I recently finished a couple of major projects and I am approaching my final exam period, so I needed an easier topic for this post. A few months ago, I completed my graduate project, entitled Systematic Review of Sinus Allergies on Susceptibility to Covid-19. I thought it would be fun to do an abridged version of this project for you. To keep this from becoming completely self-indulgent, I will focus on how scientific publishing works, how studies interact and contribute to each other, and how this process used to build consensus on how something works using my graduate thesis as an example.
My project was a literature search, meaning I compiled disparate studies on a similar topic into one project in order to try and answer a question. It’s…somewhat similar to what I do here, albeit intended for a different audience. The question I wanted to answer was ‘what effect did having allergic rhinitis have on one’s susceptibility to Covid-19?’ Allergic rhinitis, more commonly known as seasonal allergies, occurs in the same part of the body as Covid infections (the upper respiratory tract). Whether other viruses that infect the upper respiratory tract, such as cold and flu, are more or less able to infect patients who also have seasonal allergies has been a topic of research in the past. It makes sense in theory; having allergies means one’s immune system is more active, meaning it could potentially put up more of a defense against viruses like Covid-19. I wanted to see what research had been done on this topic and if any strong conclusions had been drawn from it.
ACE2
For coronaviruses in particular, the idea that allergies might make one resistant against them makes sense. For a coronavirus to enter a cell to infect it, it latches onto a protein on the surface of the cell called angiotensin-converting enzyme 2 (ACE2). The exact function ACE2 plays in the human body isn’t fully understood; most proteins are like pieces in extremely elaborate Rube Goldberg machines that perform the processes of our cells. Figuring out exactly what machine any one piece belongs to and what it does within that machine is exceptionally difficult. What is known is that when one has seasonal allergies, their upper respiratory tract will produce less ACE2. In theory, this would make it harder for coronaviruses to infect cells, making allergy sufferers less susceptible to Covid-19 and making any cases that do arise less severe.
In February of 2020, with the pandemic starting to grow beyond the borders it started in, scientists were trying to understand (among other things) who was at the most risk for Covid-19. A study published by two scientists, Wu and McGoogan, was a collection of data from Covid patients in Wuhan that included factors such as these patient’s age, disease severity, and other conditions they were suffering from. Two months later, a group of scientists I will call Jackson et al* looked at Wu and McGoogan’s data and noticed a trend; the conditions that correlated with worse Covid cases (old age, smoking, hypertension, etc.) were also correlated with an upregulation of ACE2. They also noticed that allergies and asthma were smaller risk factors than one would expect, given that chronic respiratory conditions are usually severe risk factors for these types of viruses. So Jackson et al did an experiment; they took nasal epithelial samples from allergy and asthma patients and measured how much ACE2 was being expressed. Sure enough, allergy sufferers had lower ACE2, both in general and when they were experiencing allergies.
Of course, this isn’t hard proof that this is what’s happening and there were other studies that found the opposite. In October 2020, a group I’ll call Yang et al used South Korean insurance information to do what Wu and McGoogan did; use demographics and Covid severity to identify risk factors, albeit on a larger scale than Wu and McGoogan’s study. Yang et al found that having allergies or asthma increased a patient’s odds of catching Covid and worsened the severity of cases. Another study by Wang et al collected nasal epithelial samples from a thousand Wuhan Covid patients, measured their ACE2 expression, then used telephone follow-ups to determine if these patients had allergies. They found that allergies had no significant difference on Covid susceptibility. There is a possible explanation for this; ACE2 isn’t the only protein Covid uses to enter a cell. Coronaviruses use another membrane protein, transmembrane protease serine 2 or TMPRSS2, to prime the virus so it can use ACE2 to get inside. Yang et al cite another study which found that while allergies downregulate ACE2, they upregulate TMPRSS2. It’s possible that this upregulation of TMPRSS2 balances out any benefit that ACE2’s downregulation causes. That said, like any good paper, both Yang et al and Wang et al list the flaws in their methodology. While these two studies were much larger than the previous two, Yang et al had to rely solely on insurance information for its data. Since seasonal allergies usually aren’t listed on one’s medical charts unless they’re extremely severe, this likely meant they were only measuring the susceptibility of the worst allergy sufferers. Wang et al had the opposite problem; since they were using telephone follow-ups to determine if patients had seasonal allergies, they weren’t able to count the worst Covid cases to their study, since those with the worst cases of Covid-19 weren’t able to return their calls. All of these studies had their flaws, but all of their data is still useful to understanding this question, even if it can’t provide a definitive answer.
Factors besides ACE2
There are of course reasons besides just ACE2 regulation that might give allergy sufferers some Covid resistance. Allergies means that one’s immune system is on high alert and that their sinuses are clogged with virus-blocking mucus, after all. A study published in March 2020, Shi et al, found that the percentage of Covid patients in a Wuhan hospital who were allergy sufferers was smaller than the national average. They took blood samples from 65 Covid patients (again, small sample size) and found that the number of lymphocytes in their blood was significantly lower than normal. Several other studies have found that lymphocyte count is lower throughout the bodies of Covid patients, suggesting that the virus is killing these immune cells or inhibiting their growth. Shi et al suggest that since lymphocyte count is heightened in allergy sufferers, this might create a buffer against severe Covid.
A pair of studies identify another factor at play which…turns this whole question on its head. Gilles et al performed a study in 2019, before the pandemic, that looked at how tree pollen affected the functioning of the immune system in the nasal mucosa. It was found that high pollen concentration can interfere with the communication systems of the innate immune system, making one more susceptible to upper respiratory infections. This has nothing to do with whether one is allergic to pollen, the pollen itself is having this effect. Gilles et al was cited by another study in early 2021, Damialis et al. They measured the concentration of pollen in 80 regions worldwide and found that higher pollen concentrations correlated with spikes in the number of Covid cases. This…would seem to suggest that allergies would be correlated with worse Covid susceptibility, but it’s hard to say if that’s closely related enough to draw that conclusion.
Allergic Asthma
While allergic rhinitis is when the upper respiratory tract (nose to larynx) has an allergic reaction to airborne allergens, allergic asthma is when the lower respiratory tract (trachea to lungs) has an allergic reaction to airborne allergens. While the majority of Covid infections don’t make it all the way to the lower respiratory tract, the cases that do make it this deep are far more severe. And while we’ve been talking about debate on what effect seasonal allergies have on Covid, even the studies that suggest allergies give one resistance to Covid find that Covid is measurably worse in asthma patients. But while it’s universally agreed that asthma is associated with more severe Covid, why this is isn’t well understood. Asthma is a much more complex condition, with at least four different types that each have different effects on immune system regulation and the environment of the respiratory tract, including different effects on ACE2. The most common type of asthma usually results in higher immune activation (less Covid susceptibility) but also higher ACE2 (more Covid susceptibility). There doesn’t appear to be a single mechanism to affect an asthma patient’s susceptibility to Covid, so why are the effects so much simpler?
There might already be an explanation for this, one that was explored as far back as the first SARS epidemic. As I said before, the exact function of ACE2 is still being researched, though it does seem to be involved with inflammation and immune responses. While ACE2 doesn’t seem to be irreplaceable in most tissues, it has been observed that when ACE2 is significantly downregulated in the tissues of the lower respiratory tract, it can cause widespread inflammation that leads to Acute Respiratory Distress Syndrome (ARDS). ARDS was one of the ways that severe SARS or Covid-19 could manifest, causing severe and possibly permanent lung damage. Because coronaviruses remove ACE2 proteins when they enter a cell, an infection could wind up “using up” enough ACE2 to cause ARDS. It's been proposed that this is why asthma sufferers are universally more susceptible to severe Covid; both upregulating and downregulating ACE2 in the lungs puts them at risk.
Allergies and Other Viruses
Lastly, I looked at whether seasonal allergies provided any resistance to upper respiratory infections other than Covid-19, hoping that would provide some indirect insight. This is a complex topic due to how complex the immune system is, so other literature searches have been written about this exact topic. Most of the research that has been done on this topic was on allergic asthma instead of allergic rhinitis, since it is a more serious condition. But what research has been done on rhinitis specifically wasn’t consistent. A study by Głobińska et al details an experiment where they cultured nasal epithelial samples from subjects with and without seasonal allergies before infecting these cultures with one of two different viruses. The population of virus in each sample was measured over the course of 48 hours. It was found that the population of one virus species rose faster in the allergic samples but also plateaued earlier in allergic samples, so it’s hard to tell what difference that would make for a patient. For the other virus species, there was no measurable difference between allergic and non-allergic samples. So, whether or not seasonal allergies can provide resistance against viral infection entirely depends on the virus, so trying to answer this question about Covid-19 by looking at other viruses won’t help.
Conclusions
I ultimately couldn’t find an answer to this question as there is currently no field-wide consensus on whether or not allergies help or hurt against Covid-19. This isn’t too uncommon in science; we only have the data that we have and ‘I don’t know’ is always an acceptable answer. Since we’re still in a pandemic, this type of research really shouldn’t be anyone’s priority. Most of these studies were analysing data from other sources instead of collecting data specifically for an experiment to answer this question (an approach which has the potential to skew the results). The best thing anyone could do to answer this question is to create a purpose-built experiment to collect data with this specific question in mind. But analyzing the available data has shown just how dependent our body’s response to diseases is on the thousands of tiny variations in how our bodies work. The Covid-19 pandemic is arguably the first major health crisis in the era of data-driven biology and precision medicine. A growing body of research is being done into how different diseases, conditions, and environmental factors can minutely increase or decrease one’s Covid risks. By observing the interactions between Covid and other conditions, it can point researchers toward what proteins, genes, and molecular mechanisms are shared between the two conditions, which can be used to deduce their exact function, how they interact with other molecules and systems, and further improve our understanding of human biology.
For More Details
I’ve included the studies I reference by name in case anyone is interested in reading more, but they are by no means required reading.
*I debated what names to give these papers for this post. I’ve gone with the names of the authors since that’s usually how papers are cited in a text format. The words ‘et al’ stand for et alia, latin for ‘and others’, and is how these citations refer to a group of authors.
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