Neurologic Critical Care Heparin-binding protein: A diagnostic marker of acute bacterial meningitis* Adam Linder, MD; Per Åkesson, MD, PhD; Magnus Brink, MD; Marie Studahl, MD, PhD; Lars Bjo ¨ rck, MD, PhD; Bertil Christensson, MD, PhD A cute bacterial meningitis (ABM) is a life-threatening dis- ease and may cause substantial neurologic sequelae in survi- vors (1). In adults, Streptococcus pneu- moniae and Neisseria meningitidis are the predominant agents, with an overall fatality rate of approximately 30% and 10%, respectively. Early treatment with antibiotics and dexamethasone improves prognosis, and therefore, rapid diagnosis is vital (2). Diagnosis and treatment re- main a major challenge, mainly due to the often difficult distinction between ABM and viral central nervous system (central nervous system) infection at pre- sentation. This may result in administra- tion of broad-spectrum antibiotics in pa- tients with cerebrospinal fluid (CSF) pleocytosis pending the results of bacte- rial culture (3). The CSF white blood cell (WBC) count and lactate, protein, glu- cose, and plasma C-reactive protein levels are often not discriminative enough in the early phase of the disease (4 – 6). In addition, current diagnostic methods with bacterial detection by CSF Gram- negative stain or blood or CSF culture may be insufficient, especially in patients receiving antibiotics before lumbar punc- ture (7, 8). Viruses, most commonly En- terovirus, account for most cases of acute meningitis, and neurologic complica- tions are relatively uncommon (9). How- ever, herpes simplex virus type 1 (HSV-1) encephalitis is a potentially life-threaten- ing condition with 70% mortality if un- Background: The early detection of bacterial meningitis is crucial for successful outcome. Heparin-binding protein, a potent inducer of increased vascular permeability, is released from ac- tivated neutrophils in severe sepsis. Objective: In this study we investigated whether heparin- binding protein levels in cerebrospinal fluid could be used as a diagnostic marker for acute bacterial meningitis. Design: One prospective and one retrospective patient cohort from two university hospitals in Sweden were analyzed. Setting and Patients: Cerebrospinal fluid samples were collected from 174 patients with suspected central nervous system infection. Thirty-seven patients with acute community-acquired bacterial men- ingitis, four patients with neurosurgical bacterial meningitis, 29 pa- tients with viral meningitis or encephalitis, seven patients with neu- roborreliosis, and 97 control patients were included. Interventions: None. Measurements and Main Results: Cerebrospinal fluid samples were analyzed for the concentrations of heparin-binding protein, lactate, protein, glucose, neutrophils, and mononuclear cells. Hepa- rin-binding protein levels were significantly higher (p < .01) in patients with acute bacterial meningitis (median 376 ng/mL, range 12– 858 ng/mL) than in patients with viral central nervous system infection (median 4.7 ng/mL, range 3.0 – 41 ng/mL) or neuroborrelio- sis (median 3.6 ng/mL, range 3.2–10 ng/mL) or in control patients with a normal cerebrospinal fluid cell count (median 3.5 ng/mL, range 2.4 – 8.7 ng/mL). In the prospectively studied group, a heparin- binding protein concentration exceeding 20 ng/mL gave a sensitivity of 100%, a specificity of 99.2%, and positive and negative predictive values of 96.2% and 100%, respectively, in diagnosing acute bacte- rial meningitis. The area under the receiver-operating characteristic curve for heparin-binding protein was 0.994, which was higher than for the other investigated parameters. Conclusion: Elevated cerebrospinal fluid levels of heparin- binding protein distinguish between patients with acute bacterial meningitis and patients with other central nervous system infec- tions. (Crit Care Med 2011; 39:812– 817) KEY WORDS: bacterial meningitis; heparin-binding protein; vas- cular leakage *See also p. 910. From the Department of Clinical Sciences (AL, PÅ, LB, BC), Division of Infection Medicine, Lund University Hospital, Lund, Sweden; and Department of Infectious Diseases (MB, MS), Sahlgrenska University Hospital, Gothenburg, Sweden. Supported, in part, by the Swedish Research Council, Stockholm, Sweden (projects 7480 and 13,413), the Royal Physiographic Society, Lund, Swe- den, the Swedish Government Funds for Clinical Re- search (ALF), Lund, Sweden, the Lund University Hos- pital, Lund, Sweden, Hansa Medical AB, Lund, Sweden, and the Foundations of Greta and Johan Kock, Trelleborg, Sweden; Alfred O ¨ sterlund, Malmo ¨, Sweden; and Torsten and Ragnar So ¨ derberg, Stock- holm, Sweden. AL initiated the study, participated in the study design, included and followed patients, performed the HBP enzyme-linked immunosorbent assays, performed analysis of the data, and wrote parts of the manu- script. PÅ initiated the study, participated in the design of the clinical study, assisted in analysis of the data, and wrote parts of the manuscript. MB included and followed patients and wrote parts of the manuscript. MS included and followed patients and wrote parts of the manuscript. LB participated in the study design, assisted in analysis of the data, and wrote parts of the manuscript. BC participated in the study design, as- sisted in analysis of the data, and wrote parts of the manuscript. All authors approved the final version of the manuscript. Hansa Medical AB has filed a patent application on the use of HBP as a diagnostic tool in meningitis. Dr. Linder, Dr. Christensson, Dr. Bjo ¨ rck, and Dr. Åkesson are listed as inventors. The patent application is pend- ing. Drs. Brink and Studahl have not disclosed any potential conflicts of interest. The sponsors of this study had no role in study design, data collection, data analysis, data interpretation, writing of the paper, or the decision to submit the report. Address requests for reprints to: Dr. Adam Linder, MD, Department of Clinical Sciences, Division of In- fection Medicine, Lund University Hospital, SE-221 85 Lund, Sweden. E-mail: adam.linder@med.lu.se Copyright © 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e318206c396 812 Crit Care Med 2011 Vol. 39, No. 4