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Immunocompromised patients can harbour persistent SARS-CoV-2 infection for up to 505 days, show data from a patient who had the longest COVID-19 infection on record, according to a UK study looking at evolution of the virus.
An immunocompromised patient who was initially infected with a pre-Alpha variant (most likely the original Wuhan) tested positive for a total of 505 days before they died. Prior to this patient, the longest PCR confirmed persistent SARS-CoV-2 case was thought to be 335 days.
Infectious diseases registrar, Luke Blagdon Snell, MBBS, of Guy’s and St Thomas’ NHS Foundation Trust, London, who led the study, will present the work at this year’s annual European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), being held in Lisbon, Portugal over the next few days.
“With severely immunocompromised individuals, at risk of persistent SARS-CoV-2 infection, we need to test them regularly and often,” said Mr Snell in an interview with Medscape UK. “This is especially true if we know they have had an infection and it has cleared. Also, these particular patients are more likely to have poorer outcomes with a significant proportion dying, and this is probably due to a combination of underlying disease and COVID-19.”
With respect to clinical management of these patients, he added that, “we would suggest trying to clear persistent infection in these patients, however, right now we don’t have any good strategies for this”.
He stressed that treatment strategies for these immunocompromised patients with persistent SARS-CoV-2 infections were needed urgently, “especially because the current BA2 variant does not respond to UK-licensed antibody therapies. Any strategy is most likely to involve multiple therapies including antivirals and monoclonal antibodies”.
Mr Snell emphasised that this would not only benefit the individual patient but might also reduce the chance of new variants emerging.
Virus Evolution – Emergence of Mutations
The study investigated which mutations arise and if variants of SARs-CoV-2 can evolve in immunocompromised patients with persistent infections.
SARS-CoV-2 is a new virus because it only jumped from animal to human in late 2019 so it is still adapting to the human host. “Persistent infections provide one way to look at the evolutionary adaptations of this virus,” said Mr Snell.
The patients, who were studied between March 2020 and December 2021 (so from Wuhan through Alpha and Delta variants), were immunocompromised due to organ transplantation, HIV, cancer, or due to treatments such as chemotherapies or biologic antibody therapies associated with their underlying diseases.
Most patients received routine clinical care at Guy’s and St Thomas’ Hospital, where SARS-CoV-2 testing was done during patients’ regular clinical visits, and viruses were whole genome sequenced and analysed for minority variants.
Unique Genetic Signature and Consistent Over Time
Patients tested positive for the virus for at least eight weeks and these infections persisted for a mean of 73 days. However, two patients had persistent infections for over a year.
“We knew that this wasn’t reinfection because the genetic signature of each patient’s virus was unique and the same over time,” explained Mr Snell.
Around 30-50% of the study patients were asymptomatic, but in others COVID-19 was considered a significant contributory factor in cause of death. Four of the nine patients died. “However, it’s hard to know to what extent persistent virus contributed to their deaths given their underlying disease,” added Mr Snell.
Five of the nine patients developed at least one mutation seen in variants of concern. Some individuals developed multiple mutations associated with variants of concern, such as the Alpha, Delta, and Omicron variants. However, the virus from one individual contained 10 mutations that have arisen separately in the Alpha, Gamma, and Omicron variants.
Of the five surviving patients, two cleared SARS-CoV-2 infection without treatment, two cleared the infection after treatment with antibody therapies and antivirals, and one individual has ongoing infection.
In the latter patient, at last follow-up (early 2022), their infection had lasted for 412 days. The patient has already received monoclonal antibodies, but if they remain SARS-CoV-2 positive at next follow-up, then they will surpass the 505 days of the longest persistent infection to date.
Variants Arising in Immunocompromised Patients
Although mutations that have been found in variants of concern were seen in the virus isolated from the study patients, none of these variants gave rise to the known pandemic variants.
Mr Snell explained how variants could arise. Variants have arisen through evolution, and maybe more transmissible (for example Omicron), or maybe more virulent (for example Alpha), or may escape a vaccine (Omicron). He provided three possible explanations for the emergence of variants and added that these are not mutually exclusive.
“Firstly, these mutations gradually accumulate during transmission between people in the community; a secondly, in someone who is severely immunocompromised with persistent infection there is opportunity for mutations to arise as the virus continues to replicate and over time there is selection for certain mutations. Thirdly, variants can arise through infections across species, for example the outbreak we had between humans and mink in Denmark some time ago.”
He added that it is unknown whether the variants of concern, for example Alpha and Delta, arose from a persistent infection or from some other means. Mr Snell stressed that the evidence is weak but there is a hint that the Alpha variant may have arisen from an immunocompromised patient with a persistent infection.
“Where it arose in Kent, where there was a lot of genetic sequencing going on, the Alpha arose suddenly. This event is less consistent with a chain of transmission of mutation accrual and is more consistent with development within one individual.
“However, it is important to note,” he added, “that even though mutations accrue that doesn’t mean to say that the variant will be more transmissible to others.”
One of the First Cases of Occult Virus
The study also reports that one of the nine cases was one of the first cases of an occult COVID-19 infection identified to date.
“Occult infection describes someone who is thought to have cleared the virus, for instance with negative tests, but is later found to have an ongoing infection [the same virus],” explained Mr Snell.
A similar situation has been described with Ebola and hepatitis B. Mr Snell pointed out this is different to long COVID where the virus is generally thought to be cleared from the body but symptoms persist.
“If occult infection exists, and it is controversial, it is most likely that these patients represent a subset of persistent infection patients, and that the virus is somewhere in the body but goes unnoticed because the patient is asymptomatic.”
The patient in the study was symptomatic and tested positive for COVID-19 before recovering. They later tested negative several timesbefore developing COVID-19 symptoms again several months later. “A PCR test was positive and genome sequencing of the virus at this point showed the infection was caused by the Alpha variant, which had, by then, been eliminated from the UK, suggesting the virus had been present in the body ever since the initial infection but remained undetected.”
Créditos: Comité científico Covid