CMV is a double-stranded DNA virus, which is one of the β-herpesvirus family members. The virus is widespread among the general population, and the CMV seroprevalence may be > 60% [5]. CMV infection can be initiated through close contact, intravenous injection, blood transfusion, sexual intercourse, placental transmission, or organ transplantation. CMV disorder is an opportunistic infection that may threaten human life, and it is frequently seen among HIV/AIDS patients. Typically, GI CMV infection is one of the most common clinical manifestations, which represents a severe complication that affects HIV/AIDS patients; besides, it is the primary factor leading to mortality and morbidity [6]. In this article, we discussed the CMV cell tropism in GI tract, pathological features and clinicopathological correlations of GI CMV disorder.

Among cases infected with HIV, the susceptibility to symptomatic disorder is related to the immunosuppression degree, which elevates markedly at the case of number of CD4 cells < 200 cells/μL. According to one study, CMV infection is remarkably prevalent in HIV-infected patients who have the number of CD4 cells < 50 cells/μL, compared with those having the number of CD4 cells> 50 cells/μL [7]. Similar results were obtained in this study, the CD4 cell number in all patients dropped to < 200 cells/μL, among them, 27 cases had that of < 50 cells/μL.

CMV can affect any GI site, among which, colon is the most susceptible site. Among GI CMV patients, colon involvement has been commonly detected, which accounts for 94% patients [8, 9]. Colon was also the most commonly affected site in our results, which accounted for 26.1%. Stomach was most susceptible to CMV infection in upper GI tract, including cardia, antrum and gastric body in 10 patients. Similar results were also noted by Bonetti et al. [10]. But another study finds that, esophagus ranks the second place in terms of its susceptibility to CMV infection in the GI tract, which is only second to colon [11]. CMV-induced esophagitis was found in 7 cases in our study, only second to the stomach. CMV duodenitis is exceedingly rare, which is found in only 1 out of 30 cases with duodenum involvement, as reported in one study [10]. There were 4 cases with CMV duodenitis identified in our study. Patient demographic characteristics and other laboratory measurements, including serum CD4+ T cells, CD8+ T cells, leukocyte, erythrocyte, hemoglobin, platelet, and HIV viral loads, were not significantly different in CMV infection between the upper and lower GI tracts.

Several methods, including viral culture, serological tests, polymerase chain reaction (PCR), and shell viral assay, are proposed to diagnose GI CMV infection. However, virologic and serologic tests may be restricted in diagnosing the GI-restricted CMV disorder [12]. The primary process for diagnosis is endoscopy for identifying mucosal lesion, as well as tissue biopsy to confirm the infection. CMV infection is histopathologically diagnosed according to those virus-infected cells in the biopsied tissues (namely, the viral cytopathic effect). Typically, these virus-infected cells show the characteristic intracellular inclusions, with an ‘owl’s eye’ appearance on slides subjected to routine HE staining, or IHC detection of CMV viral inclusions [13, 14]. Histological findings have been shown with a sensitivity of 93% and a specificity of 100% in confirming the diagnosis [15]. However, it is impossible that all viral inclusions are identified by HE staining alone, because the complex inflammatory background may mask the inclusions, or the “atypical” viral inclusion may be characterized by the affluent rough eosinophilic inclusions of cytoplasm in those enlarged cells with no distinct inclusions of nucleus, as seen in our cases. Furthermore, IHC may yield ambiguous results for various reasons, it is also not the approach with the highest sensitivity in CMV detection. It remains controversial about the necessity of the routine implementation of CMV IHC in biopsy with moderate-severe inflammation [16]. PCR is a sensitive, specific, and rapid molecular tool that may be helpful to aid in early diagnosis of CMV infection on equivocal or clinically highly suspicious small GI biopsies [17], but it cannot show the position of positive cells in situ. Therefore, ISH was applied in this study to detect CMV in GI tract.

Notably, the significant active inflammation, especially with ulceration, stands for a vital clue to suspect GI CMV infection. 27 of our enrolled cases showed significant inflammation, and 14 had ulceration. Nonetheless, CMV infection can not be completely excluded when there is no distinct inflammation. For instance, the inflammation was not significant in 5 of our cases. The less inflammation background may be related to the Highly Active Antiretroviral Therapy (HAART) after CMV infection, or the absence of inflammation may represent a sampling error, specimens were taken from near the lesion [6]. Ulceration was detected in 14 cases in our study, with the deepening of ulcer, vascular erosion might result in substantial bloody diarrhea [18]. The progression of CMV disorder is associated with ulcer formation in the GI tract [13]. We demonstrated that, CMV DNA positive in blood was correlated with ulceration in the GI tract. In addition, if ulcers were observed in the GI tract, the CMV DNA in blood was more likely to be positive.

CMV demonstrates broad tropism in the GI tract. The CMV-infected cell types involve epithelial cells and mesenchymal cells, including histiocytes, endothelial cells fibroblasts and smooth muscle cells. However, we found that, the main types of CMV-infected cells were different at the diverse locations of GI tract. In the duodenum, CMV most frequently infects epithelial cells, whereas mesenchymal cells are the primary target in the esophagus, cardia, cecum, colon and rectum. In the stomach, both epithelial cells and mesenchymal cells can be infected by CMV. The cell tropism may relate to the viral entry machinery. Genetic analysis showed that CMV cell tropism require products of viral genes UL128L, together with gH/gL, forming the gH/gL/pUL128L pentamer complex (PC) that is required for the infection of epithelial or endothelial cells, whereas gH/gL and gO form the gH/gL/gOtrimer complex (TC), required for the infection of both cell types [19]. In 2016, a receptor for the TC that mediates entry into fibroblasts was identified as PDGFRα [20], while in 2018, a receptor for the PC that mediates entry into endothelial/epithelial cells was identified as neuropilin2 (Nrp2) [21]. Therefore, we detected the two receptors in different cell types in GI tract. We found that PDGFRα and Nrp2 all expressed in the epithelial cells and mesenchymal cells, and the expression levels of PDGFRα and Nrp2 in the mesenchymal cells were higher than those in the epithelial cells in cardia, cecum, colon, sigmoid, and rectum, especially in areas with ulcers. These may be the reason for markedly more positive mesenchymal cells than epithelial cells in these sites. The results of some studies were similar to ours. A flow cytometry analysis showed that an Nrp2 receptor was expressed on the cell surface of both epithelial/endothelial cells and fibroblasts. Thus, fibroblasts expressed similar levels of PDGFRα and Nrp2, which made the fibroblasts more susceptible to CMV infection compared to the epithelial cells [4].

Those affected cells become larger, which can comprise the cytoplasmic and nuclear inclusions. The nuclear inclusions are amphophilic, which are encompassed via a rarified chromatin zone, leading to the appearance of “owl’s eye”, while the cytoplasmic inclusions are eosinophilic and granule-like. Because the owl’s eye sign is not often seen in daily clinical practice, ISH serves as the most efficient approach when HE staining is unable to identify the inclusions, particularly when CMV infection is clinically suspected or the endoscopic results of HIV/AIDS cases are abnormal [6].

Peripheral blood CMV DNA test at molecular level is extensively utilized for monitoring those cases susceptible to infection [22]. According to some studies, the viral load of CMV shows poor association with CMV infection burden within GI tissues [23, 24]. Meanwhile, it is indicated in another study that, cell number found in the biopsied GI tissues is related to the systemic CMV viremia [16]. In our study, we also demonstrated that, positive CMV DNA in blood was related to the CMV-positive cell number within the GI tract. Therefore, we speculated that, the lower CMV-infected cell number led to the higher probabilities of negative blood CMV DNA and as a “bystander”; in addition, a higher number of CMV-infected cells resulted in the higher chances of positive blood CMV DNA and a systemic disorder that induces pathological changes, like ulceration or serious inflammation observed in the biopsied tissues. Nonetheless, it’s not uncommon to have isolated GI CMV disease without detectable CMV DNA, as observed among 14 of our cases.

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