Hemorrhagic cystitis associated with adenovirus infection in bone marrow transplantation

A retrospective study of bone marrow transplant recipients shedding adenovirus type 11 in the urine was carried out to determine the association between viral shedding and hemorrhagic cystitis in this population. Weekly urine virology surveillance cultures were obtained during the first 100 days following transplantation. Adenovirus type 11 was cultured from five of 502 bone marrow transplant recipients from 1977 through 1984. In four of these five patients there was associated hemorrhagic cystitis. This contrasts with an overall incidence of hemorrhagic cystitis of 20% in this bone marrow transplant population. A case of hemorrhagic cystitis occurred in a patient following bone marrow transplantation. Recognition of a viral origin of hemorrhagic cystitis may explain the occurrence of late hemorrhagic cystitis in patients despite interventions designed to prevent cyclophosphamide-induced hemorrhagic cystitis. Hemorrhagic cystitis may be the presenting sign of a lethal adenoviral infection.     

Ureteric obstruction after allogeneic bone marrow transplantation: an unusual complication

A patient with acute myeloid leukemia (M4) in the first complete remission received a bone marrow transplantation (BMT) from an HLA-compatible sibling. Sustained engraftment was achieved, but she developed colicky pain at the back and lower quadrant of both sides on days 19-21 post-BMT, followed by hemorrhagic cystitis 13 days later. Ultrasonogram, intravenous pyelogram and computed tomogram of the abdomen showed hydronephrosis and ureteric obstruction of both sides. There was no stone in the urinary tract or abnormality of the bladder. The cortex of the right kidney was rather hypertrophic in spite of the persistent presence of hydronephrosis. Viral culture of urine and electron microscopic examination of urine sediments revealed the presence of adenovirus type II. Infection of the urinary tract with adenovirus type II may have been the underlying cause of the hemorrhagic cystitis and possibly also of the otherwise unexplained ureteric obstruction.     

Polyomavirus BK infection in blood and marrow transplant recipients

The association of BK virus infection with hemorrhagic cystitis in blood and marrow transplant (BMT) recipients was first demonstrated two decades ago. During this time, therapeutic interventions focused on supportive measures such as hyperhydration, continuous bladder irrigation and topical administration of agents that alter the mucosal surface of the bladder wall. In recent years, PCR amplification of viral DNA in the urine and plasma has solidified the association of BK virus infection with hemorrhagic cystitis, demonstrating that higher urine and plasma viral loads occur in the setting of disease. The evaluation of virus-specific therapy has lagged behind assessment of the viral load and theories of pathogenesis. Extrapolating from successes in the treatment of BK virus nephropathy in the renal transplant population, cidofovir and leflunomide are identified as potential effective agents for the treatment of BK virus-associated hemorrhagic cystitis. The fluoroquinolone antibiotics may prove to be effective as prophylactic agents. Given the manifestation of BK virus infection in organs outside of the urinary tract in an increasing immunocompromised patient population and the availability of potential antiviral agents, therapeutic trials need to progress beyond the small case series in order to improve the morbidity and mortality caused by BK virus-associated hemorrhagic cystitis in the BMT population.     

Cyclic recovery of adenovirus in a stem cell transplant recipient: an inverse association with graft-versus-host disease

Adenovirus (AdV) infections have been increasingly recognized as significant pathogens that may cause severe morbidity and mortality among stem cell transplant (SCT) recipients. AdV can cause localized infections such as hemorrhagic cystitis (HC), pneumonia, hepatitis and also disseminated disease that can lead to death. We report a case of severe hemorrhagic cystitis in a SCT recipient who died 83 days after transplant. In this patient, AdV recovery was not constantly detected. In fact, fluctuations of the AdV detection in leukocytes and urine were observed by culture and PCR. When analyzing this viral cyclic recovery with different signs or symptoms in the patient, we observed an inverse association with the presence of acute graft-versus-host disease (GVHD). Whether these fluctuations represent donor-derived reactivity, indirectly manifested by the presence of GVHD, requires further study. This is the first case describing a dynamic pattern of AdV replication in leukocytes and urine samples from a patient with severe HC and the temporal correlation with GVHD.     

Junín virus infection of guinea pigs: electron microscopic studies of peripheral blood and bone marrow.

Thin sections of peripheral white blood cells and samples of bone marrow from guinea pigs infected with Junín virus were examined by electron microscopy. In peripheral blood cells, 40% of the granulocytes showed cytoplasmic lysis seven days after viral infection. After day 11 up to 80% of these cells showed morphological alterations. However, no intra- or extracellular viral particles were detected in these samples. Microscopy of bone marrow preparations revealed that 10% of the cells were altered five days after infection, and approximately 50% were affected after nine days. At this stage the megakaryocyte channels were seen to contain pleomorphic particles with a mean diameter of 80-100 nm. These particles had a unit membrane envelope and internal dense granules similar to those observed during other arenavirus infections. Therefore, it is suggested that the effect of Junín virus upon megakaryocytes may be a factor responsible for the acute thrombocytopenia observed in Argentine hemorrhagic fever.     

Successful hyperbaric oxygen therapy for refractory BK virus‐associated hemorrhagic cystitis after cord blood transplantation

BK virus‐associated hemorrhagic cystitis (BKV‐HC) is a common and major cause of morbidity in recipients of allogeneic hematopoietic stem cell transplantation. A 32‐year‐old woman developed severe BKV‐HC on day 24 after cord blood transplantation (CBT). Despite supportive therapies – such as hyperhydration, forced diuresis, and urinary catheterization – macroscopic hematuria and bladder irritation persisted for over a month. Hyperbaric oxygen (HBO) therapy at 2.1 atmospheres for 90 min per day was started on day 64 after CBT. Macroscopic hematuria resolved within a week, and microscopic hematuria was no longer detectable within 2 weeks. Hematuria did not recur after 11 sessions of HBO therapy, and no significant side effects were observed during or after treatment. HBO therapy could thus be useful in controlling refractory BKV‐HC after CBT.     

Viral lower urinary tract infections

Lower urinary tract infections (UTIs) are common among the general population and are most often caused by bacterial pathogens. Viruses are an uncommon cause of UTIs in an immunocompetent host; however, viruses are increasingly recognized as the cause of lower UTI, especially hemorrhagic cystitis, among immunocompromised patients. BK virus, adenovirus, and cytomegalovirus are predominant pathogens involved in hemorrhagic cystitis after stem cell and solid organ transplantation, and their early diagnosis and treatment may prevent significant morbidity of hemorrhagic cystitis. The diagnosis of viral lower UTI is based on molecular techniques, and real-time polymerase chain reaction is often the method of choice because it allows for quantification of viral load. Cidofovir is becoming a drug of choice in viral UTIs because it is active against the most common viral pathogens. This review discusses the epidemiology, pitfalls in diagnosis, and current treatment of viral UTIs.     

Severe hematuria in a hematopoietic cell transplant recipient caused by Ureaplasma urealyticum not by BK virus or adenovirus infection

A 17‐year‐old male with acute lymphoblastic leukemia developed severe hematuria and scrotal swelling after haploidentical hematopoietic cell transplantation (HCT). Urine culture was negative. BK virus and adenovirus were negative. However, Ureaplasma urealyticum was detected. He showed dramatic improvement after doxycycline treatment. This is the first report in the literature of hemorrhagic cystitis caused by U. urealyticum in a HCT recipient. In HCT recipients with hemorrhagic cystitis, U. urealyticum should be considered as a potential cause.     

Low-dose cidofovir treatment of BK virus-associated hemorrhagic cystitis in recipients of hematopoietic stem cell transplant

In recipients of hematopoietic stem cell transplants (HSCTs), BK virus (BKV) has been associated with late-onset hemorrhagic cystitis (HC). In our institution, HSCT recipients with BKV-associated HC are treated with 1 mg/kg of cidofovir weekly. We identified HSCT recipients with BKV-associated HC, treated with weekly cidofovir. Microbiological response was defined as at least a one log reduction in urinary BKV viral load; clinical response was defined as improvement in symptoms and stability or reduction in the grade of cystitis. Nineteen allogeneic HSCT patients received a mean of 4.5 weekly doses of cidofovir. HC occurred at a mean of 68.7 days after transplant. A clinical response was detected in 16/19 (84%) patients, and 9/19 (47%) had a measurable microbiological response (8/10 nonresponders had a BKV viral load above the upper limit of the assay before treatment). Fourteen out of nineteen (74%) patients had no significant increase in serum creatinine. Five patients with renal dysfunction resolved after completion of the therapy and removal of other nephrotoxic agents. We conclude that weekly low-dose cidofovir appears to be a safe treatment option for BKV-associated HC. Although the efficacy of low-dose cidofovir is not proven, a prospective trial is warranted.     

Hemorrhagic cystitis associated with urinary excretion of adenovirus type 11 following allogeneic bone marrow transplantation

We studied a total of 50 recipients who had received allogeneic bone marrow transplantation (BMT) and evaluated both the presence of hemorrhagic cystitis (HC) and the urinary excretion of adenovirus. Twelve recipients developed HC and eight of these 12 patients excreted adenovirus type 11 at the onset of cystitis. Urine for virus isolation was attempted 30, 60 and 100 days after BMT. Among 137 specimens examined, eight were positive for adenovirus type 11. Of these eight samples, six were collected during HC; while in the 129 samples which were negative for adenovirus, only three specimens was collected during HC. Female patients, seropositivity for the antibody to adenovirus prior to BMT and acute graft-versus-host disease (grade 2-4) showed a significant impact on the risk of adenovirus HC. It may be said that adenovirus type 11 is one of the causative agents of HC in BMT recipients.     

Human polyomavirus: lack of relationship of viruria to prolonged or severe hemorrhagic cystitis after bone marrow transplant

Urine cytology was studied prospectively for the presence of human polyomavirus (HPV) in 17 consecutive patients undergoing marrow transplantation and correlated with hematuria and hemorrhagic cystitis. Of the 15 evaluable patients, nine had cytologic findings consistent with HPV infection during the first month after transplantation. Of these nine patients, two had gross and seven had microscopic hematuria, all without symptoms of cystitis. Hematuria resolved within 30 days of onset, although three patients had persistent cytologic evidence of HPV until 100 days after transplantation. During the follow-up ranging from 8 to 14 months, none of the patients developed hemorrhagic cystitis. Our data do not support the relationship between HPV and prolonged or severe hemorrhagic cystitis previously suggested by others, nor did we see any late onset hemorrhagic cystitis.     

Incidence and predictors of urotoxic adverse events in cyclophosphamide‐treated patients with systemic necrotizing vasculitides

Objective

To assess hemorrhagic cystitis and urinary tract cancer incidence and predictors in cyclophosphamide (CYC)–treated patients with systemic necrotizing vasculitis (SNV).

Methods

The French Vasculitis Study Group database, which contains longitudinal data on SNV patients, was searched for urinary tract cancer and/or hemorrhagic cystitis occurrences in patients diagnosed as having Wegener's granulomatosis (WG), microscopic polyangiitis, Churg‐Strauss syndrome, or polyarteritis nodosa. The observed incidence of urinary tract cancer was compared to the expected incidence in the general population by calculating standardized incidence ratios (SIRs). Relationships between urinary tract cancer and/or hemorrhagic cystitis and 10 variables, including CYC dosage and administration route, were investigated by survival analyses for a nested subgroup of patients for whom detailed information on CYC exposure was available.

Results

Among the 805 patients observed over 4,230 patient‐years (mean followup 5.3 years), 22 cases of hemorrhagic cystitis and 7 of urinary tract cancer were identified in 27 patients. The SIRs for urinary tract cancer were 5.00 for all patients with SNV (P = 0.001) and 5.96 for patients with WG (P = 0.03). Based on 467 patients with detailed CYC information, cumulative CYC dose (hazard ratio [HR] for 10‐gm increments 1.09; P = 0.03), ever‐oral CYC administration (HR 5.50; P = 0.001), and WG (HR 2.96; P = 0.01) independently predicted urinary tract cancer and/or hemorrhagic cystitis. According to univariate analyses, smoking (ever) (HR 8.20; P = 0.02) and a prior hemorrhagic cystitis episode (HR 5.20; P = 0.046) significantly predicted urinary tract cancer.

Conclusion

Our findings indicate that CYC treatment of SNV is associated with a 5‐fold higher risk of developing urinary tract cancer. Urotoxicity risk in SNV is associated with the cumulative CYC dose and its oral administration, and might be higher in WG.

     

No requirement of HCV 5‘NCR for HCV-like particles assembly in insect cells

AIM: To express all three HCV structural proteins in the presence or absence of HCV 5‘‘NCR to investigate the requirement of 5‘NCR for the assembly of HCV-like particles in insect cells. METHODS: HCV structural protein encoding sequences CEIE2 and 5‘‘NCR-CEIE2 were amplified with PCR. Recombinant baculovirus were constructed with recombinant DNA techniques. HCV structural proteins expressed in insect cells were analyzed by immunofluorescence and SDS-PAGE. Immunoprecipitation experiment of insect cell lysates with anti-E2 monoclonal antibody (Mab) was carried out and the immunoprecipitated proteins were subjected to SDS-PAGE and immunoblotting with anti-C, anti-E2 Mabs and HCV positive serum. The virus-like particles in insect cells were visualized by electron microscopy (EM). The HCV-like particles were purified by sucrose gradient centrifugation and identified by EM and immune aggregation EM. RESULTS: The recombinant baculovirus reBV/CEIE2 containing HCV C, E1, E2 genes and reBV/CS containing the same structural protein genes plus 5‘‘NCR were constructed. The insect cells infected with either reBV/CE1E2 or reBV/CS expressed HCV C, E1 and E2 proteins with amolecular weight of 20 kD, 35 kD and 66 kD respectively. The results of immunoprecipitation and the immunoblotting revealed the coimmunoprecipitation of C, E1, and E2 proteins, indicating the interaction of HCV structural proteins expressed in insect cells. Electron microscopy of insect cells infected with reBV/CE1E2 or reBV/CS demonstrated spherical particles (40 to 60 nm in diameter) similar to the HCV virions from sera or hepatic tissues of HCV infected humans. The HCV-like particles were partially purified by sucrose gradient centrifugation, and the purified VLPs showed immuno-reactivity with anti-HCV antibodies.CONCLUSION: HCV 5‘‘NCR is not required for the assemblyof HCV-like particles in insect cells, HCV core and envelope proteins are sufficient for viral particle formation.     

Acute monoarticular arthritis caused by herpes simplex virus and cytomegalovirus

In three patients acute arthritis developed during the course of generalized herpes virus infections. Two patients with no known immunologic impairment had disseminated herpes simplex disease, and one patient, a renal transplant recipient, had cytomegalovirus infection.Patient 1 presented with diffuse vesicular rash and a painful, swollen right knee. Herpes simplex type 1 was isolated from vesicles present on the chest and in synovial fluid from the right knee. Patient 2 presented with right ankle pain and swelling, sore throat, fever and a diffuse vesicular rash. Herpes simplex type 1 was isolated from vesicles on the arms and chest and from a throat culture. The joint disease subsided within two weeks in Patient 1, and four months in Patient 2. In Patient 3 fever, and right hip and knee pain developed as well as urinary retention three months following renal transplantation. The right knee was erythematous, warm and swollen. Cytomegalovirus was isolated from the synovial fluid in the right knee, buffy coat, urine and throat cultures, and viral-like particles were seen within synovial fluid cells by electron microscopy. This patient died without resolution of the joint disease. The demonstration of acute arthritis during herpes simplex virus and cytomegalovirus infection adds a newly recognized feature to the protean manifestations of these viral infections and enlarges the spectrum of viral agents known to be associated with arthritis.     

鸡红细胞吸附H5N1病毒超薄切片的形态学观察

目的应用电子显微镜对鸡胚分离的高致病性H5N1病毒进行观察鉴定。方法分别用不同浓度的甲醛和戊二醛灭活H5N1病毒,超速离心浓缩病毒分离物后,负染观察病毒形态;用鸡红细胞吸附H5N1病毒后超薄切片观察病毒形态。结果负染观察可见1‰的甲醛处理的禽流感病毒呈多形性,表面有许多突起,超薄切片观察可见鸡红细胞表面存在有囊膜的病毒颗粒,多为椭圆形,表面有许多突起,直径为80～120nm。结论鸡红细胞似可代替传代细胞吸附H5N1病毒进行超薄切片的形态学观察,该法安全、简便。     

Hemorrhagic cystitis complicating untreated necrotizing vasculitis

Although the genitourinary system is frequently affected in polyarteritis nodosa, involvement of the wall of the urinary bladder is extremely uncommon; moreover, when reported, it has been merely as an incidental finding late in the disease course. In contrast, hemorrhagic cystitis is a well-recognized complication of cyclophosphamide therapy for the systemic vasculitides, but has not previously been reported to complicate untreated vasculitis. Herein is described a patient who presented with non–treatment-related hemorrhagic cystitis which was found to be due to nongranulomatous necrotizing vasculitis of the wall of the urinary bladder. This represents both a novel presentation of polyarteritis and a previously unreported etiology of hemorrhagic cystitis. The differential diagnosis of apparently spontaneous hemorrhagic cystitis should therefore include active necrotizing vasculitis, independent of prior therapy.     

CD4+ T helper cell responses against human bocavirus viral protein 2 viruslike particles in healthy adults

BACKGROUND: Human bocavirus (HBoV) was recently described as a new member of the Parvoviridae family, and its possible association with respiratory illness in infants has been discussed. To date, HBoV genomes have been detected worldwide in respiratory tract samples obtained from children with pulmonary diseases, whereas only limited data on virus-specific immunity are available, mainly because of the lack of recombinant viral antigens. METHODS: HBoV viruslike particles (VLPs) were produced in insect cells and characterized by electron microscopy and cesium chloride gradient centrifugation. HBoV viral protein 2 (VP2)-specific antibodies and CD4+ T helper cell responses were analyzed by enzyme-linked immunosorbent assay and enzyme-linked immunospot assay. RESULTS: VP2 capsid proteins of HBoV were produced in insect cells infected with a recombinant baculovirus, and the formation of icosahedral VLPs (diameter, 21-25 nm; sedimentation density, 1.33 g/cm(3)) was demonstrated. A significant increase in secretion of VP2-specific interferon-gamma was detected in cultures of peripheral blood mononuclear cells obtained from 69 healthy adults found to be positive for HBoV-specific immunoglobulin G antibodies, compared with control stimulations. In parallel, T cell responses against identically expressed parvovirus B19 VP2 VLPs were frequently observed in the individuals studied, without there being obvious cross-reactions between HBoV and parvovirus B19. CONCLUSIONS: Data suggest the presence of HBoV-specific immune responses in adults and strongly support a high prevalence of HBoV among humans.     

Cidofovir bladder instillation for the treatment of BK hemorrhagic cystitis after allogeneic stem cell transplantation

We report a case of severe hemorrhagic cystitis after allogeneic transplantation in association with high BK viral load. After failure of aggressive hydration, platelet and blood transfusions, continuous bladder irrigation, and tapering of the immune suppression, we instilled cidofovir into the bladder, which resulted in decreased BK viral load and significant clinical improvement. Our case suggests that local cidofovir therapy for viral hemorrhagic cystitis is effective and well tolerated with no observed side effects.     

Advances in Therapeutic Development for Radiation Cystitis

Radiation treatment for pelvic malignancies is typically associated with radiation injury to urinary bladder that can ultimately lead to radiation cystitis (RC). The late sequelae of radiation therapy may take many years to develop and include bothersome storage symptoms such as hematuria, which may be life‐threatening in severe cases of hemorrhagic cystitis. Although no definitive treatment is currently available, various interventions are used for radiation and hemorrhagic cystitis including blood transfusion, bladder irrigation, intravesical instillation of substances such as alum, silver nitrate, prostaglandins or formalin, and fulguration of intravesical bleeding sites and surgery options such as supravesical urinary diversions and cystectomy. Effects of non‐surgical treatments for radiation and hemorrhagic cystitis are of modest success and studies are lacking to control the effects caused by RC. When such measures have proven ineffective, use of bladder botulinum toxin injection has been reported. New therapy, such as intravesical immunosuppression with local tacrolimus formulation is being developed for the treatment of radiation hemorrhagic cystitis.