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Eur Respir J 2004; 23:851-856
Copyright ©ERS Journals Ltd 2004

Epidemiology of Burkholderia cepacia complex colonisation in cystic fibrosis patients

K. De Boeck1, A. Malfroot2, L. Van Schil3, P. Lebecque4, C. Knoop5, J.R.W. Govan7, C. Doherty7, S. Laevens6 and P. Vandamme6 on behalf of the Belgian Burkholderia cepacia study group

1 University Hospital Gasthuisberg, Leuven, 2 Academisch Ziekenhuis, Vrije Universiteit Brussels, Brussels, 3 St. Vincentiusziekenhuis, Antwerpen, 4 Université Catholique de Louvain, Brussels, 5 Hôpital Erasme, Brussels, 6 Ghent University, Gent, Belgium. 7 University of Edinburgh, Edinburgh, UK

CORRESPONDENCE: K. De Boeck, Dept Pediatric Pulmonology, University of Leuven, Herestraat 49, 3000 Leuven, Belgium. Fax: 32 16343842. E-mail:christiane.deboeck@uz.kuleuven.ac.be

Keywords: Burkholderia cepacia complex, cystic fibrosis, epidemiology, lung infection, microbiology

Received: October 23, 2003
Accepted February 4, 2004

P. Vandamme is indebted to the Fund for Scientific Research-Flanders for financial support.


   Abstract
TOP
 Abstract
Methods
 Results
 Discussion
 Acknowledgements
 References
 
In Belgian cystic fibrosis (CF) clinics, sputum samples are evaluated on selective MAST medium routinely every 3 months. In this study, in 1993 and 1999, isolates were further examined by recA restriction fragment length polymorphism analysis and pulsed-field gel electrophoresis of genomic DNA restricted with SpeI.

In 1993, 12 patients were colonised with Burkholderia cepacia complex (Bcc): B. cenocepacia (n=6), B. multivorans (n=3), B. stabilis (n=3). Four patients were colonised with the same B. cenocepacia strain; two with the same B. stabilis strain. After 5 yrs, three B. cenocepacia- and one B. multivorans-colonised patients had died.

In 1999, Bcc was isolated in 12 patients: B. multivorans (n=9), B. stabilis (n=1) and B. cenocepacia (n=2). Three patients were colonised by the same B. multivorans strain. Compared to matched controls, the 5 yr outcome was poor; four B. cepacia patients died and none of the control patients died. Lung-function evolution was poor.

In conclusion, the rate of colonisation in Belgian cystic fibrosis patients is stable and low. Burkholderia cenocepacia was most prevalent in 1993; Burkholderia multivorans in 1999. The cross-infection rate is low. Three patients had transient colonisation. The impact of Burkholderia cepacia complex on morbidity in the Belgian cystic fibrosis population is high and not limited to Burkholderia cenocepacia.

Chronic respiratory tract infections with intercurrent acute exacerbations are the hallmark of cystic fibrosis (CF) lung disease. Pseudomonas aeruginosa and Staphylococcus aureus are recovered most frequently from respiratory secretions of CF patients 1. Burkholderia cepacia infection is much less common, but it is notorious for being associated with cross infection and the possibility of rapid deterioration, known as the cepacia syndrome 2–4. B. cepacia colonisation frequency differs greatly between CF centres; overall, the prevalence is low, but the impact on individual patient survival may be very high 5. Furthermore, the possibility of B. cepacia colonisation induces a high level of anxiety in the CF population.

Optimal isolation of B. cepacia from CF sputum requires the use of selective culture media 6. Remarkable heterogeneity among presumed B. cepacia strains and the lack of reliable identification schemes makes correct identification of B. cepacia colonisation a complex problem 5, 6. Several distinct genomovars are collectively referred to as B. cepacia complex (Bcc) 7. The most commonly isolated Bcc species in CF patients are B. multivorans, B. cenocepacia and B. stabilis. A rapid deterioration and patient-to-patient transmission is probably more likely with B. cenocepacia infection and colonisation 8, 9. A Belgian surveillance study in 1993 revealed that 12 out of 465 Belgian CF patients were Bcc colonised. These strains belonged to three different genomovars i.e. B. multivorans, B. cenocepacia and B. stabilis) 10.

The aims of the present study were to critically re-evaluate the prevalence of Bcc colonisation in Belgian CF patients during a new national 1-yr surveillance study to determine the genomovar status of the isolates and to evaluate the clinical status of patients colonised with Bcc, as compared to patients not colonised with Bcc. In addition, the clinical course of CF patients, colonised during the 1993 surveillance study, was evaluated.


   Methods
TOP
 Abstract
 Methods
Results
 Discussion
 Acknowledgements
 References
 
In Belgium, since 1993 CF centres have used selective MAST medium (Mast Diagnostics, Meyerside, UK) to inoculate all sputum samples and upper airway samples from CF patients. Sputum samples are examined routinely every 3 months. A throat swab is taken in patients unable to produce sputum. All 11 Belgian health facilities caring for CF patients agreed to participate in the current study and to send all B. cepacia-like isolates to the reference laboratory between February 1999 and February 2000. The isolates were first examined by means of whole-cell protein electrophoresis, and compared to a database comprising a large number of Gram-negative, nonfermentative bacteria, isolated from CF and environmental specimens 11–15. Extensive taxonomic studies have revealed that this method allows species-level identification of a wide range of Gram-negative nonfermenting bacteria, commonly misidentified as Bcc, and confirms the identification of putative Bcc isolates at the complex level 14, 15. The method has proved to be insufficiently discriminatory to identify all species within Bcc 14, 15. Therefore, Bcc bacteria were further examined by means of recA restriction fragment length polymorphism (RFLP) analysis 16 and pulsed-field gel electrophoresis (PFGE) of genomic DNA restricted with SpeI 17. Non-Bcc bacteria were further examined by using whole-cell fatty acid analysis 7. Presence of the cable pilus subunit gene 18 and the epidemic strain marker BCESM 19 were determined by PCR using established primers.

For every patient colonised by Bcc, a control patient was identified from the same CF centre as the index patient and matched for sex, pancreatic status and genotype (a homozygous F508del patient was chosen for a F508del homozygous index case, a heterozygous F508del/other severe mutation was chosen for a heterozygous F508del/other severe mutation index case; mutations were considered severe when associated with pancreatic insufficiency and reported as such in the Toronto CF consortium database 20. Patients were also matched for respiratory colonisation status, with chronic P. aeruginosa colonisation being defined as at least three sputum cultures positive for P. aeruginosa over the course of 6 months 21. If several patients qualified, the patient with the birth date closest to the index patient was chosen. There was no difference in mean age between index cases and controls (table 1Go).


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  		Table 1— Data on Burkholderia cepacia complex-colonised patients (Bcc) and their controls (Con)

 
For both index and control patients, body mass index (BMI) was calculated and expressed as sd score 22. Maximal expiratory flow manoeuvres were performed according to 1994 American Thoracic Society criteria 23. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were expressed as per cent of the normal value, according to Zapletal for children and the European Community for Coal and Steel for adults 24. For the time period outside the surveillance year, lung function data were extracted from the patient's chart. For every Bcc-colonised patient, the time of first colonisation was determined from the patient's chart. Data on all reported patients are included in the Belgian CF database. These patients all sign an informed consent and agree that their clinical data may be analysed and reported in an anonymous way in clinical studies.

Median age of colonised patients was compared to median age of CF patients included in the Belgian CF registry. The age distribution for the Belgian CF population in 1999 was not normal and, therefore, for this purpose, median age is reported and Mann-Whitney U-test was used for analysis.

Since 1995, specific infection control measures have been taken in all Belgian centres to prevent patient-to-patient spread of Bcc. These include: stressing hand wash policy for all patients and personnel; individual rooms for all hospitalised CF patients; and isolation during hospital admission, as well as during outpatient clinic visits for patients colonised with Bcc.


   Results
TOP
 Abstract
 Methods
 Results
Discussion
 Acknowledgements
 References
 
MAST isolates during study period 1999
During the study period, the sputum or throat samples of 650 CF patients were evaluated on selective media. In eight of the 11 participating centres, Bcc-like strains were isolated and sent to the reference laboratory. A total of 67 isolates from 26 different patients were examined. Twelve patients from six different centres were genuinely colonised with Bcc: B. multivorans (n=9), B. stabilis (n=1) and B. cenocepacia (n=2). The recA RFLP type of each isolate is listed in table 2Go. None of the B. cepacia isolates carried the BCESM or cable pilus genes. In one patient colonised with B. cenocepacia, Stenotrophomonas maltophilia and Achromobacter xylosoxidans were also isolated. Other bacteria isolated on MAST medium not belonging to Bcc complex were identified as Sphingobacterium sp. 1, Chryseobacterium meningosepticum 2, P. aeruginosa 4 and Pandoraea pnomenusa 2. Five strains could not be identified.


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  		Table 2— RecA restriction fragment length polymorphism (RFLP) type by patient number

 
Typing results using pulsed field gel electrophoresis
An overview of typing results for Bcc isolates is given in figure 1Go. Typing results confirmed that the patients remained colonised by the same strain during the course of the study (data not shown). Three patients were colonised by an identical strain; two patients were followed at centre E (PFGE type III) and one was followed at centre H (PFGE type III'). The PFGE DNA profile of the latter isolate differed in four DNA fragments from the profiles of the former two isolates. Such a limited degree of genomic variability is well known to occur in genomically versatile organisms like Bcc bacteria 25, and unrelated isolates differ in larger numbers of DNA fragments, as can be seen in figure 1Go. The centres E and H are 50 km apart and the three patients claim not to have any contact with each other. Three colonised patients had already been detected as positive during the 1993 cohort study. Typing results indicate that these patients continue to be colonised by the same B. cepacia strain. In one patient, during 2002, a temporary switch from colonisation by B. stabilis to colonisation by B. multivorans occurred. At present, the patient is again colonised with B. stabilis, as he has been for 10 yrs.



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  		Fig. 1.— Pulsed-field gel electrophoresis (PFGE) pattern of the Burkholderia cepacia complex isolates in the 12 patients as indicated by their number in table 1Go in 1999. Different PFGE banding patterns are numbered sequentially. Types III' and IV' differ in 4 and 3 fragments, respectively, from the types III and IV banding patterns. Patients 4, 8 and 5 were included in the 1993 study and were identified as having PFGE type IV', VI and VIII respectively. For patient 4, the 1993 isolate with IV' banding pattern is also shown which differs slightly from type IV. For patients 5 and 8, the PFGE pattern of the strain was identical in 1993 and 1999. Number of samples: patient 1, n=5; patient 2, n=6; patient 3, n=2; patient 4, n=2; patient 5, n=2; patient 6, n=3; patient 7, n=1; patient 8, n=8; patient 9, n=4; patient 10, n=2; patient 11, n=1; patient 12, n=8.

 
Clinical patient data
All 12 index patients had pancreatic insufficiency. Nine patients were homozygous F508del, and three patients were heterozygous for F508del and another mutation known to be associated with a severe phenotype. Three patients were not colonised by P. aeruginosa or other nonfermentative Gram-negative bacteria at the time of Bcc acquisition (table 1Go). In one 7-yr-old patient, colonisation by B. cenocepacia was transient during the study period. However, this patient became positive again in 2001.

Median age (quartile ranges) of Bcc-colonised patients was 19.5 yrs (14.4–24.5) compared to 15.6 yrs (6.5–21.5) in the 1999 Belgian CF cohort (p<0.05, Mann-Whitney U-test; C. Sevens, Vrije Universiteit Brussels, Brussels, personal communication).

Clinical status in 1999 differed between Bcc-colonised patients and controls for lung function, but not for weight and BMI (table 1Go). FVC and FEV1 were significantly lower in colonised patients compared to control patients ((mean±sem) FVC 57±6% versus 80±8%, unpaired t-test, p<0.01; FEV1 41±7% versus 64±8%, unpaired t-test, p<0.05).

At the end of the special surveillance period (i.e. February 2000), the mean duration of Bcc colonisation in the index cases was 3.8 yrs (range 0.5–7.25 yrs). Therefore, the 5-yr evolution was evaluated since the onset of colonisation with Bcc in the colonised patients, and in the corresponding time period in the control patients. The evolution is unfavourable in Bcc patients (p<0.01, Chi-squared test). None of the control patients died. Four B. cepacia colonised patients died: three were colonised with B. multivorans; one with B. cenocepacia. The latter died of B. cepacia sepsis 2 months post lung transplant. At the time of first isolation of B. cepacia, lung function values were lower in the index patients as compared to controls, but this difference was not statistically significant: FVC 65±7% versus 76±6%, unpaired t-test, p=0.27; FEV1 50±7% versus 62±8%, unpaired t-test, p=0.15). However, lung-function evolution from 1 yr before colonisation to 5 yrs after colonisation was significantly worse in the Bcc-colonised patients as compared to the matched controls (p<0.01, repeated measurement ANOVA) (table 3Go).

Clinical evolution of patients in the 1993 cohort
In 1993, 12 out of 465 Belgian CF patients tested were detected as colonised with Bcc. These patients were followed at three out of six participating centres. Six patients were colonised with B. cenocepacia, three with B. multivorans and three with B. stabilis. All clinical follow-up data could be collected in 11 patients. Transient colonisation was documented in three of these 11 patients. In all of the patients, more than 10 sputum samples were grown onto MAST medium in an attempt to isolate Bcc. Five patients have died; four patients within 5 yrs after acquiring Bcc.

Four of the six patients colonised with B. cenocepacia have died. Three of these patients harboured the same (therefore called "epidemic") strain, as documented by PFGE. Of these, two patients died after prolonged colonisation (7 and 11 yrs). One patient died 2 yrs after becoming Bcc culture negative. The patient not carrying the epidemic strain died 2 yrs after lung transplantation, having remained positive for B. cenocepacia after transplant. Two B. cenocepacia-colonised patients are still alive; one is no longer culture positive, after 5 years of colonisation with the epidemic strain.

The three patients colonised with B. multivorans remained colonised for a long time. One was transplanted in March 1998, temporarily cleared but became positive again with a unique strain in 2001. Two patients remained positive and are also included in the 1999 cohort; one died in December 1999 and one underwent a lung transplant in August 2001.

No data are available in one patient for B. stabilis. The two other patients have been colonised by the same strain and are followed at the same centre. One young adult male is also included in the 1999 cohort and continues to be colonised with the same B. stabilis isolate. This patient suffers from moderate lung disease. One adolescent male became negative for B. stabilis 3 yrs before a right upper lobectomy performed in 1997 and continues to be negative ever since.

In three patients, transient colonisation is thus documented, even when several sputum cultures on selective media have been examined year after year.


   Discussion
TOP
 Abstract
 Methods
 Results
 Discussion
Acknowledgements
 References
 
In 1999, only 12 out of 650 Belgian CF patients were colonised by Bcc. The prevailing genomovar was B. multivorans; only two patients were colonised by B. cenocepacia. The 5-yr evolution following onset of Bcc colonisation was poor: four of the 12 index cases died, although none of the matched controls died. In addition, lung-function evolution was significantly worse in index cases than in controls. In 11 out of 12 Belgian CF patients colonised with Bcc in 1993, the outcome could be evaluated: three patients had transient colonisation, five patients died, of whom four within 5 yrs of acquiring Bcc.

The Bcc colonisation rate in Belgian CF patients is low and remains low. In 1993, 12 patients out of 465 screened were Bcc positive. In the second national surveillance study, 12 out of 650 patients were Bcc positive. For the second study, all centres were able to cooperate and that study comprised all of the CF patients known in Belgium (the Belgian CF registry for 1999 contains data on 605 patients (C. Sevens, personal communication)). This suggests that there was no increase in Bcc colonisation in Belgian CF patients from 1993 to 2000.

In the Belgian CF community, the prevailing B. cepacia genomovar varied over time. In the 1993 cohort, six of the 12 patients were colonised with B. cenocepacia; the species most commonly associated with epidemic spread of disease and rapid deterioration 8, 9. In the 1999 cohort, the majority (9 out of 12) of the patients were colonised with B. multivorans; only two patients were colonised with B. cenocepacia. This differs from the USA and Canada, where the majority of the isolates belong to B. cenocepacia 9, 26, 27. In the study by Chen et al. 27, 59 out of 60 Bcc isolates in CF patients were B. cenocepacia, and 57 of these 59 isolates represented the same clone. In Belgium, in between the two evaluation periods, strict isolation measures for Bcc-colonised patients have been instituted. These seem to have been successful so far.

The prevailing Bcc genomovar has been reported in few countries. The Belgian data differ somewhat from that which is known in both Italy and the UK as well. A nationwide survey was not reported from these countries, but a large number of Bcc isolates from CF patients was studied. A high incidence of infection caused by a single B. cenocepacia epidemic clone, possessing the cable A gene and closely related to the USA–UK clone "ET12", was reported from two Sicilian CF centres 28. A recent study on 117 patient isolates from 40 UK hospitals reported that B. cenocepacia is most prevalent, with most isolates belonging to the epidemic clone 29. However, both in Italy and the UK, other Bcc species were isolated from CF patients. It appears that in the absence of epidemic spread of one particular strain, the incidence of Bcc infection is low (such as in Belgium) and the distribution of genomovars is more varied.

The possibility of patient-to-patient transfer of B. cepacia in the CF community has always been worrisome. From DNA fingerprinting by AP-PCR and PFGE results in the 1993 cohort, it was demonstrated that four Belgian patients with B. cenocepacia were colonised by the same strain. These patients all attended the same clinic 10. Two patients with B. stabilis colonisation, attending distinct clinics, shared the same strain.

For the 1999 cohort, three patients with B. multivorans shared an identical strain. In the UK, most reports stress the importance of the epidemic B. cenocepacia strain; however, B. multivorans is second in prevalence and several clusters of cross-infection have been identified 29. In addition, in Italy, patient-to-patient spread was observed with genomovars other than B. cenocepacia 28. The fact that the number of patients sharing the same strain decreases, suggests that for Belgian patients cross-infection is at present less likely than acquisition from an environmental source. Bcc is being used in agriculture for plant disease control 30 and strains from all genomovars have been isolated from the environment 31.

Patients colonised with Bcc may remain colonised during prolonged periods of time. Three patients were colonised by the same strain from 1993–1999. However, transient colonisation does seem to occur. It was documented in three patients of the total group of 21 patients described in this paper. Since in these patients several sputum samples were grown on B. cepacia selective media, it is unlikely that the pathogen was missed. In some patients, however, Bcc was not isolated for several years and then their first strain reappeared up to 10 yrs later. In some of these patients, it cannot be excluded that reacquisition from the environment occurred. Reports from UK 32 and Canada 33 also incidentally mention transient Bcc infection, but a thorough evaluation of a cohort to assess the frequency of this event has not been reported previously.

Unlike the initial reports 2, 3 suggested, Bcc acquisition is not limited to patients with P. aeruginosa colonisation nor patients with severe lung disease. In the Belgian study, several patients were not colonised with P. aeruginosa prior to Bcc colonisation. At the onset of Bcc colonisation, there was no significant difference in lung function abnormality between Bcc positive patients and controls. However, in the 5 yrs following onset of colonisation, the mortality is higher and lung function deterioration is faster.

In this Belgian study, the mortality amongst Bcc-colonised patients is high; from the 1993 cohort, four of the six patients colonised with B. cenocepacia have died. One of the remaining six patients has died; this patient was included in the 1999 cohort. Four other patients out of the 1999 cohort have also died, whereas none of the control patients have died. Only the transplanted patient died with the typical febrile bacteraemic "cepacia syndrome". The big impact of Bcc colonisation on disease severity and mortality has been reported previously 2, 3, 32 and is confirmed by the present study. This study in a low-Bcc-incidence country clearly corroborates that the Bcc problem is not limited to B. cenocepacia.

In conclusion, in the Belgian cystic fibrosis population, Burkholderia cepacia complex colonisation rate is low and stable. Burkholderia multivorans and Burkholderia cenocepacia colonisation is most common. Although most patients are colonised for a longer time, in some patients transient colonisation seems to occur. The impact of Burkholderia cepacia complex on morbidity and mortality in a cystic fibrosis population is high and not limited to Burkholderia cenocepacia isolates. In Belgian cystic fibrosis patients, most patients carry a different strain and the cross-infection rate is low.


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  		Table 3— Five-yr evolution of forced expiratory volume in one second in Burkholderia cepacia complex-colonised patients (Bcc) and control patients

 

   Acknowledgements
TOP
 Abstract
 Methods
 Results
 Discussion
 Acknowledgements
References
 
The Belgian Burkholderia cepacia study group: L. Van Schil, J-P. Ursi (St. Vincentiusziekenhuis, Antwerpen); K. Desager, G. Ieven (Universitair Ziekenhuis Antwerpen, Antwerpen); A. Mertens (Algemeen Ziekenhuis Middelheim, Antwerpen); A. Malfroot, I. Dab, S. Lauwers (Academisch Ziekenhuis, Vrije Universiteit Brussels, Brussels); P. Lebecque, J. Gigi (Université Catholique de Louvain, Brussels); C. Knoop, M. Struelens (Hôpital Erasme, Brussels); H. Franckx (Zeepreventorium, De Haan); F. De Baets, S. Vandaele, G. Verschraegen (U.Z. Gent, Gent); P. Vandamme, S. Laevens (Universiteit Gent, Gent); K. De Boeck, M. Proesmans, J. Van Eldere (Universitair Ziekenhuis Gasthuisberg, Leuven); F. Lebrun, F. Pauquay (Clinique de l'Espérance, Montegnée); E. Bodart, Y. Glupczynski (Clinique Universitaire de Mont-Godinne, Mont-Godinne); C. Sevens from the Belgian cystic fibrosis registry (Vrije Universiteit Brussels, Brussels).


   References
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 Abstract
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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