Policy Change and Public Health Impact RSV Prophylaxis: Policy Change and Public Health Impact Suzanne Staebler, DNP, APRN, NNP-BC Assistant Director, Advanced Practice Nursing Monroe Carell, Jr. Children’s Hospital at Vanderbilt

RSV Prophylaxis: Disclosures Successful Completion of the continuing Nursing Education activity: In order to receive full contact-hour credit for the CNE activity, you must: Be present no less than 54 minutes of the presentation (90%), Complete and submit the Evaluation form to the registration desk before you leave at the conclusion. Conflict of Interest A conflict of interest occurs when an individual has an opportunity to affect educational content about healthcare products or services of a commercial interest with which she/he has a financial relationship The speaker has declared no conflict of interest. Commercial Support There is no commercial support for this CNE program.

RSV Prophylaxis: Disclosures (cont.) Non-Endorsement of Products Accredited status does not imply endorsement by Vanderbilt Medical Center, TNA or ANCC of any products that might be displayed in conjunction with this program. Off-label Product Use This CNE activity does not include any unannounced information about off-label use of a product for a purpose other than that for which it was approved by the Food & Drug Administration (FDA). Accreditation Statement Vanderbilt University Medical Center, Department of Nursing Education and Professional Development is an approved provider of continuing nursing education by the Tennessee Nurses Association, an accredited approver by the American Nurses Credentialing Commission on Accreditation.

RSV Prophylaxis: Objectives Discuss RSV risk categories and current evidence related to Prophylaxis Compare and Contrast Prophylaxis guidelines (2007 and 2009) and potential impact on disease state Describe current advocacy effort related to RSV Prophylaxis      

Respiratory Development

RSV This is the photomicrographic detection of RSV using indirect immunofluorescence technique. RSV is a negative-sense, single-stranded RNA virus of the family Paramyxoviridae, which includes common respiratory viruses such as those causing measles and mumps.

High-Risk Categories for RSV Preterm infants BPD Congenital Heart Defects Immuno-compromised patients

Preterm Births United States Percent 12.6 2006 rate: 12.7% 2007 rate: 12.6% 2008 rate: 12.3% Healthy People Objective March of Dimes Objective 27 percent increase from 1981 to 2001 © 2006, March of Dimes

High-Risk Categories for RSV Preterm infants BPD Congenital Heart Defects Immuno-compromised patients

Prevention is the Key Researchers and yr (reference no.) Location No. of human subjects Outcome/comment Rooney and Williams, 1971 (115) Gurwitz et al., 1981 (46) Hall et al., 1984 (49) Mok and Simpson, 1984 (85, 86) Welliver and Duffy, 1993 (141) Sigurs et al., 1995 (126) Stein et al., 1999 (131) Sigurs et al., 2000 (125) Australia Canada United States United Kingdom Sweden 62 (2–7 yrs of age) 48 29 200 43 47 >180 A significant association of asthma in 56% of children who subsequently experience wheeze Incidence of bronchial hyperreactivity is 57% An association between RSV infection and chronic abnormalities of pulmonary function Atopy and bronchial hyperreactivity independently contribute to augmented response to RSV postinfection Decreased pulmonary function following bronchiolitis is related to atopy RSV infection during first yr is an important risk for asthma and allergy in the subsequent 2 yrs, especially in genetically predisposed children Lower respiratory tract RSV infections are associated with increased risk of frequent wheeze by age 6; risk decreased markedly with age and was not significant by age 13 RSV-induced bronchiolitis severe enough to cause hospitalization is highly associated with the development of asthma and allergic sensitization at age 7.5 yrs Studies with positive association of RSV infection in early infancy and subsequent asthma

Prevention is the Key There is no vaccine… but immunoprophylaxsis is available Synagis (palivizumab) is a humanized monoclonal antibody (IgG1κ) produced by recombinant DNA technology Synagis exhibits neutralizing and fusion-inhibitory activity against RSV. These activities inhibit RSV replication

Immunoprophylaxsis / Synagis Specifics Mechanism of Action: Synagis exhibits neutralizing and fusion-inhibitory activity against RSV. These activities inhibit RSV replication Pharmacokinetics: In pediatric patients < 24 months of age without congenital heart disease (CHD), the mean half-life of Synagis was: 20 days and monthly intramuscular doses of 15 mg/kg achieved mean ± SD 30 day trough serum drug concentrations of 37 ± 21 mcg/mL after the first injection 57 ± 41 mcg/mL after the second injection 68 ± 51 mcg/mL after the third injection 72 ± 50 mcg/mL after the fourth injection Trough concentrations following the first and fourth Synagis dose were similar in children with CHD and in non-cardiac patients

Immunoprophylaxsis / Synagis Trials Safety and efficacy of Synagis were assessed in two randomized, double-blind, placebo-controlled trials of prophylaxis against RSV infection in pediatric patients at high risk of an RSV-related hospitalization Trial 1: Conducted during a single RSV season; n= total of 1,502 patients ≤ 24 months of age with bronchopulmonary dysplasia (BPD) or infants with premature birth (≤ 35 weeks gestation) who were ≤ 6 months of age at study entry (7). Trial 2: Conducted over four consecutive seasons; n= total of 1287 patients ≤ 24 months of age with hemodynamically significant congenital heart disease. In both trials participants received 15 mg/kg Synagis or an equivalent volume of placebo IM monthly for five injections and were followed for 150 days from randomization

Immunoprophylaxsis / Synagis Trials Table 1: Incidence of RSV Hospitalization by Treatment Group Trial Placebo Synagis Difference Between Groups Relative Reduction p-Value Trial 1 Impact-RSV N 500 1002 Hospitalization 53 48 5.8% 55% < .001 (10.6%) (4.8%) Trial 2 CHD N 648 639 Hospitalization 63 34 4.4% 45% 0.003 (9.7%) (5.3%) In Trial 1, the reduction of RSV hospitalization was observed both in patients with BPD (34/266 [12.8%] placebo vs. 39/496 [7.9%] Synagis), and in premature infants without BPD (19/234 [8.1%] placebo vs. 9/506 [1.8%] Synagis). In Trial 2, reductions were observed in acyanotic (36/305 [11.8%] placebo versus 15/300 [5.0%] Synagis) and cyanotic children (27/343 [7.9%] placebo versus 19/339 [5.6%] Synagis). The clinical studies do not suggest that RSV infection was less severe among RSV hospitalized patients who received Synagis compared to those who received placebo.

Immunoprophylaxsis / Synagis Trials Table 1: Incidence of RSV Hospitalization by Treatment Group Trial Placebo Synagis Difference Between Groups Relative Reduction p-Value Trial 1 Impact-RSV N 500 1002 Hospitalization 53 48 5.8% 55% < .001 (10.6%) (4.8%) BPD 12.8% 7.9% Preemie/no BPD 8.1% 1.8% In Trial 1, the reduction of RSV hospitalization was observed both in patients with BPD (34/266 [12.8%] placebo vs. 39/496 [7.9%] Synagis), and in premature infants without BPD (19/234 [8.1%] placebo vs. 9/506 [1.8%] Synagis). In Trial 2, reductions were observed in acyanotic (36/305 [11.8%] placebo versus 15/300 [5.0%] Synagis) and cyanotic children (27/343 [7.9%] placebo versus 19/339 [5.6%] Synagis). The clinical studies do not suggest that RSV infection was less severe among RSV hospitalized patients who received Synagis compared to those who received placebo.

Immunoprophylaxsis / Synagis Trials Incidence of RSV Hospitalization by Treatment Group Trial Placebo Synagis Difference Between Groups Relative Reduction p-Value Trial 2 CHD N 648 639 Hospitalization 63 34 4.4% 45% 0.003 (9.7%) (5.3%) Acyanotic 11.8% 7.9% Cyanotic 7.9% 5.6% In Trial 1, the reduction of RSV hospitalization was observed both in patients with BPD (34/266 [12.8%] placebo vs. 39/496 [7.9%] Synagis), and in premature infants without BPD (19/234 [8.1%] placebo vs. 9/506 [1.8%] Synagis). In Trial 2, reductions were observed in acyanotic (36/305 [11.8%] placebo versus 15/300 [5.0%] Synagis) and cyanotic children (27/343 [7.9%] placebo versus 19/339 [5.6%] Synagis). The clinical studies do not suggest that RSV infection was less severe among RSV hospitalized patients who received Synagis compared to those who received placebo.

Immunoprophylaxsis / Synagis Specifics Precautions Synagis is for intramuscular use only…. give with caution to patients with thrombocytopenia or any coagulation disorder. The safety and efficacy of Synagis have not been demonstrated for treatment of established RSV disease. The most serious adverse reactions occurring with Synagis treatment are anaphylaxis and other acute hypersensitivity reactions. Other adverse reactions most commonly observed in Synagis-treated patients were upper respiratory tract infection, otitis media, fever, rhinitis, rash, diarrhea, cough, vomiting, gastroenteritis, and wheezing.

EBP Dosing Guidelines (2006-07) < 32 weeks- dose 32-35wks- consider risk factors; if 2+ present, dose for season

The rest of the story…. The American Academy of Pediatrics Committee on Infectious Diseases (COID) made revisions to the recommendations for immunoprophylaxis (passive antibody protection) against RSV Disease in the new publication of the RedBook guidelines (summer 2009)… In an effort to balance cost versus benefits, these recommendations from the COID limited dosing and chronological ages for intervention in selected infants based on gestational ages at birth and published a complex schedule of initiation and termination of dosing for primary care providers… all contrary to the evidence in the RCTs

Cost-utility analysis of palivizumab in Italy: results from a simulation model in the prophylaxis of respiratory syncytial virus infection (RSV) among high-risk preterm infants Based on the results of the present cost-effectiveness assessment it appears realiable to state that compared to absence of prophylaxis, the administration of palivizumab in preterm infants of varying gestational ages, with or without complications, does improve survival (quality-weighted or not) at reasonable costs in terms of resources covered by the NHS, when compared to internationally accepted threshold values. However, there is not general consensus concerning palivizumab prophylaxis for preterm infants born between 32 and 35 weeks of gestational age without chronic lung disease and haemodynamically significant congenital heart disease. Italian Journal of Pediatrics 2009, 35:4 doi:10.1186/1824-7288-35-4

The rest of the story…. NEW ORIGINAL 2009 Redbook Guidelines Clinical trials and Synagis® Package Insert 32-35 wk preterm infants1 Research-based data (2006 guidelines)2 GA eligibility: For prophylaxis, defined as Safety and efficacy were established 32 wks, 0 d to 34 wks, 6d. in infants with a history of 35 week infants are excluded premature birth who were <35 GA Age cutoff: Eligibility criteria of < 3 months The phase III trial included preterm of age at start of RSV season infants who were < 6 months of or born during RSV season age at the beginning of the season. Dosing: Maximum of 3 doses: The efficacy and safety of Stop dosing when infant is Synagis® has only been evaluated 90 days of age even if this using monthly doses throughout occurs during the RSV season the entire RSV season. 5 monthly This means that many infants doses were given in Phase III will receive only 1 or 2 doses. trials. Risk Factors: Must have 1 of 2 risk factors: Must have 2 of 5 previously listed Day care attendance or risk factors. Sibling < 5 years of age.

The rest of the story…. Advocating for our patients Healthcare provider and public ‘uprising’ and petition to the CDC to intervene… Advisory Committee on Immunization Practices (ACIP) convened RSV work-group to evaluate issue National Perinatal Association: Respiratory Syncytial Virus Prevention 2010 Position Statement (published Spring 2010)

The rest of the story…. Advocating for our patients NANN/NANNP: Leading advocacy effort on behalf of nurses caring for these patients… Member alert on Advocacy list-serv Information sessions at national meeting (Sept 2010) On-line petition Consensus building with other nursing organizations (NAPNAP, AWHONN, SPN) Represented NANN and NAPNAP members at Oct CDC ACIP meeting

The rest of the story…. Advocating for our patients NANN/NANNP: On-line petition… “We believe that recent changes in the AAP guidelines for immunoprophylaxis (passive antibody protection) leave many fragile infants vulnerable by reducing the number of doses they can receive during the RSV season. We believe that denial of full seasonal coverage on the basis of gestational age, without consideration of other risk factors, is discriminatory to a select population of ex- premature infants and may put certain populations at even greater risk as a result of healthcare disparities.”

The rest of the story…. Advocating for our patients

The rest of the story…. Advocating for our patients National Medical Association and National Black Nurses Association Consensus Panel Paper: Respiratory Syncytial Virus and African Americans “The recent proposed change to the FDA approved dosage may have an unintended consequence of disproportionately affecting African American infants. Not only are African Americans over‐represented among infants who are premature and/or low birth weight, they are also over‐represented within the ranks of almost all other RSV risk factors,” 5 state Medicaid programs have continued to dose using the 2006-07 dosing guidelines based on risk factors Texas, New York, Florida

The rest of the story…. Advocating for our patients American Lung Association November is National Prematurity Awareness Month November is National Prematurity Awareness Month and the American Lung Association is raising awareness about a virus that has an impact on this country’s most vulnerable patient population: infants and small children. Respiratory Syncytial Virus (RSV) infection causes pneumonia and acute bronchiolitis, particularly during fall and winter.  In fact, RSV is so common that it affects almost all children by their second birthday.  For older children, the symptoms are like those of a mild cold.  However about 75,000 to 125,000 children under a year old get very sick and are hospitalized with RSV infection each year.  The major risk factors for serious RSV infection are pre-existing conditions such as chronic lung disease and congenital heart disease.  However, research also points to two additional RSV risk factors: prematurity and living with people who smoke.  A study found that there are 22,000 hospitalizations of children from RSV each year related to parental secondhand smoke. Much of this is preventable.  The U.S. Surgeon General has concluded there is no safe level of exposure to secondhand smoke.  It is a risk factor not only for acute respiratory infections such as RSV bronchitis and pneumonia but also sudden infant death syndrome (SIDS), ear problems and asthma attacks for children. Premature infants exposed to secondhand smoke are particularly at risk because of underdeveloped defenses.  Secondhand smoke can increase the potential severity of a commonplace infection like RSV—and severely impact the health of infants and small children nationwide.  So, it’s critical for all homes to be smokefree. 

Next steps…. Advocating for our patients

Next steps…. Advocating for our patients National Association of Neonatal Nurses / National Association of Neonatal Nurse Practitioners Latest on RSV: www.nann.org American Academy of Pediatrics RSV: Brief Overview American Lung Association Understanding RSV Disease Centers for Disease Control and Prevention Respiratory Syncytial Virus National Institute of Allergy and Infectious Diseases Respiratory Syncytial Virus National Library of Medicine/National Institutes of Health MedlinePlus: RSV

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