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Add-On Testing for Urinary-Associated Viruses

Emery Haley, PhD, Scientific Writing Specialist

Add-On Testing for Urinary-Associated Viruses

Urinary Viruses Clinical Summary

  • Viral UTIs are most often diagnosed in immunocompromised individuals, especially solid organ and stem-cell transplant recipients, presenting with hemorrhagic cystitis.
  • Since viruses are not cellular organisms, they cannot grow in standard urine culture. Therefore, the gold-standard for diagnosing viral UTIs is advanced molecular techniques including polymerase chain reaction (PCR).
  • Viral bladder infections may increase patients’ susceptibility to bacterial UTIs.
  • Viral UTIs have been associated with nephropathy, transplant rejection, and bladder cancer.

Clinical Relevance of Viruses in UTI

The human urinary tract of healthy asymptomatic individuals is home not only to bacteria and yeasts, but also to viruses.[1]  However, under specific circumstances, some viruses can cause symptomatic cystitis infection of the urinary tract.[2–5]

Since viruses are not cellular organisms, they cannot grow in standard urine culture. Specialized viral cultures may be possible for certain viruses, but often require weeks, making them too slow for most clinical diagnostic applications.[3] Immunoglobulin (antibody) titers from patients’ serum are often used to tell if a patient has ever been exposed to a particular virus, and occasionally, to indicate active infections with the virus.[3] However, the gold-standard for diagnosing viral UTIs is advanced molecular techniques including polymerase chain reaction (PCR).[3,6]

Viral UTIs are most often diagnosed in immunocompromised individuals, especially solid organ and stem-cell transplant recipients, presenting with hemorrhagic cystitis.[3,7–12]  Therefore, testing for viral uropathogens is recommended for this population.

BK Virus

BK virus is a common polyomavirus, with a seropositivity of around 70-97% in healthy adults.[3,13,14] However, BK virus is also a known opportunistic uropathogen.[15–17]  In fact, it is the most commonly identified cause of hemorrhagic cystitis in transplant recipients.[3,18] BK virus reactivation and shedding into the urine is also associated with post-transplant nephropathy [19] or ureteric stenosis [20,21], and with increased risk of bladder cancer.[3,22,23] Urine cytology for “decoy cells” can be indicative of BK virus UTI, but molecular diagnostics are the gold-standard.[3,24]

Treatment

Treatment of BK viral UTI is primarily supportive care and reduction of immunosuppressive treatment, when possible.[2]  Cidofovir, an antiviral may be used either intravenously or as an intravesicular instillation, to treat BK viruria, especially in patients with hemorrhagic cystitis.[3,25,26]

Human Herpes Virus 5 (HHV-5) [also called Cytomegalovirus (CMV)]

CMV is a common virus with a seropositivity of around 60% in healthy adults.[3] However, reactivation of dormant CMV infection had been associated with ureteritis, ureteral stenosis, cystitis, and hematuria/hemorrhagic cystitis in both immunocompetent and immunocompromised individuals.[3,27–32] CMV infection is the most common viral infection in kidney transplant recipients.[33,34]  CMV UTI is usually diagnosed by PCR testing.[3,35]

Treatment

Intravenous Ganciclovir is a common prophylactic against CMV after solid organ transplants.[3] Treatment of HHV UTI is primarily supportive care and reduction of immunosuppressive treatment, when possible. Intravenous Foscarnet is also used against active CMV infection.[3,36] Cidofovir, which is active against both BK virus and CMV is the most common choice for transplant recipients with hemorrhagic cystitis.[3,37] Cidofovir may be given intravenously or as an intravesicular instillation.[3,25,26]

Human Herpes Virus 6 (HHV-6)

HHV-6 has been shown to act as an opportunistic uropathogen causing hemorrhagic cystitis in transplant recipients.[38,39] HHV-6 UTI is typically diagnosed by advanced molecular tests, such as PCR.[40]

Treatment

Treatment of HHV UTI is primarily supportive care and reduction of immunosuppressive treatment, when possible.[41] Antiviral agents including ganicyclovir, foscarnet, and cidofovir are used to treat active HHV-6 infection.[41]

Human Herpes Viruses 1 & 2 (HHV-1 & HHV-2) [also called Herpes Simplex Virus 1 & 2 (HSV-1 & HSV-2)]

HSV is a common cause of genital ulcers in immunocompetent individuals.[3] However, it is also known to cause cystitis in individuals with comorbidities such as diabetes mellitus.[3,32,42] It is also recognized as a cause of hemorrhagic cystitis in immunocompromised individuals.[3,43,44] HSV bladder infection has been shown to increase the susceptibility of human bladder cells to uropathogenic bacterial infections in vitro.[45]

Treatment

Treatment of HSV UTI is primarily supportive care and reduction of immunosuppressive treatment, when possible. Acyclovir or Valacyclovir oral medication is the most common treatment for active HSV infection.[3,46]

JC Virus

JC virus is a common polyomavirus with a seropositivity of around 58% in healthy adults.[13,14] However, JC virus is also a known opportunistic uropathogen.[16,32,47–49] JC virus reactivation and shedding into the urine is also associated with post-transplant nephropathy.[19,47]

Treatment

Treatment of JC viral UTI is primarily supportive care and reduction of immunosuppressive treatment, when possible.[2]  Cidofovir, an antiviral may be used either intravenously or as an intravesicular instillation, to treat JC viruria, especially in patients with hemorrhagic cystitis.[3,25,26]

References

  1. Santiago-Rodriguez, T.M.; Ly, M.; Bonilla, N.; Pride, D.T. The Human Urine Virome in Association with Urinary Tract Infections. Front. Microbiol. 2015, 6, 14, doi:10.3389/fmicb.2015.00014.
  2. Luciani, L.G.; Mattevi, D. Encyclopedia of Infection and Immunity. Ref. Modul. Biomed. Sci. 2022, 32–43, doi:10.1016/b978-0-12-818731-9.00139-7.
  3. Paduch, D.A. Viral Lower Urinary Tract Infections. Current Urology Reports 2007, 8, 324–335, doi:10.1007/s11934-007-0080-y.
  4. Jhang, J.-F.; Hsu, Y.-H.; Peng, C.-W.; Jiang, Y.-H.; Ho, H.-C.; Kuo, H.-C. Epstein–Barr Virus Presence As A Potential Etiology of Persistent Bladder Inflammation in Human Interstitial Cystitis/Bladder Pain Syndrome. The Journal of urology 2018, doi:10.1016/j.juro.2018.03.133.
  5. Kuo, H.-C.; Peng, C.-W.; Jiang, Y.-H.; Jhang, J.-F. Urinary Viral Spectrum in Patients with Interstitial Cystitis/Bladder Pain Syndrome and the Clinical Efficacy of Valacyclovir Treatment. Biomedicines 2024, 12, 522, doi:10.3390/biomedicines12030522.
  6. Park, S.; Kim, E.T.; Huh, J.-S. Virus in the Urine of Healthy People and Patients with Infectious Diseases. Urogenit Tract Infect 2021, 16, 44–48, doi:10.14777/uti.2021.16.2.44.
  7. Yusuf, U.; Hale, G.A.; Carr, J.; Gu, Z.; Benaim, E.; Woodard, P.; Kasow, K.A.; Horwitz, E.M.; Leung, W.; Srivastava, D.K.; et al. Cidofovir for the Treatment of Adenoviral Infection in Pediatric Hematopoietic Stem Cell Transplant Patients. Transplantation 2006, 81, 1398–1404, doi:10.1097/01.tp.0000209195.95115.8e.
  8. Singh, D.; Kiberd, B.; Gupta, R.; Alkhudair, W.; Lawen, J. Polyoma Virus-Induced Hemorrhagic Cystitis in Renal Transplantation Patient with Polyoma Virus Nephropathy. Urology 2006, 67, 423.e11-423.e12, doi:10.1016/j.urology.2005.08.042.
  9. Giraud, G.; Bogdanovic, G.; Priftakis, P.; Remberger, M.; Svahn, B.-M.; Barkholt, L.; Ringden, O.; Winiarski, J.; Ljungman, P.; Dalianis, T. The Incidence of Hemorrhagic Cystitis and BK-Viruria in Allogeneic Hematopoietic Stem Cell Recipients According to Intensity of the Conditioning Regimen. Haematologica 2006, 91, 401–404.
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About the Author

Dr. Emery Haley is a scientific writing specialist with over ten years of experience in translational cell and molecular biology. As both a former laboratory scientist and an experienced science communicator, Dr. Haley is passionate about making complex research clear, approachable, and relevant. Their work has been published in over 10 papers and focuses on bridging the gap between the lab and real-world patient care to help drive better health outcomes.

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