Background: Patients on extracorporeal membrane oxygenation (ECMO) are often among the most severely ill in the intensive care unit. They are often receiving broad-spectrum antibiotics; they have multiple entry points for pathogens; and their immune system is impaired by blood circuit interaction. These factors are thought to predispose them to fungal infections. We thus aimed to evaluate the prevalence, risk factors, and prognosis of fungal infections in adults on ECMO. Methods: We conducted a retrospective cohort study using the Extracorporeal Life Support Organization registry, which compiles data on ECMO use from hundreds of international centers. We included all adult patients from 2006 to 2016 on any mode of ECMO with either a diagnosis of fungal infection or a positive fungal culture. Results: Our study comprised 2129 adult patients (10.8%) with fungal colonization or infection. Aspergillus involvement (colonization or infection) was present in 272 patients (1.4%), of whom 35.7% survived to hospital discharge. There were 245 patients (1.2%) with Candida invasive bloodstream infection, with 35.9% survival. Risk factors for Aspergillus involvement included solid organ transplant (OR 1.83; p = 0.008), respiratory support (OR 2.75; p < 0.001), and influenza infection (OR 2.48; p < 0.001). Risk factors for candidemia included sepsis (OR 1.60; p =0. 005) and renal replacement therapy (OR 1.55; p = 0.007). In multivariable analysis, Aspergillus involvement (OR 0.40; p < 0.001) and candidemia (OR 0.47; p < 0.001) were both independently associated with decreased survival. Conclusions: The prevalence of Aspergillus involvement and Candida invasive bloodstream infection were not higher in patients on ECMO than what has been reported in the general intensive care population. Both were independently associated with a reduced survival. Aspergillus involvement was strongly associated with ECMO for respiratory support and influenza. Keywords: Extracorporeal membrane oxygenation [D015199], Invasive fungal infections [D000072742], Aspergillus [D001230], Aspergillosis [D001228], Candida [D002175], Candidemia [D058387] Background and attributable mortalities of 5–71% have been reported Critically ill patients are at increased risk of fungal infec- in patients with Candida infection in the ICU [4–6]. Inva- tions. Candida and Aspergillus are the most frequently sive aspergillosis (IA) has typically been described in pa- isolated fungi in the intensive care unit (ICU). In fact, tients with hematological malignancies and profound Candida is the third most prevalent microorganism in immunosuppression, but recent evidence has suggested patients with infections the ICU . It is responsible for that it may be present in a significant proportion of critic- 12% of ICU-acquired bloodstream infections . Noso- ally ill patients without these conventional risk factors . comial Candida bloodstream infection (CBSI) is associ- Researchers in previous studies have reported a 1–2% ated with increased morbidity and mortality as well as a prevalence of Aspergillus [8–11] in the respiratory tract of prolonged hospital length of stay compared with other mechanically ventilated patients and up to 8% in those bloodstream infections . Crude mortalities of 40–60% with acute respiratory distress syndrome (ARDS) . In an autopsy series of patients who died of ARDS, a preva- * Correspondence: email@example.com lence of 12.5% was described . Even in the absence of Département de Soins Critiques, Hôpital Sacré-Coeur de Montréal, 5400 hematological malignancy, isolation of Aspergillus in Boul Gouin Ouest, Montreal, QC H4J 1C5, Canada Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cavayas et al. Critical Care (2018) 22:98 Page 2 of 7 critically ill patients has been associated with mortality as Classification of Diseases, Ninth Revision, or any positive high as 86% . fungal culture (see Additional file 1:Appendix 2). In the last decade, use of extracorporeal membrane oxygenation (ECMO) has significantly increased in the Statistical analysis adult population . It is now routinely used to sup- Analyses were performed using IBM SPSS Statistics for port critically ill patients with severe respiratory or car- Mac software version 24.0 (IBM, Armonk, NY, USA). Cat- diac failure in whom conventional therapies have failed. egorical variables were summarized using frequencies and The severity of their illness and blood circuit interac- percentages, and continuous variables were summarized tions are thought to impair their immune system. They using mean and SD. Pearson’s chi-square test was used to have catheters, cannulas, and oxygenators that can be- test for univariate associations of categorical variables, and come colonized with microorganisms. They are often the Mann-Whitney U test was used for continuous vari- treated with broad-spectrum antibacterial agents. These ables. Missing variables were excluded from analyses. factors are thought to predispose them to fungal To determine factors independently associated with As- colonization and infection. Recently reported data sug- pergillus involvement (colonization or infection) and Can- gest that up to 15% of all bloodstream infections while dida bloodstream infection, we performed a multivariable on ECMO are of fungal origin . A 6.4% prevalence logistic regression using a stepwise backward selection of CBSI in an Australian center has been reported . model with a p value less than 0.20 for inclusion and In another study, yeast DNA was retrieved in 7% of oxy- greater than 0.15 for exclusion. In order to determine if As- genators after weaning . pergillus involvement and CBSI were independently associ- All of these studies were performed in single centers. ated with a lower survival rate, we also used a multivariable Fungal infection rates can vary greatly between units, de- logistic regression with a stepwise backward selection pending on the type of patients treated and differences model with the same conditions for inclusion and exclu- in local antibiotic and antifungal prescription practices. sion. All of the models were validated by bootstrapping Robust multicenter data are lacking. Therefore, the ob- with 1000 samples. The variables entered into the models jective of the present study was to establish the preva- can be found in Additional file 1: Appendixes 5–7. lence, risk factors, and prognosis of fungal infection and colonization in an adult ECMO population composed of Results a large international cohort of patients. There were 19,697 adult patients in ELSO registry dur- ing the study period. Of these, 2129 had either a diagno- sis of fungal infection or a positive fungal culture, Methods resulting in a prevalence of 10.8% (95% CI 10.4–11.2%) Study design of infection and colonization. Their mean age was 48. We performed a retrospective cohort study using data 5 years. The majority (67.3%) of patients received ECMO from the Extracorporeal Life Support Organization for respiratory support, and a majority (57.8%) were on (ELSO) registry. The registry compiles data on ECMO venovenous ECMO (Table 1). The overall survival of pa- use in more than 300 international centers after approval tients with fungus did not significantly differ from the by local institutional review boards. For each ECMO survival of those without (49.7% vs 48.7%; p = 0.559). run, participating centers complete a standardized data However, two main subgroups emerged as having a dif- sheet containing patient demographics, diagnosis and ferent survival in univariate analyses: patients with an procedure information, ECMO technique, physiological aspergillosis diagnosis or any Aspergillus-positive culture and microbiological data, complications, and outcomes (35.7%; p < 0.001) and those with Candida in blood cul- (see Additional file 1: Appendix 1). After approval by the ture (35.9%; p < 0.001) (Fig. 1). There were 272 patients ELSO Registry Committee, limited de-identified datasets with Aspergillus involvement in the registry, which re- are released to participating centers for research pur- sulted in a prevalence of 1.4% (95% CI 1.2–1.5%), and poses without the need for further approval from indi- 245 patients with CBSI, which resulted in a prevalence vidual centers. This study was conducted in accordance of 1.4% 1.2% (95% CI 1.1–1.4%) (Table 2). Positive Can- with the amended Declaration of Helsinki. dida cultures in sites other than blood did not affect sur- vival, no matter how many sites were affected (see Population Additional file 1: Appendix 4). We included all consecutive adult patients with fungal In multivariable analysis, male sex, hematological ma- infection or colonization from January 2006 to September lignancy, influenza, solid organ transplant, and ECMO 2016 on any mode of extracorporeal life support. These for respiratory support were associated with an increased patients were identified as those having either a diagnosis risk of Aspergillus involvement. Increased weight, of fungal infection according to the International nonviral pneumonia, aspiration pneumonitis, ARDS, and Cavayas et al. Critical Care (2018) 22:98 Page 3 of 7 Table 1 Characteristics of patients with fungal colonization or acute respiratory failure were associated with a de- infection creased risk of Aspergillus involvement (Table 3). With Variable Summary (N = 2129) bootstrapping, the associations with hematological ma- lignancies and ARDS were not statistically significant Age, years, mean ± SD 48.5 ± 15.7 (see Additional file 1: Appendix 5). Although steroid ad- Sex, male, n (%) 1264 (59.7%) ministration was positively associated with Aspergillus Weight, kg, mean ± SD 85.1 ± 26.7 involvement in univariate analysis (OR 1.50, 95% CI 1. Support type, n (%) 07–2.10, p = 0.017), this association did not reach statis- Respiratory 1433 (67.3%) tical significance in the multivariable backward selection Cardiac 563 (26.4%) model. There was no significant association between As- pergillus involvement and chronic pulmonary condition, ECPR 133 (6.2%) tobacco use, tuberculosis, or human immunodeficiency ECMO configuration, n (%) virus (HIV). VA only 742 (34.8%) Advanced age, increased weight, sepsis, and renal re- VV only 1231 (57.8%) placement therapy (RRT) were independent risk factors Hybrid or conversion 134 (6.3%) for CBSI. Although increased weight, nonviral pneumonia, Sepsis, n (%) 505 (23.7%) intra-aortic balloon pump, and cardiopulmonary bypass were associated with the risk of CBSI in the backward se- Pneumonia, n (%) 464 (21.8%) lection model, the association could not be validated by Influenza, n (%) 301 (14.1%) bootstrapping (p > 0.05) (Table 4; see also Additional file 1: Acute respiratory distress syndrome, n (%) 297 (14.0%) Appendix 6]. Diabetes, steroids, femoral cannulation, Other acute respiratory failure, n (%) 711 (33.4%) laparotomy, and pancreatitis were not significantly associ- Heart failure, n (%) 554 (26.0%) ated with CBSI. The registry does not collect information Abbreviations: ECPR Extracorporeal cardiopulmonary resuscitation, VA on antibiotic or parenteral nutrition use. Venoarterial, VV Venovenous As hypothesized, Aspergillus involvement (OR 0.40, p < 0.001) and CBSI (OR 0.47, p < 0.001) were both inde- pendently associated with decreased survival. The other factors associated with worse survival in multivariable analysis were advanced age, hematological malignancy, acute kidney injury (AKI), HIV, ARDS, sepsis, nitric Fig. 1 Survival of patients with Aspergillus involvement and Candida bloodstream infection compared with the overall survival in the Extracorporeal Life Support Organization (ELSO) registry during study the period. *Statistically significant difference compared with overall survival in the ELSO registry during the study period Cavayas et al. Critical Care (2018) 22:98 Page 4 of 7 Table 2 Prevalence and outcome of colonization and fungal infections Fungus/diagnosis Total Prevalence Survival Survivors Nonsurvivors No. % % No. % No. % Chi-square p value Diagnosis of aspergillosis 69 0.4% 28% 19 1.8% 50 4.7% 0.003 Culture of Aspergillus without diagnosis 203 1.0% 38% 78 7.4% 125 12% 0.009 Aspergillus (all) 272 1.4% 36% 97 9.2% 175 16% < 0.001 Diagnosis of systemic candidiasis 27 0.1% 44% 12 1.1% 15 1.4% 0.959 Culture of Candida in blood 245 1.2% 36% 88 8.3% 157 15% < 0.001 Culture of Candida in respiratory tract 1254 6.4% 55% 688 65% 566 53% < 0.001 Culture of Candida in urine 295 1.5% 53% 155 15% 140 13% 0.783 Candida (all) 1907 9.7% 51% 977 92% 930 87% 0.001 Diagnosis of blastomycosis 17 0.1% 53% 9 0.8% 8 0.7% 0.995 Diagnosis of other fungal infection 33 0.2% 42% 14 1.3% 19 1.8% 0.869 Total 2129 11% 50% 1059 – 1070 –– oxide, ECMO for cardiac support, and extracorporeal car- 41). Similarly, CBSI was associated with poor survival diopulmonary resuscitation. However, increased weight, as- (35.9%) independently (OR 0.47). piration pneumonitis, influenza, solid organ transplant, The prevalence of fungus-positive samples in general nonviral pneumonia, and neuromuscular blockers were in- ICU patients with a length of stay more than 7 days has dependently associated with increased survival in our co- been reported to be as high as 59.7% with systematic hort (Table 5). The associations with AKI, sepsis, and solid sampling, much higher than in our cohort . How- organ transplant were not statistically significant with boot- ever, cultures reported in the ELSO registry are per- strapping (see also Additional file 1: Appendix 7). formed at the discretion of clinicians rather than systematically. It is highly probable that fungi were sim- Discussion ply undetected in a significant number of patients. This We found a 10.8% prevalence of fungal infection or could have resulted in a significant underestimation of colonization in the ELSO registry, including 1.3% of pa- the overall prevalence of fungal colonization and infec- tients with Aspergillus involvement and 1.2% of patients tion as well as of the prevalence of specific infections. with CBSI. These prevalence rates are lower than ex- Moreover, information about antifungal agent adminis- pected in a population of mechanically ventilated critic- tration was not available. A more liberal use of antifun- ally ill patients with indwelling catheters and an ICU gal prophylaxis in this very sick population of patients length of stay generally exceeding 1 week. Aspergillus in- could also have contributed to a lower rate of fungus- volvement was associated with classic factors that cause positive samples. immunosuppression, such as hematological malignancy The overall prevalence of any microbiological or histo- and solid organ transplant, as well as with influenza and logical evidence of Aspergillus in a medical ICU has ECMO for respiratory support. Not surprisingly, CBSI been reported to be 6.9%, and a combined prevalence of was associated with typical risk factors such as sepsis proven, probable, or possible IA has been reported to be and RRT. The survival of patients with any Aspergillus 5.8% . These data are more in line with the 7.2% involvement (37.5%) was significantly lower than that of prevalence found in an Australian ICU in a review of the rest of the ELSO population, even after adjusting for their ECMO cases between 2005 and 2011 . There other predictive factors in multivariable analysis (OR 0. Table 4 Risk factors for Candida bloodstream infection Table 3 Risk factors for Aspergillus colonization or infection Variable OR 95% CI p Value Variable OR 95% CI p Value Age/10 years 1.13 1.03–1.25 0.011 Male sex 1.55 1.16–2.08 0.003 Weight/10 kg 1.05 1.00–1.10 0.061 Weight/10 kg 0.87 0.82–0.93 < 0.001 Sepsis 1.60 1.15–2.23 0.005 Hematological malignancy 2.18 0.99–4.78 0.052 Renal replacement therapy 1.55 1.12–2.13 0.007 Aspiration pneumonitis 0.33 0.12–0.93 0.036 Nonviral pneumonia 0.70 0.48–1.03 0.068 ARDS 0.75 0.50–1.12 0.154 Intra-aortic balloon pump 1.46 0.94–2.26 0.091 Acute respiratory failure NOS 0.58 0.42–0.79 0.001 Cardiopulmonary bypass 0.56 0.28–1.15 0.112 ARDS Acute respiratory distress syndrome, NOS Not otherwise specified Cavayas et al. Critical Care (2018) 22:98 Page 5 of 7 Table 5 Independent predictors of survival evidence of Aspergillus involvement . The higher sur- vival that we found could be due to the fact that ECMO Variable OR 95% CI p Value patients, although acutely very ill, are younger and have Age/10 years 0.81 0.77–0.87 < 0.001 fewer comorbidities than the general ICU population. Pa- Weight/10 kg 1.04 1.01–1.08 0.018 tients with Aspergillus involvement in the ELSO registry Hematological malignancy 0.44 0.21–0.95 0.035 had a mean age of 46 years, and only 8.5% of them had Acute kidney injury 0.83 0.66–1.05 0.116 chronic pulmonary disease, as compared with a mean age HIV infection 0.09 0.02–0.42 0.002 of 61 years and 42% with chronic pulmonary disease in Aspiration pneumonitis 1.87 1.14–3.09 0.014 the Meersseman study. The strong association between influenza and Asper- ARDS 0.66 0.50–0.88 0.004 gillus found in our cohort has been described before in Influenza 1.67 1.26–2.22 < 0.001 case series and case-control studies. Coinfection rates Sepsis 0.80 0.63–1.02 0.07 ranging from 29% to 75% have been reported [27, 28]. Solid organ transplant 1.37 0.96–1.96 0.086 Proposed mechanisms for this increased susceptibility to Nonviral pneumonia 1.33 1.05–1.68 0.02 Aspergillus invasion include both local and systemic ef- Nitric oxide 0.55 0.42–0.73 < 0.001 fects . Indeed, influenza induces tracheitis and bron- chitis and impairs normal ciliary function . The virus Neuromuscular blockers 1.26 1.03–1.55 0.027 also impairs phagocytosis and induces anti-inflammatory Cardiac support 0.59 0.47–0.75 < 0.001 cytokine production leading to T-cell dysfunction and ECPR 0.45 0.30–0.67 < 0.001 apoptosis [31–33]. Candida bloodstream infection 0.47 0.34–0.63 < 0.001 In recent large multicentric cohort studies of unse- Aspergillus colonization or infection 0.40 0.30–0.54 < 0.001 lected patients admitted to mixed ICUs, the prevalence Abbreviations: ARDS Acute respiratory distress syndrome, HIV Human of candidemia ranged from 0.33% to 0.69% [3, 34]. Al- immunodeficiency virus, ECPR Extracorporeal cardiopulmonary resuscitation though the rate we found was higher than the one re- ported in these large studies, in a cohort of patients with was a much lower prevalence of Aspergillus involvement severe critical illness and a long ICU length of stay, we in the ELSO registry. The first caveat in interpreting the expected a much higher rate. A prevalence of 3.3% has rates of Aspergillus involvement is that microscopic been reported in patients with a length of stay in the examination and culture of respiratory tract specimens ICU more than 7 days . Moreover, a prevalence of 6. have a combined sensitivity of only 50% for IA . Sec- 4% of CBSI was found in a retrospective review of ond, discriminating between colonization and infection ECMO cases in an Australian center . In keeping is always challenging without histology. Biopsies are with these findings, yeast DNA has been detected in 7% rarely performed in ECMO patients, because they are at of patients on oxygenators . In theory, this should high risk of bleeding owing to systemic anticoagulation, translate to positive fungal cultures at some point. The platelet and coagulation factor consumption, and in- discrepancy could be explained by undersampling or a creased fibrinolysis associated with the extracorporeal more liberal use of antifungal prophylaxis. circuit. Nonneutropenic patients most often do not dis- In contrast, CBSI survival was strikingly worse than play the characteristic radiological signs of IA . Fur- previously described in the literature. León and col- thermore, many patients had respiratory failure with leagues found an overall survival of 43.4% in critically ill already abnormal chest imaging results before develop- patients with invasive Candida infection hospitalized for ing IA. Newer tests such as galactomannan and PCR of more than 7 days . Others have even found a sur- serum or bronchoalveolar lavage specimens have been vival of 57–60% in general ICU cohorts [3, 34]. Patients developed to improve the diagnostic yield for IA . on ECMO could simply have a higher illness severity However, results of such tests, if performed, were not than these cohorts. It is also possible that the presence collected in the database. Blot and colleagues have de- of foreign material makes it more difficult to eradicate scribed and validated an algorithm for use in diagnosing Candida, as seen with prosthetic valve endocarditis. aspergillosis in critically ill individuals . However, the Multiple hospitals across the globe in very different ELSO registry did not collect all the variables needed to settings participate in the ELSO registry. These centers apply their definitions. In addition, whether Aspergillus collect data on all their ECMO cases. This confers isolated in the lower respiratory tract of critically ill pa- strong external validity to our study. However, the in- tients can be viewed as a contaminant or colonizer re- ternal validity of the study is affected by multiple factors mains a matter of debate [25, 26]. partly inherent to its retrospective nature. For instance, Meersseman and colleagues reported an overall survival microbiological sampling was nonsystematic. This may of 20% in patients without hematological malignancy with have caused underestimation of the prevalence of fungal Cavayas et al. Critical Care (2018) 22:98 Page 6 of 7 infections. This also weakened the analysis of risk factors Ethics approval and consent to participate After approval by the ELSO Registry Committee, limited de-identified datasets by making them highly susceptible to observer bias. In- are released to participating centers for research purposes without the need for deed, fungal cultures may have been performed more further approval from individual centers. No patient consent is required. This often in patients with presenting factors that were sus- study was conducted in accordance with the amended Declaration of Helsinki. pected by clinicians to increase the risk of fungal infec- Competing interests tion. Moreover, limited data were available on potential The authors declare that they have no competing interests. confounding factors such as antifungal therapy and prophylaxis. This may have decreased certain associa- Publisher’sNote tions with risk factors if antifungal therapy was pre- Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. scribed more often in those patients. Such limitations could be avoided or minimized in a prospective study. Author details Département de Soins Critiques, Hôpital Sacré-Coeur de Montréal, 5400 Boul Gouin Ouest, Montreal, QC H4J 1C5, Canada. University Hospitals of Conclusions Leicester, ECMO program, Glenfield Hospital, Groby Rd, Leicester LE3 9QP, Patients on ECMO do not seem to develop fungal UK. colonization or infection more frequently than other Received: 17 January 2018 Accepted: 28 March 2018 critically ill patients. Aspergillus involvement and CBSI were independently associated with decreased survival. CBSI mortality was higher than described in the general References 1. Vincent JL, Rello J, Marshall J, et al. International study of the prevalence ICU population. Aspergillus involvement was associated and outcomes of infection in intensive care units. JAMA. 2009;302:2323–9. with respiratory ECMO and influenza. Clinicians should 2. Hidron AI, Edwards JR, Patel J, et al. 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Predicting invasive fungal disease due to Candida species in non-neutropenic, critically ill, adult patients in United Kingdom critical care units. BMC Infect Dis. 2016;16:480. Submit your next manuscript to BioMed Central and we will help you at every step: • We accept pre-submission inquiries � Our selector tool helps you to ﬁnd the most relevant journal � We provide round the clock customer support � Convenient online submission � Thorough peer review � Inclusion in PubMed and all major indexing services � Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit
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