving the innate and adaptive responses, inflammation, and coagulation – as a result of the selective pressure of thousands of years of exposure to infections, zoonoses, and resulting epidemics and pandemics.
This dysregulated immune response can be as harmful as, or more harmful than, the pathogens themselves.
Accordingly, two original studies showed significant reduction in mortality due to sepsis among solid organ transplant recipients compared with patients without transplants.
This finding suggests that immunosuppressive drugs, required lifelong to avoid transplant graft rejection, might have been protective by decreasing dysfunctional responses to sepsis. These lessons learned from bacterial sepsis are highly relevant in the context of COVID-19 treatment.
Although one antiviral, Remdesivir, has already shown significant clinical benefits in hospitalised patients with COVID-19, death from COVID-19 can occur because of a dysregulated immune response.
This fact poses the question of whether any host immune interventions could improve the survival of patients with COVID-19. Again, similar to bacterial sepsis, studies evaluating steroid use in COVID-19 have produced both positive and negative results.
However, the only positive study was an open-label trial, and no placebo-controlled double-blind studies have shown positive results to date.
Another immunomodulatory approach that has been evaluated is the use of Janus kinase inhibitors (JAK) – Baricitinib, an inhibitor of JAK1 and JAK2 has been appraised in artificial intelligence and mechanistic laboratory studies and human clinical trials, with multiple mechanisms of action identified.
Potential side effects of the drug, such as secondary infections and venous thrombosis, are related to changes in the inflammatory and coagulation cascades. However, these side effects have been rare in patients with rheumatoid arthritis – the approved indication for Baricitinib.
Marconi and colleagues assessed the use of Baricitinib in a randomised, placebo-controlled double-blind trial and described it in The Lancet Respiratory Medicine.
Importantly, the study’s randomisation was done strictly. The trial was conducted in 101 centres across 12 countries and enrolled 1525 patients.
Compared with placebo, patients who received Baricitinib had a 38.2% relative reduction and 5 percentage point’s absolute reduction in 28-day all-cause mortality.
No other anti-COVID-19 therapy has shown such a profound reduction in mortality.
For comparison, the only other two immunomodulatory treatments that were associated with a reduction in mortality were dexamethasone, which showed a 17% relative reduction and tocilizumab, which showed a 15% relative reduction. However, these treatments were assessed in open-label trials with a high-risk of bias.
The safety of Baricitinib was almost identical to that of placebo in more than 2500 patient. In fact, in one study, the number of secondary infections was significantly lower in the Baricitinib group than in the placebo group, suggesting that the immunomodulation provided by Baricitinib might be protective and not as immunosuppressive as other drugs such as steroids.
In fact, the combination of Baricitinib with steroids was not associated with more infections and this finding confirmed the safety profile but also provided reassurance for the first time that the combination of Baricitinib and steroids might be safe. Because both Baricitinib and steroids come in tablet form and are affordable, they lend themselves to use in low income and middle income countries. Baricitinib has few drug interactions, is excreted largely unchanged and can be used in older patients with comorbidities.
This is an exciting study which is encouraging and suggests that there are treatments now to be found which can help prevent mortality from COVID-19 disease.
LGP, the leading London doctors’ clinic in Harley Street provides full support for all aspects of COVID-19 infection from diagnosis including:
- PCR swabs including Day 2 Covid Testing
- Lateral flow antigen tests
- A COVID assist service for those suffering with COVID-19
- A Long COVID service involving a multidisciplinary team approach for those with Long COVID.
Dr Paul Ettlinger
Founder, The London General Practice