Rationale:The clinical pathology describing infants with chronic lung disease of infancy (CLDI) has been limited and obtained primarily from infants with severe lung disease, who either died or required lung biopsy. As lung tissue from clinically stable outpatients is not available, physiological measurements offer the potential to increase our understanding of the pulmonary pathophysiology of this disease. Objectives: We hypothesized that if premature birth and the development of CLDI result in disruption of alveolar development, then infants and toddlers with CLDI would have a lower pulmonary diffusing capacity relative to their alveolar volume compared with full-term control subjects. Methods: We measured pulmonary diffusing capacity and alveolar volume, using a single breath-hold maneuver at elevated lung volume. Subjects with chronic lung disease of infancy (23-29 wk of gestation; n 5 39) were compared with full-term control subjects (n 5 61) at corrected ages of 11.6 (4.8-17.0) and 13.6 (3.2-33) months, respectively. Measurements and Main Results: Alveolar volume and pulmonary diffusing capacity increased with increasing body length for both groups. After adjusting for body length, subjects with CLDI had significantly lower pulmonary diffusing capacity (2.88 vs. 3.23 ml/ min/mm Hg; P 5 0.0004), but no difference in volume (545 vs. 555 ml; P 5 0.58). Conclusions: Infants and toddlers with CLDI have decreased pulmonary diffusing capacity, but normal alveolar volume. These physiological findings are consistent with the morphometric data obtained from subjects with severe lung disease, which suggests an impairment of alveolar development after very premature birth.

We retrospectively studied the clinical presentation, treatment modalities and outcome in 16 patients with heterozygous NKX2-1 mutation associated with chronic lung disease. Twelve different NKX2-1 mutations, including 4 novel mutations, were identified in the 16 patients. Nine patients presented with brain-lung-thyroid syndrome, 3 had neurological and lung symptoms and 4 had only pulmonary symptoms. Ten patients had neonatal respiratory distress, and 6 of them developed infiltrative lung disease (ILD). The other patients were diagnosed with ILD in childhood (n = 3) or in adulthood (n = 3). The median age at diagnosis was 36 months (IQ 3.5-95). Patient testing included HRCT (n = 13), BALF analysis (n = 6), lung biopsies (n = 3) and lung function tests (n = 6). Six patients required supplemental oxygen support with a median duration of 18 months (IQ 2.5-29). All symptomatic ILD patients (n = 12) benefited from a treatment consisting of steroids, azithromycin (n = 9), and/or hydroxychloroquine (n = 4). The median follow-up was 36 months (IQ 24-71.5). One patient died of respiratory failure at 18 months and another is waiting for lung transplantation. In summary, the initial diagnosis was based on clinical presentation and radiological features, but the presentation was heterogeneous. Definitive diagnosis required genetic analysis, which should be performed, even in absence of neurological or thyroid symptoms.

Rationale: Early in life, lung growth can occur by alveolarization, an increase in the number of alveoli, as well as expansion. We hypothesized that if lung growth early in life occurred primarily by alveolarization, then the ratio of pulmonary diffusion capacity of carbon monoxide (DL CO ) to alveolar volume (V A ) would remain constant; however, if lung growth occurred primarily by alveolar expansion, then DL CO /V A would decline with increasing age, as observed in older children and adolescents. Objectives: To evaluate the relationship between alveolar volume and pulmonary diffusion capacity early in life. Methods: In 50 sleeping infants and toddlers, with equal number of males and females between the ages of 3 and 23 months, we measured DL CO and V A using single breath-hold maneuvers at elevated lung volumes. Measurements and Main Results: DL CO and V A increased with increasing age and body length. Males had higher DL CO and V A when adjusted for age, but not when adjusted for length. DL CO increased with V A ; there was no gender difference when DL CO was adjusted for V A . The ratio of DL CO /V A remained constant with age and body length. Conclusions: Our results suggest that surface area for diffusion increases proportionally with alveolar volume in the first 2 years of life. Larger DL CO and V A for males than females when adjusted for age, but not when adjusted for length, is primarily related to greater body length in boys. The constant ratio for DL CO /V A in infants and toddlers is consistent with lung growth in this age occurring primarily by the addition of alveoli rather than the expansion of alveoli.Keywords: pulmonary diffusion capacity; alveolar volume; lung development The lung, which provides surface area for gas exchange, begins alveolarization of the lung parenchyma in late gestation; however, the number of alveoli present at birth is estimated to be less than 20% of the number in adults (1-3). In addition, alveolar size of an infant is smaller than the alveolar size of an adult (1-3). Therefore, postnatal growth and development of the lung parenchyma includes increases in number as well as size of alveoli. Lung volume early in life is thought to occur primarily by the addition of alveoli during the rapid phase of somatic growth, and then, following alveolarization of the lung parenchyma, lung volume increases by the expansion of existing alveoli. However, from the limited number of morphometric studies of relatively few autopsied lungs from infants and toddlers, which have used differing morphometric techniques to estimate alveolar number, it remains unclear whether the addition of alveoli is complete by 6 months, 2 to 3 years, or 8 years of age (2, 4-6).In vivo physiologic measurements of alveolar volume (V A ) and pulmonary diffusing capacity for carbon monoxide (DL CO ) can provide a functional assessment of the volume and surface area available for gas exchange, which indirectly reflects the cumulative effects of alveolar number and size. In older subjects from 8 years of age to...

Introduction: Neuroendocrine cell hyperplasia of infancy (NEHI) is one of the most common interstitial lung diseases in children. Both the etiology and pathophysiological mechanisms of the disease are still unknown. Prognosis is usually favorable; however, there are significant morbidities during the early years of life.Objective: To describe the clinical course, infant pulmonary function tests and computed tomography (CT) findings in a cohort of patients with NEHI in Argentina.Methods: This is a observational multicenter cohort study of children diagnosed with NEHI between 2011 and 2020.Results: Twenty patients participated in this study. The median age of onset of symptoms was 3 months and the median age at diagnosis was 6 months. The most common clinical presentation was tachypnea, retractions and hypoxemia. The chest CT findings showed central ground glass opacities and air trapping. Infant pulmonary function tests revealed an obstructive pattern in 75% of the cases (10/12). Most patients (75%) required home oxygen therapy for 17 months (interquartile range 12-25). In 85% of them, tachypnea and hypoxemia spontaneously resolved between the second and third years of life. Conclusion:In this cohort, the first symptoms appeared during the early months of life. The typical clinical, CT, and functional findings allowed the diagnosis without the need of a lung biopsy. Although most patients required home oxygen therapy, they showed a favorable evolution.children's interstitial lung disease, computed tomography, infant pulmonary function, neuroendocrine cell hyperplasia, persistent tachypnea | INTRODUCTIONInterstitial lung diseases of infancy constitute a heterogeneous and rare group of respiratory conditions. 1 One of the most common entities is persistent tachypnea of infancy 2 or neuroendocrine cell hyperplasia of infancy (NEHI), as it was later known. 3 Although most cases are sporadic, there are familial cases. 4,5 During their first months, patients develop tachypnea, failure to thrive and hypoxemia.Their chest computed tomography (CT) reveal ground-glass opacities (GGO) and air trapping areas. 6 Early publications reported