Prediction of invasive candidal infection in critically ill patients with severeacute pancreatitis

Infections caused by fungal pathogens have increased in the last two decades with datafrom the USA between 1979 and 2000 demonstrating a 207% increase [1]. In the Extended Prevalence of Infection in Intensive Care (EPIC II) study,candida was the fourth most common cause of infection in ICUs worldwide [2]. Infections in Europe are less frequent; however, in the Sepsis Occurrence inAcutely Ill Patients (SOAP) study, candidal organisms still accounted for 17% ofinfections [3]. Other data demonstrate that candidaemia in intensive care patients, however,has remained static or even decreased in recent years [4]. Most cases are caused by Candida albicans, but there are numerousother species, and antifungal resistance spectrums of these vary.

Numerous risk factors have been identified for the development of Candida spp bloodstream infection. These include the presence of invasive lines, for examplecentral venous catheters (CVCs), antibiotic therapy, acute kidney injury requiring renalreplacement therapy (RRT), malignancy and neutropenia, previous abdominal surgery, totalparenteral nutrition (TPN), long term hospitalisation and prior fungal colonisation [5‐8].

Severe acute pancreatitis (SAP) has also been identified as a risk factor for candidalinfection [9]. Candidal infection has been identified as a cause of increased mortality inpatients post-operatively and in the critically ill [8, 10, 11] but its effect on the outcome of SAP has been disputed [12‐15]. A healthy pancreas is relatively resistant to fungal infection; however,pancreatic necrosis carries a disproportionately higher risk of infection with bacterialand fungal organisms. Prior use of antibiotics has been demonstrated to increase therisk of fungal infection [5]. Prophylactic or empirical antifungal treatment has been advocated forhigh-risk surgical patients [16‐19] and demonstrated to prevent fungal infection in SAP patients [12]. 'Prophylactic' antifungal treatment is defined as administration ofantifungals to patients identified as having a particular diagnosis or particularfactors that confer a high risk of subsequent fungal infection. 'Empirical' treatment isdefined as antifungal therapy given to patients with clinical features of aninflammatory response consistent with infection but without microbiologicalconfirmation. As delays in treatment are associated with increased mortality and fungalculture can take up to 72 hours, it would be desirable to identify patients at risk forinvasive infection whilst minimising unnecessary treatment and reducing the risk ofresistance through increases in non-albicans species [7, 20].

As a consequence, several risk scoring systems have been developed in an attempt to aiddiscrimination between candida colonisation and invasive candidal infection (ICI) [6, 8, 9]. These combine the identification of high-risk patients with clinical andmicrobiological data to identify those patients at risk of developing ICI. The aim ofthis study was to identify the prevalence of ICI in a population of critically illpatients with SAP, to identify risk factors for the development of ICI and to evaluateits impact on patient outcome. In addition we assessed the accuracy and discriminationof three previously described risk scores for ICI in this cohort of patients [6, 8, 9].

A single centre, retrospective study was conducted at a tertiary referral centre forpatients with SAP. After discussion with the local Research Ethics Committee, the studyprotocol was approved and the requirement for written informed consent was waived, sinceinformed consent for collection and analysis of patient data recorded in the Case MixProgramme database is not required under Section 251 of the NHS Act 2006 (approvalnumber PAIG 2-10(f)/2005). All patients admitted to the ICU with a diagnosis of SAPbetween July 2003 and February 2011 were screened for inclusion in the study. Suitablecases were identified from the admissions database. Patients who were re-admitted to theICU during the same hospital stay or who were transferred from other ICUs were excludedfrom further analysis. SAP was defined as acute pancreatitis with true organ dysfunctionirrespective of local complications as per consensus guidelines in 2004 [21]. 'Significant necrosis' was defined as the presence of more than 30% necrosisseen on abdominal computed tomography scans, as reported by a radiologist. Threeindependent workers extracted data from the case notes and electronic records of eachadmission onto an Excel spreadsheet. The aetiology of SAP was classified into 'alcohol','gallstones', 'drug', or 'idiopathic'. 'Unknown' was recorded if no cause could beidentified from the case notes. Acute Physiology and Chronic Health Evaluation (APACHEII) scores were extracted from the ICU admission database. For admissions without APACHEII scores due to a unit length of stay less than eight hours, admission physiology datawere entered into a web-based calculator [22] in order to calculate an admission APACHE II score.

All patients were treated according to a routine standard of care. This includedadherence to care bundles, no prophylactic antibiotics, daily measurement of C-reactiveprotein and early enteral feeding. Naso-gastric feeding was used for nutritionalsupport, guided by the patient's ideal body weight. Prokinetics were started whenabsorption was poor and, if necessary, a post-pyloric feeding tube was inserted. TPN wasconsidered if post-pyloric feeding was unsuccessful. Abdominal computed tomography scanswere performed on admission and then every seven to ten days, and minimally invasivepancreatic necrosectomy (MIRPN), open necrosectomy or radiologically-guided drainage wasperformed, as surgically indicated.

Samples for candidal colonisation were taken routinely from tracheal aspirates and/orbronchial lavage, skin swabs and drainage fluid (if drains were in situ).Further sampling (for example, culture of blood, line tips and pancreatic tissuesamples) was performed if indicated by clinical need. Patients were classified as havingICI if they had: 1) ≥ 1 positive blood culture or 2) ≥ 1 positive pancreatictissue culture or 3) ≥ 1 pancreatic drain fluid culture positive for Candida spp. and in addition received antifungal drugs after the positive drain fluidculture. Antifungal therapy is only initiated after discussion between an intensive careconsultant and a medical microbiologist with an interest in intensive care. Patientswith Candida cultured from one or more samples from respiratory secretions,urine, line tips, or wound or skin swabs alone were classified as colonised.

For determination of risk in the scoring systems, the following were considered riskfactors: 1) severe sepsis as defined by the 2001 SCCM/ESICM/ACCP/ATS/SIS InternationalSepsis Definitions Conference criteria [23]; 2) central venous access: presence of a CVC or peripherally inserted centralvenous catheter (PICC) on days one to three post ICU admission; 3) systemic antibiotics:any intravenous antibiotics on days one to three post ICU admission (excludingprophylactic antibiotics given after surgery or to treat reduced gastric motility); 4)renal replacement therapy (RRT): any form of RRT given on day one to three post ICUadmission; 5) steroids: any dose of corticosteroids given during the seven days priorand three days after admission to ICU; 6) immunosuppressive drugs: any immunosuppressivedrugs (as listed in the British National Formulary version 59 section 8.2) given duringthe seven days prior to admission; 7) surgery: any intra-abdominal surgical procedureduring the seven days prior to admission; and 8) TPN: any TPN delivered via a CVC orPICC on days one to three post ICU admission.

There were 213 ICU admissions with SAP during the study period. There were 32re-admissions of 26 patients during the same hospital stay. Seventy-six patients wereexcluded as they were directly transferred to the ICU from other hospitals. Fourpatients already had established candidal infection on admission to ICU and wereexcluded from further analysis (Figure 1). Therefore, 101 patientswere included of whom 58 (57%) were men. The median (IQR) age was 60 (50 to 73) years,and the most common causes of SAP were gallstones (45 (44.6%)) and alcohol (30 (29.7%)(Table 1)

There was no significant difference in APACHE II scores between the two groups. Eighteen(17.8%) patients developed ICI. Patients with ICI had a longer median length of ICU stay(16.9 versus 7.3 days, P = 0.0043). There was a significant association betweenopen necrosectomy and subsequent ICI (Table 1, P =0.0171) on univariate analysis, but this was not significant in regression analysis.Overall, 18 (17.8%) patients died in ICU with a higher mortality in patients with ICI(5/18 (27.8%) versus 13/83 (15.7%)). Overall hospital mortality was 29.7% (30/101) whichwas significantly higher in patients who developed ICI: 10/18 patients (55.6%) died,compared to 20 deaths in 83 patients without ICI (24.1%) (P = 0.0201) (Table1).

Table 2 displays the risk factors for development of ICI for thosepatients with and without ICI. There were no significant differences in incidence ofsevere sepsis, or use of CVC lines, antibiotics, RRT, steroids, immunosuppressivetherapy, previous surgery or TPN between the two groups. Of the known risk factors, onlycolonisation with Candida spp. was significantly greater in the ICI group.Sixteen (88.9%) patients with invasive candida infection were colonised with candida, asopposed to 37 (44.6%) without subsequent infection (P = 0.0006) (Table 2). Using logistic regression analysis, colonisation with candida (OR4.33) was the only factor significantly associated with invasive candidal infection(Table 3).

An increase in Candida infection in non-neutropenic critically ill patients has beendemonstrated to put them at increased risk of mortality and morbidity [4, 6]. Whilst there is a concern that this is the case in patients with SAP [10, 11, 25‐28], this has not been universally demonstrated [12‐15]. It is, however, likely that colonisation plays an important instigating rolein these invasive infections. Patients with SAP are at particular risk of ICI. In thisstudy both colonisation with Candida spp. and a CCIS >0.5 were associated withsubsequent infection [8]. It can be difficult to distinguish colonisation from ICI. There is evidencethat delaying antifungals in ICI is associated with increased mortality [29]; however, current antimicrobial culture techniques can still take up to 72hours to grow yeasts [30]. Therefore, the unanswered question is whether critically ill patients withSAP should receive routine prophylactic antifungals with the risk of selecting outresistant strains of candida or whether treatment should be delayed until a positiveculture is obtained.

Patients with SAP are known to be at high risk for ICI. We have demonstrated that ICI inSAP patients is associated with increased hospital mortality and longer duration of ICUstay. We have also shown that one of the existing risk scoring systems (CCIS [8]) in a population of critically ill patients with SAP has good discriminationto identify patients who are at low risk of developing ICI. Patients who have a CCIS of<0.5 are unlikely to go on to develop invasive candida infections. Further studiesinvestigating the benefit of prophylactic antifungal treatment in patients with SAP anda CCIS of ≥ 0.5 are needed.