Preventing Burkholderia cepacia complex infection in cystic fibrosis: Is there a middle ground?

Abstract

See related article, p 512. The emergence of Burkholderia cepacia from a seemingly harmless soil commensal to a respiratory pathogen in persons with cystic fibrosis (CF) during the early 1980s occurred just as the development of CF care support networks was in full stride. Programs such as CF summer camps, educational retreats, exercise classes and summer internships held great promise for improving the quality of life for CF patients of all ages. But in the early 1990s, conventional epidemiologic investigation augmented by molecular genotyping showed that B cepacia could be transmitted between persons with CF,1LiPuma JJ Dasen SE Nielson DW Stern RC Stull TL Person-to-person transmission of Pseudomonas cepacia between patients with cystic fibrosis.Lancet. 1990; 336: 1094-1096Abstract PubMed Scopus (259) Google Scholar, 2Govan JR Brown PH Maddison J Doherty CJ Nelson JW Dodd M et al.Evidence for transmission of Pseudomonas cepacia by social contact in cystic fibrosis.Lancet. 1993; 342: 15-19Abstract PubMed Scopus (393) Google Scholar thereby effectively ruining these blossoming social support efforts. Recognizing the risk of unrestricted contact between B cepacia -infected and -uninfected patients, the CF Foundation reluctantly recommended that care centers discontinue support for CF summer camps in 1993. Since then infection control policies for CF have grown steadily more stringent. The CF Foundation recently convened a consensus conference on infection control, the recommendations of which will be published soon and will reiterate a stance of limiting contact among patients, irrespective of infection status. In Europe, even more restrictive policies separate CF patients in an attempt to prevent cross-infection. There the recent finding that some strains of Pseudomonas aeruginosa 3Jones AM Govan JRW Doherty CJ Dodd ME Isalska BJ Stanbridge TN et al.Spread of a multiresistant strain of Pseudomonas aeruginosa in an adult cystic fibrosis clinic.Lancet. 2001; 358: 557-558Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 4McCallum SJ Corkill J Gallagher M Ledson MJ Hart CA Walshaw MJ Superinfection with a transmissible strain of Pseudomonas aeruginosa in adults with cystic fibrosis chronically colonised by P. aeruginosa.Lancet. 2001; 358: 558-560Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar may also spread among patients in the same clinic raises the specter of even greater isolation for CF patients. The effects of these policies cannot be overstated. Although B cepacia infects a relatively small proportion of CF patients, it affects the entire CF community. Prevention of cross-infection places an extraordinary psychosocial, financial, and logistic burden on patients and CF care providers. The report by Walsh et al5Walsh NM Casano AA Manangan LP Sinkowitz-Cochran RL Jarvis WR Risk factors for Burkholderia cepacia complex colonization and infection among cystic fibrosis patients.J Pediatr. 2002; 141: 512-517Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar in this issue of The Journal further fuels the infection control engine. This report revives data generated several years ago in a well designed prospective study to identify factors associated with person-to-person transmission of B cepacia among CF patients. Although there is nothing startling in these findings, they are important in confirming results from previous smaller retrospective studies, and adding support to current infection control recommendations. Unfortunately, because the study was conducted during the late 1980s, we are unable to place these findings in the context of what has been learned more recently about the taxonomy and molecular epidemiology of B cepacia infection in CF. During the past several years, comprehensive taxonomic work by Vandamme and colleauges6Vandamme P Holmes B Vancanneyt M Coenye T Hoste B Coopman R et al.Occurrence of multiple genomovars of Burkholderia cepacia in cystic fibrosis patients and proposal of Burkholderia multivorans sp. nov.Int J Syst Bact. 1997; 47: 1188-1200Crossref PubMed Scopus (445) Google Scholar, 7Vandamme P Mahenthiralingam E Holmes B Coenye T Hoste B De Vos P et al.Identification and population structure of Burkholderia stabilis sp. nov. (formerly Burkholderia cepacia genomovar IV).J Clin Microbiol. 2000; 38: 1042-1047PubMed Google Scholar, 8Coenye T LiPuma JJ Henry D Hoste B Mahenthiralingam E Vandemeulebroecke K et al.Burkholderia cepacia genomovar VI, a new member of the Burkholderia cepacia complex isolated from cystic fibrosis patients.Int J Syst Evol Microbiol. 2001; 51: 271-279Crossref PubMed Google Scholar, 9Coenye T Mahenthiralingam E Henry D LiPuma JJ Laevens S Gillis M et al.Burkholderia ambifaria sp. nov., a novel member of the Burkholderia cepacia complex comprising biocontrol and cystic fibrosis-related isolates.Int J Syst Evol Microbiol. 2001; 51: 1481-1490Crossref PubMed Scopus (135) Google Scholar, 10Vandamme P Henry D Coenye T Nzula S Vancanneyt M LiPuma JJ et al.Burkholderia anthina sp. nov. and Burkholderia pyrrocinia, two additional Burkholderia cepacia complex bacteria, may confound test results of new molecular diagnostic tools.FEMS Immunol Med Microbiol. 2002; 33: 143-149Crossref PubMed Google Scholar has identified 9 distinct bacterial species (or genomovars) among strains previously identified merely as “B cepacia.” Most of these species, now collectively referred to as the B cepacia complex, have received new binomial designations (Table). Recent surveys of large numbers of “B cepacia” -infected CF patients in North America and Europe11LiPuma JJ Spilker T Gill L Campbell PW Liu L Mahenthiralingam E Disproportionate distribution of Burkholderia cepacia complex species and transmissibility factors in cystic fibrosis.Am J Respir Crit Care Med. 2001; 164: 92-96Crossref PubMed Scopus (232) Google Scholar, 12Agodi A Mahenthiralingam E Bachitta M Giannino V Sciacca A Stefani S Burkholderia cepacia complex infection in Italian patients with cystic fibrosis: Prevalence, epidemiology, and genomovar status.J Clin Microbiol. 2001; 39: 2891-2896Crossref PubMed Scopus (87) Google Scholar, 13Speert DP Henry D Vandamme P Corey M Mahenthiralingam E Epidemiology of Burkholderia cepacia complex in patients with cystic fibrosis, Canada.Emerg Infect Dis. 2002; 8: 181-187Crossref PubMed Scopus (210) Google Scholar indicate that most are infected with either B multivorans (genomovar II) or genomovar III (which still awaits a formal species name). What makes this admittedly confusing nomenclature positively maddening is that relatively few CF patients are actually infected with B cepacia (the species name now reserved for genomovar I). At a subspecies level, bacterial genotyping (or DNA fingerprinting) studies indicate that in some CF treatment centers,many infected patients harbor the same B cepacia complex strain. Such shared strains have been variously referred to as “hypertransmissible” or “epidemic,” implying a behavior for which the biologic underpinnings are unknown. The best studied of these is the ET12 strain, common among patients in Ontario, Canada and the United Kingdom14Johnson WM Tyler SD Rozee KR Linkage analysis of geographic and clinical clusters in Pseudomonas cepacia infections by multilocus enzyme electrophoresis and ribotyping.J Clin Microbiol. 1994; 32: 924-930PubMed Google Scholar, 15Pitt TL Kaufmann ME Patel PS Benge LC Gaskin S Livermore DM Type characterisation and antibiotic susceptibility of Burkholderia (Pseudomonas ) cepacia isolates from patients with cystic fibrosis in the United Kingdom and the Republic of Ireland.J Med Microbiol. 1996; 44: 203-210Crossref PubMed Scopus (92) Google Scholar and characterized by distinctive cable pili and an associated adhesin, which promotes bacterial binding to respiratory epithelia.16Sajjan US Sun L Goldstein R Forstner JF Cable (cbl ) type II pili of cystic fibrosis-associated Burkholderia (Pseudomonas) cepacia : Nucleotide sequence of the cblA major subunit pilin gene and novel morphology of the assembled appendage fibers.J Bacteriol. 1995; 177: 1030-1038PubMed Google Scholar Other epidemic strains, such as PHDC17Chen JS Witzmann K Spilker T Fink R LiPuma JJ Endemicity and inter-city spread of Burkholderia cepacia genomovar III in cystic fibrosis.J Pediatr. 2001; 139: 643-649Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar and the “Midwest clone”,18Kumar A Dietrich S Schneider W Jacobson R Pouch Downes F Robinson-Dunn BE et al.Genetic relatedness of Burkholderia (Pseudomonas ) cepacia isolates from five cystic fibrosis centers in Michigan.Resp Med. 1997; 91: 485-492Abstract Full Text PDF PubMed Scopus (17) Google Scholar, 19Coenye T LiPuma JJ Multilocus restriction typing, a novel tool for studying global epidemiology of Burkholderia cepacia complex infection in cystic fibrosis.J Infect Disease. 2002; 185: 1454-1462Crossref PubMed Scopus (51) Google Scholar common in the United States, do not express cable pili. All 3 strains, however, as well as most other shared strains,20Mahenthiralingam E Simpson DA Speert DP Identification and characterization of a novel DNA marker associated with epidemic Burkholderia cepacia strains recovered from patients with cystic fibrosis.J Clin Microbiol. 1997; 35: 808-816Crossref PubMed Google Scholar are genomovar III; strains residing in other B cepacia complex species and common to multiple patients have been less frequently described,21Segonds C Heulin T Marty N Chabanon G Differentiation of Burkholderia species by PCR-restriction fragment length polymorphism analysis of the 16S rRNA gene and application to cystic fibrosis isolates.J Clin Microbiol. 1999; 37: 2201-2208PubMed Google Scholar although large-scale systematic genotyping surveys are lacking. In the absence of genomovar determination and strain genotyping analyses of the B cepacia complex isolates recovered from the patients studied by Walsh et al,5Walsh NM Casano AA Manangan LP Sinkowitz-Cochran RL Jarvis WR Risk factors for Burkholderia cepacia complex colonization and infection among cystic fibrosis patients.J Pediatr. 2002; 141: 512-517Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar we are left to wonder about the degree to which these results may have been affected by the presence in some centers (or summer camps) of epidemic strains. Put another way, the study begs the questions...Do the risk factors identified apply equally to all B cepacia complex species?...to all strains? Are there ways to prospectively identify strains with an apparent enhanced capacity for spread? More importantly, can we confidently identify strains with very little potential for transmission? If so, could (or should) infection control measures be stratified so these can be applied in a more selective, humane and efficient manner?22Clode FE Kaufmann ME Malnick H Pitt TL Distribution of genes encoding putative transmissibility factors among epidemic and nonepidemic strains of Burkholderia cepacia from cystic fibrosis patients in the United Kingdom.J Clin Microbiol. 2000; 38: 1763-1766PubMed Google Scholar Is there a middle ground? Compounding this uncertainty are questions pertaining to the acquisition of B cepacia complex from the natural environment. These species are inhabitants of soil, being particularly abundant in the rhizosphere of several types of plants. In 2000, Govan et al23Govan JRW Balendreau J Vandamme P Burkholderia cepacia —friend and foe.ASM News. 2000; 66: 124-125Google Scholar demonstrated clonality between a genomovar I strain isolated from a CF patient and strain ATCC25416, the species type strain isolated in the 1940s from onion. Genomovar III strains were subsequently identified from among isolates recovered from soil,24Balandreau J Viallard V Cournoyer B Coenye T Laevens S Vandamme P Burkholderia cepacia genomovar III is a common plant-associated bacterium.Appl Environ Microbiol. 2001; 67: 982-985Crossref PubMed Scopus (126) Google Scholar and more recently, the epidemic strain PHDC was identified in agricultural fields in the same region of the United States, where it has been endemic among CF patients for the past 20 years.25LiPuma JJ Spilker T Coenye T Gonzalez CF An epidemic Burkholderia cepacia complex strain identified in soil.Lancet. 2002; 359: 2002-2003Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar The degree to which acquisition from the natural environment contributes to infection in CF is not clear. On the one hand, strict infection control clearly decreases the incidence of infection, particularly in centers plagued with an epidemic strain.17Chen JS Witzmann K Spilker T Fink R LiPuma JJ Endemicity and inter-city spread of Burkholderia cepacia genomovar III in cystic fibrosis.J Pediatr. 2001; 139: 643-649Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 26Thomassen MJ Demko CA Doerschuk CF Stern RC Klinger JD Pseudomonas cepacia : Decrease in colonization in patients with cystic fibrosis.Am Rev Respir Dis. 1986; 134: 669-671PubMed Google Scholar On the other hand, even the most draconian measures have not entirely eliminated new infection, suggesting ongoing infection from undefined reservoirs. What then are we to do? The benefits to persons with CF of social and educational support programs are without question. The positive impact of CF summer camp on nutritional status, exercise tolerance, and overall well-being has been again recently documented. 27Blau H Mussaffi-Georgy H Fink G Kaye C Szeinberg A Spitzer SA et al.Effects of an intensive 4-week summer camp on cystic fibrosis: Pulmonary function, exercise tolerance, and nutrition.Chest. 2002; 121: 1117-1122Crossref PubMed Scopus (43) Google Scholar Thus, we enforce harsh infection control, restrict contact between our patients, and burden caregivers while we endeavor to provide optimal care and quality of life. Will the recent advances in our understanding of the biology of the B cepacia complex soon lead us to the middle ground wherein exists the right balance between protection from infection and freedom from the oppression of rigid infection control? Or, given the dire consequences of B cepacia infection, will any retreat from our current conservative approach invite disaster? The answers of course are not clear. We will only be able to move forward, however, through improved methods of species and strain identification, enhanced efforts at CF sputum surveillance, and elucidation of the bacterial and host factors contributing to interpatient transmission. Well designed clinical outcomes and risk assessment studies, such as that performed by Walsh et al,5Walsh NM Casano AA Manangan LP Sinkowitz-Cochran RL Jarvis WR Risk factors for Burkholderia cepacia complex colonization and infection among cystic fibrosis patients.J Pediatr. 2002; 141: 512-517Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar but which also take into account species and strain differences among B cepacia complex isolates, will provide much needed information. Until then prudence would seem to dictate an unfortunate, steady, and perhaps overly cautious course. Risk factors for Burkholderia cepacia complex colonization and infection among patients with cystic fibrosisThe Journal of PediatricsVol. 141Issue 4PreviewObjectives: To determine risk factors for acquiring Burkholderia cepacia complex among patients with cystic fibrosis (CF). Study design: A case-control study was conducted with active surveillance for B cepacia complex colonization/infection among patients at 21 CF centers from April 1986 to March 1989 (study period). A case-patient was defined as any CF patient with B cepacia complex colonization for the first time during the study period. Control patients were patients with CF not B cepacia complex colonized during the study period. Full-Text PDF