The acute illness caused by COVID-19 has had a wide range of symptoms and severity – ranging from asymptomatic (no symptoms), to mild symptoms, to severe illness. Since the beginning of the pandemic there have been tens of thousands of variants, each with unique disease severity and even classic symptoms.
The original virus was primarily a respiratory infection, that in severe cases caused severe respiratory distress and death. It also likely had a large number of asymptomatic cases, which led to the rapid worldwide spread. Since that original strain there have been five(5) variants identified by the World Health Organization as "Variants of Concern" (VOC),.The most consequential of these VOCs were Alpha, Delta, and Omicron.
The Alpha (B.1.1.7) variant was first identified in the United Kingdom in September 2020 and designated a Variant of Concern on December 8, 2020. However, it was not named Alpha until the World Health Organization announced their new simpler labels for variants in May 2021. It was initially referred to as the "UK variant" or the "English variant", as was common early in the pandemic to name variants after where they were first identified.
The B.1.1.7 variant was found to be 50-75% more transmissible than the original (wild type) SARS-CoV-2 virus, which triggered the WHO to designate it, at first as the "first variant of interest" (VOI) and then several days later a "variant of concern" (VOC) due to the combination of increased transmission and disease severity. It also was likely highly under-reported across the world, as some of the tests available at the time failed to detect this new variant.
The Delta (B.1.617) variant was first identified in India in October 2020, with the earliest cases outside of India in early 2021. It was designated a VOI on April 4, 2021 and a VOC on May 11, 2021. It became known as "Delta" when the WHO announced their new Greek Letter designations on May 31, 2021. By summer 2021 Delta became the first variant to claim global dominance.
The Delta variant was the first variant to exhibit a significant shift in symptoms, from the common fever and cough seen in 2020 to symptoms such as headaches, sore throats, and runny noses. This lead many people to believe they simply had a cold, rather than COVID-19. Delta was also the first variant to produce large numbers of breakthrough infections (post-vaccination infections).
Delta was also found to be significantly more severe, causing close to double the risk of hospitalization and ICU admission, compared to the Alpha variant. The risk of death from Delta was also significantly higher compared to both wild type and Alpha variants.
However, vaccination was strongly protective of serious illness with the Delta variant, with a directly inverse association between U.S. counties with high vaccination coverage and incidence severe cases of Delta infections.
The Omicron (B.1.1.529 or BA.1) variant was first identified in South Africa and Botswana on November 22, 2021, from samples collected in early November. It was reported to the World Health Organization by the Network for Genomics Surveillance in South Africa on November 24, 2021 and was immediately designated a "variant under monitoring" by the WHO. Two days later on November 26, 2021, the WHO designated it a Variant of Concern, giving it the name Omicron.
Omicron's origin story diverged from the expected convergent evolution, where one variant evolves directly into another variant. Omicron likely evolved in a single person, most likely immunocompromised, from a prolonged infection that was able to heavily mutate.
Compared to the four previous VOCs (Alpha, Beta, Gamma, and Delta), Omicron was significantly more mutated, with 50 unique mutations throughout the genome, and 32 mutations found in the spike protein. This was twice as many mutations as the Delta variant. These mutations were responsible for the unique characteristics of the Omicron variant, including increasing the transmissibility, immune escape (both from previous COVID-19 infection and vaccination), and enhanced the virulence of the Omicron variant.
The case case of Omicron in the U.S. was detected on December 1, 2021 and by Christmas day, December 25, 2021, it was the dominant strain circulating in the U.S.
Another seriously troubling development with Omicron was reduced efficacy of many standard therapies and vaccines. Beginning as early as January 2022, concerns were mounting that many of the therapies that had become standard in treating COVID-19 infections, were becoming less-effective in the Omicron Era.
On January 24, 2022 the FDA announced they were limiting the use of certain monoclonal antibodies to treat COVID-19 due to the Omicron variant. By late February, the BA.2 sub-variant was increasing in prevalence in the U.S. and another monoclonal antibody, Sotrovimab was found to not be susceptible to BA.2; on April 5, 2022 the FDA announced that sotrovimab was no longer authorized to treat COVID-19 in any U.S. state or territory.
By the end of 2022 the "variant soup" of Omicron sub-variants were circulating in the U.S., including the BQ family. These BQ variants were highly alarming as they appeared unlikely to be susceptible to one of the last monoclonal antibodies available, Bebtelovimab. So on November 30, 2022 the FDA announced that the monoclonal antibody, Bebtelovimab, was no longer authorized in any U.S. region.
And the final nail in the coffin was the announcement, almost exactly one year to the day after the FDA initially announced limits on monoclonal antibodies, that the last monoclonal antibody on the market, Evusheld (a prophylactic treatment for immunocompromised individuals who were contraindicated or non-responsive to standard COVID-19 vaccines) lost its emergency use authorization due to it no longer being effective for currently circulating variants. Within the span of a single year, the Omicron variant rendered every single monoclonal antibody for the treatment and prevention of COVID-19 ineffective and not authorized by the FDA.
The Omicron variant, from it's initial emergence was highly mutated, and the speed and breadth of it's ability to mutate and enhance its transmission has been unparalleled. Within months of the emergence of BA.1 in In late November 2021, new sub-variants emerged. By the end of March 2022, the Omicron sub-variant BA.2 overtook BA.1 as the dominant variant in the U.S. In April 2022 the WHO announced they were tracking two more Omicron sub-lineages., BA.4 and BA.5 and the two sub-variants took over as the dominant strains in the U.S. by late June 2022.
However, unlike previous variants that quickly took dominance over other variants leading to their disappearance and extinction, Omicron quickly mutated and began co-circulating with its own sub-variants. This led to "variant soup", where not one single variant/subvariant could claim dominance over all the others.
It also led to sustained high viral transmission levels instead of the wave-like ebb and flow that was characteristic of previous variants. Instead of waves that were concerning, it became the "area under the curve" that was causing problems. That is, while there were no huge surges after the initial Omicron (BA.1) surge in January 2022, there was instead sustained high transmission that never subsides. This is actually more alarming, as it does not give healthcare systems any break.
By mid-2022, the situation with variant evolution had become considerably more complex, with hundreds of (sub)variants identified, all of them falling within “Omicron”. This meant that discussions of the most important variants have only two formal naming options: WHO Greek letters (which is all currently “Omicron”) or an increasingly complex collection of PANGO lineages (in many cases now several layers of “aliases” deep), and no longer even remotely resembling the BA.1-BA.5 lineages.
SARS-CoV-2 variant trackers began to identify the most concerning subvariants with informal "nicknames". In September 2021, the subvariant BA.4.6 became the first Omicron variant with a nickname, "Aeterna". Since then almost two-dozen Omicron subvariants have been given informal nicknames based on Greek mythological creatures. In early 2023 a new proposal for consistent assignment of "common names" to variants was established, of which there have so far been 3 variants named.
In March 2023 the World Health Organization finally acknowledged that the idea that "everything is Omicron" was not helpful, but instead of announcing new Greek letter variants they changed the criteria. On March 15, 2023, the WHO announced that:
going forward, the Greek letters will only be assigned to VOCs, while VOIs will be referred to using established scientific nomenclature systems such as those used by Nextstrain and Pango (e.g. XBB.1.5/23A for the latest VOI). WHO and TAGVE will undertake regular risk assessments for both VOIs and VOCs.
XBB* is a recombinant of two earlier Omicron sub-variants (BA.2.75 and BA.2.10). It first emerged in Southeast Asia in fall 2022 and quickly spread across the globe. By early 2023 nearly all circulating variants around the globe (except China) were descendants of XBB*. When the WHO updated their criteria in March 2023, XBB.1.5 (nicknamed "Kraken") was identified as a Variant of Interest. However, with their new criteria, it was not given a new Greek letter name since it was not seen as being significantly more severe to warrant the designation of "Variant of Concern".
The XBB family of variants are all extremely immune evasive, so while they are not necessarily contributing to severe disease, their transmission rates are unprecendented. Thankfully, nearly every person on earth has some level of previous immunity, either through previous infection and/or vaccination. But the XBB family are so heavily mutated that they are genetically distinct from the original strain of SARS-CoV-2 as SARS-CoV-2 is genetically distinct from SARS-CoV-1 (the virus that caused SARS in the early 2000s).
According to the NIH COVID-19 Treatment Guidelines, the clinical spectrum of infection for adults with confirmed COVID-19 acute infection includes presymptomatic/asymptomatic infection, mild illness, moderate illness, severe illness, and critical illness.
A large number of studies have shown that between 10-20% of people with acute COVID-19 infections go on to develop post-acute conditions (aka "Long COVID"). And that each infection increases individual risk of developing Long COVID. Although post-COVID conditions are more common in patients who were hospitalized with acute COVID-19 infection, it is clear that even patients who had mild or asymptomatic acute infections still can develop a wide range of debilitating symptoms, including neurocognitive, respiratory, and cardiovascular complications.
While the rates of Long Covid symptoms appears to be lower for patients with reported Omicron infections (compared to earlier variants), the risks posed by repeated infections could be catastrophic. It is also unclear what future variants might cause, or the possibility of developing complications in the months and years following an acute COVID-19 infection.
A January 2023 study published in BMJ found that "patients who were diagnosed with mild COVID-19 were up to 4.6 times more likely than uninfected patients to have some symptoms associated with post–COVID-19 condition (PCC) for 6 to 12 months." Symptoms associated with post-COVID conditions were more significant for altered sense of smell and/or taste, cognitive issues, shortness of breath, weakness, and heart palpitations. There was also a lower but still significant risk for dizziness. Risks were more apparent from 30 to 180 days after infection compared to 180 to 360 days, suggesting that many symptoms subsided in these patients within a year after infection.
The signs and symptoms of SARS-CoV-2 infection in symptomatic children may be similar to those in adults; however, a greater proportion of children may be asymptomatic or have only mild illness when compared with adults. The most common signs and symptoms of COVID-19 in hospitalized children are fever, nausea/vomiting, cough, shortness of breath, and upper respiratory symptoms.
The signs and symptoms of COVID-19 may overlap significantly with those of influenza and other respiratory and enteric viral infections. Critical disease, including respiratory failure, acute respiratory distress syndrome, and, less commonly, shock, may occur in children with COVID-19. The overall incidence of SARS-CoV-2 infection and, by extension, COVID-19-related hospitalizations among children has increased substantially with the the emergence of the Omicron variant and its descendants.
The reported clinical manifestations and duration of post-COVID conditions in children are highly variable. Not all pediatric studies included controls without SARS-CoV-2 infection, which makes determining the true incidence a challenge. However, the incidence of post-COVID symptoms appears to increase with age.
The most common symptoms reported include persistent fatigue, headache, shortness of breath, sleep disturbances, and altered sense of smell.
