© 2008 American Thoracic Society doi: 10.1164/rccm.200804-502ED
Reduced Lung Function in Cystic FibrosisA Primary or Secondary Phenotype?
University of North Carolina at Chapel Hill
The Hospital for Sick Children During the past decade, advances in the early assessment of cystic fibrosis (CF) lung disease have led to an improved understanding of its pathophysiology, but many questions still remain unanswered (1). The earliest airway abnormalities of focal, distal mucous plugging leading to peripheral airway dilatation (2) have been difficult to detect with the current armentarium of clinical tests. Recently, objective measures have been developed demonstrating that CF lung disease begins early, often prior to clinical manifestations (3–5). Diminished physiologic measurements (3–5), increased airway inflammation, and early infection (6–8) as well as developing bronchiectasis (9, 10) have been demonstrated during early infancy. Longitudinal data during infancy have also shown that this reduction in lung function does not "catch up," even after initiation of treatment (3). Despite these advances, the triggering factor for the cascade of events leading to early airway infection, inflammation, and flow limitation has not been entirely clear. In this issue of the Journal (pp. 42–49), Kozlowska and colleagues (11) eloquently describe the evolution of lung function from infancy through the preschool years in children with CF compared with healthy control subjects. The longitudinal measures were performed using the raised-volume rapid thoracoabdominal compression technique and incentive spirometry and were carefully conducted based on standardized, published guidelines (12). The prospective inclusion of a parallel control group strengthens the findings in this study and is unique, given the difficulty of assessing sedated lung function during infancy in a healthy population. These novel results better define the specific physiologic measures that identify early lung disease throughout the first years of life. While diminished values of forced expiratory volume at 0.75 second (FEV0.75) and forced expiratory flows between 25 and 75% of forced vital capacity (FEF25–75) were documented across all ages, FEV at 0.5 second (FEV0.5) only differentiated children with CF from healthy controls during infancy, not during preschool years. This interesting finding likely reflects the predominance of the central airway component in the measure of FEV0.5. Because early CF lung disease is located in the distal airways, identifying longitudinal physiologic markers that best represent peripheral airway mucous plugging is critical for future therapeutic trials conducted in this young age group. Newborn screening was not available in London during the time period when this study was conducted and infants were diagnosed on the basis of clinical symptoms. The question of whether the reduction in lung function represents a primary rather than secondary abnormality can therefore not be answered by this study. Autopsy specimens (13) obtained immediately after birth have revealed lungs without evidence of morphologic damage, but the methodology in these studies may have been inadequate to detect subtle abnormalities in lung growth as well as functional changes induced by alterations in smooth muscle tone. Therefore, the pertinent question of when physiologic abnormalities truly begin, in utero, at birth or later, is still unresolved. The implementation of newborn screening offers the opportunity to study infants prior to the development of clinical signs and symptoms and will allow researchers to address this issue more effectively. Longitudinal evaluation of the infant with CF, diagnosed by newborn screening, from birth through the school-age years is important in linking structural damage, physiologic findings, and the presence of lower airway inflammation and/or infection. Whereas it has been difficult in the past to evaluate CF lung disease adequately in the youngest children, measures such as the raised-volume rapid thoracoabdominal compression technique, controlled breathing chest computed tomography scans, and bronchoalveolar lavage are now available, which will help tackle these important research questions (1). While demarcating the physiologic markers of early CF peripheral airway disease remains important, discovering the etiology of diminished lung function is of equal significance. Outlining the cause of reduced lung function helps to monitor and guide future modes of early CF management. If the CF lungs are normal at birth, what is triggering the cascade of events leading to chronic inflammation and infection? Kozlowska and colleagues (11) report that the presence of Pseudomonas aeruginosa infection, wheezing, and recent cough was independently associated with reduced lung function. In fact, lung function remained decreased even in those children with apparent eradication of P. aeruginosa. Despite these significant associations, P. aeruginosa may not be the cause of the reduced lung function but simply a marker of more significant lung disease in this subpopulation. Because these infants were diagnosed with CF based on clinical symptomatology, lung damage may have already occurred, thus providing a rich environment for growth of P. aeruginosa. Nevertheless, the lack of improvement in lung function measures, despite aggressive treatment and apparent eradiation of P. aeruginosa, is concerning. This finding emphasizes the importance of employing preventative therapy before the development of airway inflammation and infection. Driven by detailed work performed in laboratories such as that described in this issue of the Journal, infant lung function testing has now entered a new stage and can be considered a clinical outcome measure, similar to spirometry in the older child. The raised-volume technique has been standardized (12), published reference values are available (14), procedural risks are acceptable, and studies have clearly demonstrated that this technique is suitable to discriminate lung disease from health (3–5). Results from a recently completed trial performed in infants with CF in the United States are encouraging as they demonstrate the feasibility of studying infant lung function in a multicenter setting when strict quality assurance and training is implemented (15). The tremendous progress in this area of measuring infant physiology will naturally lead to intervention studies using these parameters as outcome measures. Over the next decade, we expect that techniques such as infant and preschool lung function testing will not only improve our understanding of the once "silent" and mysterious young CF lung but will also help us to develop stronger evidence for potential early intervention strategies in this vulnerable age group (16). FOOTNOTES Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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