Chronic Stenotrophomonas maltophilia infection and exacerbation outcomes in cystic fibrosis☆☆☆★

Article Outline

• Abstract
• 1. Introduction
• 2. Materials and methods
  • 2.1. Study design and definitions
  • 2.2. Statistical analysis
  • 2.3. Power analysis
• 3. Results
  • 3.1. Baseline patient characteristics
  • 3.2. FEV1 recovery following pulmonary exacerbation
  • 3.3. Effect of S. maltophilia antibiotic therapy on FEV1 recovery and time to subsequent pulmonary exacerbation
• 4. Discussion
• Acknowledgments
• References
• Copyright

Abstract 

Background

Chronic Stenotrophomonas maltophilia infection is a risk factor for pulmonary exacerbation in cystic fibrosis (CF) but its impact on subsequent clinical outcomes is unknown. The aim of this study was to determine the effect of chronic S. maltophilia infection and associated antimicrobial therapy on the recovery of forced expiratory lung volume in 1s (FEV₁) following pulmonary exacerbation.

Methods

This was a retrospective cohort study of patients with CF followed at The Hospital for Sick Children and St. Michael's Hospital from 1997 to 2008. The primary outcome was the difference in FEV₁ percent predicted from baseline to follow up after a pulmonary exacerbation. Secondary outcomes for the effect of antimicrobial therapy included time to subsequent exacerbation.

Results

There were 1667 pulmonary exacerbations in 440 CF patients. Patients with chronic S. maltophilia infection did not recover their baseline FEV₁ following 31% of exacerbations and had an overall mean FEV₁ decline of 1.84% predicted after exacerbation. Older (p=0.02), female (p=0.02) patients with lower BMI z score (p=0.002) and Burkholderia cepacia complex infection (p=0.005), but not chronic S. maltophilia infection (p=0.86), had a greater decrease in follow up FEV₁% pred compared to baseline. The number of days of antibiotic therapy against S. maltophilia during a pulmonary exacerbation was not associated with a significant difference in the FEV₁ recovery (p=0.69) or with a longer time to subsequent pulmonary exacerbation (p=0.56).

Conclusions

Although CF patients experience a significant decline in lung function following exacerbation, chronic S. maltophilia infection and associated antimicrobial therapy do not affect subsequent lung function recovery.

Abbreviations: ABPA, allergic bronchopulmonary aspergillosis, BMI, body mass index, CF, cystic fibrosis, FEV₁, forced expiratory volume in 1s, MRSA, methicillin resistant Staphylococcus aureus

Keywords: Cystic fibrosis, Stenotrophomonas maltophilia, Pulmonary exacerbation

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1. Introduction 

Chronic Stenotrophomonas maltophilia infection in cystic fibrosis (CF) patients has recently been shown to be an independent risk factor for pulmonary exacerbation [1]. Antibiotic use, however, is a known risk factor for the isolation of S. maltophilia in the respiratory tract of CF patients and increased treatment of pulmonary exacerbations may simply be selecting out S. maltophilia in the airways of sicker CF patients [2], [3], [4], [5]. The consequences of the increased number of pulmonary exacerbations in CF patients with chronic S. maltophilia infection are unknown.

Using the CF Foundation Patient Registry, Goss and colleagues have shown that a quarter of CF patients do not recover their baseline pulmonary function following an exacerbation and have identified risk factors associated with failure to recover baseline lung function [6]. We hypothesized that chronic S. maltophilia infection is associated with poorer outcome during pulmonary exacerbations in CF patients and that outcome may be influenced by whether or not specific antimicrobial therapy against S. maltophilia was initiated. The aim of this study was to determine the impact of chronic S. maltophilia infection on the recovery of forced expiratory lung volume in 1s (FEV₁) following pulmonary exacerbation and the role of anti-S. maltophilia antimicrobial therapy on FEV₁ recovery.

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2. Materials and methods 

2.1. Study design and definitions 

This was a retrospective cohort study using the Toronto CF Database of patients with CF followed at The Hospital for Sick Children and St. Michael's Hospital (Toronto, Canada) from 1997 to 2008. Patients were included in the study if they had a confirmed diagnosis of CF based on the following: a) the presence of clinical features consistent with CF, or b) a positive family history for CF plus either 2 documented sweat chloride values>60mEq/L measured by quantitative pilocarpine iontophoresis test, genetic testing showing 2 CF-causing mutations or a nasal potential difference consistent with CF [7]. Patients were excluded once they had received a lung transplant.

As previously, a pulmonary exacerbation was defined as a hospitalization for respiratory symptoms requiring antibiotics [1]. Each pulmonary exacerbation was classified into one of three groups based on previous definitions [1]: 1) chronic S. maltophilia: 2 or more positive sputum or bronchoalveolar cultures for S. maltophilia in previous 12months, 2) intermittent S. maltophilia: 1 positive sputum or bronchoalveolar cultures for S. maltophilia in previous 12months or a previous positive culture, and 3) never S. maltophilia: never having a positive sputum or bronchoalveolar culture for S. maltophilia. For baseline characteristics, patients were classified into one of these three groups based on respiratory tract culture results from the 12months prior to the first year of observation.

The primary outcome was the difference in FEV₁ percent predicted from baseline to follow up after a pulmonary exacerbation in each of these three groups. Baseline FEV₁ was defined as the best FEV₁ in the 6months before the hospitalization date for pulmonary exacerbation. Follow up FEV₁ was defined as the best FEV₁ in the 3months following the hospitalization date for pulmonary exacerbation [6]. Hospitalization FEV₁ was defined as the worst FEV₁ 7days prior or 4days after the date of hospital admission for pulmonary exacerbation [8]. FEV₁ recovery was defined as a follow up FEV₁ greater than or equal to 90% of the baseline FEV₁ [6]. Consecutive pulmonary exacerbations within 3weeks of antibiotic treatment were considered as a single event.

Antibiotic therapy for S. maltophilia was defined as the use of antibiotics with activity against S. maltophilia, such as trimethoprim–sulfamethoxazole, levofloxacin, ticarcillin–clavulanate and doxycycline [9], [10], in the 14days before or 21days after the date of hospital admission for pulmonary exacerbation.

This study was approved by the Research Ethics Board at The Hospital for Sick Children (1000013759) and St. Michael's Hospital (09-087^c).

2.2. Statistical analysis 

Analysis of variance (ANOVA) was used to compare continuous variables at baseline and chi-square independent test was used to assess the association to the three levels of S. maltophilia groups. A generalized linear mixed model (with appropriate covariance structures of power to account for the longitudinal nature of repeated data structure of FEV₁% of each subject) was generated to analyze the relationship between chronic S. maltophilia infection and change in FEV₁% predicted accounting for age, gender, BMI z score, pancreatic insufficiency, Pseudomonas aeruginosa, Burkholderia cepacia complex or methicillin-resistant Staphylococcus aureus (MRSA) infection, allergic bronchopulmonary aspergillosis (ABPA) (as defined by the treating physician in combination with increased IgE levels), drop in FEV₁% predicted from baseline to exacerbation, time since baseline FEV₁ measurement, and use of antibiotic therapy specific for S. maltophilia, based on risk factors identified in previous studies [6], [11]. Medicaid insurance was not included due to the existence of universal healthcare insurance in Canada. A second model, adjusting for significant variables identified in the first model, was generated to analyze the relationship between days of S. maltophilia antibiotic therapy during pulmonary exacerbation and change in FEV₁% predicted and time to subsequent pulmonary exacerbation.

2.3. Power analysis 

This study had 80% power, at the 5% level of significance, to detect a minimum difference of 1.4% predicted in FEV₁ recovery between the never and chronic S. maltophilia groups. Linear regression power analysis demonstrated that, this study had greater than 87% power to detect a minimum difference in the slope of 0.1 for FEV₁% predicted (SD 8.30) and 80% power to detect a minimum difference in the slope for time to subsequent exacerbation (days) of 4.0 (standard deviation of up to 429) regressed on the number of days of antibiotic therapy (SD 12.68).

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3. Results 

3.1. Baseline patient characteristics 

From 1997 to 2008, of the 881 CF patients followed in the Toronto CF Database, 440 patients had at least one pulmonary exacerbation requiring hospitalization and antibiotics. Of these 440 patients, 23 (5%) patients had chronic S. maltophilia infection, 29 (7%) had intermittent S. maltophilia infection and 388 (88%) had never had S. maltophilia isolated from the respiratory tract. Baseline patient characteristics are summarized by S. maltophilia infection status in Table 1, demonstrating no significant differences. Of note, patients in each of the three groups had a similar average number of respiratory cultures taken per year (chronic 2.9, intermittent 3.4 and never 3.0 cultures/yr p=0.49).

Table 1. Baseline characteristics of patients with pulmonary exacerbations.

	Chronic S. maltophilia (n=23)	Intermittent S. maltophilia (n=29)	Never S. maltophilia (n=388)	p value
No. resp cultures/yr, mean (IQR)	2.9 (1–4)	3.4 (1–4)	3.0 (2–4)	0.49
Age in years, mean (IQR)	19.8 (11.7–26.9)	18.6 (12.3–21.9)	20.0 (10.0–27.4)	0.85
Sex (male)	52.2%	58.6%	50.1%	0.67
Pancreatic insufficient	91.3%	89.7%	86.6%	0.91
CFRD	4.3%	17.2%	13.7%	0.36
Mean BMI z score (IQR)	−0.5 (−1.3 to 0.1)	−0.8 (−1.5 to 0.1)	−0.7 (−1.3 to 0.1)	0.77
Mean baseline FEV1% pred (IQR)	56.3 (42.5–67.3)	62.8 (47.4–73.8)	62.2 (45.3–77.1)	0.52
P. aeruginosa positive	40.9%	57.7%	61.6%	0.05
B. cepacia positive	4.5%	15.4%	18.1%	0.20

IQR: interquartile range.

3.2. FEV₁ recovery following pulmonary exacerbation 

During the study period, there were 1667 pulmonary exacerbations identified that required hospitalization and antibiotics. Of these, 366 (22%) were in patients with chronic S. maltophilia infection, 184 (11%) were in patients with intermittent S. maltophilia infection and 1117 (67%) were in patients who never had S. maltophilia. The adjusted difference in FEV₁% predicted from baseline to follow up after exacerbation is represented, according to S. maltophilia infection status, in Fig. 1. Patients with chronic S. maltophilia infection had a mean difference in FEV₁% predicted from baseline to follow up of −1.84% pred (SE 1.49), patients with intermittent S. maltophilia infection had a difference of −1.86% pred (SE 1.53) and patients who never had S. maltophilia had a difference of −2.25% pred (SE 1.40).

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• Fig. 1 

  Box plot of difference in forced expiratory volume in 1s (FEV₁) percent predicted from baseline to follow up after pulmonary exacerbation in patients with chronic S. maltophilia infection (Chronic S. maltophilia), intermittent S. maltophilia infection (Intermittent S. maltophilia) and in those who never had S. maltophilia infection (Never S. maltophilia).

The effect of chronic S. maltophilia infection on the difference in FEV₁% predicted from baseline to follow up after each exacerbation was evaluated using a linear regression model, adjusting for the previous identified variables. In this model, older (p=0.02), female (p=0.02) patients with lower BMI z score (p=0.002) and B. cepacia complex infection (p=0.005), had a greater decrease in follow up FEV₁% pred compared to baseline (Table 2). Patients who had a greater FEV₁ drop from baseline to the time of exacerbation also had lower FEV₁ in follow up after exacerbation (p<0.0001). Of note, patients with ABPA had a greater FEV₁ in follow up after exacerbation (p=0.0008). Patients with chronic S. maltophilia infection (p=0.86) or who had S. maltophilia antibiotic therapy (p=0.53) did not have a significant difference in FEV₁% pred recovery following exacerbation. Using previous definitions to dichotomize FEV₁ recovery [6], our data showed that FEV₁ was not recovered after 31% of exacerbations with chronic S. maltophilia infection, 23% of exacerbations with intermittent S. maltophilia infection and 31% of exacerbations with no S. maltophilia infection. Lower BMI z score, B. cepacia complex infection and greater FEV₁ drop were identified as significant risk factors for failing to recover FEV₁ in a generalized mixed model.

Table 2. Adjusted model results of FEV₁% predicted recovery following pulmonary exacerbation.

Variable	Regression estimate	SE	p value
Increasing age	−0.06	0.02	0.02
Gender (female)	−1.11	0.49	0.02
P. aeruginosa	−1.23	0.82	0.13
B. cepacia complex	−1.64	0.58	0.005
Lower BMI z score	−0.65	0.21	0.002
Allergic bronchopulmonary aspergillosis (ABPA)	3.16	0.94	0.0008
Greater FEV1 drop from baseline to exacerbation	−0.40	0.02	<0.0001
Chronic S. maltophilia	0.03	0.59	0.86
S. maltophilia antibiotic treatment	−0.008	0.01	0.53

3.3. Effect of S. maltophilia antibiotic therapy on FEV₁ recovery and time to subsequent pulmonary exacerbation 

To examine the effect of antibiotic therapy directed against S. maltophilia on FEV₁ recovery after a pulmonary exacerbation, a linear regression model was generated only for patients with S. maltophilia infection (chronic and intermittent S. maltophilia infections). Of the 366 exacerbations with chronic S. maltophilia infection, 121 (33%) of them were treated with S. maltophilia antibiotic therapy which eliminated S. maltophilia for at least 1year in only 31 (26%) of these exacerbations. Of the 184 exacerbations with intermittent S. maltophilia infection, 26 (14%) of them were treated with S. maltophilia antibiotic therapy which eliminated S. maltophilia for at least 1year in 15 (58%) of these exacerbations. Fig. 2 illustrates the number of days of S. maltophilia antibiotic therapy received for every exacerbation (mean 20days; median 14days; range 1–134days). The majority of these exacerbations (95%) were treated with only one S. maltophilia antimicrobial agent and in most cases (76%), S. maltophilia antimicrobial treatment was initiated on the day of hospitalization.

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• Fig. 2 

  Histogram of total number of days of S. maltophilia antibiotic therapy received per episode of pulmonary exacerbation in patients treated with S. maltophilia antibiotic therapy.

The difference in FEV₁% predicted from baseline to follow up after pulmonary exacerbations with chronic or intermittent S. maltophilia infection was evaluated adjusting for significant variables from the previous model. In this adjusted model, patients with a greater FEV₁ drop from baseline to the time of exacerbation (p<0.0001) had a greater decrease in follow up FEV₁ and patients with ABPA had a greater FEV₁ in follow up after exacerbation (p=0.03). The number of days of antibiotic therapy against S. maltophilia during a pulmonary exacerbation was not associated with a significant difference in the FEV₁ recovery following a pulmonary exacerbation (p=0.69). The results were similar when the gain in FEV₁% predicted from hospitalization to follow up after pulmonary exacerbation was evaluated.

For patients with chronic and intermittent S. maltophilia infections, the time to subsequent pulmonary exacerbation was then determined. The estimate of the time to subsequent pulmonary exacerbation was 574.85days (SE 113.45). A linear regression model was then generated to examine the relationship between time to subsequent exacerbation and number of days of antibiotic therapy against S. maltophilia during the exacerbation, adjusting for the previously identified variables. Lower BMI z score (p=0.04) was significantly associated with a shorter time to subsequent pulmonary exacerbation. Antibiotic treatment against S. maltophilia during a pulmonary exacerbation was not associated with a longer time to subsequent pulmonary exacerbation (p=0.56). When S. maltophilia antibiotic therapy was dichotomized into ≥14days or <14days of antibiotic therapy [12], the same variables were significant in evaluating FEV₁ and time to subsequent pulmonary exacerbation.

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4. Discussion 

We have previously shown that chronic S. maltophilia infection in CF patients is an independent risk factor for pulmonary exacerbation requiring hospitalization and antibiotic therapy and this study confirms that there are more pulmonary exacerbations per patient with chronic S. maltophilia infection [1]. This study showed that chronic S. maltophilia status does not affect FEV₁ recovery and S. maltophilia antibiotic treatment does not influence the recovery of, or the gain in, FEV₁ during a pulmonary exacerbation or the time to subsequent pulmonary exacerbation, regardless of the length of therapy.

Recurrent pulmonary exacerbations are associated with significant increases in morbidity and mortality in CF [11], [13], [14], [15], [16]. Similar to a previous study by Sanders et al., there was a failure to recover baseline FEV₁ in approximately 30% of exacerbations in our study [6]. As a population whole, patients had an approximately 2% predicted decrease in follow up FEV₁ compared to baseline; other studies have noted an approximately 3% decrease in FEV₁ following pulmonary exacerbations [8]. Adjusting for similar variables as previous analyses [6], this study noted that older age, female gender, lower BMI, B. cepacia complex infection, and a larger drop in FEV₁ at the time of exacerbation, negatively affected lung function recovery after a pulmonary exacerbation. In contrast, patients with ABPA had improved lung function following pulmonary exacerbation, likely reflecting the effect of steroid therapy which was administered to the majority (59%) of them [17]. Although persistent P. aeruginosa, B. cepacia complex and MRSA were risk factors for worse lung function following exacerbation in the Sanders study, chronic S. maltophilia infection was not a risk factor in our study. Thus, while CF patients chronically infected with S. maltophilia have more pulmonary exacerbations [1], it does not appear as though they do worse, in terms of lung function, following a pulmonary exacerbation than patients who have intermittent or who never had S. maltophilia. This is in keeping with our previous findings that the rate of FEV₁ decline over time is not greater in chronic S. maltophilia infected patients [1]. It is still not clear, however, how chronic S. maltophilia is associated with more exacerbations and more exacerbations are associated with greater FEV₁ decline [18] but chronic S. maltophilia infection is not associated with greater FEV₁ decline. Exactly how pulmonary exacerbations contribute to the rate of FEV₁ decline has yet to be determined.

Although the primary aim of this study was to examine the effect of chronic S. maltophilia infection on lung function recovery following pulmonary exacerbations, the inclusion of detailed information regarding antibiotic therapy permitted us to investigate, albeit in a limited retrospective manner, its effect on clinical outcomes. The goal of antibiotic treatment during a CF pulmonary exacerbation is to decrease the bacterial load in the airways (possibly eliminating the bacteria) and decrease the associated inflammation thereby improving lung function and prolonging the time to subsequent exacerbation [19], [20]. Antibiotic therapy targeting S. maltophilia during pulmonary exacerbations did not affect the degree of FEV₁ recovery following the exacerbation or the time to subsequent exacerbation despite the fact that the median number of days of antibiotic therapy was 14days, which is standard of care for the treatment of pulmonary exacerbations [12]. It is important to note, however, that there was a wide variation in the number of days of antibiotic therapy. In addition, almost all patients were treated with only one antimicrobial drug targeting S. maltophilia, resulting in elimination of S. maltophilia from the airways in only one quarter of chronic S. maltophilia pulmonary exacerbations. This raises the question of whether the antimicrobial treatment of S. maltophilia in these patients was truly effective. S. maltophilia is notorious for its intrinsic resistance to a broad spectrum of antimicrobial agents and it is often recommended to treat S. maltophilia infections with two antibiotics with different mechanisms of action [9]. In the analysis of the effect of antimicrobial therapy on clinical outcomes, patients with intermittent infection were included with patients with chronic infection due to the small sample size. It is possible that chronically infected patients may benefit more from antimicrobial therapy during exacerbations. Alternatively, it has been suggested that it is the occurrence of the pulmonary exacerbation itself, as evidenced by the initial drop in FEV₁ at the time of exacerbation, rather than any of the antimicrobial therapy we administer during an exacerbation, which is the most important determinant of long-term outcome. Other large epidemiologic studies have demonstrated that the duration of antibiotic treatment during pulmonary exacerbations does not affect the lung function decline seen after pulmonary exacerbations in CF patients [8], [12]. Prospective interventional studies with measurements of sputum bacterial density are needed to definitively address the role of S. maltophilia antimicrobial therapy during exacerbations.

This study has several limitations. The definition of chronic infection was based on previous work which identified a specific serologic response to S. maltophilia in this group of patients [1]. It does not take into account, however, the number of respiratory cultures done per year. It is possible that sicker patients have more respiratory cultures taken, have more S. maltophilia detected as a result and chronic S. maltophilia status thus simply reflects a sicker patient population. Chronic definitions based on the percentage of positive cultures may therefore also be appropriate. However, the average number of respiratory cultures taken per year was similar in our three study groups. In addition, we did not do molecular typing on the S. maltophilia isolates as the isolates were not available due to the retrospective nature of the study. This limits our ability to state that these patients were truly chronically infected with the same clone of S. maltophilia over time. The study also had a limited number of patients with chronic S. maltophilia infection which may affect its power to identify risk factors for failing to recover FEV₁ [6]. However, the study was adequately powered to detect a minimum difference of 1.4% predicted in FEV₁ recovery between patients with chronic versus no S. maltophilia and for the effect of S. maltophilia antibiotic therapy, a difference of 0.1 in the slope for FEV₁% predicted and of 4days in the slope for time to subsequent exacerbation, all clinically relevant minimum differences. In addition, this study analyzed repeated exacerbations which are not independent events and hence a generalized linear mixed model with an appropriate covariance structure was used to account for the longitudinal nature of the repeated data. Finally, antimicrobial susceptibility data for infecting S. maltophilia strains was not collected; it is possible that these strains were resistant to the antibiotics chosen to treat S. maltophilia during the exacerbation. However, the authors presume that antibiotics were chosen based on the most recent culture results and the role of sensitivity testing in chronic airway infection is being debated.

In conclusion, a significant proportion of CF patients do not recover their lung function following pulmonary exacerbation, particularly older, undernourished female patients infected with B. cepacia complex. CF patients with chronic S. maltophilia infection, however, are not at increased risk of lung decline after an exacerbation. In addition, currently used antimicrobial therapies directed at S. maltophilia during a pulmonary exacerbation do not appear to affect lung function recovery or time to subsequent exacerbation. Future clinical trials may be required to identify more effective therapies to prevent the increased rate of hospitalization seen in CF patients chronically infected with S. maltophilia.

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Acknowledgments 

Dr. Waters, Mr. Atenafu, Dr. Giraldo Salazar, Ms. Lu, Dr. Yau, Dr. Matukas, Dr. Tullis, and Dr. Ratjen contributed to conception and design, acquisition of data, or analysis and interpretation of data; drafting the article and/or revising it critically for important intellectual content; and final approval of the version to be published. Dr. Waters is the guarantor of the paper.

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