Epidemiology, Biology, and Impact of Clonal Pseudomonas aeruginosa Infections in Cystic Fibrosis

Abstract

Chronic lower airway infection with Pseudomonas aeruginosa is a major contributor to morbidity and mortality in individuals suffering from the genetic disease cystic fibrosis (CF). Whereas it was long presumed that each patient independently acquired unique strains of P. aeruginosa present in their living environment, multiple studies have since demonstrated that shared strains of P. aeruginosa exist among individuals with CF. Many of these shared strains, often referred to as clonal or epidemic strains, can be transmitted from one CF individual to another, potentially reaching epidemic status. Numerous epidemic P. aeruginosa strains have been described from different parts of the world and are often associated with an antibiotic-resistant phenotype. Importantly, infection with these strains often portends a worse prognosis than for infection with nonclonal strains, including an increased pulmonary exacerbation rate, exaggerated lung function decline, and progression to end-stage lung disease. This review describes the global epidemiology of clonal P. aeruginosa strains in CF and summarizes the current literature regarding the underlying biology and clinical impact of globally important CF clones. Mechanisms associated with patient-to-patient transmission are discussed, and best-evidence practices to prevent infections are highlighted. Preventing new infections with epidemic P. aeruginosa strains is of paramount importance in mitigating CF disease progression.

Keywords: Liverpool epidemic strain; Pseudomonas aeruginosa; bronchiectasis; clone C; cystic fibrosis; epidemic strains; genotyping; infection control; shared strains; strain typing; transmissible strain.

FIG 1

Features required to fulfill the definition of an epidemic P. aeruginosa strain. For a strain to be considered epidemic, many individual traits should be demonstrated, including the following: (i) a strain must exist at a disproportionately increased prevalence in a defined CF population, be it a clinic, region, or nation; (ii) within a region of increased prevalence, there should be epidemiological linkages showing the potential for spread among patients, including common exposures (camps, fundraising, clinics, or hospitalizations) and increased connectivity among those patients infected with the clone relative to nonclonal isolates; (iii) the clone should either not be found in local non-CF human populations or the natural environment or exist at a greatly increased prevalence in CF populations relative to these non-CF reservoirs; (iv) through the use of prospective sampling, patients who were previously observed either to not be infected with P. aeruginosa or to be infected with unique, nonclonal P. aeruginosa strains should be observed to acquire the putative epidemic strain; and (v) the use of emerging whole-genome sequencing tools enables researchers to demonstrate that the numbers of single nucleotide polymorphisms existing between successive isolates are no higher intrapatient than interpatient, suggesting direct ancestral linkages. Progressive shading indicates those elements with greater weight.

FIG 2

Evaluating globally important P. aeruginosa CF clones for formal epidemic strain designation.

FIG 3

Events required for P. aeruginosa transmission. A series of events is required for the transmission of P. aeruginosa from one patient to another. The first is patient factors. Both an infected patient capable of transmitting a pathogen and a susceptible host with a lower airway microbiome conducive to invasion with or without superinfection are required. Whether specific demographics increase the risk of either transmission or acquisition is as yet unknown. The second is pathogen factors. While epidemic strains have been shown to differ with respect to several genotypic and phenotypic features, no defining feature of epidemic strains has been identified. An epidemic strain must be able to survive external to the host as a droplet aerosol and resist desiccation. Furthermore, it must be able to outcompete organisms already colonizing the lower airway of the new host. The third is environmental factors. Risk for infection transmission directly correlates with intensity of exposure between the two hosts, which can potentially be minimized with infrastructural controls and/or personal protective equipment.

FIG 4

Global prevalence of clonal P. aeruginosa strains. This map is, however, limited. In many cases, a single center's data are extrapolated to an entire country, and admittedly, rates of shared clonal strains have been shown to be highly clinic dependent. Furthermore, rates reported here are from aggregates of the most recently available data. As rates of clonal strain prevalence may change over time, what was once true may no longer be the case. Whereas newer studies have employed technologies such as MLST and VNTR, enabling investigators of individual studies to directly comment on the prevalence of this organism in distant CF populations as well as in non-CF infections and environmental samples, older studies typically used noncomparative genotyping technologies.