Apparatus and method for determining sedimentation velocity

Abstract

The apparatus for determining sedimentation rate comprises at least one member (8) for sampling a blood sample, and a sensor (20) having an infrared light source (12) and an optical sensor (14), the infrared light source (12) and the optical sensor (14) being arranged substantially opposite each other around the substantially transparent portion (16) of the sampling member (8) such that light emitted by the infrared light source (12) reaches the optical sensor (14) after passing through the substantially transparent portion (16). The optical sensor (14) is arranged to perform blank measurements, the apparatus further comprising a converter arranged to receive one or more light transmission measurements from the optical sensor (14), calculate a ratio between the blank measurement and the one or more light transmission measurements, and return the sedimentation rate.

Description

[Technical Field]

[0001] The present invention relates to the field of hematology, and more particularly to the measurement of sedimentation rate (hereinafter also called ESR, in English "erythrocyte sedimentation rate" or "ESR"). [Background technology]

[0002] The sedimentation rate is a routine part of a complete blood count (CBC) and can detect the presence of inflammatory or infectious conditions, such as rheumatism, cancer, and other diseases that cause changes in blood protein concentrations. A high ESR indicates an inflammatory state, regardless of its nature. However, a low ESR may remain during the presence of an inflammatory syndrome. Therefore, a high ESR generally indicates the presence of a pathological condition. Combining this nonspecific test with complementary tests allows for a more accurate diagnosis.

[0003] The standard method for measuring ESR is the Westergren method. A thin tube with standardized dimensions is filled with a blood sample, sampled with an anticoagulant, e.g., EDTA, and diluted with sodium citrate, and placed vertically. The ESR measurement is the height (in millimeters) of the plasma column after one hour of sedimentation. For example, for an adult male, a height of less than 10 mm after the first hour of sedimentation is considered normal. The limits of normality are not absolute and vary depending on the patient's age and gender.

[0004] ESR is the result of three steps: aggregation, sedimentation, and roll sedimentation of blood cells.

[0005] The phenomenon of red blood cell aggregation is caused by proteins in blood, and the higher their concentration, the greater the force they exert. The formation of aggregates means that red blood cells "roll" together and form three-dimensional structures. The sedimentation rate depends on the size of the aggregates and the viscosity of the plasma.

[0006] In the final step, the aggregates settle, i.e., they gradually fall to the bottom of the tube and are then compressed, separating the sample into a clear, translucent portion at the top (plasma) and a much darker portion at the bottom (red blood cells). The ESR is measured by the height of the translucent portion.

[0007] The most important inflammatory parameter is aggregation, which is directly dependent on plasma protein concentration. This is what the present invention measures to return ESR values. Although this is a nonspecific parameter, it suppresses interference arising from the last two steps of ESR. There are no standardized parameters that can express the rate or kinetics of aggregation. Therefore, it is important to translate aggregation measurements into ESR.

[0008] Due to the volume of blood (1.6 ml) and the time required to complete (1 hour), the Westergren method is not compatible with hematology equipment for CBC analysis. To overcome these problems, research has been conducted using extinction optical measurements (absorption and scattering) to determine sedimentation velocity, such as in patent US 6,632,679.

[0009] Some patents have proposed incorporating improved ESR measurements into hematology testing devices, such as that described in EP 2921862, in which a volume of blood is drawn and separated into two parts for count (CBC) and sedimentation rate measurement, respectively.

[0010] Therefore, this device is disadvantageous because it links counting measurement with sedimentation velocity measurement and requires a complex device to dispense two blood sample portions via one sample, one to the counting portion on one side and one to the sedimentation velocity measurement portion on the other side, and further because the CBC and ESR measurement operations do not have similar requirements in sample preparation.

[0011] Some have proposed portable devices that can measure sedimentation velocity by measuring transmittance, such as the patent described in WO2011 / 101815. This device uses a disposable capillary, but requires a blood suction system for the measurement. In addition, the method of inserting the capillary makes the device less ergonomic. Furthermore, since transmittance measurements use a capillary, there are accuracy issues.

[0012] Document ITUA20163693A1 describes a device that makes it possible to carry out hematological analyses on blood samples and to integrate the detection of the blood sedimentation rate (ESR) with the detection of other chemical and physical parameters of the blood.

[0013] Document FR2955392 describes an agglutination rate measuring device comprising a removable nozzle support, suction means connected to the support, capture means facing the support for picking up at least one physical quantity representative of agglutination of blood components, and means for determining the agglutination rate according to the at least one physical quantity.

[0014] No device is known that can perform sedimentation velocity determinations quickly and reproducibly with a simple structure. Summary of the Invention

[0015] The present invention remedies this situation by providing an apparatus for determining sedimentation velocity, the apparatus comprising at least one member for sampling a blood sample, and a sensor having an infrared light source and an optical sensor arranged substantially opposite each other around the periphery of the substantially transparent portion of the sampling member such that light emitted by the infrared light source reaches the optical sensor after passing through the substantially transparent portion of the sampling member, the optical sensor arranged to perform blank measurements, and the apparatus further comprising a converter arranged to receive one or more light transmission measurements from the optical sensor, calculate a ratio between the blank measurement and the one or more light transmission measurements, and return the sedimentation velocity.

[0016] This device is particularly advantageous as it allows reproducible determination of sedimentation velocity measurements.

[0017] According to various embodiments, the invention may have one or more of the following features. the converter is arranged to determine the time of the lowest light transmittance measurement and the time of the final light transmittance measurement; the optical sensor is positioned to achieve a maximum gain between the time of the lowest light transmittance measurement and the time of the final light transmittance measurement, and to achieve a minimum gain at other times; the converter is arranged to calculate the sedimentation velocity based on the ratio between the blank measurement and the measurement at the time of the final light transmittance measurement on the one hand, and the ratio between the blank measurement and the measurement at the time of the lowest light transmittance measurement on the other hand, The optical sensor is controlled at a low gain before the blood passes through the substantially transparent portion and at a high gain after the blood passes through the substantially transparent portion; the sampling member is a needle that can be controlled for sampling a blood sample, to which a tube formed with a substantially transparent portion is connected, the infrared light source and the optical sensor are positioned less than 10 cm from the sampling end of the needle; the device is arranged to perform a rinse of the needle and the tube between two sedimentation velocity measurement determinations, the sampling member is a capillary, and the sensor has a bore arranged to receive the capillary; The capillary has a lug arranged to abut against the sensor.

[0018] The present invention also relates to a method for determining sedimentation velocity, the method comprising: a) taking a blood sample; b) passing the blood sample through a substantially transparent portion disposed between the infrared light source and the optical sensor; c) measuring one or more light transmittances during operation b); and d) performing a blank measurement in the absence of a blood sample; e) calculating a ratio between the blank measurement and one or more light transmittance measurements and inferring the sedimentation velocity therefrom; Includes the operation of

[0019] Operation d) may be performed before operation c).

[0020] Other characteristics and advantages of the invention will appear better from a reading of the following description with reference to embodiments given for illustrative and non-limiting purposes and with reference to the drawings, in which: [Brief explanation of the drawings]

[0021] [Figure 1] Overall schematic diagram of the device according to the present invention [Figure 2] Figure 1: Detail of the creation of the elements [Figure 3] Measurement diagram of the device in Figure 1 [Figure 4] Schematic diagram of a first embodiment of the device of FIG. [Figure 5] Schematic diagram of a second embodiment of the device of FIG. 1. DETAILED DESCRIPTION OF THE INVENTION

[0022] The drawings and description below contain elements of an essentially constant nature, which therefore serve not only to better understand the invention but may also, where appropriate, contribute to its definition.

[0023] 1 is a general schematic diagram of an apparatus 2 for performing a complete blood count and determining sedimentation velocity measurements according to the present invention. The apparatus 2 comprises a first group 4, a second group 6, a sampling member 8 and a converter 10.

[0024] The first group 4 is arranged to sample the blood sample in the tube and primarily perform a complete blood count on this sample. This measurement can be performed using conventional methods and is known elsewhere. There are many blood testing devices that specialize in this measurement. Blood analyses other than CBC, such as glycated hemoglobin (HbA1c) measurement and C-reactive protein (CRP), can also be performed within group 4.

[0025] The second group 6 is arranged to determine the ESR measurement, and it is to this second group that the present invention is primarily directed. Indeed, as mentioned at the beginning, this test, whether carried out according to the conventional method or by measuring the change in absorbance, is either tedious or, being coupled to a CBC measurement, slows down the operation of the entire device.

[0026] Implementation of the second group 6 according to the present invention allows for the extrapolation of sedimentation velocity measurements by varying absorbance in a manner that is decoupled from CBC or other blood measurements. To this end, the second group 6 is arranged to control the sampling member 8, here a needle, independently of the first group 4, i.e., the sample sampled by the first group 4 is used only for CBC or other blood measurements, and the sample sampled by the second group 6 is used only for ESR measurements.

[0027] Thus, as shown in Figure 1, the first group 4 or the second group 6 controls the needle 8 to sample a blood sample in a blood tube 11. This sample is then brought to the first group 4 for a blood measurement, such as a CBC measurement, or to the second group 6 for a measurement of the change in absorbance. In the latter case, the measurement is sent to the converter 10, which returns an ESR signal and / or an ESR measurement.

[0028] 2 shows an embodiment of the second measuring group 6. According to this embodiment, the second measuring group 6 is formed by a light source 12 and an optical sensor 14 assembled opposite each other around a tube 16 intended to transport the blood sample sampled by the needle 8 from the blood tube 11 towards the interior of the device 2.

[0029] In the embodiment described herein, the light source 12 is preferably an LED type with an infrared wavelength in the range of 700-980 nm, particularly 800 nm, which is the iso-saturation point between oxyhemoglobin and deoxyhemoglobin, making the measurement less sensitive to blood oxygen saturation. In the embodiment described herein, the optical sensor 14 is a photodiode type and may be selected from PMT, PDA, CMOS, and other sensors. In the embodiment described herein, the tube 16 is made of Teflon and is connected to the needle 8. Alternatively, the tube 16 may be made of glass or plastic and should be selected to provide good transparency to the wavelength of the light source 12.

[0030] The light source assembly 12 and the optical sensor 14 can be seen as one sensor 20 of the second group 6. As in the example described here, they may be made as two parts that are assembled to sandwich the needle 8 (e.g., made of metal) and the tubing 16. Alternatively, the light source 12 and the optical sensor 14 may be integrated. Preferably, the sensor 20 is placed fairly close to the tip of the needle 8, less than 10 cm, to optimize shearing of the red blood cells. Preferably, this distance is about 5 cm for best results. In some variations, the sensor 20 may be placed directly at the exit of the needle 8.

[0031] Whatever its configuration, the second group 6 can advantageously use needle 8 diameters conventionally in the range of 1 mm. Indeed, during sampling by the needle 8, the red blood cells undergo a continuous deformation, as will be explained below and shown in FIG. 3.

[0032] Thus, when the needle 8 is immersed in the blood tube 11, the second group 6 controls the aspiration by the needle 8, which is already primed with diluent, in order to sample the blood. This is achieved by known automated control means, a preparation tray, a solenoid valve, and a syringe, which are not shown for simplicity. These means cause the movement of the diluent occupying the tube 16. During this step, the sensor 20 measures a constant light signal, since the tube 16 and the diluent contained therein are translucent.

[0033] An aliquot of blood is then moved by suction to the sensor 20. The red blood cells are sheared and clumps are broken down. At this step, the optical signal remains at a maximum because the blood has not yet confronted the sensor 20. In Figure 3, this is indicated by the reference numeral 30.

[0034] When the blood reaches the sensor, the optical signal represents the shear state of the blood, during which the red blood cells have an elongated shape as shown by reference numeral 31.

[0035] When suction is stopped to stop the shearing, the optical transmission signal decreases as the red blood cells return to their biconcave disk-relieved form, shown as 32 in FIG. 3. The optical signal then increases in a pseudo-logarithmic progression. The gradual increase in optical signal measured by optical sensor 14 is associated with the gradual aggregation of free red blood cells. Aggregation occurs by the red blood cells stacking and rolling, and then forming three-dimensional structures shown as 34 and 36 in FIG. 3.

[0036] After about 40 s, depending on the blood, clumping slows significantly and sedimentation begins. This onset of sedimentation interferes with the correlation between clumping, the measurement of interest, and sedimentation velocity. After t4, an aliquot of blood is removed, for example, by moving needle 8 over the tray. This removes the blood and rinses tube 16 with diluent; at the end of this step, tube 16 is completely filled with diluent, just as it was at the beginning of the procedure described hereinabove.

[0037] The four time points are shown in FIG. Before time t1, the tube 16 is filled with diluent. - Time t1 indicates the time when the blood reaches the level of the sensor 20 by suction. - Time t2 indicates the time when suction stops. - Time t3 marks the time from which the red blood cells regain their relaxed shape and begin to aggregate. - Time point t4 marks the end of the treatment with the blood being drained and replaced again by diluent, as before time point t1.

[0038] 3, it may seem paradoxical that after time t4, while tube 16 is filled with diluent, the optical signal is less significant than when tube 16 is filled with blood. This is explained in the embodiment described herein by the fact that optical sensor 14 is conditioned differently before time t1 and after time t4 in FIG.

[0039] Therefore, before time t1 and after time t4, the measurements are determined to correspond to "blank" measurements. During this period, the optical sensor 14 is adjusted by the converter 10 with a minimum measurement gain.

[0040] Time t3 corresponds to the lowest point in the period t1-t4, beyond which the optical signal begins to increase, which indicates the onset of the phenomenon the present invention is intended to measure, as described herein above. For this reason, and because the fluctuations in the optical signal remain small between time t0 and time t1, in the embodiment described herein, optical sensor 14 is conditioned at minimum gain until time t1, at maximum gain between time t1 and time t4, and again at minimum gain after time t4 for the next measurement.

[0041] This is further advantageous because in the embodiment described herein, converter 10 is arranged to determine the measurement based on the optical density of the signal measured by optical sensor 14. Here, optical density is defined by the formula DO(t)=log(KI / I(t)), where I(t) is the measurement of the optical sensor at time t and K is the maximum gain / minimum gain ratio. More specifically, converter 10 is arranged to return a sedimentation velocity measurement based on the ratio DO(t3) / DO(t4). Applicant has performed a large number of sedimentation velocity measurements using the Westergren criteria method, which allows converter 10 to relate the measurement thus calculated to an ESR value.

[0042] The applicant has found it particularly advantageous to use optical density, which allows independence from variations in transmittance measurements. The applicant has also found that the converter 10 can operate based on the ratio I(t4) / I(t3), without taking into account optical density in the Beer-Lambertian sense and without using I0 differently in the calculation.

[0043] Converter 10 may be created in various ways, such as in the form of suitable computer code running on one or more processors. By processor, we mean any processor suitable for the calculations described herein. Such processors may be created in any known manner, such as microprocessors for personal computers, laptops, tablets, or smartphones; dedicated chips of the FPGA or SoC type; grid or cloud computing resources; clusters of graphical processors (GPUs); microcontrollers; or any other form capable of providing the computing power necessary to complete the processes described herein. One or more of these elements may be created in the form of specialized electronic circuits, such as ASICs. Combinations of processors and electronic circuits are also contemplated. In the case of a gradient boosting-based machine learning unit, a dedicated processor for machine learning is also contemplated. Alternatively, converter 10 may be an analog computer without any programming or computer code.

[0044] As a further alternative, the converter 10 can use machine learning algorithms (in English "machine learning"), which may or may not include neural networks (deep or not). This involves correlating the intensity measurements of the optical sensor 14 with values ​​of sedimentation velocity. This variant may be particularly useful to implement without optical density. As a further alternative, the gain of the optical sensor 14 can be the same for all measurements.

[0045] Figure 4 is a schematic diagram showing an embodiment of the device of Figure 1. As shown in this figure, device 2 is a conventional blood testing device that includes a 1.5 mm diameter syringe 40 and a 16 mm diameter syringe 42, both of which are connected to a needle 8. Sensor 20 is integrated into needle 8 so as to cover the end of tubing 16 connected to needle 8.

[0046] Apparatus 2 of FIG. 4 is adapted to perform CBC measurements, ESR measurements, or both.

[0047] For a CBC measurement, the entire circuit is primed with diluent, the needle 8 is placed in the blood tube 11, and 10 μl is sampled with the syringe 40. The needle 8 is then lifted and placed on the preparation tray, the exterior of which is washed in this tray and expelled to waste. Finally, a mixture of 10 μL of sample and 1 mL of diluent (for example) is dispensed immediately after sampling into the preparation tray with the syringe 42. This initial diluent is then used for the various preparations required to perform the CBC measurement.

[0048] The ESR measurement proceeds as described herein with reference to Figures 1 to 3. The entire circuit is primed with diluent drawn from reservoir 44, and a few μL of air bubble is created at the tip of needle 8. Needle 8 is lowered into blood tube 11, and a 50 μL to 100 μL aliquot is sampled with syringe 42. Needle 8 is raised, the aliquot is transferred to sensor 20, and an optical measurement of agglutination is made. Finally, the interior and exterior of needle 8 is rinsed in a tray and drained to waste. An empty measurement (I0) may be taken before sampling or at the end of the rinse. An optional before-and-after comparison of the empty measurement allows for exception handling, e.g., rinsing control.

[0049] The CBC and ESR cycles are carried out independently of each other, in particular with separate sampling by needle 8. The aliquot for the CBC measurement cannot be used for the ESR measurement and vice versa.

[0050] A mixture of 10 μL of sample and 1 mL of diluent (for example) is dispensed immediately after sampling in the preparation tray with syringe 42. This initial diluent is then used for the various preparations for performing the CBC measurement.

[0051] This allows the two measurements to be separated without problematic blood sampling if both measurements are required. This independence means that the ESR measurement does not significantly impact the work rate of Device 2, allowing for low-cost integration in terms of both equipment and personnel.

[0052] FIG. 5 is a schematic diagram illustrating another embodiment suitable for implementation in a portable device for determining ESR.

[0053] In this embodiment, the sampling member 8 is implemented by a disposable capillary 54. This allows sampling of just a single drop of blood from the patient's finger, avoiding blood collection by venipuncture.

[0054] The device 2 therefore comprises a case 50 which houses the converter 10 and the sensor 20. The case 50 therefore encloses the light source 12 and the optical sensor 14 which are received opposite each other around a bore 52 in the case 50.

[0055] As before, the light source 12 is preferably of the LED type with an infrared wavelength in the range of 700-980 nm, in particular 800 nm, and the optical sensor 14 is of the photodiode type and may be selected from among PMT, PDA, CMOS sensor, etc.

[0056] As shown in FIG. 6, when capillary 54 is inserted into bore 52, blood contained in the capillary can rise to case 50 by capillary action.

[0057] In the example described herein, the capillary 54 is made of Teflon and has a diameter of 0.8 mm. Alternatively, the capillary 54 may be made of glass or plastic and should be selected to provide good transparency to the wavelength of the light source 12. As a further alternative, the diameter of the capillary 54 may be configured between 0.5 mm (lower values ​​may prevent the formation of large aggregate structures and make the optical measurement window too small) and 1.5 mm (higher values ​​may result in insufficient capillary forces).

[0058] In the embodiment described herein, the capillary has a lug 56 that abuts against the case 50 to control the entry of the tube 14 into the bore 52. The distance from the lug 56 to the end of the capillary 54 is set to 15 mm in the embodiment described herein. The upper and lower limits are determined by the following constraints: too close and the sensor 20 will interfere with the finger blood sampling, and too far and too much capillary force will be required. Alternatively, the tube 54 can have markings or other means by which the placement of the tube 54 within the bore 52 can be monitored. Alternatively, none is provided.

[0059] In this embodiment, the shape of the signal is slightly different, since the suction is by capillary action.Figure 7, which is equivalent to Figure 3, also shows the course of the measured signal at the output of the optical sensor 14.

[0060] As shown in this figure, the portion before time t1 and the portion after time t4 do not exist because the capillary is intended for single use. Reference 1 corresponds to the period before time t1 in Figure 3. Measurements are taken through an empty capillary 54 and constitute I0 for the low-gain calculation. The transmittance of the empty capillary 54 is 30 times that of blood. Under these conditions, it is preferable to maintain high-gain / low-gain mode. Criterion 2 corresponds to time t2-t3 in Figure 3. Blood reaches the sensor and the transmittance drops to 0 instantaneously. This edge can be detected and used to control the flip-flop from low gain to high gain. Reference 3 corresponds to a point after time t3 in Figure 3. Blood is flowing through the capillary. It is in a sheared state. This slight slope is due to the blood slowing down and shearing. - Criterion 4 corresponds to the end of sampling. When the blood passes the sensor, the user disconnects the system. The separation of the capillary and the blood drop causes an "abrupt" stop of the capillary rise. This is reflected by a peak and then a decline (pointed out by criterion 4). - Criterion 5 corresponds to the aggregation stage.

[0061] The converter 10 can be connected to any type of interface, such as a laptop computer or notebook computer. It can also be a smartphone-type interface with a dedicated application. In this case, the sensor 20 incorporates optical components and electronic resources that allow interfacing with standard communication means, such as USB. The interface can also be a proprietary system. This solution allows for a strict reduction in the number of components (LEDs and photodiodes) built into the sensor, as well as a human-machine interface perfectly suited to the needs. Preferably, a touchscreen is used, which can provide a virtual keyboard for entering identifiers and other information related to the performed analysis.

Claims

1. 1. An apparatus for determining sedimentation velocity, comprising: At least one member (8) for sampling a blood sample; a sensor (20) having an infrared light source (12) and an optical sensor (14); the infrared light source (12) and the optical sensor (14) are disposed substantially opposite each other around the substantially transparent portion (16) of the member (8) such that light emitted by the infrared light source (12) reaches the optical sensor (14) after passing through the substantially transparent portion (16); the optical sensor (14) is arranged to perform a blank measurement based on light emitted from the infrared light source (12) and passing through the substantially transparent portion (16) in the absence of a blood sample; The apparatus further comprises a converter (10) arranged to receive one or more light transmission measurements from the optical sensor (14), calculate a ratio of a blank measurement to the one or more light transmission measurements, and output a sedimentation velocity based on the ratio.

2. 2. The device according to claim 1, wherein the converter (10) is arranged to determine the time (t3) of the lowest light transmittance measurement and the time (t4) of the final light transmittance measurement.

3. 3. The apparatus of claim 2, wherein the optical sensor (14) is positioned to achieve maximum gain between the time (t3) of the lowest light transmittance measurement and the time (t4) of the final light transmittance measurement, and to achieve minimum gain at other times.

4. 3. The device according to claim 2, wherein the converter (10) is arranged to calculate the sedimentation velocity based on the ratio of the blank measurement to the measurement at the time (t4) of the final transmittance measurement, on the one hand, and the ratio of the blank measurement to the measurement at the time (t3) of the lowest light transmittance measurement, on the other hand.

5. 2. The apparatus of claim 1, wherein the optical sensor is controlled at a low gain before blood passes through the substantially transparent portion and at a high gain after blood passes through the substantially transparent portion.

6. 6. The device according to claim 1, wherein the member is a needle (8) that can be controlled for sampling a blood sample to which a tube (16) having the substantially transparent portion (16) formed thereon is connected.

7. 7. The device according to claim 6, arranged to carry out a rinsing of the needle (8) and the tube (16) between two determinations of sedimentation velocity measurements.

8. The member (8) is a capillary (54), 6. The apparatus of claim 1, wherein the sensor (20) has a bore (52) positioned to receive the capillary (54).

9. 9. The apparatus of claim 8, wherein the capillary (54) has a lug (56) positioned to abut the sensor (20).

10. 1. A method for determining sedimentation velocity, comprising: a) Sampling a blood sample from a blood tube (11); b) passing the blood sample through a substantially transparent portion disposed between the infrared light source and the optical sensor; c) measuring one or more light transmittances during operation b); and d) performing a blank measurement in the absence of a blood sample; e) calculating a ratio between said blank measurement and said one or more light transmittance measurements and inferring a sedimentation velocity from said ratio.

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