Urinary Tract Infection and Inflammation at Onset of Interstitial Cystitis/Painful Bladder Syndrome

doi:10.1016/j.urology.2007.12.091

Urology

Volume 71, Issue 6, June 2008, Pages 1085-1090

https://doi.org/10.1016/j.urology.2007.12.091 Get rights and content

Objectives

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic disease primarily in women that is of low incidence and unknown etiology and manifests as bladder pain and urinary symptoms. Acute urinary tract infection (UTI) is of high incidence in women, presents as dysuria and urinary symptoms, and is caused by uropathogenic bacteria. We hypothesized that UTI is present at the onset of IC/PBS in some women.

Methods

For a case-control study seeking risk factors for IC/PBS, women with IC/PBS symptoms of 12 months or less were recruited and evaluated by interview and medical record review. The date of symptom onset was identified by a six-step process. Three evidence-based methods using culture, urinalysis, and symptoms were used separately and in combination to diagnose UTI at IC/PBS onset.

Results

Of 1177 screened women, 314 with recent-onset IC/PBS, including numerous confirming characteristics, were enrolled in the study; 98% of the requested medical records were obtained and reviewed. Evidence of a UTI at the onset of IC/PBS was found in 18% to 36% of women. Common UTI features not used in its diagnosis (short interval to medical care, hematuria, antibiotic treatment, and improvement after antibiotics) were significantly more common in those with onset UTI than in those without.

Conclusions

These retrospective data suggest that a proportion, probably a minority, of women at IC/PBS onset had evidence of UTI or inflammation. Our results indicate that UTI is present at the onset of IC/PBS in some women and might reveal clues to IC/PBS pathogenesis.

Section snippets

Recruitment

For the case-control study, Events Preceding Interstitial Cystitis, to minimize confounding by prostatic disease and to enhance recall of antecedent events, we sought female patients with recent IC/PBS onset. The inclusion criteria were female sex, age 18 years old or older, and a syndrome of 12 months or less comprising perceived bladder pain and two or more symptoms of urinary frequency, urgency, or nocturia lasting 4 weeks or longer that had been evaluated by one or more physicians. The

Recruitment

We screened 1177 of the 1240 individuals who contacted us; 314 women were eligible and were enrolled. The reasons for nonenrollment were symptoms of greater than 12 months duration (n = 623), no consent for interview or medical records (n = 121), exclusionary diseases (n = 43), insufficiently severe symptoms (n = 24), failure to interview within the required time (n = 15), and other (n = 37).

The data in Table 1 demonstrate that these 314 patients with recent-onset IC/PBS had a bladder pain

Comment

The separate and combined use of the three diagnostic methods suggest a proportion, probably a minority, of patients with IC/PBS have UTI at IC/PBS onset. Several features suggest that this is not spurious. First, the identification of a uropathogen by culture or nitrites is specific for UTI.2, 10, 12 Second, the present study did not simply reveal concurrent asymptomatic bacteriuria; in women of this age, the prevalence of asymptomatic bacteriuria is 4% to 5%.¹⁹ Finally, although a number of

Conclusions

These evidence-based UTI definitions indicated that 18% to 36% of 314 patients at IC/PBS onset had UTI. Those with evidence of UTI were significantly more likely than those without to have other UTI characteristics, including a short interval to medical care, hematuria, and improvement after antibiotic therapy. UTI might initiate IC/PBS in some patients and could reveal clues to the pathogenesis of IC/PBS.

Acknowledgment

To the women with Interstitial cystitis/painful bladder syndrome who participated in this study, to their physicians, to the Interstitial Cystitis Association and Interstitial Cystitis Network, and to our colleagues: Christina Diggs, Linda Horne, and Teresa Yates.

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Bladder hypersensitivity occurs following neonatal cystitis and an adult insult such as somatic inflammation. This paper demonstrates that CRFR2-related mechanisms are associated with this hypersensitivity. This supports the therapeutic value of these agents in the treatment of painful bladder disorders, particularly when triggered by somatic events.
Neonatal cystitis leads to alterations in spinal corticotropin releasing factor receptor-type 2 content and function in adult rats following bladder re-inflammation
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Spinal mechanisms associated with visceral hypersensitivity are poorly understood. One model of bladder hypersensitivity with phenotypic features similar to the disorder interstitial cystitis/bladder pain syndrome is the neonatal bladder inflammation (NBI) model. In this model, rat pup bladders are infused with zymosan solutions on post-partum days 14–16 and then rats are retested as adults. Studies of other sites of deep tissue hypersensitivity have suggested a role for corticotropin-releasing factor (CRF) receptors type 1 and 2 (CRFR1 and CRFR2). Using neurochemical measures, pharmacological manipulations and both reflex and neuronal responses to urinary bladder distension as endpoints, the present study probed the role of CRFR2s in bladder hyperalgesia secondary to NBI and acute bladder re-inflammation as an adult (ABI). ELISA measures of the lumbosacral spinal cord demonstrated increased CRFR1s and CRFR2s following pretreatment with both NBI + ABI as well as NBI-related increases in the CRFR2 agonist urocortin 2. Intrathecal CRFR2 antagonists, but not a CRFR1 antagonist, blocked the augmentation of visceromotor responses to distension following pretreatment with both NBI + ABI. Lumbosacral dorsal horn neuronal responses to distension in rats pretreated with NBI + ABI were attenuated by the spinal topical administration of a CRFR2 antagonist. These studies suggest therapeutic value of CRFR2 antagonists in the treatment of painful bladder disorders.
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Patients with bladder pain syndrome experience debilitating pain and extreme frequency of urination. Numerous therapeutic approaches have been tested, but as the molecular basis of disease has remained unclear, specific therapies are not available.
Recently, a systematic gene deletion strategy identified interleukin-1 (IL-1) hyperactivation as a cause of severe cystitis in a murine model. Treatment with an IL-1 receptor antagonist (IL-1RA) restored health in genetically susceptible mice, linking IL-1–dependent inflammation to pain and pathology in the bladder mucosa. The study objective was to investigate whether IL-1RA treatment might be beneficial in patients with bladder pain syndrome.
Patients diagnosed with bladder pain syndrome were invited to participate and subjected to daily IL-1RA injections for 1 wk, followed by a treatment break. Patients with other urological disorders accompanied by pain were included as controls.
When symptoms returned, treatment was resumed and responding patients were maintained on treatment long term, with individualized dosing regimens. Symptom scores were recorded and molecular effects were quantified by neuropeptide and gene expression analysis. DNA samples were subjected to exome genotyping.
IL-1RA treatment reduced bladder pain and the frequency of urination in 13/17 patients (p < 0.001). Substance P levels in urine were lowered, and responders returned to a more normal lifestyle. Neuroinflammatory-dependent and IL-1–dependent gene networks were inhibited, as well as regulators of innate immunity. Genotyping revealed disease-associated IL1R1, NLRP3, and IL1RN DNA sequence variants in the responders. Controls did not benefit from IL-1RA treatment, except for one patent with cystitis cystica.
In this clinical study, IL-1RA treatment is proposed to reduce chronic bladder pain, immediately and in the long term. Despite the limited number of study patients, the potent acute effect and lasting symptom relief indicate that this therapeutic approach may be worth exploring in controlled clinical trials.
Treatment with an interleukin-1 (IL-1) receptor antagonist is proposed for treating bladder pain syndrome, as it can result in symptom relief and increase quality of life. Reduced neuroinflammation and IL-1 signaling provided molecular evidence of the treatment effects.
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Nature has bestowed valuable gifts from plants that serve mankind with food and medicine. The folklore systems of medicine has led to a scientific revolution in various fields of nutraceutics and phytopharmacotherapy. The use of polyherbal formulations have also not been scientifically proven yet for their active principles. Thus the study was framed to analyze an edible standardized polyherbal formulation which is consumed by women especially where the requirement of dietary food supplements increases during the parturition and postpartum period to fight Urinary tract infections. The formulation was analysed showing presence of secondary metabolites higher in ethyl acetate extract for phenolics (346.88 ± 35.53 mg GAE/g extract), tannins (100.32 ± 3.23 mg TAE/g extract) and flavonoids (53.17 ± 4.58 mg QE/g extract). Efficient activity was found in methanol extract with 98.63% inhibition (DPPH scavenging potential); 117.67 ± 1.17 mM Fe (II) E/g extract (FRAP assay) and 87.55 ± 5.62 μM TEAC/g extract (ABTS scavenging potential) in hexane extract. Also found to have 36.54% inhibition in water extract for anti-inflammatory activity. The ethyl acetate extract of the formulation readily proves to be highly effective against pathogens such as Escherichia coli (ZOI- 19 ± 1 mm; MIC- 100 μg/ml; MBC- 125 μg/ml), Klebsiella pneumoniae (ZOI- 9.5 ± 0.5; MIC- 450 μg/ml; MBC- 475 μg/ml) and Proteus mirabilis (10.5 ± 1.32; MIC- 375 μg/ml; MBC- 400 μg/ml), however methanol extract was highly significant against Pseudomonas aeroginosa. The results were evident for the nutritional, antioxidant, anti-inflammatory and antimicrobial potential of the polyherbal formulation.
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Sixty-five of 169 patients (38.5%) reported an active pain condition. Among the 73 patients with pain, the most common pain symptoms were headache (n=22; 30.1%), chest pain (n=17; 23.3%), spinal pain (n=18; 24.7%), myalgia (n=13; 17.8%), abdominal or pelvic pain (n=13; 17.8%), arthralgia (n=11; 15.1%), and generalized pain (n=9; 12.3%). Those reporting headache as their main symptom were less likely to require ICU admission (P=.003). Acetaminophen or nonsteroidal anti-inflammatory drugs were prescribed to 80.8% (n=59), opioids to 17.8% (n=13), adjuvants to 8.2% (n=6), and ketamine to 5.5% (n=4) of patients with pain. When age 65 years and older and sex were controlled for in multivariable analysis, the absence of pain was associated with ICU admission (odds ratio, 2.92; 95% CI, 1.42 to 6.28; P=.004) and death (odds ratio, 3.49; 95% CI, 1.40 to 9.76; P=.01).
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: The study was funded by the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases (DK 064880) and approved by the University of Maryland institutional review board.

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Female UrologyUrinary Tract Infection and Inflammation at Onset of Interstitial Cystitis/Painful Bladder Syndrome

Objectives

Methods

Results

Conclusions

Section snippets

Recruitment

Recruitment

Comment

Conclusions

Acknowledgment

J Urol

Ann Epidemiology

Urology

Urology

Urology

Urology

J Urol

J Urol

Urology

Urology

J Urol

J Med Hypotheses

Painful bladder syndrome (including interstitial cystitis)

Evaluation of new anti-infective drugs for the treatment of urinary tract infection

Clin Infect Dis

Epidemiology of interstitial cystitis

Female Urology
Urinary Tract Infection and Inflammation at Onset of Interstitial Cystitis/Painful Bladder Syndrome