NOBICS - NOvel BIomarker In Invasive CandidiasiS/Candida Sepsis (NOBICS)

Invasive Candida infections are serious complications in immunocompromised patients including those undergoing treatment for cancer but occur also in patients treated in ICUs. Survival rate of invasive candidiasis is associated with early initiation of antifungal therapy (15% mortality rate for candidemic patients with antifungal therapy on day 0 related to the culture date of the first blood sample positive for yeasts compared to 41% for patients who received antifungal therapy on day 3). Up to date, no laboratory method or clinical decision rule is available for correct anticipation of invasive candidiasis which would avoid delays in appropriate antifungal therapy initiation. In clinical practice culture based methods (e.g. blood cultures) miss up to 50% of invasive candidiasis cases. Preemptive antifungal therapy is therefore often initiated in critically ill patients after Candida has been isolated from various non-sterile patient samples even without any sufficient evidence for invasive candidiasis. The disadvantages of this approach include over- and undertreatment of patients (up to 50% of candidemia cases are missed, and on the other hand 89% patients are treated unnecessarily), increased selective pressure for the development of antifungal resistance, potential risk of adverse drug reactions, and increased costs (expenses for antifungal therapy account for half of the antimicrobial medication budget in tertiary care hospitals). In addition, no survival benefit could be demonstrated by this strategy in ICU patients.

The aim of this study is to identify biological markers to anticipate or support the diagnosis of invasive candidiasis in ICU patients, to overcome current deficiencies in detection of invasive candidiasis and consequently to differentiate between Candida spp. colonization and invasive Candida infection. The investigators intend to examine time dependent courses of potential host and pathogen derived biomarkers as well as innate or acquired predispositions for invasive candidiasis; e.g. automated (1→3) ß- D- Glucan tests, DNA in serum blood samples, pathogen recognition receptors and serum markers like interleukin (IL)-1, IL-2, IL-6, IL-10, IL-12, IL-17A, IL-17F, IL-22, IL-23, Tryptophan, Kynurenine, composition of indigenous microbiota of gastrointestinal and lower respiratory tract and skin, and risk factors for invasive candidiasis like underlying diseases and treatments. The study should contribute to improved assessment of ICU patients at risk for invasive candidiasis and to improved diagnosis of invasive candidiasis in ICU patients. In clinical practice the reliable differentiation between infection and colonization will allow more targeted antifungal therapy leading to enhanced antifungal treatment initiation on the one hand (in cases of true invasive candidiasis) and to reduction of unnecessary antifungal treatments and treatment costs on the other hand.

Study Overview

• Status: Completed
• Conditions: Invasive Candidiasis

• Study Type: Observational
• Enrollment (Actual): 200

Contacts and Locations

Study Locations

• Austria
  • Stmk
    • Graz, Stmk, Austria, 8036
      • Medical University of Graz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

1. Healthy subjects
2. Patients with invasive candidiasis/Candida sepsis
3. Patients with sepsis and bacteremia
4. ICU Patients without infectious disease

Description

ad 1:

Inclusion Criteria:

-subjects without any evidence of current or chronic infectious diseases

Exclusion Criteria:

• Clinical or radiological or laboratory evidence of current infectious disease (temperature >38°C, elevated CRP >5mg/dl, leukocytosis >11400, elevated neutrophiles)
• antifungal therapy within 8 weeks prior to inclusion
• immunosuppressive therapy (e.g. glucocorticoids, methotrexate, azathioprin, etc)
• active haematooncological diseases
• HIV positivity

ad 2:

Inclusion criteria:

-Patients with invasive Candidias/Candida sepsis as defined in recent EORTC/MSG definitions.

Exclusion criteria:

• glucocorticoid treatment with prednisone equivalent of ≥20mg/d
• inherited neutrophil deficiency
• absolute neutrophil count of ≤500cells/mm3
• antifungal therapy within 8 weeks prior to inclusion
• immunosuppressive therapy (glucocorticoids with prednisone equivalent of ≥20mg/d, methotrexate, azathioprin etc)
• active hematooncological disease
• HIV positivity

ad 3:

Inclusion criteria:

-ICU patients with sepsis and proven bacteremia (Staph. aureus or E. coli)

Exclusion criteria:

• Antifungal therapy within 8 weeks prior to inclusion
• immunosuppressive therapy (glucocorticoids with prednisone equivalent of ≥20mg/d, methotrexate, azathioprin etc)
• active hematooncological disease HIV positivity

ad 4:

Inclusion criteria:

-ICU patients without invasive candidiasis as defined above, without bacteremia and without clinical and laboratory markers of infection(e.g. intubated and mechanically ventilated patients with stroke or CPR)

Exclusion criteria:

• Clinical or radiological or laboratory evidence of current infectious disease (temperature >38°C, elevated CRP >5mg/dl, leukocytosis >11400, elevated neutrophiles)
• antifungal therapy within 8 weeks prior to inclusion
• immunosuppressive therapy (e.g. glucocorticoids, methotrexate, azathioprin, etc)
• active haematooncological diseases
• HIV positivity

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Healthy Controls
Invasive Candidiasis
Bacterial Sepsis (Bacteremia)
ICU patients without infectious disease

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers indicating or excluding invasive Candidiasis	Automated (1→3) ß- D- Glucan tests (pg/ml) DNA in serum blood samples (quantity and sequences) pathogen recognition receptors (% of cells as assessed by FACS analysis) serum markers like IL-1, IL-2, IL-6, IL-10, IL-12, IL-17A, IL-17F, IL-22, IL-23, Tryptophan, Kynurenine (quantity) composition of indigenous microbiota of gastrointestinal and lower respiratory tract and skin (comparison of detection rates and abundances of different classes or genera)	through study completion, an average of 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Risk factors for Invasive Candidiasis	Risk factors as described in previous literature, e.g. Eggimann, Lancet Infect Dis 2003; 3: 685-702	through study completion, an average of 2 years

Collaborators and Investigators

• Sponsor: Medical University of Graz
• Collaborators: Medical University Innsbruck
• Investigators: Principal Investigator: Robert Krause, MD, Section of Infectious Diseases and Tropical Medicine, Dpt of Internal Medicine, Medical University of Graz

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2016
• Primary Completion (Actual): August 1, 2021
• Study Completion (Actual): August 1, 2021

Study Registration Dates

• First Submitted: June 9, 2016
• First Submitted That Met QC Criteria: June 13, 2016
• First Posted (Estimate): June 16, 2016

Study Record Updates

• Last Update Posted (Actual): September 22, 2021
• Last Update Submitted That Met QC Criteria: September 21, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Mycoses; Invasive Fungal Infections; Candidiasis; Candidiasis, Invasive
• Other Study ID Numbers: KLI 561-B31

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No