Biomarkers in Infection

The body's immune system and a subsequent inflammatory response are triggered during infection. The detection of an activated immune system, and an indication of the degree of the host response, is helpful to the clinician both in assessing the severity of infection and in patient treatment and management. Currently, the white blood cell count and the differential are the most common laboratory parameters for measuring host response. The sedimentation rate and CRP are also used to detect inflammation. However, these tests are all imperfect predictors, and a test providing a better assessment of immune response would be helpful to the clinician in patient care. Additionally, understanding host response to infection may be helpful in understanding the biology and pathophysiology of sepsis. There are other biomarkers and inflammatory markers that may be found early in the initial presentation of infection such as cytokines (VEGF IL-1,IL-4,IL-6, IL-10, PAF, TNF, lectins iNoS,etc.) and clotting factors (protein C, d-dimer, complements involved in the clotting cascade, CRP, etc) that may provide a means of early detection of systemic inflammation, cell dysfunction, and related conditions. Early identification of patients at risk for systemic inflammatory syndromes, sepsis and septic shock may help direct patients to earlier antibiotic administration and early intervention with goal directed therapy. It may also serve as a tool for risk stratification when components such as age, comorbid illness and infection type are included.

The endothelium and endothelial cell markers are important in sepsis, yet a somewhat under-studied field of research. Additionally, the endothelium is a key regulator of the microcirculation, a place where oxygen diffusion occurs. One focus of this study is to measure endothelial markers (ie VEGF) and other cytokines with the goal of correlating these markers with severity of sepsis. Another focus is to study the response of various components in the blood, including the leukocytes, red cells, the endothelium, as well as cellular components such as the mitochondria. We will specifically look at alterations in thiamine, Vitamin D, CoQ10,l-carnitine and other nutrients as part of (and as related to) the body's response. Recently, a non-invasive method of assessing microvascular circulation by orthogonal polarization spectral (OPS) imagery has become available using a non-invasive technology known as orthogonal polarization spectroscopy. This technique enables direct visualization and quantification of microcirculatory blood flow, and represents an important surrogate outcome to which endothelial cell marker may be correlated. This will involve placing the microscopy probe gently against the sublingual mucosa and collecting a videotape of the circulation lasting about twenty seconds. This process involves minimal (or no) risk - it is akin to taking a temperature and uses no radiation. This videotape will be examined later by a novel software program that quantifies the circulation and used as an important surrogate outcome measure. Additionally, we are going to perform echocardiography to better understand the heart's response to sepsis, and correlated the molecular responses that we find with the changes in the responses by the heart. In addition, we will assess microvascular flow in the skeletal muscle in the forearm using diffuse correlation spectroscopy (DCS). DCS is a novel technique that can be used to measure peripheral tissue perfusion noninvasively and has the potential to provide insight into microcirculatory health and end-organ perfusion. DCS measurement is performed using a small sensor, similar to a pulse oximeter sensor, that attaches to the skin using adhesive. It uses near-infrared light to illuminate the tissue. The change in the transmitted light through the tissue due to the moving red blood cells is characterized to quantify the microvascular flow. DCS is noninvasive, uses no radiation, and involves minimal (or no) risk. DCS measurement will be performed in conjunction with vascular occlusion test (VOT), which involves having a blood pressure cuff placed on the upper arm to cause occlusion and reperfusion of blood flow distally to measure dynamic changes in microvascular flow. We will measure endothelial glycocalyx degradation products (e.g. heparin sulfate, syndecan, etc) in the urine.

This is a multicenter, observational pilot study which aims to evaluate how early biomarkers of infection an inflammation perform in identifying patients at risk for poor outcomes in sepsis and septic shock. The study will utilize a cohort of patients presenting to the ED with suspected infection as well as non-infected control population.

These patients will be compared with a non-infected population.

Enrolled subjects in the infected group will have blood samples and chart review obtained at enrollment, 24, 48 and 72 hours. For the control group, only a single blood draw will be collected at enrollment. Urine may be collected in a convenience sample of patients

Enrolled subjects will also undergo physiologic assessments using echocardiography, Microscan, Non-invasive cardiac output monitor (NICOM), DCS, extremity temperature as well as End-Tidal C02 measurements if a trained researcher is present.

Inclusion criteria

for Infected subjects:

• Age 18 years of age or older
• Confirmed or suspected infection

Inclusion criteria

for Control Subjects:

• Age 18 years of age or older
• A non-infectious clinical presentation to include
• Normal white blood cell count ( > 4,000 and/or < 12,000)
• Normothermia ( > 96.5 and/or less 100.4)
• Absence of the following clinical complaints: productive cough, fever, pyuria, rash
• No evidence of acute coronary syndrome

Exclusion criteria

for Control Subjects:

• Suspected infection