COVID-19, Aromatherapy and Anosmia – an update

In preparing for my first webinar for 2022, I have referred to the most up-to-date research – which is constantly being updated and revealing the true nature of COVID-19 related anosmia. Much of what I wrote about in my first blog in November 2021 was based on data from the Delta and earlier variants of COVID-19. The situation has now changed with the omicron variant.

Thanks to COVID-19, researchers and health professionals are starting to pay serious attention to anosmia and the implications that loss of smell has at a physiological and sociological level.

At one stage during the pandemic, loss of smell was being used one of the diagnostic criteria for COVID-19 infection. However, most reports now state the loss or sense of smell and/or taste that were once a signature symptom of COVID-19 does not necessarily apply to the omicron variant.^1,2
A study in the UK found that the loss of smell or taste in omicron cases was only 13%, whereas those infected with the delta variant reported loss of smell or taste in about 34% of all cases.¹

The most common omicron symptoms include:¹

• runny nose
• headache
• fatigue
• sneezing
• sore throat
• persistent cough

Loss of smell now ranks 17th according to the *ZOE list of COVID-19 symptoms. This means it is relatively rare compared with loss of smell being ranked as the sixth most common symptom when the delta variant was dominant.¹
As many as 1.6 million individuals in the USA alone have experienced chronic olfactory dysfunction because of COVID-19.³

I was surprised to learn that before the COVID-19 pandemic up to 19.1% of adults and 80% of people over the age of 75 suffer from complete or partial loss of smell.⁴

^{* the ZOE Covid study app is a not-for-profit initiative that was launched in the UK to support vital COVID-19 research. The app was launched by health science company ZOE together with King’s College London. It provides the world’s largest ongoing study of COVID-19 and is led by ZOE co-founder, Professor Tim Spector.}

One study compared COVID-19 related anosmia with olfactory dysfunction associated with the common cold and upper respiratory tract infection (URTI). It appears that COVID-19 behaves differently compared to other respiratory viruses, especially as the COVID-19 virus targets the olfactory epithelium, the olfactory bulb and other olfactory structures.⁵

It was also reported that taste functions were significantly worse with COVID-19 patients compared with the common cold.⁵

Another interesting feature was that some people with COVID-19 may have experienced temporary loss of smell and taste because their nasal passages are blocked; much like what happens with a common cold. A 2020 study found that people with COVID-19 lost their sense of smell, even when they could breathe freely and their noses were not runny or congested.⁵

A 2021 study reported one in five people who experience smell loss as a result of COVID-19 reported that their sense of smell had not returned to normal eight weeks after falling ill. The report states that 90% of people fully recovered their sense of smell after six months.⁶
Another study evaluating a small group of patients with COVID-19 related anosmia beyond 7 days. The results found that 28.2% reported satisfactory recovery of olfaction within 4 months while the remaining 71.7% did so by 12 months.⁷
A study from Virginia Commonwealth University reports that sense of smell or taste returns within six months for four out of every five COVID-19 patients who have lost these senses, and those under 40 are more likely to recover these senses compared to older patients.⁸
This paper went on to report that using smell training using essential oils may help.⁸

A report from the University of East Anglia also suggested smell training could be beneficial. This involves sniffing at least four different odours twice a day every day for several months. Smell training is reported as an inexpensive, simple and side-effect free treatment option for various causes of smell loss, including COVID-19.⁶

Research has found that 60% of patients experience loss of smell within the first four days of COVID-19 symptom onset, however for most people this improves over time.⁹
If it does not improve, many suggest that smell training should be used instead of corticosteroids because it has no known side effects, its low cost and is supported by a robust evidence base.⁹

Olfactory disorders

The loss of olfaction has been associated with decreased general quality of life, impaired food intake, inability to detect harmful gas and smoke, enhanced worries about personal hygiene, diminished social wellbeing and the initiation of depressive symptoms.
There is often some disagreement in literature regarding the terminology.

I have decided to use the definitions in a 2017 paper - Position paper on olfactory dysfunction.¹⁰

• Anosmia – total loss of smell
• Ageusia – loss of taste function of the tongue
• Specific anosmia – the inability to detect a particular smell or smells
• Hyposmia – reduced olfactory function.
• Dysosmia – a qualitative change of the sense of smell.
• Hyperosmia – increased ability to smell odours to abnormal levels. This is very rare and often associated with migraines.
• Parosmia – a distorted sense of smell, that is a smell is perceived as another, usually a very unpleasant smell
• Phantosmia – perceiving a smell that is not actually there.

Loss of smell is accompanied by reduction in taste and appetite.¹¹
The most common reported causes of smell loss are:¹¹
• post-viral upper respiratory tract infections (18-45% of the clinical population)
• nasal or sinus disease (7-56%)
• head traumas (8to20%)
• exposure to toxins or drugs (2 to 65)
• congenital loss (0-4%)
Fortunately, most postinfectious olfactory dysfunction (PIOD) experience high rates of recovery.¹²

Pathophysiology of SARS-CoV-2 infection on olfaction

Inflammatory damage

It is was originally suggested that COVID-19 anosmia occurs with the increase in the levels of interleukin-6 (IL-6), an important pro-inflammatory cytokine which leads to inflammatory damage to the olfactory epithelium. It is suggested that an inflammatory cytokine environment in the nasal cavity would also potentially affect olfactory neuronal function, as in rhinosinusitis.¹³

Infection of the olfactory epithelium

Researchers have confirmed the olfactory cells in the upper nasal cavity are most vulnerable to infection by SARS-CoV-2. However, the sensory neurons that sense smell are not the vulnerable cell types.¹³

SARS-CoV-2 infects host cells by the virus’s spike protein binding to the viral receptors angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Both of these receptors are highly expressed in the gastrointestinal tract, in the nasal and bronchial epithelium as well as in the type II alveolar epithelial cells.¹³

Olfactory neurons do not express the gene that encodes the ACE2 receptor protein, which SARS-CoV-2 virus uses to enter human cells. Instead, ACE2 is expressed in the cells that provide support to olfactory sensory neurons. Research suggests the infection of nonneuronal support olfactory cells is responsible for anosmia in COVID-19 patients. This is good news as it indicates that it is unlikely that SARS-CoV-2 infection will cause permanent damage to the olfactory pathway circuits.¹⁴

The data from research indicates that COVID-19 related anosmia may arise from temporary loss of function of the supporting cells in the olfactory epithelium, which results in the impairment of olfaction. The researchers do not fully understand why olfactory impairment occurs.^14,15

New research published online on 2 Feb 2022, in the journal Cell, found that SARS-CoV-2 indirectly dials down the action of the olfactory receptors that detect the odour molecules. The presence of the virus near nerve cells in the olfactory tissues is associated with an influx of immune cells, microglia and T cells. These cells release cytokines that change the genetic activity of olfactory nerve cells, even though the viruses cannot infect them. The researchers believe that whereas the immune cell activity would normally dissipate quickly, in the brain, the immune signalling persists in a way that reduces the activity of the genes responsible for building the olfactory receptors. It was also suggested that ongoing immune cell reactions in the nasal cavity could influence emotions, and the ability to think clearly which is consistent with the symptoms associated with long COVID.¹⁶
It is suggested if olfactory gene expression is interrupted by immune system, then the lost sense of smell may provide the early warning that the COVID-19 virus is damaging brain tissue before other symptoms are present.¹⁶

Anosmia and COVID-19 fatigue syndrome

Wotsyn believes that anosmia could be a predictor for post-COVID-19 fatigue syndrome. In those COVID-19 patients who remain anosmic for longer periods of time, it is likely that a larger area of the olfactory epithelium is affected; possibly with a more profound destruction of the epithelium which also results in the death of a large number of olfactory neurons.¹⁷

Wotsyn proposed that post-COVID-19 fatigue syndrome may result from damage to olfactory sensory neurons, causing an increased resistance to cerebrospinal fluid outflow through the cribriform plate, and further leading to congestion of the glymphatic system which leads to toxic build-up within the brain.17
He believes those COVID-19 patients with persistent anosmia and persistent fatigue at month four are interconnected.¹⁷

COVID-19 and the brain

While significant progress has been made to understand the cellular and molecular mechanisms of COVID-19 induced anosmia, researchers are now investigating if and how the COVID-19 virus may utilise a route from the nose to infect the brain and the implications of this.¹⁸
A paper published in the Neuroscientist confirms what we already know: that the virus does not infect the olfactory receptor neurons. (By the way, when olfactory receptor neurons die, their replacement requires 8 to 10 days to regenerate.)¹⁸

We know the virus does not infect the ORN as they do not express ACE2, however, the virus entry point is the olfactory epithelium and the damage to the epithelium diminishes the sense of smell. What researchers have also identified is that death of the sustentacular cells does not seem to necessarily cause death of ORNs. Death of the sustentacular cells occurs much faster than the death and regeneration of the ORNs. The rapid replenishment of the sustentacular cells is consistent with the rapid recovery of the sense of smell.¹⁸

The sustentacular cells maintain the structural integrity of the olfactory epithelium and are closely associated both metabolically and functionally with olfactory neurons and odorant signal transduction. This may then lead to dysfunction of the ORNs, since the sustentacular cells play an important role in protecting the ORNs.¹⁸

Butowt et al. state there is evidence that COVID-19 viruses can move beyond the sustentacular cells and can reach the brain via the cribriform plate.¹⁸

The long-term presence of virus in the brain may lead to inflammation and aggravate chronic neurological diseases such as multiple sclerosis and Parkinson’s disease.¹⁸

Koyama et al. explain the olfactory epithelium has a regenerative capacity and the basal cells in the neuroepithelium undergo continuous cell division to give rise to new olfactory neurons. When the neuroepithelium is injured, its regenerative ability is up-regulated and the epithelium is rapidly regenerated. Despite this, the regenerative capacity especially in the elderly population could be deteriorated due to a pathological condition associated with inflammation or aging.¹⁹

For the first time, scientists and researchers are beginning to take the loss of smell seriously because of COVID-19 and the fact that so many people have experienced anosmia. This has led to so much more research into anosmia. 

The genetic link

Another recent study indicated that there could be a genetic link. Researchers compared genetic differences related to those infected by COVID-19 with and without a loss of taste and smell. The study found that the difference in a fixed location of two olfactory genes, UGT2A1 and UGT2A2 which play a role in metabolizing odorants are involved.²⁰

The study found the loss of smell is related to damage of the olfactory support cells of the olfactory epithelium, inside the nasal cavity. These support cells are metabolically and functionally associated with the integrity of the olfactory neurons and with odorant signal transduction and maintaining the cilia of mature olfactory receptor neurons. Olfactory impairment occurs when these essential functions are disrupted; however, how UGT2A1 and UGT2A2 are involved is still not clear, however it is suggested that these genes may play a role in the physiology of the infected cells resulting in functional impairment that contributes to loss of ability to smell.²⁰

Impact of altered smell and taste

Burges Watson et al. examined the feedback from over 9,000 individuals who experienced altered smell and taste following COVID-19 infection. The loss of taste and smell associated with COVID-19 led to severe disruption to daily life which impacted psychological wellbeing, physical health, relationships and sense of smell.²¹

It is very likely that many individuals would rank their sense of sight as far more important than their sense of smell.²¹

However, when you read the feedback made by individuals who experienced loss of smell and taste in the research paper by Burges Watson et al., Altered smell and taste: anosmia, parosmia and the impact of long COVID-19, I have no doubt that you soon realise how important smell is.²¹

For example, many individuals who experience loss of smell described food as being bland and unappetizing, this had a major impact on appetite, enjoyment, fullness and satiety. Dining out with friends and other people is an important daily pleasure and form of social bonding; however, impaired sense of smell and taste means it is no longer enjoyable.²¹

The sense of smell also plays an important role in the way we interact with our environment, to other people and places and to ourselves. The feedback from those experiencing anosmia found that their relationship to the world, self and others had changed.²¹

I really need to share some of the comments so that you truly understand how stressful it must be to experience anosmia:

The world is very blank. Or if not blank, shades of decay. I feel alien from myself. It’s also kind of a loneliness in the world. Like part of me is missing as I can no longer smell and experience the emotions of everyday basic living. Detached from normality. Lonely in my body. It’s so hard to explain. ²¹

Another person explained:

You feel so detached from reality when you can’t smell your surroundings.²¹

Sensory confusion was also very common:

wine smells like sewage. Prosecco is even worse.²¹

or

poo now smelled better than coffee.²¹

Body odour plays a very important role in establishing social bonds and in the way we develop close and intimate relationships. It is therefore not surprising that so many people experiencing anosmia following COVID-19 infection were concerned about not being able to smell their partner.²¹

I can’t smell my boyfriend’s natural scent, which makes me feel more distant from him. Like he is a stranger. I used to feel comforted being able to smell him while cuddling. Worse is that his kisses taste really bad to me know, so I avoid that, but I haven’t told him because I don’t want to hurt his feelings. Also, I am constantly worried that I smell bad myself and it makes me feel very insecure.²¹

or

The worst bit is not knowing if I smell. It makes me really self-conscious. If we get intimate, I can’t get lost in the moment anymore because I’m constantly worried that I smell bad myself and it makes me very insecure^.21

The loss of smell not only affected romantic and sexual relationships, the inability to smell your own body odour creates a sense of anxiety about one’s body odour not being socially acceptable. This results in a sense of paranoia for some who felt the need to shower frequently and multiple change of clothing throughout the day, constant cleaning and frequent deodorising.²¹

This very detailed report gives us a very clear understanding into the challenges associated with loss of smell and taste or distorted sense of smell associated with COVID-19.

In conclusion, the following comment highlights the profound the impact on one’s mental wellbeing:

I’m losing hope and I’ve never been more depressed in my life. Will I ever get better? This has left me so low in mood. It’s really quite debilitating – physically, mentally and professionally. I’m 6 months in and losing hope.²¹

Burges Watson et al point out that until now health care professionals had overlooked the seriousness of smell and taste loss and as a result of the serious impact that COVID-19 is having on the senses now means we may see more research in developing strategies to manage the impact of sensory disruption.²¹

Olfactory/Smell training

One of the first studies involving olfactory training was by Damm et al. in 2013. Their randomized controlled multicenter study found that in subjects with post infectious olfactory dysfunction for up to 12 months, olfactory function improved in 15/24 participants (63%) of the high-training group and in 6/31 participants (19%) of the low-training group.¹²

Neta et al. state that olfactory training is considered one of the only current therapeutic strategies for treating post-viral olfactory loss.¹³
Olfactory training involves repeated daily exposure to a range of odorants.

The original study by Damm et al. involved using four odorants – phenylethyl alcohol (a rose odour), 1,8-cineole (found in rosemary or eucalyptus), lemon odour and eugenol (found in clove bud). Since this original study, these are the essential oils that are often recommended.¹²
Rimmer however suggests you should choose scents from four smell categories – flowery, fruity, spicy and resinous.9 (From what I understand the term resinous refers to the scent of eucalyptus).

You can choose any smell you feel comfortable with, have available and would normally enjoy.

My suggestion is to use a rich floral such as ylang ylang or rose, a spicy aroma such as clove bud, a eucalyptol-rich oil such as rosemary or eucalyptus, and a rich lemon scented oil such as lemon, lemon myrtle or citronella.

It is recommended that the olfactory training be done with each oil for 20 seconds, twice a day for at least 3 months as a treatment for anosmia associated with COVID-19.

While the efficacy of olfactory training has been disputed, a systematic review supports the use of olfactory training for all patients with a loss of smell.¹³

It is also noted that the Rhinology Society recommend olfactory training for patients who complain of hyposmia or anosmia for more than 2 weeks.¹⁰

It is highly recommended that smell training be considered as a treatment. Smell training has no known side effects and is low cost.

Even the Royal Australasian College of Surgeons promotes smell training as therapy. A recent blog by Dr Peter Friedland states if any four different odours are used, it does not appear to decrease the efficacy of the therapy.²³

The key factors to consider are to perform the sessions twice daily for about 20 seconds, for four months or until recover, and to be mindful and focused during the task. This is done by opening each bottle separately and taking gentle ‘bunny’ sniffs for 20 seconds while concentrating on what you are trying to smell. Then continue with the next fragrance.²³

The exact mechanism of olfactory training is not known however it is assumed that repeated exposure to an odorant may modulate regenerative capacity of the olfactory mucosa.¹⁰

The aim of smell training may also help recovery based on neuroplasticity, allowing the brain to reorganise itself to compensate for a change or injury.^6,12

The regeneration of olfactory neurons decreases with age, leading to a reduced number of olfactory neurons. A high recovery rate was found in patients under 40 years of age (47%) while patients over 69 years of age had a lower rate of recovery (7%).¹²

Other possible role of essential oils

A paper published in August 2021, by Koyama et al., Possible use of phytochemicals for recovery from COVID-19 induced anosmia and Ageusia, explored the role of essential oils in smell training and asked whether the essential oils used for smell training also have a pharmacological basis.

Koyama is a prolific researcher in the field of neuroscience, olfaction, cellular biology and social sciences.¹⁹

Koyama explains that the essential oils chosen for smell training were not selected according to their chemical constituents; however, she and her colleagues state that there may be better combinations of essential oils for facilitating recovery based on the bioactive properties of the oils such as the essential oils wound healing, antiviral or anti-inflammatory activity.¹⁹

The comprehensive paper is 71 pages long and provides us with an in-depth understanding of the olfactory pathway. In this presentation I am more interested in what they had to say about the potential role of essential oils.

I totally endorse the authors statement that the lack of acknowledgement of the bioactive properties is rather striking, and they are critical of statements made by some clinicians who claim that the bioactivity of the chemical constituents in essential oils is completely unsupported by any science.
They state that the essential oils should be chosen on the scientific evidence of the bioactive properties and the mechanisms of action of the major chemical constituents.¹⁹

For example, β-caryophyllene a sesquiterpene found in essential oils such as black pepper and lavender is a ligand of cannabinoid receptor 2 (CB2) and is involved in the release of b-endorphin and suppresses inflammatory nociception. It activates the pathways involved in cell proliferation and cell migration and suppresses the pathways related to inflammation and improves re-epithelialization. In addition to β -caryophyllene, citral found in lemongrass and many other essential oils is also an agonist of CB2 and has anti-inflammatory activity.¹⁹

They cite another study that found geraniol and citronellol significantly down-regulated the expression of ACE2 in epithelial tissues. This indicates they may be useful as a treatment for COVID-19.^19,24

Koyama et al. provide us with extensive examples where the terpenes found in essential oils have many bioactive properties such as anti-inflammatory, antimicrobial, antiviral, enhancing cell proliferation or enhancing cell migration.¹⁹

They believe that the essential oils used in smell training may support the process of regeneration of the damaged neuroepithelial tissue.¹⁹

The authors provide a comprehensive table listing examples of essential oil constituents and the effect that the compound may have on the olfactory pathway and examples of essential oils with these constituents. 

Other therapies for smell disorders

Texture of food

Research from the University of Cincinnati has suggested common coping mechanisms that help COVID-19 patients deal with a loss of smell and the impact that this has on the sense of taste. To compensate for the loss of taste patients ate food with distinct textures such the different textures associated with fruits such as strawberries or apples. Patients also enjoyed cold drinks and carbonated drinks which would provide different sensation and texture.²⁵

Zinc Sulphate

Some reports suggest that zinc deficiency can cause dysfunction in smell and taste. One clinical trial involving patients with COVID-19 who received zinc therapy experienced significantly less olfactory recovery time.¹³

Vitamin A

Retinoic acid which is a metabolite of vitamin A is reported to promote olfactory neurogenesis due to its ability to regenerate the olfactory neuroepithelium. However, another randomised, double-blind, placebo-controlled clinical trial evaluating the oral administration of 10,000 IU of vitamin A per day for 3 months in patients with post infectious olfactory dysfunction.¹³

Alpha-lipoic acid (ALA)

According to previous studies, alpha-lipoic acid may decrease ACE2 activity after SARS-C0V-2 replication and may also lead to the suppression of inflammatory cytokines. While an uncontrolled study found that 600 mg/day of ALA for an average of 4-5 months resulted in a moderate improvement in smell in 61% of the participants involved in the study, its use may be associated with neurological side effects including headache, dizziness and confusion. The British Rhinological Society does not recommend ALA for a patient with loss of smell as an isolated symptom for more than 2 weeks or following resolution of any other COVID-19 symptoms.^13,26

Omega 3 fatty acids

It is reported that omega-3 supplementation may aid in the recovery after post-viral olfactory loss, although this has not been formally tested in post-COVID-19 patients. It is believed that omega 3 fatty acids may act through neuro-regenerative and anti-inflammatory mechanisms, which helps the olfactory nerve to heal and may also serve as an adjuvant therapy in olfactory training.¹³

Corticosteroids

Neta et al. state that corticosteroids have a very important role in the management of patients with SARS-CoV-2 who need mechanical ventilation but may also be effective in relieving the symptoms of anosmia and dysgeusia.¹³

Corticosteroids have been considered as a treatment for the olfactory loss in the past; however, a recent report indicates that there is no evidence that any kind of corticosteroid treatment is beneficial.²⁷

Neta et al. reported that patients who have anosmia as a result of COVID-19 should avoid oral or topical corticosteroids as there is no robust evidence to demonstrate any benefits over their potential risks.¹³

However, another study by Singh et al. found that olfactory and gustatory functions improved significantly in patients with COVID-19 after receiving nasal spray of fluticasone and oral triamcinolone after one week.²⁸

References

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24. Senthil Kuma KJ et al. Geranium and lemon essential oils and their active compounds downregulate angiotensin-converting enzyme 2 (ACE2), a SARS-CoV-2 spike receptor-binding domain, in epithelial cells. Plants. 2020;9:770. doi: 10.3390/plants9060770
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