998 TRANSPLANTATION Vol. 71, No. 7 FATAL DISSEMINATED ADENOVIRAL INFECTION IN A RENAL TRANSPLANT PATIENT HOSSEIN ARDEHALI,1 KEITH VOLMAR,2 CAROLINE ROBERTS,2 MICHAEL FORMAN,2 AND LEWIS C. BECKER1,3 Department of Medicine, Division of Cardiology, and Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287 Immunosuppressed patients are more susceptible to adenoviral infection and carry a significantly higher mortality than immunocompetent patients. Renal transplant patients with adenoviral infection most often present with infection of the kidney and urinary tract within weeks to months of transplant surgery, suggesting reactivation of the latent adenovirus in the immunosuppressed host as the source of infection. We describe the first case of a fatal adenovirus infection after several years of immunosuppression in a kidney transplant patient. Postmortem examination of several tissues, using standard viral culture and polymerase chain reaction, was positive for adenovirus serotype 21. This case is unusual in that the fatal disseminated viral infection occurred after 6 years of immunosuppression, suggesting that the source of adenovirus was a novel infection rather than reactivation of latent infection, or infection from the transplanted tissue. Furthermore, this is the first report of adenovirus type 21 in an immunosuppressed patient. The adenoviruses are a group of DNA viruses that infect the epithelial cells of respiratory, gastrointestinal, and genitourinary tracts. In the immunocompetent population, adenoviral infections are self-limiting within 2 weeks and induce type-specific immunity. Endemic adenoviral infections have been reported in pediatric populations and in nonvaccinated military recruits. Immunosuppressed patients are more susceptible to adenoviral infection and carry a significantly higher mortality than immunocompetent patients (1). Adenovirus infections in immunosuppressed renal transplant patients are often seen as acute hemorrhagic cystitis or pneumonia (2, 3). These patients often present shortly after transplant surgery, suggesting reactivation of the latent adenovirus in the immunosuppressed host. This has been supported by the presence of type-specific antibody before transplantation in either the organ recipient or donor (4). The source of the latent virus in renal transplant patients is often the donor organ and, to a lesser extent, the immunosuppressed organ recipient (1). In this report, we discuss a case of fatal disseminated adenoviral infection in a renal transplant patient six years after transplant surgery, suggesting a novel infection as the source of the virus. A 45-year-old man was transferred from an outside hospital to the coronary care unit (CCU) with a 2-day history of chest pain, high troponin I levels, and electrocardiogram changes consistent with ischemic heart disease. The patient had been diagnosed with end-stage renal disease secondary 1 Department of Medicine. Department of Pathology. 3 Address correspondence to: Lewis C. Becker, M.D., Department of Medicine, Division of Cardiology, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287. 2 to focal segmental glomerulosclerosis in 1988, and underwent a cadaveric renal transplant in 1993. He had been maintained on immunosuppressive medications (prednisone, cyclosporine, and mycophenolate mofetil) since his transplant surgery. The patient underwent a coronary artery catheterization, which showed diffuse lesions in three coronary vessels. A surgical revascularization procedure was then considered. The patient became febrile to 39.2°C on the second day of admission, and was noted to have crackles in the bases of his lungs. A chest radiograph showed right lower lobe infiltrates. He was started on levofloxacin for presumed communityacquired pneumonia. Sputum, blood, and cerebrospinal fluid were cultured and stained for bacteria, fungi, and mycobacteria. These studies were all negative except for moderate yeast in sputum. Blood cytomegalovirus antigen and culture were also negative. A bronchoscopy with bronchoalveolar lavage was performed, and cultures and microbiological analyses were negative. The patient’s respiratory function continued to deteriorate, requiring mechanical intubation. Furthermore, additional antibiotics were added, and his immunosuppressive medications were discontinued. It was then decided to perform an open lung biopsy, which showed acute and organizing diffuse alveolar damage, as well as viral cytopathology. Immunohistochemical staining demonstrated adenovirus in pneumocytes (Fig. 1). The patient became hypotensive, and despite aggressive medical therapy, he suffered cardiac arrest and died 12 days after admission. On postmortem examination, the lungs were severely congested, and very heavy. Cut section revealed bronchopneumonia, and histological examination confirmed the open lung biopsy findings of diffuse alveolar damage and adenoviral infection. The transplanted kidney was pale and soft and on histological examination, it showed acute tubular injury, borderline acute rejection, and chronic rejection changes. Adenovirus was isolated from postmortem lung, kidney, and gastrointestinal tract using standard viral culture. Additionally, DNA from fresh frozen postmortem tissue was extracted using the QIAamp DNA Mini Kit (Qiagen, Valencia, CA). Extracts were analyzed for adenovirus by polymerase chain reaction that amplifies a 139 basepair region of the highly conserved hexon gene (5, 6). Specificity of product was confirmed by Southern-blot hybridization using a [32P]-labeled adenovirus specific probe. Samples of lung, heart, liver, kidney, and gastrointestinal tract were positive for adenovirus (data not shown). The State of Maryland Department of Health and Mental Hygiene virology laboratories determined that the adenovirus isolates were serotype 21. Adenoviruses are capable of causing debilitating and often fatal illnesses in immunosuppressed patients (1). In renal transplant patients, adenovirus infection is often localized to the kidneys resulting in hemorrhagic cystitis, or, to a lesser BRIEF COMMUNICATIONS April 15, 2001 999 FIGURE 1. Open lung biopsy. A, Hematoxylin and eosin stained section showing diffuse alveolar damage with viral cytopathological changes. B, Immunohistochemical stain for adenovirus showing strong positivity in pneumocytes. extent, to the lungs causing pneumonia (2, 3). This infection causes less severe clinical findings in renal transplant population compared with other immunosuppressed patients. However, a case of disseminated adenoviral infections that occurred within 2 months of renal transplant has been reported (7). It was postulated that the virus originated from a latent infection of the donor kidneys. The source of most adenoviral infections in immunosuppressed patients is believed to be latent infections. In fact, Shields et al. (8) were unable to determine an exogenous source for 51 bone marrow transplant patients who were infected with adenovirus. Our patient is unusual in that the fatal disseminated viral infection occurred after six years of immunosuppression. Particularly unusual is the observation that the patient’s illness started with a pulmonary infection. These findings suggest that the source of the adenovirus in the patient described was a novel infection rather than reactivation of latent infection, or infection from the transplanted tissue. This report also describes the first case of adenovirus type 21 in an immunosuppressed patient. Because adenoviral infections of transplant patients may result in serious complications and it may occur years after transplant surgery, adenovirus should be included in laboratory screening tests for kidney transplant patients with evidence of an infection. REFERENCES 1. Hierholzer JC. Adenovirus in the immunocompromised host. Clin Microbiol Rev 1992; 5: 262. 2. Yagisawa T, Nakada T, Takahashi K, Toma H, Ota K, Yaguchi H. Acute hemorrhagic cystitis caused by adenovirus after kidney transplantation. Urol Int 1995; 54: 142. 3. Umekawa T, Kurita T. Acute hemorrhagic cystitis by adenovirus type 11 with and without type 37 after kidney transplantation. Urol Int 1996; 56: 114. 4. Harnett GB, Bucens MR, Caly SJ, Saker BM. Acute hemorrhagic cystitis caused by adenovirus type 11 in a recipient of a transplanted kidney. Med J Aust 1982; 1: 565. 5. Yeo AC, Cooper RJ, Morris DJ, Storey CC. Development of a multiplex polymerase chain reaction for detection of adenovirus, herpes simplex and Chlamydia trachomatis DNA using eye swabs (Abstr. C-416) In: Abstracts of the97th General Meeting of the American Society for Microbiology. Washington, DC: American Society for Microbiology, 1997; 192. 6. Echavarria M, Forman M, Ticehurst J, Dumler JS, Charache P. PCR Method for detection of adenovirus in urine of healthy and human immunodeficiency virus-infected individuals. J Clin Microbiol 1998; 36 (11): 3323. 7. Myerowitz RL, Stalder H, Oxman MN, et al. Fatal disseminated adenovirus infection in a renal transplant recipient. Am J Med 1975; 59: 591. 8. Shield AF, Hackman RC, Fife KH, Corey L, Meyers JD. Adenovirus infections in patients undergoing bone marrow transplantation. N Engl J Med 1985; 312: 529. Received 7 June 2000. Provisionally accepted 20 July 2000. Accepted 12 September 2000.