Gastrointestinal Cytomegalovirus Disease

  1. Richard W. Goodgame, MD
  1. From Baylor College of Medicine, Houston, Texas. Requests for Reprints: Richard Goodgame, MD, Baylor College of Medicine, One Baylor Plaza, Room 525D, Houston, TX 77030. Acknowledgments: The author thanks Dr. Robert Genta for preparing the pathology specimens for Figures 1, 3, and 4 and taking the photographs; Dr. Boris Yoffe for helping with the immunohistochemical stains shown in Figure 3; Dr. Atilla Ertan for taking the photograph in Figure 2, Right; and Drs. Linda Rabeneck, Wayne Shandera, Thomas Cate, Stephen Greenberg, and Fred Sutton for their suggestions and assistance. Grant Support: In part by clinical research grants from the American College of Gastroenterology and the American Society for Gastrointestinal Endoscopy.
     
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    Abstract

    Objective: To describe the pathogenesis of gastrointestinal cytomegalovirus (CMV) disease, the types and locations of gastrointestinal lesions, the clinical settings in which they occur, and the specific methods available to diagnose and treat the disease.

    Data Sources: Relevant English-language articles were identified through a MEDLINE search from 1985 to 1992. Articles referenced in the bibliographies of these articles and others were searched by hand.

    Study Selection: All articles that documented the occurrence of gastrointestinal CMV infection in humans, based on the finding of typical cytomegalic cells in histologic specimens, were selected for review.

    Data Extraction: Studies were grouped by content pertaining to pathogenesis, clinical setting, gastrointestinal location, diagnosis, or treatment.

    Data Synthesis: Gastrointestinal CMV disease is an erosive or ulcerative process that can occur at any location in the gastrointestinal tract, from mouth to rectum. Cytomegalovirus infection of columnar epithelial cells, endothelial cells, myocytes, and fibroblasts causes tissue destruction and ulceration. Serious CMV disease most frequently occurs with immune deficiency, such as the acquired immunodeficiency syndrome, after organ transplantation, after cancer chemotherapy, and after steroid therapy. Symptoms and signs depend on which part of the gastrointestinal tract is involved. Diagnosis depends on a positive mucosal biopsy that shows the presence of CMV by histopathologic or other techniques. In patients with persistent immune deficiency, progressive intestinal disease and death are frequent. Treatment with ganciclovir or foscarnet often heals intestinal lesions.

    Conclusions: Internists should be aware of the various clinical settings and locations in the gastrointestinal tract in which CMV disease occurs. Patients with immune deficiency and gastrointestinal signs and symptoms should have imaging tests and mucosal biopsies to investigate the possibility of CMV intestinal disease. Treatment with antiviral chemotherapy improves outcome in many patients.

    Cytomegalovirus (CMV) is a common human viral infection, affecting 40% to 100% of adults. Acute infections are frequently asymptomatic, but once the infection is acquired, there is lifelong latency coupled with the risk for intermittent reactivation. Although gastrointestinal CMV disease can occur in persons with normal immune function, it most frequently occurs in adults with immune deficiency, such as the acquired immunodeficiency syndrome (AIDS), organ transplantation, cancer chemotherapy, and steroid therapy. Because the number of patients with immune deficiency has increased dramatically in recent years, and because CMV is one of the most common infectious complications in these settings, the number of patients with CMV disease is also increasing. New diagnostic tests and treatments have been developed to help physicians address this growing problem.

    Cytomegalovirus can damage many organs, including the lung, retina, liver, and gastrointestinal tract. This review describes the pathogenesis of gastrointestinal CMV disease, the types and locations of gastrointestinal lesions, the clinical settings in which they occur, and the specific methods available to diagnose and treat the disease. Cytomegalovirus infection of the liver and pancreas will not be discussed.

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    Pathogenesis

    Primary Infection and Latency

    Most CMV infections are acquired either in the perinatal period and infancy or in adulthood through sexual contacts [1]. Although congenital infections due to primary CMV infection in pregnancy are a cause of substantial morbidity and death [2], most primary CMV infections in immunologically healthy adults are asymptomatic or are associated with a mild mononucleosis-like syndrome. Serious gastrointestinal disease due to primary infection is rare (see below in Healthy Persons). All primary infections resolve and enter a state of latency in which live virus is sequestered in a nonreplicative state. Persons with latent infection have no symptoms but do have antibody to CMV.

    The predominant tissue site of viral latency is not known [3-5], but circulating lymphocytes, monocytes, and polymorphonuclear leukocytes all probably contain latent virus [4]. Organs at risk for subsequent CMV disease, including the gastrointestinal tract, may contain latent virus that may cause local disease with reactivation [5-7].

    Infection Compared with Disease

    Because most patients previously exposed to CMV have latent virus in various organs without evidence of organ damage, infection with CMV is more common than disease caused by CMV. In pregnant women, intermittent asymptomatic viremia and viruria, not associated with organ damage, are common. In immunodeficient patients, CMV infection can be detected (see below, Diagnostic Techniques) in salivary glands and saliva as well as in the kidney and urine; however, substantial CMV disease in these organs does not occur [8]. Asymptomatic infection of the gastrointestinal tract has also been detected (see below). Therefore, the identification of CMV in tissue or body fluids may indicate infection but not necessarily disease.

    Some authors have suggested that gastrointestinal CMV is frequently a nonpathogenic bystander or secondary invader [9-12]. Furthermore, it has been suggested that the presence of CMV in areas of inflammation reflects the propensity of the virus to infect rapidly growing tissues, especially endothelial cells in granulation tissue [10, 13-17]. Clearly in an individual patient, the clinical significance of finding evidence of tissue CMV infection may be unclear. For example, an AIDS patient with endoscopic evidence of esophageal Candida infection may have detectable cytomegalic cells Figure 1 in a mucosal biopsy [18]; or cytomegalic cells may be seen in an area of gastric inflammation that also contains Helicobacter pylori; or a colonic biopsy taken from a patient with an exacerbation of chronic ulcerative colitis may show the presence of CMV [19]. However, strong evidence exists that CMV is a true gastrointestinal pathogen: 1) CMV is often detected in the absence of other pathogens; 2) the severity of the mucosal lesion reflects the number of CMV-infected cells [14]; 3) antiviral therapy benefits patients with histologically confirmed disease; and 4) in patients with persistent immune deficiency (for example, AIDS), virologic, histologic, and symptomatic relapse occurs after cessation of antiviral therapy.

    Figure 1. The gastric glands are normal except for the typical cytomegalic cell indicating cytomegalovirus infection. The cell shows a large, densely staining nucleus and abundant cytoplasm with intracytoplasmic inclusions (original magnification, 400).
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      Figure 1. The gastric glands are normal except for the typical cytomegalic cell indicating cytomegalovirus infection. The cell shows a large, densely staining nucleus and abundant cytoplasm with intracytoplasmic inclusions (original magnification, 400). Endoscopic gastric mucosal biopsy specimen from an AIDS patient with severe nausea, vomiting, and epigastric pain.

      A reasonable definition of CMV intestinal disease (as opposed to infection only) is an erosive or ulcerative process in the wall of the gut in which the presence of CMV is shown by routine histologic examination, culture, or antigen or DNA staining, in a person in whom other explanations for the lesion(s) have been excluded.

      Reactivation and Reinfection

      Cytomegalovirus disease in the setting of immunodeficiency can be the result of either a primary CMV infection in a previously uninfected (seronegative) host, reactivation of latent virus, or reinfection with a new virus [8]. Most CMV disease is due to reactivation of latent virus [1, 3, 17]. Reactivation is associated with adequate anti-CMV antibody but defective cell-mediated immunity, characterized by decreased numbers of cytotoxic T lymphocytes and natural killer cells [3, 20-22]. In transplant patients, all three mechanisms listed above have been shown to lead to CMV disease, and in these patients the source of infection influences disease severity [3, 23, 24]. However, no comparable data exist about the influence of the source of CMV on gastrointestinal CMV infection in the setting of transplantation.

      In most AIDS patients, the source of CMV must be either reactivation or reinfection, because previous infection is almost universal [8]. However, reinfection with new virus subtypes has been documented in AIDS patients [8]. In theory, the frequent occurrence of esophagogastric and colonic CMV disease in patients with AIDS could occur because homosexual men swallow CMV-laden semen or engage in receptive anal intercourse. However, CMV of the esophagus and colon are common in transplant patients who are not at such high risk for direct gastrointestinal CMV inoculation. Furthermore, the frequent occurrence of CMV retinitis in AIDS patients is unlikely to be due to direct inoculation of new virus subtypes. In both AIDS and organ transplant patients, the incidence and severity of gastrointestinal CMV disease closely parallel the degree of cellular immune dysfunction, suggesting that CMV disease is related more closely to the severity of immunodeficiency than to the source or subtype of virus.

      Gastrointestinal Cytomegalovirus Disease

      The organ system manifesting CMV disease varies depending on the cause of the host's immunodeficiency. For example, pneumonitis is more common in bone marrow transplant patients, but retinitis and gastrointestinal disease are more common in AIDS patients [1, 3, 5, 8, 17, 25]. The factors that make the intestine vulnerable to CMV injury are unknown.

      In gastrointestinal CMV disease, the gross appearance and location of the lesions are similar regardless of the cause of the host's immunodeficiency [17, 26]. Ulcerations, erosions, and mucosal hemorrhage are the primary macroscopic findings (Figure 2). Although such lesions may have other causes, microscopic identification of the cytomegalic cell (see Figure 1) provides evidence of tissue infection with CMV [see below, Histopathology] [14, 27, 28]. Special stains for CMV antigens and DNA have shown that many more cells are infected than those that have classic cytomegalic changes (Figure 3) [14, 30, 31, 33]. Many gastrointestinal cell types can be infected in active disease, most commonly vascular endothelial cells [14, 27, 29-31], but fibroblasts, smooth muscle cells, and glandular epithelium are also infected (see Figures 1 and 4) [14, 26, 29, 30, 32].

      Figure 2. Esophageal ulcer in a 25-year-old AIDS patient. Center. Ulcer in the gastric cardia seen by retroflexing the endoscope back toward the gastroesophageal junction. The patient was a 57-year-old man receiving corticosteroid therapy for severe chronic obstructive lung disease. A yellow-based, irregular, colonic ulcer in a 54-year-old renal transplant patient.
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        Figure 2. Esophageal ulcer in a 25-year-old AIDS patient. Center. Ulcer in the gastric cardia seen by retroflexing the endoscope back toward the gastroesophageal junction. The patient was a 57-year-old man receiving corticosteroid therapy for severe chronic obstructive lung disease. A yellow-based, irregular, colonic ulcer in a 54-year-old renal transplant patient. Three endoscopic photographs of gastrointestinal cytomegalovirus disease causing mucosal ulceration.Left.Right.
        Figure 3. Special stains for cytomegalovirus (CMV) are shown. Cytomegalic cells were rare in the glandular epithelium of this patient, but they were easily identified by this in situ DNA hybridization that stains the enlarged nucleus purple (original magnification, 200). Center. In the same patient, many smooth muscle cells and fibroblasts stain purple, indicating the presence of CMV DNA (original magnification, 400). Immunoperoxidase stain (using a monoclonal antibody against a CMV antigen) that stains infected cells brownish-red (original magnification, 400).
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          Figure 3. Special stains for cytomegalovirus (CMV) are shown. Cytomegalic cells were rare in the glandular epithelium of this patient, but they were easily identified by this in situ DNA hybridization that stains the enlarged nucleus purple (original magnification, 200). Center. In the same patient, many smooth muscle cells and fibroblasts stain purple, indicating the presence of CMV DNA (original magnification, 400). Immunoperoxidase stain (using a monoclonal antibody against a CMV antigen) that stains infected cells brownish-red (original magnification, 400). A surgical specimen from an AIDS patient who had a small-bowel resection for a perforated cytomegalovirus ulcer.Left.Right.

          The pathogenesis of intestinal lesions has recently been reviewed [8]. It is a complex process involving mucosal CMV infection with inflammation and tissue necrosis [20] and vascular endothelial involvement with subsequent ischemic mucosal injury [26, 29, 31, 32, 34-37]. Vascular occlusion may be an important cause of tissue injury (see Figure 4). However, surface epithelial cells (columnar, never squamous) are frequently infected at the edge of the ulcerations and in nearby mucosa that is not inflamed (see Figure 1) [29-33, 38, 39], results suggesting that vascular involvement is not necessarily the only or predominant cause of tissue injury. Local immune suppression or autoimmune factors may play a role in the pathogenesis of gastrointestinal CMV disease [4, 8], but they do not appear to be central to the pathogenesis as they are in CMV pneumonitis in bone marrow transplant recipients [8].

          Figure 4. . The many cytomegalic cells show infection of various cell types including vascular endothelium (small arrow), fibroblasts (medium arrow), and smooth muscle cells (large arrow) (original magnification, 200). Most of the endothelial cells in the three blood vessels shown are cytomegalic. Ischemia as a result of vascular occlusion may be important in the pathogenesis of ulceration (original magnification, 200).
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            Figure 4. . The many cytomegalic cells show infection of various cell types including vascular endothelium (small arrow), fibroblasts (medium arrow), and smooth muscle cells (large arrow) (original magnification, 200). Most of the endothelial cells in the three blood vessels shown are cytomegalic. Ischemia as a result of vascular occlusion may be important in the pathogenesis of ulceration (original magnification, 200). Routine histologic section from the patient described in Figure 3Left.Right.
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            Gastrointestinal Cytomegalovirus Disease in Different Hosts

            Gastrointestinal CMV disease is suspected when gastrointestinal symptoms or lesions develop in a patient with a recognized high risk for CMV disease (Table 1).

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            Table 1. Clinical Features Suggesting Possible Gastrointestinal Cytomegalovirus Disease

            The Acquired Immunodeficiency Syndrome

            As discussed above, most AIDS patients have serologic evidence of CMV infection [40-42], and the virus can frequently be isolated from body fluids [43]. Important interactions between human immunodeficiency virus (HIV) and CMV have been reviewed [44]. In AIDS patients, the risk for CMV disease increases when CD4 counts decrease to less than 100/mm3 [41]. Cytomegalovirus disease is the most common serious opportunistic infection observed in some postmortem studies [27, 45]. Gastrointestinal CMV disease is the most common cause for emergency or elective abdominal surgery in AIDS patients [15, 46-51]. Patients with AIDS can have CMV disease of any site in the gastrointestinal tract, including the mouth [52-54], esophagus [55-64], stomach [14, 30, 56, 58, 61, 65-70], small bowel [48, 49, 57, 71-73], appendix [50, 74], and colon [15, 28, 32, 35, 47, 51, 57, 64, 72-84]. Primary peritonitis has been reported [85].

            Organ Transplant Recipients

            Cytomegalovirus is the most common infectious complication of organ transplantation, occurring in 60% to 70% of kidney, liver, bone marrow, and heart transplant recipients [3, 25, 86-88]. At least one half of these infections are symptomatic. Gastrointestinal CMV disease occurs in about 10% of all transplants [89]. Three descriptive studies have documented a high incidence (30% to 50%) of asymptomatic CMV infections in endoscopically normal gastroduodenal mucosa during the first month after transplantation [87, 90, 91]. However, as in AIDS patients, symptomatic gastrointestinal CMV disease has been observed in all parts of the gastrointestinal tract, including the esophagus [87, 92-94], stomach [89, 93, 95-100], small intestine [87, 91, 101, 102], and colon [9, 29, 103, 104].

            Cancer and Cancer Chemotherapy Patients

            Case reports and postmortem series have documented severe gastrointestinal CMV disease in this group of patients, mostly in those with myelo-or lymphoproliferative disorders, particularly those treated with steroids [37-39, 70, 105-107]. Gastrointestinal CMV disease was described in cancer patients well before the AIDS and transplantation eras [34, 105, 106]. Although CMV ulcers sometimes have preceded the diagnosis of cancer [108], more commonly they have complicated the clinical course of a patient with an established cancer [37, 109].

            Steroid Therapy

            Oral, gastric, duodenal, and colonic lesions that contain cytomegalic cells have been reported in association with steroid therapy [36, 38, 39, 54, 105, 106, 110]; in patients with cancer (see above); with rheumatic diseases [54, 110]; and with asthma [36]. Several pathologists have suggested that steroid-associated peptic ulcer disease is, in fact, CMV disease of the stomach and duodenum [39, 110, 111]. Evidence derived from case series provides support for this concept in some patients [38].

            Inflammatory Bowel Disease

            The relationship between inflammatory bowel disease and CMV has been reviewed [19]. Evidence from case reports published during the last 20 years shows that 1) CMV colitis can mimic the clinical features of acute idiopathic proctocolitis [112-114]; 2) acute CMV colitis can initiate a chronic disease indistinguishable clinically, endoscopically, and histologically from ulcerative colitis [115]; 3) in patients with exacerbations of ulcerative colitis and toxic megacolon, cytomegalic cells may be detected in colonic biopsy or surgical specimens [13, 19, 116-119]; and 4) patients with exacerbations of ulcerative colitis, which are resistant to steroid therapy, who have cytomegalic cells in mucosal biopsy specimens, may improve clinically and histologically after steroid withdrawal [19, 117]. In such patients with ulcerative colitis and cytomegalic cells in mucosal biopsy specimens, it is unclear whether the CMV is localizing in areas of pre-existing inflammation or whether the virus is causing disease [13, 19, 31, 80, 118, 120, 121].

            Other Immunodeficiency States

            The late-onset adult immunodeficiency syndrome has been associated with gastrointestinal CMV disease [122], including gastric erosions and severe chronic colitis.

            Elderly Patients

            A small number of patients older than 65 years, without other illness, have had gastrointestinal CMV disease including colitis [123, 124], gastric ulcer [12], and small-bowel perforation [38, 125]. Follow-up observations and detailed immunologic studies in these patients are lacking.

            Healthy Persons

            A descriptive study published in 1964 suggested that CMV may cause gastrointestinal disease in patients without detectable immunodeficiency [12]. Immunocompetent patients have developed gastrointestinal CMV disease associated with community-acquired, acute primary CMV infection [112, 113, 115, 126, 127], blood transfusions [111, 128], or sexual transmission [129]. Several authors have reported [130-133] an acute, self-limited gastropathy in children, associated with marked hypertrophy of gastric folds and protein-losing enteropathy. These patients had serologic, histologic, or culture evidence of CMV infection, or all three.

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            Clinical Presentation and Sites of Involvement

            Mouth

            Although uncommon, oral manifestations of CMV infection have included painful erosions or ulcers [52, 54, 106, 134], enlarged, painful salivary glands [135], and odynophagia due to an epiglottic [14] or posterior pharyngeal ulcer [134].

            Esophagus

            The esophagus is frequently involved in symptomatic CMV disease [57]. The large, solitary, distal esophageal ulcer (see Figure 2) causes odynophagia or constant substernal pain or both in AIDS patients [55, 56, 59, 60, 62-64, 136, 137] and transplant recipients [94] (see Table 1. Diffuse esophagitis [58], upper gastrointestinal bleeding [138], and a distal esophageal mass [55] are less common clinical manifestations. Esophageal stricture formation after healing with anti-CMV therapy has been described [55, 61].

            Stomach

            Patients who have symptomatic gastric CMV disease see their physicians for complaints of epigastric pain, nausea, and vomiting (see Table 1) [26, 58, 66, 95, 100, 107, 108, 110, 126, 127]. Complications of CMV gastric ulcers (see Figure 2) include bleeding [93, 97, 98, 106, 109, 111], gastric outlet obstruction [68], and perforation [26, 70, 109]. Unusual presentations have included gastrocolic fistula [109], recurrent stomal ulcer with afferent limb obstruction in a postgastrectomy patient [12], submucosal antral mass [69], and an acute, self-limited gastropathy in children that is associated with protein-losing enteropathy (see above, Healthy Persons [130-133]).

            Small Intestine

            The clinical spectrum of small-bowel CMV infection Table 1 ranges from the previously described asymptomatic transplant recipient with endoscopically normal duodenal mucosa [91] to a patient with progressive diarrhea followed by fatal perforation of a severely ulcerated mucosa [48]. Terminal ileal disease may mimic Crohn disease clinically, endoscopically, and radiologically [49, 102]. Massive gastrointestinal bleeding due to small-bowel ulceration has been reported in infants with AIDS [71, 73] and in pancreatic transplant recipients [101]. Small-bowel perforation, although less common than colonic perforation, has been reported in AIDS patients (see Figures 3 and 4) [47] and in a patient with lymphoma [37]. Small-bowel erosions and ulcerations have been observed in a healthy adult with acute CMV infection [127] and in an elderly patient with no apparent immune disorder [123]. Cytomegalovirus ulceration of the appendix has occurred as acute appendicitis in AIDS patients [50, 74].

            Colon

            Patients who have colonic CMV disease (see Table 1) may have diarrhea, hematochezia, urgency, tenesmus, and abdominal pain, often with associated constitutional symptoms such as fever, malaise, anorexia, and weight loss [15, 32, 35, 51, 57, 64, 65, 76, 78, 79, 81, 82, 114, 122, 123, 139, 140]. The presentation can be acute [124, 129] or chronic [76, 78]. Massive acute bleeding has been reported [34, 72, 76], especially from cecal ulcers in transplant patients (see Figure 2) [29, 103, 104]. Colonic perforation has been described frequently [9, 10, 15, 76]. Barium radiographs and endoscopy may show diffuse mucosal lesions indistinguishable from ulcerative colitis or focal ulcerations with skip areas that mimic Crohn disease [32, 75, 76]. Less commonly, pseudopolyps [122] or pseudomembranes [32, 76, 77] may be observed. Toxic megacolon may complicate CMV colitis in AIDS patients [36, 64] and in ulcerative colitis patients receiving steroid therapy [116].

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            Diagnosis

            The utility of various diagnostic tests for CMV disease has been reviewed [141] (Table 2). Although many methods are discussed below, the best approach is to confirm the presence of CMV with histologic analysis and to rule out other pathogens using standard techniques.

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            Table 2. Methods Used To Diagnose Gastrointestinal Cytomegalovirus Disease

            Serologic Analysis

            Because of the high prevalence of IgG anti-CMV antibodies in most adults, this assay is not helpful as a diagnostic tool to detect CMV disease [27, 141, 142]. The presence of IgM anti-CMV antibody suggests recent infection but does not establish the diagnosis of tissue-invasive disease [4, 27, 142-145]. Although sensitivity varies according to the assay method used, a negative assay for IgM anti-CMV antibody may occur in more than 10% of patients with active CMV infection [143, 145, 146].

            Blood, Urine, Stool, and Oropharyngeal Culture

            Cytomegalovirus viremia is frequently associated with CMV disease and has been correlated with increased morbidity and mortality in some patients [89, 141, 147]. Positive blood and oropharyngeal (throat) cultures from organ transplant patients identify those who are at high risk for developing gastrointestinal CMV disease [147, 148]. However, a positive test result from blood, throat, or urine culture does not prove that gastrointestinal signs or symptoms are due to CMV disease nor does a negative culture from these sites rule out gastrointestinal CMV disease [27, 43, 141, 142]. Urine culture test results may be intermittently positive in healthy adults and bear little relation to disease [27]. Cytomegalovirus can be isolated from stool specimens in only one third of patients with documented CMV colitis [27] and from oropharyngeal secretions in about 30% of patients with proved esophageal CMV disease. Stool and oropharyngeal cultures may also be positive for CMV in the absence of gastrointestinal disease, limiting the utility of viral culture of body fluids as a diagnostic test [89, 94]. Multiple positive cultures from distant sites suggest the diagnosis of gastrointestinal CMV disease when gastrointestinal biopsy specimens are not available or are negative; however, culturing distant sites is not usually an efficient diagnostic approach. Detection of CMV antigen or DNA in blood as a substitute for culture has been studied [149-152]. Quantitative polymerase chain reaction (PCR) assays on blood may be more useful than culture in predicting active organ CMV disease [148].

            Radiology

            Barium radiographs from patients with proved CMV disease have been published [56, 66, 70, 108, 153-155]. In the esophagus, the most common finding is the distal, solitary ulcer [56, 63]. In the stomach, thick gastric folds, antral narrowing, or ulcers of various size and number, or all three, have all been described [56, 58, 66, 70, 107, 108, 126, 130-133, 154]. Computerized tomography scans in patients with gastric CMV infection have shown a thickened antral wall [67, 70] and a submucosal antral mass [69]. Ileal narrowing resembling Crohn disease has been observed [49, 103]. In the colon, the radiographic findings can be focal or diffuse, and the mucosal changes may be superficial or may be deep ulcerations [75, 82, 103]. Despite their striking appearance, these radiographic findings described above are nonspecific and are less sensitive than endoscopic examination with biopsy in diagnosing CMV gastrointestinal disease [83].

            Endoscopic Examination

            The definitive diagnosis of CMV gastrointestinal disease depends on invasive procedures and biopsies. Upper [55, 59-64, 87, 93, 94] and lower [32, 35, 64, 75-78, 82-84, 102] gastrointestinal endoscopic examinations have frequently been used to evaluate gastrointestinal symptoms and signs in patients at risk for CMV infection. The mucosa may appear grossly normal despite the presence of cytomegalic cells seen in biopsy specimens [82, 91, 156]. However, CMV disease usually appears as a mucosal erosion or ulceration (see Figure 2). Because no endoscopic feature is pathognomonic for CMV disease, the diagnosis depends on the changes detected in endoscopic biopsy specimens [see below]. Endoscopic examination is generally well tolerated, but perforation of a CMV esophageal ulcer after upper gastrointestinal endoscopic examination has been reported [62]. Full colonoscopic examination may identify more patients with CMV colitis than does flexible sigmoidoscopic examination [82, 83].

            Histopathologic Analysis

            Cytomegalovirus infection produces a characteristic cytopathic effect: a large 25- to 35-µmcell containing a basophilic intranuclear inclusion, which is sometimes surrounded by a clear halo (owl's eye effect) and is frequently associated with clusters of intracytoplasmic inclusions (see Figure 1). The presence of cytomegalic cells on mucosal biopsy specimens stained with hematoxylin and eosin has been considered the gold standard for establishing a diagnosis of CMV gastrointestinal disease [14, 27, 40, 55, 57, 84, 94, 157]. Many studies have confirmed the specificity of cytomegalic cells for diagnosing CMV because they are always associated with CMV antigen [13, 29, 55, 94] or CMV DNA [13, 27, 28, 33, 158], or both, as shown by special staining techniques. However, in some proved cases of gastrointestinal CMV disease, cytomegalic cells may be rare and difficult to detect [33, 41, 63, 94, 113, 159, 160], requiring great time and effort by the pathologist [27, 28, 30, 59]. Success in finding these cells is a function of the number of biopsy specimens examined and the diligence of the pathologist [160]. This lack of sensitivity is a disadvantage of routine histopathologic examination. Several techniques have been proposed to enhance diagnostic sensitivity in mucosal biopsy specimens; however, none is more specific than the presence of cytomegalic cells.

            Culture of Mucosal Biopsy Specimens

            The sensitivity and specificity of endoscopic biopsy specimen culture compared with histopathologic examination is controversial. Some studies have shown good agreement between histologic and culture results [32, 80]. Culture may be positive in the absence of symptoms or endoscopic lesions [87, 90, 91, 142]. However, it was reported positive in only 50% of colonic and esophageal specimens containing cytomegalic cells [55, 84]. Some studies have found that culture of endoscopic specimens enhances diagnostic sensitivity [60, 94, 159]. But culture positivity rates in non-CMV lesions may be as high as 17% [84] in AIDS patients. Our own studies found positive CMV cultures in about 15% of biopsy specimens from both endoscopically normal and abnormal mucosa [160]. Our conclusion is that culture of endoscopic biopsy specimens adds expense that may not be justified by an improvement in diagnostic yield when compared with routine histopathologic analysis coupled with a vigorous search for cytomegalic cells.

            Immunochemical Staining of Histologic Specimens

            To enhance the sensitivity of histopathologic analysis, two techniques have been developed: immunoperoxidase or immunofluorescence staining for CMV antigens using monoclonal antibodies [27, 28, 30, 59, 137, 157-159] and in situ DNA hybridization using a biotin-labeled probe (see Figure 3) [28, 33, 80, 84, 137, 158, 161-164]. Although antigen stains are being used more frequently, neither technique is widely available. Whereas antigen staining indicates viral replication, DNA staining occurs with latent viral infection. Most published studies have not shown these assays to be more sensitive than routine histologic analysis, but the data are conflicting. Two studies [30, 59] reported that the immunoperoxidase stain was positive when routine histologic analysis failed to show cytomegalic cells. Similar increased sensitivity was reported for in situ DNA hybridization [80]. In a study of 80 symptomatic AIDS patients who had gastrointestinal mucosal biopsies taken from various locations in the gastrointestinal tract, 13 of 80 biopsies (16.3%) were positive for CMV using in situ DNA hybridization [158]. Tested in these same 13 biopsy specimens, the immunoperoxidase stain (7 of 13 positive) and histopathologic stains (5 of 13 positive) were less sensitive. However, in none of these studies did the investigators describe how many biopsies were examined before they concluded that cytomegalic cells were absent using routine histopathologic analysis. Further study of these new techniques is needed before recommending them over a careful, intensive search for cytomegalic cells using routine histologic techniques.

            Polymerase Chain Reaction

            Polymerase chain reaction (PCR) has been used to identify CMV DNA in urine [165], blood [166, 167], and tissue [23, 168-171]. Initial studies have reported increased sensitivity and equal specificity compared with culture, or histologic analysis [170-172], or both. Its utility in gastrointestinal mucosal biopsy has only recently been reported [160]. In this small pilot study in AIDS patients, PCR had greater sensitivity for detecting gastrointestinal CMV disease than culture and immunoperoxidase stain. However, the positivity rate was 20% in normal mucosa. Specificity for disease may be improved by quantitative PCR techniques [173, 174]. However, PCR is a technique with many technical pitfalls and is not standardized for CMV diagnosis.

            Treatment

            Because gastrointestinal CMV disease in immunologically normal hosts is frequently self-limited, only supportive therapy is needed [111, 113, 126-129, 131]. Similarly, patients receiving corticosteroids or cancer chemotherapy and those transplant recipients who receive immunosuppressive therapy may have spontaneous cures of their CMV disease when therapy is reduced or stopped [91, 110]. However, with rare exceptions [78], the evidence strongly suggests that in the absence of therapy, gastrointestinal CMV disease in a host with sustained immunodeficiency is progressive and associated with a high mortality rate [14, 15, 56-58, 97, 140]. However, antiviral therapies have recently become available to treat these patients.

            Ganciclovir

            Ganciclovir (Cytovene, Syntex Laboratories, Palo Alto, California), a nucleoside analog structurally similar to acyclovir, is an inhibitor of viral DNA polymerase. In a randomized, placebo-controlled trial, prophylactic ganciclovir prevented gastrointestinal CMV disease in patients who had positive body fluid cultures after bone marrow transplantation [147]. Ganciclovir treatment was associated with negative cultures within 2 weeks of beginning therapy. Evidence from uncontrolled clinical studies of patients with histologically confirmed gastrointestinal CMV disease supports the use of ganciclovir therapy [57, 95, 175-177]. Ganciclovir in post-transplant patients with gastrointestinal CMV disease causes resolution of symptoms and promotes healing of lesions [9, 88, 95]. In AIDS patients, ganciclovir therapy for CMV esophageal ulcers results in improved symptoms in about 75% of patients [55, 57, 175-177]. Therapy for CMV colitis is associated with weight gain and improved quality of life [57, 79, 81, 82]. A randomized, placebo-controlled trial of ganciclovir in the treatment of CMV gastrointestinal disease showed virologic but not a clinically significant benefit [178]. However, only 20 of 37 patients had histologic evidence of CMV disease before treatment. Lack of clinical benefit from ganciclovir may have been due to including patients without histologic evidence of CMV disease.

            Guidelines for the use of ganciclovir to treat CMV disease, including a schedule for dose reduction in patients with renal impairment, are given in recent reviews [88, 179]. Ganciclovir must be given intravenously and is infused over 1 hour. The usual induction dose is 10 to 15 mg/kg per day administered in 2 to 3 divided doses daily for 3 weeks. In patients with severe and persistent immune deficiency, because infection is suppressed but not eliminated, the relapse rate is high [82]. The decision to repeat endoscopic examination to assess response to therapy and to detect relapse must be individualized [55]. Relapse is treated with repeated induction therapy if the patient responded initially, followed by maintenance therapy of 5 mg/kg daily. Because of the high relapse rate, some physicians advise maintenance therapy for all patients after induction therapy to prevent or delay relapse. Even with maintenance therapy, gastrointestinal CMV disease can relapse or progress because of ganciclovir-resistant CMV [180, 181]. The most frequent toxicities reported with ganciclovir are neutropenia, thrombocytopenia, rash, hypotension, nausea, vomiting, and headache, which require discontinuation of the drug or switching to alternative therapy in more than 10% of patients [182].

            Foscarnet

            Foscarnet (Foscavir; Astra Pharmaceutical Products, Westboro, Massachusetts) is an inhibitor of viral DNA polymerases that is active against all the herpes viruses (including CMV) and HIV. The clinical pharmacologic characteristics of foscarnet have recently been reviewed [183]. Unlike acyclovir and ganciclovir, the drug does not require phosphorylation to be activated; therefore, it is usually effective when ganciclovir resistance occurs [184]. Experience is limited using foscarnet for the treatment of gastrointestinal CMV disease [64, 185-187]. In a recent report [185], 18 patients with CMV esophageal ulceration and 27 patients with CMV colitis were treated with foscarnet (200 mg/kg per day) by continuous intravenous infusion for 3 weeks. Symptom resolution and endoscopic healing occurred within 2 weeks in 15 of 18 patients with esophageal disease and in 15 of 27 patients with colitis. Except for one patient with refractory CMV colitis, all therapeutic failures were related to concomitant disease or poor compliance. In another uncontrolled study [187] of AIDS patients with gastrointestinal CMV disease, 3 weeks of foscarnet therapy led to resolution of symptoms and endoscopic findings in 17 of 22 esophagitis patients (77%) and in 16 of 28 colitis patients (57%). Relapse occurred in about one fourth of patients by 7 months.

            Most evidence concerning toxicity with foscarnet has been obtained in patients treated for CMV retinitis [182, 188-190], but the results are probably generalizable to patients with gastrointestinal CMV disease. Side effects of foscarnet, including hypomagnesemia, hypocalcemia, hypophosphatemia, anemia, and renal insufficiency, occur in more than 20% of patients. Substantial gastrointestinal side effects include nausea, vomiting, diarrhea, and abdominal pain. In clinical practice, ganciclovir is usually the drug of first choice because the risk for renal dysfunction and electrolyte disturbances is much less.

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            Conclusions

            Gastrointestinal CMV disease is an increasingly recognized clinical problem that occurs in various settings characterized by impaired host immunity. It should be suspected when patients with abnormal immune function develop symptoms and signs of gastrointestinal mucosal ulceration, which is the major macroscopic feature of CMV gastrointestinal disease. A diagnosis of CMV in immunodeficient patients can be confirmed by identifying cytomegalic cells in mucosal biopsy specimens of gastrointestinal lesions. The pathologist can also identify CMV using special stains for viral markers. Although many questions about dose, duration, maintenance, complications of therapy, and the indications for maintenance therapy are unanswered, treatment with ganciclovir or foscarnet can heal gastrointestinal CMV lesions. Future research should be directed toward developing effective CMV prophylactic treatment in immunosuppressed patients at high risk for CMV disease. In addition, more sensitive diagnostic techniques and more effective and less toxic therapies are urgently needed.

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            Abbreviation

            CMV: cytomegalovirus

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