Value of the LightCycler® SeptiFast Test MGRADE for the Pathogen Detection in Neutropenic Hematological Patients

• The number of changes in empirical antimicrobial therapy [ Time Frame: up to the end of study participation ] [ Designated as safety issue: No ]
• Time to the change to the targeted antimicrobial therapy [ Time Frame: at time point of change to the targeted antimicrobial therapy ] [ Designated as safety issue: No ]

• The number of patients with a potential pathogen identified by the SeptiFast Test, compared with the number of patients likely to have bloodstream infection or sepsis, as determined by a constructed clinical comparator [ Time Frame: at day 1 and 72h after study inclusion ] [ Designated as safety issue: No ]
• Number of patients having a change to a more appropriate antimicrobial (evaluated retrospectively by susceptibility) [ Time Frame: up to the end of study participation ] [ Designated as safety issue: No ]
• Time to identification of a potential pathogen [ Time Frame: at time point of identification of a potential pathogen ] [ Designated as safety issue: No ]
• Time to change antimicrobial to a more appropriate antimicrobial [ Time Frame: at time point of change to a more appropriate antimicrobial ] [ Designated as safety issue: No ]
• Duration (in days) of antimicrobials [ Time Frame: up to the end of study participation ] [ Designated as safety issue: No ]
• Change in condition severity (clinical parameters) [ Time Frame: daily ] [ Designated as safety issue: No ]
• Days in intensive care unit (ICU) [ Time Frame: at the end of study participation ] [ Designated as safety issue: No ]
• Ventilation duration in ICU (hours) [ Time Frame: at the end of study participation ] [ Designated as safety issue: No ]
• Days in hospital (from study inclusion) [ Time Frame: at the end of study participation ] [ Designated as safety issue: No ]
• All-cause death [ Time Frame: at the end of study participation ] [ Designated as safety issue: No ]
• Treatment costs [ Time Frame: up to the end of study participation ] [ Designated as safety issue: No ]

• The number of patients with a potential pathogen identified by the SeptiFast Test, compared with the number of patients likely to have bloodstream infection or sepsis, as determined by a constructed clinical comparator [ Time Frame: at day 1 and 72h after study inclusion ] [ Designated as safety issue: No ]
• Number of patients having a change to a more appropriate antimicrobial (evaluated retrospectively by susceptibility) [ Time Frame: up to the end of study participation ] [ Designated as safety issue: No ]
• Time to identification of a potential pathogen [ Time Frame: at time point of identification of a potential pathogen ] [ Designated as safety issue: No ]
• Time to change antimicrobial to a more appropriate antimicrobial [ Time Frame: at time point of change to a more appropriate antimicrobial ] [ Designated as safety issue: No ]
• Duration (in days) of antimicrobials [ Time Frame: up to the end of study participation ] [ Designated as safety issue: No ]
• Change in condition severity (clinical parameters) [ Time Frame: daily ] [ Designated as safety issue: No ]
• Days in ICU [ Time Frame: at the end of study participation ] [ Designated as safety issue: No ]
• Ventilation duration in ICU (hours) [ Time Frame: at the end of study participation ] [ Designated as safety issue: No ]
• Days in hospital (from study inclusion) [ Time Frame: at the end of study participation ] [ Designated as safety issue: No ]
• All-cause death [ Time Frame: at the end of study participation ] [ Designated as safety issue: No ]
• Treatment costs [ Time Frame: up to the end of study participation ] [ Designated as safety issue: No ]

The overall objective of this study is to assess the clinical value of the SeptiFast Test as an adjunct to traditional microbiological, clinical, and other laboratory assessments in early detection and identification of a potential pathogen and therefore early targeted antimicrobial management of neutropenic hematological patients with suspected infection or sepsis.

Infections, including sepsis, continue to be a major cause of morbidity and mortality in patients with hematologic diseases. Early diagnosis of infection, rapid identification of the causative pathogen(s), and prompt initiation of appropriate antimicrobial treatment (the first 24 hours are most critical) all have a major impact on mortality.

The LightCycler® SeptiFast Test MGRADE (SeptiFast Test) is an in vitro nucleic acid amplification test for the direct detection and identification of DNA from bacterial and fungal microorganisms in human EDTA whole blood. The SeptiFast test can detect nucleic acids from the most common pathogens (approximately 90%) responsible for hospital-associated bacteremia. The test is used in conjunction with the patient's clinical presentation and established microbiological assays and other laboratory markers as an aid in antimicrobial treatment decision making for patients with suspected sepsis and other bloodstream infections.

This is a randomized prospective study of the use of the SeptiFast Test as an adjunct to traditional management of neutropenic haematological patients suspected of having infection or sepsis. The study will be performed in a two-armed manner. The blood sample for the SeptiFast Test will be collected from all included patients. However, analysis of the SeptiFast Test in the control group will only be performed at a later point in time; thus, in the control group results will not become available until the end of the study and, therefore, cannot be used for guiding clinical decisions.

Patients complete the study when the episode of infection or sepsis resolves, or the patient is discharged from a hospital, or the patient died.

• Hematologic Diseases
• Neutropenia
• Febrile Neutropenia
• Sepsis

• Other: Detection of microbial DNA in blood by SeptiFast Test
  The SeptiFast Test is a multiplex polymerase chain reaction (PCR) test that can detect nucleic acids from the most common pathogens (approximately 90%) responsible for hospital-associated bacteremia and takes approx. 6 hours to perform
• Other: Pathogen detection by blood culture
  Blood culture is a conventional microbiological method of pathogen detection. Results from blood cultures are usually not available until 24 to 72 hours after sampling

• Experimental: SeptiFast Test
  Pathogen detection by SeptiFast Test as an adjunct to traditional microbiological assessments including blood culture
  Intervention: Other: Detection of microbial DNA in blood by SeptiFast Test
• Active Comparator: Only Conventional Diagnostics
  Pathogen detection only by conventional microbiological assessments, e.g. blood culture
  Intervention: Other: Pathogen detection by blood culture

Inclusion Criteria:

1. Patient with hematological disease and neutropenia < 500/µl (or < 1000/µl, if criterion 5A is fulfilled)
2. Known or acute infection, or suspected infection, or sepsis, which clinically indicates investigation by blood culture
3. Time-frame after diagnosis or suspicion of infection or sepsis: < 72 hours
4. Species causing infection not known before inclusion

5. Patient fulfils criterion A or/and B

   A. Indication for an initiation of antimicrobial therapy in patients with febrile neutropenia

   • Neutropenia <500/µl or <1000/µl if decline to <500/µl is expected in the next 48h.
   • Single (oral) temperature of ≥ 38.3°C, or temperature ≥ 38.0°C lasting for at least 1h or measured twice within 12h.
   • No evidence of non-infectious cause of fever (blood products, drugs reactions, etc)

   B. At least two of the following criteria:

   • Temperature >38°C or <36°C
   • Heart rate >90 beats/minute
   • Respiratory rate >20 breaths/minute or PaCO2 <32 mmHg / 4,3 kPa
6. Patient is able to provide written informed consent

Exclusion Criteria:

1. Moribund patients with survival expectation < 24h
2. Younger than 18 years
3. Patient is not able to provide informed consent
4. Patients not suitable for study participation in the opinion of investigator

• Pfizer
• Hoffmann-La Roche