Patients with cancer have a more challenging time with infections while undergoing treatment — placing them as high-risk for severe COVID-19 illness and death. However, how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with cancer therapies remains poorly understood.
New research out of France led by Lisa Derosa of the Institut Gustave Roussy finds the increase in death from cancer may be due to SARS-CoV-2-induced lymphopenia that further exacerbates cancer-induced lymphocyte loss. Patients with cancer showed viral shedding 40 days after diagnosis compared to 21 days of viral shedding in noncancerous healthcare workers.
The authors write:
“We concluded that virus-induced or -associated lymphopenia that coincided with T cell exhaustion, abnormalities in polyamine and biliary salt pathways, and circulation of Enterobacteriaceae and Micrococcaceae bacterial DNA, is a dismal prognosis factor in cancer patients, likely participating in the vicious circle of immunosuppression-associated chronic virus shedding.”
The researchers suggest patients with cancer — especially blood cancers and cancers that have spread to other body areas — should be carefully monitored during the pandemic. Patients with cancer may benefit from passive immunization from monoclonal antibodies targeting SARS-CoV-2 combined with therapeutic stimulation of lymphopoiesis, but more work in this field is needed.
The study “Prolonged SARS-CoV-2 RNA virus shedding and lymphopenia are hallmarks of COVID-19 in cancer patients with poor prognosis” is available as a preprint on the medRxiv* server, while the article undergoes peer review.
How they did it
The team looked at viral shedding in 1,106 patients across France and Canada. About 59% of those patients had cancer. Of the 1,106 patients, 1,063 tested positive for COVID-19. Healthcare workers were used as the control group.
Because the cycle threshold (Ct) values from the first COVID-19 test could correlate with symptoms, the researchers also performed a longitudinal follow-up of Ct values. They evaluated several genes coding for the envelope, nucleocapsid, or the replication-transcription complex of the virus. Orf1a is a subgenomic RNA for SARS-CoV-2 used to measure viral shedding for up to 6 months.
They also evaluated viral-host interactions by profiling several immune cells, including innate, B, and T cells of 51 soluble markers. They analyzed how the immune response changed during infection using blood metabolomics and metagenomics.
Chronic viral shedding observed in patients with cancer
Patients with cancer showed more viral shedding of SARS-CoV-2 40 days after developing symptoms. For comparison, only 2% of healthcare workers showed prolonged viral RNA shedding. Viral shedding was correlated with high viral loads when diagnosed with COVID-19 infection.
Having prolonged viral shedding changed the immune response. At the early course of infection, the researchers observed immature neutrophils, reduced non-conventional monocytes with general lymphopenia that activated follicular T helper cells, and non-naive Granzyme B+FasL+, EomeshighTCF7high, PD-1+CD8+ Tc1 cells.
Lymphocyte loss is a significant characteristic in severe COVID-19 infection in patients without cancer, and having low lymphocyte counts in the blood was linked to a higher positive test rate for COVID-19.
The lymphopenia caused by SARS-CoV-2 further impaired cancer-induced lymphocyte loss. The low lymphocyte count correlated with prolonged RNA shedding, severe COVID-19 illness, and a higher risk of death in the first and second pandemic waves.
Alterations in the gut microbiome may explain lymphocyte loss
Results also showed that lymphocyte loss was associated with decreased metabolites from the secondary biliary salts in patients who showed long-term viral shedding. The increasing circulating blood DNA observed for Micrococcaceae and Enterobacteriaceae family members suggests the changes may be due to increased permeability allowing for bacteria to move from the gut to more sterile body areas.
Viral shedding may come before severe COVID-19 infection
Patients who initially presented with high viral loads or had long-term viral shedding tended to have poorer prognoses. Being older than 66, having more cancer metastasis during diagnosis, and increased hospitalization also contributed to a poor prognosis.
Having SARS-CoV-2-induced lymphopenia was linked to death for patients after the first 2-3 months after diagnosis. The results suggest patients undergoing cancer treatment should temporarily halt chemotherapy or immunosuppressant steroids during the acute phase of viral infection.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.