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Pediatr Transplantation 2007: 11: 121–123.
Copyright Ó 2007 Blackwell Munksgaard A daring treatment and a successfuloutcome: The need for targeted therapies forpediatric respiratory viruses The report by Stankova et al. in this issue tells ribavirin was used to treat nine of 27 HPIV- the fascinating and inspiring story of a child with infected stem cell transplant patients, without SCID who underwent two sequential human effect on mortality rate (18).
stem cell transplantations (HSCT), a myeloabla- In a small pilot study designed to address tive pre-conditioning regimen, and many post- preemptive therapy in HSCT patients, Chakrabar transplant complications, all while she was et al. treated five patients with HPIV3 infection – actively infected with human parainfluenza virus one asymptomatic and four symptomatic with type 3 (HPIV3). The child never developed severe URTI – with oral ribavirin. Three of these respiratory disease, and three yr later had no individuals, including the patient who had been evidence of damage to the respiratory tract. The asymptomatic at the initiation of therapy, had no child's physicians had elected to initiate aeroso- virologic response. One of those three died; the lized ribavirin two wk before HSCT, and con- other two (including the person with no symp- tinued this medication for 10 months in an effort toms of respiratory disease) were placed on IV to prevent the HPIV3 infection from progressing ribavirin and resolved. The role of ribavirin in in severity; the report cautiously suggests that preventing progression of URTI is uncertain, at this therapy may have contributed to the grat- best. In the patient treated by Stankova et al., the ifying outcome.
question of the significance of risk factors makes This brave physiciansÕ report begs the ques- interpretation even more difficult. Known risks tion: Why are we relying on untested, unproven, for increased mortality from HPIV3 after trans- partially active agents for a virus that is so plantation include graft vs. host disease, steroid important in children? The valiant attempt to use, and the presence of copathogens (2, 11, 17); treat parainfluenza viral respiratory tract disease the child had none of these. However, infection with ribavirin points to our more general with HPIV3 within the first 100 days after trans- dilemma for pediatric respiratory viral diseases; plant has also been associated with increased we are often guessing, trying therapies based mortality (2), and this patient was certainly upon thin evidence for their use for a different infected throughout the high-impact period. This pathogen, or on inadequate in vitro data. Even combination of high and low risk factors makes it for RSV, ribavirin is a nucleoside analog that has even more difficult to evaluate the role of ribavirin good activity against RSV in vitro but has in the positive outcome.
produced conflicting clinical data and uncer- The child in this case was treated for upper tainty with regard to its utility in most cases.
respiratory tract infection (URTI), in an effort to As far as ribavirin use in cases of HPIV3 prevent progression to lower respiratory tract infection, most reports have focused on early disease (LRTI). LRTI is a well-known conse- diagnosis and treatment. The authors of this quence of URTI infection with HPIV3; in one piece seem to have been the first to treat active study of 228 patients who underwent bone HPIV3 infection, in anticipation of transplant.
marrow transplantation and acquired HPIV3 Published reports do not suggest a strong link infection, 198 individuals presented with symp- between ribavirin use in cases of HPIV infection toms of URTI, and 24% of these progressed to and improved outcome. In one large series, LRTI (11). Although the authors of that study did not specifically comment on the role of The F-triggering process itself also may be a ribavirin in preventing progression of disease target for antiviral strategies. First, based upon an from URTI to LRTI, there was no difference in analysis of the F-triggering process, peptides the 30-day mortality for treated patients and corresponding to specific domains of the F protein untreated patients. The child in the Stankova can be designed to prevent the F protein from et al. case report did go on, in fact, to develop reaching its fusion-active state. This strategy is HPIV3 LRTI, from which she recovered.
proving to be effective at improving the design of Why did the physicians in this case have no antiviral peptides for related viruses (13). Finally, specific, targeted, tested, and effective agents at while we have shown that specific mutations in the their disposal? The pediatric respiratory viral stalk region of HN affect HN's ability to trigger F pathogens – including the well-known RSV and protein (16), and that specific features of the the parainfluenza viruses – have lagged far globular head region of HN modulate this trig- behind influenza virus in terms of research gering function (12), we do not yet know how the focus and funding. For influenza, effective signal for activation is transmitted from HN to F antiviral drugs have emerged from the scientific protein. An understanding of this pathway should advances of the last two decades. Antiviral lead to additional targets for interruption of entry development for RSV and parainfluenza has, in and new antiviral agents. These several potential comparison, been strikingly absent. Pediatric therapeutic targets are being actively pursued. It is respiratory diseases have received low levels of to be hoped that future dedicated physicians like funding compared with other fields of health Stankova et al. will not have to rely on a long shot research (7), and only limited resources have or a guess, but will have at the ready several been devoted to RSV or parainfluenza antiviral strategies to protect and treat children with drug development, despite the recognized im- parainfluenza virus infection.
pact of these diseases in children (6). And whileeffective strategies of prophylaxis for RSV are Patricia DeLaMora1 and Anne Moscona1,2 available to protect the groups at most risk (3), 1Departments of Pediatrics and 2Microbiology and there are no tools for the parainfluenza viruses.
Immunology, Weill Medical College of Cornell University Stankova et al. therefore had to go out on a New York, NY, USA limb, and they were lucky.
Several advances, based upon basic research, are ready to be applied to the prevention of acuterespiratory disease (6, 8). These strategies are worth pursuing, to develop targeted antiviral 1. Alymova IV, Portner A, Takimoto T, Boyd KL, Babu YS, compounds for parainfluenza virus. The parain- McCullers JA. The novel parainfluenza virus hemagglutinin- fluenza viruses enter their target cell by binding neuraminidase inhibitor BCX 2798 prevents lethal synergism to a receptor molecule and then fusing their viral between a paramyxovirus and Streptococcus pneumoniae.
envelope with the cell membrane to access the Antimicrob Agents Chemother 2005: 49: 398–405.
cytoplasm. Binding is mediated by the viral 2. Elizaga J, Olavarria E, Apperley J, Goldman J, Ward K.
hemagglutinin-neuraminidase (HN), which then Parainfluenza virus 3 infection after stem cell transplant:Relevance to outcome of rapid diagnosis and ribavirin treat- activates an adjacent fusion protein (F) to ment. Clin Infect Dis 2001: 32: 413–418.
mediate viral fusion into the cell (8, 12, 16).
3. Groothuis J, Simoes E, Levin M, et al. Prophylactic admin- Both binding and fusion are critical steps, and istration of respiratory syncytial virus immune globulin to interfering at the entry stage of the viral life cycle high-risk infants and young children. N Engl J Med 1993: 329: could prevent disease. We identified and func- tionally characterized specific receptor-interact- 4. Huberman K, Peluso R, Moscona A. The hemagglutinin- neuraminidase of human parainfluenza virus type 3: Role of ing sites on the HPIV3 HN molecule (4, 9, 10), the neuraminidase in the viral life cycle. Virology 1995: 214: and once the 3-D crystal structure of the HN protein was solved (5), we mapped these func- 5. Lawrence MC, Borg NA, Streltsov VA, et al. Structure of tional sites onto the HN structure (14). Making the haemagglutinin-neuraminidase from human parainfluenza use of this information, binding inhibitors can virus type III. J Mol Biol 2004: 335: 1343–1357.
6. Loughlin GM, Moscona A. The cell biology of acute child- now be designed specifically to fit into the hood respiratory disease: Therapeutic implications. Pediatr binding pocket on the globular head of HN (1, Clin North Am 2006: 53: 929–959.
15). In addition to interfering with receptor 7. Michaud CM, Murray CJ, Bloom BR. Burden of disease – binding by the HN protein, this blockade would implications for future research. JAMA 2001: 285: 535–539.
interfere with the F-triggering function of the 8. Moscona A. Entry of parainfluenza virus into cells as a target HN protein, which can only occur when the HN for interrupting childhood respiratory disease. J Clin Invest2005: 115: 1688–1698.
protein is in contact with its receptor.
9. Moscona A, Peluso RW, Relative affinity of the human enza type 3 and Newcastle disease virus hemagglutinin-neura- parainfluenza virus 3 hemagglutinin-neuraminidase for sialic minidase receptor binding: Effect of receptor avidity and steric acid correlates with virus-induced fusion activity. J Virol 1993a: hindrance at the inhibitor binding sites. J Virol 2004: 78: 67: 6463–6468.
10. Murrell M, Porotto M, Weber T, Greengard O, Moscona 15. Porotto M, Fornabaio M, Greengard O, Murrell MT, A. Mutations in human parainfluenza virus type 3 HN causing Kellogg GE, Moscona A. Paramyxovirus receptor-binding increased receptor binding activity and resistance to the molecules: Engagement of one site on the hemagglutinin- transition state sialic acid analog 4-GU-DANA (zanamivir).
neuraminidase protein modulates activity at the second site.
J Virol 2003: 77: 309–317.
J Virol 2006: 80: 1204–1213.
11. Nichols WG, Corey L, Gooley T, Davis C, Boeckh M.
16. Porotto M, Murrell M, Greengard O, Moscona A. Trig- Parainfluenza virus infections after hematopoietic stem cell gering of human parainfluenza virus 3 fusion protein(F) by the transplantation: Risk factors, response to antiviral therapy, hemagglutinin-neuraminidase (HN): An HN mutation dimin- and effect on transplant outcome. Blood 2001: 98: 573–578.
ishing the rate of F activation and fusion. J Virol 2003: 77: 12. Porotto M, Murrell M, Greengard O, Doctor L, Mosc- ona A. Influence of the human parainfluenza virus 3 attach- 17. Sparrelid E, Ljungman P, Ekelof-Andstrom E, et al.
ment protein's neuraminidase activity on its capacity to Ribavirin therapy in bone marrow transplant recipients with activate the fusion protein. J Virol 2005: 79: 2383–2392.
viral respiratory tract infections. Bone Marrow Transplant 13. Porotto M, Doctor L, Carta P, et al. Inhibition of Hendra 1997: 19: 905–908.
virus membrane fusion. J Virol 2006: 80: 9837–9849.
18. Wendt C, Weisdorf D, Jordan M, Balfour H, Hertz M.
14. Porotto M, Murrell M, Greengard O, Lawrence M, Parainfluenza virus respiratory infection after bone marrow McKimm-Breschkin J, Moscona A. Inhibition of parainflu- transplantation. N Engl J Med 1992: 326: 921–926.


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