Assay Measuring Three Human Response Proteins Differentiates Bacterial and Viral Infections

A blood test that measures three proteins produced by the human immune system in response to exposure to pathogenic microorganisms has been commercialized into an assay system capable of rapidly distinguishing infections caused by bacteria from those caused by viruses.

Bacterial and viral infections are often clinically indistinguishable, leading to inappropriate patient management and antibiotic misuse. Investigators at the biomedical company MeMed, Ltd. (Tirat Carmel, Israel) sought to identify novel viral-induced host proteins that would complement bacterial-induced proteins to increase diagnostic accuracy and allow physicians to distinguish bacterial from viral infections.

To accomplish this task, they initially conducted a bioinformatic screen to identify putative circulating host immune response proteins. The resulting 600 candidates were then quantitatively screened for diagnostic potential using blood samples from 1,002 prospectively recruited patients with suspected acute infectious disease and controls with no apparent infection. For each patient, three independent physicians assigned a diagnosis based on comprehensive clinical and laboratory investigation including PCR for 21 pathogens. This process yielded 319 bacterial and 334 viral infections, 112 healthy control patients, and 98 with indeterminate diagnoses. A further 139 patients were excluded from the study based on predetermined criteria.

Results revealed that the best performing host-protein was TNF-related apoptosis-inducing ligand (TRAIL), which was consistently up-regulated in viral infected patients. They further developed a multi-protein signature using logistic-regression on half of the patients and validated it on the remaining half. The signature with the highest precision included both viral- and bacterial-induced proteins: TRAIL, interferon gamma-induced protein-10 (IP-10), and C-reactive protein (CRP). In the screening phase, host-proteins were measured using enzyme-linked immunosorbent-assay (ELISA), Luminex (Austin, TX, USA) protein-arrays, and flow-cytometry. The three proteins used in the final signature were measured as follows: CRP using the Roche (Pleasanton, CA, USA) Cobas-6000, Cobas-Integra-400/800, or Modular-Analytics-P800; TRAIL and IP-10 using commercial ELISA kits (MeMed Ltd.).

"We conducted big data filtering, followed by extensive screening of 600 immune system-related proteins," said first author Dr. Kfir Oved, CTO of MeMed. "A few of the proteins showed distinctly different patterns in bacterial and viral infected patients. In particular, the most informative protein we found, called TRAIL, dramatically increased in the blood of patients infected with a wide range of viruses, but surprisingly, decreased in bacterial infections. Our team developed an algorithm that computationally integrates TRAIL with other immune proteins to diagnose the cause of the infection with high accuracy."

The MeMed ImmunoXpert in vitro diagnostic blood test is CE marked and approved for clinical use in the European Union and Israel. It is currently in pilot distribution in these territories, with a broader commercial roll-out planned for later this year. The paper was published in the March 18, 2015, online edition of the journal PLOS ONE.

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