Severe hemorrhagic cystitis often arises from anticancer chemotherapy or radiotherapy for pelvic malignancies. Infectious etiologies are less common causes except in immunocompromised hosts. These cases can be challenging problems for the urologist and a source of substantial morbidity and sometimes mortality for the patients. A variety of modalities of treatment have been described for the management of hemorrhagic cystitis but there is none that is uniformly effective. Some progress has been made in the understanding and management of viral hemorrhagic cystitis. This article reviews the common causes of severe hemorrhagic cystitis and the currently available management options.
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Severe hemorrhagic cystitis often arises from anticancer chemotherapy or radiotherapy for pelvic malignancies. Infectious etiologies are less common causes except in immunocompromised hosts. These cases can be challenging problems for the urologist and a source of substantial morbidity and sometimes mortality for the patients.
A variety of modalities of treatment have been described for the management of hemorrhagic cystitis but there is none that is uniformly effective. Some progress has been made in the understanding and management of viral hemorrhagic cystitis.
This article reviews the common causes of severe hemorrhagic cystitis and the currently available management options. Hemorrhagic cystitis is defined as a diffuse inflammatory condition of the urinary bladder due to an infectious or noninfectious etiology resulting in bleeding from the bladder mucosa. The most common cause is bacterial infection that usually responds promptly to treatment. But chronic and recurrent hemorrhagic cystitis often arises from anticancer chemotherapy or radiotherapy for the treatment of pelvic malignancies.
Infectious etiologies are less common causes of chronic hemorrhagic cystitis except in immunocompromised hosts like bone marrow transplant patients. These cases can be challenging and frustrating problems for the urologist and a source of substantial morbidity and sometimes mortality for the patients.
This article reviews the important causes of recurrent hemorrhagic cystitis, its pathophysiology and the currently available management options to treat this disabling condition. Relevant articles, including review articles and clinical trials, were selected from these. In addition, standard textbooks were also reviewed. Important cross references were also selected for the review. A wide variety of agents including chemotherapeutic drugs are implicated in the development of hemorrhagic cystitis [ Table 1 ].
The most important among these are the oxazaphosphorine compounds such as cyclophosphamide and ifosfamide synthetic analogues that are used in many chemotherapeutic protocols for cancers like solid tumors and lymphomas. The dose-limiting toxicity with these agents is usually urinary tract toxicity. Urinary tract symptoms include storage lower urinary tract symptoms such as frequency, urgency, nocturia and dysuria.
Hepatic microsomal cells cause the breakdown of cyclophosphamide to hydroxycyclophosphamide which is then converted to aldophosphamide by target cells. They undergo further metabolism to phosphoramide mustard, the active antineoplastic metabolite, and acrolein, which has no significant antitumor activity but is toxic to the urothelium.
The bladder being a reservoir for urine is most vulnerable due to the prolonged exposure of its urothelium to acrolein. Acrolein causes release of inflammatory mediators such as tumor necrosis factor-alpha, interleukin-1 beta and endogenous nitric oxide[ 3 ] causing bladder mucosal edema, vascular dilatation and increased capillary fragility resulting in hemorrhage.
In chronic cases progressive fibrosis of the wall can result in a small fibrotic non-compliant bladder. The onset of hematuria usually occurs within 48 hours of treatment. Hemorrhagic cystitis is managed by stopping the drug or reducing the drug dosage. An alternative drug like azathioprine may need to be substituted in some of these patients.
Continuous bladder irrigation CBI is also helpful in these patients as it decreases the duration of exposure of the urothelium to acrolein thereby reducing the toxicity.
The drug sodium 2-mercaptoethane sulfonate mesna has also been used to prevent hemorrhagic cystitis caused by ifosfamide and less commonly by cyclophosphamide. Mesna is a sulfhydryl compound that is administered intravenously and rapidly excreted by the urinary tract where the sulfhydryl group of mesna complexes with the terminal methyl group of acrolein forming a nontoxic thioether.
The half-life of mesna is 35 minutes. The side effects include diarrhea, headaches and limb pain. Similarly, Vose et al. In the CBI group there was significant reduction in the mean duration of hemorrhagic cystitis 10 vs. In general, CBI was well tolerated. Malignant lesions, predominantly transitional cell carcinoma, occur in 2.
Other systemic chemotherapeutic agents less commonly cause hemorrhagic cystitis. Alkylating agents like thiotepa, temozolomide, and 9-nitrocamptothecin a topoisomerase I inhibitor have also been implicated to cause hemorrhagic cystitis. Symptoms can take two weeks to develop after the medication is started. Urinalysis frequently reveals sterile pyuria, hematuria and eosinophiluria. Hematuria occurs after a long interval of symptom-free period and is unrelated to dose.
The symptoms can occur within days of starting the medication or years later. The etiology may be due to direct toxicity to the bladder urothelium or due to immune mediated hypersensitivity reaction. Certain topical agents can cause hemorrhagic cystitis through direct irritation of the bladder mucosa.
Accidental intraurethral insertion of nonoxynol-9 has been implicated in hemorrhagic cystitis. This is due to the acidic nature of the suppository pH 3. Immediate bladder irrigation should be initiated to reduce the symptoms.
The balloon invariably ruptures and causes ether cystitis resulting in severe hematuria. Long-term sequelae include decreased bladder capacity and lower urinary tract storage symptoms.
Other medications that have been implicated in the development of hemorrhagic cystitis include allopurinol,[ 25 ] methaqualone,[ 26 ] methenamine mandelate,[ 27 ] gentian violet[ 28 ] and intravesical instillation of acetic acid. Occupational exposure to chemicals such as aniline constituent of dyes, marking pens and shoe polish and toluidine found in pesticides and shoe polish are known to cause hemorrhagic cystitis besides predisposing to developing urothelial cancer.
Ingestion, inhalation or direct skin contact of the pesticide chlorodimeform, commonly used on cotton plants and fruit trees, can cause hemorrhagic cystitis which is due to its metabolite 2-methylaniline, an aniline derivative.
Usually the hematuria is self-limiting once exposure to the offending chemical agent is eliminated. Radiation cystitis is a late complication of radiotherapy for pelvic malignancies like prostate and cervix and occurs at least 90 days after the initiation of radiation treatment but may occur in a delayed manner even beyond 10 years. Histological features include microscopic progressive obliterative endarteritis that leads to mucosal ischemia. The ischemic bladder mucosa then ulcerates and bleeding occurs.
Neovascularity occurs in the damaged areas which causes the characteristic vascular blush on cystoscopic evaluation. The newly formed vessels are more fragile and bleed with bladder distension, minor trauma or any mucosal irritation.
Submucosal hemorrhages and frank hematuria occurs. Acute episodes usually wane within 12 to 18 months in most of these patients. In contrast to acute changes, late radiation injuries are irreversible and progressive. The time interval between the treatment and development of delayed symptoms is inversely proportional to the dose received. Radiation induced hemorrhagic cystitis is very difficult to treat because of the ischemic nature of the disease.
Since there are no well controlled trials available comparing the existing treatment options, firm guidelines cannot be made. Currently, accurately tailoring the irradiation field and limiting the radiation dose to the bladder are employed in reducing the incidence of hematuria.
Hyperbaric oxygen HBO therapy has been extensively investigated in the management of radiation induced injuries. Initially introduced in as a radiosensitizer in radiation oncology, HBO was later found to decrease the radiation effects on various organs including the bladder. Under these conditions, alveolar, arterial and tissue oxygen levels are driven to supraphysiologic levels, thereby stimulating angiogenesis, fibroblast proliferation and collagen formation.
At three months follow-up, an overall response rate of Initially concerns were raised regarding the risk of tumor growth because of HBO mediated angiogenesis, immunosuppression and free radical toxicity.
Following a review of all the available literature in , Fieldmeier et al. Pediatric and immunocompromised patients are susceptible to develop viral hemorrhagic cystitis. The BK polyoma virus, adenovirus types 7, 11, 34 and 35, Cytomegalovirus, JC virus and herpes virus have been implicated. When the immune system is compromised, as in persons undergoing chemotherapy or chemical immunosuppression after bone marrow, stem cell and solid organ transplantation, the virus gets reactivated leading to cystitis.
Polyomavirus has been reported to cause hemorrhagic cystitis in 5. Onset is usually within one to four months after transplantation. Early diagnosis and treatment of viral cystitis may prevent significant morbidity of hemorrhagic cystitis. The diagnosis is based on molecular techniques, and real-time polymerase chain reaction, which allows quantification of viral load, is often the method of choice.
Leflunomide has been shown to significantly reduce BK viral load in blood and urine in renal transplant patients with biopsy-proven BK nephropathy. Although its use in BK associated-hemorrhagic cystitis has not been reported leflunomide may also be a potential agent to treat BK-virus associated cystitis.
The most common bacterial causes are Escherichia coli, Staphylococcus saprophyticus, Proteus mirabilis and Klebsiella species. On cystoscopic examination, whitish pseudo membranes or pale plaques may be seen covering the urothelium in candidal infection. The hemorrhage usually resolves in these cases with the treatment of the underlying condition.
Schistosoma haematobium lives in the perivesical venous plexuses in infected humans and the eggs produced by the parasite are excreted into the urine or feces. The ova present in the urine implant in the mucosa resulting in hyperplasia and dysplasia and predispose to development of squamous cell carcinoma of urinary bladder. A grading system for severity of hemorrhagic cystitis has been proposed by Droller et al. In all patients of hemorrhagic cystitis a thorough evaluation should be done to determine the cause.
If an etiology is not obvious, the patient should undergo hematuria workup including urine cytology, upper tract imaging and cystoscopy. Patients on chemotherapy may have thrombocytopenia and other coagulation abnormalities which must be corrected. Laboratory evaluation includes hemoglobin, complete blood count, blood urea, serum creatinine, and coagulation profile and urine culture. Patient should be hemodynamically stabilized with intravenous fluids and blood transfusion. Antibiotics are given until sterile cultures are obtained.
Symptomatic treatment with drugs like oxybutynin and analgesics helps in alleviating symptoms. As a first step a large bore three-way Foley urethral catheter is inserted to decompress the bladder and start saline irrigation. This simple maneuver may slow or stop the bleeding altogether. In some instance cystoscopic clot evacuation may be necessary. During cystoscopy, bladder should be carefully evaluated for the source of bleeding and biopsy of suspicious malignant lesions or fulguration of bleeding spots can be done at the same time.
Patients not responding to clot evacuation, and those with diffuse bleeding, require supplemental therapeutic techniques with systemic or intravesical agents. Conjugated estrogens have been employed for the treatment of viral and radiation induced hemorrhagic cystitis.
Hemorrhagic cystitis: A challenge to the urologist
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Hemorrhagic cystitis or haemorrhagic cystitis is an inflammation of the bladder defined by lower urinary tract symptoms that include dysuria , hematuria , and hemorrhage. The disease can occur as a complication of cyclophosphamide , ifosfamide and radiation therapy. In addition to hemorrhagic cystitis, temporary hematuria can also be seen in bladder infection or in children as a result of viral infection. Causes of hemorrhagic cystitis include chemotherapy e. Ifosfamide is the most common cause of hemorrhagic cystitis. Radiation-induced hemorrhagic cystitis develops in similar or smaller patient numbers when compared to cyclophosphamide-induced cases.
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Increasing incidence of adenovirus disease in bone marrow transplant recipients.