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(12) Patent Application Publication (10) Pub. No.: US 2014/0037649 A1 Brandon Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0037649 A1 Brandon Et Al US 20140037649A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0037649 A1 Brandon et al. (43) Pub. Date: Feb. 6, 2014 (54) DAGNOSTIC AND/OR SCREENINGAGENTS Publication Classification AND USES THEREFOR (51) Int. Cl. (75) Inventors: Richard Bruce Brandon, Boonah (AU); CI2O I/68 (2006.01) Mervyn Rees Thomas, Chapel Hill (52) U.S. Cl. (AU); Glenn Stone, Glenwood (AU) CPC .................................... CI2O I/6876 (2013.01) USPC ............. 424/164.1; 506/9:435/6.12: 514/1.4 (73) Assignee: IMMUNEXPRESS PTY LTD, TOOWONG (AU) (57) ABSTRACT (21) Appl. No.: 13/989,738 Disclosed are methods and apparatus for diagnosis, detection PCT Filed: Nov. 24, 2011 of host response, monitoring, treatment or management of (22) sepsis, infection-negative systemic inflammatory response (86) syndrome (SIRS) and post-Surgical inflammation in mam mals. More particularly, the present invention discloses S371 (c)(1), marker genes and their splice variant transcripts as well as (2), (4) Date: Oct. 17, 2013 their expression products, which are useful for distinguishing between sepsis and infection-negative SIRS, including post Related U.S. Application Data Surgical inflammation, and to the use of these markers in (60) Provisional application No. 61/417.381, filed on Nov. grading, monitoring, treatment and management of these 26, 2010. conditions. US 2014/0037649 A1 Feb. 6, 2014 DAGNOSTIC AND/OR SCREENINGAGENTS of a circulating pathogen is not necessary to confirm the AND USES THEREFOR diagnosis of sepsis. Severe sepsis includes hypotension and evidence of organ dysfunction. When hypotension cannot be FIELD OF THE INVENTION managed with intravenous fluids, the diagnosis of septic shock is applied (Bone et al., 1992, Chest 101: 1644-55; 0001. This invention relates generally to methods and American College of Chest Physicians/Society of Critical apparatus for diagnosis, detection of host response, monitor Care Medicine Consensus Conference. Definitions of sepsis ing, treatment or management of sepsis, infection-negative and organ failure and guidelines for the use of innovative systemic inflammatory response syndrome (SIRS) and post therapies in sepsis. 1992, Crit Care Med. 20(6):864-874; Surgical inflammation in mammals. More particularly, the Bernard et al., (PROWESS Study Group), 2001, N Engl J present invention relates to marker genes and their splice Med. 344(10):699-709). It was thus recommended at the variant transcripts as well as their expression products that are 1991 Consensus Conference that, when patients are identified useful for distinguishing between sepsis and infection-nega as having SIRS or multiple organ dysfunction syndrome tive SIRS, including post-Surgical inflammation, and to the (MODS), sequential (i.e., daily or more frequently) risk use of these markers in grading, monitoring, treatment and stratification or probability estimate techniques should be management of these conditions. The invention has practical applied to describe the course of the syndrome (Bone et al., use in early diagnosis, diagnosis of mild or Sub-clinical sepsis 1992, supra; American College of Chest Physicians/Society or infection-negative SIRS or post-Surgical inflammation, in of Critical Care Medicine Consensus Conference, 1992, the detection of specific cell immune responses as part of Supra). active or progressive disease, in monitoring clinically 0004 Sepsis is a life-threatening disorder and the leading affected Subjects, and in enabling better treatment and man cause of mortality in the adult intensive care unit (ICU) rang agement decisions to be made in clinically and Sub-clinically ing from between 18-50% (Sundararajan et al., 2005, Crit. affected Subjects. Additionally, the invention has practical use Care Med. 33:71-80: Finfer et al., 2004, Care Med. 30:589 in monitoring and grading patients in critical care or intensive 596: Martin et al., 2003, N Engl J. Med. 348:1546-1554; care units for sepsis or infection-negative SIRS or post-sur Australian Institute of Health & Welfare, Canberra (2006). gical inflammation, and in predicting clinical outcome. Mortality over the twentieth century in Australia. Trends and patterns in major causes of death. Mortality Surveillance BACKGROUND OF THE INVENTION Series, Number 4, p49). In developed countries, the incidence 0002 Systemic Inflammatory Response Syndrome of sepsis is expected to rise due to aging populations, (SIRS) is characterized by fever or hypothermia, leukocytosis immune-compromised patients (e.g., patients on chemo or leukopenia, tachypnea and tachycardia. SIRS may have an therapy, or have had a transplant or are on chronic corticos infectious or non-infectious etiology and is described in asso teroids), increasing longevity of patients with chronic dis ciation with critical conditions that include pancreatitis, eases, antimicrobial resistance, especially in younger people, ischemia, multi-trauma and severe tissue injury. Major open as well as viral illnesses such as AIDS. Surgery is a controlled form of physical insult that results in 0005 Antimicrobial resistance is becoming a significant varying degrees of systemic inflammation. In fact, it has been problem in critical care patient management, particularly reported that the occurrence of SIRS following cardiac with Gram-negative bacilli (Hotchkiss and Donaldson. 2006, bypass surgery (Chello et al., 2006, Critical Care Medicine Nature Reviews Immunology 6:813-822; Eber et al., 2010, 34(3):660-667), open abdominal aortic repair (Brown et al., Arch Intern Med. 170(4):374-353). Recent evidence suggests 2003, Journal of Vascular Surgery 37(3):600-606) and open that indiscriminate use of antibiotics has contributed to resis colorectal resection (Haga et al., 1997, Critical Care Medi tance and hence, guidance on antibiotic treatment duration is cine 25(12): 1994-2000) is very common, as well as a major now imperative in order to reduce consumption in tertiary cause of postoperative complications including death. Pub care ICU settings (Hanberger et al., 1999, JAMA. 281:61-71). lished findings by Michalopoulos and colleagues indicate 0006. Approximately 20 million cases of severe sepsis 100% of cardiac surgical patients (n=2615; mean age 60.8.7 arise globally per annum, and account for up to 135,000 yrs) in their unit develop SIRS during the first 12 hours of deaths in Europe and 215,000 in the USA (Neuhauser et al., post-operative care (Michalopoulos et al., 2005, Intensive 2003, JAMA. 289:885-888). Care Medicine 22(1):S134). Recent research has suggested 0007 While half of these infections are estimated to be that because of the amount of cellular damage (necrosis) from community-acquired in the United States, research Suggests major physical injury and trauma, mitochondrial proteins are that the other half relate to hospital acquired infections (HAI), released into circulation and stimulate damage-associated which account for increased hospital in-patient admission by molecular patterns (DAMPs). This is significant as mitochon as much as 14 days, at an average cost of $46,000 per patient dria are cellular organelles which were originally derived (Goldmann et al., 1996, JAMA. 275:234-40). Bacterial and from bacteria via a process known as evolutionary endosym fungal sepsis is a significant medical challenge not only in biosis. It is these DAMPS that stimulate an acute phase critical care but also for hematology, transplant, medical response by the innate immune system that is biologically oncology and post-Surgical in-patients. concordant with pathogen-associated molecular patterns 0008 Sepsis initiates a complex immunologic response (PAMPs) released during infection (Zhang et al., 2010, that varies over time and is dependent on pre-existing co Nature 464:104-107). morbidities. Although recent research demonstrates that both 0003) If infection is suspected in addition to the any of the inflammatory and anti-inflammatory responses are occurring above SIRS clinical presentations, the term sepsis is applied. in this condition, during the early host response to microbial Sepsis can be defined as a systemic inflammatory response to invasion, there is generally a hyperinflammatory signal. That infection; typically a Gram negative or Gram positive bacte is, the majority of the sepsis cases are the product of bacteria rial or fungal infection. However, microbiological evidence and fungi that do not ordinarily cause systemic disease in US 2014/0037649 A1 Feb. 6, 2014 immunocompetent hosts. The local innate immune mecha function is not compromised. Differential diagnosis is expo nisms essentially stimulate the release of cytokines, chemok nentially more difficult when a patient presents to the Emer ines, prostanoids and leukotrienes that increase blood flow to gency Department with clinically significant changes to vital local sources of infection and result in an influx of white signs such as heart rate and blood pressure in addition to a blood cells. During this processes, toll-like receptors (TLRs) fever. These are signs and symptoms of the early stages of are also activated as part of the innate immune response and infection-negative SIRS and infection-positive SIRS (sepsis), have direct anti-microbial activity in addition to influencing and impossible to delineate the two conditions clinically. the antigen-specific adaptive response. TLRs are a type of However, although the two conditions can be separated based pattern recognition receptor that can identify PAMPs as soon on physiological endpoints, the molecular
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