De novo circumscribed pulmonary lobar cystic lymphatic anomaly in a young boy. A possible sequela of bronchopulmonary dysplasia.

This report describes a massive pulmonary lymphatic cystic anomaly affecting the right lower lobe of a nine-year-old boy. A year earlier, only an ill-defined small infiltrate could be seen in the affected lobe radiologically. The pathogenesis of this highly unusual lesion is discussed, taking into consideration the possible role of three months of mechanical ventilation in the neonatal period.

Epithelial modulation of preterm airway smooth muscle contraction.

To determine if epithelium from immature airways can modulate the responsiveness of smooth muscle, we studied paired trachealis muscle strips from preterm sheep. The epithelium was removed from one strip and left undisturbed in the other. Concentration-effect (CE) curves to acetylcholine (ACh), KCl, and isoproterenol were obtained. To evaluate maturational effects, responses to ACh and isoproterenol were studied in trachealis strips from adult airways. Maximal stress (Po) to ACh increased after epithelium removal in preterm (P < 0.05) but not adult strips. Epithelium removal caused a leftward shift of the ACh CE curves in both preterm and adult strips (P < 0.001) and a decrease in the dose required to achieve a one-half maximal response (ED50) in both preterm (P < 0.005) and adult strips (P < 0.05). The magnitude of the change in Po as well as in the ED50 for ACh between preterms and adults was similar. Epithelium removal did not alter either the Po or the CE curves of preterm strips stimulated by KCl. Response to isoproterenol in precontracted strips was enhanced in the presence of an intact epithelium in both groups (P < 0.05). These data demonstrate that preterm airway epithelium is able to modulate the responsiveness of smooth muscle. Additionally, the magnitude of the effect is unchanged with maturation. We speculate that damage of airway epithelium from mechanical ventilation may contribute to the increased incidence of airway hyperreactivity observed in preterm infants.

Developmental changes in chest wall compliance in infancy and early childhood.

Development of chest wall stiffness between infancy and adulthood has important consequences for respiratory system function. To test the hypothesis that there is substantial stiffening of the chest wall in the first few years of life, we measured passive chest wall compliance (Cw) in 40 sedated humans 2 wk-3.5 yr old. Respiratory muscles were relaxed with manual ventilation applied during the Mead-Whittenberger technique. Respiratory system compliance (Crs) and lung compliance (Cl) were calculated from airway opening pressure, transpulmonary pressure, and tidal volume. Cw was calculated as 1/Cw = 1/Crs - 1/Cl during manual ventilation. Mean Cw per kilogram in infants < 1 yr old was significantly higher than that in children > 1 yr old (2.80 +/- 0.87 vs. 2.04 +/- 0.51 ml.cmH2O-1.kg-1; P = 0.002). There was an inverse linear relationship between age and mean Cw per kilogram (r = -0.495, slope -0.037; P < 0.001). In subjects with normal Cl during spontaneous breathing, Cw/spontaneous Cl was 2.86 +/- 1.06 in infants < 1 yr old and 1.33 +/- 0.36 in older children (P = 0.005). We conclude that in infancy the chest wall is nearly three times as compliant as the lung and that by the 2nd year of life chest wall stiffness increases to the point that the chest wall and lung are nearly equally compliant, as in adulthood. Stiffening of the chest wall may play a major role in developmental changes in respiratory system function such as the ability to passively maintain resting lung volume and improved ventilatory efficiency afforded by reduced rib cage distortion.

A comparison of preterm and adult airway smooth muscle mechanics.

To determine whether airway smooth muscle undergoes a maturational change regarding force generation, length-tension relationships were determined in isolated trachealis strips from adult and preterm sheep. At the length of maximum force generation, passive active and total tensions of the adult muscle were 2.5 times greater than preterm values (P less than 0.001). KCl stimulation yielded a greater peak tension in the adult strips than in the preterm strips (P less than 0.01). Preterm strips required higher concentrations of KCl to initiate contractions and higher concentrations to reach peak tension. Acetylcholine- (ACh) induced contraction resulted in greater force development at each dose in the adult strips compared with preterm strips (P less than 0.001). The dose of ACh required to reach a half-maximal response was significantly less for the adult strips than for the preterm strips (P less than 0.005). These data demonstrate that both force generation and receptor sensitivity increase with age. This inability of immature smooth muscle to generate as much force as adult smooth muscle may help explain why very preterm neonates requiring intermittent positive-pressure ventilation are at risk for developing structural airway problems.

Bronchiolitis in children.

Bronchiolitis is an acute inflammation of the airways. In infancy, it usually results from viral infection, with RSV the most common agent. The clinical syndrome is characterized by symptoms of lower respiratory tract infection and obstruction. In most patients, the duration of illness is 1 week, but bronchiolitis can cause serious morbidity in patients with pre-existing cardiopulmonary disease. In addition, patients may be left with serious sequelae, including PBAR and OB. RSV causes direct damage to airways, but an exaggerated host immune response may contribute to the pathogenesis of airway obstruction in bronchiolitis. The mainstays of therapy include oxygen supplementation and fluid resuscitation, and other modalities remain controversial. There are no studies to support the use of corticosteroids alone in the treatment of bronchiolitis, but several recent reports demonstrate the value of bronchodilator therapy in some patients. Antiviral agents such as ribavirin show great promise in a therapy for bronchiolitis. In addition, ribavirin may modify some aspects of the immune response during acute infection with RSV, and therefore may play a role in the prevention of long-term sequelae.

Nonbronchoscopic approach to bronchoalveolar lavage in children with artificial airways.

Bronchoalveolar lavage (BAL) performed with a fiberoptic bronchoscope (FOB) is a useful method for sampling alveolar contents. Since the smallest FOB with a channel has a diameter of 3.6 mm, BAL is difficult to accomplish through artificial airways (AA) less than 5.0 mm I.D. We used a 4F balloon wedge pressure catheter to perform BAL through small AA. Supplemental O2 or ventilatory support was delivered via an adaptor through which the catheter was introduced. After it was passed distal to the AA, the balloon was inflated with normal saline (NS) to a predetermined volume, and advanced until resistance was felt. The balloon was deflated, advanced slightly, and then reinflated to achieve airway occlusion. Five aliquots of 0.75 mL/kg of NS were used for BAL. The procedure was performed in 20 children from 1 month (950 g) to 6 1/2 years of age (median, 9 months). All specimens contained abundant alveolar macrophages, indicating good recovery of alveolar contents. Clinically significant information was obtained in 17 (85%) cases, and no patient required an open lung biopsy. In conclusion, nonbronchoscopic bronchoalveolar lavage is a valuable method for obtaining alveolar contents in children with small AA that preclude the use of an FOB, and it obviates the need for open lung biopsy in many patients. This technique could be used as a research tool for measuring constituents of alveolar contents in infants and small animals.

Effect of altering smooth muscle tone on maximal expiratory flows in patients with tracheomalacia.

We obtained maximal partial expiratory flow-volume (PEFV) curves using the rapid compression technique in three infants with intrathoracic tracheomalacia. Maximum flows were quantitated at functional residual capacity (VmaxFRC). Studies were performed at baseline, after inhalation of methacholine (MCh) and after inhalation of albuterol. At baseline, all three patients had significantly lower than normal VmaxFRC values, and two patients displayed expiratory flow limitation during tidal breathing. VmaxFRC improved significantly after MCh administration, but fell back toward or below baseline after albuterol. Additionally, the ratio of forced to tidal flows at mid-tidal volume (Vmid(forced/tidal), a reflection of expiratory flow reserve, increased after MCh administration and decreased after albuterol. Two patients also received oral bethanechol: 2.9 mg/M2, q 8 hr for 10 days, after which PEFV curves were repeated. Both Vmax FRC and Vmid(forced/tidal) were increased over baseline after bethanechol administration, but decreased after albuterol. These results suggest that in patients with abnormally collapsible tracheae, stimulation of tracheal smooth muscle can improve airway stability, thereby increasing forced expiratory flows. Additionally, relaxation of airway smooth muscle by bronchodilators can have the opposite effect and exacerbate obstruction.

Chiari type I malformation in children and adolescents with cystic fibrosis.

Chiari type I malformation is characterized by herniation of the cerebellar tonsils through the foramen magnum. An association between Chiari type I malformation and cystic fibrosis (CF) has not previously been established. We report on five children and adolescents with CF in whom Chiari type I malformations were diagnosed. Three patients were 17-18 years old at time of diagnosis, one was 3 years old, and one was 10 months of age. All patients were followed at the Cystic Fibrosis Center at St. Christopher's Hospital for Children and were diagnosed with the malformations between June 1988 and June 1997. Over this same period, 400 CF patients 18 years or younger were followed routinely. All patients had the diagnosis of Chiari type I confirmed by brain-stem MRI. Neurologic findings included swallowing dysfunction, syncopal episodes, numbness of extremities, recurrent vomiting, and headaches. No two patients had the same presenting neurologic findings. Our data suggest that Chiari type I malformation is more common in CF than in the general population. The possibility of Chiari type I malformation should be included in the differential diagnosis of unexplained neurologic complaints in patients with CF.

Maturational aspects of human airway smooth muscle function.

Maturational changes in the contractility and sensitivity of airway smooth muscle have been studied in an attempt to explain the increased incidence of asthma in children compared with adults. These changes are not uniform between species, however, and a clear relationship between in vitro muscle function and clinical disease does not yet exist. Over the last several years, investigators have used bronchoconstrictor challenge tests to assess airway reactivity in infants, with pulmonary functions reflecting drug effects. These tests represent changes in airway calibre, which may or may not result from differences in muscle sensitivity or contractility. Instead, the forces which oppose smooth muscle shortening, and which themselves undergo maturational change, may be responsible for the perceived heightened airway responsiveness of infants and young children. This paper reviews current knowledge regarding maturational changes in the properties of airway smooth muscle, and in the physiological forces which oppose smooth muscle shortening and airway narrowing.

Bronchiolitis in infants.

Bronchiolitis is a common cause of wheezing among infants. Respiratory syncytial virus (RSV) is the most common infectious agent to cause bronchiolitis, and RSV infection accounts for more than 125,000 hospitalizations per year in the United States. Beyond supportive measures, the care of infants with bronchiolitis remains controversial. Practitioners continue to treat infants with a variety of pharmacologic agents, despite limited evidence of their efficacy. Investigators continue to search for the safest and most cost-effective methods to treat infants with bronchiolitis, not only to overcome obstructive symptoms during the acute illness, but also to prevent recurrent symptoms of airway obstruction that occur in some children for years after their initial episode of bronchiolitis. Improved understanding of the pathogenesis of RSV infection and of virus-host interactions may one day lead to the development of agents that alter the initial inflammatory response and strategies that help prevent recurrent episodes of wheezing and the development of asthma after acute bronchiolitis.

Chest wall compliance in infants and children with neuromuscular disease.

Respiratory muscle weakness is the primary cause of respiratory dysfunction in neuromuscular disease (NMD), but structural abnormalities of the chest wall also play a role. In adults with NMD, restrictive lung disease is in part caused by reduced chest wall compliance (C(W)), believed to reflect stiffening of connective tissue resulting from chronically reduced chest wall motion in the presence of respiratory muscle weakness. We hypothesized that chronic limitation of chest wall motion in young children with NMD leads to structural underdevelopment of the chest wall, and results in increased, rather than decreased, C(W). In 18 subjects with NMD, ranging from 3 mo to 3.8 yr of age, we compared C(W) with values obtained in children without NMD. A modification of the Mead-Whittenberger technique was used, with respiratory muscle relaxation provided by brief manual ventilation. Respiratory system compliance (Crs) and lung compliance (C(L)) were calculated from airway opening pressure, transpulmonary pressure, and tidal volume. C(W) was calculated as 1/C(W) = 1/Crs - 1/C(L) during manual ventilation. C(W)/kg was higher in subjects with NMD than in controls, at 5.2 +/- 2.8 (mean +/- SD) versus 2.4 +/- 0.8 ml/cm H2O (p < 0.001). In subjects who had normal lung compliance values during spontaneous breathing (C(Lspont)), C(W)/C(Lspont) was significantly greater in subjects with NMD (5.5 +/- 3.2) than in controls (1.9 +/- 1.0) (p < 0.001). By predisposing to rib cage deformation and reduced end-expiratory lung volume, abnormally high C(W) in infants and young children with NMD may contribute to respiratory dysfunction.

Dissociation between the effects of theophylline and caffeine on premature airway smooth muscles.

Xanthine derivatives relax adult airway smooth muscle (ASM). To determine whether caffeine and theophylline relax preterm ASM contracted by acetylcholine, 27 tracheal rings obtained from seven preterm lambs (120-135 d gestation) were studied. ASM was contracted using 10(-5) M acetylcholine (control) after the muscle was stretched to the length at which maximum active tension was developed isometrically. Concentration-effect curves for each xanthine were obtained by cumulative addition of the drug. Theophylline produced a significant decrease (p less than 0.001) in active tension at each dose, whereas caffeine significantly increased (p less than 0.001) active tension at 10(-4) and 10(-3) M concentrations. Addition of caffeine and theophylline to previously uncontracted ASM did not alter tension. Thus, it appears that, in contrast to their effect on adult ASM, the xanthine derivatives caffeine and theophylline have differential effects on prestimulated ASM in preterm lambs. These findings raise important questions about various aspects of the current therapeutic use of caffeine and theophylline.

Effects of CPAP on lung mechanics in infants with acquired tracheobronchomalacia.

Continuous positive airway pressure (CPAP) has been used in the treatment of infants with tracheobronchomalacia (TBM). However, the effects of CPAP on lung mechanics in these infants are unknown. We hypothesized that CPAP prevents airway collapse and improves forced exhalation. We studied respiratory mechanics of nine infants (age 15 +/- 3 mo, SEM) with acquired TBM documented by bronchoscopy, during quiet respiration and forced exhalation, using the esophageal balloon and rapid thoracic compression techniques, respectively. Measurements were made when infants received no CPAP and repeated when 5 and 8 cm H2O CPAP were applied to the airway opening via a modified Mapleson anesthesia circuit. Expiratory resistance (RL), midexpiratory tidal flow (VE50), and maximal flow at functional residual capacity (Vmax FRC) were compared at each level of CPAP. Vmax FRC increased threefold from baseline to 8 cm H2O CPAP (p < 0.005). In contrast, there was no difference in expiratory RL or in VE50 at any level of CPAP. These data suggest that in infants with acquired TBM, assessments of forced expiratory flow reflect the amount of CPAP necessary to prevent airway collapse during forced exhalation better than can measurements of tidal mechanics.

Lipid aspiration pneumonia due to gastroesophageal reflux. A complication of nasogastric lipid feedings.

The development of lipid aspiration pneumonia after chronic nasopharyngeal installation of mineral oil was first described in 1925 by Laughlin. Since that time this entity has been well recognized and numerous substances have been identified or implicated as the aspirated material. The classic radiographic appearance of severe chronic lipid aspiration pneumonia has been described as consisting of intense perihilar infiltrates. However, the radiographic findings are more often non-specific and usually consist of varying degrees of diffuse interstitial infiltrates that tend to be more prominent in the perihilar regions and the right lung. We are reporting a case of biopsy-proven lipid aspiration pneumonia in an infant with known gastro-esophageal reflux (GER) who had medium-chain triglyceride oil administered via nasogastric tube. Serial roentgenograms demonstrated a changing pulmonary pattern from diffuse bilateral interstitial infiltrates initially to a diffuse alveolar pattern at the time of the lung biopsy. Modern medicine has developed new methods for providing nourishment to sick newborns and infants to improve their nutritional status and help them to grow. One such method involves the administration of medium-chain triglycerides (MCT oil) into the GI tract via a nasogastric or nasoenteral tube. The purpose of this report is to describe a significant complication of this method of providing nutrition to an infant with gastroesophageal reflux (GER) and the diagnostic dilemma it presented.

Quantitative bronchoscopic assessment of airway collapsibility in newborn lamb tracheae.

To date, quantitative studies of the inherent characteristics of the developing airway wall have required excision of an airway segment or surgical creation of an isolated segment. We hypothesized that airway wall characteristics, at various collapsing pressures, and attendant changes in stiffness after smooth muscle stimulation could be quantitated bronchoscopically from airway pressure-area relationships. Neonatal lamb tracheal segments (n = 12) were suspended over hollow mounts, in a buffer-filled chamber, and subjected to a range (0 to -4.0 kPa) of pressures to determine wall stiffness under collapsing forces before and after stimulation of the trachealis with methacholine. Luminal images were recorded through a 3.6-mm flexible bronchoscope under the same conditions, subsequently corrected for distortion, and a cross-sectional area was quantitated. Both pressure-volume and pressure-area relationships detected significant changes in airway wall stiffness after methacholine administration (p < 0.002), and the magnitude of change was similar between methods. These data suggest that quantitative flexible bronchoscopy can be used clinically in the intact airway to assess wall stiffness.

Purpuric rashes in cystic fibrosis.

Sixteen patients with cystic fibrosis experienced vasculitic rashes of the lower extremities that resembled hypergammaglobulinemic purpura. The rashes were associated with increased serum gammaglobulin G levels and rather severe lung disease. The rashes are probably the expression of chronic lung infection and high antigenic load in these patients. Their appearance was associated, in most cases, with poor long-term survival.