Issue #11: On the nose with COVID-19

Setting it Straight - Issue #11

Written by Nobel Laureate Professor Peter Doherty

The 16th century French philosopher, Montaigne, remarks in his Essay on Smell that: “I have ever found myself little subject to epidemic diseases, that are caught, either by conversing with the sick or bred by the contagion of the air.” Maybe he practiced social distancing but, when Montaigne mentions contagion, his understanding was different from ours. Back then, people believed in the ‘miasma theory’, that infection is a consequence of breathing in the odoriferous, ‘bad air’ that reflects proximity to rotting organic material. Given 16th century sanitation practices, there was always plenty of that around in towns of any size. Women carried a posie, or nosegay, of sweet-smelling flowers to provide some relief and, no doubt, to keep any plagues away. Montaigne goes on to observe that: “Physicians might…extract greater utility from odours than they do.”

As now, everyone would have been aware that eating food that ‘smells a bit off’ due to unwanted bacterial fermentation is not a great health strategy. Replicating bacteria give off their own distinctive aromas. There’s a recent history of trialling electronic ‘smell detectors’, like those used to find explosives, for the differential diagnosis of the bacterial pneumonias. Like the sensors in the smell centre at the top of the nose, the machine detects a spectrum of aromatic chemicals that register as signals.

Located in specialised neuroepithelium that has its own mucus-secreting apparatus, and enwrapped by protective sustentacular cells, the sensory olfactory neurons, or nerve cells, have hair-like projections (cilia) carrying one of 400 signalling proteins, or scent receptors, that bind individual airborne chemicals dissolved in the bathing mucus layer. Depending on which, and how many, of the 10 million or more olfactory neurons are triggered, signals pass via their long extensions, the axons, through to other nerve cells located in the nearby olfactory bulb of the brain. That complex of signals is relayed up through the neuronal networks of the olfactory cortex to register ultimately in our consciousness as a particular smell.

In some cases, a compromised sense of smell, called anosmia, is a prominent, first symptom of COVID-19. Of course, we often lose our sense of smell for a time in respiratory infections when there’s a lot of mucus around and we’re sneezing copious snot. But the anosmia of COVID-19 can precede any evidence of respiratory involvement, or just be accompanied by a dry cough. And, though COVID-19 can be characterised by severe pneumonia and major lung damage, many who experience relatively mild symptoms may have a continuing loss of smell and taste. Then there are others who, again, don’t cough or splutter, but develop evidence of neurological impairment, or become anoxic due to the blood clotting problem associated with this infection that I’ve mentioned earlier: COVID-19 is much more than a viral pneumonia.

With regard to neurological involvement, the central nervous systems (CNS) is protected by a tight blood-brain-barrier that keeps entities as small as protein molecules out. Rabies virus, for instance, gets to the brain by retrograde flow along the axons of infected neurons. If that loss of odour detection in COVID-19 is due to direct virus-induced damage of the nasal neuroepithelium, it would indeed be concerning if the primary target cells were the olfactory neurons. The SARS-CoV-2 particles could potentially be transported via the axons of infected nerve cells as they pass through the olfactory foramina (holes) in the bony cribriform plate that separates the nasal cavity from the brain where, like the related mouse hepatitis virus, they might cause encephalomyelitis.

Current evidence indicates, however, that the sustentacular cells, which can express high levels of the ACE-2 receptor for SARS-CoV-2, may be the main site of infection in the olfactory epithelium. The loss of the sense of smell in COVID-19 could thus reflect a disruption of the protective architecture that the sustentacular cells provide for olfactory neurons. Additional to that, the essential mucus layer may be perturbed. Communities are important: localised interactions between different cell types are basic to optimal body function.

When it comes to community, many regard dogs as our best friends. As we all know, dogs have an infinitely better sense of smell than we do due to the fact that they have a much better developed and more extensive olfactory apparatus. Dogs can, at times, detect human diseases, including malaria and some cancers, by smelling aromatic compounds that we produce. When, for instance, diabetics are at risk of going into a hypoglycaemic coma, they breathe out an excess of isoprene, the main hydrocarbon in human breath.

It’s not clear that the noses of diabetic-alert-dogs are in some way ‘titrating’ the levels of exhaled isoprene, but it is the case that they can provide a warning. Diabetics are at major risk from SARS-CoV-2 infection and, whether or not the two may be related in the smell sense, a number of groups that train dogs as human disease detectors are looking at their possible use for COVID-19 diagnosis. What is obvious is that, contrary to Montaigne’s advice, it’s not safe for physicians to get too close to patients and use the sniff test in this disease!