Science of COVID-19 Impact on Olfactory Dysfunction
COVID-19 pandemic has caused global catastrophe with over 92 million cases, 2 million deaths in 191 countries and loss of millions of jobs and significant socio-economic impacts despite various measures to control it . Several researchers including neuroscientists at Harvard Medical School has identified the olfactory cell types in the upper nasal cavity most vulnerable to infection by SARS-CoV-2, the virus that causes COVID-19. To understand Olfactory Dysfunction, we need to understand how coronavirus impacts the sense of smell and why loss of smell is number one indicator of coronavirus infection. There is clinical data to support the efficacy of smell test and imperative need to demonstrate the need for mass regular testing to control the spread of this pandemic by identifying contagious people and keep everyone safe until 100% vaccination compliance.
COVID-19 spreads from an infected person to others through respiratory droplets and aerosols that are airborne transmission with particles <5μm  created when an infected person coughs, sneezes, sings, shouts, or talks. Infectious droplets or aerosols may come into direct contact with the mucous membranes are inhaled by another person's nose, mouth or eyes, airways, and lungs.
Anosmia is total loss of smell and hyposmia is partial loss of smell owing to olfactory dysfunction that is caused by coronavirus infection. A number of scientific studies have demonstrated that sudden loss of smell is one of the key symptoms of COVID-19 infection, and it is also recognized by several health organizations including Canadian Government and Center for Disease Control (CDC), USA. Studies show that anosmia and hyposmia are early symptoms of COVID-19 infection preceding fever, and infected people can lose sense of smell early on, hence it is more sensitive screening method for asymptomatic patients [2, 11]. In fact, the loss of smell has been found to be ten times more accurate than fever when screening for coronavirus infection  and should be treated as diagnostic test.
Coronavirus is spreading rapidly despite various measures to control it. It is estimated that about 40% infected with COVID-19 are asymptomatic and don’t even know they have the disease . In addition, it takes 3-5 days for symptoms to manifest themselves and another 2-4 days to get the test results. In certain provinces such as Alberta and Ontario, an asymptomatic person cannot even get tested using RT- PCR method as it is fairly expensive (>$200 / test), there is a huge demand and limited resources .
Figure 1 (Brann et al 2020 & 13)
Figure 2 (Olfactory System -Wikipedia)
The virus attacks the support cells and stem cells of the nasal cavities that support the olfactory receptor neurons, shutting them down. [2, 7, 8]. The support cells in the olfactory respiratory epithelium (RE), the tissue that lines the nasal cavities responsible for odors, and olfactory sensory epithelium (OSE) are covered with ACE-2 receptors that SARS-CoV-2 uses to enter cells. Epithelial cells become infected very early in the disease process before the body’s immune system responds resulting in fever.
COVID-19 infected patients were found to have extremely high levels of ACE-2 (Angiotensin converting enzyme II) enzyme in the area that the nose is responsible for smelling. It is believed that this enzyme is the “entry point” that allows coronavirus to get into the cells of the body causing the infection. Studies showed that SARS-CoV-2 infection causes olfactory epithelia to become detached in two days of infection, causing the cilia of olfactory neurons to be removed. Removing the olfactory receptors causes inability to detect odorants [3, 7, 8, 10].
Figure 3 [7, Scientific American]
The upper nasal cavity shows the interface between the olfactory sensory epithelium (OSE) and the olfactory bulb (OB) in the brain (Figure 3). The olfactory nerve (ON) carries signals from the OSE to the OB. In the OSE there are several types of cells in addition to olfactory sensory neurons (OSNs). Damage to any of these cells by coronavirus affects proper functioning of OSNs .
The loss of smell as a result of coronavirus is unique and different than experienced by someone with bad cold or flu. Anosmia symptom is very specific to SARS-CoV-2 and not typical of other diseases caused by viruses. When COVID-19 patients lose smell, it tends to be sudden, severe and the patient is able to breathe freely [3, 8].
A majority of COVID-19 patients experience some level of anosmia, most often temporary. Analyses of electronic health records in a study led by neuroscientists at Harvard Medical School indicate that COVID-19 patients are 27 times more likely to have smell loss but are only around 2.2 to 2.6 times more likely to have fever, cough or respiratory difficulty, compared to patients without COVID-19 .
A Monell analysis of 47 studies finds that about 80% of COVID-19 patients have lost their sense of smell [3, 8]. It was found that only about 50% of people self-reported loss of smell as symptom, and generally people don’t realize they have partially or completely lost the sense of smell. Therefore, objective testing is better than asking people. A scientific study done at University of Pennsylvania with 40-odorant test showed that 98% patients exhibited some smell dysfunction . This was also confirmed in clinical studies that were sponsored by Virocule Inc.
It is important to note that one can lose the sense of smell for multiple reasons such as cold, sinus infection, neurological diseases like Alzheimer’s and Parkinson’s, or simply aging. About 3% of Americans have anosmia and 12.4% over 40 have hyposmia .
Therefore, in order to control the spread of coronavirus and keep everyone safe, it is very important for everyone to be tested on daily basis and take appropriate action to isolate themselves and obtain adequate medical treatment . Current methods of testing using RT-PCR and antigen are not practical and feasible for mass testing . An objective smell test can be an early and accurate indicator of coronavirus infection and is suitable for mass self-test [8, 11, 12]. ANOSMIC COVID-19 Smell Tester is the only practical method for screening as it fast, cost effective, accurate, non-invasive, and easy to use by everyone anytime without visiting healthcare testing facility.
 Johns Hopkins Corona Virus Resource Center. Home - Johns Hopkins Coronavirus Resource Center (jhu.edu)
 Sharon Begley, “Fever checks are flawed way to flag Covid-19 cases. Experts say smell tests might help”, Statnews, July 2, 2020. https://www.statnews.com/2020/07/02/smell-tests-temperature-checks-covid19/
 Michelle Roberts, “Coronavirus smell loss ‘different from cold and flu", BBC News online, 18 August 2020. https://www.bbc.com/news/health-53810610
 Shima T. Moein et al., “Smell dysfunction: a biomarker for COVID-19”, International Forum of Allergy & Rhinology, Vol 10, Issue 8, Smell dysfunction: a biomarker for COVID‐19 - Moein - 2020 - International Forum of Allergy & Rhinology - Wiley Online Library
 Carla K. Johnson et al., “Scientist struggle to follow COVID-19’s silent spread”, Global News, July 23, 2020. Scientists struggle to follow COVID-19’s silent spread - National | Globalnews.ca
 Rachael D’Amore, “Why coronavirus testing strategies are changing as numbers spike”, Global News, October 21, 2020. https://globalnews.ca/news/7410049/coronavirus-targeted-testing-asymptomatic/amp/
 Leslie Kay, “Why COVID-19 Makes People Lose Their Sense of Smell”, Scientific America, June 13, 2020. Why COVID-19 Makes People Lose Their Sense of Smell - Scientific American
 Stephani Sutherland, “Mysteries of COVID Smell Loss Finally Yield Some Answers”, Scientific America, November 18, 2020. https://www.scientificamerican.com/article/mysteries-of-covid-smell-loss-finally-yield-some-answers1/
 Kieran Leavitt, “Canada has been reluctant to embrace rapid tests. This Harvard epidemiologist says we cant afford to wait", Toronto Star, December 6, 2020. Canada has been reluctant to embrace rapid tests. This Harvard epidemiologist says we can’t afford to wait | The Star
 Quentin Fottrell, “Johns Hopkins scientists examining weird side effects of COVID-19 suggest one way coronavirus ‘gains a foothold in the body’. Johns Hopkins scientists examining weird side effects of COVID-19 suggest one way coronavirus ‘gains a foothold in the body’- MarketWatch
 Alek Korab, “This is the #1 Indicator You Have COVID, Study Shows”, Yahoo Life, August 23m 2020. This is the #1 Indicator You Have COVID, Study Shows (yahoo.com)
 Daniel B. Larremore, “Modeling the effectiveness of olfactory testing to limit SARS-2-CoV transmission”, medRxiv, December 02, 2020. Modeling the effectiveness of olfactory testing to limit SARS-2- CoV transmission | medRxiv
. David H. Brann et al, Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Science Advances 31, Jul 2020: Vol. 6, no.31.
 World Health Organization, “Modes of transmission of virus causing COVID-19: implications for IPC precaution recommendations, 29 March 2020. Modes of transmission of virus causing COVID-19: implications for IPC precaution recommendations (who.int)
Summary of Clinical Studies of ANOSMIC COVID-19 Smell Tester
Three pilot clinical studies (September-December 2020) were conducted at Rajasthan University of Health Sciences (RUHS), Sawai Man Singh Hospital (SMS) and on two construction sites in Jaipur (India) to determine the sensitivity and specificity of Virocule’s ANOSMIC COVID-19 Smell Tester for screening COVID-19 patients using anosmia and hyposmia as indicators for the infection. Following is a summary of these studies:
- First Study: The first study was retrospective with 156 randomly selected subjects, where 56 (n=56) had been previously tested COVID-19 positive, 50 (n=50) had been previously tested COVID-19 negative with RT-PCR and digital X-Rays, and another 50 (n=50) healthy previously untested subjects. The odorant from ANOSMIC tester was sprayed on the back of the wrist of the subjects. The test method included intensity of smell from 0-10, reaction of subject to smell, and odorant identification. We also conducted a placebo test with these patients. The result of the first study demonstrated that 98% of COVID-19 patients had either anosmia or hyposmia, with sensitivity of 91% and specificity of 96% was observed. In addition, we were able to determine the criteria of assessing whether a person was COVID-19 positive or negative with 95% confidence level.
- Second Study: The second study was prospective with 55 (n=55) randomly selected subjects with various COVID-19 symptoms such as fever, cough, diarrhea, and not previously tested on RT-PCR or CT Scan / X-Ray. The odorant from ANOSMIC tester was sprayed on the back of the wrist of the subject. Test method included intensity of smell from 0-10, reaction of subject to smell, and odorant identification. These patients were tested with RT-PCR and X-Rays after four days for confirmation. There was no placebo test used this time. The result of the second study showed that 90% people who were infected with COVID-19 had anosmia or hyposmia, with observed sensitivity of 91% and specificity of 100% with 95% confidence level. One patient with ANOSMIC test suggesting COVID positivity was found to be RT-PCR test negative but after 4 days RT-PCR test confirmed positive status, demonstrating that the ANOSMIC test is more accurate for early detection of COVID-19 than RT-PCR test.
- Third Study: The third study was prospective with 420 (n=420) randomly selected subjects. Here three groups were created, where Group A consisted of 120 symptomatic subjects (n=120) that had not been previously tested on RT-PCR at RUHS hospital, and Groups B and C consisted of 300 asymptomatic healthy subjects (n=300) in two different locations that had not been previously tested on RT-PCR or Digital X-Rays. The test method was similar to the previous studies where the odorant from ANOSMIC tester is sprayed on the back of the wrist of the subject. Test method included intensity of smell from 0-10, reaction of subject to smell, and odorant identification from menu of 10 common odors. For Group A all COVID positive and negative subjects had to be tested for confirmation with RT-PCR and Digital X-ray. For Groups B and C, if the subject was COVID-19 positive, then they had to be tested with RT-PCR and Digital X-Ray for confirmation. The result of this study showed that 90% of all COVID positive subjects had olfactory dysfunction. The ANOSMIC test achieved in identifying COVID-19 positive patients with had 92% precision. The percentage of healthy asymptomatic population that were found to have COVID infection was 11%. These subjects were isolated and treated by medical professionals. About 4.4% of subjects tested COVID positive by ANOSMIC tests but tested negative initially by RT-PCR and Digital X-ray tests, but after 4 days they were retested and found positive by RT-PCR and Digital X-ray methods, indicating that ANOSMIC test is a good indicator of early identification of olfactory dysfunction.
In conclusion, the three pilot clinical studies conducted in India demonstrated that there were over 90% of COVID-19 infected subjects had some olfactory dysfunction, and our ANOSMIC was able to identify these subjects with over 92% precision. In addition, we found about 11% of asymptomatic subjects were infected with coronavirus, and we successfully isolated and medical professionals treated them. The ANOSMIC tester was able to successfully identify the infection earlier than RT-PCR test.
The ANOSMIC tester is fast, accurate, cost-effective, non-invasive, and easy to use by everyone everywhere. This is the most practical way of mass testing to reduce the spread of coronavirus and reopen the economy safely.