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American Journal of Respiratory and Critical Care Medicine Vol 171. pp. 545-553, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.2412007

Year in Review

Cystic Fibrosis, Pediatrics, Control of Breathing, Pulmonary Physiology and Anatomy, and Surfactant Biology in AJRCCM in 2004

Andrew Bush, Frank Accurso, William MacNee, Stephen C. Lazarus and Edward Abraham

Department of Pediatric Respiratory Medicine, Royal Brompton Hospital, London; MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, United Kingdom; The Children's Hospital, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado; Division of Pulmonary and Critical Care Medicine, University of California–San Francisco, San Francisco, California

Correspondence and requests for reprints should be addressed to Edward Abraham, M.D., University of Colorado Health Sciences Center, Division of Pulmonary Sciences and Critical Care Medicine, 4200 East 9th Avenue, Box C272, Room 5503, Denver, CO 80262-0001. E-mail: edward.abraham{at}uchsc.edu


   CONTROL OF BREATHING
TOP
 CONTROL OF BREATHING
CYSTIC FIBROSIS
 PEDIATRICS
 PULMONARY PHYSIOLOGY AND ANATOMY
 SURFACTANT BIOLOGY
 REFERENCES
 
Pathophysiologic Studies in Volunteers
Vassilakopoulos and colleagues (1) studied the phenomenon of cytokine release during strenuous resistive breathing. Anesthetized, tracheostomized, spontaneously breathing rats were subjected to 1, 3, or 6 hours of inspiratory resistive loading, corresponding to 45 to 50% of the maximum inspiratory pressure. The diaphragm and the gastrocnemius muscles were excised at the end of the loading period, and mRNA expression for cytokines was studied. Unloaded sham-operated rats breathing spontaneously were used as control animals. mRNA for interleukin 6 (IL-6) and IL-1ß and, to a lesser extent, tumor necrosis factor ß, IL-10, IFN-{gamma}, and IL-4 were significantly increased in a time-dependent fashion in the diaphragm, but not in the gastrocnemius muscle of loaded animals or in the diaphragm of control animals. The levels of IL-6 and IL-1ß protein in the diaphragm of loaded animals also were increased. Immune staining revealed IL-6 protein localized in diaphragmatic muscle fibers. The authors concluded that increased ventilatory muscle activity during resistive loading induces differential elevation of proinflammatory and antiinflammatory cytokine expression in the ventilatory muscles.

Control of Breathing in Clinical Disorders
To study the mechanisms involved in idiopathic hyperventilation, Jack and colleagues (2) assessed ventilatory response to isocapnic hypoxia, hyperoxic hypercapnia, and exercise. Thirty-nine patients with idiopathic hyperventilation and 23 control subjects were studied. All the patients showed hyperventilation at rest with hypocapnia. Hyperventilation was sustained during exercise despite hyperoxic-hypercapnic ventilatory responses being normal and isocapnic-hypoxic ventilatory responses being low relative to controls. Breath-hold tolerance was also studied and was attenuated. Dyspnea during exercise was significantly greater in patients than in control subjects and was not simply caused by the high ventilation. These studies suggest that patients with idiopathic hyperventilation have a sustained hyperventilatory and dyspneic drive, which, although not caused by central chemosensitivity, may have peripheral chemoreflex contributions. The nature of this chronic hyperventilatory drive remains unclear.


   CYSTIC FIBROSIS
TOP
 CONTROL OF BREATHING
 CYSTIC FIBROSIS
PEDIATRICS
 PULMONARY PHYSIOLOGY AND ANATOMY
 SURFACTANT BIOLOGY
 REFERENCES
 
Genetics
Airway inflammation in cystic fibrosis (CF) is intense and sustained, in part because of high levels of IL-8, a potent neutrophil chemoattractant. Secretory component, the polymeric immunoglobulin receptor produced by airway cells, plays an important role in host defense and regulation of inflammation in normal airways, but has not been fully characterized in CF. Marshall and colleagues (3) examined secretory component in sputum from individuals with CF, individuals with asthma, and normal control subjects. They found that secretory component levels were increased in CF; however, much of the protein was degraded, and its ability to bind IL-8 was decreased. Failure of secretory component to bind IL-8 could contribute to sustained airway inflammation. In addition, the authors reported on the carbohydrate content of secretory component because glycosylation abnormalities have been reported in CF in other settings. They found that secretory component reflected known glycosylation defects in CF, including overfucosylation and undersialyation.

Mutations in the CF transmembrane conductance regulator (CFTR) are common in men with congenital bilateral absence of the vas deferens (CBAVD), and it has been suggested that this syndrome represents a mild form of CF. Gilljam and colleagues (4) hypothesized that men with CBAVD also have subclinical pulmonary disease. Bronchoscopy with bronchoalveolar lavage (BAL), viral and quantitative bacterial cultures, and analyses of total and differential cell count, cytokines, and free neutrophil elastase were performed in eight men with CBAVD, who had mutations in the CFTR and intermediate or elevated sweat chloride levels, and in four healthy control subjects. There was light growth of Staphylococcus aureus in one of eight men with CBAVD, and small numbers of opportunistic gram-negative bacteria in six of eight men with CBAVD and in one control subject. BAL cell counts and neutrophil elastase were within the normal range. IL-8 and tumor necrosis factor {alpha} levels were higher for men with CBAVD than for control subjects. These data suggest that mutations in the CFTR in men with CBAVD, in addition to causing infertility, lead to subclinical bacterial pulmonary infection and inflammation consistent with mild CF.

Lung Inflammation
Burkholderia infection in CF is associated with poor outcome. To investigate mechanisms of Burkholderia-induced inflammation, De Soyza and colleagues (5) examined cytokine response in a monocytic cell line. They characterized the lipid A component of Burkholderia LPS through mass spectroscopy and were able to detect a biochemical difference that was associated with differing cytokine response. These studies provide further insight into Burkholderia-related inflammation in CF.

Induction of heme oxygenase-1 is believed to play a role in protection against oxidant injury as likely occurs in the CF airway. Zhou and colleagues (6) found that heme oxygenase expression was increased in CF lung samples compared with controls and also was correlated with myeloperoxidase levels, a measure of airway inflammation. They further examined response to Pseudomonas aeruginosa–induced injury/apoptosis in a CF cell line capable of overexpression of heme oxygenase-1. They found that cells overexpressing heme oxygenase-1 had decreased injury/apoptosis, suggesting that augmentation of heme oxygenase-1 may be of therapeutic benefit in CF.

Abnormalities in surfactant composition and function have been described in CF but are incompletely characterized. Using BAL samples from 76 patients with normal lung function participating in the European study by the Bronchoalveolar Lavage for the Evaluation of Anti-inflammatory Treatment (BEAT) Study Group in CF, Griese and coworkers (7) examined surfactant protein levels and function. They found that surfactant protein A levels were markedly decreased in CF. They also found through in vitro experiments that the function of surfactant relating to maintaining patency of small airways was decreased. The degree of neutrophil inflammation and infection in BAL samples could be related to the concentration of surfactant protein D levels. This study demonstrates alterations in surfactant composition and function that could be therapeutic targets in CF.

Controversy exists as to whether there are endogenous pathways to exaggerated inflammation in CF. Becker and coworkers (8) examined CF and non-CF passage 2 human tracheobronchial epithelial cells cultured physiologically. They found no difference in constitutive production of proinflammatory cytokines (IL-1ß, IL-8, IL-6) or nuclear factor–{kappa}B activation. They did find that the CF cells produced more IL-8 in response to stimuli, including tumor necrosis factor {alpha}, Toll-like receptor 2 activation, or filtrate from S. aureus culture. The authors concluded that exaggerated responses may develop under certain conditions, but their results do not support an intrinsically hyperinflammatory phenotype in CF epithelial cells.

To determine if oxidative stress in CF is an important feature early in the disease, Kettle and coworkers (9) investigated a group of infants and young children with CF to establish whether oxidants are produced in their airways. BAL fluid was assayed for myeloperoxidase as a measure of neutrophilic inflammation and 3-chlorotyrosine as a biomarker of the potent oxidant hypochlorous acid, which is formed by myeloperoxidase. Protein carbonyls were also measured as a nonspecific indicator of reactive oxidant production. Myeloperoxidase and 3-chlorotyrosine levels in BAL fluid from children with CF were 10- and 5-fold higher, respectively, than in disease control subjects. There was a strong correlation between myeloperoxidase and 3-chlorotyrosine. Myeloperoxidase levels were fourfold higher in children with infections in their airways. Median protein carbonyls were elevated by only twofold compared with disease control subjects, but some children had extremely high levels of protein oxidation. The authors concluded that hypochlorous acid is produced early in CF and that it is a candidate for precipitating the fatal decline in lung function associated with this disease. Also, there must be other sources of oxidants because protein carbonyls were not related to either inflammation or infection.

Microbiology
Aaron and coworkers (10) sought to determine whether pulmonary exacerbations in adults with CF were associated with acquisition of a new strain of P. aeruginosa. They performed pulsed-field gel electrophoresis on Pseudomonas isolates from 36 patients. Thirty-four of 36 isolates were the same as previously identified during clinical stability. Two new isolates were found. The authors concluded that most pulmonary exacerbations in adults are not associated with new Pseudomonas isolates.

Pathophysiology and Exercise Performance
To determine new directions in CF research, the National Heart Lung and Blood Institute and the Office of Rare Diseases held a conference focusing on the role of other proteins and processes that could impact CF transmembrane regulator (CFTR) (11).

Goss and colleagues (12) determined the association between pollutants and the occurrence of pulmonary exacerbation and decline in lung function in CF. They used pulmonary function data from the Cystic Fibrosis Foundation National Patient Registry in patients older than 6 years and pollution data from the Aerometric Information Retrieval System linked by the patient's home zip code. Increases in particulate matter were associated with an increase in pulmonary exacerbation rate (8%, 95% confidence interval [CI]: 2–15%) and an accelerated decline in lung function. There was no difference in mortality rate. The authors suggested that environmental exposures may play a role in prognosis in CF in view of the association between particulate air pollution and decline in lung function and pulmonary exacerbation rate.

Description of lung function in infants with CF is important in determining the need for early treatment as well as for providing clues to early pathophysiology. Tepper and coworkers (13) examined the elastic properties of the respiratory system in 10 infants with CF and 34 control infants using the raised lung volume technique. This technique has several advantages over previously used techniques, including measurement of expiratory pressures and the use of increased lung volume rather than tidal range. Although infants with CF had lower flows, there was no difference in compliance. Thus, elastic properties of the respiratory system are normal in CF, further supporting the notion that the airway is the primary site of disease in early CF.

Ranganathan and colleagues (14) examined lung function on two occasions in 34 infants with CF after diagnosis and in 32 healthy subjects. They used the raised lung volume technique and also compared results to published norms after adjusting for age, length, sex, and exposure to maternal smoking. They found decreased FEV at 0.5 seconds, a measure of flow, in the patients with CF at diagnosis. Furthermore, the decrease in flow rates in the infants with CF became worse over time when compared with control infants. This study provides the strongest evidence thus far that airway function is diminished at diagnosis in CF and continues to be abnormal 6 months after diagnosis.

Nielsen and coworkers (15) performed a 4-year prospective, serial study of lung function in 30 children with CF between the ages of 2 and 8 years. They found in children with CF that specific airway resistance by whole body plethysmography was 2.5 SDs below the mean for control subjects. Neither respiratory resistance by the interrupter technique nor respiratory resistance and reactance by impulse oscillation detected differences between children with CF and control children. Response to bronchodilators and cold air was not different between children with CF and control subjects. This study demonstrates that determination of specific airway resistance by whole body plethysmography is the most sensitive technique for demonstrating lung function abnormalities in young children with CF. In addition, this study confirms that there is marked airway involvement in young children with CF.

Oxidant injury likely plays a role in CF airways disease. In addition, glutathione, an important antioxidant, is decreased in BAL fluid from patients with CF, suggesting potential as a treatment. Griese and colleagues (16) demonstrated excellent intrathoracic delivery (86%) of radiolabeled glutathione using an AKITA inhalation device (Inamed, Gauting, Germany) and Pari LC Star nebulizer (Allergy Asthma Technology, Morton Grove, IL) in six patients. In addition, BAL glutathione levels remained increased after a single inhalation treatment of glutathione for up to 12 hours. The authors then examined the effects of 2 weeks of open-label treatment thrice daily with 300 or 400 mg of glutathione. FEV1 improved by roughly 5%. However, lavage content of oxidized proteins and lipids did not change. The authors concluded that glutathione treatment of the lower airway is feasible; however, the observation of no change in oxidized proteins and lipids indicates that other antioxidant treatment strategies may be necessary. The improvement in lung function by itself points to the need for further studies of inhaled antioxidants in CF.

Bone Demineralization and Metabolic Disorders
Patients with CF often develop low bone density. Aris and coworkers (17) performed a double-blind trial of alendronate, an antiresorptive agent, in CF. Adults with CF were randomized to 1 year of alendronate (n = 24) or placebo (n = 24). Both groups received cholecalciferol and calcium carbonate oral supplementation. The alendronate-treated patients improved spine and femur bone density significantly by 4.9 ± 3.0% and 2.8% ± 3.2%, respectively, whereas the placebo group lost bone density significantly by 1.8 ± 4.0% and 0.7% ± 4.7%, respectively. Another bone resorption marker, N-teleopeptide, declined in the treatment group more than in the control group, further suggesting decreased resorption with alendronate. The authors concluded that alendronate was more effective than placebo in improving spine and femur bone mineral density and holds promise as a long-term treatment for bone disease in CF.

Treatment
Mucolytic agents.
Treatment with dornase improves lung function and decreases pulmonary exacerbations in patients with CF over a 6-month period, but longer term effects have received little attention. This is a concern, particularly in terms of airway inflammation, because dornase alfa in vitro increases elastase activity in sputum. Paul and coworkers (18) used the BEAT study to examine BAL levels of elastase activity and IL-8 levels in patients with CF randomized to treatment as well as a group of patients with CF who had normal BAL neutrophil counts. At the end of 3 years, patients treated with dornase alfa had no change in elastase or IL-8 levels, whereas patients in the control groups had increases in both. The authors concluded that treatment with dornase alfa positively influences the increase in neutrophilic airway inflammation that is characteristic with CF.


   PEDIATRICS
TOP
 CONTROL OF BREATHING
 CYSTIC FIBROSIS
 PEDIATRICS
PULMONARY PHYSIOLOGY AND ANATOMY
 SURFACTANT BIOLOGY
 REFERENCES
 
Pulmonary Function Testing and Diagnostic Techniques
Normative values.
Although lung function testing in infancy and later childhood has a long pedigree, the toddler age (2–5 years) has not been well explored because the child is too old to sedate and too young to offer much in the way of cooperation. In particular, spirometry has been seen as being impractical much below the age of 5 years. The American Thoracic Society standards of acceptability for older children and adults are not appropriate given the considerable physiologic differences in the young lung—for example, the greater rapidity of emptying. Aurora and coworkers (19) attempt to set standards for this age group. Forty-two children with CF and 37 normal children were studied. Acceptable results were obtained in nearly two thirds of the children aged 2 to less than 4 years old. The following five quality control recommendations were made:

  1. All curves must be visually inspected to check for quality.
  2. Curves with volume of back extraction of more than 80 ml or more than 12.5% of FEV should be inspected critically, but not automatically rejected.
  3. FEV in time t (FEVt) should only be reported if total expiratory time is greater than t.
  4. In all preschool children, FEV1, FEV0.75, and FEV0.5 should be reported.
  5. Repeatability of 100 ml (FVC) and 10% of best effort (FEVt) may be more appropriate than adult criteria.

It is suggested that these criteria of acceptable quality should be applied to future studies of spirometry in this age group.

Exhaled nitric oxide.
Highlighting the complex relationships between environmental influences on the developing airway, Frey and coworkers (20) reported on exhaled nitric oxide in 98 babies, measured as the time-based third quartile during tidal breathing while in quiet sleep, 23 to 58 days after birth. A total of 35 of 98 mothers had a self-reported history of atopic disease. Exhaled nitric oxide was significantly higher in males than females, and in infants exposed to postnatal maternal smoking. Maternal atopic disease per se had no effect on exhaled nitric oxide. Prenatal smoke exposure resulted in a higher exhaled nitric oxide level in the infants of mothers with asthma, but a lower value in those of mothers without asthma. Maternal coffee consumption in pregnancy resulted in a lower exhaled nitric oxide level. Paternal atopy had no effect. The sample size was too small for other genetic influences, such as glutathione-S-transferase phenotype, which is well known to modulate the effect of maternal smoking in pregnancy on infant lung function to be evaluated. The function of nitric oxide in this age group, and the significance of these results, is not clear at the moment, and long-term follow-up may clarify some of these issues.

Respiratory muscles and mechanics.
The American Thoracic Society (21) published a paper on the respiratory care of patients with Duchenne muscular dystrophy and recent advances in treatment.

Mechanical Ventilation
In preterm infants receiving supplemental oxygen, manual control of the inspired oxygen fraction is often time-consuming and inappropriate. Urschitz and coworkers (22) developed a system for automatic oxygen control and hypothesized that this system is more effective than routine manual oxygen control in maintaining target arterial oxygen saturation levels. A randomized, controlled, crossover clinical trial in 12 preterm infants receiving nasal continuous positive airway pressure (CPAP) and supplemental oxygen was performed. Periods with automatic and routine manual oxygen control were compared with periods of optimal control by a fully dedicated person. The median (range) percentage of time with arterial oxygen saturation levels within target range (87–96%) was 81.7% (39.0–99.8%) for routine manual oxygen control, 91.0% (41.4–99.3%) for optimal control, and 90.5% (59.0–99.4%) for automatic control (analysis of variance: p = 0.01). The authors suggested that automatic oxygen control may optimize oxygen administration to preterm infants receiving nasal CPAP and reduce nursing time spent with oxygen control.

Pediatric Asthma
Genetics.
A number of observations have linked a high prevalence of early infections with a reduced risk of later asthma. Early use of a daycare facility is associated with a high rate of viral infections, and more early-wheezing illness, but a reduced prevalence of later wheeze. To examine early events in immune development, Guerra and colleagues (23) performed a prospective cohort study (n = 238 infants) on the interactions between wheezing in the first year of life, IFN-{gamma} production to concanavalin A, and the plasma levels of CD14, a molecule pivotal to endotoxin recognition by the innate immune system. Blood was obtained at birth and at 3 months of age. The odds ratio for developing recurrent but not infrequent wheeze was 4.5 times higher in the lowest quartile of IFN-{gamma} production when measured at 3 months of age, and 3.2 times for the lowest quartile of soluble CD14 levels when measured at birth, and the effects appeared to be additive. Low levels of IFN-{gamma} production at birth were irrelevant to wheeze development or phenotype, and levels increased over the first 3 months of age.

Epidemiology.
The interrupter technique is a deceptively simple means of measuring preschool lung function. Brussee and coworkers (24) used this technique in their cohort of 838 children at age 4 years, and correlated the results with wheezing phenotype. Independent of maternal atopic status, children with persistent wheeze, but not those in the early-transient or never-wheezed groups, had a raised airway resistance. As is almost inevitable in a study like this, there is the possibility of selection bias, in that children who used medication within 12 hours of the measurements were omitted rather than being restudied, and fewer children whose mothers were of lower educational status were brought up for study. The normal values in the early-transient wheeze group are different from the finding of reduced function in this group in the Tucson study, and may reflect the fact that the interrupter technique is possibly largely measuring proximal airway function. The findings with persistent wheeze underscore the need for effective and very early intervention in this phenotype if long-term airflow obstruction is to be averted. As stated by the authors, the real significance of the measurements will become apparent by age 8 years, when it will be clear which of the children have developed true atopic asthma. It is unlikely that this technique will have sufficient predictive value to be useful in individual children, but this cohort will continue to give useful information on the evolution of childhood wheezing illnesses.

The challenge of pediatric asthma management is not merely to prevent symptoms, but to ensure normal lung and somatic growth. Covar and colleagues (25) highlighted the factors predictive of a decline in postbronchodilator FEV1 in patients from the Childhood Asthma Management Program. Of the total cohort with at least four measurements, 25.7%, or 990 children, had a progressive decline, predefined as a negative slope of more than 1%/year. Interestingly, treatment group (budesonide, nedocromil, placebo) had no effect. The rapid decliners started from a higher baseline, raising the possibility that some of the effect seen might merely be regression to the mean. However, predictors included younger age at asthma diagnosis, younger age at enrollment, and male sex. In the one center in which this was measured, markers of airway inflammation did not predict a more rapid decline. The authors concluded that the investigation of pathophysiologic mechanisms, immunologic processes, and genetic markers of airway remodeling should be considered in identifying mechanisms and risk factors for altered lung growth.

Longitudinal studies have taught us much about wheezing phenotypes in infancy; as the cohort subjects reach adolescence, new information about later phenotypes is anticipated. Popular belief is that asthma remits around puberty. However, Guerra and coworkers (26) reported that 97 of 166 (58%) of children with asthma before puberty continued to report symptoms after puberty (asthma defined as either frequent wheezing or a physician diagnosis plus any wheezing). Of those with infrequent wheeze before puberty, 39 of 131 (30%) reported wheeze after puberty. Factors predictive of frequent wheeze persisting beyond puberty included early onset of puberty, obesity, active sinusitis, and skin-test sensitivity to Alternaria, but not other allergens. Prepubertal bronchial responsiveness was a risk factor for persistence of wheeze. There was a dose effect; the more frequent the wheeze before puberty, the more likely it was to persist afterwards. The role of obesity in asthma is the subject of debate; as stated, this study cannot determine whether severe asthma caused obesity by interfering with exercise capacity or resulted from obesity in some way. Obesity is associated with early puberty, but they remained independent risk factors after statistical adjustment.

O'Donnell and coworkers (27) studied the complexities of genetic influence on clinical phenotype for asthma and atopy. Helper T-cell type 2 (TH2) T-lymphocyte responses predominate in infancy, and normally there is a switch to a TH1 phenotype. Failure of this switch may result in the development of atopic disease. One factor believed to be important in this switch is LPS, signaling through the CD14 receptor. The authors studied polymorphisms in the CD14 promotor region, which have previously been associated with IgE levels and skin-prick positivity in cross-sectional studies in other populations. The –159TT allele is associated with greater CD14 expression, higher soluble CD14, and lower serum IgE. In the present study, 305 individuals were assessed at least four times by questionnaire, skin-prick test, and histamine challenge, between ages 8 and 25, and also gave permission for the genetic studies. They were classified as early, late, or never wheezing, atopic, or with airway hyperreactivity. In comparison with subjects with the –159CT and –159TT polymorphisms, subjects with –159CC had an odds ratio of 2.2 for early-onset atopy and 2.6 for early-onset airway hyperresponsiveness. By adult life, these effects had disappeared. The study is of importance for two reasons. First, it provides further evidence for the importance of LPS in T-lymphocyte phenotype switching and suggests a possible mechanism. Second, and of more general importance, it highlights the need to consider age as a factor when looking for important polymorphisms. It is always tempting to lump subjects of all ages together to increase the power of a study, but this work highlights that important effects may be missed. Age effects must be added to the mix of environmental factors and other modifier genes in assessing potential genetic influences on pathophysiologic mechanisms.

The lack of a true diagnostic gold standard makes it difficult to determine which tests are useful in excluding or diagnosing asthma in a community setting. Joseph-Bowen and colleagues (28) contributed to the debate as to the role of airway hyperresponsiveness measurements. The authors took a history, undertook a physical examination, and measured spirometry in more than 2,000 6-year-old children. A subset of 537 successfully underwent a methacholine challenge. The results showed higher FEV1 and FVC for males, even when corrected for body habitus. This provides important normal data for children, albeit in a very narrow age range. Asthma was diagnosed in any child with a physician-given diagnosis and who had symptoms and used asthma therapy within the last 12 months. With regard to airway hyperresponsiveness, the best sensitivity and specificity for a diagnosis of asthma was a concentration of 1.8 mg/ml methacholine causing a 15% fall in FEV1. The authors commented that a 10% change is so close to the limits of reproducibility as to be not useful in this population. The conclusions from this work are that measurements of methacholine sensitivity are feasible and safe even in quite young children and that a negative challenge militates against a diagnosis of asthma, although it does not allow the complete exclusion of that diagnosis. Methacholine challenge is not the gold-standard tool for the assessment of an individual as opposed to a population in this age group (nor in any other) and should merely form part of the global assessment as to whether the child has asthma.

In an occasional essay, Spahn and colleagues (29) debated how best to define asthma severity in children.

Risk factors: aeroallergens.
The link between allergen exposure and asthma is not well understood. Polk and colleagues (30) used a multicenter prospective birth cohort, the Asthma Multicenter Infants Cohort Study, to examine the relationship between exposure to common domestic aeroallergens, such as cat allergen (Fel d1) and house dust mite (Der p1), and wheezing in early childhood. Exposure was estimated by analyzing dust samples obtained at children's homes in their first year of life. Families provided complete outcome data for 1,289 children. House dust mite did not impact incidence of wheeze at any age in this cohort. However, a high level of domestic cat allergen in early life appeared to protect against early wheeze, while increasing the risk of wheeze in 3- and 4-year-olds, a risk magnified if the child's mother had asthma. The authors concluded that several patterns of wheezing with different risk profiles exist among young children and that the effect of Fel d1 exposure varies according to age and maternal asthma.

Airway inflammation.
Turner and coworkers (31) aimed to determine whether impaired lung function, measured as maxFRC using the rapid thoracoabdominal technique, still exerted an effect on wheeze at age 11. The children's symptoms were assessed by questionnaire, and skin-prick test reactivity and airway responsiveness to histamine were determined at age 11. A total of 185 of the original 243 in the cohort were studied. Recent wheeze (i.e., any wheeze in the past year) at age 11 was associated with a reduced maxFRC Z-score in infancy. Persistent wheeze (i.e., present at age 4–6 years, still present at age 11) was most present in those with reduced maxFRC at 1 month and either atopy or airway reactivity at age 11. Considering all factors, reduced maxFRC and airway reactivity at 11 years were independently associated with persistent wheeze. This important study clearly demonstrates that, despite the increasing exposure to potential adverse environmental effects, intrauterine effects are still important at age 11. Reduced maxFRC in infancy is associated with reduction in a crude index of small airway function at age 11, namely, mean forced expiratory flow during the middle half of the FVC. This study would suggest that persistence of wheeze requires both a decrement in infant airway function and the later development of airway reactivity associated with atopy. This may explain why not all infant wheezers have persistent symptoms, and why not all atopic children develop asthma. The mechanisms for the "second hit" of the development of airway responsiveness and subsequent asthma require further elucidation.

Treatment.
Influenza immunization is a topical subject, given the current crisis precipitated by the difficulty of obtaining supplies of the vaccine. Most guidelines recommend that all children with asthma, irrespective of severity, should be offered annual immunization. However, the evidence base for this is far from stellar. Bueving and coworkers (32) studied nearly 700 children who were randomized to placebo or influenza immunization. Nearly 90% were using some form of prophylactic medication. There was no effect on the number of exacerbations in which influenza A was isolated from a pharyngeal swab, nor was there any effect on the severity of asthma exacerbations related to influenza isolation. Despite a power calculation suggesting that 300 children in each limb would be adequate, the confidence intervals were fairly wide in both cases (a 30% reduction in positive swabs and a 6-day shortening of exacerbation time by immunization could not be excluded). The children studied were recruited from primary care, so this study cannot exclude the possibility that children with more severe asthma, followed up in hospital clinics, may not benefit from influenza immunization (less than half of the study group had ever been treated by an asthma specialist). What the study does show quite clearly is that the policy of mass and indiscriminate immunization for all children with asthma should be reconsidered, both on the grounds of low prevalence (only 44 positive swabs) and the lack of any obvious effect on exacerbation duration.

Current guidelines for asthma care categorize asthma severity based on the frequency of asthma symptoms, medication use, and lung function measures. To determine whether lung function measures are consistent with levels of asthma severity as defined by the National Asthma Education and Prevention Program/Expert Panel Report 2 guidelines, Bacharier and coworkers (33) had the parents of children with asthma aged 5 to 18 years seen in two outpatient subspecialty clinics complete questionnaires regarding asthma medication use and symptom frequency over the preceding 1 and 4 weeks, respectively. All children performed spirometry. When asthma severity was based on the higher severity of asthma symptom frequency or medication use, asthma was mild intermittent in 6.9% of participants, mild persistent in 27.9%, moderate persistent in 22.4%, and severe persistent in 42.9% of children. FEV1/FVC decreased as asthma severity increased (p < 0.0001) and was abnormal in 33% of the participants, and a greater percentage of participants had an abnormal FEV1/FVC as asthma severity increased (p = 0.0001). In children, asthma severity classified by symptom frequency and medication usage does not correlate with FEV1 categories defined by National Asthma Education and Prevention Program guidelines. FEV1 is generally normal, even in severe persistent childhood asthma, whereas FEV1/FVC declines as asthma severity increases.

In an open-randomized, parallel-group, controlled trial, Wensley and Silverman (34) studied children aged 7 to 14 years with moderate asthma to determine whether the additions of PEF recordings to a symptom-based, self-management plan improved outcome. After a 4-week run-in, 90 children were randomized to receive either PEF plus symptom-based management or symptom-based management alone for 12 weeks. Thresholds for action based on PEF were 70% of best (for increasing inhaled steroids) and 50% of best (for commencing prednisolone). Children were asked to perform twice-daily spirometry at home (using an electronic recording spirometer that revealed only PEF to the study group alone) and to record a symptom diary. The mean daily symptom score was the main outcome. There were no differences between groups in mean symptom score or in spirometric lung function, PEF, quality of life score, or reported use of health services over 12 weeks. During acute episodes, children responded to changes in symptoms by increasing their inhaled steroids at a mean value of PEF of greater than 70% of best so that overall PEF did not contribute to this important self-management decision. The authors concluded that knowledge of PEF did not enhance self-management, even during acute exacerbations.

Other Pediatric Issues
Air pollution.
Woodcock and coworkers (35) investigated whether environmental control during pregnancy and early life affects sensitization and lung function at the age of 3 years. High-risk children (n = 251) were prenatally randomized to stringent environmental control (active) or no intervention (control). Questionnaires, skin testing, IgE, and specific airway resistance (sRaw) measurement were completed at the age of 3 years. Children in the active group were significantly more frequently sensitized compared with control subjects (at least one allergen by skin tests—risk ratio: 1.61; 95% CI: 1.02–2.55; p = 0.04; mite by IgE—risk ratio: 2.85; 95% CI: 1.02–7.97; p = 0.05). However, sRaw was significantly better in the active group (kPa/second, geometric mean [95% CI]: 1.05 [1.01–1.10] vs. 1.19 [1.13–1.25], p < 0.0001, active vs. control). Maximal flow at functional residual capacity was measured using rapid thoracic compression at the age of 4 weeks in a subgroup. Prospective lung function data (at infancy and 3 years) were obtained in 32 children (14 active and 18 control). There was no difference in infant lung function between the groups, but at 3 years, sRaw was significantly lower in the active compared with control children (p = 0.003).

Passive smoking.
Sudden infant death syndrome is the nightmare of every parent, and the connection with maternal cigarette smoking is well known. To examine the effects of maternal smoking on apnea and arousal, Sawnani and colleagues (36) performed polysomnographic studies in preterm infants. Sixteen infants of smoking mothers and 14 control infants underwent detailed polysomnography over a single night, scored independently by two blinded observers. Mean gestational age was younger than 30 weeks for both groups. The infants spent a mean of just over 8 weeks in the neonatal intensive care unit. Maternal smoking history was from a questionnaire, which might lead to smokers being included in the control group, lessening the power of the study and thus making it more likely that significant findings are real. Prenatal smoke exposure led to a more than doubling of the apnea index in active sleep, with a 2.5-fold increase in obstructive events. There was a 25% reduction in arousal index in the babies exposed to smoke prenatally, and specifically, there were only a third of the arousals after apneic events, suggesting a worrying increase in arousal threshold. The authors suggested that this combination of increased likelihood of obstructive apnea and reduced response may underlie the increased risk of sudden infant death in those born preterm to smoking mothers.

Hoo and colleagues (37) compared lung growth and development during the first year of life in healthy term infants of low or appropriate birth weight for gestation. Paired measurements of FEV in 0.4 second, FVC, and forced expiratory flow when 75% of FVC has been exhaled were obtained, using the raised volume technique, at approximately 7 weeks and 9 months of age in 80 infants (32 low and 48 appropriate birth weight for gestation) of white, nonsmoking mothers. Forced flows and volumes increased with growth. After adjustment for sex, age, and length, FEV was significantly reduced by an average (95% CI) of 9% (2–16%) in low birth weight compared with appropriate birth weight for gestation infants throughout the first year of life, with a similar trend in forced expiratory flow (8% [–2–17%]) and FVC (4% [–3–11%]). These findings suggest that lung function is reduced in low birth weight for gestation infants born to nonsmoking, white mothers and that this is independent of somatic growth during infancy.

Lung development.
The treatment of extreme preterm infants has been one of the success stories of the past decades, but it is still a race to see if the babies can mature their lungs and grow quickly enough before the lungs are irretrievably damaged by the very treatments that have preserved life in the acute situation. Thomson and coworkers (38) hypothesized that early use of nasal CPAP combined with prophylactic surfactant therapy would permit continuation of lung development. Baboons were delivered by caesarean section at 125 days (normal gestation, 185 days), given surfactant, and caffeine, and then weaned from low-volume conventional ventilation to nasal CPAP attempted at 24 hours. Lung histology at 28 days was compared with that of normal-term baboons and 125-day gestation controls. The nasal CPAP–treated baboons had virtually identical lung histology to that of term animals. This study supports the view that arrest of alveolar development is not an inevitable consequence of preterm birth, and that normal lung development can be preserved, at least in the short term, by a gentle ventilation strategy. The hypothesis that this would result in the normal alveolar growth in numbers over 2 years in humans is unproven, but attractive. Furthermore, any neurodevelopmental consequences of the nasal CPAP strategy were not evaluated in this article. Nonetheless, this elegant work strongly supports the continued use of the nasal CPAP strategy in the neonatal intensive care unit.

Oxygen is toxic in high concentrations, and particularly to the developing lung. Superoxide dismutase (SOD) is one of the major body antioxidant defenses, and SOD3 (extracellular SOD) is the only known defense against the free radical O2–. SOD3 is well known to be protective in adult rats against the damaging effects of hyperoxia, and is developmentally regulated. Mamo and colleagues (39) tested the hypothesis that hyperoxia disrupts this regulation. Newborn rats were exposed for 1 week to 95% oxygen and then sacrificed to determine SOD3 gene and protein expression and activity. The results demonstrated that SOD3 protein measured by immunohistochemistry doubled with exposure to hyperoxia, but enzymatic activity did not change. SOD3 mRNA expression also did not change. Whether the increase in protein was related to increased mRNA stability, translation, or protein stability was not investigated. Whole lung SOD3 enzymatic activity was unchanged despite the increased protein, and further examination revealed the protein to be strongly nitrated. Thus, the increase in SOD3 seen in neonatal rats was not protective against hyperoxic damage.

In a multicenter, randomized, controlled study, Thomas and coworkers (40) examined the early use of high-frequency oscillation ventilation in very preterm infants. Seventy-six infants from 12 trial centers were recruited for pulmonary function testing at a single center. Each underwent lung function to see if high-frequency oscillation ventilation protected against subsequent airflow obstruction. They were sedated with chloralhydrate and underwent measurements of tidal volume indices, body plethysmography (functional residual capacity, airway resistance), and helium dilution functional residual capacity. There was no difference between the baseline characteristics of the two groups, and no significant difference in any of the lung function parameters measured. There are a number of limitations that need to be considered before it is concluded that high-frequency oscillation ventilation offers no advantage. First, the sample size unavoidably fell below the level the authors had ideally wished to study from their power calculation. Second, more sophisticated measurements of airway function, such as the raised-volume rapid thoracoabdominal technique, may be a more sensitive measure of airway function. Third, indices of gas mixing, such as inert gas washout techniques, may have detected differences in small airway function. Finally, the authors were not able to make any measurement of alveolar-capillary bed size—for example, by using carbon monoxide transfer—and there is considerable pathologic evidence of alveolar-capillary hypoplasia in severe chronic lung disease of prematurity. The authors continue to follow up this cohort, and future results will be eagerly awaited.

Lung maturation has been shown to be delayed in male fetuses compared with female fetuses. This finding is attributed to higher levels of androgens in the male lung. Provost and coworkers (41) studied androgen synthesis by human epithelial type II–like cells (A549 cells) and human lung fibroblasts. Studies showed that 17ß-hydroxysteroid dehydrogenase (17ß-HSD) type 2 and type 5 genes are upregulated with the emergence of mature epithelial cells in both male and female developing lungs of the mouse. In contrast, the androgen receptor gene is expressed equally in both sexes with no temporal regulation. The authors concluded that the expression profile of the 17ß-HSD type 5 gene does not explain the higher levels of androgens in the male fetal lung, but that androgen synthesis must be a normal feature of mature pulmonary epithelial cells in both sexes. The authors suggested a role for androgens in cell reprogramming.

The American Thoracic Society (42) published an article summarizing relevant recent advances, with the objectives of promoting an integrative understanding of the potential for postnatal lung growth and providing an update on the mechanisms and functional limits of induced lung growth.

Recent evidence suggests that impaired lung development is linked with diminished lung function and an increased risk of chronic obstructive airway disease in adulthood. To examine environmental influences on early lung development, Lucas and coworkers (43) measured lung function in 131 normal-term infants aged 5 to 14 weeks. Adjusting for age at measurement, FEV at 0.4 seconds fell by 4.4% for each SD decrease in birth weight (p = 0.047). When adjusted for FVC, FEV at 0.4 seconds was not related to birth weight, but fell by 3.2% per SD increase in infant weight gain (p = 0.001). Age- and sex-adjusted total respiratory system compliance fell by 7.0% per SD decrease in birth weight (p < 0.001), but was not related to infant weight gain. In univariate analyses, age-adjusted forced expiratory flow at functional residual capacity was not related to birth weight, but decreased by 11.0% per SD increase in infant weight gain (p = 0.007). The respiratory rate rose by 5.1% per SD increase in infant weight gain (p = 0.001). The results suggest that lower rates of fetal growth and higher rates of early-infancy weight gain are associated with impaired lung development.

The lungs of newborn rats exposed to 60% oxygen for 14 days develop an injury that shares morphologic similarities to human bronchopulmonary dysplasia (BPD). Neutrophil influx into the lung, as part of an inflammatory response, may play a pivotal role in the development of BPD. A neutrophil chemokine, cytokine-induced neutrophil chemoattractant-1, which signals through the neutrophil CXC chemokine receptor-2, is increased in the lung tissue of newborn rats exposed to 60% oxygen. Yi and colleagues (44) explored the role of neutrophils in the rat model of BPD by inhibiting neutrophil influx using SB265610, a selective CXC chemokine receptor-2 antagonist. SB265610, administered to 60% oxygen–exposed newborn rats from birth to 14 days, completely inhibited neutrophil influx. It also attenuated increased production of reactive oxygen species in newborn rat lung tissue after exposure to 60% oxygen for 4 days. Lung morphometric analysis revealed that 60% oxygen for 14 days, when accompanied by treatment with SB265610 to prevent neutrophil accumulation, increased alveolar formation over that seen in newborn rats exposed to air. These data suggest that exposure of the neonatal lung to moderate hyperoxia may enhance postnatal lung growth, provided postnatal pulmonary inflammation is suppressed.

Bronchopulmonary dysplasia.
Pulmonary hypertension contributes significantly to morbidity and mortality in BPD, but little is known about the relative contribution of arterial tone, structural remodeling, and vessel density to pulmonary hypertension, especially in older patients. To determine the role of high pulmonary vascular tone in pulmonary hypertension, Mourani and coworkers (45) studied the acute effects of oxygen tension, inhaled nitric oxide, and calcium channel blockers in 10 patients with BPD who underwent cardiac catheterization for evaluation of pulmonary hypertension. During normoxic conditions, mean pulmonary arterial pressure and pulmonary to systemic vascular resistance ratio were 34 ± 3 mm Hg and 0.42 ± 0.07 mm Hg, respectively. In response to hypoxia, pulmonary arterial pressure and pulmonary to systemic vascular resistance ratio increased by 50 ± 8% and 82 ± 14%, respectively (p < 0.01). Hyperoxia decreased pulmonary to systemic vascular resistance ratio by 28 ± 9% (p = 0.05). The addition of inhaled nitric oxide treatment (20–40 ppm) to hyperoxia decreased pulmonary arterial pressure and pulmonary to systemic vascular resistance ratio by 29 ± 5% (p < 0.01) and 45 ± 6% (p < 0.05) from baseline values, respectively, achieving near normal values. The authors concluded that hyperoxia plus inhaled nitric oxide causes marked pulmonary vasodilatation in older patients with BPD, suggesting that heightened pulmonary vascular tone contributes to pulmonary vascular disease in BPD.

Infections.
To examine the immunologic changes at birth and during the first year of life, Copenhaver and colleagues (46) collected cord blood samples from 285 babies who were followed up for at least a year, and the IFN-{gamma} response basally and to phytohemagglutin stimulation was measured. Nasal lavages were performed at the time of any moderate or severe viral illness. Daycare attendance or having an older sibling unsurprisingly resulted in increased numbers of positive viral isolates, in particular rhinovirus and respiratory syncytial virus. Rhinovirus-associated wheeze was greater in those in daycare or exposed to siblings. Interestingly, a vigorous IFN-{gamma} response by cord blood to phytohemagglutin predicted fewer moderate or severe infections. There was no relationship with cord blood IL-5, IL-10, and IL-13 responses. As previously reported by some but not all studies, the phytohemagglutin IFN-{gamma} responses declined with age, but declined more in those who had had fewer viral respiratory infections. IFN-{gamma} responses both influence and are influenced by viral infections. These intriguing data add further to the debate about the importance of the intrauterine environment, the Th1–Th2 balance, and environmental exposure to the development of early and persisting wheezing phenotypes.

Pulmonary hypertension.
Schindler and colleagues (47) studied norepinephrine responses in isolated pulmonary arteries, pulmonary veins, and femoral arteries taken from normal pigs from birth to adulthood and from pigs subjected to chronic hypoxia either from birth for 3 days or from 3 to 14 days of age. Normally, the contractile response of pulmonary arteries and veins to norepinephrine decreased after birth (p < 0.01), and {alpha}2-adrenoceptor–mediated relaxation increased in pulmonary arteries and veins and in femoral arteries. Hypoxic exposure from birth prevented the normal postnatal reduction in pulmonary arterial contractile response, and there was no postnatal increase in pulmonary arterial adrenoceptor–mediated relaxation. When hypoxic exposure followed a period of normal adaptation, the pulmonary arterial contractile response was not enhanced, but relaxation was significantly impaired. The response of pulmonary veins and femoral arteries was not affected by hypoxic exposure. The contractile effect of norepinephrine was 15- to 60-fold greater in isolated systemic arteries than in pulmonary arteries taken from both normal and pulmonary hypertensive piglets at all ages. The authors suggested that use of norepinephrine to manage systemic hypotension in infants and children will not compromise the pulmonary vasculature.

Tracheomalacia.
Infantile tracheomalacia is a potentially life-threatening disease requiring prolonged artificial respiratory support. Diagnosis and management of this disease may be further improved by establishing a suitable objective and quantitative assessment protocol for tracheal collapsibility. To test the hypothesis that the tracheal collapsibility can be represented by the relationship between intraluminal pressure and the cross-sectional area of the trachea, Okazaki and colleagues (48) obtained static pressure/area relationships of the trachea from anesthetized and paralyzed infants, who were diagnosed as having tracheomalacia by endoscopic observation. These relationships were fitted on a linear regression model, followed by calculation of the estimated closing pressure. The tracheal closing pressure ranged from –8 to –27 cm H2O, suggesting easy collapsibility of the trachea during crying or coughing and noncollapsibility during the spontaneous respiratory cycle, which coincided with the infants' symptoms. The authors concluded that tracheal collapsibility of infants with tracheomalacia can be quantitatively assessed by the static pressure/area relationship of the trachea obtained under general anesthesia and paralysis.


   PULMONARY PHYSIOLOGY AND ANATOMY
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Anatomy
Ochs and colleagues (49) studied a design-based stereologic approach using two-dimensional topology in three-dimensional space to assess the alveoli. Alveolar number was estimated by counting alveolar openings at the level of free septal edges where they form a two-dimensional network. The Euler number of this network was then estimated using physical dissectors at a light microscopic level. Six adult human lungs were studied. The mean alveolar number was 480 million (range 274–790 million). There was a close correlation between alveolar number and total lung volume, with larger lungs having more alveoli. Mean size of a single alveolus was rather constant at 4.2 x 106 µm3 (range 3.3–4. 8 x 106 µm3), independent of lung size. This technique, which was easy to apply in practice, will be useful for the quantification analysis of lung structure.

Gas Exchange
Glucose intolerance is frequently observed in hypoxic respiratory diseases. Oltmanns and coworkers (50) studied whether hypoxia caused glucose intolerance in healthy subjects. They conducted a double-blind study with subject crossover design of hypoxia versus nonhypoxic conditions in 14 men. Oxygen saturations were decreased to 75% for 30 minutes versus 96% in control subjects under conditions of a euglycemic clamp. The rate of dextrose infusion needed to maintain stable blood glucose levels was assessed. The neurohormonal stress responses were evaluated by measuring catecholamine and cortisol concentrations as well as cardiovascular parameters and symptoms of anxiety. The study showed a significant decrease in dextrose infusion rate over a period of 150 minutes after the start of hypoxia (p < 0.01). Hypoxia also increased plasma epinephrine concentrations (p < 0.01), heart rate (p < 0.01), and symptoms of anxiety (p < 0.05). Similar glucose intolerance was observed in hypoxic and hypoglycemic conditions despite clear differences in stress hormonal responses. The studies suggest that acute hypoxia causes glucose intolerance and that this effect could be mediated by an elevated release of epinephrine.


   SURFACTANT BIOLOGY
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Pathophysiology
Bernhard and coworkers (51) used deuteriated choline coupled with electrospray ionization tandem mass spectrometry to study surfactant metabolism in human volunteers. The major component of surfactant was found to be the dipalmitoyl-phosphatidylcholine species (PC). Endogenous PC from induced sputum from healthy volunteers is composed largely of PC 16:0/16:0 (54.0 ± 1.5%). Infusion of deuteriated choline chloride over 3 hours resulted in linear incorporation into PC over 30 hours. Stable PC reached a plateau between 30 and 38 hours, and incorporation decreased to low levels over 7 days. The technique may be useful to investigate surfactant metabolism in humans in vivo.


   FOOTNOTES
 
Conflict of Interest Statement: A.B. has received lecture fees and support for travel to academic meetings from GlaxoSmithKline (GSK) AstraZeneca (AZ) Altana and MSD. Total personal benefit from each company is less then $10,000 and none of these companies have any connection with the subject matter of this manuscript; F.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; W.M. has been reimbursed for travel by GSK, Zambon, AZ, Boehringer Ingelheim, Pfizer,and Micromet and has received honoraria from GSK, AZ, Zambon, and Pfizer for participating as a speaker at scientific meetings. He serves on Advisory Boards for GSK, Pfizer, Aimirall, Amgen, Bayer, and Micromet and serves as a consultant for Pfizer and SMB Pharmaceuticals. He has received research grants to support work carried out in W.M.'s laboratory from SMB, Pfizer, Ceremedix, GSK, Chugi, and Novartis; S.C.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; E.A. has been a consultant for Eli Lilly in 2002 and 2003 and also received clinical research contracts from Eli Lilly.


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 SURFACTANT BIOLOGY
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