Thursday, June 9, 2022

Covid's Parosmia Uncovered

Covid has a smell. Not that you can smell sick people, although you can actually. Dogs have proven that it's possible; only that humans have never been trained, and for obvious reasons.

Instead, we mean that things "smell like Covid." That's because everyone who got pre-Omicron Covid also got hit with a neuroplastic time bomb where their olfactory neurons got attacked and then reconfigured. Half the people who got Covid, and its anosmic introduction, knew they had it, and the other half didn't. (This according to a May 2022 study, linked here, and repasted below.)

Lost of people would argue with that stat. And I would have to argue back. The absolute worst source of data for testing anosmia etc is the subjective reporting of the people themselves. We don't even know we have a sense of smell in the first place, nevermind detecting that it's been removed. There are congential anosmics (can't smell from birth) who don't realize they're anosmic until they're teenagers! How do you not realize that? Because we don't talk about smells. They're outright lingua-phobic. And so when we lose it, especially in the midst of a respiratory infection that messes with our breathing, we don't even notice. We also think it's our sense of taste, so when someone asks "have you experienced any change in your sense of smell," you say no, but I did lose my sense of taste. In that study, they used Sniffin' Sticks, so an objective measure, and so they got the 100% stat. 

Next, things "smell like Covid" because after a bout of anosmia, your olfactory system needs to reboot, retrain, pick your computer analogy, and in the process, there's some bugs in the code. Eggs smell like Covid, coffee smells like Covid. Shit? Smells like biscuits. Wait, what? Yes, the Faeces Paradox, see below, it's all been explained for us. Thanks, Flavor Center at University of Reading:

Researchers find cause of disordered smell
May 2022,

Among the 29 volunteers with post-viral parosmia, scientists found 15 commonly identified compounds that triggered parosmia. They also found reduced sensitivity in some people, via lower TDI scores from Sniffin’ Sticks, although some who were considered functionally anosmic could still detect some of the trigger smells...

Some of the most cited food and drinks that set off parosmia in sufferers include:
  • Coffee
  • Onions
  • Garlic
  • Chicken
  • Green peppers

The most common trigger molecules are grouped into four distinct categories based on structure: 
  • thiols
  • trisubstituted pyrazines
  • methoxypyrazines
  • disulfides
  • (and as always with smell-things: some less common triggers did not fall into any one of these categories)
  • (these molecules tend to be potent, have very low olfactory detection thresholds and, in isolation, are neither distorted nor unpleasant for nonparosmics)

Trigger Molecules and their Parosmic Descriptions:
  • 2-furanmethanethiol ("coffee") is the most frequently reported trigger. Whereas NONPAR (non-parasmics) used a range of food-related terms to describe it (coffee, roasty, popcorn, smoky), PAR (parosmics) often struggled to find suitable descriptors, as they were unable to relate it to anything they had smelled before. PAR typically used words describing its hedonic quality (disgusting, repulsive, and dirty) or new coffee (relating to the altered smell of coffee since onset of parosmia) as described previously. Four PAR described it in the same way as NONPAR (biscuit, toasty or roasty) indicating that it is not universally parosmic, but certainly an important and frequent molecular trigger of parosmia.
  • 2-methyl-3-furanthiol and its corresponding methyl disulfide  ("meaty") were detected but reported less frequently as distorted. 
  • 2-Ethyl-3,6-dimethylpyrazine (also "coffee") was the second most frequent trigger in coffee; described with a variety of food terms by NONPAR, but by “new coffee”, “unpleasant” and “distorted” by PAR.
  • 2,3-diethyl-5-methylpyrazine, 2-ethyl-3,5-dimethylpyrazine and trimethylpyrazine (found in roasted, fried and baked goods) were common triggers. These compounds also triggered a parosmic response to cocoa, grilled chicken, and peanut butter
  • 2-Ethyl-3-methoxypyrazine, 2-isobutyl-3-methoxypyrazine and 2-isopropyl-3-methoxyprazine (green peppers) were common triggers in coffee.
  • 3-methyl-2-butene-1-thiol (pungent and weedy) was reported as a trigger 9/29 times.
  • 3-mercapto-3-methylbutanol and its formyl ester are potent aroma compounds in coffee, and were detected in half the cases, but only reported as distorted 5 or 6 times.

  • The unknown compound has been tentatively identified as 4-methylthio-4-methyl-pentan-2-one, but this is yet unconfirmed. (What the heck is "the unknown compound?)
  • Although thiols and disulfides seem to effectively trigger a parosmic response, there are two notable exceptions.
  • Methanethiol, detected by some NONPAR, was not detected by any PAR. Likewise, dimethyl trisulfide is detected by 12/15 NONPAR but only by 4 PAR, and only reported once as a trigger.
  • A few compounds were detected but never reported as triggers.
  • 4-Ethylguaiacol was detected by 7 PAR and always described as spicy, sweet and smoky, but never parosmic.
  • Similarly, (E)-β-Damascenone, a key odour-active compounds in coffee, was detected by 6 PAR and always described as jammy and fruity.

The Faeces Paradox
  • Foods smell of faeces yet faeces smell of food (biscuity or pleasant)
  • Two parosmic researchers did not detect these compounds in a faecal slurry and were unaware of any foul smells.
  • However, they detected several other compounds, many of which they had also detected in coffee, and only some of which triggered parosmia.
  • In comparison, a normosmic scored the intensity of indole and skatole as close to the strongest imaginable. 
  • This provides a neat explanation as to why the changes in valence for faecal samples is reversed. 

How did they do it?
They GCMSd different sources, like coffee or onions, so that the individual molecules could be separated and presented one-at-a-time to the volunteers, so they could detect the specific molecules in the source that repulses them.

Why did they do it?
Prior to the global pandemic caused by COVID-19, parosmia was a rare condition known to occur after infections such as cold, flu or sinus infections, with very little awareness about the causes and treatments for the disease.

During the pandemic COVID-19 symptoms included loss of smell and taste in 50–60% of cases, of which about 10% developed parosmia. Since the omicron variant, loss of smell and taste has become a less common symptom (estimated to occur in about 10–20% of cases) and parosmia cases are likely to be fewer in number, parosmia is still estimated to affect 2 million people in Europe.
Not exactly. See below.

via the Flavor Center at University of Reading: Jane K. Parker et al, Insights into the molecular triggers of parosmia based on gas chromatography olfactometry, Communications Medicine (2022). DOI: 10.1038/s43856-022-00112-9

Study finds sensory loss in ~100% of active COVID infections, which is twice as high as self-reports
May 2022,

In participants with active infections during the delta surge, a majority (22 of 25) had been vaccinated. Objective screenings found that 100% were experiencing a diminished or lost sense of smell—but only 54.5% self-reported any problem with odor detection.

via Ohio State University: Kym Man et al, Chemosensory losses in past and active likely Delta variant break-through COVID-19 cases, Med (2022). DOI: 10.1016/j.medj.2022.05.004

Image credit: Free Photos at img freepic dot com [link]

Post Script:
Can 'smell' trigger tumors?
May 2022,
"Now that glioma preferentially emerges in the OB, will neuronal activity in the olfactory circuit affect the emergence of glioma?" the researchers wondered. This "mind-blowing" flash of inspiration became a turning point in this study. The research team attested to this hypothesis through a series of experiments.

In this study, they employed a cutting-edge chemogenetic technology to specifically manipulate the neuronal excitability of ORNs. They found that inhibiting the activity of ORNs reduced the size of the tumor significantly, whereas activating their activity increased the size of the tumor. It was therefore concluded that the neuronal excitability of ORNs was the root of gliomagenesis.

To further verify this conclusion, the researchers suppressed olfactory inputs through naris occlusion by using small plugs. They found that with naris occlusion, tumors were significantly hindered in the olfactory bulb, indicating that olfactory stimuli could regulate gliomagenesis.

via Zhejiang University: Pengxiang Chen et al, Olfactory sensory experience regulates gliomagenesis via neuronal IGF1, Nature (2022). DOI: 10.1038/s41586-022-04719-9

Post Post Script:
Clinical trial led by Thomas Jefferson University Hospital paves the way for innovative topical treatment
Mar 2022, Jefferson Hospital

Platelet-rich plasma (PRP) is a common restorative therapy used to regenerate cells, heal tissue, and address an array of medical conditions from healing injured muscles and tendons to increasing hair growth and reducing the appearance of scars. Animal studies have shown that PRP helps regenerate the olfactory epithelium, which may be the site affected in COVID-19 induced olfactory dysfunction (OD). As smell and taste are closely interrelated, improved sense of smell can help with sense of taste as well. Until now, PRP has been used as a nasal injectable in several small clinical trials for smell loss. Although the results were promising, nasal injections can be uncomfortable and invasive for patients.

A recent phase I clinical trial of eight patients who had at least six months of olfactory disturbance has shown preliminary success with 50 percent of participants (4 people) experiencing clinically significant improvements in smell and taste.

Autopsies suggest COVID’s smell loss is caused by inflammation, not virus
Apr 2022, Ars Technica

via Johns Hopkins: Ho C, Salimian M, Hegert J, et al. Postmortem Assessment of Olfactory Tissue Degeneration and Microvasculopathy in Patients With COVID-19. JAMA Neurol. Published online April 11, 2022. doi:10.1001/jamaneurol.2022.0154

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