Correspondence

Chronic Lung Disease after Premature Birth

N Engl J Med 2008; 358:743-746February 14, 2008

Article

To the Editor:

In their review article on chronic lung disease after premature birth, Baraldi and Filippone (Nov. 8 issue)1 comment on the absence of pathological findings in the lungs beyond infancy in survivors of bronchopulmonary dysplasia or prematurity. They also note that the characterization of the long-term pulmonary outcome after premature birth, including the development of bronchial asthma, remains primarily clinical, with no insight from tissue examination to guide management. We report a case of a 12-year-old boy with a history of prematurity (26 weeks' gestation; birth weight, 596 g) and bronchopulmonary dysplasia who died of an acute asthma attack. The lungs at autopsy showed markedly enlarged air spaces with reduced alveolar septation characteristic of the arrested acinar development seen in bronchopulmonary dysplasia2 (Figure 1A and 1BFigure 1Pulmonary Findings at Autopsy in a 12-Year-Old Boy with Bronchopulmonary Dysplasia.). The airways showed changes of chronic bronchial asthma with airway remodeling (Figure 1C) and an inflammatory-cell infiltrate, including eosinophils and mast cells that were immunoreactive for IgE3 (Figure 1D and 1E). This case provides evidence of the persistence of changes of bronchopulmonary dysplasia into childhood and, at least in some cases, the development of classic changes of bronchial asthma.4

Ernest Cutz, M.D.
David Chiasson, M.D.
Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
ernest.cutz@sickkids.ca

4 References

1. 1

   Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med 2007;357:1946-1955
   Full Text | Web of Science | Medline

2. 2

   Husain AN, Siddiqui NH, Stocker JT. Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia. Hum Pathol 1998;29:710-717
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3. 3

   Busse WW, Lemanske RF Jr. Asthma. N Engl J Med 2001;344:350-362
   Full Text | Web of Science | Medline

4. 4

   Cutz E, Levison H, Cooper DM. Ultrastructure of airways in children with asthma. Histopathology 1978;2:407-421
   CrossRef | Web of Science | Medline

To the Editor:

Baraldi and Filippone do not mention congenital surfactant deficiency as a possible cause of chronic lung disease after preterm birth,1 both in the neonatal period and later in infancy and childhood.2,3 Moreover, it has been suggested that some genetic variants of surfactant proteins are risk factors for the development of bronchopulmonary dysplasia.4

We have observed premature monozygotic male twins, repeatedly hospitalized since the age of 8 months because of acute respiratory failure from respiratory infections. By the age of 2 years, they had all the symptoms of chronic respiratory insufficiency. Pulmonary biopsy revealed the presence of alveolar cholesterol granulomas and macrophage infiltrates. Genetic analysis showed a new mutation (I73T) in the surfactant protein C gene.

Since the progression of pulmonary dysfunction in patients with protein C deficiency may be controlled by hydroxychloroquine,5 as happened in our two patients, we suggest that congenital surfactant protein disorders, although rare, should be considered in patients with chronic lung disease after premature birth.

Valentina Kiren, M.D.
Egidio Barbi, M.D.
Alessandro Ventura, M.D.
Burlo Garofolo University Hospital, 34100 Trieste, Italy
valentinakappa@libero.it

5 References

1. 1

   Somaschini M, Nogee LM, Sassi I, et al. Unexplained neonatal respiratory distress due to congenital surfactant deficiency. J Pediatr 2007;150:649-653
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2. 2

   Hamvas A. Inherited surfactant protein-B deficiency and surfactant protein-C associated disease: clinical features and evaluation. Semin Perinatol 2006;30:316-326
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3. 3

   Nogee LM, Dunbar AE III, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 2001;344:573-579
   Full Text | Web of Science | Medline

4. 4

   Pavlovic J, Papagaroufalis C, Xanthou M, et al. Genetic variants of surfactant proteins A, B, C, and D in bronchopulmonary dysplasia. Dis Marker 2006;22:277-291
   Web of Science | Medline

5. 5

   Rosen DM, Waltz DA. Hydroxychloroquine and surfactant protein C deficiency. N Engl J Med 2005;352:207-208
   Full Text | Web of Science | Medline

Author/Editor Response

Cutz and Chiasson provide an interesting pathological study of the lungs of a child who was very preterm, several years after bronchopulmonary dysplasia developed. As we note in our review, any information on lung morphologic features in survivors of prematurity and bronchopulmonary dysplasia is of great value.

The long-term persistence of features of alveolar simplification is an important finding. The airway study shows that changes induced by bronchopulmonary dysplasia and bronchial asthma may coexist. Asthma can develop naturally in survivors of bronchopulmonary dysplasia, especially those with a family history of asthma or allergies. The child studied died of an acute broncho-obstructive episode, suggesting a genuinely atypical clinical course. Survivors of bronchopulmonary dysplasia rarely have severe bronchoconstrictive episodes as adolescents, even in cases with spirometric evidence of severe airflow obstruction. Moreover, they do not usually show signs of significant eosinophilic airway inflammation.1 Analyzing tissue from survivors of bronchopulmonary dysplasia with no clinical evidence of coexisting bronchial asthma or from patients with bronchopulmonary dysplasia who died from nonpulmonary causes2 remains a research priority in this field.

Kiren et al. say that we failed to mention congenital surfactant anomalies in our review. A thorough discussion of the pathogenesis of chronic lung disease was beyond the scope of our article, but we do say that “hereditary influences on the expression of genes that are critical for surfactant synthesis . . . probably also have a role” in perinatal lung injury and bronchopulmonary dysplasia.

Although surfactant protein C gene polymorphisms have been linked to preterm delivery,3 in the neonatal period, surfactant protein C mutations usually present as severe respiratory distress syndrome at or near term. Their clinical onset is more likely to come later, however, with progressive interstitial pulmonary involvement, as in the patients described by Kiren et al., whose symptoms developed at 8 months of age. Differentiation with respect to chronic lung disease after premature birth is not an issue in such cases, but we agree that it might be necessary to rule out surfactant protein anomalies in selected premature infants with chronic lung disease, particularly if their clinical course is severe or progressive.

Marco Filippone, M.D.
Eugenio Baraldi, M.D.
University of Padua, 35128 Padua, Italy
baraldi@pediatria.unipd.it

3 References

1. 1

   Baraldi E, Bonetto G, Zacchello F, Filippone M. Low exhaled nitric oxide in school-age children with bronchopulmonary dysplasia and airflow limitation. Am J Respir Crit Care Med 2005;171:68-72
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2. 2

   Jobe AH. An unknown: lung growth and development after very preterm birth. Am J Respir Crit Care Med 2002;166:1529-1530
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3. 3

   Lahti M, Marttila R, Hallman M. Surfactant protein C gene variation in the Finnish population -- association with perinatal respiratory disease. Eur J Hum Genet 2004;12:312-320
   CrossRef | Web of Science | Medline

Citing Articles (6)

Citing Articles

1. 1

   Rajesh S. Alphonse, Bernard Thébaud. (2011) Growth Factors, Stem Cells and Bronchopulmonary Dysplasia. Neonatology 99:4, 326-337
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2. 2

   ARUL VADIVEL, JUDY L. ASCHNER, GLORIA J. REY-PARRA, JORDAN MAGARIK, HENG ZENG, MARSHALL SUMMAR, FARAH EATON, BERNARD THÉBAUD. (2010) l-Citrulline Attenuates Arrested Alveolar Growth and Pulmonary Hypertension in Oxygen-Induced Lung Injury in Newborn Rats. Pediatric Research 68:6, 519-525
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3. 3

   Przemko Kwinta, Jacek Józef Pietrzyk. (2010) Preterm birth and respiratory disease in later life. Expert Review of Respiratory Medicine 4:5, 593-604
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4. 4

   Bernard Thébaud, Thierry Lacaze-Masmonteil. (2010) If Your Placenta Doesn't Have It, Chances Are Your Lungs Don't Have It Either: The “Vascular Hypothesis” of Bronchopulmonary Dysplasia Starts In Utero. The Journal of Pediatrics 156:4, 521-523
   CrossRef

5. 5

   Francesca Gotsch, Francesca Gotsch, Roberto Romero, Offer Erez, Edi Vaisbuch, Juan Pedro Kusanovic, Shali Mazaki-Tovi, Sun Kwon Kim, Sonia Hassan, Lami Yeo. (2009) The preterm parturition syndrome and its implications for understanding the biology, risk assessment, diagnosis, treatment and prevention of preterm birth. Journal of Maternal-Fetal and Neonatal Medicine 22:s2, 5-23
   CrossRef

6. 6

   Ettore Capoluongo, Franco Ameglio, Cecilia Zuppi. (2008) Insulin-like growth factor-I and complications of prematurity: a focus on bronchopulmonary dysplasia. Clinical Chemistry and Laboratory Medicine 46:8, 1061-1066
   CrossRef