Journal of Infection (2014) 68, S115eS118
www.elsevierhealth.com/journals/jinf
Respiratory syncytial virus: How, why and what to do Rosa Rodriguez a, Octavio Ramilo b,* a b
Hospital Materno-Infantil Gregorio Maran~on, Madrid, Spain Nationwide Children’s Hospital and Ohio State University, Columbus, OH, USA
Accepted 20 September 2013 Available online 27 October 2013
KEYWORDS Respiratory Syncytial Virus, RSV; Viral coinfections; Bronchiolitis; Palivizumab; RNAi
Summary Bronchiolitis is the leading cause of hospitalization of infants and young children worldwide. Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Studies conducted using molecular diagnostic assays confirmed that RSV accounts for over 50% of bronchiolitis in young children requiring hospitalization. Those studies demonstrate that it is common to identify RSV in association with a second viral agent but it is yet unclear whether the simultaneous detection of two or even three viruses is associated with increased disease severity. Despite extensive efforts, a vaccine for prevention of RSV infection is not yet available. Palivizumab a humanized monoclonal antibody directed against the F protein of RSV is the only agent licensed to prevent severe RSV disease in high-risk children. Among the new antivirals being developed for treatment of RSV infections, an RNAinterference based agent has demonstrated promising results for treatment of lung transplant recipients with acute RSV infection. ª 2013 Published by Elsevier Ltd on behalf of The British Infection Association.
The virus RSV is a member of the Mononegavirales in the Paramyxoviridae family, and Pneumovirinae subfamily. RSV is an enveloped virus with a negative sense, single-stranded RNA genome. These viruses are 150e200 nm in diameter with a helical nucleocapside. RSV has 10 genes encoding 11 proteinsdthere are 2 open reading frames of M2. The NS1 and NS2 proteins inhibit type I interferon activity. N protein
encodes the nucleocapsid protein that associates with the genomic RNA forming the nucleocapsid, and the M protein encodes the Matrix protein required for viral assembly. The G protein is a surface protein that is heavily glycosylated. It functions as the attachment protein. The F protein is another surface protein that mediates fusion, allowing entry of the virus into the cell cytoplasm and also allowing the formation of syncytia. The F protein is relatively conserved in both subtypes of RSV A and B; antibodies
* Corresponding author. Nationwide Children’s Hospital, Section of Infectious Diseases, Room ED161, Columbus, OH 43215, USA. Tel.: þ1 614 722 3416. E-mail address: [email protected] (O. Ramilo). 0163-4453/$36 ª 2013 Published by Elsevier Ltd on behalf of The British Infection Association. http://dx.doi.org/10.1016/j.jinf.2013.09.021
S116
R. Rodriguez, O. Ramilo
directed at the F protein are neutralizing. In contrast, the G protein differs considerably between the two subtypes.1
Vitamin D and bronchiolitis
Epidemiology and global burden of RSV
Vitamin D status is determined largely from ultraviolet B ray exposure at all ages. Vitamin D also is available from dietary sources, which are more important at higher latitudes at which ultraviolet B ray exposure is inadequate for skin synthesis of vitamin D during winter. The diverse sources of vitamin D, which involve environmental conditions and complex behaviors, complicate vitamin D research. Fortunately, serum 25(OH)D levels provide an excellent measure of overall vitamin D status. In a recent population-based study of 922 healthy New Zealand children, Camargo et al. found that low cord-blood levels of 25(OH)D were associated with a higher risk of respiratory infection during the first months of life and a higher risk of cumulative wheeze throughout early childhood.6 Additional studies conducted in Finland7 and the Netherlands8 found a similar association between low cord-blood vitamin D levels and increased risk of respiratory infections and more precisely RSV bronchiolitis. These are intriguing observations, and it is possible that the inverse correlation between cord-blood 25(OH)D levels and respiratory infections may explain the association between low vitamin D levels and wheezing. Although it is unclear how a single cord-blood level could explain wheeze risk over several years, the authors suggest that it is possible that vitamin D levels during pregnancy might affect the subsequent development of the immune system. More recently, a randomized trial conducted during winter in Mongolia showed that vitamin D supplementation was associated with reduced risk of acute respiratory infections.9 Taken together, these studies indicate a potentially important role for vitamin D in modifying the risk of respiratory infections.
Acute lower respiratory infection (ALRI) is the leading cause of global child mortality. Respiratory syncytial virus (RSV) is the most frequent viral pathogen causing ALRI in young children. The global burden of RSV is significant.2,3 A recent meta-analysis suggests that RSV causes up to 33.8 million ALRIs among children under age 5 (22% of all Lower Respiratory Tract Infections) each year. At least 3.4 million cases required hospital admission, and an estimated 66,000e199,000 of children died, nearly all in developing countries.2 In the United States, RSV is the most common cause of hospitalization in infants, with an estimated hospitalization rate of 2350/100,000 (95% CI, 2220e2520) in children less than 1 year of age.4 However the estimates of RSV-associated ALRI incidence are highly variable within countries or regions and between regions. The RSVassociated ALRI incidence estimates are more likely to underestimate than to overestimate true incidence in developing countries. Results of a study of a large hospital-based cohort in Texas (Children’s Medical Center Dallas) conducted from 2002 to 2007 offer a comprehensive description of the burden of bronchiolitis in the inpatient setting.5 Because 95% of children hospitalized with bronchiolitis had a viral diagnostic test performed the authors were able to compare the differences in demographic, clinical, microbiological, and radiologic characteristics and the presence of risk factors predictive of severe disease in children younger than 2 years with RSV versus non-RSV bronchiolitis. In agreement with previous studies conducted in the 1990s, the proportion of hospitalizations for bronchiolitis significantly increased during the study period, from 3.3% in 2002 to 5.5% in 2007. Whereas the percentage of hospitalizations attributed to non-RSV bronchiolitis decreased throughout the study, those caused by RSV significantly increased during the same period so that, during the last 4 years of the study, they were double the number of non-RSV bronchiolitis hospitalizations (63%e67% vs 33%e 37%, respectively).5 Seventy three percent of children hospitalized with RSV infection had no underlying medical conditions. In fact, the proportion of children with underlying medical conditions was significantly higher for those with non-RSV bronchiolitis, which may possibly reflect the impact of targeted antiRSV prophylaxis. There were several factors that were independently correlated with the severity of illness regardless of the etiology of the bronchiolitis. Although prematurity, chronic lung disease (CLD), and congenital heart disease (CHD) have been previously associated with severe disease in patients with RSV infection, the authors also found that trisomy 21, respiratory abnormalities and neuromuscular disorders were also associated with increased disease severity. RSV infection, per se, was an independent predictor for severe bronchiolitis. Altogether, these findings underscore the need for an effective RSV vaccine and, in the mean time, the necessity to develop novel strategies that may allow the implementation of antiRSV prophylaxis in broader patient populations.
Molecular diagnosis and co-infections The development of sensitive molecular diagnostic assays has increased the number of viruses detected in respiratory samples compared with conventional methods. A number of studies have used PCR-based assays to study the etiology of bronchiolitis in hospitalized children. Using these methods several investigators have identified viruses in >90% cases of bronchiolitis. In hospitalized infants, RSV was the most frequent agent of bronchiolitis in winter, but other viruses were present in up to 47% of the patients. Those studies confirmed that RSV is the most frequent etiologic agent of bronchiolitis as a single pathogen (40e45%) and second as a copathogen (18e20%) followed by rhinovirus (HRV), human metapneumovirus (hMPV) and adenovirus as single pathogens. Although the clinical characteristics were similar amongst them, the seasonality was different.10e13 The use of molecular techniques for viral detection has increased the identification of multiple viruses in a single sample. The prevalence of co-infections in some studies has ranged from 19 to 35% in young children with diverse types of respiratory tract infection admitted to hospital or evaluated in the emergency department. The question as to whether infection by multiple viruses is associated with increased disease severity remains
RSV: How, why and what to do controversial.11,12,14,15 An initial study conducted in the United Kingdom suggested that co-infection with RSV and hMPV was associated with a 10-fold higher risk of admission to the intensive care unit. Subsequent studies have not confirmed this finding. More recently, a multicenter study conducted in USA in children hospitalized with bronchiolitis found that co-infections with RSV and HRV were associated with longer hospitalizations.16 Further studies are needed that include precise quantitation of the different viruses detected, analysis of host responses and precise assessment of disease severity in appropriate patient populations.
Viral load The relationships between host factors, virus strain, viral load, and illness severity in respiratory syncytial virus (RSV)-induced bronchiolitis are still poorly defined. In this area studies offer contradictory results.17e19 Most studies that have attempted to associate viral load measured by quantitative real time PCR with disease severity have failed to establish any significant correlation.20e23 However, two studies that measured viral load using quantitative cultures and adjusted for disease duration have demonstrated that RSV viral load correlates with markers of disease severity17,24 although, unfortunately, parallel measurements of viral load using PCR were not done.
Etiologic diagnosis of bronchiolitis: is it relevant? As the application of molecular diagnostic assays for respiratory viruses becomes more frequent both in research studies and academic medical centers, physicians raise questions concerning the value of such tests in clinical practice. One argument favoring their use, from the infection control perspective, is the importance, were feasible, of isolating patients according to etiology to prevent hospital-associated infections. In addition, a recent study conducted by Finnish investigators suggests that the type of etiologic agent causing bronchiolitis may have therapeutic implications. Lehtinen and colleagues found that 3-day treatment with oral prednisolone in children with bronchiolitis caused by HRV was associated with a significant reduction in wheezing episodes in the subsequent 12 months. In contrast, there was no benefit in children with bronchiolitis caused by RSV.25 If follow-up studies, which are ongoing are confirmatory, viral testing will assume additional importance in routine clinical practice as results will directly affect management.
S117 greater neutralization activity against RSV in preclinical studies. A pivotal study assessed the efficacy and safety of motavizumab versus palivizumab for prevention of RSV hospitalization in high-risk infants. Because the investigators anticipated a low rate of hospitalization among palivizumab recipients both a non-inferiority trial design (i.e. to show whether motavizumab is no worse than palivizumab), as well as a superiority design (i.e. to show whether motavizumab is superior to palivizumab), were used. Treatment with motavizumab met the noninferiority criteria for RSV hospitalization (1.4%) and showed a 26% relative reduction in RSV hospitalization compared with palivizumab. However, since the rate of RSV hospitalization among palivizumab recipients was also very low (1.9%) motavizumab was not shown to be clinically significantly superior.27 Because palivizumab has an excellent record of safety both in clinical trials and in postmarketing experience and there was a higher frequency of cutaneous reactions in the motavizumab recipients, the Food and Drug Administration decided not to license motavizumab for clinical use. Since both placebo-controlled and comparative studies have consistently demonstrated the efficacy of palivizumab for prevention of RSV hospitalization in high-risk children, this monoclonal antibody remains the only available agent for prevention of severe RSV infection in high-risk children.
RNA interference Among novel agents being developed against RSV, the most innovative approach is the use of siRNAs (small inhibitory RNAs) with specific anti-RSV activity.28 ALN-RSV01 is the first of these RNAi agents being developed for clinical use. Since in vitro and in vivo studies demonstrated excellent activity against RSV, it is currently undergoing clinical evaluation. Initial studies conducted in healthy volunteers who were experimentally infected with RSV demonstrated a good safety profile as well as antiviral activity.29 Further studies with ALN-RSV01 conducted in lung transplant recipients with acute RSV infection showed that it was safe and well tolerated, and that it was associated with a statistically significant improvement in symptoms and decrease in the incidence of new or progressive bronchiolitis obliterans (BOS) compared to placebo.30 These positive results continue to support the development of this novel therapeutic strategy for RSV infections.
Conflict of interest Dr. Ramilo has served as a consultant for Abbvie, Gilead and Alios.
Update on therapies References Palivizumab and motavizumab Palivizumab, a humanized monoclonal antibody directed against the F protein of RSV, has been used since 1998 in USA and 61 other countries for prevention of severe RSV infection in high-risk children.26 Motavizumab is a neutralizing antibody derived from palivizumab that showed
1. Collins PL, Graham BS. Viral and host factors in human respiratory syncytial virus pathogenesis. J Virol 2008;82:2040e55. 2. Nair H, et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 2010;375(9725): 1545e55.
S118 3. Simoes EA. Respiratory syncytial virus infection. Lancet 1999; 354(9181):847e52. 4. Zhou H, et al. Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993e2008. Clin Infect Dis 2012;54(10):1427e36. 5. Garcia CG, et al. Risk factors in children hospitalized with RSV bronchiolitis versus non-RSV bronchiolitis. Pediatrics 2010; 126(6):e1453e60. 6. Camargo Jr CA, et al. Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma. Pediatrics 2011;127(1):e180e7. 7. Jartti T, et al. Low serum 25-hydroxyvitamin D levels are associated with increased risk of viral coinfections in wheezing children. J Allergy Clin Immunol 2010;126(5):1074e6. 1076.e1e4. 8. Belderbos ME, et al. Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis. Pediatrics 2011;127(6):e1513e20. 9. Camargo Jr CA, et al. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics 2012;130(3):e561e7. 10. Miron D, et al. Sole pathogen in acute bronchiolitis: is there a role for other organisms apart from respiratory syncytial virus? Pediatr Infect Dis J 2010;29(1):e7e10. 11. Richard N, et al. The impact of dual viral infection in infants admitted to a pediatric intensive care unit associated with severe bronchiolitis. Pediatr Infect Dis J 2008;27(3):213e7. 12. Semple MG, et al. Dual infection of infants by human metapneumovirus and human respiratory syncytial virus is strongly associated with severe bronchiolitis. J Infect Dis 2005; 191(3):382e6. 13. Calvo C, et al. Detection of new respiratory viruses in hospitalized infants with bronchiolitis: a three-year prospective study. Acta Paediatr 2010;99(6):883e7. 14. Brand HK, et al. Infection with multiple viruses is not associated with increased disease severity in children with bronchiolitis. Pediatr Pulmonol 2012;47(4):393e400. 15. Stempel HE, et al. Multiple viral respiratory pathogens in children with bronchiolitis. Acta Paediatr 2009;98(1):123e6. 16. Mansbach JM, et al. Prospective multicenter study of viral etiology and hospital length of stay in children with severe bronchiolitis. Arch Pediatr Adolesc Med 2012;166(8):700e6.
R. Rodriguez, O. Ramilo 17. DeVincenzo JP, El Saleeby CM, Bush AJ. Respiratory syncytial virus load predicts disease severity in previously healthy infants. J Infect Dis 2005;191(11):1861e8. 18. Sheeran P, et al. Elevated cytokine concentrations in the nasopharyngeal and tracheal secretions of children with respiratory syncytial virus disease. Pediatr Infect Dis J 1999;18(2):115e22. 19. Wright PF, et al. Illness severity, viral shedding, and antibody responses in infants hospitalized with bronchiolitis caused by respiratory syncytial virus. J Infect Dis 2002;185(8):1011e8. 20. Fodha I, et al. Respiratory syncytial virus infections in hospitalized infants: association between viral load, virus subgroup, and disease severity. J Med Virol 2007;79(12):1951e8. 21. Houben ML, et al. Disease severity and viral load are correlated in infants with primary respiratory syncytial virus infection in the community. J Med Virol 2010;82(7):1266e71. 22. Marguet C, et al. In very young infants severity of acute bronchiolitis depends on carried viruses. PLoS One 2009;4(2):e4596. 23. Martin ET, et al. Clinical disease and viral load in children infected with respiratory syncytial virus or human metapneumovirus. Diagn Microbiol Infect Dis 2008;62(4):382e8. 24. El Saleeby CM, et al. Respiratory syncytial virus load, viral dynamics, and disease severity in previously healthy naturally infected children. J Infect Dis 2011;204(7):996e1002. 25. Lehtinen P, et al. Prednisolone reduces recurrent wheezing after a first wheezing episode associated with rhinovirus infection or eczema. J Allergy Clin Immunol 2007;119(3):570e5. 26. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998; 102(3):531e7. 27. Carbonell-Estrany X, et al. Motavizumab for prophylaxis of respiratory syncytial virus in high-risk children: a noninferiority trial. Pediatrics 2010;125(1):e35e51. 28. Bitko V, et al. Inhibition of respiratory viruses by nasally administered siRNA. Nat Med 2005;11(1):50e5. 29. DeVincenzo J, et al. A randomized, double-blind, placebocontrolled study of an RNAi-based therapy directed against respiratory syncytial virus. Proc Natl Acad Sci U S A 2010;107(19): 8800e5. 30. Zamora MR, et al. RNA interference therapy in lung transplant patients infected with respiratory syncytial virus. Am J Respir Crit Care Med 2011;183(4):531e8.
www.elsevierhealth.com/journals/jinf
Respiratory syncytial virus: How, why and what to do Rosa Rodriguez a, Octavio Ramilo b,* a b
Hospital Materno-Infantil Gregorio Maran~on, Madrid, Spain Nationwide Children’s Hospital and Ohio State University, Columbus, OH, USA
Accepted 20 September 2013 Available online 27 October 2013
KEYWORDS Respiratory Syncytial Virus, RSV; Viral coinfections; Bronchiolitis; Palivizumab; RNAi
Summary Bronchiolitis is the leading cause of hospitalization of infants and young children worldwide. Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Studies conducted using molecular diagnostic assays confirmed that RSV accounts for over 50% of bronchiolitis in young children requiring hospitalization. Those studies demonstrate that it is common to identify RSV in association with a second viral agent but it is yet unclear whether the simultaneous detection of two or even three viruses is associated with increased disease severity. Despite extensive efforts, a vaccine for prevention of RSV infection is not yet available. Palivizumab a humanized monoclonal antibody directed against the F protein of RSV is the only agent licensed to prevent severe RSV disease in high-risk children. Among the new antivirals being developed for treatment of RSV infections, an RNAinterference based agent has demonstrated promising results for treatment of lung transplant recipients with acute RSV infection. ª 2013 Published by Elsevier Ltd on behalf of The British Infection Association.
The virus RSV is a member of the Mononegavirales in the Paramyxoviridae family, and Pneumovirinae subfamily. RSV is an enveloped virus with a negative sense, single-stranded RNA genome. These viruses are 150e200 nm in diameter with a helical nucleocapside. RSV has 10 genes encoding 11 proteinsdthere are 2 open reading frames of M2. The NS1 and NS2 proteins inhibit type I interferon activity. N protein
encodes the nucleocapsid protein that associates with the genomic RNA forming the nucleocapsid, and the M protein encodes the Matrix protein required for viral assembly. The G protein is a surface protein that is heavily glycosylated. It functions as the attachment protein. The F protein is another surface protein that mediates fusion, allowing entry of the virus into the cell cytoplasm and also allowing the formation of syncytia. The F protein is relatively conserved in both subtypes of RSV A and B; antibodies
* Corresponding author. Nationwide Children’s Hospital, Section of Infectious Diseases, Room ED161, Columbus, OH 43215, USA. Tel.: þ1 614 722 3416. E-mail address: [email protected] (O. Ramilo). 0163-4453/$36 ª 2013 Published by Elsevier Ltd on behalf of The British Infection Association. http://dx.doi.org/10.1016/j.jinf.2013.09.021
S116
R. Rodriguez, O. Ramilo
directed at the F protein are neutralizing. In contrast, the G protein differs considerably between the two subtypes.1
Vitamin D and bronchiolitis
Epidemiology and global burden of RSV
Vitamin D status is determined largely from ultraviolet B ray exposure at all ages. Vitamin D also is available from dietary sources, which are more important at higher latitudes at which ultraviolet B ray exposure is inadequate for skin synthesis of vitamin D during winter. The diverse sources of vitamin D, which involve environmental conditions and complex behaviors, complicate vitamin D research. Fortunately, serum 25(OH)D levels provide an excellent measure of overall vitamin D status. In a recent population-based study of 922 healthy New Zealand children, Camargo et al. found that low cord-blood levels of 25(OH)D were associated with a higher risk of respiratory infection during the first months of life and a higher risk of cumulative wheeze throughout early childhood.6 Additional studies conducted in Finland7 and the Netherlands8 found a similar association between low cord-blood vitamin D levels and increased risk of respiratory infections and more precisely RSV bronchiolitis. These are intriguing observations, and it is possible that the inverse correlation between cord-blood 25(OH)D levels and respiratory infections may explain the association between low vitamin D levels and wheezing. Although it is unclear how a single cord-blood level could explain wheeze risk over several years, the authors suggest that it is possible that vitamin D levels during pregnancy might affect the subsequent development of the immune system. More recently, a randomized trial conducted during winter in Mongolia showed that vitamin D supplementation was associated with reduced risk of acute respiratory infections.9 Taken together, these studies indicate a potentially important role for vitamin D in modifying the risk of respiratory infections.
Acute lower respiratory infection (ALRI) is the leading cause of global child mortality. Respiratory syncytial virus (RSV) is the most frequent viral pathogen causing ALRI in young children. The global burden of RSV is significant.2,3 A recent meta-analysis suggests that RSV causes up to 33.8 million ALRIs among children under age 5 (22% of all Lower Respiratory Tract Infections) each year. At least 3.4 million cases required hospital admission, and an estimated 66,000e199,000 of children died, nearly all in developing countries.2 In the United States, RSV is the most common cause of hospitalization in infants, with an estimated hospitalization rate of 2350/100,000 (95% CI, 2220e2520) in children less than 1 year of age.4 However the estimates of RSV-associated ALRI incidence are highly variable within countries or regions and between regions. The RSVassociated ALRI incidence estimates are more likely to underestimate than to overestimate true incidence in developing countries. Results of a study of a large hospital-based cohort in Texas (Children’s Medical Center Dallas) conducted from 2002 to 2007 offer a comprehensive description of the burden of bronchiolitis in the inpatient setting.5 Because 95% of children hospitalized with bronchiolitis had a viral diagnostic test performed the authors were able to compare the differences in demographic, clinical, microbiological, and radiologic characteristics and the presence of risk factors predictive of severe disease in children younger than 2 years with RSV versus non-RSV bronchiolitis. In agreement with previous studies conducted in the 1990s, the proportion of hospitalizations for bronchiolitis significantly increased during the study period, from 3.3% in 2002 to 5.5% in 2007. Whereas the percentage of hospitalizations attributed to non-RSV bronchiolitis decreased throughout the study, those caused by RSV significantly increased during the same period so that, during the last 4 years of the study, they were double the number of non-RSV bronchiolitis hospitalizations (63%e67% vs 33%e 37%, respectively).5 Seventy three percent of children hospitalized with RSV infection had no underlying medical conditions. In fact, the proportion of children with underlying medical conditions was significantly higher for those with non-RSV bronchiolitis, which may possibly reflect the impact of targeted antiRSV prophylaxis. There were several factors that were independently correlated with the severity of illness regardless of the etiology of the bronchiolitis. Although prematurity, chronic lung disease (CLD), and congenital heart disease (CHD) have been previously associated with severe disease in patients with RSV infection, the authors also found that trisomy 21, respiratory abnormalities and neuromuscular disorders were also associated with increased disease severity. RSV infection, per se, was an independent predictor for severe bronchiolitis. Altogether, these findings underscore the need for an effective RSV vaccine and, in the mean time, the necessity to develop novel strategies that may allow the implementation of antiRSV prophylaxis in broader patient populations.
Molecular diagnosis and co-infections The development of sensitive molecular diagnostic assays has increased the number of viruses detected in respiratory samples compared with conventional methods. A number of studies have used PCR-based assays to study the etiology of bronchiolitis in hospitalized children. Using these methods several investigators have identified viruses in >90% cases of bronchiolitis. In hospitalized infants, RSV was the most frequent agent of bronchiolitis in winter, but other viruses were present in up to 47% of the patients. Those studies confirmed that RSV is the most frequent etiologic agent of bronchiolitis as a single pathogen (40e45%) and second as a copathogen (18e20%) followed by rhinovirus (HRV), human metapneumovirus (hMPV) and adenovirus as single pathogens. Although the clinical characteristics were similar amongst them, the seasonality was different.10e13 The use of molecular techniques for viral detection has increased the identification of multiple viruses in a single sample. The prevalence of co-infections in some studies has ranged from 19 to 35% in young children with diverse types of respiratory tract infection admitted to hospital or evaluated in the emergency department. The question as to whether infection by multiple viruses is associated with increased disease severity remains
RSV: How, why and what to do controversial.11,12,14,15 An initial study conducted in the United Kingdom suggested that co-infection with RSV and hMPV was associated with a 10-fold higher risk of admission to the intensive care unit. Subsequent studies have not confirmed this finding. More recently, a multicenter study conducted in USA in children hospitalized with bronchiolitis found that co-infections with RSV and HRV were associated with longer hospitalizations.16 Further studies are needed that include precise quantitation of the different viruses detected, analysis of host responses and precise assessment of disease severity in appropriate patient populations.
Viral load The relationships between host factors, virus strain, viral load, and illness severity in respiratory syncytial virus (RSV)-induced bronchiolitis are still poorly defined. In this area studies offer contradictory results.17e19 Most studies that have attempted to associate viral load measured by quantitative real time PCR with disease severity have failed to establish any significant correlation.20e23 However, two studies that measured viral load using quantitative cultures and adjusted for disease duration have demonstrated that RSV viral load correlates with markers of disease severity17,24 although, unfortunately, parallel measurements of viral load using PCR were not done.
Etiologic diagnosis of bronchiolitis: is it relevant? As the application of molecular diagnostic assays for respiratory viruses becomes more frequent both in research studies and academic medical centers, physicians raise questions concerning the value of such tests in clinical practice. One argument favoring their use, from the infection control perspective, is the importance, were feasible, of isolating patients according to etiology to prevent hospital-associated infections. In addition, a recent study conducted by Finnish investigators suggests that the type of etiologic agent causing bronchiolitis may have therapeutic implications. Lehtinen and colleagues found that 3-day treatment with oral prednisolone in children with bronchiolitis caused by HRV was associated with a significant reduction in wheezing episodes in the subsequent 12 months. In contrast, there was no benefit in children with bronchiolitis caused by RSV.25 If follow-up studies, which are ongoing are confirmatory, viral testing will assume additional importance in routine clinical practice as results will directly affect management.
S117 greater neutralization activity against RSV in preclinical studies. A pivotal study assessed the efficacy and safety of motavizumab versus palivizumab for prevention of RSV hospitalization in high-risk infants. Because the investigators anticipated a low rate of hospitalization among palivizumab recipients both a non-inferiority trial design (i.e. to show whether motavizumab is no worse than palivizumab), as well as a superiority design (i.e. to show whether motavizumab is superior to palivizumab), were used. Treatment with motavizumab met the noninferiority criteria for RSV hospitalization (1.4%) and showed a 26% relative reduction in RSV hospitalization compared with palivizumab. However, since the rate of RSV hospitalization among palivizumab recipients was also very low (1.9%) motavizumab was not shown to be clinically significantly superior.27 Because palivizumab has an excellent record of safety both in clinical trials and in postmarketing experience and there was a higher frequency of cutaneous reactions in the motavizumab recipients, the Food and Drug Administration decided not to license motavizumab for clinical use. Since both placebo-controlled and comparative studies have consistently demonstrated the efficacy of palivizumab for prevention of RSV hospitalization in high-risk children, this monoclonal antibody remains the only available agent for prevention of severe RSV infection in high-risk children.
RNA interference Among novel agents being developed against RSV, the most innovative approach is the use of siRNAs (small inhibitory RNAs) with specific anti-RSV activity.28 ALN-RSV01 is the first of these RNAi agents being developed for clinical use. Since in vitro and in vivo studies demonstrated excellent activity against RSV, it is currently undergoing clinical evaluation. Initial studies conducted in healthy volunteers who were experimentally infected with RSV demonstrated a good safety profile as well as antiviral activity.29 Further studies with ALN-RSV01 conducted in lung transplant recipients with acute RSV infection showed that it was safe and well tolerated, and that it was associated with a statistically significant improvement in symptoms and decrease in the incidence of new or progressive bronchiolitis obliterans (BOS) compared to placebo.30 These positive results continue to support the development of this novel therapeutic strategy for RSV infections.
Conflict of interest Dr. Ramilo has served as a consultant for Abbvie, Gilead and Alios.
Update on therapies References Palivizumab and motavizumab Palivizumab, a humanized monoclonal antibody directed against the F protein of RSV, has been used since 1998 in USA and 61 other countries for prevention of severe RSV infection in high-risk children.26 Motavizumab is a neutralizing antibody derived from palivizumab that showed
1. Collins PL, Graham BS. Viral and host factors in human respiratory syncytial virus pathogenesis. J Virol 2008;82:2040e55. 2. Nair H, et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 2010;375(9725): 1545e55.
S118 3. Simoes EA. Respiratory syncytial virus infection. Lancet 1999; 354(9181):847e52. 4. Zhou H, et al. Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993e2008. Clin Infect Dis 2012;54(10):1427e36. 5. Garcia CG, et al. Risk factors in children hospitalized with RSV bronchiolitis versus non-RSV bronchiolitis. Pediatrics 2010; 126(6):e1453e60. 6. Camargo Jr CA, et al. Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma. Pediatrics 2011;127(1):e180e7. 7. Jartti T, et al. Low serum 25-hydroxyvitamin D levels are associated with increased risk of viral coinfections in wheezing children. J Allergy Clin Immunol 2010;126(5):1074e6. 1076.e1e4. 8. Belderbos ME, et al. Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis. Pediatrics 2011;127(6):e1513e20. 9. Camargo Jr CA, et al. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics 2012;130(3):e561e7. 10. Miron D, et al. Sole pathogen in acute bronchiolitis: is there a role for other organisms apart from respiratory syncytial virus? Pediatr Infect Dis J 2010;29(1):e7e10. 11. Richard N, et al. The impact of dual viral infection in infants admitted to a pediatric intensive care unit associated with severe bronchiolitis. Pediatr Infect Dis J 2008;27(3):213e7. 12. Semple MG, et al. Dual infection of infants by human metapneumovirus and human respiratory syncytial virus is strongly associated with severe bronchiolitis. J Infect Dis 2005; 191(3):382e6. 13. Calvo C, et al. Detection of new respiratory viruses in hospitalized infants with bronchiolitis: a three-year prospective study. Acta Paediatr 2010;99(6):883e7. 14. Brand HK, et al. Infection with multiple viruses is not associated with increased disease severity in children with bronchiolitis. Pediatr Pulmonol 2012;47(4):393e400. 15. Stempel HE, et al. Multiple viral respiratory pathogens in children with bronchiolitis. Acta Paediatr 2009;98(1):123e6. 16. Mansbach JM, et al. Prospective multicenter study of viral etiology and hospital length of stay in children with severe bronchiolitis. Arch Pediatr Adolesc Med 2012;166(8):700e6.
R. Rodriguez, O. Ramilo 17. DeVincenzo JP, El Saleeby CM, Bush AJ. Respiratory syncytial virus load predicts disease severity in previously healthy infants. J Infect Dis 2005;191(11):1861e8. 18. Sheeran P, et al. Elevated cytokine concentrations in the nasopharyngeal and tracheal secretions of children with respiratory syncytial virus disease. Pediatr Infect Dis J 1999;18(2):115e22. 19. Wright PF, et al. Illness severity, viral shedding, and antibody responses in infants hospitalized with bronchiolitis caused by respiratory syncytial virus. J Infect Dis 2002;185(8):1011e8. 20. Fodha I, et al. Respiratory syncytial virus infections in hospitalized infants: association between viral load, virus subgroup, and disease severity. J Med Virol 2007;79(12):1951e8. 21. Houben ML, et al. Disease severity and viral load are correlated in infants with primary respiratory syncytial virus infection in the community. J Med Virol 2010;82(7):1266e71. 22. Marguet C, et al. In very young infants severity of acute bronchiolitis depends on carried viruses. PLoS One 2009;4(2):e4596. 23. Martin ET, et al. Clinical disease and viral load in children infected with respiratory syncytial virus or human metapneumovirus. Diagn Microbiol Infect Dis 2008;62(4):382e8. 24. El Saleeby CM, et al. Respiratory syncytial virus load, viral dynamics, and disease severity in previously healthy naturally infected children. J Infect Dis 2011;204(7):996e1002. 25. Lehtinen P, et al. Prednisolone reduces recurrent wheezing after a first wheezing episode associated with rhinovirus infection or eczema. J Allergy Clin Immunol 2007;119(3):570e5. 26. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998; 102(3):531e7. 27. Carbonell-Estrany X, et al. Motavizumab for prophylaxis of respiratory syncytial virus in high-risk children: a noninferiority trial. Pediatrics 2010;125(1):e35e51. 28. Bitko V, et al. Inhibition of respiratory viruses by nasally administered siRNA. Nat Med 2005;11(1):50e5. 29. DeVincenzo J, et al. A randomized, double-blind, placebocontrolled study of an RNAi-based therapy directed against respiratory syncytial virus. Proc Natl Acad Sci U S A 2010;107(19): 8800e5. 30. Zamora MR, et al. RNA interference therapy in lung transplant patients infected with respiratory syncytial virus. Am J Respir Crit Care Med 2011;183(4):531e8.
