COVID-19 and The Loss of Smell, Pt 1

One of the Many Devastating Costs of Covid

COVID 2019 is predominantly a lung infection, causing cough, fever, and fatigue, but other symptoms have been reported, especially anosmia (loss of smell) and ageusia (loss of taste.) In this substack, I’m only going to address the loss of smell because much has been written and published about it; I’ve done my best to make it concise, but there was so much to say, it necessitated breaking the article into two parts.

Also, most taste-related symptoms seem to resolve rather quickly, unlike anosmia. It is hypothesized that taste is so closely associated with smell that it is uncommon for it to be a stand-alone symptom. If I find more info about the loss of taste, I’ll write about it in a subsequent substack.

How We Smell

Let’s start with a brief overview of the anatomy of the olfactory pathway. In our nose, the nostrils are separated into two parts by a septum made of cartilage. Each nasal cavity has its own olfactory area on the roof of the nose. The back of the nasal cavity is lined by cells that are covered with cilia, tiny hair-like receptors that also line the trachea and bronchial passages. (cilia are described below). Sensory nerves and the tips of cilia bind to odorant molecules and transport them to the brain.

The olfactory epithelium covers the olfactory cleft where our sense of smell begins. These cilia on the surface of the cleft coalesce to form Cranial Nerve I – the olfactory nerve. That important nerve is part of the brain; it extends through the paper-thin cribriform plate of the ethmoid bone of the skull. On the brain side of the bone are the olfactory bulbs, organs that process and triage the millions of incoming sensory signals that result in recognizing a “smell.”

In 1964, Scientific American published an article, “The Stereochemical Theory of Odor,” by John Amoore, James Johnston Jr, and Martin Rubin. At that time, more than 30 different theories had been proposed to explain how the nose and brain detect, identify, and recognize an odor. As it turns out, they discovered it is the geometry of the molecule that is the main determinant of odor.

According to the stereochemical theory, different olfactory nerve cells are stimulated by different molecules on the basis of their size, shape, and electromagnetic charge. These properties determine how it fits into the receptors at the tip of the cilia and other olfactory nerve endings. Curiously, if two molecules are identical in every way except they are mirror images of each other, the molecule may produce a completely different odor.

In 1952, Amoore made an extensive search of the organic chemistry literature, concluding there were seven primary odors. These are:

Camphor, musky, floral, peppermint, ethereal (ether-like), pungent and putrid. From these seven primaries odors, every known odor could be made by mixing them in certain proportions. In this respect, it is similar to the three primary colors (red, green, and blue) and the four primary tastes (sweet, salt, sour, and bitter).

To test the model, Amoore and a team of chemists built three-dimensional models of the molecules. If the formula of a chemical compound is known, a scalable model can be made. Amoore also tested the theory of odors on humans, honeybees, and even frogs. The theory of primary odors held up every time! Amoore’s hypothesis remained quite popular until around 2015 when other models were advanced.

In 2004, Richard Axel and Linda B. Buck were awarded the Nobel Prize in medicine or physiology for their research on odor receptors and the structure of the olfactory system. They hypothesized that odor molecules activate specific G proteins and odor receptors can interact with a great number of molecules simultaneously resulting in the complex aromas we perceive from food, nature, oils, and perfumes.

The number of molecules humans are able to distinguish is vast. While the exact number remains controversial, estimates range from 400,000 to 1 million different chemical ‘smells.’ Couple that with the approximately 400 unique receptors in the olfactory bulbs, somehow the brain makes sense of the matrix and sorts it all out. The ability to smell also has a genetic component; more than 1,000 genes in the mammalian genome create olfactory receptor proteins.

Use this article for a good and thorough review of odor recognition.

Anosmia and The Pandemic

Early on in the pandemic, anosmia (the loss of smell) and ageusia (the loss of taste) were frequently reported by those who were ill with a SARS-CoV2 infection.

A Korean phone survey of 3,191 patients found that acute anosmia or ageusia was observed in 15.3% (488) patients in the early stage of COVID-19 and in 15.7% (367) patients with only very mild disease.

In fact, anosmia was so prevalent some researchers wondered if this could be deemed a clinical marker for “the Covid.” For example, in this case report a 40-year-old woman presented with an acute loss of smell without nasal congestion. MRI revealed bilateral obstructive inflammation of her olfactory clefts (see below).

The researchers concluded:

“We believe that the association of sudden and complete loss of olfactory function [loss of smell], without nasal congestion, found in patients with other symptoms, such as cough or fever, should alert the clinician to suspect SARS-CoV-2 infection.”

As it turns out, many persons with covid illness did not experience loss of smell/taste AND there are other pathogens/conditions that can cause those symptoms. So, while loss of taste and smell can be markers of a COVID-19 infection, they are not pathognomonic. (i.e., not decisively indicative of a COVID-19 infection).

Long-haul Loss of Smell

Research has estimated that 63−78% of the patients with COVID-19-related anosmia had partial or full recovery of their smell within about 30 days. However, a sizable population of patients may experience one of these ongoing disorders:

• Anosmia [ah-NOSE-mee-ah] is the complete inability to detect odors.  

• Hyposmia [high-POSE-mee-ah] is a reduced ability to detect odors.

• Parosmia [pahr-OZE-mee-ah] is a change in the normal perception of odors, such as something that normally smells pleasant now smells foul or vice versa.

• Phantosmia [fan-TOES-mee-ah] is the perception of an odor that isn’t there, frequently the smell of burned toast or hot rubber.  

Although the majority of COVID-19-related olfactory dysfunctions seem to recover, some patients report long-term anosmia; for some people, it’s been for nearly two years.

What We Know

It is surprising how little is really known and understood about the sense of smell, even with years of research and hundreds of published papers. What is generally accepted about Covid19-related anosmia is that is caused by one of three mechanisms:

1. Damage and disruption of the cilia, preventing odorant molecules from binding to the receptors.

2. Damage within the CNS (central nervous system) where the olfactory bulb, the olfactory cleft, and olfactory nerves are damaged or destroyed.

3. Overall inflammation of the tissues within the entire olfactory system, causing it to malfunction.  

What are cilia?

I’ve mentioned the cilia a few times. What are they? Cilia are tiny, complex, hair-like structures that occur on the surface of all mammalian cells. Each cilium has a microtubular backbone of 9 outer microtubules – called an axoneme – which is surrounded by a plasma membrane.

Ciliary proteins, called dynein, are highly regulated and are transported to the tip of the axoneme through a very complex mechanism. Interestingly, ciliary dysfunction has been associated with more than 35 different diseases, collectively termed ‘ciliopathies.’  (See a diagram of cilia and read about ciliopathies here) 

Two types of human cilia have been identified, called motile vs. non-motile cilia.

Examples of motile cilia are those located in the bronchial passages and in the middle ear. They rhythmically sweep debris up and away from the lungs and move wax/dirt toward to opening of the ear canal. Motile cilia are also found in the kidneys. They assess the flow of urine from the kidneys, down the ureter to the bladder.

Non-motile cilia, known as primary cilia, act as sensory organs. Primary cilia in the nose are responsible for the sense of smell.  

Destroying Cilia

Cilia provide a large surface area where odorous molecules can interact in isolation or in combination. When a Coronavirus infects the ciliated cells in the human nasal epithelium, the cells can die. Afzelius showed that in the nose, the loss of cilia was the most striking abnormality of coronavirus-infected cells. Studies examining tissue taken from patients who were post-covid demonstrated a complete absence of cilia. 

Several studies have shown that cilia can sometimes regenerate, leading to the restoration of smell. If corruption of the cilia was the reason for the loss of smell, as the tissue regenerates, the ability to smell will return.

Watch for Part 2:

1. What if anosmia occurs due to a brain injury?

2. Did PCR testing cause damage to the smell organ?

3. Lost your smell? What you can do about it.

(Have you seen it? I write a Sunday Substack called “Walking With God.” You can find it here.)