Review
Early onset children’s interstitial lung diseases: Discrete entities or manifestations of pulmonary dysmaturity?

https://doi.org/10.1016/j.prrv.2018.09.004Get rights and content

Abstract

Interstitial lung diseases in children (chILD) are rare and diverse. The current classifications include a group of early onset chILD specific to infancy, namely neuro-endocrine cell hyperplasia of infancy (NEHI), pulmonary interstitial glycogenosis (PIG) and the alveolar capillary–congenital acinar dysplasia (ACD–CAD) spectrum, as well as alveolar growth disorders. NEHI and PIG cells are seen in the normal developing foetal lung. We hypothesise that these conditions are in fact overlapping manifestations of pulmonary dysmaturity, respectively of airway, mesenchymal and vascular elements, rather than discrete clinical conditions in their own right. Clinically, these present as respiratory distress in early life. Mild cases rightly never undergo lung biopsy, and for these the clinical description ‘persistent tachypnoea of infancy’ has been proposed. In terms of pathology, we reviewed current literature, which showed that NEHI cells decline with age, and are not specific to NEHI, which we confirmed by unpublished re-analysis of a second dataset. Furthermore, specific genetic disorders which affect pulmonary maturation lead to a histological picture indistinguishable from NEHI. PIG and ACD–CAD are also associated with pulmonary growth disorders, and manifestations of PIG and NEHI may be present in the same child. We conclude that, contrary to current classifications, NEHI, PIG, and ACD–CAD should be considered as overlapping manifestations of pulmonary dysmaturation, frequently associated with disorders of alveolar growth, rather than as separate conditions. Identification of one of these patterns should be the start, not the end of the diagnostic journey, and underlying in particular genetic causes should be sought.

Section snippets

NEHI: Dysmaturation of the foetal airways?

NEHI is a term which was coined to describe otherwise well infants with any or all of chronic tachypnoea, retractions, crackles and hypoxaemia; in lung biopsies haematoxylin and eosin (H&E) staining was essentially normal, but there was increased staining for the neuropeptide bombesin in the most distal airway cells [16], [17], [18]. If performed, infant pulmonary function tests show evidence of air trapping [18], [19], and airflow obstruction persists into childhood [20]. High resolution CT

Dysmaturation of the foetal mesenchyme (PIG)

PIG was first described [14] in seven infants who presented with tachypnoea, respiratory distress and non-specific pulmonary infiltrates in the first month of life. Light and electron microscopy confirmed the presence of glycogen granules within spindle shaped cells which expanded the interstitium. These cells were vimentin positive but negative for macrophage markers. There was no pathological extrapulmonary glycogen deposition. Six infants survived; the seventh died of the complications of

Dysmaturation of the foetal pulmonary vasculature

The foetal pulmonary vascular resistance (PVR) is high, leading to physiological right to left shunting because the foetal lung has no gas-exchange function. Reflecting this, there is substantially more muscularisation of the distal pulmonary arteries and arterioles than in childhood. Furthermore, the greatly reduced numbers of alveoli in the foetal lung compared to the mature lung contributes to the elevated PVR. At birth, as the lung expands with the first breaths, PVR normally falls and

Conclusions

Just as elsewhere it has been argued that deconstructing the airway is a good way to approach treatment [83], here we advance the hypothesis that growth and maturational disorders should be deconstructed into dysregulated development of alveoli, airway, mesenchyme and pulmonary circulation. This is a controversial hypothesis which requires testing. Perhaps these should be called ‘lung dysmaturation syndromes’ if lung tissue is available, specifying which compartment(s) are affected. As with

Educational aims

The reader will come to:

  • 1.

    Appreciate the spectrum of interstitial lung diseases presenting early in life related to abnormalities of lung development (NEHI, PIG, alveolar-capillary dysplasia spectrum).

  • 2.

    Realise that these may not be specific entities, but there are overlap syndromes and associations with extrapulmonary abnormalities.

  • 3.

    Understand that these histological patterns are the beginning not the end of the diagnostic journey, and should trigger a search for underlying in particular genetic

Directions for future research

  • 1.

    Determine the spectrum of genes important in antenatal lung development, in which mutations may present as interstitial lung disease.

  • 2.

    By moving from identification of histological patterns to underlying gene mutations, to move from non-specific or no therapies to specific, targeted molecular treatments for these conditions.

Acknowledgements

AB is an NIHR Senior Investigator. Supported by chILD-EU (FP7, No, 305653) and the European Cooperation in Science and Technology COST A16125.

References (89)

  • F. Pasutto et al.

    Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation

    Am J Hum Genet

    (2007)
  • P. Sen et al.

    Expanding the phenotype of alveolar capillary dysplasia (ACD)

    J Pediatr

    (2004)
  • Y. Kitayama et al.

    Nitric oxide therapy for an infant with PPH caused by misalignment of pulmonary veins with alveolar capillary dysplasia

    J Pediatr Surg

    (1997)
  • K. Al-Hathlol et al.

    Alveolar capillary dysplasia Report of a case of prolonged life without extracorporeal membrane oxygenation (ECMO) and review of the literature

    Early Hum Dev

    (2000)
  • I.D. Pavord et al.

    After asthma – redefining airways diseases

    Lancet

    (2018)
  • G.H. Deutsch et al.

    Diffuse lung disease in young children: application of a novel classification scheme

    Am J Respir Crit Care Med

    (2007)
  • M. Griese et al.

    Incidence and classification of pediatric diffuse parenchymal lung diseases in Germany

    Orphanet J Rare Dis

    (2009)
  • C. Langston et al.

    Diffuse lung disease in infancy: a proposed classification applied to 259 diagnostic biopsies

    Pediatr Dev Pathol

    (2009)
  • A. Rice et al.

    Diffuse lung disease in infancy and childhood: expanding the chILD classification

    Histopathology

    (2013)
  • R.L. Emanuel et al.

    Bombesin-like peptides and receptors in normal fetal baboon lung: roles in lung growth and maturation

    Am J Physiol

    (1999)
  • K.A. King et al.

    CD10/neutral endopeptidase 24.11 regulates fetal lung growth and maturation in utero by potentiating endogenous bombesin-like peptides

    J Clin Invest

    (1993)
  • S.M. Aguayo et al.

    Regulation of lung branching morphogenesis by bombesin-like peptides and neutral endopeptidase

    Am J Respir Cell Mol Biol

    (1994)
  • M.E. Sunday et al.

    Bombesin increases fetal lung growth and maturation in utero and in organ culture

    Am J Respir Cell Mol Biol

    (1990)
  • M.E. Sunday et al.

    Anti-bombesin antibodies modulate fetal mouse lung growth and maturation in utero and in organ cultures

    Anat Rec

    (1993)
  • E. Cutz

    Cytomorphology and differentiation of airway epithelium in developing human lung

  • Y. Kikkawa et al.

    Morphologic development of fetal rabbit lung and its acceleration with cortisol

    Am J Pathol

    (1971)
  • W.M. Maniscalo et al.

    Development of glycogen and phospholipid metabolism in fetal and newborn rat lung

    Biochem Biophys Acta

    (1978)
  • N.K. Tyler et al.

    Cytodifferentiation of two epithelial populations of the respiratory bronchiole during fetal lung development in the Rhesus monkey

    Anat Rec

    (1989)
  • A.M. Canakis et al.

    Pulmonary interstitial glycogenosis: a new variant of neonatal interstitial lung disease

    Am J Respir Crit Care Med

    (2002)
  • Brooke A. King et al.

    Pulmonary maturational arrest and death in a patient with pulmonary interstitial glycogenosis

    Pediatr Pulmonol

    (2011)
  • R.R. Deterding et al.

    Persistent tachypnea of infancy is associated with neuroendocrine cell hyperplasia

    Pediatr Pulmonol

    (2005)
  • J. Popler et al.

    Familial neuroendocrine cell hyperplasia of infancy

    Pediatr Pulmonol

    (2010)
  • G.S. Kerby et al.

    Abnormal infant pulmonary function in young children with neuroendocrine cell hyperplasia of infancy

    Pediatr Pulmonol

    (2013)
  • H. Lukkarinen et al.

    Neuroendocrine cell hyperplasia of infancy: a prospective follow-up of nine children

    Arch Dis Child

    (2013)
  • A.S. Brody et al.

    Neuroendocrine cell hyperplasia of infancy (NEHI)

    Pediatr Radiol

    (2006)
  • A.S. Brody et al.

    Neuroendocrine cell hyperplasia of infancy: diagnosis with high-resolution CT

    AJR Am J Roentgenol

    (2010)
  • S.G. Yancheva et al.

    Bombesin staining in neuroendocrine cell hyperplasia of infancy (NEHI) and other childhood interstitial lung diseases (chILD)

    Histopathology

    (2015)
  • D. Rauch et al.

    Persistent tachypnea of infancy. Usual and aberrant

    Am J Respir Crit Care Med

    (2016)
  • R.J. Nevel et al.

    Persistent lung disease in adults with NKX2.1 mutation and familial neuroendocrine cell hyperplasia of infancy

    Ann Am Thorac Soc

    (2016)
  • L. Zhou et al.

    Thyroid transcription factor-1, hepatocyte nuclear factor-3beta, surfactant protein B, C, and Clara cell secretory protein in developing mouse lung

    J Histochem Cytochem

    (1996)
  • M.T. Stahlman et al.

    Expression of thyroid transcription factor-1(TTF-1) in fetal and neonatal human lung

    J Histochem Cytochem

    (1996)
  • S. Li et al.

    Foxp1/4 control epithelial cell fate during lung development and regeneration through regulation of anterior gradient2

    Development

    (2012)
  • W. Shu et al.

    Foxp2 and Foxp1 cooperatively regulate lung and esophagus development

    Development

    (2007)
  • A. Myers et al.

    FOXP1 haploinsufficiency: phenotypes beyond behavior and intelectual disability?

    Am J Med Genet A

    (2017)
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