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..

The COVID-19 pandemic has prompted the search for animal models that recapitulate the pathophysiology observed in humans infected with SARS-CoV-2 and allow rapid and high throughput testing of drugs and vaccines. Exposure of larvae to SARS-CoV-2 Spike (S) receptor binding domain (RBD) recombinant protein was sufficient to elevate larval heart rate and treatment with captopril, an ACE inhibitor, reverted this effect. Intranasal administration of SARS-CoV-2 S RBD in adult zebrafish recombinant protein caused severe olfactory and mild renal histopathology.

Zebrafish intranasally treated with SARS-CoV-2 S RBD became hyposmic within minutes and completely anosmic by 1 day to a broad-spectrum of odorants including bile acids and food. Single cell RNA-Seq of the adult zebrafish olfactory organ indicated widespread loss of expression of olfactory receptors as well as inflammatory responses in sustentacular, endothelial, and myeloid cell clusters. Exposure of wildtype zebrafish larvae to SARS-CoV-2 in water did not support active viral replication but caused a sustained inhibition of ace2 expression, triggered type 1 cytokine responses and inhibited type 2 cytokine responses. Combined, our results establish adult and larval zebrafish as useful models to investigate pathophysiological effects of SARS-CoV-2 and perform pre-clinical drug testing and validation in an inexpensive, high throughput vertebrate model.

Preprint available in bioRxiv (Nov. 8 , 2020):

https://doi.org/10.1101/2020.11.06.368191

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

The aim of this study is to evaluate if the sweat produced by COVID-19 persons (SARS-CoV-2 PCR positive) has a different odour for trained detection dogs than the sweat produced by non COVID-19 persons. The study was conducted on 3 sites, following the same protocol procedures, and involved a total of 18 dogs. A total of 198 armpits sweat samples were obtained from different hospitals. For each involved dog, the acquisition of the specific odour of COVID-19 sweat samples required from one to four hours, with an amount of positive samples sniffing ranging from four to ten. For this proof of concept, we kept 8 dogs of the initial group (explosive detection dogs and colon cancer detection dogs), who performed a total of 368 trials, and will include the other dogs in our future studies as their adaptation to samples scenting takes more time.

The percentages of success of the dogs to find the positive sample in a line containing several other negative samples or mocks (2 to 6) were 100p100 for 4 dogs, and respectively 83p100, 84p100, 90p100 and 94p100 for the others, all significantly different from the percentage of success that would be obtained by chance alone. We conclude that there is a very high evidence that the armpits sweat odour of COVID-19+ persons is different, and that dogs can detect a person infected by the SARS-CoV-2 virus.

Preprint Available in bioRxiv (June 5, 2020):

https://doi.org/10.1101/2020.06.03.132134

The symptoms suggest SARS-CoV-2 might infect neurons, raising questions about whether there could be effects on the brain that play a role in patients’ deaths, but the data are preliminary. Nearly two weeks ago, Alessandro Laurenzi, a biologist working as a consultant in Bologna, Italy, was mowing the grass in his garden when a friend stopped him and said the mower reeked of fuel. “I couldn’t smell anything at all,” he tells The Scientist. That was in the morning. A few hours later, he went to have lunch and realized he couldn’t smell the food he was about to eat and when he took a bite, he couldn’t taste it either. Within a few days, he developed symptoms of COVID-19 and called his doctor to ask if he could get tested. Because his symptoms were mild, Laurenzi says, his doctor said no. Laurenzi had heard anecdotally that many COVID-19 patients in Italy suffered from a loss of smell, so he started reading all the scientific papers he could find to see if his anosmia and ageusia would ever abate. One of the papers, a review published March 13, mentioned that SARS-CoV-2, like other coronaviruses such as SARS-CoV and MERS-CoV, could target the central nervous system, possibly infecting neurons in the nasal passage and disrupting the senses of smell and taste. 

Reading this, Laurenzi immediately reached out to the corresponding author, Abdul Mannan Baig, a researcher at Aga Khan University in Pakistan, and asked if his symptoms were reversible. The evidence, Mannan told Laurenzi and reiterated to The Scientist, indicates they will abate, possibly because the loss of sense is caused by inflammation in the area as the body fights the virus, so those symptoms could disappear in seven to 14 days. “Let’s hope so,” Laurenzi tells The Scientist. Documenting such peculiar symptoms is important, Mannan tells The Scientist, because the loss of smell and taste could be an early warning sign of SARS-CoV-2 infection. Based on the literature, British ear, nose, and throat doctors have now called for adults who lost those senses to quarantine themselves in an attempt to tamp down the spread of the disease, The New York Times reports. The symptoms, Mannan adds, also suggest that the virus has the ability to invade the central nervous system, which could cause neurological damage and possibly play a role in patients dying from COVID-19.

Canines seem to detect coronavirus infections with remarkable accuracy, but researchers say large-scale studies are needed before the approach is scaled up. Asher is an eccentric, Storm likes sunbathing and Maple loves to use her brain. All three could play a part in controlling the COVID-19 pandemic, but they are not scientists or politicians. They are dogs.  And they are not alone. Around the world, canines are being trained to detect the whiff of COVID-19 infections. Dog trainers are claiming extraordinary results — in some cases, they say that dogs can detect the virus with almost perfect accuracy. Scientists involved with the efforts suggest that canines could help to control the pandemic because they can screen hundreds of people an hour in busy places such as airports or sports stadiums, and are cheaper to run than conventional testing methods such as the RNA-amplification technique PCR. But most of these findings have not yet been peer reviewed or published, making it hard for the wider scientific community to evaluate the claims. Researchers working on more conventional viral tests say that initial results from dog groups are intriguing and show promise. But some question whether the process can be scaled up to a level that would allow the animals to make a meaningful impact. On 3 November, groups working with the animals met in an online workshop called International K9 Team to share preliminary results from experiments and to improve how their research is coordinated. “No one is saying they can replace a PCR machine, but they could be very promising,” says veterinary neurologist Holger Volk at the University of Veterinary Medicine Hanover in Germany, who is leading an effort to train and study COVID-sniffing dogs and did not speak at the event.

Sense of wonder

Humans have taken advantage of canines’ superior sense of smell for decades. Dogs’ noses bear 300 million scent receptors, compared with humans’ 5 million or 6 million. That enables them to detect tiny concentrations of odour that people can’t. Sniffer dogs are already a familiar sight in airports, where they detect firearms, explosives and drugs. Scientists have also trained dogs to detect some cancers and malaria, but the animals are not routinely used for this purpose. Researchers don’t know for sure what the dogs are smelling, but many suspect that these illnesses cause the human body to let off a distinct pattern of volatile organic compounds (VOCs). These molecules readily evaporate to create scent that dogs can pick up. Previous work with non-COVID viruses has suggested that viral infections might also cause the body to do this.  Many sniffer-dog scientists turned their attention to COVID-19 early in the pandemic. They have trained their canines to smell samples, most often of sweat, in sterile containers, and to sit or paw the floor when they detect signs of infection. Trials at airports in the United Arab Emirates, Finland and Lebanon are using dogs to detect COVID-19 in sweat samples from passengers; these are then checked against conventional tests. According to data presented at the K9 meeting, dogs in Finland and Lebanon have identified cases days before conventional tests picked up the virus, suggesting that they can spot infection before symptoms start. Riad Sarkis, a surgeon and researcher at Saint Joseph University in Beirut, is part of a French–Lebanese project that has trained 18 dogs. Sarkis used the best two performers for the airport trial in Lebanon. The dogs screened 1,680 passengers and found 158 COVID-19 cases that were confirmed by PCR tests. The animals correctly identified negative results with 100% accuracy, and correctly detected 92% of positive cases, according to unpublished results. “This is very accurate, feasible, cheap and reproducible,” says Sarkis, who has been approached about using the dogs in schools, banks and prisons, and is working with a shopping mall to offer COVID-19 testing using the animals. Low-income countries with limited lab space could particularly benefit from the approach, says Isabella Eckerle, a virologist at the University Hospitals of Geneva in Switzerland....

Published in Nature (Nov. 23, 2020):

https://doi.org/10.1038/d41586-020-03149-9

About two-thirds of the London NHS staffers surveyed reported diminished ability to taste or smell, a prominent, early Covid symptom, shows new research. A large proportion of U.K. health-care workers may have been infected with coronavirus early in the pandemic, according to a survey suggesting that loss of smell and taste may be a guide to determining its prevalence in populations. About two-thirds of the London National Health Service staffers surveyed reported diminished ability to taste or smell — one of the prominent, early symptoms of Covid-19 — just weeks after the coronavirus arrived in the U.K., according to research published Thursday in The Lancet Microbe journal.

Health-care professionals on the front lines are far more likely to contract the virus compared with individuals in the general community, earlier studies have found. Yet it’s unclear how many NHS staff have contracted the virus as testing has been limited. The high rate of the loss of smell, called anosmia, suggests that a larger proportion may have been infected than previously thought. “Some people get smell loss before other symptoms, or as the only symptom,” of Covid, said Carl Philpott, professor of rhinology at the University of East Anglia’s Norwich Medical School, in an interview. “It has a sudden onset, so people really notice the difference.” 

In a Finnish study, dogs learned to recognize the distinctive odor of a coronavirus infection. In the future, dogs might be able to detect infected people in nursing homes or at airports. In a pilot study at the University of Helsinki, dogs trained as medical diagnostic assistants were taught to recognize the previously unknown odor signature of the COVID-19 disease caused by the novel coronavirus. And they learned with astonishing success: After only a few weeks, the first dogs were able to accurately distinguish urine samples from COVID-19 patients from urine samples of healthy individuals. "We have solid experience in training disease-related scent detection dogs. It was fantastic to see how fast the dogs took to the new smell," says DogRisk group leader Anna Hielm-Björkman. After only a short time, the animals identified the urine of people infected by the novel coronavirus, known as  SARS-CoV-2, almost as reliably as a standard PCR test. The Finnish scientists are now preparing a randomized, double-blind study in which the dogs will sniff a larger number of patient samples. Only then will the scent tests be used in clinical practice.

The very rapid and promising findings from Finland are also important for other research teams, such as those in Great Britain and France, who are training sniffer dogs to detect COVID-19. Fellow researchers from the German Assistance Dog Center (TARSQ) have also benefited from the Finnish results. "No one could tell us with certainty whether training with the aggressive virus is dangerous or not for humans and dogs. We wanted to gather more information first before we started training because the German virologists advised us against it — after all, so little is known about the virus so far," explains Luca Barrett from TARSQ.

It is still unclear which substances in urine produce the apparently characteristic COVID-19 odor. Since SARS-CoV-2 not only attacks the lungs, but also causes damage to blood vessels, kidneys and other organs, it is assumed that the patients' urine odor also changes. This is something which the dogs, with their highly sensitive olfactory organs, notice immediately. Certain diseases appear to have a specific olfactory signature that trained dogs can sniff out with amazing accuracy, Barrett says. "According to one study, dogs can detect breast cancer with a 93% probability, for example. And lung cancer with a 97% probability," she says.

See also study in BMC Inf. Dis. (July 23, 2020):

https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-020-05281-3

The dogs are already trained to detect odours of cancers, malaria and Parkinson's disease. The first phase of the trial will be led by the London School of Hygiene & Tropical Medicine, along with the charity and Durham University.  It has been backed with £500,000 of government funding. Innovation minister Lord Bethell said he hoped the dogs could provide "speedy results" as part of the government's wider testing strategy.

The trial will explore whether the "Covid dogs" - made up of Labradors and cocker spaniels - can spot the virus in humans from odour samples before symptoms appear. It will establish whether so-called bio-detection dogs, which could each screen up to 250 people per hour, could be used as a new early warning measure to detect Covid-19 in the future. The first phase will involve NHS staff in London hospitals collecting odour samples from those infected with coronavirus and those who are uninfected. Samples of breath and body odour could come from a number of sources, including used face masks....