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This highlights the need for new vaccines
Influenza gets a lot of attention each winter, but respiratory syncytial virus (RSV) and other respiratory viruses have as much or more impact on pediatric populations, particularly certain high-risk groups. But currently there are no vaccines for noninfluenza respiratory viruses. That said, several are under development, for RSV and parainfluenza.
Which groups are likely to get the most benefit from these newer vaccines?
We all are aware of the extra vulnerability to respiratory viruses (RSV being the most frequent) in premature infants, those with chronic lung disease, or those with congenital heart syndromes; such vulnerable patients are not infrequently seen in routine practice. A recent report shined a brighter light on such a group.
Real-world data from a nationwide Canadian surveillance system (CARESS) was used to analyze relative risks of categories of young children who are thought to be vulnerable to respiratory viruses, with a particular focus on those with neuromuscular disease. The CARESS investigators analyzed 12 years’ data on respiratory hospitalizations from among palivizumab-prophylaxed patients (including specific data on RSV when patients were tested for RSV per standard of care).1 Unfortunately, RSV testing was not universal despite hospitalization, so the true incidence of RSV-specific hospitalizations was likely underestimated.
Nevertheless, more than 25,000 children from 2005 through 2017 were grouped into three categories of palivizumab-prophylaxed high-risk children: standard indications (SI), n = 20,335; chronic medical conditions (CMD), n = 4,063; and neuromuscular disease (NMD), n = 605. This study is notable for having a relatively large number of neuromuscular disease subjects. Two-thirds of each group were fully palivizumab adherent.
The SI group included the standard American Academy of Pediatrics–recommended groups, such as premature infants, congenital heart disease, etc.
The CMD group included conditions that lead clinicians to use palivizumab off label, such as cystic fibrosis, congenital airway anomalies, immunodeficiency, and pulmonary disorders.
The NMD participants were subdivided into two groups. Group 1 comprised general hypotonic neuromuscular diseases such as hypoxic-ischemic encephalopathy, Prader-Willi syndrome, chromosomal disorders, and migration/demyelinating diseases. Group 2 included more severe infantile neuromuscular disorders, such as spinal muscular atrophy, myotonic dystrophy, centronuclear and nemaline myopathy, mitochondrial and glycogen storage myopathies, or arthrogryposis.
Overall, 6.9% of CARESS RSV-prophylaxed subjects were hospitalized. About one in five hospitalized patients from each group was hospitalized more than once. Specific respiratory hospitalization rates for each group were 6% (n = 1,228) for SI subjects and 9.4% (n = 380) for CMD, compared with 19.2% (n = 116) for NMD subjects.
It is unclear what proportion underwent RSV testing, but a total of 334 were confirmed RSV positive: 261 were SI, 54 were CMD and 19 were NMD. The RSV-test-positive rate was 1.5% for SI, 1.6% for CMD and 3.3% for NMD; so while a higher number of SI children were RSV positive, the rate of RSV positivity was actually highest with NMD.
RSV-positive subjects needing ICU care among NMD patients also had longer ICU stays (median 14 days), compared with RSV-positive CMD or SI subjects (median 3 and 5 days, respectively). Further, hospitalized RSV-positive NMD subjects presented more frequently with pneumonia (42% vs. 30% for CMD and 20% for SI) while hospitalized RSV-positive SI subjects more often had apnea (17% vs. 10% for NMD and 5% for CMD, P less than .05).
These differences in the courses of NMD patients raise the question as to whether the NMD group was somehow different from the SI and CMD groups, other than muscular weakness that likely leads to less ability to clear secretions and a less efficient cough. It turns out that NMD children were older and had worse neonatal medical courses (longer hospital stays, more often ventilated, and used oxygen longer). It could be argued that these differences may have been in part due to the muscular weakness inherent in their underlying disease, but they appear to be predictors of worse respiratory infectious disease than other vulnerable populations as the NMD children get older.
Indeed, the overall risk of any respiratory admission among NMD subjects was nearly twice as high, compared with SI (hazard ratio, 1.90, P less than .0005); but the somewhat higher risk for NMD vs. CMD was not significant (HR, 1.33, P = .090). However, when looking specifically at RSV confirmed admissions, NMD had more than twice the hospitalization risk than either other group (HR, 2.26, P = .001 vs. SI; and HR, 2.74, P = .001 vs. CMD).
Further, an NMD subgroup analysis showed 1.69 times the overall respiratory hospitalization risk among the more severe vs. less severe NMD group, but a similar risk of RSV admission. The authors point out that one reason for this discrepancy may be a higher probability of aspiration causing hospitalization because of more dramatic acute events during respiratory infections in patients with more severe NMD. It also may be that palivizumab evened the playing field for RSV but not for other viruses such as parainfluenza, adenovirus, or even rhinovirus.
Nevertheless, these data tell us that risk of respiratory disease severe enough to need hospitalization continues to an older age in NMD than SI or CMD patients, well past 2 years of age. And the risk is not only from RSV. That said, RSV remains a player in some patients (particularly NMD patients) despite palivizumab prophylaxis, highlighting the need for RSV as well as parainfluenza vaccines. While these vaccines should help all young children, they seem likely to be even more beneficial for high-risk children including those with NMD, and particularly those with more severe NMD.
Eleven among 60 total candidate RSV vaccines (live attenuated, particle based, or vector based) are currently in clinical trials.2 Fewer parainfluenza vaccines are in the pipeline, but clinical trials also are underway.3-5 Approval of such vaccines is not expected until the mid-2020s, so at present we are left with providing palivizumab to our vulnerable patients while emphasizing nonmedical strategies that may help prevent respiratory viruses. These only partially successful preventive interventions include breastfeeding, avoiding secondhand smoke, and avoiding known high-risk exposures, such as large day care centers.
My hope is for quicker than projected progress on the vaccine front so that winter admissions for respiratory viruses might decrease in numbers similar to the decrease we have noted with another vaccine successful against a seasonally active pathogen – rotavirus.
Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospital–Kansas City, Mo. Children’s Mercy Hospital receives grant funding to study two candidate RSV vaccines. The hospital also receives CDC funding under the New Vaccine Surveillance Network for multicenter surveillance of acute respiratory infections, including influenza, RSV, and parainfluenza virus. Email Dr. Harrison at [email protected].
References
1. Pediatr Infect Dis J. 2019 Apr 10. doi: 10.1097/INF.0000000000002297.
2. “Advances in RSV Vaccine Research and Development – A Global Agenda.”
3. J Pediatric Infect Dis Soc. 2015 Dec;4(4): e143-6.
4. J Virol. 2015 Oct;89(20):10319-32.
5. Vaccine. 2017 Dec 18;35(51):7139-46.
This highlights the need for new vaccines
This highlights the need for new vaccines
Influenza gets a lot of attention each winter, but respiratory syncytial virus (RSV) and other respiratory viruses have as much or more impact on pediatric populations, particularly certain high-risk groups. But currently there are no vaccines for noninfluenza respiratory viruses. That said, several are under development, for RSV and parainfluenza.
Which groups are likely to get the most benefit from these newer vaccines?
We all are aware of the extra vulnerability to respiratory viruses (RSV being the most frequent) in premature infants, those with chronic lung disease, or those with congenital heart syndromes; such vulnerable patients are not infrequently seen in routine practice. A recent report shined a brighter light on such a group.
Real-world data from a nationwide Canadian surveillance system (CARESS) was used to analyze relative risks of categories of young children who are thought to be vulnerable to respiratory viruses, with a particular focus on those with neuromuscular disease. The CARESS investigators analyzed 12 years’ data on respiratory hospitalizations from among palivizumab-prophylaxed patients (including specific data on RSV when patients were tested for RSV per standard of care).1 Unfortunately, RSV testing was not universal despite hospitalization, so the true incidence of RSV-specific hospitalizations was likely underestimated.
Nevertheless, more than 25,000 children from 2005 through 2017 were grouped into three categories of palivizumab-prophylaxed high-risk children: standard indications (SI), n = 20,335; chronic medical conditions (CMD), n = 4,063; and neuromuscular disease (NMD), n = 605. This study is notable for having a relatively large number of neuromuscular disease subjects. Two-thirds of each group were fully palivizumab adherent.
The SI group included the standard American Academy of Pediatrics–recommended groups, such as premature infants, congenital heart disease, etc.
The CMD group included conditions that lead clinicians to use palivizumab off label, such as cystic fibrosis, congenital airway anomalies, immunodeficiency, and pulmonary disorders.
The NMD participants were subdivided into two groups. Group 1 comprised general hypotonic neuromuscular diseases such as hypoxic-ischemic encephalopathy, Prader-Willi syndrome, chromosomal disorders, and migration/demyelinating diseases. Group 2 included more severe infantile neuromuscular disorders, such as spinal muscular atrophy, myotonic dystrophy, centronuclear and nemaline myopathy, mitochondrial and glycogen storage myopathies, or arthrogryposis.
Overall, 6.9% of CARESS RSV-prophylaxed subjects were hospitalized. About one in five hospitalized patients from each group was hospitalized more than once. Specific respiratory hospitalization rates for each group were 6% (n = 1,228) for SI subjects and 9.4% (n = 380) for CMD, compared with 19.2% (n = 116) for NMD subjects.
It is unclear what proportion underwent RSV testing, but a total of 334 were confirmed RSV positive: 261 were SI, 54 were CMD and 19 were NMD. The RSV-test-positive rate was 1.5% for SI, 1.6% for CMD and 3.3% for NMD; so while a higher number of SI children were RSV positive, the rate of RSV positivity was actually highest with NMD.
RSV-positive subjects needing ICU care among NMD patients also had longer ICU stays (median 14 days), compared with RSV-positive CMD or SI subjects (median 3 and 5 days, respectively). Further, hospitalized RSV-positive NMD subjects presented more frequently with pneumonia (42% vs. 30% for CMD and 20% for SI) while hospitalized RSV-positive SI subjects more often had apnea (17% vs. 10% for NMD and 5% for CMD, P less than .05).
These differences in the courses of NMD patients raise the question as to whether the NMD group was somehow different from the SI and CMD groups, other than muscular weakness that likely leads to less ability to clear secretions and a less efficient cough. It turns out that NMD children were older and had worse neonatal medical courses (longer hospital stays, more often ventilated, and used oxygen longer). It could be argued that these differences may have been in part due to the muscular weakness inherent in their underlying disease, but they appear to be predictors of worse respiratory infectious disease than other vulnerable populations as the NMD children get older.
Indeed, the overall risk of any respiratory admission among NMD subjects was nearly twice as high, compared with SI (hazard ratio, 1.90, P less than .0005); but the somewhat higher risk for NMD vs. CMD was not significant (HR, 1.33, P = .090). However, when looking specifically at RSV confirmed admissions, NMD had more than twice the hospitalization risk than either other group (HR, 2.26, P = .001 vs. SI; and HR, 2.74, P = .001 vs. CMD).
Further, an NMD subgroup analysis showed 1.69 times the overall respiratory hospitalization risk among the more severe vs. less severe NMD group, but a similar risk of RSV admission. The authors point out that one reason for this discrepancy may be a higher probability of aspiration causing hospitalization because of more dramatic acute events during respiratory infections in patients with more severe NMD. It also may be that palivizumab evened the playing field for RSV but not for other viruses such as parainfluenza, adenovirus, or even rhinovirus.
Nevertheless, these data tell us that risk of respiratory disease severe enough to need hospitalization continues to an older age in NMD than SI or CMD patients, well past 2 years of age. And the risk is not only from RSV. That said, RSV remains a player in some patients (particularly NMD patients) despite palivizumab prophylaxis, highlighting the need for RSV as well as parainfluenza vaccines. While these vaccines should help all young children, they seem likely to be even more beneficial for high-risk children including those with NMD, and particularly those with more severe NMD.
Eleven among 60 total candidate RSV vaccines (live attenuated, particle based, or vector based) are currently in clinical trials.2 Fewer parainfluenza vaccines are in the pipeline, but clinical trials also are underway.3-5 Approval of such vaccines is not expected until the mid-2020s, so at present we are left with providing palivizumab to our vulnerable patients while emphasizing nonmedical strategies that may help prevent respiratory viruses. These only partially successful preventive interventions include breastfeeding, avoiding secondhand smoke, and avoiding known high-risk exposures, such as large day care centers.
My hope is for quicker than projected progress on the vaccine front so that winter admissions for respiratory viruses might decrease in numbers similar to the decrease we have noted with another vaccine successful against a seasonally active pathogen – rotavirus.
Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospital–Kansas City, Mo. Children’s Mercy Hospital receives grant funding to study two candidate RSV vaccines. The hospital also receives CDC funding under the New Vaccine Surveillance Network for multicenter surveillance of acute respiratory infections, including influenza, RSV, and parainfluenza virus. Email Dr. Harrison at [email protected].
References
1. Pediatr Infect Dis J. 2019 Apr 10. doi: 10.1097/INF.0000000000002297.
2. “Advances in RSV Vaccine Research and Development – A Global Agenda.”
3. J Pediatric Infect Dis Soc. 2015 Dec;4(4): e143-6.
4. J Virol. 2015 Oct;89(20):10319-32.
5. Vaccine. 2017 Dec 18;35(51):7139-46.
Influenza gets a lot of attention each winter, but respiratory syncytial virus (RSV) and other respiratory viruses have as much or more impact on pediatric populations, particularly certain high-risk groups. But currently there are no vaccines for noninfluenza respiratory viruses. That said, several are under development, for RSV and parainfluenza.
Which groups are likely to get the most benefit from these newer vaccines?
We all are aware of the extra vulnerability to respiratory viruses (RSV being the most frequent) in premature infants, those with chronic lung disease, or those with congenital heart syndromes; such vulnerable patients are not infrequently seen in routine practice. A recent report shined a brighter light on such a group.
Real-world data from a nationwide Canadian surveillance system (CARESS) was used to analyze relative risks of categories of young children who are thought to be vulnerable to respiratory viruses, with a particular focus on those with neuromuscular disease. The CARESS investigators analyzed 12 years’ data on respiratory hospitalizations from among palivizumab-prophylaxed patients (including specific data on RSV when patients were tested for RSV per standard of care).1 Unfortunately, RSV testing was not universal despite hospitalization, so the true incidence of RSV-specific hospitalizations was likely underestimated.
Nevertheless, more than 25,000 children from 2005 through 2017 were grouped into three categories of palivizumab-prophylaxed high-risk children: standard indications (SI), n = 20,335; chronic medical conditions (CMD), n = 4,063; and neuromuscular disease (NMD), n = 605. This study is notable for having a relatively large number of neuromuscular disease subjects. Two-thirds of each group were fully palivizumab adherent.
The SI group included the standard American Academy of Pediatrics–recommended groups, such as premature infants, congenital heart disease, etc.
The CMD group included conditions that lead clinicians to use palivizumab off label, such as cystic fibrosis, congenital airway anomalies, immunodeficiency, and pulmonary disorders.
The NMD participants were subdivided into two groups. Group 1 comprised general hypotonic neuromuscular diseases such as hypoxic-ischemic encephalopathy, Prader-Willi syndrome, chromosomal disorders, and migration/demyelinating diseases. Group 2 included more severe infantile neuromuscular disorders, such as spinal muscular atrophy, myotonic dystrophy, centronuclear and nemaline myopathy, mitochondrial and glycogen storage myopathies, or arthrogryposis.
Overall, 6.9% of CARESS RSV-prophylaxed subjects were hospitalized. About one in five hospitalized patients from each group was hospitalized more than once. Specific respiratory hospitalization rates for each group were 6% (n = 1,228) for SI subjects and 9.4% (n = 380) for CMD, compared with 19.2% (n = 116) for NMD subjects.
It is unclear what proportion underwent RSV testing, but a total of 334 were confirmed RSV positive: 261 were SI, 54 were CMD and 19 were NMD. The RSV-test-positive rate was 1.5% for SI, 1.6% for CMD and 3.3% for NMD; so while a higher number of SI children were RSV positive, the rate of RSV positivity was actually highest with NMD.
RSV-positive subjects needing ICU care among NMD patients also had longer ICU stays (median 14 days), compared with RSV-positive CMD or SI subjects (median 3 and 5 days, respectively). Further, hospitalized RSV-positive NMD subjects presented more frequently with pneumonia (42% vs. 30% for CMD and 20% for SI) while hospitalized RSV-positive SI subjects more often had apnea (17% vs. 10% for NMD and 5% for CMD, P less than .05).
These differences in the courses of NMD patients raise the question as to whether the NMD group was somehow different from the SI and CMD groups, other than muscular weakness that likely leads to less ability to clear secretions and a less efficient cough. It turns out that NMD children were older and had worse neonatal medical courses (longer hospital stays, more often ventilated, and used oxygen longer). It could be argued that these differences may have been in part due to the muscular weakness inherent in their underlying disease, but they appear to be predictors of worse respiratory infectious disease than other vulnerable populations as the NMD children get older.
Indeed, the overall risk of any respiratory admission among NMD subjects was nearly twice as high, compared with SI (hazard ratio, 1.90, P less than .0005); but the somewhat higher risk for NMD vs. CMD was not significant (HR, 1.33, P = .090). However, when looking specifically at RSV confirmed admissions, NMD had more than twice the hospitalization risk than either other group (HR, 2.26, P = .001 vs. SI; and HR, 2.74, P = .001 vs. CMD).
Further, an NMD subgroup analysis showed 1.69 times the overall respiratory hospitalization risk among the more severe vs. less severe NMD group, but a similar risk of RSV admission. The authors point out that one reason for this discrepancy may be a higher probability of aspiration causing hospitalization because of more dramatic acute events during respiratory infections in patients with more severe NMD. It also may be that palivizumab evened the playing field for RSV but not for other viruses such as parainfluenza, adenovirus, or even rhinovirus.
Nevertheless, these data tell us that risk of respiratory disease severe enough to need hospitalization continues to an older age in NMD than SI or CMD patients, well past 2 years of age. And the risk is not only from RSV. That said, RSV remains a player in some patients (particularly NMD patients) despite palivizumab prophylaxis, highlighting the need for RSV as well as parainfluenza vaccines. While these vaccines should help all young children, they seem likely to be even more beneficial for high-risk children including those with NMD, and particularly those with more severe NMD.
Eleven among 60 total candidate RSV vaccines (live attenuated, particle based, or vector based) are currently in clinical trials.2 Fewer parainfluenza vaccines are in the pipeline, but clinical trials also are underway.3-5 Approval of such vaccines is not expected until the mid-2020s, so at present we are left with providing palivizumab to our vulnerable patients while emphasizing nonmedical strategies that may help prevent respiratory viruses. These only partially successful preventive interventions include breastfeeding, avoiding secondhand smoke, and avoiding known high-risk exposures, such as large day care centers.
My hope is for quicker than projected progress on the vaccine front so that winter admissions for respiratory viruses might decrease in numbers similar to the decrease we have noted with another vaccine successful against a seasonally active pathogen – rotavirus.
Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospital–Kansas City, Mo. Children’s Mercy Hospital receives grant funding to study two candidate RSV vaccines. The hospital also receives CDC funding under the New Vaccine Surveillance Network for multicenter surveillance of acute respiratory infections, including influenza, RSV, and parainfluenza virus. Email Dr. Harrison at [email protected].
References
1. Pediatr Infect Dis J. 2019 Apr 10. doi: 10.1097/INF.0000000000002297.
2. “Advances in RSV Vaccine Research and Development – A Global Agenda.”
3. J Pediatric Infect Dis Soc. 2015 Dec;4(4): e143-6.
4. J Virol. 2015 Oct;89(20):10319-32.
5. Vaccine. 2017 Dec 18;35(51):7139-46.