COVID-19's lasting impact on smell and brain health unveiled

By Neha MathurReviewed by Benedette Cuffari, M.Sc.Feb 12 2024

In a recent study published in the journal Diagnostics, researchers investigate the relationship between olfactory dysfunction associated with the coronavirus disease 2019 (COVID-19) and subsequent neurocognitive disorders. 

Study: A Comprehensive Review of COVID-19-Related Olfactory Deficiency: Unraveling Associations with Neurocognitive Disorders and Magnetic Resonance Imaging Findings. Image Credit: Mariia Boiko / Shutterstock.com

Background

Acute olfactory dysfunction is one of the earliest and most common symptoms associated with COVID-19, with an incidence rate of up to 75%. The manifestation of both olfactory and gustative dysfunction in COVID-19 can range from reduced or distorted perception to a complete loss of smell and/or taste.

In the context of COVID-19, acute olfactory dysfunction is defined as the altered sense of smell that persists for 14 days or less. Typically, olfactory dysfunction arises around the third day following initial infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with complete resolution of smell perception occurring within four to six weeks. However, up to 27% of COVID-19 patients will continue to experience altered olfactory perception for up to four months, with 21.3% of patients reporting an altered sense of smell for up to one year.

In addition to COVID-19, various other viral infections can lead to olfactory dysfunction, in addition to traumas, neurodegenerative pathological processes, and the secondary effects of sinus diseases. Despite the high prevalence of COVID-19-related olfactory dysfunction, few studies have discussed neuroimaging abnormalities associated with this symptom, including those that may affect the olfactory bulb (OB), olfactory sulcus (OS), olfactory cleft, and olfactory tract (OT).

About the study

In the present study, researchers performed a literature review on OB changes observed in patients with clinically confirmed olfactory dysfunction following a diagnosis of COVID-19. They also discussed current treatments for olfactory dysfunction associated with COVID-19.  

To this end, the researchers searched multiple databases including PubMed, Scopus, and Google Scholar until December 5, 2023, using keywords including ‘COVID-19,’ ‘olfactory deficit,’ ‘anosmia,’ ‘imaging,’ ‘SARS-CoV-2,’ ‘magnetic resonance imaging (MRI),’ ‘olfactory bulbs,’ ‘neurocognitive deficits,’ ‘mood disorders,’ ‘neuropsychiatric sequelae,’ and ‘treatments.’ This search led to a total of 12 observational studies and one case report included in the analysis.

How does SARS-CoV-2 cause olfactory dysfunction?

SARS-CoV-2 is considered neurotropic, neuroinvasive, and neurovirulent, with some viral variants associated with a greater affinity for the central nervous system (CNS) than others. In particular, the ancestral D614G strain, followed by the Gamma, Delta, and Omicron BA1 variants, have been associated with the greatest neurotropism in descending order.

Despite several studies evaluating the impact of SARS-CoV-2 infection on olfaction, the precise pathogenesis and molecular mechanisms responsible for this dysfunction remain unclear. Some proposed hypotheses include mechanical obstruction due to congestion and rhinitis, which can compromise airflow and the transportation of odorants for smell perception. However, this hypothesis has been disproven, as several studies have found that olfactory dysfunction often persists for longer durations than respiratory symptoms, with many COVID-19 patients experiencing olfactory dysfunction without the associated nasal congestion needed to support this theory.

Researchers have also hypothesized that SARS-CoV-2 causes direct damage to olfactory neurons, which subsequently leads to olfactory dysfunction. Despite the absence of both the angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) on olfactory neurons, both of which are crucial for viral entry into cells, SARS-CoV-2 may use other pathways such as Basigin (BSG), neuropilin-1 (NRP1), TMPRSS11A, and furin receptors to infect the olfactory system and cause dysfunction.

MRI imaging to elucidate olfactory dysfunction in COVID-19

The reviewed studies included several descriptions of MRI findings in patients with COVID-19, such as volumetric abnormalities and altered signal intensity of OBs, altered depth of OS, abnormalities within the olfactory cortex, as well as irregularities of neuron filia.

Measuring OB volume (OBV) and OS depth is the most common approach to evaluating the olfactory system. To this end, reduced OBV and OS depth in both the right and left side of hospitalized COVID-19 patients has been observed in several studies, thus suggesting that SARS-CoV-2 causes direct damage to olfactory neuronal pathways.

Up to one-third of patients who have recovered from COVID-19 report neurological symptoms, some of which include brain fog, insomnia, headache, depression, anxiety, and mental fatigue. In COVID-19, prolonged olfactory dysfunction has been associated with severe cognitive consequences, which may be attributed to inflammation, altered neurogenesis of the olfactory system, and functional changes within the brain structures.  

Treating olfactory dysfunction in COVID-19

Although olfactory dysfunction often spontaneously resolves in COVID-19 patients, a significant proportion of these individuals experience chronic olfactory dysfunction. Thus, a wide range of treatment approaches have been proposed for the treatment of COVID-19-related olfactory dysfunction, some of which include corticosteroids and intranasal insulin, dietary intake of various supplements, and olfactory training.

Future studies are needed to determine the efficacy of combining these treatment strategies to restore olfactory function.