Introduction
Cytomegalovirus (CMV) infection, usually associated with an immunosuppressed host,
can cause symptomatic gastrointestinal disease in an immunocompetent patient. Although
CMV can affect the entire gastrointestinal tract, the colon is most commonly involved,
followed by the small bowel [1]. Clinical manifestations may range from mild anorexia to obvious gastrointestinal
bleeding and perforation. Prototypical endoscopic findings are hyperemic edemas, longitudinal
ulceration, and well-defined ulcerations with a punched-out appearance. There are
few reports of diaphragm-like intestinal strictures caused by CMV infection [1]
[2].
Diaphragm disease (DD) was first reported by Lang et al. in 1988 [3]. It is relatively rare and characterized by multiple thin, diaphragm-like strictures
narrowing the intestinal lumen. DD sometimes causes obstruction of the small bowel
requiring surgery and it is difficult to diagnose both preoperatively and intraoperatively
[4]. Although DD is generally related to long-term intake of nonsteroidal anti-inflammatory
drugs (NSAIDs), pathogenesis is poorly understood, and it can occur in patients without
long-term NSAID use [5].
We report a rare case of DD related to CMV infection in an immunocompetent patient
who was not taking NSAIDs.
Case report
A 72-year-old man presented to a nearby hospital with epigastric pain and vomiting
lasting 4 weeks. He received antibiotic therapy and parenteral nutrition, as bacterial
enteritis was suspected at first. Because his symptoms persisted despite treatment,
he was referred to our hospital. He had a history of appendicitis and prostate cancer,
both of which were cured by surgery. He was on no medications including NSAIDs at
transfer to our hospital.
Physical examination revealed tenderness of the epigastrium and abdomen. The patient’s
legs had pitting edema, probably due to hypoalbuminemia because his heart function
was normal. Laboratory tests showed a white blood cell count of 9290/μL, hemoglobin
of 7.3 g/dL, C-reactive protein of 13.6 mg/dL, and albumin of 1.1 g/dL. Human immunodeficiency
virus antibody was negative. Stool culture was negative for pathogenic bacteria. Enhanced
computed tomography revealed intestinal wall thickening and fluid collection in the
jejunum.
Push enteroscopy showed extensive mucosal detachment with small islands of residual
epithelium in the upper jejunum ([Fig. 1]). Immunohistochemical staining of biopsy specimens showed CMV positivity ([Fig. 2]). CMV antigenemia was also positive.
Fig. 1 Endoscopic images of push enteroscopy on admission to our hospital. Extensive mucosal
detachment with small islands of residual epithelium was observed in the upper jejunum.
a White light endoscopic image and b indigo carmine chromoendoscopic image are indicated.
Fig. 2 Microscopic images of endoscopic biopsy specimens at push enteroscopy. Immunohistochemical
staining for CMV was positive (arrows).
The patient was diagnosed with CMV enteritis and received ganciclovir intravenously
for 14 days. At the end of treatment, his epigastric pain, vomiting and leg edema
had improved. CMV antigenemia became negative and the patient’s serum albumin levels
improved to 2.8 g/dL. We performed wireless capsule endoscopy 1 month after the antiviral
treatment to evaluate the entire small intestine. Although the detached mucosa of
the jejunum was almost regenerated, multiple diaphragm-like strictures in the jejunum
were observed ([Fig. 3]). Because the capsule was retained, we performed anterograde double-balloon enteroscopy
(DBE), which also revealed multiple thin stenoses with regenerative mucosa in the
jejunum ([Fig. 4]). The capsule was not able to pass through the most distal stricture of the middle
jejunum. We dilated the stenosis with a balloon and removed the capsule with a basket-catheter.
Histologic examination of biopsy specimens from the stenotic lesions revealed nonspecific
inflammatory changes and immunohistochemical staining for CMV was negative. Thereafter,
the patient’s clinical course was unremarkable without recurrence of CMV infection.
Follow-up anterograde DBE at 6 months after antiviral therapy showed almost normal
jejunal mucosa without strictures.
Fig. 3 An image of wireless capsule enteroscopy. Multiple thin stenoses with regenerative
mucosa in the jejunum were observed.
Fig. 4 a, b Endoscopic and c fluoroscopic images of peroral DBE 1 month after antiviral treatment. a, b, c Multiple diaphragm-like stenoses with ulceration (arrows) and b, c a retained capsule (arrowheads) were observed in the middle jejunum.
Discussion
DD is defined by presence of multiple thin, diaphragm-like strictures narrowing the
intestinal lumen to a pinhole. These lesions are histologically characterized by submucosal
fibrosis with normal overlying epithelium and submucosal ulcers not extending to the
muscularis propria. Many symptoms of DD are reported, including iron deficiency anemia,
hypoalbuminemia, and gastrointestinal bleeding. DD sometimes results in obstructive
symptoms presenting as a surgical emergency. Almost all cases of DD are related to
long-standing NSAID intake; 96 % of patients with DD had taken NSAIDs for more than
a year [4].
In our case, the patient did not take NSAIDs before symptom onset. Although the existence
of CMV in the stricture lesions was not confirmed, CMV was detected by immunohistochemistry
in biopsy specimens from the jejunal ulcer and both symptoms and endoscopic findings
improved after ganciclovir treatment, strongly suggesting that the multiple thin strictures
of the jejunum were induced by CMV infection. There are a few reports of colonic and
ileal strictures like DD that occurred secondary to CMV infection in infants [6] and adults [7]. To our knowledge, this is the first report of jejunal DD related to CMV infection.
DD occurs mostly in the ileum (34.6 %), followed by the right colon (27.7 %), whereas
it is uncommon in the jejunum (8.8 %) [8], where multiple strictures were observed in our case. CMV enteritis can affect both
the jejunum and ileum, without a significant difference in frequency. Because of the
rarity of DD associated with CMV enteritis, it is unknown whether the site of stenosis
differs between DD related to NSAIDs and DD related to CMV infection. Further studies
are necessary to reveal the specific clinical findings of DD caused by CMV infection.
The pathogenesis of DD remains poorly understood. It is hypothesized that NSAIDs cause
microvascular injury leading to reduced villous circulation and mucosal damage. This
leads to inflammation and ulceration, followed by reparative fibrosis and stricture
formation [8]. Pathogenesis of CMV enteritis is also presumed to relate to its infection of vascular
endothelial cells, which causes ischemic mucosal injury [1]. In our case, intestinal ischemia associated with CMV infection may have been involved
in formation of multiple thin stenoses.
Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) [9] and chronic enteropathy associated with SLCO2A1 (CEAS) [10] are important differential diagnoses for DD. These two entities and DD have similar
macroscopic findings of multiple thin ulcers in a linear or circumferential configuration
and concentric strictures [9]
[10]. On the other hand, CMUSE and CEAS share common clinicopathologic features that
differ from those in our case: age of onset (adolescence to middle age), chronic and
recurrent clinical course, and normal laboratory findings of inflammatory reactants
[9]
[10]. The etiologies of CMUSE and CEAS are not elucidated completely. Some reports suggested
that CMUSE may be associated with mutations in the PLA2G4A gene encoding cytoplasmic
phospholipase A2-α [9], and CEAS with mutations in the SLCO2A1 gene encoding a prostaglandin transporter
[10]. Both PLA2G4A and SLCO2A1 are presumed to play an important role in the physiology
of prostaglandins, which could explain the similarity between these two chronic enteritis
and DD.
Before the development of endoscopic techniques, resection of the involved intestine
was the only available treatment for DD. Endoscopic balloon dilation (EBD) has been
performed successfully in patients with DD, as in our case [5]. EBD is less-invasive therapy and can be repeated with each recurrence. Discontinuation
of NSAIDs is essential for preventing recurrence of DD associated with NSAIDs. In
our case, neither CMV infection nor intestinal stenosis had recurred at the last follow-up. The
long-term prognosis of DD with CMV infection remains to be elucidated.
Conclusion
We reported on a case of DD related to CMV. CMV infection should be considered in
the differential diagnosis of DD, especially in patients not taking NSAIDs.
