Method, device and program for obtaining information related to respiratory infection, method and kit for monitoring measured values ​​of biomarkers

Abstract

The present invention aims to provide a new means for obtaining information related to respiratory infections using biomarkers capable of determining the risk of acute kidney injury and pulmonary fibrosis caused by respiratory infections. The present inventors have solved the above problem by a method for obtaining information related to respiratory infections, the method comprising measuring at least one biomarker in a test sample collected from a subject suffering from a respiratory infection or a subject suspected of having a respiratory infection, the biomarker comprising at least one selected from CXCL9, CCL3, and IL-18, and the measurement result of the biomarker serving as an index of the risk of acute kidney injury or pulmonary fibrosis caused by a respiratory infection.

Description

Technical Field

[0001] The present invention relates to a method for obtaining information related to respiratory infections. The present invention relates to a method for monitoring measured values of biomarkers. The present invention relates to a kit used in these methods. The present invention relates to an apparatus for obtaining information related to respiratory infections. The present invention relates to a computer program for obtaining information related to respiratory infections.

Background Art

[0002] When a respiratory infection becomes severe, it sometimes causes complications such as acute kidney injury or pulmonary fibrosis. Such complications caused by respiratory infections sometimes progress to a severe state. In addition, when a complication occurs, sequelae remain even after the respiratory infection is cured. For example, in pulmonary fibrosis caused by a respiratory infection, the fibrotic part does not recover and fibrosis remains.

[0003]

Prior Art Documents

[0004]

Non-Patent Documents

[0005]

Non-Patent Document 1

[0006]

Summary of the Invention

[0007]

Problems to be Solved by the Invention

[0008] The treatment policies for respiratory infections and the complications caused thereby are different. When the risk of complications caused by a respiratory infection can be determined, a treatment policy corresponding to the risk can be formulated. Non-Patent Document 1 reports that among patients with COVID-19 (Coronavirus disease 2019), the measured values of IL (Interleukin)-6 and IL-10 in the serum of the severe patient group are significantly higher than those of the mild patient group, and IL-6 and IL-10 can be predictive markers for the severity of COVID-19. However, this document does not describe biomarkers for determining the risk of complications caused by a respiratory infection.

[0009] An object of the present invention is to provide a new means for obtaining information related to a respiratory infection by using biomarkers capable of determining the risk of acute kidney injury and pulmonary fibrosis caused by a respiratory infection.

[0010]

Means for Solving the Problem

[0011] The present inventors found that CXCL9 (CXC chemokine ligand 9), CCL3 (CC chemokine ligand 3), and IL-18 can be used as biomarkers for determining the risk of acute kidney injury and pulmonary fibrosis caused by respiratory tract infection, and thus completed the present invention. Accordingly, the present invention provides a method for obtaining information related to respiratory tract infection, which includes measuring at least one biomarker in a test sample collected from a subject suffering from respiratory tract infection or a suspected respiratory tract infection subject, the biomarker including at least one selected from CXCL9, CCL3, and IL-18, and the measurement result of the biomarker being an index of the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0012] The present invention provides a method for monitoring the measured value of a biomarker, which includes using test samples collected from a subject suffering from respiratory tract infection or a suspected respiratory tract infection subject at multiple time points, obtaining the measured value of at least one biomarker in each test sample, the biomarker including at least one selected from CXCL9, CCL3, and IL-18, and the measured value of the biomarker being an index of the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0013] The present invention provides a method for obtaining information related to respiratory tract infection, which includes a step of measuring at least one biomarker in a test sample collected from a subject suffering from respiratory tract infection or a suspected respiratory tract infection subject, and a step of determining the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection based on the measured value of the biomarker, the biomarker including at least one selected from CXCL9, CCL3, and IL-18.

[0014] The present invention provides a kit for use in the above method, including at least one selected from a reagent containing a substance capable of specifically binding to CXCL9, a reagent containing a substance capable of specifically binding to CCL3, and a reagent containing a substance capable of specifically binding to IL-18.

[0015] The present invention provides a device for acquiring information related to respiratory infections, which includes a computer having a processor and a memory under the control of the processor. In the memory, a computer program is recorded for causing the computer to execute steps of acquiring measurement values of biomarkers in a specimen collected from a subject suffering from a respiratory infection or a suspected respiratory infection, and steps of outputting the measurement values of the biomarkers. The biomarkers include at least one selected from CXCL9, CCL3, and IL-18, and the measurement values of the biomarkers serve as an index for the risk of developing acute kidney injury or pulmonary fibrosis caused by a respiratory infection.

[0016] The present invention provides a computer program for acquiring information related to respiratory infections, which is a computer program recorded on a computer-readable medium. The computer program is for causing the computer to execute steps of acquiring measurement values of biomarkers in a specimen collected from a subject suffering from a respiratory infection or a suspected respiratory infection, and steps of outputting the measurement values of the biomarkers. The biomarkers include at least one selected from CXCL9, CCL3, and IL-18, and the measurement values of the biomarkers serve as an index for the risk of developing acute kidney injury or pulmonary fibrosis caused by a respiratory infection.

[0017]

Effects of the Invention

[0018] According to the present invention, the risk of developing acute kidney injury or pulmonary fibrosis caused by a respiratory infection can be determined.

[0019]

Brief Description of the Drawings

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Detailed implementation manners

[0045] In the method for obtaining information related to respiratory infections in this embodiment (hereinafter, also referred to as the "obtaining method"), at least one biomarker in the test sample collected from a subject suffering from a respiratory infection or a subject suspected of having a respiratory infection is measured.

[0046] Respiratory infections refer to diseases that occur through the infection of respiratory organs such as the nasal cavity, pharynx, trachea, bronchi, and alveoli by pathogens. The pathogens are not particularly limited, and examples include viruses, bacteria, fungi, parasites, etc. As viruses, examples include coronaviruses, influenza viruses, etc. Coronaviruses are not particularly limited, and examples include α-coronavirus, β-coronavirus, γ-coronavirus, and δ-coronavirus. As β-coronavirus, examples include SARS-CoV-2, SARS-CoV, MERS-CoV, etc. In a preferred embodiment, the respiratory infection is a respiratory infection caused by SARS-CoV-2, that is, COVID-19.

[0047] As subjects, patients suffering from respiratory infections and those suspected of having such respiratory infections can be cited. A patient suffering from a respiratory infection refers to a person confirmed to be infected by detecting pathogens, etc. In this embodiment, among the patients suffering from respiratory infections, patients in whom the respiratory infection has not become severe, patients who have not developed acute kidney injury caused by the respiratory infection, and patients who have not developed pulmonary fibrosis caused by the respiratory infection are preferably used as subjects.

[0048] A person suspected of having a respiratory infection refers to a person in whom infection has not yet been confirmed and who has a possibility of suffering from a respiratory infection. For example, those who show cold symptoms such as fever, cough, runny nose, pharyngeal pain, etc. and / or specific symptoms of a designated respiratory infection such as dyspnea, shortness of breath during labor, and abnormalities in taste and smell, those who have come into contact with a patient suffering from a respiratory infection, and those suspected of having come into contact, etc. Contact with a patient suffering from a respiratory infection refers to, for example, having a conversation with the patient at a distance of within 1 m, staying in an enclosed space where the patient is present, and being exposed to droplets such as the patient's saliva and cough.

[0049] The test substance is not particularly limited as long as it can be collected from the subject and contains the above-mentioned biomarker. As such a sample, examples include blood samples, lymph fluid, cerebrospinal fluid, saliva, nasopharyngeal swab fluid, sputum, bronchoalveolar lavage fluid, urine, feces, etc. As a blood sample, examples include blood (whole blood) collected from the subject and plasma or serum prepared from the blood. In this embodiment, whole blood, plasma, and serum are preferred, and plasma and serum are particularly preferred.

[0050] When there are insoluble impurities such as cells in the subject, the impurities can be removed from the subject by known means such as centrifugation, filtration, etc. In addition, the subject can be diluted with a suitable aqueous medium as needed. Such an aqueous medium is not particularly limited as long as it does not interfere with the measurement of the biomarker described below, and examples thereof include water, physiological saline, buffer solutions, etc. The buffer solution is not particularly limited as long as it has a buffering action at a pH near neutrality (for example, a pH of 6 or more and 8 or less). Examples of such buffer solutions include Good buffer solutions such as HEPES, MES, and PIPES, phosphate buffered saline (PBS), Tris-HCl buffer solution, Tris-buffered saline (TBS), etc.

[0051] In the present embodiment, the biomarker contains one or more protein molecules selected from CXCL9, CCL3, and IL-18. CXCL9 is also known as MIG (Monokine induced by interferonγ) and is a type of Th1 chemokine. CCL3 is also known as MIP1a (Macrophage inflammatory protein 1α) and is a chemokine related to acute inflammation. IL-18 is a type of inflammatory cytokine that induces both Th1 response and Th2 response. These protein molecules themselves are well-known, and their amino acid sequences can be obtained from known databases such as NCBI (National Center for Biotechnology Information), etc.

[0052] In the present embodiment, it is preferable to obtain the measurement values of two or more biomarkers selected from CXCL9, CCL3, and IL-18. As two or more biomarkers, for example, any of the following combinations can be cited:

[0053] - A combination of CXCL9 and at least one selected from CCL3 and IL-18;

[0054] - A combination of CCL3 and at least one selected from CXCL9 and IL-18;

[0055] - A combination of IL-18 and at least one selected from CXCL9 and CCL3; and

[0056] - A combination of IL-18, CXCL9, and CCL3.

[0057] In this specification, "measuring a biomarker" includes obtaining a value reflecting the amount or concentration of the biomarker and determining the value of the amount or concentration of the biomarker. The "value reflecting the amount or concentration of the biomarker" refers to a value based on the type of labeling substance described below and can be obtained by a measuring device corresponding to the type of labeling substance. As such values, for example, measured values of luminescence intensity, fluorescence intensity, radiation intensity, optical density, etc. can be cited. The "value of the amount or concentration of the biomarker" can be determined based on the value reflecting the amount or concentration of the biomarker and the measurement results of the calibrator. A calibrator is a type of control sample and refers to a quantitative sample of a test substance containing a known concentration of a standard substance corresponding to the test substance or its counterpart. In the present embodiment, for example, recombinant proteins of CXCL9, CCL3, and IL-18 can be used as calibrators.

[0058] In the present embodiment, the measured value of the biomarker can be a value reflecting the amount or concentration of the biomarker in the subject. In addition, the measured value of the biomarker can be a value of the amount or concentration of the biomarker in the subject determined based on the measurement results of the calibrator.

[0059] The means for measuring the biomarker is not particularly limited and can be appropriately selected from known measurement methods. In the present embodiment, a method of capturing the biomarker using a substance that can specifically bind to the biomarker is preferably included. By detecting the biomarker captured by such a substance using a known method, the biomarker contained in the subject can be measured.

[0060] Examples of substances that can specifically bind to the biomarker include antibodies, aptamers, etc. Among them, antibodies are particularly preferred. In this specification, the term "antibody" includes full-length antibodies and their fragments. Examples of antibody fragments include reduced IgG (rIgG), Fab, Fab', F(ab')2, Fv, single-chain antibody (scFv), diabody, triabody, etc. The antibody can be either a monoclonal antibody or a polyclonal antibody. Antibodies that specifically bind to the above-mentioned various biomarkers are known per se and can be generally obtained. For example, the antibody can also be obtained by producing a hybridoma that produces an antibody specifically binding to the biomarker by the method described in Kohler G. and Milstein C., Nature, vol. 256, pp. 495-497, 1975. Alternatively, commercially available antibodies can also be used.

[0061] The method for measuring a biomarker using an antibody is not particularly limited, and can be appropriately selected from known immunological measurement methods such as enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunoassay, immunoturbidimetry, immunonephelometry, latex agglutination method, etc. In the present embodiment, the ELISA method is preferably used. The type of ELISA method can be any one of sandwich method, competitive binding method, direct method, indirect method, etc., and the sandwich method is particularly preferred. As an example, the case of measuring a biomarker in a subject by the sandwich ELISA method will be described below.

[0062] The measurement of a biomarker by the sandwich ELISA method includes a step of forming a complex of an antibody and a biomarker and a step of detecting the complex. In the step of forming the complex, a complex containing a biomarker, an antibody for capturing the biomarker (hereinafter, also referred to as "capture antibody") and an antibody for detecting the biomarker (hereinafter, also referred to as "detection antibody") is formed on a solid phase. When the subject contains a biomarker, by mixing the subject, the capture antibody and the detection antibody, a complex containing the biomarker, the capture antibody and the detection antibody can be formed. Further, by bringing the solution containing the complex into contact with a solid phase capable of immobilizing the capture antibody, the above-mentioned complex can be formed on the solid phase. Alternatively, a solid phase pre-immobilized with the capture antibody can also be used. That is, by bringing the solid phase immobilized with the capture antibody, the subject and the detection antibody into contact, the above-mentioned complex can be formed on the solid phase. Furthermore, when both the capture antibody and the detection antibody are monoclonal antibodies, it is preferable that their epitopes are different from each other.

[0063] The solid phase only needs to be an insoluble carrier capable of immobilizing the capture antibody. The implementation mode of immobilizing the capture antibody on the solid phase is not particularly limited. For example, the capture antibody can be directly bound to the solid phase, or the capture antibody can be indirectly bound to the solid phase via another substance. Examples of direct binding include physical adsorption and the like. Examples of indirect binding include immobilizing a molecule that specifically binds to the antibody on the solid phase, and immobilizing the antibody on the solid phase through the binding of this molecule and the antibody. Examples of molecules that specifically bind to the antibody include Protein A or G, an antibody that specifically recognizes the antibody (second antibody), and the like. In addition, a combination of substances can also be used between the antibody and the solid phase to immobilize the capture antibody on the solid phase. Examples of such a combination of substances include the combination of biotin and avidin, hapten and anti-hapten antibody, and the like. Biotin includes biotin, and biotin analogs such as desthiobiotin and oxybiotin. Avidin includes avidin, and avidin analogs such as streptavidin and Tamavidin (registered trademark). Examples of the combination of hapten and anti-hapten antibody include the combination of a compound having a 2,4-dinitrophenyl (DNP) group and an anti-DNP antibody. For example, by using a capture antibody pre-modified with biotin (or a compound having a DNP group) and a solid phase pre-bound with avidin (or anti-DNP antibody), the capture antibody can be immobilized on the solid phase through the binding of biotin and avidin (or the binding of the DNP group and anti-DNP antibody).

[0064] The raw material of the solid phase is not particularly limited, and can be selected, for example, from organic high molecular compounds, inorganic compounds, biological macromolecules, etc. Examples of organic high molecular compounds include latex, polystyrene, polypropylene, etc. Examples of inorganic compounds include magnetic substances (such as iron oxide, chromium oxide, and ferrite), silica, alumina, glass, etc. Examples of biological macromolecules include insoluble agarose, insoluble dextran, gelatin, cellulose, etc. Two or more of these can also be used in combination. The shape of the solid phase is not particularly limited, and examples include particles, membranes, microplates, microtubes, test tubes, etc. Among them, particles are also preferred, and magnetic particles are particularly preferred.

[0065] In the present embodiment, between the complex formation step and the complex detection step, B / F (Bound / Free) separation for removing unreacted free components that have not formed a complex may also be performed. The unreacted free components refer to components that do not constitute the complex. For example, capture antibodies and detection antibodies that have not bound to the biomarker can be cited. The means for B / F separation is not particularly limited. When the solid phase is a particle, B / F separation can be performed by centrifugally separating and only recovering the solid phase of the capture complex. When the solid phase is a container such as a microplate or a microtube, B / F separation can be performed by removing the liquid containing the unreacted free components. In addition, when the solid phase is magnetic particles, B / F separation can be performed by aspirating the liquid containing the unreacted free components with a pipette while magnetically confining the magnetic particles with a magnet, which is preferable from the viewpoint of automation. After removing the unreacted free components, the solid phase of the capture complex can also be washed with a suitable aqueous medium such as PBS.

[0066] In the complex detection step, by detecting the complex formed on the solid phase by a method known in the prior art, a measurement value of the biomarker can be obtained. For example, when an antibody labeled with a labeling substance is used as the detection antibody, a measurement value of the biomarker can be obtained by detecting the signal generated by the labeling substance. Alternatively, when using a labeled second antibody against the detection antibody, a measurement value of the biomarker can be obtained in the same manner.

[0067] In the present embodiment, as a method for measuring a biomarker using an antibody, the immunocomplex transfer method described in Japanese Patent Laid-Open No. 1-254868 can also be used.

[0068] In this specification, "detection signal" includes detecting the presence or absence of a qualitative detection signal, quantifying the signal intensity, and semi-quantifying the signal intensity. Semi-quantitative detection means expressing the signal intensity in stages such as "no signal occurs", "weak", "medium", "strong", etc. In the present embodiment, it is preferable to quantitatively or semi-quantitatively detect the signal intensity, and quantitative detection is particularly preferable.

[0069] The labeling substance is not particularly limited. For example, it can be a substance that generates a signal by itself (hereinafter, also referred to as a "signal generating substance"), or a substance that catalyzes the reaction of other substances to generate a signal. As the signal generating substance, for example, a fluorescent substance, a radioactive isotope, etc. can be cited. As a substance that catalyzes the reaction of other substances to generate a detectable signal, for example, an enzyme can be cited. As the enzyme, alkaline phosphatase, peroxidase, β-galactosidase, luciferase, etc. can be cited. As the fluorescent substance, fluorescent dyes such as fluorescein isothiocyanate (FITC), rhodamine, Alexa Fluor (registered trademark), and fluorescent proteins such as GFP can be cited. As the radioactive isotope, 125 I, 14 C,32 Substances such as P. As the labeling substance, an enzyme is preferred, and alkaline phosphatase (ALP) and peroxidase are particularly preferred.

[0070] The method for detecting the signal itself is well-known in the prior art. In the present embodiment, a measurement method corresponding to the type of signal derived from the above-mentioned labeling substance may be appropriately selected. For example, when the labeling substance is an enzyme, signals such as light and color generated by reacting the substrate for the enzyme can be measured using a well-known device such as a spectrophotometer.

[0071] The substrate of the enzyme can be appropriately selected from well-known substrates corresponding to the type of the enzyme. For example, when using alkaline phosphatase as the enzyme, as the substrate, chemiluminescent substrates such as CDP-Star (registered trademark) (sodium 4-chloro-3-(methoxyspiro[1,2-dioxetane-3,2'-(5'-chloro)tricyclo[3.3.1.13,7]decane]-4-yl)phenyl phosphate) and CSPD (registered trademark) (sodium 3-(4-methoxyspiro[1,2-dioxetane-3,2-(5'-chloro)tricyclo[3.3.1.13,7]decane]-4-yl)phenyl phosphate), and chromogenic substrates such as 5-bromo-4-chloro-3-indolyl phosphate (BCIP), sodium 5-bromo-6-chloro-indolyl phosphate, and p-nitrophenyl phosphate can be cited. In addition, when using peroxidase as the enzyme, as the substrate, chemiluminescent substrates such as LUMINOR and its derivatives, and chromogenic substrates such as 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid ammonium) (ABTS), 1,2-phenylenediamine (OPD), and 3,3',5,5'-tetramethylbenzidine (TMB) can be cited.

[0072] When the labeling substance is a radioactive isotope, a well-known device such as a scintillation counter can be used to measure the radiation as the signal. In addition, when the labeling substance is a fluorescent substance, a well-known device such as a fluorescence microplate reader can be used to measure the fluorescence as the signal. Furthermore, the excitation wavelength and the fluorescence wavelength can be appropriately determined corresponding to the type of the fluorescent substance used.

[0073] The detection result of the signal can be used as the measurement result of the biomarker. For example, when quantitatively detecting the intensity of the signal, the measured value of the signal intensity itself or a value obtained from the measured value can be used as the measured value of the biomarker. As a value obtained from the measured value of the signal intensity, for example, a value obtained by subtracting the measured value of the negative control sample or the background value from the measured value can be cited. The negative control sample can be appropriately selected, and examples include a buffer solution containing no biomarker, a subject obtained from a healthy person, and a subject obtained from a patient with mild or asymptomatic respiratory tract infection.

[0074] In the present embodiment, it is preferable to measure a biomarker contained in a test subject by a sandwich ELISA method using a capture antibody immobilized on magnetic particles and a detection antibody labeled with an enzyme. The measurement can also be performed using a commercially available measuring device such as the HISCL (registered trademark) series (manufactured by Sysmex Corporation).

[0075] As shown in the examples described later, in the patient group with significantly higher measured values of CXCL9, CCL3, or IL-18 in serum, compared with other patient groups, there are significantly more patients suffering from acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. Thus, in the present embodiment, the measurement result of the biomarker becomes an index of the risk of developing acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. In the present embodiment, the risk of developing acute kidney injury or pulmonary fibrosis caused by respiratory tract infection refers to the possibility that, after a specified period (e.g., 1 day to 1 month) has elapsed since the day when the test subject was collected from the subject, the subject develops either or both of acute kidney injury and pulmonary fibrosis caused by respiratory tract infection.

[0076] In the present embodiment, the measurement result of the biomarker can be obtained as information related to respiratory tract infection. Examples of information related to respiratory tract infection include information indicating a high or low risk of developing acute kidney injury and pulmonary fibrosis caused by respiratory tract infection, information indicating a high or low risk of developing acute kidney injury caused by respiratory tract infection, and information indicating a high or low risk of developing pulmonary fibrosis caused by respiratory tract infection.

[0077] In one embodiment, acute kidney injury caused by respiratory tract infection refers to a sudden decrease in renal function and renal tissue damage accompanying respiratory tract infection. Acute kidney injury can be diagnosed, for example, based on the diagnostic criteria of RIFLE, AKIN, or KDIGO. In these diagnostic criteria, the serum creatinine value and urine volume of the subject are referred to.

[0078] In one embodiment, pulmonary fibrosis caused by respiratory tract infection refers to a state in which the interstitial connective tissue of the alveoli damaged by respiratory tract infection increases and a part or all of the lungs hardens. Pulmonary fibrosis can be diagnosed by, for example, chest X-ray examination, chest CT examination, or lung biopsy.

[0079] In the pulmonary fibrosis caused by respiratory infections, after the respiratory infection is cured, the fibrotic part does not recover, and pulmonary fibrosis remains as a sequela. In the following examples, the measured values of CXCL9, CCL3, or IL-18 in the serum are also significantly high, and among the patients who develop pulmonary fibrosis caused by respiratory infections, those in whom fibrosis is still confirmed in the lungs after the infection by the pathogen is determined to be negative. In the present embodiment, the measurement result of the biomarker can be an index of the risk of remaining pulmonary fibrosis caused by respiratory infections. That is, the information related to respiratory infections can be information indicating a high or low risk of remaining pulmonary fibrosis caused by respiratory infections. In the present embodiment, the risk of remaining pulmonary fibrosis caused by respiratory infections refers to the possibility that in a subject, after being determined to have developed pulmonary fibrosis caused by respiratory infections and the infection by the pathogen is negative, pulmonary fibrosis is still confirmed. The determination of the infection by the pathogen is performed by a known detection method corresponding to the type of the pathogen. For example, when the pathogen is a virus, it is preferable to determine whether the infection by the pathogen is negative by a known PCR method.

[0080] In the present embodiment, it is also possible to compare the measured value of the obtained biomarker with a specified threshold corresponding to the biomarker, and use the measured value of the biomarker as an index of the risk of developing acute kidney injury or pulmonary fibrosis caused by respiratory infections. In one embodiment, when the measured value of the biomarker is equal to or higher than the specified threshold corresponding to the biomarker, it indicates a high risk of developing acute kidney injury or pulmonary fibrosis caused by respiratory infections.

[0081] In a further embodiment, when the measured value of the biomarker is lower than the specified threshold corresponding to the biomarker, it indicates a low risk of developing acute kidney injury or pulmonary fibrosis caused by respiratory infections.

[0082] In one embodiment, the biomarker contains CXCL9. When the measured value of CXCL9 is equal to or higher than the specified threshold corresponding to CXCL9, it indicates a high risk of developing acute kidney injury or pulmonary fibrosis caused by respiratory infections. In addition, when the measured value of CXCL9 is lower than the specified threshold corresponding to CXCL9, it indicates a low risk of developing acute kidney injury or pulmonary fibrosis caused by respiratory infections.

[0083] In one embodiment, the biomarker contains CCL3. When the measured value of CCL3 is equal to or higher than the specified threshold corresponding to CCL3, it indicates a high risk of developing acute kidney injury or pulmonary fibrosis caused by respiratory infections. In addition, when the measured value of CCL3 is lower than the specified threshold corresponding to CCL3, it indicates a low risk of developing acute kidney injury or pulmonary fibrosis caused by respiratory infections.

[0084] In one embodiment, the biomarker includes IL-18. When the measured value of IL-18 is above the designated threshold corresponding to IL-18, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. Additionally, when the measured value of IL-18 is lower than the designated threshold corresponding to IL-18, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0085] In a further embodiment, at least two biomarkers in the test sample collected from a subject can also be measured. In this embodiment, the biomarkers include at least two selected from CXCL9, CCL3, and IL-18, and the measurement results of these biomarkers can be an indicator of the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. For example, when at least one of the measured values of the obtained biomarkers is above the designated threshold corresponding to the biomarker, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. Additionally, when all of the measured values of the obtained biomarkers are lower than the designated thresholds corresponding to the respective biomarkers, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0086] In one embodiment, the biomarkers are two selected from CXCL9, CCL3, and IL-18. When at least one of the measured values of these two biomarkers is above the designated threshold corresponding to the biomarker, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. Additionally, when both of the measured values of the two biomarkers are lower than the designated thresholds corresponding to the respective biomarkers, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0087] In a further embodiment, at least three biomarkers in the test sample collected from a subject can also be measured. In this embodiment, the biomarkers include CXCL9, CCL3, and IL-18, and the measurement results of these biomarkers can be an indicator of the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. For example, when at least one of the measured values of the obtained biomarkers is above the designated threshold corresponding to the biomarker, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. Additionally, when all of the measured values of the obtained biomarkers are lower than the designated thresholds corresponding to the respective biomarkers, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0088] In one embodiment, the biomarkers are CXCL9, CCL3, and IL-18. When at least one of the measured values of these three biomarkers is above the specified threshold corresponding to the biomarker, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. Additionally, when the measured values of all three of these biomarkers are lower than the specified threshold corresponding to each biomarker, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0089] In another embodiment, the acquisition method includes measuring at least two biomarkers in a test sample collected from a subject. The biomarkers include at least two selected from CXCL9, CCL3, and IL-18. Based on the measured values of these biomarkers, the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is classified into three stages. Specifically, as follows:

[0090] · When all of the measured values of the acquired biomarkers are above the specified threshold corresponding to each biomarker, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection;

[0091] · When at least one of the measured values of the acquired biomarkers is above the specified threshold corresponding to the biomarker, it indicates a moderate risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection;

[0092] · When all of the measured values of the acquired biomarkers are lower than the specified threshold corresponding to each biomarker, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0093] In one embodiment, the biomarkers are two selected from CXCL9, CCL3, and IL-18. When both of the measured values of these two biomarkers are above the specified threshold corresponding to each biomarker, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. Additionally, when at least one of the measured values of these two biomarkers is above the specified threshold corresponding to the biomarker, it indicates a moderate risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. Additionally, when both of the measured values of these two biomarkers are lower than the specified threshold corresponding to each biomarker, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0094] In one embodiment, the biomarkers are CXCL9, CCL3, and IL-18. When all of the measured values of these three biomarkers are above the specified thresholds corresponding to each biomarker, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. In addition, for the biomarkers CXCL9, CCL3, and IL-18, when at least one of the measured values of these three biomarkers is above the specified threshold corresponding to that biomarker, it indicates a moderate risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. Further, for the biomarkers CXCL9, CCL3, and IL-18, when all of the measured values of these three biomarkers are lower than the specified thresholds corresponding to each biomarker, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0095] In the present embodiment, in addition to at least one selected from CXCL9, CCL3, and IL-18, other biomarkers can also be measured. Examples of such biomarkers include IL-6 and CRP. IL-6 is a type of Th2 cytokine. CRP is a type of acute-phase protein. As shown in the examples described later, in the patient group with high measured values of IL-6 and CRP in serum, compared with other patient groups, there is a tendency for more patients to suffer from acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. In the present embodiment, at least one measurement result selected from IL-6 and CRP and at least one measurement result selected from CXCL9, CCL3, and IL-18 can also be an indicator of the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. The amino acid sequences of IL-6 and CRP themselves are well-known and can be obtained from publicly known databases such as NCBI. IL-6 and CRP can be measured in the same manner as CXCL9, CCL3, and IL-18.

[0096] In one embodiment, the biomarker includes at least one selected from CXCL9, CCL3, and IL-18 and at least one selected from IL-6 and CRP. In this embodiment, among CXCL9, CCL3, and IL-18, when at least one of the measured values of the obtained biomarker is above the specified threshold corresponding to that biomarker, and among IL-6 and CRP, when at least one of the measured values of the obtained biomarker is above the specified threshold corresponding to that biomarker, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0097] The designated threshold values corresponding to each biomarker are not particularly limited and can be appropriately set. For example, specimens are collected from multiple patients with respiratory infections, and the biomarker in the specimen is measured to obtain a measured value. After a designated period (e.g., 2 weeks) has elapsed since the specimen collection, it is confirmed whether acute kidney injury or pulmonary fibrosis caused by respiratory infection has occurred. The data of the obtained measured values are classified into the data of the patient group in which acute kidney injury or pulmonary fibrosis has occurred and the data of the patient group in which acute kidney injury and pulmonary fibrosis have not occurred. Furthermore, for each biomarker, a value that can most accurately distinguish the two patient groups is obtained, and this value is set as the threshold value. In setting the threshold value, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), etc. can be considered.

[0098] In one embodiment, the designated threshold value corresponding to CXCL9 is set in a range of, for example, 100 pg / mL or more and 365 pg / mL or less. The designated threshold value corresponding to CCL3 is set in a range of, for example, 47.7 pg / mL or more and 66.7 pg / mL or less. The designated threshold value corresponding to IL-18 is set in a range of, for example, 600 pg / mL or more and 750 pg / mL or less. The designated threshold value corresponding to IL-6 is set in a range of, for example, 67.4 pg / mL or more and 96.2 pg / mL or less. The designated threshold value corresponding to CRP is set in a range of, for example, 0.75x10 4 μg / L or more and 6.2x10 4 μg / L or less.

[0099] Medical practitioners such as physicians can also combine the indication of the measured value of the biomarker with other information to determine the risk of acute kidney injury or pulmonary fibrosis caused by respiratory infection. Among them, "other information" includes serum creatinine level, urine volume, opinions on chest X-ray images or CT images of the lungs, and other medical opinions.

[0100] In the present embodiment, when it is indicated that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is high, medical intervention for acute kidney injury or pulmonary fibrosis can be performed on the subject. Medical interventions include, for example, administration of drugs, dialysis, surgery, immunotherapy, gene therapy, oxygen supply treatment, treatment using a cardiopulmonary bypass device, and the like. The drug can be appropriately selected from known therapeutic drugs for acute kidney injury or pulmonary fibrosis or drugs that are candidates therefor. As medical interventions for acute kidney injury, fluid replacement therapy, renal replacement therapy by dialysis, anti-inflammatory therapy such as administration of steroid drugs, and the like are preferred. As medical interventions for pulmonary fibrosis, administration of steroid drugs, immunosuppressive drugs, anti-fibrotic drugs, and the like are preferred. As the fluid replacement, isotonic crystalloid solutions are preferred, and examples thereof include physiological saline, Ringer's lactate solution, and the like. As the steroid drug, corticosteroids are preferred, and examples thereof include dexamethasone, prednisolone, and the like. As the immunosuppressive drug, examples include azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil, and the like. In addition, specific immunotherapy using antibody drugs such as anti-IL-6 antibody and anti-IL-1β antibody, or immunomodulatory anti-inflammatory therapy using biological agents such as intravenous immunoglobulin (IVIG) is also considered. As anti-fibrotic drugs, examples include pirfenidone, nintedanib, αvβ6 integrin blocker, Gal-3 inhibitor, autotaxin inhibitor, lysophosphatidic acid inhibitor, JNK inhibitor, mTOR pathway regulator, serum amyloid P component (SAP), angiotensin II receptor (AT2R) inhibitor, and the like.

[0101] In the present embodiment, as the measurement result of the biomarker, the change over time of the measured value of the biomarker in the subject can also be obtained. The change over time of the measured value of the biomarker is not particularly limited as long as it is information indicating the change of the measured value of the biomarker in the subject collected regularly or irregularly multiple times from the subject. Examples of such change over time include values calculated from multiple measured values (for example, the difference, ratio, etc. of the measured values of two subjects collected at any two time points), records of the measured values (for example, a table of the measured values or a coordinate graph obtained by plotting the measured values), and the like.

[0102] In the present embodiment, as the measurement result of the biomarker, a value obtained by multivariate analysis using the measured values of at least two biomarkers can also be obtained. As the value obtained by multivariate analysis, a predicted value obtained by multiple logistic regression analysis is preferred. Such a predicted value can be calculated by the following regression formula.

[0103] P = 1 / [1 + exp{-(a1x1 + a2x2 + … + a n x n + b)}]

[0104] In the above regression formula, x1 to x n are the measured values of each biomarker, a1 to a n are the regression coefficients of each biomarker, and b is a constant. The regression coefficients and the constant can be appropriately set according to the types of biomarkers used. For example, the regression coefficients and the constant can be set by creating a multiple logistic model that discriminates between the occurrence group and the non-occurrence group from the data of the measured values of biomarkers in test subjects collected from multiple patients (occurrence group) with acute kidney injury or pulmonary fibrosis caused by spontaneous ventilator-associated infection and multiple patients (non-occurrence group) without the disease. The multiple logistic model can be created using statistical analysis software such as SPSS Statistics (IBM Corporation). In the present embodiment, it is preferable to create a multiple logistic model in advance from the data of the measured values of biomarkers of ventilator-associated infection patients.

[0105] The acquisition method of the present embodiment may also include a step of determining the risk of acute kidney injury or pulmonary fibrosis caused by ventilator-associated infection based on the measured value of the biomarker. In this step, for example, the measured value of the obtained biomarker may be compared with the threshold value corresponding to the biomarker, and based on the comparison result, it may be determined whether the risk of acute kidney injury or pulmonary fibrosis caused by ventilator-associated infection is high or low. The details of the specified threshold value are as described above.

[0106] In one embodiment, when the measured value of the biomarker is equal to or higher than the specified threshold value corresponding to the biomarker, it may be determined that the risk of acute kidney injury or pulmonary fibrosis caused by ventilator-associated infection is high. In a further embodiment, when the measured value of the biomarker is lower than the specified threshold value corresponding to the biomarker, it may be determined that the risk of acute kidney injury or pulmonary fibrosis caused by ventilator-associated infection is low.

[0107] In one embodiment, the biomarker includes CXCL9. When the measured value of CXCL9 is equal to or higher than the specified threshold value corresponding to CXCL9, it may be determined that the risk of acute kidney injury or pulmonary fibrosis caused by ventilator-associated infection is high. Additionally, when the measured value of CXCL9 is lower than the specified threshold value corresponding to CXCL9, it may be determined that the risk of acute kidney injury or pulmonary fibrosis caused by ventilator-associated infection is low.

[0108] In one embodiment, the biomarker includes CCL3. When the measured value of CCL3 is equal to or higher than the specified threshold value corresponding to CCL3, it may be determined that the risk of acute kidney injury or pulmonary fibrosis caused by ventilator-associated infection is high. Additionally, when the measured value of CCL3 is lower than the specified threshold value corresponding to CCL3, it may be determined that the risk of acute kidney injury or pulmonary fibrosis caused by ventilator-associated infection is low.

[0109] In one embodiment, the biomarker contains IL-18. When the measured value of IL-18 is above the specified threshold corresponding to IL-18, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is high. In addition, when the measured value of IL-18 is lower than the specified threshold corresponding to IL-18, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is low.

[0110] In a further embodiment, at least two biomarkers in the test sample collected from the subject can also be measured. In this embodiment, the biomarkers can also contain at least two selected from CXCL9, CCL3, and IL-18, and the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is determined based on the measured values of these biomarkers. For example, when at least one of the measured values of the obtained biomarkers is above the specified threshold corresponding to the biomarker, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is high. In addition, when all of the measured values of the obtained biomarkers are lower than the specified thresholds corresponding to the respective biomarkers, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is low.

[0111] In one embodiment, the biomarkers are two selected from CXCL9, CCL3, and IL-18. When at least one of the measured values of these two biomarkers is above the specified threshold corresponding to the biomarker, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is high. In addition, when both of the measured values of the two biomarkers, which are selected from CXCL9, CCL3, and IL-18, are lower than the specified thresholds corresponding to the respective biomarkers, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is low.

[0112] In a further embodiment, at least three biomarkers in the test sample collected from the subject can also be measured. In this embodiment, the biomarkers can also contain CXCL9, CCL3, and IL-18, and the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is determined based on the measured values of these biomarkers. For example, when at least one of the measured values of the obtained biomarkers is above the specified threshold corresponding to the biomarker, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is high. In addition, when all of the measured values of the obtained biomarkers are lower than the specified thresholds corresponding to the respective biomarkers, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is low.

[0113] In one embodiment, the biomarkers are CXCL9, CCL3, and IL-18. When at least one of the measured values of these three biomarkers is above the designated threshold corresponding to the biomarker, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is high. Additionally, when the measured values of all three of these biomarkers are lower than the designated threshold corresponding to each biomarker, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is low.

[0114] In another embodiment, the acquisition method includes measuring at least two biomarkers in a test sample collected from a subject. The biomarkers may also include at least two selected from CXCL9, CCL3, and IL-18. The risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is determined in three stages based on the measured values of these biomarkers. Specifically, as follows:

[0115] · When all of the measured values of the acquired biomarkers are above the designated threshold corresponding to each biomarker, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is high;

[0116] · When at least one of the measured values of the acquired biomarkers is above the designated threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is moderate;

[0117] · When all of the measured values of the acquired biomarkers are lower than the designated threshold corresponding to each biomarker, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is low.

[0118] In one embodiment, the biomarkers are two selected from CXCL9, CCL3, and IL-18. When both of the measured values of these two biomarkers are above the designated threshold corresponding to each biomarker, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is high. Additionally, when any one of the measured values of these two biomarkers is above the designated threshold corresponding to the biomarker, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is moderate. Additionally, when both of the measured values of these two biomarkers are lower than the designated threshold corresponding to each biomarker, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is low.

[0119] In one embodiment, the biomarkers are CXCL9, CCL3, and IL-18. When all of the measured values of these three biomarkers are above the specified thresholds corresponding to each biomarker, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is high. Additionally, for the biomarkers CXCL9, CCL3, and IL-18, when at least one of the measured values of these three biomarkers is above the specified threshold corresponding to that biomarker, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is moderate. Further, for the biomarkers CXCL9, CCL3, and IL-18, when all of the measured values of these three biomarkers are lower than the specified thresholds corresponding to each biomarker, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is low.

[0120] In a further embodiment, the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection can also be determined based on at least one measured value selected from CXCL9, CCL3, and IL-18 and at least one measured value selected from IL-6 and CRP. In this embodiment, among CXCL9, CCL3, and IL-18, when at least one of the measured values of the obtained biomarker is above the specified threshold corresponding to that biomarker, and among IL-6 and CRP, when at least one of the measured values of the obtained biomarker is above the specified threshold corresponding to that biomarker, it can be determined that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is high.

[0121] In this embodiment, for a subject determined to have a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection, medical intervention for acute kidney injury or pulmonary fibrosis can be performed. Thus, one embodiment of the present invention relates to a treatment method for acute kidney injury or pulmonary fibrosis caused by respiratory tract infection (hereinafter, also referred to as the "treatment method"). The treatment method of this embodiment includes a step of measuring at least one biomarker in a test sample collected from a subject suffering from respiratory tract infection or a subject suspected of having the above-mentioned respiratory tract infection, a step of determining the risk of acute kidney injury or pulmonary fibrosis caused by the above-mentioned respiratory tract infection based on the measured value of the above-mentioned biomarker, and a step of performing medical intervention for acute kidney injury or pulmonary fibrosis on a subject determined to have a high risk of the above-mentioned risk. The above-mentioned biomarker includes at least one selected from CXCL9, CCL3, and IL-18. The details of the subject, the test sample, the biomarker and its measurement, medical intervention, etc. are the same as those described for the acquisition method of this embodiment.

[0122] In the present embodiment, it is also possible to monitor the measured values of biomarkers in a subject. In the method for monitoring the measured values of biomarkers in the present embodiment (hereinafter, also referred to as the "monitoring method"), a subject collected from a subject at multiple time points is used. At least one biomarker in each subject is measured, and at least one measured value of the biomarker is obtained from each subject. Among them, the details of the subject, the subject, the biomarker, and its measurement are the same as those described for the acquisition method of the present embodiment.

[0123] In the present embodiment, the multiple time points only need to be two or more different time points from each other. For example, the multiple time points include a first time point and a second time point different from the first time point. The first time point is not particularly limited and is an arbitrary time point. For example, the first time point may also be the time point when the subject is confirmed to have a respiratory tract infection, the time point when the subject shows symptoms of a respiratory tract infection, the time point when the subject is hospitalized, etc. The second time point is not particularly limited as long as it is different from the first time point. Preferably, the second time point is a time point within a period of one month from the first time point. For example, the second time point is a time point after 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 12 days, 2 weeks, 3 weeks, 4 weeks, or 1 month from the first time point.

[0124] In the present embodiment, the "subject collected from a subject at multiple time points" is a subject collected from the same subject at each of the multiple time points. For example, the subject collected from a subject at multiple time points includes a first subject collected from the subject at the first time point and a second subject collected from the subject at a second time point different from the first time point. In the monitoring method of the present embodiment, the biomarker can be measured when the subject is collected, or each collected subject can be stored and comprehensively measured.

[0125] In the monitoring method of the present embodiment, the measured values of biomarkers in the same subject are monitored, and the measured values of the biomarkers serve as an index for the risk of developing acute kidney injury or pulmonary fibrosis caused by a respiratory tract infection. In a preferred embodiment, the measured values of the same biomarker at multiple time points are obtained. It is also possible to compare the measured value of the biomarker obtained from each subject with a specified threshold corresponding to the biomarker, and use the measured value of the biomarker as an index for the risk of developing acute kidney injury or pulmonary fibrosis caused by a respiratory tract infection. The details of the specified threshold are the same as those described for the acquisition method of the present embodiment.

[0126] In one embodiment, among multiple time points, when the measured value of a biomarker is above a specified threshold corresponding to the biomarker at at least one time point, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. In a further embodiment, when the measured value of the biomarker is lower than the specified threshold corresponding to the biomarker at all time points among the multiple time points, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0127] In one embodiment, the biomarker includes CXCL9. Among multiple time points, when the measured value of CXCL9 is above a specified threshold corresponding to CXCL9 at at least one time point, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. When the measured value of CXCL9 is lower than the specified threshold corresponding to CXCL9 at all time points among the multiple time points, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0128] In one embodiment, the biomarker includes CCL3. Among multiple time points, when the measured value of CCL3 is above a specified threshold corresponding to CCL3 at at least one time point, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. When the measured value of CCL3 is lower than the specified threshold corresponding to CCL3 at all time points among the multiple time points, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0129] In one embodiment, the biomarker includes IL-18. Among multiple time points, when the measured value of IL-18 is above a specified threshold corresponding to IL-18 at at least one time point, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. When the measured value of IL-18 is lower than the specified threshold corresponding to IL-18 at all time points among the multiple time points, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0130] In a further embodiment, at least two biomarkers in each subject may also be measured. In this embodiment, the biomarkers include at least two selected from CXCL9, CCL3, and IL-18. Among multiple time points, when at least one of the measured values of the biomarkers obtained at at least one time point is above a specified threshold corresponding to the biomarker, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. In addition, among multiple time points, when all of the measured values of the biomarkers obtained at all time points are lower than the specified thresholds corresponding to the respective biomarkers, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0131] In one embodiment, the biomarkers are two selected from CXCL9, CCL3, and IL-18. Among multiple time points, when at least one of the measured values of the two biomarkers obtained at at least one time point is above a specified threshold corresponding to the biomarker, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. In addition, the biomarkers are two selected from CXCL9, CCL3, and IL-18. Among multiple time points, when both of the measured values of the two biomarkers obtained at all time points are lower than the specified thresholds corresponding to the respective biomarkers, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0132] In a further embodiment, at least three biomarkers in each subject may also be measured. In this embodiment, the biomarkers include CXCL9, CCL3, and IL-18. Among multiple time points, when at least one of the measured values of the biomarkers obtained at at least one time point is above a specified threshold corresponding to the biomarker, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. In addition, among multiple time points, when all of the measured values of the biomarkers obtained at all time points are lower than the specified thresholds corresponding to the respective biomarkers, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0133] In one embodiment, the biomarkers are CXCL9, CCL3, and IL-18. Among multiple time points, when at least one of the measured values of the three biomarkers is above the designated threshold corresponding to the biomarker at at least one time point, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection. Additionally, when the biomarkers are CXCL9, CCL3, and IL-18, and at all time points among the multiple time points, all of the measured values of the three biomarkers are lower than the designated thresholds corresponding to each biomarker, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0134] The conditions for ending the monitoring method of this embodiment are not particularly limited and can be appropriately determined by medical practitioners such as physicians. For example, it can also be based on the measured values of biomarkers obtained from the subject collected at multiple time points. When it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection, the monitoring method of this embodiment is ended. At this time, in this subject, it is preferable to perform medical intervention for acute kidney injury or pulmonary fibrosis. The details of the medical intervention are as described above. Or, it can also be based on the measured values of biomarkers obtained from the subject collected at multiple time points. When it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection and no signs of acute kidney injury and pulmonary fibrosis are confirmed in this subject, the monitoring method of this embodiment is ended.

[0135] In each of the above embodiments, when the measured value of the biomarker is the same as the designated threshold corresponding to the biomarker, it can indicate or determine a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection, or it can also indicate or determine a low risk.

[0136] One embodiment of the present invention is a kit for use in the acquisition method, monitoring method, or treatment method of the above-described embodiment. The kit of this embodiment contains at least one selected from a reagent containing a substance that can specifically bind to CXCL9, a reagent containing a substance that can specifically bind to CCL3, and a reagent containing a substance that can specifically bind to IL-18. In a further embodiment, the kit may also contain at least one selected from a reagent containing a substance that can specifically bind to IL-6 and a reagent containing a substance that can specifically bind to CRP. Examples of substances that can specifically bind to each biomarker include, for example, antibodies and aptamers. Among them, antibodies are also preferred.

[0137] In the present embodiment, the kit may also be provided to the user with the containers of the respective reagents bundled in a box. In the box, an attached document may also be included. In the attached document, the composition of the kit, the composition of each reagent, the method of use, etc. may be described. An example of the kit of the present embodiment is shown in Figure 1A . In Figure 1A , 11 represents the kit, 12 represents the container for accommodating the reagent containing a substance that can specifically bind to CXCL9, 13 represents the bundling box, and 14 represents the attached document. In the kit of this example, a reagent containing a substance that can specifically bind to CCL3 or a reagent containing a substance that can specifically bind to IL-18 may be included instead of the reagent containing a substance that can specifically bind to CXCL9. At this time, in the attached document, the reagent composition, the method of use, etc. are described for the reagent containing a substance that can specifically bind to CCL3 or the reagent containing a substance that can specifically bind to IL-18. In addition, in addition to the reagent containing a substance that can specifically bind to CXCL9, the kit may also contain a reagent containing a substance that can specifically bind to CCL3 or a reagent containing a substance that can specifically bind to IL-18. At this time, in the attached document, the reagent composition, the method of use, etc. are described for the reagent containing a substance that can specifically bind to CXCL9 and the reagent containing a substance that can specifically bind to CCL3 or the reagent containing a substance that can specifically bind to IL-18. In addition, the kit may contain a reagent containing a substance that can specifically bind to CXCL9, a reagent containing a substance that can specifically bind to CCL3, and a reagent containing a substance that can specifically bind to IL-18. At this time, in the attached document, the reagent composition, the method of use, etc. are described for the reagent containing a substance that can specifically bind to CXCL9, the reagent containing a substance that can specifically bind to CCL3, and the reagent containing a substance that can specifically bind to IL-18.

[0138] In a preferred embodiment, the kit of the present embodiment contains an antibody for capturing a biomarker and a detection antibody. The detection antibody may also be labeled with a labeling substance. The details of the capture antibody, the detection antibody, and the labeling substance are the same as those described for the acquisition method of the above-described present embodiment. The kit may also contain a solid phase. When the labeling substance used in the detection antibody is an enzyme, the kit may also contain the substrate of the enzyme. The details of the solid phase and the matrix are the same as those described for the acquisition method of the above-described present embodiment.

[0139] An example of the kit of a further embodiment is shown in Figure 1B . In Figure 1BIn [the description], 21 represents a kit, 22 represents a first container for accommodating a reagent containing a capture antibody for CXCL9, 23 represents a second container for accommodating a reagent containing a detection-labeled antibody for CXCL9, 24 represents a packing box, and 25 represents an attached document. In the kit of this example, instead of the respective reagents containing the capture antibody for CXCL9 and the detection-labeled antibody for CXCL9, the respective reagents containing the capture antibody for CCL3 and the detection-labeled antibody for CCL3 or the respective reagents containing the capture antibody for IL-18 and the detection-labeled antibody for IL-18 may be contained. Further, in addition to the respective reagents containing the capture antibody for CXCL9 and the detection-labeled antibody for CXCL9, the kit may also contain the respective reagents containing the capture antibody for CCL3 and the detection-labeled antibody for CCL3, and / or the respective reagents containing the capture antibody for IL-18 and the detection-labeled antibody for IL-18.

[0140] In any of the above kits, it is also preferable to contain a calibrator. As the calibrator, for example, a calibrator for the quantification of CXCL9 (CXCL9 calibrator), a calibrator for the quantification of CCL3 (CCL3 calibrator), and a calibrator for the quantification of IL-18 (IL-18 calibrator) can be mentioned. The CXCL9 calibrator may also, for example, comprise a buffer solution not containing CXCL9 (negative control) and a buffer solution containing CXCL9 at a known concentration. The CCL3 calibrator may also, for example, comprise a buffer solution not containing CCL3 (negative control) and a buffer solution containing CCL3 at a known concentration. The IL-18 calibrator may also, for example, comprise a buffer solution not containing IL-18 (negative control) and a buffer solution containing IL-18 at a known concentration.

[0141] An example of a kit according to a further embodiment is shown in Figure 1C . In Figure 1CIn this case, 31 represents a kit, 32 represents a first container for accommodating a reagent containing a capture antibody for CXCL9, 33 represents a second container for accommodating a reagent containing a labeled antibody for detecting CXCL9, 34 represents a third container for accommodating a buffer solution without CXCL9, 35 represents a fourth container for accommodating a buffer solution containing CXCL9 at a specified concentration, 36 represents a packing box, and 37 represents an attached document. The buffer solution without CXCL9 and the buffer solution containing CXCL9 at a specified concentration can be used as a calibrator for CXCL9. The kit in this example can also contain the respective reagents of the capture antibody and the labeled antibody for detecting CCL3 and the calibrator for CCL3, or the respective reagents of the capture antibody and the labeled antibody for detecting IL-18 and the calibrator for IL-18, instead of the respective reagents of the capture antibody and the labeled antibody for CXCL9 and the calibrator for CXCL9. In addition, the kit can also contain the respective reagents of the capture antibody and the labeled antibody for CCL3 and the calibrator for CCL3, and / or the respective reagents of the capture antibody and the labeled antibody for IL-18 and the calibrator for IL-18, in addition to the respective reagents of the capture antibody and the labeled antibody for CXCL9 and the calibrator for CXCL9.

[0142] One embodiment of the present invention is the use of a reagent containing a substance that can specifically bind to a biomarker for manufacturing the above-mentioned kit. This embodiment relates to the use of a reagent for manufacturing a kit for obtaining information related to respiratory infections, and the above-mentioned reagent contains at least one selected from a reagent containing a substance that can specifically bind to CXCL9, a reagent containing a substance that can specifically bind to CCL3, and a reagent containing a substance that can specifically bind to IL-18.

[0143] A further embodiment relates to the use of a reagent for manufacturing a kit for monitoring the measured value of a biomarker, and the above-mentioned reagent contains at least one selected from a reagent containing a substance that can specifically bind to CXCL9, a reagent containing a substance that can specifically bind to CCL3, and a reagent containing a substance that can specifically bind to IL-18.

[0144] One embodiment of the present invention is a device for obtaining information related to respiratory infections, and a computer program for obtaining information related to respiratory infections. A further embodiment of the present invention is a device for monitoring the measured value of a biomarker, and a computer program for monitoring the measured value of a biomarker.

[0145] An example of the obtaining device of this embodiment will be described with reference to the accompanying drawings. However, this embodiment is not limited to the form shown in this example. Figure 2The acquisition device 10 shown in the figure includes an immunoassay device 20 and a computer system 30 connected to the immunoassay device 20. The monitoring device of the present embodiment may have the same configuration as the acquisition device of the present embodiment.

[0146] The type of the immunoassay device is not particularly limited and can be appropriately selected according to the measurement method of the biomarker. When the biomarker is measured by the ELISA method, the immunoassay device is not particularly limited as long as it can detect the signal based on the labeling substance used. In the example shown in Figure 2 the immunoassay device 20 is a commercially available automatic immunoassay device that can detect the chemiluminescence signal generated by the sandwich ELISA method using magnetic particles with a fixed capture antibody and an enzyme-labeled detection antibody.

[0147] When a reagent containing magnetic particles with a fixed capture antibody, a reagent containing an enzyme-labeled detection antibody, and a test specimen collected from a subject are set in the immunoassay device 20, the immunoassay device 20 performs an antigen-antibody reaction using each reagent, obtains a chemiluminescence signal as optical information based on the enzyme-labeled antibody specifically binding to the biomarker, and sends the obtained optical information to the computer system 30.

[0148] Refer to Figure 2 , the computer system 30 includes a computer main body 300, an input unit 301, and a display unit 302 that displays test specimen information, determination results, etc. The computer system 30 receives optical information from the immunoassay device 20. Furthermore, the processor of the computer system 30 executes a computer program for obtaining information related to respiratory infections installed on a solid-state drive (hereinafter referred to as "SSD") 313 based on the optical information. Moreover, the computer system 30, as shown in Figure 2 , may be a machine different from the immunoassay device 20 or may be a machine that incorporates the immunoassay device 20. In the latter case, the computer system 30 itself may also be the acquisition device 10. A computer program for obtaining information related to respiratory infections may also be installed on a commercially available automatic immunoassay device. The acquisition device 10 may also be a device integrally formed by the immunoassay device 20 and the computer system 30.

[0149] Refer to Figure 3, the computer main body 300 includes a CPU (Central Processing Unit) 310, a ROM (ReadOnly Memory) 311, a RAM (Random Access Memory) 312, an SSD 313, an input / output interface 314, a reading device 315, a communication interface 316, and an image output interface 317. The CPU 310, ROM 311, RAM 312, SSD 313, input / output interface 314, reading device 315, communication interface 316, and image output interface 317 are connected by a bus 318 so as to enable data communication. In addition, the immunoassay device 20 is communicably connected to the computer system 30 via the communication interface 316.

[0150] The CPU 310 can execute programs stored in the ROM 311 or SSD 313 and programs loaded onto the RAM 312. The CPU 310 calculates the measured value of the biomarker and displays it on the display unit 302.

[0151] The ROM 311 is composed of a mask ROM, PROM, EPROM, EEPROM, etc. In the ROM 311, computer programs executed by the CPU 310 and data used in the execution of the computer programs are recorded as described above. Among the computer programs recorded in the ROM 311, there is a BIOS (Basic Input Output System). The specified threshold values for each biomarker can be pre-stored in the ROM 311 or SSD 313 at the time of manufacturing the computer system, or can be stored in the ROM 311 or SSD 313 by input from the input unit 301.

[0152] The RAM 312 is composed of SRAM, DRAM, etc. The RAM 312 is used in the reading of programs recorded in the ROM 311 and SSD 313. In addition, the RAM 312 is used as the working area of the CPU 310 when executing these programs.

[0153] The SSD 313 installs computer programs such as an operating system and application programs to be executed by the CPU 310 and data used in the execution of the computer programs. Furthermore, a hard disk drive can be used instead of the SSD.

[0154] The reading device 315 is composed of a floppy disk drive, CD-ROM drive, DVD-ROM drive, USB port, SD card reader, CF card reader, memory stick reader, etc. The reading device 315 can read programs or data recorded on the removable recording medium 40 corresponding to the above-mentioned reading device 315.

[0155] The input / output interface 314 is composed of a serial interface such as USB, IEEE 1394, etc. and an analog interface composed of a D / A converter, an A / D converter, etc. An input unit 301 such as a keyboard and a mouse is connected to the input / output interface 314. An operator can input various instructions to the computer main body 300 through the input unit 301.

[0156] The communication interface 316 is a wireless interface or the like according to the specifications of an Ethernet (registered trademark) interface or the like. The computer main body 300 can also send print data to a printer or the like through the communication interface 316. When the communication interface 316 is a wireless interface, the computer main body 300 can send data to a mobile device such as a mobile phone and a tablet terminal.

[0157] The image output interface 317 is an interface according to the specifications of D-Sub, DVI-I, DVI-D, HDMI (registered trademark), DisplayPort, etc. The image output interface 317 is connected to a display unit 302 composed of an LCD, a CRT, etc. through a cable corresponding to its specifications. Thus, the display unit 302 can output a video signal corresponding to the image data given from the CPU 310. The display unit 302 displays an image (screen) according to the input video signal.

[0158] The processing program executed by the acquisition device 10 of the present embodiment will be described with reference to the accompanying drawings. Refer to Figure 4A , the processing program when obtaining the measurement value of one biomarker and outputting it will be described. In this example, the measurement value of CXCL9 is obtained from the chemiluminescence signal generated by the sandwich ELISA method using magnetic particles with a fixed capture antibody and an enzyme-labeled detection antibody, and output. Instead of the measurement value of CXCL9, the measurement values of CCL3 or IL-18 can also be obtained.

[0159] In step S101, the CPU 310 obtains optical information (chemiluminescence signal) from the immunoassay device 20. In step S102, the CPU 310 calculates the measurement value of CXCL9 from the obtained optical information, and obtains the measurement value of CXCL9 as the measurement result. The CPU 310 stores the measurement value in the SSD 313. In step S103, the CPU 310 outputs the measurement value of CXCL9. For example, the CPU 310 displays the measurement value of CXCL9 on the display unit 302, prints it with a printer, or sends it to a mobile device. When outputting the measurement value of CXCL9, a specified threshold value corresponding to CXCL9 can also be output as reference information. In this way, the acquisition device of the present embodiment can provide the measurement value of the biomarker as information related to respiratory tract infections to a doctor or the like. As described above, the measurement value of the biomarker becomes an index of the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infections.

[0160] In a further embodiment, measurement values of two biomarkers are obtained and output. For example, when obtaining and outputting the measurement values of CXCL9 and CCL3, the CPU 310 acquires optical information (chemiluminescence signal) from the immunoassay device 20, calculates the measurement values of CXCL9 and CCL3 from the acquired optical information, and stores them in the SSD 313. The CPU 310 outputs the measurement values of CXCL9 and CCL3. For example, the CPU 310 displays the measurement values of CXCL9 and CCL3 on the display unit 302, prints them with a printer, or sends them to a mobile device. When outputting the measurement values of CXCL9 and CCL3, designated thresholds corresponding to each of CXCL9 and CCL3 may also be output as reference information. The measurement value of IL-18 may be obtained instead of the measurement value of CXCL9 or CCL3.

[0161] In a further embodiment, measurement values of CXCL9, CCL3, and IL-18 are obtained and output. At this time, the CPU 310 acquires optical information (chemiluminescence signal) from the immunoassay device 20, calculates the measurement values of CXCL9, CCL3, and IL-18 from the acquired optical information, and stores them in the SSD 313. The CPU 310 outputs the measurement values of CXCL9, CCL3, and IL-18. For example, the CPU 310 displays the measurement values of CXCL9, CCL3, and IL-18 on the display unit 302, prints them with a printer, or sends them to a mobile device. When outputting the measurement values of CXCL9, CCL3, and IL-18, designated thresholds corresponding to each of CXCL9, CCL3, and IL-18 may also be output as reference information.

[0162] Reference Figure 4B, a process for determining the risk of acute kidney injury or pulmonary fibrosis caused by ventilator-associated infection based on the measured value of one biomarker will be described. In step S201, the CPU 310 obtains optical information (chemiluminescence signal) from the immunoassay device 20. In step S202, the CPU 310 calculates the measured value of CXCL9 from the obtained optical information, and as the measurement result, obtains the measured value of CXCL9. The CPU 310 stores the measured value in the SSD 313. In step S203, the CPU 310 compares the calculated measured value of CXCL9 with a specified threshold value corresponding to CXCL9 stored in the SSD 313. When the measured value of CXCL9 is equal to or higher than the threshold value, the process proceeds to step S204. In step S204, the CPU 310 stores the determination result of a high risk of acute kidney injury or pulmonary fibrosis in the SSD 313. In step S203, when the measured value of CXCL9 is lower than the threshold value, the process proceeds to step S205. In step S205, the CPU 310 stores the determination result of a low risk of acute kidney injury or pulmonary fibrosis in the SSD 313. In step S206, the CPU 310 outputs the determination result. For example, the CPU 310 displays the determination result on the display unit 302, prints it with a printer, or sends it to a mobile device. In this example, the measured value of CCL3 or IL-18 may be obtained instead of the measured value of CXCL9. In this way, the acquisition device of the present embodiment can provide the determination result of the risk of acute kidney injury or pulmonary fibrosis caused by ventilator-associated infection to a doctor or the like as information related to ventilator-associated infection.

[0163] Hereinafter, the specified threshold value corresponding to CXCL9 will be referred to as the "first threshold value", the specified threshold value corresponding to CCL3 will be referred to as the "second threshold value", and the specified threshold value corresponding to IL-18 will be referred to as the "third threshold value".

[0164] Refer to Figure 4C, a process for determining the risk of acute kidney injury or pulmonary fibrosis caused by ventilator-associated infection based on the measured values of two biomarkers will be described. In step S301, the CPU 310 obtains optical information (chemiluminescence signal) from the immunoassay device 20. In step S302, the CPU 310 calculates the measured values of CXCL9 and CCL3 from the obtained optical information, and as the measurement results, obtains the measured values of CXCL9 and CCL3. The CPU 310 stores the measured values in the SSD 313. In step S303, the CPU 310 compares the calculated measured value of CXCL9 with the first threshold value stored in the SSD 313. When the measured value of CXCL9 is lower than the first threshold value, the process proceeds to step S304. In step S304, the calculated measured value of CCL3 is compared with the second threshold value stored in the SSD 313. When the measured value of CCL3 is lower than the second threshold value, the process proceeds to step S305. In step S305, the CPU 310 stores the determination result of low risk of acute kidney injury or pulmonary fibrosis in the SSD 313.

[0165] In step S303, when the measured value of CXCL9 is equal to or higher than the first threshold value, the process proceeds to step S306. In step S304, when the measured value of CCL3 is equal to or higher than the second threshold value, the process proceeds to step S306. In step S306, the CPU 310 stores the determination result of high risk of acute kidney injury or pulmonary fibrosis in the SSD 313. In step S307, the CPU 310 outputs the determination result. For example, the CPU 310 displays the determination result on the display unit 302, prints it with a printer, or sends it to a mobile device. In this example, the processes of step S303 and step S304 can be switched in order. In this example, instead of the measured values of CXCL9 or CCL3, the measured value of IL-18 can also be obtained. When the measured value of IL-18 is obtained, the CPU 310 compares the measured value of CCL3 with the third threshold value.

[0166] In other embodiments, the acquisition device may also determine that the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection is high when the measured values of both of the two biomarkers are above the specified thresholds corresponding to the respective biomarkers. The process at this time will be described. The CPU 310 acquires optical information (chemiluminescence signal) from the immunoassay device 20, calculates the measured values of CXCL9 and CCL3 from the acquired optical information, and stores them in the SSD 313. The CPU 310 compares the measured value of CXCL9 with the first threshold. When the measured value of CXCL9 is above the first threshold, the CPU 310 compares the measured value of CCL3 with the second threshold. When the measured value of CCL3 is above the second threshold, the CPU 310 stores the determination result of a high risk of acute kidney injury or pulmonary fibrosis in the SSD 313. When the measured value of CXCL9 is lower than the first threshold, or when the measured value of CCL3 is lower than the second threshold, the CPU 310 stores the determination result of a low risk of acute kidney injury or pulmonary fibrosis in the SSD 313. The CPU 310 outputs the determination result. For example, the CPU 310 displays the determination result on the display unit 302, prints it with a printer, or sends it to a mobile device. In this example, the measured value of IL-18 may be acquired instead of the measured value of CXCL9 or CCL3. When the measured value of IL-18 is acquired, the CPU 310 compares the measured value of CCL3 with the third threshold.

[0167] Refer to Figure 4D , the process for determining the risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection based on the measured values of CXCL9, CCL3, and IL-18 will be described. In step S401, the CPU 310 acquires optical information (chemiluminescence signal) from the immunoassay device 20. In step S402, the CPU 310 calculates the measured values of CXCL9, CCL3, and IL-18 from the acquired optical information, and as the measurement results, acquires the measured values of CXCL9, CCL3, and IL-18. The CPU 310 stores the measured values in the SSD 313. In step S403, the CPU 310 compares the calculated measured value of CXCL9 with the first threshold stored in the SSD 313. When the measured value of CXCL9 is lower than the first threshold, the process proceeds to step S404. In step S404, the calculated measured value of CCL3 is compared with the second threshold stored in the SSD 313. When the measured value of CCL3 is lower than the second threshold, the process proceeds to step S405. In step S405, the calculated measured value of IL-18 is compared with the third threshold stored in the SSD 313. When the measured value of IL-18 is lower than the third threshold, the process proceeds to step S406. In step S406, the CPU 310 stores the determination result of a low risk of acute kidney injury or pulmonary fibrosis in the SSD 313.

[0168] In step S403, when the measured value of CXCL9 is above the first threshold, the processing proceeds to step S407. In step S404, when the measured value of CCL3 is above the second threshold, the processing proceeds to step S407. In step S405, when the measured value of IL-18 is above the third threshold, the processing proceeds to step S407. In step S407, the CPU 310 stores in the SSD 313 a determination result indicating a high risk of developing acute kidney injury or pulmonary fibrosis. In step S408, the CPU 310 outputs the determination result. For example, the CPU 310 displays the determination result on the display unit 302, prints it using a printer, or sends it to a mobile device. In this example, the processing of steps S403, S404, and S405 can be performed in a different order.

[0169] In another embodiment, the acquisition device may also determine that there is a high risk of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection when all of the measured values of CXCL9, CCL3, and IL-18 are above the specified thresholds corresponding to the respective biomarkers. The procedure at this time will be described. The CPU 310 acquires optical information (chemiluminescence signal) from the immunoassay device 20, calculates the measured values of CXCL9, CCL3, and IL-18 from the acquired optical information, and stores them in the SSD 313. The CPU 310 compares the measured value of CXCL9 with the first threshold. When the measured value of CXCL9 is above the first threshold, the CPU 310 compares the measured value of CCL3 with the second threshold. When the measured value of CCL3 is above the second threshold, the CPU 310 compares the measured value of IL-18 with the third threshold. When the measured value of IL-18 is above the third threshold, the CPU 310 stores in the SSD 313 a determination result indicating a high risk of developing acute kidney injury or pulmonary fibrosis. When the measured value of CXCL9 is lower than the first threshold, when the measured value of CCL3 is lower than the second threshold, or when the measured value of IL-18 is lower than the third threshold, the CPU 310 stores in the SSD 313 a determination result indicating a low risk of developing acute kidney injury or pulmonary fibrosis. The CPU 310 outputs the determination result. For example, the CPU 310 displays the determination result on the display unit 302, prints it using a printer, or sends it to a mobile device.

[0170] Next, the present invention will be described in detail by way of examples, but the present invention is not limited to these examples. Hereinafter, "HISCL" is a registered trademark of Sysmex Corporation.

[0171]

Examples

[0172]

Example 1

[0173] Identify a biomarker that can distinguish patients at high risk of developing acute kidney injury or pulmonary fibrosis caused by respiratory infections using specimens collected from patients with respiratory infections. In addition, during the hospitalization of patients with respiratory infections, monitor the measured values of the biomarker.

[0174] (1) Subjects and Specimens

[0175] The subjects were 56 COVID-19 patients who were confirmed to be infected with SARS-CoV-2 by PCR testing and hospitalized at the Kobe City Medical Center General Hospital. Blood was collected from each subject within 3 days of the hospitalization date. Thereafter, blood was also collected from each subject at multiple time points. The obtained blood was used as the specimen. For each subject, the occurrence of acute kidney injury was diagnosed based on the KDIGO diagnostic criteria. In addition, the occurrence of pulmonary fibrosis was diagnosed by chest CT examination. Among the subjects, 16 were confirmed to have acute kidney injury during hospitalization. Among them, 8 subjects had already developed acute kidney injury on the hospitalization date, and the remaining 8 developed acute kidney injury after the initial blood collection date. Among the subjects confirmed to have pulmonary fibrosis during hospitalization, 28 were identified. Among them, 14 had residual pulmonary fibrosis after being determined to be negative for SARS-CoV-2 infection by PCR testing, and the remaining 14 did not have residual pulmonary fibrosis. Furthermore, among the numbers of subjects confirmed to have acute kidney injury and the numbers of subjects confirmed to have pulmonary fibrosis, the number of subjects with both acute kidney injury and pulmonary fibrosis was included.

[0176] (2) Measurement of Biomarker

[0177] (2.1) Measurement of Protein Biomarkers in Serum

[0178] Serum was prepared from the blood initially collected from each subject. The concentrations of IL-6, IL-10, IL-18, CXCL9, CCL3, CCL17, VEGF, SP-A, KL-6, NT-pro-BNP, and P-SEP in the serum of each subject were measured using the fully automated immunoassay device HISCL-5000 (Sysmex Corporation). The measurement by HISCL-5000 was performed by sandwich ELISA using a capture antibody and a detection antibody that specifically bind to each biomarker and magnetic particles as the solid phase. For example, CXCL9 was measured using the following R1 to R5 reagents. For the remaining biomarkers, except for substituting the capture antibody and the detection antibody, the measurement was performed in the same manner as for CXCL9.

[0179]

R1 Reagent

[0180] The anti-MIG monoclonal antibody (RANDOX) was digested with pepsin or the like by a conventional method to obtain Fab fragments. The Fab fragments were biotin-labeled by a conventional method and dissolved in a buffer containing 1% bovine serum albumin (BSA) and 0.5% casein to obtain R1 reagent.

[0181]

R2 reagent

[0182] Magnetic particles with streptavidin immobilized on the surface (hereinafter also referred to as "STA-binding magnetic particles", average particle size 2 μm, the amount of streptavidin per 1 g of magnetic particles is 2.9 - 3.5 mg) were washed 3 times with 10 mM HEPES buffer (pH 7.5). The washed STA-binding magnetic particles were added to 10 mM HEPES (pH 7.5) until the streptavidin concentration became 18 - 22 μg / ml (the concentration of STA-binding magnetic particles was 0.48 - 0.52 mg / ml) to obtain R2 reagent.

[0183]

R3 reagent

[0184] The anti-MIG monoclonal antibody (RANDOX) was digested with pepsin or the like by a conventional method to obtain Fab fragments. The Fab fragments were ALP-labeled by a conventional method and dissolved in a buffer containing 1% BSA and 0.5% casein to obtain R3 reagent.

[0185]

R4 reagent and R5 reagent

[0186] As the R4 reagent, HISCL R4 reagent (Sysmex Corporation), which is a buffer for measurement, was used. As the R5 reagent, HISCL R5 reagent (Sysmex Corporation) containing CDP-Star (registered trademark) (Applied Biosystems), which is a chemiluminescent substrate for ALP, was used.

[0187] The measurement procedure of HISCL-5000 is as follows. After mixing serum (20 μL) and R1 reagent (50 μL), R2 reagent (30 μL) is added. The magnetic particles in the resulting mixture are magnetically collected, the supernatant is removed, and the magnetic particles are washed with HISCL washing solution (300 μL). The supernatant is removed, and R3 reagent (100 μL) is added to the magnetic particles and mixed. The magnetic particles in the resulting mixture are magnetically collected, the supernatant is removed, and the magnetic particles are washed with HISCL washing solution (300 μL). The supernatant is removed, R4 reagent (50 μL) and R5 reagent (100 μL) are added to the magnetic particles, and the chemiluminescence intensity is measured. As a calibrator, a buffer solution containing recombinant CXCL9 is used. The calibrator is measured in the same manner as the serum to prepare a calibration curve. The chemiluminescence intensity obtained in the measurement of each serum is applied to the calibration curve to determine the concentration of CXCL9.

[0188] (2.2) Measurement of markers in blood

[0189] CRP, LD, and blood cell counts (lymphocytes and neutrophils) in the blood initially collected from each subject were measured by conventional methods, and their measurement results were recorded in the medical records. In this example, the measured values of these markers were obtained from the medical records of each subject.

[0190] (3) Cluster analysis

[0191] Fifty-six subjects were classified by unsupervised clustering analysis based on the concentrations of 8 markers (CCL17, VEGF, IL-6, CRP, IL-10, IL-18, CXCL9, and CCL3) associated with inflammation. The cluster analysis was performed using Cluster 3.0 (The University of Tokyo) by the complete linkage method based on the Euclidean distance. The results are shown in Figure 5 . As shown in Figure 5 , the subjects were classified into 4 clusters: I, II, III, and IV. Cluster I is the group with only a high CCL17 concentration, Cluster II is the group with overall low concentrations of the above 8 markers, Cluster III is the group with high concentrations of CRP, IL-6, and VEGF, and Cluster IV is the group with high concentrations of CXCL9, CCL3, IL-18, IL-10, CRP, IL-6, and VEGF.

[0192] The proportion of subjects who developed acute kidney injury or pulmonary fibrosis in each cluster was studied. The results are shown in Figure 6A and B. In Figure 6A , "non-AKI" are subjects who did not develop acute kidney injury, "Pre-AKI" are subjects who developed acute kidney injury after hospitalization, and "AKI" are subjects who had already developed acute kidney injury on the day of hospitalization. In Figure 6BAmong them, "non-fibrotic" refers to subjects in whom pulmonary fibrosis has not occurred, and "fibrotic" refers to subjects in whom pulmonary fibrosis has occurred. As Figure 6A shown, in Cluster IV, significantly more subjects with acute kidney disorders were included compared to other clusters. Additionally, as Figure 6B shown, in Cluster IV, significantly more subjects with pulmonary fibrosis were included compared to other clusters.

[0193] Subjects with acute kidney disorders and those without were classified into Cluster IV and those outside Cluster IV (Clusters I - III). Additionally, regarding subjects with pulmonary fibrosis, subjects in whom pulmonary fibrosis remained after being determined to be negative for SARS-CoV-2 infection and those in whom pulmonary fibrosis did not remain were classified into Cluster IV and those outside Cluster IV. The sensitivity, specificity, PPV, and NPV were calculated when determining the risk of acute kidney disorders caused by COVID-19 based on this classification. The results are shown in Tables 1 and 2. Similarly, the sensitivity, specificity, PPV, and NPV were calculated when determining the risk of remaining pulmonary fibrosis caused by COVID-19. The results are shown in Table 3. The P-values shown in Tables 1 - 3 were calculated based on Fisher's exact test.

[0194]

Table 1

[0195] AKI / PreAKI Non-AKI Total Outside Cluster IV 3 33 36 Cluster IV 13 7 20 Total 16 40

[0196] Sensitivity 81％ Specificity 83％ PPV 65％ NPV 92％

[0197] P < 0.0001

[0198]

Table 2

[0199] PreAKI Non-AKI Total Outside Cluster IV 2 33 35 Cluster IV 6 7 13 Total 8 40

[0200] Sensitivity 75％ Specificity 83％ PPV 46％ NPV 94％

[0201] P = 0.0028

[0202]

Table 3

[0203]

[0204]

[0205] P = 0.021

[0206] From the results shown in Tables 1 to 3, subjects belonging to Cluster IV had a higher risk of acute kidney injury caused by respiratory tract infection and a higher risk of residual pulmonary fibrosis compared to subjects outside Cluster IV. Thus, it is suggested that biomarkers that can distinguish Cluster IV from outside Cluster IV (especially Cluster III) are useful for determining the risks of acute kidney injury and pulmonary fibrosis caused by respiratory tract infection.

[0207] (4) Comparison of biomarker measurement values between clusters

[0208] The concentrations of each biomarker in Clusters I to IV are shown in Figure 7 . In the figure, "Lym" represents lymphocytes and "Neut" represents neutrophils. Among the 15 biomarkers, IL-18, CCL3, and CXCL9 were significantly higher in Cluster IV compared to Clusters I to III, as shown in Figure 7 F, G, and H. The results suggest that CXCL9, CCL3, and IL-18 can be biomarkers for determining the risks of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection.

[0209] As shown in Figure 7 C and D, IL-6 and CRP were significantly higher in Clusters III and IV compared to Clusters I and II. On the other hand, no significant difference was confirmed in the measurement values of IL-6 and CRP between Clusters III and IV. The results suggest that IL-6 and CRP are useful for determining the risks of acute kidney injury or pulmonary fibrosis caused by respiratory tract infection when used in combination with CXCL9, CCL3, and IL-18.

[0210] (5) Monitoring of biomarker measurement values

[0211] Serum was prepared from blood collected from each subject at multiple time points during hospitalization, and six biomarkers (CXCL9, CCL3, IL-18, IL-6, CRP, and LD) were measured. The measurement values of each biomarker for subjects who did not develop acute kidney injury (non-AKI), subjects who developed acute kidney injury after hospitalization (PreAKI), and subjects who had already developed acute kidney injury on the day of hospitalization (AKI) were plotted to create a coordinate graph. The results are shown in Figure 8A to F. In addition, the measurement values of each biomarker for subjects who did not have residual pulmonary fibrosis after testing negative for SARS-CoV-2 infection (non-fibrosis) and subjects who had residual pulmonary fibrosis (fibrosis) were plotted to create a coordinate graph. The results are shown in Figure 9A~F. Furthermore, among the subjects with PreAK and AKI, those with a serum creatinine value higher than the baseline value on the day of hospitalization were classified as having a high creatinine value, and those with a serum creatinine value below the baseline value on the day of hospitalization were classified as having normal creatinine.

[0212] As Figure 8A ~C shows, the measured values of CXCL9, CCL3, and IL-18 in subjects with PreAK and AKI tended to be higher than those in non-AKI subjects during the hospitalization period, regardless of whether the serum creatinine value was high or normal. On the one hand, as Figure 8D ~F shows, the measured values of IL-6, CRP, and LD in subjects with PreAK and AKI tended to decrease over time even when the serum creatinine value was high.

[0213] As Figure 9A ~C shows, the measured values of CXCL9, CCL3, and IL-18 in subjects with residual pulmonary fibrosis (fibrosis) tended to be higher than those in subjects without residual pulmonary fibrosis (non-fibrosis) during the hospitalization period. On the one hand, as Figure 9D ~F shows, no significant difference was confirmed in the measured values of IL-6, CRP, and LD between subjects with residual pulmonary fibrosis (fibrosis) and subjects without residual pulmonary fibrosis (non-fibrosis).

[0214]

Explanation of symbols

[0215] 11, 21, 31: Kits

[0216] 12, 22, 32: First containers

[0217] 23, 33: Second containers

[0218] 34: Third container

[0219] 35: Fourth container

[0220] 13, 24, 36: Packing boxes

[0221] 14, 25, 37: Enclosed documents

[0222] 10: Acquisition device

[0223] 20: Immunoassay device

[0224] 30: Computer system

[0225] 40: Recording medium

[0226] 300: Computer main body

[0227] 301: Input unit

[0228] 302: Display unit

[0229] 310: CPU

[0230] 311: ROM

[0231] 312: RAM

[0232] 313: SSD

[0233] 314: Input / output interface

[0234] 315: Reading device

[0235] 316: Communication interface

[0236] 317: Image output interface

[0237] 318: Bus

[0238] This specification also includes the following content:

[0239] 1. A method for obtaining information related to respiratory tract infections, which includes measuring at least one biomarker in a test sample collected from a subject suffering from a respiratory tract infection or a subject suspected of having said respiratory tract infection,

[0240] wherein the biomarker includes at least one selected from CXCL9, CCL3, and IL-18,

[0241] and the measurement result of the biomarker becomes an indicator of the risk of acute kidney injury or pulmonary fibrosis caused by said respiratory tract infection.

[0242] 2. The method according to Embodiment 1, wherein when the measured value of the biomarker is above a specified threshold corresponding to the biomarker, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by said respiratory tract infection.

[0243] 3. The method according to Embodiment 1, wherein when the measured value of the biomarker is lower than a specified threshold corresponding to the biomarker, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by said respiratory tract infection.

[0244] 4. The method according to Embodiment 1, wherein

[0245] the biomarker includes CXCL9,

[0246] and when the measured value of CXCL9 is above a specified threshold corresponding to CXCL9, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by said respiratory tract infection.

[0247] 5. The method according to Embodiment 1 or 4, wherein

[0248] The biomarker contains CXCL9,

[0249] When the measured value of CXCL9 is lower than the specified threshold corresponding to CXCL9, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0250] The method according to Embodiment 1, wherein

[0251] The biomarker contains CCL3,

[0252] When the measured value of CCL3 is equal to or higher than the specified threshold corresponding to CCL3, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0253] The method according to Embodiment 1 or 6, wherein

[0254] The biomarker contains CCL3,

[0255] When the measured value of CCL3 is lower than the specified threshold corresponding to CCL3, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0256] The method according to Embodiment 1, wherein

[0257] The biomarker contains IL-18,

[0258] When the measured value of IL-18 is equal to or higher than the specified threshold corresponding to IL-18, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0259] The method according to Embodiment 1 or 8, wherein

[0260] The biomarker contains IL-18,

[0261] When the measured value of IL-18 is lower than the specified threshold corresponding to IL-18, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0262] The method according to Embodiment 1, wherein

[0263] The biomarker contains CXCL9, CCL3 and IL-18,

[0264] When the measured value of at least one of the biomarkers is equal to or higher than the specified threshold corresponding to the biomarker, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0265] 11. The method according to Embodiment 1 or 10, wherein

[0266] the biomarker includes CXCL9, CCL3, and IL-18,

[0267] when the measured values of all the biomarkers are lower than the specified threshold corresponding to the biomarker, it indicates a low risk of developing acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0268] 12. A method for monitoring the measured values of biomarkers, which includes using specimens collected from a subject suffering from a respiratory tract infection or a subject suspected of having the respiratory tract infection at multiple time points, obtaining the measured values of at least one biomarker in each of the specimens,

[0269] the biomarker includes at least one selected from CXCL9, CCL3, and IL-18,

[0270] the measured values of the biomarker serve as an indicator of the risk of developing acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0271] 13. The method according to Embodiment 12, wherein among the multiple time points, at at least one time point, when the measured value of the biomarker is equal to or higher than the specified threshold corresponding to the biomarker, it indicates a high risk of developing acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0272] 14. The method according to Embodiment 12 or 13, wherein among the multiple time points, at all time points, when the measured values of the biomarker are lower than the specified threshold corresponding to the biomarker, it indicates a low risk of developing acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0273] 15. The method according to Embodiment 12, wherein

[0274] the biomarker includes CXCL9,

[0275] among the multiple time points, at at least one time point, when the measured value of CXCL9 is equal to or higher than the specified threshold corresponding to CXCL9, it indicates a high risk of developing acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0276] 16. The method according to Embodiment 12 or 15, wherein

[0277] the biomarker includes CXCL9,

[0278] Among the plurality of time points, at all time points, when the measured value of CXCL9 is lower than the specified threshold corresponding to CXCL9, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0279] 17. The method according to embodiment 12, wherein

[0280] the biomarker contains CCL3,

[0281] Among the plurality of time points, at at least one time point, when the measured value of CCL3 is equal to or higher than the specified threshold corresponding to CCL3, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0282] 18. The method according to embodiment 12 or 17, wherein

[0283] the biomarker contains CCL3,

[0284] Among the plurality of time points, at all time points, when the measured value of CCL3 is lower than the specified threshold corresponding to CCL3, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0285] 19. The method according to embodiment 12, wherein

[0286] the biomarker contains IL-18,

[0287] Among the plurality of time points, at at least one time point, when the measured value of IL-18 is equal to or higher than the specified threshold corresponding to IL-18, it indicates a high risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0288] 20. The method according to embodiment 12 or 19, wherein

[0289] the biomarker contains IL-18,

[0290] Among the plurality of time points, at all time points, when the measured value of IL-18 is lower than the specified threshold corresponding to IL-18, it indicates a low risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0291] 21. The method according to any one of embodiments 12 to 20, wherein the test samples collected from the subject at a plurality of time points include:

[0292] a first test sample collected from the subject at a first time point, and

[0293] A second subject collected from the subject at a second time point different from the first time point.

[0294] 22. A method for obtaining information related to respiratory tract infections, comprising:

[0295] a step of measuring at least one biomarker in a subject collected from a subject suffering from a respiratory tract infection or a subject suspected of having the respiratory tract infection, and

[0296] a step of determining the risk of developing acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection based on the measured value of the biomarker,

[0297] wherein the biomarker includes at least one selected from CXCL9, CCL3, and IL-18.

[0298] 23. The method according to embodiment 22, wherein when the measured value of the biomarker is equal to or higher than a specified threshold corresponding to the biomarker, it is determined that the risk of developing acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is high.

[0299] 24. The method according to embodiment 22, wherein when the measured value of the biomarker is lower than a specified threshold corresponding to the biomarker, it is determined that the risk of developing acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is low.

[0300] 25. The method according to embodiment 22, wherein

[0301] the biomarker includes CXCL9,

[0302] when the measured value of CXCL9 is equal to or higher than a specified threshold corresponding to CXCL9, it is determined that the risk of developing acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is high.

[0303] 26. The method according to embodiment 22 or 25, wherein

[0304] the biomarker includes CXCL9,

[0305] when the measured value of CXCL9 is lower than a specified threshold corresponding to CXCL9, it is determined that the risk of developing acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is low.

[0306] 27. The method according to embodiment 22, wherein

[0307] the biomarker includes CCL3,

[0308] When the measured value of CCL3 is above the specified threshold corresponding to CCL3, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is high.

[0309] 28. The method according to embodiment 22 or 27, wherein

[0310] the biomarker contains CCL3,

[0311] When the measured value of CCL3 is lower than the specified threshold corresponding to CCL3, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is low.

[0312] 29. The method according to embodiment 22, wherein

[0313] the biomarker contains IL-18,

[0314] When the measured value of IL-18 is above the specified threshold corresponding to IL-18, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is high.

[0315] 30. The method according to embodiment 22 or 29, wherein

[0316] the biomarker contains IL-18,

[0317] When the measured value of IL-18 is lower than the specified threshold corresponding to IL-18, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is low.

[0318] 31. The method according to embodiment 22, wherein

[0319] the biomarker contains CXCL9, CCL3 and IL-18,

[0320] When the measured value of at least one of the biomarkers is above the specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is high.

[0321] 32. The method according to embodiment 22 or 31, wherein

[0322] the biomarker contains CXCL9, CCL3 and IL-18,

[0323] When the measured values of all the biomarkers are lower than the specified thresholds corresponding to the biomarkers, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is low.

[0324] 33. The method according to any one of Embodiments 1 to 32, wherein the subject is whole blood, plasma or serum.

[0325] 34. The method according to any one of Embodiments 1 to 33, wherein the respiratory tract infection is an infection caused by a virus.

[0326] 35. The method according to Embodiment 34, wherein the virus is SARS-CoV-2, SARS-CoV or MERS-CoV.

[0327] 36. A kit for use in the method according to any one of Embodiments 1 to 35, comprising at least one selected from the following: a reagent containing a substance capable of specifically binding to CXCL9, a reagent containing a substance capable of specifically binding to CCL3, and a reagent containing a substance capable of specifically binding to IL-18.

[0328] 37. An acquisition device for respiratory tract infection-related information, comprising a computer including a processor and a memory under the control of the processor,

[0329] wherein a computer program for causing the computer to execute the following steps is recorded in the memory:

[0330] a step of acquiring a measured value of a biomarker in a subject collected from a subject suffering from a respiratory tract infection or a subject suspected of having the respiratory tract infection, and

[0331] a step of outputting the measured value of the biomarker,

[0332] the biomarker includes at least one selected from CXCL9, CCL3 and IL-18,

[0333] the measured value of the biomarker becomes an index of the risk of developing acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0334] 38. The device according to Embodiment 37, wherein the computer program causes the computer to further execute a step of determining the risk of developing acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection based on the measured value of the biomarker.

[0335] 39. The device according to Embodiment 38, wherein when the measured value of the biomarker is equal to or higher than a specified threshold corresponding to the biomarker, it is determined that the risk of developing acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is high.

[0336] The device according to Embodiment 38, wherein when the measured value of the biomarker is lower than a specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is low.

[0337] 41. The device according to Embodiment 38, wherein

[0338] the biomarker contains CXCL9,

[0339] when the measured value of CXCL9 is equal to or higher than a specified threshold corresponding to CXCL9, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is high.

[0340] 42. The device according to Embodiment 38 or 41, wherein

[0341] the biomarker contains CXCL9,

[0342] when the measured value of CXCL9 is lower than a specified threshold corresponding to CXCL9, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is low.

[0343] 43. The device according to Embodiment 38, wherein

[0344] the biomarker contains CCL3,

[0345] when the measured value of CCL3 is equal to or higher than a specified threshold corresponding to CCL3, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is high.

[0346] 44. The device according to Embodiment 38 or 43, wherein

[0347] the biomarker contains CCL3,

[0348] when the measured value of CCL3 is lower than a specified threshold corresponding to CCL3, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is low.

[0349] 45. The device according to Embodiment 38, wherein

[0350] the biomarker contains IL-18,

[0351] when the measured value of IL-18 is equal to or higher than a specified threshold corresponding to IL-18, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is high.

[0352] 46. The device according to Embodiment 38 or 45, wherein

[0353] The biomarker contains IL-18,

[0354] When the measured value of IL-18 is lower than the specified threshold corresponding to IL-18, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is low.

[0355] The apparatus according to Embodiment 38, wherein

[0356] The biomarker contains CXCL9, CCL3, and IL-18,

[0357] When the measured value of at least one of the biomarkers is equal to or higher than the specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is high.

[0358] The apparatus according to Embodiment 38 or 47, wherein

[0359] The biomarker contains CXCL9, CCL3, and IL-18,

[0360] When the measured values of all of the biomarkers are lower than the specified thresholds corresponding to the biomarkers, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is low.

[0361] A computer program for obtaining information related to a respiratory tract infection, which is a computer program recorded on a computer-readable medium,

[0362] The computer program is a computer program for causing the computer to execute the following steps:

[0363] A step of obtaining a measured value of a biomarker in a test sample collected from a subject suffering from a respiratory tract infection or a subject suspected of having the respiratory tract infection, and

[0364] A step of outputting the measured value of the biomarker,

[0365] The biomarker contains at least one selected from CXCL9, CCL3, and IL-18,

[0366] The measured value of the biomarker serves as an indicator of the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection.

[0367] The computer program according to Embodiment 49, which causes the computer to further execute a step of determining the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection based on the measured value of the biomarker.

[0368] 51. The computer program according to Embodiment 50, wherein when the measured value of the biomarker is above a specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is high.

[0369] 52. The computer program according to Embodiment 50, wherein when the measured value of the biomarker is lower than a specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is low.

[0370] 53. The computer program according to Embodiment 50, wherein

[0371] the biomarker contains CXCL9,

[0372] when the measured value of CXCL9 is above a specified threshold corresponding to CXCL9, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is high.

[0373] 54. The computer program according to Embodiment 50 or 54, wherein

[0374] the biomarker contains CXCL9,

[0375] when the measured value of CXCL9 is lower than a specified threshold corresponding to CXCL9, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is low.

[0376] 55. The computer program according to Embodiment 50, wherein

[0377] the biomarker contains CCL3,

[0378] when the measured value of CCL3 is above a specified threshold corresponding to CCL3, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is high.

[0379] 56. The computer program according to Embodiment 50 or 55, wherein

[0380] the biomarker contains CCL3,

[0381] when the measured value of CCL3 is lower than a specified threshold corresponding to CCL3, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is low.

[0382] 57. The computer program according to Embodiment 50, wherein

[0383] the biomarker contains IL-18,

[0384] When the measured value of IL-18 is above the specified threshold corresponding to IL-18, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is high.

[0385] 58. The computer program according to embodiment 50 or 57, wherein

[0386] the biomarker contains IL-18,

[0387] When the measured value of IL-18 is lower than the specified threshold corresponding to IL-18, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is low.

[0388] 59. The computer program according to embodiment 50, wherein

[0389] the biomarker contains CXCL9, CCL3 and IL-18,

[0390] When the measured value of at least one of the biomarkers is above the specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is high.

[0391] 60. The computer program according to embodiment 50 or 59, wherein

[0392] the biomarker contains CXCL9, CCL3 and IL-18,

[0393] When the measured values of all the biomarkers are lower than the specified thresholds corresponding to the biomarkers, it is determined that the risk of acute kidney injury or pulmonary fibrosis caused by the respiratory tract infection is low.

Claims

1. Use of a substance that can specifically bind to at least one biomarker in a test sample collected from a subject suffering from a respiratory infection caused by SARS-CoV-2 or a subject suspected of having said respiratory infection in the manufacture of a kit for obtaining information related to a respiratory infection caused by SARS-CoV-2, wherein the obtaining of the information is carried out by a method comprising the following steps: a step of measuring the biomarker with a substance that can specifically bind to the biomarker, and a step of determining the risk of acute kidney injury caused by said respiratory infection based on the measured value of the biomarker, and wherein the biomarker contains CXCL9.

2. The use according to claim 1, wherein the biomarker contains a combination of CXCL9 and at least one selected from CCL3 and IL-18.

3. The use according to claim 1 or 2, wherein when the measured value of the biomarker is above a specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury caused by said respiratory infection is high, and / or wherein when the measured value of the biomarker is lower than a specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury caused by said respiratory infection is low.

4. The use according to claim 1, wherein when the measured value of CXCL9 is above a specified threshold corresponding to CXCL9, it is determined that the risk of acute kidney injury caused by said respiratory infection is high, and / or wherein when the measured value of CXCL9 is lower than a specified threshold corresponding to CXCL9, it is determined that the risk of acute kidney injury caused by said respiratory infection is low.

5. The use according to claim 2, wherein the biomarker contains CCL3, when the measured value of CCL3 is above a specified threshold corresponding to CCL3, it is determined that the risk of acute kidney injury caused by said respiratory infection is high, and / or when the measured value of CCL3 is lower than a specified threshold corresponding to CCL3, it is determined that the risk of acute kidney injury caused by said respiratory infection is low.

6. The use according to claim 2, wherein the biomarker contains IL-18, when the measured value of IL-18 is above a specified threshold corresponding to IL-18, it is determined that the risk of acute kidney injury caused by said respiratory infection is high, and / or When the measured value of IL-18 is lower than the specified threshold corresponding to IL-18, it is determined that the risk of acute kidney injury caused by the respiratory infection is low.

7. The use according to claim 2, wherein the biomarker comprises CXCL9, CCL3 and IL-18, When the measured value of at least one of the biomarkers is above the specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury caused by the respiratory infection is high, and / or When the measured values of all the biomarkers are lower than the specified thresholds corresponding to the biomarkers, it is determined that the risk of acute kidney injury caused by the respiratory infection is low.

8. The use according to claim 1, wherein the subject is whole blood, plasma or serum.

9. A device for obtaining information related to a respiratory infection caused by SARS-CoV-2, comprising a computer including a processor and a memory under the control of the processor, A computer program for causing the computer to execute the following steps is recorded in the memory: A step of obtaining the measured value of a biomarker in a subject collected from a subject suffering from a respiratory infection caused by SARS-CoV-2 or a subject suspected of having the respiratory infection, and A step of outputting the measured value of the biomarker, The biomarker comprises CXCL9, Based on the measured value of the biomarker, the risk of acute kidney injury caused by the respiratory infection is determined.

10. The device according to claim 9, wherein the biomarker comprises a combination of CXCL9 and at least one selected from CCL3 and IL-18.

11. The device according to claim 9 or 10, wherein the computer program causes the computer to further execute a step of determining the risk of acute kidney injury caused by the respiratory infection based on the measured value of the biomarker.

12. The device according to claim 11, wherein when the measured value of the biomarker is above the specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury caused by the respiratory infection is high, and / or wherein when the measured value of the biomarker is lower than the specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury caused by the respiratory infection is low.

13. The device according to claim 11, When the measured value of CXCL9 is above the specified threshold corresponding to CXCL9, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is high, and / or When the measured value of CXCL9 is lower than the specified threshold corresponding to CXCL9, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is low.

14. The apparatus according to claim 11, wherein the biomarker comprises CCL3, When the measured value of CCL3 is above the specified threshold corresponding to CCL3, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is high, and / or When the measured value of CCL3 is lower than the specified threshold corresponding to CCL3, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is low.

15. The apparatus according to claim 11, wherein the biomarker comprises IL-18, When the measured value of IL-18 is above the specified threshold corresponding to IL-18, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is high, and / or When the measured value of IL-18 is lower than the specified threshold corresponding to IL-18, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is low.

16. The apparatus according to claim 11, wherein the biomarker comprises CXCL9, CCL3 and IL-18, When the measured value of at least one of the biomarkers is above the specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is high, and / or When the measured values of all the biomarkers are lower than the specified thresholds corresponding to the biomarkers, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is low.

17. A computer-readable medium having recorded thereon a computer program for obtaining information related to a respiratory tract infection caused by SARS-CoV-2, The computer program is a computer program for causing the computer to execute the following steps: A step of obtaining a measured value of a biomarker in a subject collected from a subject suffering from a respiratory tract infection caused by SARS-CoV-2 or a subject suspected of having the respiratory tract infection, and A step of outputting the measured value of the biomarker, The biomarker comprises CXCL9, Based on the measured value of the biomarker, the risk of acute kidney injury caused by the respiratory tract infection is determined.

18. The medium according to claim 17, wherein the biomarker comprises a combination of CXCL9 and at least one selected from CCL3 and IL-18.

19. The medium according to claim 17 or 18, which further causes the computer to perform a step of determining the risk of acute kidney injury caused by the respiratory tract infection based on the measured value of the biomarker.

20. The medium according to claim 19, wherein when the measured value of the biomarker is above a specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is high, and / or wherein when the measured value of the biomarker is lower than a specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is low.

21. The medium according to claim 19, wherein when the measured value of CXCL9 is above a specified threshold corresponding to CXCL9, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is high, and / or wherein when the measured value of CXCL9 is lower than a specified threshold corresponding to CXCL9, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is low.

22. The medium according to claim 19, wherein the biomarker comprises CCL3, when the measured value of CCL3 is above a specified threshold corresponding to CCL3, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is high, and / or when the measured value of CCL3 is lower than a specified threshold corresponding to CCL3, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is low.

23. The medium according to claim 19, wherein the biomarker comprises IL-18, when the measured value of IL-18 is above a specified threshold corresponding to IL-18, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is high, and / or when the measured value of IL-18 is lower than a specified threshold corresponding to IL-18, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is low.

24. The medium according to claim 19, wherein the biomarker comprises CXCL9, CCL3 and IL-18, when the measured value of at least one of the biomarkers is above a specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury caused by the respiratory tract infection is high, and / or When the measured values of all the biomarkers are lower than the specified threshold corresponding to the biomarker, it is determined that the risk of acute kidney injury caused by the respiratory infection is low.

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