Diagnostic Biomarkers for Adult Hemophagocytic Lymphohistiocytosis in Critically Ill Patients (HEMICU)

Hemophagocytic lymphohistiocytosis in adults (HLH) is at 68% mortality whereas 78% of all cases remain undiagnosed though therapies are available which clearly reduce mortality. The investigators aim to systematically investigate this life-threatening hyperinflammatory syndrome in intensive care units (ICU) in order to detect biomarkers that are highly sensitive and highly specific for HLH in ICU compared to patients with sepsis.

Study Overview

• Status: Completed
• Conditions: Hemophagocytic Lymphohistiocytosis

Detailed Description

The investigators will draw blood samples of 100 patients at the time of diagnosis (each 50 with suspected or diagnosed HLH/sepsis) to determine a cytokine panel (c reactive protein (CRP), procalcitonin (PCT), interleukin (IL) 1β, IL-6, IL-8, IL-10, IL-18, IL-33, tumor necrosis factor (TNF) α, interferon (IFN) ɣ, soluble IL-2 receptor (sIL-2R), the EBV and CMV viral loads, human immunodeficiency virus (HIV) antibodies and -antigen, perforin, fibrinogen, triglycerides, bilirubin, lactate dehydrogenase, liver transaminases, sodium, serum albumin, electrophoresis, glycosylated ferritin, the microRNAs miR-205-5p, miR-194-5p and miR-30c-5p, perforin, CD107a and high immune status (differential blood count, T cells, B cells, NK cells, T helper cells, cytotoxic T cells, CD4 / CD8 ratio, HLA-DR of CD8 +, CD11a of CD8, CD57 of CD8, CD28 of CD8 +, HLA-DR of monocytes, CD56bright and CD69 of NK cells). The results of this study serve the development of new clinical concepts in order to safely diagnose HLH at an early stage, to distinguish from sepsis and to reduce the fatal consequences.

• Study Type: Observational
• Enrollment (Actual): 100

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Male and female critically ill patients admitted to any ICU of the Charité - Universitätsmedizin Berlin.

Description

Inclusion Criteria:

• Male or female critically ill patients
• At least 18 years old
• Suspected or diagnosed HLH

Exclusion Criteria:

• Female patients: Pregnancy
• Female patients: Breastfeeding

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Patients; 50 patients with sepsis versus 50 patients with HLH [anticipated]

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of HLH in intensive care units based on HLH-2004 criteria	HLH patients are followed up until the end of hospital stay or death.	Up to 180 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intensive care unit stay		Participants will be followed up for the duration of hospital length of stay, an expected average of 4 weeks
Hospital stay		Participants will be followed up for the duration of hospital length of stay, an expected average of 8 weeks
Mortality	Mortality after 30 and 180 days	Up to 180 days
Cytokine panel	1 blood sample of Cytokine panel (CRP, PCT, IL-1β, IL-6, IL-8, IL-10, IL-18, IL-33, TNF-α, IFN-ɣ, sIL-2R, ferritin) collection at time of diagnosed HLH	Up to 180 days
Epstein Barr Virus (EBV) and Cytomegalovirus (CMV) viral loads	1 blood sample collection at time of diagnosed HLH	Up to 180 days
Glycosylated ferritin	1 blood sample collection at time of diagnosed HLH	Up to 180 days
microRNAs miR-205-5p, miR-194-5p and miR-30c-5p	1 blood sample collection at time of diagnosed HLH	Up to 180 days
Perforin and CD107a	1 blood sample collection at time of diagnosed HLH	Up to 180 days
Human immunodeficiency virus antibodies and -antigen	1 blood sample collection at time of diagnosed HLH	Up to 180 days
Fibrinogen		Up to 180 days
Triglycerides		Up to 180 days
Bilirubin		Up to 180 days
Lactate dehydrogenase	Lactate dehydrogenase is measured in U/l	Up to 180 days
Liver transaminase (ASAT)	ASAT [U/l]	Up to 180 days
Liver transaminases (ALAT)	ALAT [U/l]	Up to 180 days
Sodium		Up to 180 days
Serum albumin		Up to 180 days
Serum protein electrophoresis	Serum protein Electrophoresis (%) is used to separate and quantify the serum protein components into serum albumin, alpha-1 globulins, alpha-2 globulins, beta 1 and 2 globulins, and gamma Globulins.	Up to 180 days
Detailed immune status	The immune status is analyzed by differential blood count [/nl], T cells [/nl], B cells [/nl], NK cells [/nl], T helper cells [/nl], cytotoxic T cells [/nl], CD4 / CD8 ratio, HLA-DR of CD8+ [%], CD11a of CD8 [%], CD57 of CD8 [%], CD28 of CD8+ [%], HLA-DR of monocytes [antigen/cell], CD56bright [%] and CD69 [%] of NK cells.	Up to 180 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
HLA Typing	HLA testing identifies the major HLA genes a person has inherited and their corresponding antigens that are present on the surface of their cells.	At the beginning of the investigation

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany

Publications and helpful links

General Publications

• Barba T, Maucort-Boulch D, Iwaz J, Bohe J, Ninet J, Hot A, Lega JC, Guerin C, Argaud L, Broussolle C, Jamilloux Y, Richard JC, Seve P. Hemophagocytic Lymphohistiocytosis in Intensive Care Unit: A 71-Case Strobe-Compliant Retrospective Study. Medicine (Baltimore). 2015 Dec;94(51):e2318. doi: 10.1097/MD.0000000000002318.
• Lachmann G, Knaak C, von Haefen C, Paeschke N, Meisel C, Nyvlt P, Schuster FS, Piper SK, Kruppa J, Vorderwulbecke G, Balzer F, La Rosee P, Schenk T, Unterwalder N, Kolsch U, Lachmann N, Akyuz L, Brunkhorst FM, Volk HD, Keh D, Spies C. Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients (HEMICU): a prospective observational study protocol. BMJ Open. 2019 Oct 30;9(10):e032695. doi: 10.1136/bmjopen-2019-032695.

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2018
• Primary Completion (Actual): June 26, 2022
• Study Completion (Actual): December 26, 2022

Study Registration Dates

• First Submitted: April 5, 2018
• First Submitted That Met QC Criteria: April 26, 2018
• First Posted (Actual): April 27, 2018

Study Record Updates

• Last Update Posted (Estimate): January 4, 2023
• Last Update Submitted That Met QC Criteria: January 2, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: critically ill; Hemophagocytic Lymphohistiocytosis (HLH); Hemophagocytic syndrome (HPS); Intensive care unit (ICU)
• Additional Relevant MeSH Terms: Pathologic Processes; Lymphatic Diseases; Disease Attributes; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Critical Illness; Lymphohistiocytosis, Hemophagocytic
• Other Study ID Numbers: HEMICU

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No