The Evolution of COVID-19 Symptoms: From Smell Loss to Pink Eye

As we explore the intricate world of virology, it's essential to understand how COVID-19 symptoms have transformed over time.

When COVID-19 first emerged in late 2019 and 2020, a sudden loss of smell and taste afflicted nearly half of those infected, becoming a hallmark symptom of the disease. One notable case involved a man consuming raw onions and garlic to demonstrate his loss of taste due to SARS-CoV-2, the virus responsible for COVID-19.

However, the predictability of a virus can make it less formidable. As SARS-CoV-2 continues to mutate, its symptoms have evolved:

In 2021, the Delta variant emerged, leading to an increase in runny noses and sore throats among those infected, resembling common cold symptoms. Loss of smell was no longer among the top ten symptoms reported.
By 2022, the milder yet more immune-evasive Omicron variant took precedence, with sore throats and hoarse voices becoming more prevalent than runny noses.
In 2023, the Omicron subvariant named Arcturus gained traction, bringing with it ocular symptoms, including pink eye.

Understanding how SARS-CoV-2 has biologically altered over time is a fascinating journey into virology.

The Shift from Smell Loss to Nasal Symptoms

The initial smell loss associated with COVID-19 was peculiar, as it did not come with nasal congestion, suggesting a neurological origin linked to damaged olfactory neurons. (Given that smell and taste are closely connected, the loss of one often affects the other.)

A pivotal study in 2020 revealed that human olfactory neurons lack the ACE2 and TMPRSS2 receptors necessary for SARS-CoV-2 infection. Instead, these receptors were found in sustentacular cells, which support olfactory neurons. A subsequent autopsy study of COVID-19 patients confirmed that while their olfactory neurons remained intact, they were disorganized and had lost their ability to sense smell.

These findings indicated that the original SARS-CoV-2 variant had a tendency to infect sustentacular cells (see Figure 1), leading to disruptions in smell and taste.

Schematic of olfactory epithelium and its connection to the brain.

As the virus evolved through the Alpha, Beta, Delta, and Omicron variants, reports of smell loss decreased significantly.

Did Delta and Omicron lose their affinity for sustentacular cells?

Yes, according to a 2022 study utilizing human nasal tissue and hamster models, researchers discovered:

The original SARS-CoV-2 variant effectively infected sustentacular cells, resulting in significant cell death. However, with Delta and even fewer with Omicron, this infection decreased, explaining the reduced reports of smell loss as the variants changed.
Delta showed a 21-fold increase in infecting Bowman’s glands, responsible for mucus production, which correlated with the rise of nasal symptoms.
Omicron barely affected any cells in the olfactory system, including the Bowman’s glands, further justifying the shift in symptomatology from smell loss to sore throats (see Figure 2).

Infection patterns of SARS-CoV-2 variants in olfactory epithelium.

The Rise of Sore Throats

As SARS-CoV-2 evolved into Delta and Omicron, the incidence of sore throats increased among patients. Specifically, sore throats were approximately 30% more frequent in Delta infections compared to Alpha, and around 20% more common in Omicron than Delta.

What could explain this inclination towards sore throats in COVID-19 cases? While research is still developing, several theories may provide insights.

For one, sore throats and runny noses often occur together due to inflammation. Immune responses may be more concentrated in the lower nose-throat area (the primary infection site for Delta and Omicron) than in the upper nose-brain area (the site for the original variant), considering that the brain has restricted immune reactions.

Moreover, Omicron is known to cause milder COVID-19, leading to fewer hospitalizations and fatalities. This is partly because Omicron preferentially targets the upper airways, avoiding heavy infection of the lower airways, where the lungs are located.

Omicron's efficiency in utilizing the ACE2-cathepsin L endocytic pathway for cell infection, as opposed to the ACE2-TMPRSS2 fusion pathway, contributes to this phenomenon.

In the ACE2-TMPRSS2 route, viral and cell membranes fuse, sometimes resulting in cell death, which halts viral replication. Conversely, the ACE2-cathepsin L route allows the virus to enter cells without causing significant cell death (see Figure 3).

Comparison of SARS-CoV-2 infection routes.

The preference for the ACE2-cathepsin L pathway also explains why Omicron struggles to infect olfactory sustentacular cells (see Figure 2), as these cells express IFITM3, which inhibits this entry pathway.

The higher viral loads in the upper airways may enhance Omicron's transmissibility compared to Delta, leading to localized inflammatory responses in the throat.

The Emergence of Pink Eye Symptoms

The latest variant, Arcturus XBB.1.16, has spread to over 30 countries since its introduction earlier this year, outperforming other Omicron subvariants, including the notable Kraken XBB.1.5.

While it remains uncertain if Arcturus is more virulent or immune evasive, reports indicate that infected individuals, particularly children, often experience itchy pink eyes or conjunctivitis as a primary symptom.

However, these claims stem from anecdotal evidence from specialists and lack formal research to back them. If confirmed, it would indicate a new phenotypic target for SARS-CoV-2, specifically the ocular system.

This is plausible, given previous documentation of ocular symptoms with earlier variants. Various eye structures have been shown to express ACE2, facilitating potential SARS-CoV-2 infection.

A 2020 study demonstrated that SARS-CoV-2 from the human nose could infect conjunctival cells as efficiently as respiratory cells. Another study successfully infected monkeys through their eyes, leading to mild COVID-19 and viral shedding through their respiratory pathways. Notably, a high viral load was discovered in the monkeys' nasolacrimal system.

The nasolacrimal system channels tear fluid from the eyes to the nasal cavity, providing a potential route for viral exchange (see Figure 4).

Nasolacrimal system and its connection to the nasal cavity.

Infecting the respiratory system via the eyes is not unprecedented. Other viruses, such as respiratory syncytial virus, can replicate in the eyes before migrating to the lungs, causing respiratory diseases.

However, research on whether Arcturus has developed the ability to infect through the nasolacrimal system is sparse. If true, this may warrant the reconsideration of protective measures like eye shields during surges.

Ultimately, SARS-CoV-2 has demonstrated its unpredictability, evolving from the distinctive loss of smell and taste to symptoms like runny noses, sore throats, and now pink eye. As we look ahead, we can only anticipate what further changes the virus may present.

Some researchers have even suggested classifying SARS-CoV-2 into different serotypes, highlighting the significant divergence of Omicron from its ancestral variants (see Figure 5).

Is COVID-19 today comparable to what it was in 2019? No, it is now markedly different in both symptomatology and genetics.

Genetic evolution and divergence of SARS-CoV-2 variants.

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Update on June 6: As noted by several commenters, COVID-19 is capable of causing a wide array of symptoms beyond those discussed, including severe conditions like pneumonia and long-term effects such as long COVID. This article may have oversimplified COVID-19 to illustrate its evolving pattern.