Hemorrhagic cystitis after bone marrow transplantation: importance of a thin sectioning technique on urinary sediments for diagnosis.

We used a thin-sectioning technique for the electron microscopic detection of viral particles within the cells of urinary sediments in three recipients who developed hemorrhagic cystitis after allogeneic bone marrow transplantation. Results of viral cultures of urine and electron microscopic (EM) observations on urinary sediments were consistent in only one recipient. In this recipient, EM observations revealed many viral particles within the cells of urinary sediments with diameter of about 80 nm corresponding to adenovirus, of which type 11 was produced in viral cultures. In one of the other two recipients many viral particles with a mean diameter of 41.6 nm corresponding to papovavirus were observed, but viral cultures using conventional cells were negative. Re-cultures using HEK cells produced polyomavirus BK. EM observation was a clue to the correct diagnosis. In the remaining recipient, no viral particles were observed within the cells of urinary sediments, suggesting the hemorrhagic cystitis to be of non-viral origin, despite a positive result of viral culture. These results suggest that a thin-sectioning technique on the cells of urinary sediments is important for the differential diagnosis between a viral-induced and non-viral hemorrhagic cystitis.     

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.     

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.     

Hemorrhagic Cystitis and Possible Neurologic Disease from BK Virus Infection in a Patient with AIDS

BK virus (BKV)-associated hemorrhagic cystitis occurs in bone marrow transplant recipients but is rare among other immunosuppressed patients. We present a rare case of BKVassociated hemorrhagic cystitis in a 48-year-old man with AIDS and previously diagnosed progressive multifocal leukoencephalopathy.     

Severe BK polyomavirus‐induced hemorrhagic cystitis in a kidney transplant recipient with the absence of renal allograft involvement

BK polyomavirus mostly manifests as polyomavirus‐associated nephropathy (PyVAN) in kidney transplant patients and polyoma virus‐associated hemorrhagic cystitis (PyVHC) in bone marrow transplant patients. PyVHC in kidney transplant patients is only reported in four cases in the literature. Our patient had severe hemorrhagic cystitis without renal involvement. We postulate that our patient's exposure to ifosfamide and radiation 8 years prior transplantation might predispose him to this disease.     

Dual infection with Pneumocystis carinii and respiratory viruses complicating bone marrow transplantation.

Pneumonia due to dual infection with Pneumocystis carinii and respiratory viruses is a rare but formidable complication of bone marrow transplantation. We report here two cases of viral infections complicating P. carinii pneumonia in bone marrow transplant recipients who, at the time of infection, were not taking P. carinii prophylaxis. Both patients died following the pneumonia. Potential factors contributing to the dual infection included graft-versus-host disease, high-dose steroids and cyclosporin A. P. carinii prophylaxis should be continued for 12 months, or longer in bone marrow transplant recipients requiring prolonged immunosuppressive therapy. As specific antiviral therapy becomes available for some respiratory viral infections, performing regular viral surveillance cultures and responding with active early treatment may help improve the outcome in these immunocompromised patients.     

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.     

A prospective analysis interstitial pneumonia and opportunistic viral infection among recipients of allogeneic bone marrow grafts.

A prospective study of 80 bone marrow transplant recipients with acute leukemia and aplastic anemia employed serial viral cultures, determination of complement-fixing antibody to cytomegalovirus (CMV), and study of material obtained from open lung biopsy and autopsy. There were 43 episodes of interstitial pneumonia, 28 of which were fatal. About 40% of the cases were idiopathic. CMV was the most common candidate pathogen, present in 47% of affected lungs. By a median of 53 days following transplantation, 46% of the recipients were shedding CMV from some site. This event was three times more frequent among recipients who had positive titers of antibody to CMV before transplantation than among seronegative recipients. Failure to respond werologically to CMV infection markedly increased the hazard of dying of interstitial pneumonia. Graft-vs-host disease significantly increased the incidence and lethality of interstitial pneumonia. The presence of leukemia (rather than aplastic anemia) and/or certain factors in the technique of preparation for engraftment may have been significant.     

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.     

The use of vidarabine in the treatment of human polyomavirus associated acute haemorrhagic cystitis.

The human BK and JC polyomaviruses are known to be reactivated and excreted in the urine following bone marrow transplantation (BMT). A proportion of patients who excrete BK virus following BMT experience a haemorrhagic cystitis (HC), which may persist for many months. We report a case of human polyomavirus-associated HC, in whom treatment with vidarabine was associated with a dramatic response.     

Adenovirus-related hemophagocytic syndrome after bone marrow transplantation

Four weeks following autologous bone marrow transplantation for Wilms' tumor, a patient developed fever, hepatomegaly, coagulation disorders and pancytopenia. Bone marrow studies showed progressively increased hemophagocytosis of normal hematopoietic progenitors by histiocytes resulting in aplasia. Adenovirus type 11 was consistently isolated from urine and stool cultures, and one of the marrow aspirates. At autopsy, adenovirus was isolated from the lungs, liver, heart, intestine and spleen. These findings are consistent with the previously described virus-associated hemophagocytic syndrome, which have not been associated with bone marrow transplantation. This case suggests that this diagnosis should be considered in any bone marrow transplant patient who has evidence of secondary graft failure.     

Adenovirus causing hepatic abscess formation and unexplained fever in adult liver transplant recipients

Adenovirus infection is commonly associated with self‐limited respiratory and gastrointestinal illnesses. However, infection in immunocompromised individuals, such as transplant recipients, can cause severe life‐threatening illness including pneumonitis, hemorrhagic cystitis, nephritis, hepatitis, and enterocolitis. In orthotopic liver transplant recipients, adenovirus viremia can cause hepatitis leading to marked transaminitis, allograft loss, and death. Although hepatic abscesses mediated by adenovirus have been described in other immunosuppressed patient populations, it has very rarely been described in liver transplant recipients. Here, we report two adult cases of hepatic abscesses following liver transplantation secondary to adenovirus infection and describe the successful treatment of these patients. Adenovirus should be considered as an uncommon etiology of hepatic abscess and unexplained fevers in adults following liver transplantation.     

Acute renal failure due to adenovirus-associated obstructive uropathy and necrotizing tubulointerstitial nephritis in a bone marrow transplant recipient

Management of post-transplant complications caused by severe adenoviral infection remains a major therapeutic challenge. A 17-year-old male who had undergone bone marrow transplantation for the treatment of acute lymphoblastic leukemia developed complete anuria following hemorrhagic cystitis 34 days after the transplant procedure. The computed tomogram scan revealed bilateral hydronephrosis, indicating acute renal failure because of obstructive uropathy. The emergency procedure of percutaneous nephrostomy caused massive bleeding in the left kidney, which eventually required a nephrectomy. Adenovirus-positive severe necrotizing tubulointerstitial nephritis was the histopathological diagnosis. Post-transplant acute renal failure because of hydronephrosis, which could be complicated by adenovirus-induced renal parenchymal disease, is of great concern and may cause significant problems with interventional treatment.     

Decreased hematopoietic accessory cell function following bone marrow transplantation

Hematologic engraftment following bone marrow transplantation requires not only pluripotent stem cells but also functioning accessory cells whose trophic factors support the proliferation and differentiation of stem cells and progenitors to mature blood cells. To better understand the regulation of hematopoiesis following transplantation, we studied hemopoietic accessory cell function in bone marrow transplant recipients 3 weeks to 10 months following transplantation. In general, hematopoietic accessory cell function was decreased following bone marrow transplantation. Sequential fractionation of accessory cells demonstrated that adherent cells often produced near-normal functional burst-promoting activity (BPA) and granulocyte-macrophage colony-stimulating activity (GM-CSA), but Fc receptor-positive (Fc+) cells and T cells uniformly produced greatly reduced BPA and GM-CSA, as compared to transplant donor cells. This cellular deficiency was corrected by soluble burst-promoting activity and granulocyte-macrophage colony-stimulating activity and so appeared to be due to the failure of accessory cells to produce trophic hormones. Limiting-dilution analysis (LDA) for proliferating T-cell precursors demonstrated a greatly reduced frequency in phytohemagglutinin-responsive cells, supporting the role of deficient hematopoietic growth factor production by activated T cells in transplant recipients. This hemopoietic accessory cell defect may thus reflect more generalized lymphocyte dysfunction in these patients. Hematopoiesis following bone marrow transplantation appears to rely upon growth factors released by accessory cells in the adherent layer.     

BK and JC virus infections in recipients of bone marrow transplants

Fifty-five recipients of bone marrow transplants were monitored prospectively for urinary excretion of BK (BKV) and JC (JCV) viruses and for infections with other viruses. For both BKV and JCV, viruria occurred exclusively in patients who were seropositive at transplantation, a finding indicating that shedding of virus was very likely the result of reactivation. BKV reactivation, which occurred in 26 (55%) of 47 BKV-seropositive patients, was far more common than JCV reactivation, which was detected in only two (7%) of 30 JCV-seropositive patients (P less than .0001). In most patients, BK viruria began two to eight weeks after transplantation and resolved spontaneously after a two- to three-week period. Posttransplantation, there was a temporal pattern in the onsets of infection with the different viruses; herpes simplex virus infections occurred first (mean, 7 d), followed by BKV infections (mean, 33 d) and then cytomegalovirus infections (mean, 51 d). BK viruria was associated with hemorrhagic cystitis.     

Haemorrhagic cystitis associated with adenovirus in a patient with AIDS treated for a non-Hodgkin's lymphoma

Adenovirus-induced haemorrhagic cystitis has been reported chiefly in bone marrow or kidney transplant recipients. We report here on an HIV-positive patient treated for a Burkitt's lymphoma who developed gross haematuria associated with fever and burning urination. Usual causes of haematuria were ruled out: lithiasis, urinary tract lesions, glomerulonephritis, mycobacterium and schistosoma infections, and drug toxicity. Adenovirus was detected by cellular cultures and BK/JC virus DNA sequences were detected using a polymerase chain reaction method. Because BK/JC virus shedding is very common (75%) in HIV patients receiving chemotherapy, our data strongly suggest that adenovirus was responsible for the haemorrhagic cystitis in our patient. In conclusion, adenovirus should be considered as a potential cause of haemorrhagic cystitis in AIDS patients whose immunosuppression is aggravated by cytotoxic drugs.     

Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplants is the complex result of BK virus infection, preparative regimen intensity and donor type

Background

Hemorrhagic cystitis is a common cause of morbidity after allogeneic stem cell transplantation, frequently associated with BK virus infection. We hypothesized that patients with positive BK viruria before unrelated or mismatched related donor allogeneic hematopoietic stem cell transplantation have a higher incidence of hemorrhagic cystitis.

Design and Methods

To test this hypothesis, we prospectively studied 209 patients (median age 49 years, range 19–71) with hematologic malignancies who received bone marrow (n=78), peripheral blood (n=108) or umbilical cord blood (n=23) allogeneic hematopoietic stem cell transplantation after myeloablative (n=110) or reduced intensity conditioning (n=99). Donors were unrelated (n=201) or haploidentical related (n=8).

Results

Twenty-five patients developed hemorrhagic cystitis. Pre-transplant BK viruria detected by quantitative PCR was positive in 96 patients. The one-year cumulative incidence of hemorrhagic cystitis was 16% in the PCR-positive group versus 9% in the PCR-negative group (P=0.1). The use of umbilical cord blood or a haploidentical donor was the only significant predictor of the incidence of hemorrhagic cystitis on univariate analysis. There was also a trend for a higher incidence after myeloablative conditioning. Multivariate analysis showed that patients who had a positive PCR pre-transplant and received haploidentical or cord blood grafts with myeloablative conditioning had a significantly higher risk of developing hemorrhagic cystitis (58%) than all other recipients (7%, P<0.001).

Conclusions

Hemorrhagic cystitis is the result of a complex interaction of donor type, preparative regimen intensity, and BK viruria.     

Chronic graft versus host disease: a syndrome of disordered immunity.

A chronic, debilitating syndrome related to graft-versus-host disease (GVHD) has been recognized in long-term survivors following allogeneic bone marrow transplantation. In six of 20 marrow graft recipients who survived for more than one year after receiving a transplant, this complication developed; they were studied to better define the syndrome. There was no association between the sex of either donor or recipient, HLA type, blood group, conditioning regimen or marrow cell dose and subsequent development of chronic GVHD. All six patients had mild to moderate manifestations of acute GVHD following prompt engraftment. Chronic GVHD was characterized in each patient by progression to scleroderma-like skin involvement with hyperkeratosis, reticular hyperpigmentation, atrophy with ulceration and fibrosis with limitation of joint movement. A sicca syndrome was prominent in five patients. Four patients had idiopathic interstitial pneumonitis. Infectious complications were frequent, and DNA viral infections were prominent. Autoimmune hemolytic anemia was present in three patients, and one patient had antinuclear antibody (ANA). A spectrum of immune abnormalities was observed including hypergammaglobulinemia, immunoglobulin M (IgM) paraprotein, elevated circulating immune complexes, plasma cell hyperplasia, lymphocytotoxic antibodies and autoantibodies to autologous or donor lymphocytes. Despite clinical similarity to collagen vascular diseases, none of these patients had anti-DNA antibodies or antibodies to smooth muscle, thyroid or extractable nuclear antigens. In one patient, a skin graft from the marrow donor remained healthy despite progressive involvement in recipient skin, whereas unrelated skin grafts were rejected. Immunosuppressive therapy and plasmapheresis have not been effective. Four patients have died (median survival 458 days from transplantation). Chronic GVHD appears to be a syndrome of disordered immune regulation features of immunodeficiency and autoimmunity.     

Identification of patients with increased risk of infection with herpes simplex virus after renal transplantation.

Forty-nine recipients of renal allografts were studied for infection with herpes simplex virus (HSV) before and at sequential intervals after transplantation. Forty-four (90%) of the patients studied were initially seropositive for neutralizing antibody to HSV type 1. HSV was not shed prior to transplantation nor by any of the five seronegative recipients after transplantation. Twenty-nine (66%) of the 44 seropositive patients shed virus postoperatively: 23 in saliva, three in urine, and three in both sites. Twenty (63%) of 32 seropositive patients examined developed herpetic mucocutaneous lesions. Both viral shedding and lesions were most prevalent during the first four weeks after transplantation. Twenty-nine (85%) of 34 patients with antibody titers of 1:256-1:4,096 and zero of 10 with titers of 1:8-1:128 shed HSV postoperatively (P less than 0.0001). The group with high antibody titers before transplantation were also more likely to develop lesions after transplantation (P = 0.002) as were those with a positive history (P = 0.017). The ability to predict symptomatic HSV recurrences in renal transplant patients could be a valuable aid in identifying individuals with which to evaluate antiviral compounds.     

CD5 — T lymphocytes in renal transplant recipients

Summary The CD3 + CD5— subpopulation of T cells has been shown to be increased in patients following allogeneic bone marrow transplantation, and a statistical association has been found with graft-versus-host disease (GVHD). We studied this population in renal transplant recipients. There was no correlation with rejection episodes but we found an increase in this CD3 + CD5 — population in patients on cyclosporin, and we suggest that these cells may be involved in the mechanism of action of this drug. In patients on azathioprine the absolute number of CD3 + CD5 — lymphocytes is reduced, along with other lymphoid subpopulations.