Impact of invasive fungal infection on outcomes of severe sepsis: a multicenter matched cohort study in critically ill surgical patients

Invasive fungal infection (IFI) is a severe clinical complication in immunocompromised patients, such as neutropenic patients, recipients of bone marrow or solid organ transplants, cancer patients receiving chemotherapy, and HIV-infected patients. However, during the past two decades, with advances in diagnostic and therapeutic interventions, critically ill patients with lesser degrees of immunocompromise, especially those in surgical and neonatal intensive care units (ICUs), have emerged as another population at high risk for IFI [1‐3].

Sepsis is the body's systemic inflammatory response to infection. It is considered severe when it is associated with acute organ dysfunction. According to epidemiologic studies [4‐13], severe sepsis has become a leading cause of morbidity and mortality in critical illness, and etiologic evidence [14] indicates that the incidence of fungal infection in septic patients is increasing. Fungal organisms are common pathogens in surgical patients and patients suffering from severe sepsis. Raymond and coworkers [15] observed that fungal infection accounted for 12.3% of all episodes of surgical infection in a study conducted over 38 months. Finfer and colleagues [8] reported that fungi accounted for approximately 12.1% of all microbial isolates in their study of severe sepsis among adult admissions to ICUs in Australia and New Zealand [8]. Recently, the large pan-European Sepsis Occurrence in Acutely Ill Patients (SOAP) study [4] reported that fungal infection was observed in 17% of all septic patients in European ICUs. Furthermore, IFI was found to be associated with excess mortality, hospital stay, and cost [16, 17]. Annane and coworkers [18] identified fungal infection as an independent risk factor for increased mortality among patients with septic shock. However, fungal infection was not found to be among the significant predictors of fetal outcome in some other studies [4].

In the present study we attempted to determine the impact that IFI has on outcomes of severe septic patients in multiple surgical ICUs in China. We undertook a matched cohort study in which severe septic patients with and without IFI were matched for unit, age, sex and severity of illness.

The present study focused on IFI in patients with severe sepsis in surgical ICUs, and it contributes important additional information to that from the large studies on epidemiology of severe sepsis published thus far. The study identified a 28.3% incidence of IFI in critically ill patients with severe sepsis. Lung and abdomen were the most common sites of IFI. C. albicans, C. tropicalis, and C. glabrata were the predominant species and comprised 90% of all isolated strains. Mechanical ventilation (>3 days), APACHE II score, infection with both Gram-positive and Gram-negative bacteria, and urinary catheterization (>3 days) were identified as independent risk factors for IFI in patients with severe sepsis. Compared with the control patients with severe sepsis but without IFI, the matched patients with severe sepsis and IFI had higher hospital mortality, ICU LOS, hospital LOS and hospital costs, and received more aggressive interventions.

We found a high incidence of IFI (28.3%) in critically ill surgical patients suffering from severe sepsis. This is higher than that reported in the SOAP study [4], which identified fungal infection in approximately 17% of the critically ill septic patients in several European countries. This may be because the cohort we studied was more susceptible to fungal infection, as factors that may compromise the integrity of gastrointestinal mucosa and facilitate fungal translocation (such as poor nutrition, trauma, hypotension and therapy with steroids, as well as ischemia and reperfusion) are common in the ICU population. Moreover, injury, trauma, and blood loss in surgical patients, which result in marked depression in cell-mediated immunity, may specifically be associated with high incidence of IFI [26]. However, some factors other than underlying disease and characteristics of patients admitted to the ICU may also contribute to the high incidence. First, in accordance with the criteria used in this study, some of the patients were diagnosed as having IFI but without biopsy, which may lead to enrollment of patients with fungal colonization and overestimation of IFI in surgical patients with severe sepsis. Secondly, most of the enrolled patients with severe sepsis had been hospitalized in the surgical wards before their ICU admission and were routinely administered prophylactic antibiotic treatment; hence, they were more susceptible to nosocomial fungal infection. Third, lung is the most commonly impaired organ in severe sepsis, and mechanical ventilation is instituted in most patients suffering from severe sepsis. Consequently, these individuals are prone to pulmonary fungal infection, because endotracheal tubes may facilitate the intrusion of endogenous or exogenous fungal organisms. In the present study, lung was the major site of fungal infection, and 82.3% of IFI patients who suffered from pulmonary fungal infection received mechanical ventilation for at least 3 days. Finally, the higher occurrence of IFI may also reflect a horizontal transmission of fungal infection in the ICU, because a previous study [27] found Candida spp. to be present on the hands of 39% of surgical ICU staff.

Lack of DNA analysis of fungal isolates prevented interpretation, but our findings are in accordance with those of a previous study [28] that identified a 23.96% incidence of fungal infection among patients admitted to an ICU in a Chinese university hospital. Therefore, infection control in ICUs within China may require improvement and standardization. More attention should be given to sanitary precautions in ICU in order to prevent fungal infection; such precautions include using high-efficiency particulate air filters, changing the breathing circuits of ventilators periodically, and applying endotracheal tubes with a dorsal lumen to allow drainage of respiratory secretions. Standard protocols should be established to evaluate the appropriateness of administered aggressive interventions.

The spectrum of fungal species identified in this study was consistent with that in previous studies [29‐31], which found that C. albicans and non-albican species accounted for approximately half of reported cases of IFI. We found four factors to be independently associated with risk for IFI in severe sepsis (mechanical ventilation [>3 days], APACHE II score, infection with both Gram-positive and Gram-negative bacteria, and urinary catheterization [>3 days]). This is congruent with the findings of previous studies focusing on fungal infection in critical illness [32‐34], except for coexisting infection with both Gram-positive and Gram-negative bacteria. The latter may be associated with greater severity of infection or use of broad-spectrum antibiotics. However, logistic regression did not identify combination antibiotic therapy as an independent factor influencing the occurrence of IFI in this study. In the present study, combination antibiotic therapy was administered to 50% of the patients with IFI before the onset of IFI, which was similar to the proportion in patients without IFI during their ICU stay (57%, P = 0.263).

In order to minimize the influence of confounding factors in our evaluation of the relationship between IFI and outcome, a matched cohort study was conducted. Among the 90 patients with IFI, the 60 patients who could be matched to a control patient were similar to the 30 unmatched patients in terms of age, hospital LOS, ICU LOS, and hospital mortality, which indicates that these matched patients are representative of the whole group of IFI patients. Compared with the control patients with severe sepsis, the matched patients with severe sepsis and IFI had significantly greater hospital mortality. Therefore, this matched cohort study allowed rational estimation that IFI in patients with severe sepsis in surgical ICUs is associated with an excess risk for hospital death of 20%, which is close to that reported in previous correlative studies [35‐37]. Patients with IFI also had longer ICU and hospital LOSs than did control patients. Although the present study showed that IFI did not contribute to excess daily costs, it did correlate with excess hospital costs and consumption of medical resources as a result of the prolonged ICU and hospital LOSs.

A major advantage of our study is that a matched cohort study was conducted, and hence the fungus-related mortality was apparent. However, there are several limitations of this study. First, patients diagnosed as having IFI but without biopsy conformation were enrolled, in accordance with the criteria used, which may to a certain degree cause over-diagnosis of IFI. However, there is no consensus definition on IFI in non-neutropenic critically ill patients. Because of hemodynamic and/or respiratory insufficiency and coagulopathy of critical illness, and refusal by most of the Chinese families to allow antemortem or postmortem biopsy, it was rather difficult to diagnose IFI by positive culture from normally sterile sites, especially lower respiratory tract. Exclusion of all patients without biopsy conformation would inevitably have resulted in severe underestimation of IFI in the study population and altered the spectrum of fungal species identified. Therefore, we employed criteria to diagnose IFI patients without biopsy confirmation partly based on the findings of previous studies. Although our criteria may lead to over-diagnosis IFI in the study cohort, the findings based on it may be more objective. Second, this was a retrospective cohort study, although the database was constructed prospectively. Third, selection of control patients was mainly based on severity of illness at admission, as indicated by APACHE II score, but the severity of illness might have drifted apart between case patients and control patients since before the onset of IFI [38]. However, Blot and coworkers [39] found that expected mortality estimated from characteristics obtained on the first day of ICU admission correlated well with observed mortality in candidemic patients. Finally, this study included a relatively small sample to define the characteristics of IFI in a cohort with severe sepsis, in the most populous country in the world. However, there are no national hospital databases of sepsis available on the internet in today's China, and the financial and personnel resources supporting the present study were limited, both of which prevented our team from extending the study to more medical centers on a greater geographic scale.

The present study found IFI to be frequent in patients with severe sepsis in surgical ICUs, and to be associated with excess risk for death in hospital and greater consumption of medical resources. Therefore, in the process of diagnosing and treating severe sepsis in the ICU, attention should be given to the identification of patients who are at high risk for IFI, as well as prevention of and early intervention in IFI in these patients.