The Journal of Pediatrics
Volume 154, Issue 2 , Pages 162-163, February 2009

Infection, Inflammation, and the Downward Spiral of Cystic Fibrosis Lung Disease

  • Richard B. Moss, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Richard B. Moss, MD, The Center for Excellence in Pulmonary Biology, Department of Pediatrics, Stanford University Medical Center, 770 Welch Road Suite 350, Palo Alto CA 94304-5882

The Center for Excellence in Pulmonary Biology, Department of Pediatrics, Stanford University Medical Center, Palo Alto, California

Article Outline

Abbreviations: CF, Cystic fibrosis, OP, Oropharyngeal, PA, Pseudomonas aeruginosa, SA, Staphylococcus aureus

 

Clinicians caring for children with cystic fibrosis (CF) are often found explaining the disease process to their patients' families—and to themselves—as a “vicious cycle” of airway obstruction, infection, and inflammation wherein each of these 3 components contributes to both the overall progression of lung disease and the negative impact of the other 2 processes. Phenomenologically this makes perfect sense, because all 3 elements are easily demonstrated early in CF by a variety of methods and approaches. Pathogenetically, however, the waters remain muddied—which came first? Is this important? If early intervention is key to control of CF lung disease, as most now believe, therapy is both most logically and effectively geared to addressing the initiating insult. As we are now in the era of widespread newborn screening for CF, the opportunity for preventive therapy has at least theoretically arrived. If the initiating insult in CF is obstruction due to airway surface fluid volume depletion and impaired mucociliary clearance, rehydration and airway clearance therapies are warranted as soon as possible after diagnosis.1, 2, 3 This is the current paradigm of CF pulmonary pathogenesis. However, antimicrobial or antiinflammatory therapy would be immediately indicated if these processes precede or accompany impaired clearance and obstructive lesions.4, 5, 6, 7, 8 Although studies of infants and young children with CF have yielded important insights to the “vicious cycle” question, the final answer remains elusive.

See related article, p 183

In this issue of The Journal, Sagel et al9 give results from the largest reported cohort of young children assessed for 2 components of the CF vicious cycle, infection and inflammation. These young children between 6 months and 6 years of age (mean, ∼3 years) were selected for study on the basis of positive oropharyngeal (OP) cultures for Pseudomonas aeruginosa (PA) within the preceding year and at screening. Bronchoalveolar lavage was then performed within 3 weeks to evaluate infection by means of quantitative bacterial cultures and inflammatory markers such as neutrophil counts, neutrophil elastase, and proinflammatory cytokines. This study in CF analyzes effects of lower airway infection with several bacterial species on local inflammation and clinical status, and compares inflammatory responses to PA and Staphylococcus aureus (SA). The results suggest that lower airways infection at least in part drives the inflammatory process, in that inflammation was clearly linked to positive bronchoalveolar lavage culture, in a manner specific for and dependent on the bacterial pathogen, so that both PA and SA increase inflammation in an additive fashion that is related to bacterial density when both are present. PA infection also correlated with poorer clinical scores. The presence of a positive OP culture did not necessarily predict lower airway infection and attendant inflammation, confirming the primarily negative predictive usefulness of OP cultures, the backbone of current microbial surveillance in CF.10

Before considering the implications, it is useful to point out the limitations of the study design. First, many CF physicians intervene with antibiotic therapy for positive PA OP cultures; indeed, a large multicenter study is in progress in the United States to evaluate the safety and efficacy of several different approaches to early PA “eradication” therapy.11 Some physicians also apply an aggressive antibiotic approach to positive SA OP cultures.12 The study of Sagel et al9 does not allow an assessment of such interventions as treatment, and monitoring strategies were not evaluated before enrollment. Second, because of the cross-sectional study design, the duration of lower airway PA infection in the subjects of Sagel et al9 cannot be determined, and thus we do not know whether chronic infection causes more inflammation than transient or intermittent infection. The situation is even less clear for SA because no historical or screening SA cultures were required for entry. Third, Sagel et al9 and others have found inflammation in culture-negative infants and children with CF but have not documented the prior infection history. So, this design does not improve our understanding of whether CF lung inflammation represents an exaggerated response to infection, a failure of homeostatic antiinflammatory mechanisms after an episode of infection has been cleared, or an intrinsic feature of CF.

The possibility of intrinsic lung inflammation in CF has been suggested by several lines of evidence. Some, but by no means all, in vitro experiments show spontaneous proinflammatory CF epithelial cell activation, certain murine models of CF (or CF-like) molecular lesions and human fetal CF airway xenografts develop noninfectious airway inflammation, and airway inflammation has been documented in culture-negative patients with CF.4, 5, 6, 7, 8, 9 While offensive to parsimony of explanation, the potentially dual nature of CF lung disease pathogenesis leads to a paradigm wherein a “downward spiral” of ongoing interactive but independent impairments of mucociliary clearance and inflammatory responses predispose to episodes of acute and chronic infection associated with progressive pulmonary impairment. This has clear implications for the clinical, as well as the basic, research agenda in CF.

The study of Sagel et al9 also highlights the importance of polymicrobial infection in CF. In addition to surveillance cultures with selective media,13, 14 new culture-independent techniques detecting pathogen-specific DNA sequences have indicated an ecologic jungle in the CF airway, which appears to be filled with previously unappreciated microbes.15, 16 Sagel et al9 correlated lung inflammation with increasing diversity, as well as density of bacterial species detected (eg, they also found evidence of inflammation independently associated with Haemophilus influenzae, another commonly cultured CF pathogen). Together these findings suggest that, as our sophistication regarding the plethora of CF pathogens improves, we may come to appreciate the capability of many microbes to contribute to or initiate CF lung inflammation, and perhaps to rethink the targeting, as well as the timing of our antimicrobial interventions. Future prospective studies in cohorts of screened infants, possibly with novel noninvasive techniques used to track infection and inflammation,17, 18 will likely be needed if we are ever to understand fully the pathogenesis of the CF lung's downward spiral.

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References 

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PII: S0022-3476(08)00818-4

doi:10.1016/j.jpeds.2008.09.042

Refers to article:

  • Impact of Pseudomonas and Staphylococcus Infection on Inflammation and Clinical Status in Young Children with Cystic Fibrosis , 26 September 2008

    Scott D. Sagel, Ronald L. Gibson, Julia Emerson, Sharon McNamara, Jane L. Burns, Jeffrey S. Wagener, Bonnie W. Ramsey, Inhaled Tobramycin in Young Children Study Group, Cystic Fibrosis Foundation Therapeutics Development Network
    The Journal of Pediatrics February 2009 (Vol. 154, Issue 2, Pages 183-188.e3)

The Journal of Pediatrics
Volume 154, Issue 2 , Pages 162-163, February 2009

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