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R.K. Avery / Biol Blood Marrow Transplant 19 (2013) 1137e1139
>1000 copies/mL causes increased risk of HC [14]. Interestingly Cesaro’s study showed BK viruria occurred at a median
of 18 days (range, 2 to 30), before overt HC, whereas BK
viremia preceded HC by a median of 17 days (range, 0 to 23),
which provides an opportunity for HC prevention.
In conclusion, the study of Laskin et al. demonstrates
a very strong association between BK viremia and risk of HC
in pediatric recipients of HSCT. BK PCR in plasma is a sensitive method to monitor for BK reactivation, and it could be
used in clinical trials to evaluate preemptive treatment for BK
with the primary endpoint of decreasing HC incidence,
similar to the prevention and preemptive guidelines used in
CMV-reactivation management. The ultimate goal of
decreased HC will lead to decreased morbidity and improved
outcomes. This goal also underscores the need for effective
specific prophylaxis and treatment for BK-associated HC in
our HSCT population. Finally, in light of this study, a larger
multicenter trial is needed with the aim of comparing BK
plasma PCR and BK urine PCR with a universal assay that
detects all 4 genotypes of BK virus.
ACKNOWLEDGMENTS
Financial disclosure: The author has nothing to disclose.
REFERENCES
1. Gardner SD, Field AM, Coleman DV, Hulme B. New human papovavirus
(B.K.) isolated from urine after renal transplantation. Lancet. 1971;297:
1253-1257.
2. Knowles WA. Discovery and epidemiology of the human polyomaviruses BK virus (BKV) and JC virus (JCV). Adv Exp Med Biol. 2006;
577:19-45.
3. Jiang M, Abend JR, Johnson SF, Imperiale MJ. The role of polyomaviruses in human disease. Virology. 2009;84:266-273.
4. Hale GA, Rochester RJ, Heslop HE, et al. Hemorrhagic cystitis after
allogeneic bone marrow transplantation in children: clinical characteristics and outcome. Biol Blood Marrow Transplant. 2003;9:
698-705.
5. Silva Lde P, Patah PA, Saliba RM, et al. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplants is the complex result of BK
virus infection, preparative regimen intensity and donor type. Haematologica. 2010;95:1183-1190.
6. Verghese PS, Finn LS, Englund JA, et al. BK nephropathy in pediatric
hematopoietic stem cell transplant recipients. Pediatr Transplant. 2009;
13:913-918.
7. Cesaro S, Facchin C, Tridello G, et al. A prospective study of BK-virusassociated haemorrhagic cystitis in paediatric patients undergoing
allogeneic haematopoietic stem cell transplantation. Bone Marrow
Transplant. 2008;41:363-370.
8. Arthur RR, Shah KV, Baust SJ, et al. Association of BK viruria with
hemorrhagic cystitis in recipients of bone marrow transplants. N Engl J
Med. 1986;315:230-234.
9. Laskin BL, Denburg M, Furth S, et al. BK viremia precedes hemorrhagic
cystitis in children undergoing allogeneic hematopoietic stem cell
transplantation. Biol Blood Marrow Transplant. 2013;19:1176-1183.
10. Bedi A, Miller CB, Hanson JL, et al. Association of BK virus with failure of
prophylaxis against hemorrhagic cystitis following bone marrow
transplantation. J Clin Oncol. 1995;13:1103-1119.
11. Leung AY, Suen CK, Lie AK, et al. Quantification of polyoma BK viruria in
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12. Erard V, Kim HW, Corey L, et al. BK DNA viral load in plasma:
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hematopoietic cell transplant recipients. Blood. 2005;106:11301132.
13. Gaziev J, Paba P, Miano R, et al. Late-onset hemorrhagic cystitis in
children after hematopoietic stem cell transplantation for thalassemia
and sickle cell anemia: a prospective evaluation of polyoma (BK) virus
infection and treatment with cidofovir. Biol Blood Marrow Transplant.
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14. Cesaro S, Facchin C, Tridello G, et al. A prospective evaluation of
sensitivity and specificity of BK viruria and BK viraemia in paediatric
patients given allogeneic haematopoietic stem cell transplantation
with haemorrhagic cystitis. Bone Marrow Transplant. 2007;39:
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Human Metapneumovirus Infection: Worthy of Recognition
Robin Kimiko Avery*
Division of Infectious Disease (Transplant/Oncology), Johns Hopkins University, Baltimore, Maryland
Article history:
Received 7 June 2013
Accepted 10 June 2013
Human metapneumovirus (hMP) is a relatively recently
described virus (only known since 2001), although studies
of stored blood samples suggest it has been present in
the community going back at least to 1958 [1]. It is a paramyxovirus, related to respiratory syncytial virus (RSV),
and accounts for between 2% and 7% of community respiratory viral illnesses. As with other community respiratory
viruses, symptoms are frequently nonspecific at the outset
and include cough, nasal congestion, sore throat, and
Financial disclosure: See Acknowledgments on page 1139.
* Correspondence and reprint requests: Robin Kimiko Avery, MD, FIDSA
Professor-At-Rank, Division of Infectious Disease (Transplant/Oncology),
Johns Hopkins, 1830 E. Monument St., #434, Baltimore, MD 21205.
E-mail address: [email protected].
1083-8791/$ e see front matter Ó 2013 American Society for Blood and
Marrow Transplantation.
http://dx.doi.org/10.1016/j.bbmt.2013.06.009
fever. However, progression to lower respiratory tract
infection can occur. Case series have suggested a high
mortality associated with this infection in transplant
recipients; a report by Englund et al. [2] documented the
association between hMP, respiratory failure, and a septic
shock-like presentation, with death from acute respiratory
failure occurring in 4 of 5 hematopoietic stem cell transplantation (HSCT) recipients. However, despite such reports,
hMP remains an under-recognized cause of infection in
immunocompromised patients.
In this issue an article by Renaud et al. entitled “Mortality
rates of human metapneumovirus and respiratory syncytial
virus lower respiratory tract infections in hematopoietic
stem cell transplant recipients” [3] represents the latest of
many valuable contributions by the group at Fred Hutchinson Cancer Research Center to our understanding of
infections after HSCT. Previous work by this group has
elucidated the epidemiology of many different infections
(viral, fungal, bacterial) in this high-risk patient population.
This group’s prior work on respiratory viruses has established risk factors and outcomes for these infections and has
R.K. Avery / Biol Blood Marrow Transplant 19 (2013) 1137e1139
supported the utility of ribavirin therapy for RSV, although
less strongly for parainfluenza virus [4]. The group has also
studied the use of the RSV monoclonal antibody palivizumab
in the HSCT population [5]. They have documented the
challenges involves in performing randomized trials of
therapy for respiratory virus infections in this population, for
example a multicenter study of pre-emptive ribavirin
therapy for RSV upper respiratory tract infection for the
prevention of progression to lower respiratory tract disease
(pneumonia) [6]. Although this study was discontinued due
to slow accrual, valuable lessons were learned, including
a trend toward decreasing viral loads in the ribavirin-treated
group [6]. Most recently, published in this journal earlier this
year, the same group identified stem cell source and oxygen
requirement as risk factors for poorer outcome in HSCT
recipients with RSV infection [7].
Although RSV infection has been more extensively
studied, hMP infection in this population has been the
subject mainly of case reports and small case series. Thus,
a carefully performed comparative study of risk factors and
outcomes is a welcome addition to the literature. The authors
report that the mortality of RSV and hMP lower respiratory
tract infections in this population was high but notably
exactly the same (43%) with either virus. Their discussions of
different radiographic patterns, which may possibly be
associated with differential outcomes, as well as exploration
of the significance of viral load (very high bronchoalveolar
lavage viral loads and detectable viremia were associated
with high mortality) provide new insights into hMP infection. Risk factors for poor outcome appear to be similar to
those identified for RSV; in particular, steroid therapy, stem
cell source, oxygen requirement, and mechanical ventilation
were identified as risk factors for mortality.
The authors attempted to determine whether ribavirin
therapy had any impact on the course of hMP infection. This
analysis was not conclusive, for several reasons. Whereas
aerosolized ribavirin was administered to RSV patients per
institutional protocol, it was given only per clinician choice
in the case of hMP and not as part of a protocol. Immunoglobulin preparations were also administered to some hMP
patients but not to others. Although multiple in vitro studies
and case reports suggest possible utility of ribavirin and
intravenous immunoglobulin (IVIg) in hMP infection, further
studies are needed to determine optimal therapy. In addition, the current study does not address the possible utility
of oral ribavirin, which has been reported by other investigators [8]. The current study also does not address the
possible utility of IVIg, although this therapy is commonly
administered with or without ribavirin as in the patients
reported herein.
There are several other questions the current study
cannot answer. Given the high mortality of hMP infection,
rapid pre-emptive therapy would seem to be a logical
intervention to try, yet the initiation of therapy for hMP was
later in time after diagnosis than that for RSV in this study.
This may reflect the existence of an institutional protocol and
greater clinician confidence in the utility of therapy for RSV.
Nonetheless, studies involving larger numbers of patients
who were treated earlier after diagnosis of hMP would be of
interest. A randomized controlled trial would be ideal, but
this would likely not be easy to accomplish, as the case of RSV
illustrates. A further question of interest in future studies
would be the risk of infections, including fungal infections, in
the aftermath of hMP infection. The current study reported
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copathogens but did not specifically study infections occurring later after hMP. Marr and colleagues [9] reported that
respiratory virus infections constitute a risk factor for the
subsequent development of invasive aspergillosis. It will be
of interest to explore this issue further with respect to hMP.
Although many unanswered questions remain, one of the
main implications of the current study is the idea that
clinicians and centers should make sure to include hMP,
particularly by PCR testing, in their diagnostic panels for
respiratory viruses, at least for prognostic reasons if not as
a prelude to initiation of therapy. Finally, the authors make
the point that newer antivirals are needed for treatment of
respiratory viruses, and if and when such agents are developed, hMP should be among the viruses to be tested
regarding the efficacy of these new agents.
In conclusion, hMP infection appears to be on an equal
footing with RSV in terms of high mortality after HSCT. Risk
factors for poorer outcome were similar between these two
viruses. Therapy with ribavirin and with IVIg preparations
was administered to some patients per clinician choice, but
from the current study it is not possible to establish whether
or not this therapy was helpful, unlike the case of RSV in
which the utility of ribavirin is clearer. Further studies
including larger numbers of patients are needed to answer
the questions of optimal therapy and the utility of preemptive therapy. These investigators are to be commended
for highlighting the importance of hMP virus as a pathogen
and enlarging our understanding of its role in the HSCT
recipient.
ACKNOWLEDGMENTS
Financial disclosure: R.K.A. has been a co-investigator on
multicenter studies funded by Viropharma, Astellas, Chimerix, Schering-Plough, and Roche. She receives no personal
financial remuneration from any pharmaceutical entity, and
all research grant support is paid directly to Research
Accounting.
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2. Englund JA, Boeckh M, Kuypers J, et al. Brief communication: fatal
human metapneumovirus infection in stem-cell transplant recipients.
Ann Intern Med. 2006;144:344-349.
3. Renaud C, Xie H, Seo S, et al. Mortality rates of human metapneumovirus
and respiratory syncytial virus lower respiratory tract infections in
hematopoietic stem cell recipients. Biol Blood Marrow Transplant. 2013;
19:1221-1227.
4. Boeckh M, Berrey MM, Bowden RA, et al. Phase 1 evaluation of the respiratory syncytial virus-specific monoclonal antibody palivizumab in recipients of hematopoietic stem cell transplants. J Infect Dis. 2001;184:350-354.
5. Nichols WG, Gooley T, Boeckh M. Community-acquired respiratory
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6. Boeckh M, Englund J, Li Y, et al. Randomized controlled multicenter trial
of aerosolized ribavirin for respiratory syncytial virus upper respiratory
tract infection in hematopoietic cell transplant recipients. Clin Infect Dis.
2007;44:245-249.
7. Seo S, Campbell AP, Xie H, et al. Outcome of respiratory syncytial virus
lower respiratory tract disease in hematopoietic cell transplant recipients receiving aerosolized ribavirin: significance of stem cell source and
oxygen requirement. Biol Blood Marrow Transplant. 2013;19:589-596.
8. Egli A, Bucher C, Dumoulin A, et al. Human metapneumovirus infection
after allogeneic hematopoietic stem cell transplantation. Infection. 2012;
40:677-684.
9. Marr KA, Carter RA, Boeckh M, et al. Invasive aspergillosis in allogeneic
stem cell transplant recipients: changes in epidemiology and risk
factors. Blood. 2002;100:4358-4366.