Abstract
Rationale: The prevalence in cystic fibrosis (CF) of respiratory cultures with methicillin-resistant Staphylococcus aureus (MRSA) has dramatically increased over the last 10 years, but the effect of MRSA on FEV1 decline in CF is unknown.
Objectives: To determine the association between MRSA respiratory infection and FEV1 decline in children and adults with CF.
Methods: This was a 10-year cohort study using the Cystic Fibrosis Foundation patient registry from 1996–2005. We studied individuals who developed new MRSA respiratory tract infection. Repeated-measures regression was used to assess the association between MRSA and FEV1 decline, adjusted for confounders, in individuals aged 8–21 years and adults (aged 22–45 yr). Two different statistical models were used to assess robustness of results.
Measurements and Main Results: The study cohort included 17,357 patients with an average follow-up of 5.3 years. During the study period, 1,732 individuals developed new persistent MRSA infection (≥3 MRSA cultures; average, 6.8 positive cultures) and were subsequently followed for an average of 3.5 years. Even after adjustment for confounders, rate of FEV1 decline in individuals aged 8–21 years with persistent MRSA was more rapid in both statistical models. Their average FEV1 decline of 2.06% predicted/year was 43% more rapid than the 1.44% predicted/year in those without MRSA (difference, −0.62% predicted/yr; 95% confidence interval, −0.70 to −0.54; P < 0.001). Effect of MRSA on FEV1 decline in adults was not clinically significant.
Conclusions: Persistent infection with MRSA in individuals with CF between the ages of 8 and 21 years is associated with a more rapid rate of decline in lung function.
The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in individuals with cystic fibrosis has increased in recent years. Whether MRSA contributes to a more rapid rate of lung function decline is unknown.
This study suggests that, even after controlling for severity of illness, persistent infection with MRSA in individuals with cystic fibrosis aged 8–21 is associated with a more rapid decline of lung function.
Methicillin-resistant Staphylococcus aureus (MRSA) is one particularly important emerging pathogen in CF. Over the last several years, there has been a dramatic increase in the proportion of patients with CF infected with MRSA. Although only 2.1% of patients with CF who were reported to the registry in 1996 had one or more positive culture(s) for MRSA, the prevalence increased to 18.9% of patients in 2006 (2). In non-CF populations, MRSA bacteremia has been associated with higher mortality than methicillin-sensitive S. aureus MSSA bacteremia (3) and individuals harboring MRSA for more than a year are at high risk for subsequent MRSA morbidity and mortality (4). S. aureus can also be associated with virulence factors that damage host tissue (5, 6). For example, there has been recent recognition of the association between Panton-Valentine leukocidin (PVL)–positive MRSA and invasive lung infections in individuals with CF (7).
Surprisingly, despite the increase in prevalence of MRSA and the serious potential morbidity from MRSA in patients with CF, very little is known about its effect on lung function. It is unclear if MRSA is simply a marker of more severe lung disease or an independent contributor to decline in lung function. Previous studies have been small, retrospective, and unable to draw conclusions about the effect of MRSA on rate of decline in lung function (8–12). A cross-sectional study of 208 individuals with MRSA alone found lower absolute lung function compared with those with MSSA alone (13). No study has thoroughly examined the longitudinal relationship between persistent MRSA and rate of lung function decline. Persistent MRSA is particularly important to study because previous work has shown that approximately one-third of individuals with CF and with MRSA demonstrate only transient infection (10, 14).
Because of virulence factors potentially associated with MRSA and previous cross-sectional studies demonstrating MRSA to be associated with decreased lung function, we hypothesized that MRSA independently contributes to more rapid lung function decline in individuals with CF. We used the Cystic Fibrosis Foundation patient registry (CFFPR) to comprehensively analyze the longitudinal effect of MRSA in CF, with the primary goal of determining the effect of MRSA on rate of lung function decline. Some of the results of this study have been previously reported in the form of an abstract (14).
The CFFPR contains demographic and clinical data collected at U.S. Cystic Fibrosis Foundation–accredited centers using a standardized entry form. A description of the database has been previously published (15). The CFFPR began collecting data on MRSA in 1996. Individuals followed in the CFFPR from January 1, 1996, through December 31, 2005, were eligible. We excluded individuals younger than 6 years (unreliable pulmonary function testing data) and individuals older than 45 (represents a milder phenotype not typical of the CF population in general). In an effort to create a truly MRSA-negative cohort upon entry and allow us to assess the effect of new MRSA infection on lung function, subjects were excluded if they had MRSA anytime during the first 2 years in the cohort, less than two cultures in the first 2 years in the cohort, or less than 2 years of observation.
The design was a cohort study comparing patients who had new MRSA respiratory cultures with those who never cultured MRSA from the respiratory tract. MRSA status was recorded every 3 months. The primary outcome of interest was the mean rate of lung function decline.
MRSA status was determined from respiratory tract cultures, either sputum or throat swab. Persistent MRSA was defined as three or more MRSA cultures during follow-up. Cultures did not necessarily have to be in consecutive quarters. The highest recorded value of the percent-predicted FEV1 in each quarter was used for calculations, with percent-predicted values calculated using equations from Hankinson and colleagues and Wang and coworkers (16, 17). Pancreatic insufficiency was a dichotomous variable defined by pancreatic enzyme usage. Diabetes mellitus was defined as CF-related diabetes with or without fasting hyperglycemia (18).
A descriptive analysis was performed with calculation of means, standard deviations, and medians for continuous variables in each cohort at the time of first visit. Categorical variables were measured using proportions. Bivariate analyses (unadjusted) were conducted for continuous variables using Student t tests or the Wilcoxon rank sum tests. Categorical variables were compared using χ2 or Fisher's exact tests.
We developed multiple linear regression models using population-averaged generalized estimating equations to assess the effect of MRSA on FEV1% predicted over time, with adjustment for potential confounders (19). Confounders were identified a priori based on prior review of the literature. The variables of age, sex, infection with MRSA, Burkholderia cepacia complex (BCC) and/or Pseudomonas aeruginosa, baseline FEV1% predicted, CF-related diabetes, and pancreatic enzyme usage were included in the model. Each patient contributed a maximum of four measurements per year and time was captured in the model using age in years. Variables collected during the 2-year observation period did not contribute to the analysis, as no one could be MRSA positive during this period. Sensitivity analyses to control for center effect and missing FEV1 data were performed.
To assess the effect of new MRSA infection on lung function over time, provide confidence in the conclusions, and strengthen the clinical relevance of the analysis, two models were investigated (full details are available in the online supplement):
Model 1: Impact of persistent MRSA. Persistent MRSA was defined as individuals with three or more MRSA cultures. Individuals meeting persistent criteria were then considered persistently positive from the time of their first positive culture. Comparison of rate of FEV1% predicted decline was made between those persistently positive and those never culturing MRSA, adjusted for confounders. Those with only one or two MRSA cultures were not included in the analysis.
Model 2: Lung function before and after MRSA detection. A paired analysis of effect of MRSA on FEV1 was performed using only the 1,732 individuals in the persistently infected cohort. Each persistently infected individual was used as his/her own control, and the rate of decline in their FEV1% predicted before and after detection of MRSA was compared, adjusted for confounders.
To assess the effect of MRSA on rate of decline in lung function, we tested the interaction between MRSA and time (measured as age in years) in each model. Decline in lung function was calculated as the change in FEV1% predicted per year. During exploratory analysis investigating the shape of the relationship between each variable and lung function decline, the relationships were linear except for age. FEV1 decline was different before and after age 21; therefore, we performed analyses from ages 8 to 21 and ages 22 to 45 to model the nonlinear relationship.
A P value less than 0.05 was considered statistically significant for all analyses. Because of our large sample size, we had more than 99% power to detect a clinically meaningful difference of greater than 0.5 FEV1% predicted/year. Analyses were performed using STATA 10.0 special edition (StataCorp, College Station, TX). The institutional review board at the Johns Hopkins University School of Medicine approved the study.
Among all accredited pediatric and adult CF centers in the United States, there were 26,664 individuals with CF between the ages of 6 and 45 years entered into the CFFPR during the study period. Subjects entered the study at any point from January 1, 1996, to December 31, 2003, and were monitored until they underwent solid-organ transplantation, died, were lost to follow-up, or until the end of the study period was reached in the fourth quarter of 2005. In an effort to create a truly MRSA-negative cohort upon entry, subjects were excluded if they had fewer than 2 years of observation in the cohort (n = 3,529), MRSA in the first 2 years of observation (n = 2,480), or fewer than two cultures in the first 2 years (n = 3,298). The total number of patients in the study cohort was 17,357, of whom 3,435 had cultured MRSA and 13,922 never cultured MRSA. Of the 3,435 individuals who cultured MRSA, 1,703 (49%) demonstrated only transient MRSA (just one or two MRSA cultures over the course of the study period). Persistent MRSA (≥3 cultures) was found in 1,732 individuals (50%) (Figure 1).
Figure 1. Diagram of study population with number of patients excluded from the analysis. CF = cystic fibrosis; MRSA = methicillin-resistant Staphylococcus aureus.
[More] [Minimize]The baseline characteristics of the study cohort (after the 2-yr observation period) comparing those who would eventually develop persistent MRSA with those who would stay MRSA negative throughout the study period are shown in Table 1. At baseline, the group that would go on to develop MRSA was younger (14.7 vs. 16.5 yr; P < 0.001), had slightly better lung function (FEV1% predicted, 77.5 vs. 76.0%; P = 0.025), and was more likely to be colonized with P. aeruginosa (69.3 vs. 61.1%; P < 0.001) and methicillin-sensitive S. aureus (52.7 vs. 47.5%; P < 0.001). The use of pancreatic enzymes, a marker for pancreatic insufficiency, was higher in the patients who went on to develop MRSA (95.7 vs. 92.3%; P < 0.001).
Will Become MRSA Persistently Positive* (n = 1,732) | Will Stay MRSA Negative (n = 13,922) | P Value | |
|---|---|---|---|
| Age, yr | 14.7 ± 7.6 | 16.5 ± 9.2 | <0.001 |
| Sex, female | 854 (49.3) | 6,574 (47.2) | 0.103 |
| FEV1, % predicted | 77.5 ± 24 | 76.0 ± 27 | 0.025 |
| FEV1, L | 1.77 ± 0.77 | 1.82 ± 0.87 | 0.020 |
| Pancreatic insufficient† | 1,658 (95.7) | 12,851 (92.3) | <0.001 |
| Pseudomonas | 1,192 (69.3) | 8,302 (61.1) | <0.001 |
| Burkholderia cepacia complex | 53 (3.1) | 502 (3.7) | 0.218 |
| MRSA | 905 (52.7) | 6,449 (47.5) | <0.001 |
| CF-related diabetes | 116 (6.7) | 1,084 (7.8) | 0.114 |
| ΔF508‡ | 791 (45.7) | 5,663 (40.7) | <0.001 |
The average characteristics during follow-up for the persistently positive MRSA group (after becoming positive) and MRSA-negative group are shown in Table 2. The average follow-up of the entire cohort was 5.3 years. After the first MRSA-positive culture, those with persistent MRSA were monitored for an average of 3.5 ± 1.9 years (average time for being MRSA negative before becoming MRSA positive was 3.2 ± 2.0 yr). Those with persistent MRSA averaged 6.8 ± 3.9 MRSA-positive cultures, with no more than one culture contributed per quarter. Given that those who were MRSA positive averaged 8.9 ± 5.7 total cultures after becoming MRSA positive, 76% of the quarterly cultures from the persistent MRSA cohort demonstrated MRSA. During this time, those who cultured MRSA had an average of 3.6 ± 0.5 visits per year and 2.4 ± 0.8 cultures per year. Those without MRSA had an average of 3.3 ± 0.7 visits per year and 2.0 ± 0.9 cultures per year (Table 2).
MRSA Persistently Positive* (n = 1,732) | MRSA Negative (n = 13,922) | |
|---|---|---|
| Follow-up, yr | 3.5 ± 1.9 | 5.2 ± 2.7 |
| Visits, per yr | 3.6 ± 0.5 | 3.3 ± 0.7 |
| Cultures, per yr | 2.4 ± 0.8 | 2.0 ± 0.9 |
| Total cultures | 8.9 ± 5.7 | 9.9 ± 6.6 |
| MRSA cultures† | 6.8 ± 3.8 | 0.0 ± 0.0 |
| MRSA cultures, % | 76 | 0.0 |
The average characteristics during the follow-up period categorized by both MRSA status and age are shown in Table 3. Individuals could potentially contribute data to both age groups if they turned 22 during the study period. On average, the 8- to 21-year-old persistently positive MRSA group was older, had worse lung function (71.0 vs. 79.6 FEV1% predicted), and was more likely to have diabetes and culture Pseudomonas than the 8- to 21-year-old MRSA-negative group.
Age 8–21 yr | Age 22–45 yr | |||||
|---|---|---|---|---|---|---|
| MRSA Persistently Positive† (n = 1,217) | MRSA Negative (n = 11,691) | MRSA Persistently Positive (n = 740) | MRSA Negative (n = 6,571) | |||
| Age, yr | 14.8 ± 3.2 | 13.9 ± 3.7 | 28.6 ± 5.9 | 29.4 ± 6.4 | ||
| Sex, female | 602 (49.5) | 5,587 (47.8) | 372 (50.3) | 3,082 (46.9) | ||
| FEV1, % predicted | 71.0 ± 20 | 79.6 ± 21 | 48.8 ± 23 | 56.7 ± 22 | ||
| Pancreatic insufficient‡ | 1,202 (98.8) | 11,313 (96.8) | 716 (96.8) | 6,273 (95.5) | ||
| Pseudomonas | 1,027 (84.4) | 9,007 (77.4) | 668 (90.5) | 5,740 (89.0) | ||
| Burkholderia cepacia complex | 77 (6.3) | 713 (6.1) | 61 (8.3) | 576 (8.9) | ||
| CF-related diabetes | 341 (28.0) | 2,126 (18.8) | 358 (48.4) | 2,598 (39.5) | ||
To determine if someone with an MRSA-positive culture would go on to become persistently infected, we analyzed the outcomes of patients whose first two MRSA cultures were in consecutive quarters (n = 959). A total of 777 (81%) went on to become persistently MRSA positive (≥3 MRSA cultures). In contrast, among those who had an initial positive culture followed by a negative culture, 69% demonstrated only transient MRSA infection during follow-up (≤2 MRSA cultures).
Model 1 compared decline in FEV1% predicted between the persistently positive MRSA group and the never-cultured-MRSA group. Because these groups differed significantly in other known physiologic and clinical characteristics that influence lung function, we adjusted for the effect of age, sex, FEV1% predicted at entry into the study, pancreatic insufficiency, CF-related diabetes, P. aeruginosa, and BCC. The adjusted analysis indicated a clinically significant more rapid decline in lung function in individuals aged 8 to 21 years with persistent MRSA infection (−2.06 FEV1% predicted/yr) than those without MRSA (−1.44 FEV1% predicted/yr); which represented a difference in rates of −0.62 FEV1% predicted/year (95% confidence interval [CI], −0.70 to −0.54; P < 0.001) (Figure 2 and Table 4). This represented a 43% more rapid rate of decline in those with persistent MRSA compared with those without MRSA. There was a statistically, but not clinically, significant effect in those aged 22 to 45 years (difference between rates, 0.12 FEV1 % predicted/yr; 95% CI, 0.05 to 0.20; P = 0.001).
Figure 2. Model 1: linear predictor of FEV1% predicted decline for patients with cystic fibrosis aged 8 to 21 years with persistent methicillin-resistant Staphylococcus aureus (MRSA) (≥3 MRSA cultures) (solid line) compared with those without MRSA (dotted line). Average follow-up for each individual in the cohort was 5.3 years. FEV1 was adjusted for group differences in the confounders listed in Table 4.
[More] [Minimize]Coefficient | 95% CI | P Value | |
|---|---|---|---|
| Difference in rate of decline with MRSA* | −0.62 | −0.70 to −0.54 | <0.001 |
| Age, yr | −1.44 | −1.46 to −1.41 | <0.001 |
| Positive for MRSA† | −3.36 | −3.66 to −3.06 | <0.001 |
| Sex, female | −1.52 | −1.97 to −1.08 | <0.001 |
| Pancreatic insufficient‡ | −1.01 | −1.43 to −0.59 | <0.001 |
| CF-related diabetes | −3.61 | −3.86 to −3.36 | <0.001 |
| Positive for Pseudomonas aeruginosa | −0.17 | −0.34 to −0.01 | 0.046 |
| Positive for Burkholderia cepacia complex | −1.42 | −1.89 to −0.95 | <0.001 |
| Baseline FEV1 | 0.76 | 0.75 to 0.77 | <0.001 |
To further test our hypothesis, we investigated for the presence of an MRSA “dose effect.” First, we found that as the total number of MRSA cultures among the persistently positive group increased, so did the rate of lung function decline. Second, in an analysis comparing individuals with persistent MRSA with those with transient MRSA, the persistent MRSA group had a significantly faster rate of decline (difference between rates, −0.53 FEV1% predicted/yr; 95% CI, −0.62 to −0.44; P < 0.001). In contrast, a separate analysis comparing individuals aged 8 to 21 years with only a single MRSA culture with those without MRSA demonstrated no significant effect on rate of decline of FEV1 (difference between rates, −0.14 FEV1% predicted/yr; 95% CI, −0.36 to 0.08; P = 0.202). See Table E1 of the online supplement for further details of these analyses.
In an effort to confirm the accuracy of our conclusions about the effect of persistent MRSA infection on rate of lung function decline, we used a second model to further study the 1,732 individuals with persistent MRSA infection (≥3 MRSA cultures). Each persistently infected individual was used as his/her own control, and the rate of decline in each individual's FEV1% predicted before and after detection of MRSA was compared, adjusted for confounders. Once again, after adjustment for severity of disease among those aged 8 to 21 years, the analysis indicated a significantly more rapid decline in lung function after persistent MRSA infection (−2.42 FEV1% predicted/yr) compared with the time period before MRSA infection (−1.93 FEV1% predicted/yr), with a difference between rates of −0.49 FEV1% predicted/year (95% CI, −0.59 to −0.39; P < 0.001) (Figure 3 and Table 5). This represented a 25% increase in the rate of decline in FEV1 in the persistent MRSA group once MRSA was detected. Consistent with the first analysis model, there was a statistically, but not clinically, significant effect in those aged 22 to 45 years (difference between rates, 0.18 FEV1% predicted/yr; 95% CI, 0.10 to 0.27; P < 0.001).
Figure 3. Model 2: average decline in FEV1% predicted in those aged 8–21 years, adjusted for severity of illness, before and after methicillin-resistant Staphylococcus aureus (MRSA) detection among the 1,732 individuals with persistent MRSA (≥3 MRSA cultures). Solid vertical line at Time 0 separates time before and after MRSA detection. The hypothetical line represents the slope if MRSA was never detected.
[More] [Minimize]Coefficient | 95% CI | P Value | |
|---|---|---|---|
| Difference in rate of decline with MRSA* | −0.49 | −0.59 to −0.39 | <0.001 |
| Age, yr | −1.93 | −2.04 to −1.81 | <0.001 |
| Positive for MRSA† | −0.76 | −1.21 to −0.30 | 0.001 |
| Positive for Pseudomonas aeruginosa | −0.19 | −0.64 to 0.26 | 0.415 |
| Positive for Burkholderia cepacia complex | −0.85 | −2.11 to 0.41 | 0.118 |
| CF-related diabetes | −3.76 | −4.41 to −3.11 | <0.001 |
To further address the possibility of MRSA acting only as a marker for more severe illness, we performed analyses identical to those for models 1 and 2 but focused specifically on a group from the cohort with mild disease: those who during their time in the cohort cultured only MSSA or MRSA and never cultured Pseudomonas or BCC. Even in this group with mild disease, persistent MRSA infection for ages 8 to 21 years was associated with a greater rate of decline of adjusted FEV1% predicted compared with infection with MSSA alone (−1.57% vs. −1.10% FEV1% predicted; difference, −0.47%; 95% CI, −0.66 to −0.29; P < 0.001). A paired before and after analysis of individuals who started with only MSSA but subsequently developed persistent MRSA alone also demonstrated a significant increase in the rate of decline in FEV1 after MRSA acquisition (change in rate, −0.38%; 95% CI, −0.58 to −0.18; P < 0.001).
We performed numerous sensitivity analyses to assess the robustness of our results. These included multilevel, repeated-measures, mixed-regression models to account for the random effects of individuals (level 1) and effect of the center in which individuals received care (level 2). In addition, adjustment for number of courses of intravenous antibiotics and hospitalizations was performed. Finally, because information on FEV1% predicted measurements were not available at every visit for all study subjects, imputation using last observation carried forward was performed. Results with and without these analyses did not significantly differ; the results with the more parsimonious models are shown. See the online supplement for further details.
Our cohort study is the first to comprehensively examine the association between respiratory infection with MRSA and decline of FEV1 in CF. Rate of decline of FEV1 is an important outcome measure because it is closely related to morbidity and mortality in CF and may allow better assessment of whether a pathogen is only a marker of disease severity or an independent contributor to loss of lung function (20). On the basis of previous studies demonstrating MRSA to be associated with lower FEV1 (7, 13), our hypothesis was that respiratory infection with MRSA would result in a more rapid decline in lung function.
The most important finding of this study is that persistent MRSA respiratory infection in individuals with CF aged 8 to 21 years is associated, on average, with an increase in rate of decline in lung function of approximately 0.5 FEV1% predicted per year. Although MRSA respiratory infection is associated in general with a lower FEV1 and more severe lung disease, several aspects of the results suggest that MRSA may not be just a marker of severity but may independently contribute to lung function decline. First, the MRSA effect is present even after adjusting for differences in severity of illness and known confounders between the MRSA-positive and MRSA-negative groups. Second, a separate analysis comparing FEV1% predicted decline in individuals before and after MRSA detection (model 2) demonstrates a similar detrimental MRSA effect and decreases the likelihood that residual confounding alone accounts for the findings. Third, even when limiting the analysis to a group of patients with mild disease, better FEV1, and no P. aeruginosa or BCC, transition from MSSA to MRSA respiratory infection in those aged 8 to 21 years results in the same increase in rate of lung function decline of approximately 0.5 FEV1% predicted per year. Finally, persistence of the MRSA infection must be present to result in an increase in rate of decline of lung function; one or two transient MRSA-positive respiratory cultures do not increase the rate of lung function decline.
A second important finding of this study is that approximately one-half of the individuals with CF who culture MRSA from the respiratory tract do so only transiently. The transient nature of the infection in these patients was demonstrated by monitoring them for an average of 2.0 ± 1.8 years after their last MRSA-positive culture. During that time, they averaged 5.0 ± 4.8 MRSA-negative cultures. This observation has important implications for future studies of MRSA, because persistent infection with MRSA will need to be documented to accurately categorize patients. When a patient initially cultures MRSA, is there any way to determine if he or she will become “persistent” or “transient”? In our cohort, for which we collected data quarterly and counted only one culture per quarter, an individual who cultured MRSA in consecutive quarters went on to develop persistent MRSA 81% of the time. The threshold of three positive cultures was chosen as the criterion to enter the persistent-MRSA cohort in our study because it represented the best combination of clearly documenting true MRSA infection while not requiring so many cultures as to make the analysis clinically irrelevant. A threshold of three positive cultures also identified the affected group as early in their clinical course as possible. This threshold resulted in identification of a clearly MRSA-positive cohort: subjects averaged 6.8 ± 3.9 MRSA-positive cultures during the subsequent 3.5 ± 1.9 years they were monitored, and 76% of their quarterly cultures were MRSA positive. In addition, 50% of patients had their third positive MRSA culture within a year of their first MRSA culture, with only one positive culture being counted per quarter. Using a higher number than three positive cultures as the threshold to define the persistent MRSA cohort did not alter the findings of MRSA effect. In fact, it demonstrated a larger rate of decline in FEV1% predicted with greater numbers of MRSA-positive cultures (Table E1).
The mechanisms by which MRSA may lead to lung function decline have not been elucidated and deserve further study. Staphylococci can be associated with virulence factors including membrane-damaging toxins and invasins that promote bacterial spread in tissues (5, 6). Some community-acquired strains of MRSA are known to have enhanced virulence compared with nosocomial strains (5). Recent work by Glikman and coworkers also suggests that community-acquired MRSA strains are most common in children with CF and incident MRSA (21). In one recent report in patients with CF, PVL + MRSA was associated with an increased rate of decline in FEV1 and the development of invasive lung infection (7). Other studies have failed to demonstrate an association between PVL + MRSA and inferior pulmonary status in CF (21, 22), and a recent large cohort of Italian patients with CF and community-acquired MRSA were all found to be negative for the PVL gene (23). One important limitation to our study is that the CFFPR does not provide any information about the molecular characteristics of MRSA and does not differentiate between hospital- and community-acquired strains. To fully delineate the clinical effect of MRSA in CF, longitudinal studies linking MRSA molecular epidemiology to clinical outcomes will be required.
Before our study, there were conflicting results about the importance of recovering MRSA from sputum in patients with CF. Previous studies were not longitudinal and therefore could not determine the effect of MRSA over time (12, 13). Those that were longitudinal were very small (7–10). Some of these studies demonstrated no effect of MRSA on lung function (9, 12), whereas others demonstrated lower lung function or deterioration in lung function (7, 10, 13). The largest study to date was by Ren and colleagues, who performed a cross-sectional analysis of the Epidemiologic Study of Cystic Fibrosis database and demonstrated that patients with CF infected with MRSA alone had a lower absolute FEV1% predicted compared with patients with MSSA (13). Because this was a cross-sectional study, no determination could be made whether MRSA was associated with a more rapid decline in lung function or was simply a marker of lower FEV1. Our cohort study of the CFFPR (which most likely has some overlap with the Ren and colleagues' study population), allowed a longitudinal analysis adjusted for severity of illness and other known confounders.
Although our study demonstrates an association between MRSA and lung function decline in individuals aged 8 to 21 years, epidemiologic studies can have biases that may influence outcomes. Therefore, our results should be interpreted conservatively. We took steps to avoid potential biases. We attempted to limit initial group misclassification by imposing stringent inclusion and exclusion criteria, which required observation for 2 years and multiple MRSA-negative cultures. Recent work by the Cystic Fibrosis Foundation also helped to minimize microbiologic laboratory misclassification by ensuring compliance with the use of selective media for S. aureus cultures (65% in the 1990s; 82% in the 2000s) (24). We also paid close attention to the potential for sampling bias, particularly the risk that our results would be influenced toward finding an MRSA effect because sicker individuals tend to have more frequent cultures performed and would be more likely to be identified as having MRSA. Analysis suggests that this was most likely not a factor because the cohorts had similar numbers of quarters with cultures. Children are more likely to have pharyngeal cultures, and the effect that this had on our outcomes is unknown. Failure to identify MRSA would likely result in underestimation of MRSA effect by mixing MRSA-positive subjects into the MRSA-negative cohort. Finally, although we used robust population-averaged general estimating equations and investigated lung function decline before and after MRSA infection in an attempt to limit confounding, unknown or imprecise measurement of confounding could be present and contribute to the observed MRSA effect.
What is the explanation for the different observed effect of MRSA on decline in FEV1% predicted in adults? A similar difference in effect by age has been observed with ibuprofen, where there appears to be a beneficial effect in children and adolescents, but not adults (25). One possibility is that adults with CF are more likely to already have significant structural lung disease with established chronic infection and inflammation, making the effect of any additional inflammation from MRSA only incremental. It is also likely that older adults with CF infected with S. aureus alone represent a different population than the CF population as a whole, because it is known that infection with S. aureus alone in older adults with CF is often a marker of mild disease (26). Finally, FEV1 may not be as sensitive a marker of lung pathology in adults as in children, because it has been observed that adults with low absolute FEV1 demonstrate a slower overall rate of FEV1 decline and less variability in FEV1 with changes in lung health (27).
Because the majority of individuals with CF in the United States are monitored in the CFFPR (15), this study's findings are likely applicable to the entire adult and pediatric CF population in the United States. Although our results are also most likely generalizable to the international CF community, they should be interpreted with caution, because it is plausible that the presence of different MRSA strains in the international community may result in different outcomes.
Although our results suggest an association between MRSA and lung function decline, it would be premature to recommend antibiotic treatment of individuals with CF aged 8 to 21 years with persistent respiratory MRSA infection. Prospective studies should be undertaken to determine (1) patient and pathogen characteristics that identify persistent infection and (2) if it is possible to eradicate incident MRSA. On the basis of the results of these studies, a randomized, double-blind, placebo-controlled trial of the risks and benefits of antibiotic therapy in persistent MRSA can be appropriately designed and conducted.
In conclusion, to assess the effect of MRSA infection in CF on lung function we have longitudinally analyzed over 17,000 individuals with CF for an average follow-up period of 5.3 years. During that period, 1,732 individuals developed new persistent infection with MRSA and were subsequently monitored for an average of 3.5 years. Even after controlling for severity of disease and other potential confounders, the results suggest that new persistent infection with MRSA in individuals with CF between the ages of 8 and 21 is associated with an increased rate of decline in lung function.
The authors thank the Cystic Fibrosis Foundation for its support of this project and for providing the CF registry data.
| 1. | Rosenstein BJ, Zeitlin PL. Cystic fibrosis. Lancet 1998;351:277–282. |
| 2. | Cystic Fibrosis Foundation. Patient registry 2006 annual report. Bethesda, MD: Cystic Fibrosis Foundation; 2007. |
| 3. | Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, Carmeli Y. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis 2003;36:53–59. |
| 4. | Datta R, Huang SS. Risk of infection and death due to methicillin-resistant staphylococcus aureus in long-term carriers. Clin Infect Dis 2008;47:176–181. |
| 5. | Foster TJ. Immune evasion by staphylococci. Nat Rev Microbiol 2005;3:948–958. |
| 6. | Stone A, Saiman L. Update on the epidemiology and management of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus, in patients with cystic fibrosis. Curr Opin Pulm Med 2007;13:515–521. |
| 7. | Elizur A, Orscheln RC, Ferkol TW, Atkinson JJ, Dunne WM Jr, Buller RS, Armstrong JR, Mardis ER, Storch GA, Cannon CL. Panton-Valentine leukocidin–positive methicillin-resistant Staphylococcus aureus lung infection in patients with cystic fibrosis. Chest 2007;131:1718–1725. |
| 8. | Garske LA, Kidd TJ, Gan R, Bunting JP, Franks CA, Coulter C, Masel PJ, Bell SC. Rifampicin and sodium fusidate reduces the frequency of methicillin-resistant Staphylococcus aureus (MRSA) isolation in adults with cystic fibrosis and chronic MRSA infection. J Hosp Infect 2004;56:208–214. |
| 9. | Miall LS, McGinley NT, Brownlee KG, Conway SP. Methicillin resistant Staphylococcus aureus (MRSA) infection in cystic fibrosis. Arch Dis Child 2001;84:160–162. |
| 10. | Thomas SR, Gyi KM, Gaya H, Hodson ME. Methicillin-resistant Staphylococcus aureus: impact at a national cystic fibrosis centre. J Hosp Infect 1998;40:203–209. |
| 11. | Steinkamp G, Wiedemann B, Rietschel E, Krahl A, Gielen J, Barmeier H, Ratjen F. Prospective evaluation of emerging bacteria in cystic fibrosis. J Cyst Fibros 2005;4:41–48. |
| 12. | Boxerbaum B, Jacobs MR, Cechner RL. Prevalence and significance of methicillin-resistant Staphylococcus aureus in patients with cystic fibrosis. Pediatr Pulmonol 1988;4:159–163. |
| 13. | Ren CL, Morgan WJ, Konstan MW, Schechter MS, Wagener JS, Fisher KA, Regelmann WE. Presence of methicillin resistant Staphylococcus aureus in respiratory cultures from cystic fibrosis patients is associated with lower lung function. Pediatr Pulmonol 2007;42:513–518. |
| 14. | Dasenbrook EC, Merlo CA, Lechtzin N, Diener-West M, Boyle MP. The effect of persistent MRSA infection on outcomes in CF: an eleven year longitudinal analysis of the CFF patient registry data [abstract]. Pediatr Pulmonol 2007;42:363. |
| 15. | FitzSimmons SC. The changing epidemiology of cystic fibrosis. J Pediatr 1993;122:1–9. |
| 16. | Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med 1999;159:179–187. |
| 17. | Wang X, Dockery DW, Wypij D, Fay ME, Ferris BG Jr. Pulmonary function between 6 and 18 years of age. Pediatr Pulmonol 1993;15:75–88. |
| 18. | Moran A, Hardin D, Rodman D, Allen HF, Beall RJ, Borowitz D, Brunzell C, Campbell PW III, Chesrown SE, Duchow C, et al. Diagnosis, screening and management of cystic fibrosis related diabetes mellitus: a consensus conference report. Diabetes Res Clin Pract 1999;45:61–73. |
| 19. | Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986;42:121–130. |
| 20. | Milla CE, Warwick WJ. Risk of death in cystic fibrosis patients with severely compromised lung function. Chest 1998;113:1230–1234. |
| 21. | Glikman D, Siegel JD, David MZ, Okoro NM, Boyle-Vavra S, Dowell ML, Daum RS. Complex molecular epidemiology of methicillin-resistant Staphylococcus aureus isolates from children with cystic fibrosis in the era of epidemic community-associated methicillin-resistant S aureus. Chest 2008;133:1381–1387. |
| 22. | Boyle MP, Ross T, Goldberg JD, Podliska MZ, Cai M, Mogayzel PJ, Carroll KC. Molecular epidemiology of MRSA infection in cystic fibrosis and its clinical implications [abstract]. Pediatr Pulmonol 2005;28:288–289. |
| 23. | Campana S, Cocchi P, Doring G, Taccetti G, Moroney SM. Emergence of an epidemic clone of community-associated methicillin-resistant panton-valentine leucocidin-negative Staphylococcus aureus in cystic fibrosis patient populations. J Clin Microbiol 2007;45:3146–3147. |
| 24. | Zhou J, Garber E, Desai M, Saiman L. Compliance of clinical microbiology laboratories in the United States with current recommendations for processing respiratory tract specimens from patients with cystic fibrosis. J Clin Microbiol 2006;44:1547–1549. |
| 25. | Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 1995;332:848–854. |
| 26. | Rodman DM, Polis JM, Heltshe SL, Sontag MK, Chacon C, Rodman RV, Brayshaw SJ, Huitt GA, Iseman MD, Saavedra MT, et al. Late diagnosis defines a unique population of long-term survivors of cystic fibrosis. Am J Respir Crit Care Med 2005;171:621–626. |
| 27. | VandenBranden SL, McMullen A, Konstan MW, Morgan W, Wagener JS, Schechter MS, Watts K, McColley S. Characteristic changes in lung function decline from adolescence to young adulthood [abstract]. Pediatr Pulmonol 2007;42:365–366. |
