Anosmia & Conjunctivitis in COVID-19, Is Fever Helpful (Lecture 44)
Welcome to another MedCram COVID-19 update. We are headed to a half a million total confirmed worldwide, over 20,000 deaths, and 115,000 total recovered with most of that growth outside of China at this point. If we look at the Worldometer website, most of the deaths that are occurring are in Italy and Spain with the United States starting to move up as well.
The number of new cases in Italy looks as though might have peaked. We’ll have to see more in the future in terms of its direction. While the total deaths in Italy continue to escalate, over in the United States the total number of cases continues to grow. Total number of deaths is over a thousand here in the United States already.
New York City seems to be the epicenter of what’s going on here in the states. They are predicting that the peak number is still about two to three weeks away in New York. Remember that New York is ahead of just about everybody else. Of course, if we were able to flatten the curve, then that’s going to delay that even more, but hopefully, the peak won’t be as high.
Okay, I want to talk to you about a couple of updates in terms of signs and symptoms. This is from the American Academy of Ophthalmology, which is warning us that there have been several reports that the virus may cause conjunctivitis and possibly be transmitted by aerosol contact with the conjunctiva. The academy is recommending protection from the mouth, nose and eyes when caring for patients potentially infected with SARS-CoV-2.
Also, there are recommendations on how to sterilize the equipment that’s used. The other name for conjunctivitis is pink eye. It’s not uncommon to have conjunctivitis when you have an upper respiratory viral infection, so be aware of that.
The other sign and symptom is related to the loss of smell as a marker of COVID-19 infection. This is a letter that was written by the president of the Ear, Nose and Throat Association in the UK, Dr. Kumar. He’s talking here about post-viral anosmia that by itself is not unusual. What they’re seeing, however, is a huge rise in the number of patients that are complaining of the inability to temporarily smell after a viral infection. They mention here that in South Korea where testing has been more widespread, 30% of patients testing positive have had anosmia as their major presenting symptom in otherwise mild cases.
On the flip side of that, they’re also noticing that patients without any other signs or symptoms consistent with asymptomatic COVID-19 are presenting with the only sign being anosmia, and that may be suggestive of asymptomatic infection with COVID-19. He’s talking about him personally having seen 4 patients in one week all under the age of 40, and otherwise asymptomatic except for the recent onset of anosmia. He usually sees only about once a month, so this is something to be on the lookout for.
He also has some recommendations at the bottom of the letter. He says that there is potential that if any adult with anosmia but no other symptoms was asked to self-quarantine for seven days, in addition to the current symptom criteria used to trigger quarantine, we might be able to reduce the number of otherwise asymptomatic individuals who continue to act as vectors, not realizing the need to self-isolate.
It would also be an important trigger for healthcare personnel to employ full PPE or personal protective equipment and help to counter the higher rates of infection found amongst ENT surgeons compared to our other health care workers. Of course, we’ll put links to these articles as well as other ones in the description below.
So we’re going to talk about the immune system as promised. Remember what we talked about how a good immune system in both of these situations could help not only the person having the good immune system, but also reducing the number of people going into our healthcare system.
So here is what is represented as the population at a whole, and then there is a certain amount that will catch the infection which is here, and then about 80% of those people will not need to go to the hospital because they have a sufficient immune system, but the 20% here we could improve, and perhaps if we had a good immune system we might be able to not even become infected in the first place.
We talked about in our last update what they were doing by giving a BCG vaccine even if they were given one earlier in life to give another one, they’re hoping to see that their immune system will be heightened not just against tuberculosis as it’s designed for, but also an improvement in your innate immune system. So that’s your lymphocytes, your leukocytes, your natural killer cells, your neutrophils Etc. What is it that we can do to improve our own immune system?
So the first thing I want to talk about is fever. Fever is one of those signs that you get when you have a viral infection, and it’s one of those things that you might see also with COVID-19, although it’s not universal.
So here’s a paper that was published in 2017 looking at the presence of fever in adults. One of the things in the article that’s interesting to note is they looked at a number of different viruses, and you can see here for coronavirus. If we were to take this as a representative of the current COVID-19 cases, only two out of seven cases presented with fever, giving it about a 28% incidence of fever.
In the discussion, they say here we have shown using prospectively collected data that the rate of fever in adults with confirmed viral respiratory infections is much lower than described in children. Nevertheless, it is present and it would behoove us to take a look at the mechanisms of fever both in adults and children.
So here’s another paper that was published in the World Journal of Clinical Pediatrics back in 2012 titled: Fever management, evidence versus current practice. I found it to be a very good source of some interesting studies regarding fever. Under the heading that says evidence that fever is beneficial, they had a number of points. It talks about fever having an adverse effect on bacteria, on viruses, how it improves the activity of a lot of signaling like interleukin 1, also cells that are involved in the immune system that we’ve talked about, including T cells, B cells and antibody production.
A lot of these things are mediated at temperatures that are just above normal around 38, 39, 40°C. 38°C correlates to about a 100.4 F. There are also some studies here that show that interferon, which is of course an antiviral agent, has enhanced antiviral activity above 40°C. So there are a number of references here and I’ll include all of those papers in the description below.
In those references, we can see here in vitro that, as we increase the temperature here on the x-axis, the percent yield in this case of poliovirus starts to drop. Similarly, if we look at the development of poliovirus at 37°C in that paper, it was quite prolific over a period of time. Repeat the experiment here at 40°C, there is a precipitous drop. Again, these are in vitro studies, so let’s look at some human studies.
So, while there have been a lot of bacterial studies, I want to highlight a viral study with rhinovirus, which is a virus that causes a common cold as well. This paper was published back in 1990. There were 56 healthy subjects and all of them had rhinovirus introduced into them. But then there were four arms; there was an aspirin arm, there was a Tylenol arm, there was an ibuprofen arm and then there was a placebo arm.
And in each of these arms, they measured something called a serum neutralizing antibody response. So we’re looking for the antibody response after these people that were infected with rhinovirus. And what they found is that in the aspirin and in the Tylenol group, these together were statistically significantly lower in terms of that antibody response when it was compared to placebo and that P value was less than .05.
And what we’re finding more and more recently is that temperature is intricately related to the immune function of the cell. Here’s a paper that was published in 2018 that shows that temperature regulates certain cellular messaging systems that allow the immune system to respond to infections. The signaling pathway known as NF-κB is a signaling mechanism that allows the cell to respond to these infections.
And it was recently highlighted in an article in Medical News Today, a signaling pathway called Nuclear Factor kappa B plays an important role in the inflammation response in the context of infection or disease. This protein helps the expression and the production of certain immune cells.
These proteins respond to the presence of viral or bacterial molecules in the system and that is when they start switching relevant genes related to the immune response at the cellular level. They also note here that this NF-κB becomes more active at higher temperatures and less active at lower temperatures.
So the question is, is it the fever that’s causing the NF Kappa beta to go up or is it the NF Kappa beta that’s causing the fever. Well, they did some experiments and they found this protein called the A20 protein is what tells the NF-κB protein to go up. And so if you knock out this A20, then that is going to prevent the NF-κB from activating, and when it doesn’t it’s no longer going to be doing the things that it needs to do to augment the immune system.
所以问题是，是发烧导致NF Kappa beta升高还是NF Kappa beta导致发烧。不过，他们做了一些实验，他们发现这种叫做A20蛋白的蛋白质告诉NF-κB蛋白上升。因此，如果摧毁此A20，则将阻止NF-κB激活，而当它不激活时，它将不再在执行其增强免疫系统所需的操作。
So in essence, fever somehow stimulates A20, which then stimulates NF-κB, and NF-κB is essential for immune system. How do we deal with fever? Well, remember what we talked about a couple of lectures ago. We have something called arachidonic acid, which is converted into prostaglandin and specifically prostaglandin E2, that’s mediated through something called the COX-2 enzyme. And what are one of the big inhibitors of the COX-2 enzyme? but NSAIDs. Remember what NSAIDs are, aspirin, ibuprofen and indomethacin.
So because of this and other studies, many scientists and many practitioners, especially in the pediatric population, are advocating that fevers based on known viral infections shouldn’t be treated just based on the number itself and the fact that the temperature is elevated. That in fact the fever may actually be beneficial to the recovery of the patient and unless the fever is excessive, or the patient is dehydrated, or there’s lethargy, which means that the patient doesn’t want to move very much, then fever shouldn’t be treated.
A couple of points here to remember, number one a fever is not hyperthermia. Hyperthermia is what one might get if they were running on a very hot day and their temperature was 105, 106, 107. Those are clearly very dangerous temperatures and they need to be treated aggressively; otherwise, someone could die. But in the sense where there is a viral infection and a fever is being caused and there’s no other complication as a result of that fever, there is a question about whether or not that fever should be treated.
The other point I want to make and it’s very important is that there are a number of adults in this country that are on aspirin for very good reasons and this is not a reason to stop it. You should never stop any medication without consulting your physician. There are people with stents, people with strokes, for which aspirin is lifesaving. Not to mention that people take ibuprofen and indomethacin for rheumatological conditions as well. I’m simply saying that perhaps an elevated temperature in your body may be part of the solution to getting better over the viral infection and not part of the problem.
I would be interested in your comments below regarding this issue. I think one of the conclusions that I draw from this is that there is a benefit in infectious disease to having an elevated body temperature.
Thanks for joining us.