Virus World

Loss of smell may predict persistent cognitive impairment after Covid-19 recovery, suggests results presented at the Alzheimer's Association International Conference. Very little is known about the long term effects of Covid-19, especially in relation to the brain. Who gets what symptoms may feel like a mystery. And with the current seven day average of new cases hovering around 1,000,000 cases worldwide, the issue of long term sequelae only grows more pertinent as infections increase. In this regard, a study presented at this year’s Alzheimer's Association International Conference (AAIC) may have uncovered a key to solving this riddle: loss of smell.

Study Design

The Argentinian research team investigated the long term Covid-19 cognitive impairment in older adults through a one-year prospective study design. All 766 participants were randomly invited from the health registry in Jujuy, Argentina, which holds all Covid-19 testing information for its region. Investigators split the group by polymerase chain reaction (PCR) testing status: 88.4% who had Covid-19 and 11.6% without—in other words, the control group. The adults’ ages ranged between 55 to 95 years old, with the mean age landing on 66.9 years old. More than half of the group, 57% specifically, were female. The group averaged 10.4 years of education; the Argentine education system consists of 12 years of school before university.  The researchers followed recommended measures from the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection (CNS SC2) to evaluate the long term cognitive consequences of Covid-19. They tested four cognitive domains: memory, attention, language and executive function (ex: flexible thinking, self-control and working memory). The degree of anosmia (loss of smell) was confirmed through an olfactory test. An individual would attempt to identify three distinct odors; depending on the results, the team categorized the anosmia as either nonexistent, mild, moderate or severe.

Study Results

The investigators stratified cognitive performance by number of impacted domains: normal cognition, memory-only impairment (single domain; 11.7%), impairment in attention and executive function without memory impairment (two domains; 8.3%), and multiple domain impairment (11.6%). Study investigator Gabriela Gonzalez-Alemán, PhD, told Medscape Medical News that the participants displayed “a predominance of memory impairment as would be seen in Alzheimer's disease,” with a large group presenting “a combination of memory and attention problems.”  None of the controls had olfactory dysfunction, but 40% of the study sample notably did. Furthermore, all participants with severe cognitive impairment also had anosmia. In this study, the degree of anosmia—rather than the severity of Covid-19—significantly predicted cognitive impairment. This is of particular importance to this study group, as cognitive impairment and loss of smell can be persistent for those over 60 years of age. Researchers also collected participant vaccination status through a one year phone survey. The majority of the participants received vaccinations. Around 71.8% of the study cohort had three vaccine doses, while 24.9% had two. Of those groups, around 12.5% of individuals with three doses were infected, and 23.3% of participants with two doses were reinfected.

Possible Implications

Instead of disease severity, loss of smell seems a more promising avenue for predicting who develops persistent cognitive changes after SARS-CoV-2 infection. The presented study results provide an intriguing foundation for further investigation. As described by Dr. Gonzalez-Aleman in Neurology Today, anosmia could be a sign of SARS-CoV-2 infection entering the brain through the olfactory bulb, or a sign of a continuing disease process after infection. With additional research, the hope would be to more thoroughly understand this correlation and thus develop a means to prevent such brain damage.

William A. Haseltine

I am a scientist, businessman, author, and philanthropist. For nearly two decades, I was a professor at Harvard..

COVID-19 has heterogeneous manifestations, though one of the most common symptoms is a sudden loss of smell (anosmia or hyposmia). We investigated whether olfactory loss is a reliable predictor of COVID-19.

This preregistered, cross-sectional study used a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified singular and cumulative predictors of COVID-19 status and post-COVID-19 olfactory recovery.

Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean±SD, C19+: -82.5±27.2 points; C19-: -59.8±37.7). Smell loss during illness was the best predictor of COVID-19 in both single and cumulative feature models (ROC AUC=0.72), with additional features providing no significant model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms, such as fever or cough. Olfactory recovery within 40 days was reported for ~50% of participants and was best predicted by time since illness onset.

Conclusions: As smell loss is the best predictor of COVID-19, we developed the ODoR-19 tool, a 0-10 scale to screen for recent olfactory loss. Numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (10<OR<4), especially when viral lab tests are impractical or unavailable.

Preprint available at medRxiv (July 26, 2020):

https://doi.org/10.1101/2020.07.22.20157263

When Covid-19 patients have smell loss it tends to be sudden and severe. And they usually don't have a blocked, stuffy or runny nose - most people with coronavirus can still breathe freely Another thing that sets them apart is their "true" loss of taste. It's not that their taste is somewhat impaired because their sense of smell is out of action, say the researchers in the journal Rhinology. Coronavirus patients with loss of taste really cannot tell the difference between bitter or sweet 

Experts suspect this is because the pandemic virus affects the nerve cells directly involved with smell and taste sensation.

The main symptoms of coronavirus are:

• high temperature
• new, continuous cough
• loss of smell or taste

Anyone with these symptoms should self-isolate and arrange to have a swab test to check if they have the virus. Members of their household should isolate too to prevent possible spread.

Lead investigator Prof Carl Philpott, from the University of East Anglia, carried out smell and taste tests on 30 volunteers: 10 with Covid-19, 10 with bad colds and 10 healthy people with no cold or flu symptoms.  Smell loss was much more profound in the Covid-19 patents. They were less able to identify smells, and they were not able to discern bitter or sweet tastes at all. Prof Philpott, who works with the charity Fifth Sense, which was set up to help with people with smell and taste disorders, said: "There really do appear to be distinguishing features that set the coronavirus apart from other respiratory viruses. "This is very exciting because it means that smell and taste tests could be used to discriminate between Covid-19 patients and people with a regular cold or flu." He said people could do their own smell and taste tests at home using products like coffee, garlic, oranges or lemons and sugar. He stressed that diagnostic throat and nose swab tests were still essential if someone thought they might have coronavirus. The senses of smell and taste return within a few weeks in most people who recover from coronavirus, he added.

Recent reports suggest that sudden smell loss might be a symptom of SARS-CoV-2 infection. The aim of this study was to investigate the frequency of olfactory loss in an out-patient population who presented to a coronavirus testing center during a 2-week period and to evaluate the diagnostic value of the symptom sudden smell loss for screening procedures. 

In this cross-sectional controlled cohort study, 500 patients who presented with symptoms of a common cold to a corona testing center and fulfilled corona testing criteria, completed a standardized diagnostic questionnaire which included the patients main symptoms, time course and an additional self-assessment of the patients current smell, taste function and nasal breathing compared to the level before onset of symptoms. 

Out of the 500 patients, 69 presented with olfactory loss. Twenty-two of them subsequently tested positive for SARS-CoV-2. Only twelve out of the patients without olfactory loss tested positive, resulting in a frequency of 64.7% for the symptom sudden smell loss in COVID-19 patients. Compared to COVID-19 patients without smell loss, they were significantly younger and less severely affected. Changes in nasal airflow were significantly more pronounced in SARS-CoV-2 negative patients with olfactory complaints compared to the patients with smell loss who were tested positive for SARS-CoV-2. By excluding patients with a blocked nose, the symptom sudden smell loss can be attested a high specificity (97%) and a sensitivity of 65% with a PPV of 63% and NPV of 97% for COVID-19.

Considering the high frequency of smell loss in non-hospitalized COVID-19 patients, acute olfactory impairment should be included in the WHO symptoms list and should be recognized as an early symptom of the disease. In contrast to other acute viral smell impairment, COVID-19 associated smell loss seems to be only rarely accompanied by a severely blocked nose.

Preprint Available at medRxiv (April 27.2020):

https://www.medrxiv.org/content/10.1101/2020.04.27.20081356v1