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The value of RVP in children's hospitals
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Journal of Clinical Virology 40 Suppl. 1 (2007) S51–S52 www.elsevier.com/locate/jcv
The value of RVP in children’s hospitals Christine C. Robinson* The Children’s Hospital, Aurora, CO, USA Keywords: Respiratory virus; PCR; Multiplex
Children acquire more respiratory virus infections than adults, many of which progress to lower respiratory tract (LRT) disease requiring medical attention or hospitalization (Henrickson et al., 2004; Iwane et al., 2004). Children also present with a variety of syndromes uncommon in adults, including croup and bronchiolitis. Infants and toddlers less than 5 years of age are at highest risk due in part to the small caliber of their airways and immunologic naivet´e. Older children, especially those with immune system defects or underlying cardiopulmonary or neuromuscular disease, can also be affected (Coffin et al., 2007). Most pediatric LRT viral illnesses resolve completely with supportive measures, but some progress to airway hyper-reactivity, permanent lung damage, or are fatal. Indeed LRT disease, 50−90% of which is virus-induced, remains the 4th leading cause of death in children of ages 0–14 years, even in developed countries (Mathers et al., 2006). The net impact of these infections is substantial, especially to hospitals caring exclusively for children. In the USA, more than 500,000 children younger than 18 years of age are hospitalized annually with LRT disease, 50–90% of which is due to respiratory viruses (Henrickson et al., 2004; Lee et al., 2005). Annual direct medical costs for managing RSV infections alone in the USA are estimated at $394 million, not including the fiscal drain and emotional toll on parents for losses from work or the consequences of antibiotic overuse (Paramore et al., 2004). From 3% to 18% of all admissions to a children’s hospital in the USA is due to LRT disease, most of which occur in the 4 month period of December through March. This annual influx stresses resources of even the most efficient facility. Accurate clinical diagnosis of LRT disease in the pediatric age group is especially difficult due to the number of different viral pathogens, the many syndromes each virus can cause, the overlap in seasonality of individual viruses, and the non-viral etiologic possibilities that must be considered (McIntosh, 2002). Diagnosis of influenza typifies this problem. Most influenza-virus infected adults present with “influenza-like illness” (ILI). In contrast, chil* Correspondence: Christine Robinson PhD. Tel.: +1 720 777 6215. E-mail address: [email protected] (C.C. Robinson) 1590-8658/ $ – see front matter © 2007 Elsevier B.V. All rights reserved.
dren with influenza virus infection tend to have vague upper respiratory tract symptoms, or fever and few respiratory tract signs. Influenza-virus infected infants can also have a sepsis-like picture or present with croup, bronchiolitis, or pneumonia suggestive of bacterial or another viral infection. Even patients with a classic ILI presentation can be infected with viruses other than influenza (Friedman and Attia, 2002; Lamson et al., 2006). As a result, physicians confronted with infants or children with possible viral LRT disease frequently order empiric antibiotics and numerous ancillary diagnostic tests including sepsis workups with blood cultures, urinalyses, complete blood counts, and even lumbar punctures with bacterial cultures or herpes simplex viral PCR (Bonner et al., 2003). Children’s hospitals therefore have a pressing need for rapid, accurate and cost-effective respiratory virus diagnostic tests to provide more focused care, administer antimicrobials appropriately, limit nosocomial infections, collect accurate surveillance data, and improve fiscal outcomes. Until recently, RSV and influenza virus immunoassays were the only commercially available and approved rapid tests for respiratory viruses in the USA. Unfortunately, the performance of these assays is now known to be less than ideal (Abels et al., 2001; Grijalva et al., 2007) and similar tests for other viruses were unavailable. Rapid centrifugation culture was therefore a welcome technical advance in that the parainfluenza viruses and adenovirus as well as RSV and influenza virus could be detected (Rabelais et al., 1992). Unfortunately the turnaround time for results exceeded the length of stay of most children with LRT disease (Adcock et al., 1997; Barenfanger et al., 2000). Whether mixed cell centrifugation culture can decrease this turnaround time remains controversial (Weinberg et al., 2004; LaSala et al., 2007). Direct immunofluorescence (DIF) of respiratory tract secretions has now been adopted by many children’s hospitals because the array of viruses detectable by centrifugation culture could also identified by DIF in a few hours time with reasonable specificity and sensitivity. Several studies have now demonstrated that DIF can significantly improve outcomes for hospitalized children with LRT disease by reducing antibiotic use, decreasing lengths of stay, and lowering costs (Woo et al.,
S52
C.C. Robinson / Journal of Clinical Virology 40 Suppl. 1 (2007) S51–S52
1997; Barenfanger et al., 2000; Byington et al., 2002). Throughput for DIF, however, is limited, readings are subjective, and reagents for some of the newly discovered respiratory viruses are either not yet available or not approved for in vitro diagnostic use. This experience suggests that the test most able to positively impact the care of hospitalized children with LRT disease is one that can be completed in less than a day, has high sensitivity for the broadest array of viruses know to infect children, and can be performed in a costeffective manner during times of high and low respiratory virus circulation. Real-time multiplex respiratory virus PCR has many of these attributes. Multiplex PCR can also detect more mixed viral infections than traditional methods in children with LRT (Kehl et al., 2001; Freymuth et al., 2006; Kuypers et al., 2006). This capability may have important prognostic value if these infections have a more aggressive clinical course, which is currently under evaluation. Unfortunately most real-time PCR platforms can detect just a few viruses in a single reaction (Freymuth et al., 2006; Kuypers et al., 2006), so multiple tubes are required to assess a single sample, compromising throughput and complicating analysis. In contrast, bead-based respiratory virus multiplex PCR assays such as RVP can detect nearly all respiratory viruses described to date in one tube, greatly simplifying testing and analysis. Results can also be reported in a day. RVP may soon be available for in vitro diagnostic use in the USA, contributing to reimbursement and acceptance. Preliminary unpublished results using RVP in specimens from hospitalized children with LRT disease in our laboratory demonstrate its high sensitivity compared to DFA and viral culture, and ease of use for laboratories familiar with molecular technology. Inclusion of multiplex PCR tests such as RVP into diagnostic testing strategies for children, either as stand-alone assays or performed in concert with existing rapid tests such as direct immunofluorescence, shows great promise to improve patient care and other outcomes at children’s hospitals. Broadening our understanding of the pathogenesis and epidemiology of respiratory virus disease may be additional important benefits of this new technology as well.
Conflict of interest statement None declared.
References Abels S, Nadal D, Stroehle A, Bossart Wet. Reliable detection of respiratory syncytial virus infection in children for adequate hospital infection control management. J Clin Microbiol 2001;39:3135−9. Adcock PM, Stout GG, Hauck MA, Marshall GS. Effect of rapid viral diagnosis on the management of children hospitalized with lower respiratory tract infection. Pediatr Infect Dis J 1997;16:842−6. Barenfanger J, Drake C, Leon N, Mueller T, Troutt T. Clinical and financial benefits of rapid detection of respiratory viruses: an outcomes study. J Clin Microbiol 2000;38:2824−8.
Bonner AB, Monroe KW, Tallye LI, Klasner AE, Kimberlin DW. Impact of the rapid diagnosis of influenza on physician decision-making and patient management in the pediatric emergency room department: results of a randomized, prospective, controlled trial. Pediatrics 2003;112:363−7. Byington CL, Castillo H, Gerber K, Daly JA, Brimley LA, Adams S, et al. The effect of rapid respiratory virus testing on antibiotic use in a children’s hospital. Arch Pediatr Adolesc Med 2002;156:1230−4. Coffin SE, Zaoutis TE, Rosenqiuist ABW, Heydon K, Herrera G, Bridges CB, et al. Incidence, complications, and risk factors for prolonged stay in children hospitalized with community acquired pneumonia. Pediatr 2007;119:740−8. Freymuth F, Vabret A, Cuvillon-Nimal D, Simons S, Dina J, Gourain S, et al. Comparison of multiplex PCR assay and conventional techniques for the diagnostic of respiratory virus infections in children admitted to hospital with an acute respiratory illness. J Med Virol 2006;78:1498–1504. Friedman MJ, Attia MW. Influenza A in young children with suspected respiratory syncytial virus infection. Acad Emerg Med 2002;10:1400−3. Grijalva CG, Poehling KA, Edwards KM, Weinberg GA, Staat MA, Iwane MK, et al. Accuracy and interpretation of rapid influenza tests in children. Pediatrics 2007;1196−11. Henrickson KJ, Hoover S, Kehl KS, Fan J. National disease burden of respiratory viruses detected in children by polymerase chain reaction. Pediatr Infect Dis J 2004;23:211−8. Iwane MK, Edwards KM, Szilagyi PG, Walker FJ, Griffin MR, Weinberg GA, et al. Population-based surveillance for hospitalization associated with respiratory syncytial virus, influenza virus, and parainfluenza viruses among young children. Pediatrics 2004;113: 1758−64. Kehl S, Henrickson KJ, Hua W, Fan J. Evaluation of the Hexaplex assay for detection of respiratory viruses in children. J Clin Microbiol 2001; 39:1696–1701. Kuypers J, Wright N, Ferrenberg J, Huang ML, Cent A, Corey L, et al. Comparison of real-time PCR assays with fluorescent assays for diagnosis of respiratory virus infections in children. J Clin Micro 2006; 44:2382−8. Lamson D, Renwick N, Kapoor V, Lui Z, Palacios G, Ju J, et al. MassTag polymerase-chain-reaction detection of respiratory pathogens, including a new rhinovirus genotype that caused influenza-like illness in New York State during 2004–2005. J Infect Dis 2006;194:1398–402. LaSala PR, Bufton KK, Ismail M, Smith MB. Prospective comparison of R-Mix shell vial system with direct antigen tests and conventional cell culture for respiratory virus detection. J Clin Virol 2007;38:210−6. Lee MS, Walker RE, Mendelman PM. Medical burden of respiratory syncytial virus and parainfluenza virus type 3 infection among US children. Implications for design of vaccine trials. Hum Vaccin 2005;1: 6−11. Mathers CD, Lopez AD, Murray CJL. The burden of disease and mortality by condition: data, methods, and results for 2001. In: Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL, editors. Global Burden of Disease and Risk Factors. Oxford University Press/World Bank, Washington DC, 2006; 45–240. McIntosh K. Community acquired pneumonia in children. N Engl J Med 2002;346:429−37. Paramore LC, Ciuryla V, Ciesla G, Liu L. Economic impact of respiratory syncytial virus-related illnesses in the US: an analysis of national databases. Pharmacoeconomics 2004;22:275−84. Rabelais GP, Stout GG, Ladd KL, Cost KM. Rapid diagnosis of respiratory viral infections by using a shell vial assay and monoclonal antibody pool. J Clin Microbiol 1992;30:1505−8. Weinberg A, Brewster L, Clark J, Simoes E. Evaluation of R-Mix shell vials for the diagnosis of viral respiratory tract infections. J Clin Virol 2004;30:100−5. Woo PC, Chiu SS, Seto WH, Peris M. Cost-effectiveness of rapid diagnosis of viral respiratory tract infections in pediatric patients. J Clin Microbiol 1997;35:1579−81.
Journal of Clinical Virology 40 Suppl. 1 (2007) S51–S52 www.elsevier.com/locate/jcv
The value of RVP in children’s hospitals Christine C. Robinson* The Children’s Hospital, Aurora, CO, USA Keywords: Respiratory virus; PCR; Multiplex
Children acquire more respiratory virus infections than adults, many of which progress to lower respiratory tract (LRT) disease requiring medical attention or hospitalization (Henrickson et al., 2004; Iwane et al., 2004). Children also present with a variety of syndromes uncommon in adults, including croup and bronchiolitis. Infants and toddlers less than 5 years of age are at highest risk due in part to the small caliber of their airways and immunologic naivet´e. Older children, especially those with immune system defects or underlying cardiopulmonary or neuromuscular disease, can also be affected (Coffin et al., 2007). Most pediatric LRT viral illnesses resolve completely with supportive measures, but some progress to airway hyper-reactivity, permanent lung damage, or are fatal. Indeed LRT disease, 50−90% of which is virus-induced, remains the 4th leading cause of death in children of ages 0–14 years, even in developed countries (Mathers et al., 2006). The net impact of these infections is substantial, especially to hospitals caring exclusively for children. In the USA, more than 500,000 children younger than 18 years of age are hospitalized annually with LRT disease, 50–90% of which is due to respiratory viruses (Henrickson et al., 2004; Lee et al., 2005). Annual direct medical costs for managing RSV infections alone in the USA are estimated at $394 million, not including the fiscal drain and emotional toll on parents for losses from work or the consequences of antibiotic overuse (Paramore et al., 2004). From 3% to 18% of all admissions to a children’s hospital in the USA is due to LRT disease, most of which occur in the 4 month period of December through March. This annual influx stresses resources of even the most efficient facility. Accurate clinical diagnosis of LRT disease in the pediatric age group is especially difficult due to the number of different viral pathogens, the many syndromes each virus can cause, the overlap in seasonality of individual viruses, and the non-viral etiologic possibilities that must be considered (McIntosh, 2002). Diagnosis of influenza typifies this problem. Most influenza-virus infected adults present with “influenza-like illness” (ILI). In contrast, chil* Correspondence: Christine Robinson PhD. Tel.: +1 720 777 6215. E-mail address: [email protected] (C.C. Robinson) 1590-8658/ $ – see front matter © 2007 Elsevier B.V. All rights reserved.
dren with influenza virus infection tend to have vague upper respiratory tract symptoms, or fever and few respiratory tract signs. Influenza-virus infected infants can also have a sepsis-like picture or present with croup, bronchiolitis, or pneumonia suggestive of bacterial or another viral infection. Even patients with a classic ILI presentation can be infected with viruses other than influenza (Friedman and Attia, 2002; Lamson et al., 2006). As a result, physicians confronted with infants or children with possible viral LRT disease frequently order empiric antibiotics and numerous ancillary diagnostic tests including sepsis workups with blood cultures, urinalyses, complete blood counts, and even lumbar punctures with bacterial cultures or herpes simplex viral PCR (Bonner et al., 2003). Children’s hospitals therefore have a pressing need for rapid, accurate and cost-effective respiratory virus diagnostic tests to provide more focused care, administer antimicrobials appropriately, limit nosocomial infections, collect accurate surveillance data, and improve fiscal outcomes. Until recently, RSV and influenza virus immunoassays were the only commercially available and approved rapid tests for respiratory viruses in the USA. Unfortunately, the performance of these assays is now known to be less than ideal (Abels et al., 2001; Grijalva et al., 2007) and similar tests for other viruses were unavailable. Rapid centrifugation culture was therefore a welcome technical advance in that the parainfluenza viruses and adenovirus as well as RSV and influenza virus could be detected (Rabelais et al., 1992). Unfortunately the turnaround time for results exceeded the length of stay of most children with LRT disease (Adcock et al., 1997; Barenfanger et al., 2000). Whether mixed cell centrifugation culture can decrease this turnaround time remains controversial (Weinberg et al., 2004; LaSala et al., 2007). Direct immunofluorescence (DIF) of respiratory tract secretions has now been adopted by many children’s hospitals because the array of viruses detectable by centrifugation culture could also identified by DIF in a few hours time with reasonable specificity and sensitivity. Several studies have now demonstrated that DIF can significantly improve outcomes for hospitalized children with LRT disease by reducing antibiotic use, decreasing lengths of stay, and lowering costs (Woo et al.,
S52
C.C. Robinson / Journal of Clinical Virology 40 Suppl. 1 (2007) S51–S52
1997; Barenfanger et al., 2000; Byington et al., 2002). Throughput for DIF, however, is limited, readings are subjective, and reagents for some of the newly discovered respiratory viruses are either not yet available or not approved for in vitro diagnostic use. This experience suggests that the test most able to positively impact the care of hospitalized children with LRT disease is one that can be completed in less than a day, has high sensitivity for the broadest array of viruses know to infect children, and can be performed in a costeffective manner during times of high and low respiratory virus circulation. Real-time multiplex respiratory virus PCR has many of these attributes. Multiplex PCR can also detect more mixed viral infections than traditional methods in children with LRT (Kehl et al., 2001; Freymuth et al., 2006; Kuypers et al., 2006). This capability may have important prognostic value if these infections have a more aggressive clinical course, which is currently under evaluation. Unfortunately most real-time PCR platforms can detect just a few viruses in a single reaction (Freymuth et al., 2006; Kuypers et al., 2006), so multiple tubes are required to assess a single sample, compromising throughput and complicating analysis. In contrast, bead-based respiratory virus multiplex PCR assays such as RVP can detect nearly all respiratory viruses described to date in one tube, greatly simplifying testing and analysis. Results can also be reported in a day. RVP may soon be available for in vitro diagnostic use in the USA, contributing to reimbursement and acceptance. Preliminary unpublished results using RVP in specimens from hospitalized children with LRT disease in our laboratory demonstrate its high sensitivity compared to DFA and viral culture, and ease of use for laboratories familiar with molecular technology. Inclusion of multiplex PCR tests such as RVP into diagnostic testing strategies for children, either as stand-alone assays or performed in concert with existing rapid tests such as direct immunofluorescence, shows great promise to improve patient care and other outcomes at children’s hospitals. Broadening our understanding of the pathogenesis and epidemiology of respiratory virus disease may be additional important benefits of this new technology as well.
Conflict of interest statement None declared.
References Abels S, Nadal D, Stroehle A, Bossart Wet. Reliable detection of respiratory syncytial virus infection in children for adequate hospital infection control management. J Clin Microbiol 2001;39:3135−9. Adcock PM, Stout GG, Hauck MA, Marshall GS. Effect of rapid viral diagnosis on the management of children hospitalized with lower respiratory tract infection. Pediatr Infect Dis J 1997;16:842−6. Barenfanger J, Drake C, Leon N, Mueller T, Troutt T. Clinical and financial benefits of rapid detection of respiratory viruses: an outcomes study. J Clin Microbiol 2000;38:2824−8.
Bonner AB, Monroe KW, Tallye LI, Klasner AE, Kimberlin DW. Impact of the rapid diagnosis of influenza on physician decision-making and patient management in the pediatric emergency room department: results of a randomized, prospective, controlled trial. Pediatrics 2003;112:363−7. Byington CL, Castillo H, Gerber K, Daly JA, Brimley LA, Adams S, et al. The effect of rapid respiratory virus testing on antibiotic use in a children’s hospital. Arch Pediatr Adolesc Med 2002;156:1230−4. Coffin SE, Zaoutis TE, Rosenqiuist ABW, Heydon K, Herrera G, Bridges CB, et al. Incidence, complications, and risk factors for prolonged stay in children hospitalized with community acquired pneumonia. Pediatr 2007;119:740−8. Freymuth F, Vabret A, Cuvillon-Nimal D, Simons S, Dina J, Gourain S, et al. Comparison of multiplex PCR assay and conventional techniques for the diagnostic of respiratory virus infections in children admitted to hospital with an acute respiratory illness. J Med Virol 2006;78:1498–1504. Friedman MJ, Attia MW. Influenza A in young children with suspected respiratory syncytial virus infection. Acad Emerg Med 2002;10:1400−3. Grijalva CG, Poehling KA, Edwards KM, Weinberg GA, Staat MA, Iwane MK, et al. Accuracy and interpretation of rapid influenza tests in children. Pediatrics 2007;1196−11. Henrickson KJ, Hoover S, Kehl KS, Fan J. National disease burden of respiratory viruses detected in children by polymerase chain reaction. Pediatr Infect Dis J 2004;23:211−8. Iwane MK, Edwards KM, Szilagyi PG, Walker FJ, Griffin MR, Weinberg GA, et al. Population-based surveillance for hospitalization associated with respiratory syncytial virus, influenza virus, and parainfluenza viruses among young children. Pediatrics 2004;113: 1758−64. Kehl S, Henrickson KJ, Hua W, Fan J. Evaluation of the Hexaplex assay for detection of respiratory viruses in children. J Clin Microbiol 2001; 39:1696–1701. Kuypers J, Wright N, Ferrenberg J, Huang ML, Cent A, Corey L, et al. Comparison of real-time PCR assays with fluorescent assays for diagnosis of respiratory virus infections in children. J Clin Micro 2006; 44:2382−8. Lamson D, Renwick N, Kapoor V, Lui Z, Palacios G, Ju J, et al. MassTag polymerase-chain-reaction detection of respiratory pathogens, including a new rhinovirus genotype that caused influenza-like illness in New York State during 2004–2005. J Infect Dis 2006;194:1398–402. LaSala PR, Bufton KK, Ismail M, Smith MB. Prospective comparison of R-Mix shell vial system with direct antigen tests and conventional cell culture for respiratory virus detection. J Clin Virol 2007;38:210−6. Lee MS, Walker RE, Mendelman PM. Medical burden of respiratory syncytial virus and parainfluenza virus type 3 infection among US children. Implications for design of vaccine trials. Hum Vaccin 2005;1: 6−11. Mathers CD, Lopez AD, Murray CJL. The burden of disease and mortality by condition: data, methods, and results for 2001. In: Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL, editors. Global Burden of Disease and Risk Factors. Oxford University Press/World Bank, Washington DC, 2006; 45–240. McIntosh K. Community acquired pneumonia in children. N Engl J Med 2002;346:429−37. Paramore LC, Ciuryla V, Ciesla G, Liu L. Economic impact of respiratory syncytial virus-related illnesses in the US: an analysis of national databases. Pharmacoeconomics 2004;22:275−84. Rabelais GP, Stout GG, Ladd KL, Cost KM. Rapid diagnosis of respiratory viral infections by using a shell vial assay and monoclonal antibody pool. J Clin Microbiol 1992;30:1505−8. Weinberg A, Brewster L, Clark J, Simoes E. Evaluation of R-Mix shell vials for the diagnosis of viral respiratory tract infections. J Clin Virol 2004;30:100−5. Woo PC, Chiu SS, Seto WH, Peris M. Cost-effectiveness of rapid diagnosis of viral respiratory tract infections in pediatric patients. J Clin Microbiol 1997;35:1579−81.