New Research Shows “Y” Men Are More Likely to Have Severe COVID-19

Since the beginning of the COVID-19 pandemic, men have been more likely than women to experience severe or fatal disease progression.

Up to 75% of patients in the intensive care unit (ICU) have been male, and the proportion of men who died of COVID-19 is higher than the proportion of women. This disparity increases with age.

New research from Uppsala University suggests this could be due to loss of the Y chromosome in the men’s white blood cells. Loss of chromosome Y (LOY) was considered as a potential COVID-19 risk factor due to its prior correlation with chronic age-related diseases and its impact on immune gene transcription.

This observational study utilized publicly available scRNA-seq records of peripheral blood mononuclear cell (PBMC) samples. The samples were collected from 29 men who were critically ill with COVID-19. The cohort ranged from 64-94 years of age, with an average age of 80 years.

The Uppsala investigators added LOY status to their analysis of these samples. They examined LOY in whole blood from 211 COVID-19 patients treated in ICU during the first and second waves of the pandemic. Of this cohort, 139 patient samples were cell sorted for LOY analysis in granulocytes, low-density neutrophils (LDNs), monocytes, and PBMCs. Other study patients included 11 milder COVID-19 patients and 16 patients who had recovered (3-6 months post hospital discharge).

“Our analyses showed that LOY was linked both to the severity of the disease [based on World Health Organization classifications], and to the risk of dying,” said author Bożena Bruhn-Olszewska, a researcher at Uppsala University.

Reanalysis of the scRNA-seq samples showed LDNs and monocytes were the cell types most affected by LOY. “DNA analysis indicated that 46%, 32%, and 29% of critically ill patients showed LOY above 5% cut-off in LDNs, granulocytes, and monocytes, respectively,” the study authors wrote. “Hence, the myeloid lineage that is crucial for the development of severe COVID-19 phenotype is affected by LOY.”

LOY was correlated with severe COVID-19 disease, risk of death during ICU treatment, and history of vessel disease. LOY is also the most prominent clonal mutation to affect the myeloid cell lineage during emergency myelopoiesis.

In the 16 patients who recovered from COVID-19 disease, LOY decreased dramatically in whole blood and PBMCs. The number of LDNs in recovering patients also decreased significantly.

“We had the opportunity to analyse samples taken from some of the patients 3 to 6 months after they were discharged from the ICU," said Hanna Davies, one of the investigators. "In these samples, the proportion of cells with LOY had drastically decreased. As far as we know, this is the first time anyone has shown that LOY has dynamic properties linked to an acute infectious disease."

The study authors concluded that there is a definite link between LOY and “acute, life-threatening” COVID-19 disease. The correlation between LOY level and COVID-19 severity could indicate LOY affects the function of monocytes and neutrophils, potentially weakening male innate immunity.

With these findings, the investigators believe LOY can be used to predict which patients are at high risk of severe COVID-19 disease progression.