Longest documented Covid-19 infection warns of risks of new vaccine-resistant mutations

Following the discovery of the longest known chronic SARS-CoV-2 infection, lasting 613 days, experts from the University of Amsterdam in the Netherlands warn of the risk of developing new, potentially immune-resistant variants of SARS-CoV-2 due to persistent infections in immunocompromised patients . .

The research will be presented at the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) World Congress, ESCMID (formerly ECCMID), which takes place next week in Barcelona, ​​Spain, from 27 to 30 April. This is the work of PhD student Magda Vergouwe from the Center for Experimental and Molecular Medicine (CEMM) at the University Medical Center Amsterdam (UMC Amsterdam) and her colleagues.

The authors describe the long-term evolution of the virus in a patient infected with SARS-CoV-2 over a period of 613 days, leading to the emergence of a new highly mutated variant. To the authors’ knowledge, this is the longest-lasting SARS-CoV-2 infection to date, although several cases have previously been reported lasting hundreds of days.

While healthy patients infected with SARS-CoV-2 may clear the virus within days or weeks, an immunocompromised person may develop a persistent infection with prolonged replication and evolution of the virus.

For example, the initial emergence of the omicron variant is thought to have occurred in an immunocompromised individual, highlighting the importance of careful genomic surveillance of this patient population.

In addition, the use of targeted immune pressure, including new treatments with antivirals and/or monoclonal antibodies, may further promote the emergence of escape viral variants.

CASE DESCRIPTION

Vergouwe and colleagues describe in their report a 72-year-old immunocompromised male patient who was admitted to the University Medical Center Amsterdam in February 2022 with SARS-CoV-2 infection. Due to a history of allogeneic stem cell transplantation for the treatment of overlapping myelodysplastic and myeloproliferative syndrome, he was classified as immunocompromised.

This was complicated by the development of post-transplant lymphoma, for which he received rituximab, which depletes all available B cells, including those that normally produce antibodies directed against SARS-CoV-2. He previously received several allogeneic stem cell transplants to treat myelodysplastic and myeloproliferative overlap syndrome.

In addition, at the time of admission, he had already received multiple SARS-CoV-2 vaccines without a measurable SARS-CoV-2 IgG antibody response. Routine genomic surveillance identified infection with SARS-CoV-2 Omicron variant BA.1.17. He was treated with the anti-SARS-CoV-2 targeted antibody sotrovimab, the anti-IL6 antibody sarilumab, and dexamethasone without clinical response.

Subsequent sequencing of SARS-CoV-2 showed the development of the known sotrovimab resistance mutation S:E340K as early as 21 days after sotrovimab infusion.

SARS-CoV-2-specific T cell activity and anti-spike antibody production were minimal in the first month, indicating that the patient’s immune system was unable to clear the virus. Long-term infection led to the emergence of a new immune evasion variant due to extensive evolution within the host. The patient ultimately died due to hematologic relapse after remaining SARS-CoV-2 positive with a high viral load for a total of 613 days.

Fortunately, there have been no reported cases of the highly mutated variant being transmitted to secondary cases in the community.

In more detail, 613 days after the initial detection of SARS-CoV-2 were characterized by multiple symptomatic episodes, related and not related to the virus, requiring hospitalization.

Persistent SARS-CoV-2 infection resulted in the patient undergoing long periods of isolation during hospitalization and increased use of personal protective equipment, which, according to his self-assessment, significantly reduced his quality of life.

Whole genome sequencing of SARS-CoV-2 was performed on 27 nasopharyngeal samples collected between February 2022 and September 2023. It identified more than 50 nucleotide mutations compared to current globally circulating BA.1 variants with multiple amino acid substitutions, including ACE. -2 receptor binding site replacements S:L452M/K and S:Y453F. In addition, several deletions occurred in the N-terminal spike domain, indicating immune escape.

“This case highlights the risk of persistent SARS-CoV-2 infection in immunocompromised individuals, as unique viral variants may arise due to extensive evolution within the host,” the authors said.

Thus, they highlight the importance of continuing genomic surveillance of SARS-CoV-2 evolution in immunocompromised individuals with persistent infections, given the potential public health threat posed by the possible introduction of escape viral variants into society.

Although careful surveillance is necessary, the authors emphasize that there must be a balance between protecting the population from possible new variants and providing compassionate, supportive home care for critically ill patients at the end of life.

Possible solutions include increased awareness of potential risks coupled with diagnostic testing available to known contacts (family) as soon as they develop symptoms.

This should be combined with genomic surveillance to assess the threat to public health in collaboration with professionals in the field.

The authors emphasize that while there may be an increased risk of developing new variants in immunocompromised patients, not all new variants in these patients will become a new variant of concern (VOC) for the community. The underlying mechanisms involved in the development of VOC are much more complex because they also depend on factors in the population surrounding the patient, including the prevalence of B- and T-cell immunity.

“The duration of SARS-CoV-2 infection in this reported case is extreme, but long-term infections in immunocompromised patients are much more common compared to the general population. Other work from our team includes a description of a cohort of long-term infections in immunocompromised patients in our hospital, with infection durations ranging from 1 month to 2 years. However, from the perspective of the general public, long-term infections remain rare as the immunocompromised population constitutes only a very small percentage of the total population,” he concluded.