Methods for detecting sepsis using vital signs including systolic blood pressure, blood parameters, and combinations thereof

Abstract

The use of vital sign measurements (e.g., systolic blood pressure (SBP)) when combined with blood parameters (e.g., white blood cell count (WBC) and monocyte distribution width (MDW)) has been identified as an improved method for detecting sepsis. The probability of having or developing sepsis is determined when each measurement is compared to a predetermined standard, and the combination of measurements that are within the reference range determines this probability. According to a first aspect, some embodiments may provide a method for assessing the probability that a patient will develop sepsis. In some embodiments, such a method may include receiving, in a data processing system, measurements including white blood cell count (WBC), monocyte distribution width (MDW), and one or more vital signs.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is related to and claims the benefit of Provisional Application No. 62 / 873,651, entitled "Method of detecting sepsis using vital signs, including systolic blood pressure, hematology parameters, and combinations thereof," filed in the U.S. Patent and Trademark Office on July 12, 2019, and Provisional Application No. 62 / 927,835, entitled "Method of detecting sepsis using vital signs, including systolic blood pressure, hematology parameters, and combinations thereof," filed in the U.S. Patent and Trademark Office on October 30, 2019. This application is related to the subject matter of PCT Patent Application No. PCT / US17 / 14708, filed January 24, 2017, entitled "Infection Detection and Differentiation Systems and Methods," which claims the benefit of U.S. Provisional Patent Application No. 62 / 288,091, filed January 28, 2016, entitled "Infection Detection and Differentiation Systems and Methods." This application is also related to U.S. Provisional Patent Application No. 62 / 660,795, filed April 20, 2018, entitled "Sepsis Infection Detection Systems and Methods."

[0002] Field The present disclosure relates to a method for detecting infections (including infections that result in sepsis) by using vital signs in combination with parameters measured by a blood analyzer. It has been found that measuring systolic blood pressure, alone or in combination with additional blood parameters, improves sepsis prediction accuracy. [Background technology]

[0003] background Sepsis is a systemic inflammatory response to infection that can rapidly spiral down into a life-threatening condition. Patient mortality increases by 8% for each hour that passes without diagnosis and treatment. In the past, diagnosis of sepsis has been hampered by the lack of a clear definition and a timely and accurate diagnosis. Sepsis is now the number one cause of hospitalization costs and the third leading cause of death in the United States alone.

[0004] In 1992, the first definition of sepsis was published. In this definition, the systemic inflammatory response syndrome (SIRS) was proposed to define the condition. SIRS occurs when two or more of the following criteria are met: body temperature above 38°C or below 36°C, a heart rate above 90 beats per minute (bpm), a respiratory rate above 20 breaths per minute (breaths / min), or a count of 4,000 cells per μL of blood (4,000 / mm 3 ) (leukopenia) or 12,000 / mm 3White blood cell count (WBC) above (leukocytosis). At that time, sepsis was defined as a condition that occurs when two or more SIRS criteria are met and infection persists in the body. However, the state of sepsis is still not fully understood, and this definition has since changed. In 2016, this definition "sepsis-2" was updated and is now called "sepsis-3", which includes organ dysfunction. Instead of SIRS, "sequential organ failure assessment" (SOFA) was proposed, which is often first evaluated by rapid SOFA (qSOFA) due to its broadness. In the hospital setting, rapid sequential organ failure assessment is performed first. If qSOFA indicates that the patient is at risk for sepsis, a full SOFA test can be performed.

[0005] Like SIRS, qSOFA also evaluates the patient's vital signs. With a sensitivity of around 84%, SIRS is much more sensitive than qSOFA, which has a sensitivity of 49%. However, at 79%, qSOFA is much more specific for sepsis than SIRS, which has a specificity of around 35%. Despite its high sensitivity, SIRS has still been shown to miss around 12.5% ​​of patients (1 in 8) with sepsis who do not test positive for at least two SIRS criteria. Neither qSOFA nor SIRS perform well enough to consistently help healthcare professionals identify sepsis early and without waiting for any test results. Furthermore, if the patient does not display signs of inflammation, it may not be obvious to utilize these criteria. This is crucial because these signs may not be present for several critical hours.

[0006] Biomarkers (e.g., procalcitonin (PCT) and C-reactive protein (CRP)) have been previously identified as another tool that may indicate sepsis, but such biomarkers still lack the specificity and sensitivity to detect all sepsis cases. PCT is widely considered the most reliable of these biomarkers, with a sensitivity and specificity of approximately 75% and 79%, respectively, but it can still produce both false-positive and false-negative results. Furthermore, PCT cannot robustly distinguish sepsis from non-infectious cases. PCT is further hindered by cost, and testing is only ordered by clinicians when the patient is already displaying signs of inflammation. A significant delay can occur before the patient displays signs of inflammation, especially in certain infections where organ dysfunction does not result in a host systemic response. These factors hinder the use of PCT for early diagnosis of sepsis, and patients can become life-threatening before testing is ordered.

[0007] Although an elevated WBC is commonly associated with bacterial infection, it has been shown that a significant patient population does not exhibit this change, thus missing a significant number of at-risk patients. Furthermore, elevated WBC is associated with a variety of other conditions (e.g., trauma or severe burns), so WBC alone is not useful in diagnosing sepsis. Other tests, including complete blood count with differential (CBC-diff), serum lactate, erythrocyte sedimentation rate (ESR), and bacterial cultures, have also been used in the past to diagnose sepsis, but similarly lack sufficient specificity and sensitivity, and may be further hampered by the high cost or length of time it takes to complete these tests.

[0008] More recently, an additional blood analyzer parameter, monocyte distribution width (MDW), has been shown to indicate sepsis (sensitivity and specificity 74% and 72%, respectively), especially when combined with other measurements associated with infection (e.g., WBC). The use of this tool is particularly advantageous because this value is measured on all patient samples, and therefore these blood parameters can be useful in detecting sepsis even before the patient displays signs of inflammation. However, there remains a need to improve the specificity and sensitivity of tests for sepsis to further reduce the number of patients who experience delays in diagnosis and treatment.

[0009] For these and other reasons, improved methods and systems for identifying infection and sepsis are desirable. Summary of the Invention [Means for solving the problem]

[0010] A brief summary In the past, the assessment of sepsis, or the probability of developing sepsis, has been hindered by the lack of clear criteria and timely diagnostic tools with acceptable sensitivity and specificity. In addition to SIRS criteria and various biomarkers, sepsis can be assessed in part by assessing MDW measured from blood samples. Exemplary methods are disclosed, for example, in PCT patent application number PCT / US17 / 14708 and US Provisional Patent Application No. 62 / 660,795. An embodiment of the present disclosure can improve the predictive ability of MDW through the combination of WBC and vital signs. The system for assessing infection status can include any of the methods described herein.

[0011] According to a first aspect, some embodiments may provide a method of assessing a probability that a patient will develop sepsis. In some embodiments, such a method may include receiving, in a data processing system, measurements including a white blood cell count (WBC), a monocyte distribution width (MDW), and one or more vital signs. In some embodiments, such a method may include the data processing system processing the received measurements to (i) determine whether each measurement meets a corresponding predetermined criterion, and (ii) assign a probability that the patient will develop sepsis.

[0012] According to a second aspect, in some embodiments according to the first aspect, the patient may be assigned a risk of developing sepsis for each of two or more measurements, including at least one of the one or more vital signs: (a) if the corresponding predetermined criteria for that measurement is within a predetermined range; and (b) if the measurement is within its corresponding predetermined range.

[0013] According to a third aspect, in some embodiments according to either the first or second aspect, the one or more vital signs may include blood pressure.

[0014] According to a fourth aspect, in some embodiments according to any of the first to third aspects, the one or more vital signs may include systolic blood pressure (SBC).

[0015] According to a fifth aspect, in some embodiments according to the fourth aspect, the predetermined standard for SBP may be a value of about 100 mmHg or less.

[0016] According to a sixth aspect, in some embodiments according to any of the first to fifth aspects, at least one measurement may be received from an electronic medical record and at least one measurement may be received from an analyzer.

[0017] According to a seventh aspect, in some embodiments according to any of the first to sixth aspects, the predetermined criterion for the MDW may be a value greater than 20.0 channels.

[0018] According to an eighth aspect, in some embodiments according to the first to seventh aspects, the predetermined WBC threshold is about 4.0×10 3 / μL or less than 12.0 × 10 3 / μL.

[0019] According to a ninth aspect, in some embodiments according to the first to seventh aspects, the predetermined WBC threshold is about 5.0×10 3 / μL or less than 10.0 × 10 3 / μL.

[0020] According to a tenth aspect, in some embodiments according to the first to ninth aspects, at least one of the one or more vital signs may be a SIRS or qSOFA vital sign measurement.

[0021] According to an eleventh aspect, in some embodiments according to any of the first to tenth aspects, at least one of the predetermined criteria may be a SIRS or qSOFA vital signs criterion.

[0022] According to a twelfth aspect, in some embodiments according to the first to eleventh aspects, the measurement may be a measurement taken within 12 hours of patient presentation.

[0023] According to a thirteenth aspect, in some embodiments according to the first to eleventh aspects, the measurements may include values ​​taken 12 hours or more after patient presentation.

[0024] According to a fourteenth aspect, some embodiments may provide a computer-readable medium having instructions operable, when executed, to cause a data processing system to perform the method of any of the first to thirteenth aspects.

[0025] According to a fifteenth aspect, some embodiments may provide a data processing system configured with instructions to cause it to perform the method of any of the first to thirteenth aspects. According to certain aspects, for example, the following items are provided: (Item 1) 1. A method for assessing the likelihood that a patient will develop sepsis, the method comprising: a. receiving in a data processing system measurements including white blood cell count (WBC), monocyte distribution width (MDW), and one or more vital signs; and b. the data processing system processes the received measurements to (i) determine whether each measurement meets a corresponding predetermined criterion, and (ii) assign a probability that the patient will develop sepsis; The method includes: (Item 2) For each of two or more measurements, the patient may measure at least one of the one or more vital signs. a. the corresponding predetermined criterion for that measurement is within a predetermined range; and b. If the measured value is within its corresponding prescribed range, 2. The method according to item 1, wherein a risk of developing sepsis is assigned to the individual. (Item 3) 3. The method according to any of items 1 to 2, wherein the one or more vital signs comprises blood pressure. (Item 4) 4. The method according to any of items 1 to 3, wherein the one or more vital signs comprises systolic blood pressure (SBP). (Item 5) 5. The method according to item 4, wherein the predetermined standard for SBP is less than or equal to about 100 mmHg. (Item 6) 6. The method of any of items 1 to 5, wherein at least one measurement is received from an electronic medical record and at least one measurement is received from an analyzer. (Item 7) 7. The method according to any one of items 1 to 6, wherein the predetermined criterion for MDW is a value greater than 20.0 channels. (Item 8) The predetermined standard for the WBC is about 4.0×10 3 / μL or less than 12.0 × 10 3 8. The method according to any one of items 1 to 7, wherein the value is greater than 1 / μL. (Item 9) The predetermined standard for WBC is about 5.0×10 3 / μL or less than 10.0 × 10 3 8. The method according to any one of items 1 to 7, wherein the value is greater than 1 / μL. (Item 10) 10. The method according to any of items 1 to 9, wherein at least one of the one or more vital signs is a SIRS or qSOFA vital sign measurement. (Item 11) 11. The method according to any of items 1 to 10, wherein at least one of the predetermined criteria is a SIRS or qSOFA vital signs criterion. (Item 12) 12. The method according to any of items 1 to 11, wherein the measurements are taken within 12 hours of patient presentation. (Item 13) 12. The method of any of items 1 to 11, wherein the measured value comprises a value taken 12 hours or more after patient presentation. (Item 14) A computer readable medium having instructions operable, when executed, to cause a data processing system to perform the method according to any one of items 1 to 13. (Item 15) 14. A data processing system configured with instructions to perform the method according to any one of items 1 to 13. [Brief description of the drawings]

[0026] [Figure 1] FIG. 1 provides a simplified block diagram of an exemplary infection detection method according to an embodiment of the present disclosure.

[0027] [Diagram 2] FIG. 2 provides a flow chart of an exemplary hematology analyzer process.

[0028] [Figure 3-1] 3A-3D provide charts illustrating the additive improvement of MDW to early sepsis detection when combined with each SIRS vital sign criterion and certain combinations of SIRS vital sign criteria. [Figure 3-2] 3A-3D provide charts illustrating the additive improvement of MDW to early sepsis detection when combined with each SIRS vital sign criterion and certain combinations of SIRS vital sign criteria.

[0029] [Figure 4] 4A-4B provide charts illustrating the additive improvement of MDW to early sepsis detection when combined with the qSOFA vital sign criteria of altered mental state and blood pressure.

[0030] [Diagram 5] FIG. 5 provides a chart illustrating the improvement in sepsis detection when incorporating MDW, including when WBC is normal. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] Detailed Description Sepsis is a systemic inflammatory response to infection that can become life-threatening. Sepsis occurs when the body's response to infection goes out of balance, and chemicals released into the bloodstream to fight infection cause inflammation and severe damage to the body's own tissues and organs. In most severe cases, this can lead to septic shock (now also called "sepsis-3"), where circulatory and cellular damage rapidly increases mortality.

[0032] Sepsis is a complex condition that is constantly being redefined. In 2016, the Third International Consensus Definitions of Sepsis and Sepsis were redefined. Due to insufficient specificity and sensitivity, SIRS has been replaced by SOFA, which, due to its broadness, is initially assessed by the qSOFA score. qSOFA is scored on a scale of 0 to 3 points, with 1 point for each vital sign that is positive on the test. These qSOFA vital sign criteria are respiratory rate ≥ 22 breaths / min, systolic arterial blood pressure less than or equal to 100 / mmHg, and altered state of consciousness (Glasgow Coma Scale score less than 15). It has been determined that patients with a qSOFA score of at least 2 have a 24% in-hospital mortality rate, and for patients with a qSOFA score less than 2, it is 3%. Typically, if the qSOFA score is at least 2, patients are evaluated with a full SOFA test. The SOFA test is scored on a scale of 0 to 24 and involves evaluating specific organ systems (respiratory, cardiovascular, hepatic, renal, coagulation, and central nervous systems). If the SOFA score is also greater than or equal to 2, the patient is considered septic.

[0033] Although initially meant to be an early detection method rather than a replacement for SIRS, the use of qSOFA has generally been an improvement over the SIRS criteria. SIRS (developed in 1991) has high sensitivity but very low specificity. The SIRS criteria (which may also be referred to as SIRS vital sign criteria or SIRS vital sign measurements) are a temperature greater than 38°C (fever) or less than 36°C (hypothermia), a heart rate greater than 90 beats per minute (tachycardia), a respiratory rate greater than 20 breaths per minute (tachypnea), and 4,000 cells per microliter of blood (4,000 / mm 3 ) (leukopenia) or 12,000 / mm 3 Hyper(leukocytosis) WBC. Previous studies have shown that approximately 75% of patients presenting to the emergency department (ED) with suspected infection showed at least two SIRS points, but very few had severe organ dysfunction. Similarly, other studies have reported that 68-93% of patients admitted to the ICU generally had at least two elements of SIRS. This indicates that having two or more elements of SIRS does not adequately distinguish organ dysfunction. This is thought to be broad due to the fact that changes in temperature, heart rate, respiratory rate, or WBC are representative of the body's response to many infections and illnesses, and not necessarily the response of a life-threatening organ failure or dysregulated body. Despite this high sensitivity, one in eight septic patients still did not test positive for sepsis by SIRS criteria.

[0034] Although qSOFA may be an improvement over SIRS criteria, the American Medical Association (AMA) noted that there are still significant shortcomings. The qSOFA was developed for patients already suspected of having an infection, which means that it is not meant to be a warning that can distinguish between patients with and without infection, but rather is defined to identify patients who are most likely to die. The qSOFA score is not sensitive enough for early sepsis indication, but rather serves to identify the sickest and most at higher risk of mortality. Secondly, the altered state of consciousness (which may be referred to as AMS or sepsis-associated delirium (SAD)) is a subjective measurement and may vary clinically. Finally, qSOFA does not include any blood measurements (e.g., WBC) that have previously been shown to be effective for screening for sepsis.

[0035] The present disclosure relates to methods for detecting infections (including infections resulting in sepsis) by using vital signs in combination with parameters measured by a blood analyzer. Measuring the vital sign systolic blood pressure (SBP) has been found to improve sepsis prediction accuracy, especially when combined with parameters measured by a blood analyzer. Other qSOFA or SIRS vital sign measurements, when combined with abnormal MDW and WBC, have also been found to improve sepsis detection, including altered state of consciousness, body temperature, heart rate, respiratory rate, and combinations of these criteria (e.g., heart rate and respiratory rate). Furthermore, the benefits of these methods have been observed using only vital sign measurements collected in the early stages of patient triage, beginning within the first few hours of symptom presentation. This includes measurements taken anywhere from the first 0-12 hours of symptom presentation. Further benefits may be achieved by including measurements taken beyond the first 12 hours of symptom presentation. The patient may present with symptoms in any healthcare setting, including, for example, a hospital ED, an emergency vehicle, an emergency center, an in-hospital nursing facility, an outpatient nursing facility, a hospice home, a specialist clinic, a long-term patient care facility, a senior home, a rehabilitation center, an urgent care clinic, telemedicine, or a specialist treatment center.

[0036] FIG. 1 illustrates a schematic diagram of an embodiment 100 of an infection detection method according to the present disclosure. In this embodiment, a patient's vital signs may be measured and recorded in an EMR 101, and a blood sample may be obtained 102. The blood sample may then be processed by a blood analyzer 103. The vital signs and blood sample measurements may be entered into a laboratory information system (LIS) for processing, either manually or automatically 104. These measurements may be obtained by the LIS from the patient record (e.g., an electronic medical record (EMR)) or from laboratory equipment (otherwise referred to as an analyzer). These measurements may be obtained during early patient triage. Early patient triage may be defined by the first measurement of the patient's vital signs by a trained professional and may include the first 0-12 hours of patient presentation. Patient presentation of symptoms occurs upon the patient's arrival at the healthcare setting and may be noted by the time the patient is administratively registered, or, in an emergency, the time the patient is triaged. Patient presentation may also refer to when a patient is referred to a trained professional in a medical setting. A medical setting may include a hospital ED, an emergency vehicle, an emergency medical center, an in-hospital nursing facility, an outpatient nursing facility, a hospice home, a specialist clinic, a long-term patient care facility, a senior home, a rehabilitation center, an urgent care clinic, a telemedicine, or a specialist treatment center. A trained professional may include a doctor, a nurse, a therapist, a physician assistant, a hospice worker, an emergency medical technician, and any other trained caregiver. In the examples disclosed herein, the first measurement of vital signs by a trained professional was performed, on average, within 2 hours after being referred to a nurse in the ED. The blood sample measurements may include WBC and MDW. The vital sign measurements may include any SIRS or qSOFA vital sign measurements. The vital sign measurements may include a blood pressure measurement. In some aspects, the LIS includes a processor and a non-transitory computer-readable storage medium.The computer readable medium may be programmed with an application that causes the processor to evaluate the input measurements to determine whether each measurement meets a predetermined criterion based on an algorithm 105. Based on the predetermined criteria being met for the input measurements, a probability that the patient will develop sepsis may be determined 106. The predetermined criteria for these measurements may be ranges of values ​​that are considered abnormal for a healthy adult and are predicted, alone or in combination with other measurements, to be developing sepsis.

[0037] As stated, these measurements may be extracted from the EMR by the LIS. The EMR is a real-time comprehensive collection of patient data including medical history, physician notes, diagnoses, medications, allergies, immunology, laboratory test results, and vital signs. The LIS is a software system that stores, processes, and manages laboratory analytical instrument data and patient information, including patient sample measurements. Laboratory test results obtained from a patient's biological sample (e.g., WBC and MDW) may also be entered into the LIS manually by a laboratory professional or directly from the analyzer. The analyzer is a clinical diagnostic instrument that may measure one or more anatomical or physiological characteristics of a sample, including: metabolic measurements (also referred to as blood chemistry); cell counts; viral protein, viral gene, or microbial cell measurements; urinalysis; genomic characterization; or immunological measurements. FIG. 2 illustrates a schematic of an exemplary blood analyzer process 200. In this embodiment, a patient's blood sample may be sent to the analyzer 201. At this point, the analyzer may prepare the sample for analysis. Once the sample preparation is complete 202, the sample may be passed through a conductivity measurement module 203 and through a light scattering module 204. The sample measurements may then be evaluated by a data processing module 205, and once completed, the measurements may be displayed by a reporting module 206.

[0038] As stated, embodiments of the present disclosure may improve the predictive ability of MDW through combination with WBC and vital signs. This may be accomplished by evaluating these measurements against predefined criteria, which may be a range of values ​​considered abnormal for a healthy adult. In some aspects, an abnormal WBC count is greater than 4,000 / mm 3 (4.0×10 3 / μL) or less than 12,000 / mm 3 (12.0×10 3 / μL) is equivalent to SIRS criteria. In some aspects, an abnormal WBC count is approximately 5,000 / mm 3 Less than and about 10,000 / mm 3 In some aspects, abnormal MDW may be greater than 20.0 channels. In some aspects, abnormal SBP may be less than or equal to 100mmHg. Notably, this differs from the standard medical definition of hypotension, which is less than or equal to 90mmHg. Those skilled in the art will understand that these cutoffs may be modified, for example, to address specific patient subpopulations (e.g., cancer patients, pediatric patients, etc.), or to modify the sensitivity and / or specificity of the test (e.g., by opening the range to be more inclusive, or further restricting the range to be more exclusive).

[0039] In the hospital setting, there are four measurements (referred to as vital signs) routinely monitored by medical professionals. Vital signs are typically recorded during any visit, but particularly during ED triage, which is used to identify the patient's level of urgency and treatment pathway. These measurements are temperature, pulse rate, respiratory rate, and blood pressure. Temperature can be measured in a number of different ways, including orally, rectally, under the arm (arm), ear, or on the skin. Normal body temperature in a healthy adult is considered to be any temperature within the range of 97.8 degrees Fahrenheit to 99.1 degrees Fahrenheit, with an average value of 98.6 degrees Fahrenheit, although this is highly variable with respect to condition information such as measurement method, location, or time. Higher than normal body temperature is referred to as hyperthermia or fever, and lower than normal body temperature is referred to as hypothermia.

[0040] "Pulse rate" or "heart rate" is a measurement of the number of times the heart beats in one minute. It can be measured by a variety of machines or by a person pressing their fingertips against either the patient's neck or wrist and counting the number of beats per unit of time. Normal pulse rates for healthy adults range from 60 to 100 beats per minute.

[0041] Respiratory rate is the number of breaths a person takes in one minute. This measurement may be taken by counting the number of breaths a patient takes per unit of time. The normal respiratory rate for a healthy adult is between 12 and 16 breaths per minute.

[0042] Blood pressure is a measurement of the pressure that results from blood pushing against the arterial walls. Blood pressure is recorded as two numbers, often in millimeters of mercury (mmHg). The first number is typically the systolic pressure, the pressure in the arteries that results from the heart contracting and pumping blood into the arteries. The second number is typically the diastolic pressure, the pressure in the arteries when the heart relaxes and refills with blood between contractions. Blood pressure can be approximated through non-invasive measurements using an instrument called a sphygmomanometer, in which an inflatable cuff is placed around the arm. The cuff is inflated until circulation in the patient's arm is reduced. At this point, the air is slowly released and the person measuring blood pressure will listen with a stethoscope to the blood moving through the patient's arteries. The first sound heard corresponds to the systolic blood pressure (SBP), and the point at which this sound disappears coincides with the diastolic blood pressure. Blood pressure can also be measured non-invasively by other means, including automated instruments. More accurate determinations of blood pressure can be obtained invasively through catheter-type measuring devices that can be inserted into various parts of the cardiovascular system. The average blood pressure measurement for a healthy adult is considered to be 120 / 80 mmHg. Low blood pressure ("hypotension") is a reading of 90 / 60 mmHg or lower. High blood pressure ("hypertension") is a reading of 140 / 90 mmHg or higher.

[0043] Other vital signs are also recognized in the medical field, including: pain (measured on a pain scale of 0 to 10), oxygen saturation (measured by pulse oximetry), blood glucose levels (measured in mmol / L), menstrual cycle indications (e.g., length and regularity), end-tidal carbon dioxide pressure (ETCO2) (measured as a percentage of CO2 or in mmHg), gait speed (measured in meters / second), altered state of consciousness, or delirium (which can be measured by several different rating scales, including the Glasgow Coma Scale (GCS), which can range in scores from 3 to 15).

[0044] For the calculation of qSOFA, altered states of consciousness are measured by the GCS, a scoring system used to assess a patient's level of consciousness. The GCS is measured on a 15-point scale based on criteria of eye opening, speech, and movement, where low scores are associated with the most severe brain dysfunction. Eye opening response is scored from 1 to 4, where no eye opening is given a score of 1 and spontaneous eye opening response is given a score of 4. Speech response is measured from 1 to 5, from no speech response (1) to an oriented speech response (5). Motor response is measured from 1 to 6, from no motor response (1) to following commands (6). A GCS score of 8 or less is associated with severe brain dysfunction or injury, a GCS score of 9 to 12 is associated with moderate brain dysfunction or injury, a GCS score of 13 to 14 is associated with mild brain dysfunction or injury, and a score of 15 is considered normal. qSOFA criteria for altered states of consciousness include any GCS score less than 15.

[0045] "Patient" may refer to any individual currently receiving medical care, in need of medical care, waiting to receive medical care, or already receiving medical care. "Patient" does not necessarily mean that the individual is suffering from any condition and may include individuals undergoing routine medical checkups. Patient refers to individuals in hospital settings, long-term care facilities, nursing homes, emergency vehicles, home care settings, urgent care facilities, and anywhere a person may receive medical attention from trained professionals. Trained professionals may include physicians, nurses, therapists, clinical assistants, hospice personnel, paramedics, and any other trained caregivers. Patients admitted to hospitals for less than 24 hours may also be referred to as "outpatients," while those who stay in hospitals for more than 24 hours may be referred to as "inpatients."

[0046] Patient information is typically stored in a patient medical record, or EMR (also referred to as an EHR). This information may include SIRS measurements, qSOFA measurements, and vital signs recorded during ED triage. The EMR may collect this information directly from medical devices, or measurements may be manually entered into the EMR by a medical professional.

[0047] WBC is a test that measures the number of white blood cells (also called leukocytes) in a patient's body. These cells are important for fighting infection in the body, and an increased WBC count can indicate an infection, or in some cases, other underlying conditions in the body before the patient presents with clinical symptoms or when the patient presents with vague clinical symptoms. A normal WBC count in a healthy adult is 100% in one microliter (μl or mcL) or cubic milliliter (mm 3 ), which differs from the normal count defined by the SIRS criteria (4,000-12,000 WBC / mcL).

[0048] White blood cell subtypes can be measured as differentials (CBC-diff), with each subtype within a representative percentage of total WBCs: neutrophils (55-73%), lymphocytes (20-40%), eosinophils (1-4%), monocytes (2-8%), and basophils (0.5-1%).

[0049] Measuring a patient's WBC may require a blood draw (otherwise known as venipuncture). This procedure, often performed by a phlebotomist, involves inserting a thin needle into the patient's vein and collecting blood in a 3-10 mL tube. The blood tube may then be transferred to an automated instrument that analyzes the sample to determine the white blood cell count. An embodiment of this is shown in FIG. 2. In an automated embodiment, it is possible to obtain detailed morphological information about the blood cells (e.g., volume and size) in addition to the percentage of each white blood cell type. This automated measurement may be based on direct current (DC) impedance measured from cells in the blood sample. This traditional method, also known as the Coulter principle, is accomplished by the analyzer through passing an electric current through the blood sample and measuring the number of individual cells based on the change in impedance resulting from the cells passing through a measurement module. Another automated method is the laser flow cytometry system, which transmits light through the blood sample. One or more absorption signals are measured, and the resulting light scattering is measured at different angles to determine cell morphology. Another method is fluorescent flow cytometry, which works like flow cytometry but with the addition of fluorescent reagents and has the broad ability to measure more specific cell populations and more specific morphological information (e.g., nucleus-to-plasma ratio of certain cells). Imaging methods are another method and include a camera that can automatically collect images of stained cells and, using image processing and pattern recognition techniques, automatically classify the cells or present detailed cell images to an expert for review. Cell counts and morphological information can also be measured manually by a medical professional by transferring a blood sample to a microscope slide, staining the slide, and performing a visual morphological evaluation and cell count. This process involves placing a drop of blood on a slide and using a "spreader slide" to spread the blood across the slide so that the blood cells are far enough apart to be manually fractionated.Once the blood (also called a blood smear) is fixed on the slide, it may be stained, typically through immersion in methanol. Routine blood analysis is typically performed on blood smears stained with Romanowsky stain, which allows for detection of cell types and morphology.

[0050] MDW is the standard deviation of monocyte volume. Monocytes are a type of white blood cell. Monocyte volume measurements can be determined by passing an electric current through a blood sample and measuring the volume of individual cells passing through a measurement module based on measuring the amplitude of the resulting impedance measurement. This volume can also be measured by a system that transmits light through a blood sample and measures the resulting light scatter to determine cell volume. Methods of detecting the presence of sepsis and / or SIRS using WBC population data (including MDW) are described, for example, in U.S. Provisional Patent Application No. 62 / 288,091, filed January 28, 2016; PCT Application No. PCT / US2017 / 014708, filed January 24, 2017; and Park, D.-H., "Screening of sepsis using leukocyte cell population data from the Coulter automatic blood cell analyzer DxH800," Int. Jnl. 15 Lab. Hem., 2011, 33, 391-399, the entire contents of which are incorporated by reference for all purposes.

[0051] The analyzer information may be stored directly on the analyzer's software system or may be collected by the LIS. The LIS is a software-based laboratory information management system that involves inputting, processing, and storing various information from analyzers and patient information throughout the laboratory. This includes processing and storing patient sample measurements (e.g., MDW or WBC). The LIS may also gather patient information from the EMR (e.g., vital sign measurements) and completed patient sample measurements from the analyzer. This information may be combined with information in the LIS. It may be analyzed by the software to make a disease state prediction. This analysis may be performed by evaluating whether selected measurements meet predefined criteria. Based on which predefined criteria are met for the input measurements, the probability of the patient developing sepsis may be determined. A predictive report or alert may be sent to medical professionals so that they may determine how to best treat the patient. EXAMPLES

[0052] The presently disclosed embodiments were tested on 2158 adult subjects aged 18-89 years who had a CBC with differential ordered upon presentation to the ED with symptoms, were tested for SIRS and qSOFA criteria, and were hospitalized for at least 12 hours. Vital signs and blood measurements associated with these patients were taken during early ED triage within the first 12 hours of symptom presentation. Table 1 shows the observed laboratory values ​​and the predefined ranges used to evaluate whether the patient's measurements were normal or abnormal. WBC data was obtained from SIRS testing, and the normal ranges referred to herein are consistent with the SIRS criteria definitions. Table 1. Predefined ranges for MDW, WBC, and SBP that determine whether a value is "normal" or "abnormal" [Table 1]

[0053] Table 2A shows the positive likelihood ratio (LR+) and post-test probability of sepsis based on whether MDW and WBC values ​​were within a given range. Likelihood ratios are used in diagnostic testing to evaluate the value of performing a given test. LR+ evaluates the ratio of sensitivity to specificity (sensitivity / 1-specificity), and the result indicates the probability that the test result is accurate. For further definitions, sensitivity is the ratio of TP to the sum of TP and false negative (FN) results combined (TP / TP+FN). Specificity is the ratio of true negative results (TN) to the sum of TN and FP results combined (TN / TN+FP).

[0054] LR scores range from zero to infinity. The higher the score, the higher the probability that a person has a condition. A value equal to 10 indicates that the patient is 10 times more likely to have the condition than not have it. Values ​​between 0 and 1 indicate diminishing evidence for the disease; that is, the closer to zero, the less likely the patient is to have a given condition. A value equal to 1 is of no diagnostic value. Clinically, values ​​between 1 and 2 indicate a minimal increase in the likelihood of disease, values ​​between 2 and 5 indicate a small increase in the likelihood of disease, values ​​between 5 and 10 mean a moderate increase in the likelihood of disease, and values ​​greater than 10 mean a large, and often definitive, increase in the likelihood of disease.

[0055] Table 2A shows that patients with both normal WBC and MDW are less likely to have sepsis, which is supported by the low LR+ and post-test probability of 2.83%. In this example, the initial (pre-test) sepsis prevalence was 17.8% as determined by an embodiment of the present disclosure. By evaluating MDW and WBC together, the test provided a sepsis probability assessment of 64% and an LR+ of 8.21 when patients displayed abnormal MDW and WBC values. Table 2B shows the detailed results, including the LR+ confidence interval. Table 2A. Diagnostic statistics for determining sepsis using MDW and WBC [Table 2A] Table 2B. Diagnostic statistics for determining sepsis using MDW and WBC, including LR+ confidence intervals and detailed data. [Table 2B]

[0056] Table 3A shows the diagnostic statistics when evaluating SBP in addition to MDW and WBC. When abnormal SBP (≦100 mmHg) was included, the post-test probability of sepsis increased to 76% and the LR+ increased to 14.74. This represents a large, and often definitive, increase in the likelihood of disease. Combining abnormal SBP and WBC measurements was an improvement over combining abnormal WBC and MDW alone. In this case, there was an increase in the post-test probability from 62% to 67%, and both LR+ scores represented a moderate increase in the likelihood of disease, but there was an increase from 7.55 to 9.21. Table 3B shows the detailed results, including the LR+ confidence intervals. Table 3A. Diagnostic statistics for determining sepsis using MDW, WBC, and SBP vs. SIRS [Table 3A] Table 3B. Diagnostic statistics for determining sepsis using MDW, WBC, and SBP versus SIRS, including LR+ confidence intervals and detailed data. [Table 3B]

[0057] Table 4A shows the results when other normal SIRS criteria were incorporated. For MDW and WBC alone, with all SIRS criteria normal, the post-test sepsis probability prediction was 29% with an LR+ of 1.91. An LR+ score between 1 and 2 is recognized as a minimal increase in the likelihood of disease. In this scenario, even accounting for other SIRS criteria being in the normal healthy range, abnormal SBP values ​​combined with abnormal MDW and WBC produced a post-test sepsis probability assessment of 61.47% and an LR+ of 7.37, which represents a moderate increase in the likelihood of disease. Table 4B shows the detailed results, including the LR+ confidence intervals. Table 4A. Diagnostic statistics for determining sepsis using MDW, WBC, and SBP when all other SIRS criteria are normal. [Table 4A] Table 4B. Diagnostic statistics for determining sepsis using MDW, WBC, and SBP when all other SIRS criteria are normal, including LR+ confidence intervals and detailed data. [Table 4B-1] [Table 4B-2]

[0058] Improvements to sepsis probability assessment were also observed when incorporating other vital sign measurements with MDW. Table 5 shows the finding that the odds of sepsis diagnosis (as defined by Sepsis-3) increased 4-fold when abnormal MDW was combined with various qSOFA parameters compared to normal MDW. In this scenario, sepsis was defined by Sepsis-3 criteria because qSOFA was developed to align with the Sepsis-3 definition. Table 5. Demonstration of added value of MDW in combination with qSOFA vital signs criteria [Table 5]

[0059] Table 6 shows the finding that the odds of a sepsis-2 diagnosis increased six-fold when abnormal MDW was combined with any number of SIRS criteria compared to normal MDW. In this scenario, sepsis was defined by the sepsis-2 criteria because SIRS was developed to match the sepsis-2 definition. Table 6. Demonstration of added value of MDW in combination with SIRS vital signs criteria [Table 6]

[0060] 3A-3D further illustrate how improvements in sepsis detection are also observed when MDW and WBC are used in combination with certain SIRS vital sign criteria. MDW and WBC improve early sepsis detection when combined with abnormal vital signs: tachycardia (FIG. 3A), tachypnea (FIG. 3B), both tachycardia and tachypnea (FIG. 3C), or abnormal temperature (FIG. 3D). The highest probability of sepsis occurs when the combination of abnormal MDW, abnormal WBC, and one or more abnormal (SIRS) vital sign criteria is present.

[0061] 4A-4B illustrate that MDW and WBC in combination with the qSOFA vital sign criteria of altered consciousness (FIG. 4A) and blood pressure (FIG. 4B) also significantly improve sepsis detection. In this scenario, the highest probability of sepsis occurs when both MDW and WBC are also abnormal.

[0062] Figure 5 shows the finding that MDW does improve the detection of sepsis in ED patients across a range of WBC values, including those where the WBC was normal. The shaded areas in this figure indicate abnormal WBC measurements.

[0063] These scenarios illustrate the added value of incorporating SBP measurements and other vital sign measurements along with WBC and MDW. Various modifications to this embodiment may be used without departing from the essence of the invention.

[0064] The dimensions and values ​​disclosed herein should not be understood to be strictly limited to the exact numerical values ​​recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range around that value, including at least the variability due to the reproducibility of measurements made using the testing methods described herein, or standard testing methods in the industry if no testing method is expressly disclosed.

[0065] All documents cited herein (including any cross-referenced or related patents or patent applications) are incorporated herein by reference in their entirety unless expressly excluded or otherwise limited. The citation of any document is not an admission that the document is prior art with respect to any invention disclosed or claimed herein, or that the document alone, or in any combination with any other reference, teaches, suggests or discloses any such invention. Furthermore, to the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall control.

[0066] While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended in the appended claims to cover all such changes and modifications that are within the scope of this invention.

Claims

1. 1. A method for assessing the likelihood that a patient will develop sepsis, the method comprising: a. receiving in a data processing system measurements including white blood cell count (WBC), monocyte distribution width (MDW), and one or more vital signs; and b. the data processing system processes the received measurements to (i) determine whether each measurement satisfies a corresponding predetermined criterion, and (ii) assign a probability that the patient will develop sepsis; The method includes:

2. For each of two or more measurements, the patient may measure at least one of the one or more vital signs. a. the corresponding predetermined criterion for that measurement is within a predetermined range; and b. If the measurement is within its corresponding predetermined range, The method of claim 1, wherein a risk of developing sepsis is assigned to a subject.

3. The method of any of claims 1 to 2, wherein the one or more vital signs comprises blood pressure.

4. The method of any of claims 1 to 3, wherein the one or more vital signs comprises systolic blood pressure (SBP).

5. 5. The method of claim 4, wherein the predetermined standard for SBP is less than or equal to a value of 100 mmHg.

6. The method of any of claims 1 to 5, wherein at least one measurement is received from an electronic medical record and at least one measurement is received from an analyzer.

7. The method according to any one of claims 1 to 6, wherein the predetermined criterion for MDW is a value above 20.0 channels.

8. The predetermined standard for the WBC is 4.0×10 ３ / μL or less than 12.0 × 10 ３ The method according to any one of claims 1 to 7, wherein the value is greater than 1 / μL.

9. The predetermined standard for the WBC is 5.0×10 ３ / μL or less than 10.0 × 10 ３ The method according to any one of claims 1 to 7, wherein the value is greater than 1 / μL.

10. The method of any of claims 1 to 9, wherein at least one of the one or more vital signs is a SIRS or qSOFA vital sign measurement.

11. The method according to any of claims 1 to 10, wherein at least one of the predetermined criteria is a SIRS or qSOFA vital signs criterion.

12. The method of any preceding claim, wherein the measurements are taken within 12 hours of patient presentation.

13. The method of any preceding claim, wherein the measurements include values ​​taken 12 hours or more after patient presentation.

14. A computer readable medium having instructions operable, when executed, to cause a data processing system to perform the method according to any of claims 1-13.

15. A data processing system including a processor and a non-transitory computer readable storage medium, the non-transitory computer readable storage medium having instructions which, when executed by the processor, cause the data processing system to perform a method according to any one of claims 1 to 13.

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