Transcript RSV Epidemiology

Respiratory Infections and the Infant
Rees Oliver MD
Assistant Professor
Department of Pediatrics
Division of Neonatology
University of Alabama at
Birmingham
Disclosure statement:
I do speak as a consultant on behalf of MedImmune for the
product Synagis.
Causes of Acute Respiratory Infections in
Children <5 Years of Age
Adenovirus 7%
C. pneum. 0%
M. pneum. 9%
RSV 62%
H. infl. 6%
Parainfluenza 2%
Infl. B 2%
Infl. A 3%
S. pneum. 8%
Data from the Belgian sentinel network’s epidemiology surveillance (2000–2001 season)
3
With permission from Simoes EAF and Carbonell-Estrany X. Pediatr Infect Dis J. 2003;22:S13-S20.
Leading Viral Causes
of Infant Mortality
Estimated mortality for underlying pneumonia and influenza deaths,
based on data from Centers for Disease Control and Prevention
Mortality Rate per
100,000 Person-Years
4
3.1
RSV
Influenza
3
2
1
0
0.3
<1
0.1
<0.01
0.2
1–4
0.2
5–49
Age Bracket (years)
12
Thompson WW et al. JAMA. 2003;289:179-186.
Clinical Features: Infant With
Respiratory Distress
Chest wall retractions
Nasal flaring
Hypoxemia
and cyanosis
Expiratory
grunt
Expiratory wheezing, prolonged
expiration, rales and rhonchi
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Tachypnea with
apneic episodes
Adapted from Netter F. The Ciba Collection of Medical Illustrations. Vol. 7, Respiratory System. CIBA, 1979.
Collins PL et al. In: Fields BN, Knipe DM, Howley PM, et al, eds. Fields Virology. 5th ed.
Philadelphia, Pa: Lippincott-Raven Publishers; 2007:1601-1646.
Signs and Symptoms of Respiratory
Distress in Infants
Mild symptoms: moderate tachypnea, rhinorrhea,
low-grade fever, and, frequently, otitis media. Recovery occurs
after an illness of 7 to 12 days
Severe symptoms: coughing and wheezing followed by dyspnea;
severe tachypnea is common; in cases of extreme hypoxemia,
respiratory failure occurs
In high-risk infants, respiratory failure severe enough to require
airway intubation can occur early in the course
of illness
17
Collins PL et al. In: Fields BN, Knipe DM, Howley PM, et al, eds. Fields Virology. 5th ed.
Philadelphia, Pa: Lippincott-Raven Publishers; 2007:1601-1646.
Transmission of Viruses
•
Viruses can be transmitted by
droplets, large particles, and
fomites
•
Can survive for as long periods of
time on nonporous surfaces
•
Medical personnel transmit these
viruses readily
•
Nosocomial infection remains an
enormous problem
Blydt-Hansen T, et al. Pediatr Infect Dis J. 1999;18(2):164; Hall CB, et al. J Pediatr. 1980;141:98-102;
Hall CB. Clinical Infectious Diseases; 2000;31:590-6; Cohen B, et al. Pediatric Infectious Disease
Journal. 2003;22:494-9
Epidemiology of Viral Processes
• Several of these viruses produce outbreaks each year
particularly RSV
• In the case of these outbreaks they can vary in length
from region to region, and from season to season and
can last for months throughout much of the U.S.
• Year-round epidemics have been reported
Mavunda K, et al. Am J Crit Care Pulm Med. 2000;ATS Abstr # G55:348; Ledbetter JC, et al.
Ped ResAPS/SPR/APA. 2002;Abstr #2787; Doraisingham S, Ling ,AE. Ann Acad Med Singapore. 1986;15:9-14
Viral Epidemiology
• During any given season a large portion of the
population develops an upper or lower respiratory
tract infection (LRTI), Bronchiolitis
• More than half of all children will be infected by their
first birthday especially with RSV
• By two years of age essentially all children have been
experienced Bronchiolitis
Glezen WP, et al. Am J Dis Child. 1986;140:543-6
Re-infection
• If you look at studies looking at these viruses there are
reports that between 6% and 83% of children followed
longitudinally have been re-infected each year
• Antibody response is sometimes not sufficient to prevent
subsequent re-infection
• 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
Recent Trends in Hospitalizations
• Up to 126,300 annual hospitalizations among U.S. infants for
bronchiolitis or pneumonia may be attributed to RSV alone.
• Bronchiolitis hospitalizations 1980-1996
– 1.65 million hospitalizations
– 7 million inpatient days
– 57% were in children <6 mo
– 81% were in children <1 yo
– 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
Top Causes of Infant Hospitalization
Based on National Hospital Discharge Survey, 1997-1999
RSV Bronchiolitis
220,379
Bronchiolitis
(cause unspecified)
181,662
Pneumonia
(cause unspecified)
121,558
87,826
Jaundice
Dehydration
73,250
0
50,000
100,000
Leader S, Kohlhase K. Pediatr Infect Dis J. 2002;21:629-32
150,000
200,000
250,000
• Several prospective studies have shown that even
RSV bronchiolitis is associated with recurrent
wheezing during subsequent years
• Recurrent wheezing tends to diminish by early
adolescence (age 13)
• Conclusion: RSV bronchiolitis appears to be linked
to recurrent childhood wheezing through early
adolescence
Sigurs N, et al. Am J Crit Care Med. 2000;161:1501-7
Taussig LM, et al. Am J Epidemiol. 1989;129:1219-31
Stein RT, et al. The Lancet. 1999;354:541-5
Children at Highest Risk for Severe
Respiratory Distress as an Infant
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
Adapted from a presentation by L Weisman, MD: 1st International Congress RSV, 2002
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
Prematurity: Increased Disease Severity
•
Several studies have confirmed the high-risk
status of premature infants
•
Among premature infants hospitalized with RSV
and other viral pathogens:
–
28-34% were admitted to the ICU
–
7-22% required mechanical ventilation
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, Pereira GR, et al. APS/SPR/APA – 2001 convention 4-28-2001. Abstract
Premature Infants are at High-Risk
Altered lung development
• Altered airway anatomy
• Reduced lung function through early
childhood
Immature immune system
• Impaired humoral and cellular immunity
Prematurity: Interrupts Lung Development
Premature
Term
Pseudoglandular Period
Canalicular Period
Saccular Period
Alveolar Period
(7 to 16 weeks GA)
(16 to 26 weeks GA)
(26 to 36 weeks GA)
(36 to 41 weeks GA)
•
•
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
*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
Serum Antibody (IgG) Levels at Birth:
Premature & Term infants
1100
Serum IgG (mg/100ml)
1200
1000
800
520
600
320
400
200
200
0
<28 wks GA
28-31 wks GA 32-35 wks GA
Term
Adapted from data and formulas as published by Yeung CY, Hobbs JR. Lancet. 1968;7553:1167-70
Summary: Risk of Severe Disease in
Premature Infants
•
Hospitalization rates demonstrate that premature
infants up to 36 wks GA are potentially high risk
for severe respiratory distress
•
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
Congenital Heart Disease
• Increased morbidity and mortality. Statistics among
children hospitalized:
– 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.
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
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
Chronic Lung Disease:
Increased Risk of Severe
Respiratory Distress
•
Studies have confirmed the high-risk
status of children with Chronic Lung
Disease (CLD)
•
Among CLD children hospitalized viral
processes:
–
32% were admitted to the ICU
–
17% required mechanical ventilation
–
3.5% died within two weeks
Navas L, et al. J Pediatr. 1992;121:348-54
Therapeutic Options for Bronchiolitis
• Prevention
– Limit exposure
– Avoid daycare
– Excellent hand washing
– Passive immunoprophylaxis:
Synagis® (palivizumab)
• Supportive care
• Overcoming airway obstruction and
inflammation
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
IMpact-RSV Clinical Trial:
Study Design
Multicenter, randomized, placebo-controlled trial
Infants 35 weeks gestational age (GA) or with
bronchopulmonary dysplasia (BPD) were randomized (N=1502)
to receive 5 injections of Synagis® (palivizumab) (15 mg/kg) or
equivalent volume of placebo every 30 days
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The IMpact-RSV Study Group. Pediatrics. 1998;102:531-537.
Please see full prescribing information for Synagis® (palivizumab).
IMPACT-RSV TRIAL
RSV Hospitalization Rates by Subgroup
Placebo: 1996-1997 IMpact-RSV trial (n=500)
Synagis® (palivizumab): 1996-1997 IMpact-RSV trial (n=1,002)
12
10
11.0
10.6
9.8
8
6
4
5.8
4.8
2
2.0
0
All patients
55%
All < 32 weeks GA
47%
Reduction
The IMpact-RSV Study Group. Pediatrics. 1998;102(3):531-7
All 32-35 weeks GA
80%
Summary
• There is significant viral pathogens, some producing
annual epidemics and others that are common to our
communities
• Bronchiolitis is a major threat to the health of all infants
and can lead to hospitalization and death
• The threat of these viruses is greatest in high-risk groups,
such as infants born prematurely and children with CLD
or CHD
• Treatment options are limited