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Health care associated infection (HAI) among patients in the intensive care unit (ICU) has been identified as an independent risk factor for hospital mortality.1 Patients presenting to the ICU are at high risk for development of HAI 2 which can result in prolonged ICU stay, as well as sequelae leading to organ dysfunction and death.2-5 The mechanism for development of all HAI is unclear; although, predisposing factors such as invasive devices6-8 may be responsible for approximately half of all HAI9 and severity of illness is a predisposing factor.9,10 Although the central role of the inflammatory response is to control infections, an exaggerated response may also play a role in the development of HAI.

Cytokines are proteins that orchestrate the inflammatory response. The inflammatory response begins locally and may become systemic. There is usually a balanced inflammatory response, with pro-inflammatory cytokines (i.e., IL-1β, TNF-α, and IL-6) initiating the inflammatory process against infection, and anti-inflammatory cytokines (i.e., IL-1ra and IL-10) functioning to down regulate the inflammatory response.11 Systemic inflammation is usually manifested with fever or hypothermia, tachycardia, hyperpnea, and leukocytosis or leukopenia.

Baseline severity of illness (measured by APACHE II) correlates with baseline inflammatory response and this process is independent of the causative organism.12 The relationship between the development of new HAI and the degree of baseline systemic inflammation or severity of illness has not been fully explored in patients with sepsis.

Excessive inflammation has harmful effects and may be a contributing cause of HAI in the ICU.

Sepsis is a complex disease involving a large number of genes. Several polymorphisms have been well characterized in sepsis.13-19 Knowledge is accumulating regarding the genetic susceptibility to infectious disease; however, gene-gene, geneenvironment, and host-pathogen interactions should also be considered.20-22 Identification of promoter polymorphisms is important when examining an exaggerated inflammatory response. There are a number of important candidate polymorphisms that may be involved in the development of HAI.

Specific Aims

The purpose of this study is to determine the impact of baseline systemic inflammation (pro-inflammatory cytokine, anti-inflammatory cytokines, and their ratio), genetic variability, and environment on the development of HAI among patients with sepsis during their ICU stay. One of the primary goals of this study is to determine whether exaggerated baseline systemic inflammation increases risk for development of HAI during ICU stay. If true, this recognition may promote earlier detection and treatment of infections. Another goal of this study is to identify candidate genes involved in susceptibility of recurrent infections (new HAIs) in sepsis. It is unknown if these genes may differ from genes responsible for the sentinel sepsis event.

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1. Investigate whether baseline protein expression levels of pro-inflammatory cytokines, anti-inflammatory cytokines, or their ratios influence the development of subsequent HAI in patients with sepsis.

2. Investigate the variance in cytokine genes to determine if they influence levels of protein expression or development of HAI.

3. Investigate the effects of protein expression levels, genetic variation, and environment on development of HAI.

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The findings of this study may provide important new insights into risk factors that contribute to the development of HAI in patients presenting to the ICU with sepsis. It is possible that these findings may be relevant for all patients who develop HAI, as patients may develop sepsis as the result of developing HAI. Targeting early exaggerated inflammation and increased severity of illness may allow earlier detection of HAIs, and promote earlier diagnosis and treatment, perhaps reducing the cost of care (by reducing hospital length of stay) and sequelae that lead to organ dysfunction and death. Thus, these findings may impact nursing and other critical care clinician practice first by helping to identify patients at risk, then implementing stricter targeted infection control practices in efforts to prevent development of HAIs (in addition to current standard and recommended practices), and lastly in early recognition and treatment when HAI occur.

Conceptual Model

The effects of sepsis and severe sepsis are far-reaching, with severe sepsis affecting approximately 751,000 annually in the US, with a 29-38% mortality rate.23 It is unclear how many of these cases represent new HAI (sepsis occurring at least three days after hospital admission) versus those who were admitted to the hospital or ICU with sepsis. Patients admitted with sepsis seem to be at higher risk for development of HAI.3,4,24 An appropriate immune response to an infectious insult 25 as well as early intervention of appropriate antibiotics, fluid resuscitation, and supportive care26-28 are key to a favorable outcome in sepsis. Sepsis is the clinical manifestations of an infectious insult and was defined by Consensus Conference in 1992.29 These definitions are still commonly used by clinicians today, and their usefulness was reaffirmed by international experts attending the 2001 International Sepsis Definitions Conference, who also proposed a new staging classification system using the acrostic PIRO (P=predisposition, I=insult infection, R=response, O=organ dysfunction), similar to the TMN approach used for tumor staging, to better characterize sepsis.30-34 Use of the PIRO model has been described as an effective classification system for researchers given the diversity and heterogeneity of patients with sepsis.35 Aspects of this system were incorporated into the conceptual model.

The conceptual model for the development of HAI in sepsis (Figure 1-1) is very complex; yet, this map represents a simplified depiction and incorporates the work of others.4,31-33,35 The infectious insult, predisposing factors, severity of illness, and inflammatory response are all key factors to understanding the development of HAIs.

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The following terms and definitions are provided for the major concepts in the model. These were the operational definitions used for this study.

Elements of Sepsis

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Severe Sepsis: The manifestation of sepsis with organ dysfunction.29 • Sequential Organ Dysfunction Assessment (SOFA): The SOFA was used to • assess the degree of organ failure among participants. The SOFA score include assessment of six organs (Respiratory, Coagulation, Liver, Cardiovascular, Central nervous system, and Renal). The score for each organ ranges from 0 to 4, with a total SOFA score ranging from 0 to 24.36 Multiple Organ Dysfunction Score (MODS): The MODS score is an • alternative approach for assessing these 6 organs assessed by SOFA.37 For this study the MODS is used to measure of the number of organs with clinically significant organ dysfunction (range 0 to 6). Similar to the SOFA score, the MODS score also provides a range of categories based on organ function from normal to extreme dysfunction. The cutoff for moderate dysfunction is considered to be clinically significant organ dysfunction. One point is assigned for each clinically significant organ dysfunction using the

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Figure 1-1. Development of Health Care Associated Infections in Sepsis.

Note: This conceptual model incorporates the work of others.4,31-33,35 following criteria for each organ: (A) Cardiovascular failure is defined by systolic blood pressure less than or equal to 90 mmHg which is not responsive to fluids; (B) Pulmonary failure is defined by a PaO2:FiO2 of 300 mmHg or less; (C) Central nervous system failure is defined as a Glascow Coma Score of 12 or less; (D) Coagulation failure is defined as a platelet count of 80,000 or less; (E) Renal failure is defined as a creatinine of 2 mg/dl or less; and (F) Hepatic failure is defined as a total bilirubin of 2 mg/dl or less.37 to fluids; (B) Pulmonary failure is defined by a PaO2:FiO2 of 300 mmHg or less; (C) Central nervous system failure is defined as a Glascow Coma Score of 12 or less; (D) Coagulation failure is defined as a platelet count of 80,000 or less;

(E) Renal failure is defined as a creatinine of 2 mg/dl or less; and (F) Hepatic failure is defined as a total bilirubin of 2 mg/dl or less.37 Infectious insult: Any definitive or suspected infection present at ICU • admission will be described as a baseline infection. Suspected infections were defined clinically by the healthcare team.

Elements of Severity of Illness Severity of illness: An objective measure of each participant’s illness.

• Acute Physiology and Chronic Health Evaluation II (APACHE II): A • commonly used severity of illness classification system designed to capture the worst of 12 physiological variables within the first 24 hours of ICU admission. APACHE II scores range from 0 to 71 with a higher scores associated with a worse outcome.38 APACHE II will be used as a measure of severity of illness in this study.

Elements of Predisposing Factors Predisposing factors: Potential risk factors for development of HAI.

• Invasive Devise: Any artificial device that bypasses the body’s first line of • defense, the integument, is considered an invasive devise. Common invasive devices in this study include endotracheal tubes, tracheostomy tubes, central venous catheters, peripheral venous catheters, arterial catheters, chest tubes, surgical drains, nasal and oral feeding tubes, percutaneous endoscopic gastrostomy tubes, and Foley catheters.

Genetic Predisposition: Increased susceptibility to a disease due to the • presence of one or more gene mutations, and/or a combination of alleles (haplotype), that are associated with an increased risk for the disease.39 In this study, single nucleotide polymorphisms (SNPs) will be used to detect genetic variation among participants.

Single nucleotide polymorphisms (SNPs): A difference in a single DNA • nucleotide which can be measured and may be associated with disease.39 Environmental Exposure: Any potential exposure in a patient’s environment • that could introduce an infection. In this study, environmental exposure includes invasive devices, nurse-patient ratios 2:1, and administration of blood products. Universal precautions are expected to be followed on all subjects and this includes appropriate hand-washing, protective equipment use, and aseptic technique to prevent cross-infections.

Elements of Inflammatory Response Gene Expression: The process of translating genes into a functional protein • product. For the purpose of this study, gene expression will be limited to measurement of cytokine proteins by multiplex bead based assays.

Cytokines: Protein mediators of the inflammatory response.

• Health Care Associated Infections Health care associated infection refers to any infection that occurs after at • least three days of hospitalization which is not a recurrence of the baseline infection.

Specific HAIs are defined by CDC guidelines as described in the methods • section. The operational definition for this study will include NEW HAIs that occur after at least three days of admission to the ICU which are not a recurrence of the baseline ICU infection.

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The following assumptions were made for the purpose of the study:

1. An underlying assumption of this study is that baseline systemic inflammation will be prolonged.

2. HAI will be detected when they occur.

3. Subjects will be classified correctly in analyses based on degree of baseline systemic inflammation and development of HAI.

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This study included the following potential limitations:

1. The usage of corticosteroid therapy may impact the degree and duration of systemic inflammation; thus, potentially limiting the possible impact of systemic inflammation on the development of HAI in participants receiving corticosteroids.

2. The use of corticosteroids may limit fever among participants experiencing HAI, and may result in failure to detect HAI when they occur. It is recommended clinical practice in our ICU to use sepsis surveillance, and thus a high degree of suspicion when steroids are used.

3. There may be predisposing factors for development of HAI that were not measured.

4. Participants receiving mechanical ventilation may have lower DNA yields from buccal swabs due to the presence of a large obtrusive bite block which limited access to swab the inside of the entire cheek as recommended.

5. The investigator is a novice bench researcher, and although efforts were made to accurately follow protocols, it is possible that errors could have influenced results.

6. Endpoint genotyping of the single nucleotide polymorphisms RS1800896 required manual calls in seven samples.

7. Interleukin 6 was selected as a proinflammatory cytokine; however, it does have some anti-inflammatory properties.

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Health care associated infections (HAI) affect more than 2 million persons annually in the US, with approximately 35% occurring in the ICU. A 1999 Institute of Medicine report attributed 44,000-98,000 annual deaths and the associated cost was as high as $29 billion.40 HAIs (or hospital acquired infections) are typically referred to as infections that are not present or incubating at the time of hospital admission. Infections are “considered to be hospital-acquired if they develop at least 48 [hours] after hospital admission without proven prior incubation.”40 Common HAI’s in the ICU are bloodstream infection, pneumonia, and urinary tract infections. Despite standard practices to prevent them, HAIs remain a significant public health care concern.

HAI Incidence and Infection Patterns

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