Journal of Gastroenterology and Hepatology (1999) 14, 973–976
OESOPHAGOGASTRODUODENAL DISORDERS
Cytomegalovirus infection of the human gastrointestinal tract
SUSAMA PATRA, SUBASH C SAMAL, ASHOK CHACKO, VADAKENADAYIL I MATHAN1 AND MINNIE M MATHAN1
The Wellcome Trust Research Laboratory, Department of Gastrointestinal Sciences, Christian Medical College and Hospital,Vellore,India
Abstract Background: Current interest in cytomegalovirus (CMV) is largely due to an increase in the number of cases of acquired immunodeficiency syndrome and organ transplantation in recent years.The proper recognition of CMV-infected cells in gastrointestinal mucosal biopsies is critical for effective treatment of this condition. Methods: A total of 6580 endoscopic mucosal biopsies from 6323 patients in the 8-year period (1989–1996) were examined for CMV inclusion bodies. The endoscopic appearance and particularly the presence of ulcers were also analysed. Results and Conclusions: The prevalence of cytomegalovirus (CMV) inclusions was 9 per thousand in the gastrointestinal mucosal biopsies from an unselected group of patients. Of the 54 patients with CMV infection, 37 were immunocompromised and 17 apparently immunocompetent. Typical Cowdry inclusions and atypical inclusions were present, the latter more frequently in immunocompromised patients. The maximum prevalence of inclusions was in the oesophageal mucosa in immunocompro- mised individuals. © 1999 Blackwell Science Asia Pty Ltd
Key words: cytomegalovirus, gastrointestinal tract, immunocompetent, immunocompromised, inclu- sion bodies, mucosal biopsies.
INTRODUCTION in haematoxylin and eosin (HE)-stained histological samples is regarded as being sensitive and specific for Cytomegalovirus (CMV), first described in 1956,1 is a CMV infection,6–9 especially for samples from the gas- double-stranded DNA virus belonging to the herpes trointestinal tract. Evidence of CMV infection of the virus family. Cytomegalovirus infection is prevalent gastrointestinal mucosa, as shown by the presence of worldwide, although symptomatic CMV illness is intranuclear or intracytoplasmic inclusions, were found usually confined to immunocompromised individuals.2 in 54 of 6323 patients who had mucosal biopsies during Earlier reports from the Christian Medical College, the period January 1989 to December 1996 (0.85%) at Vellore, showed that in southern India, more than 70% the Christian Medical College and Hospital, Vellore. A of children had complement-fixing antibodies to CMV detailed analysis of this material is reported. by the age of 4 years and there was a higher pre- valence of antibody (98%) in cord blood samples.3 A survey using a sensitive ELISA test demonstrated immunoglobulin G antibodies in 92% of older children METHODS and adults.4 These prevalence rates are much higher than reports from temperate zone, industrialized coun- A total of 6580 mucosal biopsies were available from tries.2,5 The presence of characteristic inclusion bodies different parts of the gastrointestinal tract from diag-
Correspondence: Dr S Patra, Department of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore, Tamil nadu 632004, India. Email:
Ta bl e 1 Prevalence of cytomegalovirus inclusions in 6580 gastrointestinal mucosal biopsies from 6323 patients
Immuno- Immuno- Total compromised competent Prevalence per Site of biopsies biopsy (n = 37) (n = 17) Total 1000 biopsies Ulcer
Oesophagus 616 21 — 21 34.1 11 Stomach 704 4 1 5 7.1 2 Duodenum 334 1 — 1 3.0 1 Jejunum 207 2 — 2 9.7 — Colon and rectum 4719 16 16 32 6.8 18 Total 6580 44 17 61 9.3 32
Figure 2 Photomicrograph showing (a) a type I atypical Figure 1 Photomicrograph showing a typical or Cowdry-A cytomegalovirus (CMV) inclusion body (arrow) in an inclusion: an enlarged cell with an intranuclear eosinophilic enlarged endothelial cell with an eccentric nucleus, an ill- inclusion surrounded by a clear halo with chromatin mar- defined nuclear margin surrounded by an amphophilic zone gination (arrow), HE. and with occasional minute intracytoplasmic granules. (b) Type II atypical CMV inclusion body (arrow) in an enlarged smooth muscle cell with a elongated dense eosinophilic smudged nucleus, moderate to scant cytoplasm and absence nostic investigations carried out in the Department of of a well-formed inclusion body. (c) Type III atypical CMV Gastrointestinal Sciences on 6323 patients in the 8-year inclusion body (arrow) is only seen in the glandular epithe- period from January 1989 to December 1996. These lium with cytomegaly and enlarged nucleus, with an occa- included endoscopic biopsies from the rectum, colon, sional crystalline texture but lacking the well-formed inclusion ileum, duodenum, stomach and oesophagus and and halo, HE. suction mucosal biopsies of the jejunum (Table1). All biopsies were fixed in Bouin’s or buffered neutral for- malin and paraffin sections were stained with HE. Sec- tions were examined by two pathologists independently appearance and, particularly, the presence of ulcers was and CMV inclusions were noted. Typical CMV inclu- also analysed. sions (Fig. 1) have ‘owl’s eye’ nuclear inclusions (Cowdry bodies) and eosinophilic inclusions in the cytoplasm of enlarged cells.10,11 In addition, three types RESULTS of atypical inclusions (Fig. 2) as described by Schwartz and Wilcox12 were also found.The cell types (epithelial, The 54 patients, from whom the 61 biopsies with evi- stromal, endothelial, macrophage) in which the inclu- dence of CMV inclusions were obtained, ranged in age sions were found were noted (Table2).The endoscopic from 5 to 71 years (mean 38, median 45 years). There CMV infection of the human GI tract 975
Ta bl e 2 Types of cells with cytomegalovirus inclusion bodies
Immunocompromised Immunocompetent Ulcerated No ulcer Cell type (n = 37) (n = 17) (n = 32) (n = 22)
Epithelial 3 — 3 1 Stromal 34 9 29 12 Endothelial 22 10 19 11 Macrophage 2 2 2 2
were more males (40:14), but this reflects the sex viduals raises the possibility of reactivation of a latent distribution of patients who underwent endoscopic infection in a population with a high prevalence of biopsies. The 37 patients who were immunocompro- CMV infection.2 mised included six with acquired immune deficiency Oesophageal lesions were found only in immuno- syndrome, four post-bone marrow transplants, seven compromised individuals. Two reports from the tem- post-renal transplants, 12 with ulcerative colitis on perate zones9,13 reported a less than 10% prevalence of steroid therapy and eight patients with malignant neo- CMV in oesophageal biopsies although another plasms on chemotherapy. The other 17 patients were reports a higher prevalence.12 The high prevalence of apparently immunocompetent, but all of them were oesophageal CMV infection in the present study raises severely ill. the possibility that this may be the result of ingestion of The most frequent site of detection of CMV inclu- the virus from the environment in an area with a high sions was the oesophagus (Table1) with a prevalence of prevalence of the infection. It may also be that the 34 per thousand. All these patients were immunocom- oesophageal mucosa is a common site for latent infec- promised individuals. The jejunal mucosa had the next tion that is activated when the immune response is highest frequency (9.7 per thousand), followed by the compromised. stomach and the large intestine and rectum (Table1). The characteristic inclusions make the histopatho- In 16 of the 17 immunocompetent patients, the large logical diagnosis straightforward. Several reports sug- intestine or rectum was the site of the lesion. gested that the use of immunohistochemical or DNA Ulcerated lesions were detected endoscopically in 32 hybridization techniques may only marginally enhance of the 54 patients (Table1). Ulcerated lesions were the diagnostic yield and are not more specific or sensi- found in 70% (26) of the 37 immunocompromised tive techniques.8,9,14–18 The presence of CMV inclusion individuals, but in only 35% (6) of the 17 patients with bodies indicates active viral replication leading to patho- normal immune status. This difference was not statis- logical lesions.19,20 Atypical inclusions were seen more tically significant. Stromal cells (41 patients) and frequently in immunocompromised individuals sug- endothelial cells (30 patients) were the most commonly gesting that the typical inclusions are the end result of infected cell type. Epithelial cell and macrophage viral infection and tissue response in an immunocom- involvement were relatively infrequent (Table2) and petent host, the nature of which is as yet poorly under- there was no evidence of epithelial cell infection at or stood. The most commonly affected cell types were near ulcer margins. Significantly more involvement of stromal cells and endothelial cells. It has been suggested stromal cells was found in the ulcerated group that vascular occlusion from the infection of endo- (P < 0.02), while there was no such difference in thelial cells may play a role in the pathogenesis of endothelial cell involvement. ulceration, which is frequently associated with CMV Twelve patients had typical inclusion bodies only infection.9 The results reported here do not support this while 17 had atypical inclusions only. In 25 patients hypothesis as a significantly higher prevalence of CMV both typical and atypical inclusions were present. in patients with ulcerated lesions was found only in Atypical inclusions were only found in macrophages. stromal cells. Atypical inclusions were more common in the immuno- This retrospective survey of gastrointestinal mucosal compromised (90%) than in the immunocompetent biopsies from a population with a high prevalence of (47%). CMV infection suggests that it is important to keep this diagnosis in mind and search for CMV inclusion bodies, especially when mucosal biopsies from ulcer- DISCUSSION ated lesions are being evaluated and to be aware of the significance of atypical inclusions, especially in The detection of CMV inclusions in 9 per thousand immunocompromised patients. endoscopic biopsies of the gastrointestinal mucosa is a reflection of the high prevalence of CMV infection in this population.3,4 While this high prevalence can be ACKNOWLEDGEMENTS attributed to the prevalence of ulcerated CMV lesions in the small number of immunocompromised subjects The Wellcome Trust Research Laboratory was sup- who were investigated, the detection of CMV inclusion ported by the Wellcome Trust UK and Indian Council bodies in 17 immunocompetent but severely ill indi- of Medical Research. 976 S Patra et al.
REFERENCES clinico-pathological correlation. Am. J. Gastroenterol. 1986; 81: 944–50. 1 Smith MG. Propagation in tissue cultures of a cytopath- 10 Cowdry EV. The problem of intranuclear inclusions in ogenic virus from human salivary gland virus (SGV) virus diseases. Arch. Pathol. 1934; 14: 528–42. disease. Proc. Soc. Exp. Biol. Med. 1956; 92: 424–30. 11 Strano A. Light microscopy of selected viral disease (mor- 2 Weller TH.The cytomegalovirus. Ubiquitous agents with phology of viral inclusion bodies). Pathol. Annu. 1976; 11: protean clinical manifestation. N. Engl. J. Med. 1971; 285: 53–47. 267–74. 12 Schwartz DA, Wilcox CM. Atypical CMV inclusion in 3 Mukundan P, Jadhav M, John TJ. Prevalence of gastrointestinal biopsy specimens from patients with cytomegalovirus antibody in young children in Vellore. AIDS. Hum. Pathol. 1992; 23: 1019–26. Indian J. Med. Res. 1977; 65: 584–92. 13 Cheung ANY, Ng IOL. CMV infection of the gastroin- 4 Venkitaraman AR, Seigneuriu JN, Lenoir GM, John TJ. testinal tract in non-AIDS patient. Am. J. Gastroenterol. Infections due to the human herpes viruses in Southern 1993; 88: 1882–6. India. A seroepidemiological survey. Int. J. Epidemiol. 14 Grundy J. Virologic and pathogenetic aspects of 1986; 15: 561–6. cytomegalovirus infection. Rev. Infect. Dis. 1990; 12: 5 Ukkonen P, Hovi T, Von Bonsdorff GH, Saikku P, S711–19. Penttinen K. Age specific prevalence of complement- 15 Iwasaki T. Alimentary tract lesions in cytomegalovirus fixing antibodies to sixteen viral antigens. J. Med. 1984; infection. Acta Pathol. Jpn. 1987; 37: 549–65. 13: 131–48. 16 Roberts W, Sneddon J, Waldman J, Stephen R. 6 Culpepper Morgan JA, Kolter DP, Scholes JV, Tierney Cytomegalovirus infection of gastrointestinal endothelium AR. Evaluation of diagnostic criteria for mucosal cytome- demonstrated by simultaneous nucleic acid hybridisation galic inclusion disease in the acquired immunodeficiency and immunohistochemistry. Arch. Pathol. Lab. Med. 1989; syndrome. Am. J. Gastroenterol. 1987; 82: 1264–70. 113: 461–4. 7 Wilcox C, Diehl D, Cello J et al. Cytomegalovirus 17 Theise N, Rotterdam H, Dieterich D. Cytomegalovirus esophagitis in patients with AIDS. A clinical, endoscopic esophagitis in AIDS. Diagnosis by endoscopic biopsy. Am. and pathologic correlation. Ann. Intern. Med. 1990; 113: J. Gastroenterol. 1991; 86: 1123–6. 589–93. 18 Robert W, Hammond S, Sneddon J et al. In situ DNA 8 Clayton F, Klein E, Kolter D. Correlation of in situ hybridization for cytomegalovirus in colonoscopic hybridization with histology and viral culture in patients biopsies. Arch. Pathol. Lab. Med. 1988; 112: 1106–9. with acquired immunodeficiency syndrome with CMV 19 Reichert LM, O’Leary TJ, Levens DL et al. Autopsy colitis. Arch. Pathol. Lab. Med. 1989; 113: 1124–6. pathology in the acquired immunodeficiency syndrome. 9 Hinnam KL, Rotterdam HZ, Evan TB, Tapper ML. Am. J. Pathol. 1983; 12: 357–82. Cytomegalovirus infection of the alimentary tract. A 20 Gazzard B. AIDS. Clin. Gastroenterol. 1987; 1: 567–87.