Defining chronic Pseudomonas aeruginosa infection in cystic fibrosis

Cystic fibrosis (CF) is a genetic, multi-system disease due to mutations in the cystic fibrosis conductance regulator (CFTR) gene, leading to ineffective anion channel activity [[1]Tsui L.C. Buchwald M. Barker D. Braman J.C. Knowlton R. Schumm J.W. et al.Cystic fibrosis locus defined by a genetically linked polymorphic DNA marker.Science. 1985; 230: 1054-1057Crossref PubMed Scopus (326) Google Scholar]. The resulting impaired mucociliary clearance permits initial acquisition of Pseudomonas aeruginosa and, if untreated, the establishment of persistent infection in the CF airways. It has long been recognized that chronic infection, often characterized by a mucoid P. aeruginosa phenotype, is associated with more rapid lung function decline and earlier death in individuals with CF [2Emerson J. Rosenfeld M. McNamara S. Ramsey B. Gibson R.L. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis.Pediatr Pulmonol. 2002; 34: 91-100Crossref PubMed Scopus (792) Google Scholar, 3Henry R.L. Mellis C.M. Petrovic L. Mucoid Pseudomonas aeruginosa is a marker of poor survival in cystic fibrosis.Pediatr Pulmonol. 1992; 12: 158-161Crossref PubMed Scopus (311) Google Scholar, 4Konstan M.W. Morgan W.J. Butler S.M. Pasta D.J. Craib M.L. Silva S.J. et al.Risk factors for rate of decline in forced expiratory volume in one second in children and adolescents with cystic fibrosis.J Pediatr. 2007; 151 ([9 e1]): 134-139Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar]. Defining chronic P. aeruginosa infection is therefore an important step in identifying CF patients most at risk of lung disease progression. Traditionally, the Leed's criteria has been used to define chronicity (as having >50% of sputum cultures being P. aeruginosa positive in the preceding 12 months), as it is the only clinically validated definition [[5]Lee T.W. Brownlee K.G. Conway S.P. Denton M. Littlewood J.M. Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients.J Cyst Fibros. 2003; 2: 29-34Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar]. However, the Leed's criteria are difficult to implement in young children unable to provide sputum and further limited by the required number of sputum samples and follow-up time [[6]Ramsay K.A. Sandhu H. Geake J.B. Ballard E. O'Rourke P. Wainwright C.E. et al.The changing prevalence of pulmonary infection in adults with cystic fibrosis: A longitudinal analysis.J Cyst Fibros. 2017; 16: 70-77Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. In this issue of the Journal, studies by Heltshe et al. and Boutin et al. aim to re-define what chronic P. aeruginosa infection means in CF. In a retrospective cohort study using data from the US CF Foundation Patient Registry, Heltshe et al. followed close to 6000 early-diagnosed CF children for approximately 6 years [[7]Heltshe S.L. Khan U. Beckett V. Baines A. Emerson J. Sanders D.B. et al.Longitudinal development of initial, chronic and mucoid Pseudomonas aeruginosa infection in young children with cystic fibrosis.J Cyst Fibros. 2018; 17: 341-347Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. Two-thirds acquired P. aeruginosa infection and of those, 6% had an initial mucoid phenotype. Furthermore, the majority (87%) of children who developed mucoid infection did so before meeting the definition of chronic infection (at least 3 yearly quarters P. aeruginosa positive in the preceding year). Initial P. aeruginosa infection with a mucoid phenotype has been previously described and is a recognized risk factor for failure of antimicrobial eradication therapy [8Vidya P. Smith L. Beaudoin T. Yau Y.C. Clark S. Coburn B. et al.Chronic infection phenotypes of Pseudomonas aeruginosa are associated with failure of eradication in children with cystic fibrosis.Eur J Clin Microbiol Infect Dis. 2016; 35: 67-74Crossref PubMed Scopus (27) Google Scholar, 9Mayer-Hamblett N. Ramsey B.W. Kulasekara H.D. Wolter D.J. Houston L.S. Pope C.E. et al.Pseudomonas aeruginosa phenotypes associated with eradication failure in children with cystic fibrosis.Clin Infect Dis. 2014; 59: 624-631Crossref PubMed Scopus (51) Google Scholar, 10Douglas T.A. Brennan S. Gard S. Berry L. Gangell C. Stick S.M. et al.Acquisition and eradication of P. aeruginosa in young children with cystic fibrosis.Eur Respir J. 2009; 33: 305-311Crossref PubMed Scopus (129) Google Scholar]. Whether this initial acquisition of a mucoid phenotype represents prior adaptation of P. aeruginosa in the CF host (either undetected or transmitted from a patient with chronic infection) or simply infection with an environmental strain particularly well-suited to the CF airways, is as of yet unknown [[11]Kidd T.J. Ramsay K.A. Vidmar S. Carlin J.B. Bell S.C. Wainwright C.E. et al.Pseudomonas aeruginosa genotypes acquired by children with cystic fibrosis by age 5-years.J Cyst Fibros. 2015; 14: 361-369Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar]. It is clear, though, that mucoid P. aeruginosa does have an adaptive advantage in early CF infection as mucoidy was associated with an almost three-fold increased risk of transition to chronic infection in this current study. Despite the presence of this risk factor, however, only 13% of P. aeruginosa infected patients went on to develop chronic infection. Although Heltshe et al. did not provide details as to eradication strategies used in this cohort, this low incidence of persistent infection does speak to the overall effectiveness of current antimicrobial treatment for early P. aeruginosa infection. Boutin et al. took their investigation a step further by using molecular methods, specifically quantitative polymerase chain reaction (qPCR), to define chronic P. aeruginosa infection [[12]Boutin S. Weitnauer M. Hassel S. Graeber S.Y. Stahl M. Dittrich A.S. et al.One time quantitative PCR detection of Pseudomonas aeruginosa to discriminate intermittent from chronic infection in cystic fibrosis.J Cyst Fibros. 2018; 17: 348-355Scopus (21) Google Scholar]. In their study, patients with chronic infection had significantly higher levels of P. aeruginosa as measured by qPCR compared to those with intermittent infection. A single P. aeruginosa qPCR measurement in sputum had a sensitivity of 84% (with a specificity of 85%) in detecting chronic infection using a threshold of 103.4 colony forming units (CFU)/ml. A single sputum PCR measure had the advantage of not requiring 12 months of culture results as per the Leed's criteria [[5]Lee T.W. Brownlee K.G. Conway S.P. Denton M. Littlewood J.M. Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients.J Cyst Fibros. 2003; 2: 29-34Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar]. Furthermore, in their small study sample size, PCR was more discriminatory than mucoidy status in predicting chronicity, not surprisingly, given that alginate production (conferring mucoidy) is only one of several virulence factors contributing to the establishment of persistent P. aeruginosa infection in CF [[13]Hogardt M. Heesemann J. Adaptation of Pseudomonas aeruginosa during persistence in the cystic fibrosis lung.Int J Med Microbiol. 2010; 300: 557-562Crossref PubMed Scopus (170) Google Scholar]. When used in throat swab samples, qPCR had a considerably lower sensitivity (82%) and specificity (56%) in detecting chronic infection, likely due in part to the lower bacterial burden observed in this specimen, compared to sputum. The low specificity of PCR in this setting (positive PCR, negative culture) may reflect the fact that a molecular signal may precede culture positivity. Early detection of P. aeruginosa infection, before culture conversion, in CF patients was originally suggested decades ago using serologic and, more recently, molecular methods [14Burns J.L. Gibson R.L. McNamara S. Yim D. Emerson J. Rosenfeld M. et al.Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis.J Infect Dis. 2001; 183: 444-452Crossref PubMed Scopus (483) Google Scholar, 15Xu J. Moore J.E. Murphy P.G. Millar B.C. Elborn J.S. Early detection of Pseudomonas aeruginosa--comparison of conventional versus molecular (PCR) detection directly from adult patients with cystic fibrosis (CF).Ann Clin Microbiol Antimicrob. 2004; 3: 21Crossref PubMed Scopus (79) Google Scholar, 16Hery-Arnaud G. Nowak E. Caillon J. David V. Dirou A. Revert K. et al.Evaluation of quantitative PCR for early diagnosis of Pseudomonas aeruginosa infection in cystic fibrosis: a prospective cohort study.Clin Microbiol Infect. 2017; 23: 203-207Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. Serology, however, has proven disappointing at identifying early P. aeruginosa infection [[17]Taccetti G. Sly P.D. Early detection of infection with Pseudomonas aeruginosa in cystic fibrosis: the Holy Grail or an achievable goal?.J Cyst Fibros. 2014; 13: 491-493Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. Nevertheless, early detection may still be possible using highly-sensitive PCR techniques for identifying lower airway P. aeruginosa infection in a young, non-expectorating child. In the study by Boutin et al., P. aeruginosa detection in throat swabs by PCR alone was linked to a positive culture in sputum in three-quarters of cases. Previous studies comparing oropharyngeal cultures to bronchoalveolar lavage (BAL) cultures in children with CF demonstrated that oropharyngeal cultures had a positive predictive value of only 44%, but a negative predictive value of 95% in diagnosing lower airway P. aeruginosa infection [[18]Rosenfeld M. Emerson J. Accurso F. Armstrong D. Castile R. Grimwood K. et al.Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis.Pediatr Pulmonol. 1999; 28: 321-328Crossref PubMed Scopus (296) Google Scholar]. Performing P. aeruginosa qPCR on culture negative throat swabs may further improve the diagnosis of lower airway infection in young children with CF who are unable to produce sputum, but this approach will still need to be validated by comparative studies employing BAL fluid samples. Unfortunately, using confirmatory induced sputum samples as suggested by Boutin et al., may produce unreliable results as these specimens are poor predictors of lower airway pathogens cultured from BAL specimens in young children with CF [[19]D'Sylva P. Caudri D. Shaw N. Turkovic L. Douglas T. Bew J. et al.Induced sputum to detect lung pathogens in young children with cystic fibrosis.Pediatr Pulmonol. 2017; 52: 182-189Crossref PubMed Scopus (31) Google Scholar]. Finally, it is yet to be determined whether earlier diagnosis of P. aeruginosa infection leads to improved eradication success rates and superior clinical outcomes. In summary, the recent studies by Heltshe et al. and Boutin et al. further our understanding of how chronic P. aeruginosa infection develops in CF and how to better recognize it [[7]Heltshe S.L. Khan U. Beckett V. Baines A. Emerson J. Sanders D.B. et al.Longitudinal development of initial, chronic and mucoid Pseudomonas aeruginosa infection in young children with cystic fibrosis.J Cyst Fibros. 2018; 17: 341-347Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar,[12]Boutin S. Weitnauer M. Hassel S. Graeber S.Y. Stahl M. Dittrich A.S. et al.One time quantitative PCR detection of Pseudomonas aeruginosa to discriminate intermittent from chronic infection in cystic fibrosis.J Cyst Fibros. 2018; 17: 348-355Scopus (21) Google Scholar]. Ultimately, prevention of chronic P. aeruginosa infection and its deleterious effects on lung function and survival is the goal. None.

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