Cytomegalovirus-Associated Protein-Losing Enteropathy

Jpn. J. Infect. Dis., 62, 236-238, 2009

Short Communication Cytomegalovirus-Associated Protein-Losing Enteropathy Resulting from Lymphangiectasia in an Immunocompetent Child Takayuki Hoshina*, Koichi Kusuhara, Mitsumasa Saito, Takuya Hara, Shuji Matsuura1, Takashi Yao2, Tomonobu Aoki3, and Toshiro Hara Department of Pediatrics, 1Department of Clinical Radiology, and 2Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, and 3Fukuoka Children’s Hospital and Medical Centre for Infectious Diseases, Fukuoka 810-0063, Japan (Received January 20, 2009. Accepted April 14, 2009) SUMMARY: An immunocompetent 8-year-old boy with cytomegalovirus (CMV)-associated transient protein- losing enteropathy (PLE) is described. Colonoscopic examination revealed lymphoid hyperplasia of the terminal ileum. Histological examination of the biopsied specimens showed marked dilation of the lymphatic vessels. Primary CMV infection was demonstrated by serological test and polymerase chain reaction. The child had complete resolution of the disease without antiviral treatment. The present case suggests the etiologic role of CMV infection in PLE resulting from intestinal lymphangiectasia in childhood.

Protein-losing enteropathy (PLE) is a condition resulting lactate dehydrogenase of 293 U/l. Serum IgG, IgA, and IgM from enhanced mucosal permeability, mucosal desquama- levels were 458 mg/dl (normal range [NR], 775-1,767), 76 tion, or lymphatic obstruction. It is often caused by inflam- mg/dl (NR, 104-331), and 94 mg/dl (NR, 55-227), respec- matory bowel disease, infections, celiac disease, intestinal tively. Surface marker analysis of the peripheral blood lym- lymphangiectasia, and cardiac disease (1). Many reports have phocytes by flow cytometer showed a reversed CD4/CD8 indicated that acute cytomegalovirus (CMV) infection could ratio (36.9/59.5 = 0.62; NR, 1.2-2) and an increased propor- play a causative role in immunocompetent children who de- tion of CD3+/HLA-DR+ T cells (33.3%; NR, 0-5%). Pe- veloped PLE. Most of the pediatric cases of CMV-associated ripheral blood lymphocyte responsiveness to phytohem- PLE have been related to Menetrier’s disease (2). We report agglutinin (PHA) was normal (stimulation index 281; NR, 254- a case of an immunocompetent child with CMV-associated 388) and natural killer (NK) activity was slightly increased PLE resulting from lymphangiectasia at the terminal ileum. (58.6%; NR, 20.8-40.8). Serum CMV IgM and IgG anti- An 8-year-old boy was admitted to our hospital because of bodies were both positive by enzyme immunoassay (5.13 and edema caused by hypoproteinemia. Two weeks earlier, he had 17.5, cutoff 0.80 and 2.0, respectively). The plasma level of complained of nausea. Subsequently, he developed edema CMV-DNA was positive at 2 × 102 copy/ml (NR, <2 × 102 on his eyelids and lower extremities, and was evaluated at a copy/ml) by real-time automated polymerase chain reaction hospital 5 days prior to admission. Serum total protein level (PCR) detection described previously (3). The bacterial cul- was 3.7 g/dl and albumin level was 1.9 g/dl. Serum liver ture of a stool specimen was unremarkable and 13C-urea breath enzyme levels were slightly elevated (aspartate aminotrans- test was negative. Urinalysis was normal. Serum antibody ferase [AST] 107 U/l, alanine aminotransferase [ALT] 71 U/ titers against Epstein-Barr virus (EBV) assayed by indirect l). Abdominal ultrasonography revealed thickening of the immunofluorescence method indicated past infection as fol- intestinal wall and a small amount of ascites. Chest X-ray lows: viral capsid antigen (VCA) IgG, 1:40; VCA IgM, <1:10; showed a substantial amount of bilateral pleural effusion. He EBV-nuclear antigen, 1:40. Bilateral pleural effusion was still was then referred to our hospital for further investigation. The present on chest X-ray, but thickening of the intestinal wall patient’s past history and family history were not remarkable. and ascites had disappeared on abdominal ultrasonography. On admission, he was afebrile and his body weight was Alpha-1-antitrypsin clearance was 21.6 g/day (NR, <13 g/ the same as prior to the onset of symptoms. The edema on his day), which was consistent with PLE. 99mTc human serum eyelids had improved but that on the lower extremities albumin scintigraphy revealed abnormal leakage from the remained. Respiratory sound was weak at the bilateral lower terminal ileum. Gastroscopy showed normal gastric and lung field and liver size was slightly enlarged, but neither duodenal folds. Colonoscopic examination revealed lymphoid enlargement of cervical lymph nodes nor splenomegaly was hyperplasia of the terminal ileum (Figure 1). Histological observed. Peripheral blood counts showed leukocyte 8.11× examination of the biopsied specimens taken from the lesion 109/l with 22.5% neutrophils, 55.5% lymphocytes, and 3.0% showed marked dilatation of lymphatic vessels (Figure 2). atypical lymphocytes. Both erythrocyte and platelet counts These findings suggested that the patient suffered from PLE were normal. Blood chemistries showed total protein of 4.1 resulting from lymphangiectasia at the terminal ileum. No g/dl, albumin of 2.5 g/dl, AST of 55 U/l, ALT of 40 U/l, and inclusion bodies, CMV antigens, or CMV-DNA were not detected in the intestinal lesion by hematoxylin-eosin staining, *Corresponding author: Mailing address: Department of Pediat- immunohistochemical staining with anti-CMV monoclonal rics, Graduate School of Medical Sciences, Kyushu University, antibody (M0864-1; DAKO, Glostrup, Denmark) or PCR, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Tel: +81- respectively. 92-642-5421, Fax: +81-92-642-5435, E-mail: hoshina@pediatr. A few days after admission, the patient’s edema disappeared med.kyushu-u.ac.jp completely. Serum total protein and albumin levels continued

236 that he had primary CMV infection accompanied by PLE with lymphangiectasia. A common presentation of CMV-associated PLE in childhood is Menetrier’s disease, which is characterized by gastric foveolar hyperplasia and usually has a benign clinical course in contrast to that in adults (2,6). Although a few pediatric cases of CMV-associated PLE without gastric lesions have been reported, neither colonoscopic nor histological finding was described in these case reports (7,8). Intestinal lymphangiectasia is characterized by obstruction of the intestinal lymphatic vessels and increased lymphatic pressure. Nakase et al. reported an adult case of CMV-associated PLE with intestinal lymphangiectasia (9). In this report, although no Fig. 1. Endoscopic view of the terminal ileum showing lymphoid intranuclear cytomegalic inclusion bodies were seen, CMV- hyperplasia. DNA was detected in the lesion using PCR amplification, indicating direct invasion. Direct viral invasion is the most common pathological mechanism of CMV diseases, such as retinitis, hepatitis, and colitis (10), and can be confirmed by identification of CMV or CMV-DNA in the lesion using virus culture, immunohistochemical staining, PCR or in situ hybridization (11). On the other hand, interstitial pneumonitis and vasculitis can be caused by an immunopathological mechanism (12). In this condition, it has been speculated that activation of NK cells and tumor necrosis factor-α released from macrophages stimulated by interferon-γ derived from activated NK cells might be involved in the disease process (12,13). In the present case, no findings indicating direct invasion of CMV were detected in the lesion. As biopsy specimens were taken when the patient was in rapid recovery before admission, it is possible that CMV had already been eliminated from the lesion. Alternatively, intestinal lymphan- Fig. 2. Histological examination of mucosa of the terminal ileum show- giectasia might be a presentation of an immunopathological ing markedly dilated lymphatic vessels (hematoxylin and eosin stain, mechanism induced by CMV infection. To examine the latter original magnification ×50). possibility, accumulation and analysis of similar cases is required. to increase without any specific treatment. Serum immuno- In summary, we report a pediatric case of CMV-associated globulin and liver enzyme levels also showed improvement. PLE resulting from intestinal lymphangiectasia. Our experi- He was discharged 8 days after admission. Serum total pro- ence suggests that evaluation of intestinal lesions is neces- tein, albumin, and immunoglobulin levels returned to a sary in children of CMV-associated PLE without findings normal range 4 weeks after discharge. Four weeks later, indicating Menetrier’s disease. liver enzyme levels were normalized, and the follow-up was completed uneventfully. 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