WO2022163384A1 - Measuring method and measuring device for inflammation index parameter of blood sample - Google Patents

Measuring method and measuring device for inflammation index parameter of blood sample Download PDF

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Publication number
WO2022163384A1
WO2022163384A1 PCT/JP2022/001079 JP2022001079W WO2022163384A1 WO 2022163384 A1 WO2022163384 A1 WO 2022163384A1 JP 2022001079 W JP2022001079 W JP 2022001079W WO 2022163384 A1 WO2022163384 A1 WO 2022163384A1
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esr
measuring
inflammation
blood sample
crp
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PCT/JP2022/001079
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French (fr)
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Yutaka Nagai
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Nihon Kohden Corporation
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Priority to CN202280011011.2A priority Critical patent/CN116724237A/en
Publication of WO2022163384A1 publication Critical patent/WO2022163384A1/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/06—Investigating concentration of particle suspensions
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/80—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood groups or blood types or red blood cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/06—Investigating concentration of particle suspensions
    • G01N15/075—Investigating concentration of particle suspensions by optical means
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N2015/0092—Monitoring flocculation or agglomeration
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4737—C-reactive protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/585—Calcitonins
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/745—Assays involving non-enzymic blood coagulation factors
    • G01N2333/75—Fibrin; Fibrinogen
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/70—Mechanisms involved in disease identification
    • G01N2800/7095—Inflammation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood

Definitions

  • the present invention relates to a measuring method and measuring device for an inflammation index parameter of a blood sample.
  • An erythrocyte sedimentation rate (hereinafter, also referred to as ESR) is a non-specific inflammation marker, which is also called an erythrocyte sedimentation or a blood sedimentation. Despite being based on a simple test, it often reflects inflammation, tissue breakdown, plasma protein abnormalities, and the like, and thus has been widely used for screening for inflammatory diseases for a long time due to its highly usefulness for initial diagnosis and follow-up of chronic diseases.
  • the ESR value is measured by measuring, as the length of the plasma layer, the rate (the value per hour) at which erythrocytes settle in the blood to which an anticoagulant is added.
  • the measurement result of ESR is influenced by plasma protein components, such as globulin and fibrinogen, erythrocyte morphology and volume, and charged state of erythrocyte membrane.
  • the surface of the erythrocyte membrane in the blood is negatively charged mainly by sialic acid and surrounded by a positively charged electrolyte to form an electric double layer.
  • the index of the state of charge that accompanies the movement of erythrocytes is called the zeta potential, and erythrocytes are usually suppressed from agglutination by the repulsion of the zeta potential.
  • CRP C-reactive protein
  • ESR is useful for follow-up of acute inflammation.
  • chronic inflammatory diseases such as rheumatoid inflammation
  • ESR is clearly enhanced even though the production amount of acute phase proteins such as CRP is low and often within a reference range.
  • ESR is used as an index for monitoring the activity of inflammation of rheumatoid and the like, and is used for determining the remission and the like thereof.
  • ESR and CRP have in common that they are non-specific inflammation markers but have different clinical usefulness, and hence only play their respective roles as inflammation markers in different situations such as acute phase and chronic phase. At the present, therefore, these are not used together to determine the presence or absence of inflammation indexes or risk factors for pathological changes associated with inflammation.
  • an automated hematology analyzer In a blood test for measuring ESR or CRP, an automated hematology analyzer is commonly used to measure various hematological parameters at the same time. Automated hematology analyzers are configured so that the numbers of erythrocytes, white blood cells, and platelets in the peripheral blood, and hematocrit value and hemoglobin concentration measurements can be obtained by only one aspiration of blood. Modern instruments cannot only measure blood count, hematocrit value, hemoglobin concentration, MCV (mean corpuscular volume), MCH (mean corpuscular hemoglobin amount), and MCHC (mean corpuscular hemoglobin concentration), but also classify leukocytes into five classes. In addition, instruments that can measure the size of erythrocytes and platelets and even erythroblasts have been developed, and are indispensable equipment in clinical practice because of their high-speed, high-accuracy, and precision properties.
  • an agglutination measurement function for estimating ESR using a syllectogram based on photometric rheology and a blood cell measurement function for counting the number of blood cells are also integrated into a single instrument (see Patent Literature 1, for example).
  • Patent Literature 1 International Publication No. WO 2005/022125
  • Patent Literature 1 allows a flow path for circulating a blood sample to be shared between an ESR measuring device and a measuring assembly having a cell counter function, thereby permitting the devices to perform their respective measurements sequentially on the same blood sample.
  • the technique described in Patent Literature 1 simulates that the results of measurements of the respective devices are independently referred to. Therefore, the effect of this technique is limited to the miniaturization of the device.
  • the technique only exerts an effect of making the device smaller and has no supposition that the measurement results from the respective devices are used together to determine the degrees of progression of pathological processes of various inflammatory diseases.
  • an object of the present invention is to provide a means capable of determining the degrees of progression of pathological processes of various inflammatory diseases based on the measurement results of inflammation markers obtained from blood samples.
  • a method for measuring an inflammation index parameter of a blood sample contains: measuring an erythrocyte sedimentation rate (ESR) from the blood sample; measuring an inflammation marker different from the ESR from the blood sample; and calculating an inflammation index parameter, which serves as an index of inflammation, based on the measured value of the ESR and the measured value of the inflammation marker.
  • ESR erythrocyte sedimentation rate
  • a device for measuring an inflammation index parameter of the above aspect of the present invention is for measuring an inflammation index parameter of a blood sample, containing: an erythrocyte sedimentation rate (ESR) measuring section that measures an ESR from the blood sample; an inflammation marker different from the ESR measuring section that measures an inflammation marker from the blood sample; and an inflammation index parameter measuring section that calculates an inflammation index parameter, which serves as an index of inflammation, based on the measured value of the ESR and the measured value of the inflammation marker.
  • ESR erythrocyte sedimentation rate
  • FIG. 1 is a block diagram schematically illustrating an inflammation index parameter measuring device.
  • FIG. 2 is a diagram illustrating an exemplary syllectogram.
  • FIG. 3 is a block diagram illustrating the configuration of a control unit which is a component of an inflammation index parameter measuring device.
  • FIG. 4 is a flowchart illustrating the steps of a method for measuring an inflammation index parameter.
  • FIG. 5 is a graph plotting CRP/ESR values calculated from ESR and CRP measurement data from patients with Coronavirus Disease 2019 (COVID-19).
  • FIG. 6 is a graph plotting ESR/NLR values calculated from ESR and NLR measurement data from patients for the same population as that shown in FIG. 5.
  • One aspect of the present invention is a method for measuring an inflammation index parameter of a blood sample, containing: measuring an erythrocyte sedimentation rate (ESR) from the blood sample; measuring an inflammation marker different from the ESR from the blood sample; and calculating an inflammation index parameter, which serves as an index of inflammation, based on the measured value of the ESR and the measured value of the inflammation marker.
  • ESR erythrocyte sedimentation rate
  • another aspect of the present invention is a device for measuring an inflammation index parameter of a blood sample, containing: an erythrocyte sedimentation rate (ESR) measuring section that measures an ESR from the blood sample; an inflammation marker measuring section that measures an inflammation marker different from the ESR from the blood sample; and an inflammation index parameter measuring section that calculates an inflammation index parameter, which serves as an index of inflammation, based on the measured value of the ESR and the measured value of the inflammation marker.
  • ESR erythrocyte sedimentation rate
  • inflammation marker measuring section that measures an inflammation marker different from the ESR from the blood sample
  • an inflammation index parameter measuring section that calculates an inflammation index parameter, which serves as an index of inflammation, based on the measured value of the ESR and the measured value of the inflammation marker.
  • inflammation index parameter herein means a parameter that is an index of the state of inflammation in various inflammatory diseases.
  • inflammation index parameters measured by the method and device for measuring inflammation index parameters of the present aspect can be used as indexes of inflammation statuses, such as prediction of severity, determination of likelihood of termination of treatment after remission, and prognostic management, to determine the degrees of progressions of pathological processes of various inflammatory diseases.
  • inflammation index parameters useful for determining the degrees of progressions of pathological processes of various inflammatory diseases based on the measurement results of blood samples.
  • FIG. 1 is a block diagram schematically illustrating an inflammation index parameter measuring device.
  • the method for measuring an inflammation index parameter of the present aspect essentially includes measuring an erythrocyte sedimentation rate (ESR) from a blood sample and measuring an inflammation marker different from the ESR from the blood sample.
  • the "inflammation marker different from ESR” may be one or two or more selected from the group consisting of C-reactive protein (CRP), neutrophil/lymphocyte ratio (NLR), procalcitonin (PCT), D-dimer (DD), fibrinogen (Fib), neutrophil count (Neu), lymphocyte count (Ly) and mean platelet volume (MPV).
  • C-reactive protein (CRP) is adopted as the inflammation marker different from ESR.
  • the inflammation index parameter measuring device 10 includes a blood sampling unit 100, a blood count measuring unit 110, a syllectogram measuring unit 120, a CRP reaction unit 130, a blood discharging unit 140, an operation input unit 150, a data output unit 160, a power supply unit 170, and a control unit 180.
  • the control unit 180 is connected to and controls each of the blood sampling unit 100, the blood count measuring unit 110, the syllectogram measuring unit 120, the CRP reaction unit 130, the blood discharging unit 140, the operation input unit 150, the data output unit 160, and the power supply unit 170.
  • the syllectogram measuring unit 120 and the control unit 180 constitute an ESR measuring section
  • the CRP reaction unit 130 and the control unit 180 constitute a CRP measuring section as an inflammation marker measuring section.
  • the blood sampling unit 100 acquires a blood sample from a blood collection tube set in an inlet (not shown) of the inflammation index parameter measuring device 10 by a healthcare worker or the like, and then distributes the obtained blood sample to the blood count measuring unit 110, syllectogram measuring unit 120, and CRP reaction unit 130.
  • the blood sampling unit 100 includes a dispensing portion, a pipe arrangement, a suction pump, a solenoid valve, a nozzle, and the like, and is not particularly limited to a specific configuration.
  • One end of the pipe arrangement may be provided with a supply port for supplying a diluted solution for diluting the blood sample through the nozzle.
  • a blood sample is collected from a patient in advance and housed in a blood collection tube.
  • An anticoagulant such as EDTA (ethylenediaminetetraacetic acid) may be added to the blood collection tube.
  • the blood count measuring unit 110 may include, for example, a first measuring unit for measuring the white blood count and the like and a second measuring unit for measuring the red blood count and the like.
  • the first measuring unit and the second measuring unit have chambers and detection units, respectively.
  • the chamber holds the blood sample infused through the nozzle.
  • the detection unit counts the blood cells in the blood sample.
  • the blood sample is first injected into the chamber of the first measuring unit, diluted 200-fold with a diluent, and hemolyzed with a hemolytic agent, followed by being subjected to the detection unit to measure the white blood count and the like. Further, the blood sample is injected into the chamber of the second measuring unit, diluted 40,000 fold with a diluent, and a red blood count and the like are measured by the detection unit.
  • Each chamber is connected to a blood discharging unit 140, so that the used blood sample can be discharged to the blood discharging unit 140.
  • Examples of measurement items by the blood count measuring unit 110 include, but not limited to, white blood count (WBC), red blood count (RBC), hemoglobin concentration (HGB), hematocrit value (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin amount (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count (PLT), mean platelet volume (MPV), lymphocyte percentage (LY%), monocyte percentage (MO%), granulocyte percentage (GR%), neutrophil percentage (NE%), eosinophil percent (EO%), basophil percent (BA%), immature granulocyte percentage (IG%), neutrophil count (NE), lymphocyte count (LY), monocyte count (MO), eosinophil count (EO), basophil count (BA), immature granulocyte count (IG), and granulocyte count (GR).
  • WBC white blood count
  • RBC red blood count
  • HGB hemoglobin concentration
  • HCT hematocrit value
  • MCV mean corpuscular volume
  • the blood count and the blood cell size are measured by electric resistance method.
  • the HGB is measured based on the measurement principle of colorimetric method.
  • the HCT is measured from blood cell pulses by the cumulative pulse height method (calculated by an RBC histogram). Since all of techniques for these blood count measurements are known, the explanation thereof will be omitted.
  • the data of the blood count measurement are sent to the control unit 180.
  • the syllectogram measuring unit 120 may include, for example, a chamber, a transparent tube, a transmitted light detection unit, a pipe arrangement, a suction pump, and the like.
  • the syllectogram measuring unit 120 measures the syllectogram of the blood sample.
  • the syllectogram is a graph showing the transition of transmitted light intensity before and after the flow of the blood sample, which was caused by applying a shear stress to the blood sample, flowing through the transparent tube is stopped.
  • the syllectogram measuring unit 120 may be integrated with the blood count measuring unit 110 in a single measurement device, or the units may be provided in different measurement devices.
  • a commercially available device with these integrated units is, for example, a fully automated blood counting/erythrocyte sedimentation rate measuring device MEK-1305 Celltac ⁇ + (manufactured by NIHON KOHDEN CORPORATION.).
  • the chamber houses the blood sample infused through the nozzle.
  • the transparent tube is, for example, a transparent glass tube, and the lower end thereof communicates with the chamber.
  • the blood sample in the chamber is sucked into the transparent tube by a suction pump, so that a constant shear stress can be applied to the blood sample.
  • the shear stress By applying the shear stress to the blood sample, the blood sample flows through transparent tube at a constant flow rate. After that, the flow of the blood sample is stopped by stopping the suction pump or switching or shutting off the solenoid valve installed between the transmitted light detection unit and the suction pump.
  • the transmitted light detection unit includes a light source and a photodetector.
  • the light source irradiates the blood sample in the transparent tube with light.
  • the photodetector detects the intensity of transmitted light transmitted through the blood sample among the irradiation light irradiated to the blood sample (hereinafter, also referred to as "transmitted light intensity").
  • the light source may be configured, for example, by a near infrared generator.
  • the photodetector may be configured by a photodiode.
  • the transmitted light detection unit detects the transmitted light intensity before and after the flow of the blood sample flowing through the transparent tube is stopped, and sends the detection result to the control unit 180.
  • the transmitted light detection unit measures a syllectogram and sends it to the control unit 180.
  • the syllectogram measuring unit 120 and the CRP reaction unit 130 described later are heated by a heater or the like and adjusted to keep the temperature of the blood sample at the time of measurement constant.
  • FIG. 2 is a diagram showing an example of a syllectogram.
  • the abscissa of the syllectogram indicates the time, and the ordinate indicates the transmitted light intensity.
  • an output voltage of a photodiode which is used as the photodetector of the transmitted light detection unit is indicated as the transmitted light intensity.
  • the transmitted light intensity has the minimum value V min at time t 0 when the flow of the blood sample flowing through the transparent tube is stopped.
  • a parameter related to erythrocyte aggregation (hereinafter, also referred to as an "aggregation parameter”) is calculated based on the syllectogram obtained as described above.
  • the aggregation parameter include a variety of parameters associated with the erythrocyte aggregation.
  • time t A after a given period of time from time t 0 is set.
  • the predetermined time may be set as an arbitrary time at which the rate of increase in transmitted light intensity decreases to some extent and is saturated in the syllectogram.
  • the transmitted light intensity at the time t A is set as the maximum value V max of the aggregation parameter in calculation of the aggregation parameter.
  • the parameter AI calculated as follows based on the syllectogram is adopted as the aggregation parameter.
  • the parameter AI is calculated as a proportion (B/S) of an area of region B to an area of region S in the syllectogram, the region S being a rectangle having one side defined by the time interval t A-0 and another side defined by the difference AMP between the maximum value V max and the minimum value V min of the transmitted light intensity, and the region B being a portion of the region S below the curve of the syllectogram.
  • the region S is illustrated as a shaded- area in FIG. 2.
  • the parameter AI is calculated as the proportion of the area of the region B to the sum of the area of the region A and the area of the region B (i.e., B/(A + B)).
  • the aggregation parameter in addition to the parameter AI, any of the area of the region B, the area of the region A, the AMP, and a time t 1/2 may be employed.
  • the time t 1/2 is a time when the transmitted light intensity is increased by AMP/2 from the minimum value V min of the transmitted light intensity at time t 0 .
  • the CRP reaction unit 130 may include, for example, a chamber, a reagent holding unit, a transmitted light detection unit, a pipe arrangement, a suction pump, and the like.
  • the CRP reaction unit 130 measures the amount (concentration) of CRP in the blood sample.
  • the CRP reaction unit 130 measures the amount (concentration) of CRP in a blood sample by the latex agglutination immunoturbidimetry method.
  • the CRP reaction unit 130 may be integrated with the blood count measuring unit 110 and/or the syllectogram measuring unit 120 in a single measurement device, or these units may be provided in different measurement devices.
  • a commercially available device in which the CRP reaction unit 130 is installed separately from the blood count measuring unit 110 and the syllectogram measuring unit 120 is, for example, a clinical chemistry analyzer CHM-4100 Celltac Chemi (manufactured by NIHON KOHDEN CORPORATION.).
  • the reagent holding unit holds a reagent for measuring CRP.
  • the reagent contains an antibody that specifically binds to CRP (anti-CRP antibody).
  • the reagent is an anti-CRP antibody sensitized latex in which latex particles are sensitized (bound) to the antibody (hereinafter, also referred to as "sensitized latex").
  • the chamber houses the blood sample injected through the nozzle and the reagent injected from the reagent holder through the nozzle.
  • the transmitted light detection unit may have a configuration similar to that described for the above syllectogram measuring unit 120.
  • the sensitized latex in the latex reagent and the CRP antigen in the blood sample are bound and aggregated by the antigen-antibody reaction. This aggregate grows over time.
  • near infrared rays are emitted from the light source constituting the transmitted light detection unit toward the aggregate from the onset of aggregation up to the elapse of three minutes, and the change in transmitted light intensity (absorbance) detected by a photodiode is sent to the control unit 180 as the output voltage of the photodiode.
  • the antigen-antibody reaction aggregates produced by the immunoturbidimetry method are very small, making it difficult to optically detect the degree of aggregation in a low concentration region where the amount of antigen is small.
  • the antigen-antibody reaction appears in the form of latex agglutination. Therefore, it is possible to measure the antigen as large aggregation even when the amount of antigen is small in the low concentration range, and there is an advantage that even a slight change in aggregates can be captured optically.
  • the blood discharging unit 140 may include a suction pump, a drainage tank, a pipe arrangement, and the like. As described above, the suction pump also serves as a component of the syllectogram measuring unit 120. This suction pump sucks used blood samples from the blood count measuring unit 110, the syllectogram measuring unit 120, and the CRP reaction unit. The drainage tank stores the used blood sample sucked by the suction pump.
  • the operation input unit 150 is, for example, a touch panel, and receives instructions and data input by a healthcare worker or the like.
  • the instructions by the healthcare worker or the like include instructions for measuring ESR and CRP, as well as instructions for measuring blood counts.
  • the input data include a function for calculating the ESR.
  • the function for calculating the ESR is a non-linear function for calculating the ESR based on the agglutination parameter and the parameter related to the density of erythrocytes.
  • the parameter for the density of erythrocytes can be, for example, at least one of HCT, RBC, HGB, and the transmitted light intensities transmitted through the blood sample.
  • the power supply unit 170 supplies electric power required for the blood sampling unit 100, the blood count measuring unit 110, the syllectogram measuring unit 120, the CRP reaction unit 130, the blood discharging unit 140, the operation input unit 150, the data output unit 160, and the control unit 180.
  • the control unit 180 controls the blood sampling unit 100, the blood count measuring unit 110, the syllectogram measuring unit 120, the CRP reaction unit 130, the blood discharging unit 140, the operation input unit 150, the data output unit 160, and the power supply unit 170 and receives the required data from each of the units.
  • FIG. 3 is a block diagram illustrating the configuration of the control unit, which is a component of the inflammation index parameter measuring device.
  • the control unit 180 includes a CPU (Central Processing Unit) 181, one or more RAM (Random Access Memory) 182, one or more ROM (Read Only Memory) 183, and one or more HDD (Hard Disk Drive) 184, the components being communicably connected to each other by bus 185.
  • CPU Central Processing Unit
  • RAM Random Access Memory
  • ROM Read Only Memory
  • HDD Hard Disk Drive
  • the CPU 181 is one or more processor that controls each component of the control unit 180 according to a program and performs various operations.
  • the CPU 181 executes an inflammation index parameter measurement program P stored in the HDD 184 to measure ESR and CRP that is another inflammation marker different from the ESR.
  • the CPU 181 calculates the ESR based on agglutination parameters obtained from the syllectogram as shown in FIG. 2 and on a parameter related to the density of erythrocytes (for example, HCT). Calculating the ESR in this way makes it possible to quickly obtain the measured value of ESR having a small deviation from the value measured by the Westergren method, which is a reference method.
  • Japanese Unexamined Patent Application Publication No. 2018-124264 which is incorporated herein by reference, can be appropriately referred to.
  • the CPU 181 calculates an inflammation index parameter based on the measured value of ESR and the measured value of CRP (inflammation marker).
  • the inflammation index parameter is the ratio of CRP to ESR (CRP/ESR).
  • CRP/ESR the inflammation index parameter
  • RAM 182 is a volatile storage device and temporarily stores the inflammation index parameter measurement program P, measurement data, and a function for calculating ESR and a function for calculating CRP, which will be described later.
  • the ROM 183 is a non-volatile storage device, and stores various data including various setting data used when the inflammation index parameter measurement program P is executed.
  • the HDD 184 stores various programs including an operating system and the inflammation index parameter measurement program P, as well as various data including measurement data, a function for calculating ESR, a function for calculating CRP, and basic information of a patient.
  • the basic information of a patient includes the ID, name, and age of the patient.
  • a label printed with the patient's ID is attached to the blood collection tube to allow the blood collection tube and measurement data to be managed by the patient's ID.
  • the data output unit 160 outputs blood counts and measurement data including ESR and CRP, various setting menus, various operation menus, and messages.
  • the outputs include, for example, an output as a data signal, an output of paper on which data is printed, and a view on a display screen of a display.
  • the data output unit 160 includes a data transmission/reception connector, a printer, and a display.
  • the data output unit 160 can display the measurement results of blood count, the measurement results of ESR and CRP, and the measurement results of inflammation index parameters (ESR/CRP), together.
  • FIG. 4 is a flowchart illustrating the steps of a method for measuring an inflammation index parameter. This flowchart can be executed by the control unit 180 according to the inflammation index parameter measurement program P.
  • the control unit 180 acquires blood samples from a blood collection tube by the blood sampling unit 100 and supplies the samples to the blood count measuring unit 110, the syllectogram measuring unit 120, and the CRP reaction unit 130 (S101). This step is initiated based on an instruction input to the operation input unit 150 by a healthcare worker or the like.
  • the instruction given by a healthcare worker or the like will be described as the measurement of ESR/CRP as the inflammation index parameter.
  • the measured ESR value can be calculated based on the aggregation parameter, the parameter related to the density of erythrocytes, and at least one of measured values of MCV, MCH, MCHC, and HGB. Therefore, even if the instruction for measurands by the healthcare worker or the like is only provided for the measurements of ESR/CRP, a complete blood count (CBC) should be measured in parallel.
  • the control unit 180 measures CBC by the blood count measuring unit 110 and also measures a syllectogram by the syllectogram measuring unit 120 to calculate an agglutination parameter (S102). Next, the control unit 180 corrects the aggregation parameter calculated in step S102 by HCT (S103). Subsequently, the control unit 180 further corrects the agglutination parameter corrected in step S103 by a mean corpuscular volume (S104). Then, the control unit 180 calculates ESR based on the aggregation parameter corrected in step S104 (S105).
  • steps S103 to S105 are equivalent to the procedure of calculating ESR based on the agglutination parameter, the parameter relating to the density of erythrocytes, and the measured mean corpuscular volume.
  • it is equivalent to the procedure for calculating ESR by substituting the aggregation parameter, the parameter related to the density of erythrocytes, and the mean corpuscular volume into the variables of the function for calculating ESR. Therefore, the procedures of steps S103 to S105 can be performed substantially at the same time.
  • control unit 180 calculates CRP in parallel with the calculation of ESR in steps S103 to S105.
  • the CRP reaction unit 130 reacts the blood sample with a reagent (sensitized latex) to receive data on the change in absorbance (transmitted light intensity) (step S106). Subsequently, the control unit 180 calculates CRP based on the received data regarding the change in absorbance with reference to the function for calculating CRP (S107).
  • control unit 180 employs the ESR value calculated in step S105 and the CRP value calculated in step S107 to calculate the ratio (ESR/CRP) as an inflammation index parameter.
  • the ratio (CRP/ESR) measured in this embodiment can be used as an inflammation index parameter. That is, it can be used for determining the degrees of progression of pathological processes of various inflammatory diseases (predictions of severity of various inflammatory diseases, determination of possibility of termination of treatment after remission, prognosis management, etc.).
  • CRP/ESR inflammation index parameter
  • FIG. 5 is a graph plotting CRP/ESR values calculated from ESR and CRP measurement data in patients with Coronavirus Disease 2019 (COVID-19) published in two papers on Coronavirus Disease 2019 (COVID-19) (Tan C, Huang Y, Shi F, et al., J. Med. Virol., 2020;17.; https://doi.org/10.1002/jmv.25871, and Chuan Qin, Luoqi Zhou, Ziwei Hu, Shuoqi Zhang, Sheng Yang, Yu Tao MD, Cuihong Xie, Ke Ma, Ke Shang, Wei Wang, and Dai-Shi Tian, Clinical Infectious Diseases, 2020;71(15):762-8).
  • FIG. 5 is a graph plotting CRP/ESR values calculated from ESR and CRP measurement data in patients with Coronavirus Disease 2019 (COVID-19) published in two papers on Coronavirus Disease 2019 (COVID-19) (Tan C, Huang Y, Shi F, et al., J. Med.
  • the CRP/ESR values of patients were classified into those obtained at visit, progression, symptom peak, recovery, and remission, depending on the progression of the pathological process and divided into those of a group of patients who recovered with mild symptoms (mild group) and those of a group of patients who recovered after the symptoms became severe or died without recovery (severe group), and then the arithmetic mean values of the respective groups were plotted.
  • the data of healthy subjects were collected from a printed book (Barbara Bain Imelda Bates Mike Laffan, Dacie and Lewis Practical Haematology, 12th Edition, ELSEVIER, 26th Sep. 2016).
  • the CRP values are almost equal to zero in healthy subjects, and besides, the CRP values are almost zero even at the time of remission. Therefore, in the graph illustrated in FIG. 5, the plots of healthy subjects and those at the time of remission are almost zero in both the mild group and the severe group.
  • the CRP/ESR ratio (mean value) is about 50 in the mild group, but about 75, 1.5 times the value, in the severe group.
  • the severity of inflammation in a newly visited patient can be predicted by measuring the value of CRP/ESR as an inflammation index parameter by the method for measuring an inflammation index parameter according to one aspect of the present invention.
  • the lower cutoff value for the risk of aggravation is set to 30 for safety, and if the CRP/ESR value measured at "visit" is 30 or less, it can be determined that the patient is not likely to become severe.
  • the CRP/ESR ratio (mean value) decreased from about 50 at visit to about 17 in the mild group, whereas it increased from about 75 to about 81 in the severe group. Also, in the comparison between the mild group and the severe group, the severe group shows a value nearly 5 times.
  • the severity of inflammation in a patient can be predicted by measuring the value of CRP/ESR as an inflammation index parameter for the patient by the method for measuring an inflammation index parameter according to one aspect of the present invention. For example, if the lower cutoff value for the risk of aggravation is set to 10 for safety and the CRP/ESR value measured at "progression" is 10 or less, it can be determined that the patient is not likely to become severe.
  • the upper cutoff value for the risk of aggravation is set to 80 and the CRP/ESR value measured at "progression" is 80 or more, it can be determined that the patient is likely to become severe.
  • the ratio of a CRP/ESR value measured at "visit” to a CRP/ESR value measured at "progression” is calculated, and then it can be determined that the patient is not likely to become severe if this value is less than 1 and the patient is likely to become severe if this value is 1 or more.
  • C-reactive protein is adopted as an inflammation marker different from ESR.
  • CTR neutrophil/lymphocyte ratio
  • PCT procalcitonin
  • DD D-dimer
  • Fib fibrinogen
  • Neu neutrophil count
  • Ly lymphocyte count
  • MPV MPV
  • inflammation markers other than these may be used.
  • NLR neutrophil count
  • Ly lymphocyte count
  • FIG. 6 is a graph plotting ESR/NLR values calculated from ESR and NLR measurement data in patients for the same population as that shown in FIG. 5.
  • the CRP/ESR values of patients were classified into those obtained at visit, progression, symptom peak, recovery, and remission, depending on the progression of the pathological process and divided into those of a group of patients who recovered with mild symptoms (mild group) and those of a group of patients who recovered after the symptoms became severe or died without recovery (severe group), and then the arithmetic mean values of the respective groups were plotted.
  • the ESR/NLR ratio (mean value) increased more than 5 times from about 4 to about 22 in the mild group, but decreased by 2/3 times from about 12 to about 8 in the severe group.
  • the severity of inflammation in a newly visited patient can be predicted by measuring the value of ESR/NLR as an inflammation index parameter by the method for measuring an inflammation index parameter according to one aspect of the present invention.
  • the ratio of an ESR/NLR value measured at "progression” to an ESR/NLR value measured at "visit” is calculated, and then it can be determined that the patient is not likely to become severe if this value is 6 or more and the patient is likely to become severe if this value is less than 1.
  • the ratio (mean value) of ESR/NLR remains high as a value of about 22 to 25 in the mild group, but low as a value of about 7 to about 12 in the severe group.
  • measuring an ESR/NLR value as an inflammation index parameter makes it possible to determine whether or not the patient has already become serious or severe situation and to predict the morbidity risk of sequelae in the patient.
  • the upper cutoff value for the morbidity risk of sequelae is set to 25 for safety, and the ESR/NLR value measured from "progression" to "recovery” is 25 or more, it can be determined that the patient is not serious and is not likely to suffer from sequelae.
  • the upper cutoff value for the morbidity risk of sequelae is set to 12 and the CRP / ESR value measured from "progress” to "recovery” is 12 or less, it can be determined that the patient has already become serious and is likely to suffer from sequelae. Note that it has been reported that many patients with COVID-19 show morphological abnormalities of blood cells, such as hypersegmented neutrophils.
  • NETs neutrophil extracellular traps
  • IG immature granulocyte count
  • WBC white blood count
  • IG immature granulocyte count
  • Plt platelet count
  • HbA1c hemoglobin A1c
  • Ig immunoglobulin
  • FDP fibrin degradation product
  • Such a configuration can also contribute to subdivide the determination result and to determine the presence or absence of complications and/or concomitant sequelae or the like or the risks thereof on the premise of determining the degrees of progression of pathological processes of various inflammatory diseases based on the inflammation index parameters obtained by the above measuring method.
  • the present invention is not limited the embodiments described above.
  • the means and methods for performing various processes in the inflammation index parameter measuring device 10 according to the above embodiment can be realized by either a dedicated hardware circuit or a programmed computer.
  • the program may be provided by a computer-readable recording medium, such as a CD-ROM (Compact Disk Read Only Memory), or may be provided online via a network, such as the Internet.
  • the program recorded on the computer-readable recording medium is usually transferred to and stored in a storage unit, such as a hard disk.
  • the above program may be provided as a single application software or may be incorporated into the software of the device as one of the functions of the inflammation index parameter measuring device 10.

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Abstract

A method for measuring an inflammation index parameter of a blood sample includes: measuring an erythrocyte sedimentation rate (ESR) from the blood sample; measuring an inflammation marker different from the ESR from the blood sample; and calculating an inflammation index parameter, which serves as an index of inflammation, based on the measured value of the ESR and the measured value of the inflammation marker.

Description

MEASURING METHOD AND MEASURING DEVICE FOR INFLAMMATION INDEX PARAMETER OF BLOOD SAMPLE
The present invention relates to a measuring method and measuring device for an inflammation index parameter of a blood sample. This application claims a priority based on Japanese Patent Application No. 2021-010423, file on January 26, 2021, the contents of which are incorporated herein by reference in its entirety.
An erythrocyte sedimentation rate (hereinafter, also referred to as ESR) is a non-specific inflammation marker, which is also called an erythrocyte sedimentation or a blood sedimentation. Despite being based on a simple test, it often reflects inflammation, tissue breakdown, plasma protein abnormalities, and the like, and thus has been widely used for screening for inflammatory diseases for a long time due to its highly usefulness for initial diagnosis and follow-up of chronic diseases. The ESR value is measured by measuring, as the length of the plasma layer, the rate (the value per hour) at which erythrocytes settle in the blood to which an anticoagulant is added.
The measurement result of ESR is influenced by plasma protein components, such as globulin and fibrinogen, erythrocyte morphology and volume, and charged state of erythrocyte membrane. The surface of the erythrocyte membrane in the blood is negatively charged mainly by sialic acid and surrounded by a positively charged electrolyte to form an electric double layer. The index of the state of charge that accompanies the movement of erythrocytes is called the zeta potential, and erythrocytes are usually suppressed from agglutination by the repulsion of the zeta potential. Here, when positively charged γ-globulin or fibrinogen increases in plasma and binds to the surface of a negatively charged erythrocyte membrane, the repulsion between erythrocytes due to the zeta potential decreases, which results in an increase in ESR. On the other hand, when negatively charged albumin increases in the plasma, erythrocyte aggregation is suppressed, which results in a decrease in ESR.
By the way, there is C-reactive protein (CRP) as a non-specific inflammation marker different from ESR, and the measurement of plasma CRP levels has been clinically used in the diagnosis and management of infectious diseases and in the monitoring of a series of non-infectious inflammatory diseases. Since this CRP responds faster and disappears faster than ESR, the CRP is the most sensitive index for determining the intensity and length of inflammation in the case of acute inflammation and is now a substitute for ESR in the diagnosis of acute inflammation. On the other hand, even after the inflammatory symptoms are alleviated and the CRP concentration is lowered, ESR is enhanced for a long time due to the influence of residual fibrinogen. This is because the regulation of protein synthesis results in an increase in fibrinogen and a decrease in albumin during acute inflammatory diseases, and these tendencies persist even after CRP normalization. For this reason, ESR is useful for follow-up of acute inflammation. Further, in chronic inflammatory diseases such as rheumatoid inflammation, ESR is clearly enhanced even though the production amount of acute phase proteins such as CRP is low and often within a reference range. Hence, ESR is used as an index for monitoring the activity of inflammation of rheumatoid and the like, and is used for determining the remission and the like thereof. Thus, ESR and CRP have in common that they are non-specific inflammation markers but have different clinical usefulness, and hence only play their respective roles as inflammation markers in different situations such as acute phase and chronic phase. At the present, therefore, these are not used together to determine the presence or absence of inflammation indexes or risk factors for pathological changes associated with inflammation.
In a blood test for measuring ESR or CRP, an automated hematology analyzer is commonly used to measure various hematological parameters at the same time. Automated hematology analyzers are configured so that the numbers of erythrocytes, white blood cells, and platelets in the peripheral blood, and hematocrit value and hemoglobin concentration measurements can be obtained by only one aspiration of blood. Modern instruments cannot only measure blood count, hematocrit value, hemoglobin concentration, MCV (mean corpuscular volume), MCH (mean corpuscular hemoglobin amount), and MCHC (mean corpuscular hemoglobin concentration), but also classify leukocytes into five classes. In addition, instruments that can measure the size of erythrocytes and platelets and even erythroblasts have been developed, and are indispensable equipment in clinical practice because of their high-speed, high-accuracy, and precision properties.
Furthermore, an agglutination measurement function for estimating ESR using a syllectogram based on photometric rheology and a blood cell measurement function for counting the number of blood cells are also integrated into a single instrument (see Patent Literature 1, for example).
Patent Literature 1: International Publication No. WO 2005/022125
Technical Problem
The technique described in Patent Literature 1 allows a flow path for circulating a blood sample to be shared between an ESR measuring device and a measuring assembly having a cell counter function, thereby permitting the devices to perform their respective measurements sequentially on the same blood sample. However, the technique described in Patent Literature 1 simulates that the results of measurements of the respective devices are independently referred to. Therefore, the effect of this technique is limited to the miniaturization of the device. The technique only exerts an effect of making the device smaller and has no supposition that the measurement results from the respective devices are used together to determine the degrees of progression of pathological processes of various inflammatory diseases.
Therefore, an object of the present invention is to provide a means capable of determining the degrees of progression of pathological processes of various inflammatory diseases based on the measurement results of inflammation markers obtained from blood samples.
Solution to Problem
According to one aspect of the present invention, there is provided a method for measuring an inflammation index parameter of a blood sample. The method contains: measuring an erythrocyte sedimentation rate (ESR) from the blood sample; measuring an inflammation marker different from the ESR from the blood sample; and calculating an inflammation index parameter, which serves as an index of inflammation, based on the measured value of the ESR and the measured value of the inflammation marker.
According to another aspect of the present invention, there is provided a device for measuring an inflammation index parameter of the above aspect of the present invention. The device is for measuring an inflammation index parameter of a blood sample, containing: an erythrocyte sedimentation rate (ESR) measuring section that measures an ESR from the blood sample; an inflammation marker different from the ESR measuring section that measures an inflammation marker from the blood sample; and an inflammation index parameter measuring section that calculates an inflammation index parameter, which serves as an index of inflammation, based on the measured value of the ESR and the measured value of the inflammation marker.
Further, according to still other aspect of the present invention, there are provided a program for executing each step of the above method for measuring an inflammation index parameter according to one aspect of the present invention on a computer and a computer-readable recording medium on which the program is recorded.
FIG. 1 is a block diagram schematically illustrating an inflammation index parameter measuring device. FIG. 2 is a diagram illustrating an exemplary syllectogram. FIG. 3 is a block diagram illustrating the configuration of a control unit which is a component of an inflammation index parameter measuring device. FIG. 4 is a flowchart illustrating the steps of a method for measuring an inflammation index parameter. FIG. 5 is a graph plotting CRP/ESR values calculated from ESR and CRP measurement data from patients with Coronavirus Disease 2019 (COVID-19). FIG. 6 is a graph plotting ESR/NLR values calculated from ESR and NLR measurement data from patients for the same population as that shown in FIG. 5.
Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings.
One aspect of the present invention is a method for measuring an inflammation index parameter of a blood sample, containing: measuring an erythrocyte sedimentation rate (ESR) from the blood sample; measuring an inflammation marker different from the ESR from the blood sample; and calculating an inflammation index parameter, which serves as an index of inflammation, based on the measured value of the ESR and the measured value of the inflammation marker. In addition, another aspect of the present invention is a device for measuring an inflammation index parameter of a blood sample, containing: an erythrocyte sedimentation rate (ESR) measuring section that measures an ESR from the blood sample; an inflammation marker measuring section that measures an inflammation marker different from the ESR from the blood sample; and an inflammation index parameter measuring section that calculates an inflammation index parameter, which serves as an index of inflammation, based on the measured value of the ESR and the measured value of the inflammation marker. Here, the "inflammation index parameter" herein means a parameter that is an index of the state of inflammation in various inflammatory diseases. Then, inflammation index parameters measured by the method and device for measuring inflammation index parameters of the present aspect can be used as indexes of inflammation statuses, such as prediction of severity, determination of likelihood of termination of treatment after remission, and prognostic management, to determine the degrees of progressions of pathological processes of various inflammatory diseases.
Thus, according to the present invention, it is possible to provide inflammation index parameters useful for determining the degrees of progressions of pathological processes of various inflammatory diseases based on the measurement results of blood samples.
Hereinafter, a preferred embodiment for carrying out the method for measuring the inflammation index parameter according to the present aspect will be specifically described with reference to the drawings. The technical scope of the present invention should be determined based on the descriptions in claims and is not limited to the following specific embodiments.
FIG. 1 is a block diagram schematically illustrating an inflammation index parameter measuring device.
The method for measuring an inflammation index parameter of the present aspect essentially includes measuring an erythrocyte sedimentation rate (ESR) from a blood sample and measuring an inflammation marker different from the ESR from the blood sample. Here, the "inflammation marker different from ESR" may be one or two or more selected from the group consisting of C-reactive protein (CRP), neutrophil/lymphocyte ratio (NLR), procalcitonin (PCT), D-dimer (DD), fibrinogen (Fib), neutrophil count (Neu), lymphocyte count (Ly) and mean platelet volume (MPV). In this embodiment, "C-reactive protein (CRP)" is adopted as the inflammation marker different from ESR.
The inflammation index parameter measuring device 10 includes a blood sampling unit 100, a blood count measuring unit 110, a syllectogram measuring unit 120, a CRP reaction unit 130, a blood discharging unit 140, an operation input unit 150, a data output unit 160, a power supply unit 170, and a control unit 180. The control unit 180 is connected to and controls each of the blood sampling unit 100, the blood count measuring unit 110, the syllectogram measuring unit 120, the CRP reaction unit 130, the blood discharging unit 140, the operation input unit 150, the data output unit 160, and the power supply unit 170. The syllectogram measuring unit 120 and the control unit 180 constitute an ESR measuring section, and the CRP reaction unit 130 and the control unit 180 constitute a CRP measuring section as an inflammation marker measuring section.
The blood sampling unit 100 acquires a blood sample from a blood collection tube set in an inlet (not shown) of the inflammation index parameter measuring device 10 by a healthcare worker or the like, and then distributes the obtained blood sample to the blood count measuring unit 110, syllectogram measuring unit 120, and CRP reaction unit 130. The blood sampling unit 100 includes a dispensing portion, a pipe arrangement, a suction pump, a solenoid valve, a nozzle, and the like, and is not particularly limited to a specific configuration. One end of the pipe arrangement may be provided with a supply port for supplying a diluted solution for diluting the blood sample through the nozzle.
A blood sample is collected from a patient in advance and housed in a blood collection tube. An anticoagulant such as EDTA (ethylenediaminetetraacetic acid) may be added to the blood collection tube.
The blood count measuring unit 110 may include, for example, a first measuring unit for measuring the white blood count and the like and a second measuring unit for measuring the red blood count and the like. The first measuring unit and the second measuring unit have chambers and detection units, respectively. The chamber holds the blood sample infused through the nozzle. The detection unit counts the blood cells in the blood sample.
The blood sample is first injected into the chamber of the first measuring unit, diluted 200-fold with a diluent, and hemolyzed with a hemolytic agent, followed by being subjected to the detection unit to measure the white blood count and the like. Further, the blood sample is injected into the chamber of the second measuring unit, diluted 40,000 fold with a diluent, and a red blood count and the like are measured by the detection unit. Each chamber is connected to a blood discharging unit 140, so that the used blood sample can be discharged to the blood discharging unit 140.
Examples of measurement items by the blood count measuring unit 110 include, but not limited to, white blood count (WBC), red blood count (RBC), hemoglobin concentration (HGB), hematocrit value (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin amount (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count (PLT), mean platelet volume (MPV), lymphocyte percentage (LY%), monocyte percentage (MO%), granulocyte percentage (GR%), neutrophil percentage (NE%), eosinophil percent (EO%), basophil percent (BA%), immature granulocyte percentage (IG%), neutrophil count (NE), lymphocyte count (LY), monocyte count (MO), eosinophil count (EO), basophil count (BA), immature granulocyte count (IG), and granulocyte count (GR). Among these measurement items, for example, the blood count and the blood cell size are measured by electric resistance method. The HGB is measured based on the measurement principle of colorimetric method. The HCT is measured from blood cell pulses by the cumulative pulse height method (calculated by an RBC histogram). Since all of techniques for these blood count measurements are known, the explanation thereof will be omitted. The data of the blood count measurement are sent to the control unit 180.
The syllectogram measuring unit 120 may include, for example, a chamber, a transparent tube, a transmitted light detection unit, a pipe arrangement, a suction pump, and the like. The syllectogram measuring unit 120 measures the syllectogram of the blood sample. The syllectogram is a graph showing the transition of transmitted light intensity before and after the flow of the blood sample, which was caused by applying a shear stress to the blood sample, flowing through the transparent tube is stopped. The syllectogram measuring unit 120 may be integrated with the blood count measuring unit 110 in a single measurement device, or the units may be provided in different measurement devices. A commercially available device with these integrated units is, for example, a fully automated blood counting/erythrocyte sedimentation rate measuring device MEK-1305 Celltac α+ (manufactured by NIHON KOHDEN CORPORATION.).
The chamber houses the blood sample infused through the nozzle. The transparent tube is, for example, a transparent glass tube, and the lower end thereof communicates with the chamber. The blood sample in the chamber is sucked into the transparent tube by a suction pump, so that a constant shear stress can be applied to the blood sample. By applying the shear stress to the blood sample, the blood sample flows through transparent tube at a constant flow rate. After that, the flow of the blood sample is stopped by stopping the suction pump or switching or shutting off the solenoid valve installed between the transmitted light detection unit and the suction pump.
The transmitted light detection unit includes a light source and a photodetector. The light source irradiates the blood sample in the transparent tube with light. The photodetector detects the intensity of transmitted light transmitted through the blood sample among the irradiation light irradiated to the blood sample (hereinafter, also referred to as "transmitted light intensity"). The light source may be configured, for example, by a near infrared generator. The photodetector may be configured by a photodiode. The transmitted light detection unit detects the transmitted light intensity before and after the flow of the blood sample flowing through the transparent tube is stopped, and sends the detection result to the control unit 180. In other words, the transmitted light detection unit measures a syllectogram and sends it to the control unit 180. The syllectogram measuring unit 120 and the CRP reaction unit 130 described later are heated by a heater or the like and adjusted to keep the temperature of the blood sample at the time of measurement constant.
FIG. 2 is a diagram showing an example of a syllectogram. The abscissa of the syllectogram indicates the time, and the ordinate indicates the transmitted light intensity. In the example of a syllectogram shown in FIG. 2, an output voltage of a photodiode which is used as the photodetector of the transmitted light detection unit is indicated as the transmitted light intensity. In the syllectogram, the transmitted light intensity has the minimum value Vmin at time t0when the flow of the blood sample flowing through the transparent tube is stopped. This is because at the moment when the flow is stopped, almost no aggregation of erythrocytes occurs, so that the irradiation light is reflected and absorbed by the erythrocytes uniformly dispersed in the transparent tube, and the transmitted light intensity becomes small. After the transmitted light intensity has the minimum value Vmin at time t0, the intensity is increased. This occurs when the flow is stopped to initiate erythrocytes to aggregate and allow the irradiated light to pass through the gaps between erythrocytes, which increase due to the aggregation. Here, the aggregation of erythrocytes occurs because repulsion between negatively charged erythrocytes is impeded by positively charged protein in the blood, such as fibrinogen, which is increased by inflammation.
In the present embodiment, a parameter related to erythrocyte aggregation (hereinafter, also referred to as an "aggregation parameter") is calculated based on the syllectogram obtained as described above. Examples of the aggregation parameter include a variety of parameters associated with the erythrocyte aggregation. To calculate the aggregation parameter, time tA after a given period of time from time t0 is set. The predetermined time may be set as an arbitrary time at which the rate of increase in transmitted light intensity decreases to some extent and is saturated in the syllectogram. Then, the transmitted light intensity at the time tA is set as the maximum value Vmax of the aggregation parameter in calculation of the aggregation parameter. In the present embodiment, the parameter AI calculated as follows based on the syllectogram is adopted as the aggregation parameter. The parameter AI is calculated as a proportion (B/S) of an area of region B to an area of region S in the syllectogram, the region S being a rectangle having one side defined by the time interval tA-0 and another side defined by the difference AMP between the maximum value Vmax and the minimum value Vmin of the transmitted light intensity, and the region B being a portion of the region S below the curve of the syllectogram. The region S is illustrated as a shaded- area in FIG. 2. In other words, in the syllectogram, when the region A is the portion of the region S above the curve of the syllectogram, the parameter AI is calculated as the proportion of the area of the region B to the sum of the area of the region A and the area of the region B (i.e., B/(A + B)). Note that, as the aggregation parameter, in addition to the parameter AI, any of the area of the region B, the area of the region A, the AMP, and a time t1/2 may be employed. In the meantime, the time t1/2 is a time when the transmitted light intensity is increased by AMP/2 from the minimum value Vmin of the transmitted light intensity at time t0.
The CRP reaction unit 130 may include, for example, a chamber, a reagent holding unit, a transmitted light detection unit, a pipe arrangement, a suction pump, and the like. The CRP reaction unit 130 measures the amount (concentration) of CRP in the blood sample. In the present embodiment, the CRP reaction unit 130 measures the amount (concentration) of CRP in a blood sample by the latex agglutination immunoturbidimetry method. The CRP reaction unit 130 may be integrated with the blood count measuring unit 110 and/or the syllectogram measuring unit 120 in a single measurement device, or these units may be provided in different measurement devices. A commercially available device in which the CRP reaction unit 130 is installed separately from the blood count measuring unit 110 and the syllectogram measuring unit 120 is, for example, a clinical chemistry analyzer CHM-4100 Celltac Chemi (manufactured by NIHON KOHDEN CORPORATION.).
The reagent holding unit holds a reagent for measuring CRP. The reagent contains an antibody that specifically binds to CRP (anti-CRP antibody). In the present embodiment, the reagent is an anti-CRP antibody sensitized latex in which latex particles are sensitized (bound) to the antibody (hereinafter, also referred to as "sensitized latex"). The chamber houses the blood sample injected through the nozzle and the reagent injected from the reagent holder through the nozzle.
The transmitted light detection unit may have a configuration similar to that described for the above syllectogram measuring unit 120. At the time of CRP measurement, the sensitized latex in the latex reagent and the CRP antigen in the blood sample are bound and aggregated by the antigen-antibody reaction. This aggregate grows over time. In the present embodiment, near infrared rays are emitted from the light source constituting the transmitted light detection unit toward the aggregate from the onset of aggregation up to the elapse of three minutes, and the change in transmitted light intensity (absorbance) detected by a photodiode is sent to the control unit 180 as the output voltage of the photodiode. Here, the antigen-antibody reaction aggregates produced by the immunoturbidimetry method are very small, making it difficult to optically detect the degree of aggregation in a low concentration region where the amount of antigen is small. In this regard, in the latex agglutination immunoturbidimetry method using a sensitized latex in which antibodies are sensitized (bound) to relatively large latex particles on the order of μm, the antigen-antibody reaction appears in the form of latex agglutination. Therefore, it is possible to measure the antigen as large aggregation even when the amount of antigen is small in the low concentration range, and there is an advantage that even a slight change in aggregates can be captured optically.
The blood discharging unit 140 may include a suction pump, a drainage tank, a pipe arrangement, and the like. As described above, the suction pump also serves as a component of the syllectogram measuring unit 120. This suction pump sucks used blood samples from the blood count measuring unit 110, the syllectogram measuring unit 120, and the CRP reaction unit. The drainage tank stores the used blood sample sucked by the suction pump.
The operation input unit 150 is, for example, a touch panel, and receives instructions and data input by a healthcare worker or the like. The instructions by the healthcare worker or the like include instructions for measuring ESR and CRP, as well as instructions for measuring blood counts. The input data include a function for calculating the ESR. As will be described later, the function for calculating the ESR is a non-linear function for calculating the ESR based on the agglutination parameter and the parameter related to the density of erythrocytes. The parameter for the density of erythrocytes can be, for example, at least one of HCT, RBC, HGB, and the transmitted light intensities transmitted through the blood sample.
The power supply unit 170 supplies electric power required for the blood sampling unit 100, the blood count measuring unit 110, the syllectogram measuring unit 120, the CRP reaction unit 130, the blood discharging unit 140, the operation input unit 150, the data output unit 160, and the control unit 180.
The control unit 180 controls the blood sampling unit 100, the blood count measuring unit 110, the syllectogram measuring unit 120, the CRP reaction unit 130, the blood discharging unit 140, the operation input unit 150, the data output unit 160, and the power supply unit 170 and receives the required data from each of the units.
FIG. 3 is a block diagram illustrating the configuration of the control unit, which is a component of the inflammation index parameter measuring device.
As illustrated in FIG. 3, the control unit 180 includes a CPU (Central Processing Unit) 181, one or more RAM (Random Access Memory) 182, one or more ROM (Read Only Memory) 183, and one or more HDD (Hard Disk Drive) 184, the components being communicably connected to each other by bus 185.
The CPU 181 is one or more processor that controls each component of the control unit 180 according to a program and performs various operations. The CPU 181 executes an inflammation index parameter measurement program P stored in the HDD 184 to measure ESR and CRP that is another inflammation marker different from the ESR. Specifically, the CPU 181 calculates the ESR based on agglutination parameters obtained from the syllectogram as shown in FIG. 2 and on a parameter related to the density of erythrocytes (for example, HCT). Calculating the ESR in this way makes it possible to quickly obtain the measured value of ESR having a small deviation from the value measured by the Westergren method, which is a reference method. For details of such a method for measuring ESR, Japanese Unexamined Patent Application Publication No. 2018-124264, which is incorporated herein by reference, can be appropriately referred to.
Subsequently, the CPU 181 calculates an inflammation index parameter based on the measured value of ESR and the measured value of CRP (inflammation marker). In this embodiment, the inflammation index parameter is the ratio of CRP to ESR (CRP/ESR). As will be described later, the inflammation index parameter (CRP/ESR) calculated in this way can be used to determine the degrees of progression of pathological processes of various inflammatory diseases.
RAM 182 is a volatile storage device and temporarily stores the inflammation index parameter measurement program P, measurement data, and a function for calculating ESR and a function for calculating CRP, which will be described later.
The ROM 183 is a non-volatile storage device, and stores various data including various setting data used when the inflammation index parameter measurement program P is executed.
The HDD 184 stores various programs including an operating system and the inflammation index parameter measurement program P, as well as various data including measurement data, a function for calculating ESR, a function for calculating CRP, and basic information of a patient. The basic information of a patient includes the ID, name, and age of the patient. A label printed with the patient's ID is attached to the blood collection tube to allow the blood collection tube and measurement data to be managed by the patient's ID.
The data output unit 160 outputs blood counts and measurement data including ESR and CRP, various setting menus, various operation menus, and messages. Here, the outputs include, for example, an output as a data signal, an output of paper on which data is printed, and a view on a display screen of a display. The data output unit 160 includes a data transmission/reception connector, a printer, and a display.
In this embodiment, in response to instructions from healthcare workers, or the like, the data output unit 160 can display the measurement results of blood count, the measurement results of ESR and CRP, and the measurement results of inflammation index parameters (ESR/CRP), together.
FIG. 4 is a flowchart illustrating the steps of a method for measuring an inflammation index parameter. This flowchart can be executed by the control unit 180 according to the inflammation index parameter measurement program P.
The control unit 180 acquires blood samples from a blood collection tube by the blood sampling unit 100 and supplies the samples to the blood count measuring unit 110, the syllectogram measuring unit 120, and the CRP reaction unit 130 (S101). This step is initiated based on an instruction input to the operation input unit 150 by a healthcare worker or the like. Hereinafter, for the sake of simplicity, the instruction given by a healthcare worker or the like will be described as the measurement of ESR/CRP as the inflammation index parameter. The measured ESR value can be calculated based on the aggregation parameter, the parameter related to the density of erythrocytes, and at least one of measured values of MCV, MCH, MCHC, and HGB. Therefore, even if the instruction for measurands by the healthcare worker or the like is only provided for the measurements of ESR/CRP, a complete blood count (CBC) should be measured in parallel.
The control unit 180 measures CBC by the blood count measuring unit 110 and also measures a syllectogram by the syllectogram measuring unit 120 to calculate an agglutination parameter (S102). Next, the control unit 180 corrects the aggregation parameter calculated in step S102 by HCT (S103). Subsequently, the control unit 180 further corrects the agglutination parameter corrected in step S103 by a mean corpuscular volume (S104). Then, the control unit 180 calculates ESR based on the aggregation parameter corrected in step S104 (S105). The procedures of steps S103 to S105 are equivalent to the procedure of calculating ESR based on the agglutination parameter, the parameter relating to the density of erythrocytes, and the measured mean corpuscular volume. In other words, it is equivalent to the procedure for calculating ESR by substituting the aggregation parameter, the parameter related to the density of erythrocytes, and the mean corpuscular volume into the variables of the function for calculating ESR. Therefore, the procedures of steps S103 to S105 can be performed substantially at the same time.
On the other hand, the control unit 180 calculates CRP in parallel with the calculation of ESR in steps S103 to S105. The CRP reaction unit 130 reacts the blood sample with a reagent (sensitized latex) to receive data on the change in absorbance (transmitted light intensity) (step S106). Subsequently, the control unit 180 calculates CRP based on the received data regarding the change in absorbance with reference to the function for calculating CRP (S107).
Then, the control unit 180 employs the ESR value calculated in step S105 and the CRP value calculated in step S107 to calculate the ratio (ESR/CRP) as an inflammation index parameter.
The ratio (CRP/ESR) measured in this embodiment can be used as an inflammation index parameter. That is, it can be used for determining the degrees of progression of pathological processes of various inflammatory diseases (predictions of severity of various inflammatory diseases, determination of possibility of termination of treatment after remission, prognosis management, etc.). Hereinafter, this point will be described with reference to the drawings.
FIG. 5 is a graph plotting CRP/ESR values calculated from ESR and CRP measurement data in patients with Coronavirus Disease 2019 (COVID-19) published in two papers on Coronavirus Disease 2019 (COVID-19) (Tan C, Huang Y, Shi F, et al., J. Med. Virol., 2020;17.; https://doi.org/10.1002/jmv.25871, and Chuan Qin, Luoqi Zhou, Ziwei Hu, Shuoqi Zhang, Sheng Yang, Yu Tao MD, Cuihong Xie, Ke Ma, Ke Shang, Wei Wang, and Dai-Shi Tian, Clinical Infectious Diseases, 2020;71(15):762-8).
In creating the graph shown in FIG. 5, the CRP/ESR values of patients were classified into those obtained at visit, progression, symptom peak, recovery, and remission, depending on the progression of the pathological process and divided into those of a group of patients who recovered with mild symptoms (mild group) and those of a group of patients who recovered after the symptoms became severe or died without recovery (severe group), and then the arithmetic mean values of the respective groups were plotted. Note that the data of healthy subjects were collected from a printed book (Barbara Bain Imelda Bates Mike Laffan, Dacie and Lewis Practical Haematology, 12th Edition, ELSEVIER, 26th Sep. 2016). Here, the CRP values are almost equal to zero in healthy subjects, and besides, the CRP values are almost zero even at the time of remission. Therefore, in the graph illustrated in FIG. 5, the plots of healthy subjects and those at the time of remission are almost zero in both the mild group and the severe group.
Looking at the data at "visit" in the graph of FIG. 5, the CRP/ESR ratio (mean value) is about 50 in the mild group, but about 75, 1.5 times the value, in the severe group. Here, the severity of inflammation in a newly visited patient can be predicted by measuring the value of CRP/ESR as an inflammation index parameter by the method for measuring an inflammation index parameter according to one aspect of the present invention. For example, the lower cutoff value for the risk of aggravation is set to 30 for safety, and if the CRP/ESR value measured at "visit" is 30 or less, it can be determined that the patient is not likely to become severe. In this way, if a patient who does not seem to have a high risk of aggravation can be identified by a simple method, no overspending of valuable medical resources can be achieved, allowing the medical resources to be efficiently used. On the other hand, if the upper cutoff value for the risk of aggravation is set to 75 and the CRP/ESR value measured at "visit" is 75 or more, it can be determined that the patient is likely to become severe. In this way, if a patient considered to be at high risk of aggravation can be identified by a simple method, it is possible to avoid the danger of being too late treatment start or the like in the case of sudden changes in symptoms caused by overlooking the risk of aggravation.
Looking at the data at "progression" in the graph of FIG. 5, the CRP/ESR ratio (mean value) decreased from about 50 at visit to about 17 in the mild group, whereas it increased from about 75 to about 81 in the severe group. Also, in the comparison between the mild group and the severe group, the severe group shows a value nearly 5 times. Here, the severity of inflammation in a patient can be predicted by measuring the value of CRP/ESR as an inflammation index parameter for the patient by the method for measuring an inflammation index parameter according to one aspect of the present invention. For example, if the lower cutoff value for the risk of aggravation is set to 10 for safety and the CRP/ESR value measured at "progression" is 10 or less, it can be determined that the patient is not likely to become severe. On the other hand, if the upper cutoff value for the risk of aggravation is set to 80 and the CRP/ESR value measured at "progression" is 80 or more, it can be determined that the patient is likely to become severe. From yet another point of view, the ratio of a CRP/ESR value measured at "visit" to a CRP/ESR value measured at "progression" (progression/visit) is calculated, and then it can be determined that the patient is not likely to become severe if this value is less than 1 and the patient is likely to become severe if this value is 1 or more.
Here, in the above embodiment, "C-reactive protein (CRP)" is adopted as an inflammation marker different from ESR. However, as described above, one or two or more selected from the group consisting of neutrophil/lymphocyte ratio (NLR), procalcitonin (PCT), D-dimer (DD), fibrinogen (Fib), neutrophil count (Neu), lymphocyte count (Ly), MPV and the like may be used as the inflammation markers different from ESR, in place of the "C-reactive protein (CRP). Obviously, inflammation markers other than these may be used.
Hereinafter, as another embodiment of the present invention, a case where "neutrophil/lymphocyte ratio (NLR)" is adopted instead of CRP as "an inflammation marker different from ESR" will be described. The value of the "neutrophil/lymphocyte ratio (NLR)" can be calculated by the control unit 180 based on the values of neutrophil count (Neu) and lymphocyte count (Ly) measured by a blood cell counter.
FIG. 6 is a graph plotting ESR/NLR values calculated from ESR and NLR measurement data in patients for the same population as that shown in FIG. 5. In creating the graph shown in FIG. 5, the CRP/ESR values of patients were classified into those obtained at visit, progression, symptom peak, recovery, and remission, depending on the progression of the pathological process and divided into those of a group of patients who recovered with mild symptoms (mild group) and those of a group of patients who recovered after the symptoms became severe or died without recovery (severe group), and then the arithmetic mean values of the respective groups were plotted.
Looking at the data at "visit" and "progression" in the graph of FIG. 6, the ESR/NLR ratio (mean value) increased more than 5 times from about 4 to about 22 in the mild group, but decreased by 2/3 times from about 12 to about 8 in the severe group. Here, the severity of inflammation in a newly visited patient can be predicted by measuring the value of ESR/NLR as an inflammation index parameter by the method for measuring an inflammation index parameter according to one aspect of the present invention. For instance, the ratio of an ESR/NLR value measured at "progression" to an ESR/NLR value measured at "visit" (progression/visit) is calculated, and then it can be determined that the patient is not likely to become severe if this value is 6 or more and the patient is likely to become severe if this value is less than 1.
Looking at the data at "symptom peak" and "recovery" in the graph of FIG. 6, the ratio (mean value) of ESR/NLR remains high as a value of about 22 to 25 in the mild group, but low as a value of about 7 to about 12 in the severe group. Here, or a patient at the stage where the symptom progresses to the time of recovery, measuring an ESR/NLR value as an inflammation index parameter by the method for measuring an inflammation index parameter according to one aspect of the present invention makes it possible to determine whether or not the patient has already become serious or severe situation and to predict the morbidity risk of sequelae in the patient. For example, if the upper cutoff value for the morbidity risk of sequelae is set to 25 for safety, and the ESR/NLR value measured from "progression" to "recovery" is 25 or more, it can be determined that the patient is not serious and is not likely to suffer from sequelae. On the other hand, if the upper cutoff value for the morbidity risk of sequelae is set to 12 and the CRP / ESR value measured from "progress" to "recovery" is 12 or less, it can be determined that the patient has already become serious and is likely to suffer from sequelae. Note that it has been reported that many patients with COVID-19 show morphological abnormalities of blood cells, such as hypersegmented neutrophils. It has also been reported that such abnormal blood cell morphology is an index of the occurrence of neutrophil extracellular traps (NETs), which are runaway reactions of the host immune system that occur after a cytokine storm (see, for NETs, Lee KH, Cavanaugh L, Leung H, et al., Int. J. Lab. Hematol., 2018; 40: 392-399; see https://doi.org/10.1111/ijlh.12800). Therefore, for a patient who has already been determined to be serious in the determination described above with reference to FIG. 6, it is possible to further determine whether the patient has (or is at high risk of) severe pneumonia with NETs by classifying blood cells from blood samples using flow cytometry to investigate the presence or absence of hypersegmented neutrophils (or ratio of hypersegmented neutrophils). Similarly, the immature granulocyte count (IG) has been reported to be useful as a pathological marker for sepsis (Ayres LS, Sgnaolin V, Munhoz TP., Int. J. Lab. Hematol. 2019; 41:392-396.; https://doi.org/10.1111/ijlh.12990). Therefore, it is possible to further determine whether a patient who has already been determined to be serious in the determination described above with reference to FIG. 6 has (or is at high risk of) sepsis by classifying blood cells from blood samples using flow cytometry to investigate the immature granulocyte count (IG). As described above, in the method for measuring an inflammation index parameter according to this aspect, it is preferable to further include measuring one or two or more selected from the group consisting of white blood count (WBC), ratio of hypersegmented neutrophils, immature granulocyte count (IG), platelet count (Plt), hemoglobin A1c (HbA1c), immunoglobulin (Ig) and fibrin degradation product (FDP). Such a configuration can also contribute to subdivide the determination result and to determine the presence or absence of complications and/or concomitant sequelae or the like or the risks thereof on the premise of determining the degrees of progression of pathological processes of various inflammatory diseases based on the inflammation index parameters obtained by the above measuring method.
While the inflammation index parameter measuring method, the inflammation index parameter measuring device, the inflammation index parameter measurement program, and the recording medium on which the program is recorded according to the embodiments of the present invention have been described above, the present invention is not limited the embodiments described above. For example, the means and methods for performing various processes in the inflammation index parameter measuring device 10 according to the above embodiment can be realized by either a dedicated hardware circuit or a programmed computer. The program may be provided by a computer-readable recording medium, such as a CD-ROM (Compact Disk Read Only Memory), or may be provided online via a network, such as the Internet. In this case, the program recorded on the computer-readable recording medium is usually transferred to and stored in a storage unit, such as a hard disk. Further, the above program may be provided as a single application software or may be incorporated into the software of the device as one of the functions of the inflammation index parameter measuring device 10.

Claims (15)

  1. A method for measuring an inflammation index parameter of a blood sample, comprising:
    measuring an erythrocyte sedimentation rate (ESR) from the blood sample;
    measuring an inflammation marker different from the ESR from the blood sample; and
    calculating an inflammation index parameter, which serves as an index of inflammation, based on the measured value of the ESR and the measured value of the inflammation marker.
  2. The measuring method according to claim 1, wherein the inflammation marker is one or two or more selected from the group consisting of C-reactive protein (CRP), neutrophil/lymphocyte ratio (NLR), procalcitonin (PCT), D-dimer (DD), fibrinogen (Fib), neutrophil count (Neu), lymphocyte count (Ly) and mean platelet volume (MPV).
  3. The measuring method according to claim 2, wherein the inflammation index parameter is a ratio of the CRP to the ESR (CRP/ESR) or a ratio of the ESR to the NLR (ESR/NLR).
  4. The measuring method according to claim 3, further comprising predicting the severity of inflammation based on the value of the ratio.
  5. The measuring method according to any one of claims 1 to 4, further comprising measuring, from the blood sample, one or two or more selected from the group consisting of white blood count (WBC), hyperfractionated neutrophil ratio, immature granulocyte count (IG), platelet count (Plt), hemoglobin A1c (HbA1c), immunoglobulin (Ig), and fibrin degradation products (FDP).
  6. The measuring method according to any one of claims 1 to 5, wherein measuring the ESR comprises measuring the ESR based on a syllectogram.
  7. The measuring method according to claim 6, wherein measuring the ESR comprises calculating the ESR using a non-linear function having, as variables, a parameter related to erythrocyte aggregation calculated based on the syllectogram and a parameter related to the density of erythrocytes measured from the blood sample.
  8. A device for measuring an inflammation index parameter of a blood sample, comprising:
    an erythrocyte sedimentation rate (ESR) measuring section that measures an ESR from the blood sample;
    an inflammation marker measuring section that measures an inflammation marker different from the ESR from the blood sample; and
    an inflammation index parameter measuring section that calculates an inflammation index parameter, which serves as an index of inflammation, based on the measured value of the ESR and the measured value of the inflammation marker.
  9. The measuring device according to claim 8, wherein the inflammation marker is one or two or more selected from the group consisting of C-reactive protein (CRP), neutrophil/lymphocyte ratio (NLR), procalcitonin (PCT), D-dimer (DD), fibrinogen (Fib), neutrophil count (Neu), lymphocyte count (Ly), and mean platelet volume (MPV).
  10. The measuring device according to claim 9, wherein the inflammation index parameter is a ratio of the CRP to the ESR (CRP/ESR) or a ratio of the ESR to the NLR (ESR/NLR).
  11. The measuring device according to any one of claims 8 to 10, wherein the inflammation marker measuring section further measures, from the blood sample, one or two or more selected from the group consisting of white blood count (WBC), hyperfractionated neutrophil ratio, immature granulocyte count (IG), platelet count (Plt), hemoglobin A1c (HbA1c), immunoglobulin (Ig), and fibrin degradation products (FDP).
  12. The measuring device according to any one of claims 8 to 11, wherein the ESR measuring section measures the ESR based on a syllectogram.
  13. The measuring device according to claim 12, wherein the ESR measuring section calculates the ESR using a non-linear function having, as variables, a parameter related to erythrocyte aggregation calculated based on the syllectogram and a parameter related to the density of erythrocytes measured from the blood sample.
  14. A program instructing a computer to execute procedures of:
    measuring an erythrocyte sedimentation rate (ESR) from a blood sample;
    measuring an inflammation marker different from the ESR from the blood sample; and
    calculating an inflammation index parameter, which serves as an index of inflammation, based on the measured value of the ESR and the measured value of the inflammation marker.
  15. A computer-readable recording medium on which the program according to claim 14 is recorded.
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