Patent Application
20130236910
The present invention relates to a test method and apparatus for testing a diseased state of a subject based on a sample collected from the subject.
Recently, a large number of assay devices that allow a simple and rapid testing have been developed in which a specimen (sample) which is likely to contain a test substance is held on a carrier, and the test substance is tested by immunological measurement or the like. Further, extracorporeal diagnostic agents and various devices for testing poisonous substances have also been commercially available. As an example of such devices, a device that uses an immunochromatographic method is known as described, for example, in Japanese Unexamined Patent Publication No. 2008-139297. Use of the device that utilizes the immunochromatographic method allows a test result to be obtained by holding a specimen solution and keeping the carrier stationary for 5 to 10 minutes, in the quickest case. For this reason, test methods that use assay methods, such as immunological testing and the like, are widely used, for example, in clinical inspection in hospitals and certification testing in laboratories, as simple and rapid test methods.
In particular, in medical care sites, such as doctor's office, clinic, home medical care, and the like, immunochromatographic test devices (immunochromato-reader) are widely used as test devices for POCT (Point of Care Testing) in which a simple test is performed by a person who is not a specialist of clinical inspection. The immunochromatographic test device may measure a color development state of a reagent loaded in the device with high sensitivity, thereby allowing high sensitivity and high reliability testing even when the color development state is so low that visual judgment is difficult. An example of such type of test device is described in Japanese Unexamined Patent Publication No. 2009-133813.
In the test method described above, it is demanded that a small amount of test substance is detected with high sensitivity. As a test method that responds to such demand, a method that performs amplification (sensitization) is known as described, for example, in Japanese Unexamined Patent Publication No. 2009-287952. In the method, a test substance is deployed on the carrier, then a cleaning solution is supplied to the carrier to clean the carrier other than a labeled substance captured by the reaction site on the carrier through specific binding, and a sensitizing solution is supplied to the carrier to effect sensitization, thereby allowing a small amount of test substance to be detected with high sensitivity.
Note that the sensitization may be performed on an as-required basis. That is, in the case where the color development state can be measured through the ordinary processing, the measurement is terminated, while if the color development state cannot be measured through the ordinary processing, the color development state may be measured after sensitization.
The aforementioned conventional test devices, such as the immunochromatographic test device, and the like, are often structured to perform testing using a reaction vessel having therein a carrier with a reagent held thereon. The reaction vessel is generally referred to as a cartridge, package, or test kit, and often configured to allow for a plurality of different diseases to be determined positive or negative by a plurality of different types of reagents.
Now,
The patient waits for a test result in a waiting lounge until the test is completed and a test result becomes available (step S4). In the mean time, the doctor or the like performs diagnosis or treatment for the next patient (step S5).
Then, the doctor confirms the test result sent from the inspection center after the estimated completion time of the test (step S6). Thereafter, the doctor calls in the patient again and explains the diagnostic result and treatment based on the result, and writes down the diagnostic result and treatment in the medical record (step S7). The patient returns home after receiving the treatment (step S8).
PCT Japanese Publication No. 2008-518617 describes that a test result is conveyed to a doctor by a communication means, and such conveying method may be applied to the test and diagnosis described above.
The test and associated processing flow shown in
But, this will result in that a patient needs to wait for a long time in the waiting lounge or the like before being called in by the doctor, and if the patient is affected and if, in particular, the disease is highly infectious, in-hospital infection may occur. Further, in the case where the patient is affected, an adverse situation may also arise in which the symptom is aggravated due to a prolonged time of waiting.
In view of the circumstances described above, it is an object of the present invention to provide, in a method for testing a patient for a plurality of diseases, a test method capable of preventing in-hospital infection and aggravation of the symptom of a patient arising from a prolonged stay in a medical institution.
A test method according to the present invention is a method for testing with a test apparatus whether a subject is positive or negative for a plurality of diseases using a specimen collected from the subject,
wherein, if the subject is determined to be positive for one of the plurality of diseases, a test result indicating the positive is outputted from the test apparatus without waiting for completion of the testing of the other diseases.
Generally, the specimen is sent in spot applied to a test cartridge or the like from a person making an inspection request, such as the doctor or the like, to the operator of the test device, such as a medical technologist. In such a case, when the test result is outputted, it is preferable to generate a notice of test result to be sent to the person who has made the inspection request from the test apparatus. The term “notice of test result to be sent to the person who has made the inspection request” as used herein refers to all notices issued with the person who has made the inspection request as the destination. For example, a notice sent to a nurse working with the doctor, the person who has made the inspection request, via FAX or telephone and a printed notice with a note saying like “deliver this to doctor ∘∘ of ΔΔ department” are included in such notices, as well as a notice sent to the person who has made the inspection request via the communication means described in PCT Japanese Publication No. 2008-518617.
In the test method of the present invention, it is preferable that the testing for the one disease described above is performed first among the plurality of diseases to be tested.
Preferably, the testing for the one disease is arbitrarily selectable from the plurality of diseases to be tested.
Preferably, the test result indicating positive for the one disease is outputted by a means different from that for outputting test results of the other diseases. More specifically, if for example, the latter outputting means is FAX or telephone, the former output, the output indicating positive for the one disease may be via an electronic mail system, or vice versa. Further, if the means for implementing the latter output is a white facsimile paper, then the means for implementing the former output may be a colored facsimile paper, or vice versa.
More preferably, the test method of the present invention is applied to the case in which the disease to be tested is an infectious disease.
Preferably, the test method of the present invention is applied to the case in which a plurality of diseases whose therapeutic agents are the same is set as the test targets.
In the mean time, the test apparatus of the present invention is an apparatus configured to allow a. subject to be tested positive or negative for a plurality of diseases using a specimen collected from the subject,
wherein, the apparatus includes a means for outputting, if the subject is determined to be positive for one of the plurality of diseases, a test result indicating the positive without waiting for completion of the testing of the other diseases.
According to the test method of the present invention, if a subject is determined to be positive for one of a plurality of diseases, a test result indicating the positive is outputted from the test apparatus without waiting for completion of the testing of the other diseases. This allows the person who has made the inspection request, such as the doctor, to know a positive test result for a particular disease, for example, highly infectious disease or the like, for the time being before all of the tests are completed after a long time. Then, the doctor or the like may immediately call in the patient waiting in the waiting lounge of a. medical institution for treatment only for the disease and the patient may return home after that. This may prevent a. prolonged stay of the patient in the hospital or the like, whereby in-hospital infection or aggravation of the symptom of the patient may be prevented.
In the case where a notice of test result to be sent to the person who has made the inspection request is generated from the test apparatus, in particular, the test result may be delivered to the person who has made the inspection request in a shorter period of time.
Further, in the test method of the present invention, if the one disease described above is a disease to be tested first among a plurality of diseases, in particular, the time for the patient to stay in the hospital or the like may be minimized, so that the advantageous effects of preventing in-hospital infection or prevention of symptom aggravation of the patient become significant.
In the test method of the present invention, in particular, if the testing for the one disease described above is made arbitrarily selectable from a plurality of diseases to be tested, then, the in-hospital infection maybe prevented more reliably by, for example, making an appropriate response in which the testing for the influenza of increased infectiousness is completed sooner according to the occurrence of influenza in each year.
If the test method of the present invention is applied to the case where the test target is an infectious disease, such as influenza or the like, in-hospital infection of the disease may be prevented as described above. In the case where the test target is not an infectious disease also, the application of the present invention may provide advantageous effects of preventing symptom aggravation of the patient due to prolonged stay in the hospital or the like for a test result.
If the test method of the present invention is applied to the case where a plurality of diseases is those whose therapeutic agents are the same, in particular, a test result is outputted at the time when one test result is determined to be positive and the test result is notified to the doctor, so that the doctor may prescribe an appropriate therapeutic agent without exactly knowing what kind of the disease it is which has been determined to be positive.
In the mean time, the test apparatus of the present invention includes a means for outputting, if the subject is determined to be positive for one of the plurality of diseases, a test result indicating the positive without waiting for completion of the testing of the other diseases, as described above. Thus, the test method of the present invention described above may be implemented with the apparatus.
Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings.
As illustrated in these drawings, the immunochromatographic test device 1 includes a housing 10 having an opening 10a in front, a display unit 11 disposed on the upper surface of the housing 10, an operation unit 12 for operating a menu displayed on the display unit 11, a power switch 13, and a cartridge loading unit 14 for loading an immunochromatographic cartridge 20 inside of the device. The device 1 further includes, inside of the housing 10, a rail 15 for movably guiding the cartridge loading unit 14 in left-right directions in
The cartridge loading unit 14 is movable automatically or manually along the rail 15. When a most part of the unit is drawn out of the housing 10 past the opening 10a, the cartridge 20 supplied with a test solution in a manner to be described later is placed thereon. Then the cartridge loading unit 14 is pushed into the housing 10, as illustrated in
The pressing piece 32 of the pressing unit 30 and the pressing piece 36 of the pressing unit 34 are arranged so as to locate immediately above the cleaning solution pot 27 and sensitizing solution pot 28 disposed inside of the kit respectively when the cartridge 20 is placed at a given position in the housing 10.
The insoluble carrier 21 has an immobilized labeling substance. Each of the test lines A, B has a specific binding substance for a specimen (test substance) immobilized thereon as a reagent and the control line C is provided to determine the end of the measurement.
Further a solution sending insoluble carrier 72 and an absorption insoluble carrier 73 are arranged inside of the cartridge 20 so as to sandwich the insoluble carrier 21. The cleaning solution pot 27 is fixed above the solution sending insoluble carrier 72 and the sensitizing solution pot 28 is fixed above the end portion of the insoluble carrier 21 on the control line C side. The upper surface portion of the case 22 of the cartridge 20 deforms easily when pressed down from above by the pressing pieces 32 and 36 described above to allow the cleaning solution pot 27 and sensitizing solution pot 28 to be crushed.
The first measurement unit 40 measures a color development state of the test region (portions of the test lines A, B and control line C) through the observation window 24 of the cartridge 20. As illustrated in
The optical density is defined by the formula given below when the intensity of the incident light incident on the test region of the cartridge 20 is taken as I and the intensity of the reflection light from the test region is taken as Ir:
Optical density=−log 10(Ir/I)
The chromaticity is a quantitative representation of hue and saturation and is calculated from the RGB luminance signal captured by the camera. As for the color system of the chromaticity, the general CIE color system may be used.
The camera 42 includes, for example, a plurality of photodiodes arranged in a line or an image sensor formed of an area sensor, and generates an output according to the amount of light received. The light receiving range of the camera 42 is set to the strip-like range extending in the longitudinal direction of the cartridge 20. The light source 44 is, for example, a module having an LED therein and configured to emit white light. The light source 44 may be, for example, a monochromatic light source if it allows distinction between chromaticity values before and after sensitization, to be described later. In the case where the light source 44 includes a plurality of modules, each module may emit monochromatic light of a different wavelength. The light emitted from the light source 44 is set to reach a predetermined range in the longitudinal direction of the cartridge 20.
In the mean time, the second measurement unit 50 directs illumination light to the information display section 25 of the cartridge 20 and obtains information displayed on the information display section 25. The information display section 25 is a place where information related to the test is displayed by handwriting, attaching a seal, or the like. The information related to the test may include, for example, information of the patient from which the test substance has been collected (name, age, gender, and the like) and information of sample and reagent used in the testing (test target specimen, names of the cleaning solution and sensitizing solution used, and the like). There is not any specific restriction on the method of obtaining the information, and the information display section 25 may be imaged directly or information may be read from bar coded information.
As illustrated in
The electrical configuration of the device will now be described with reference to
Further, a battery level monitoring unit 103 as a remaining battery level detection means for detecting a remaining amount of power in the battery 102 is connected to the switching unit 101. Generally, a battery has a property that the internal resistance increases as the battery level is reduced due to its chemical characteristics and the terminal voltage is reduced. Thus, the amount of remaining power in the battery can be detected by measuring the terminal voltage. In this way, the battery level monitoring unit 103 keeps monitoring the amount of remaining power in the battery 102 and a signal representing the amount of remaining power is inputted to the control unit 80.
Next, measurement performed by the test device 1 of the present embodiment will be described. In principle, the present device performs a first stage measurement followed by a second stage measurement. As the first stage measurement, a color development state of the test region is measured without sensitization, to be described later, and the color development state of the test region is measured after the sensitization, as the second stage measurement.
First, a specific operational procedure for the measurement will be described.
In the first stage measurement, for example, a specimen solution 90 is injected into the cartridge 20 from the solution injection opening 23 outside of the test device 1, as illustrated in
The image processing unit 81 calculates a color development state of reagent portion, i.e., optical density and chromaticity of the portion based on the two-dimensional signal and displays the calculated values together with a positive or negative judgment for disease made based on the values on the display unit 11 as the detection results.
In the second stage measurement, the pressing unit 30 shown in
Next, the pressing unit 34 shown in
After the sensitization, the test region of the cartridge 20 is imaged by the camera 42 in the manner described above. The control unit 80 shown in
Associated processing performed in the hospital or the like before and after the testing performed in the manner described above will now be described with reference to
The testing described above is shown in
Normally, therefore, the positive test result is obtained before the negative test result, and if a test result of either one of the test lines (for example, test line A) is positive for the infectious disease “a”, the image processing unit 81 shown in
The nurse received the information or the like changes the order in waiting list by changing medical cards (step S11) so that the patient, the subject of the testing described above, will be called in by the doctor next to the patient currently being examined or treated by the doctor. Then, the doctor explains the positive item and treatment for the item (step S12) and performs the treatment. The patient returns home after receiving the treatment (step S8).
Thereafter, all of the test results including a positive or negative judgment for the infectious disease “b” are delivered to the doctor from the medical technologist who performed the testing, and the doctor writes down the contents of the aforementioned treatment and all of the test results in the medical record (step S13), thereby completing a. series of diagnosis for the patient.
As described above, according to the present embodiment, if positive is confirmed for an infectious disease “a”, an output representing the positive is generated and the output is informed to the doctor who have made an inspection request without waiting for completion of the test for the other infectious disease “b”. This allows the doctor to know the positive test result for the infectious disease “a” for the time being before all of the tests are completed after a long time. Then, the doctor may return the patient home early after the explanation and treatment described above. This may prevent a prolonged stay of the patient in the hospital or the like, whereby in-hospital infection or aggravation of the symptom of the patient may be prevented.
The test method of the present invention may perform positive or negative testing for a plurality of diseases. There may be a case in which the same therapeutic agent may be used even when any of the plurality of diseases becomes positive. For example, in the case of type A influenza and type B influenza testing, the same antiviral medicine is administered in either case in which the type A influenza or type B influenza is positive. In such a case, if a test result is outputted at the time when one test result is determined to be positive, the doctor informed of the test result may prescribe an appropriate therapeutic agent without exactly knowing what kind of the disease it is which has been determined to be positive.
In the present embodiment, testing for two types of diseases is performed, but the present invention is applicable to the case in which positive or negative detection is performed for three or more diseases. In such a case, the test whose result needs to be preferentially informed to the person who has made the inspection request may be any test other than that performed last in any event. But, if the test whose result needs to be preferentially informed to the person who has made the inspection request is arranged to be performed first, the time for the patient to stay in the hospital or the like may be reduced the most if the test result thereof is positive, so that advantageous effects of the prevention of in-hospital infection or aggravation of the symptom of the patient become significant.
In particular, in the case where the test whose result needs to be preferentially informed is made arbitrarily selectable from a plurality of tests in the test method of the present invention, then, the in-hospital infection may be prevented more reliably by, for example, making an appropriate response in which the test for the influenza of increased infectiousness is completed sooner according to the occurrence of influenza in each year.
In the case where the display unit 11 shown in
Further, if an arrangement is adopted in which a sound alarm is issued when the positive test result is obtained for the infectious disease “a” in the manner described above, the medical technologist or the like may be informed reliably that a test result which should be sent to the person who has made the inspection request is obtained.
Items associated with the aforementioned measurement will be described briefly.
There is not any specific restriction on the specimen solutions which can be analyzed by the test device of the present invention as long as they are likely to include test substances (natural products, poisons, biologically active agents such as hormones, agricultural chemicals, and the like, or environmental pollutants, and the like). For example, biological samples, in particular, animal (in particular, human) body fluids (e.g., bloods, serums, blood plasmas, spinal fluids, tear fluids, sweats, urines, purulent matters, snivels, or sputum), or body wastes (e.g., faces), organs, tissues, mucous membranes, skins, or scratched specimens (swabs) believed to include these, gargled solutions, animals or plants themselves, or dried bodies thereof diluted by a diluting fluid, to be described later.
The specimen solution may be used directly, in the form of extraction liquid extracted using an appropriate extraction solvent, in the form of diluted solution obtained by diluting the extraction liquid with an appropriate diluting agent, or in the condensed form of the extraction liquid condensed by an appropriate method.
There is not any specific restriction on the labeling substance that can be used in the present invention as long as it can be visually recognizable or detectable through reaction, such as metal fine particles (or metallic colloids) used in general immunochromatographic methods, colored latex particles, enzymes, and the like. In the case where a signal is sensitized through deposition of metal on the labeling substance due to reduction reaction of metal ions with the labeling substance as the catalyst, however, metal particles are preferably used in view of the catalytic activity.
As for the material of the metal fine particles, single metal body, metallic sulfide, metal alloy, or polymer particle that includes the metal may be used. Preferably, the average particle diameter of the particles (colloids) is in the range of 1 nm to 10 μm. The average particle diameter as used herein refers to an average value of diameters (longest diameters) of a plurality of particles measured by a transmission electron microscope (TEM). More specifically, gold colloids, silver colloids, platinum colloids, iron colloids, aluminum hydroxide colloids, and complex colloids of these may be cited, and gold colloids, silver colloids, platinum colloids, and complex colloids of these are preferably used. Among them, the gold colloids and silver colloids are particularly preferable in view of the fact that the gold colloids and silver colloids having an appropriate particle diameter appear in red and yellow respectively, thereby providing high visibility. The use of gold colloids and performance of sensitization process using a silver-ion containing compound cause the chromaticity of the label to be changed before and after the sensitization process (the gold colloids are colored red which turn to black after the sensitization due to deposition of reduced silver ions on the gold colloids). Thus, this change may be used for the judgment of a test error as described later. Preferably, the average particle diameter of the metal colloids is 1 to 500 nm and more preferably, 1 to 100 nm.
There is not any specific restriction on the specific binding substance as long as it has affinity to the test substance. For example, if the test substance is an antigen, the specific binding substance may be the antibody to the antigen, if the test substance is protein or a metal ion or low molecular organic compound, the specific binding substance may be an aptamer to these, if the test substance is a nucleic acid, such as DNA or RNA, the specific binding substance may be a nucleic acid molecule such as DNA or RNA having a complementary sequence to these, if the test substance is an avidin, the specific binding substance may be a biotin, and if the test substance is a particular peptide, the specific binding substance may be a complex that specifically bind to the peptide. Further, the relationship between the specific binding substances and test substances described above maybe replaced and, for example, if the test substance is an antibody, the antigen to the antibody may be used as the specific binding substance. Further, compounds which partially include substances having affinity to those test substances described above may be used as the specific binding substances.
As for the antibody describes above, an antiserum prepared from an animal serum immunized by the test substance, an immunoglobulin faction purified from the antiserum, a monoclonal antibody obtained by cell fusion using an animal spleen cell immunized by the test substance, or fragments of these (such as F(ab′)2, Fab, Fab′, or Fv) may specifically used. These antibodies may be prepared by an ordinary method.
Preferably, the material of the insoluble carrier 21 is porous and, for example, nitrocellulose membranes, cellulose membranes, cellulose acetate membranes, polysulfone membranes, polyether sulfone membranes, nylon membranes, glass fibers, nonwoven fabrics, fabrics, threads, or the like are preferably used.
A test line is created on a chromatograph carrier by immobilizing a specific binding substance for a test substance with a control region as required. The specific binding substance may be directly immobilized on a portion of the chromatograph carrier physically or through chemical bonding. Alternatively, the specific binding substance may be immobilized on fine particles, such as latex particles or the like, physically or through chemical bonding, and the particles may be immobilized on a portion of the chromatograph carrier by trapping.
The sensitizing solution is a solution that produces a compound that develops a color or emits light through a reaction of the chemical agent included therein by way of catalytic action of the labeling substance or test substance, thereby capable of sensitizing a signal. For example, it may be a silver ion solution that causes deposition of metallic silver on a metallic labelling due to physical development. More specifically, so-called developers may be used as described in general books in the field of photographic chemicals (for example, “Revised Basic Photographic Engineering—Silver Halide Photography”, Edited by Society of Photographic Science and Technology of Japan, Corona Publishing Co., Ltd., “Chemicals of Photography”, Akira Sasai, Photography Industry Publishing Co., Ltd. and “Handbook of Recent Prescription”, Shinich Kikuchi et al., AMIKO Publishing). For example, the use of a physical developer which includes a compound having silver ions as the sensitizing solution may reduce silver ions in the solution around metal colloids serving as cores of development or the like by the reducing agent of the silver ions.
Another example is to use enzyme reaction. For example, a solution of phenylenediamine compound and naphthol compound which becomes a dye by the action between a peroxidase label and hydrogen peroxide may be used. Further, a chromogenic substrate used in horseradish peroxidase detection as described in a non-patent document “Staining Utilizing H2O2-POD System”, Clinical Examination, Vol. 41, No. 9, pp. 1020-1024, may also be used. The chromogenic substrate described in Japanese Unexamined Patent Publication No. 2009-156612 is particularly preferable. Still further, a system utilizing a metal catalyst, such as platinum fine particles, instead of enzyme may also be used.
As for another example that utilizes a different enzyme, a system that develops a color with alkaline phosphatase as the labelling and 5-bromo-4-chloro-3-indolyl phosphate disodium salt (BCIP) as the substrate is known. So far, chromogenic reactions have been described as representative examples, but any combination of enzyme and substrate may be used, in which the substrate may be that which emits chemiluminescence or fluorescence.
As for the silver ion containing compound, an organic silver salt, inorganic silver salt, or silver complex may be used. Silver ion containing compounds having high solubility in solvent, such as water, are preferable, and such compounds includes silver nitrate, silver acetate, silver lactate, butanoic acid silver, silver thiosulfate, and the like. Among them, silver nitrate is particularly preferable. As for the silver complex, a silver complex coordinated with a ligand having a water-soluble group such as a hydroxyl group or a sulfone group is preferable. An example of such a silver complex may be hydroxy thioether silver or the like. Preferably, the inorganic silver salt or silver complex is included as silver generally in the amount of 0.001 mole/m2 to 0.2 mole/m2, and more preferably 0.01 mole/m2 to 0.05 mole/m2.
As for the reducing agent used for silver ions, any material, such as an inorganic material, organic material, or a mixture thereof, can be used, as long as it can reduce silver ions to silver.
Preferable examples of inorganic reducing agent include reducing metal salts and reducing metal complex salts whose valence can be changed with metal ions such as Fe2+, V2+, or Ti3+. In the case where an inorganic reducing agent is used, it is necessary to remove or render harmless oxidized ions through complexation or reduction. For example, in a system that uses Fe2+ as the reducing agent, a complex of Fe3+, as an oxide, is formed with citric acid or EDTA, whereby the oxidized ions can be rendered harmless. In the present system, it is preferable to use such an inorganic reducing agent, and metal salt of Fe2+ is more preferably used.
In the embodiment described above, a method in which labeling substance is sensitized by reducing a silver ion containing compound by a reducing agent as the sensitizing method for color development, but the sensitizing method in the present invention is not limited to this. The sensitizing solution may be any solution as long as it is capable of producing a compound that develops a color or emits light through a reaction of the chemical agent included therein by way of catalytic action of the labeling substance or test substance and sensitizing a signal. An example may be a solution of the enzyme described above.
In the embodiment described above, the immunochromatographic method has been described as an assay method, but the assay method of the present invention is not limited to this. It is applicable to a system that does not use so-called immunoreactions. For example, the present invention may be applied to a system in which a test substance is captured by a nucleic acid, such as DNA or RNA without using the antibody or a system in which a test substance is captured by a different small molecule having affinity to the test substance, peptide, protein, complex forming substance, or the like.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2010-222248 | Sep 2010 | JP | national |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/JP2011/005441 | Sep 2011 | US |
| Child | 13852919 | US |
