Prematurez y enfermedad respiratoria

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