METHOD AND APPARATUS FOR MEASURING INFLAMMATION INDEX PARAMETERS IN BLOOD SAMPLES

Abstract

To provide means that can determine the progress degree of a pathological process for each type of inflammatory disease on the basis of a measurement result on an inflammation marker acquired from a blood sample.SOLUTION: A measuring method for an inflammation index parameter in a blood sample includes the steps of: measuring the erythrocyte sedimentation rate (ESR) from the blood sample; measuring an inflammation marker that differs from the ESR from the blood sample; and calculating an inflammation index parameter, which is an index of inflammation, on the basis of the measurement value of the ESR and the measurement value of the inflammation marker.SELECTED DRAWING: Figure 5

Description

[Technical Field]

[0001] The present invention relates to a method and a device for measuring an inflammation index parameter in a blood sample. [Background technology]

[0002] The erythrocyte sedimentation rate (ESR), also known as the erythrocyte sedimentation rate or blood sedimentation rate, is a nonspecific inflammatory marker. Although it is a simple test, it accurately reflects inflammation, tissue breakdown, and plasma protein abnormalities, making it highly useful at initial consultations and in the follow-up of chronic diseases, and has long been used to screen for inflammatory diseases. The ESR value is measured as the length of the plasma layer, which is the rate at which red blood cells sediment in anticoagulant-containing blood (1-hour value).

[0003] ESR measurement results are affected by plasma protein components such as globulin and fibrinogen, red blood cell shape and volume, and the charged state of the red blood cell membrane. The surface of red blood cell membranes in blood is negatively charged, primarily due to sialic acid, and is surrounded by positively charged electrolytes, forming an electric double layer. The zeta potential is an indicator of the charge state associated with red blood cell movement, and red blood cells are normally inhibited from agglutinating due to the repulsion of their zeta potential. When positively charged γ-globulin and fibrinogen increase in plasma and bind to the negatively charged red blood cell membrane surface, the repulsion between red blood cells due to the zeta potential decreases, and the ESR increases. On the other hand, when negatively charged albumin increases in the plasma, red blood cell aggregation is inhibited, and the ESR decreases.

[0004] Another nonspecific inflammatory marker, C-reactive protein (CRP), is commonly used clinically for the diagnosis and management of infectious diseases and the monitoring of a range of noninfectious inflammatory diseases. Because CRP reacts more quickly and disappears more rapidly than ESR, it is the most sensitive indicator for determining the intensity and duration of acute inflammation. Therefore, ESR is now used instead of ESR for the diagnosis of acute inflammation. On the other hand, ESR remains elevated for a long time even after the inflammatory symptoms have subsided and CRP levels have decreased due to the influence of residual fibrinogen. This is because, during acute inflammatory diseases, fibrinogen increases and albumin decreases due to the regulation of protein synthesis, but their fluorescence persists even after CRP levels return to normal. For this reason, ESR is useful for monitoring the progression of acute inflammation. Furthermore, in chronic inflammatory diseases such as rheumatoid arthritis, the production of acute-phase proteins such as CRP is low and often within the normal range, but ESR is clearly elevated. For this reason, ESR is used as an indicator for monitoring the activity of rheumatoid inflammation and for assessing its remission. Although ESR and CRP are both non-specific inflammatory markers, their clinical utility differs, and each plays a role as an inflammatory marker independently in different situations, such as the acute and chronic phases. Currently, they are not used together to assess the presence or absence of inflammatory indicators or risk factors for pathological changes related to inflammation.

[0005] In addition, blood tests for measuring ESR and CRP typically involve simultaneous measurement of various hematological parameters using an automated hematology analyzer. Recent automated hematology analyzers can measure peripheral blood red blood cell (RBC), white blood cell (WBC), and platelet counts, as well as hematocrit and hemoglobin concentrations, with only a single blood draw. Furthermore, recent instruments can not only measure blood cell counts, hematocrit, hemoglobin concentrations, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC), but also five types of WBC differentials. Furthermore, instruments capable of measuring RBC and platelet size variations and erythroblasts have been developed. These instruments, with their high speed, accuracy, and precision, have become essential in clinical settings.

[0006] Here, it has been proposed to integrate an agglutination measurement function that estimates ESR using an osmogram based on photometric rheology and a blood cell measurement function that measures the number of blood cells into a single device (see, for example, Patent Document 1). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2005 / 022125 Brochure Summary of the Invention [Problem to be solved by the invention]

[0008] In the technology described in Patent Document 1, an ESR measurement device and a measurement assembly with a cell counter function share a flow path for circulating a blood sample, making it possible for these devices to perform measurements sequentially on the same blood sample. However, the technology described in Patent Document 1 assumes that the measurement results obtained by each device will be referenced independently. Therefore, the effect achieved by this technology is limited to making the device more compact, and it was not anticipated that the measurement results from each device would be used together to determine the degree of progression of the pathological process of various inflammatory diseases.

[0009] Therefore, an object of the present invention is to provide a means that enables determination of the degree of progression of the pathological process of various inflammatory diseases based on the measurement results of inflammatory markers obtained from blood samples. [Means for solving the problem]

[0010] According to one embodiment of the present invention, there is provided a method for measuring an inflammation index parameter in a blood sample, the method comprising: 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 that is an indicator of inflammation based on the measured ESR value and the measured inflammation marker value.

[0011] According to another aspect of the present invention, there is provided an apparatus for measuring an inflammation index parameter in a blood sample, which can be used in the method for measuring an inflammation index parameter according to the above-mentioned aspect of the present invention, and which includes an ESR measurement unit that measures an erythrocyte sedimentation rate (ESR) from a blood sample, an inflammation marker measurement unit that measures an inflammation marker other than the ESR from the blood sample, and an inflammation index parameter measurement unit that calculates an inflammation index parameter that serves as an inflammation index based on the measured ESR value and the measured values of the inflammation marker.

[0012] Furthermore, according to yet another aspect of the present invention, there are also provided a program for causing a computer to execute each step in the method for measuring an inflammation index parameter according to one aspect of the present invention described above, and a computer-readable recording medium on which the program is recorded. [Effects of the Invention]

[0013] According to the present invention, it is possible to provide inflammation index parameters that are useful for determining the degree of progression of the pathological process of various inflammatory diseases based on the measurement results of blood samples. [Brief explanation of the drawings]

[0014] [Figure 1] FIG. 1 is a block diagram showing an outline of an inflammation index parameter measuring device. [Figure 2] FIG. 2 is a diagram showing an example of a silectogram. [Figure 3] FIG. 3 is a block diagram showing the configuration of the control unit, which is a component of the inflammation index parameter measuring device. [Figure 4] FIG. 4 is a flowchart showing the steps of the method for measuring an inflammation index parameter. [Figure 5] Figure 5 is a graph plotting the CRP / ESR values calculated from ESR and CRP measurement data in patients with coronavirus disease 2019 (COVID-19). [Figure 6] FIG. 6 is a graph plotting ESR / NLR values calculated from ESR and NLR measurement data in patients for the same population as shown in FIG. DETAILED DESCRIPTION OF THE INVENTION

[0015] Hereinafter, an embodiment of the present invention will be described with reference to the accompanying drawings.

[0016] One aspect of the present invention is a method for measuring an inflammation index parameter in a blood sample, comprising measuring the erythrocyte sedimentation rate (ESR) from a blood sample, measuring an inflammation marker other than the ESR from the blood sample, and calculating an inflammation index parameter serving as an indicator of inflammation based on the measured ESR and the measured values of the inflammation marker. Another aspect of the present invention is a device for measuring an inflammation index parameter in a blood sample, comprising an ESR measurement unit for measuring the erythrocyte sedimentation rate (ESR) from the blood sample, an inflammation marker measurement unit for measuring an inflammation marker other than the ESR from the blood sample, and an inflammation index parameter measurement unit for calculating the inflammation index parameter serving as an indicator of inflammation based on the measured ESR and the measured values of the inflammation marker. Here, in this specification, "inflammatory index parameter" refers to a parameter serving as an indicator of the inflammatory state in various inflammatory diseases. The inflammation index parameter measured by the inflammation index parameter measurement method and measurement device according to this embodiment can be used as an index of the inflammatory state to predict the severity of various inflammatory diseases, determine the possibility of ending treatment after remission, and determine the degree of progression of the pathological process, such as for prognosis management.

[0017] Hereinafter, preferred embodiments for carrying out the method for measuring an inflammation index parameter according to the present invention will be specifically described with reference to the drawings. However, the technical scope of the present invention should be determined based on the claims and is not limited to the specific embodiments described below.

[0018] FIG. 1 is a block diagram showing an outline of an inflammation index parameter measuring device.

[0019] The method for measuring an inflammation index parameter according to this embodiment essentially comprises measuring the erythrocyte sedimentation rate (ESR) from a blood sample and measuring an inflammation marker other than ESR from the blood sample. Here, the "inflammatory marker other than ESR" includes C-reactive protein (CRP), neutrophil / lymphocyte ratio (NLR), ProcalcitoninThe inflammatory markers include one or more selected from the group consisting of 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 used as an inflammatory marker different from ESR.

[0020] The inflammation index parameter measuring device 10 has a blood acquisition unit 100, a blood cell counting and measuring unit 110, a silectogram measurement unit 120, a CRP reaction unit 130, a blood discharge unit 140, an operation input unit 150, a data output unit 160, a power supply unit 170, and a control unit 180. The blood acquisition unit 100, the blood cell counting and measuring unit 110, the silectogram measurement unit 120, the CRP reaction unit 130, the blood discharge unit 140, the operation input unit 150, the data output unit 160, and the power supply unit 170 are each connected to and controlled by the control unit 180. The silectogram measurement unit 120 and the control unit 180 constitute an ESR measurement unit, and the CRP reaction unit 130 and the control unit 180 constitute a CRP measurement unit serving as an inflammation marker measurement unit.

[0021] The blood acquiring 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 medical professional or the like, and distributes the acquired blood sample to the blood cell counting and measuring unit 110, the sielectogram measuring unit 120, and the CRP reaction unit 130. The blood acquiring unit 100 is composed of a dispensing unit, piping, a suction pump, a solenoid valve, a nozzle, etc., and its specific form is not particularly limited. One end of the piping may be provided with a supply port for supplying a diluent for diluting the blood sample through a nozzle.

[0022] A blood sample is collected from a patient in advance and placed in a blood collection tube, to which an anticoagulant such as EDTA (Ethylenediamine tetraacetic acid) may be added.

[0023] The blood cell counting / measuring unit 110 may have, for example, a first measuring unit for measuring the number of white blood cells and a second measuring unit for measuring the number of red blood cells. The first measuring unit and the second measuring unit each have a chamber and a detection unit. The chamber holds a blood sample injected through a nozzle. The detection unit counts the blood cells in the blood sample.

[0024] The blood sample is first injected into the chamber of the first measurement unit, diluted 200 times with a diluent, and hemolyzed with a hemolytic agent, after which the white blood cell count and other parameters are measured by the detection unit. The blood sample is then injected into the chamber of the second measurement unit, diluted 40,000 times with a diluent, and the red blood cell count and other parameters are measured by the detection unit. Each chamber is connected to a blood discharge unit 140, and the used blood sample is discharged into the blood discharge unit 140.

[0025] Examples of measurement items by the blood cell count measurement unit 110 include, but are not limited to, white blood cell count (WBC), red blood cell count (RBC), hemoglobin concentration (HGB), hematocrit value (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (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 percentage (EO%), basophil percentage (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). Of these measurement items, for example, the blood cell count and blood cell size are measured by the electrical resistance method. HGB is measured based on the measurement principle of colorimetry. HCT is measured using a pulse height integration method (calculated using an RBC histogram) using blood cell pulses. Note that these blood cell count measurement techniques are all well known, so explanations will be omitted. Blood cell count measurement data is sent to the control unit 180.

[0026] The silectogram measurement unit 120 may include, for example, a chamber, a transparent tube, a transmitted light detection unit, piping, and a suction pump. The silectogram measurement unit 120 measures the silectogram of a blood sample. A silectogram is a graph showing the transition of the intensity of light transmitted through a blood sample before and after the flow of the blood sample, which is generated by applying shear stress to the blood sample, is stopped. The silectogram measurement unit 120 may be integrated with the blood cell count measurement unit 110 within a single measurement device, or may be provided in a separate measurement device. An example of a commercially available device that integrates these functions is the MEK-1305 Celltac α+ fully automated blood cell counter and erythrocyte sedimentation rate measurement device (manufactured by Nihon Kohden Corporation).

[0027] The chamber contains the blood sample injected through the nozzle. The transparent tube is, for example, a transparent glass tube, and its lower end is connected to the chamber. The blood sample in the chamber is sucked through the transparent tube by the suction pump, which applies a constant shear stress to the blood sample. The application of shear stress causes the blood sample to flow through the transparent tube at a constant flow rate. The flow of the blood sample is then stopped by stopping the suction pump or by switching or shutting off a solenoid valve installed between the transmitted light detection unit and the suction pump.

[0028] The transmitted light detection unit has a light source and a photodetector. The light source irradiates light onto the blood sample in the transparent tube. The photodetector detects the intensity of the transmitted light (hereinafter also referred to as "transmitted light intensity") that has passed through the blood sample from the irradiated light onto the blood sample. The light source may be composed of, for example, a near-infrared emitter. The photodetector may be composed of a photodiode. The transmitted light detection unit detects the transmitted light intensity before and after the flow of the blood sample through the transparent tube is stopped, and transmits the detection result to the control unit 180. In other words, the transmitted light detection unit measures the silectogram and transmits it to the control unit 180. The silectogram measurement unit 120 and the CRP reaction unit 130 (described later) are heated by a heater or the like, and the temperature of the blood sample during measurement is adjusted to be constant.

[0029] FIG. 2 is a diagram showing an example of a silectogram. The horizontal axis of the silectogram indicates time, and the vertical axis indicates transmitted light intensity. In the example of the silectogram shown in FIG. 2, the output voltage of the photodiode used as the photodetector of the transmitted light detection unit is shown as the transmitted light intensity. In the silectogram, the transmitted light intensity reaches a minimum value V at time t0 when the flow of the blood sample through the transparent tube is stopped. min This is because at the moment the flow is stopped, there is almost no aggregation of red blood cells, and the irradiated light is reflected and absorbed by the red blood cells uniformly dispersed in the transparent tube, reducing the transmitted light intensity. The transmitted light intensity reaches its minimum value V at time t0. min After reaching this value, the value increases. This is because the cessation of flow initiates aggregation of red blood cells, and the irradiated light passes through the gaps between the red blood cells that increase with aggregation. Here, red blood cells aggregate because the repulsion between negatively charged red blood cells is prevented by positively charged blood proteins such as fibrinogen, which increase with inflammation.

[0030] In this embodiment, a parameter relating to the aggregation of red blood cells (hereinafter also referred to as "aggregation parameter") is calculated based on the sielectogram obtained as described above. The aggregation parameter may include a wide range of parameters that correspond to the aggregation of red blood cells. In order to calculate this aggregation parameter, first, a time t A The predetermined time can be set as an arbitrary time at which the rate of increase in the transmitted light intensity in the sielectogram slows down to a certain degree and saturates. A The transmitted light intensity at this time is the maximum value V of the aggregation parameter when calculating the aggregation parameter. max In this embodiment, the parameter AI is used as the aggregation parameter, which is calculated based on the inlectogram as follows: The parameter AI is calculated based on the inlectogram over a time interval t A-0 is one side, and the maximum transmitted light intensity V max and the minimum value of transmitted light intensity V minThe parameter AI is calculated as the ratio (B / S) of the area of region B below the inlectogram curve in region S to the area of region S, a rectangle whose other side is the difference AMP between the inlectogram and the area B. Region S is shown as a shaded area in Figure 2. In other words, if the region above the inlectogram curve in region S is region A in the inlectogram, the parameter AI is calculated as the ratio of the area of region B to the sum of the areas of region A and region B (i.e., B / (A+B)). However, as agglutination parameters, in addition to the above-mentioned AI, the area of B, the area of A, AMP, and time t 1 / 2 Any of the following may be adopted. 1 / 2 is the minimum value V of the transmitted light intensity at time t0 min This is the time when the transmitted light intensity increases by AMP / 2 from the

[0031] The CRP reaction unit 130 may include, for example, a chamber, a reagent holder, a transmitted light detector, piping, and a suction pump. The CRP reaction unit 130 measures the amount (concentration) of CRP in a blood sample. In this embodiment, the CRP reaction unit 130 measures the amount (concentration) of CRP in a blood sample by latex agglutination immunoturbidimetry. The CRP reaction unit 130 may be integrated with the blood cell counting unit 110 and / or the sielectogram measurement unit 120 within a single measurement device, or may be provided in different measurement devices. An example of a commercially available device that includes the CRP reaction unit 130 separately from the blood cell counting unit 110 and the sielectogram measurement unit 120 is the clinical chemistry analyzer CHM-4100 Celltac Chemi (manufactured by Nihon Kohden Corporation).

[0032] The reagent holding section holds a reagent for measuring CRP. The reagent contains an antibody (anti-CRP antibody) that specifically binds to CRP. In this embodiment, the reagent is anti-CRP antibody-sensitized latex (hereinafter also referred to as "sensitized latex") in which latex particles are sensitized (bound) to the antibody. The chamber contains the blood sample injected through the nozzle and the reagent injected from the reagent holding section through the nozzle.

[0033] The transmitted light detection unit may have a configuration similar to that described for the lectogram measurement unit 120. During CRP measurement, sensitized latex in the latex reagent and CRP antigen in the blood sample bind and agglutinate through an antigen-antibody reaction. The agglutinates grow over time. In this embodiment, near-infrared light is irradiated onto the agglutinates from a light source constituting the transmitted light detection unit for three minutes from the start of agglutination. Changes in the transmitted light intensity (absorbance) detected by a photodiode are transmitted to the control unit 180 as the photodiode's output voltage. The antigen-antibody reaction agglutinates generated in immunoturbidimetry are very small, making it difficult to optically detect the degree of agglutination in the low antigen concentration range. In contrast, in latex agglutination immunoturbidimetry, which uses sensitized latex in which antibodies are sensitized (bound) to relatively large latex particles on the order of μm, the antigen-antibody reaction appears as latex agglutination. Therefore, even when the amount of antigen is small in the low concentration range, it can be measured as a large agglutination, and there is an advantage that even a slight change in the agglutinate can be optically detected.

[0034] The blood discharge unit 140 may include a suction pump, a discharge tank, piping, etc. As described above, the suction pump also serves as a component of the sielectogram measurement unit 120. This suction pump aspirates used blood specimens from the blood cell counting and measurement unit 110, the sielectogram measurement unit 120, and the CRP reaction unit. The discharge tank stores the used blood specimen aspirated by the suction pump.

[0035] The operation input unit 150 is, for example, a touch panel, and accepts input of instructions and data from a medical professional or the like. The instructions from the medical professional or the like include instructions to measure ESR and CRP, and instructions to measure blood cell counts. The input data includes a function for calculating ESR. As will be described later, the function for calculating ESR is a nonlinear function for calculating ESR based on an aggregation parameter and a parameter related to the density of red blood cells. The parameter related to the density of red blood cells may be, for example, at least one of HCT, RBC, HGB, and the intensity of light transmitted through the blood sample.

[0036] The power supply unit 170 supplies the necessary power to the blood acquisition unit 100 , blood cell counting and measurement unit 110 , sphingogram measurement unit 120 , CRP reaction unit 130 , blood discharge unit 140 , operation input unit 150 , data output unit 160 , and control unit 180 .

[0037] The control unit 180 controls the blood acquisition unit 100, blood cell counting and measurement unit 110, sphingogram measurement unit 120, CRP reaction unit 130, blood discharge unit 140, operation input unit 150, data output unit 160, and power supply unit 170, and receives necessary data from each unit.

[0038] Fig. 3 is a block diagram showing the configuration of a control unit, which is a component of the inflammation index parameter measuring device. As shown in Fig. 3, the control unit 180 has a CPU (Central Processing Unit) 181, a RAM (Random Access Memory) 182, a ROM (Read Only Memory) 183, and an HDD (Hard Disk Drive) 184, and these components are connected to each other via a bus 185 so that they can communicate with each other.

[0039] The CPU 181 is a processor that controls each component of the control unit 180 according to a program and performs various calculations. The CPU 181 executes an inflammation index parameter measurement program P stored in the HDD 184 to measure ESR and CRP, an inflammation marker different from ESR. Specifically, the CPU 181 calculates the ESR based on aggregation parameters obtained from an erythrocyte sieve gram as shown in FIG. 2 and parameters related to red blood cell density (e.g., hematocrit value (HCT)). Calculating the ESR in this manner makes it possible to quickly obtain an ESR measurement value that is close to the measurement value obtained by the Westergren method, which is a reference method. For details of this ESR measurement method, please refer to Japanese Patent Application Laid-Open No. 2018-124264, the entire text of which is incorporated herein by reference.

[0040] Next, the CPU 181 calculates an inflammation index parameter based on the measured ESR value and the measured CRP value (inflammatory 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 manner can be used to determine the degree of progression of the pathological process of various inflammatory diseases.

[0041] The 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.

[0042] 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.

[0043] The HDD 184 stores an operating system, various programs including the inflammation index parameter measurement program P, measurement data, a function for calculating ESR, a function for calculating CRP, and various data including basic patient information. The basic patient information includes the patient's ID, name, and age. A label with the patient's ID printed on it is attached to each blood collection tube, and the blood collection tube and measurement data can be managed by the patient's ID.

[0044] The data output unit 160 outputs blood cell counts and measurement data including ESR and CRP, various setting menus, various operation menus, and messages. Here, output includes, for example, output as a data signal, output on paper with data printed on it, and display on a display screen. The data output unit 160 includes a data transmission / reception connector, a printer, and a display.

[0045] In this embodiment, the data output section 160 can display the measurement results of the blood cell count, the measurement results of ESR and CRP, and the measurement results of the inflammation index parameter (ESR / CRP) together in response to an instruction from a medical professional or the like.

[0046] 4 is a flowchart showing the steps of the inflammation index parameter measurement method. This flowchart can be executed by the control unit 180 in accordance with the inflammation index parameter measurement program P.

[0047] The control unit 180 acquires a blood sample from a blood collection tube using the blood acquisition unit 100 and supplies it to the blood cell counting and measurement unit 110, the sphingogram measurement 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 medical professional or the like. For simplicity, the following description will be given assuming that the instruction from the medical professional or the like is to measure ESR / CRP as inflammation index parameters. The ESR measurement value can be calculated based on an aggregation parameter, a parameter related to red blood cell density, and at least one measurement value of mean corpuscular volume, mean corpuscular hemoglobin amount, mean corpuscular hemoglobin concentration, and HGB. Therefore, even if the instruction from the medical professional or the like is to measure ESR / CRP only, a blood cell count measurement can be performed in parallel.

[0048] The control unit 180 measures a blood cell count (CBC) using the blood cell count measurement unit 110 and measures a silectogram using the silectogram measurement unit 120 to calculate an aggregation 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 aggregation parameter corrected in step S103 by the mean corpuscular volume (S104). Then, the control unit 180 calculates an ESR based on the aggregation parameter corrected in step S104 (S105). Note that the procedure of steps S103 to S105 is equivalent to the procedure of calculating an ESR based on the aggregation parameter, a parameter related to the density of red blood cells, and the measured value of the mean corpuscular volume. In other words, it is equivalent to the procedure of calculating an ESR by substituting the aggregation parameter, the parameter related to the density of red blood cells, and the mean corpuscular volume into the variables of a function for calculating the ESR. Therefore, the procedures of steps S103 to S105 can be performed substantially simultaneously.

[0049] Meanwhile, 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), and receives data relating to changes in absorbance (transmitted light intensity) (step S106). Next, the control unit 180 refers to a function for calculating CRP and calculates CRP based on the received data relating to changes in absorbance (S107).

[0050] Then, the control unit 180 uses the ESR value calculated in step S105 and the CRP value calculated in step S107 to calculate the ratio thereof (ESR / CRP) as an inflammation index parameter.

[0051] The ratio (CRP / ESR) measured in this embodiment can be used as an inflammation index parameter. That is, it can be used to determine the degree of progression of the pathological process of various inflammatory diseases (predicting the severity of various inflammatory diseases, determining the possibility of treatment termination after remission, prognosis management, etc.). This point will be explained below with reference to the drawings.

[0052] Figure 5 is a graph plotting the CRP / ESR values calculated from ESR and CRP measurement data in patients with coronavirus disease 2019 (COVID-19) published in two papers (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). To create the graph shown in Figure 5, patients' CRP / ESR values were classified according to the progression of the disease process: at the time of admission, at progression, at peak symptom level, at recovery, and at remission. The patients were divided into two groups: those who recovered with mild symptoms (mild group) and those whose symptoms worsened and then died without recovery or recovery (severe group). The arithmetic mean values for each group were plotted. Data for healthy individuals was collected from a book (Barbara Bain, Imelda Bates, Mike Laffan, Dacie, and Lewis, Practical Haematology, 12th Edition, ELSEVIER, September 26, 2016). In healthy individuals, CRP levels are nearly zero, and CRP levels are also nearly zero during remission. Therefore, in the graph shown in Figure 5, the plots for healthy individuals and those in remission are nearly zero for both the mild and severe groups.

[0053] Looking at the data for "at the time of hospital visit" in the graph of Figure 5, the CRP / ESR ratio (average) in the mild group was approximately 50, while in the severe group it was approximately 75, a value 1.5 times higher. Here, by measuring the CRP / ESR value as an inflammation index parameter for a newly admitted patient using an inflammation index parameter measurement method according to one embodiment of the present invention, the severity of inflammation in the patient can be predicted. For example, if the lower cutoff value for the risk of aggravation is set to 30 for safety, and the CRP / ESR value measured at "at the time of hospital visit" is 30 or less, it can be determined that the patient is not likely to develop severe inflammation. In this way, if patients who are not considered to be at high risk of developing severe inflammation can be identified using a simple method, it can be achieved to efficiently utilize valuable medical resources without wasting them. 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 "at the time of hospital visit" is 75 or more, it can be determined that the patient is likely to develop severe inflammation. In this way, if it were possible to identify patients who are considered to be at high risk of developing severe symptoms using a simple method, it would be possible to avoid the risk of overlooking the risk of developing severe symptoms and making it too late to act if their symptoms suddenly worsen.

[0054] Similarly, looking at the data for "progression" in the graph of FIG. 5, the CRP / ESR ratio (average value) in the mild group decreased from approximately 50 at the time of admission to approximately 17, while in the severe group it increased from approximately 75 to approximately 81. Furthermore, comparing the mild and severe groups, the severe group showed a value nearly five times higher. Here, by measuring the CRP / ESR value as an inflammation index parameter for a patient whose symptoms have progressed using the method for measuring an inflammation index parameter according to one embodiment of the present invention, the severity of inflammation in the patient can be predicted. For example, if the lower cutoff value for the risk of progression is set to 10 to be on the safe side, and the CRP / ESR value measured at "progression" is 10 or less, it can be determined that the patient is not likely to develop severe symptoms. On the other hand, if the upper cutoff value for the risk of progression is set to 80, and the CRP / ESR value measured at "progression" is 80 or higher, it can be determined that the patient is likely to develop severe symptoms. From yet another perspective, the ratio of the CRP / ESR value measured at "the time of admission" to the CRP / ESR value measured at "the time of progression" (time of progression / time of admission) can be calculated, and if this value is less than 1, it can be determined that the patient is not likely to develop severe disease, and if this value is 1 or greater, it can be determined that the patient is likely to develop severe disease.

[0055] In the above-described embodiment, "C-reactive protein (CRP)" is used as an inflammatory marker different from ESR. However, as described above, other than "C-reactive protein (CRP)," other inflammatory markers different from ESR may include one or more selected from the group consisting of neutrophil / lymphocyte ratio (NLR), procytocarnin (PCT), D-dimer (DD), fibrinogen (Fib), neutrophil count (Neu), lymphocyte count (Ly), and mean platelet volume (MPV). Of course, inflammatory markers other than these may also be used.

[0056] In the following, as another embodiment of the present invention, a case where "neutrophil / lymphocyte ratio (NLR)" is used instead of CRP as "an inflammatory marker different from ESR" will be described. The value of "neutrophil / lymphocyte ratio (NLR)" can be calculated by the control unit 180 based on the values of the neutrophil count (Neu) and lymphocyte count (Ly) measured by the blood cell counter.

[0057] Figure 6 is a graph plotting ESR / NLR values calculated from ESR and NLR measurement data in patients for the same population as shown in Figure 5. In creating the graph shown in Figure 6, the patients' ESR / NLR values were classified according to the progression of the disease process: at the time of hospital visit, at the time of progression, at the peak of symptoms, and at the time of recovery, and the patients were divided into a group of patients who recovered with mild symptoms (mild group) and a group of patients whose symptoms worsened and then died without recovering or recovering (severe group), and the arithmetic mean values for each group were plotted.

[0058] Looking at the data for "at the time of admission" and "at the time of progression" in the graph of Figure 6, the ESR / NLR ratio (average value) in the mild group increased more than five-fold, from about 4 to about 22, while in the severe group it decreased two-thirds, from about 12 to about 8. Here, for a patient who newly visits the hospital, the severity of inflammation in that patient can be predicted by measuring the ESR / NLR value as an inflammation index parameter at the time of "at the time of admission" and "at the time of progression" using the inflammation index parameter measurement method according to one embodiment of the present invention. For example, the ratio (at the time of progression / at the time of admission) of the ESR / NLR value measured at "at the time of admission" to the ESR / NLR value measured at "at the time of progression" can be calculated. If this value is 6 or greater, it can be determined that the patient is not likely to develop severe symptoms, and if this value is less than 1, it can be determined that the patient is likely to develop severe symptoms.

[0059] Similarly, looking at the data for "symptom peak" and "recovery" in the graph of FIG. 6 , the ESR / NLR ratio (average) in the mild group remains high at approximately 22 to 25, whereas the severe group shows a low value of approximately 7 to 12. Here, by measuring the ESR / NLR value as an inflammation index parameter for a patient whose symptoms have progressed to the stage of recovery using the method for measuring an inflammation index parameter according to one embodiment of the present invention, it is possible to determine whether the patient has already become seriously ill or to predict the patient's risk of developing sequelae. For example, if the upper cutoff value for the risk of developing sequelae is set to 25 to be on the safe side, and the ESR / NLR value measured from "progression" to "recovery" is 25 or higher, it can be determined that the patient has not become seriously ill and is not highly likely to develop sequelae. On the other hand, if the upper cutoff value for risk of developing sequelae is set at 12, and the CRP / ESR value measured during progression or recovery is 12 or below, the patient can be determined to have already progressed to a severe state and to be at a high risk of developing sequelae. It has been reported that many COVID-19 patients exhibit abnormal blood cell morphology, such as hypersegmented neutrophils. Furthermore, it has been reported that such abnormal blood cell morphology is an indicator of the formation of neutrophil extracellular traps (NETs), a runaway response of the host immune system that occurs after a cytokine storm (for details on NETs, see Lee KH, Cavanaugh L, Leung H, et al., Int. J. Lab. Hematol., 2018;40:392-399; https: / / doi.org / 10.1111 / ijlh.12800). Therefore, for patients who have already been determined to have become seriously ill as described above with reference to Figure 6, flow cytometry can be used to classify blood cells from blood samples and examine the presence or absence of hypersegmented neutrophils (or the hypersegmented neutrophil ratio), which can further determine whether or not severe pneumonia associated with NETs has developed (or whether or not there is a high risk of this occurring).Similarly, it has been reported that immature granulocyte (IG) counts are 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, for patients who have already been determined to be severely ill as described above with reference to Figure 6, it is possible to further determine whether sepsis has developed (or whether the risk of sepsis is high) by classifying blood cells from blood samples using flow cytometry and examining the immature granulocyte (IG) count. As described above, the method for measuring an inflammation index parameter according to the present embodiment preferably further comprises measuring one or more items selected from the group consisting of white blood cell count (WBC), hypersegmented neutrophil ratio, immature granulocyte count (IG), platelet count (Plt), hemoglobin A1c (HbA1c), immunoglobulin (Ig), and fibrin degradation products (FDP). This configuration can contribute to subclassifying the results of the determination and determining the occurrence or risk of complications and / or sequelae, etc., based on the determination of the degree of progression of the pathological process of various inflammatory diseases based on the inflammation index parameter obtained by the above-mentioned measurement method.

[0060] The above describes an inflammation index parameter measurement method, an inflammation index parameter measurement device, an inflammation index parameter measurement program, and a recording medium on which the program is recorded according to embodiments of the present invention. However, the present invention is not limited to the above-described embodiments. For example, the means and methods for performing various processes in the inflammation index parameter measurement device 10 according to the above-described embodiments can be realized by either a dedicated hardware circuit or a programmed computer. The program may be provided, for example, by a computer-readable recording medium such as a CD-ROM (Compact Disc Read Only Memory) or online via a network such as the Internet. In this case, the program recorded on the computer-readable recording medium is typically transferred and stored in a storage unit such as a hard disk. The program may also be provided as standalone application software or may be incorporated into the software of the inflammation index parameter measurement device 10 as a function of the device. [Explanation of symbols]

[0061] 10. Inflammation index parameter measuring device; 100 Blood Acquisition Department; 110 Blood cell counting unit, 120 lectogram measurement unit, 130 CRP reaction section, 140 Blood drain, 150 operation input unit, 160 data output section, 170 Power supply section, 180 Control section.

Claims

1. measuring the erythrocyte sedimentation rate (ESR) from the blood sample; measuring an inflammatory marker different from the ESR from the blood sample; calculating an inflammation index parameter that is an index of inflammation based on the ESR measurement value and the inflammatory marker measurement value; measuring one or more items selected from the group consisting of white blood cell count (WBC), hypersegmented neutrophil ratio, immature granulocyte count (IG), platelet count (Plt), hemoglobin A1c (HbA1c), immunoglobulin (Ig), and fibrin degradation products (FDP) from the blood sample; Including, A method for measuring an inflammation index parameter in a blood sample, wherein the inflammation index parameter is a ratio of CRP to ESR (CRP / ESR) or a ratio of ESR to NLR (ESR / NLR).

2. The method of claim 1 , further comprising predicting the severity of inflammation based on the value of the ratio.

3. The method according to claim 1 or 2, wherein measuring the ESR comprises measuring the ESR based on a selectogram.

4. 4. The measurement method according to claim 3, wherein measuring the ESR includes calculating the ESR using a nonlinear function having variables: a parameter related to red blood cell aggregation calculated based on the sielectogram; and a parameter related to red blood cell density measured from the blood sample.

5. an erythrocyte sedimentation rate (ESR) measurement unit that measures the erythrocyte sedimentation rate from a blood sample; an inflammation marker measurement unit for measuring, from the blood sample, an inflammation marker other than the ESR, and one or more selected from the group consisting of white blood cell count (WBC), hypersegmented neutrophil ratio, immature granulocyte count (IG), platelet count (Plt), hemoglobin A1c (HbA1c), immunoglobulin (Ig), and fibrin degradation products (FDP); an inflammation index parameter measurement unit that calculates an inflammation index parameter serving as an index of inflammation based on the ESR measurement value and the inflammatory marker measurement value; Including, The inflammation index parameter is a ratio of CRP to ESR (CRP / ESR) or a ratio of ESR to NLR (ESR / NLR).

6. The measuring device according to claim 5 , wherein the ESR measuring unit measures the ESR based on a selectogram.

7. 7. The measurement device according to claim 6, wherein the ESR measurement unit calculates the ESR using a nonlinear function having variables of a parameter related to red blood cell aggregation calculated based on the sielectogram and a parameter related to red blood cell density measured from the blood sample.

8. Measure the erythrocyte sedimentation rate (ESR) from the blood sample; measuring an inflammatory marker different from the ESR from the blood sample, and one or more selected from the group consisting of white blood cell count (WBC), hypersegmented neutrophil ratio, immature granulocyte count (IG), platelet count (Plt), hemoglobin A1c (HbA1c), immunoglobulin (Ig), and fibrin degradation products (FDP); A program for causing a computer to execute a procedure for calculating an inflammation index parameter that serves as an indicator of inflammation based on the measurement value of the ESR and the measurement value of the inflammatory marker, wherein the inflammation index parameter is the ratio of CRP to the ESR (CRP / ESR) or the ratio of the ESR to NLR (ESR / NLR).

9. A computer-readable recording medium on which the program according to claim 8 is recorded.

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