| | Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patientsAbstract Background: Patients were defined each successive month as either ‘chronic’ when more than 50% of the preceding 12 months were PA culture positive, ‘intermittent’ when ≤50% of the preceding 12 months were PA culture positive, ‘free of PA’, with no growth of PA for the previous 12 months, having previously been PA culture positive, or ‘never infected’, when PA had never been cultured. Methods: Cross-sectional analysis of 146 children attending the Leeds Regional Cystic Fibrosis Centre was performed to assess relationship between the new definition and clinical scores and investigations. The response variable was regressed on age and sex and the residuals analysed using the Kruskal–Wallis test. Results: The ‘chronic’ group (18% of patients) had significantly worse Shwachman–Kulczycki (SK) and Northern chest X-ray scores, and % predicted FEV1 values than the ‘free’ (28%) or ‘never’ (20%) categories (P<0.004). The ‘intermittent’ group (34%) had a significantly higher SK score than the ‘chronic’ group (P<0.0001), and a significantly lower % predicted FEV1 value than the ‘free’ or ‘never’ groups (P<0.0003). ‘Chronic’ patients were significantly associated with a positive, and ‘never’ patients with a negative, PA antibody result (P<0.001). Conclusions: The validity and importance of identifying these four subgroups is demonstrated. Previous definitions may over-estimate the prevalence of chronic infection.
1. Introduction  Pseudomonas aeruginosa is the most common pathogen causing chronic infection in people with cystic fibrosis (CF) [1]. Chronic infection with this organism has been shown to be associated with a lower FEV1 in childhood [2], a faster decline in FEV1 despite optimal respiratory management [3], [4], a worse mortality rate [5], and shorter median survival [1]. Currently there is no universally accepted definition for chronic P. aeruginosa infection. In the UK the Cystic Fibrosis Trust use the definition proposed by Brett et al. in 1992 as ‘the regular culture of P. aeruginosa from the sputum or respiratory secretions, on two or more occasions, extending over 6 months or a shorter period if accompanied by a sustained rise of anti-Pseudomonas antibodies’ [6]. In Copenhagen chronic P. aeruginosa infection is defined as ‘persistent presence of P. aeruginosa for at least 6 consecutive months, or less when combined with the presence of two or more P. aeruginosa precipitins’, with intermittent P. aeruginosa colonisation defined as ‘culture of P. aeruginosa at least once and the presence of normal levels of precipitating antibodies against P. aeruginosa’ [7]. In Germany and North America chronic P. aeruginosa colonisation is defined as having more than 50% of cough swab or sputum samples positive in a 12-month period [2], [8], or by whether a patient's last sputum sample of each year grows P. aeruginosa [1]. Modern CF care, particularly the success of P. aeruginosa eradication policies [9], has resulted in these definitions becoming less appropriate for many patients with CF. For example, a patient may grow P. aeruginosa on two or more occasions and then, following eradication, not grow the organism again for many years. A validated, universally accepted, and clinically useful classification of patients infected with P. aeruginosa, particularly those chronically infected, would improve patient care for the following reasons:
1.Treatment: Determining which patients require chronic P. aeruginosa treatment protocols [10], [11].
2.Clinic Management: Enabling cohort isolation of those patients that are at high risk of infecting other CF patients with P. aeruginosa [12], [13], [14].
3.Prognosis: Allowing better prognostic information for patients and parents.
4.Audit: Enabling clinical effectiveness of anti-Pseudomonal strategies within the clinic to be assessed quantitatively over time [7].
5.Research: Facilitating the comparison of results from different CF centres, and cumulative analyses such as national CF databases. As there is presently no established ‘gold-standard’ definition for P. aeruginosa infection it is not possible to directly validate any new definition. However, it is possible to assess face-validity by determining if a new definition classifies patients appropriately in relation to relevant clinical scores and investigations. Face validity demonstrates that the measure reflects the content of the concept in question [15], and as the association of chronic P. aeruginosa infection with clinical score [16], chest X-ray score [4], percent predicted FEV1 [2], [3], height and weight [3], and P. aeruginosa antibody level [6] is already established, the validity of a new definition can be best assessed in this way. The accuracy of any definition will depend on the frequency of sampling. The UK Cystic Fibrosis Trust suggests sputum sampling at least every 2 months (six times per year) in children and every 3 months (four times per year) in adults [17]. If patients are sampled less than this then any categorisation is likely to be inaccurate. We would recommend that sampling should be taken three monthly as a minimum as recommended by the European Consensus on Antibiotic Therapy against P. aeruginosa [10]. The definition of chronic infection should be based on microbiological results from cough swabs or sputum samples as few centres have access to well-validated, prompt P. aeruginosa antibody results. The monthly categorisation should be independent of the multiplicity of samples taken within any given month, to avoid bias caused by patients having more frequent sampling during exacerbations. The aim of this study was to assess the validity of a new definition for chronic P. aeruginosa infection that meets these requirements. 2. Methods 2.1. Monthly culture status Patients were defined each successive calendar month as either:
1.Pseudomonas aeruginosa culture positive (one or more P. aeruginosa positive cough swabs or sputum cultures that month).
2.P. aeruginosa culture negative (all cough swab or sputum cultures that month negative for P. aeruginosa).
3.No cough swab or sputum culture performed that month. 2.3. Microbiological methods Standard practice for patients receiving all of their care at our Centre is to have a sputum or cough swab sample taken at every clinic visit, with no more than twelve weeks between visits. Sputum samples were collected from all children who could expectorate. Parents were encouraged to collect sputum samples at home if their children expectorated only rarely. When it was not possible to obtain sputum samples and the child was well, cough swabs were taken. If new infection was suspected clinically sputum induction was attempted using hypertonic saline [18]. P. aeruginosa was isolated from samples using standard microbiological methods. Briefly, sputum samples were homogenised with an equal volume of Sputasol (Oxoid Ltd, Basingstoke, UK) and incubated at 37 °C for 30 min. 0.1 ml of homogenate was added to 5 ml of peptone water, agitated, and 10 μl of this was used to inoculate bactracin (10 mg/l)—chocolate agar. Cough swabs were applied directly without dilution. All plates were incubated at 37 °C in air for 48 h. Presumptive P. aeruginosa isolates were identified by colonial morphology, gram stain, positive cytochrome oxidase test, and biochemical profiling using API 20NE (bioMerieux, Marcy l'Etoile, France). 2.4. Patients Initially an 11-year retrospective analysis of all 232 patients receiving all their CF care at the Leeds Regional Paediatric Cystic Fibrosis Centre between October 1989 and December 2000 was performed to determine the proportion of patients in each category per month, and the future risk of growing P. aeruginosa for patients defined as ‘free’ or ‘never’ (Total patient months assessed 17230). The relationship between categorisation and clinical data was assessed in April 1999. All patients who had received all their CF care at the Leeds Paediatric CF Centre for at least 12 months were included in the cross-sectional analysis. Clinical and demographic data was collected as near as possible to the end of the 12-month period. Two investigators (KB and SC) assessed Shwachman–Kulczycki (SK) [19] and Northern chest X-ray scores [20], and another investigator (TL) then determined patients’ P. aeruginosa infection categories for April 1999. The percent-predicted FEV1 was recorded for all patients old enough to perform this test reproducibly [21] and height and weight measurements, and calculated body mass indices were compared to a standard non-CF population [22]. P. aeruginosa antibody levels were also recorded, and were considered positive if >16 [6]. The value of the categorisation in predicting future infection status was assessed by taking all those patients who had been attending the clinic and having cough swabs or sputum samples taken for at least 12 months in April 1994, and who were still present in the clinic in April 1999. Patients were classified by the new definition both in April 1994 and April 1999. The clinical variables associated with each P. aeruginosa infection category were then compared. All variables changed linearly with age. Since age and sex were possible confounding factors the analyses have adjusted for these when appropriate with age included in the parametric models (analysis of covariance) as a linear covariate. For non-parametric analyses the response variable was regressed on age (and sex, if appropriate) and the residuals were analysed using the Kruskal–Wallis test. The χ2 test was used to assess the relationships between P. aeruginosa infection category and a positive P. aeruginosa antibody test, and infection category in 1994 to infection category in 1999. 3. Results Microbiological data allowing classification on the basis of Pseudomonas aeruginosa sputum culture status was available for all 232 patients receiving full-care at the centre during the period 1990–2000. During the total 17 230 patient months assessed, patients were defined as ‘chronic’ for 3793 months (22.0%), ‘intermittent’ for 5355 months (31.1%), ‘free’ for 4084 months (23.7%), and ‘never’ for 3998 (23.2%) months. During this period the risk of a new growth of P. aeruginosa in those patients classified as ‘free’ or ‘never’ was 4.1 and 2.2% per month, respectively (P<0.02). Clinical data was available for all 146 patients who had been receiving their full care at the centre for at least 12 months in April 1999 (Table 1), although the 28 youngest children were unable to perform FEV1 assessment. The largest group was the ‘intermittent’ category, and there was a high proportion of males in the ‘free’ category. The association between infection category and SK score was highly significant (P<0.0001), with progressively lower SK scores as severity of P. aeruginosa categorisation increased from ‘never’ through to ‘chronic’ (Table 2). Age and sex had no significant association with SK score, and were removed from the model. The difference between the ‘chronic’ group and the other categories was significant. Northern chest X-ray score was significantly associated with age and sex, and when these were adjusted for the effect of P. aeruginosa infection category remained highly significant (P<0.0043), with the ‘chronic’ score significantly worse than in the ‘free’ and ‘never’ categories. The percent-predicted FEV1 was significantly associated with sex, and following appropriate adjustment the association with infection category was highly significant (P<0.0003). The ‘chronic’ and ‘intermittent’ groups’ percent-predicted FEV1s were significantly lower than those in the ‘free’ and ‘never’ groups. | | |  | | Chronic | Intermittent | Free | Never | |
|---|
| Mean SK score (S.D.) | 74.5 (14.9) | 86.6 (8.9) | 88.3 (10.4) | 92.7 (5.4) | |
| Mean Northern score (S.D.) | 9.2 (3.9) | 6.3 (2.8) | 5.7 (2.9) | 4.0 (1.7) | |
|  [mean adjusted for age and sex] | [8.0] | [6.3] | [5.8] | [5.2] | |
| Mean percent-predicted FEV1 (S.D.) | 64.4 (19.2) | 69.8 (17.6) | 83.1 (19.8) | 83.4 (12.3) | |
| [mean adjusted for sex] | [65.1] | [69.6] | [81.1] | [84.9] | | | | |
It was necessary to adjust for age when analysing the association between infection category and height, and following this infection category had no significant association (Table 3). However, when height standardised scores (SDS) were assessed, it was demonstrated that those in the ‘chronic’ group were significantly shorter than the ‘never’ group (P=0.032). Adjustment for age was also required when assessing the association between infection category and weight and body mass index, after which infection category was not significantly associated with these parameters. Similarly, after age adjustment, there was no significant association between infection category and weight and body mass index SDS scores. | | | | | Chronic | Intermittent | Free | Never | |
|---|
| Mean height (S.D.) | 148.3 (14.3) | 130.7 (28.0) | 135.1 (23.4) | 111.6 (24.4) | |
| [mean adjusted for age] | [128.7] | [131.1] | [132.0] | [132.5] | |
| Mean height SDS (S.D.) | −0.94 (0.98) | −0.75 (1.13) | −0.45 (0.92) | −0.49 (0.99) | |
| [mean adjusted for age] | [−1.11] | [−0.74] | [–0.47] | [−0.30] | |
| Mean weight (S.D) | 40.7 (11.2) | 31.5 (15.3) | 33.9 (15.8) | 22.4 (11.4) | |
| [mean adjusted for age] | [30.0] | [31.8] | [32.5] | [33.6] | |
| Mean weight SDS (S.D.) | −0.73 (1.00) | −0.52 (1.06) | −0.16 (0.96) | −0.14 (0.99) | |
| [mean adjusted for age] | [−0.71] | [−0.52] | [−0.16] | [−0.16] | |
| Mean BMI (S.D.) | 18.1 (2.3) | 17.3 (2.3) | 17.5 (2.3) | 16.0 (1.8) | |
| [mean adjusted for age] | [17.3] | [17.3] | [17.4] | [17.8] | |
| Mean BMI SDS (S.D.) | −0.25 (0.99) | −0.05 (1.02) | 0.18 (0.92) | 0.30 (0.87) | |
| [mean adjusted for age] | [−0.04] | [−0.06] | [0.21] | [0.07] | | | | |
The association between infection category and P. aeruginosa antibody level required adjustment for age (Table 4). Following this the association with infection category was highly significant (P<0.0001), with a significantly higher P. aeruginosa antibody level in the chronic group when compared to the other three categories. When a P. aeruginosa antibody level of >16 was considered positive [6], ‘chronic’ patients were significantly associated with a positive antibody result (P<0.001), and ‘never’ with a negative antibody result (P<0.001). | | | | | Chronic | Intermittent | Free | Never | |
|---|
| Mean P. aeruginosa antibody | 156.0 (105.9) | 35.0 (56.2) | 24.0 (72.9) | 2.0 (8.0) | |
| level (S.D.) | | | | | |
| Number P. aeruginosa | 26 (100%) | 19 (38%) | 12 (29%) | 2 (7%) | |
| antibody positive (%) | | | | | |
| Number P. aeruginosa antibody | 0 | 31 (62%) | 29 (71%) | 27 (93%) | |
| negative (%) | | | | | | | | |
The predictive value of infection status in determining status five years later was assessed among the 84 patients who had been seen in the centre since 1994 (Table 5). Of those patients defined as ‘chronic’ in 1994 seven (88%) remained chronic in 1999, significantly more than would be expected if this definition had no predictive value (P<0.001). In contrast, only 29% of those classed as ‘intermittent’ in 1994 had progressed to ‘chronic’ by 1999. | | | | 1999 | 1994 | |
|---|
| | Chronic | Intermittent | Free | Never | |
|---|
| Chronic | 7 | 5 | 6 | 2 | |
| Intermittent | 1 | 7 | 11 | 11 | |
| Free | 0 | 5 | 13 | 9 | |
| Never | 0 | 0 | 0 | 7 | | | | |
4. Discussion The purpose of this study was to determine the value of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients, allowing patients to be categorised into one of four groups according to the results of monthly sputum cultures over the preceding year. The results show that this new definition has good face validity, and demonstrates the importance of identifying these four subgroups of patients. We therefore suggest that this new definition is more useful than previous definitions. The clinical data demonstrates that chronic P. aeruginosa infection is associated with worse SK clinical score, worse Northern chest X-ray score, worse percent-predicted FEV1, and a reduction in height standard deviation score when compared to uninfected patients, in keeping with previous studies [2], [7], [23], [24]. The latter acknowledge that many patients grow P. aeruginosa intermittently, but the clinical characteristics of this subgroup have not previously been separately analysed. Nor are there any studies assessing patients free of P. aeruginosa for more than 12 months (these have been previously categorised within the intermittent or first detection group) [7], [8]. It is clear from our data that these patients are very different clinically and prognostically from other children with cystic fibrosis. 4.1. Relevance for treatment These present data suggest that our previous definition ‘the regular culture of P. aeruginosa from the sputum or respiratory secretions, on two or more occasions, extending over six months’ would falsely categorise the many patients with a new incidence of P. aeruginosa as chronically infected [6]. When a routine cough swab or sputum culture demonstrates a new growth of P. aeruginosa the patient is called back to clinic for commencement of early eradication therapy and further cultures are taken [7], [9]. Patients with chest exacerbations requiring treatment also receive more frequent cultures than obtained in routine surveillance. This biases heavily towards a definition of chronic P. aeruginosa according to our previous definition [6]. Indeed 46 patients would have been classified as chronic in April 1999 compared to 28 under our new definition. Many such patients become free of P. aeruginosa following treatment, and it would be inappropriate for them to receive intensive chronic P. aeruginosa treatment protocols. The Copenhagen definition uses a precipitin technique, which is well validated but not widely available [7]. When precipitins have not been measured, chronic P. aeruginosa infection is defined as persistent presence of P. aeruginosa for 6 consecutive months. Patients classified as ‘chronic’ under our new definition have only 82.2% of months when sputum samples are taken in which P. aeruginosa is cultured. These patients are clinically very different from those who are classified as ‘intermittent’, and are significantly predisposed to remaining chronically infected. Only 15 of these 28 patients would be identified by the Copenhagen criteria without the support of precipitin results. The German definition uses a similar chronic P. aeruginosa infection definition as in our study, although they further subdivide this based on the presence of non-mucoid or mucoid strains [8]. In practice this subdivision does not affect treatment decisions, as evidence suggests that the entire group should be on intensive antibiotic treatment and mucolytics such as DNase [10], [25]. They do not differentiate between those classed as ‘intermittent’ and ‘free’, but our data demonstrates that these are very different groups. 4.2. Relevance for clinic management We have assessed the relative risk of patients in each diagnostic category growing P. aeruginosa in their sputum in any given month. For those patients classed as ‘never’ or ‘free’, the chance of growing P. aeruginosa is small (2 and 4%, respectively), and they are not a high risk for infecting other patients. ‘Chronic’ patients have an 82% chance of growing P. aeruginosa, strengthening the case for cohorting these patients to reduce the risk of cross-infection. Patients who are classed as ‘intermittent’ have a 24% risk of growing P. aeruginosa each month and ideally these patients should also be kept separate from those classed as ‘never’ or ‘free’ [26]. 4.3. Relevance for predicting future infection status An important feature for any definition of chronic P. aeruginosa infection should be that it has predictive value. As well as demonstrating an association with changes in respiratory function and clinical scores, it should also be shown to be of value in predicting a patient's P. aeruginosa infection status in the future. In our study 88% of patients defined as chronically infected remained in this category five years later. This is also of value over the short term, as of the 26 patients defined as ‘chronic’ in April 1999, 22 remained ‘chronic’ in April 2000 (85%). This compares favourably to both the Copenhagen definition (11 of 15 remaining chronic (73%)) [7], and our previous definition (34 of 46 remaining chronic (74%)) [6]. In addition, our data demonstrate that with appropriate treatment patients defined as ‘intermittent’ are most likely to remain in this category when reassessed 5 years later, with as many patients (29%) in this category reverting to ‘free’ as progressing to ‘chronic’. A high proportion (71%) of the patients in the ‘free’ group were male. Females outnumbered males in the other three groups. The relevance of this finding requires further investigation. 4.4. Relevance for research and audit P. aeruginosa is an important pathogen in cystic fibrosis, and much research into the effects of this organism as well as improved treatment strategies is being undertaken worldwide. For valid comparisons to be made between different studies it is important that a consensus is reached on the most appropriate definition for chronic P. aeruginosa infection. The increasing use of national databases to compare the results between centres also requires a definition that does not bias against those centres who perform sputum surveillance more frequently, or places too much emphasis on differing precipitin or antibody tests. 5. Conclusions This study demonstrates the value of an improved clinical definition for chronic P. aeruginosa infection. 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PII: S1569-1993(02)00141-8 doi:10.1016/S1569-1993(02)00141-8 © 2002 European Cystic Fibrosis Society. Published by Elsevier Inc. All rights reserved. | 1 of 14  |
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