Respiratory Infections and the Infant

Rees Oliver MDAssistant Professor

Department of PediatricsDivision of NeonatologyUniversity of Alabama at

Birmingham

Disclosure statement:

I do speak as a consultant on behalf of MedImmune for the product Synagis.

With permission from Simoes EAF and Carbonell-Estrany X. Pediatr Infect Dis J. 2003;22:S13-S20.

Causes of Acute Respiratory Infections in Children <5 Years of Age

Data from the Belgian sentinel network’s epidemiology surveillance (2000–2001 season)

Adenovirus 7%

C. pneum. 0%

M. pneum. 9%

H. infl. 6%

Parainfluenza 2%

Infl. B 2%

Infl. A 3%

S. pneum. 8%

RSV 62%

3

Leading Viral Causesof Infant Mortality

Thompson WW et al. JAMA. 2003;289:179-186.

<1 1–4 5–49

Age Bracket (years)

Mo

rtal

ity

Rat

e p

er10

0,00

0 P

erso

n-Y

ears

RSV

Influenza

0

1

2

3

4

Estimated mortality for underlying pneumonia and influenza deaths, based on data from Centers for Disease Control and Prevention

3.1

0.3 0.10.2 0.2

<0.01

12

Expiratory wheezing, prolonged expiration, rales and rhonchi

Chest wall retractions

Tachypnea with apneic episodes

Nasal flaring

Hypoxemia and cyanosis

Expiratory grunt

Clinical Features: Infant With Respiratory Distress

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

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

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

Leader 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

• 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

Children at Highest Risk for Severe Respiratory Distress as an Infant

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

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

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

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

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

*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

Adapted 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

Ig

G (

mg

/100

ml)

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

Navas L, et al. J Pediatr. 1992;121:348-54

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

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

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

65

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

55% 47% 80%

Reduction

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

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