Clinical outcomes associated with Staphylococcus aureus and Pseudomonas aeruginosa airway infections in adult cystic fibrosis patients

Pulmonary disease is the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). Most patients experience acute symptoms during episodes of pulmonary exacerbations, and develop progressive lung disease caused by both chronic airway infections and host inflammation [ 1]. While it is increasingly recognised that CF airway infections are polymicrobial, Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA) are the most prevalent organisms [ 2, 3]. PA, the dominant airway pathogen, chronically infects up to 60–75 % of adult CF patients [ 4], and is strongly associated with inflammation, decline in lung function and increased mortality [ 1, 5– 7]. SA, on the other hand, is the most prevalent organism during childhood, and often the first one isolated in CF children [ 4, 8].

The overall prevalence of SA infections has increased over time, both with methicillin sensitive (MSSA) and methicillin resistant (MRSA) SA [ 4, 9]. Several studies have examined the clinical impact of SA infections, but all have focused on infants and children [ 10– 14]. In the pre-antibiotic era, SA was a major cause of death in CF children. In more recent studies, SA infection in young children is associated with a decline in lung function [ 11, 12], as well as increased markers of pulmonary inflammation [ 15, 16]. Consequently, antibiotic therapy to eradicate SA is used in some centers, but its routine use remains controversial [ 10, 17– 20]. As patients transition from adolescence into adulthood, the prevalence of SA decreases gradually but remains significant, with over 40 % of adults harbouring SA [ 4]. In older children, SA infections are not consistently associated with poor prognosis, but perhaps even better survival post-transplantation, as SA infection prior to transplantation is an independent factor associated with improved survival [ 21, 22]. The clinical significance of SA in adult CF patients remains unknown.

We carried out a retrospective cross-sectional study to examine the association between airway infection (SA alone, PA, or neither) and lung function (FEV ₁ % predicted) as well as pulmonary exacerbation rate. We also examined several secondary outcomes, namely plasma C-reactive protein (CRP) and clinical scores.

A total of 91 adult patients were followed at the Montreal Chest Institute CF clinic during the study period, and 84 patients were included in this study. We analyzed the microbiology of a total of 366 sputum samples collected during the study period (average 4.3 samples per patient): 37 % of samples were positive for SA (including n = 4 for MRSA), and 70 % were positive for PA. The study patients were classified into one of 3 groups based on their PA and SA airway infection status, namely “PA” ( n = 50; 59 %), “SA only” ( n = 20; 24 %), and “no PA/SA” ( n = 14; 17 %) for patients infected with neither PA nor SA. The patients’ demographic and clinical outcomes for each group are presented in Table  1. The identification of microorganisms other than PA and SA, namely Aspergillus and Stenotrophomonas maltophilia, in each of the 3 groups are summarized in Additional file 1: Table S1. The patients in the different infection groups were similar in age, sex and BMI. There was a trend suggesting that “PA” patients were associated with worse FEV ₁ and FVC % than “SA only” and “no PA/SA” patients. In univariate analyses, the infection groups significantly differed in their exacerbation rate, clinical scores and CRP levels. Across these clinical outcomes, “SA only” patients were similar to “no PA/SA” patients, while “PA” patients experienced the highest rate of exacerbation, CRP and lowest clinical score.

To adjust for confounding factors that affect CF disease such the age and sex, we next performed multivariable analyses. Although there was a trend suggesting that “no PA/SA” patients had better FEV ₁ compared to “PA” patients using a linear regression model, we found no statistically significant association between airway infection status and FEV ₁, (Table  2). Next, we compared the exacerbation rate of the different airway infection groups using a Poisson regression model, as presented in Table  3. Compared to “PA” patients, both “SA only” and those with “no PA/SA” were associated with a significantly lower rate of pulmonary exacerbation. In the adjusted model, “SA only” patients were associated with a relative risk of 0.2 (95 % CI [0.1-0.4]) compared to “PA” patients. We also examined several secondary outcomes, namely CRP (Table  4) and the modified Matouk total clinical score (Table  5), a clinical subscore (which quantifies signs, symptoms and complications of CF disease). The “SA only” patients were associated with reduced CRP levels (in both unadjusted and adjusted models) and higher clinical scores (unadjusted model only) compared to “PA” patients. Interestingly, patients with “no PA/SA” showed similar results to “SA only” patients. Taken together, these analyses suggest that “SA only” patients overall have significantly better clinical outcomes than “PA” patients.

In all four crude models, “no PA/SA” and “SA only” groups had better total clinical scores and subscores than the reference “PA only” group. These trends were also observed in the adjusted models, although only the comparison between “no PA/SA” and “PA only” groups remained statistically significant. Consistent with the observation that patients infected with “no PA/SA” and “SA only” had less active disease than those infected with “PA only”, their plasma CRP levels were lower in both crude and adjusted models.

Among PA infected patients in the “PA” group, 10 out of 50 were co-infected with both PA and SA. The demographic and clinical characteristics of patients based on their infection group, with the “PA only” and “PA + SA” groups separated, are presented in the Additional file 1: Table S2, and both groups showed no significant differences (Table  6). In order to determine whether including the “PA + SA” patients to the “PA” group had a significant effect on our results, we excluded the “PA + SA” patients and repeated the univariate and multivariate analyses. As shown in the Additional file 1: Table S3 to S6, all results were similar. Furthermore, 4 out of 84 patients (4.8 %) in our cohort were MRSA, and all were co-infected with both PA and SA. The results of all univariate and multivariate analyses remained unchanged after exclusion of the MRSA patients (data not shown).

To date, studies reporting on SA infections have exclusively focused on CF children where the prevalence of SA infections is higher. In children under 12 months, 27 % of bronchoalveolar lavage fluids are positive for SA [ 26]. The prevalence of SA increases during childhood and is highest in children 6 to 10 years old [ 4]. In young children under the age of 2, SA infections are associated with a decline in lung function [ 11, 12, 15, 27, 28]. In those under 7, SA infections are associated with pulmonary inflammation, increased neutrophil counts, elevated IL-8, and free neutrophil elastase on BAL [ 15]. Consequently, antibiotic therapies can be used to prevent or eradicate SA [ 29– 31], but their routine use remains controversial [ 10, 17– 19].

In contrast to children, the clinical significance of SA infections in adult is not established. The presence of SA infections may in fact be a marker of less severe disease, as it could represent the absence of PA. Reports that SA infections in older children are associated with better 5-year survival following transplantation suggest that this may be the case [ 21, 22]. In our cohort of adult CF patients, 24 % of patients are colonized with SA only, without PA. Patients with SA were associated with lower rates of pulmonary exacerbations and CRP than those with “PA”, suggesting that infection with SA is a marker of less severe disease. Interestingly, we did not identify any significant association between the airway infection status and lung function (FEV ₁ and FVC). Although FEV ₁ is the most commonly used clinical outcome in studies of CF lung disease due to its association with mortality and quality of life [ 32– 35], it may not be as sensitive to the disease activity as the rate of pulmonary exacerbations and clinical scores, particularly in light of our small sample size for the “no PA/SA” and “SA only” groups.

It is also worth noting that among those infected with PA, 20 % ( n = 10) were co-infected with both PA and SA. In children, several studies have reported that PA + SA co-infections are associated with diminished survival, greater decline in lung function and increased airway inflammation in CF children [ 11, 15, 16]. Unfortunately, the small size of this group in our study precluded any meaningful subgroup analyses. However, we compared patients with only PA and those with PA + SA and found no significant differences in demographic or clinical parameters. Our findings also did not differ when the PA + SA patients were excluded from our analyses.

In the face of the global rise in MRSA, the prevalence of MRSA has also increased in many CF clinics [ 36, 37]. Methicillin-resistant SA (MRSA) is present in 4.1 % of CF patients in Canada [ 38] and has been associated with faster decline in lung function than methicillin-susceptible SA (MSSA) [ 39]. It has also been shown to be a risk factor for failure to recover from exacerbation [ 40], and persistent infection has been linked to increased mortality [ 39]. The prevalence of MRSA in our cohort was 4.8 % and the small number of MRSA+ patients precluded any subgroup analyses. However, our results were unchanged when we performed the analysis of our cohort excluding the MRSA patients. Finally, our study and others likely underestimate the true prevalence of SA infection. Standard clinical laboratories typically do not detect small colony variant SA strains that are slow growing [ 41] which may be associated with a greater decline in FEV ₁ in CF children [ 42] and more severe lung disease [ 43].

Our study suggests that, in contrast to children, the presence of SA in CF adults, in the absence of PA, is a marker of milder lung disease.