SARS-CoV-2 infection prolongs virus shedding and lymphocyte loss in cancer patients

Cancer patients have a harder time with infections while being treated – they are at high risk of serious COVID-19 illness and death. However, little is known about how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with cancer therapies.

New research from France, led by Lisa Derosa of the Gustave Roussy Institute, has shown that the increase in cancer deaths may be due to SARS-CoV-2-induced lymphopenia, which further exacerbates cancer-related lymphocyte loss. Patients with cancer demonstrated viral shedding 40 days after diagnosis compared to 21 days of viral shedding in non-cancer healthcare workers.

The authors write:

“We concluded that virus-induced or associated lymphopenia, which coincided with T-cell exhaustion, abnormalities in the polyamine and bile salt pathways, and the circulation of bacterial DNA from Enterobacteriaceae and Micrococcaceae, is a dire prognostic factor in cancer patients that is likely immunosuppression-associated chronic virus excretion participates in the vicious circle. “

The researchers suggest that cancer patients – particularly blood cancer and cancer that has spread to other areas of the body – should be carefully monitored during the pandemic. Cancer patients can benefit from passive immunization against monoclonal antibodies against SARS-CoV-2 in combination with therapeutic stimulation of lymphopoiesis. However, more work is needed in this area.

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 is being peer-reviewed.

How they did it

The team looked at virus shedding in 1,106 patients in France and Canada. About 59% of these patients had cancer. Of the 1,106 patients, 1,063 tested positive for COVID-19. Health care workers were used as a control group.

Because the cycle thresholds (Ct) from the initial COVID-19 test might correlate with symptoms, the researchers also conducted a longitudinal study of the Ct values. They assessed several genes that code for the envelope, nucleocapsid, or replication-transcription complex of the virus. Orf1a is a subgenomic RNA for SARS-CoV-2 that is used to measure virus shedding for up to 6 months.

They also assessed virus-host interactions by profiling multiple immune cells, including innate, B, and T cells by 51 soluble markers. Using blood metabolomics and metagenomics, they analyzed how the immune response changed during infection.

Chronic virus shedding observed in cancer patients

Patients with cancer showed increased viral shedding of SARS-CoV-2 40 days after developing symptoms. By comparison, only 2% of healthcare workers showed prolonged viral RNA release. Virus shedding correlated with high viral load when diagnosed with COVID-19 infection.

Prolonged virus excretion changed the immune response. At the onset of infection, the researchers observed immature neutrophils, reduced unconventional monocytes with generalized lymphopenia that activated follicular T helper cells, and non-naive Granzyme B + FasL +, EomeshighTCF7high, PD-1 + CD8 + Tc1 cells.

Lymphocyte loss is a significant feature of severe COVID-19 infection in patients without cancer, and low lymphocyte counts in the blood were associated with a higher positive rate for COVID-19.

The lymphopenia caused by SARS-CoV-2 further impaired cancer-induced lymphocyte loss. The low lymphocyte count correlated with longer RNA shedding, severe COVID-19 illness, and a higher risk of death in the first and second wave of pandemics.

Changes in the gut microbiome can explain the loss of lymphocytes

The results also showed that lymphocyte loss in patients with long-term virus shedding was associated with a decrease in metabolites from secondary bile salts. The increase in circulating blood DNA observed in members of the Micrococcaceae and Enterobacteriaceae families suggests that the changes are due to increased permeability, which allows bacteria to move from the intestines to more sterile areas of the body.

Virus shedding can occur before severe COVID-19 infection

Patients who initially had a high viral load or who had long-term virus shedding tended to have poorer prognoses. Age over 66, more cancer metastases during diagnosis, and increased hospital stay also contributed to a poor prognosis.

SARS-CoV-2-induced lymphopenia was associated with death in patients within the first 2-3 months after diagnosis. The results suggest that patients undergoing cancer treatment should temporarily discontinue chemotherapy or immunosuppressive steroids during the acute phase of viral infection.

* Important NOTE

medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice / health-related behavior, or treated as established information.

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