Hofbauer Cells and COVID-19 in Pregnancy

Abstract

Context.– Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can undergo maternal-fetal transmission, heightening interest in the placental pathology findings from this infection. Transplacental SARS-CoV-2 transmission is typically accompanied by chronic histiocytic intervillositis together with necrosis and positivity of syncytiotrophoblast for SARSCoV-2. Hofbauer cells are placental macrophages that have been involved in viral diseases including HIV and Zika virus, but their involvement in SARS-CoV-2 in unknown. Objective.– To determine whether SARS-CoV-2 can extend beyond the syncytiotrophoblast to enter Hofbauer cells, endothelium and other villous stromal cells in infected placentas of liveborn and stillborn infants. Design.– Case-based retrospective analysis by 29 perinatal and molecular pathology specialists of placental findings from a preselected cohort of 22 SARS-CoV-2-infected placentas delivered to pregnant women testing positive for SARS-CoV-2 from 7 countries. Molecular pathology methods were used to investigate viral involvement of Hofbauer cells, villous capillary endothelium, syncytiotrophoblast and other fetal-derived cells. Results.– Chronic histiocytic intervillositis and trophoblast necrosis was present in all 22 placentas (100%). SARS-CoV-2 was identified in Hofbauer cells from 4/22 placentas (18%). Villous capillary endothelial staining was positive in 2/22 cases (9%), both of which also had viral positivity in Hofbauer cells. Syncytiotrophoblast staining occurred in 21/22 placentas (95%). Hofbauer cell hyperplasia was present in 3/22 placentas (14%). In the 7 cases having documented transplacental infection of the fetus, 2 occurred in placentas with Hofbauer cell staining positive for SARS-CoV-2. Conclusions.– SARS-CoV-2 can extend beyond the trophoblast into the villous stroma, involving Hofbauer cells and capillary endothelial cells, in a small number of infected placentas. Most cases of SARS-CoV-2 transplacental fetal infection occur without Hofbauer cell involvement.

Molecular Pathology Demonstration of SARS-CoV-2 in Cytotrophoblast from Placental Tissue with Chronic Histiocytic Intervillositis, Trophoblast Necrosis and COVID-19

“…In this placenta, the syncytiotrophoblast was also positive using both immunohistochemical and RNA in situ hybridization methods, but Hofbauer cell and villous capillary endothelial staining was not present. This observation is interesting in view of the recent demonstration by Schwartz et al [29] that among 22 placentas infected with SARS-CoV-2, four (18%) placentas had positive staining of Hofbauer cells and two (9%) placentas demonstrated staining of villous capillary endothelial cells for the virus. Because the syncytiotrophoblast and cytotrophoblast are in intimate physical contact with one another, and the villous cytotrophoblast has been demonstrated to stain using antibody to the ACE2 receptor protein [52,53], it appears likely that our observation of the simultaneous presence of SARS-CoV-2 antigen and nucleic acid in both cell types indicates cell-to-cell passage of the virus.…”

“…However, there are data suggesting that term placentas from pregnant women infected with SARS-CoV-2 have increased levels of the ACE2 protein [48]. In addition to the syncytiotrophoblast, small numbers of infected placentas have been found to demonstrate positive immunohistochemical staining for SARS-CoV-2 in other fetal-derived placental cells including Hofbauer cells and villous capillary endothelial cells [29].…”

“…Among all placental cell types, the syncytiotrophoblast appears to be the most frequently involved cell type that stains for SARS-CoV-2 antigens or RNA [28]. To a much lesser extent, recent research has identified SARS-CoV-2 staining in placental stromal macrophages, termed Hofbauer cells [29], and endothelial cells of the villous capillaries in a small number of infected placentas [29]. In this report we provide immunohistochemical and molecular pathology evidence of SARS-CoV-2 staining in villous cytotrophoblast cells of the placenta which occurred in a placenta from a fetus having acquired the infection following transplacental transmission.…”

COVID-19 in 28-Week Triplets Caused by Intrauterine Transmission of SARS-CoV-2—Case Report

“…Pronounced inflammation due to SARS-CoV-2 has also been reported in two at-term placentas, both at the cytokine and at the genetic level (21). Placental SARS CoV-2 infectionas demonstrated e.g., by systematic investigation of 22 SARS CoV-2 positive placentas (22)-is consistently associated with chronic histiocytic intervillositis, trophoblast necrosis (22)(23)(24) and it is frequently accompanied by fibrin depositions (23,25). These findings-chronic histiocytic intervillositis and trophoblast necrosis-were shown in both liveborn and stillborn neonates infected by transplacental transmission (24).…”

“…It should also be noted that the extensive placental damage induced by SARS CoV-2 has caused pathologists to be concerned about potential neurologic sequelae in affected children (25). Schwartz et al further showed that Hofbauer cell positivity is not required for transplacental fetal infections (22). Another group found that maternal clinical COVID-19 symptoms did not predict the severity of the SARS-CoV-2related placental signature (26).…”