American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 988-993, (2002)
© 2002 American Thoracic Society
Epidemiology of Pseudomonas aeruginosa in Cystic Fibrosis in British Columbia, Canada
David P. Speert,
Maureen E. Campbell,
Deborah A. Henry,
Ruth Milner,
Fatma Taha,
Anna Gravelle,
A. George F. Davidson,
Lawrence T. K. Wong and
Eshwar Mahenthiralingam
Divisions of Infectious and Immunological Diseases and Biochemical Diseases, Department of Pediatrics, University of British Columbia; and British Columbia Institute for Children's and Women's Health and Cystic Fibrosis Clinic, Children's and Women's Hospital of British Columbia, Vancouver, British Columbia, Canada
Correspondence and requests for reprints should be addressed to Dr. David P. Speert, Research Centre, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4 Canada. E-mail: speert{at}interchange.ubc.ca
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ABSTRACT
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Pseudomonas aeruginosa is the most common respiratory pathogen in patients with cystic fibrosis (CF), but the predominant mechanism by which it is acquired is controversial. To determine the frequency of patient-to-patient spread, we evaluated P. aeruginosa isolates from 174 patients treated at the CF clinics in Vancouver, BC, Canada, since 1981. Multiple isolates were obtained from each patient and genetically typed by random amplified polymorphic DNA and pulsed field gel electrophoresis analyses. A total of 157 genetic types of P. aeruginosa was identified, 123 of which were unique to individual patients. A total of 34 types was shared by more than one patient; epidemiologic evidence linked these individuals only in the cases of 10 sibships and 1 pair of unrelated patients. We conclude that there is an extremely low risk in Vancouver for patients with CF to acquire P. aeruginosa from other patients. It appears that prolonged close contact, such as occurs between siblings, is necessary for patient-to-patient spread. The major source of acquisition of P. aeruginosa in CF appears to be from the environment. Considering these observations, we do not recommend segregation of patients with CF on the basis of their colonization status with P. aeruginosa.
Key Words: cystic fibrosis • epidemiology • Pseudomonas aeruginosa
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INTRODUCTION
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Pseudomonas aeruginosa is the predominant respiratory pathogen in patients with cystic fibrosis (CF), but the means by which the organism is acquired is controversial (1). Most patients with CF are ultimately infected with P. aeruginosa, and once acquired, the infection is not readily eradicated (2, 3). The unique tropism of P. aeruginosa for the CF respiratory tract has not been adequately explained; competing and complementary hypotheses abound (4–6). None of these theories has been widely accepted as the single unifying explanation for the peculiar propensity of P. aeruginosa to infect the CF airway.
Currently, there is great concern about the possible emergence and spread of transmissible strains of P. aeruginosa in CF centers (1). It has been suggested that P. aeruginosa is spread from patient to patient (7–11) and that stringent infection control policies should be able to limit the acquisition by uninfected patients. Others have failed to find evidence of patient-to-patient spread (12–15) and have suggested that specific hygienic measures to prevent nosocomial acquisition are not indicated. Data supporting these divergent views have been based on surveys of bacterial isolates from patients with CF in different geographic locations. The most compelling evidence for patient-to-patient spread has been in the form of reports of unique bacterial clones shared by multiple patients (9, 11).
Since 1981, we have saved isolates of P. aeruginosa from all patients with CF who received care at clinics in Vancouver. These isolates have been evaluated by genetic "fingerprinting" in an attempt to determine whether patient-to-patient spread has occurred. The data from the 20-year analysis of these strains forms the basis of this report.
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METHODS
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Bacterial Isolates
Purified isolates of gram-negative, nonfermentative bacteria cultured from the respiratory secretions of patients with CF were obtained weekly from the Vancouver clinical microbiology laboratories. All initial isolates and those from patients who were culture-positive intermittently were evaluated to confirm species identification (16) and then frozen. Once a patient became persistently culture-positive for P. aeruginosa, isolates of each colonial morphotype were frozen twice yearly. Bacterial cultures from each patient representing the first and most recent isolates and the midpoint of the course of the infection, were selected and typed by pulsed field gel electrophoresis (PFGE) and/or random amplified polymorphic DNA analysis (RAPD) (see below).
Genetic Strain Typing
Two genetic typing analyses were performed to determine P. aeruginosa strain types, RAPD typing and PFGE fingerprinting. RAPD analysis was performed as previously described (17) using Primer 272. RAPD fingerprints obtained were analyzed both visually and by using Molecular Analyst Fingerprinting software (Bio-Rad Laboratories, Hercules, CA) as described previously (18). Isolates that appeared similar in RAPD were then evaluated by PFGE, as previously described for Burkholderia cepacia isolates (19). The guidelines of Tenover and coworkers (20) were used to assess the PFGE patterns. As observed in our previous studies (17–19), the results of both typing methods were concordant, and genetically distinct strains were assigned a strain code.
Epidemiology
Patients who harbored P. aeruginosa of the same genetic type were assessed using information obtained from CF clinics and from previous studies (13, 21) to determine if they had had any contact with one another in the clinic. All patients are followed by a full-time team of physicians, social workers, nurses, and dieticians. The social interactions of each patient are known to the CF clinical care team, and the patients were monitored for activities both within and outside the hospital. Many patients with CF who are friends and who socialize are known to the clinical care team. When strain types were shared by two or more patients, social interactions among them were specifically assessed. To assess possible transmission outside the clinic, which could have been unrelated to social interaction, domicile location was determined for each patient by home postal code. The possibility of social interactions outside the hospital setting was also assessed on the basis of clinic information and knowledge of the individual patients and their families.
The current pediatric policy of the clinic is to have patients wait for their outpatient appointments in individual rooms; however, before 1995, patients shared a common waiting room before they were seen in the clinic. Clinic records were reviewed to determine whether these outpatients with CF may have occupied the waiting room simultaneously.
Patients were frequently assigned to the same inpatient hospital ward irrespective of their P. aeruginosa colonization status but were assigned to separate rooms when possible. While in hospital, they attended school or shared a common playroom in the ward. Clinic and hospital records of each patient were reviewed to determine whether they had been in contact with one another at any time during hospitalization. This contact risk assessment was also routinely done by the clinic the first time a patient was diagnosed with Pseudomonas.
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RESULTS
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Patients
All patients with CF who were studied attended the outpatient clinics in Vancouver or were hospitalized in Children's and Women's Hospital of British Columbia, Shaughnessy Hospital, or St. Paul's Hospital (all in Vancouver) between 1981 and 1999. P. aeruginosa was recovered from the respiratory tract secretions of 346 patients with CF during the study period. Other than patients who had participated in previously published studies (13, 16), no additional adult patients (19 years or older) or patients who had moved to British Columbia when they were culture-positive were included. A total of 174 patients (160 children and 14 adults at the time of first stored culture) was evaluated. At the time the study was concluded, 63 patients were children, 50 were adults, 35 had died, 5 had received cadaveric lung transplantation, and 21 no longer attended clinics in Vancouver. A total of 12 sibling pairs was studied; in each case, both harbored P. aeruginosa.
Comparison of Strain Typing by PFGE and RAPD
The PFGE analysis was performed on all P. aeruginosa isolates from different patients who showed closely related patterns in RAPD (Figure 1)
. In all cases, when the RAPD patterns were identical, the PFGE patterns were isotypic, according to the criteria of Tenover and coworkers (20). For all isolates in which the RAPD patterns differed by two or more bands, the PFGE patterns were also different. Grossly different RAPD types were always different in PFGE. Thus, we found perfect concordance between the RAPD and PFGE results.
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Figure 1. Genetic fingerprints of unique and shared types of P. aeruginosa from patients attending Vancouver CF clinics. (A) RAPD fingerprints of P. aeruginosa isolates from different patients with CF. The RAPD fingerprints of 13 isolates obtained with Primer 272 are shown. The assigned RAPD strain type is shown for each isolate. The panel is a composite of fingerprints taken from 10 separate gels and aligned against molecular weight standards. (B) Spe I–derived PFGE fingerprints of the same P. aeruginosa isolates as in A. The isolates were run on a single PFGE gel. Molecular weight standards are shown in the first lane. Results from the RAPD and PFGE typing methods were concordant. Strain type 002 isolates from five different patients are shown to be identical or closely related.
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Epidemiology of Patients with CF with P. aeruginosa
A total of 157 distinct genotypes of P. aeruginosa was recovered from patients with CF in British Columbia (Table 1)
; of these, 123 strains were unique to a single patient, 7 were unique to a single sibling pair, 24 were shared by unrelated patients with CF, and 3 were shared by 1 or more sibling pairs and with other unrelated patients with CF. There was no known contact among patients harboring 11 strain types of the 27 that were shared by unrelated patients. Patients with 15 shared strain types were infected before 1981, so epidemiologic information could not be obtained. One of these patients was transiently culture-positive for a shared strain type that was subsequently replaced by a unique strain.
One strain type was recovered from two patients who were very close friends and spent a great deal of time together, both in and out of the hospital. Patient A was infected with a nonmucoid isolate and within 1 year also harbored dwarf and mucoid variants of the same strain type. Patient B was infected in 1997 at 14 years of age with nonmucoid and dwarf phenotypes of the same strain.
Most of the shared types were from two-, three-, or four-patient clusters, one type was shared by five patients, and two types were harbored by six patients. Except for the one example described previously, there was no evidence of patient-to-patient spread suggested by direct personal contact, whether at home or in hospital, year of acquisition, or clustering of domicile.
Only two types were recovered from a large number of patients. Type A002 was recovered from 21 patients with CF (including 1 sibling pair) (Table 2)
. Twelve of these patients had no contact with each other, seven did not have contact information, and one patient was hospitalized in the same room as a patient infected with this type; however, initial colonization for this one patient was transient, and subsequent respiratory cultures yielded no P. aeruginosa for 2 years. The patient eventually became consistently infected with a different type. A further 9 patients were culture-positive only transiently for this type, whereas 11 became persistently infected. Type A097 was recovered from 18 patients with CF (including 2 sibling pairs) (Table 3) . With the exception of the sibling pairs, 12 had no known contact with the other patients, and 6 did not have contact information; 7 of the patients were only transiently culture-positive for this type, and 10 became persistently infected.
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TABLE 2. Patients with cystic fibrosis attending vancouver clinics from whom pseudomonas aeruginosa strain type A002 was recovered
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TABLE 3. Patients with cystic fibrosis attending vancouver clinics from whom pseudomonas aeruginosa rapd strain type A097 was recovered
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The date of initial acquisition of P. aeruginosa was evaluated for each of the patients from whom type A002 or A097 was recovered (Figure 2)
. For neither strain type was there extensive temporal clustering. Finally, the residence of each patient culture-positive for these two strain types was evaluated (Figure 3)
. Because the majority of patients with CF in British Columbia reside within 100 km of Vancouver, the distribution of residences was predominantly in the Greater Vancouver region. Nonetheless, there was no obvious geographic clustering to support patient-to-patient spread outside the hospital or to support acquisition of the bacteria from a common environmental source.
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Figure 2. Acquisition of P. aeruginosa by patients with CF attending the Vancouver CF clinics. (A) Acquisition of strain type A002. Both acquisitions in 1990 and two of the three in 1996 were transient. Two acquisitions of the six before 1991 were in a sibling pair. (B) Acquisition of strain type A097. Two of the four acquisitions before 1981 were in sibling pairs. Among the five acquisitions in 1997, two were in a sibling pair and two of the other three were transient.
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Figure 3. Geographic location of domiciles of patients with CF from whom P. aeruginosa of either of the two commonly shared types was recovered. The home address of each patient with either of the two commonly shared strain types of P. aeruginosa was determined by postal code. Geographic location of each patient is indicated with yellow circles for RAPD strain type A002 and red circles for strain type A097. The province of British Columbia is shown in A and the lower mainland (where approximately half of the provincial population resides) is shown in B.
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Situations that were thought to enhance patient-to-patient spread were further evaluated. None of the hospital roommate pairs demonstrated durable cross-infection. All social cohorts were evaluated by the clinic staff, and in none was there any evidence of infection with common strains of P. aeruginosa.
P. aeruginosa Recovered from Siblings with CF
Of the 12 sibling pairs culture-positive for P. aeruginosa, 10 shared a common type, and 2 did not. Of the two sibling pairs not sharing a common type, siblings from one pair were each sporadically culture-positive for different strains. The second discordant pair included a child born 2 years after the older sibling had died. Further, the parents had moved before the birth of the second child; therefore, the two patients had contact neither with each other nor with a common environment.
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DISCUSSION
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Isolates of P. aeruginosa from patients with CF are phenotypically unusual; they are often mucoid, have a "rough" lipopolysaccharide (lacking a fully developed O-polysaccharide side chain), and are nonmotile (3, 22, 23). These characteristics separate CF isolates from those recovered from other compromised hosts, such as patients with thermal injuries or neutropenia or those who require mechanical ventilation. It has been suggested that the peculiar "CF phenotype" of P. aeruginosa evolves in the CF respiratory tract during chronic infection after patients become culture-positive for a more typical phenotype—nonmucoid, lipopolysaccharide smooth and motile (24). P. aeruginosa is a hydrophilic bacterium that is commonly found in environments, such as sink drains, vegetables, and other moist environments. It therefore seems logical to speculate that patients with CF can acquire bacteria with the typical phenotype from the environment and that transition to the CF phenotype occurs under the conditions found in the CF endobronchial space. Indeed, transition to the CF phenotype can be induced in vitro under conditions of nutrient limitation similar to those likely present in the endobronchial space before the onset of an inflammatory response (25).
The respiratory tracts of patients with CF are infected with very high densities of P. aeruginosa; they cough frequently and receive medical care and social support in centralized clinics. These conditions should enhance the spread of the bacteria among patients if such transmissions were possible. In an effort to determine whether P. aeruginosa is indeed acquired by patient-to-patient spread, we have been evaluating the microbial epidemiology in Vancouver CF clinics since 1981. Our initial studies were of patients who were in close contact with one another either in hospital (13) or at a recreational summer camp (12). In neither case were we able to document any evidence of patient-to-patient spread. The purpose of the current study was to evaluate the molecular epidemiology of P. aeruginosa from all patients attending the Vancouver CF clinics since 1981 to determine if there was any evidence of patient-to-patient spread. By combining molecular typing and epidemiologic investigation, we were able to demonstrate apparent patient-to-patient spread in 10 of the 12 sibling pairs and in only 1 pair of unrelated patients with CF. It is conceivable that the bacteria shared by siblings are acquired from their common environment rather than from patient-to-patient spread. We conclude that, for a patient with CF, the risk of acquiring P. aeruginosa from another patient is very small in the Vancouver CF treatment centers.
Experience from other CF centers is highly variable with regard to apparent patient-to-patient spread of P. aeruginosa. To our knowledge, there are only two published reports that provide clear evidence for epidemic spread of P. aeruginosa among patients with CF (9, 11). The authors of these reports suspected spread because many of the isolates from their clinic demonstrated an unusual antibiotic susceptibility profile or phenotype. Had the identified clone been more typical of isolates from that clinic, the epidemic spread may have been overlooked. Other suggestions of patient-to-patient spread have not been clearly supported by molecular and epidemiologic data. One investigation from Wisconsin in a clinic that segregated patients newly diagnosed with CF from patients culture-positive for P. aeruginosa demonstrated that the patients became culture-positive at a later age than did patients who were not cohorted (10). Bacterial isolates from that study were not evaluated, so there is no evidence of a common type or support for patient-to-patient spread.
The Burkholderia cepacia complex, another important group of pathogens in patients with CF, can spread from patient to patient, and this has been documented in several studies in different geographic areas (26). The B. cepacia complex is a highly heterogeneous group of bacteria that comprises multiple novospecies or "genomovars" (27). There is evidence of patient-to-patient spread of bacteria from only certain genomovars, and markers of transmissibility have been demonstrated in many of these "transmissible" strains (28, 29). Therefore, it is quite likely that transmissibility is not a characteristic of the entire B. cepacia complex but rather is limited to a subset of strains. The same may be true for P. aeruginosa, especially in the light of the unusual phenotypes of the clones from recently documented outbreaks of infection in the UK (9, 11).
Recommendations for prudent infection control are difficult to formulate on a global scale in view of the differences in propensity for patient-to-patient spread in different clinics. On the basis of the experience in Liverpool (9) and the incidence of similar problems elsewhere in the UK (11), CF caregivers have been advised to separate patients who are culture-positive for P. aeruginosa from those who are culture-negative (Pseudomonas aeruginosa infection control document, http://www.cftrust.org.uk/library/default.do). Similar approaches have been advocated elsewhere in Europe on the basis of local experience (N. Høiby; G. Döring; personal communication). The experience from most North American clinics does not support a substantial risk of patient-to-patient spread of P. aeruginosa. Therefore, specific separation of patients with CF on the basis of their culture status regarding P. aeruginosa has not been widely advocated either in Canada or in the U.S. It should be appreciated that careful prospective surveillance for possible cross-infection with P. aeruginosa has not been conducted in most CF treatment centers. Therefore, the risk for patient-to-patient spread, especially in North America, may be greater than currently appreciated.
In light of the currently available data, one cannot draw universal conclusions about the risk of patient-to-patient spread of P. aeruginosa among patients with CF; it is clear that there are regional differences and that the likelihood in certain geographic locations such as Vancouver, Canada, is very low. Nonetheless, there are situations under which patient-to-patient spread may occur, as demonstrated in the UK (9, 11) and between siblings (30). Furthermore, there is substantial risk for patient-to-patient spread of other CF pathogens, such as the B. cepacia complex and methicillin-resistant Staphylococcus aureus. Careful hygienic practices should continue to be followed at all CF centers to limit the risk of spread of any pathogen from one patient with CF to another. In an effort to limit infection with P. aeruginosa among patients with CF and the attendant adverse effect on health (31), efforts should be directed at better understanding the source of acquisition of this common CF pathogen and also the circumstances that may facilitate its acquisition. With a clearer understanding of its epidemiology, strategies might then be designed to delay or eliminate acquisition of P. aeruginosa by patients with CF.
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Acknowledgments
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The authors gratefully acknowledge the excellent assistance of Gary Probe and Jocelyn Bischof and the staff of the clinical microbiology laboratories at British Columbia's Children's Hospital, Shaughnessy Hospital, and St. Paul's Hospital.
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FOOTNOTES
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Supported with grants from the Canadian Cystic Fibrosis Foundation (D. P. S. and E. M.) and by an establishment award from the British Columbia Lung Association (E. M.).
Received in original form March 6, 2001;
accepted in final form April 23, 2002
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A.L. Griffiths, D. Armstrong, R. Carzino, and P. Robinson
Cystic fibrosis patients and families support cross-infection measures
Eur. Respir. J.,
September 1, 2004;
24(3):
449 - 452.
[Abstract]
[Full Text]
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M.R. O'Carroll, M.W. Syrmis, C.E. Wainwright, R.M. Greer, P. Mitchell, C. Coulter, T.P. Sloots, M.D. Nissen, and S.C. Bell
Clonal strains of Pseudomonas aeruginosa in paediatric and adult cystic fibrosis units
Eur. Respir. J.,
July 1, 2004;
24(1):
101 - 106.
[Abstract]
[Full Text]
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F. W. Scott and T. L. Pitt
Identification and characterization of transmissible Pseudomonas aeruginosa strains in cystic fibrosis patients in England and Wales
J. Med. Microbiol.,
July 1, 2004;
53(7):
609 - 615.
[Abstract]
[Full Text]
[PDF]
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J. V. Kus, E. Tullis, D. G. Cvitkovitch, and L. L. Burrows
Significant differences in type IV pilin allele distribution among Pseudomonas aeruginosa isolates from cystic fibrosis (CF) versus non-CF patients
Microbiology,
May 1, 2004;
150(5):
1315 - 1326.
[Abstract]
[Full Text]
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L. Saiman and J. Siegel
Infection Control in Cystic Fibrosis
Clin. Microbiol. Rev.,
January 1, 2004;
17(1):
57 - 71.
[Abstract]
[Full Text]
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R. L. Gibson, J. L. Burns, and B. W. Ramsey
Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis
Am. J. Respir. Crit. Care Med.,
October 15, 2003;
168(8):
918 - 951.
[Abstract]
[Full Text]
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M. J. Tobin
Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2002
Am. J. Respir. Crit. Care Med.,
February 1, 2003;
167(3):
333 - 344.
[Full Text]
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Pseudomonas Colonization in CF: Environmental or Person-to-Person Spread?
Journal Watch Infectious Diseases,
October 25, 2002;
2002(1025):
10 - 10.
[Full Text]
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B. W. Ramsey
To Cohort or Not to Cohort: How Transmissible Is Pseudomonas aeruginosa?
Am. J. Respir. Crit. Care Med.,
October 1, 2002;
166(7):
906 - 907.
[Full Text]
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Copyright © 2002 American Thoracic Society
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ABSTRACT
INTRODUCTION