On 2020-05-17 16:22:51, user Sinai Immunol Review Project wrote:
Main findings<br />
The impact of SARS-CoV-2 infection and subsequent COVID-19 disease in pregnant women at different trimesters is not well described. The precise influence of a potentially dysregulated antiviral response to this pathogen during pregnancy is unclear, so a better understanding would guide management for pregnant women, who may be more susceptible to infection. Here, Hosier et al. profile a case of a woman with COVID-19 in the second trimester of pregnancy with severe hypertension, elevated liver enzymes, and coagulopathy. These symptoms led to a diagnosis of severe preeclampsia.
The patient initially presented with a high fever, non-productive cough, nausea, diarrhea, diffuse myalgias, anorexia, and malaise. A RT-PCR test for SARS-CoV-2 RNA in a nasopharyngeal swab of the patient was positive. Upon admission, the patient was treated for hypertension, disseminated intravascular coagulopathy, and she eventually elected to terminate via dilation and evacuation. During surgical management and recovery, the patient developed lymphopenia, though she was able to be extubated and weaned to room air on post-operative day 1. The patient was given hydroxychloroquine. Two days later, her coagulation markers improved, and she was discharged.
RT-PCR and sequencing and phylogenetic analyses showed that the placenta and umbilical cord were positive for SARS-CoV-2 RNA, but no other major fetal tissues tested positive. Saliva and urine, collected from the patient, also tested positive, although the oral and nasal swabs did not. Whole genome sequencing of the viral genome isolated from the placenta was phylogenetically similar to those isolated from local cases of SARS-CoV-2 infection and those identified in Europe and Australia.
Serologic testing for patients' antibodies revealed high titers of anti-SARS-CoV-2 IgG and IgM antibodies. These levels were reportedly the highest of the 56 COVID-19 patients admitted to the Yale New Haven Hospital, suggesting that the patient was not unsuccessful in eliciting a humoral response.
Gross pathological examination revealed a marginally adherent blood clot, presenting as a focal placental infarct, while histological analyses using CD3 and CD68 as markers revealed an infiltration of T cells and macrophages, which suggests that fibrin-dense intervillositis may have contributed to the coagulopathy observed in the patient. No necrotic tissue was seen. Immunohistochemistry staining for the SARS-CoV-2 spike protein and in situ hybridization for the SARS-CoV-2 RNA revealed that the infection of fetal tissue was localized preferentially to the syncytiotrophoblasts of the placenta.
Electron microscopy confirmed the presence of viral particles (75-100 nm in diameter) in the cytosol of placental cells.
Limitations<br />
Technical<br />
This report profiles a single patient to describe the impact of COVID-19 in pregnant women. Without a larger sample size, it is difficult to assess, however, how infection or peak disease at a given trimester differentially influence prognosis and clinical outcome. It is also important to note that this patient was diagnosed with an underlying autoimmune disease, psoriasis. It will also be important for future studies to consider the stage of pregnancy and whether COVID infection leads to other pregnancy-related disorders, such as recurring miscarriage, fetal growth restriction and possibly even increase in size of fetus creating challenges for delivery.
Biological<br />
Finally, it is unclear whether these placental cells express the ACE2 receptor. Though electron microscopy, among other methods, identified viral particles in placental cells and indicated SARS-CoV-2 infection of the placenta, the authors did not demonstrate that the syncytiotrophoblasts expressed the ACE2 receptor, which has been shown to be the target of SARS-CoV-2 viral entry into host cells.
Additional considerations<br />
The immunology of pregnancy is not static - the myeloid and T cell repertoire of the placental micro-environment is dynamic throughout the different trimesters. For instance, during the first trimester, trophoblastic cells secrete cytokines and chemokines that promote the recruitment and infiltration of circulating monocytes, neutrophils, NK cells, and T cells (1,2). This trafficking is essential, and disruption of any elements of this signaling axis results in poor pregnancy outcomes (1). Notably, NK cells and monocyte-derived macrophages are responsible for decidual vascular and tissue remodeling (1,2).
The second trimester, however, is described as an anti-inflammatory stage, characterized by the induction of regulatory T cells by decidual CD56brightCD16- NK cells and monocyte-derived macrophages. Interestingly, a population of TH17 cells are also present and expand during the second trimester (1). The third trimester is then marked by a return to an inflammatory phenotype (1). It is unclear how these differential states are influenced by an antiviral response to SARS-CoV-2 infection. The authors reported the presence of macrophages and T cells, but a lack of more specific stains and analyses make it difficult to precisely characterize the immunological anomalies of the placental micro-environment in pregnant women with COVID-19. The role of decidual NK cells is likely to be especially important, given their role in trophoblast-mediated immune modulation during the different trimesters of pregnancy and their role in the antiviral response to viral infections.
Significance<br />
Hypertensive disorders, like preeclampsia, in pregnant women increase the likelihood for complicated pregnancies, and recent studies of the field suggest that dysregulated immune activity may partially be responsible for these outcomes. The trimesters of pregnancy exhibit different immune landscapes, so the presence of certain microbes, including viral pathogens, is likely to perturb homeostatic immune processes that are required for a normal pregnancy. The impact of SARS-CoV-2 infection, therefore, warrants its own investigation, as the health outcomes of COVID-19 are especially poor. The authors report direct infection of the syncytiotrophoblast by SARS-CoV-2. These cells are derived from trophoblasts, which play an important immuno-modulatory role in all three trimesters of pregnancy. So, collectively, given the role of the ACE2 receptor as the target of SARS-CoV-2 viral entry and the involvement of ACE2 in the physiology of preeclampsia, the two pathologies likely share altered immune states and a dysfunctional renin-angiotensin-aldosterone system (RAAS) as etiologies.
This review was undertaken by Matthew D. Park as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn school of medicine, Mount Sinai.
References<br />
1 Mor, G., Aldo, P., & Alvero, A.B. The unique immunological and microbial aspects of <br />
pregnancy. Nat. Rev. Immunol. 17, 469-482 (2020).<br />
2 Yockey, L.J., Lucas, C., & Iwasaki, A. Contributions of maternal and fetal antiviral <br />
immunity in congenital disease. Science. 368, 608-612 (2020).