Gastrointestinal cytomegalovirus disease.

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. 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. 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. Three endoscopic photographs of gastrointestinal cytomegalovirus disease causing mucosal ulceration. Left. Right. Figure 3. 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. Routine histologic section from the patient described in Figure 3 Left. Right. 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). 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 opp