Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in immunocompromised patients (ICPs), particularly those with hematological malignancies receiving immunosuppressive therapies, presents serious clinical and public health challenges. This review summarizes key findings from our recent clinical and basic virological investigations into prolonged infections in this vulnerable population. Prolonged PCR positivity and the presence of infectious virus were occasionally observed, particularly among patients with profound immunosuppression. Marked depletion of CD4⁺T cells and exposure to chemotherapeutic regimens involving bendamustine and anti-CD20 antibodies were strongly associated with impaired viral clearance. Among ICPs with antiviral treatment failure, sequencing analysis of viral isolates revealed mutations in the RNA-dependent RNA polymerase (RdRp) gene that are associated with reduced susceptibility to remdesivir. By using recombinant viruses, we demonstrated that while these mutations induced antiviral resistance, they also reduced viral replication efficiency and pathogenicity, suggesting an inherent fitness cost. Persistent infections were characterized by high levels of intra-host genetic diversity, reflecting ongoing viral evolution under selective pressure. Additionally, co-infections with opportunistic pathogens, including cytomegalovirus, were more commonly observed in ICPs than in immunocompetent individuals, complicating clinical management. These findings underscore the need for individualized clinical approaches for ICPs, incorporating close immunological monitoring, rational use of combination antiviral therapies, and adapted vaccination strategies. A comprehensive understanding of the interplay between host immune dysfunction, antiviral resistance, and viral evolution is essential for improving patient outcomes and limiting the emergence of resistant variants in immunocompromised populations.

Invasive pulmonary aspergillosis (IPA) remains a serious disease with a high mortality rate. Although antifungal drugs such as azole, polyene, and echinocandin have been effective when evaluating fungal load and survival rate as indicators in mouse lung infection models, there are discrepancies between non-clinical and clinical efficacy, and drugs with higher therapeutic efficacy are needed. If clinical therapeutic effects can be predicted more accurately in non-clinical practice, drugs with higher clinical efficacy could be developed. We investigated the usefulness of galactomannan and certain cytokines for the pathology and treatment evaluation of IPA. We performed various evaluations using clinical isolates of Aspergillus fumigatus with different virulence (Lethal Dose 50) in a mouse lung infection model. Detection timing and amount of galactomannan and interleukin-6 in serum were closely related to virulence, indicating that the timing and amount of A. fumigatus dissemination from the lungs into the bloodstream are involved in virulence. As increases in galactomannan and interleukin-6 are also used as indicators for clinical diagnosis, they could become important indicators for establishing non-clinical IPA models to more accurately predict the clinical effect of antifungal drugs.