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Keywords:

  • Candida albicans;
  • candidaemia;
  • non-albicans candida spp.;
  • predictors;
  • prognosis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. Transparency Declaration
  10. References
  11. Appendix

Clin Microbiol Infect 2010; 16: 1676–1682

Abstract

Although Candida albicans (CA) is the most common cause of Candida bloodstream infections (BSIs), recent studies have observed an increasing percentage of candidaemias caused by non-albicans Candida species (NAC). In the present study, we attempted to identify the predictors of candidaemia due to NAC compared to CA. We analyzed data from an active population-based surveillance in Barcelona (Spain) from January 2002 to December 2003. Factors associated with NAC fungaemia were determined by multivariate analysis. A total of 339 episodes of Candida BSI, in 336 patients (median age 63 years, interquartile range: 41–72 years), were included. CA was the most commonly isolated (52%), followed by Candida parapsilosis (23%), Candida tropicalis (10%), Candida glabrata (8.6%), Candida krusei (3.4%) and other NAC spp. (3%).Overall, 48% of cases were due to NAC spp. Multivariate logistic regression analysis identified factors associated with a risk of BSI due to NAC spp.: having received a haematologic transplant (OR 10.8; 95% CI 1.31–90.01; p 0.027), previous fluconazole exposure (OR 4.47; 95% CI 2.12–9.43; p <0.001) and neonatal age (OR 4.42; 95% CI 1.63–12.04; p 0.004). Conversely, previous CA colonization (OR 0.33; 95% CI 0.19–0.57; p 0.001) and previous antibiotic use (OR 0.42; 95% CI 0.21–0.85; p 0.017) were associated with CA fungaemia compared to NAC. In conclusion, NAC candidaemia comprised 48% of cases in our series. Predictors of NAC include having received a haematologic transplant, neonatal age and previous fluconazole use.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. Transparency Declaration
  10. References
  11. Appendix

Candida species accounted for 8–10% of all nosocomial bloodstream infections (BSIs) in the USA during the 1990s and were considered the fourth leading cause of nosocomial BSI [1,2]. Although Candida albicans (CA) continues to be the most common cause of Candida BSI, longitudinal studies have detected an increase of other Candida species in this condition [3–6]. Non-albicans Candida species (NAC) currently account for approximately half of all cases of candidaemia, although there is little published information on the factors associated with the increase in NAC candidaemia [4,5,7–10].

The changing epidemiology of Candida BSI has generated concern about the emergence of azole drug resistance and its clinical relevance [5,9,11]. Although CA is generally susceptible to fluconazole, Candida glabrata, the second cause of candidaemia in the USA, shows decreased susceptibility to this agent in up to 65% of cases [10–12]. The emergence of azole-resistant strains and the discovery of new antifungal drugs (new triazoles and echinocandins) have raised important questions about the use of fluconazole as a first-line drug. Therefore, it is of great value to identify the risk factors that distinguish CA infections from those due to NAC to aid clinicians in choosing an empiric anti-Candida therapy [13].

Various studies in immunocompromised and intensive care unit (ICU) patients with candidaemia have examined the clinical features that differentiate CA infection from NAC infection; however, the predictors of NAC BSI have not been prospectively studied in a general patient population [3,14–16]. The present study aimed to identify the risk factors associated with fungaemia due to NAC species compared to CA in a general patient population in the hope that this information can be used to guide the initial empiric therapy.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. Transparency Declaration
  10. References
  11. Appendix

Study and study population

We conducted a prospective, population-based active surveillance for Candida BSI in the Barcelona (Spain) area (population, 3.9 million), between 1 January 2002 and 31 December 2003. Fourteen major institutions participated, ranging in size from 214 to 1200 beds. A case was defined as the incident isolation of any Candida species from the blood of a surveillance area resident. Candidaemia episodes that occurred >30 days after the initial case were considered a new episode. Patients with candidaemia caused simultaneously by different species of Candida were excluded from the analysis because they had both CA and NAC species.

Data collection

The case report was laboratory-based. All blood cultures in which a Candida species had been isolated were reported to the study coordinator (DR). The coordinator visited the hospital to confirm the infection, completed the case report form, and recorded the outcome. The clinical laboratories were periodically audited to ensure that all cases of candidaemia were reported. A standardized case report form was used to abstract the medical records. The data collected included patient demographic characteristics; comorbid conditions; concomitant infections; previous Candida colonization; exposure to antibiotic, antifungal and immunosuppressive therapy; total parenteral nutrition received; surgical procedures; central venous catheter (CVC) use; haemodialysis; mechanical ventilation; treatment of candidaemia and outcome.

To measure disease severity, we used the Acute Physiology and Chronic Health Evaluation II score [17] for adult patients admitted to ICUs and the Karnofsky performance status scale for adults outside the ICU [18]. No standardized paediatric severity of illness score was used. Risk factors were assessed within 30 days prior to the diagnosis by positive sample.

Microbiological methods

Candida detection and species identification were performed at the participating laboratories according to their standard protocols. Isolates were sent to the Mycology Reference Laboratory (MRL), National Center for Microbiology, Madrid, Spain, for species confirmation and antifungal susceptibility testing, using standard morphological and physiological methods, including fermentation of and growth on carbon sources, growth on nitrogen sources and growth at various temperatures. Candida parapsilosisATCC 22019 and Candida kruseiATCC 6258 were used as quality control organisms for antifungal drug susceptibility testing [12]. When MRL and submitting laboratory identifications differed, the MRL identification was used for the study. MICs of fluconazole and voriconazole were determined by the broth microdilution method as recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Interpretive breakpoints proposed by EUCAST for fluconazole and voriconazole resistance are >4 and >0.12 mg/L, respectively [19].

Statistical analysis

Population incidences of CA and NAC were calculated using denominator data obtained from the 2001 local census. Statistical analyses were performed using spss software, version 15.0 (SPSS Inc., Chicago, IL, USA). The results for categorical variables are expressed as a percentage, and numerical data are expressed as the mean (SD), median, and interquartile range for ages. The chi-square test or Fisher’s exact test (two-tailed) were used to compare categorical variables, and an unpaired Student’s t-test was used for continuous variables. Multivariate stepwise logistic regression analysis was carried out to identify predictors of candidaemia due to NAC. p <0.05 was considered statistically significant in the multivariate modeling.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. Transparency Declaration
  10. References
  11. Appendix

During the study period, 345 cases of Candida BSI were detected. Six episodes of polyfungal candidaemia were excluded, leaving 339 episodes in 336 patients (median age 63 years, interquartile range: 41–72 years). A total of 176 (52%) patients had fungaemia due to C. albicans and 163 (48%) had infection due to NAC. The average annual incidence of candidaemia was 4.3 cases per 100 000 population (2.2 cases per 100 000 population for CA and 2.1 cases per 100 000 population for NAC). Demographics, clinical characteristics, underlying comorbid conditions and the outcome of patients with NAC BSI compared to those with CA BSI are summarized in Table 1.

Table 1.   Demographics, epidemiological data and clinical characteristics of the patients included in the present study
Characteristics (n = 339 episodes in 336 patients)C. albicans, n = 176 (52%)Non-albicans Candida spp., n = 163 (48%)p
  1. Categorical variables are expressed as total number and percentages, and numerical data are expressed as the mean and standard deviation (SD).

  2. aPatients hospitalized within 3 months prior to candidaemia.

  3. APACHE, Acute Physiology and Chronic Health Evaluation score system.

  4. bIncludes patients with APACHE >20 (only patients admitted to ICU).

  5. ICU, intensive care unit.

  6. cNAC in the neonatal ICU were due to Candida parapsilosis in 16 cases and Candida glabrata in one case.

  7. dSome patients had more than one predisposing factor.

  8. eIncludes corticoids, chemotherapy, and other immunosuppressive drugs.

  9. CVC, central venous catheter.

  10. fPrevious Candida colonization due to the same Candida spp. that caused candidaemia (includes candiduria).

  11. gDefined as at least 5 days of adequate antifungal treatment.

Age (years), mean (SD)57.9 (24.07)47.7 (27.45)0.011
Elderly (>65 years)95 (54)66 (40.5)0.013
Male sex101 (57.4)98 (60.1)0.659
Nosocomial candidaemia158 (89.8)149 (91.4)0.573
Prior hospitalizationa86 (48.9)77 (47.2)0.770
APACHE II (severity high)b29 (26.9)20 (19)0.176
Length of stay before candidaemia (days), mean (SD)30.1 (35.3)29.7 (33.6)0.752
Location of the patients
 Medical ward49 (27.8)64 (39.3)0.026
 Surgical ward44 (25)22 (13.5)0.008
 ICU hospitalization (except neonates)52 (29.5)37 (22.7)0.152
 Neonatal ICU hospitalizationc7 (4)17 (10.4)0.032
 Pediatric ward (excluding neonates)7 (4)9 (5.5)0.611
 Outpatient17 (9.7)14 (8.6)0.851
Predisposing factorsd
 Diabetes mellitus44 (25)26 (16)0.037
 Chronic renal failure73 (41.5)44 (27.0)0.006
 Solid tumour45 (25.6)27 (16.6)0.043
 Haematological malignancy16 (9.1)32 (19.6)0.005
 Neutropaenia11 (6.3)28 (17.2)0.002
 Solid organ transplant recipient2 (1.1)8 (4.9)0.054
 Haematological transplant recipient1 (0.6)15 (9.2)<0.001
 Surgery in previous 3 months85 (48.3)69 (4236)0.271
 Prior immunosuppressive drugse66 (37.5)66 (40.5)0.479
 Prior antibiotics (1 previous month)158 (89.8)137 (84.0)0.146
 Prior fluconazole therapy12 (6.8)41 (25.2)<0.001
 CVC placement130 (73.9)138 (84.7)0.015
 Total parenteral nutrition57 (32.4)67 (41.1)0.096
 Previous Candida colonizationf74 (42.0)34 (20.9)<0.001
 Candiduria due to Candida albicans36 (20.5)12 (7.4)0.001
Portal of entry
 Primary candidaemia105 (59.7)95 (58.3)0.797
 CVC-related candidaemia54 (30.7)53 (32.5)0.717
 Secondary candidaemia17 (9.7)15 (9.2)1
 Optimal antifungal treatmentg82 (52.2)86 (52.8)0.36
Outcome
 Shock46 (26.1)43 (26.4)0.967
 Mechanical ventilation55 (31.3)46 (28.2)0.592
 ICU admission during outcome15 (8.5)10 (6.1)0.533
 Acute renal failure37 (21.0)26 (16.0)0.242
 Early mortality (<7 days)47 (26.7)35 (21.5)0.261
 Overall mortality (<30 days)75 (42.6)60 (36.8)0.275

The NAC species isolated included 78 C. parapsilosis (23%), 34 Candida tropicalis (10%), 29 Candida glabrata (8.6%), 12 C. krusei (3.6%), three Candida kefyr (0.9%), two Candida lusitaniae (0.6%), two Candida guilliermondii (0.6%), one Candida famata (0.3%), one Candida inconspicua (0.3%) and one Candida norvegensis (0.3%). Percentages of in vitro fluconazole and voriconazole resistance among the 339 incident bloodstream isolates of Candida spp. are shown in Table 2.

Table 2.   Species distribution and in vitro susceptibilities to fluconazole and voriconazole (European Committee on Antimicrobial Susceptibility Testing breakpoint for Candida susceptibilitya)
SpeciesFluconazole resistant isolates/n total isolates (%)Voriconazole resistant isolates/n total isolates (%)
  1. aFluconazole-resistant isolates: MIC >4 mg/L.

  2. Voriconazole-resistant isolates: MIC >0.12 mg/L.

Candida albicans2/176 (1.1)1/176 (0.6)
Candida parapsilosis2/78 (2.6)2/78 (2.6)
Candida tropicalis1/34 (2.9)1/34 (2.9)
Candida glabrata13/29 (44.8)19/29 (65.5)
Candida krusei12/12 (100)12/12 (100)
Candida kefyr0/3 (0)0/3 (0)
Candida lusitaniae0/2 (0)0/2 (0)
Candida guillierrmondii0/2 (0)0/2 (0)
Candida famata1/1 (100)1/1 (100)
Candida inconspicua1/1 (100)0/1 (0)
Candida norvegensis1/1 (100)1/1 (100)
Total33/339 (9.7)37/339 (11)

Subgroup analysis for specific Candida spp. showed that patients with C. albicans fungaemia were admitted more often to surgical wards (25% CA vs. 13.5% NAC; p 0.008), had diabetes mellitus (25% CA vs. 16% NAC; p 0.03) or chronic renal failure (41.5% CA vs. 27.2% NAC; p 0.006) and had been previously colonized with C. albicans (42.3% CA vs. 20.9% NAC; p <0.001). Cases with C. parapsilosis were more likely to be infants (28% vs. 5%; p <0.001) and have an indwelling CVC (97% vs. 87%; p 0.006), and less likely to die within 30 days (23% vs. 45%; p 0.001) compared to the other cases. C. krusei cases had received previous fluconazole (75% vs. 14%; p <0.001) and immunosuppressive therapy (75% vs. 38%; p 0.01) more often, were more frequently neutropaenic (67% vs. 9%; p <0.001) and had haematological malignancies (58% vs. 12%; p <0.001) more often than non-krusei cases. C. tropicalis cases were also likely to be neutropaenic (24% vs. 10%; p 0.04), have haematological malignancies (29% vs. 11%; p 0.007), and die within 30 days (56% vs. 38%), although this latter difference did not reach statistical significance (p 0.06). Overall mortality tended to be lower in patients with NAC BSI compared to CA BSI, although this trend did not reach statistical significance (36.8% NAC vs. 42.6% CA; p 0.27).

Factors associated with NAC fungaemia were determined by univariate analysis (Table 1) and multivariate analysis (Table 3). In the multivariate analysis, the fact of having undergone haematological transplantation (OR 10.8; 95% CI 1.31–90.1; p 0.027) or previous exposure to fluconazole (OR 4.47; 95% CI 2.12–9.43; p <0.001), and neonatal age (OR 4.42; 95% CI 1.63–12.04; p 0.004) were significantly associated with NAC fungaemia, whereas previous CA colonization (OR 0.33; 95% CI 0.19–0.57; p <0.001) and previous antibiotic use (OR 0.42; 95% CI 0.21–0.85; p 0.017) were associated with CA candidaemia.

Table 3.   Multivariate analysis of risk factors associated with non-albicans Candida infection among all patients with candidaemia
VariableOR95% CIp
  1. aAt least 3 days of fluconazole treatment within 30 days prior to candidaemia.

  2. bAt least 3 days of any antibiotic treatment within 30 days prior to candidaemia.

Haematological transplant recipient10.81.31–90.010.027
Previous fluconazole usea4.472.12–9.43<0.001
Neonatal intensive care unit admission4.421.63–12.040.004
Previous antibiotic useb0.420.21–0.850.017
Previous Candida albicans colonization0.330.19–0.57<0.001

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. Transparency Declaration
  10. References
  11. Appendix

In the general population of Barcelona, 48% of all cases of candidaemia were caused by NAC. The distribution of Candida species was generally similar to those reported from other European countries, such as France and Italy [20,21], with C. parapsilosis being the second most common Candida spp. isolated. An exception is the incidence of C. glabrata, which was the fourth most common species in the present study, but the second most common in England and Wales [22], Switzerland [23], Denmark [24] and the USA [10,25,26]. An increase in the percentage of C. glabrata BSI was first reported in the USA during the 1990s [6,25,26]. However, this trend is not universal, and C. glabrata is less common in other areas, including South America, Canada and some European countries (e.g. Italy and France) which, again, is in keeping with our results [20,21,27]. The changing pattern of candidaemia may be attributable in part to the large number of immunocompromised hosts and the widespread use of prophylactic or empiric antifungal therapy [9], although the role of widespread azole use in the emergence of species other than CA as causes of candidaemia remains controversial. Knowledge of the local epidemiological trends in Candida species isolated in blood cultures is important to guide the choice of empiric therapy.

Previous studies of risk factors for candidaemia due to NAC compared to CA have focused on critically ill ICU patients or patients with a haematological malignancy [14–16,28] and have investigated a single species, such as C. parapsilosis or C. glabrata [8,14,29,30]. To our knowledge, the risk factors for NAC vs. CA have not been prospectively described in a general patient population.

The results obtained in the present study and those of Chow et al. [15] contrast with the results reported by Shorr et al. [16] who found no differences in the clinical characteristics of ICU patients with BSI caused by NAC or CA. These authors theorized that clinical variables do not allow one to successfully predict the microbiology of fungaemia in a particular patient because NAC species are essentially endemic [16]. Nonetheless, we found several differences in patients with NAC fungaemia compared to those with CA: they were significantly younger, had a higher incidence of haematological malignancies, were neutropaenic or had undergone haematological transplantation, or had been exposed to fluconazole previously. NAC was not associated with an increase in mortality or length of hospital stay compared to CA, probably because C. parapsilosis accounted for a considerable percentage of NAC isolates in our series, and this species is known to be less virulent, more frequently associated with a CVC infectious origin, and uniformly susceptible to fluconazole [8,30].

Subsequent to multivariate analysis, NAC fungaemia was found to be independently associated with having undergone haematological transplantation (p 0.027). The potential risk factors for developing NAC BSI identified in previous studies have included neutropaenia and an underlying haematological disease and, in these cases, C. tropicalis, C. krusei and even C. glabrata were more prevalent [7,14,28]. Because it is a general practice to use fluconazole prophylaxis in high-risk haematological patients, it is reasonable to conclude that undergoing haematological transplantation could be a confounding risk factor, with previous fluconazole exposure being the determining predictor in these cases. Although fluconazole prophylaxis is associated with a reduction in the incidence of candidaemia and attributable mortality, several studies have investigated the way in which fluconazole can influence the development of azole resistance [9,31].

In our series, the predominant Candida species varied according to the hospital care unit. C. parapsilosis was the most prevalent species in the neonatal ICU (16 of 24 [67%] cases), whereas CA was the most prevalent in surgical areas. In our series, all except one case of NAC among neonates were caused by C. parapsilosis. Considering that multivariate analysis identified neonatal age as a risk factor for NAC, we were able to determine that neonatal age is a predictor for C. parapsilosis fungaemia. The association between neonatal fungaemia and C. parapsilosis has been extensively described, and some studies suggest that it may reflect the intensive use of intravascular devices to treat neonates and children [32,33].

We also found that fluconazole exposure is a risk factor for the development of NAC BSI. The results obtained in the present study agree with the findings reported in previous studies postulating that widespread fluconazole use would result in selection of yeast species that are less sensitive to this antifungal agent, such as C. krusei, C. glabrata and C. tropicalis [9,15,31]. Fluconazole use and selection of fluconazole-resistant Candida spp. has been extensively described in studies performed in ICU patients and in patients with cancer or haematological malignancies [3,30,31]. In patients without cancer, the association between previous fluconazole exposure and NAC fungaemia is not as clear, with some studies suggesting an independent relationship and others failing to note this association [15,16,34]. Moreover, the important percentage of C. parapsilosis, a yeast species that is almost always susceptible to fluconazole, is not explained by the increase of fluconazole use. It is likely that fungemia due to C. parapsilosis reflects acquisition associated with the widespread use of parenteral feeding and intravascular devices [30–32].

We also found that patients were more likely to develop CA fungemia if they had been treated previously with antibiotics at the onset of candidaemia or if they had been colonized previously by CA. Previous antibiotic exposure has been associated with CA in non-neutropaenic patients [34] and previous Candida colonization by the same Candida spp. has also been described as a risk factor for candidaemia [35].

The observations made in the present study are subject to limitations. First, the data were obtained 6 years ago. Several new treatment options subsequently have been developed (e.g. echinocandins and new triazoles) but, in all probability, the epidemiology and species distribution of Candida has not changed substantially, and these data are still relevant. Second, only the presence or absence of risk factor exposure was considered, and not the duration of exposure. Because the study was not designed to quantify the length of exposure, this variable is not available and any associated bias cannot be assessed. Third, it may not have been appropriate to pool all NAC species together because certain NAC species are uniformly susceptible to fluconazole. To address this limitation, other studies [16] have analyzed C. krusei and C. glabrata together vs. C. albicans, C. tropicalis and C. parapsilosis. However, the main goal of the present study was not to investigate potential fluconazole resistance but, instead, to identify predictors of candidaemia due to NAC. Nonetheless, the small number of fluconazole-resistant isolates precluded a risk factor analysis for individual Candida species. On the other hand, some strengths of the present study include the fact that risk factors for NAC fungaemia were examined in a general population, the sample size is relatively large, and the study design is prospective.

In summary, a number of factors were found to be independently associated with an increased risk of candidaemia due to NAC compared to CA. Neonatal age, having undergone haematological transplantation, and prior fluconazole use were associated with NAC BSI. Physicians can take these specific characteristics into consideration when empiric treatment with an antifungal agent must be started while waiting for Candida species to be identified.

Author Contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. Transparency Declaration
  10. References
  11. Appendix

D. Rodriguez, B. Almirante and A. Pahissa made a substantial contribution to the conception and design of the manuscript; acquisition, analysis and interpretation of data; drafting the article and revising it critically for important intellectual content; and giving final approval of the version to be published. M. Cuenca-Estrella and J. L. Rodriguez-Tudela performed all microbiological studies in the Mycology Reference Laboratory and made a substantial contribution to the acquisition and interpretation of data; revising the manuscript critically for important intellectual content; and giving final approval of the version to be published. J. Mensa, J. Ayats and F. Sanchez made a substantial contribution to the acquisition and interpretation of data; revising the manuscript critically for important intellectual content; and giving final approval of the version to be published.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. Transparency Declaration
  10. References
  11. Appendix

This study was presented, in part, as a poster (M-2141a) at the 48th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America, Washington, DC, 25–28 October 2008. We thank C. Cavallo for assistance with the English language.

Transparency Declaration

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. Transparency Declaration
  10. References
  11. Appendix

This study was supported by research grants from Pfizer, Inc., Gilead Sciences S.A., and the Sociedad Española de Enfermedades Infecciosas y Microbiologia Clinica (SEIMC, Spanish Society of Infectious Diseases and Clinical Microbiology) and by a medical research grant from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Spanish Network for the Research in Infectious Diseases (REIPI RD 06/0008). None of the authors has any conflicts of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. Transparency Declaration
  10. References
  11. Appendix
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Appendix

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Author Contributions
  8. Acknowledgements
  9. Transparency Declaration
  10. References
  11. Appendix
Other members of the Barcelona Candidaemia Project Study Group

S. Fridkin, R. Hajjeh, B. Park, J. Morgan, D. W. Warnock (Centers for Disease Control and Prevention, Atlanta, GA); A. M. Planes (Hospital de Vall d’Hebron, Barcelona, Spain); M. Almela, F. M. Reverter, C. M. Soler (Hospital Clinic, IDIBAPS, Barcelona, Spain); M. Salvadó, P. Saballs (Hospital del Mar, Barcelona, Spain); A. Gener (Hospital Sant Joan de Deu, Esplugues de Llobregat, Barcelona, Spain); D. Fontanals (Hospital Parc Taulıí, Sabadell, Barcelona, Spain); M. Xercavins (Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain); L. Falgueras, M. T. Torroella, M. de Ramon (Hospital General de Catalunya, Sant Cugat del Valles, Barcelona, Spain); Carles Alonso (Hospital Creu Roja, Hospitalet de Llobregat, Barcelona, Spain); J. de Otero (Hospital Creu Roja, Barcelona, Spain); M. Sierra and J. Martinez-Montauti (Hospital de Barcelona, Barcelona, Spain); M. A. Morera (Hospital de Terrassa, Terrassa, Barcelona, Spain); and M. Giménez (Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain).