Should Ibuprofen Be Used to Combat Coronavirus Fever?
The mechanism of attack by the novel coronavirus SARS-CoV-2 on human cells is thought to involve a specific region, known as the receptor-binding domain (RMD), located on its now-infamous glycoprotein spikes; the RMD binds to a host receptor protein (angiotensin-converting enzyme 2 or ACE2) located on the surface of certain cells, most notably the epithelial cells of the lung. The novel coronavirus is reported to bind to ACE2 with approximately 10- to 20-fold higher affinity than the original SARS virus, which may help explain why it is more contagious.
On March 11, the medical journal Lancet published on-line a 1-page letter from scientists in Switzerland and Greece (Fang et al.) stating that the abundance of ACE-2 can be increased by certain drugs taken for diabetes and hypertension. The authors suggested that patients taking ACE2-increasing drugs for diabetes or hypertension might, therefore, be at increased risk for COVID-19.
However, they also observed that ACE2 could be increased by ibuprofen, which caused the French Health Minister, Olivier Véran, to tweet that taking anti-inflammatories such as ibuprofen to treat the symptoms of COVID-19 could be a factor in aggravating the infection, and proposed the use of paracetamol (acetaminophen) instead. The tweet apparently went viral, and an official alert on this topic was subsequently issued on March 14 by the French Ministry of Health, stating that use of NSAIDs (non-steroidal anti-inflammatory drugs, which include ibuprofen) to treat the fever resulting from COVID-19 should be prohibited and that paracetamol (acetaminophen) should be used instead, at a dose not to exceed 60 mg/kg/day and 3 g/day. (Both acetaminophen and ibuprofen are antipyretics – fever-reducers – but acetaminophen is not usually classed as an NSAID, having little anti-inflammatory activity.)
Garret Fitzgerald, Chair of the Department of Pharmacology at the University of Pennsylvania School of Medicine, quickly published a rebuttal of the French Ministry’s advice in Science (on-line on March 20), calling it misguided advice and stating that there is no scientific evidence to indicate that consumption of NSAIDs like ibuprofen by patients with mild symptoms could put them at risk of more severe disease. This view has been supported by the WHO, which tweeted on March 18 (using a double negative) that “Based on currently available information, WHO does not recommend against the use of ibuprofen” for people with COVID-19. FDA followed on March 19, stating the following:
"At this time, FDA is not aware of scientific evidence connecting the use of NSAIDs, like ibuprofen, with worsening COVID-19 symptoms. The agency is investigating this issue further and will communicate publicly when more information is available.”
Update on Asymptomatic Carriers
New studies continue to appear in which certain percentages of defined populations test positive for the COVID-19 but are asymptomatic, indicating that such carriers could unwittingly help spread the virus. For example, in one small study currently available as a pre-print by Nishiura et al. in the International Journal of Infectious Diseases, 13 out of a total of 565 Japanese citizens evacuated from Wuhan by early February tested positive for the virus, but 4 of the 13 (31%) never developed symptoms.
Another study, published March 12 as a Rapid Communication in Eurosurveillance (Mizumoto et al.) reports that, as of February 20, 328 (50.5%) out of a total of 634 people (many elderly) from the Diamond Princess cruise ship who had tested positive for coronavirus were asymptomatic, and the authors estimate that 17.9% remained so. Similar results have just been reported in an Early Release paper by CDC: following complete disembarkation of all passengers and crew from the Diamond Princess on February 24, 332 (46.5%) of the 712 people with positive results were asymptomatic at the time of testing.
At the other end of the infection spectrum, a MedRxiv pre-publication paper from Germany (Wölfel et al.) reports that the novel coronavirus actively replicates in the upper respiratory tract at the onset of infection, and is shed for a prolonged time in the sputum after symptoms end. This indicates that recovered patients who have become asymptomatic may still be infectious.
Is Reinfection a Possibility?
There have recently been a handful of anecdotal cases, originating from Japan and China and reported in the press, suggesting the possibility of reinfection of previously cleared COVID-19 victims by the novel coronavirus. See, for example, this report in the Los Angeles Times of March 13. However, the scientific consensus is that either (i) the tests were faulty, giving false negatives to clear a still-infected patient or a false positive when retesting a previously cleared patient; or (ii) the patient was never completely cured in the first place and suffered a relapse.
Dr. Anthony Fauci, the Director of NIAID, testified at Day 2 of the House Oversight Committee Hearing on Coronavirus Response on March 12, and participated in the following exchange with a Committee member:
- Q: Let me ask you a science question.
- A: Sure.
- Q: So I understand, if somebody got the virus three, four weeks ago, just thought they had the flu or a bad cold or something, recovered from it, they're now essentially immune from getting the virus again, is that correct?
- A: We have not formally proved it, but it is strongly likely that that's the case.
- Q: Okay.
- A: Because if this acts like... any other virus, once you recover, you won't get reinfected.
- Q: If they then came down with another cold, not related to coronavirus, thought maybe it was coronavirus, got tested, would that test show that they had gotten the coronavirus or not?
- A: If you do an antibody test, if you wait weeks and months after you have recovered, the antibody test will tell you whether that person was formerly infected with coronavirus.
- Q: Following up on that, if somebody has the immunity and in that sense is not a carrier, they could still transmit, right, if they were in a space where they got the virus somehow on their skin or something else so they could still put someone else at risk, even though in their mind they're thinking I'm immune so I'm safe to move around in a sense. Is that true? No?
- A: Absolutely not. Thank you for asking the question. Let's say I get infected. And whether I get sick or not, I clear the infection from my body. I do two tests 24 hours apart, which is the standard to say I'm no longer infected. A month and a half from now, you do an antibody test and that test is positive. I'm not transmitting to anybody because my body has already cleared the virus. So even though my antibody test says you were infected a month or two ago, right now if there's no virus in me, I'm not going to be able to transmit it to anyone.
Thus, Dr. Fauci, the nation’s leading expert on infectious diseases, has clearly stated that if the novel coronavirus “acts like... any other virus, once you recover, you won't get reinfected.”
BioRxiv has just published on-line a preprint of a study by a group of Chinese scientists (Bao et al.) demonstrating that reinfection cannot occur, at least in rhesus macaque monkeys, which have long been used as human substitutes in preclinical testing. Four monkeys were infected with the novel coronavirus; one was euthanized during the course of the infection and the other three were allowed to recover. Once they were all cleared of infection, two were challenged with another dose of the virus while the third monkey was used as a control. Viral loads in all three monkeys were measured multiple times over the next 5 days, and all tested negative. One of the challenged monkeys was autopsied, but no viral replication was found in any tissues, further demonstrating a complete lack of reinfection.
However, it is possible that some people do not elicit an immune response in the first place, and may suffer a relapse as a result. A paper by Chinese, Italian, US and UK scientists published March 23 in the Nature journal Cell Death & Differentiation makes the following observation:
Alarmingly, after discharge from hospital, some patients remain/return viral positive and others even relapse. This indicates that a virus-eliminating immune response to SARS-CoV-2 may be difficult to induce at least in some patients and vaccines may not work in these individuals.
Human and Animal Food Safety
FDA has just expanded its recent statement on the safety of the human food supply. In a March 24 newsletter entitled “FDA Offers Assurance About Food Safety and Supply for People and Animals During COVID-19,” Frank Yiannas, the Deputy Commissioner for Food Policy and Response, provides the following assurance:
So, let me assure you first that the US food supply remains safe for both people and animals. There is no evidence of human or animal food or food packaging being associated with transmission of the coronavirus that causes COVID-19.
He does not anticipate that any food products would need to be recalled or withdrawn from the market for reasons related to the outbreak, even if a worker (such as a food packager) in a human or animal food facility is confirmed to be positive for the COVID-19 virus. He also notes that there are no nationwide shortages of food for humans, pets or livestock, and no widespread disruptions in the supply chain.