Persistent SARS-CoV-2 Infections: Implications for Epidemiology, Evolution, and Long Covid

A study analyzing genetic, symptomatic, and epidemiological data from the UK’s Office for National Statistics Covid Infection Survey (ONS-CIS) reveals significant findings about persistent SARS-CoV-2 infections and their implications​​.

Key Findings:

  1. Persistence of Infections: The study identified 381 persistent SARS-CoV-2 infections, with 54 lasting at least 60 days. These persistent cases had a 50% higher likelihood of developing Long Covid compared to controls. The research estimates that 0.09-0.5% of SARS-CoV-2 infections can become persistent for at least 60 days​​​​.
  2. Evidence of Transmission: There was suggestive evidence of transmission from persistently infected individuals within households. However, these did not involve highly divergent sequences, indicating that they did not lead to the emergence and spread of highly divergent lineages​​.
  3. Reinfections with the Same Lineage: The study identified 60 reinfections with the same major lineage, suggesting that reinfections are relatively rare compared to persistent infections​​.
  4. Non-replicating Virus During Infection: In nearly 70% of persistent infections, no nucleotide differences at the consensus level were observed between sequenced samples taken at least 26 days apart, indicating the prolonged presence of non-replicating virus​​.
  5. Emergence of Notable Mutations: The study found multiple amino acid substitutions in the Spike and ORF1ab genes emerging independently in different individuals, including mutations that are lineage-defining for SARS-CoV-2 variants and target sites for several monoclonal antibodies​​.
  6. Positive Selection in Spike: There was a strong signal for positive selection in the Spike protein, with nearly nine-fold more nonsynonymous compared to synonymous mutations​​.
  7. Relapsing Viral Load Dynamics: Over 30% of persistent infections showed relapsing viral load dynamics, with some cases being misidentified as reinfections​​.
  8. Viral Load and Symptom Differences: Persistent infections typically had higher Ct values (indicating lower viral titers) at the last sequenced time point compared to the first. Persistently infected individuals reported fewer symptoms in later stages of infection or remained asymptomatic, yet they had a higher likelihood of developing Long Covid​​.
  9. Implications for Epidemiology and Evolution: The large number of persistent infections suggests a significant pool of potential sources for divergent variants. This finding challenges the hypothesis that variants of concern mainly emerged in immunocompromised individuals​​.
  10. Latent Evolutionary Dynamics: Some infections showed no genome changes for months, suggesting decelerated evolutionary rates as a common outcome of persistent infection, possibly due to the infection of long-lived cells​​.

In summary, this study provides critical insights into the nature of persistent SARS-CoV-2 infections, their potential role in the emergence of new variants, and their association with Long Covid. It underscores the importance of continued surveillance and research to understand the long-term impacts of COVID-19.

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