Overview

Anosmia, a sudden loss of smell and taste, has been recognised as one of the earliest and most distinctive symptoms of COVID-19.¹ Unlike other respiratory infections, such as Influenza, Rhinovirus, and SARS, where the reason for loss of smell is nasal congestion, anosmia due to COVID-19  happens without any nasal inflammation.²

Even though it is not life-threatening, anosmia can significantly impact a patient’s quality of life. Loss of smell leads to imbalanced food intake and a sense of uneasiness for people. This article examines the mechanisms behind anosmia associated with SARS-CoV-2 infection, its clinical symptoms, diagnosis, and management.

Understanding anosmia

Anosmia or a complete loss of the sense of smell often occurs along with a loss of the sense of taste (Ageusia), as both these senses are closely linked.³

Upper respiratory tract viral infections are among the common causes of Anosmia, but it can also result from the formation of nasal polyps, head trauma or injury, or even neurodegenerative diseases like Parkinson’s and Alzheimer’s.^4,5

During a typical viral infection, like; SARS, Influenza, and Rhinovirus, there is inflammation of the nasal mucosa. This prevents the odorant stimuli from reaching the olfactory neurons to be processed. Hence, the loss of smell occurs. However, in early 2020,  reports of a sudden loss of smell and taste without nasal congestion began to emerge. This led to various studies, and a strong association between SARS-CoV-2 pathogenesis and anosmia was confirmed.⁶

Mechanism of anosmia in COVID-19

The sudden anosmia in the absence of nasal congestion was a commonly found symptom in many COVID-19 patients during early 2020.⁶ This unusual occurrence led to a wave of research to try and understand the mechanisms by which SARS-CoV-2 induces anosmia. 

A three-tiered model of infection and damage was envisaged, and it was elucidated as follows:

Viral entry

SARS-CoV-2 enters the body through sustentacular cells found in the upper part of the nasal cavity. These cells play an important role in maintaining the integrity of the olfactory epithelium.  These cells contain a receptor called Angiotensin-converting enzyme 2 (ACE2) and produce an enzyme called Transmembrane protease, serine 2(TMPRSS2). The SARS virus uses the ACE2 receptor and, with the help of the TMPRSS2 enzyme, enters the sustentacular cell and replicates.⁷

Local infection of the olfactory epithelium                                              

When SARS-CoV-2 infects the sustentacular cells, it leads to inflammatory reactions within the nasal cavity, which causes damage to olfactory neurons. This results in functional anosmia. This is typically observed in the early stages of COVID-19. These cases resolve within 2–3 weeks as the Olfactory Epithelium can regenerate.⁸

Inflammation of olfactory epithelium

When SARS-CoV-2 infects the olfactory epithelium, in some individuals with prolonged symptoms, it leads to a cascade of inflammatory reactions. This includes the release of cytokines such as tumor necrosis factor-alpha (TNF-α) and interferons, which have been shown to induce apoptosis (programmed cell death) of olfactory neurons. It is also found to reduce mucus secretion from Bowman’s glands, affecting odorant stimuli transport. These cases are likely to be chronic anosmia, also known as hyposmia, or parosmia, lasting for several months.⁹

Central Nervous System (CNS) Involvement 

Some studies have also suggested that SARS-CoV-2 may affect the olfactory bulb in the brain via the olfactory nerve. This can trigger inflammation and further prolong olfactory dysfunction.¹⁰ At this stage, the condition is best referred to as central olfactory dysfunction or neuroinflammatory olfactory dysfunction, rather than simply anosmia. Recovery in these cases may be partial or prolonged, depending on the extent of damage.¹¹

Understanding the mechanisms of SARS-CoV-2-induced anosmia is important, as it is also an early clinical marker of COVID-19. Hence, accurate diagnosis becomes essential for the timely identification and management of affected patients.

Diagnosis:

The sudden development of anosmia, without nasal congestion, is a clinically significant symptom and a valuable early diagnostic indicator of COVID-19.¹²

Independently, Anosmia in patients has been diagnosed using both subjective (opinion-based) and objective (measurement-based) methods.

Subjective methods include using questionnaires that commonly ask patients whether they had a decreased sense of smell before diagnosis of  COVID-19, whether the loss was partial or complete, and how long this dysfunction persisted.¹³

Objective methods include numerical values gathered from smell tests. Numerous smell tests have been developed to evaluate anosmia. Among these, the Connecticut Chemosensory Clinical Research Center (CCCRC) olfactory test and the University of Pennsylvania Smell Identification Test (UPSIT) have been widely used.^14,15 

The CCCRC Test: The CCCRC test assesses the patient’s sense of smell in two parts: an odor threshold test and an odor identification test.¹⁴  

The threshold test uses decreasing concentrations of n-butanol, and a mark is set when the patient consistently identifies the odor.

The identification test presents ten familiar smells and ten distractor smells, one nostril at a time, with patients choosing the correct odor from a list. If they can’t smell it, guessing isn’t required. 

A composite score is formed from the results of both the threshold and identification tests. While useful, these tests have drawbacks. They lack standardised odors, guessing cannot be detected, and it takes about 35 minutes to complete.

The UPSIT test: This test consists of four booklets, each containing 10 “scratch and sniff” pages with microencapsulated odorants and a multiple-choice question offering four answer options¹⁵ 

The subject smells each odor using one or both nostrils and selects the most likely response, even if the scent is not detected. 

The test is quick and practical, taking about 10 to 15 minutes, with established cut-off points that can support accurate clinical diagnosis.

These tests provide scores that help categorize the severity of Anosmia. The categories range from normal (normosmia) to complete loss of smell (anosmia). Intermediate stages are termed as hyposmia. Understanding this classification helps clinicians in accurately diagnosing anosmia in COVID-19 patients.

Below is the standardised score table: 

Management and treatment of COVID-19 anosmia: 

COVID-19-related anosmia is treated in different timelines based on the severity. In the initial stages, smell training or exposure to specific odors over time has been found to show consistent benefits.¹³ This is usually followed by treatment with an Intranasal corticosteroid like mometasone furoate. It is hypothesised that the corticosteroid acts locally on the nasal mucosa and helps to reduce epithelial damage and olfactory dysfunction.¹⁴ However, they do have potential complications like immunosuppression.¹⁵

At times, nasal saline irrigations with ACE2-inhibiting agents followed by topical steroid treatment have also been explored.¹⁶ Saline irrigation with ACE2-inhibiting agents not only clears viral particles and mucus but also competitively blocks the virus from binding to ACE2, thus reducing viral entry into nasal cells. However, one should also consider that ACE2 has a protective role in cardiovascular and lung function. Blocking it might interfere with important physiological processes.¹⁷

If anosmia persists beyond 4–6 weeks in COVID-negative patients or over 3 months in COVID-positive individuals with neurological symptoms, an ENT specialist referral is recommended.¹⁸ In these cases, an MRI scan would be advised. 

As a Final intervention, surgeries can be suggested in some persistent cases, though their outcomes remain uncertain.¹⁹

Even though anosmia is a common symptom of upper respiratory tract infections that often resolves on its own, a sudden onset in the absence of nasal congestion should be considered a potential early indicator of COVID-19 infection. This has made anosmia a valuable clinical sign for the diagnosis of SARS-CoV-2.

As research into the mechanisms of viral-induced olfactory dysfunction continues, it holds promise for the development of more targeted and effective treatment strategies for managing COVID-19-related anosmia.

Summary:

Anosmia (loss of sense of smell), associated with COVID-19, is an important symptom that can occur in the early stages of SARS-CoV-2 infection.

SARS-CoV-2 enters sustentacular cells found in the nasal cavity via the ACE2 receptor, with the help of the enzyme TMPRSS2. This viral infection causes local inflammation and damage to the olfactory epithelium, resulting in loss of sense of smell or anosmia. In severe cases, the viral infection progresses up the olfactory bulbs to the central nervous system, leading to long-term damage.

Various diagnostic tools, such as olfactory tests and MRI scans, are used to assess severity and rule out other causes.

Treatment options include smell training, corticosteroid therapy (mainly intranasal), and nasal saline irrigation with ACE2-inhibiting agents. While steroids have limited use, smell training remains the safest therapy. Surgical options are rarely considered due to uncertain outcomes.  Persistent anosmia post-COVID should be referred to ENT evaluation, as it may signal ongoing inflammation or neurological involvement.

A personalised and stepwise treatment approach is the only key to managing this complex and often frustrating symptom.