After excluding some confounding factors, our results showed that the detection of latent EBV infection in colon tissue of IBD patients was inversely related to the severity of the disease, and patients with latent EBV infection in their colon tissues were severely ill. Studies have confirmed that EBV can cause immune disorders, and IBD is an autoimmune disease. Therefore, we hypothesized that combined EBV infection could aggravate the severity of IBD through complex immune mechanisms. In addition, advanced stage IBD patients with altered immune response and immunosuppressive therapy could also show increased susceptibility to EBV pathogenesis. Eventually, the immune imbalance following EBV infection and the resulting deterioration of the IBD stage are most likely to be mutually causal, leading to a vicious cycle of disease aggressiveness and poor prognosis. However, unlike the effect of EBV on multiple myeloma, we observed that not all the patients with severe IBD had EBV-positive diagnosis, which led us to postulate that EBV infection could be one of the critical factors in inducing severe IBD symptoms, but was not an indispensable etiological factor. In addition to the involvement of EBV, the severity of IBD must have involved other complex pathophysiological mechanisms. Based on our findings, we suggest that patients with latent EBV infection should be closely monitored, and the effect of EBV infection on the IBD patients should be given attention, and the pathogenesis between them should be clearly defined.
The clinic-pathological relationship between EBV and IBD has always attracted the attention of researchers and clinicians. For example, Dimitroulia E et al., and Li X et al., have shown that the prevalence of EBV in the intestinal tissue of patients with IBD is significantly higher than that in the control group. Moreover, patients with a high prevalence of EBV infection exhibit worsening disease symptoms, as compared to non-EBV infected patients who present remission incidences, suggesting that the severity of IBD may be related to the EBV infection [12, 13]. In addition, it has also been found that the positive expression of EBV in IBD patients is higher in refractory patients than in the control group. Further, the higher EBV positive expression has been linked to the mucous damage and high clinical indexes of activity [6, 11, 14] Our results were consistent with these findings, suggesting that the positive expression of EBV in latent infection might be related to the severity of IBD. However, most of the above studies used specimens from patients' serum or colonoscopy biopsies, while the specimens used in our study were specimens removed from bowel surgery. Relative to the determination of EBV in serum, EBV in bowel resection specimens can better reflect the direct role of EBV in the IBD pathology. In addition, compared to the EBV determination in colonoscopy biopsy specimens, the EBV of the bowel resection specimens can better reflect the EBV infiltration of the entire layer of the bowel wall. Therefore, our results based on the bowel resection specimens were more reliable and precise. We also obtained morphological data of EBV by IHC analysis of the colon wall of IBD patients to determine the exact location of EBV in the B lymphocytes of intestinal tissue, which was also the verification and supplementary to the previous studies.
In our study, we found that latent EBV infection rates were related to the pre-op corticosteroid administration. Crosstalk between EBV-positivity and corticosteroid administration has also been found in another study . We thought two aspects should be considered to explain these reasons. Firstly, latent EBV infection might be related to the severity of the disease, and the disease severity was directly proportional to the increasing dose of corticosteroids, indicating EBV infection was related to corticosteroids. Secondly, following the corticosteroid therapy, the immunosuppressive condition of patients might have increased their susceptibility toward EBV infection. However, the exact reason is needed to be confirmed by cohort research in the future.
Interestingly, we also found that the proportion of latent EBV infection in UC patients was higher than that in CD patients. In addition, all UC patients with latent EBV infection exhibited full colon type pathology. The reason for the difference in the proportion of EBV latent infection in the UC and CD patients and the relationship between latent EBV infection and subtypes in UC patients are worthy of further research and discussion.
So far, there is no consensus on whether all IBD patients mandatorily require EBV infection testing at the early stage. At present, the detection of EBV infection in IBD patients is mainly focused on patients who require azathioprine treatment, which may increase the activation of EBV and the incidence of related lymphatic system proliferative diseases. Studies suggest that before starting to use azathioprine, detection of EBV serology should be performed first, following the counting of natural killer cells during treatment to determine whether the patient has the risk of developing an abnormally serious primary EBV infection and EBV-related malignancies [5, 8, 15–17]. But other studies have also shown that the activation of EBV has no direct connection with the impact of immunosuppressive therapy [13, 18]. Notably, the exposure to EBV in adulthood is almost universal, and the incidences of hematological malignancies in IBD are rare. In the cost-benefit analysis, it seems that the value of EBV detection before the IBD patient starts treatment is limited [9, 19–21]. Our results suggest that it is important not only to consider the activation of EBV by immunosuppressive drugs that can lead to related malignant tumors but also to understand the relationship between EBV infection and the severity of IBD. With regard to the question of whether to carry out EBV testing first in IBD patients, we suggest that determination should be made after the role of EBV infection on IBD progression rate and deterioration are clarified, or it can be used in high-risk patient populations (such as patients with full colon UC or those who require corticosteroid therapy for the disease).
In addition to the aforementioned obstacles, there are still several unsolved questions about the relation of EBV infection with IBD severity. For example, whether IBD patients with latent EBV infection should be treated for EBV. And recent studies have shown that different EBV strains have inconsistent pathogenic effects on nasopharyngeal carcinoma . However, the exact causal relationship between different EBV strains and the progression of IBD is not clear yet.
Small sample size and one-center study were also considerable drawbacks of this retrospective study. A large sample size and multi-center studies to explain the serious relationship between latent EBV infection and the condition of IBD patients are needed for detailed investigation in the future.