From the onset of the coronavirus disease 2019 (COVID-19) pandemic, a disease that is caused by infection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), pregnancy has been considered a high-risk condition.
A new study published on the bioRxiv* server describes the changes in the representation of a subset of activated monocytes in this group of patients. This could explain, in part, the increased incidence of adverse outcomes in pregnant women with COVID-19.
Study: The percentage of Monocytes CD39+ is higher in Pregnant COVID-19 than in Non-Pregnant COVID-19 patients. Image Credit: Simon Kadula / Shutterstock.com
How was the study conducted?
The authors of the current study focused on profiling the immunologic parameters in pregnant COVID-19 patients. Previously, a marked drop in lymphocytes and a higher ratio of neutrophils to lymphocytes had been reported in this cohort. The latter is also linked to increased odds of death.
Inflammatory cytokines and chemokines are often elevated in COVID-19 patients, especially interleukin (IL)-2, IL-7, IL-10, as well as factors such as granulocyte colony-stimulating factor (G-CSF), tumor necrosis factor (TNF)-α, and chemokines IP10 (CXCL-10), monocyte chemoattractant protein 1 (MCP-1) (CCL2), and macrophage inflammatory proteins 1a (MIP1a) (CCL3). The release of these factors likely originates from lung epithelial cells, endothelial cells, or leukocytes.
If the immune balance in pregnancy is disrupted by a violent inflammatory reaction, the risk of poor outcomes, including death, rises for both the fetus and the mother. In this study, the investigators found that leukocyte counts were similar in both non-pregnant and pregnant COVID-19 patients and pregnant patients without COVID-19.
Reduced activated monocytes in COVID-19
The heart rate of pregnant women with COVID-19, for example, was faster when compared to that of uninfected pregnant women. Serum lactate dehydrogenase (LDH) and D-dimer levels were also higher in pregnant women with COVID-19, whereas oxygen saturation levels were maintained at higher levels in uninfected pregnant women, compared to all COVID-19-positive women.
Among leukocytes, monocytes with the activation markers human leukocyte antigen (HLA)-DR+ or CD69+ were decreased to comparable levels between pregnant and non-pregnant women with COVID-19 as compared to that which was measured in uninfected pregnant women. This is similar to the fall in HLA-DR+ expressing monocytes in patients with critical sepsis, thus indicating its utility as a biomarker of COVID-19 severity.
This phenomenon may signal the viral downregulation of host immunity or immune evasion. Conversely, it may also be a host response to avert the cytokine storm and mitigate tissue damage resulting from the viral infection.
This difference was not seen with CD4+ or CD8+ T cells expressing either HLA-DR or CD69, thereby indicating that pregnancy does not completely abolish the activation of these cells.
Anti-inflammatory monocyte profile
Monocytes with CD39+ inflammation-regulating molecules were lower among non-pregnant COVID-19 patients as compared to those who were pregnant, though not as low as in the group of uninfected pregnant women. CD39+ B cells were also increased in pregnant women; however, CD39+ T cells were found to be higher in non-pregnant women. These differences were small in both cases.
In contrast, CD73+ monocytes were increased in non-pregnant women with COVID-19 as compared to both other groups. CD73+ B cells were similar in all groups, irrespective of pregnancy or COVID-19, while CD73+ T cells were decreased in all women with COVID-19, independent of pregnancy, as compared to pregnant uninfected women.
Both CD39 and CD73 are enzymes that break down adenosine triphosphate (ATP) to adenosine, which is an anti-inflammatory event. Thus, pregnancy may allow the regulation of inflammation via CD39+/CD73+ monocytes (but not lymphocytes). Their levels may also be used to determine the stage of the illness.
Stimulation results independent of COVID-19
Stimulation increased the proportion of CD4 and CD8 interferon (IFN)-γ+ cells in pregnancy irrespective of COVID-19. The percentage of IL-1+ or IL-6+ monocytes in both groups was found to be less than 10%. Since IL-1 and IL-6 are secreted by activated leukocytes, their reduced expression may indicate that the presence of IL-6 in patients with COVID-19 fails to potently stimulate the synthesis of pro-inflammatory cytokines from these cells.
Pregnancy does not significantly alter the immune response to COVID-19, which is normally associated with a rise in IL-6. The failure to exhibit an anti-inflammatory response to COVID-19 in pregnancy could be due to the elevated levels of pro-inflammatory IL-4 in this group.
In addition to these immunologic parameters, both serum urea levels and prothrombin time were found to be higher in non-pregnant women with COVID-19 as compared to pregnant women, with or without this illness. This could be attributed to coagulation system alterations that occur as a result of pregnancy.
D-dimer levels in pregnancy are normally higher as compared to those which are present in nonpregnant women. Notably, the rise of D-dimer seen with SARS-CoV-2 infection is lower than that which occurs during pregnancy.
What are the implications?
The current study's findings indicate that pregnancy-related immunosuppression is not the cause of severe COVID-19 in pregnancy. This is evident by the presence of circulating white blood cells that are capable of exerting the same immune response to SARS-CoV-2 in pregnant women.
All pregnant women regulate inflammation via CD39+/CD73+ monocytes, the former being higher and the latter lower as compared to nonpregnant women with COVID-19. These markers may be useful in monitoring the clinical course of the illness in pregnant women.
Notably, D-dimer levels in pregnant COVID-19 patients are not raised above the levels that are often expected in pregnancy. This finding indicates that this biomarker is not valuable to determine severe COVID-19 during gestation or whether the infected pregnant patient is at a greater risk of thromboembolic events.
Further studies will be required to understand the significance of the fall in HLA-DR+ in COVID-19; however, this reduction appears to not be the result of pregnancy. This study contributes to the understanding of immune function in pregnancy complicated by COVID-19.
bioRxiv 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.