NEHI
Since first described, NEHI has gained its place as a distinct entity
amongst rare causes of infantile diffuse lung
disease37. NEHI clinically presents with persistent
tachypnea, retractions, crackles, and hypoxemia and physiologically as
small airway obstruction evidenced by reduction of
FEF75, FEF85, and FVC38-40. Symptoms are not detectable at birth but
usually present before 12 months (mean: 4 months, interquartile range =
2-6 months) 41. Remarkable in their absence are
prematurity, evidence of pulmonary dysmaturation, underlying causes of
diffuse lung disease, congenital heart disease, or genetic
characteristics 3,39,40,42,43. However, a recent
review on 117 NEHI children demonstrated that 17% of them had evidence
of immune system abnormalities including low immunoglobulin (Ig)G and
IgA levels, low complement 3 concentrations, and cyclic neutropenia of
infancy41. Steroids and bronchodilators show no effect
in NEHI and the sole effective element of supportive care is
supplemental oxygen. While resolution is predictable and spontaneous,
disease duration often lasts years 39,44. Chest x-ray
findings are non-specific. However, high-resolution CT scans display
characteristic findings of ground glass opacities, involving more than
one lobe, and air-trapping. These changes are deemed diagnostic and have
largely replaced lung biopsy for the diagnosis40,42,44,45. Bronchoscopy reveals no structural
changes or inflammation. Lung biopsy, the standard diagnostic method for
diffuse interstitial lung diseases, shows a paucity of airway or
parenchyma abnormalities, no inflammation, but characteristically,
increased bombesin positive NEC cells in bronchioles and
alveoli3,18,39,40,42,44. The positive correlation
between pulmonary bombesin-positive NEC density and small airway
obstruction severity suggests that bombesin plays a causative role in
the pathophysiology of NEHI 39,40. Finally,
bronchoalveolar lavage in NEHI revealed low white blood cell counts and
decreased inflammatory markers, paralleling lung biopsy findings of
sparse inflammation46. Hence, despite the positive
correlation between the load of pulmonary NEC and severity of
obstruction, a discrepancy remains between abundant pulmonary NEC and
paucity of inflammation and histological abnormalities, as compared to
BPD and other conditions with increased pulmonary NEC. An alternative
explanation for NEHI proposed by recent publications, suggests that
pulmonary neuroendocrine cells are a marker of airway underdevelopment
and immaturity 18,19,43 and persistence of bombesin is
shared in postnatal life by a variety of infantile
pathologies.18 Due to low prevalence and lack of
animal models, the etiology and pathophysiology of NEHI remain elusive.