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1138 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 hemorrhagic cystitis complicating bone marrow transplantation. Blood. 2001;98:1971-1978. 12. Erard V, Kim HW, Corey L, et al. BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic 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. 2010;16:662-671. 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: S164-S165. 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 1139 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. REFERENCES 1. Schildgen V, van den Hoogen B, Fouchier R, et al. Human metapneumovirus: lessons learned over the first decade. Clin Microbiol Rev. 2011;24:734-754. 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 syncytial virus and parainfluenza virus infections after hematopoietic stem cell transplantation: the Fred Hutchinson Cancer Research Center experience. Biol Blood Marrow Transplant. 2001;7(Suppl):11S-15S. 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.