Discussion
CAEBV usually occurs in persons with congenital or acquired immunodeficiency[14]. The presence of CAEBV in nonimmunodeficient individuals has been reported relatively rarely. In addition to the manifestations of fever, hepatosplenomegaly, and lymphadenopathy, CAEBV often has multiorgan involvement. The liver,bone marrow, spleen, skin, and lymph nodes are the most frequently involved, and digestive tract involvement is very rare[15]. However, CAEAE is diagnosed when digestive symptoms and intestinal lesions combine on the basis of CAEBV and cannot be explained by other diseases and when a malignant lymphoproliferative disorder is lacking[6]. Currently, the cases of CAEAE occurring in nonimmunodeficient individuals are very limited, and all have been case reports[7-13]. We excluded patients who had a diagnosis of (1) EBV-positive lymphoproliferative disorder (EBV-LPD); (2) EBV recessive infection; (3) acute EBV infectious enteritis; (4) opportunistic infection with EBV in inflammatory bowel disease (IBD); (5) intestinal EBV infection with haemophagocytic syndrome; And (6) intestinal EBV-associated malignancies. After we excluded the patients described above, a total of 27 patients diagnosed with CAEAE were included in the analysis. We summarized their clinical features to provide the most comprehensive currently available resource to help increase the awareness of such disorders to clinicians.
From the 27 patients with CAEAE, we found the following characteristics: (1) There were significantly more males than females (77.7% were male), and most patients were young (mean age 40 years). The median age of disease onset was 12 years and ranged from 20 to 40 years. Early screening enteroscopy is recommended for individuals older than 20 years. (2) Clinical symptoms often start with fever, abdominal pain, diarrhoea, and bloody stools accompanied by lymphadenopathy and hepatosplenomegaly. (3) Decreased haemoglobin, cytopenia, and elevated inflammatory indicators are often observed during the course of the disease. (4) Endoscopic findings are mostly multiple ulcers in the gastrointestinal tract, with ulcers of varying sizes that are not pathognomonic, which are difficult to differentiate from IBD and can easily be misdiagnosed as CD, UC, TB, etc. (5) All patients who underwent EBER testing had positive results, and EBER in situ hybridization is considered the gold standard for detecting EBV latent infection[16]. An elevated serum EBV DNA load was evident. (6) The disease is progressive, and severe complications, including massive lower gastrointestinal bleeding, haemorrhagic shock, and intestinal perforation, occur in all patients late in the course, resulting in a high rate of emergency surgery. However, the conditions of patients often do not improve after surgery, and some patients soon experience reperforation or massive haematochezia, resulting in a high rate of reoperations. Consistent with reported case characteristics[10,17]. (7) Multiple regimens, including antiviral therapy and chemotherapy, are ineffective. The proportion of patients who die within 6 months is as high as 51%, with rapid progression and an extremely poor prognosis. Combined with our findings, it is suggested that the case fatality rate of patients with this group of diseases is extremely high and very insidious.
In addition to the manifestations described above in 11 of 27 patients, Liu R, a Chinese scholar, conducted a multicentre study to compare the clinical characteristics of 11 patients with CAEAE to those of 100 patients with IBD and found the following[10]: (1) Patients with CAEAE had intermittent fevers, hepatomegaly, splenomegaly, and lymph node involvement, which were more common systemic manifestations than in patients with IBD, and the fevers in CAEAE patients were febrile (greater than 39 °C). (2) The percentage of patients with positive EBV DNA (100%) and serum EBV DNA load (1.9 * 10 ^ 6) was higher than the percentage of patients with IBD (23%) and viral load (9.8 * 10 ^ 3). These differences were statistically significant, at P < 0.01. (3) CAEAE is more insidious than IBD and progress more rapidly in the late stages. Three patients underwent total colectomy, two of whom died of infection and intra-abdominal bleeding within 1 month of surgery. The 5-year survival rate was 100% (6/6) in the nonsurgery group and 40% (2/5) in the surgery group. Combined with the statistical findings of this study, the 1-year survival rate after surgery was 22.2% (2/9) in the surgery group and 58.3% (7/12) in the nonsurgery group, and there was a correlation between prognosis and surgery (P < 0.05). It can be seen that the conditions of patients do not significantly improve after surgery, and they are at an increased risk of death. However, the survival rate after total colectomy was smaller than after nonsurgical treatment, but a larger study is needed to further address the prognosis and association of total colectomy with survival.
Intestinal lesions are the main and prominent manifestation of CAEAE, but they are currently poorly recognized. CAEBV infection involving the intestine shares endoscopic and pathomorphological similarities with IBD and is difficult to differentiate from IBD. Through the analysis of 27 cases, the key points for the differential diagnosis, as summarized initially, were as follows: (1) Rare manifestations of UC, such as mucopurulent stools and tenesmus, are seen in CAEAE. In contrast to UC, its pathology often lacks diffuse cryptic architectural changes, and crypt abscesses are rare[16,18]. (2) Endoscopic lesions were more extensive and involved most of the small bowel and colon and rectum. The ulcers are shallow and variable in size and are uncharacteristic, and there are no common classic cobblestone-like ulcers, slit-like ulcers, or aphthous ulcers in other locations, such as genital ulcers and ocular lesions[10,16]. (3) Although CAEAE can also have transmural inflammation with occasional granuloma-like structures, it is easily confused with CD. However, CAEAE generally lacks typical chronic interstitial changes, such as granulomas, mucosal muscle hyperplasia, and nerve hypertrophy[10,16,19]. On the basis of our experience with this case, the pathological diagnosis could not be obtained to differentiate it from IBD, but cooperation can be sought from global healthcare institutions through internet systems, leading to a better diagnosis and treatment.
Treatment of CAEBV infection is more difficult. Anti-herpesvirus drugs such as acyclovir and ganciclovir are not effective for active EBV infections. Drugs such as glucocorticoids, immunosuppressive agents, immunomodulatory agents, and cytotoxic chemotherapy can provide short-term relief for CAEAE, but there is no cure[20]. Haematopoietic stem cell bone marrow transplantation is a curative procedure for CAEBV infection, but there is also an associated risk of transplantation complications[21]. Recently, Lingling Xu reported a case of CAEBV with intestinal[22], vascular, and neurological involvement. The patient had uncontrollable major digestive bleeding, and the patient’s clinical symptoms improved after a new treatment regimen combining thalidomide and propranolol. This holds promise as a new and effective treatment but still requires further clinical validation.
In 2008, the International Conference on the classification of lymphoproliferative disorders of EBV held at the National Institutes of Health (NIH) designated CAEBV as EBV + LPD[23]. EBV + LPD includes the CAEBV-b cell type, the CAEBV-T/NK cell type, lymphomatoid granulomatosis, and EBV + immunodeficiency-associated LPD[23]. Therefore, CAEBV is not a single infectious disease and is essentially a group of lymphoproliferative disorders ranging from proliferative to borderline to neoplastic. It can be said that LPD is a precancerous lesion. Enteric EBV infection can lead to recurrent infections in immunocompetent individuals and develop into EBV-associated enteritis, which eventually develops into LPD. A possible reason is that EBV infects lymphocytes, possibly giving them an enhanced ability to activate and proliferate, leading to the development of lymphoproliferative disorders[11]. Finally, lymphomas may develop as a result of enhanced cell tumorigenicity and inhibited apoptosis[11]. Yu Zhang reported a case of CAEAE diagnosed in an immunocompetent male who eventually developed LPD. In 2018, Yaxin Wang[24] similarly reported a case of an immunocompetent middle-aged woman who developed IBD-like manifestations after EBV infection and was ultimately diagnosed with adult EBV + T-LPD (II: borderline). We believe that EBV latent infection develops into CAEBV during the development of CAEAE and then to lymphoid value-added disease. CAEAE is just an intermediate state, and eventually, CAEAE will develop into LPD and ultimately to malignant lymphoma. Many similar studies could demonstrate[25-27]. From the EBV-infected intestine to the development of LPD, the disease features and prognosis are more severe than those of CAEAE[25-27].
In summary, it is difficult to differentiate IBD at the early stage from CAEAE, and the advanced stage is associated with rapid disease progression, a high case fatality rate, and carcinogenesis. Therefore, early identification is required, and early administration of the corresponding treatment becomes particularly critical. However, because CAEAE is relatively rare, in clinical work, patients with recurrent fever accompanied by abdominal pain, diarrhoea, bloody stools, and multiple ulcers in the intestine whose pathological diagnosis of IBD is again not very supportive, should be considered for the diagnosis of CAEAE. Screening for EBV DNA, along with endoscopic biopsy, is recommended for EBER testing. Combined with the clinical features and discriminating points summarized in this article, the diagnosis of CAEAE should be made as early as possible, and it should be treated early to improve the survival rate of patients. Moreover, early screening enteroscopy is recommended in patients over 20 years of age with intestinal symptoms.