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Stenotrophomonas maltophilia: A marker of lung disease severity

Abstract Background While the prevalence of Stenotrophomonas maltophilia lung infection in cystic fibrosis (CF) patients has increased in the last decades, its pathogenicity remains controversial. The aim of this study was to investigate the effects of S. maltophilia initial infection on the progression of lung disease in CF children. Methods This case‐control retrospective study took place in a pediatric CF center. A total of 23 cases defined by at least one sputum culture positive for S. maltophilia, were matched for age, sex, and CFTR mutations to 23 never infected CF controls. The clinical data were collected for 2 years before and after S. maltophilia initial infection and comprised lung function analyses, rates of exacerbations and of antibiotic courses. Results Compared with controls, cases had lower lung function (P = 0.05), more frequent pulmonary exacerbations (P = 0.01), hospitalizations (P = 0.02), and intravenous antibiotic courses (P = 0.04) before S. maltophilia acquisition. In the year following S. maltophilia initial infection, lung function decline was similar in cases and controls but cases remained more severe, with more frequent pulmonary exacerbations (P = 0.01), hospitalizations (P = 0.02) and intravenous antibiotic courses (P = 0.02). Conclusions S. maltophilia seems to be a marker of CF lung disease severity and international recommendations to reduce lung infection by this pathogen should rapidly emerge.

respiratory infections contribute to the lung disease, leading to a respiratory insufficiency.
Although the prevalence of Stenotrophomonas maltophilia (S. maltophilia) lung infection in patients with CF has increased in the last decades, its pathogenicity is still controversial. [5][6][7][8] While its prevalence varies worldwide and according to the CF centers, it reached in 2015 almost 14% in the US and 10.4% in France. 9,10 There is no recommendation concerning the management of S. maltophilia infection as it is actually unclear whether antimicrobial treatments directed against S. maltophilia alter its course in CF. [11][12][13][14] Therefore, we conducted a retrospective study to investigate the effects of S. maltophilia initial infection on the progression of lung disease in CF children.

| Patients
This retrospective study took place in a pediatric CF center in Paris where 213 CF patients are registered. The cases were defined as CF patients with at least one positive sputum culture with S. maltophilia during the follow-up. These cases were matched for age, sex, and CFTR mutations with CF patients for whom S. maltophilia had never been identified (CF controls).
The clinical data were retrospectively collected from electronic patient records, supplemented when necessary with data from the paper patient records. The database and data collection have been approved by French national data protection authorities (CNIL n°9 08324 and CCTIRS n°08.015bis) and each patient and/or his legal guardians were informed prior to entering their data into the database.

| Statistical analysis
The data were expressed as means ± SD for continuous variables and numbers (%) for categorical variables. The paired Wilcoxon rank sum test was used to compare quantitative data and Fisher's exact test for categorical data. A random effects linear regression was used for longitudinal data. The differences were considered significant for P-values less than 0.05.

| Analyses of the cases infected with S. maltophilia
The demographic data for the cases included are described in Table 1.
aeruginosa and methicillin-resistant Staphyloccocus aureus (MRSA) was only present in the cases (incidence 13% in the cases vs 0% in the controls for both bacteria, NS).
In the year following S. maltophilia initial infection, FEV 1 rate of decline was similar in the cases and the controls (P = 0.8, Table 3 & Figure 2A). The cases remained more severe, with more frequent pulmonary exacerbations (P = 0.015, Figure 2B), hospitalizations (P = 0.018, Figure 2C) and intravenous antibiotic courses (P = 0.024) ( Table 3). New P. aeruginosa airway colonization was more frequent in the cases, although not significantly (incidence 43% in the cases vs 4.3% in the controls, P = 0.18, Table 3).    10 Similarly, a large US cohort also shows a recent increase in the prevalence. 16 This recent increasing prevalence may be secondary to the improvement of S. maltophilia detection that requires expert laboratories as evidenced by the study of Burns et al. 17 Our results are in accordance to those of Goss et al who evaluated the effect of S. maltophilia on the lung function of CF patients from the US registry. 6 They observed indeed that patients with S. maltophilia had a worse lung function at the time of positivity but no modification in the lung function rate of decline. Talmaciu et al further questioned whether long-term antibiotics may have predisposed the patients to acquisition of this bacterium. 14 We also observed in this pediatric cohort that only the cases were colonized by P. aeruginosa and MRSA, two pathogens known to be associated with an accelerated lung function decline in CF patients. 18 Moreover, Junge et al recently showed that S. maltophila co-infection was a risk factor of a worse lung function in CF patients with persistent S. aureus airway colonization. 19 Besides, Waters et al showed that chronic S. maltophilia infection was associated with an almost three-fold increased risk of death or lung transplant in CF patients. 20 It is however still unclear whether S. maltophilia infection is only a marker of CF lung disease severity or whether it leads to an acceleration of the disease progression. 20 In a large cohort of young CF patients, a recent study identified that a respiratory culture positive for S. maltophilia was one of the risk factors identified associated with a larger annual FEV 1 rate of decline. 21 Altogether, these studies along with ours, agree that S. maltophilia infection is associated with a severe CF lung disease. The data are the means (SD) or % (numbers) unless otherwise indicated. FEV 1 , forced expiratory volume in one second; BMI, body mass index, P. aeruginosa, Pseudomonas aeruginosa; MRSA, methicillin-resistant Staphyloccocus aureus.
a For the comparison of sex, age, and CFTR matched cases and controls. *P < 0.05.