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General Urology
Arch. Esp. Urol. 2014; 67 (2): 167-173
HEMORRHAGIC CYTITIS AFTER BONE MARROW TRANSPLANTATION
B. Padilla-Fernandez1, J.M. Bastida-Bermejo2, A.J. Virseda-Rodriguez3, J. Labrador-Gomez2,
D. Caballero-Barrigon2, J.M. Silva-Abuin4, J.F. San Miguel-Izquierdo2 and M.F. Lorenzo-Gomez3.
Urology Department. University Hospital Canarias. Tenerife.
Hematology Department. University Hospital Salamanca.
3
Urology Department. University Hospital Salamanca. Universidad de Salamanca.
4
Urology Department. San Pedro Hospital. Logroño. Spain.
1
2
Summary.- OBJECTIVES: Hemorrhagic cystitis (HC)
presenting with gross hematuria, bladder pain and
urinary frequency develops in 13-38% of patients
following bone marrow transplantation (BMT). The
objective of the study was to study the characteristics of
patients suffering hemorrhagic cystitis after hematopoietic
stem cell transplantation in our center.
METHODS: We conducted a retrospective chart review
of all patients who underwent BMT at our institution
between January 1996 and August 2012. We recorded
the age, sex, diagnosis, conditioning regimen, interval
between BMT and development of symptoms of cystitis
and treatment instituted.
RESULTS: Five hundred patients underwent BMT in
the period of time studied. 52 of them developed
hemorrhagic cystitis. The mean age of the affected
@
patients was 39 years; there were 34 males and 18
females. The diagnoses include AML (n=11), ALL (n=8),
CML (n=6), MDS (n=11), CLL (n=5), NHL (n=1), HD
(n=5), MM (n=2), Medular aplasia (n=3). HC appeared
59.48 days after BMT. There were no differences
between sexes. Mortality among the 52 patients was
51.14 % but HC was not the cause of death in any
patient. Polyomaviruses were detected in the urine of
78.94 % of survivors.
CONCLUSIONS: Polyomavirus infection with BK and JC
types is usually acquired in infancy and the virus remains
latent in renal tissue. Immunosuppression facilitates
reactivation of the renal infection and replication of
the virus responsible for the clinical manifestations of
HC. The differential diagnoses include other urinary
infections, lithiasis, thrombocytopenia and adverse
effects of pharmacological agents. The urologist plays a
limited role in the management of this disease.
Keywords: Hemorrhagic cystitis. Hematopoietic
stem cell transplantation. Polyomavirus.
CORRESPONDENCE
Bárbara Padilla Fernández
Ctra. Ofra, s/n
38320 San Cristóbal de La Laguna
Santa Cruz de Tenerife (Spain)
[email protected]
Accepted for publication: February 25th, 2013
Resumen.- OBJETIVOS: Tras trasplante alogénico de
células hematopoyéticas aparece cistitis hemorrágica en
13-38% de casos, siendo los síntomas más frecuentes
hematuria macroscópica con/sin coágulos, polaquiuria, dolor y espasmos vesicales.
Estudiar las características de los pacientes que sufren
cistitis hemorrágica tras trasplante de progenitores hematopoyéticos en nuestro centro.
MÉTODOS: 500 pacientes recibieron trasplante alogénico de progenitores hematopoyéticos (TAPH) entre
enero de 1996 y agosto de 2012, de los cuales 52
168
B. Padilla-Fernández, J.M. Bastida-Bermejo, A.J. Virseda-Rodríguez, et al.
sufrieron cistitis hemorrágica. Investigamos edad, sexo,
diagnóstico principal, régimen de acondicionamiento,
tiempo desde TAPH hasta la cistitis, presencia de poliomavirus en orina, duración de la clínica, tratamiento
recibido, supervivencia de los pacientes.
RESULTADOS: Edad media 39 años (rango 19-66).
34 varones:18 mujeres. Diagnóstico: LMA (n=11), LLA
(n=8), LMC (n=6), SMD (n=11), LLC (n=5), LNH (n=1),
EH (n=5), MM (n=2), Aplasia Medular (n=3). Cistitis
hemorrágica a los 59,48 días post-trasplante, sin diferencia entre varones y mujeres. No hubo diferencias en
el tipo de acondicionamiento administrado entre varones y mujeres. Se demostró la presencia en orina de Poliomavirus en 78,94% de los supervivientes. 8 pacientes
requirieron evaluación por Urología durante el ingreso.
Mortalidad de la muestra del 46,15%, ninguna muerte
por la cistitis hemorrágica.
CONCLUSIONES: La cistitis hemorrágica en pacientes
sometidos a trasplante de médula ósea es una patología de alta prevalencia, apareciendo los poliomavirus
BK y JC como virus emergentes en su etiología. Se ha
de realizar un diagnóstico diferencial con infecciones
urinarias de otro origen, causas farmacológicas, trombopenias secundarias a la enfermedad de base y litiasis
urinarias. El urólogo participa poco en el manejo de
esta patología.
Palabras clave: Cistitis hemorrágica. Trasplante
de progenitores hematopoyéticos. Poliomavirus.
INTRODUCTION
Haemorrhagic cystitis (HC) is closely
associated with allogeneic haematopoietic stem cell
transplantation and develops in 13 to 38 % of the
cases (1). The manifestations of HC include gross
haematuria (frequently with clots), urinary frequency,
dysuria, suprapubic pain and bladder spasms.
Occasionally clot retention and renal insufficiency
develop (2).
Haematuria that develops early is often
caused by damage to the bladder epithelium by the
drugs used for induction such as cyclophosphamide
and busulfan and is usually self-limiting. When the
symptoms develop after the graft has taken, replication
of polyomavirus appears to play and important role.
In these cases the symptoms tend to be more severe
and haematuria can be life-threatening.
In the present study we review our experience
with HC especially looking at the symptoms, aetiology
and treatment.
MATERIALS AND METHODS
We conducted a retrospective chart review
of all patients who underwent BMT at our institution
between January 1996 and August 2012. We
recorded the age, sex, diagnosis conditioning
regimen, type of transplantation, interval between
BMT and development of symptoms of cystitis,
symptoms present, severity of the HC and treatment
instituted.
The severity of HC was graded as follows (3):
Grade 1. Microscopic haematuria.
Grade 2. Gross haematuria.
Grade 3. Gross haematuria with clots.
Grade 4. Gross haematuria with clots and renal
insufficiency secondary to obstruction.
Urine samples of patients with suspected HC
were examined for the presence of viral particles
by electron microscopy at the Centro Nacional de
Microbiología de Majadahonda (Madrid, Spain).
Virus was considered to be present when 45 nm
icosahedral particles were identified in the nuclei of
urothelial cell and or when viral DNA was detected
by PCR.
Statistical analysis was conducted using the
Student t test and Fisher’s exact test. A p value <0.05
was considered significant.
RESULTS
A summary of the main characteristics of the
series is set on Table I.
Five hundred patients underwent BMT during
the study period. Of these 52 (34 male, 18 female)
with a mean age of 39.44 years developed HC.
The diagnosis leading to BMT were acute myeloid
leukaemia (AML) in 11 patients, acute lymphocytic
leukaemia (ALL) in 8, chronic myeloid leukaemia in 6,
chronic lymphocytic leukaemia in 5, myelodysplastic
syndrome in 11, non-Hodgkin lymphoma in 1,
Hodgkin’s disease in 5, multiple myeloma in 2 and
bone marrow aplasia in 3.
There were 28 allogeneic transplantations
from related donors, 17 from unrelated donors and 7
from umbilical cord cells. In 4 cases there was an HLA
mismatch. The conditioning regime was the same in
men and women (p=0.7541). Cyclophosphamide
was used in 27 of the 52 cases and simultaneous
total body radiation in 8.
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HEMORRHAGIC CYTITIS AFTER BONE MARROW TRANSPLANTATION
Table I. Summary of the most important characteristics
of the series.
Haemorrhagic Cystitis
Median age
39,34 years (19-66)
Male/Female
34/18
Cyclophosphamide
27 patients
Total body irradiation
8 patients
Clnical course Grade 1
7 patients
Grade 2
27 patients
Grade 3
10 patients
Grade 4
0 patients
Blood transfusion
38,46%
Positive virus in urine
Blood transfusions for severe anaemia were
required in 46.66% of affected men and 18.18% of
women. There was a statistically significant difference
(p=0002) in the incidence of massive bleeding
between patients who survived and those who did
not (Figure 1). Although survivors had more time
free of bleeding (6.1± SD 13.89 days) than nonsurvivors (3.84± SD 5.58 days), the difference was
not significant (p=0.4613).
Viruses were identified in the urine samples of
78.94% of surviving patients. Polyomavirus was found
in 31 cases (60%), cytomegalovirus was identified in
1 case and in another patient both polyomavirus JC
and adenovirus were found.
38 patients
51,14%
Mortality
6 of 26 males and 2 of 17 women mainly because of
pain or severe haematuria. A 41.17% of men and a
61.11% of women died but the cause of death was
never HC. The follow up time for was 57.47 days
(range 3-136).
The predominant clinical presentation
consisted of urinary frequency, dysuria, bladder
spasms, tenesmus and micro or gross haematuria. The
severity of HC was grade 1 in 7 patients, grade 2 in
27, grade 3 in 10 and grade 4 in none. Only 33% of
patients had signs of urinary obstruction. Symptoms
of HC started at a mean of 59.48 (range 1 to 269)
days after BMT. There were no differences between
men and women (p=0.802).
An urological consultation was requested in
No virus was identified by electron microscopy
in 9 patients (17.3%). In 7 of these patients the
conditioning regime had included cyclophosphamide,
in 5 busulfan and in 4 cases both drugs were used.
One patient in whom no virus was found had a
severe coagulopathy related to the original disease.
These data are summarized in Table II. The suspected
aethiological agents on each case are explained in
Table III.
The mean time of onset of symptoms was 54
days post BMT in patients in whom the presence of
a virus in the urine was not documented versus those
in whom polyomavirus was found (mean 73 days)
a difference not statistically significant (p=0.4837).
Figure 2 shows the difference in symptoms between
patients with confirmed virus in the urine and those
without. Patients with virus in the urine had more
Table II. Haemorrhagic cystitis’ characteristics in male and female patients.
Male
Female
Signification
56.21 days
60.25 days
p=0,802
6
2
p=0,698
14 (41.17%)
11 (61,11%)
p=0,245
Platelets transfusion
7
7
p=0,196
Red cells transfusion
16
3
p=0,037
Median symptoms’ beginning time
Urologist’s opinion asked
Mortality
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B. Padilla-Fernández, J.M. Bastida-Bermejo, A.J. Virseda-Rodríguez, et al.
frequency and tenesmus vesicae but no differences in
other manifestations of HC.
The severity of the symptoms was equal in
both sexes (p=0.2077). Comparing survivors and
non-survivors, there were no differences between the
groups in the presence of virus in the urine (p=0.6906),
the severity of the disease (p=0.2765), or the number
of days without bleeding (p=0.4613). Regarding time
without bleeding, we found no differences between
the presence and absence of virus in the urine either in
survivors (p=0.9845) or non-survivors (p=0.3736).
The most commonly used treatments for HC
were: hyper hydration, bladder catheter drainage
with or without irrigation, platelet transfusion,
anticholinergic medications (tolterodine, oxybutynin),
antiseptics and antibiotics (ciprofloxacin, amoxicillin)
and morphine chloride. Six patients received
intravesical cidofovir.
DISCUSSION
The aetiology of HC can be divided into
2 categories, one is related to conditioning regime
(drug induced and actinic) and viral. Drugs that
can cause HC include cytostatic agents, among
others cyclophosphamide, Ifosfamide, busulfan and
etoposide. The other aetiological agents are viruses,
mainly polyomavirus, adenovirus (usually type 11,
prevalent in Japan) and rarely cytomegalovirus.
BK type and 10 to 14 for the JC type (5). The route
of infection is respiratory and the virus settles in the
kidneys. The virus can remain dormant for many years
in the kidneys, bladder mucosa, lymphatic tissue and
circulating leukocytes (6). It is estimated that 80 % of
the population has been infected and has antibodies
against the virus (7).
Immunosuppression facilitates the reactivation
of the virus in the kidneys as can be seen in
immunodeficiency, pregnancy and following organ
transplantation (1). The excretion of the virus in the
urine (viruria) is associated with ureteral stenosis,
interstitial nephritis and graft failure after renal
transplantation as well as haemorrhagic cystitis after
BMT (8). In HC, viruria precedes viremia but viremia
is more specific and has a greater predictive value (9).
The BK virus has also been implicated y neoplasms
(10) and pneumonitis (11).
The following 3 related factors play a role
in the development of HC (3, 12, 13): 1) damage
to the transitional urothelium during conditioning
therapy; 2) massive viral replication facilitated by
immunosuppression; and 3) early recovery of the
immune system after transplantation.
Polyomaviruses consist of small double
stranded DNA viral particles without an envelope
belonging to the family of Papoviridae (4) and are
the most frequent cause of HC. The first infection
occurs in childhood, at the age of 3 or 4 years for the
Figure 1. Cases of mild cystitis and massive bleeding
(%) in living and deceased patients.
Figure 2. Difference in symptoms between patients with
confirmed virus in the urine and those without (%).
HEMORRHAGIC CYTITIS AFTER BONE MARROW TRANSPLANTATION
Table III. Aetiological agents implicated in the
development of haemorrhagic cystitis in the series.
Haemorrhagic Cystitis’ Aetiology
Positive virological examination
Polyomavirus BK
10
Polyomavirus JC
1
Polyomavirus BK+JC
5
Polyomavirus not specified
17
Adenovirus
2
Adenovirus+Polyomavirus
2
CMV
1
Positive virological examination
Cyclophosphamide
3
Bulsufan
1
Cyclophosphamide +Busulfan
4
Coagulopathy
1
Total Body Irradiation
8
Lithiasis
0
Thrombopenia
15
The development of acute graft versus
host disease (GVH) and prior treatment with
cyclophosphamide are considered risk factors for the
development of HC (14).
Clearly,
the
administration
of
2mercaptoethane sulfonate (MESNA) and hyper
hydration before and during the administration of
cyclophosphamide have decreased the incidence
of chemical cystitis caused by acrolein, an urotoxic
metabolite of cyclophosphamide (15). Busulfan is
also important for the development of HC and its role
is increasing as the toxicity of cyclophosphamide has
decreased. The simultaneous administration of both
drugs increases the risk of HC (16).
GVH disease plays a facilitating role. It
171
is postulated that viral replication in the urothelium
induces expression of antigens that are detected by
the newly developed immune competent cells from
the donor which aggravates and perpetuates the
urothelial lesion (17).
The diagnosis of HC is based on the history,
the physical examination and the exclusion of
other causes of painful haematuria. The differential
diagnosis includes bacterial, fungal and parasitic
urinary tract infections, pharmacological causes,
urinary lithiasis and thrombocytopenia secondary to
the primary disease or the BMT (1).
The initial treatment of HC with micro or
gross is hyper hydration, forced diuresis (9, 18). If
the haematuria is intense, there is suprapubic pain,
or irritative voiding symptoms, a bladder catheter
with continuous irrigation with normal saline solution
is the usual method of treatment (8, 18). The catheter
allows easier evacuation of clots and the instillation of
intravesical medications (18) and is helpful to aliviate
voiding discomfort and pain.
Pain medication such as morphine chloride
are needed in half of the patients. Antispasmodic
medications are also used often. Cystoscopy under
general anaesthesia with evacuation of clots and
fulguration of bleeding points is widely accepted (2).
The platelet count should be kept above
5x104 to minimize bleeding tendencies. Given the
nature of the diseases and tratments these patiens
have, this may require platelet transfusion. According
to the intensity of bleeding, red cell transfusion may
br needed.
Have been reported in 66% of cases and
partial responses in 13% (9). Since the discovery
that many cases of post BMT haemorrhagic cystitis
have a viral aetiology, systemic administration of
antiviral medications has been used (18). Cidofovir
is an acyclic nucleoside analog which has proven
to have wide spectrum antiviral activity through the
selective inhibition of viral DNA synthesis. It must
be administered with Probenecid (9, 19). Dose
dependent neurotoxicity is frequently seen with the
use of Cidofovir that can be minimized using low
doses (0.5 -1 mg/kg per week) (20) or by using it
for intravesical instillation (21). Complete responses
of HC have been observed following Cidofovir in a
66% of patients, and partial responses in a 13% (9).
Other treatments for HC have been reported in
single cases or small series of patients without clear
advantages over what we just discussed. They include:
1) Fibrin glue (22); 2) Intravesical hyaluronic acid
(23); 3) Prostaglandin E2 bladder instillation (24);
4) Intravenous Vidarabine (25); and 5) Hyperbaric
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B. Padilla-Fernández, J.M. Bastida-Bermejo, A.J. Virseda-Rodríguez, et al.
oxygen (26).
In our Centre, HC is usually managed by
haematologists and a urologic evaluation is seldom
requested. This and the fact that there are few centres
where BMT is performed contribute to make HC little
known in our speciality and among our colleagues.
In our experience what is important in the care of
these patients is to maintain good bladder drainage,
evacuate clots and provide appropriate analgesia.
CONCLUSIONS
Polyomaviruses BK and JC are emergent
viruses that often cause an infection in childhood
and remain latent in renal tissue for long periods
of time. Immunosuppression facilitates reactivation
and viral replication is responsible for the clinical
manifestations. Haemorrhagic cystitis in patients
undergoing bone marrow transplantation is difficult
to manage and can cause life threatening bleeding in
46.66% of the cases.
Haemorrhagic
cystitis
cause
by
cyclophosphamide toxicity is declining in frequency
thanks to the routine use of hyper hydration and
MESNA. In contrast busulfan is becoming increasingly
more important as an urotoxic agent.
Viral haemorrhagic cystitis appears to be
related to acute graft versus host disease and is usually
seen after the 40th post-transplant day. The detection
of the virus and the severity of urinary symptoms such
as pain, frequency and urgency are unrelated to the
disease prognosis.
Although long-term sequelae of HC after renal
transplantation have been described this is not the
case for HC following BMT. It appears reasonable to
provide long-term urologic follow-up to male patients
after recovering from HC. In young males because of
the possibility of urethral strictures developing after
prolonged catheterization and in adults because of the
likely development of urological diseases associated
with aging. Urologist should improve knowledge of
this disease in order to provide better care for these
patients.
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