esearchers reported this week in Science Immunology that acalabrutinib, a
drug approved by the FDA for lymphoid malignancies, blocks cytokine storm in
COVID-19.
Acalabrutinib is an inhibitor of an enzyme called Bruton's (or Bruton) tyrosine kinase. What the heck, you might ask, is Bruton's tyrosine kinase? More commonly known simply as Btk, it's a protein found in B cells that activates the phospholipase enzyme PLC-γ, which hydrolyzes PIP2 (phosphatidylinositol 4,5-bisphosphate) to form diacylglycerol and inositol triphosphate, which are important signaling molecules. Btk is required for the development and functioning of B cells, which make antibodies. Patients lacking Btk have a genetic disease called Bruton's X-linked agammaglobulinemia, or XLA, in which no B cells are produced.
You might think that inhibiting Btk, which would knock out antibody production, would be the worst possible strategy. But it turns out that Btk is also found in macrophages where it's activated by TLR7 and TLR8, which are pattern recognition receptors that signal the presence of single-stranded RNA to the inflammasome and thereby cause the release of cytokines. This suggests it might prevent cytokine storm.
The authors gave acalabrutinib to 19 patients with severe COVID-19 and evidence of inflammation. All were on ventilators or supplemental oxygen and some patients also got other drugs, including glucocorticoids (which aren't recommended for COVID-19) and hydroxychloroquine, but not tocilizumab (the anti-IL6 receptor antibody).
The paper is very confusing about what happened and gives an impression of utter chaos. As far as I can tell, here are the results:
| Group | Total N | Died | Discharged |
|---|---|---|---|
| Oxygen | 11 | 1 | 8 |
| Ventilator | 8 | 4* | 2 |
* One died of pulmonary embolism, one died after removal from ventilator, and two during treatment. One of the oxygen patients died later.
There was no control group, so there's no indication of whether it affected the course of the disease. The main effect was on markers of inflammation. C-reactive protein (CRP), a marker of inflammation, returned to normal in 10 of the 11 patients on oxygen and 2 of the 8 patients who were on ventilators. IL-6 (interleukin-6), the main cytokine behind cytokine storm, decreased in 5 of the 7 patients in which it was measured.
Other disease indicators, such as D-dimer (a marker of disseminated intravascular coagulation) didn't show any clear pattern. Oxygenation seemed to improve. No measurements of the virus itself were taken. Since the drug quite drastically suppresses their immune response, it would be necessary to give patients an antibiotic to prevent an opportunistic infection.
The results suggest that acalabrutinib might be useful against cytokine storm, but a clinical trial will be needed to determine whether this new drug has any benefit in the disease.
Given the high fatality rate in their preliminary trial, it's unlikely that anyone would ever run a clinical trial on this drug. The main significance of this paper is that it raises doubt about the benefit of inhibiting the innate immune system for infectious diseases. If these authors are right, it seems we must work upstream of cytokines and leave the macrophages alone.
jun 06 2020, 6:33 am. edited jun 09 2020, 7:25 am
