Annual Deaths From Acute Respiratory Infections in Under Fives*

Annual Deaths From AcuteRespiratory Infections in Under Fives*

2,896,000

578,000

230,000

56,000

Measles

Pertussis

URI/AOM

ALRI

3.76 Million Deaths Totally

*WHO Estimates

RSV: Global Importance

•Directly or indirectly accounts for 600,000 to

1,000,000 deaths under 5 years of age annually

•Most important pathogen after S. pneumoniae

Simoes EAF. Infect Med 1999; 16:Supplement C: 24-30.

Seasonal Epidemics of RSV

From Shay, Holman, Newman, Liu, Stout and Anderson (1999) J Am Med Assoc 282:1440-46

March 22, 2005Leader S, Kohlhase K. Pediatr Infect Dis J. 2002;21:629-32

Top Causes of Infant Hospitalization

73,250

87,826

121,558

181,662

220,379

0 50,000 100,000 150,000 200,000 250,000

Dehydration

Jaundice

Pneumonia(cause unspecified)

Bronchiolitis (cause unspecified)

RSV Bronchiolitis

Based on National Hospital Discharge Survey, 1997-1999

March 22, 2005

Respiratory syncycial virus (RSV) General Features

Single-stranded, nonsegmentedRNA virus in the

paramyxoviridae family

•Attachment (G) proteins assist with viral adherence to the

host cells

•Fusion (F) proteins aid with viral penetration

RSV diagram by Dr J Randhawa available at: http://www.bio.warwick.ac.uk/easton/

RSV Subtypes

• There are two subtypes of RSV - A & B

• There are two glycoproteins targets for neutralizing antibodies: G-binds to a specific cellular receptor F-fusion of the virus to the cell

Inflammatory mediators, chemokines and cells in epithelial infection

virus

Neutrophils activation,chemotaxis

Eosinophils survival, chemotaxis

Macrophages

NK cells activation

T lymphocytes activation, chemotaxis

IL-8, Gro

IL-1, MIP-1, MCP-1, TNF

GM-CSF, Eotaxin, RANTES, MIP-1

RANTES, IL-6

MCP-1 (Th2)

IFN, MIP-1

MHC I, ICAM-1,VCAM-1 IFN

Normal bronchiole

Inflamed bronchiole

16-fold

Spectrum of RSV infections

By age 2-3 all children have antibodies to RSV

• Subclinical infection • Upper respiratory tract infection

• Lower respiratory tract infection– Bronchiolitis – Pneumonia

Spectrum of RSV infections

• 12 -40 % of infants get symptoms of lower respiratory tract infection

• 5% get more severe bronchiolitic symptoms

• 1-2% require hospitalization2

1. Holberg CJ, Wright et al. Risk factors for respiratory syncytial virus-associated lower respiratory ilnesses in the first year of life. Am J Epidemiol 1991;133:1135-51.

2. Ruuskanen O, Ogra P. Current problemsin Pediatrics. Chicago Year Book. Medical Publishers. February 1993.

Risk Factors for Severe RSV Bronchiolitis 1Host factors :

• Extremes of age : < 6 weeks, geriatric .

• Children with premature birth < 35W .

• Chronic illness :

- Broncho-Pulmonary Dysplasia (BPD).

- Chronic Lung Disease (CLD) .

- Congenital Heart Disease (CHD).

- Immune deficiency/Immunosuppression.

Risk Factors for Severe RSV Infection - 2

Environmental factors:

• Poverty.

• Crowding (day care).

• Passive smoker.

• Malnutrition.

Abreu e Silva et al: sleep apnea in bronchiolitis AJDC, 1982;57:467

•Apnea occurs in 18-20% of hospitalized infants with bronchiolitis, particularly if:

– < 32 weeks gestation– < 44 weeks post conception– if neonatal apnea

•Apnea may occur early, even at presentation. It is usually non-obstructive, centrally mediated, usually while asleep. The apnea lasts for a few days; about 10% may need to be intubated.

Apnea and bronchiolitis

Non-respiratory manifestations

• Non-respiratory manifestations

– otitis media (86%) (Andrade, Peds:1998)

– myocarditis – supraventricular tachycardia– ventricular dysrrhythmias

(Thomas CCM 1997)

– SIADH (Rivers Arch Dis Chil, 1981)

– encephalitis

Is there a link between RSV bronchiolitis and reactive

airway disease?

Follow-up studies with control groups after RSV bronchiolitis and unspecified bronchiolitis

• Higher prevalence of bronchial obstructive symptoms in children after bronchiolitis compared to controls

• In some studies lower FEV1 and FEF25-75 many years after bronchiolitis

• In some studies increased airway hyperresponsiveness many years after bronchiolitis

• Family history atopy/asthma the same

Questions

Does RSV bronchiolitis per se increase the risk of asthma and bronchial symptoms?

or

Do children with some inherent risk factor(s) develop bronchiolitis and subsequent wheezing?

Is there a difference in the risk for subsequent bronchial obstructive symptoms between children with RSV infection which requires hospitalization and milder infections?

Sigurs N, Bjarnason R et al 1995 and 2000. Prospectively followed up to age 7

• 47 infants hospitalized with RSV bronchiolitis winter season 1989-90– mean age 116 days, 91% <6 months, the eldest

10 months– first episode of bronchial obstructive symptoms

• 93 controls recruited during infancy, matched for age, sex and place of living

Ref: N.Sigurs, R. Bjarnason, F. Sigurbergsson, B. Kjellman. Respiratory Syncytial Virus Bronchiolitis in Infancy Is an Important Risk Factor forAsthma and Allergy at Age 7, American Journal of Respiratory and Critical Care Medicine VOL 161 2000; 1501-1507.

Combination of RSV bronchiolitis and family history of asthma and development of asthma at

age 7, Sigurs et al 2000

0%

10%

20%

30%

40%

50%***

* p<0.05** p<0.01*** p<0.001

n.s.

*

n.s.

* ***

Family history of asthma No No Yes YesRSV- bronchiolitis No Yes No YesAsthma / all 3/66 6/26 0/27 8/21

Asthma

Some possible predisposing factors for bronchiolitis and/or post-bronchiolitic symptoms

• Diminished lung function before RSV 1, 2, 3

• Family history atopy/asthma 4, 5

• Smoking in family 4, 5

• Length of breast feeding 4, 5

.

1. Martinez FD, Wright AL et al. Asthma and wheezing in the first six years of life. N Engl J Med 1995.332:133-8.

2. Young S, O´Keefe, AJ, LandauLI. Lung function, airway responsiveness and respiratory symptoms before and after bronchiolitis. Arch Dis Child 1995.72:16-24.

3. Palmer LJ, Rye P et al. Airway responsiveness in early childhood predicts asthma, lung function and respiratory symptoms by school age. Am J Respir Crit Care Med 2001.163:37-42.

4. Noble V, Murray M et al. 1997. Respiratory status and allergy nine to 10 years after acute bronchiolitis. Arch Dis Child. 76:315-19.

5. Sigurs N, Bjarnason R et al. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med. 2000.161:1501-7.

5.6(1.7 - 18.49)

Double heredity atopy

parents

2.4(1.1 - 5.5)

RSV bronchiolitis

Sensitization

Odds ratio

Risk factor

Multivariate test of risk factors for allergic sensitization in all 140 children

Ref: N.Sigurs, R. Bjarnason, F. Sigurbergsson, B. Kjellman. Respiratory Syncytial Virus Bronchiolitis in Infancy Is an Important Risk Factor forAsthma and Allergy at Age 7, American Journal of Respiratory and Critical Care Medicine VOL 161 2000; 1501-1507.

RSV Bronchiolitis --Prevention

• General Measures

• Active Immunity – Vaccine

• Passive Immunity Polyclonal antibody(IVIG) Monoclonal antibody( IMI )

Prevention•RSV is transmitted via secretions. Prevention includes:

– hand washing– gowns and gloves (Hall, Peds:1978)

– cohorting patients– reducing visits by children

•But… asymptomatic adults may transmit infection. And day care centers are common sites of epidemics.

RSV-IGIV Conclusions

RSV LRIRSV hospitalizationRSV LRI hospitalizationAcute otitis media

RSV hospitalization < 6 months

PREMIES

CARDIAC

WHAT IS ABBOSYNAGIS® ?

• Generic name is palivizumab (pal ee VEE zoo mab).

• It is a humanized monoclonal antibody (IgG1) produced by recombinant DNA technology to bind the F protein and neutralize RSV.

• The mean half-life of ABBOSYNAGIS® is 20 days. Abbosynagis® should be given by IM injection every 30 days.

• The serum mean trough levels of ABBOSYNAGIS® remain above an ideal therapeutic threshold of 40 µg/mL with repeated monthly injections.

Humanization of a Murine MabHumanization of a Murine Mab

Mouse Mab Human Frame Humanized Mab

IMPACT RSVIMPACT RSV

• Randomized, double-bind, placebo-controlled 2:1 randomization Multicenter US, Canada, UK

• Sample Size 1281(13.5% attack rate, 41% reduction) 1502 enrolled

• Intent-to-treat Analysis of all patients as randomized

IMpact Hospitalization RatesIMpact Hospitalization Rates

(The IMpact-RSV Study Group. Pediatrics. 1998;102(3):531-537.)

9.8

2.0

32-35wGA

80%12.8

7.9

CLD

39%

< 32 wGA

47%

11.0

5.8

8.1

1.8

PreemiesNo CLD

78%

Placebo

Synagis

RSV prophylaxis (Combined Analysis)Infants with BPD / CLD < 2 years (N=3,675)

Mean RSV hospitalization rates showing 95% CI

RSV prophylaxis (Combined Analysis)Infants with BPD / CLD < 2 years (N=3,675)

Mean RSV hospitalization rates showing 95% CI

21.0%

6.5%

15.7%

4.8%

18.4%

5.6%

Not Prophylaxed(N=811; 5 studies)

SYNAGIS(N=2864; 7 studies)

RS

V H

osp

ital

izat

ion

R

ate

Conclusions: RSV Prevention

Conclusions: RSV Prevention

• Active prevention for RSV is problematic and no current vaccines are available or will be in the foreseeable future

• Passive prophylaxis with Palivizumab is currently the only option for RSV prevention in High risk patients

RSV Epidemiology, Populations at Risk, and Interventions

March 22, 2005

Distinct Disease Syndromes Associated with RSV Infection

Bronchiolitis in infants

Sudden infant death syndrome (SIDS)/apnea

Post-infection wheezing/childhood asthma

Severe disease in the institutionalized elderly leading to excess mortality and exacerbation of underlying disease conditions

Giant cell pneumonia in persons with deficient T-cell immunity

Vaccine-enhanced disease

Hull J, et al. Thorax. 2000;55:1023-7; Kneyber MC, et al. Eur J Pediatr. 1998;157:331-5; Lindgren C. Acta Paediatr. 1993;82(Suppl)389:67-9; Martinez FD. Pediatr Infect Dis J. 2003;22(2 Suppl):S76-82; Openshaw PJ, et al. Vaccine 2001;20(Suppl1):S27-31

March 22, 2005

The Burden of RSV Disease

RSV is the leading cause of infant hospitalization and a leading viral cause of death in infants

More than 120,000 hospitalizations annually in the US.

Infects up to 70-80% of children <2 years each winter

Of those infected, 30% will have prolonged wheezing

Mortality rate for those hospitalized is <1% in healthy children but ~3.5% in those with high-risk conditions (CLD, CHD, etc.)

Leader S, Kohlhase K. PIDJ. 2002; 21:629; Thompson WT, et al. JAMA. 2003;289:179-86;Shay DK, et al. JAMA. 1999; 282:1440-9; Glezen WP, et al. Am J Dis Child. 1986; 140:543;Welliver RC. Semin Perinatol. 1998; 22:87; Navas L, et al. J Pediatr. 1992;121: 348-54; LaVia WV, et al. J Pediatr. 1992; 121 (4): 503-10

March 22, 2005

RSV Re-infection

•Studies report that between 6% and 83% of children followed longitudinally have been re-infected each year .

•Antibody response is not sufficient to prevent subsequent RSV reinfection.

•RSV-infected lymphocytes and macrophages may suppress

secondary immune responses.

Feigin RD, Cherry JD, (Eds.). Textbook of Pediatric Infectious Diseases, 4th Ed. 1998. 185.2095; Hall CB, et al. Journal of Infectious Diseases. 163,no.4(1991):693-8;Openshaw, P.J.M. Respiratory Research 3, Suppl 1. (2002):S15

March 22, 2005

Recent Trends in RSV HospitalizationsIn the US

•Up to 126,300 annual hospitalizations among U.S. infants for bronchiolitis or pneumonia may be attributable to RSV infection.

•Annual mortality due to RSV in infants and children is estimated to range from 200 to over 2,700.

•Bronchiolitis hospitalizations 1980-1996

–1.65 million hospitalizations

–7 million inpatient days

–57% were in children <6 mo

–81% were in children <1 year

–239% increase in bronchiolitis hospitalizations in children less than six months of age

Shay DK, et al. J Infect Dis. 2001;183:16-22; Institute of Medicine. In: New Vaccine Development: Establishing Priorities. Vol I. Wash DC Nat Aca Press 1986: 397-409; Shay DK, et al. JAMA. 1999;282:1440-9

March 22, 2005

The RSV-Asthma Link

Several prospective studies have shown that RSV bronchiolitis is associated with recurrent wheezing during subsequent years.

Recurrent wheezing tends to diminish by early adolescence (age 13)

Conclusion: RSV appears to be linked to recurrent childhood wheezing through early adolescence

Sigurs N, et al. Am J Crit Care Med. 2000;161:1501-7Taussig LM, et al. Am J Epidemiol. 1989;129:1219-31Stein RT, et al. The Lancet. 1999;354:541-5

March 22, 2005

Children at Highest Risk for RSV

Adapted from a presentation by L Weisman, MD: 1st International Congress RSV, 2002

Premature birth

Chronic Lung Disease

Congenital Heart disease

Neuromuscular disease

Immune deficiency

Altered airway anatomy Absence of maternal antibody

Bronchial hyper-responsiveness Reduced lung capacity

Pulmonary vascular hyper-responsiveness Pulmonary hypertension Increased pulmonary blood flow

Decreased respiratory muscle strength and endurance Decreased host defenses

Impaired capacity to eliminate virus

March 22, 2005

Problems in Premature Infants

Respiratory: Airway alteration, respiratory distress/failure, apnea, air leaks, CLD/BPD

Cardiovascular: Patent ductus arteriosus

CNS: Intraventricular hemorrhage, periventricular leukomalacia, seizures

Renal: Electrolyte imbalance, acid-base disturbances, renal failure

Ophthalmologic: Retinopathy of prematurity, strabismus, myopia

Gastrointestinal-nutritional: Feeding intolerance, necrotizing enterocolitis, inguinal hernias, failure to thrive

Immunologic: Poor defense to infection

March 22, 2005

*Pictures are artistic renditions of lung development and are designed to emphasize terminal acinus development & not the entire conducting airway system

Behrman: Nelson Textbook of Pediatrics, 16th ed., 2000. Langston C, et al.

Am Rev Respir Dis. 1984;129:607-13

Pseudoglandular Period

(7 to 16 weeks GA)

Canalicular Period

(16 to 26 weeks GA)

Saccular Period

(26 to 36 weeks GA)

Alveolar Period

(36 to 41 weeks GA)

Premature Term

• The lungs of premature infants are underdeveloped at birth

• Although alveoli are present in some infants as early as 32 weeks GA, they are not uniformly present until 36 weeks GA

Prematurity: Interrupts Lung development

March 22, 2005Hoo A-F, et al. J Pediatrc. 2002;141:652-8; Mansell AL, et al. J Pediatrc. 1987;110:111-5;Hjalmarson O, et al. Am J Resp Crit Care Med. 2002;165:83-7; Hislop AA, et al. Am Rev Resp Dis. 1989;140:1717-26

Prematurity: Alters Airway Anatomy

Prematurity leads to altered airway development, even in the absence of clinical respiratory disease

Premature exposure to the extrauterine environment can alter airways, even without mechanical ventilation or oxygen use

Altered development is evidenced by

diameters of major airways = obstruction

bronchial muscle = airway hyper-reactivity

number of goblet cells = mucus production & plugging

March 22, 2005Hoo A-F, et al. J Pediatrc. 2002;141:652-8; Hislop AA, et al. Am Rev Resp Dis. 1989;140:1717-26; Mansell AL, et al. J Pediatrc. 1987;110:111-5

Prematurity: Alters Airways

Premature Infant LungTerm Infant Lung

March 22, 2005Friedrich L, et al. Am J Resp Crit Care Med. 2003;167(7 Suppl):A593; Hoo A-F, et al. J Pediatrc. 2002;141:652-8; Mansell AL, et al. J Pediatrc. 1987;110:111-5

Prematurity: Significantly reduced lung function

Seemingly healthy premature infants (<36 wk GA) have persistent abnormal lung function

6-10 weeks after birth: significant obstruction ( FEF) in otherwise healthy 30-34 wk GA infants (p<0.001)

At age 1: significant peripheral obstruction ( VmaxFRC) in otherwise healthy 29-36 wk GA infants (p<0.05)

At age 6-7: significant obstruction (13% FEV1) in moderately low birth weight infants (p<0.01)

The Point: Premature infants have less pulmonary reserve and are more susceptible to severe respiratory disease

March 22, 2005

Prematurely: Decreased Maternal Antibody Transfer

Antibody transfer occurs during the third trimester (after

28 weeks)

Antibody levels at birth are proportional to gestational age

Antibody levels are also influenced by birthweight,

independent of gestational age

Yeung CY, Hobbs JR. Lancet. 1968;7553:1167-70; Okoko JB, et al. Trop Med Int Health. 2001;6:529-34

March 22, 2005Adapted from data and formulas as published by Yeung CY, Hobbs JR. Lancet. 1968;7553:1167-70

Serum Antibody (IgG) Levels at Birth: Premature & Term infants

200

320

520

1100

0

200

400

600

800

1000

1200

<28 wks GA 28-31 wks GA 32-35 wks GA Term

Ser

um

IgG

(m

g/1

00m

l)

March 22, 2005

Summary: Risk of RSV in Premature Infants

Hospitalization rates demonstrate that premature infants up to 36 wks GA are potentially high risk for severe RSV

Premature infants, even those without a history of ventilation or oxygen use, are high risk due to

Altered airway anatomy-significant obstruction seen throughout early childhood

Immature immunity-impaired cellular and humoral immunity

March 22, 2005

RSV and Congenital Heart Disease

RSV is associated with increased morbidity and mortality. Statistics among children hospitalized with RSV:

25-33% admission to PICU

11-24% mechanical ventilation

3.4% fatality rate

CHD patients with associated pulmonary hypertension are at highest risk for complications.

Elective cardiac surgery should not be performed in an infant who has not fully recovered from RSV infection.

Navas L, et al. J Pediatr. 1992;121:348-54; Altman CA, et al. Pediatr Cardiol. 2000;21:433-8;Moler FW, et al. Crit Care Med. 1992;20:1406-13; MacDonald NE, et al. N Engl J Med. 1982;307:397-400; Khongphatthanayothin A, et al. Crit Care Med. 1999;27:1974-81

March 22, 2005

Risk Factors in CHD Patients

Compromised cardiorespiratory status at baseline

Altered pulmonary mechanics may contribute to disease severity

Pulmonary hypertension may exacerbate the adverse effects of respiratory disease

Inability to properly compensate for intercurrent disease

March 22, 2005

Other Risk Factors for Severe RSV

•Prematurity, CHD, CLD, and age at season onset are well established risk factors

•Several other risk factors have been documented.

Exposure Factors

Daycare

Siblings and crowded living conditions

Multiple birth

Maternal education level

Susceptibility Factors

Low Birth Weight

Exposure to tobacco smoke and other air pollutants

Multiple birth

Family history of asthma

Minimal breast feeding

Holman R, Shay D, et al. Pediatr Infect Dis J. 2003;22:483-9; Boyce TG, et al. J Pediatr. 2000;137:865-70; Carbonell-Estrany X, et al. Ped Infect Dis J. 2001;20:874-9; Carbonell-Estrany X, Quero J, Bustos G, et al. Pediatr Infect Dis J. 2000;19(7):592-7; Eriksson M, et al. Acta Paediatr. 2002;91:593-9;8; McConnochie KM, Roghmann KJ. Am J Dis Child. 1986;140: 806-12; Holberg CJ, et al. Am. J. Epidemiol. 1991;133:1135-51; Meissner HC, et al. Pediatr Infect Dis J. 1999;18:223

March 22, 2005

CDC Bronchiolitis Mortality Study: LBW as a Risk Factor

Multiple cause-of-death and linked birth/infant death data for 1996-1998 were used to examine bronchiolitis-associated infant deaths. Deaths

were compared to surviving infants.

Birthweight <2500 g was a key risk factor for bronchiolitis-associated death, even when taking into account other factors (including GA):

Holman R, Shay D, et al. Pediatr Infect Dis J, 2003; 22: 483-9

Birthweight Odds Ratio (95% CI)

<1500 g 25.5 (14.6, 44.6)

1500-2499 g 4.6 (3.2, 6.8)

2500 g Referent

March 22, 2005

Therapeutic Options for RSV Bronchiolitis

Prevention

Limit exposure

Passive immunoprophylaxis:Abbosynagis® (palivizumab)

Supportive care

Overcoming airway obstruction and inflammation

Antiviral agents

March 22, 2005

RSV Prophylaxis: Reserved for the Highest Risk Children

RSV immunoprophylaxis is the only available safe and effective method for preventing severe RSV disease

Prophylaxis is reserved for high risk infants and children

–Premature infants <36 wks GA are at a significantly elevated risk of severe RSV disease

–Children with chronic lung disease, congenital heart disease, immunodeficiencies, and other high-risk conditions

The IMpact-RSV Study Group. Pediatrics. 1998;102(3):531-7; Boyce TG, et.al. J. Pediatr. 2000;137:865-70;Imaizumi S, et al. Abstract # 2311:APS/SPR/APA-2001;Law BJ, et al. CAAC 1998 (abstract #MN-9);Meissner HC, et al. Pediatr Infect Dis J. 1999;18:223

March 22, 2005

RSV Prophylaxis: Reserved for the Highest-Risk Children

All high-risk groups have significant need for ICU care and mechanical ventilation when hospitalized:

Boyce TG, et al., J. Pediatr. 2000; 137:865-70; Law BJ, et al., Paediatr. Child Health 1998;3:402-4;

Imaizumi S, Agarwal, S., and Pereira, G.R. APS/SPR/APA – 2001 convention. 4-28-2001. Abstract.; Navas L, et al. J Pediatr. 1992; 121: 348-54; Altman CA et al. Pediatr Cardiol. 2000; 21: 433-8.; Moler FW et al. Crit Care Med.

High-Risk Group

ICU AdmissionVentilation

Premature28-34%7-22%

CLD32%17%

CHD25-33%11-24%

March 22, 2005

Abbosynagis® (Palivizumab):Mechanism of Action

Palivizumab is a monoclonal antibody that binds the F protein of RSV

Produced using recombinant DNA technology

Palivizumab blocks the fusion of infected cells

Reduces viral activity and cell-to-cell transmission of the virus

Synagis

RSV

March 22, 2005

IMPACT-RSV TRIAL RSV Hospitalization Rates by Subgroup

10.6 11.09.8

4.85.8

2.00

2

4

6

8

10

12

All patients All < 32 weeks GA All 32-35 weeks GA

Placebo: 1996-1997 IMpact-RSV trial (n=500)Abbosynagis® (palivizumab): 1996-1997 IMpact-RSV trial (n=1,002)

55% 47% 80%

The IMpact-RSV Study Group. Pediatrics. 1998;102(3):531-7

Reduction in hospitalization rate (%)

March 22, 2005

Palivizumab CHD Study: RSV Hospitalization Rates

9.7%

5.3%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

All patients

RS

V H

osp

ital

izat

ion

Rat

e (%

)

Placebo (n=648)

Palivizumab (n=639)

45% relative reduction (p=0.003)

(63/648) (34/639)

Pediatric Cardiology. 2002; 23(6) 664, Data on file, MedImmune, Inc

Reduction in hospitalization rate (%)

March 22, 2005

SYNAGIS® (PALIVIZUMAB) OUTCOMES REGISTRY 2000-2002 RSV Hospitalization Outcomes

The IMpact-RSV Study Group. Pediatrics. 1998; 102(3): 531-7; Palivizumab Outcomes Study Group, Pediatric Pulm. 2003;35:484-9; Hudak et al. J Perinatol. 2002; 22:619, abstract P32; Data on file, MedImmune Inc

8.1

119.8

12.8

4.8

1.8

5.8

2

7.9

2.92.1

4.5

1.6

5.8

1.51.2

1.7

1.3

2.2

1.1 1.2

1.6 1.9

10.6

0.7

0

2

4

6

8

10

12

14

All Patients Prematurew/o CLD

All <32 weeksGA

All 32-35weeks

Patients withCLD

RS

V H

osp

Ra

te

1996-1997 Impact-RSV Trial-Placebo 1996-1997 Impact-RSV Trial- Abbosynagis

2000-2001 Abbosynagis Outcomes Registry 2001-2002 Abbosynagis Outcomes Registry

2002-2003 Abbosynagis Outcomes Registry

March 22, 2005

American Academy of Pediatric Vs. MOHGuidlines1,2

 

 

 

 

 

1.The Israeli MOH guidlines for RSV prophylaxis (Nov 05)

2 .Revised indications for the use of palivizumab and resperatory synsycial virus immune globulin intravenous for the prevention of respiratory syncycial virus infections. AAP policy statement; Pediatrics Vol 112 1442-1446, December 2003.

 

 

 

 

March 22, 2005

Synagis® (Palivizumab):Timing & Duration of Prophylaxis

RSV prophylaxis should be initiated prior to the onset of RSV season and terminated at the end of the RSV season .

In Israel the RSV season lasts from November to March.

Abbosynagis® (palivizumab) does not interfere with vaccine administration.

High-risk patients, including those who develop an RSV infection, should receive monthly doses of Abbosynagis® throughout the RSV season.

Acquisition of RSV is not protective against subsequent exposures.

Synagis® (palivizumab) Package Insert

March 22, 2005

Synagis® (Palivizumab) Package Insert (PI)

INDICATIONS

“Abbosynagis® is indicated for the prevention of serious LRT disease caused by RSV in pediatric patients at high risk of RSV disease and Haemodynamically

Significant Congenital Heart Disease (CHD) in Children Less Than 2 Years of age.

Safety and efficacy were established in infants with BPD and infants with a history of prematurity (£35 weeks gestational age)”.

March 22, 2005

Synagis® (Palivizumab) Package Insert (PI)

Precautions:

Abbosynagis® (palivizumab) is for IM use only and should be given with caution to patients with thrombocytopenia or any coagulation disorder.

Adverse Events:

In clinical trials, the most common adverse events potentially related to Abbosynagis were fever, injection site reactions and nervousness.

March 22, 2005

Synagis® (Palivizumab) Package Insert (PI)

Contraindications:

Should not be used in pediatric patients with a history of a severe prior reaction to Abbosynagis® (palivizumab) or other components of this product.

Warnings:

Very rare cases of anaphylaxis (<1 case per 100,000 patients) have been reported following re-exposure to Abboynagis (palivizumab). Rare severe acute

hypersensitivity reactions have also been reported on initial exposure or re-exposure to palivizumab .

March 22, 2005

Importance of Compliance

Compliance is key for ensuring good outcomes

In a study of 10,390 infants receiving Abbosynagis®, non-compliant patients had 2.2x increase in hospitalization risk (95% Cl 1.4-3.5,

p<0.001) 3.1% vs. 1.4% hospitalization rate

Compliance was defined as having on average ≤35 days between doses

Berger J, et al. APA/SPR/APS 2003. [Abstract #2646]

March 22, 2005

Summary

RSV is a significant viral pathogen, producing annual epidemics

RSV bronchiolitis is a major threat to the health of all infants and can lead to hospitalization and death

The threat of RSV is greatest in high-risk groups, such as infants born prematurely and children with CLD or CHD

Treatment options are limited and thus RSV prophylaxis is essential for minimizing RSV’s impact on high-risk children

March 22, 2005

Structure of RSV

Bart N Lambrecht Clin Exp Allergy 31(2):206-218 (2001)