Analysis of viruses present in urine from patients with interstitial cystitis.

The question of whether some cases of interstitial cystitis may have an infectious etiology has been debated for some time. Previous studies have looked for the presence of certain specific viruses, but generally did not use the types of sensitive and unbiased approaches that are currently available. As part of the MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain) Research Network, we examined urine specimens from interstitial cystitis patients who provided specimens over time and also reported various symptoms at the time of urine collection. We first performed next-generation sequencing to look for the presence of viruses in urines, and detected two human polyomaviruses that are known to be excreted into urine, BKPyV and JCPyV. We were especially interested in BKPyV because it is a known cause of another bladder disease, hemorrhagic cystitis, in bone marrow transplant recipients. Further analysis of individual samples indicates a trend toward higher excretion of polyomaviruses in patients experiencing increased symptoms.

Association between Chronic Interstitial Cystitis and Herpes Zoster.

OBJECTIVES: Herpes zoster (HZ) infection has been associated with disease burdens such as infection and depression. However, the relationship between chronic interstitial cystitis (CIC) and HZ is unknown. This study investigated HZ risk in patients with CIC. PATIENTS AND METHODS: The Longitudinal Health Insurance Database, which is a subset of the Taiwan National Health Insurance Research Database, was used in the study. The case cohort consisted of patients with newly diagnosed CIC between 2000 and 2012. Each patient with CIC was matched to four controls by age and index year. All participants were traced from the index date to HZ diagnosis, and loss to follow-up or death, or to the end of the study (31 December 2013). RESULTS: A total of 1096 patients with CIC and 4384 controls were enrolled. The incidence rate of HZ in patients with CIC was 10.8 per 1000 person-years, whereas that for controls was 7.25 per 1000 person-years. HZ risk for the case cohort was 1.48 times that for the control cohort. Among participants aged ≤49 years, patients with CIC had a 1.91-fold-increased HZ risk compared to those without CIC. CONCLUSION: Patients with CIC had a higher risk of HZ than those without CIC. CIC should not be ignored, particularly in young adults.

Epstein-Barr Virus as a Potential Etiology of Persistent Bladder Inflammation in Human Interstitial Cystitis/Bladder Pain Syndrome.

PURPOSE: Interstitial cystitis/bladder pain syndrome is characterized by bladder inflammation without bacterial infection. Although viral infection is a potential etiological cause, few studies have been reported. MATERIALS AND METHODS: Bladder specimens were obtained from patients with interstitial cystitis/bladder pain syndrome and from patients with stress urinary incontinence as controls. Bladder specimens were tested for Epstein-Barr encoded RNAs by in situ hybridization and for Epstein-Barr DNA by quantitative real-time polymerase chain reaction, serology and immunohistochemical staining. RESULTS: Enrolled in study were 16 patients with interstitial cystitis/bladder pain syndrome and Hunner lesions, 23 without interstitial cystitis/bladder pain syndrome or Hunner lesions and 10 controls. The positive rate of Epstein-Barr encoded RNA on in situ hybridization in bladder specimens from patients with vs without interstitial cystitis/bladder pain syndrome and Hunner lesions was 50% vs 8.6%. No Epstein-Barr encoded RNA was found in control specimens. On quantitative real-time polymerase chain reaction Epstein-Barr DNA was detected in 68.8% vs 16.7% of bladder specimens in patients with vs without interstitial cystitis/bladder pain syndrome and Hunner lesions. The median viral load was 1,836 copies per ml (range 216 to 75,144). Only 1 control specimen was Epstein-Barr positive on quantitative real-time polymerase chain reaction. All serum samples from patients with interstitial cystitis/bladder pain syndrome showed past Epstein-Barr viral infection. Epstein-Barr infection was present in 87.5% vs 17.4% of bladder specimens from patients with vs without interstitial cystitis/bladder pain syndrome and Hunner lesions for a total of 46.2% with interstitial cystitis/bladder pain syndrome. Immunohistochemical staining of CD3 and CD20 revealed that Epstein-Barr infection was mainly restricted to T lymphocytes in bladders showing interstitial cystitis/bladder pain syndrome. CONCLUSIONS: Bladder Epstein-Barr infection in T cells may be linked to the pathogenesis of persistent inflammation in patients with interstitial cystitis/bladder pain syndrome.

A Case Control Study Reveals that Polyomaviruria Is Significantly Associated with Interstitial Cystitis and Vesical Ulceration.

OBJECTIVES: To investigate whether polyomaviruses contribute to interstitial cystitis pathogenesis. SUBJECTS AND METHODS: A prospective study was performed with 50 interstitial cystitis cases compared with 50 age-matched, disease-free controls for the frequency of polyomaviruria. Associations between polyomaviruria and disease characteristics were analysed in cases. Polyomavirus in urine and bladder tissue was detected with species (JC virus vs. BK virus) specific, real-time PCR. RESULTS: Case patients were reflective of interstitial cystitis epidemiology with age range from 26-88 years (median 58) and female predominance (41/50 F). There was a significant increase in the frequency of polyomavirus shedding between cases and controls (p<0.02). Polyomavirus shedding, in particular BK viruria, was associated with vesical ulceration, a marker of disease severity, among interstitial cystitis cases after adjustment for age and sex (OR 6.8, 95% CI 1.89-24.4). There was a significant association among cases between the presence of BK viruria and response to intravesical Clorpactin therapy (OR 4.50, 95% CI 1.17-17.4). CONCLUSION: The presence of polyomaviruria was found to be associated with the ulcerative form of interstitial cystitis. Clorpactin, which has anti-DNA virus activity, was more likely to improve symptoms in the presence of BK viruria. These data from this pilot study suggest associations between polyomaviruria and interstitial cystitis warranting further investigation.

Polyomavirus BK--a potential new therapeutic target for painful bladder syndrome/interstitial cystitis?

AIMS: To investigate the role of urinary BK polyoma virus (BKPyV) in the pathophysiology and prognosis of patients with painful bladder syndrome/interstitial cystitis (PBS/IC). METHODS: Urine samples were collected from 15 patients with PBS/IC and 8 control patients (with urolithiasis, overactive bladder and benign prostatic hyperplasia). BKPyV titres were quantitatively determined using real time PCR. Fisher's exact test was used to compare virus titre levels between the two groups. The PBS/IC patients subsequently underwent cystoscopy, hydrodistension and bladder biopsy. Finally, a chart review was performed in order to correlate PBS/IC subtype and treatment outcomes with BKPyV status. RESULTS: Positive BKPyV titres were found in 11 out of 15 PBS/IC patients but none of the controls. Cystoscopy was performed in 13 of the 15 PBS/IC patients (in 2 BKPyV positive patients, cystoscopy was not performed). Bladder ulceration and glomerulations were observed in all 9 BKPyV positive PBS/IC patients but only 1 out of 4 BKPyV negative patients. None of the non-ulcerative PBS/IC patients had BKPyV positive urine. Viral titres were not predictive of the clinical course however, 3 patients with the highest viral titres eventually underwent cystectomy. CONCLUSIONS: We identified BKPyV in the urine of virtually all our patients with ulcerative PBS/IC. This finding suggests there may be a pathophysiological association between the virus and the haemorrhagic manifestations of PBS/IC. Classifying PBS/IC patients into BKPyV positive or negative groups may prove useful in future research on markers of disease prognosis and the subtypes of PBS/IC. We believe that BKPyV may therefore have a role as a potential therapeutic target in PBS/IC.

Un nuevo modelo experimental de inducción de cistitis intersticial mediante estrés oxidativo empleando instilación vesical de un gel donante de óxido nítrico / A new experimental model for inducing interstitial cystitis by oxidative stress using bladder instillation of a nitric oxide donor gel

Objetivo: La principal finalidad de este estudio es el desarrollo de un nuevo modelo experimental para la inducción de cistitis intersticial (CI) mediante la instilación vesical de una solución polimérica que contiene el S-nitrosoglutatión donante de óxido nítrico (GSNO), y su comparación con la cistitis intersticial experimental inducida por instilación vesical de protamina y cloruro potásico. Material y métodos: Para la consecución de nuestro objetivo utilizamos 40 hembras de rata Wistar divididas en cuatro grupos: a) solución salina + GSNO; b) solución salina + solución polimérica (sin GNSO); c) sulfato de protamina + KCl; y d) sulfato de protamina + GSNO. Se realizó bien una aplicación a las ratas (5 animales), bien 3 aplicaciones (5 animales) de la sustancia correspondiente mediante instilación vesical, y al cabo de 6 días (5 animales) o 9 días (5 animales)se les practicó la eutanasia y se les extrajeron las vejigas para su evaluación macroscópica y estudio histológico. Resultados: En términos de evaluación macroscópica observamos edema e hiperemia de la mucosa en dos (22%) de los animales del grupo 1, en 0 (0%) de los del grupo 2, en 10 (100%) de los del 3 y en 5 (50%) de los animales del grupo 4. En el grupo de protamina + KCl y en solución salina + GSNO se observaron efectos similares en la pared vesical. Los animales del grupo 2 (solución salina + polimérica) mostraban congestión vascular, bastante menos significativa que en el resto después de 9 días de instilaciones (p = 0,0035). Se observó un aumento de la fibrosis tras las instilaciones en los grupos 3 y 4 a los 6 días (p = 0,3781) y a los 9 días (p = 0,0459) respectivamente, en comparación con los controles (grupo 2). En todos los grupos aparecía un infiltrado de neutrófilos con intensidad variable a los 6 días de las instilaciones (p = 0,7277). Al cabo de 9 días se producía una regresión del infiltrado, y sin evidencias de reacción neutrofílica marcada en todos los grupos (p = 0,2301). Conclusión: La respuesta inflamatoria a la instilación vesical de una solución acuosa de Snitrosoglutatión fue muy parecida a la inducida por la instilación vesical de protamina y KCl. La instilación de una solución acuosa de GSNO puede considerarse un nuevo modelo para la inducción experimental de cistitis intersticial (AU)

Purpose: The aim of this study is to develop a new experimental model of inducing interstitial cystitis (IC) through vesical instillation of a polymeric solution containing the NO donor S-nitrousglutathione (GSNO) and to compare it to the experimental interstitial cystitis inducedby vesical instillation of protamine and potassium chloride. Material and method: For that purpose 40 female Wistar rats were used, divided in four groups: 1. saline solution + GSNO; 2. saline solution + polymeric solution (without GNSO); 3. Protamine sulphate + KCl; 4. protamine sulphate + GSNO. The rats received one application (5 animals) or 3 applications (5 animals) of the corresponding substance through intravesical instillation, and after 6 days (5 animals) or 9 days (5 animals) they were euthanized and their bladders were removed for macroscopic evaluation and histological study. Results: In the macroscopic evaluation we observed edema and hyperemia of the mucosa in2 (22%) of the animals in group 1, in 0 (0%) of the animals in group 2, in 10 (100%) of the animals in group 3, and in 5 (50%) of the animals in group 4. In the protamine + KCl group and in saline + GSNO similar effects were observed on the bladder wall. The animals in group2 (saline + polymeric) showed vascular congestion, significantly smaller than the rest after9 days instillations (p = 0.0035). Significant increased fibrosis was observed after instillations in groups 3 and 4, after 6 days (p = 0.3781) and 9 days (p = 0.0459) respectively, when compared to control (group 2). All groups presented neutrophilic infiltrate of variable intensity 6 days after instillations (p = 0.7277). After 9 days, there was a regression of the infiltrate, with no evidence of accentuated neutrophilic reaction in all the groups (p = 0.2301). Conclusion: The inflammatory response to bladder instillation of an aqueous solution of Snitrousglutathione was very similar to that induced by bladder instillation of protamine and KCl. Instillation of an aqueous solution of GSNO can be considered a new model for experimental induction of interstitial cystitis (AU)

Decreased viral load and symptoms of polyomavirus-associated chronic interstitial cystitis after intravesical cidofovir treatment.

Interstitial cystitis causes disabling bladder pain and is usually diagnosed in the absence of infection. We describe a patient with interstitial cystitis who had high urinary levels of polyomavirus that decreased dramatically after initiation of intravesical cidofovir treatment; the patient also showed substantial improvement in symptoms. Another patient had milder symptoms of cystitis and intermittent polyomavirus shedding. Polyomaviruses, particularly BK virus, may cause some cases of interstitial cystitis.

Interstitial cystitis and infectious agents.

Interstitial cystitis (IC) is a syndrome consisting of severe refractory bladder symptoms of unknown etiology. The disease tends to affect Caucasian women with a mean age of 40 years, with 25% of patients under the age of 30. Few population based epidemiological studies of IC have been performed. We analyzed a case of interstitial cystitis in a 42-year-old non-smoker woman. In two biopsy samples the presence of viral DNA of human polyomavirus BK (BKV), human herpes virus type 1 and type 2 (HHV- 1 and HHV-2), adenovirus, human papillomavirus (HPV) and bacterial DNA (Chlamydia trachomatis and Mycoplasma genitalium) were evaluated by means of polymerase chain reaction (PCR). Both samples resulted positive only for BKV and HPV DNA. HPV genotyping revealed the presence of HPV-66 that is associated with a high risk of cancer development. Thus the finding of a viral co-infection could support the hypothesis of the multi-factorial origin of this pathology.

Is interstitial cystitis an infectious disease?

Interstitial cystitis (IC) is a chronic bladder disorder of unknown aaetiology. Although several investigators have attempted to identify an infectious cause for IC, none has yet been found. Our own studies to search for an infectious cause discovered instead, a toxic factor in the urine of approximately 95% of IC patients that is made by and inhibits, the normal proliferation of bladder epithelial cells. Additional research is necessary to determine whether this factor is encoded by the eucaryotic cells themselves or an unidentified intracellular microorganism.

Viruses and interstitial cystitis: adenovirus genomes cannot be demonstrated in urinary bladder biopsies.

Microbes may be involved in the pathogenesis of interstitial cystitis (IC). Adenoviruses and BK virus (BKV) can infect epithelial cells in urinary bladder and they are causative agents for hemorrhagic cystitis. We therefore studied the presence of adenovirus and BKV genomes in urinary bladder tissue specimens of patients with IC using polymerase chain reaction (PCR) and in situ hybridization (ISH). Controls were specimens from cases with transitional cell carcinoma of the bladder. Nucleic acids were extracted from paraffin sections of the bladder tissue for PCR. Primers detecting all adenovirus types were used. In situ hybridization was carried out for the paraffin sections using digoxigenin-labeled DNA probes for adenovirus and BKV. The adenovirus DNA PCR was able to detect one to two infected cells/specimen. All the seven IC cases studied and six controls were negative for adenovirus DNA by PCR and ISH. The ISH test for BKV genomes was also considered negative in IC cases and controls. The specimens which were negative in PCR tests yielded a signal with beta-globin primers, thus being amplifiable. We conclude that adenovirus and BKV do not play a major pathogenetic role in interstitial cystitis.