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Original Research: CYSTIC FIBROSIS |

Panton-Valentine Leukocidin-Positive Methicillin-Resistant Staphylococcus aureus Lung Infection in Patients With Cystic Fibrosis* FREE TO VIEW

Arnon Elizur, MD; Rachel C. Orscheln, MD; Thomas W. Ferkol, MD; Jeffrey J. Atkinson, MD; W. Michael Dunne, Jr, PhD; Richard S. Buller, PhD; Jon R. Armstrong, MS; Elaine R. Mardis, PhD; Gregory A. Storch, MD; Carolyn L. Cannon, MD, PhD
Author and Funding Information

*From the Departments of Pediatrics (Drs. Elizur, Orscheln, Ferkol, Buller, Storch, and Cannon), Medicine (Dr. Atkinson), and Pathology and Immunology (Dr. Dunne), and the Genome Sequencing Center (Mr. Armstrong and Dr. Mardis), Washington University School of Medicine, St. Louis, MO.

Correspondence to: Arnon Elizur, MD, Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, Campus Box 8116, 660 S Euclid Ave, Saint Louis, MO 63110; e-mail: Elizur_A@kids.wustl.edu



Chest. 2007;131(6):1718-1725. doi:10.1378/chest.06-2756
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Background: Panton-Valentine Leukocidin-expressing (PVL+) methicillin-resistant Staphylococcus aureus (MRSA) is an emerging pathogen worldwide causing fatal necrotizing pneumonias in otherwise healthy individuals but has not been described in patients with cystic fibrosis (CF). Following two cases of patients with CF admitted with lung abscesses in association with PVL+ MRSA, we examined the incidence and the clinical characteristics of MRSA acquisition in our CF patient population.

Methods: Newly acquired MRSA isolates from patients with CF followed up at St. Louis Children’s Hospital were analyzed for the presence of Panton-Valentine leukocidin coding region, clindamycin susceptibility, staphylococcal cassette chromosome (SCC) mec type, and multilocus sequence type. Medical records and pulmonary function studies at the time of MRSA isolation were reviewed.

Results: MRSA isolates from 40 CF patients were available for analysis. Six children (15%) had PVL+ MRSA infection. All PVL+ organisms were clindamycin susceptible. Patients who acquired a PVL+ organism were more likely to have a focal pulmonary infiltrate on chest radiograph, including cavitary lung lesions in two patients (p = 0.04), a markedly greater decline in FEV1 at the time of MRSA detection (p = 0.01), and a significantly higher WBC count (p = 0.04) and absolute neutrophil count (p = 0.04). These patients were more likely to be admitted for IV antibiotic therapy for respiratory illnesses (p < 0.01).

Conclusions: We describe the emergence of PVL+ MRSA in our CF population in association with development of invasive lung infections including lung abscesses. Early identification and treatment of CF patients with newly acquired PVL+ MRSA may be crucial.

Figures in this Article

Cystic fibrosis (CF) is an inherited disease characterized by chronic airway inflammation and colonization by pathogenic bacteria.1Early in infancy, the lungs of neonates with CF are structurally normal, with the exception of plugging and distension of submucosal gland ducts. Bacterial cultures of respiratory secretions from young infants often fail to yield a specific pathogen, but the respiratory epithelial surface eventually becomes chronically infected.2Staphylococcus aureus is often isolated from patients early in life, and can chronically infect or colonize the lungs of patients with CF.2However, its role in the progression of CF lung disease and the need for antibiotic prophylaxis is unclear.34

During the past decade, infections with methicillin-resistant S aureus (MRSA) have increased dramatically.57 Similar to methicillin-sensitive S aureus (MSSA), the acquisition of MRSA has not been shown to significantly affect the clinical course or cause acute respiratory disease in children with CF.8 However, a new strain of MRSA has recently emerged, originating from the community and typi cally expressing the virulence factor, Panton-Valentine leukocidin (PVL). Community-acquired MRSA (CA-MRSA) differs from the traditional hospital-acquired MRSA (HA-MRSA) in its antibiotic susceptibility profile, and in the staphylococcal cassette chromosome (SCC) mec type. SCC-mec is the locus for the gene encoding methicillin resistance, and CA-MRSA usually has the smaller type IV mec cassette as opposed to types II or III mec cassettes harbored by HA-MRSA. This smaller type IV mec cassette lacks other antibiotic-resistance determinants, and is frequently associated with the expression of newly described virulence factors, of which PVL is the most well known. Thus, compared with strains harboring mec cassettes type II or III, a significantly higher proportion of type IV mec cassette-harboring MRSA strains are sensitive to antibiotics such as clindamycin and express the PVL gene.

First described in 1932 by Panton and Valentine,9PVL is now known as a cytotoxin that causes leukocyte destruction and tissue necrosis. Although it is produced by < 5% of Staphylococcus aureus strains, PVL genes were detected worldwide in the majority of MRSA strains isolated from otherwise healthy individuals treated for soft-tissue infections11 and fatal necrotizing pneumonias.6,1213 PVL-producing MRSA strains have not been previously reported as pathogens infecting the CF lung.

In this report, we describe the prevalence of MRSA, specifically PVL-expressing (PVL+) MRSA, in our CF patient population. We also describe the clinical characteristics, including the development of lung abscesses in two infected patients. This report represents the first description of the prevalence and acute clinical consequences of PVL+ MRSA in children and adolescents with CF.

Incidence and Prevalence of MRSA Among CF Patients

Patients with CF who were followed up at the St. Louis Children’s Hospital Pediatric Cystic Fibrosis Center for three or more visits per year for at least a year from 2001 to 2004 were included in analyses. Patients who were seen fewer than three times per year were excluded because they were routinely followed up at a satellite center and not all their clinical and microbiological data were available. In order to determine the incidence of MRSA acquisition at our center, patients who had undergone lung or liver transplantation were also excluded, since most had been referred from other centers. The incidence was calculated as the number of MRSA isolates obtained during a calendar year from patients not previously colonized with MRSA, divided by the total number of patients followed up during that year minus patients already colonized with MRSA. Samples for sputum cultures were obtained routinely once a year and with worsening of respiratory symptoms.

Characterization of MRSA Isolates From CF Patients

Antibiotic susceptibility was tested in all MRSA isolates obtained from patients with CF using the Kirby-Bauer disk diffusion method and the D-test for inducible resistance.14 All new MRSA isolates were frozen as a routine practice in the clinical microbiology laboratory at St. Louis Children’s Hospital and were available for further analysis. New isolates were defined as either initial isolates obtained from patients without previous MRSA colonization, or as isolates demonstrating a change in antibiotic susceptibility profile compared to isolates recovered before 2001.

To determine the relatedness of isolates of MRSA with a new susceptibility profile obtained from a patient with previously MRSA colonization, we performed repetitive-sequence polymerase chain reaction (PCR).15 Isolates with a similarity index > 95% were considered related and were not analyzed further.

SCC-mec type and the presence of the lukF-PV gene associated with PVL were evaluated by multiplex PCR using a modification of an established assay.16Primers and probes were as described by Francois et al,16 with the exception that the ccrB type IV probe was labeled with NED (Applied Biosystems; Foster City, CA) as the 5′ dye and the ccrB Type III probe was labeled with VIC (Applied Biosystems) as the 5′ dye. Multilocus sequence typing (MLST) was performed according to the method described by Enright et al17 on a representative subset of isolates selected based on patterns obtained by repetitive-sequence PCR, and results were expressed as sequence type.

Comparison of CF Patients With PVL+ and PVL-Nonexpressing MRSA Infection

To determine the clinical impact of acquisition of PVL+ MRSA by CF patients, we reviewed medical records, chest radiographs (based on radiology report), and pulmonary function studies of affected patients at the time of acquisition of the new isolate of MRSA. Baseline FEV1 (percentage of predicted) was determined based on the maximal value the year before acquisition. Patients with end-stage lung disease defined as FEV1 < 30% predicted were excluded. The patients were then classified as PVL+ or PVL nonexpressing (PVL) based on the results of PCR testing on their new isolate.

Statistical Analysis

Analyses were performed using statistical software (SPSS 12.0 for Windows; SPSS; Chicago, IL). Fisher exact test was used to analyze the relationship between categorical variables, and the unpaired Student t test was used to analyze the relationship between continuous variables. All analyses were two tailed, and p < 0.05 was considered significant.

Lung Abscesses in Two CF Patients

During the summer of 2004, two adolescents with CF presented with acute febrile respiratory illnesses and were found to have lung abscesses (Fig 1 ). Both patients had only mild lung disease at baseline, characterized by normal spirometric measures and infrequent pulmonary exacerbations. They were chronically colonized with Pseudomonas aeruginosa and PVL MRSA isolates that were clindamycin resistant, SCC-mec type II, and sequence type 5, all features consistent with HA-MRSA. At the time of hospital admission, the MRSA isolates recovered from both patients’ sputa were PVL+, representing a change from previous MRSA isolates. The isolates were also clindamycin susceptible without inducible resistance, SCC-mec type IV, and sequence type 8, typical of CA-MRSA. P aeruginosa was recovered from respiratory secretions in one patient; while in the other patient, although cultures had previously grown P aeruginosa, MRSA was the only pathogen isolated.

Both patients were initially treated with IV vancomycin and antipseudomonal antibiotics. One patient exhibited rapid resolution of systemic symptoms and eventual resolution of the cavitary lesion. The other patient continued to be febrile despite 7 days of systemic antibiotic therapy prompting repeat CT of the chest, which showed enlargement of the abscess cavity with greater extension into the lung parenchyma. Vancomycin was replaced with IV linezolid, and the patient promptly defervesced. Subsequent chest imaging studies showed a decrease in the size of the cavitary lesion with resolution of the surrounding infiltrate.

Incidence and Prevalence of MRSA Among CF Patients

The total number of patients followed up each year was as follows: 2001, n = 164; 2002, n = 160; 2003, n = 171; and 2004, n = 178, corresponding to 226 patients followed up for at least 1 year. An average of 1.4 sputum cultures per patient per year was obtained (range, 1 to 6 cultures). The prevalence of MRSA colonization in our CF population at the beginning of 2001 was 22%, while at the end of the study period it had increased to 27%. The incidence of MRSA acquisition for each year of the study was 4.5% for 2001, 6% for 2002, 4.3% for 2003, and 10.3% for 2004.

Characterization of MRSA Isolates From CF Patients

Of the 226 patients analyzed, 40 patients had a new MRSA isolate recovered from a sputum culture during the 4-year period (36 initial isolates and 4 isolates with a change in antibiotic susceptibility profile). Three additional MRSA isolates had a change in antibiotic susceptibility, but a similarity index > 95% on repetitive-sequence PCR and were thus not considered to represent new isolates and were excluded. Thirty of the new isolates (75%) contained SCC-mec type II, and 10 isolates (25%) had SCC-mec type IV. Isolates containing SCC-mec type IV initially appeared in 2002 (Fig 2 ). Six isolates (15%) representing 2.7% of all patients analyzed, all with SCC-mec type IV, were PVL+ and were first detected in 2003.

The grouping of MRSA isolates with respect to clindamycin susceptibility, PVL, SCC-mec type, and sequence type as determined by MLST is shown in Figure 3 . All six PVL+ isolates were clindamycin susceptible without inducible resistance, SCC-mec type IV, and sequence type 8 by MLST. In contrast, the majority (n = 30) of the 34 PVL isolates were clindamycin resistant (23 constitutive and 7 inducible), SCC-mec type II, and sequence type 5 by MLST (performed on 8 isolates). Interestingly, among the 34 PVL isolates, 4 were clindamycin susceptible without inducible resistance, of which 2 were SCC-mec type IV, and 2 were SCC-mec type II. In addition, two of the PVL clindamycin-resistant isolates were SCC-mec type IV.

Analysis of genomic relatedness by repetitive-sequence PCR revealed several clusters of MRSA (Fig 4 ). The first (lanes 1–8) included all six PVL+, SCC-mec type IV, sequence type 8 isolates plus two additional isolates that were SCC-mec type IV and PVL. One of these two isolates, shown in lane 7, was characterized by MLST and was also found to be sequence type 8. A second cluster (lanes 9–13) consisted of five MRSA isolates that were SCC-mec type II and PVL, in which four strains were clindamycin resistant. The isolate shown in lane 13 was characterized by MLST and was sequence type 5. A third cluster consisted of six isolates that were all PVL but varied with respect to SCC-mec type and clindamycin susceptibility. The isolates, shown in lanes 16, 18, and 19, were characterized by MLST and were sequence type 5.

Clinical Comparisons of CF Patients With PVL+ and PVL MRSA Infection

Children with PVL+ or PVL MRSA infection did not differ with respect to age, baseline FEV1 (percentage of predicted), or P aeruginosa carriage (Table 1 ). In contrast, patients with PVL+ and PVL MRSA differed significantly in their clinical presentation at the time of first detection of MRSA. Patients who acquired a PVL+ organism were more likely to be admitted for IV antibiotic therapy for respiratory illnesses (p < 0.01), had a significantly higher rate of focal pulmonary infiltrates on chest radiographs (p = 0.04), and a markedly greater decline in FEV1 at the time of MRSA detection compared to their maximum value in the preceding year (p = 0.01). These patients also had significantly higher values of measures of systemic inflammation including total WBC count (p = 0.04) and absolute neutrophil count (p = 0.04) [Table 1]. Other systemic markers of inflammation (ie, erythrocyte sedimentation rate, C-reactive protein) were not available for analysis because they are not routinely obtained from patients with CF during acute pulmonary exacerbations at our center. One of the patients who acquired PVL+ MRSA presented with hemoptysis. During the 6 months preceding their index admission, these patients had been clinically stable and only half had required IV antibiotic therapy.

All the patients with PVL+ MRSA infection who did not present with lung abscess responded well to antibiotic therapy. On follow-up cultures, five of the six patients had clindamycin-resistant strains of MRSA, suggesting eradication of the PVL+ MRSA; one patient was tested for PVL and results were negative. One patient continued to have a clindamycin-sensitive strain, although inducible resistance was not tested. That strain was found to be PVL. The clinical course of these six patients following the PVL+ MRSA infection was not significantly different from their preillness course. In most patients, FEV1 (percentage of predicted) returned to its preinfection value, and mean maximal FEV1 (percentage of predicted) in the year following the infection was not significantly different from before the infection (90.6% vs 96%, p = 0.59). Also, the average number of hospitalizations per year was not different from the 3 years before the infection (0.78) and the year after (1.0) [p = 0.78].

In this report, we describe the recent emergence of PVL+ MRSA and clinical manifestations in CF children and adolescents with infection followed up at a pediatric center. Acquisition of this virulent pathogen was associated with acute and severe pulmonary involvement, including lung abscesses in two patients. Despite the fact that CF is characterized by chronic, progressive pulmonary infection, the alveoli are usually spared and lung abscesses are only a rare complication.1819 Both patients with lung abscesses described in this report had previous colonization with hospital-associated PVL MRSA for a prolonged period of time with no detectable clinical consequences. Although microbiological confirmation was not obtained from the abscesses, in accordance with recommended clinical practice, the disease course and response to antistaphylococcal antibiotic therapy suggest that the acute respiratory illnesses were caused by the PVL+ MRSA strains. It is important to emphasize that this description focuses on acute clinical sequelae of PVL+ MRSA. The long-term effects of acute infection and the impact of chronic PVL+ MRSA colonization, if it occurs, on the clinical course of CF patients have yet to be determined.

These acute clinical manifestations, specifically the development of lung abscesses, of PVL+ MRSA infection in CF patients differ from the typically described manifestations of both MSSA and MRSA in patients with CF. While MSSA is frequently isolated from the respiratory tract of children with CF,2its impact on the development or progression of CF lung disease is controversial.34,2022 MRSA colonization has been increasing worldwide in CF patients.8,2324 In the United States, approximately 12% of CF patients reported in the Cystic Fibrosis Foundation Patient Data Registry had infection with this organism, although its prevalence greatly varies among care centers.25 The clinical impact of MRSA in CF lung has been unclear, but it did not appear to cause more rapid pulmonary deterioration.8,2324,26 Indeed, in our previous experience, acquisition of MRSA was not associated with obvious acute clinical manifestations.

Several studies11,13,27 have indicated that PVL+ MRSA has enhanced virulence compared to PVL MRSA. Severe skin and bone infections have been described,,6,10 often associated with increase in systemic markers of inflammation. Life-threatening sepsis and Waterhouse-Friderichsen syndrome have been reported.2831 Severe necrotizing pneumonia in otherwise normal hosts has also been described in association with PVL+ MRSA.,6,12 Our report extends these observations, and suggests that CF patients are a population that is vulnerable to the growing threat of PVL+ MRSA. Because S aureus transmission to CF patients has been reported, including from individuals who do not have CF, there is a real potential for this virulent pathogen to enter and disseminate within centers.,8,3233

Most of the MRSA isolates from the CF patient population had the characteristics of the predominant HA-MRSA at our institution (ie, PVL, SCC-mec type II, clindamycin resistant, and sequence type 5. In contrast, the PVL+ organisms were distinct, all having the following characteristics: SCC-mec type IV, susceptible to clindamycin, and sequence type 8. This pattern matches that of CA-MRSA isolates that are present in our community and appears to correspond with the predominant CA-MRSA in the United States.34 Indeed, these virulent forms of CA-MRSA have increased dramatically in our community since 2001 (data not shown). As shown in this description, the first PVL+ MRSA was isolated from our CF population in 2003.

Several small clusters of MRSA with different characteristics were also present in the CF population. An interesting pair of MRSA isolates had SCC-mec type IV, but unlike the typical CA-MRSA, were PVL and clindamycin resistant, characteristics usually found in HA-MRSA. Repetitive-sequence PCR and MLST results suggested that these organisms were indeed genomically related to the CA-MRSA isolates. A second, different pair of SCC-mec type IV MRSA isolates was also PVL but clindamycin susceptible, and they were distinct from the usual HA-MRSA or CA-MRSA based on findings from repetitive-sequence PCR. These observations indicate that there have been multiple introductions of MRSA into our center, and show that our infected CF population reflects the complexity of the current MRSA epidemic.34 These clusters suggest that MRSA, including PVL+ and PVL organisms, has the potential to spread from person to person, and that precautions that are already being taken to prevent transmission of multiple-resistant Gram negative organisms may be required. As this is a retrospective study, the data to accurately determine patient-to-patient transmission are not available. Thus, we do not have data from this study to determine whether even more stringent requirements might be required. As the numbers of patients with infection were small, it is difficult to draw conclusions about relative virulence of different MRSA types. However, it is notable that the PVL+ isolates appeared to be associated with greater virulence, and that no clindamycin-resistant (constitutive or induced) organism expressed PVL. Since PVL testing is not widely available, a patient with CF admitted with an exacerbation associated with focal pulmonary infiltrates, marked decline in lung function, and systemic markers of inflammation, who is found to harbor a clindamycin-sensitive MRSA that does not exhibit inducible resistance should be suspected of having PVL+ organism infection.

In conclusion, we describe the emergence of highly virulent PVL+ MRSA in a pediatric CF center, which parallels the dramatic increase in infections caused by this pathogen seen in our community. This report serves as a portent of the potential for clinically severe infections in CF patients with PVL+ MRSA infection.

Abbreviations: CA-MRSA = community-acquired methicillin-resistant Staphylococcus aureus; CF = cystic fibrosis; HA-MRSA = hospital-acquired methicillin-resistant Staphylococcus aureus; MLST = multilocus sequence typing; MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillin-sensitive Staphylococcus aureus; PCR = polymerase chain reaction; PVL = Panton-Valentine leukocidin; PVL+ = Panton-Valentine leukocidin expressing; PVL = Panton-Valentine leukocidin nonexpressing; SCC = staphylococcal casette chromosome

Drs. Elizur and Orscheln contributed equally to this work.

The study protocol was reviewed and approved by the Washington University Human Studies Committee.

The authors have no conflicts of interest to disclose.

Figure Jump LinkFigure 1. Radiographic evidence of lung abscess secondary to PVL+ MRSA in two adolescent CF patients. Top left, A, and bottom left, D: Chest radiographs obtained before hospital admission in case 1 and case 2, respectively. Top center, B, and bottom center, E. Chest radiographs obtained during hospitalization that showed interval development of cavitary lesions in the left upper lobe in case 1 and in the left lower lobe in case 2. Top right, C, and bottom right, F. CT of the chest of case 1 and case 2 shortly after hospital admission that demonstrated thick-walled, contrast-enhancing cavitary lesions in the left upper lobe and left lower lobe, respectively.Grahic Jump Location
Figure Jump LinkFigure 2. Increasing incidence of PVL+ MRSA in CF patients followed up at St. Louis Children’s Hospital during a 4-year period. CA = CA-MRSA; HA = HA-MRSA.Grahic Jump Location
Figure Jump LinkFigure 3. Characteristics of MRSA isolates from CF patients classified according to presence of absence of clindamycin susceptibility (S) [white boxes, sensitivity not determined; light gray, sensitive; dark gray, resistant (R)], PVL gene, SCC-mec type, and sequence type as determined by MLST. ND = not determined; clinda (S) = clindamycin susceptable; clinda (R) = clindamycin resistant; ST5 = sequence type 5; ST8 = sequence type 8. *Clinda = clindamycin. **constitutive resistance.Grahic Jump Location
Figure Jump LinkFigure 4. Characteristics of CF MRSA isolates analyzed by repetitive-sequence PCR, based on the presence of the PVL gene, SCC-mec type, and clindamycin susceptibility. Clindamycin resistance is further defined as inducible (I) or constituitive (C). The scale in the left margin shows percentage relatedness.Grahic Jump Location
Table Graphic Jump Location
Table 1. Clinical Characteristics of Patients With PVL+ MRSA Infection*
* 

Either first MRSA isolate or change in MRSA antibiotic susceptibility indicating a different strain. Data are presented as mean ± SD or No. (%).

 

Maximal value the year before acquisition.

 

FEV1 expressed as percentage of predicted value for age at the time of MRSA acquisition. The entry is the absolute decrease in FEV1 percentage of predicted, as compared to the patient’s maximum value the preceding year. Due to the severity of illness, the patients who had lung abscesses did not perform spirometry on hospital admission.

§ 

Per radiology report.

The authors thank Robert Senior and Daniel Rosenbluth for critical reviews of the manuscript. We thank Anand Patel for artistic contributions and Katherine Rivera for clinical contributions. We also thank Jane Quante for assistance with the Washington University Cystic Fibrosis Patient Database.

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Figures

Figure Jump LinkFigure 1. Radiographic evidence of lung abscess secondary to PVL+ MRSA in two adolescent CF patients. Top left, A, and bottom left, D: Chest radiographs obtained before hospital admission in case 1 and case 2, respectively. Top center, B, and bottom center, E. Chest radiographs obtained during hospitalization that showed interval development of cavitary lesions in the left upper lobe in case 1 and in the left lower lobe in case 2. Top right, C, and bottom right, F. CT of the chest of case 1 and case 2 shortly after hospital admission that demonstrated thick-walled, contrast-enhancing cavitary lesions in the left upper lobe and left lower lobe, respectively.Grahic Jump Location
Figure Jump LinkFigure 2. Increasing incidence of PVL+ MRSA in CF patients followed up at St. Louis Children’s Hospital during a 4-year period. CA = CA-MRSA; HA = HA-MRSA.Grahic Jump Location
Figure Jump LinkFigure 3. Characteristics of MRSA isolates from CF patients classified according to presence of absence of clindamycin susceptibility (S) [white boxes, sensitivity not determined; light gray, sensitive; dark gray, resistant (R)], PVL gene, SCC-mec type, and sequence type as determined by MLST. ND = not determined; clinda (S) = clindamycin susceptable; clinda (R) = clindamycin resistant; ST5 = sequence type 5; ST8 = sequence type 8. *Clinda = clindamycin. **constitutive resistance.Grahic Jump Location
Figure Jump LinkFigure 4. Characteristics of CF MRSA isolates analyzed by repetitive-sequence PCR, based on the presence of the PVL gene, SCC-mec type, and clindamycin susceptibility. Clindamycin resistance is further defined as inducible (I) or constituitive (C). The scale in the left margin shows percentage relatedness.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Clinical Characteristics of Patients With PVL+ MRSA Infection*
* 

Either first MRSA isolate or change in MRSA antibiotic susceptibility indicating a different strain. Data are presented as mean ± SD or No. (%).

 

Maximal value the year before acquisition.

 

FEV1 expressed as percentage of predicted value for age at the time of MRSA acquisition. The entry is the absolute decrease in FEV1 percentage of predicted, as compared to the patient’s maximum value the preceding year. Due to the severity of illness, the patients who had lung abscesses did not perform spirometry on hospital admission.

§ 

Per radiology report.

References

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