Disclaimer

1. Disclaimer The speaker has no financial ties of relevance to this topic or any conflict of interest to disclose. If you would like to create a financial conflict of interest, please contact the speaker

2. Respiratory Syncytial Virus: Beyond fluids and oxygen Joseph Y. Allen, MD Pediatric Emergency Medicine Texas Children’s Hospital Baylor College of Medicine Good morning.Good morning.

3. Objectives Review virology and epidemiology Discuss clinical aspects of RSV Discuss evaluation of comorbidities Review treatment modalities

4. Anatomy of a virus 1st identified in 1956 Paramyxoviridae family Single strand RNA Two subtypes: A & B F and G surface proteins induce antibody G surface protein is variable Bronchiolitis was first described at the turn of the century with RSV identified in 1956. It is a member of the paramyxoviridae family that includes measles and is an enveloped single stranded RNA virus. It is divided into two main subgroups, the A and B variants. There are 10 surface glycoproteins that are involved in RSV attaching to the surface but the F and G are the most crucial as they can induce viral neutralizing antibody The G surface protein is diverse creating the different strains that cause a child to have bronchiolitis more than once. Usually several types circulate concurrently.Bronchiolitis was first described at the turn of the century with RSV identified in 1956. It is a member of the paramyxoviridae family that includes measles and is an enveloped single stranded RNA virus. It is divided into two main subgroups, the A and B variants. There are 10 surface glycoproteins that are involved in RSV attaching to the surface but the F and G are the most crucial as they can induce viral neutralizing antibody The G surface protein is diverse creating the different strains that cause a child to have bronchiolitis more than once. Usually several types circulate concurrently.

5. Immunopathology B and T cells involved in clearance Antibody blocks entry Tc lymphocytes terminate infection TH lymphocytes may modulate disease RSV attaches to the bronchioles via the F and G subunit proteins. Antibody to these surface proteins from Endogenous B-cells or from passively given synagis can block attachment and replication. However Cytotoxic T-cell CD8+ lymphocytes are necessary for illness resolution as well. The need for T-cell function is evidenced by patients with T cell dysfunction (such as in digeorge or HIV) have more severe illness and longer recovery times. The interaction of the viral genotype with the patient’s genotype may alter cytokines that CD4+ t-helper cells secrete. The type of cytokines released has been shown to at least partly affect illness severity.RSV attaches to the bronchioles via the F and G subunit proteins. Antibody to these surface proteins from Endogenous B-cells or from passively given synagis can block attachment and replication. However Cytotoxic T-cell CD8+ lymphocytes are necessary for illness resolution as well. The need for T-cell function is evidenced by patients with T cell dysfunction (such as in digeorge or HIV) have more severe illness and longer recovery times. The interaction of the viral genotype with the patient’s genotype may alter cytokines that CD4+ t-helper cells secrete. The type of cytokines released has been shown to at least partly affect illness severity.

6. Immunopathology Markers of severity Il-8 Elastase Macrophage inflammatory protein 1a Certain markers have been implicated in RSV severity in particular levels of neutrophil elastase and Cytokine il-8 are higher in infected individuals when compared to controls Another marker of interest is the beta chemokine macrophage inflammatory protein 1-alpha. It has been shown to attract lymphocytes in RSV infection to further release of cytokines. This may offer a new target for RSV illness modulation. While this observation of increased cytokines and severity has been repeated, no association between viral genotypes (through variation at the G antigen) and disease severity has been found. Ultimately, it will probably be determined that the interaction of the particular individual’s genotype and its interaction with the viral antigen is what modulates the severity of illness. Abu harb observational study of 27 with rsv vs 20 controls to measure il8/elastase/mip1-a Smyth- observational study of 276 patients with rsvCertain markers have been implicated in RSV severity in particular levels of neutrophil elastase and Cytokine il-8 are higher in infected individuals when compared to controls Another marker of interest is the beta chemokine macrophage inflammatory protein 1-alpha. It has been shown to attract lymphocytes in RSV infection to further release of cytokines. This may offer a new target for RSV illness modulation. While this observation of increased cytokines and severity has been repeated, no association between viral genotypes (through variation at the G antigen) and disease severity has been found. Ultimately, it will probably be determined that the interaction of the particular individual’s genotype and its interaction with the viral antigen is what modulates the severity of illness. Abu harb observational study of 27 with rsv vs 20 controls to measure il8/elastase/mip1-a Smyth- observational study of 276 patients with rsv

7. Pathology This is a path slide showing the syncytial cells which led to it naming This is a path slide showing the syncytial cells which led to it naming

8. Epidemiology Humans are natural reservoirs RSV is hardy Children< 24 months infected Peak age: 2-8 months Peak occurrence in December-January RSV only infects humans in the wild. It is an extremely hardy virus lasting up to 6 hours on surfaces. young children are mostly affected with 50-60% of children affected by the first year and nearly 100% infected by the second year of life. RSV infection can occur year round. RSV season is from November through april and peaking in early January.RSV only infects humans in the wild. It is an extremely hardy virus lasting up to 6 hours on surfaces. young children are mostly affected with 50-60% of children affected by the first year and nearly 100% infected by the second year of life. RSV infection can occur year round. RSV season is from November through april and peaking in early January.

9. Epidemiology This is a graph from the national hospital discharge survey published in Peds infectious disease journals documenting hospitalizations from 1997-2000 for RSV. Note the peaks in December-FebruaryThis is a graph from the national hospital discharge survey published in Peds infectious disease journals documenting hospitalizations from 1997-2000 for RSV. Note the peaks in December-February

10. Epidemiology This same article also reported that RSV was the leading cause of admission in children < 1 year old with 70,000 admits per year from 1997-1999.This same article also reported that RSV was the leading cause of admission in children < 1 year old with 70,000 admits per year from 1997-1999.

11. Admission >70,000 /yr hospitalized Admit rate: 2-3% 1-5% deteriorate 35% fatality with coexisting illness This number only accounts for bronchiolitis known to be cause by RSV. The leader article reported another 60,000 cases per year of bronchiolitis without a cause isolated. Therefore the actual number may be over 100,000 cases. About 2-3% of children with bronchiolitis are admitted with rates being similar both here and in the UK Of those that are admitted a small percentage will deteriorate such as needing intubation or the PICU death In patients who were premature with bpd, have congenital heart disease, or some other t-cell immunodeficiency have up to a 35% fatality rate, so be cautious with those childrenThis number only accounts for bronchiolitis known to be cause by RSV. The leader article reported another 60,000 cases per year of bronchiolitis without a cause isolated. Therefore the actual number may be over 100,000 cases. About 2-3% of children with bronchiolitis are admitted with rates being similar both here and in the UK Of those that are admitted a small percentage will deteriorate such as needing intubation or the PICU death In patients who were premature with bpd, have congenital heart disease, or some other t-cell immunodeficiency have up to a 35% fatality rate, so be cautious with those children

12. Financial impact of RSV RSV in the Netherlands $2,200/patient RSV in the US $8,859/patient Total charges are significant Studies have tried to calculate the financial impact RSV has. In the Netherlands with a more socialized system and about 300 admissions per year, the cost was estimated to result in about a 600,000 cost per year A different study performed in the US, estimated the average charge for hospitalization was 9,000 dollars per person. With over 100,000 admits per year, this charge may result in nearly 1 billion dollars a year; while one can argue the exact cost- it is substantialStudies have tried to calculate the financial impact RSV has. In the Netherlands with a more socialized system and about 300 admissions per year, the cost was estimated to result in about a 600,000 cost per year A different study performed in the US, estimated the average charge for hospitalization was 9,000 dollars per person. With over 100,000 admits per year, this charge may result in nearly 1 billion dollars a year; while one can argue the exact cost- it is substantial

13. Clinical presentation Incubation period: 4-6 days Respiratory epithelium targeted Rhinorrhea/ congestion Cough Wheeze RSV has a mean incubation of 4-6 days. The terminal bronchioles are the main target although it can proliferate anywhere in the bronchial tree. Entry via the eyes or nose can also lead to infection as RSV travels cell to cell to enter the respiratory tree. Symptoms include rhinorrhea and congestion followed by cough, tachypnea and wheezing as cellular debris builds. Increased functional residual capacity, dead space, v/q mismatch, and increased airway resistance result from this airway narrowing leading to increased use of accessory muscles of breathing as the diaphragm alone is not strong enough to overcome this airway resistance in young children.RSV has a mean incubation of 4-6 days. The terminal bronchioles are the main target although it can proliferate anywhere in the bronchial tree. Entry via the eyes or nose can also lead to infection as RSV travels cell to cell to enter the respiratory tree. Symptoms include rhinorrhea and congestion followed by cough, tachypnea and wheezing as cellular debris builds. Increased functional residual capacity, dead space, v/q mismatch, and increased airway resistance result from this airway narrowing leading to increased use of accessory muscles of breathing as the diaphragm alone is not strong enough to overcome this airway resistance in young children.

14. Presentation in young infants Tachypnea Lethargy Apnea In young infants less than 90 days the first clinical presentation may be lethargy, irritabilty and apnea with respiratory failure. It is uncertain if it the work of breathing that leads to resp failure or if the RSV directly suppresses the central ventilatory mechanism to result in apneaIn young infants less than 90 days the first clinical presentation may be lethargy, irritabilty and apnea with respiratory failure. It is uncertain if it the work of breathing that leads to resp failure or if the RSV directly suppresses the central ventilatory mechanism to result in apnea

15. Initial management Diagnosis is clinical Oxygen and hydration often necessary Thickening of feeds may prevent reflux X-ray useful in selected situations The diagnosis of bronchiolitis is primarily clinical. As these patients have increased metabolic demand, supp oxygen is helpful as well as hydration. due to increased insensible losses from their tachypnea. Kids with RSV may have more reflux and thickening feeds can reduce risk of aspiration (as shown by khoshoo comparing infants with thickened feeds vs those without) Chest x-ray may be helpful to evaluate persistent focality on exam or in workup of accompanying fever The diagnosis of bronchiolitis is primarily clinical. As these patients have increased metabolic demand, supp oxygen is helpful as well as hydration. due to increased insensible losses from their tachypnea. Kids with RSV may have more reflux and thickening feeds can reduce risk of aspiration (as shown by khoshoo comparing infants with thickened feeds vs those without) Chest x-ray may be helpful to evaluate persistent focality on exam or in workup of accompanying fever

16. RSV radiography Read as normal with possible hyperinflationRead as normal with possible hyperinflation

17. RSV radiography RUL atelectasisRUL atelectasis

18. RSV radiography Mild RML perihilar markings with some peribronchial cuffingMild RML perihilar markings with some peribronchial cuffing

19. RSV radiography Worse bilateral perihilar infiltrates with flattened diaphragmsWorse bilateral perihilar infiltrates with flattened diaphragms

20. Isolating a pathogen Viral culture for identification of virus Rapid testing available with varying results 70% of bronchiolitis due to RSV Isolating RSV via viral culture is considered the gold standard but may take 3-4 days and offers little clinical utility in the ED setting. Several rapid tests are available with sensitivity and specificity ranging from 70-90+ % for each. (Other screens used include the test-pack, thermo biostar, fisher sure-vue, our lab uses the BINAX RSV with results back in 30 minutes) RSV accounts for 70% of bronchiolitis with adenovirus, parainfluenza, influenza,metapneumovirus, or a newly reported bocavirus accounting for the rest. When faced with a child with bronchiolitis a clinician can use variables to predict those who need admission.Isolating RSV via viral culture is considered the gold standard but may take 3-4 days and offers little clinical utility in the ED setting. Several rapid tests are available with sensitivity and specificity ranging from 70-90+ % for each. (Other screens used include the test-pack, thermo biostar, fisher sure-vue, our lab uses the BINAX RSV with results back in 30 minutes) RSV accounts for 70% of bronchiolitis with adenovirus, parainfluenza, influenza,metapneumovirus, or a newly reported bocavirus accounting for the rest. When faced with a child with bronchiolitis a clinician can use variables to predict those who need admission.

21. Co-morbidities and RSV Admission Apnea Serious bacterial infections

22. Predictors of admission O2 sat< 95% Ill appearing Atelectasis on x-ray Tachypnea > 70 bpm < 34 weeks premature Postnatal< 3 months To see which patients could be safely sent home Shaw and others enrolled 213 infants and looked at factors in the history, physical, or on ancillary evaluation. They found that the presence of hypoxia (RR 3.28), ill appearance (4.6), atelectasis (2.7), tachypnea (2.6), prematurity less than 34 weeks (2.55), and age of less than 3 months ((1.93) to be associated with a higher relative risk for admission All six factors together resulted in a sensitivity and specificity of 86% and 91% for those infants with RSV infection who needed to be admitted (BELOW IS ALL EXTRA STUFF) Of the severe group, 59 (80%) needed o2, 13 (18%) admitted to ICU and 8(11%) needed intubation. All factors taken together give a specificity of 91% and sensitivity of 76%. There still are patients though who will be severe who may not have all of these traits and frequent reassessment was stressed by her paper. Sens: pts with illness manifest trait (test positive), Spec pts healthy do not manifest trait To see which patients could be safely sent home Shaw and others enrolled 213 infants and looked at factors in the history, physical, or on ancillary evaluation. They found that the presence of hypoxia (RR 3.28), ill appearance (4.6), atelectasis (2.7), tachypnea (2.6), prematurity less than 34 weeks (2.55), and age of less than 3 months ((1.93) to be associated with a higher relative risk for admission All six factors together resulted in a sensitivity and specificity of 86% and 91% for those infants with RSV infection who needed to be admitted (BELOW IS ALL EXTRA STUFF) Of the severe group, 59 (80%) needed o2, 13 (18%) admitted to ICU and 8(11%) needed intubation. All factors taken together give a specificity of 91% and sensitivity of 76%. There still are patients though who will be severe who may not have all of these traits and frequent reassessment was stressed by her paper. Sens: pts with illness manifest trait (test positive), Spec pts healthy do not manifest trait

23. Predictors of deterioration RR>80 O2 sats<85% Taking this a step further, Dr. Ann brooks looked at variables at admission to predict which hospitalized patient would need ICU or intubation. She found that while only 30% of patients who deteriorated were severely tachypneic or markedly hypoxic at admission, 97% of patients that did not have these findings (a neg test) remained well (neg disease) (also called a NPV) Overall she found that 1.8% (15) of hospitalized patients deteriorated consistent with other published reports. The bottom line from these 2 studies is that clinical judgment with minimal ancillary evaluation can be useful in predicting who can go home safely. Younger infants pose a further challenge as they may not a significant degree of tachypnea or hypoxia.Taking this a step further, Dr. Ann brooks looked at variables at admission to predict which hospitalized patient would need ICU or intubation. She found that while only 30% of patients who deteriorated were severely tachypneic or markedly hypoxic at admission, 97% of patients that did not have these findings (a neg test) remained well (neg disease) (also called a NPV) Overall she found that 1.8% (15) of hospitalized patients deteriorated consistent with other published reports. The bottom line from these 2 studies is that clinical judgment with minimal ancillary evaluation can be useful in predicting who can go home safely. Younger infants pose a further challenge as they may not a significant degree of tachypnea or hypoxia.

24. RSV and apnea Risk factors Post conception age <44 weeks Premature birth History of apnea of prematurity Instead apnea may be the presenting sign of RSV in them. Nancy Church tried to find variables that would predict apnea in 261 admitted infants with RSV. Apnea was defined as a pause >15 s or associated with any cyanosis or bradycardia. She found that of the group of patients with apnea a significantly higher percentage were < 44 weeks post conceptional age (60% vs 18%), Or were born prematurely <37 weeks (58% vs 26%) or had a history of AOP (90% vs. 45%) (BELOW IS EXTRA) All patients were followed for 1 year. There was no recurrence with The two deaths in a pt with severe multiple congenital anomalies secondary to resp arrest at 4 months and the other was in a baby with a history of reflux who was found cyanotic and apneic 15 min after a feed with vomitus in her mouth and death at post mortem was from bilateral asp pneumonitis. Instead apnea may be the presenting sign of RSV in them. Nancy Church tried to find variables that would predict apnea in 261 admitted infants with RSV. Apnea was defined as a pause >15 s or associated with any cyanosis or bradycardia. She found that of the group of patients with apnea a significantly higher percentage were < 44 weeks post conceptional age (60% vs 18%), Or were born prematurely <37 weeks (58% vs 26%) or had a history of AOP (90% vs. 45%) (BELOW IS EXTRA) All patients were followed for 1 year. There was no recurrence with The two deaths in a pt with severe multiple congenital anomalies secondary to resp arrest at 4 months and the other was in a baby with a history of reflux who was found cyanotic and apneic 15 min after a feed with vomitus in her mouth and death at post mortem was from bilateral asp pneumonitis.

25. RSV and apnea Age < 2 months First 48 hours of illness More recently a retrospective European study looking at 185 admitted infants with RSV carried this further finding that age less than 2 months was the greatest risk factor for apnea, particularly if the course of illness was within the first 48 hours Take home message here is that patients with RSV less than 1-2 month old, were premature or who present in the first 48 hours of illness with RSV should be approached with caution and that strong consideration be given to admission as the risk of apnea is significantly higher (below is extra) Kneyber in 1997 looking at 185 patients under 1 year with RSV and found about the same percentage of infants who presented with apnea. In looking at historical, physical exam findings, and lab/radiography the Rel Risk was highest for age less than 2 months (1.6: 1.1-2.3 95% confidence interval), less than 1 month (2.7:1.2-6.3), atelectasis on cxr, 1.4 (1-1.9). The association of < 32 weeks birth was not found here, nor was mean sat or p co2 at admission different. The apnea group was younger by one month 2.3 vs 3.3 months. 14 in each groups were ventilated Also 88% of patients with apnea at admission developed recurrent apnea within the first 48 Hours after admission More recently a retrospective European study looking at 185 admitted infants with RSV carried this further finding that age less than 2 months was the greatest risk factor for apnea, particularly if the course of illness was within the first 48 hours Take home message here is that patients with RSV less than 1-2 month old, were premature or who present in the first 48 hours of illness with RSV should be approached with caution and that strong consideration be given to admission as the risk of apnea is significantly higher (below is extra) Kneyber in 1997 looking at 185 patients under 1 year with RSV and found about the same percentage of infants who presented with apnea. In looking at historical, physical exam findings, and lab/radiography the Rel Risk was highest for age less than 2 months (1.6: 1.1-2.3 95% confidence interval), less than 1 month (2.7:1.2-6.3), atelectasis on cxr, 1.4 (1-1.9). The association of < 32 weeks birth was not found here, nor was mean sat or p co2 at admission different. The apnea group was younger by one month 2.3 vs 3.3 months. 14 in each groups were ventilated Also 88% of patients with apnea at admission developed recurrent apnea within the first 48 Hours after admission

26. RSV and apnea Apriori defined criteria applied retrospectively FT age < 1 month Pre-term and less than 48 week post conception Witnessed apnea Identified all 19/691 admitted patients who developed apnea Defined criteria a-priori Looked at 691 admitted infants retrospectively-this criteria caught all 19 patients with apnea This is not prospectiveDefined criteria a-priori Looked at 691 admitted infants retrospectively-this criteria caught all 19 patients with apnea This is not prospective

27. RSV and SBI 30% have concomitant fever Variability exists in evaluation Viral illness damages natural barriers Risks of evaluation for SBI 30% of patients with RSV+ bronchiolitis will have fever at the time of presentation (>38 under 3 months, >39 3-36 months). The evaluation that these patients should undergo is controversial. There is tremendous variability in clinical evaluation of children with fever who have bronchiolitis. This variability increases as the age of the child decreases Viral illness can damage respiratory epithelium allowing increased translocation of bacteria as well as down regulate neutrophil activity that in theory increases the risk of an SBI. However unnecessary SBI evaluation adds costs, time, and adds the increased risk of testing and antibiotic administration30% of patients with RSV+ bronchiolitis will have fever at the time of presentation (>38 under 3 months, >39 3-36 months). The evaluation that these patients should undergo is controversial. There is tremendous variability in clinical evaluation of children with fever who have bronchiolitis. This variability increases as the age of the child decreases Viral illness can damage respiratory epithelium allowing increased translocation of bacteria as well as down regulate neutrophil activity that in theory increases the risk of an SBI. However unnecessary SBI evaluation adds costs, time, and adds the increased risk of testing and antibiotic administration

28. Viral syndrome and SBI Croup, varicella, bronchiolitis, stomatitis 2/876 blood cultures (+) To try to determine the risk of bacteremia Greenes and Harper retrospectively looked at 1347 children 3-36 months with a Recognizable viral syndrome including RSV. Of the 876 blood cultures 2 of them were positive, with 1/411 cultures of the RSV+ kids growing strep pneumo. (the other group a strep in varicella). 12 contaminants were noted. An age breakdown was not clear here (BELOW IS EXTRA) from Childrens of Boston did a retrospective analysis over 5.5 years in 1347 kids 3-36 months with fever >39 and a recognizable viral illness in the EC with bronchiolitis being one of them. They found that 6% of all kids had one of these RVS. Only 1/411 (0.2%) of these bronchiolitics had bacteremia with strep pneumo. They argued that a blood cultures routinely are not needed in well appearing. The other positive culture is in varicella with group a strep. To try to determine the risk of bacteremia Greenes and Harper retrospectively looked at 1347 children 3-36 months with a Recognizable viral syndrome including RSV. Of the 876 blood cultures 2 of them were positive, with 1/411 cultures of the RSV+ kids growing strep pneumo. (the other group a strep in varicella). 12 contaminants were noted. An age breakdown was not clear here (BELOW IS EXTRA) from Childrens of Boston did a retrospective analysis over 5.5 years in 1347 kids 3-36 months with fever >39 and a recognizable viral illness in the EC with bronchiolitis being one of them. They found that 6% of all kids had one of these RVS. Only 1/411 (0.2%) of these bronchiolitics had bacteremia with strep pneumo. They argued that a blood cultures routinely are not needed in well appearing. The other positive culture is in varicella with group a strep.

29. RSV and SBI 163 febrile bronchiolitics NO bacteremia 2% UTI 269 febrile controls 2.7% bacteremia 13.6% UTI RSV (+) <3 months (36 patients) 33 (-) CSF cultures Expanding the scope to include urine infections Kuppermann prospectively enrolled 432 patients less than 2 years old with fever and compared febrile RSV bronchiolitics with documented wheezing or retractions (163) to febrile controls (269) with no source for the fever. He found that far more patients in the controls had bacteremia and UTI's than the bronchiolitics. Additionally he had no positive CSF cultures from the 33/36 patients in the bronchiolitic group who had LP’s. (one had cell count >20, 2 >10). His conclusion was that while risk overall is low for bacteremia, A urine culture should be sent. In infants less than 3 months though the numbers were too low to draw a conclusion. All had cbc’s and less had u/a’s. With far fewer bronchiolitics having positive cultures. Of note 51/110 (46%) of the bronchiolitis had RSV done that were positive. There were only 36 patients under 2 months in the control group so it is difficult to make a conclusion about this group He then evaluated the 935 patients not enrolled to see if his results were anomalous. No positive blood cultures were found (0/48 cxs done in 100 missed bronchiolitics) and 1 uti(1/27 3.7%). In the control group of 835 missed it was (11/477) 2.3 % bacteremia and (35/403) 8.7 % uti. From this the conclusion can be drawn in healthy kids older than two months with bronchiolitis a CBC and cx is probably unnecessary. Expanding the scope to include urine infections Kuppermann prospectively enrolled 432 patients less than 2 years old with fever and compared febrile RSV bronchiolitics with documented wheezing or retractions (163) to febrile controls (269) with no source for the fever. He found that far more patients in the controls had bacteremia and UTI's than the bronchiolitics. Additionally he had no positive CSF cultures from the 33/36 patients in the bronchiolitic group who had LP’s. (one had cell count >20, 2 >10). His conclusion was that while risk overall is low for bacteremia, A urine culture should be sent. In infants less than 3 months though the numbers were too low to draw a conclusion. All had cbc’s and less had u/a’s. With far fewer bronchiolitics having positive cultures. Of note 51/110 (46%) of the bronchiolitis had RSV done that were positive. There were only 36 patients under 2 months in the control group so it is difficult to make a conclusion about this group He then evaluated the 935 patients not enrolled to see if his results were anomalous. No positive blood cultures were found (0/48 cxs done in 100 missed bronchiolitics) and 1 uti(1/27 3.7%). In the control group of 835 missed it was (11/477) 2.3 % bacteremia and (35/403) 8.7 % uti. From this the conclusion can be drawn in healthy kids older than two months with bronchiolitis a CBC and cx is probably unnecessary.

30. RSV and SBI 2396 RSV (+) children 146 < 30 days 12 blood cx contaminants 1.1% urine cx (+) A larger more recent study by Purcell from Driscoll Children’s confirmed this, as it looked retrospectively at 7 years of RSV + patients. Nearly 2400 patients were enrolled with 95% under 2 years and 34% under 90 days. He reported 12 blood culture positive for contaminants and 27 positive urine cultures. Unfortunately the stratification of risk by age, or total number of cultures drawn were not reported. The take home point is that the overall risk is low for children 3-36 months with bronchiolitis to have occult bacteremia. Now that Prevnar is in widespread use, the already low risk for bacteremia in these kids 3-36 months with bronchiolitis is probably lowered to the point that a routine cbc and culture is probably not indicated. (Below is extra) He found a mean age of 8 months with 95% under 2 years. Of these 805 were under 90 days old. The urines were typical urine pathogens that got treated. While it is a very large study that took a tremendous amount of work it did not stratify temperature or cultures obtained by age as the previous ones did. So it groups 0-24 months as having the same risk which is not correct. A larger more recent study by Purcell from Driscoll Children’s confirmed this, as it looked retrospectively at 7 years of RSV + patients. Nearly 2400 patients were enrolled with 95% under 2 years and 34% under 90 days. He reported 12 blood culture positive for contaminants and 27 positive urine cultures. Unfortunately the stratification of risk by age, or total number of cultures drawn were not reported. The take home point is that the overall risk is low for children 3-36 months with bronchiolitis to have occult bacteremia. Now that Prevnar is in widespread use, the already low risk for bacteremia in these kids 3-36 months with bronchiolitis is probably lowered to the point that a routine cbc and culture is probably not indicated. (Below is extra) He found a mean age of 8 months with 95% under 2 years. Of these 805 were under 90 days old. The urines were typical urine pathogens that got treated. While it is a very large study that took a tremendous amount of work it did not stratify temperature or cultures obtained by age as the previous ones did. So it groups 0-24 months as having the same risk which is not correct.

31. Infants and risk of SBI 262 infants < 60 days with bronchiolitis 72.5% febrile at admission 146/170 tested RSV+ 3 UTI, 1 bacteremia 2/4 were less than 29 days old Can this risk reduction in SBI’s that RSV seems to offer be extended to the youngest infants? Antonow performed a retrospective chart review of 262 pts < 60 days with dx of bronchiolitis. 73% were febrile. 146/170 tested positive for rsv. Only 122 of these patients had blood work performed. 3 patients had UTI and 1 was bacteremia with s. pneumo. These patients tended to be ill (had apnea or cyanosis at presentation) and 2 of them were under 1 month of age. Also 2 of these had no wheezing documented only congestion. They concluded that pts over1 month of age with classic symptoms of bronchiolitis could be observed without sepsis evaluations. They did state though ”we did find a strong association of younger age and SBI. . .this raises our concerns about generalizing our conclusions to the youngest infants.” (BELOW IS EXTRA) The pt with bacteremia presented with apnea and cyanosis and fever to 39.2 and needed resuscitation and grew s. pneumo in 6 hours and was 40 days old. The other 3 patient with uti’s, 2 were under 29 days they were both apnea with cyanosis and one was hypothermic (kleb oxytoca and e coli) the third was 49 days old and grew e. coli 10,000 cfu with cough only (no wheezing). Of note he was rsv negative. There was significant variability in lab work as 122 of these had lab work up and the other 140 did not. (utah) Summary is in a well appearing child over 29 days or older with RSV and fever the risk for sbi is super low. All patients under 29 days should get full w/u if fever or look bad Can this risk reduction in SBI’s that RSV seems to offer be extended to the youngest infants? Antonow performed a retrospective chart review of 262 pts < 60 days with dx of bronchiolitis. 73% were febrile. 146/170 tested positive for rsv. Only 122 of these patients had blood work performed. 3 patients had UTI and 1 was bacteremia with s. pneumo. These patients tended to be ill (had apnea or cyanosis at presentation) and 2 of them were under 1 month of age. Also 2 of these had no wheezing documented only congestion. They concluded that pts over1 month of age with classic symptoms of bronchiolitis could be observed without sepsis evaluations. They did state though ”we did find a strong association of younger age and SBI. . .this raises our concerns about generalizing our conclusions to the youngest infants.” (BELOW IS EXTRA) The pt with bacteremia presented with apnea and cyanosis and fever to 39.2 and needed resuscitation and grew s. pneumo in 6 hours and was 40 days old. The other 3 patient with uti’s, 2 were under 29 days they were both apnea with cyanosis and one was hypothermic (kleb oxytoca and e coli) the third was 49 days old and grew e. coli 10,000 cfu with cough only (no wheezing). Of note he was rsv negative. There was significant variability in lab work as 122 of these had lab work up and the other 140 did not. (utah) Summary is in a well appearing child over 29 days or older with RSV and fever the risk for sbi is super low. All patients under 29 days should get full w/u if fever or look bad

32. Infants and risk of SBI 1248 febrile infants < 60 days enrolled RSV (+) in 249 patients Risk of bacteremia: 1.1% vs 2.3% Risk of UTI: 5.4% vs 10.1% Difference in meningitis not significant Full sepsis evaluations in < 29 days At a minimum, U/A and culture in 29-60 day olds Finally, a Prospective multicenter trial of the RSV-SBI Study group of the Ped EM Collaborative research committee of the AAP in June 2004. 1248 out of 1868 potential febrile infants enrolled. 91% of these had full sepsis evaluations done.The risk of SBI was significantly lower in the RSV positive group vs RSv neg 7 vs 12.5%. Bacteremia was lower 1.1 vs 2.3% and Uti’s were lower as well. No cases of meningitis were found in the RSV + group with 8 bacterial meningitis in the rsv negative group with numbers too small to comment on. Also the patients with bacteremia in the RSV + group were 9, 10 and 19 days old with enterobacter, gbs and e coli The bottom line on this is that in infants less than 1 month of age with fever regardless of RSV status should have the full workup. In kids 1- 2 months old at a minimum a urinalysis and culture should be performed. The decision on other testing should be left then to the individual practitioner as to their comfort level. And to quote the article ‘additional study of an even larger cohort is needed to assess the risk of bacteremia and meningitis in young febrile infants with RSV infection.” Moving on to treatmentsFinally, a Prospective multicenter trial of the RSV-SBI Study group of the Ped EM Collaborative research committee of the AAP in June 2004. 1248 out of 1868 potential febrile infants enrolled. 91% of these had full sepsis evaluations done.The risk of SBI was significantly lower in the RSV positive group vs RSv neg 7 vs 12.5%. Bacteremia was lower 1.1 vs 2.3% and Uti’s were lower as well. No cases of meningitis were found in the RSV + group with 8 bacterial meningitis in the rsv negative group with numbers too small to comment on. Also the patients with bacteremia in the RSV + group were 9, 10 and 19 days old with enterobacter, gbs and e coli The bottom line on this is that in infants less than 1 month of age with fever regardless of RSV status should have the full workup. In kids 1- 2 months old at a minimum a urinalysis and culture should be performed. The decision on other testing should be left then to the individual practitioner as to their comfort level. And to quote the article ‘additional study of an even larger cohort is needed to assess the risk of bacteremia and meningitis in young febrile infants with RSV infection.” Moving on to treatments

33. RSV treatments Albuterol Racemic Epinephrine Ribavirin Dexamethasone Heliox Hypertonic saline These are treatments that are used with some controversy in the literature on their utility and role in managing bronchiolitisThese are treatments that are used with some controversy in the literature on their utility and role in managing bronchiolitis

34. RSV and albuterol 1st report in 1974 Response is variable Efficacy studies varied Clinical presentation differed Dosage amounts and intervals not standard Different outcomes used for evaluation Albuterol was first published for use for bronchiolitis in 1974. About 30% of patients will respond to albuterol therapy. Trials evaluating the efficacy of albuterol/salbutamol in bronchiolitis had different criteria for enrolling including age and duration of presentation, history of atopy, admission criteria, scoring scales, or amounts or interval of beta agonists used. Because of this, meta analyses of these trials are helpful to try to sort it out. By Phelan et al in 1974 arch dis in childhood Over 70 articles looking at the utility of albuterol were located in a recent pub med search using the terms bronchiolitis and albuterol/salbutamol. Albuterol was first published for use for bronchiolitis in 1974. About 30% of patients will respond to albuterol therapy. Trials evaluating the efficacy of albuterol/salbutamol in bronchiolitis had different criteria for enrolling including age and duration of presentation, history of atopy, admission criteria, scoring scales, or amounts or interval of beta agonists used. Because of this, meta analyses of these trials are helpful to try to sort it out. By Phelan et al in 1974 arch dis in childhood Over 70 articles looking at the utility of albuterol were located in a recent pub med search using the terms bronchiolitis and albuterol/salbutamol.

35. Albuterol: a meta-analysis Clinical score, pulse oximetry, and admission as outcomes Trend toward improved short term scores Kellner and others found 89 publications using the criteria of clinical score, oximetry, or admission as outcomes with albuterol. They then identified only published RCT’s which left 15 for evaluation. There was tremendous heterogeneity in what was defined as bronchiolitic (wheezing, cough, rsv+, age and season, whether atopy was evaluated varied in the studies ). Short term eval was from 30-240 minutes with about 54% of alb groups improving via clinical scores and 25% of controls (saline) improving after nebs. No difference in hospitalization were noted. They concluded that the nebulized solution used oxygen as the carrier which may have resulted in the slight improvement in the placebo. Kellner and others found 89 publications using the criteria of clinical score, oximetry, or admission as outcomes with albuterol. They then identified only published RCT’s which left 15 for evaluation. There was tremendous heterogeneity in what was defined as bronchiolitic (wheezing, cough, rsv+, age and season, whether atopy was evaluated varied in the studies ). Short term eval was from 30-240 minutes with about 54% of alb groups improving via clinical scores and 25% of controls (saline) improving after nebs. No difference in hospitalization were noted. They concluded that the nebulized solution used oxygen as the carrier which may have resulted in the slight improvement in the placebo.

36. Albuterol: a second meta-analysis More stringent criteria Improvement not clinically significant No effect on hospitalization Unable to conclusively recommend or refute beta agonist therapy Similarly Flores and horwitz analyzed 8 of the 15 that kellner looked at that used more strict definitions of bronchiolitis, more exclusions of atopy, shorter and defined durations of illness and only receiving beta agonist therapy (no rac epi or atrovent). They found that while the o2 sat and rr improved statistically they questioned whether it was enough clinically as the resp rate decreased 0.5 vs placebo and o2 sat improved 1.2% overall vs placebo. Because they like kellner found no increased risk of harm to these patients and the fact that some did respond they could not conclusively recommend against a trial of beta agonist therapy.Similarly Flores and horwitz analyzed 8 of the 15 that kellner looked at that used more strict definitions of bronchiolitis, more exclusions of atopy, shorter and defined durations of illness and only receiving beta agonist therapy (no rac epi or atrovent). They found that while the o2 sat and rr improved statistically they questioned whether it was enough clinically as the resp rate decreased 0.5 vs placebo and o2 sat improved 1.2% overall vs placebo. Because they like kellner found no increased risk of harm to these patients and the fact that some did respond they could not conclusively recommend against a trial of beta agonist therapy.

37. Racemic epinephrine b2 dilation a vasoconstriction Decongests mucosa Physiologic antihistamine effects As bronchiolitics have some constriction but also increased secretions an agent which would deal with both was sought. Rac epi not only has the bronchodilator effect of plain beta agonists but also a drying effect as well through alpha agonist mediated vasoconstriction to decongest mucosa. It also has physiologic antihistamine effects as well.As bronchiolitics have some constriction but also increased secretions an agent which would deal with both was sought. Rac epi not only has the bronchodilator effect of plain beta agonists but also a drying effect as well through alpha agonist mediated vasoconstriction to decongest mucosa. It also has physiologic antihistamine effects as well.

38. Epinephrine: a meta-analysis 14 studies evaluated Epinephrine has short-term benefits Data insufficient to support inpatient use Like albuterol studies evaluating the efficacy of epinephrine varied in the same enrollment criteria. In October of 2003, Hartlin and others performed a meta-analysis of racemic epinephrine vs placebo or albuterol. 14 studies were evaluated. Their summary of the studies commented on the heterogeneous scoring scales, type and dose of epi given, different outcome assessed, and comparison of inpatients and outpatients. The bottom line is that epi is favorable to placebo and is as safe as albuterol in improving clinical scores, o2 sats and resp rate in the first hour, but has no impact on affecting inpatient courses. Therefore to quote “a number of large trials is needed to substantiate the efficacy of epinephrine in bronchiolitisLike albuterol studies evaluating the efficacy of epinephrine varied in the same enrollment criteria. In October of 2003, Hartlin and others performed a meta-analysis of racemic epinephrine vs placebo or albuterol. 14 studies were evaluated. Their summary of the studies commented on the heterogeneous scoring scales, type and dose of epi given, different outcome assessed, and comparison of inpatients and outpatients. The bottom line is that epi is favorable to placebo and is as safe as albuterol in improving clinical scores, o2 sats and resp rate in the first hour, but has no impact on affecting inpatient courses. Therefore to quote “a number of large trials is needed to substantiate the efficacy of epinephrine in bronchiolitis

39. True or False? Is epinephrine sold OTC in the U.S. ? Each puff of primatene delivers 0.22 mg of epinephrine while a standard nebulized vapo is 0.5 cc of 2.25 % which is 11.125 mg. This contains cfc’s which are being phased out of the market. Each puff of primatene delivers 0.22 mg of epinephrine while a standard nebulized vapo is 0.5 cc of 2.25 % which is 11.125 mg. This contains cfc’s which are being phased out of the market.

40. Ribavirin (Virazole) Interferes with RSV transcription Challenges in administration The next drug is the The antiviral, ribavirin or Virazole from ICN pharmaceuticals, It is an aerosolized analog of guanine that inhibits viral mRNA transcription that is approved for use in RSV infections. It has a tendency to precipitate and obstruct ventilation tubes. It is also a category X drug from its tendency to cause deformed rodent fetuses (no human probs though) (Dosage is ribavirin 6g over 2 hours neb tid x 3 days The next drug is the The antiviral, ribavirin or Virazole from ICN pharmaceuticals, It is an aerosolized analog of guanine that inhibits viral mRNA transcription that is approved for use in RSV infections. It has a tendency to precipitate and obstruct ventilation tubes. It is also a category X drug from its tendency to cause deformed rodent fetuses (no human probs though) (Dosage is ribavirin 6g over 2 hours neb tid x 3 days

41. AAP Recommendations Early studies promising Efficacy reevaluated in 1996 Technology advances No difference in subsequent trials vs placebo Wording changed to “may be considered” In the early 80’s several trials showed improved arterial oxygenation and clinical improvement as well leading to the AAP in 1987 and 1993 to define usage. It was for those with chd, pulm htn, cf, bpd, immunodeficiency, transplants, severely ill pao2 of < 65, very young < 6 weeks or other neurologi probs) especially for those with confirmed RSV In 1996 as ventilation technology and critical care improved, the AAP reevaluated this statement as new data questioning the efficacy of ribavirin was created. Therefore they allowed individual practitioners to decide if ribavirin was needed and changed the official wording from “is recommended” to “may be considered” . So just as Ribavirin was about to join paraquat, dapsone, and chloramphenicol, in the historically interesting but now obsolete drugs. . . (next slide) Cost of ribavirin is $1400 per 6 g powder) Meert kl et aerosolized ribavirin in RSV mech vent pts. Crit care med 1994 22 566-72, however the more severely ill patients got ribavirin in non randomized trials (the other three not this one) and found no difference in outcomes vent times, loss or cost. In the early 80’s several trials showed improved arterial oxygenation and clinical improvement as well leading to the AAP in 1987 and 1993 to define usage. It was for those with chd, pulm htn, cf, bpd, immunodeficiency, transplants, severely ill pao2 of < 65, very young < 6 weeks or other neurologi probs) especially for those with confirmed RSV In 1996 as ventilation technology and critical care improved, the AAP reevaluated this statement as new data questioning the efficacy of ribavirin was created. Therefore they allowed individual practitioners to decide if ribavirin was needed and changed the official wording from “is recommended” to “may be considered” . So just as Ribavirin was about to join paraquat, dapsone, and chloramphenicol, in the historically interesting but now obsolete drugs. . . (next slide) Cost of ribavirin is $1400 per 6 g powder) Meert kl et aerosolized ribavirin in RSV mech vent pts. Crit care med 1994 22 566-72, however the more severely ill patients got ribavirin in non randomized trials (the other three not this one) and found no difference in outcomes vent times, loss or cost.

42. Dexamethasone RCT of 118 RSV(+) patients Outcomes Length of stay Need for oxygen Another medication that is controversial for RSV is dexamethasone with its potent anti-inflammatory properties. Genie Roosevelt study in the journal Lancet looked at the utility of dex at 1 mg/kg /day in reducing length of stay in 122 bronchiolitics. The pts were the same in rsv +, family history of atopy, age, and duration of illness. Also these were first time wheezers. Assessments were made on 12 hour intervals looking for resolution of wheezing, oxygen use, retractions, and normal feeding until they went home Another medication that is controversial for RSV is dexamethasone with its potent anti-inflammatory properties. Genie Roosevelt study in the journal Lancet looked at the utility of dex at 1 mg/kg /day in reducing length of stay in 122 bronchiolitics. The pts were the same in rsv +, family history of atopy, age, and duration of illness. Also these were first time wheezers. Assessments were made on 12 hour intervals looking for resolution of wheezing, oxygen use, retractions, and normal feeding until they went home

43. Dexamethasone The left slide from this article looked at the duration of wheezing or retractions or needing iv while The graph on the right looked at the need of 02 until discharge The graphs of dex and placebo are the same, leading to the conclusion that Dex in ineffective in inpatient treatment of bronchiolitics.The left slide from this article looked at the duration of wheezing or retractions or needing iv while The graph on the right looked at the need of 02 until discharge The graphs of dex and placebo are the same, leading to the conclusion that Dex in ineffective in inpatient treatment of bronchiolitics.

44. The last word on dexamethasone? PECARN multicenter trial of dexamethasone 600 children randomized/double blinded to receive 1mg/kg dex vs placebo Outcome of admission after 4 hour ED obs time No difference in admit rates, length of stay, or change in respiratory distress scores

45. Heliox First published use in 1935 Flow proportional to gas density Heliox is 70% less dense Heliox increases laminar flow Decreases work of ventilation Another method of supporting the care of children is the use of an 80/20 mixture called Heliox. It was first used in 1935 by Barach. In small airways infected with RSV, there is an increased turbulence in the airways that requires more force to drive ventilation. Additionally the amount of pressure needed to drive gas flow is proportional to the density of the gas moved. As Heliox is a third as dense as room air less work for breathing should be needed to deliver 02 to the terminal bronchioles. Also it is more likely to flow in a laminar fashion and generate less turbulence, further decreasing the work of ventilation.Another method of supporting the care of children is the use of an 80/20 mixture called Heliox. It was first used in 1935 by Barach. In small airways infected with RSV, there is an increased turbulence in the airways that requires more force to drive ventilation. Additionally the amount of pressure needed to drive gas flow is proportional to the density of the gas moved. As Heliox is a third as dense as room air less work for breathing should be needed to deliver 02 to the terminal bronchioles. Also it is more likely to flow in a laminar fashion and generate less turbulence, further decreasing the work of ventilation.

46. Heliox RSV (+) ICU patients Outcomes Improved Wood scores at 1 hour Decreased length of ICU stay Issues of blinding, randomization and power To date there have been 2 published comparison trials evaluating 70/30 heliox in non intubated RSV+ infants. Vs. 30% oxygen. The first used a crossover method looking at the Wood score (looking at cyanosis, insp breath, wheeze, acc musc use, and alertness) found it improved over an hour when heliox was used but worsened with oxygen alone. The second study placed the first 19 on heliox then the next 19 on O2 but the first group had a shorter stay. Some problems include small numbers with insufficient power, the fact not all patients were formally randomized and not all blinded. Also the max O2 that could be given was 30%. While these initial results are encouraging the ongoing trial by Bennett et al can better delineate the use of heliox in bronchiolitics. Hollman looked at heliox mixture of 70/30 in 19 ICU RSV+ patients in a combined random cross over trial in 13 patients and non random prospective trial in 6 patients that were more severe to avoid intubation. A single observer blinded to therapy scored the patients using wood score (for asthma) (0, 0.5, 1, 2) on cyanosis, insp breath sounds, wheezing, acc musc used, or cerebral function. All pts has less than 40% fio2 needs In the prospective pts placed on heliox first. In randomized portion the score decreased 0.46 (3.04 to 2.58, p<0.05) and in the moderate (2.5-5) decreased more. IN severe (6 pts ) with wood > 6 mean score decreased 2.67. It did not matter whether the heliox mixture was given first or not as the improvements were noted immediately when it was used and stopped when the heliox was d/c’d. In the article by Martinon-torres 38 patients with RSV from 1 month to 2 years in an ICU were prospectively enrolled to receive a 70/30 heliox mixture as well. 19 pts got heliox then 19 pts got 02 alone. Vaponephrine was given to both groups prior to beginning therapy. the mean change in wood score for the heliox pts was 4.2 vs 2.5 for just O2 with lower hr and rr. This decrease continued throughout the study period which ended when the pt went to the floor or when the pt had a mean wood score of < 2 for 6 hours. Also the ICU stay was shorter in the heliox group vs control 3.5 vs 5.4. To date there have been 2 published comparison trials evaluating 70/30 heliox in non intubated RSV+ infants. Vs. 30% oxygen. The first used a crossover method looking at the Wood score (looking at cyanosis, insp breath, wheeze, acc musc use, and alertness) found it improved over an hour when heliox was used but worsened with oxygen alone. The second study placed the first 19 on heliox then the next 19 on O2 but the first group had a shorter stay. Some problems include small numbers with insufficient power, the fact not all patients were formally randomized and not all blinded. Also the max O2 that could be given was 30%. While these initial results are encouraging the ongoing trial by Bennett et al can better delineate the use of heliox in bronchiolitics. Hollman looked at heliox mixture of 70/30 in 19 ICU RSV+ patients in a combined random cross over trial in 13 patients and non random prospective trial in 6 patients that were more severe to avoid intubation. A single observer blinded to therapy scored the patients using wood score (for asthma) (0, 0.5, 1, 2) on cyanosis, insp breath sounds, wheezing, acc musc used, or cerebral function. All pts has less than 40% fio2 needs In the prospective pts placed on heliox first. In randomized portion the score decreased 0.46 (3.04 to 2.58, p<0.05) and in the moderate (2.5-5) decreased more. IN severe (6 pts ) with wood > 6 mean score decreased 2.67. It did not matter whether the heliox mixture was given first or not as the improvements were noted immediately when it was used and stopped when the heliox was d/c’d. In the article by Martinon-torres 38 patients with RSV from 1 month to 2 years in an ICU were prospectively enrolled to receive a 70/30 heliox mixture as well. 19 pts got heliox then 19 pts got 02 alone. Vaponephrine was given to both groups prior to beginning therapy. the mean change in wood score for the heliox pts was 4.2 vs 2.5 for just O2 with lower hr and rr. This decrease continued throughout the study period which ended when the pt went to the floor or when the pt had a mean wood score of < 2 for 6 hours. Also the ICU stay was shorter in the heliox group vs control 3.5 vs 5.4.

47. Heliox 20 randomized ICU RSV(+) 80/20 heliox/oxygen vs RA/oxygen mix Modified 10 point Wood Asthma Score Endpoint 1 hour improvement Heliox group had greater score reduction Both groups had 1 intubation 20 patients randomized to heliox/02 or room air o2 in an oxyhood at 40% Given over 1 hour with scoresa t time 0, 30, 60 Wood score is 10 pt scale cyanosis, wob, wheezing, alertness, insp breath sounds Scors were 3.05 vs 5.5 (5.4, 5.5 TO START) Bigges difference was in wob and exp wheezing but not cyanosis Authors argued that it was resp exhaustion that leads to apnea and thus preventing this is key 20 patients randomized to heliox/02 or room air o2 in an oxyhood at 40% Given over 1 hour with scoresa t time 0, 30, 60 Wood score is 10 pt scale cyanosis, wob, wheezing, alertness, insp breath sounds Scors were 3.05 vs 5.5 (5.4, 5.5 TO START) Bigges difference was in wob and exp wheezing but not cyanosis Authors argued that it was resp exhaustion that leads to apnea and thus preventing this is key

48. Hypertonic saline The use of nebulized 3% NS in hospitalized bronchiolitis 96 admitted infants randomized to get 0.9% NS vs 3% NS q 2-6 hours in addition to standard meds LOS was decreased from 3.5 + 2.9 d to 2.6 + 1.9 days NO adverse effects reported

49. Potential future therapies Zileuton Perfluorooctylbromide Surfactant Engystol Inhaled small interfering RNA Because of the lack of convincing evidence for a truly effective therapy, efforts have been abundant in trying to find adequate treatments. Zileuton (zyflo) a 5-lipoxygenase inhibitor has shown success in reducing lung inflammation in mice lungs infected with RSV. In rat models by the ICU team at UTMB (led by Dr. Frances Nesti) liquid ventilation with perflubron or perfluorooctylbromide, perfluorocarbon reduced inflammation and lowered levels of macrophage inflammatory protein 1-alpha that may be used in intubated bronchiolitics in the future. Finally Surfactant has been studied in intubated bronchiolitics who have a relative surf def. Pilot studies have shown improved oxygenation and may be promising. Engystol from the asclepias vincetoxicum the swallow wort decreased rsv dna synthesis in labs Welliver RC (j inf dis 187, 2003:1773-73) Zileuton (zyflo) is a 5-lipoxygenase inhibitor used in asthmatics and some rat data shows it decreases inflammation in mice with RSV Harebell HA, Nesti F, Dieterich HJ, Gatalica Z, Garofalo RP.Am J Respir Crit Care Med. 2002 May 15;165(10):1433-8 at UTMB. Perflubron reduces inflammation in mice with RSV (reduces beta chemokine production) Tibby SM, et al (Am J Resp Crit Care Med 2000, 162, 1251-6) others based on prev studies noted a deficiency in surfactant. There were stat differences noted in OI, better compliance and reduced resistance in the first 60 hours compared to controls. There were trends towards shorter ventilation times (126 v 170 hours and shorter ICU stays (13 v 17 days both NS. If this is useful the cost of surfactant must be outweighed by the savings from decreased time in icu and intubation times. (2500 pre day for icu vs 2000 for surf) Luchetti M pedi crit care med 3(3) 2002: 261-68 also show it helps in rctBecause of the lack of convincing evidence for a truly effective therapy, efforts have been abundant in trying to find adequate treatments. Zileuton (zyflo) a 5-lipoxygenase inhibitor has shown success in reducing lung inflammation in mice lungs infected with RSV. In rat models by the ICU team at UTMB (led by Dr. Frances Nesti) liquid ventilation with perflubron or perfluorooctylbromide, perfluorocarbon reduced inflammation and lowered levels of macrophage inflammatory protein 1-alpha that may be used in intubated bronchiolitics in the future. Finally Surfactant has been studied in intubated bronchiolitics who have a relative surf def. Pilot studies have shown improved oxygenation and may be promising. Engystol from the asclepias vincetoxicum the swallow wort decreased rsv dna synthesis in labs Welliver RC (j inf dis 187, 2003:1773-73) Zileuton (zyflo) is a 5-lipoxygenase inhibitor used in asthmatics and some rat data shows it decreases inflammation in mice with RSV Harebell HA, Nesti F, Dieterich HJ, Gatalica Z, Garofalo RP.Am J Respir Crit Care Med. 2002 May 15;165(10):1433-8 at UTMB. Perflubron reduces inflammation in mice with RSV (reduces beta chemokine production) Tibby SM, et al (Am J Resp Crit Care Med 2000, 162, 1251-6) others based on prev studies noted a deficiency in surfactant. There were stat differences noted in OI, better compliance and reduced resistance in the first 60 hours compared to controls. There were trends towards shorter ventilation times (126 v 170 hours and shorter ICU stays (13 v 17 days both NS. If this is useful the cost of surfactant must be outweighed by the savings from decreased time in icu and intubation times. (2500 pre day for icu vs 2000 for surf) Luchetti M pedi crit care med 3(3) 2002: 261-68 also show it helps in rct

50. Unsuccessful therapies Ipratropium bromide Inhaled steroids Deoxyribonuclease Interferon 2-a Nitric Oxide Vitamin A Huang Lian (Coptis sinensis) Atrovent, inhaled steroids, Dnase, Intereferon 2-alpha, Nitric oxide, vitamin A and the Chinese herbal medicine coptis sinesis have been looked at with really no success. Thus efforts on prevention have been abundant as well. Schuh S, et al (Peds 1992, 90:920-924)69 first time bronchiolitics randomized to albuterol/placebo or albuterol/Atrovent No difference in RR, wheeze, acc. muscle use or admission between groups Cade A, et al (Arch Dis Child 2000, 82:126-30)161 infants less than 1 year with RSV, Looked at short term (hosp) and long term (cough, wheezing) outcomes No difference in any endpoints noted with nebulized budesonide Nasr S Chest 120 (1) 200 1therorized that as RSV causes tremendous sloughing of the epithelium the lyses of these cells leads to tremendous DNA in the airways. No difference in clinical score, oxygen use, hosp duration was noted. The cxr however improved from admit to discharge in pts with dnase. Overall this is great for radiologists only. 3 cc is 35 dollars Patel, Inten Care Med 1999, 25: 81-7) Nitric oxide is a smooth muscle bronchodilator and has been implicated as the final pathway mediator in bronchoconstriction Children’s LA PICU looked at escalating doses of 20,40 and 60 PPM of NO in intubated patients with RSV and looked at the total system resistance, resp rates and arterial oxygen gradient during before and after therapy. No change was found PIDJ 1996 15 777-782 As rsv is a paramyxoviridae , patients with measles (a paramyovirus) who were vitamin A deficient had more severe disease and vitamin A reduced morbidity. It is a cheap medicine as well to benefit third world. In two groups one from chile (Sowell also with cdc)) and one from the US (Bresee, cdc) compared it a to placebo in addition to standard therapy. Overall there was no difference Kong et al (Arch Dis Child 1993, 68:468-471) reported on coptis sinensis in kids with rsv that were discharged 2 days earlier (5 vs 7). But there were probs with randomization, duration of illness, randomization or scoring scales if they were asthmatic or had fever or anything. Needs more work Atrovent, inhaled steroids, Dnase, Intereferon 2-alpha, Nitric oxide, vitamin A and the Chinese herbal medicine coptis sinesis have been looked at with really no success. Thus efforts on prevention have been abundant as well. Schuh S, et al (Peds 1992, 90:920-924)69 first time bronchiolitics randomized to albuterol/placebo or albuterol/Atrovent No difference in RR, wheeze, acc. muscle use or admission between groups Cade A, et al (Arch Dis Child 2000, 82:126-30)161 infants less than 1 year with RSV, Looked at short term (hosp) and long term (cough, wheezing) outcomes No difference in any endpoints noted with nebulized budesonide Nasr S Chest 120 (1) 200 1therorized that as RSV causes tremendous sloughing of the epithelium the lyses of these cells leads to tremendous DNA in the airways. No difference in clinical score, oxygen use, hosp duration was noted. The cxr however improved from admit to discharge in pts with dnase. Overall this is great for radiologists only. 3 cc is 35 dollars Patel, Inten Care Med 1999, 25: 81-7) Nitric oxide is a smooth muscle bronchodilator and has been implicated as the final pathway mediator in bronchoconstriction Children’s LA PICU looked at escalating doses of 20,40 and 60 PPM of NO in intubated patients with RSV and looked at the total system resistance, resp rates and arterial oxygen gradient during before and after therapy. No change was found PIDJ 1996 15 777-782 As rsv is a paramyxoviridae , patients with measles (a paramyovirus) who were vitamin A deficient had more severe disease and vitamin A reduced morbidity. It is a cheap medicine as well to benefit third world. In two groups one from chile (Sowell also with cdc)) and one from the US (Bresee, cdc) compared it a to placebo in addition to standard therapy. Overall there was no difference Kong et al (Arch Dis Child 1993, 68:468-471) reported on coptis sinensis in kids with rsv that were discharged 2 days earlier (5 vs 7). But there were probs with randomization, duration of illness, randomization or scoring scales if they were asthmatic or had fever or anything. Needs more work

51. Passive antibody Respigam (RSV-IG) Pooled immunoglobulin 750 mg/kg IV q month Synagis (Palivizumab) Human/murine recombinant antibody 15 mg/kg IM q month two products are available to prevent RSV. Respigam (medimmune) or RSV immunoglobulin is pooled immunoglobulin from donors with very high titers to RSV. It is given IV to patients every month and the PREVENT trial showed at 48% reduction in hospitalization rates. However it is IV and is difficult to give in standard clinics. Also there is a risk of infection exposure. synagis is a purified antibody made with recombinant human Fc portions attached to a murine (mouse) anti-RSV Fab portion. This eliminated the risk of infection exposure. Also as it’s given IM, virtually any clinic could give it. Respigam 860 per 2500 mg Synagis 1200 per 100 mgtwo products are available to prevent RSV. Respigam (medimmune) or RSV immunoglobulin is pooled immunoglobulin from donors with very high titers to RSV. It is given IV to patients every month and the PREVENT trial showed at 48% reduction in hospitalization rates. However it is IV and is difficult to give in standard clinics. Also there is a risk of infection exposure. synagis is a purified antibody made with recombinant human Fc portions attached to a murine (mouse) anti-RSV Fab portion. This eliminated the risk of infection exposure. Also as it’s given IM, virtually any clinic could give it. Respigam 860 per 2500 mg Synagis 1200 per 100 mg

52. RSV and palivizumab AAP usage guidelines <28 weeks up to 12 months of age 29-32 weeks up to 6 months of age Chronic lung disease 6 months prior to RSV season in patients younger than 2 years IMPACT trial (Peds, 102, 1998: 531-7) Reduced hospitalization from 10.6% to 4.8% The AAP in 1998 established guidelines for the use of RSV for premature infants and for those with chronic lung disease. This was based primarily on the IMPACT trial done at 139 centers in us, uk and canada enrolled 1502 kids with. No differences in adverse reactions, but a significant reduction in hospitalization was noted. Studies looking at the cost/benefits of this are numerous and offer varying opinions on the issue beyond the scope of this lecture.The AAP in 1998 established guidelines for the use of RSV for premature infants and for those with chronic lung disease. This was based primarily on the IMPACT trial done at 139 centers in us, uk and canada enrolled 1502 kids with. No differences in adverse reactions, but a significant reduction in hospitalization was noted. Studies looking at the cost/benefits of this are numerous and offer varying opinions on the issue beyond the scope of this lecture.

53. RSV vaccine: a history 1st trial in 1968 Randomized to RSV or parainfluenza vaccine 12/15 RSV recipients hospitalized 1/19 in control 2 deaths in the RSV group Vaccine development against RSV started in the 60’s when Kim and others used a formalin inactivated alum precipitated RSV vaccine. It was highly immunogenic . However 12 of 15 kids in the rsv vaccine were hosp while of the 1 of 19 in the control was. also 2 of the vaccine group died. At autopsy both had extensive infiltration of the parenchymal with monocytes c/w bronchiolitis. An unfortunate conclusion of this was that the pathology of RSV was primarily due to the immune system and that any altering of it would adversely affect its clinical course. they erroneously drew the conclusion that even passively acquired antibody (such as from breast milk) could be harmful as well. Vaccine development against RSV started in the 60’s when Kim and others used a formalin inactivated alum precipitated RSV vaccine. It was highly immunogenic . However 12 of 15 kids in the rsv vaccine were hosp while of the 1 of 19 in the control was. also 2 of the vaccine group died. At autopsy both had extensive infiltration of the parenchymal with monocytes c/w bronchiolitis. An unfortunate conclusion of this was that the pathology of RSV was primarily due to the immune system and that any altering of it would adversely affect its clinical course. they erroneously drew the conclusion that even passively acquired antibody (such as from breast milk) could be harmful as well.

54. Future vaccine strategies Overcoming RSV genetic variation F component of RSV/A2 strain Conserved region of the G protein BBG2Na Cold live, attenuated RSV Maternal immunization in the third trimester The problem of RSV is due to the variation at the G component. The F component tends to be conserved across strains and wyeth has tested a new vaccine in older children with CF and adults. While it has been immunogenic and non toxic efficacy trials have not been published yet. Another target is using a recombinant subunit of the G protein called BBG2a that is conserved across species and fusing it to strep protein G that would invoke a pure response. The question is if these will be immunogenic in very young kids (even less than 2 months) who are the most susceptible to RSV infection. Live cold attenuated RSV are viruses that grow well at warmer temps but are slowed down in the temp of the lungs. this will most closely mimic the natural infection, if the antibody response is to conserved regions and not to the hypervariable regions of the G protein. Also there is a risk of reversion to wild type Finally immunizing pregnant mothers so that she can pass anti-RSV antibodies has been theorized but has not been implemented yet, because there is no effective vaccine.The problem of RSV is due to the variation at the G component. The F component tends to be conserved across strains and wyeth has tested a new vaccine in older children with CF and adults. While it has been immunogenic and non toxic efficacy trials have not been published yet. Another target is using a recombinant subunit of the G protein called BBG2a that is conserved across species and fusing it to strep protein G that would invoke a pure response. The question is if these will be immunogenic in very young kids (even less than 2 months) who are the most susceptible to RSV infection. Live cold attenuated RSV are viruses that grow well at warmer temps but are slowed down in the temp of the lungs. this will most closely mimic the natural infection, if the antibody response is to conserved regions and not to the hypervariable regions of the G protein. Also there is a risk of reversion to wild type Finally immunizing pregnant mothers so that she can pass anti-RSV antibodies has been theorized but has not been implemented yet, because there is no effective vaccine.

55. Now to make this talk obsolete. . . Clinical Practice Guideline Subcommittee on Diagnosis and Management of Bronchiolitis Pediatrics 2006 Oct;118: 1774-1793 20 recommendations made

56. AAP Bronchiolitis Guidelines Bronchiolitis is a clinical diagnosis with certain risk factors warranting more caution in management A trial of bronchodilators is appropriate, while discouraging routine use Corticosteroids are not indicated Ribavirin may be considered in select situations

57. AAP Bronchiolitis Guidelines Antibiotics should be reserved for specific co-existing bacterial infections Hydration is essential Avoid routine chest physiotherapy Administer oxygen if sats PERSISTENTLY <90% Palivizumab to selected infants

58. AAP Bronchiolitis Guidelines Handwashing prevents nocosomial spread Alcohol based preferred Avoid passive smoking Breastfeeding is protective Complementary medicine is an option

59. Take-home points Physicians must be comfortable with the nuances in management of RSV Oxygen and hydration are essential A bronchodilator trial is appropriate “Test minimizer vs. risk minimizer” Read the AAP guidelines!! In conclusion RSV is endemic and physicians must be comfortable treating affected children. Supportive care that may include supplemental oxygen and hydration remain the mainstay for bronchiolitis Treatment of bronchiolitis should include a trial of bronchodilators, either albuterol or epinephrine for symptomatic relief. Serious bacterial infections may be life threatening. Children who are well appearing with confirmed RSV+ bronchiolitis, do not automatically need extensive evaluation for an SBI outside of a urinalysis and culture, especially for those that are to be admitted regardless. The extent of sepsis evaluation should be left to the comfort of the individual practitioner who needs to decide if they are a test minimizer or risk minimizer And finally given the paucity of effective treatments and controversy surrounding current options, new therapies as well as improved delineation for their use in emergency departments need to be developed. In particular the use of outpatient nebulized epinephrine, dexamethasone, and heliox are those controversies that hopefully can be settled in the near future.In conclusion RSV is endemic and physicians must be comfortable treating affected children. Supportive care that may include supplemental oxygen and hydration remain the mainstay for bronchiolitis Treatment of bronchiolitis should include a trial of bronchodilators, either albuterol or epinephrine for symptomatic relief. Serious bacterial infections may be life threatening. Children who are well appearing with confirmed RSV+ bronchiolitis, do not automatically need extensive evaluation for an SBI outside of a urinalysis and culture, especially for those that are to be admitted regardless. The extent of sepsis evaluation should be left to the comfort of the individual practitioner who needs to decide if they are a test minimizer or risk minimizer And finally given the paucity of effective treatments and controversy surrounding current options, new therapies as well as improved delineation for their use in emergency departments need to be developed. In particular the use of outpatient nebulized epinephrine, dexamethasone, and heliox are those controversies that hopefully can be settled in the near future.

60. Questions??