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.