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.