Christina J. Tiller

Growth of Lung Parenchyma in Infants and Toddlers with Chronic Lung Disease of Infancy

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 = 39) were compared with full-term control subjects (n = 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 = 0.0004), but no difference in volume (545 vs. 555 ml; P = 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.

Growth of the lung parenchyma early in life

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.

Lung Growth in Infants and Toddlers Assessed by Multi-slice Computed Tomography

RATIONALE AND OBJECTIVES Postnatal lung growth and development have primarily been evaluated from a very limited number of autopsied lungs, but it remains unclear whether alveolarization of the lung is complete during infancy and whether the conducting airways grow proportionately. The purpose of this study was to evaluate lung growth and development in vivo in infants and toddlers using multislice computed tomography. MATERIALS AND METHODS Thirty-eight subjects (14 male, 24 female) aged 17 to 142 weeks underwent low-dose volumetric high-resolution computed tomographic imaging at an inflation pressure of 20 cm H(2)O during an induced respiratory pause. Lung volume and weight were determined, as well as airway dimensions (inner and outer area and wall area) for the trachea and the next three to four generations. RESULTS Lung volume, air volume, and tissue volume increased linearly with body length. The air and tissue components of the lung parenchyma increased at a constant rate with each other. In addition, airway caliber decreased with increasing generation from the trachea into each lobe. Airway caliber was also correlated with body length; however, there was no interaction effect between airway generation and body length on transformed airway size. CONCLUSIONS In vivo assessment suggests that the growth of the lung parenchyma in infants and toddlers occurred with a constant relationship between air volume and lung tissue, which is consistent with lung growth occurring primarily by the addition of alveoli rather than the expansion of alveoli. In addition, the central conducting airways grow proportionately in infants and toddlers. This information may be important for evaluating subjects with arrested lung development.

Evaluation of airway reactivity and immune characteristics as risk factors for wheezing early in life

BACKGROUND Childhood asthma is most often characterized by recurrent wheezing, airway hyperreactivity, and atopy; however, our understanding of these relationships from early in life remains unclear. Respiratory tract illnesses and atopic sensitization early in life might produce an interaction between innate and acquired immune responses, leading to airway inflammation and heightened airway reactivity. OBJECTIVE We hypothesized that premorbid airway reactivity and immunologic characteristics of infants without prior episodes of wheezing would be associated with subsequent wheezing during a 1-year follow-up. METHODS One hundred sixteen infants with chronic dermatitis were enrolled before episodes of wheezing. Airway reactivity, allergen-specific IgE levels, cytokine production by stimulated PBMCs, and percentages of dendritic cells were measured on entry, and airway reactivity was reassessed at the 1-year follow-up. Linear regression models were used to evaluate a predictors effect on continuous outcomes. RESULTS Milk sensitization, egg sensitization, or both were associated with heightened airway reactivity before wheezing and after the onset of wheezing; however, these factors were not associated with an increased risk of wheezing. There was an interaction between initial airway reactivity and wheezing as a determinant of airway reactivity at follow-up. In addition, cytokine production by stimulated PBMCs was a risk factor for wheezing, whereas increased percentages of conventional dendritic cells were protective against wheezing. CONCLUSION Our data in a selected cohort of infants support a model with multiple risk factors for subsequent wheezing that are independent of initial airway reactivity; however, the causative factors that produce wheezing very early in life might contribute to heightened airway reactivity.

Lung structure and function of infants with recurrent wheeze when asymptomatic

Infants with recurrent wheeze have repeated episodes of airways obstruction; however, relatively little is known about the structure and function of their lungs when not symptomatic. The current authors evaluated whether infants with recurrent wheeze have smaller airway lumens or thickened airway walls, as well as decreased airway function. High-resolution computed tomography images 1 mm thick were obtained at three anatomic locations at an elevated lung volume and at functional residual capacity. Forced expiratory flows were also measured in subjects with recurrent wheeze. Airway lumen, wall areas and lung tissue density were not significantly different for recurrent wheeze (n = 17) and control (n = 14) subjects; however, subjects with recurrent wheeze had lower forced expiratory flows than predicted. Similar findings were obtained when subjects were grouped by exposure to tobacco smoke. These findings indicate that infants with recurrent wheeze, as well as exposure to tobacco smoke, have lower airway function when not symptomatic. The lower forced expiratory flows may result from a degree of airway narrowing that could not be resolved with the methodology employed or from other mechanisms, such as more collapsible airways or decreased pulmonary elastic recoil.

An Infant With Pulmonary Interstitial Glycogenosis: Clinical Improvement Is Associated With Improvement in the Pulmonary Diffusion Capacity

Pulmonary interstitial glycogenosis (PIG) is an idiopathic interstitial lung disease of infants. The underlying pulmonary pathophysiology of PIG has not been well characterized. Herein we report a term‐gestatation infant who presented with persistent tachypnea and hypoxia. A chest CT scan demonstrated a diffuse ground glass appearance and lung biopsy demonstrated increased alveolar septae cellularity with glycogen‐containing cells, consistent with a diagnosis of PIG. At 3 months of age, pulmonary function testing included: pre‐ and post‐bronchodilator forced expiratory flows using the raised‐volume technique and the ratio of pulmonary diffusing capacity for carbon monoxide to alveolar volume (DLCO/VA). He was prescribed 5 days of oral prednisolone (2 mg/kg/day) and pulmonary function testing (PFT) was repeated at 5, 13, and 20 months of age. Initial PFTs demonstrated reduced forced vital capacity (FVC: Z‐score = −2.36) and an increased ratio of forced expiratory volume in 0.5 sec to FVC (FEV0.5/FVC: Z‐score = 1.15) with no significant change following an inhaled bronchodilator. There was also a marked reduction in DLCO/VA (Z‐score = −4.74) compared to age‐matched controls. Follow‐up demonstrated progressive clinical improvement as well as an increase in Z‐FVC and normalization of DLCO/VA. Our in vivo physiological findings are consistent with previous reports that symptom resolution correlated with histological thinning of the alveolar septae upon repeat lung biopsy. The restrictive lung disease we observed is consistent with expected reduced compliance of an alveolar interstitial lung process like PIG, whereas the absence of a reduction in FEV0.5/FVC confirms the absence of obstructive airway disease. Pediatr Pulmonol. 2014; 49:E17–E20.

Ventilation homogeneity improves with growth early in life

Some studies have suggested that lung clearance index (LCI) is age‐independent among healthy subjects early in life, which implies that ventilation distribution does not vary with growth. However, other studies of older children and adolescents suggest that ventilation becomes more homogenous with somatic growth. We describe a new technique to obtain multiple breath washout (MBWO) in sedated infants and toddlers using slow augmented inflation breaths that yields an assessment of LCI and the slope of phase III, which is another index of ventilation inhomogeneity. We evaluated whether ventilation becomes more homogenous with increasing age early in life, and whether infants with chronic lung disease of infancy (CLDI) have increased ventilation inhomogeneity relative to full‐term controls (FT). FT (N = 28) and CLDI (N = 22) subjects between 3 and 28 months corrected‐age were evaluated. LCI decreased with increasing age; however, there was no significant difference between the two groups (9.3 vs. 9.5; P = 0.56). Phase III slopes adjusted for expired volume (SND) increased with increasing breath number during the washout and decreased with increasing age. There was no significant difference in SND between full‐term and CLDI subjects (211 vs. 218; P = 0.77). Our findings indicate that ventilation becomes more homogenous with lung growth and maturation early in life; however, there is no evidence that ventilation inhomogeneity is a significant component of the pulmonary pathophysiology of CLDI. Pediatr Pulmonol. 2012; 47:373–380.

Atopy, Cytokine Production, and Airway Reactivity as Predictors of Pre-School Asthma and Airway Responsiveness

Childhood asthma is often characterized by recurrent wheezing, airway hyper‐reactivity, atopy, and altered immune characteristics; however, our understanding of the development of these relationships from early in life remains unclear. The aim of our study was to evaluate whether atopy, cytokine production by peripheral blood mononuclear cells (PBMCs), and airway responsiveness, assessed in infants and toddlers, are associated with asthma and airway responsiveness at 4‐years of age.

Membrane and Capillary Components of Lung Diffusion and Pro-Angiogenic Cells in Infants

Angiogenesis is a critical determinant of alveolarisation, which increases alveolar surface area and pulmonary capillary blood volume in infants; however, our understanding of this process is very limited. The purpose of our study was to measure the pulmonary membrane diffusion capacity (DM) and pulmonary capillary blood volume (VC) components of the diffusing capacity of the lung for carbon monoxide (DLCO) in healthy infants and toddlers, and evaluate whether these components were associated with pro-angiogenic circulating haematopoietic stem/progenitor cells (pCHSPCs) early in life. 21 healthy subjects (11 males), 3–25 months of age, were evaluated. DLCO was measured under normoxic and hyperoxic conditions, and DM and VC were calculated. From 1 mL venous blood, pCHSPCs were quantified by multiparametric flow cytometry. DM and VC increased with increasing body length; however, membrane resistance as a fraction of total resistance to pulmonary diffusion remained constant with somatic size. In addition, DLCO and VC, but not DM, increased with an increasing percentage of pCHSPCs. The parallel increase in the membrane and vascular components of pulmonary diffusion is consistent with alveolarisation during this period of rapid lung growth. In addition, the relationship between pCHSPCs and VC suggest that pro-angiogenic cells may contribute to this vascular process. Vascular components of pulmonary diffusion are associated with circulating pro-angiogenic cells in infants and toddlers http://ow.ly/r0k8A

Lung parenchymal development in premature infants without bronchopulmonary dysplasia.

Rationale: While infants who are born extremely premature and develop bronchopulmonary dysplasia (BPD) have impaired alveolar development and decreased pulmonary diffusion (DLCO), it remains unclear whether infants born less premature and do not develop BPD, healthy premature (HP), have impaired parenchymal development. In addition, there is increasing evidence that pro‐angiogenic cells are important for vascular development; however, there is little information on the relationship of pro‐angiogenic cells to lung growth and development in infants.