Background
Back in April we first wrote about a possible connection between the increasingly above-average mortality rates in European countries and their widespread use of non-steroidal anti-inflammatory drugs (NSAIDs) such as Ibuprofen.
We raised the question as to whether the cyclooxygenase (COX) enzyme inhibitor function of NSAIDs either intefered with or amplified the angiotensin-converting enzyme 2 (ACE2) enzyme function, given that SARS-CoV-2 binds to ACE2 receptors on cellular membranes. While pretty much everything is known about NSAIDs and COX (after all, it is what they are designed to target), at the time less was known about ACE2’s role in SARS-CoV-2.
As much more is now known about the significance of ACE and ACE2, it’s worth revisiting any link between COX and ACE inhibitors.
Reason One – Cyclooxygenase
Cyclooxygenase comes in two isoforms – COX1 and COX2 – both of which create prostaglandin, a hormone that manages the immediate response to the body detecting invasive infection or tissue damage. As previously set out here, this immediate response is inflammation, effectively setting up a cordon around the localised area and sending in the body’s rapid reaction force to deal with it. Inflammation consists of the four components: pain, heat, redness and swelling. So in this respect, COX1 and COX2 are good, particularly COX2 that has a dual function of setting up the cordon and sorting out the problem.
However, as most people generally don’t like to feel pain, NSAIDs were created to inhibit the COX function. In minor tissue damage, for example a muscle injury, that’s absolutely fine and you get the benefit of the healing but without the pain signalling. For invasive infection however it is less clear cut as the key signals of inflammation are signalling the presence of a pathogen.
In respect of SARS-CoV-2, those with severe symptoms of COVID-19 will often develop pneumonia as a result of cellular damage in the lungs. As NSAIDs inhibit key components of the inflammatory response, notably pain and heat (fever), they may prevent the initial detection of the pneumonia or other secondary infection. It is like yanking the battery out of the smoke alarm because the beeping is really annoying whenever it goes off, without checking whether it is that sourdough bread catching in the toaster again…or something different this time. Voirot et al go further in finding that there is a causal relationship between taking NSAIDs before hospital admission and subsequent pneumonia infection on a protracted basis.
Reason 2 – Angiotensin-converting enzyme
Angiotensin II is a hormone that narrows blood vessels and is a key factor in hypertension (high blood pressure) and other cardiovascular conditions. A standard treatment is through the use of angiotensin-converting enzyme (ACE) inhibitors. SARS-CoV-2’s spike glycoprotein binding to ACE2 receptors results in disruption to the regulation of the ‘good’ ACE2→ angiotensin1-7→ Mas receptor axis and the ‘bad’ ACE→ angiotensin II→ AT1 receptor axis. As ACE inhibitors are taken to regulate the latter then clearly you don’t want to interfere with their function.
Both COX-produced prostaglandins and ACE inhibitors are vasodilators, i.e. they widen blood vessels; prostaglandins in order to control and heal infection, and ACE inhibitors to prevent vasoconstriction, i.e. the narrowing of blood vessels. NSAID inhibition of the COX function causes a vasoconstrictive counterfunction, i.e. it works against ACE inhibitors and against the synthesis of angiotensin1-7 by ACE (from angiotensin1-9) and ACE2 (from angiotensin II).
There is also a more focused issue arising from COX inhibition which is increased water retention. This can lead to pulmonary oedema, which is the build-up of fluid in the lungs, making it difficult to breathe. This is then compounded by the disruption to the ‘good’ ACE2→ angiotensin1-7→ Mas receptor axis.
Conclusions
In a very comprehensive study earlier this year, Zolk et al wrote that;
“NSAIDs should be used at the lowest effective dose for the shortest possible period.”
While this does not suggest their use is bad in that they could worsen viral colonisation, invasion or infection, neither is it a ringing endorsement. The qualification using ‘lowest‘ and ‘shortest‘ points toward ‘only if you have to’ and effectively suggests using alternate medications if available.
Therefore, if there is nothing else in the medicine cabinet or at the all night garage fine, take some as a one-off, but don’t do what all too many people do when feeling slightly under the weather: take the maximum dosage and keep on taking them.