Epidemiology, clinical features and outcomes of pneumonia in patients with chronic kidney disease

Nephrol Dial Transplant (2011) 26: 2899 2906 doi: 10.1093/ndt/gfq798 Advance Access publication 27 January 2011 Epidemiology, clinical features and outcomes of pneumonia in patients with chronic kidney disease Diego Viasus 1, Carolina Garcia-Vidal 1, Josep M. Cruzado 2,3, Jordi Adamuz 1, Ricard Verdaguer 4, Frederic Manresa 3,5, Jordi Dorca 3,5, Francesc Gudiol 1,3 and Jordi Carratalà 1,3 1 Department of Infectious Diseases Barcelona, Spain, 2 Department of Nephrology, Hospital Universitari de Bellvitge, Institut d Investigaciò Biomèdica de Bellvitge (IDIBELL) Barcelona, Spain, 3 Department of Clinical Sciences, University of Barcelona, Barcelona, Spain, 4 Department of Microbiology, Barcelona, Spain, and 5 Department of Respiratory Medicine, Hospital Universitari de Bellvitge, Institut d Investigaciò Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain Correspondence and offprint requests to: Jordi Carratalà; E-mail: jcarratala@ub.edu Abstract Background. Although infection remains among the most common causes of morbidity and mortality in patients with chronic kidney disease (CKD), data on epidemiology, clinical features and outcomes of pneumonia in this population are scarce. Methods. Observational analysis of a prospective cohort of hospitalized adults with pneumonia, between 13 February 1995 and 30 April 2010, in a tertiary teaching hospital. CKD patients, defined as patients with a baseline glomerular filtration rate <60 ml/min/1.73m 2, were compared with non-ckd patients. Results. During the study period, 3800 patients with pneumonia required hospitalization. Two-hundred and three (5.3%) patients had CKD, of whom 46 were on dialysis therapy. Patients with CKD were older (77 versus 70 years; P < 0.001), were more likely to have comorbidities (82.3 versus 63.3%; P < 0.001) and more commonly classified into high-risk pneumonia severity index classes (89.6 versus 57%; P < 0.001) than were the remaining patients. Streptococcus pneumoniae was the most frequent pathogen (28.1 versus 34.7%; P ¼ 0.05). Mortality was higher in patients with CKD (15.8 versus 8.3%; P < 0.001). Among CKD patients, age [11 year increase; adjusted odds ratio, 1.25; 95% confidence interval (CI) 1.07 1.46] and cardiac complications during hospitalization (adjusted odds ratio, 9.23; 95% CI 1.39 61.1) were found to be independent risk factors for mortality, whereas prior pneumococcal vaccination (adjusted odds ratio, 0.05; 95% CI 0.005 0.69) and leukocytosis at hospital admission (adjusted odds ratio, 0.10; 95% CI 0.01 0.64) were protective factors. Conclusions. Pneumonia is a serious complication in CKD patients. Independent factors for mortality are older age and cardiac complications, whereas prior pneumococcal vaccination and leucokytosis at hospital admission are protective factors. These findings should encourage physicians to increase pneumococcal vaccine coverage among CKD patients. Keywords: chronic kidney disease; epidemiology; mortality; pneumonia; risk factors Introduction Mortality and morbidity remain high in patients with chronic kidney disease (CKD), predominantly due to cardiovascular and infectious complications. Although patients with CKD have an increased risk of bloodstream infection, urinary tract infection and pneumonia [1, 2], the overall scope of infections in this population has received little attention, even though some of these events may be preventable [3]. Regarding pneumonia, a recent community-based study by James et al. [4] reported that the risk of hospitalization and death with pneumonia was greater at lower glomerular filtration rates (GFR). In another study, the cumulative probability of pneumonia hospitalizations at 5 years was 36% in haemodialysis patients [5]. Moreover, CKD has been recognized as a risk factor for poor outcome in patients with community-acquired pneumonia (CAP) [6, 7]. Despite these findings, however, no study has comprehensively evaluated pneumonia in patients with CKD requiring hospitalization through the emergency department. Therefore, data on epidemiology, clinical features and outcomes of pneumonia in patients with CKD are particularly scarce. In addition, risk factors for mortality in this setting are not defined. Moreover, health care-associated pneumonia (HCAP) has been recently recognized as a new category of respiratory infection that merits a distinct approach to CAP when selecting empirical antibiotic therapy [8 11]. In this regard, patients who had recent contact with the health care system through nursing homes, home health care programmes haemodialysis clinics or prior hospitalization were considered to have HCAP. However, although it is clear that hemodialysis patients are at increased risk for bloodstream infection caused by resistant organisms [12], the role of these Ó The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

2900 D. Viasus et al. pathogens as a cause of pneumonia has yet to be adequately studied [13, 14]. The purpose of this study was to determine the epidemiology, clinical features and outcomes of patients with CKD in a large prospective cohort of non-severely immunosuppressed hospitalized adults with pneumonia. We also analyzed risk factors for mortality. A further analysis was performed to evaluate causative pathogens and prognosis in the subgroup of patients in chronic haemodialysis therapy. Materials and methods Vaccination status was assessed from interviews with the patients or their relatives and from reviews of hospital and personal health records (vaccination card). Patients were considered to be pneumococcal vaccinated if 23-valent polysaccharide pneumococcal vaccine had been administered in the 5 years before admission and influenza vaccinated if seasonal influenza vaccine had been administered during the year prior to admission. The diagnosis of septic shock was based on a systolic blood pressure of <90 mmhg and peripheral hypoperfusion with the need for vasopressors. Initial inappropriate therapy was defined as the absence of antimicrobial therapy for a specific type of organism or administration of an antibiotic to which the organism was resistant. Complications were defined as any untoward circumstances occurring during hospitalization. Time to clinical stability was defined as described elsewhere [17]. Early and overall mortality were defined as death from any cause within 48 h and during hospitalization, respectively. Setting, patients and study design This observational study was conducted at a 900-bed university hospital for adults in Barcelona, Spain. All non-severely immunosuppressed adult patients admitted to the hospital with pneumonia through the emergency department from 13 February 1995 through 30 April 2010 were prospectively recruited and followed up. Patients with neutropenia, solid organ transplantation, acquired immunodeficiency syndrome or current corticosteroid therapy (20 mg prednisone/day or equivalent) at admission were excluded. For the purposes of this study, patients with pneumonia were divided into two groups: patients with CKD (including patients in chronic haemodialysis and peritoneal dialysis therapy) and patients without CKD. Clinical assessment and antibiotic therapy Patients were seen daily during their hospital stay by one or more of the investigators, who recorded clinical data in a computer-assisted protocol. Data were collected on demographic characteristics, comorbidities (e.g. chronic pulmonary disease, chronic cardiac disease, diabetes mellitus, chronic renal disease, chronic liver disease, dementia and cancer), causative organisms, antibiotic susceptibilities, biochemical analysis, X-chest findings, empirical antibiotic therapy and outcomes. Baseline serum creatinine values for patients with chronic renal disease were obtained by reviewing the results of outpatient laboratories from the central laboratory database. The pneumonia severity index (PSI) [6] was used to stratify patients into the risk classes. All data were carefully reviewed by two clinical investigators prior to the final validation. Antibiotic therapy was initiated in the emergency department in accordance with the hospital guidelines, which recommend the administration of a b-lactam (ceftriaxone sodium or amoxicillin/clavulanate potassium) with or without levofloxacin. 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. Levofloxacin was recommended for patients with a urine antigen test result that was positive for Legionella pneumophila Serogroup 1. Combined amoxicillin/clavulanate was recommended for patients with clinical suspicion of aspiration pneumonia in order to provide adequate antianaerobic coverage, as described elsewhere [15]. Definitions Estimated GFR in patients with chronic renal disease was calculated using the baseline serum creatinine values and according to the Modification of Diet in Renal Disease equation [16]. Black ethnicity was omitted from the equation because this variable was not recorded. This is unlikely to bias the results because the black population in Barcelona is <1% (Institut d Estadística de Catalunya). Patients with chronic renal disease and GFR <60 ml/min/ 1.73m 2 or the need for chronic dialysis therapy were classified as patients with CKD. Patients with CKD were classified into CKD Stage III (GFR 30 59 ml/min/1.73m 2 ), CKD Stage IV (GFR 15 29 ml/min/1.73m 2 )orckd Stage V (GFR < 15 ml/min/1.73m 2 or chronic dialysis therapy) [16]. Patients with chronic renal disease and GFR >60 ml/min were not classified as CKD, as other evidence of renal disease, which was not available in this study, is required for this classification (e.g. proteinuria). Pneumonia was defined as the presence of a new infiltrate on a chest radiograph plus an acute illness associated with one or more of the following signs and symptoms: new cough with or without sputum production, pleuritic chest pain, dyspnoea, fever or hypothermia, altered breath sounds on auscultation or leukocytosis. CAP and HCAP were defined as described elsewhere [8]. Microbiological studies Pathogens in blood, pleural effusion, sputum and other samples were investigated using standard microbiological procedures within the first 24 48 h after admission. The Streptococcus pneumoniae antigen in urine was detected by using a rapid immunochromatographic assay (NOW Assay; Binax Inc., Portland, ME). Legionella pneumophila Serogroup 1 antigen in urine was detected by an immunochromatographic method (NOW Legionella Urinary Antigen Test; Binax Inc.) or enzyme-linked immunosorbent assay (ELISA-Bartels, Bartels, Trinity Biotech, Wicklow, Ireland). Standard serologic methods were used to determine antibodies against atypical agents (on admission and 3 4 weeks thereafter). Antimicrobial susceptibility was tested by the microdilution method, following the Clinical Laboratory Standard Institute methods and criteria. Statistical analysis Categorical variables were described using counts and percentages from the available data. Continuous variables were expressed as the mean and SD or median and interquartile range for abnormally distributed data (Kolmogorov Smirnov test). To detect significant differences between groups, we used the chi-square test or Fisher s exact test for categorical variables and the t-test or Mann Whitney test for continuous variables, as appropriate. Linear trend analysis was used to account for multiple comparisons between CKD stages. A multivariate analysis was carried out to determine independent risk factors for mortality in patients with CKD. Significant variables detected in the univariate analysis and those considered to be clinically important (age, sex, CKD stage V, comorbidities, septic shock and multilobar pneumonia) were entered into the multivariate analysis. Relative risks were expressed as odds ratios (OR) and 95% confidence intervals (CI). The results were analyzed using SPSS, version 15.0 (SPSS Inc., Chicago, IL). A <0.05 was considered statistically significant. All reported s are two tailed. Results Patient characteristics During the study period, 3800 non-severely immunosuppressed adult patients were admitted to the hospital with pneumonia. Two-hundred and three (5.3%) patients had CKD. Of these, 105 (51.7%) were classified into CKD Stage III, 42 (20.7%) into CKD Stage IV and 56 (27.6%) into CKD Stage V. Forty-six patients classified into CKD Stage V were on chronic dialysis therapy, peritoneal dialysis in two cases. The mean GFR from patients with CKD (excluding patients in dialysis) was 35.4 (SD 11.8) ml/ min/1.73m 2. Table 1 shows the demographic, clinical and laboratory findings of patients with and without CKD. Patients with CKD were older (95% CI of mean difference 5.8 9.8 years), were more likely to have chronic comorbid conditions and were more commonly classified into high-risk PSI classes. Comorbid conditions significantly associated

Epidemiology, clinical features and outcomes of pneumonia 2901 Table 1. Characteristics of patients by study groups Patients with Patients without CKD (n ¼ 203) CKD (n ¼ 3597) Demographic data, n (%) Age, median (IQR), years 77 (67 84) 70 (56 79)<0.001 Male sex 141 (69.5) 2461 (68.4) 0.75 Current smoker 30 (15.1) 972 (27.2) <0.001 Alcohol abuse 19 (9.5) 645 (18.1) 0.002 Influenza vaccine (season) 125/179 (69.8) 1540/3219 (47.8) <0.001 Pneumococcal vaccine, 5 years 50/160 (31.2) 486/3148 (15.4) <0.001 Nursing home a 16/186 (8.6) 184/2279 (8.1) 0.80 Comorbid conditions, n (%) 167 (82.3) 2278 (63.3) <0.001 Chronic pulmonary disease 58 (28.6) 996 (27.7) 0.78 Chronic heart disease 95 (46.8) 808 (22.5) <0.001 Diabetes mellitus 67 (33) 718 (20) <0.001 Chronic liver failure 7 (3.4) 225 (6.3) 0.10 Cerebrovascular disease 38 (18.7) 264 (7.3) <0.001 Clinical features at presentation, n (%) Fever (38.0 C) 80 (39.8) 1870 (52.5) <0.001 Cough and expectoration 111 (54.7) 2229 (62.2) 0.03 Tachycardia (100 beatsmin 1 ) 76 (39.8) 1512 (51.1) <0.001 Tachypnoea (30 breathsmin 1 ) 71 (42) 1467 (45) 0.44 Impaired consciousness 35 (17.3) 520 (14.5) 0.26 Septic shock 18 (8.9) 259 (7.2) 0.38 Pleuritic chest pain 65 (32) 1512 (42.2) 0.004 Laboratory and radiographic findings at presentation, n (%) Respiratory failure b 116 (65.5) 2126 (64.8) 0.83 Leukocytosis (leukocytes 12 10 9 /L) 128 (63.1) 2107 (58.7) 0.22 Anaemia (hematocrit <36%) 113 (56.2) 984 (27.5) <0.001 Hypoalbuminaemia (albumin <3.0 g/dl) 91 (52) 1479 (45.1) 0.07 Multilobar pneumonia 53 (26.5) 1192 (33.4) 0.04 Pleural effusion 23 (11.4) 625 (17.5) 0.02 Bacteraemia 14/178 (7.9) 441/3297 (13.4) 0.03 High-risk PSI classes c, n (%) 181 (89.6) 2042 (57) <0.001 a Variable recorded since January 2001. b PaO2/FiO2 < 300 or PaO2 < 60 mmhg. c Patients were stratified into the following risk classes according to the PSI score: low risk (90 points, Classes I, II and III) and high risk (>90 points, Classes IV and V). IQR, interquartile range. with patients with CKD were chronic heart disease and diabetes mellitus. CKD patients were also less likely to be current smokers or heavy alcohol drinkers. Regarding clinical features, fever, tachycardia and pleuritic chest pain were less common among CKD patients. As expected, however, CKD patients were more likely to present anaemia in laboratory findings. Multilobar infiltrates and pleural effusion in chest X-rays were more common in patients without CKD. Causative organisms Regarding microbiologic studies, they were all performed less frequently in CKD patients. Among patients with CKD, urinary antigen tests were performed less frequently in patients classified into CKD Stage V compared with patients classified into CKD Stages III IV (35.9 versus 64.1%; P ¼ 0.003 for L. pneumophila Serogroup 1 antigen and 56.1 versus 94%; P ¼ <0.001 for S. pneumoniae antigen). No significant differences were found in the other microbiological studies among CKD patients. The distribution of causative organisms in both groups is detailed in Table 2. An aetiologic diagnosis was more frequently established in non-ckd patients than in the others. Overall, S. pneumoniae was the most frequent causative pathogen, followed by Haemophilus influenzae, aspiration pneumonia and L. pneumophila. Patients with CKD presented fewer episodes of infections attributable to S. pneumoniae. There were no significant differences between the study groups regarding other pathogens. Treatment and clinical outcomes The susceptibility test for pathogen isolates indicated that most patients had received adequate initial empirical antibiotic therapy (Table 3). Significantly, patients with CKD more commonly presented cardiac complications during hospitalization, mainly acute coronary syndromes (3 versus 0.7%; P ¼ 0.004). No differences were found between the study groups regarding ICU admission and the need for mechanical ventilation. Overall mortality was higher in patients with CKD. Among the 32 CKD patients who died, causes of death were respiratory failure (15 patients), septic shock/multiorgan failure (8 patients) and acute cardiovascular events (6 patients). No cause of death was established in three patients. Overall mortality did not increase with the severity of the CKD

2902 D. Viasus et al. Table 2. Aetiology of pneumonia by study groups Patients with CKD (n ¼ 203), n (%) Patients without CKD (n ¼ 3597), n (%) Streptococcus pneumoniae 57 (28.1) 1248 (34.7) 0.05 Haemophilus influenzae 14 (6.9) 184 (5.1) 0.26 Aspiration pneumonia 13 (6.4) 291 (8.1) 0.38 Legionella pneumophila 9 (4.4) 204 (5.7) 0.45 Gram-negative bacilli 3 (1.5) 67 (1.9) 1 Pseudomonas aeruginosa 2 (1) 40 (1.1) 1 Atypical agents 7 (3.4) 225 (6.3) 0.10 Staphylococcus aureus 1 (0.5) 18 (0.5) 1 Others 3 (1.5) 32 (0.9) 0.43 No pathogen identified 100 (49.3) 1419 (39.4) 0.005 Table 3. Antibiotic therapy and outcomes of patients by study groups Patients with CKD (n ¼ 203) Patients without CKD (n ¼ 3597) Inappropriate antibiotic therapy, n (%) 3 (2.9) 156 (7.2) 0.11 In-hospital complications Cardiac complications a 29 (14.6) 279 (7.8) 0.001 Nosocomial infections 6 (3) 87 (2.4) 0.63 ICU admission 18 (8.9) 331 (9.2) 0.87 Need for mechanical ventilation 16 (7.9) 244 (6.8) 0.54 Length of hospital stay, median (IQR), days 8 (6 12) 8 (6 12) 0.94 Length of intravenous therapy, median (IQR), days 5 (3 8) 4 (2 7) 0.06 Time to clinical stability, median (IQR), days 3 (2 5) 4 (2 6) 0.24 Early mortality, 48 h 4 (2) 81 (2.3) 1 Overall mortality 32 (15.8) 290 (8.3) <0.001 a Acute coronary syndromes, arrhythmias and decompensated heart failure. IQR, interquartile range. (15.2, 19 and 14.3% in CKD Stages III, IV and V, respectively; chi-square test for trend P ¼ 0.95). Risk factors for mortality among patients with CKD The demographic and clinical features of CKD patients who died were compared with those of CKD patients who survived (Table 4). Patients who died were older and more frequently had septic shock, altered consciousness and multilobar pneumonia at hospital presentation. Conversely, pneumococcal vaccination, fever and leukocytosis were less common in patients who died. No differences were found between these groups in the severity of CKD. The results of multivariate logistic regression analysis for factors potentially associated with mortality in patients with CKD are summarized in Table 5. After adjustment, age and cardiac complications during hospital admission were found to be independent risk factors for mortality (11 yearin- crease; OR, 1.25; 95% CI 1.07 1.46 and OR, 9.23; 95% CI 1.39 61.1, respectively), whereas prior pneumococcal vaccine and leukocytosis at hospital admission were found to be protective factors (OR, 0.05; 95% CI 0.005 0.69 and OR, 0.10; 95% CI 0.01 0.64, respectively). Patients in chronic haemodialysis therapy In a further analysis, 44 patients on chronic haemodialysis therapy were compared with 2091 patients with CAP criteria (Table 6). There was no significant age difference between these groups. Patients on chronic haemodialysis were more likely to be male and to have been vaccinated against influenza and pneumococcus. Comorbid conditions were also more common in this group. Regarding clinical features, similar percentages of patients in both groups had septic shock and impaired consciousness. However, multilobar pneumonia was more frequent in patients with CAP. Streptococcus pneumoniae was the most common causative pathogen in haemodialysis patients. There were no significant differences regarding aetiologic pathogens between the groups. With respect to in-hospital complications, acute coronary syndromes were significantly more frequent in haemodialysis patients. Similarly, overall mortality was higher among these patients. Discussion This prospective study of a large cohort of patients offers a detailed evaluation of epidemiology, clinical features and outcomes of pneumonia in patients with CKD. The main findings were that (i) CKD patients had more severe pneumonia at admission compared with non-ckd patients; (ii) S. pneumoniae was the most frequent causative organism of pneumonia in patients with CKD; (iii) mortality rates were significantly higher in CKD patients and (iv) risk factors for mortality in these patients were older age and cardiac complications during hospitalization, whereas prior pneumococcal vaccination and leukocytosis at hospital admission were found to be protective factors. Hospitalization for pneumonia is a relatively common event for CKD patients [4, 5]. Moreover, the rate of chronic

Epidemiology, clinical features and outcomes of pneumonia 2903 Table 4. Factors associated with mortality in patients with CKD and pneumonia: univariate analysis Patients with CKD death (n ¼ 32) Patients with CKD alive (n ¼ 171) Demographic data, n (%) Age, median (IQR), years 83 (73.5 86.5) 75 (65.5 82) 0.002 Male sex 24 (75) 117 (68.4) 0.45 Influenza vaccine (season) 14 (66.7) 111 (70.3) 0.73 Pneumococcal vaccine, 5 years 2/19 (10.5) 48/141 (34) 0.03 CKD Stage IV, n (%) 8 (25) 34 (19.9) 0.51 CKD Stage V, n (%) 8 (25) 48 (28.1) 0.72 Comorbid conditions, n (%) Chronic pulmonary disease 11 (34.4) 47 (27.5) 0.42 Chronic heart disease 19 (59.4) 76 (44.4) 0.12 Diabetes mellitus 11 (34.4) 56 (32.7) 0.85 Cognitive deficit 7 (21.9) 9 (5.3) 0.001 Clinical features at presentation, n (%) Fever (38.0 C) 4 (12.5) 76 (45) 0.001 Impaired consciousness 10 (31.3) 25 (14.7) 0.02 Septic shock 6 (18.8) 12 (7) 0.04 Laboratory and radiographic findings at presentation, n (%) Respiratory failure a 19 (76) 97 (63.8) 0.23 Leukocytosis (leukocytes 12 10 9 /L) 15 (46.9) 113 (66.1) 0.03 Hypoalbuminaemia (albumin < 3.0 g/dl) 20 (76.9) 71 (47.7) 0.006 Multilobar pneumonia 13 (40.6) 40 (23.8) 0.04 High-risk PSI classes b, n (%) 32 (100) 149 (87.6) 0.02 Outcomes, n (%) In-hospital complications Cardiac complications c 10 (35.7) 19 (11.1) 0.002 ICU admission 9 (28.9) 9 (5.3) <0.001 a PaO2/FiO2 < 300 or PaO2 < 60 mmhg. b Patients were stratified into the following risk classes according to the PSI score: low risk (90 points, Classes I, II and III) and high risk (>90 points, Classes IV and V). c Acute coronary syndromes, arrhythmias and decompensated heart failure. IQR, interquartile range. PSI, pneumonia severity index. Table 5. Factors associated with mortality in patients with CKD and pneumonia: multivariate analysis OR (95% CI) Age (11 year increase) 1.25 (1.07 1.46) 0.004 Male sex 1.68 (0.30 9.42) 0.55 Pneumococcal vaccine 0.05 (0.005 0.69) 0.02 Comorbid conditions a 0.73 (0.10 5.12) 0.75 CKD Stage V 4.10 (0.38 43.8) 0.24 Impaired consciousness 1.44 (0.23 9.0) 0.69 Septic shock 6.02 (0.47 76.9) 0.16 Multilobar pneumonia 0.38 (0.04 3.05) 0.38 Hypoalbuminaemia (albumin < 3.0 g/dl) 1.10 (0.18 6.64) 0.91 Leukocytosis (leukocytes 12 10 9 /L) 0.10 (0.01 0.64) 0.01 Cardiac complications during hospitalization b 9.23 (1.39 61.1) 0.02 a Chronic pulmonary and heart disease, diabetes mellitus, chronic liver disease, cerebrovascular disease, cancer and cognitive deficit. b Acute coronary syndromes, arrhythmias and decompensated heart failure. renal disease among hospitalized patients with CAP is in the range 5 10% [6, 18]. In this study, the frequency of CKD was 5.3%. Interestingly, we found that many CKD patients did not exhibit some of the expected clinical and laboratory alterations during a pneumonia episode. CKD patients had less frequently fever, cough and expectoration, pleuritic chest pain and leukocytosis at hospital presentation. Our results concur with those reported by Lewis [19] who found that fever and leukocytosis cannot be relied on for the diagnosis of bacterial infection in patients with endstage renal disease due to alterations in immune response in this population. Therefore, the diagnosis and the severity of the pneumonia in CKD patients can be misjudged. In fact, we found that patients with CKD had more severe pneumonia at presentation than did the others, as shown by the fact that 90% of cases were classified into high-risk PSI classes. In this regard, patients with CKD were more likely to be older and more commonly had comorbid cardiovascular conditions (chronic heart and cerebrovascular disease), acidosis and anaemia. Patients with CKD are known to be at higher risk of infection by S. pneumoniae. In addition, CKD is often associated with diabetes mellitus and cardiovascular disease, which increases the risk for pneumococcal illness [20]. In the present study, the most frequent causative organism of pneumonia in CKD patients was S. pneumoniae, although this pathogen was more frequently documented in patients without CKD. Interestingly, an aetiologic diagnosis of pneumonia was also more often established in non- CKD patients. Nevertheless, it is important to note that microbiologic studies were performed less often in CKD patients (e.g. fewer urinary antigen tests in haemodialysis patients because most of them probably did not have residual renal function and fewer sputum cultures because CKD patients are less likely to present cough and expectoration).

2904 D. Viasus et al. Table 6. Characteristics of pneumonia in patients with and without chronic haemodialysis therapy Haemodialysis patients (n ¼ 44) Non-haemodialysis patients (n ¼ 2091) a Demographic data, n (%) Age, median (IQR), years 70 (53 77) 68 (58 77.5) 0.77 Male sex 38 (86.4) 1444 (69.1) 0.01 Influenza vaccine (season) 29 (78.4) 857 (45.3) <0.001 Pneumococcal vaccine, 5 years 14/32 (43.8) 319/1856 (17.2) <0.001 Comorbid conditions, n (%) 36 (81.8) 1241 (59.3) 0.003 Chronic pulmonary disease 12 (27.3) 535 (25.6) 0.80 Chronic heart disease 22 (50) 423 (20.2) <0.001 Diabetes mellitus 13 (29.5) 413 (19.8) 0.10 Clinical features at presentation, n (%) Fever (38.0 C) 17 (39.5) 1045 (50.5) 0.15 Impaired consciousness 4 (9.1) 272 (13) 0.44 Septic shock 6 (13.6) 164 (7.9) 0.15 Laboratory and radiographic findings at presentation, n (%) Respiratory failure b 20 (52.6) 1208 (63.3) 0.17 Multilobar pneumonia 7 (16.3) 684 (32.9) 0.02 High-risk PSI classes c, n (%) 33 (75) 1111 (53.3) 0.004 Aetiology, n (%) Streptococcus pneumoniae 15 (34.1) 832 (39.8) 0.44 Legionella pneumophila 3 (6.8) 122 (5.8) 0.74 Haemophilus influenzae 3 (6.8) 106 (5.1) 0.48 Gram-negative bacilli 1 (2.3) 34 (1.6) 0.52 Staphylococus aureus 0 (0) 8 (0.4) 1 Outcomes, n (%) In-hospital complications 14 (31.8) 653 (31.3) 0.94 Cardiac complications d 8 (18.2) 173 (8.3) 0.02 ICU admission 4 (9.1) 223 (10.7) 1 Overall-mortality rate 7 (15.9) 127 (8.3) 0.01 a Only patients with CAP criteria [8]. b PaO2/FiO2 <300 or PaO2 <60 mmhg. c Patients were stratified into the following risk classes according to the PSI score: low risk ( 90 points, classes I, II, and III) and high risk (>90 points, classes IV and V). d Acute coronary syndromes, arrhythmias and decompensated heart failure. ICU, intensive care unit; IQR, interquartile range. It is therefore necessary to improve the diagnostic accuracy for aetiology during pneumonia in this population. In this regard, the pneumococcal antigen test performed on pleural fluid samples, when available, may provide additional diagnostic information to that obtained by standard diagnostic methods, even in the case of prior antibiotic therapy [21]. Our finding of higher mortality in patients with CKD concurs with previous studies [6,7]. However, the specific factors responsible for increased mortality have not been defined. In our study, independent risk factors for mortality in CKD patients were older age and cardiac complications during hospitalization. These data are consistent with studies in which CKD patients had a higher risk of acute cardiovascular events and death following pneumonia and septicaemia [4, 22, 23]. Other reports have also found increased rates of acute cardiac events in patients with CAP [24, 25]. Accumulating evidence suggests that the systemic inflammatory response, alterations in the thrombotic state, endothelial dysfunction, biomechanical stress in arteries and hypoxaemia during infections could trigger acute cardiovascular events [26]. Further studies should be performed to develop effective strategies to prevent these complications in patients with pneumonia. It should also be noted that the US Advisory Committee on Immunization Practices recommends that patients with CKD receive annual influenza vaccination and a single vaccination against S. pneumoniae, which should be readministered after 5 years [20]. As in the present study, other reports have also documented that the implementation of this recommendation is suboptimal in this population [3, 27]. Interestingly, polysaccharide pneumococcal vaccination was found to be an independent protective factor against mortality in CKD patients in our study. This agrees with previous reports which found that pneumococcal vaccination may prevent invasive pneumococcal disease in adults, as well as improving outcomes in patients with CAP [28 30]. In addition, it has been suggested that prior pneumococcal vaccination may decrease the risk of myocardial infarction, although findings have been inconsistent across studies [31, 32]. This information underlines the relevance of pneumococcal vaccination for CKD patients. However, it is important to note that immunization may be a marker for other healthy behaviours that could improve outcomes [33]. In this regard, we did not find significant differences in the frequency of smoking, alcohol abuse and cognitive deficit between pneumococcal vaccinated and unvaccinated CKD patients (17.4 versus 16%; P ¼ 0.82, 16 versus 9.1%; P ¼ 0.20 and 6 versus 10%; P ¼ 0.55, respectively). Other factors such as diet, socioeconomic status and exercise were not recorded in the present study.

Epidemiology, clinical features and outcomes of pneumonia 2905 Moreover, CKD patients with leukocytosis at hospital admission had lower risk of mortality in our study. This finding concurs with those of previous studies that documented that leukopenia is associated with poor outcome during infections [34 36]. In addition, Reddan et al. [37] documented that a lower lymphocyte count was independently associated with increased risk of death among haemodialysis patients. In contrast, higher lymphocyte count was associated with higher serum albumin and creatinine, lower age and black race. On the other hand, it is well known that CKD is characterized by disorders in both the innate and adaptive immune systems. Studies showed that end-stage renal disease is associated with a decreased lymphocyte proliferation [38]. Also, there is evidence that immune dysfunction increases with decreasing GFR [39]. Therefore, the absence of leukocytosis at hospital admission in CKD patients with pneumonia may be a marker of an inadequate immune response or severe disease. To date, it remains unclear how patients on haemodialysis therapy contribute to the high prevalence of multidrug-resistant microorganisms in HCAP [13, 14]. Only one retrospective cohort study has addressed the aetiology of pneumonia in patients undergoing long-term haemodialysis [5]. Overall, the frequency of microbiological confirmation was very poor (18.2%). The most frequently identified bacteria were S. pneumoniae (3.4%), followed by Pseudomonas aeruginosa (2.8%), Klebsiella species (1.6%) and H. influenzae (1.5%). Staphylococcus species were relatively infrequent. In another study, Shorr et al. [40] documented that long-term aemodialysis was an independent factor associated with infection due to antibioticresistant bacteria. In contrast, the present study showed that S. pneumoniae was the most frequent microorganism causing pneumonia in patients on chronic haemodialysis, and no differences in the frequency of pathogens were found compared with patients without haemodialysis therapy. In addition, the frequency of Gram-negative bacilli and Staphylococcus aureus were quite low in this subgroup of patients. Certain methodological differences with respect to previous studies could explain these discrepancies: the present study collected data prospectively and excluded immunosuppressed patients. Our findings suggest that empirical antibiotic treatment for pneumonia in haemodialysis patients should be based on the CAP guidelines [15]. The strengths of this study are the large number of patients included, its prospective design and the comprehensive clinical and microbiologic data gathered. However, there are some limitations that should be acknowledged. The study was conducted in a single centre and the sample size was relatively small both for the subgroup of patients with CKD who died and when stratifying by CKD stages. Additionally, one must take into account the variations in pathogens, virulence and antibiotic resistance in other countries in order to evaluate the risk of multidrug-resistant microorganisms in patients on haemodialysis therapy. Also, we did not accurately document the proportion of patients using central venous catheters for dialysis access. In conclusion, patients with CKD had higher mortality during pneumonia compared with patients without CKD. In the subgroup of patients on haemodialysis, no significant difference in the causative pathogen of pneumonia was observed when compared with CAP patients, and the prevalence of Gram-negative bacilli and S. aureus was quite low. 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