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Respiratory Infections and the Infant

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.

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Respiratory Infections and the Infant

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  1. Respiratory Infections and the Infant Rees Oliver MD Assistant Professor Department of Pediatrics Division of Neonatology University of Alabama at Birmingham

  2. Disclosure statement: • I do speak as a consultant on behalf of MedImmune for the product Synagis.

  3. Causes of Acute Respiratory Infections in Children <5 Years of Age Adenovirus7% 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.

  4. Leading Viral Causesof Infant Mortality Estimated mortality for underlying pneumonia and influenza deaths, based on data from Centers for Disease Control and Prevention RSV 3.1 Influenza Mortality Rate per100,000 Person-Years 0.1 0.3 <0.01 0.2 0.2 <1 1–4 5–49 Age Bracket (years) 12 Thompson WW et al. JAMA. 2003;289:179-186.

  5. Clinical Features: Infant With Respiratory Distress Chest wall retractions Nasal flaring Hypoxemia and cyanosis Expiratory grunt Expiratory wheezing, prolonged expiration, rales and rhonchi 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. 16

  6. 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 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. 17

  7. 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

  8. 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

  9. 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

  10. 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 Research3, Suppl 1. (2002):S15

  11. 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

  12. Top Causes of Infant Hospitalization Based on National Hospital Discharge Survey, 1997-1999 RSV Bronchiolitis Bronchiolitis(cause unspecified) Pneumonia(cause unspecified) Jaundice Dehydration Leader S, Kohlhase K. Pediatr Infect Dis J. 2002;21:629-32

  13. 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;161:1501-7Taussig LM, et al. Am J Epidemiol. 1989;129:1219-31Stein RT, et al. The Lancet. 1999;354:541-5

  14. Children at Highest Risk for Severe Respiratory Distress as an Infant • Altered airway anatomy • Absence of maternal antibody Premature birth • Bronchial hyper-responsiveness • Reduced lung capacity Chronic Lung Disease • Pulmonary vascular hyper-responsiveness • Pulmonary hypertension • Increased pulmonary blood flow Congenital Heart disease • Decreased respiratory muscle strength and endurance Neuromuscular disease • Decreased host defenses • Impaired capacity to eliminate virus Immune deficiency Adapted from a presentation by L Weisman, MD: 1st International Congress RSV, 2002

  15. 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 Problems in Premature Infants

  16. 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

  17. 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

  18. Prematurity: Interrupts Lung Development Premature Term Pseudoglandular Period (7 to 16 weeks GA) Alveolar Period (36 to 41 weeks GA) Saccular Period (26 to 36 weeks GA) Canalicular Period (16 to 26 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

  19. 1100 1200 1000 800 520 Serum IgG (mg/100ml) 600 320 400 200 200 0 <28 wks GA 28-31 wks GA 32-35 wks GA Term Serum Antibody (IgG) Levels at Birth: Premature & Term infants Adapted from data and formulas as published by Yeung CY, Hobbs JR. Lancet. 1968;7553:1167-70

  20. 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

  21. 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

  22. 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

  23. 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

  24. Therapeutic Options for Bronchiolitis • Prevention • Limit exposure • Avoid daycare • Excellent hand washing • Passive immunoprophylaxis:Synagis® (palivizumab) • Supportive care • Overcoming airway obstruction and inflammation

  25. 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

  26. 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 The IMpact-RSV Study Group. Pediatrics. 1998;102:531-537.Please see full prescribing information for Synagis® (palivizumab). 65

  27. IMPACT-RSV TRIALRSV 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 5.8 4.8 4 2 2.0 0 All patients All < 32 weeks GA All 32-35 weeks GA 55% 47% 80% Reduction The IMpact-RSV Study Group. Pediatrics. 1998;102(3):531-7

  28. 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

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