Risk factors for early invasive fungal disease in critically ill patients.

BACKGROUND: The incidence of invasive fungal disease (IFD) is increasing worldwide in the past two to three decades. Critically ill patients in Intensive Care Units are more vulnerable to fungal infection. Early detection and treatment are important to decrease morbidity and mortality in critically ill patients.
OBJECTIVE: Our study aimed to assess factors associated with early IFD in critically ill patients.
MATERIALS AND METHODS: This prospective cohort study was conducted in critically ill patients, from March to September 2015. Total number of patients (74) in this study was drawn based on one of the risk factors (human immunodeficiency virus). Specimens were collected on day 5-7 of hospitalization. Multivariate analysis with logistic regression was performed for factors, with P < 0.25 in bivariate analysis.
RESULTS: Two hundred and six patients were enrolled in this study. Seventy-four patients were with IFD, majority were males (52.7%), mean age was 58 years (range 18-79), mean Leon's score was 3 (score range 2-5), majority group was nonsurgical/nontrauma (72.9%), and mean fungal isolation was positive on day 5. Candida sp. (92.2%) is the most frquently isolated fungal infection. Urine culture yielded the highest number of fungal isolates (70.1%). Mortality rate in this study was 50%. In multivariate analysis, diabetes mellitus (DM) (P = 0.018, odds ratio 2.078, 95% confidence interval 1.135-3.803) was found as an independent factor associated with early IFD critically ill patients.
CONCLUSION: DM is a significant factor for the incidence of early IFD in critically ill patients.

Introduction

Invasive fungal disease (IFD) is a disease where fungus is obtained from blood cultures or from other body parts that are normally sterile accompanied by signs of infection. The incidence of IFD is on the rise over the last two to three decades, especially in health-care facilities, representing one of the important infectious complications in hospitalized patients. Critically ill patients are more susceptible to this disease, particularly in Intensive Care Unit (ICU), due to the complexity of their underlying disease.

Majority of the fungi causing IFD is the Candida sp. In the US, a national study on sepsis epidemiology from 1979 to 2000 reported that the incidence of sepsis induced by fungal infection increased by 207%.[1] In 2006, the Health Protection Agency estimated more than 5000 cases of invasive Candida infections occurring in the UK every year and about 40% of them are found in ICU. Epidemiological survey on six sentinel hospitals in the UK reported that 45% of Candida infections in blood occur in ICU as fungal infection can be found in every group of patients in ICU.[2]

The risk factors for fungemia and candidiasis sepsis include comorbidities of severe diseases, variety of surgical interventions, catheter and intravascular invasive instruments, broad-spectrum antibiotics, parenteral nutrition, trauma and malnutrition-associated immunosuppression, and intra-abdominal or intrathoracic infections. Furthermore, intravenous cannulation, tracheostomy, urinary catheterization, pneumonia, endotracheal intubation, diabetes mellitus (DM), organ failure, and human immunodeficiency virus (HIV) are the risk factors for IFD.[3]

Data about IFD in Indonesia are still scarce, and many overseas studies show that most fungal isolation is found on day 9 of the treatment.

Materials and Methods

Study population

Two-hundred and fifty-two critically ill patients treated in ICU/High Care Unit (HCU) and common ward from March to September 2015 were included in the study. The inclusion criteria were patients aged ≥18 years with IFD risk factor based on Candida score as shown in Table 1.[4] Exclusion criteria included patient/family who refused to take part in the research, passed away, or discharged before sampling (treatment day 5–7), incomplete medical record, and patient on antifungal therapy before specimen collection.

Table 1

Candida score

Methods

Candida score[4] was used for detecting invasive candidiasis in critically ill patients. On treatment day 5–7, laboratory examination was conducted by taking blood sample (maximum 20 ml), body fluid (10 ml ascites fluid, 10 ml pleural fluid, 10 ml pericardial fluid, 2 ml cerebrospinal fluid), respiratory specimen (sputum, endotracheal aspiration, bronchoalveolar lavage [BAL]), urine (50 ml), pus, fine needle aspiration, central venous catheter (CVC), and drainage fluid/surgical tissue specimen. Blood and body fluid specimen were collected under aseptic condition in BACTEC culture vial. Other body fluids and blood specimens were processed in Microbiology Division, Clinical Pathology Department. BAL fluid was processed in Parasitology Department. Cytology and histopathology specimens were processed in Pathology Anatomy Department. Sampling technique was done according to the operational standards of Prevention and Control of Nosocomial Infections.

This research gained ethical approval (No 182/UN2.F1/ETIK/2015) from the Ethical Research Committee of Universitas Indonesia. All data were kept confidential by the researchers.

Data analysis

This is a prospective cohort study. Samples were taken using consecutive sampling. We define patients with IFD if they meet criteria as shown in Table 2.[5] Primary data were processed using computer program SPSS 20 (Armonk, NY: IBM Corp.). Numerical data are presented as mean and standard deviation. Bivariate and multivariate analyses were performed on risk factors for IFD.

Table 2

Diagnostic criteria for fungal infection

Results

Clinical characteristic

In total, 252 patients treated in the hospital (ICU, HCU, and common ward) were analyzed. A total of 206 patients fulfilled the inclusion criteria and 46 patients were excluded from the study as shown in Figure 1. Majority of the patients were male. The median age was 58 years (range, 18–79 years). Median Leon score was 3 (range score, 2–5). Nonsurgical/trauma comprised 72.9% (n = 54) of high-risk population with IFD. Median positive fungal isolation was day 5. Mortality rate was 50% (n = 37). The clinical characteristics of patients are summarized in Table 3.

Figure 1

Study design

Table 3

Clinical characteristic of patients with positive early invasive fungal disease (n=74)

Fungal distribution

Candida sp. was found in 71 (92.2%) patients, and 6 (7.7%) were infected by non-Candida sp. Among the 71 patients with Candida, 25 (32.4%) had Candida albicans and 46 (59.7%) had non-albicans Candida infection. In addition, 31 (40.2%) were confirmed as Candida tropicalis, 6 (7.7%) as Candida parapsilosis, 5 (6.4%) as Candida krusei, and 4 (5.1%) were undifferentiated. The distributions are detailed in Table 4.

Table 4

Fungal species distribution

Fungal colonization of urine specimens was detected in 54 (70.1%) patients, followed by blood specimens in 12 (15.5%) patients. From urine specimens, 23 (29.8%) patients had C. albicans, 30 (38.9%) had non-albicans Candida, and 1 (1.2%) had Trichosporon asahii infection. Among 30 patients detected with non-albicans Candida, 23 (38.9%) had C. tropicalis, 3 (3.8%) had C. krusei, 3 (3.8%) had C. parapsilosis infection, and 1 (1.2%) was undifferentiated. The distributions are detailed in Table 5.

Table 5

Fungal distribution based on culture specimen

Factors affecting incidence of early invasive fungal disease

Twelve variables were analyzed as factors related with IFD. In bivariate analysis, DM (P < 0.25) and mechanical ventilator (P < 0.25) were significantly associated with early IFD. Multivariate analysis showed DM as a risk factor for early IFD. The descriptions are given in Tables 6 and 7.

Table 6

Bivariate analysis for early invasive fungal disease (n=206)

Table 7

Multivariate analysis for early invasive fungal disease

Discussion

In this study, most patients were male (52.7%), similar to a study by Singh et al.[5] and a South Indian study where the percentage of males were 61.2% and 71.2%, respectively. Gender is not a predisposing factor of IFD. Patient's age in this study was between 18 and 79 years (oldest) with mean age of 58.0 years, similar with a study from India where the age range was between 18 and 80 years, with mean age of 43.5 years.[5] The average Candida score was 3, with most patients from the nonsurgical/trauma group (72.9%), similar to Singh et al.[5] As mentioned by León et al.,[4] early IFD detection could be performed in critically ill patient with Candida score >3.

Fungal isolates were mostly positive on day 5 of the treatment with 50% mortality. In this study, 43 patients died before day 5 of the treatment, so specimen sampling could not be done. Studies by Singh et al.[5] and Greece reported that most fungal isolates are positive on day 9, while another study from India reported that it is positive on day 15. The mortality rate in this study is not much different from other studies. Paswan et al.,[6] Leleu et al.,[7] Gudlaugsson et al.,[8] and Zaoutis et al.[9] reported a mortality rate of 61.2%, 31%, 38%, and 44%, respectively. For patients with high IFD risk, early diagnosis and therapy are essential to achieve a better end result, including reduced morbidity and mortality.[3]

Candida sp. was the most common fungus isolate (92.2%) found. Aggressive use of intravascular equipment and poor hand-washing techniques can cause nosocomial transmission.[6] Among non-albicans Candida, C. tropicalis was the most found fungal isolate (40.2%), similar to studies by Singh et al.,[5] 85.2%, Resultanti et al.,[10] 29.4%, and Paswan et al.,[6] 49%, while different results were obtained in India and the USA where Candida guilliermondii and Candida glabrata were the most common fungi isolated, respectively.[61011]

In general, Candida sp. is a commensal organism found on mucosal surface, but it can cause severe infection and death.[12] Although C. albicans is the most common mucocutaneous infection causing fungus, the incidence caused by non-C. albicans sp. is increasing. Some factors such as severe immunosuppression, prematurity, broad-spectrum antibiotic usage, and empirical antifungal therapy can be associated with this change. Candida adhesion to host epithelial cells is an important step in pathogenesis of infection.[12] Candida adhesion with host cell, host cell protein, or competition with other microbes can prevent and decrease clearance rate by host cell's defense mechanism. C. albicans is a species with high adherence to buccal epithelial cell. This is similar with the report from Mane et al.[13] C. tropicalis, C. glabrata, and Candida dubliniensis are usually located in the buccal epithelial cell.

This study analyzes 12 factors associated with early IFD in critically ill patients. From bivariate analysis, the significant factors found are DM and mechanical ventilation. On multivariate analysis, only DM was significant. In this study, malignancy is not found as significant risk factor of IFD, similar with the Singh et al.'s[5] study. Contrastingly, a study conducted in India reported malignancy as a risk factor of IFD.[5] This might be due to fungal isolations being looked for on day 5–7. Neutropenia is still regarded as the main problem in most immunocompromised patients.[14] Patients with neutropenia for more than 7 days have a higher risk for bacterial and fungal infection. Candida infection was more common during neutropenia or 2 weeks postneutropenia, whereas Aspergillus infection tends to occur during neutropenia or 3 weeks postneutropenia. Zygomycosis is less common than Candida or Aspergillus infection but is found in long-term neutropenia.

In this study, the number for IFD in critically ill patients with DM was 41.9% (31 patients), seen as a significant factor from bivariate and multivariate analyses. Different results were obtained in various studies. This might be because control of blood sugar level in Indonesia is not yet optimal. Some studies reported that in the glycosylated hemoglobin (HbA1C) level <8.0%, the T-CD4 lymphocyte response and function are not compromised. Proportional increase in HbA1C among diabetic patients can trigger glycation in immunoglobulin which may jeopardize the biological function of antibodies.[15] This study did not evaluate HbA1C further.

CVC is not a significant risk factor of IFD among critically ill patients. Similar results were found in studies by Paswan et al.[6] and Chow et al.[16] However, Fraser et al.[17] and Blumberg et al.[18] reported that CVC is a risk factor for IFD in critically ill patients. This difference might be caused by varying methods of CVC insertion.[19] Insertion and care of patients with CVC were in accordance with standard guidelines.

This study did not find a significant association between parenteral nutrition and IFD. Incidence of IFD in patients who received parenteral nutrition is 24.3% (n = 18). Contrastingly, studies by Chow et al.,[16] Fraser et al.,[17] and Blumberg et al.[18] reported that parenteral nutrition is a risk factor of IFD. This difference might be caused by early enteral nutrition in our study.

Among patients receiving broad-spectrum antibiotics, 95.9% had fungal infection. Studies from Pittet et al.,[20] Wey et al.,[21] and a large study involving 3000 ICU patients in US and Brazil reported that type and duration of antibiotic treatment affect IFD.[22] The use of broad-spectrum antibiotics may be related to the underlying surgical and medical condition. We did not find a significant association between broad-spectrum antibiotic use and IFD in critically ill patients. Duration of administration and type of antibiotic are not documented in this research though specific analysis may reveal significant differences.

Incidence of IFD among patients with postmajor surgery and steroid therapy was 27% (20 patients) and 18.9% (14 patients), respectively. A study from Chow et al.[16] and multicenter study in Spain reported postmajor surgery as a risk factor in IFD. Angele and Faist[23] reported that injury, trauma, and blood loss cause suppression of cellular immunity associated with increased susceptibility to wound infection and sepsis.

A study from Paswan et al. reported that steroid therapy was not a significant risk factor for IFD in critically ill patients.[6] Steroid is an effective treatment for skin diseases which suppresses the immune system, thus allowing fungal infection.[24] In this study, postmajor surgery and steroid therapy were not significant risk factors for IFD. The type of surgery, number of surgery, and steroid dosage in septic shock and other such conditions such as chronic obstructive pulmonary disease were not documented though specific analysis may reveal significant differences.

IFD incidence in patients with renal replacement therapy is 17.6% (13 patients). In this study, renal replacement therapy was not found as a significant factor for IFD, similar to studies by Singh et al.,[5] Paswan et al.,[6] Fraser et al.,[17] and Pittet et al.[20] In contrast, Chow et al.[16] and multicenter studies in US and Brazil reported renal replacement therapy as a significant risk factor for IFD in critically ill patients. This may be caused by differences in the studies' approach. Chow et al.[16] reported that renal replacement therapy is a risk factor of IFD because they associated this with the length of therapy. Although unclear, immune deficiency among end-stage renal disease patient might be associated with metabolic disorder and nutritional status in uremic condition.

In bivariate analysis, the relative risk (RR) of mechanical ventilation in IFD was 0.766 (confidence interval 95% 0.52–1.11 P – 0.159). However, in multivariate analysis, no significant association was found, similar to studies by Singh et al.,[5] Paswan et al.,[6] and Chow et al.[16] Contrastingly, Fraser et al.[17] reported that mechanical ventilation is a significant risk factor of IFD. Longer mechanical ventilation may increase the risk of infection. Body defense mechanism in critically ill patients changes due to the underlying diseases and medical devices used. Similarly, when they are intubated, the tube keeps the vocal cords open which increases risk of aspiration.[25] Long-term mechanical ventilation is not recorded in this study though specific analysis may reveal significant differences.

In this study, tracheostomy was not a significant factor for IFD in critically ill patients, similar to findings by Singh et al.,[5] Paswan et al.,[6] Chow et al.,[16] and Fraser et al.[17] This might be because fungal isolation was done in day 5–7 of the treatment, whereas tracheostomy is usually done in patients on mechanical ventilation for more than 2 weeks. In this study, four from seven HIV patients had IFD; however, no significant association was found between HIV and IFD, similar with studies by Paswan et al.,[6] Singh et al.,[5] and Chow et al.[16] A suppressed immune system could be ineffective against all kinds of infection, allowing fungal growth.[24]

There was no significant association between severe sepsis and IFD in this study. This is similar to findings by Singh et al.,[5] Paswan et al.,[6] Fraser et al.,[17] and Pittet et al.[20] although differs from Chow et al.[16] and a multicenter study in Spain, who reported a significant association. The usage of mechanical ventilation (>3 days), APACHE score, coinfection of positive and negative Gram bacteria, and the usage of urine catheter (>3 days) are not documented in this research though specific analysis may reveal a different result.

Conclusion

DM is a significant risk factor of early IFD in critically ill patients, justifying administration of early antifungal therapy. In addition, further research is needed to evaluate critically ill patients with high-risk factor of early IFD by performing serial fungal culture.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.