Prematurity and Respiratory Disease Renato T. Stein
Pontif铆cia Universidade Cat贸lica RGS PORTO ALEGRE, BRAZIL
Respiratory Viruses in First Time Wheezers
Positive detection in NPA (%) (n=35) RSV Rhinovirus Influenza
33 (94.3) 6 (17.1) 1 (2.9)
Adenovirus Parainfluenza
2 (5.7) 0
Pitrez PM et al. 2005 J Ped (Rio J)
Susceptibility Period Infection in early infancy: greatest impact in the immune and/or respiratory system Infants born in winter are more likely to have asthma (Aberg N, Clin Exp Allergy 1999) (Nielsen HE Acta Paediatr 2003)
Premature infants without CLD RSV LRI is associated with increased morbidity in preterm infants without underlying chronic lung disease – Hospitalization rates range from 9 - 13%
Among those hospitalized with RSV: – 28-34% admitted to the PICU – 7-22% required mechanical ventilation
Simoes EAF. Resp Res, 2002
Prematurity and RSV Disease Increased risk of
Hospital admission ICU admission Mechanical ventilation Longer hospital stays Higher mortality rates
Especially with chronic lung disease (also known as BPD (3.5%)
Anatomic Risk Factors Low birth weight and gestational age* Small, poorly formed airways Chronic lung disease (CLD/BPD) Inflammatory changes in lungs High airway resistance in lungs Pulmonary hypertension
33-35 wGA Arrested airway 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 )
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
Immunologic Risk Factors Maternal antibody is only transferred to the fetus in the last trimester of pregnancy Little or no maternal RSV antibody transferred prior to 32 weeks gestation Poorly developed cellular immunity (important for viral clearance from the lungs)
Lower Serum IgG Levels RSV IgG antibody
IgG Level (mg/dL)
700 600
25-28wGA 29-32wGA
500
Full Term
is necessary to protect lower airway from RSV infection
400 300
Passively acquired maternal RSV IgG antibody low or absent in preterms
200 100 0 0
2
4
6
Age (months)
8
10
12
Preterm infants with CLD who had at least one RSV admission during the first two years of life (n=33) compared to Control infants (n=190) Non RSV bronchiolitis Other respiratory illness No/other hospitalization
Followed prospectively over 5 years Medical and quality of life Greenough et al. Arch Dis Child 2004;89:673–8
(mean no.) RSV proven
Bronchiolitis
NonRSV LRTI
No P value admission (Between all admission groups)
Outpatient visits
24
12
18
15
0.0006
Hospital admissions
8
5
5
2
<0.0001
Days in hosp.
53
20
23
5
<0.0001
Days in PICU
3
1
0.8
0
0.005
Days in Paed ward
44
17
19
4
<0.0001
RSV in Premature Infants with CLD ``In the first 5 years of life, costs associated with morbidity were approximately 2 times higher in infants admitted at least once with an RSV infection than in infants with no RSV admissionâ&#x20AC;?
Greenough et al. Arch Dis Child 2004;89:673â&#x20AC;&#x201C;8
!" %! &!
#! # '( ) )% &
Healthcare Utilization
Cases (n=2,415)
Controls (n=20,254)
P-value
Mean number of hospitalizations
2.96 2X
1.28
<0.001
Visits to special care units
0.67
0.40
<0.001
Use of respiratory therapy
0.31 3X
0.13
<0.001
Physician consults
3.61 4X
0.89
<0.001
Mean cumulative LOS
14.71 3X
5.04
<0.001
Outpatient visits
18.4 2X
7.54
<0.001
50%
Sampalis et al J Pediatr 2003; 143:S150-S156
" ! $
RSV Inflammatory Mediators Neuroimmune interactions: (Piedimonte G, AJRCCM 2005) Low IFNg production early in life (Guerra S, AJRCCM 2003) High IL-10 predicts subsequent wheeze (Bont L, AJRCCM 2000)
Genetic markers: IL-10 genes, TLR4 mutations,â&#x20AC;Ś are related to severe bronchiolitis (Hull J et al. J Infec Dis 2005), (Guy T et al. J Infect Dis 2004)
IL-4 gene SNPs: associated with wheeze in children infected with RSV (Martinez FD, ATS 2006)
Data from Texas
Mejias, Chaves-Bueno, Ramilo O. Ped Infect Dis J. 2005
Major Questions Viral bronchiolitis contributes to asthma inception, or Identifies infants at risk for subsequent wheezing, …whether due to an atopic predisposition or preexisting abnormal lung function.
Infant Pulmonary Function: Prematures Objetives: To describe pulmonary function in healthy prematures. Methods: 62 prematures and 27 term infants (controls) Infant pulmonary function tests with full volume curves
Infant Pulmonary Function: Prematures Variables
Controls mean (SD) n=27
Preterm Mean (SD) n=62
Difference (95% CI)
Difference (95% CI) after adjustment for length, age and sex
FVC (mL)
420 (204)
163 (49)
256 (175 to 338)
*
FEF50 (mL/s)
674 (214)
332 (105)
341 (253 to 430)
*
-92 (-164 to -20)
FEF75 (mL/s)
339 (144)
140 (75)
199 (139 to 259)
*
-33 (-82 to 16)
FEF25-75 (mL/s)
588 (195)
278 (99)
310 (229 to 391)
*
-73 (-136 to -10)
FEV0.5 (mL)
305 (115)
133 (35)
172 (125 to 218)
*
-19 (-37 to -1)
Difference (95% CI) after adjustment for FVC, age and sex
0 (-30 to 30)
†
†
-135 (-208 to -62)
-55 (-103 to -6) †
‡
†
-109 (-172 to -45)
-30 (-45 to -154)
‡
‡
Reduced Lung Function in Healthy Preterm Infants in the First Months of Life Am. J. Respir. Crit. Care Med. 173: 442-447
Infant Pulmonary Function: Prematures 1600 1400
FVC (mL)
1200 1000 800 600 400 200 0 40
50
60
70
80
90
100
Length (cm) Reduced Lung Function in Healthy Preterm Infants in the First Months of Life Am. J. Respir. Crit. Care Med. 173: 442-447
Infant Pulmonary Function: Prematures 1800 1600
FEF25-75 (mL/s)
1400 1200 1000 800 600 400 200 0 40
50
60
70
80
90
100
Length (cm) Reduced Lung Function in Healthy Preterm Infants in the First Months of Life Am. J. Respir. Crit. Care Med. 173: 442-447
Infant Pulmonary Function: Prematures 3 2 1
Z-scores
0 -1 -2 -3 -4 -5 FVC
FEF50
FEF75
FEF25-75
FEV0.5
Lung Function Variables Reduced Lung Function in Healthy Preterm Infants in the First Months of Life Am. J. Respir. Crit. Care Med. 173: 442-447
Infant Pulmonary Function: Prematures Main Results: FEF50, FEF75 e FEF25–75: significant and independently associated with gest age. For each get week there is a growth of 10 ml/s (7%) in FEF75. Male sex was associated with lower flows (FEF50, FEF75, and FEF25–75) Reduced Lung Function in Healthy Preterm Infants in the First Months of Life Am. J. Respir. Crit. Care Med. 173: 442-447
Pulmonary growth in prematures Objectives: To describe pulmonary growth velocity in prematures Methods: 26 prematures and 24 controls IPFTs measured twice: first and second year of life Growth Rate of Lung Function in Preterm Infants, Proceedings of the American Thoracic Society, 2005, pA606
Pulmonary growth in prematures 550 Prematuros Controles
500
FVC (mL)
450 400 350 300 250 200 150 0
1
2
3
Momentos do teste Growth Rate of Lung Function in Preterm Infants, Proceedings of the American Thoracic Society, 2005, pA606
Pulmonary growth in prematures 800
500 Prematuros Controles
450
700
FEF2575 (mL/s)
400
FEF75 (mL/s)
Prematuros Controles
350 300 250
600
500
400
300
200 150 0
1
2
Momentos do teste
3
200 0
1
2
3
Momentos do teste
Growth Rate of Lung Function in Preterm Infants, Proceedings of the American Thoracic Society, 2005, pA606
Intra-amniotic fluid, inflammation and lung development in prematures Objetives: To study the impact of infection and inflammation on lung growth of prematures Methods: Placental examination, cord blood, amniotic fluid, cord and membranes of prematures Histopathologic studies, inflammatory mediators in the amniotic fluid and blood (ELISA), detection of infective agents (PCR) IPFT in the first year of life (RVRTC)
Pulmonary growth in prematures Preliminary results: 180 prematures recruited 2004-2005 with colection of placenta. Samples collected for the hystophatologic study in all patients Amniotic fluid in 45 patients IPFTs in 100 pacientes
Pulmonary growth in prematures (preliminary results) 1000 900 800
FVC (ml)
700 600 500 400 300 200 100 0 50
55
60
65
70 Length (cm)
75
80
85
90
Pulmonary growth in prematures (preliminary results) 1200
FEF50 (ml/s)
1000 800 600 400 200 0 50
55
60
65
70 Length (cm)
75
80
85
90