Molecular Evolution of SARS-CoV-2 in Immunocompromised Patients: Clinical Insights and Management Strategies

Replication‑competent SARS‑CoV‑2 persisted for months to years in three immunocompromised patients, driving intra‑host viral evolution and prompting reconsideration of surveillance and treatment strategies.

The team performed detailed longitudinal virologic assessment, including RT‑qPCR, subgenomic RNA detection, viral culture, and serial whole‑genome sequencing in three patients followed for months to years. The report documents replication‑competent virus persisting for 9 months, 10 months, and up to approximately 1,600 days. Endpoints included duration of RT‑qPCR positivity, subgenomic RNA, culture of replication‑competent virus, and sequential consensus genomes, supporting prolonged viral persistence with clear intra‑host diversification.

Sequence analyses show accumulation of non‑synonymous mutations across Spike, ORF1ab, N, and accessory genes, consistent with ongoing within‑host evolution. Sequential genomic sequencing identified parallel substitutions and convergent Spike changes, alongside fixation events in ORF1ab and evidence of quasispecies structure in some samples. These patterns underscore that individual prolonged infections can generate highly divergent viral lineages.

Because standard short‑term monitoring may miss adaptive change, cases with persistent shedding merit sustained virological follow‑up. The findings support repeat sequencing when shedding continues and individualized reassessment of antiviral and immune‑based therapies as part of case management, integrating diagnostic surveillance with therapeutic decision‑making.

Key Takeaways:

• Three immunocompromised patients had replication‑competent SARS‑CoV‑2 for months to years, with sequential genomic change documented.
• Mutation accumulation occurred across Spike and multiple coding regions, producing quasispecies dynamics in some cases.
• Selected prolonged cases merit sustained virological assessment and serial sequencing to define the clinical and epidemiologic significance of intra‑host evolution.