Longest Chronic Covid Case Spurs Fear of New Immune-Evasive Variants

Authors propose enhancing awareness of risks, close genomic surveillance and early diagnostic tests for symptomatic contacts as part of clinical management of these patients.

*Please mention the ESCMID Global Congress (formerly ECCMID) Barcelona, 27-30 April) if using this material*

New research to be presented at next week's ESCMID Global Congress (formerly ECCMID) in Barcelona, Spain (27-30 April) highlights the risk of new immune-evasive SARS-CoV-2 variants emerging in immunocompromised patients. The report is by PhD candidate Magda Vergouwe, Centre for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Center (Amsterdam UMC), University of Amsterdam, Netherlands, and colleagues.

They describe the extended viral evolution in a SARS-CoV-2 infected patient for 613 days leading to a highly mutated novel variant. To the authors knowledge, it is the longest SARS-CoV-2 infection duration to date, although several cases of hundreds of days have been previously recorded.

Whereas healthy SARS-CoV-2 infected patients can clear the virus within a period of days to weeks, an immunocompromised individual can develop a persistent infection with prolonged viral replication and evolution. For instance, it is thought that the initial emergence of the Omicron variant originated in an immunocompromised individual, highlighting the importance of close genomic surveillance in this patient population. In addition, the use of targeted immune pressure, including monoclonal antibody therapies and/or novel antivirals, can further promote the emergence of viral escape variants.

Vergouwe and colleagues describe in their report a 72-year-old immunocompromised male patient who was admitted to Amsterdam University Medical Center in February 2022 with a SARS-CoV-2 infection. Due to a history of allogeneic stem cell transplantation as treatment of a myelodysplastic and myeloproliferative overlap syndrome he was defined immunocompromised. This was complicated by the development of a post-transplant lymphoma for which he received rituximab that depletes all available B-cells, including those that normally produce the SARS-CoV-2 directed antibodies.

Previously, he had already received multiple SARS-CoV-2 vaccinations without a measurable SARS-CoV-2 IgG anitbody response at hospital admission. Routine genomic surveillance showed infection with Omicron SARS-CoV-2 variant BA.1.17. He received treatment with the anti-SARS-CoV-2 directed antibody sotrovimab, the anti-IL6 antibody sarilumab and dexamethasone without clinical response.

Follow-up SARS-CoV-2 sequencing showed development of known sotrovimab-resistance mutation S:E340K as early as 21 days after receiving the sotrovimab infusion. SARS-CoV-2-specific T cell activity and anti-spike antibody development in the first month were minimal, indicating that the patient's immune system was not capable of clearing the virus. The prolonged infection has led to the emergence of a novel immune-evasive variant due to the extensive within-host evolution. In the end, the patient died from a relapse of his haematological condition after remaining SARS-CoV-2 positive with high viral loads for a total of 613 days. Fortunately, no documented transmission had occurred with the highly mutated variant to secondary cases in the community.

In more detail, the 613 days following initial SARS-CoV-2 detection were characterised by multiple SARS-CoV-2-related and unrelated symptomatic episodes, requiring hospital admissions. The persistent SARS-CoV-2 infection led to the patient having prolonged isolation periods during hospital admission and enhanced use of personal protective materials, greatly reducing his self-reported quality of life. SARS-CoV-2 full genome sequencing was performed on 27 nasopharyngeal specimens, collected from February 2022 until September 2023. It revealed over 50 nucleotide mutations compared to contemporary globally circulating BA.1-variants with multiple amino acid substitutions, including ACE-2 receptor binding site substitutions S:L452M/K and S:Y453F. Furthermore, several deletions in the N-terminal domain of spike developed indicative of immune-escape.

The authors say: "This case underscores the risk of persistent SARS-CoV-2 infections in immunocompromised individuals as unique SARS-CoV-2 viral variants may emerge due to extensive intra-host evolution. We emphasise the importance of continuing genomic surveillance of SARS-CoV-2 evolution in immunocompromised individuals with persistent infections given the potential public health threat of possibly introducing viral escape variants into the community."

While close surveillance is necessary the authors highlight that there must be a balance between protecting the public from potential new variants and humane supportive care at home of severely ill patients near the end of life. Possible solutions can include an increased awareness of potential risks combined with providing early accessible diagnostic testing of known (family) contacts as soon as they develop relevant symptoms. This should be combined with genomic surveillance in order to assess the public health threat together with public health professionals. The authors highlight that although there may be an increased risk of development of novel variants in immunocompromised patients, not every novel variant in these patients will develop into a novel variant of concern (VOC) for the community. The underlying mechanisms involved in the development of a VOC are much more complex as they are also dependent of factors in the population surrounding the patient, including the prevalence of B- and T-cell related immunity.

The authors conclude: "The duration of SARS-CoV-2 infection in this described case is extreme, but prolonged infections in immunocompromised patients are much more common compared to the general community. Further work by our team includes describing a cohort of prolonged infections in immunocompromised patients from our hospital with infection durations varying between 1 month and 2 years. However, from the viewpoint of the general public, prolonged infections remain rare as the immunocompromised population is only a very small percentage of the total population."