Community-Acquired Legionella pneumophila Pneumonia A Single-Center Experience With 214 Hospitalized Sporadic Cases Over 15 Years

Legionella pneumophila has been increasingly recognized as a cause of community-acquired pneumonia (CAP) and an important public health problem worldwide. We conducted the present study to assess trends in epidemiology, diagnosis, clinical features, treatment, and outcomes of sporadic community-acquired L. pneumophila pneumonia requiring hospitalization at a university hospital over a 15-year period (1995Y2010). Among 3934 nonimmunosuppressed hospitalized patients with CAP, 214 (5.4%) had L. pneumophila pneumonia (16 cases were categorized as travel-associated pneumonia, and 21 were part of small clusters). Since the introduction of the urinary antigen test, the diagnosis of L. pneumophila using this method remained stable over the years (p = 0.42); however, diagnosis by means of seroconversion and culture decreased (p G 0.001 and p = 0.001, respectively). The median age of patients with L. pneumophila pneumonia was 58.2 years (SD 13.8), and 76.4% were male. At least 1 comorbid condition was present in 119 (55.6%) patients with L. pneumophila pneumonia, mainly chronic heart disease, diabetes mellitus, and chronic pulmonary disease. The frequency of older patients (aged 965 yr) and comorbidities among patients with L. pneumophila pneumonia increased over the years (p = 0.06 and p = 0.02, respectively). In addition, 100 (46.9%) patients were classified into high-risk classes according to the Pneumonia Severity Index (groups IVYV). Twentyfour (11.2%) patients with L. pneumophila pneumonia received inappropriate empirical antibiotic therapy at hospital admission. Compared with patients who received appropriate empirical antibiotic, patients who received inappropriate therapy more frequently had acute onset of illness (p = 0.004), pleuritic chest pain (p = 0.03), and pleural effusion (p = 0.05). The number of patients who received macrolides decreased over the study period (p G 0.001), whereas the number of patients who received levofloxacin increased (p G 0.001). No significant difference was found in the outcomes between patients who received erythromycin and clarithromycin. However, compared with macrolide use during hospital admission, levofloxacin therapy was associated with a trend toward a shorter time to reach clinical stability (median, 3 vs. 5 d; p = 0.09) and a shorter length of hospital stay (median, 7 vs. 10 d; p G 0.001). Regarding outcomes, 38 (17.8%) patients required intensive care unit (ICU) admission, and the inhospital case-fatality rate was 6.1% (13 of 214 patients). The frequency of ICU admission (p = 0.34) and the need for mechanical ventilation (p = 0.57) remained stable over the study period, but the inhospital case-fatality rate decreased (p = 0.04). In the logistic regression analysis, independent factors associated with severe disease (ICU admission and death) were current/former smoker (odds ratio EOR^, 2.96; 95% confidence interval ECI^, 1.01Y8.62), macrolide use (OR, 2.40; 95% CI, 1.03Y5.56), initial inappropriate therapy (OR, 2.97; 95% CI, 1.01Y8.74), and high-risk Pneumonia Severity Index classes (OR, 9.1; 95% CI, 3.52Y23.4). In conclusion, L. pneumophila is a relatively frequent causative pathogen among hospitalized patients with CAP and is associated with high morbidity. The annual number of L. pneumophila cases remained stable over the study period. In recent years, there have been significant changes in diagnosis and treatment, and the inhospital case-fatality rate of L. pneumophila pneumonia has decreased. (Medicine 2013;92: 51Y60) Abbreviations: AUC = area under curve, CAP = community-acquired pneumonia, CI = confidence interval, EWGLI = European Working Group for Legionella Infections, ICU = intensive care unit, IQR = interquartile range, IV = intravenous, OR = odds ratio, PSI = Pneumonia Severity Index, PCR = polymerase chain reaction, ROC = receiver operating characteristic, SD = standard deviation. INTRODUCTION Legionella species cause 2 clinical syndromes, known as Legionnaires disease and Pontiac fever. Legionnaires disease is an acute, serious, and sometimes lethal pneumonia, whereas Pontiac fever is generally a self-limited, nonpneumonic, influenzalike condition. Since the original description of Legionnaires disease in 1977, Legionella pneumophila has been increasingly recognized as a cause of sporadic and epidemic communityacquired pneumonia (CAP) in all age groups and in both healthy and immunosuppressed hosts. L. pneumophila is particularly frequent among patients with CAP who require admission to an intensive care unit (ICU). Therefore, L. pneumophila continues to be an important public health problem worldwide. Prospective studies have reported major differences in the frequencies of L. pneumophila causing CAP. These differences may be due to variances in the locations studied, the specific patient populations included, and the extent and nature of the microbiologic techniques used. Similarly, seasonal variations in the incidence of Legionnaires disease have been Medicine & Volume 92, Number 1, January 2013 www.md-journal.com 51 From the Departments of Infectious Diseases (DV, SDY, CGV, FG, JC), Microbiology (RV), and Respiratory Medicine (FM, JD), Hospital Universitari de Bellvitge, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona; and Department of Clinical Science (FM, JD, FG, JC), University of Barcelona, Barcelona, Spain. Financial support: This study was supported by the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III and co-financed by the European Regional Development Fund ‘‘A way to achieve Europe’’ ERDF, Spanish Network for Research in Infectious Diseases (REIPI RD06/0008). Dr. Viasus is the recipient of a research grant from the Institut d’Investigació Biomèdica de Bellvitge (IDIBELL). Dr Garcia-Vidal is the recipient of a Juan de la Cierva research grant from the Instituto de Salud Carlos III, Madrid, Spain. The authors have no conflicts of interest to disclose. Reprints: Diego Viasus, MD, PhD, Department of Infectious Diseases, Hospital Universitari de Bellvitge, Feixa Llarga s/n, 08907, L’Hospitalet de Llobregat, Barcelona, Spain (e-mail: dfviasusp@unal.edu.co). Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0025-7974 DOI: 10.1097/MD.0b013e31827f6104 Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. described. In addition, in recent years, new diagnostic tests (urinary antigen test and polymerase chain reaction) and antibiotic therapies (third-generation fluoroquinolones and newer macrolides) for Legionella pneumonia have become available. Although their use may have had an impact on identifying cases and on case-fatality rates, comprehensive clinical studies analyzing the issue are scarce. Most data regarding trends in Legionnaires disease are from passive surveillance systems. Therefore, new information is required for a better understanding of the disease burden. We conducted the present study to assess trends in epidemiology, diagnosis, clinical features, treatment, and outcomes of sporadic community-acquired L. pneumophila pneumonia cases in a large prospective cohort of nonimmunosuppressed patients requiring hospitalization at a university hospital over a 15-year period (1995Y2010). PATIENTS AND METHODS Setting, Patients, and Study Design This observational study was conducted at an 800-bed tertiary teaching hospital for adults in Barcelona, Spain. The hospital serves an urban area of 900,000 inhabitants. Nonimmunosuppressed patients admitted to the hospital with CAP from February 13, 1995, through December 31, 2010, were prospectively recruited and followed. Patients with CAP were identified at the emergency department by the attending physicians and/or the study investigators. Clinical and laboratory data on all patients were prospectively recorded using a computer-assisted protocol. Patients with neutropenia, solid organ transplantation, chemotherapy, acquired immunodeficiency syndrome (AIDS) or current corticosteroid therapy (Q20 mg prednisone/d or equivalent) at admission were excluded. This observational study was approved by the institutional review board, and all patients included gave informed consent. For the purposes of the study, we analyzed data from confirmed cases of sporadic community-acquired L. pneumophila pneumonia, diagnosed with 1 or more of the following methods: urine antigen test, isolation of Legionella in sputum, transthoracic needle aspiration specimen, or pleural fluid, and/or a fourfold increase in the antibody titer in serologic methods. Cases of community-acquired L. pneumophila pneumonia were defined as travel associated if the patient had stayed at or visited an accommodation site during the disease incubation period (15 d before symptom onset), in accordance with the criteria of the European Legionnaires Disease Surveillance Network. Clinical Assessment, Antibiotic Therapy, and Follow-Up Patients were seen daily during their hospital stay by 1 or more of the investigators. Data were collected on epidemiology, demographic characteristics, comorbidities, causative organisms, antibiotic susceptibilities, biochemical analysis, empirical antibiotic therapy, and outcomes, including mortality. A longterm follow-up visit took place 1 month after discharge. To stratify patients according to risk, we used the Pneumonia Severity Index (PSI). Clinical stability was considered as described elsewhere. Antibiotic therapy was initiated in the emergency department in accordance with the hospital guidelines, which recommended the administration of a A-lactam (either ceftriaxone sodium 1 g IV once/d or amoxicillin/clavulanate potassium 1 g IV 3 times/d) with or without a macrolide; from 1998 onward, levofloxacin (500 mg IV once/d) was also allowed. Combination therapy was recommended for patients with clinical suspicion of a Legionella species or an atypical pathogen, or in the absence of a demonstrative finding on sputum Gram stain results. Patients with a urine antigen test result positive for Legionella at admission were treated with macrolide (with or without rifampin, at the discretion of the physician) or levofloxacin (500 mg IVonce/d). Patients initially treated with other antibiotics were switched to appropriate therapy. Combined amoxicillin/clavulanate was recommended for patients with clinical suspicion of aspiration pneumonia in order to provide adequate antianaerobic coverage, as described elsewhere. Definitions Pneumonia was defined as an acute illness associated with 1 or more of the following signs and symptoms: new cough with or without sputum production, pleuritic chest pain, dyspnea, fever or hypothermia, altered breath sounds on auscultation, leukocytosis, plus the presence of a new infiltrate on a chest radiograph. Pneumococcal pneumonia was diagnosed in patients with 1 or more cultures positive for Streptococcus pneumoniae obtained from blood, normally sterile fluids, or sputum, and/or positive urinary antigen test detection. Only good quality samples of sputum (G10 squamous epithelial cells and 925 leukocytes per field) were accepted for processing. Tobacco smoking was recorded when a patient had smoked more than 10 cigarettes per day for at least 1 year. Alcohol abuse was considered if alcohol intake was more than 3 standard drinks per day. Vaccinated patients included all individuals who had received pneumococcal vaccine in the previous 5 years or influenza vaccine in the previous year. The diagnosis of septic shock was based on a systolic blood pressure of less than 90 mm Hg and peripheral hypoperfusion with the need for vasopressors. Empirical antibiotic therapy was defined as antibiotics received on the first day of therapy for pneumonia. Initial inappropriate therapy was defined as the absence of antimicrobial agents directed at a specific type of organism or administration of an antibiotic to which the organism was resistant, according to susceptibility test criteria for lower respiratory tract pathogens. Initial inappropriate therapy was considered in patients with Legionella pneumonia who did not receive macrolides, levofloxacin, or tetracyclines at hospital admission. Patients with aspiration pneumonia who had not received anaerobic coverage (that is, amoxicillin-clavulanate) were considered to have received inappropriate empirical antibiotic therapy. Complications were defined as any untoward circumstances occurring during hospitalization. The composite outcome of ICU admission or death was used to evaluate severe disease. Inhospital case-fatality rate was defined as death from any cause during hospitalization. Microbiologic Studies and Etiologic Diagnosis Pathogens in blood, normally sterile fluids, sputum, and other samples were investigated using standard microbiologic procedures. Isolation of Legionella species was attempted in sputum samples and other samples by the selective medium buffered charcoal yeast extract->. L. pneumophila serogroup 1 antigen in urine was detected by an immunochromatographic method (NOW Legionella Urinary Antigen Test; Binax Inc., Portland, ME) or enzyme-linked immunosorbent assay (ELISABartels, Bartels, Trinity Biotech, Wicklow, Ireland). The S. pneumoniae antigen in urine was detected by a rapid immunochromatographic assay (NOWAssay, Binax Inc.). Standard serologic methods were used to determine antibodies against atypical agents. Enzyme immunoassay was used to detect antibodies against L. pneumophila serogroups 1Y6. Microbiologic studies Viasus et al Medicine & Volume 92, Number 1, January 2013 52 www.md-journal.com * 2013 Lippincott Williams & Wilkins Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. were performed at the discretion of the physicians. Antimicrobial susceptibility was tested by the microdilution method, following methods and criteria of the Clinical and Laboratory Standards Institute. Statistical Analysis We used the chi-square test for trend analysis to account for multiple comparisons to determine whether the slope of the trend line differed from 0. To detect significant differences between FIGURE 1. Tests used to diagnose community-acquired L. pneumophila pneumonia over the study period. FIGURE 2. Number of community-acquired L. pneumophila pneumonia cases by year (A) and by month (B) over the study period, in relation to number of CAP cases from other etiologies. Medicine & Volume 92, Number 1, January 2013 Legionella pneumophila Pneumonia * 2013 Lippincott Williams & Wilkins www.md-journal.com 53 Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Legionella and pneumococcal pneumonia, we used the chi-square test or Fisher exact test for categorical variables and the t test or Mann-Whitney U test for continuous variables, depending on the results of the Kolmogorov-Smirnov normality test. A logistic regression analysis was carried out to evaluate associations between independent variables and severe disease. Significant (p G 0.10) and clinically important variables (age 970 yr, male sex, comorbidities, tobacco smoking, alcohol abuse, and high-risk PSI classes) were included in the multivariate analysis. High-risk PSI classes were chosen as a marker of severity to avoid collinearity with other variables already included in this score and due to the low number of patients who had severe disease. The relative risks were expressed as odds ratios (OR) and 95% confidence intervals (CI). The goodness-of-fit of the model was evaluated by the Hosmer-Lemeshow test. In addition, a receiver operating characteristic (ROC) curve and an area under curve (AUC) were used to evaluate the discriminatory power and predictive value of the PSI for identifying severe L. pneumophila pneumonia. P values e0.05 were considered statistically significant. All reported p values are 2-tailed. Data were analyzed using SPSS statistical software (v. 15.0, SPSS Inc., Chicago, IL).