The COVID-19 pandemic, caused by the SARS-CoV-2 virus, poses a significant threat to public health. Cancer patients are particularly vulnerable to severe COVID-19 due to various factors including age, gender, pre-existing conditions, and the immunosuppressive effects of cancer therapies such as chemotherapy, surgery, and immunotherapy. Studies have shown higher hospitalization and mortality rates in cancer patients with COVID-19, with some cancers (hematological, lung, breast) presenting a greater risk than others. The stage of cancer is also a factor, with metastatic cancers posing a higher risk of severe disease. This study aimed to investigate the dynamics between host and viral parameters in cancer patients with COVID-19 during the first and second pandemic surges, focusing on the role of lymphopenia and prolonged viral shedding in determining patient outcomes. The study used multiple cohorts of cancer patients diagnosed with COVID-19 from various cancer centers and general hospitals across France and Canada. The researchers sought to identify viral, immunological, metabolic, and metagenomic blood predictors of severe complications among cancer patients to better understand the complex interplay between cancer, cancer treatments, and the SARS-CoV-2 infection.

Existing literature highlighted the increased vulnerability of cancer patients to severe COVID-19, linking this vulnerability to age, gender, cancer-associated risk factors, metabolic syndrome, and side effects of cancer therapies. Studies demonstrated higher hospitalization and mortality rates in cancer patients with SARS-CoV-2 infection, with variations depending on cancer type, stage, and recent treatment. Previous research also suggested a correlation between viral load and COVID-19 severity, with higher viral loads predicting worse outcomes. While there was evidence of prolonged viral shedding in immunocompromised individuals, the mechanisms underlying this phenomenon and its impact on cancer patients remained unclear. This study built upon this existing knowledge, investigating these factors in a larger cohort of cancer patients using advanced techniques to analyze immunological and metagenomic factors in relation to viral shedding and prognosis.

This study analyzed data from multiple independent cohorts of cancer patients diagnosed with COVID-19 during the first and second waves of the pandemic. The cohorts included patients from various cancer centers and general hospitals in France and Canada (1063 patients, 58% with cancer). The primary outcome measures were the duration and magnitude of viral RNA shedding, assessed via longitudinal RT-qPCR testing of nasopharyngeal swabs. The study also evaluated numerous immunological parameters using high-dimensional spectral flow cytometry and multiplex ELISAs to measure various cytokines, chemokines and growth factors in blood samples. Metabolic profiling was performed by untargeted and targeted mass spectrometry-based metabolomics. Metagenomic analysis of circulating microbial populations was performed using next-generation sequencing of 16S rRNA bacterial genes. Statistical analyses included Kaplan-Meier curves for survival analysis, Cox regression models to assess the risk factors associated with survival, and Spearman correlations to assess the relationships between various parameters. The researchers compared the characteristics of patients with long-term viral shedding (≥40 days of positive RT-qPCR) to those with short-term shedding (<40 days) and those without COVID-19. They also analyzed data from healthcare workers to provide a comparison group.

The study's key findings showed that cancer patients exhibited significantly prolonged SARS-CoV-2 RNA shedding compared to non-cancer patients and healthcare workers. Patients with long-term viral shedding (LVS) had higher viral loads at diagnosis, indicated by lower cycle threshold (Ct) values. LVS in cancer patients was strongly associated with more severe COVID-19 manifestations (higher hospitalization rates, ICU admissions). Immunological analysis revealed that LVS patients had distinct immunopathological features characteristic of severe COVID-19, including increased proportions of immature neutrophils, decreased nonconventional monocytes, and overall lymphopenia. Despite lymphopenia, LVS patients showed increased plasmablasts, activated follicular T helper cells, and non-naive Granzyme B+, FasL+, EomeshighTCF-1high, PD-1+CD8+ Tc1 cells. Importantly, virus-induced lymphopenia worsened pre-existing cancer-associated lymphocyte loss, with low lymphocyte counts significantly associated with COVID-19 severity, chronic viral shedding, and increased risk of cancer-related death. Metabolic analysis showed that lymphopenia correlated with altered levels of metabolites from the polyamine and biliary salt pathways. Metagenomic analysis revealed a significant increase in circulating bacterial DNA from *Enterobacteriaceae* and *Micrococcaceae* families in long-term viral carriers. These findings were consistent across multiple independent cohorts and were validated in the second surge of the pandemic. A multivariate Cox analysis confirmed that low lymphocyte counts and high viral loads at diagnosis were independent predictors of poor overall survival in cancer patients.

The findings demonstrate a strong association between prolonged SARS-CoV-2 shedding, lymphopenia, and poor prognosis in cancer patients. The study highlights a complex interplay between the virus and the host immune system, particularly in the context of cancer and cancer therapies. Virus-induced lymphopenia appears to exacerbate pre-existing immunosuppression associated with cancer, leading to a vicious cycle of chronic viral shedding and severe disease. The study identified several potential mechanisms, including alterations in polyamine and biliary salt metabolism, as well as gut dysbiosis and bacterial translocation, contributing to the observed lymphopenia. The sustained type 1 interferon response and the expansion of exhausted T cells may also play significant roles in maintaining the chronic infection. These findings underscore the need for careful monitoring and tailored management strategies for cancer patients with COVID-19, particularly those with hematological malignancies and metastatic disease.

This study provides robust evidence for the association between prolonged SARS-CoV-2 RNA shedding, lymphopenia, and poor outcomes in cancer patients with COVID-19. The findings highlight the need for strategies to prevent or mitigate COVID-19-induced lymphopenia in this vulnerable population. Further research is needed to explore therapeutic interventions targeting the identified mechanisms, such as restoring lymphopoiesis and modulating gut microbiota, to improve outcomes in cancer patients with COVID-19. The use of high-affinity neutralizing monoclonal antibodies and the stratification of patients based on viral load, lymphopenia, and duration of viral shedding for clinical trials involving therapeutic interventions should be considered.

While the study included a large number of patients and employed advanced analytical techniques, several limitations should be considered. The observational nature of the study prevents establishing definitive causality. The retrospective nature of some data collection may introduce biases. The specific cancer therapies received by patients were not consistently reported across cohorts. The heterogeneity of cancer types and stages may also influence the results. Future studies should aim to address these limitations by conducting prospective randomized controlled trials.