Introduction
Background
Hemorrhagic cystitis (HC) is a common condition observed in pediatric oncology patients and is a cause of great morbidity and potential mortality in this already compromised group of patients. Hemorrhagic cystitis is defined by lower urinary tract symptoms that include hematuria and irritative voiding symptoms. It results from damage to the bladder transitional epithelium and blood vessels by toxins, viruses, radiation, drugs, or disease.
The pediatric oncology patient may be exposed to all of these factors. Patients who undergo bone marrow transplantation frequently have hemorrhagic cystitis because most are exposed to cyclophosphamide, total-body irradiation, or both. Patients with malignancies and those undergoing chemotherapy are often immunocompromised and are at high risk of acquiring bacterial and viral infections that can cause hemorrhagic cystitis.
Pathophysiology
Hemorrhagic cystitis results from damage to the bladder transitional epithelium and blood vessels by toxins, viruses, radiation, drugs, or disease. Reported causative infectious agents for hemorrhagic cystitis include Escherichia coli; adenoviruses 7, 11, 21, and 35, papovavirus; and influenza A.
Cyclophosphamide is the most common cause of hemorrhagic cystitis in the pediatric oncology population. Urologic adverse effects of cyclophosphamide include frequency, dysuria, urgency, suprapubic discomfort, and both microscopic and gross hematuria. In rare cases, mucosal necrosis, bladder fibrosis, contracture, vesicoureteral reflux (VUR), and tumor formation occur.
Urologic adverse effects are observed in 2%-40% of patients who have undergone cyclophosphamide chemotherapy. Hemorrhagic cystitis secondary to cyclophosphamide therapy appears to be dose-related and most prevalent in patients who are dehydrated and those receiving intravenous treatment. The urotoxicity observed with cyclophosphamide is due to its liver metabolite acrolein. Although the entire urothelium is at risk of urotoxicity, the bladder, which serves as a reservoir, is most frequently affected because the contact time between acrolein and the urothelium is greatest at this site.
Radiation-induced hemorrhagic cystitis is most common in patients receiving pelvic irradiation. The incidence in the pediatric population is less than that in adults. Hematuria may develop acutely during radiation treatment or months to years later. Mucosal ischemia secondary to radiation injury results from end arteritis that induces hypoxic surface damage, ulceration, and bleeding. Factors that contribute to radiation cystitis include bladder outlet obstruction, infection, previous radiation or surgery, and excessive radiation dosage.
Frequency
United States
Hemorrhagic cystitis is common among pediatric oncology patients. Patients treated with cyclophosphamide have a 2%-40% incidence of urologic adverse effects. Approximately 10% of patients receiving pelvic radiation develop hemorrhagic cystitis. The incidence in the pediatric population is less than that in adults.
Mortality/Morbidity
Clinically significant morbidity is associated with hemorrhagic cystitis and its treatments. Although uncommon, severe hemorrhagic cystitis refractory to several therapeutic modalities poses a risk of mortality.
Race
Hemorrhagic cystitis has no known racial predilection.
Sex
Hemorrhagic cystitis has no known sexual predilection.
Age
Hemorrhagic cystitis manifests in people of any age.
Clinical
History
Hemorrhagic cystitis (HC) is defined by lower urinary tract symptoms that include hematuria and, usually, gross and irritative voiding symptoms; these include urinary frequency, urgency, and dysuria. A history of new urinary incontinence is frequently noted. Patients with hemorrhagic cystitis are commonly oncology patients who have undergone chemotherapy or radiation therapy. Identify factors that contribute to the development of hemorrhagic cystitis. These include bladder outlet obstruction, infection, previous radiation or surgery, previous chemotherapy treatments, and excessive radiation dosage.
Physical
Patients with hemorrhagic cystitis can present with variable degrees of hematuria, ranging from slightly blood-tinged urine to massive gross hematuria with passing of clots that may cause urinary retention. Patients with this disease may have a distended, tender, palpable bladder. Clot retention is common and can be very painful. Urinary incontinence is frequently observed.
Causes
Hemorrhagic cystitis results from damage to the bladder transitional epithelium and blood vessels by toxins, viruses, irradiation, drugs, or disease. Patients with malignancies and those undergoing chemotherapy are frequently immunocompromised and at high risk of acquiring the bacterial and viral infections responsible for the hemorrhagic cystitis. Reported causative infectious agents for hemorrhagic cystitis include E coli; adenoviruses 7, 11, 21, and 35; papovavirus; and influenza A.
Hemorrhagic cystitis secondary to cyclophosphamide therapy appears to be dose-related and is most prevalent in patients who are dehydrated and those receiving intravenous treatment. The urotoxicity observed with cyclophosphamide is due to its liver metabolite, acrolein. Although the entire urothelium is at risk of urotoxicity, the bladder, as a reservoir, is most frequently affected because the contact time between acrolein and the urothelium is greatest at this site.
Mucosal ischemia secondary to radiation injury results from end arteritis, which induces hypoxic surface damage, ulceration, and bleeding. Factors that contribute to radiation cystitis include bladder outlet obstruction, infection, previous radiation or surgery, and excessive radiation dosage.
- Cyclophosphamide hemorrhagic cystitis
- Cyclophosphamide is the most common cause of hemorrhagic cystitis.
- Urologic adverse effects with cyclophosphamide have an incidence of 2%-40% and include frequency, dysuria, urgency, suprapubic discomfort, and microscopic or gross hematuria. In rare cases, mucosal necrosis, bladder fibrosis, contracture, VUR, and tumor formation may occur.
- Risk of adverse effects is dose-related (oral >90 g; intravenous >18 g).
- Risk factors include dehydration and intravenous infusion.
- The urotoxic metabolite is acrolein. Acrolein is a liver metabolite of cyclophosphamide. The bladder is most frequently affected because of its contact time with this agent.
- Radiation-induced hemorrhagic cystitis
- This is most common with pelvic radiation.
- The incidence in adults is less than that in the pediatric population.
- Hemorrhagic cystitis may develop acutely or months to years later.
- Mucosal ischemia secondary to radiation injury results from end arteritis inducing hypoxic surface damage, ulceration, and bleeding.
- Cystitis is nonspecific.
- Viral-induced hemorrhagic cystitis
- BK virus (polyoma virus): It usually subclinically infects most of the population in childhood. Polyoma viruses are known to cause hemorrhagic cystitis in children. It persists indefinitely in the kidney after primary infection. It is reactivated and excreted in the urine in patients with depressed cellular immunity.
- Adenovirus: The species most commonly isolated is adenovirus type 11, which has a propensity for the urinary tract. It reactivates with profound immunosuppression. It is the most common cause of hemorrhagic cystitis in the healthy child.
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| References |
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Further Reading
Keywords
hemorrhagic cystitis, gross hematuria, HC, urinary frequency, urgency, dysuria, cyclophosphamide HC, cyclophosphamide hemorrhagic cystitis, viral-induced HC, viral-induced hemorrhagic cystitis, radiation-induced HC, radiation-induced hemorrhagic cystitis, bone marrow transplantation
