Adenovirus

Abstract

Adenovirus infection is second only to rotavirus as a cause of childhood diarrhea and is associated with a broad spectrum of clinical disease in both children and adults. However, it has gained attention in recent years as a cause of diarrhea in immunocompromised patients, especially those with AIDS and patients who have undergone bone marrow or solid organ transplants. The incidence of adenovirus infection in bone marrow transplant patients has been reported at 5–20%; the incidence is lower in solid organ transplant patients. Pediatric transplant patients are affected more often than adults. Patients with severe combined immunodeficiency are also susceptible to gastrointestinal adenovirus infection. Virtually all patients present with diarrhea, sometimes accompanied by fever, weight loss, and abdominal pain. Risk factors for disseminated adenovirus infection include presence of concomitant graft-versus-host disease, use of immunosuppressive therapy, isolation of virus from multiple sites, and HLA-mismatched or unrelated transplants.

Adenovirus infection is second only to rotavirus as a cause of childhood diarrhea and is associated with a broad spectrum of clinical disease in both children and adults. However, it has gained attention in recent years as a cause of diarrhea in immunocompromised patients, especially those with AIDS and patients who have undergone bone marrow or solid organ transplants. The incidence of adenovirus infection in bone marrow transplant patients has been reported at 5–20%; the incidence is lower in solid organ transplant patients. Pediatric transplant patients are affected more often than adults. Patients with severe combined immunodeficiency are also susceptible to gastrointestinal adenovirus infection. Virtually all patients present with diarrhea, sometimes accompanied by fever, weight loss, and abdominal pain. Risk factors for disseminated adenovirus infection include presence of concomitant graft-versus-host disease, use of immunosuppressive therapy, isolation of virus from multiple sites, and HLA-mismatched or unrelated transplants.

Adenovirus is also one of the more common viruses described in the appendix. It is associated with ileal and ileocecal intussusception, particularly in children. The virus is thought to cause intussusception by producing lymphoid hyperplasia, altering intestinal motility, or a combination of both. Most patients do not have symptoms of appendicitis, and adenovirus is found subsequent to resection for the intussusception.

Pathologic features. In the appendix, morphological changes are subtle, including lymphoid hyperplasia (Fig. 22.1) and overlying disorderly proliferation and degeneration of surface epithelium (Fig. 22.2). Histologic changes in adenovirus colitis include degenerative changes of the surface epithelium, such as epithelial cell disorder, loss of cell orientation (especially goblet cells), focal apoptosis, and sloughing of epithelial cells (Figs. 22.3 and 22.4). Adenovirus infection with similar histologic features has also been described in the stomach and small bowel, in which mild villous blunting may be seen as well.

Fig. 22.1

Appendix with adenovirus infection shows marked lymphoid hyperplasia and overlying surface erosion with acute inflammatory exudates

Fig. 22.2

The appendiceal epithelium shows nuclear disarray, loss of nuclear polarity, and focal apoptosis

Fig. 22.3

Adenovirus colitis showing surface nuclear disarray, loss of nuclear polarity, and characteristic inclusions within goblet cells and surface epithelial cells. (Courtesy Dr. Joel Greenson)

Fig. 22.4

Surface epithelial changes in adenovirus colitis include nuclear disarray and loss of polarity, goblet cell disorder, and a patchy mononuclear cell infiltrate. Note small crescent-shaped inclusion within goblet cell

Characteristic inclusions (Figs. 22.3 and 22.4) are most often seen in areas with epithelial degenerative changes; inclusions may be widely scattered, with many apparently uninfected cells in between. Inclusions are usually present within surface epithelial cells, particularly goblet cells, in which the inclusions may be crescent-shaped (Figs. 22.3 and 22.4). Inclusions are rarely seen within the crypts (Fig. 22.5). The more common inclusions known as “smudge cells” have enlarged, basophilic nuclei without a clear nuclear membrane (Figs. 22.6 and 22.7). Homogenous, eosinophilic inclusions surrounded by halos with distinct nuclear membranes are much less common (Fig. 22.8). Adenovirus inclusions are exclusively intranuclear and fill the entire nucleus; however, the cell itself is not enlarged. In the appendix, inclusions are reportedly found in only one-third of patients with intussusception in which adenovirus is detected by other methods, such as immunohistochemistry (Fig. 22.9), PCR, and in situ hybridization.

Fig. 22.5

Multiple characteristic adenovirus inclusions are seen within the colonic glandular epithelium in a case of adenovirus colitis in a patient with AIDS

Fig. 22.6

Sloughed surface epithelial cells containing characteristic basophilic inclusions (“smudge cells”) are seen within the inflammatory exudate in an appendix with adenovirus infection

Fig. 22.7

The more common adenovirus inclusions known as “smudge cells” have enlarged, basophilic nuclei without a clear nuclear membrane. Adenovirus inclusions are intranuclear, and fill the entire nucleus, although the cell itself is not enlarged

Fig. 22.8

Rare eosinophilic inclusions surrounded by halos with distinct nuclear membranes (Cowdry type A) are much less common

Fig. 22.9

Adenovirus immunostain shows strongly positive epithelial cells within the surface epithelium of the appendix

Differential diagnosis. The differential diagnosis of adenovirus infection is primarily with other viral infections, particularly CMV (see Table 20.1). Adenovirus inclusions are usually round to crescent shaped, generally located within surface epithelium, and exclusively intranuclear in location. CMV inclusions have an “owl’s eye” morphology in the nucleus, are generally located within endothelial or stromal cells, and exist within either the nucleus or cytoplasm.

Useful aids in the diagnosis of adenovirus infection include immunohistochemistry (Fig. 22.10), stool and/or tissue examination by electron microscopy, and viral culture. Positive serologies or fecal identification of the virus do not necessarily represent current infection, as viral shedding and elevated serological titers may persist for months.

Fig. 22.10

Adenovirus immunostain highlights positive cells within the surface epithelium in a case of adenovirus colitis. (Courtesy Dr. Joel Greenson)

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