Infections in Oncology: Fulminant Hepatic Failure Due to Disseminated Adenovirus Infection in a Patient With Chronic Lymphocytic Leukemia

Eric B. Haura, MD, Mark A.Winden, PA, Alan D. Proia, MD, PhD, and James F. Trotter, MD

Disclosures

Cancer Control. 2002;9(3) 

In This Article

Discussion

Adenovirus is a ubiquitous double-stranded DNA virus commonly associated with upper respiratory illness.[2] Of the 47 known serotypes, 1, 2, 3, 5, and 7 are most commonly associated with human disease.[3] Transmission typically occurs through aerosolized droplets, fecal-oral exposure, or swimming pool water.[3] The incubation period ranges from a few days to 2 weeks.

The most common adenoviral illness is the familiar upper respiratory infection in the immunocompetent patient. This syndrome is transient and almost never causes medically significant problems. Outbreaks of respiratory disease are more common in the winter, although adenoviruses are endemic during the entire year. Epidemic keratoconjuctivitis is another less common presentation of adenovirus infection. It is more common in the summer months and is associated with transmission through swimming pool water. Following acute infection, the virus may be shed up to 12 weeks and may remain in lymphoid tissue for years where it can become reactivated following immunosuppression.

Detection of adenoviral infections in patients can occur through multiple methods including shell vial assay, conventional culture techniques using tissue monolayers, direct fluorescent antigen (DFA) using antibodies, enzyme immunoassay, polymerase chain reaction (PCR), immunohistochemistry (such as used in this case), and serology, whose use is mainly for epidemiological purposes. One study compared conventional and rapid culture, two antigen detection tests, and PCR for detection of adenovirus in nasopharyngeal aspirates and found PCR using Ad7 hexon-specific primers had a superior sensitivity and revealed positive cases that could not be confirmed by culture.[4]

In the immunocompromised patient, adenovirus may cause disseminated disease and death. Compared with self-limited infections, a wider spectrum of organ involvement is seen in disseminated disease. Cystitis, nephritis, pneumonitis, hepatitis, and gastroenteritis have all been reported in disseminated adenovirus infection in the immunocompromised patient.[1] Adenovirus has been isolated in 3.8% to 18% of bone marrow transplant recipients,[5,6,7] in 8% to 18% of liver transplant recipients,[8,9,10] and in 12% of kidney transplant recipients.[11] The most common sites of infection in these patients are urine, throat, and rectum. While the case fatality rate of disseminated adenovirus infection has been reported to be as high as 60%, not all immunocompromised patients with adenovirus infection develop disseminated disease.[2]

The source of adenovirus infection in the immunocompromised host is uncertain, but there are three possibilities.[2] The most likely cause is reactivation of latent adenovirus infection. The virus remains latent in lymphoid and renal tissue after clearance of acute infection.[3] Shields et al[5] showed that 69% of bone marrow transplant recipients were seropositive for previous adenovirus infection prior to transplantation. This suggests that most patients were infected with adenovirus prior to transplantation and reactivated virus after administration of immunosuppressive drugs. A second possibility is the exogenous transmission of adenovirus to the immunocompromised host. This may occur through nosocomial transmission[12] or during a community outbreak.[13] Third, there is evidence that adenovirus may be transmitted via transplanted organs. Koneru et al[14] reported that 67% of liver transplant recipients who developed adenovirus hepatitis after transplant were seronegative for adenovirus before transplantation and received donor organs from seropositive donors. Varki et al[15] reported a patient who developed adenovirus infection within 1 week of receiving a liver from a donor with adenovirus infection.

At least 24 cases of fulminant hepatic failure due to adenoviral hepatitis have been reported ( Table ). There are additional reports of patients with disseminated adenovirus infection who died of multiorgan system failure; although these patients had some degree of hepatitis, the contribution of liver disease to the overall clinical outcome was not clear.[8,10] All of the cases of fulminant hepatic failure caused by adenovirus have occurred in patients with a well-defined primary or secondary immunosuppressive condition. Of the 24 patients listed in the Table, 9 had a primary immunodeficiency, while 15 had a secondary immunodeficiency due to chemotherapy or immunosuppressive drugs.

The most common presentation was severe pneumonitis with associated severe hepatic necrosis. The serotype of adenovirus was reported in 20 patients. The most common were type 5 (9 patients), type 2 (5 patients), and type 1 (2 patients). Types 3, 6, 7, 12, 31, and 32 were reported in one patient each. Two patients had two serotypes reported. To our knowledge, this is the first documented example of a patient with serotype 4 adenovirus having fulminant hepatitis. The frequency of isolation of serotype 5 suggests this serotype may have a greater propensity to cause hepatitis. Animal experiments showing that human adenovirus type 5 causes hepatitis in hamsters[34] and mice[35] support this hypothesis.

While our patient did not have a defined primary immunodeficiency syndrome, immune dysfunction caused by his underlying CLL may have predisposed him to infections. Between one third and one half of patients with CLL will develop an infection at some point in their disease. The most common type of infection is bacterial; fungal and viral infections are far less common. Shaw et al[36] characterized 50 infections in a cohort of 25 CLL patients. Bacterial infections accounted for 46 (92%) of infections, viral accounted for 3 (6%), and one episode (2%) was caused by fungus. Twomey[37] reported similar results in 45 CLL patients who developed 71 infections of which 54 had identified pathogens. Of these cases, 89% were bacterial, 6% were viral, 3% were fungal, and 2% were tuberculosis. Ultmann et al[38] reported their experience with 60 patients with CLL of whom 23 developed infections. A total of 2,152 infection days were recorded in these patients, with 2,078 (97%) due to bacterial infection and 74 (3%) due to virus or tuberculosis. One limitation to these data is that viral cultures can be difficult to perform and therefore the true incidence of viral infections may be higher than reported.

The cause of the increased number of infections in CLL patients is thought to be due primarily to hypogammaglobulinemia. In fact, our patient had profound hypogammaglobulinemia. Shaw et al[36] reported that the number of infections in patients with CLL and hypogammaglobulinemia was 2.7 times higher than in patients with normal globulin levels. Ultmann and colleagues[38] reported an 89% incidence of infections in their patients with hypogammaglobulinemia compared to 15% in those with normal globulin levels. Furthermore, the severity of hypogammaglobulinemia worsens as the stage of CLL progresses.[39]

In addition to defects in humoral immunity, CLL patients also have defects in cellular immunity.[40] Although the absolute number of T cells is usually normal in these patients, the CD4/CD8 ratio is decreased,[41] and decreased natural killer cell activity has been reported.[41] Shaw et al[36] showed that 83% of CLL patients exhibited decreased response to skin antigens. Chapel and Bunch[42] found 48% of their CLL patients to be anergic. While such defects in cellular immunity in CLL patients have been documented experimentally, no clear relationship between these defects and the occurrence of infections has been established.

Our patient had profound immune dysfunction as evidenced by his fulminant adenoviral hepatitis, adenoviral/cytomegaloviral pneumonititis, and S. stercoralis and candidal infections. However, the severity of immunodeficiency was far out of proportion to the extent of his underlying CLL. He had only recently been diagnosed with Rai stage 0 CLL (manifest only by an elevated absolute lymphocyte count) and had not received any cytotoxic or corticosteroid therapy. His hypogammaglobulinemia was profound and was likely an important factor in his susceptibility to viral infections, and we suspect he had severe T-cell dysfunction as well.

While no proven efficacious therapy for adenovirus infection exists, there are several case reports of successful treatment of disseminated adenovirus infection. In one case, a patient with deficient cellular immunity and disseminated adenoviral infection recovered after the administration of thymic hormone.[43] In another case, a patient with severe pneumonitis caused by adenovirus recovered after infusion of immune globulin with high titers of antibody directed towards adenovirus.[44] Newer agents such as ribavirin,[45,46,47] ganciclovir[48,49] and vidarabine[16] have also demonstrated efficacy in the treatment of adenovirus infections.

The patient described here is an unusual case in that a fatal adenovirus infection developed in the absence of immunosuppressant or a primary immunodeficiency syndrome. The diagnosis was unexpected and was not made until an autopsy was performed. Although fatal viral infections are rare in patients with CLL, physicians should be aware of the possibility of disseminated adenovirus infection in this population.

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