Novel Mechanisms and Approaches to Treat Neonatal Sepsis

NCT02554630 | Completed

• 2 other identifiers: IRB201500447 -NR01GM097531
• Study Type: observational
• Target: 142
• Locations: 1 country
• Sites: 1

Brief Summary

Mortality related to neonatal sepsis exceeds 1 million deaths worldwide; the highest risk of mortality is in preterm neonates, especially low birth weight (LBW), and very low birth weight (VLBW) neonates. The estimated cost of caring for these patients is approximately $700 million in the US alone. In an effort to help mature the neonatal immune system, several adjuvant therapies have been studied; however, none have been implemented in clinical practice. One of the most frequently considered targets for adjuvant therapy is toll-like receptors (TLRs). TLRs detect conserved molecular products of microorganisms (lipopolysaccharide (LPS), and initiate immunity and inflammation. Early adjuvant administration in VLBW infants may be a viable approach to reducing the incidence of early and late sepsis. This research study will characterize immune genomic expression and functional capacity at the time of birth in both term and preterm neonates and determine what effects, if any, that adjuvants have on this function. Additionally, this study will seek to determine if immune function correlates with certain microbiota.

Conditions

Complication of Prematurity; Immunologic Deficiency Syndromes

Outcome Measures

Primary Outcomes (2)

• Genomic analysis

  The genomic profile will be interpreted using Ingenuity Pathway Analysis (IPA) software to make functional predictions. Additionally, a cytokine analysis, and an evaluation for the prevalence of myeloid derived suppressor cells (MDSCs) that have been shown to correlate with poorer outcomes in adult sepsis studies will be performed.

  Day 1

• Functional immunologic analysis

  Functional capacity will be confirmed directly by observing chemotaxis and quantifying generation of reactive oxygen species (ROS), rate of phagocytosis, and bacterial killing ability. Additionally, a cytokine analysis, and an evaluation for the prevalence of myeloid derived suppressor cells (MDSCs) that have been shown to correlate with poorer outcomes in adult sepsis studies will be performed.

  Day 1

Secondary Outcomes (4)

• Immune Function Correlation with Clinical Outcomes

  90 days

• Ex-vivo Adjuvant Therapies On Immune Function

  Day 1

• Ex-vivo Adjuvant Therapies Effect On Immune Cell Genomic Expression

  Day 1

• Microbiome Influences Immune Cell Function

  Day 1

Study Arms (3)

Preterm Neonate

Neonates of gestational age 24-37 weeks. Blood collection will be performed at the time of a clinically required heelstick or blood draw. Microfluidic techniques, utilizing whole blood, will be employed to characterize the baseline genomic profile and functional capacity of immune cells. Adjuvant drugs will be employed ex-vivo to determine if adjuvant therapies change genomic expression and bolster immune function. Meconium will be collected for microbiome analysis. Clinical outcomes will be recorded from the electronic medical record.

Other: Adjuvant; Other: Blood Collection

Term Neonates

Neonates of gestational age 37-42 weeks. Blood collection will be performed at the time of a clinically required heelstick or blood draw. Microfluidic techniques, utilizing whole blood, will be employed to characterize the baseline genomic profile and functional capacity of immune cells. Adjuvant drugs will be employed ex-vivo to determine if adjuvant therapies change genomic expression and bolster immune function. Meconium will be collected for microbiome analysis. Clinical outcomes will be recorded from the electronic medical record.

Other: Adjuvant; Other: Blood Collection

Healthy Adult Control

Healthy Adult aged 18-55 years will undergo a single blood collection by the way of vein puncture. Microfluidic techniques, utilizing whole blood, will be employed to evaluate the genomic profile and functional capacity of immune cells. Adjuvant drugs will be employed ex-vivo to determine if adjuvant therapies change genomic expression and bolster immune function.

Other: Adjuvant; Other: Blood Collection

Interventions

Adjuvant OTHER

Blood will be incubated, ex-vivo, with one of the adjuvant therapies or no adjuvant and then, using microfluidic techniques the immune genomic profile and the functional capacity of immune cells will be assessed.

Also known as: Lippopolysaccaride, Specific toll-like receptor 4 agonist, Non-specific toll-like receptor 4 agonist

Healthy Adult Control; Preterm Neonate; Term Neonates

Blood Collection OTHER

Blood collection will be performed on all groups.

Healthy Adult Control; Preterm Neonate; Term Neonates

Eligibility Criteria

• Age: Up to 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Preterm neonates 0-72 hours old Term Neonates 0-72 hours old Healthy Adult Controls 18-55 years old

You may qualify if:

• Consent to participate in the study

You may not qualify if:

• non- survivable condition
• Healthy Adult Controls
• Consent to participate in the study
• Age \>18 years old, \<55 years old
• Age \<18 years old, \>55 years old
• Severe pre-existing organ dysfunction
• Oncolytic therapy within 14 days
• HIV positive status
• Current use of chronic steroids

Sponsors & Collaborators

• University of Florida: lead
• National Institute of General Medical Sciences (NIGMS): collaborator
• Surgical Infection Society: collaborator

Study Sites (1)

UF Health

Gainesville, Florida, 32610, United States

Location

Related Publications (12)

• Watson RS, Carcillo JA, Linde-Zwirble WT, Clermont G, Lidicker J, Angus DC. The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med. 2003 Mar 1;167(5):695-701. doi: 10.1164/rccm.200207-682OC. Epub 2002 Nov 14.

  PMID: 12433670 BACKGROUND

• Lawn JE, Kerber K, Enweronu-Laryea C, Cousens S. 3.6 million neonatal deaths--what is progressing and what is not? Semin Perinatol. 2010 Dec;34(6):371-86. doi: 10.1053/j.semperi.2010.09.011.

  PMID: 21094412 BACKGROUND

• Cuenca AG, Wynn JL, Moldawer LL, Levy O. Role of innate immunity in neonatal infection. Am J Perinatol. 2013 Feb;30(2):105-12. doi: 10.1055/s-0032-1333412. Epub 2013 Jan 7.

  PMID: 23297181 BACKGROUND

• PrabhuDas M, Adkins B, Gans H, King C, Levy O, Ramilo O, Siegrist CA. Challenges in infant immunity: implications for responses to infection and vaccines. Nat Immunol. 2011 Mar;12(3):189-94. doi: 10.1038/ni0311-189. No abstract available.

  PMID: 21321588 BACKGROUND

• Wynn JL, Scumpia PO, Winfield RD, Delano MJ, Kelly-Scumpia K, Barker T, Ungaro R, Levy O, Moldawer LL. Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists. Blood. 2008 Sep 1;112(5):1750-8. doi: 10.1182/blood-2008-01-130500. Epub 2008 Jun 30.

  PMID: 18591384 BACKGROUND

• Wynn JL, Levy O. Role of innate host defenses in susceptibility to early-onset neonatal sepsis. Clin Perinatol. 2010 Jun;37(2):307-37. doi: 10.1016/j.clp.2010.04.001.

  PMID: 20569810 BACKGROUND

• Yost CC, Cody MJ, Harris ES, Thornton NL, McInturff AM, Martinez ML, Chandler NB, Rodesch CK, Albertine KH, Petti CA, Weyrich AS, Zimmerman GA. Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. Blood. 2009 Jun 18;113(25):6419-27. doi: 10.1182/blood-2008-07-171629. Epub 2009 Feb 12.

  PMID: 19221037 BACKGROUND

• Gessler P, Nebe T, Birle A, Haas N, Kachel W. Neutrophil respiratory burst in term and preterm neonates without signs of infection and in those with increased levels of C-reactive protein. Pediatr Res. 1996 May;39(5):843-8. doi: 10.1203/00006450-199605000-00017.

  PMID: 8726239 BACKGROUND

• Gentile LF, Nacionales DC, Lopez MC, Vanzant E, Cuenca A, Cuenca AG, Ungaro R, Szpila BE, Larson S, Joseph A, Moore FA, Leeuwenburgh C, Baker HV, Moldawer LL, Efron PA. Protective immunity and defects in the neonatal and elderly immune response to sepsis. J Immunol. 2014 Apr 1;192(7):3156-65. doi: 10.4049/jimmunol.1301726. Epub 2014 Mar 3.

  PMID: 24591376 BACKGROUND

• Cuenca AG, Cuenca AL, Gentile LF, Efron PA, Islam S, Moldawer LL, Kays DW, Larson SD. Delayed emergency myelopoiesis following polymicrobial sepsis in neonates. Innate Immun. 2015 May;21(4):386-91. doi: 10.1177/1753425914542445. Epub 2014 Aug 7.

  PMID: 25106654 BACKGROUND

• Sweeney SE, Firestein GS. Primer: signal transduction in rheumatic disease--a clinician's guide. Nat Clin Pract Rheumatol. 2007 Nov;3(11):651-60. doi: 10.1038/ncprheum0631.

  PMID: 17968336 BACKGROUND

• Kollmann TR, Crabtree J, Rein-Weston A, Blimkie D, Thommai F, Wang XY, Lavoie PM, Furlong J, Fortuno ES 3rd, Hajjar AM, Hawkins NR, Self SG, Wilson CB. Neonatal innate TLR-mediated responses are distinct from those of adults. J Immunol. 2009 Dec 1;183(11):7150-60. doi: 10.4049/jimmunol.0901481. Epub 2009 Nov 16.

  PMID: 19917677 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood Sample Meconium Sample

MeSH Terms

Conditions

Immunologic Deficiency Syndromes

Interventions

Adjuvants, Pharmaceutic; Blood Specimen Collection

Condition Hierarchy (Ancestors)

Immune System Diseases

Intervention Hierarchy (Ancestors)

Pharmaceutic Aids; Pharmaceutical Preparations; Specialty Uses of Chemicals; Chemical Actions and Uses; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Shawn Larson, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 17, 2015
• First Posted: September 18, 2015
• Study Start: February 1, 2016
• Primary Completion: October 21, 2022
• Study Completion: October 21, 2022
• Last Updated: February 10, 2023

Record last verified: 2023-02

Locations

US (1)