Pediatr Transplantation 2016
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation
DOI: 10.1111/petr.12659
Polyomaviruses BK, JC, KI, WU, MC, and
TS in children with allogeneic hematopoietic
stem cell transplantation
Rahiala J, Koskenvuo M, Sadeghi M, Waris M, Vuorinen T,
Lappalainen M, Saarinen-Pihkala U, Allander T, S€
oderlund-Venermo
M, Hedman K, Ruuskanen O, Vettenranta K. (2016) Polyomaviruses
BK, JC, KI, WU, MC, and TS in children with allogeneic
hematopoietic stem cell transplantation. Pediatr Transplant, 00: 1–8.
DOI: 10.1111/petr.12659.
Jaana Rahiala1,2, Minna Koskenvuo1,3,
Mohammadreza Sadeghi4, Matti Waris5,6,
Tytti Vuorinen5,6, Maija Lappalainen7, Ulla
Saarinen-Pihkala1, Tobias Allander8, Maria
S€oderlund-Venermo4, Klaus Hedman4,7, Olli
Ruuskanen3 and Kim Vettenranta1
1
Abstract: Timely and reliable detection of viruses is of key importance
in early diagnosis of infection(s) following allogeneic HSCT. Among
the immunocompetent, infections with BKPyV and JCPyV are mostly
subclinical, while post-HSCT, the former may cause HC and the latter
PML. The epidemiology and clinical impact of the newly identified
KIPyV, WUPyV, MCPyV, and TSPyV in this context remain to be
defined. To assess the incidence and clinical impact of BKPyV, JCPyV,
KIPyV, WUPyV, MCPyV, and TSPyV infections, we performed
longitudinal molecular surveillance for DNAemias of these HPyVs
among 53 pediatric HSCT recipients. Surveillance pre-HSCT and for
three months post-HSCT revealed BKPyV DNAemia in 20 (38%)
patients. Our data demonstrate frequent BKPyV DNAemia among
pediatric patients with HSCT and the confinement of clinical symptoms
to high copy numbers alone. MCPyV and JCPyV viremias occurred at
low and TSPyV viremia at very low prevalences. KIPyV or WUPyV
viremias were not demonstrable in this group of immunocompromised
patients.
Division of Hematology-Oncology and Stem Cell
Transplantation, Children’s Hospital, University of
Helsinki, Helsinki, Finland, 2Department of
Pediatrics, Porvoo Hospital, Porvoo, Finland,
3
Department of Pediatrics, Turku University Hospital,
Turku, Finland, 4Department of Virology, University
of Helsinki, Helsinki, Finland, 5Division of
Microbiology and Genetics, Department of Clinical
Virology, Turku University Hospital, Turku, Finland,
6
Department of Virology, University of Turku, Turku,
Finland, 7Department of Virology and Immunology,
Helsinki University Hospital Laboratory Services
(HUSLAB), Helsinki, Finland, 8Department of Clinical
Microbiology, Karolinska University Hospital,
Stockholm, Sweden
Key words: polyomavirus – hemorrhagic cystitis –
childhood – hematopoietic stem cell transplantation
Minna Koskenvuo, Division of Hematology-Oncology
and Stem Cell Transplantation, Children’s Hospital,
Helsinki University, Stenb€ackinkatu 11, Helsinki
00290, Finland
Tel.: +358 50 4270424
Fax: +358 9 471 74707
E-mail: minna.koskenvuo@hus.fi
Accepted for publication 19 November 2015
Abbreviations: ALL, acute lymphoblastic leukemia; AML,
acute myeloid leukemia; BKPyVHC, BKPyV-associated
HC; BKPyV, polyomavirus BK; BLAST, Basic Local
Alignment Search Tool; CML, chronic myeloid leukemia;
EBMT, European Society for Bone and Marrow Transplantation; GVHD, graft-versus-host disease; HC, hemorrhagic
cystitis; HPyVs, human polyomaviruses; HSCT, hematopoietic stem cell transplantation; JCPyV, polyomavirus JC;
JMML, juvenile monomyelocytic leukemia; KIPyV, polyomavirus KI; MC, Merkel cell; MCPyV, polyomavirus MC;
MDS, myelodysplastic syndrome; MUD, matched unrelated donor; PML, progressive multifocal leukoencephalopathy; PoV, polyomavirus; TSPyV, trichodysplasia
spinulosa-associated polyomavirus; TS, trichodysplasia
spinulosa; WIPyV, polyomavirus WI.
Viral infections and reactivations can cause
severe illness among immunocompromised
patients. Detection of viruses is of key importance in early diagnosis of infections following
HSCT.
The classical HPyVs are BKPyV (1) and
JCPyV (2). BKPyV infects up to 90% of
humans worldwide before the age of 10 yr
without specific signs or symptoms and remains
latent thereafter. The seroprevalence of JCPyV
increases slower and reaches 50% by the age
60–69 yr (3, 4). Their clinical manifestations
can be considered significant only among the
1
Rahiala et al.
immunocompromised. The clinical entity mostly
linked to high-level HPyV replication is BKPy
V-associated HC.
BKPyV was first isolated in 1971 from the
urine of a renal transplant recipient (1). This
virus has been suggested to be transmitted via
respiratory secretions or urine with periodical
secretion among those infected. The tropism of
BKPyV for uroepithelium has been associated
with asymptomatic hematuria and with HC in
5–15% of HSCT patients, usually at 3–6 wk
post-transplantation. Yet, urinary shedding of
BKPyV occurs in 60–80% of HSCT recipients.
A ≥ 3-log increase over baseline of urinary
BKPyV load or excretion of >1010 copies/day (or
~107 copies/mL) has been shown to be associated
with HC. However, according to several studies,
it is the degree of BKPyV viremia and not viruria
that predict the renal, urologic, and overall outcomes in the transplant setting (5–7).
JCPyV causes PML and has been diagnosed in
7% of patients with AIDS prior to the advent of
combined antiretroviral therapy. PML is associated with natalizumab treatment in patients with
multiple sclerosis (8). JCPyV can potentially
reactivate in seropositive children undergoing
HSCT.
BKPyV and JCPyV have been detected in the
blood of HSCT patients (ref). Neither BKPyV
nor JCPyV tends to be presented in the plasma
of blood donors, but urinary shedding of BKPyV
and/or JCPyV occurs in 5–20% of blood donors
(3, 4).
At least 10 additional HPyVs have been identified during recent years, including KIPyV (9) and
WUPyV (10), which are mainly found in respiratory tract samples, and MCPyV, which is prevalent, but also associated with rare MC carcinoma
of the skin (11). Another HPyV was identified in
a patient with TS, a rare follicular skin disease of
immunocompromised patients characterized by
facial spines and overgrowth of inner root sheath
cells (12). Seroepidemiological studies indicate
that TSPyV is ubiquitous and latently infects
70% of the general population (13), and the
seropositivity for KIPyV ranges from 63.3% to
70% and for WUPyV from 80% to 100% in the
adult population (14).
The overall clinical impact of the virus remains
to be determined. Other newly identified HPyVs
are HPyV-6, HPyV-7, and HPyV-9, MWPyV,
STLPyV, and NJpYV-2013. The possible disease
association of most new polyomaviruses is
unknown, except for that of MCPyV and
TSPyV. Based on what we know about other
polyomaviruses, it can be assume that pathogenicity, if any, could be observed mainly in
2
immunosupprdesssed patients. It seems that primary exposure to most of these HPyVs occurs
during childhood. The viruses then remain latent
or under immune control, and reactivation during immunosupression has been described for,
for example, KIPy, WUPyV, and MCPyV
(Sharp). MCPyV and TSPyV may during
immunosuppression lead to a severe clinical disease.
The aim of this study was to determine the
incidence and clinical impact of BKPyV, JCPyV,
KIPyV, WUPyV, TSPyV, and MCPyV viremias
among immunocompromised pediatric patients
in conjunction with allogeneic HSCT.
Materials and methods
Patients
The retrospective study included a total of 53 pediatric
patients (Table 1) with a hematologic malignancy, who
underwent allogeneic HSCT and had serum samples collected pre-SCT and at least one and two months postHSCT at the Division of Hematology-Oncology and Stem
Cell Transplantation, Children’s Hospital, University of
Helsinki, Finland, between 1997 and 2006. The time from
primary diagnosis to HSCT ranged from 0.3 to 6.5 yr,
with a mean of 1.7 yr. The patient files were studied, and
demographics and details of infectious symptoms were
reviewed.
Samples
The study material consisted of a total of 184 sera which
were collected from the 53 pediatric patients and were
stored at 70 °C. The time points of interest were preHSCT and one, two, and three months post-HSCT, and at
discharge or death.
Table 1. Characteristics of the study population
Number of patients
Type of malignancy
ALL
AML
CML
JMML
MDS
Sex (Male/Female)
Age (yrs) at diagnosis
Median (range)
Age (yr) at HCST
Median (range)
Donor
MUD
Matched family donor
Cord blood
Haploidentical
Virological samples
Pre-HSCT
1 month post-HSCT
2 months post-HSCT
3 months post-HSCT
53
37
10
4
1
1
31/22
6 (0.2–15.9)
8.2 (0.9–19)
36
10
4
3
53
53
53
25
Polyomaviruses in children undergoing HSCT
BKPyV and JCPyV PCR
For BKPyV and JCPyV, total nucleic acids were extracted
from 220 lL of serum using NucliSense easyMag extractor
(BioMerieux, Lyon, France) with a 55-lL elution volume.
Virus-specific DNA was detected by amplifying a fragment
of the large T-antigen gene by qPCR using universal BK/
JCPyV primers and specific dual-label probes. A 25-lL
reaction consisted of 19 Maxima Probe qPCR Master Mix
(Fermentas), 800 nM each of PyV.fwd and PyV.rev primers
(15), 200 nM each of JCV-FAM (50 FAM-CAGGATCCCAACACTCTACCCCACC-BHQ1 30 ) and BKV-Oran (50
CAL Fluor Orange-CAGATTCTCAACACTCAACACCACCCA-BHQ1 30 ) probes, and 5 lL of sample,
plasmid DNA standard, or no template control for extraction/PCR. Cycling was performed in a Rotor-Gene 3000
instrument (Corbett Research/Qiagen) with an initial denaturation for 10 min at 95 °C and 45 cycles of 95 °C for 15 s,
55 °C for 30 s, and 72 °C for 30 s with fluorescence acquiring to FAM and JOE channels. Copy numbers were determined by comparing sample threshold cycle values to those
obtained with a dilution series of plasmids containing fulllength genomes of BKPyV (ATCC #45024) or JCPyV
(ATCC #45027). Primers were obtained from Oligomer and
probes from Biosearch Technologies. The performance of
the PCR assay has been verified using JCBK proficiency
testing sample panels from QCMD (www.qcmd.org).
Amplifications producing a typical curve crossing the background threshold before 40 (observed values 22–39) cycles
were considered specific.
MCPyV and TSPyV PCR
DNA was extracted from 100 lL of serum by QIAamp
DNA Blood Mini Kit (Qiagen, Valencia, CA, USA) according to the manufacturer’s protocol, and real-time PCR
assays were used for the detection of MCPyV and TSPyV
DNA (16–18). Briefly, two published primer sets targeting
the conserved sequences of the MCPyV and TSPyV genome,
the large T-antigen gene, and the viral capsid-protein (VP1)
gene were used. PCR was performed with the Stratagene
Mx3005p (Stratagene, La Jolla, CA, USA) thermal cycler
using the TaqMan universal PCR master mix (PE Applied
Biosystems, Foster City, CA, USA). Serial dilutions of the
plasmids allowed determination of assay sensitivity. The
MCPyV and TSPyV qPCR products were purified for automated sequencing with the High Pure PCR product purification kit (Roche, Mannheim, Germany). The resulting DNA
sequences were aligned by means of the BLAST against the
MCPyV and TSPyV sequences in GenBank.
WUPyV and KIPyV PCR
From the sera (50 lL each), DNA was isolated with the
QIAamp DNA Blood Mini Kit. PCR with primer set A was
performed as described elsewhere (19, 20). The sensitivities
of the PCRs were assessed with serial dilutions of plasmids
containing the KIPyV and WUPyV VP2 inserts (5 9 103 to
5 9 101 copies per reaction).
Diagnostic criteria of hemorrhagic cystitis
BKPyVHC was defined by the triad of clinical cystitis (dysuria, pain, increased frequency of urination), hematuria of
grade II–IV (grade 0 = no symptoms, grade I = microscopic,
grade II = macroscopic, grade III = macroscopic hematuria
with clots, grade IV = macroscopic hematuria with clots
and/or urinary retention and possible need for clot evacuation and/or renal dysfunction) and BKPyV viruria. HC
work-up had to exclude bacterial, fungal or parasitic infections, hemorrhagic diathesis, and mechanical irritation (calculi, instrumental examination) in the urinary tract. The HCassociated viral infections were assessed both in blood and
urine (BKPyV, adenovirus, and cytomegalovirus).
Statistical analysis
Data were analyzed using Statistical Package for Social
Science (SPSS version 19, Espoo, Finland). The Student’s ttest was used to compare parametric data. Fisher’s exact and
chi-square tests were used to compare the frequency of qualitative variables. p Values <0.05 were considered statistically
significant.
Ethical considerations
The study was approved by the Ethics Committee of the
Medical Faculty of the University of Turku. Also the
Health Care Supervision Centre granted their permission
for the analysis.
Results
The sera were collected from the 53 pediatric
patients with allogeneic HSCT during a 10-yr period (1997–2006). The pretransplant sample and
those at one and two months post-HSCT were collected from all the patients, while only 25 samples
were available at three months. The mean point of
discharge was 78 days (median 64 days, range 30–
188) post-HSCT. Among the deceased, the time
from HSCT to death (n = 23, 43%) ranged from
0.2 to 5.6 yrs (mean 1.4). A total of eight deaths
(34.7%) were attributed to relapse, but others were
caused by treatment-related mortality. Two
patients died within three months post-HSCT.
BKPyV PCR and JCPyV PCR
Altogether 20 of 53 (37.7%) and three of 53
(5.7%) patients or 31 of 184 (16.8%) and three
of 184 (1.6%) samples were PCR positive for
BKPyV and JCPyV, respectively. In eight
patients, more than one sample was positive for
BKPyV (Table 2). Of those positive for BKPyV,
pre-HSCT and at one, two, and three months
post-HSCT, the viral copy numbers ranged from
50/mL to 1.8 9 105/mL (mean 3.4 9 103/mL),
50/mL to 1.6 9 106/mL (mean 3 9 104/mL)
and 50/mL to 5 9 104/mL (mean 2.6 9 103/
mL), respectively. In total, one of 53 (1.9%),
eight of 53 (15.1%), 14 of 53 (26.4%), and eight
of 25 (32%) of the samples were positive for
BKPyV pre-HSCT, one, two, and three months
post-HSCT, respectively.
For JCPyV only three patients one sample
each were PCR positive with copy numbers from
50/mL to 100/mL.
3
Rahiala et al.
Table 2. HPyV PCR-positive patients (n = 26)
Patient
number
Dg
Year of
HSCT
Age (yr)
(mean 10.3)
1
2
5
7
8
9
10
11
13
16
17
18
19
22
23
25
28
33
35
36
37
41
45
47
48
49
AML
ALL
AML
AML
ALL
ALL
ALL
AML
ALL
ALL
AML
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
ALL
Burkitt
ALL
AML
2004
2000
1997
1998
2001
1999
2001
2006
2004
2002
1998
2004
2006
2003
1999
2000
2005
2000
2003
2004
2006
1998
2003
2002
2005
2005
15
7.5
7.9
5.3
8
4.8
9
7.7
13.6
8.3
6.8
16.5
7.7
8.1
6.3
8.4
9.3
13.5
15.4
16.5
16.2
5.9
18.8
9.4
8.2
14.4
BKPyV PCR max
5 9 10E1
5 9 10E1
5.5 9 10E2
1 9 10E2
1 9 10E2
5 9 10E1
3
1
1
3
5
9
9
9
9
9
10E2
10E2
10E2
10E3
10E1
Time of BKPyV
PCR positivity
JCPyV PCR max/time
MCPyV PCR max/time
TSPyV PCR max/time
II
I
Pos/II
Pos/I
Pos/I
Pre, I, II
II, III
III
II
5 9 10E1/I
I
I
II
I, II, III
I
Pos/II
Pos/I
1 9 10E2
1 9 10E2
1 9 10E2
III
II, III
II
1.3 9 10E4
6 9 10E2
5 9 10E1
II, III
II, III
I
1.6 9 10E6
2 9 10E3
5 9 10E1
I, II, III
II, III
II
1 9 10E2/II
5 9 10E1/I
Death
No
No
Yes
No
Yes
No
No
No
No
Yes
No
Yes
No
No
No
Yes
Yes
Yes
Yes
Yes
Yes
No
No
Yes
No
Yes
ALL (n = 14); AML (n = 5); Burkitt, Burkitt’s lymphoma (n = 1); Pre, pre-HSCT; I, one month post-HSCT; II, two months post-HSCT; III, three months post-HSCT.
MCPyV, TSPyV, KIPyV, and WUPyV PCRs
MCPyV DNA was found in samples of four
patients and TSPyV DNA in only one sample.
All the samples investigated were KIPyV and
WUPyV DNA negative by PCR.
Clinical characteristics of polyomavirus infections
Two of the 53 patients had more than one
HPyV-positive serum sample. One was PCR positive for BKPyV before transplantation and at
one and two months post-transplant and was
also positive for MCPyV at one month posttransplant. Another patient was positive for both
BKPyV and TSPyV at two months post-transplant. Fifteen of 26 HPyV-positive and 10/25
HPyV-negative patients were bacteremic during
the post-transplant period (NS). In total, no clinical manifestations could be correlated with the
presence of HPyVs other than BKPyV (Table 3).
Moreover, the incidence and frequency of bacteremias, respiratory or gastrointestinal symptoms, skin manifestations, neutropenia, or fever
during the first 100 days post-HSCT did not differ between patients with or without HPyV viremia (Table 3). Furthermore, the incidence or
severity of GVHD was not associated with HPyV
4
Table 3. Key clinical data on patients positive or negative for the polyomaviruses
Signs and symptoms
Polyomavirus* PCR
positive
Polyomavirus* PCR
negative
Bacteremia
Respiratory
Gastrointestinal
Skin manifestation
Neutropenia (<1 9/L)
Fever
GVHD
Grade 1, n (%)
Grade 2, n (%)
Grade 3, n (%)
Grade 4, n (%)
Corticosteroids
Mortality
15/26 (57.7%)
11/25 (44%)
20/26 (76.9%)
24/25 (96%)
20.4 days, mean
22/22 (100%)
23/26 (88.5%)
3 (13)
5 (21.7)
13 (56.5)
2 (8.7)
19/26 (73.1%)
12/26 (46.2%)
10/25 (40%)
11/23 (47.8%)
20/24 (83.3%)
21/24 (87.5%)
21.1 days, mean
20/22 (90.9%)
23/27 (85.2%)
9 (39.1)
2 (8.7)
11 (47.8)
1 (4.3)
11/25 (44%)
11/27 (40.7%)
p Value
Ns
Ns
Ns
Ns
Ns
Ns
Ns
0.03
Ns
*BKPoV, JCPyV, MCPyV, KIPyV, WIPyV and TSPyV.
By Student t-test, p < 0.05 is statistically significant.
viremia, but the use of corticosteroids showed
statistical significance (p = 0.03) (Table 3).
As a case example, we present the history of a
nine-yr-old male patient having received an unrelated HLA-matched (5/6) umbilical cord blood
transplant (total nucleated cell dose 5.79 9 107/kg)
for relapsed Burkitt’s lymphoma. Conditioning
Polyomaviruses in children undergoing HSCT
consisted of total body irradiation, thiothepa,
and etoposide, with cyclosporin A, mycophenolate, and MTX for GVHD prophylaxis. He
engrafted at day 25 with a full donor chimerism
and no evidence of Burkitt’s lymphoma (t(8,14))
on day 60. The post-transplant course was complicated by an acute GVHD involving the liver,
and a limited chronic GVHD of the immune/hematopoietic system (Evans’s syndrome) treated
with transfusions, splenectomy, rituximab, i.v.
immunoglobulin, anti-D as well as infliximab,
prednisolone, and methylprednisolone. On day 5
post-HSCT, gross hematuria developed with
positive PCR for BKPyV in urine. The patient
was first treated with intravenous hydration,
diuretics, platelet transfusions, and analgetics.
Later, he was sedated for severe pain and needed
assisted ventilation. He received continuous
bladder irrigation and required cystoscopy with
several clot evacuations. Because of massive
bleeding problems, he underwent partial cystectomy and ureterostomy. With microscopic hematuria and BKPyV viruria continuing, the patient
recovered to be discharged after six months of
hospitalization, but died of treatment-related
causes at 11 months post-HSCT.
Discussion
We found HPyV DNAemia in half of the 53
patients with HSCT. Two different HPyVs were
detected in two cases. BKPyV DNAemia was
found in one-fifth of the patients, but only one
sample was weakly positive before transplantation. No particular clinical manifestations were
correlated with BKPyV DNAemia with copy
numbers below 104/mL.
The association between BKPyV and HC has
been studied extensively (5, 6, 19–23). The incidence of BKPyV-associated HC has been shown
to reach 25% in pediatric HSCT populations.
Yet, BKPyV viruria with high viral loads is seen
in up to 80% of pediatric HSCT recipients indicating that high-level viruria in itself is not the
sole player in the pathogenesis of HC, rendering
viremia more specific in the screening and follow-up of BKPyV-associated HC (23, 24). Our
data on two patients with copy numbers over
104/mL and developing HC are in agreement
with a recent prospective study with urine
BKPyV loads exceeding 9 9 106 copies/mL and
those in blood 1 9 103 copies/mL being predictive of the development of HC among transplanted children (25).
Multiple factors may contribute to the pathogenesis of HC among HSCT patients. Patients
with BKPyV viruria, a myeloablative chemotherapy,
an HLA-mismatched, unrelated donor, but not
GVHD as such, have been shown to convey an
increased risk for HC over those receiving
reduced intensive chemotherapy and with an
HLA-matched related donor (26). We could not
identify GVHD as a risk factor for BKPyV viremia. Yet, our patient case illustrates the spectrum of factors known to increase the risk of
severe HC (male, graft from unrelated donor, a
lower total nucleated cell dose).
The impact of a primary infection, a donor–recipient mismatch in serology, or BKPyV-specific
antibody levels in HSCT recipients is presently
unknown. Wong et al. and Arthur et al. (27, 28)
recommend the inclusion of BKPyV serology in
pretransplant evaluation to identify those at high
risk of developing HC post-HSCT. Nosocomial
transmission and control of BKPyV viruria may
also play a role (24), and isolation measures
should be considered for those with a disseminated BKPyV replication involving both the respiratory and gastrointestinal tracts. We did not
encounter differences in respiratory or gastrointestinal symptoms between those with or without
BKPyV viremia.
Severe HC following HSCT is a potentially
life-threatening complication. In the absence of a
universally accepted treatment algorithm, a tailored approach is required in children suffering
from this complication (29). Specific antiviral
therapy remains to be established for BKPyVassociated infections, while an EBMT analysis
suggests cidofovir therapy to potentially be effective in BKPyVHC (30). Less toxic, oral derivate
of cidofovir, CMX001, has been developed with
promising results among solid organ transplant
recipients with BKPyV viremia and viruria (31).
Yet, immunological recovery seems to play a key
role in the eradication of BKPyV among HC
patients with factors such as donor–recipient
mismatch, conditioning regimen, severity of
GVHD and immunosuppressive therapy affecting the speed, and quality of the immune recovery after HSCT (32). HC appears to have a
negative impact on the overall prognosis of
patients with HSCT (7, 33) as also illustrated by
our case.
JCPyV can give rise to PML among the
immunocompromised. After an asymptomatic
primary infection, the virus remains latent in
multiple tissue types, including the kidneys, bone
marrow, and B lymphocytes. During immunosuppression, the virus exits its latency state and
in the brain progressively infects and destroys
oligodendrocytes. In contrast to BKPyV, JCPyV
is very rarely found in the blood of an immunocompetent host. Siebrasse et al. (34) found one
5
Rahiala et al.
plasma sample positive for JCPyV in an HSCT
patient. We observed JCPyV DNA at low copy
numbers (50/mL to 100/mL) in the samples of
three patients without specific symptoms.
In our study, MCPyV DNA was detected in
the serum samples of four patients and TSPyV
DNA in only one, again all in the absence of any
specific symptoms. Husseiny et al. (35) investigated the presence of MCPyV in the serum and
urine from immunosuppressed kidney transplant
recipients. None developed MCPyV viremia, but
viruria was seen in 30% of recipients and in 15%
of donors. They concluded that low level shedding of MCPyV in urine occurs in both immunosuppressed and nonimmunosuppressed subjects.
Abedi Kiasari et al. (36) evaluated the prevalence
of MCPyV in the respiratory samples from
both immunosuppressed and immunocompetent
patients with respiratory symptoms. They found
3% of patients to be PCR positive, but the causative role of MCPyV in the respiratory pathology
remained to be established. Yet, their data
pointed to a pattern of symptoms similar to that
seen with JC- and BKPyV and suggested that
MCPyV also establishes latency and reactivates
with immunosuppression. Siebrasse et al. (34)
collected fecal, respiratory, plasma, and urine
samples from children undergoing transplantation (11/32 HSCT) and found MCPyV and
TSPyV in the fecal and respiratory samples, but
no viremia. Furthermore, Rockett et al. (37)
detected TSPyV only in the respiratory and fecal
samples, at low prevalences (below 1.3%). Chen
et al. (38) investigated the seroprevalence and
primary exposure time of TSPyV and showed the
former to be 5% among constitutionally healthy
children aged 1–4 yrs, and rising up to 48% at
6–10 yrs and 70% among adults. They also
found the MCPyV and TSPyV primary infections among immunocompetent children to be
asymptomatic. Because the TSPyV-related disease trichodysplasia spinulosa develops under
immunosuppression, it is tempting to speculate
that the virus might persist long after primary
infection and reactivate in defective immune
surveillance.
KIPyV or WUPyV viremias were not demonstrable in our series of immunocompromised
patients. Whereas the pathogenic potential of
KIPyV and WUPyV has not been disclosed, a
correlation between immunosuppression and
virus reactivation has been suggested (39, 40).
Notably, most studies on the two viruses have
been carried out with respiratory samples. Kuypers et al. (41) studied allogeneic HSCT recipients, and at one yr post-transplantation, their
cumulative incidence was 26% for KIPyV and
6
8% for WUPyV in respiratory samples. Sputum
production and wheezing were associated with
KIPyV detection during the past week and
WUPyV detection during the past month, with
no associations between the HPyVs and acute
GVHD, CMV reactivation, neutropenia, lymphopenia, hospitalization, or death. Rao et al.
(42) saw no higher prevalence of WUPyV or
KIPyV in the immunocompromised population
compared to the immunocompetent. Bialasiewicz
et al. (43) investigated the presence of WUPyV
and KIPyV in a variety of clinical samples. They
found WUPyV and KIPyV DNA in pediatric
respiratory samples, but in none of the blood
samples. Likewise, in our pediatric patients, no
serum samples were positive for KIPyV or
WUPyV DNA.
In conclusion, our goals were to establish a
longitudinal molecular surveillance of serum
samples from pediatric HSCT recipients and to
define the incidence and clinical impact of polyomaviruses in these patients. The incidences of
BKPyV, JCPyV, MCPyV, TSPyV, KIPyV, and
WUPyV viremias were evaluated using quantitative real-time PCR techniques in a pediatric
HSCT cohort. Our data demonstrate BKPyV
DNAemia to be frequent among pediatric
patients in association with HSCT, with no
apparent clinical associations at DNA copy
numbers below 104/mL. We detected MCPyV
and TSPyV viremias in the serum samples of
HSCT recipients, which has not been previously
reported. KIPyV or WUPyV viremias were not
demonstrable in this group of immunocompromised patients. The frequency of BKPyV DNAemia and development of potentially more
effective and less toxic antivirals encourage clinicians to establish proper screening strategies for
children undergoing HSCT.
Acknowledgments
This work has been supported by grants from the Foundation for Pediatric Research, the Nona and Kullervo V€
are
Foundation, the Research Funds of the University of Helsinki, the Juselius Foundation, the Helsinki University Central Hospital Research and Education and Research and
Development Funds, the Finnish Medical Foundation, the
Academy of Finland (project 1122539), and Turku University Foundation.
Conflict of interest
The authors declare no conflict of interest.
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