The primary goal of this proposed research is to develop a rapid point-of-care test that assesses the risk of neonatal sepsis (NS) and/or necrotizing enterocolitis (NEC) in infants based on Inter-alpha inhibitor proteins (IAIP) levels in blood. The test is expected to be simple, user-friendly, portable and suitable for use in the NICU. NS and NEC are associated with high mortality and morbidity, including adverse neuro- developmental outcomes. Furthermore, both conditions are associated with systemic inflammatory responses and their initial clinical presentations are similar, non-specific and subtle leading to a greater likelihood for misdiagnosis. It is important for clinicians to discern which patients are at risk for progressing to NEC or NS as clinical deterioration in both diseases can progress in a fulminant manner resulting in shock and death within hours of clinical presentation. There is currently no sensitive and specific test for early detection of NS and NEC. IAIP are found in plasma at a relatively high concentration and play an important role as innate immunity proteins to modulate host inflammatory response to pathological insults. During acute systemic inflammation following severe infection, trauma and injury, these proteins are rapidly depleted leading to a rapid decrease in plasma levels. We previously reported that IAIP levels are significantly decreased in adult sepsis and in infants with NS and NEC. In our recently completed studies, we confirmed that IAIP level is a sensitive and specific predictive marker for NS and NEC and more remarkably, the IAIP test has excellent high negative predictive value in both NS (98%) and NEC (100%) indicating that this test is potentially useful to influence the judgment on whether or not to discontinue antimicrobial treatment when the conventional tests are uninformative. Furthermore, our results demonstrated that it is feasible to develop a quantitative lateral flow-based test that is capable of measuring IAIP within 15 min. which is comparable to the results obtained by our 6 hr. laboratory based competitive ELISA (R2>0.8). In this proposal, we will extend these studies to improve the rapid assay design and further optimize the prototype test toward a fully developed product through design verification and design validation using clinical samples collected from infants suspected with NS and NEC at multiple clinical sites.
The specific aims of the Fast track SBIR project are: 1) Feasibility study to convert the competitive rapid lateral flow assay to a more robust and improved ?sandwich? rapid IAIP assay format; 2) Design verification study of the lateral flow IAIP rapid test; 2) Integration of the IAIP rapid test strip with the reader system and 4) Cross verification studies of the IAIP rapid test performance and confirmation studies of its predictive value using collected clinical samples. These studies are designed to obtain a robust and fully developed prototype test that is ready to enable future studies required for regulatory approval by the FDA. The impact of this project is immense as the rapid test will help reduce the high morbidity and mortality associated with the devastating diseases of NS and NEC as well as support antibiotic stewardship in infants.

Public Health Relevance

The goal of this proposed research is to develop a rapid test based on Inter-alpha inhibitor proteins that can be useful to detect infants with life-threatening conditions such as whole body infection (sepsis) and necrotizing enterocolitis using a simple, portable device suitable for a bedside testing. The potential impact of the proposed research is immense as it will reduce the devastating effects of these diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1)
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Minnicozzi, Michael
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Prothera Biologics, LLC
United States
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