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Hemorrhagic Cystitis Associated with Herpes Simplex Virus
0022-534 7/94/1511-0152$03.00 /0 THE JOURNAL OF UROLOGY Copyright© 1994 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 151, 152-153, January 1994
Printed in U.S.A.
HEMORRHAGIC CYSTITIS ASSOCIATED WITH HERPES SIMPLEX VIRUS CAROLYN McCLANAHAN, MARGARET M. GRIMES,* EDWARD CALLAGHAN AND JOHN STEWART From the Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia
ABSTRACT
A 45-year-old man presented with hemorrhagic cystitis and was found to have herpes simplex infection of the bladder by biopsy, immunohistochemistry and in situ hybridization. The patient had no clinical evidence of immunosuppression or disseminated infection. Although viral etiologies of hemorrhagic cystitis are recognized, to our knowledge only 4 cases of hemorrhagic cystitis due to herpes simplex virus have been reported. KEY WORDS:
cystitis, herpes simplex, immunohistochemistry
Although few cases of herpetic cystitis have been reported, clinical and cytological evidence suggests that ascending infection of the bladder may occur in a proportion of cases of herpes genitalis. 1• 2 Hemorrhagic cystitis associated with herpes simplex virus has been reported rarely. 3- 5 We report on a 45-yearold, presumably immunocompetent man who presented with hemorrhagic cystitis associated with herpes simplex virus that was confirmed by histology, immunohistochemistry and in situ hybridization.
RESULTS
CASE REPORT
A 45-year-old black man presented to the emergency room with a 1-day history of gross hematuria. Medical history was significant for congenital absence of the left kidney and coarctation of the aorta, which was repaired at age 26 years. Physical examination was unremarkable. Laboratory studies revealed serum urea nitrogen 14.6 mmol./1. (normal 2.1 to 7.9), creatinine 212 µmol./1. (normal 62 to 124) and numerous red blood cells in the urine. The patient was hospitalized for evaluation of hematuria and possible renal failure. Intravenous hydration and antibiotics were administered with subsequent normalization of the serum urea nitrogen and creatinine. Cultures of catheterized urine specimens yielded no organisms. Since the hematuria did not resolve, the patient was transferred to the operating room for retrograde pyelography, cystoscopy and biopsy. Cystoscopy demonstrated diffuse hemorrhagic cystitis. Several areas of white plaque resembling tuberculous cystitis were noted. Biopsies and fulguration of the bleeding sites were performed. Cultures were taken for bacteria, fungi and mycobacteria. Postoperatively the patient was treated with continuous bladder irrigation. Hematuria resolved within 2 days. He was discharged home and scheduled for 1-week followup but he failed to return. None of the cultures yielded growth. Biopsies of the bladder were fixed in Hollande's fixative and processed routinely for paraffin embedding. Sections 4 µm. thick were stained with hematoxylin and eosin. Additional sections were stained for fungi and acid-fast bacilli using ZiehlNeelsen and Gomori's methenamine silver stains. Immunohistochemical studies with antibody to herpes simplex virus types 1 and 2 were performed on paraffin-embedded sections using the peroxidase-antiperoxidase technique. In situ hybridization using a commercially available deoxyribonucleic acid probe for herpes simplex virus was also performed on paraffin-embedded sections.
The bladder mucosa in the biopsy specimen was extensively ulcerated. Isolated cells within the fibrinopurulent exudate in the ulcer bed demonstrated cytological changes, including multinucleation and ground-glass nuclei consistent with herpesvirus infection (fig. 1). Occasional Cowdry type A inclusions were found in mononucleated cells. The underlying lamina propria was acutely and chronically inflamed. Residual intact transitional cells showed moderate reactive atypia. No organisms were identified with Gomori's methenamine silver or ZiehlNeelsen stain. Immunohistochemical stains for herpes simplex virus revealed numerous immunoreactive cells within the fibrinopurulent exudate and the bladder mucosa. The staining reaction was intense and the number of stained cells was much greater than the number of infected cells identified on hematoxylin and eosin stained sections (fig. 2). In situ hybridization using a deoxyribonucleic acid probe to herpes simplex virus was also positive. DISCUSSION
Primary episodes of herpes genitalis are often associated with dysuria, and herpes simplex virus can sometimes be cultured from the urethra and urine. 1• 2' G-s Herpes simplex virus has been identified in urine sediment by cytology or immunofluorescent techniques in a small number of patients with primary or recurrent herpes genitalis. 1• 2 The large number of infected cells reported suggests that they originate in the bladder and that in
Fm. 1. Bladder biopsy shows mucosa! erosion, inflammation and multinucleated cell with ground-glass intranuclear inclusions (arrow). H & E, reduced from X400.
Accepted for publication June 18, 1993. * Requests for reprints: Department of Pathology, MCV Station, Box 662, Richmond, Virginia 23298. 152
153
.HEMORRHAGIC HERPES CYSTITIS
FIG. 2. Immunohistochemical staining with antibody to herpes simplex virus reveals numerous positive cells in bladder biopsy. H & E, reduced from X400.
some cases the dysuria associated with genital herpes may be due to herpetic cystitis. Cystitis may result from ascending infection from the external genitalia. 7 Hematogenous dissemination may also occur. In 1931 Gremme described the cystoscopic appearance of herpetic cystitis in a patient with herpes labialis. 9 Viral infections are a relatively uncommon cause of hemorrhagic cystitis and are encountered most often in children or immunocomprornised adults. Viruses linked to hemorrhagic cystitis include adenovirus types 11 and 21, and influenza A. 10• 11 We found only 4 reported cases of hemorrhagic cystitis due to herpes simplex virus. The first case was documented in 1926 and involved a young woman with hemorrhagic cystitis and urinary retention associated with herpes genitalis. 3 No biopsy was performed. In 1988 DeHertogh and Brettman reported hemorrhagic herpetic cystitis in 2 immunocompromised patients with disseminated herpes virus infection. 4 Diagnosis was confirmed by biopsy and immunohistochemistry. The fourth case involved a 67-year-old woman with diabetes mellitus and rheumatoid arthritis treated with prednisone, who had no evidence of disseminated disease. 5 Herpes simplex virus type 2 was cultured from the urine and was demonstrated on biopsy with immunohistochemical confirmation. The reported cystoscopic appearance of white plaque in the bladder mucosa is similar to that in our case. The cytological changes observed on biopsy in our case are typical of herpes simplex virus but similar changes can result from the varicella-zoster virus.12 The antibody we used reacts with herpes simplex virus types l and 2 but it has been found to cross-react with the varicella-zoster virus and cytomegalovirus. The intensity of the staining reaction in our patient suggests that the infection was due to herpes simplex virus. This
diagnosis is further supported by the positive in situ hybridization reaction. Serological studies and viral cultures would have been helpful but they could not be performed in this case. Since our patient had no obvious genital lesions at presentation he may have had latent genital herpes simplex virus infection with ascending involvement of the bladder. Asymptomatic shedding of virus has been described in some patients with herpes simplex virus infection documented by cultures and/or serology. 8 Alternatively, the bladder may have become infected via hematogenous dissemination from another site. Nongenital visceral involvement by herpes simplex virus has been described in patients with a variety of underlying illnesses most often associated with immunosuppression. 13 Our patient had no clinical or historical evidence of being immunocompromised but since he was lost to followup the status of the immune system could not be investigated. The prompt clinical resolution of disease without specific antiviral therapy supports the assumption that he was immunocompetent. It also suggests that, although rare, hemorrhagic herpetic cystitis in an immunocompetent individual may, like clinical episodes of genital herpes simplex virus infection, be a self-limited process. REFERENCES
1. Person, D.A., Kaufman, R. H., Gardner, H. L. and Rawls, W. E.: Herpesvirus type 2 in genitourinary tract infections, Amer. J,
Obst. Gynecol., 116: 993, 1973, 2. Masukawa, T., Garancis, J.C., Rytel, M. W. and Mattingly, R. F.: Herpes genitalis virus isolation from human bladder urine, Acta Cytol., 16: 416, 1972. 3. Schiffmann, J.: Herpes of bladder. Ztschr. UroL Chir., 19: 342, 1926. 4. DeHertogh, D, A. and Brettman, L. R.: Hemorrhagic cystitis due to herpes simplex virus as a marker of disseminated herpes infection. Amer. J. Med., 84: 632, 1988. 5. Nguyen, M. L, T., Borochovitz, D., Thomas, G., McClure, T. and Ruben, F. L.: Hemorrhagic cystitis with herpes simplex virus type 2 in bladder mucosa, Clin. Infect. Dis., 14: 767, 1992. 6. Esteves, J. and Pinto, M. R.: Herpetic urethritis. Brit. J, Vener. Dis., 28: 205, 1952. 7. Corey, L. and Spear, P. G.: Infections with herpes simplex viruses (1), New Engl. J. Med,, 314: 686, 1986. 8, Koutsky, L.A., Stevens, C. E., Holmes, K. K., Ashley, R. L., Kiviat, N. B., Critchlow, C. W. and Corey, L.: Underdiagnosis of genital herpes by current clinical and viral-isolation procedures. New Engl. J, Med., 326: 1533, 1992. 9. Gremme, A.: Herpes simplex der Harnblase. Zentralbl. Gyniik., 55: 1558, 1931. 10. Mufson, M. A., Belshe, R. B., Horrigan, T. J, and Zollar, L. M.: Cause of acute hemorrhagic cystitis in children. Amer. J. Dis. Child., 126: 605, 1973, 11. de Vries, C.R. and Freiha, F. S.: Hemorrhagic cystitis: a review. J. Urol., 143: 1, 1990. 12, Strano, A. J.: Light microscopy of selected viral diseases (morphology of viral inclusion bodies), Path. Ann., 11: 53, 1976. 13, Buss, D, H. and Scharyj, M.: Herpesvirus infection of the esophagus and other visceral organs in adults. Incidence and clinical significance. Amer. J. Med., 66: 457, 1979,
Vol. 151, 152-153, January 1994
Printed in U.S.A.
HEMORRHAGIC CYSTITIS ASSOCIATED WITH HERPES SIMPLEX VIRUS CAROLYN McCLANAHAN, MARGARET M. GRIMES,* EDWARD CALLAGHAN AND JOHN STEWART From the Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia
ABSTRACT
A 45-year-old man presented with hemorrhagic cystitis and was found to have herpes simplex infection of the bladder by biopsy, immunohistochemistry and in situ hybridization. The patient had no clinical evidence of immunosuppression or disseminated infection. Although viral etiologies of hemorrhagic cystitis are recognized, to our knowledge only 4 cases of hemorrhagic cystitis due to herpes simplex virus have been reported. KEY WORDS:
cystitis, herpes simplex, immunohistochemistry
Although few cases of herpetic cystitis have been reported, clinical and cytological evidence suggests that ascending infection of the bladder may occur in a proportion of cases of herpes genitalis. 1• 2 Hemorrhagic cystitis associated with herpes simplex virus has been reported rarely. 3- 5 We report on a 45-yearold, presumably immunocompetent man who presented with hemorrhagic cystitis associated with herpes simplex virus that was confirmed by histology, immunohistochemistry and in situ hybridization.
RESULTS
CASE REPORT
A 45-year-old black man presented to the emergency room with a 1-day history of gross hematuria. Medical history was significant for congenital absence of the left kidney and coarctation of the aorta, which was repaired at age 26 years. Physical examination was unremarkable. Laboratory studies revealed serum urea nitrogen 14.6 mmol./1. (normal 2.1 to 7.9), creatinine 212 µmol./1. (normal 62 to 124) and numerous red blood cells in the urine. The patient was hospitalized for evaluation of hematuria and possible renal failure. Intravenous hydration and antibiotics were administered with subsequent normalization of the serum urea nitrogen and creatinine. Cultures of catheterized urine specimens yielded no organisms. Since the hematuria did not resolve, the patient was transferred to the operating room for retrograde pyelography, cystoscopy and biopsy. Cystoscopy demonstrated diffuse hemorrhagic cystitis. Several areas of white plaque resembling tuberculous cystitis were noted. Biopsies and fulguration of the bleeding sites were performed. Cultures were taken for bacteria, fungi and mycobacteria. Postoperatively the patient was treated with continuous bladder irrigation. Hematuria resolved within 2 days. He was discharged home and scheduled for 1-week followup but he failed to return. None of the cultures yielded growth. Biopsies of the bladder were fixed in Hollande's fixative and processed routinely for paraffin embedding. Sections 4 µm. thick were stained with hematoxylin and eosin. Additional sections were stained for fungi and acid-fast bacilli using ZiehlNeelsen and Gomori's methenamine silver stains. Immunohistochemical studies with antibody to herpes simplex virus types 1 and 2 were performed on paraffin-embedded sections using the peroxidase-antiperoxidase technique. In situ hybridization using a commercially available deoxyribonucleic acid probe for herpes simplex virus was also performed on paraffin-embedded sections.
The bladder mucosa in the biopsy specimen was extensively ulcerated. Isolated cells within the fibrinopurulent exudate in the ulcer bed demonstrated cytological changes, including multinucleation and ground-glass nuclei consistent with herpesvirus infection (fig. 1). Occasional Cowdry type A inclusions were found in mononucleated cells. The underlying lamina propria was acutely and chronically inflamed. Residual intact transitional cells showed moderate reactive atypia. No organisms were identified with Gomori's methenamine silver or ZiehlNeelsen stain. Immunohistochemical stains for herpes simplex virus revealed numerous immunoreactive cells within the fibrinopurulent exudate and the bladder mucosa. The staining reaction was intense and the number of stained cells was much greater than the number of infected cells identified on hematoxylin and eosin stained sections (fig. 2). In situ hybridization using a deoxyribonucleic acid probe to herpes simplex virus was also positive. DISCUSSION
Primary episodes of herpes genitalis are often associated with dysuria, and herpes simplex virus can sometimes be cultured from the urethra and urine. 1• 2' G-s Herpes simplex virus has been identified in urine sediment by cytology or immunofluorescent techniques in a small number of patients with primary or recurrent herpes genitalis. 1• 2 The large number of infected cells reported suggests that they originate in the bladder and that in
Fm. 1. Bladder biopsy shows mucosa! erosion, inflammation and multinucleated cell with ground-glass intranuclear inclusions (arrow). H & E, reduced from X400.
Accepted for publication June 18, 1993. * Requests for reprints: Department of Pathology, MCV Station, Box 662, Richmond, Virginia 23298. 152
153
.HEMORRHAGIC HERPES CYSTITIS
FIG. 2. Immunohistochemical staining with antibody to herpes simplex virus reveals numerous positive cells in bladder biopsy. H & E, reduced from X400.
some cases the dysuria associated with genital herpes may be due to herpetic cystitis. Cystitis may result from ascending infection from the external genitalia. 7 Hematogenous dissemination may also occur. In 1931 Gremme described the cystoscopic appearance of herpetic cystitis in a patient with herpes labialis. 9 Viral infections are a relatively uncommon cause of hemorrhagic cystitis and are encountered most often in children or immunocomprornised adults. Viruses linked to hemorrhagic cystitis include adenovirus types 11 and 21, and influenza A. 10• 11 We found only 4 reported cases of hemorrhagic cystitis due to herpes simplex virus. The first case was documented in 1926 and involved a young woman with hemorrhagic cystitis and urinary retention associated with herpes genitalis. 3 No biopsy was performed. In 1988 DeHertogh and Brettman reported hemorrhagic herpetic cystitis in 2 immunocompromised patients with disseminated herpes virus infection. 4 Diagnosis was confirmed by biopsy and immunohistochemistry. The fourth case involved a 67-year-old woman with diabetes mellitus and rheumatoid arthritis treated with prednisone, who had no evidence of disseminated disease. 5 Herpes simplex virus type 2 was cultured from the urine and was demonstrated on biopsy with immunohistochemical confirmation. The reported cystoscopic appearance of white plaque in the bladder mucosa is similar to that in our case. The cytological changes observed on biopsy in our case are typical of herpes simplex virus but similar changes can result from the varicella-zoster virus.12 The antibody we used reacts with herpes simplex virus types l and 2 but it has been found to cross-react with the varicella-zoster virus and cytomegalovirus. The intensity of the staining reaction in our patient suggests that the infection was due to herpes simplex virus. This
diagnosis is further supported by the positive in situ hybridization reaction. Serological studies and viral cultures would have been helpful but they could not be performed in this case. Since our patient had no obvious genital lesions at presentation he may have had latent genital herpes simplex virus infection with ascending involvement of the bladder. Asymptomatic shedding of virus has been described in some patients with herpes simplex virus infection documented by cultures and/or serology. 8 Alternatively, the bladder may have become infected via hematogenous dissemination from another site. Nongenital visceral involvement by herpes simplex virus has been described in patients with a variety of underlying illnesses most often associated with immunosuppression. 13 Our patient had no clinical or historical evidence of being immunocompromised but since he was lost to followup the status of the immune system could not be investigated. The prompt clinical resolution of disease without specific antiviral therapy supports the assumption that he was immunocompetent. It also suggests that, although rare, hemorrhagic herpetic cystitis in an immunocompetent individual may, like clinical episodes of genital herpes simplex virus infection, be a self-limited process. REFERENCES
1. Person, D.A., Kaufman, R. H., Gardner, H. L. and Rawls, W. E.: Herpesvirus type 2 in genitourinary tract infections, Amer. J,
Obst. Gynecol., 116: 993, 1973, 2. Masukawa, T., Garancis, J.C., Rytel, M. W. and Mattingly, R. F.: Herpes genitalis virus isolation from human bladder urine, Acta Cytol., 16: 416, 1972. 3. Schiffmann, J.: Herpes of bladder. Ztschr. UroL Chir., 19: 342, 1926. 4. DeHertogh, D, A. and Brettman, L. R.: Hemorrhagic cystitis due to herpes simplex virus as a marker of disseminated herpes infection. Amer. J. Med., 84: 632, 1988. 5. Nguyen, M. L, T., Borochovitz, D., Thomas, G., McClure, T. and Ruben, F. L.: Hemorrhagic cystitis with herpes simplex virus type 2 in bladder mucosa, Clin. Infect. Dis., 14: 767, 1992. 6. Esteves, J. and Pinto, M. R.: Herpetic urethritis. Brit. J, Vener. Dis., 28: 205, 1952. 7. Corey, L. and Spear, P. G.: Infections with herpes simplex viruses (1), New Engl. J. Med,, 314: 686, 1986. 8, Koutsky, L.A., Stevens, C. E., Holmes, K. K., Ashley, R. L., Kiviat, N. B., Critchlow, C. W. and Corey, L.: Underdiagnosis of genital herpes by current clinical and viral-isolation procedures. New Engl. J, Med., 326: 1533, 1992. 9. Gremme, A.: Herpes simplex der Harnblase. Zentralbl. Gyniik., 55: 1558, 1931. 10. Mufson, M. A., Belshe, R. B., Horrigan, T. J, and Zollar, L. M.: Cause of acute hemorrhagic cystitis in children. Amer. J. Dis. Child., 126: 605, 1973, 11. de Vries, C.R. and Freiha, F. S.: Hemorrhagic cystitis: a review. J. Urol., 143: 1, 1990. 12, Strano, A. J.: Light microscopy of selected viral diseases (morphology of viral inclusion bodies), Path. Ann., 11: 53, 1976. 13, Buss, D, H. and Scharyj, M.: Herpesvirus infection of the esophagus and other visceral organs in adults. Incidence and clinical significance. Amer. J. Med., 66: 457, 1979,