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Identifying the Origins of Cystic Fibrosis Lung Disease Stephanie D. Davis, M.D., and Thomas Ferkol, M.D. Although the median survival age has improved steadily during the past half century, cystic fibrosis is still a life-shortening disease, affecting 30,000 children and adults in the United States. The airways of patients with cystic fibrosis are susceptible to infection, which induces an intense inflammatory response even in those with only modest pulmonary disease.1 Although they are often asymptomatic, infants with cystic fibrosis have neutrophilic inflammation in their airways, which is both protective and destructive. Neutrophil proteases, including elastase, are critical for killing engulfed bacteria, but these proteases escape from neutrophils during phagocytosis and in death and subsequently overwhelm antiprotease defenses (Fig. 1). Neutrophil elastase accumulates in the airways of patients with cystic fibrosis, impairs ciliary function, cripples bacterial clearance, and degrades structural proteins, thereby leading to bronchiectasis.2-4 Several lines of evidence have shown that early cystic fibrosis lung disease is not “silent” if you listen carefully. Peripheral-airway obstruction and bronchiectasis often begin early and progress during the first few years of life. The novel approach of the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) in evaluating the infant and preschooler with cystic fibrosis has led to a paradigm shift in our current understanding of early lung disease.5,6 Sly and colleagues7 now report in the Journal that the presence of neutrophil elastase activity in bronchoalveolar-lavage fluid from 3-month-old infants with cystic fibrosis is associated with persistent bronchiectasis, defined as dilated airways on at least two sequential computed tomographic (CT) scans of the chest. This finding has important implications for the assessment 2026

of cystic fibrosis lung disease, clinical-trial end points, and potentially therapeutic interventions, although it is unclear whether neutrophil elastase is central to early pathogenesis or is simply a biomarker for early disease. Choosing end points for clinical trials involving young children with cystic fibrosis has proved to be challenging, and “classic” clinical outcome measures may be too insensitive to identify a treatment effect.8 As shown by the work of Sly and colleagues, potential end points of disease in the youngest population may require a less traditional approach. With the advent of newborn screening, infants with cystic fibrosis rarely present with failure to thrive or persistent respiratory symptoms, and the designers of future clinical trials should consider less traditional outcomes. Perhaps markers of lower airway inflammation that are assessed by means of broncho­ alveolar lavage and chest CT imaging, though not without risk, are the tools needed to better assess the efficacy of certain therapies, until Figure 1 (facing page). The Pathogenic Effects of Neutrophils and Neutrophil Elastase in the Airways of Patients with Cystic Fibrosis. Neutrophil proteases, including elastase, are critical for the killing of engulfed bacteria, but large amounts escape from neutrophils in death and during phago­ cytosis, which ultimately overwhelms antiprotease de­ fenses in the airway. As unopposed neutrophil elastase accumulates, it degrades structural proteins in the air­ way, thereby leading to bronchiectasis and bronchoma­ lacia. Free, extracellular neutrophil elastase also stimu­ lates an inflammatory response from airway epithelial cells, and it interferes with bacterial clearance by im­ pairing ciliary function and cleaving surface receptors and immunoglobulins. CR1 denotes complement re­ ceptor 1, and CXCR1 chemokine receptor 1.

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Localized destruction of connective tissue leads to bronchomalacia and bronchiectasis. Elastase cleaves IgG; it also digests chemokine and complement receptors, interfering with phagocytosis and bacterial killing. IgG antibody Elastase is released from neutrophils during phagocytosis and in death.


Necrotic neutrophil





Neutrophil elastase

Proinflammatory cytokines and chemoattractants (interleukin-8)

Bronchial epithelium

Connective tissue

Neutrophil elastase Necrotic neutrophil

Elastase destroys connective tissue, leading to bronchomalacia and bronchiectasis.


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less invasive measures are fully developed and validated. These biomarkers of future lung disease could also provide direction for our therapeutic efforts in the youngest population. Aerosolized alpha1antitrypsin has been safely tested in older children and adults with cystic fibrosis with variable results, including a reduction in measures of inflammation.9,10 Because the airways of infants with cystic fibrosis are less obstructed by inflammatory exudate and mucus than those of older patients, inhaled antiprotease delivery may be more homogeneously distributed and may reach regions that are affected early. This approach could have the greatest benefits in these infants and younger children, before the massive protease burden in the airway overwhelms the antiprotease defenses. Given the morbidity and mortality associated with cystic fibrosis, coupled with the knowledge that disease begins early, why have we been so resistant to a more aggressive approach? With the advent of universal newborn screening for cystic fibrosis, we are now able to diagnose the disease in young infants and intervene earlier. The AREST CF data challenge the clinician to a more proactive approach, in which we identify disease, treat earlier, and potentially change the disease trajectory, long before irreversible airway damage occurs. A more intensive and anticipatory approach to care could lead to better longterm outcomes and could improve the chances of survival of a child born with cystic fibrosis today.

From the Section of Pediatric Pulmonology, Allergy, and Sleep Medicine, Riley Hospital for Children at Indiana University Health, Indianapolis (S.D.D.); and the Department of Pediat­ rics, Division of Pediatric Allergy, Immunology, and Pulmonary Medicine, Washington University in St. Louis, St. Louis (T.F).

Disclosure forms provided by the authors are available with the full text of this article at

DOI: 10.1056/NEJMe1303487

This article was published on May 21, 2013, at 1. Konstan MW, Hilliard KA, Norvell TM, Berger M. Broncho­

alveolar lavage findings in cystic fibrosis patients with stable, clinically mild lung disease suggest ongoing infection and inflammation. Am J Respir Crit Care Med 1994;150:448-54. [Erratum, Am J Respir Crit Care Med 1995;151:260.] 2. Nakamura H, Yoshimura K, McElvaney NG, Crystal RG. Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line. J Clin Invest 1992;89:1478-84. 3. Tosi MF, Zakem H, Berger M. Neutrophil elastase cleaves C3bi on opsonized pseudomonas as well as CR1 on neutrophils to create a functionally important opsonin receptor mismatch. J Clin Invest 1990;86:300-8. 4. Hartl D, Latzin P, Hordijk P, et al. Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat Med 2007;13:1423-30. 5. Sly PD, Brennan S, Gangell C, et al. Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening. Am J Respir Crit Care Med 2009;180:146-52. 6. Stick SM, Brennan S, Murray C, et al. Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after newborn screening. J Pediatr 2009;155:623-8. 7. Sly PD, Gangell CL, Chen L, et al. Risk factors for bronchiectasis in children with cystic fibrosis. N Engl J Med 2013;368:196370. 8. Rosenfeld M, Ratjen F, Brumback L, et al. Inhaled hypertonic saline in infants and children younger than 6 years with cystic fibrosis: the ISIS randomized controlled trial. JAMA 2012; 307:2269-77. 9. McElvaney NG, Hubbard RC, Birrer P, et al. Aerosol alpha1antitrypsin treatment for cystic fibrosis. Lancet 1991;337:392-4. 10. Griese M, Latzin P, Kappler M, et al. alpha1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients. Eur Respir J 2007;29:240-50. Copyright © 2013 Massachusetts Medical Society.

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Fibrosis quistica