As evidence piles up documenting a sudden loss of smell and/or taste as a presenting symptom of COVID-19, the call to screen for these phenomena is growing.
A number of new publications show a high proportion of people infected with COVID-19 report loss of smell and/or taste, with their authors adding to the clamor to recognize these symptoms as potentially indicative of the infection.
In particular, there is a belief that these signs may be present in many with asymptomatic COVID-19, and therefore asking about them could be a way to prioritize people for initial testing for the SARS-CoV-2 virus in the absence of other symptoms.
Anyone testing positive could then quarantine, and their contacts could be traced.
Despite this, the World Health Organization (WHO) has not listed loss of smell or taste as potential symptoms of SARS-CoV-2 infection.
But the US Centers for Disease Control and Prevention (CDC) has now added "new loss of taste or smell" as a symptom on its COVID-19 information page.
American Academy of Otolaryngology—Head and Neck Surgery (AAO-HNS) executive vice president and CEO James C. Denneny III, MD, believes the symptoms may be an early warning signal.
And there's no downside to checking for these, Denneny told Medscape Medical News.
"Given the fact that this doesn't require any surgical procedure, biopsy, or specific treatment, I think the upside of getting it early is great," he said. "The downside of using it as a symptom, and if someone doesn't turn out to have it, is virtually zero."
Claire Hopkins, MD, president of the British Rhinological Society, and colleagues, writing in Lancet Infectious Diseases, agree.
"Physicians evaluating patients with acute-onset loss of smell or taste, particularly in the context of a patent nasal airway, should have a high index of suspicion for concomitant SARS-CoV-2 infection."
They also observe that this appears to occur, in contrast to other respiratory infections, "in the absence of nasal congestion or rhinorrhea."
Newest Publications Find Smell and Taste Loss Is Common
Author of one of the newly published studies, Carol H. Yan, MD, an otolaryngologist and head and neck surgeon at the University of California San Diego, also thinks that sudden smell and taste loss seem to be fairly specific markers of COVID-19.
In her survey of patients who presented to UC San Diego Health for SARS-CoV-2 testing, Yan and colleagues reported that 68% (40 of 59) of COVID-19-positive patients reported olfactory impairment and 71% (42 of 59) reported taste impairment.
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Among the 203 people in the "control" group who were PCR-negative for SARS-CoV-2, just 16% had smell loss and 17% had taste loss, according to their results published in the International Forum of Allergy & Rhinology.
"Based on our study, if you have smell and taste loss, you are more than 10 times more likely to have COVID-19 infection than other causes of infection. The most common first sign of a COVID-19 infection remains fever, but fatigue and loss of smell and taste follow as other very common initial symptoms," said Yan.
"We know COVID-19 is an extremely contagious virus. This study supports the need to be aware of smell and taste loss as early signs of COVID-19."
Yan told Medscape Medical News that another not yet published analysis indicates that sudden loss of smell or taste "may be more representative of a mild form of disease."
Getting these people tested and isolated could therefore help prevent spread of COVID-19, she urged.
Based on Yan's report and other case reports, the UC San Diego Health system is now asking all callers to its COVID-19 hotlines, and all visitors and staff, if they've had a sudden loss of taste or smell in the last few weeks, she explained.
And Ahmad R. Sedaghat, MD, PhD, at the University of Cincinnati, Ohio, takes a similar view.
In a new systematic review of the topic published April 14 in Laryngoscope Investigative Otolaryngology, Sedaghat and colleagues write: "Anosmia (total loss of smell) without nasal obstruction, in particular, appears to be a highly specific indicator of COVID-19."
Sedaghat said a sudden loss of sense of smell wouldn't necessarily lead people to think they have COVID-19, particularly if they remain asymptomatic, so "these individuals could continue business as usual and spread the disease as a carrier."
"If someone experiences anosmia without nasal obstruction, aside from quarantining, it would not be unreasonable to reach out to one's primary care physician about getting tested," he said in a statement from his institution.
Symptom Checkers Add Weight
Several organizations around the world have begun collecting symptom reports from patients and clinicians, which has shone more light on the sudden loss of taste and smell as potential flags for COVID-19.
In an April 14 Morbidity and Mortality Weekly report from the CDC on COVID-19 infections in healthcare workers, of the 5000 who reported symptoms, 750 (16%) wrote "loss of smell or taste" as an "other" symptom.
Meanwhile, the COVID Symptom Tracker smartphone app, a joint effort by Massachusetts General Hospital, Boston, Stanford University, California, and King's College, London, UK, which as of press time, was monitoring some 2.5 million people, has had similar findings.
In a preprint publication on 400,000 people reporting one or more symptoms between March 24 and 29 on the tracker, 18% had lost their sense of smell or taste — more than the 10% who reported fever, but far less than the 53% who reported fatigue.
Only 1702 of the 400,000 had received a COVID-19 test.
Of those, 579 had tested positive and 1123 were negative.
The organizers estimated that of those who were positive, 59% reported losing smell or taste, compared with just 18% who tested negative.
"When combined with other symptoms, people with loss of smell and taste appear to be three times more likely to have contracted COVID-19 according to our data," said Tim Spector, MD, a genetic epidemiologist at King's College and the app's lead researcher, on the symptom tracker's website.
These people "should therefore self-isolate for 7 days to reduce the spread of the disease," he urged.
Anosmia Is the Initial Symptom in Many Patients With COVID-19
The AAO-HNS also began collecting data from physicians and patients on March 25 through its web-based 16-question symptom tracking tool.
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It has received more than 500 reports of sudden taste or smell loss, said Denneny.
In a report on the first 237 responses, published in Otolaryngology-Head and Neck Surgery, anosmia (profound loss of smell) was found in 73% of subjects before a COVID-19 diagnosis and was the initial symptom in 27% of those subjects.
That latter determination "was the single most important finding," said Denneny, noting it shows that smell and taste loss are "a sentinel symptom."
Anosmia led to testing in only 40% of the cases.
Half of the reports came from otolaryngologists, but a large number came from other medical specialties, especially from family medicine.
Just 2% of reports came from patients in that first group, which was based on responses through April 3.
Denneny said that more reports are now coming in from patients, which he attributes to widespread media coverage about the loss of taste and smell.
It's still not entirely clear why SARS-CoV-2 might inhibit taste or smell. More common viruses like influenza and other coronaviruses can also cause smell and taste loss.
So far, it seems like the sensory recovery is faster for SARS-CoV-2 than the other viruses, which suggests a potentially different mechanism of action, said Yan. Patients she surveyed at UC San Diego recovered the senses within a few weeks to a month, compared to months or a year with the more common viruses.
Yan's study was partially supported by the National Institutes of Health. Sedaghat has reported no relevant financial relationships. The COVID Symptom Tracker is supported by Zoe Global Limited and has received grants from the Wellcome Trust, Medical Research Council/British Heart Foundation, and Biological Informative Markers for Stratification of Hypertension.
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As of April 9, 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had infected 1,436,198 people and caused 85,522 deaths. By the time you read this, those numbers will have increased. As the numbers grow, more and more neurologic symptoms are being reported in COVID-19 patients. Neurologists, in turn, may increasingly find themselves involved in caring for patients with the novel virus.
COVID-19 may affect the nervous system via four potential mechanisms, which may overlap. The first is direct viral injury of nervous tissue, such as occurs with herpes simplex encephalitis. Although there are some suggestive case reports, there is no definite proof that the SARS-CoV-2 virus directly damages the central nervous system (CNS).
The second type of injury results from an excessive immune response in the form of a "cytokine storm." Cytokines can cross the blood-brain barrier and are associated with acute necrotizing encephalopathy. Only one case concurrent with COVID-19 has been reported.
The third mechanism of nervous tissue damage results from unintended host immune response effects after an acute infection. An example of this type of indirect CNS injury is Guillain-Barré syndrome (GBS). One case of GBS associated with COVID-19 has been reported, but the evidence for cause and effect is weak.
The fourth mechanism of indirect viral injury results from the effects of systemic illness. Neurologists are accustomed to seeing severely ill patients in the intensive care unit develop neurologic symptoms such as encephalopathy, critical illness myopathy, and neuropathy. Most cases of COVID-19-related neurologic complications appear to fall into this category.
...theoretically, the coronavirus could directly enter the brain, but this is speculative.
In February of this year, Guan and colleagues reported the clinical characteristics of SARS-CoV-2 infection in 1099 patients. Neurologic symptoms in patients with COVID-19 included headache (13.6%) and myalgias (14.9%). Only 5% required intensive care unit admission. On the basis of this large series, there seemed little reason to worry that SARS-CoV-2 might directly or indirectly attack the CNS or peripheral nervous system (PNS).
However, a separate, nearly simultaneous retrospective case series reported a high incidence of neurologic symptoms in 214 hospitalized patients with confirmed COVID-19 in Wuhan, China. Seventy-eight (36.4%) patients had CNS (24.8%), PNS (8.9%), or skeletal muscle symptoms (10.7%). The two most common CNS symptoms were dizziness (16.8%) and headache (13.1%), with acute cerebrovascular disease, ataxia, epilepsy, and impaired consciousness also reported. Severely ill patients were more likely to develop neurologic symptoms such as altered mental status, ischemic or hemorrhagic stroke, and muscle injury.
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The most common PNS symptoms were hypogeusia (5.6%) and hyposmia (5.1%), with vision impairment and nerve pain also reported (because taste and smell are dependent upon cranial nerves, these would more accurately be considered deficits due to CNS injury). Neurologic involvement carried a poor prognosis.
The authors hypothesized that SARS-CoV-2 might enter the nervous system via the angiotensin-converting enzyme 2 (ACE2) functional receptor, which is present in glial cells, neurons, skeletal muscle, and other organs. Potential entry routes to the CNS include hematogenous spread and retrograde neuronal transmission through olfactory neurons in the cribriform plate.
They noted that studies of another member of the coronavirus family, SARS-CoV, indicate that direct brain entry is possible, and direct coronavirus spread to the medullary cardiorespiratory center may partially underlie COVID-19 respiratory failure. SARS-CoV nucleic acid has been found in the cerebrospinal fluid and brain tissue of patients infected with SARS-CoV, while invasion of the brain with SARS-CoV via the olfactory system in mice can also occur.
Felicia Chow, MD, MAS, a neuro-infectious disease expert at the University of California in San Francisco, is part of a team establishing an observational cohort of COVID-19 patients to learn more about its neurologic complications. Chow commented, "Some of the best evidence that the SARS-CoV-2 virus can target the nervous system is the finding of anosmia, which could be due to viral invasion of the olfactory bulb. But the loss of smell could also could be immune-mediated due to antibodies and may not necessarily represent neurotropism."
Chow added, "It is also true that ACE receptors are present in neurons and glial cells, so theoretically, the coronavirus could directly enter the brain, but this is speculative. Researchers in Hong Kong have stated that the virus does infect neurons, but the data are not yet published. As of now, we don't know."
A review of 221 patients published in March echoed other review findings, revealing 13 patients (5.9%) with cerebrovascular disease. Eleven (5%) had an acute ischemic stroke, one had a cerebral venous sinus thrombosis (0.5%), and one a cerebral hemorrhage (0.5%). These patients were likely to be older with cardiovascular risk factors of hypertension or diabetes mellitus. Eleven of the 13 (85%) had severe SARS-CoV-2 infection. Increased inflammatory response and hypercoagulable state secondary to COVID-19 may have contributed to these events. Of the 13 patients, 5 died.
One patient with acute hemorrhagic necrotizing encephalopathy associated with COVID-19 has been described, possibly due to a cytokine storm, while a possible example of indirect viral nerve injury is a single case report of GBS associated with SARS-CoV-2 infection. However, this case was atypical as GBS occurred 1 week before the development of clinical symptoms rather than afterward. The authors concede that GBS in this setting may have been a coincidence. No postviral neurologic complications have yet been reported.
It may be premature to be certain that we are not missing patients with a primary neurologic problem...
Raymond Roos, MD, Marjorie and Robert E. Straus Professor of Neurology at the University of Chicago in Illinois, commented, "The main problem with COVID-19 cases has been a respiratory one. Sometimes patients can have confusion or a disturbed state of consciousness from the systemic involvement, especially if the oxygen level is low. In these cases, neurologists may be consulted to determine whether there is evidence of a primary neurologic problem and to provide guidance as to what tests should be carried out."
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Roos added, "Evidence that these symptoms are from systemic problems is supported by the substantial number of patients who we see with similar symptoms from a systemic disease. The absence of focal neurologic signs, such as weakness of one side, suggests a systemic rather than a neurologic problem." Yet he acknowledges that we physicians, including neurologists, have relatively little experience with this virus. "It may be premature to be certain that we are not missing patients with a primary neurologic problem," he said, pointing out that the JHM strain of the mouse hepatitis virus can cause very significant neurologic disease.
Chow offered practical tips for the management of critically ill patients with COVID-19, suggesting that neurologists continue to employ conventional logic and tools. "If patients have neurologic signs and symptoms, then I would consider a lumbar puncture or neuroimaging. Just because the patient is positive for SARS-CoV-2 doesn't mean that they don't have a different etiology for their neurologic symptoms."
She added that many patients with Alzheimer's or Parkinson's disease might be at risk for severe COVID-19 infection because they are elderly. "I would tell these patients that they are high-risk and should absolutely be staying home—the same advice I would give to someone on chemotherapy," she advised.
In theory, patients with multiple sclerosis treated with immunosuppressive drugs could be especially vulnerable to severe COVID-19 disease, but as Mount Sinai neurologist Stephen Krieger, MD, told Medscape, "Thankfully, there is...little evidence to date of increased infection susceptibility or risk for patients treated with disease-modifying therapies."
With respect to treatment, Chow opined, "At this point, there is no specific treatment even if we knew that the virus was neurotropic. If the virus is causing immune-mediated neural injury, theoretically, plasma exchange, IVIg, or steroids might be helpful. If it's direct viral injury, then you need an effective antiviral treatment, which we don't yet have."
Despite the wide variety of neurologic complications potentially associated with SARS-CoV-2 infection, it is still unclear whether these symptoms result from direct neural injury. Currently, it appears that most neurologic symptoms of COVID-19 are nonspecific and secondary to systemic illness. The literature contains only a single case of acute hemorrhagic necrotizing encephalopathy, while the patient with SARS-CoV-2–associated GBS is an atypical case.
For now, there is no convincing evidence that the SARS-CoV-2 virus directly affects the CNS or PNS in humans. As neurologists treat an ever increasing number of COVID-19 patients, our understanding of the neurologic profile of SARS-CoV-2 infection will continue to evolve. Postinfection surveillance will be necessary to identify possible post-COVID neurologic syndromes.
Additional resource: The American Academy of Neurology has created an active COVID-19 resource center at AAN.com. A recent 20-minute YouTube video with Joseph E. Safdieh, MD, editor-in-chief of Neurology Today,addresses the impact of coronavirus on the practice of neurology.
Andrew Wilner is an associate professor of neurology at the University of Tennessee Health Science Center in Memphis, a health journalist, and an avid SCUBA diver. His latest book is The Locum Life: A Physician's Guide to Locum Tenens.
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