Method and application of obtaining information related to the condition of patients with interstitial pneumonia

Abstract

The present invention relates to a method for obtaining information related to the condition of an interstitial pneumonia patient and its application. The subject of the present invention is to provide a means for distinguishing the condition of an interstitial pneumonia patient. At least one biomarker selected from CXCL9 and CXCL10 in a biological sample of an interstitial pneumonia patient is measured, and the measurement result of the biomarker is used as a distinguishing index for interstitial pneumonia with autoimmune features (IPAF) and connective tissue disease-related interstitial lung disease (CTD-ILD), so as to solve the problem.

Description

Technical Field

[0001] The present invention relates to a method for obtaining information related to the condition of an interstitial pneumonia patient. In addition, the present invention relates to a method for determining the condition of an interstitial pneumonia patient. Further, the present invention relates to a kit for use in these methods, a device for determining the condition of an interstitial pneumonia patient, and a computer program. Background Art

[0002] Interstitial pneumonia is a disease in which inflammation and fibrosis occur in the interstitial tissue of the lungs, especially the alveolar walls. If interstitial pneumonia progresses, symptoms such as decreased vital capacity and gas exchange capacity and dyspnea will appear due to pulmonary fibrosis. The causes of interstitial pneumonia involve many aspects. For example, interstitial pneumonia that occurs with collagen disease as the underlying disease is called connective tissue disease associated interstitial lung disease (CTD-ILD). Interstitial pneumonia with unknown causes such as no underlying disease is called idiopathic interstitial pneumonia (IIPs). Regarding the treatment of interstitial pneumonia, the treatment of CTD-ILD and IIPs is different. For CTD-ILD, anti-inflammatory therapy is mainly performed, and immunosuppressive drugs such as steroids are used. For idiopathic pulmonary fibrosis (IPF), which accounts for the majority of IIPs, anti-inflammatory therapy is not performed, but anti-fibrotic drugs such as pirfenidone are used.

[0003] CTD-ILD and IIPs are differentiated according to physical findings such as skin and joints, blood tests such as autoantibodies. For CTD-ILD, the diagnostic criteria of various collagen diseases are met and the pulmonary lesions unique to interstitial pneumonia are visible. For IIPs, the physical findings, autoantibodies, etc. specific to collagen diseases are not observed. In addition, it has been reported that interstitial pneumonia and IPF with collagen diseases can be differentiated by measuring biomarkers in the blood. Specifically, non-patent literature 1 records that the concentrations of CXCL9 (CXC chemokine ligand 9, CXC chemokine ligand 9) and CXCL10 (CXC chemokine ligand 10, CXC chemokine ligand 10) in the serum of interstitial pneumonia patients with anti-Jo-1 antibodies are significantly higher than those in IPF patients. Anti-Jo-1 antibodies are autoantibodies specific to polymyositis / dermatomyositis (PM / DM), one of the collagen diseases.

[0004] However, in fact, it is not easy to distinguish CTD-ILD from IIPs in the clinic. As one of the reasons, cases in which collagen disease-related symptoms, physical findings, autoantibodies, etc. can be observed in interstitial pneumonia but do not meet the diagnostic criteria of collagen disease can be listed. Although such cases have the characteristics of suspected collagen disease, they have to be classified in IIPs. However, in 2015, the European Respiratory Society (ERS) and the American Thoracic Society (ATS) proposed a new concept of interstitial pneumonia with autoimmune features (IPAF) and its diagnostic criteria (refer to Fischer A. et al., Eur Respir J., 2015, vol.46, p.976-987). The diagnostic criteria of IPAF are based on the condition that more than one item is met in at least two fields in the clinical field, serological field and morphological field. In the clinical field, it is confirmed whether the symptoms specific to collagen disease can be seen in fingers and joints. In the serological field, it is confirmed whether the autoantibodies specific to collagen disease can be seen. In the field of morphology, it is confirmed whether a predetermined pattern of interstitial pneumonia is visible in high-resolution CT images or in tissue obtained by lung biopsy.

[0005] Prior art literature

[0006] Non-patent literature

[0007] Non-patent document 1: Richards TJ et al., Characterization and Peripheral Blood Biomarker Assessment of Jo-1 Antibody-Positive Interstitial Lung Disease, Arthritis Rheum., 2009, vol. 60, p. 2183-2192 Summary of the invention

[0008] Problems to be solved by the invention

[0009] The diagnostic criteria of IPAF need to be formed by the diagnosis made by doctors in multiple professional fields such as collagen disease internal medicine, respiratory medicine, and pathological diagnosis. Therefore, for example, it is difficult for doctors in respiratory medicine to distinguish IPAF from CTD-ILD alone. In addition, cases of visible lung lesions before collagen disease also make differential diagnosis difficult. That is, there is the following situation: even if it is temporarily diagnosed as IIPs, collagen disease-related symptoms appear in the development process and it is suspected to be IPAF or CTD-ILD. Although the specific autoantibodies of each collagen disease are known, the useful biomarkers for distinguishing IPAF and CTD-ILD have not yet appeared. In view of this situation, the object of the present invention is to provide a means for distinguishing the condition of patients with interstitial pneumonia.

[0010] Means for solving problems

[0011] Therefore, the present invention provides a method for obtaining information related to the condition of an interstitial pneumonia patient, comprising the step of measuring at least one biomarker in a biological sample of the interstitial pneumonia patient, wherein the biomarker includes at least one selected from CXCL9 and CXCL10, and the measurement result of the biomarker serves as an indicator for distinguishing IPAF from CTD-ILD.

[0012] The present invention provides a method for determining the condition of an interstitial pneumonia patient, comprising: a step of measuring at least one biomarker of a biological sample of an interstitial pneumonia patient; and a step of determining whether the patient is IPAF or CTD-ILD based on the measurement result of the biomarker, wherein the biomarker comprises at least one selected from CXCL9 and CXCL10.

[0013] The present invention provides a method for obtaining information related to treatment responsiveness of an IPAF patient, comprising the step of measuring at least one biomarker in a biological sample of the IPAF patient, wherein the biomarker comprises at least one selected from CXCL9 and CXCL10, and the measurement result of the biomarker serves as an indicator for identifying treatment responsiveness to an anti-inflammatory therapy.

[0014] The present invention provides a kit for the above method, which contains a reagent comprising a substance capable of specifically binding to CXCL9 and / or a reagent comprising a substance capable of specifically binding to CXCL10.

[0015] The present invention provides a device for determining the condition of an interstitial pneumonia patient, comprising a computer including a processor and a memory under the control of the processor, wherein a computer program is recorded in the memory, and the computer program causes the computer to execute the following steps: a step of obtaining the measurement result of at least one biomarker in a biological sample of an interstitial pneumonia patient; a step of determining whether the patient is IPAF or CTD-ILD based on the measurement result of the biomarker, wherein the biomarker includes at least one selected from CXCL9 and CXCL10.

[0016] The present invention provides a computer program for determining the condition of an interstitial pneumonia patient, which is recorded on a computer-readable medium, and which records a computer program for causing a computer to execute the following steps: a step of obtaining the measurement result of at least one biomarker in a biological sample of an interstitial pneumonia patient; a step of determining that the patient is IPAF or CTD-ILD based on the measurement result of the biomarker, wherein the biomarker includes at least one selected from CXCL9 and CXCL10.

[0017] Effects of the Invention

[0018] According to the present invention, information related to the condition of a patient with interstitial pneumonia can be obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1A This is a diagram showing an example of the appearance of the kit according to the present embodiment.

[0020] Figure 1B This is a diagram showing an example of the appearance of the kit according to the present embodiment.

[0021] Figure 2 This is a schematic diagram showing an example of a device for determining the condition of a patient with interstitial pneumonia.

[0022] Figure 3 This is a block diagram showing the hardware configuration of a device for determining the condition of a patient with interstitial pneumonia.

[0023] Figure 4A The present invention is a flow chart of determination using a device for determining the condition of a patient with interstitial pneumonia.

[0024] Figure 4B The present invention is a flow chart of determination using a device for determining the condition of a patient with interstitial pneumonia.

[0025] Figure 4C The present invention is a flow chart of determination using a device for determining the condition of a patient with interstitial pneumonia.

[0026] Figure 4D The present invention is a flow chart of determination using a device for determining the condition of a patient with interstitial pneumonia.

[0027] Figure 5 It is a graph showing the CXCL9 concentration in the serum of each patient group of CTD-ILD, IPAF, and IPF.

[0028] Figure 6 It is a graph showing the CXCL10 concentration in the serum of each patient group of CTD-ILD, IPAF, and IPF.

[0029] Figure 7 Figure 3 Receiver operating characteristic (ROC) curve for determining whether a patient has CTD-ILD or IPAF based on serum CXCL9 concentration.

[0030] Figure 8 Figure 2 is the ROC curve for determining whether a patient is CTD-ILD or IPAF based on the serum CXCL10 concentration.

[0031] Fig. 9 Figure 2 is the ROC curve for determining whether a patient is IPAF or IPF based on the serum CXCL10 concentration.

[0032] Fig. 10A This is a graph showing the correlation between the serum CXCL9 concentration before anti-inflammatory therapy and the forced vital capacity recovery (ΔFVC) over 1 year in IPAF patients.

[0033] Fig. 10B This is a graph showing the correlation between the serum CXCL10 concentration before anti-inflammatory therapy and the forced vital capacity recovery (ΔFVC) over 1 year in IPAF patients.

[0034] Fig.11 This is a ROC curve for determining whether a patient is IPAF or IPF based on the prediction value calculated from the serum CXCL9 and KL-6 concentrations.

[0035] Fig.12 This is a ROC curve for determining whether a patient is IPAF or IPF based on the prediction value calculated from the serum CXCL9 and MMP9 concentrations.

[0036] Fig.13 This is a ROC curve for determining whether a patient is IPAF or IPF based on the prediction value calculated from the serum CXCL10 and KL-6 concentrations.

[0037] Fig.14 This is a ROC curve for determining whether a patient is IPAF or IPF based on the prediction value calculated from the serum CXCL10 and MMP9 concentrations. DETAILED DESCRIPTION

[0038] [1. Method for obtaining information related to the condition of patients with interstitial pneumonia]

[0039] In the method for acquiring information related to the condition of an interstitial pneumonia patient (hereinafter also referred to as “acquisition method”) of the present embodiment, at least one biomarker is measured in a biological sample of the interstitial pneumonia patient.

[0040] (Subjects and biological samples)

[0041] In this embodiment, the subject is not particularly limited as long as the subject is a patient diagnosed with interstitial pneumonia or a person suspected of having interstitial pneumonia. In this specification, the term "interstitial pneumonia patient" includes both patients diagnosed with interstitial pneumonia and people suspected of having interstitial pneumonia. The subject may be an untreated interstitial pneumonia patient. In addition, the subject may be an interstitial pneumonia patient suffering from collagen disease or an interstitial pneumonia patient suspected of having collagen disease. The types of interstitial pneumonia and collagen disease are not particularly limited.

[0042] The biological sample is not particularly limited as long as it is a sample containing the biomarkers described below. As such biological samples, for example, blood samples, bronchoalveolar lavage fluid, etc. can be cited. As blood samples, for example, blood (whole blood) collected from a subject, and plasma or serum prepared from the blood can be cited. In the present embodiment, serum is particularly preferred.

[0043] When the biological sample contains insoluble impurities such as cells, for example, the impurities can be removed from the biological sample by well-known means such as centrifugation and filtration. In addition, the biological sample can be diluted with a suitable aqueous medium as needed. This aqueous medium is not particularly limited as long as it does not interfere with the measurement described below, and examples thereof include water, saline, buffer, etc. The buffer is not particularly limited as long as it has a buffering effect at a pH near neutral (for example, a pH of 6 or more and 8 or less). Examples of such buffers include GOOD'S buffers such as HEPES, MES, and PIPES, Tris-buffered saline (TBS), and phosphate-buffered saline (PBS).

[0044] (Biomarkers and their determination)

[0045] As a biomarker, at least one selected from CXCL9 and CXCL10 can be cited. CXCL9 is also known as MIG (Monokine induced by interferonγ, interferon γ induced mononuclear factor), which is a type of Th1 chemokine. CXCL10 is also known as IP-10 (Interferon-inducible Protein-10, interferon induced protein-10), which is a Th1 chemokine like CXCL9. Both CXCL9 and CXCL10 are ligands of the CXCR3 receptor expressed on the surface of Th1 cells. The amino acid sequences of CXCL9 and CXCL10 are known in themselves, for example, they can be obtained from well-known databases such as NCBI (National Center for Biotechnology Information).

[0046] In this specification, "determining a biomarker" includes: determining the value of the amount or concentration of the biomarker, and obtaining information reflecting the amount or concentration of the biomarker. "Information reflecting the amount or concentration of the biomarker" refers to an indicator that changes according to the amount or concentration of the biomarker in the biological sample or the measurement sample prepared from the biological sample. Such an indicator is preferably an optical change indicator that can be measured visually or mechanically. Examples of optical change indicators include luminescence intensity, fluorescence intensity, absorbance, turbidity, depth of color development, etc.

[0047] Information reflecting the amount or concentration of a biomarker can be expressed qualitatively, quantitatively, or semi-quantitatively. Qualitatively expressed information is information indicating the presence or absence of a biomarker. Quantitatively expressed information is numerical information such as a numerical value obtained using a measuring instrument (hereinafter also referred to as "raw data") and a value calculated from the numerical value. As values ​​calculated from raw data, for example, values ​​obtained by subtracting the value of a negative control sample or a background value from the raw data can be cited. Based on quantitative information, the value of the amount or concentration of a biomarker can be determined. Semi-quantitatively expressed information is information that shows the amount or concentration of a biomarker in stages through statements, numbers (indicating levels), colors, etc. For example, statements such as "below the detection limit", "little", "medium", and "many" can be used.

[0048] In this embodiment, the measurement result of the biomarker includes the value, information and combination thereof obtained by measuring the biomarker. In a preferred embodiment, the measurement result of the biomarker is quantitative information reflecting the amount or concentration of the biomarker, and / or the value of the amount or concentration of the biomarker determined based on the quantitative information. Hereinafter, the quantitative information reflecting the amount or concentration of the biomarker, and / or the value of the amount or concentration of the biomarker will also be referred to as the "measurement value of the biomarker".

[0049] The measurement result of a biomarker can be the measurement value of one biomarker or the measurement value of two biomarkers. The measurement value of a biomarker is specifically the measurement value of CXCL9 and the measurement value of CXCL10. In addition, the measurement result of a biomarker can be a value calculated using the measurement values ​​of more than two biomarkers. In this calculation, any coefficient and / or constant can be further used as needed. For example, as a value calculated using the measurement values ​​of two biomarkers, the ratio, product, sum, difference, etc. of two measurement values ​​can be listed.

[0050] The method of measuring the biomarker is not particularly limited as long as it can obtain information reflecting the amount or concentration of the biomarker in the biological sample or the measurement sample prepared from the biological sample. In this embodiment, it is preferred to use a method of capturing the biomarker using a substance that can specifically bind to the biomarker. By detecting the biomarker captured using such a substance using a method known in the art, the biomarker contained in the biological sample can be measured.

[0051] As substances that can specifically bind to biomarkers, for example, antibodies, aptamers, receptor proteins, etc. can be cited. Among them, antibodies are particularly preferred. Antibodies against the above-mentioned biomarkers themselves are well known and can usually be obtained. Antibodies against biomarkers are not particularly limited as long as they can specifically bind to biomarkers. Such antibodies can be any of monoclonal antibodies, polyclonal antibodies, and their fragments (e.g., Fab, F(ab')2, Fab', etc.). In addition, commercially available antibodies can be used.

[0052] The method of using an antibody to measure a biomarker is not particularly limited and can be appropriately selected from known immunological assays. As such an assay, for example, enzyme-linked immunosorbent assay (ELISA), Western blotting, etc. can be cited. Among them, the ELISA method is preferred. The type of the ELISA method can be any one of a sandwich method, a competitive method, a direct method, an indirect method, etc., and the sandwich method is particularly preferred. As an example, the following describes the situation of measuring a biomarker in a biological sample by a sandwich ELISA method.

[0053] First, 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. The complex can be formed by mixing a biological sample that may contain a biomarker, a capture antibody, and a detection antibody. Then, a solution containing the complex is brought into contact with a solid phase that can capture the capture antibody, thereby forming the above-mentioned complex on the solid phase. Alternatively, a solid phase pre-immobilized with a capture antibody can be used. That is, the above-mentioned complex can be formed on the solid phase by bringing the solid phase to which the capture antibody is immobilized, the biological sample, and the detection antibody into contact. It should be noted that when both the capture antibody and the detection antibody are monoclonal antibodies, it is preferred that their epitopes are different.

[0054] The solid phase can be an insoluble carrier that can fix the capture antibody. The method of fixing 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 other substances. As direct binding, for example, physical adsorption can be mentioned. As indirect binding, for example, binding via a combination of biotin and avidin or streptavidin (hereinafter also referred to as "avidins") can be mentioned. In this case, by pre-modifying the capture antibody with biotin and pre-binding avidins to the solid phase, the capture antibody and the solid phase can be indirectly bound via the combination of biotin and avidins.

[0055] The material of the solid phase is not particularly limited, for example, it can be selected from organic polymer compounds, inorganic compounds, biopolymers, etc. As organic polymer compounds, latex, polystyrene, polypropylene, etc. can be listed. As inorganic compounds, magnetic bodies (iron oxide, chromium oxide and ferrite, etc.), silicon dioxide, aluminum oxide, glass, etc. can be listed. As biopolymers, insoluble agarose, insoluble dextran, gelatin, cellulose, etc. can be listed. Two or more of these can be used in combination. The shape of the solid phase is not particularly limited, for example, particles, membranes, microplates, microtubes, test tubes, etc. can be listed. Among them, particles are preferred, and magnetic particles are particularly preferred.

[0056] In the present embodiment, B / F (Bound / Free) separation can be performed between the formation process of the complex and the detection process of the complex to remove the unreacted free components that have not formed the complex. Unreacted free components refer to components that do not constitute the complex. For example, capture antibodies and detection antibodies that are not bound to biomarkers can be cited. The means of B / F separation are not particularly limited. If the solid phase is a particle, B / F separation is achieved by recovering only the solid phase that captures the complex by centrifugation. If the solid phase is a container such as a microplate or a microtube, B / F separation is achieved by removing the liquid containing the unreacted free components. In addition, when the solid phase is a magnetic particle, the liquid containing the unreacted free components is removed by suction from a nozzle under the condition that the magnetic particles are constrained by magnetic force with a magnet, thereby achieving B / F separation, which is preferred from the viewpoint of automation. After removing the unreacted free components, the solid phase captured with the complex can be washed with a suitable aqueous medium such as PBS.

[0057] Then, the complex formed on the solid phase can be detected by a method known in the art, and the biomarker contained in the biological sample can be measured. For example, when an antibody labeled with a marker is used as a detection antibody, the biomarker of the biological sample can be measured by detecting the signal generated by the marker. Alternatively, when a labeled secondary antibody against the detection antibody is used, the biomarker in the biological sample can also be measured in the same manner.

[0058] In addition, as an example of a method for measuring a biomarker using an antibody, the immune complex transfer method described in Japanese Patent Application Laid-Open No. 1-254868 can be used.

[0059] In this specification, "detection signal" includes qualitative detection of the presence or absence of a signal, quantitative signal intensity, and semi-quantitative detection of the intensity of the signal. Semi-quantitative detection refers to: the intensity of the signal is represented in stages in the form of "no signal", "weak", "medium", "strong", etc. In this embodiment, it is preferred to detect the signal intensity quantitatively or semi-quantitatively.

[0060] The labeling substance is not particularly limited as long as it generates a detectable signal. For example, it may be a substance that generates a signal by itself (hereinafter also referred to as a "signal generating substance"), or it may be a substance that generates a signal by catalyzing the reaction of other substances. Examples of signal generating substances include fluorescent substances and radioactive isotopes. Examples of substances that generate detectable signals by catalyzing the reaction of other substances include enzymes. Examples of enzymes include alkaline phosphatase, peroxidase, β-galactosidase, and luciferase. Examples of fluorescent substances include fluorescent pigments such as fluorescein isothiocyanate (FITC), rhodamine, and Alexa Fluor (registered trademark), and fluorescent proteins such as GFP. Examples of radioactive isotopes include 125 I. 14C. 32 P, etc. Among these, enzymes are preferred as labeling substances, and alkaline phosphatase and peroxidase are particularly preferred.

[0061] The method of detecting signal itself is well known in the art. In the present embodiment, the assay method corresponding to the type of the signal from the above-mentioned marker can be suitably selected. For example, when the marker is an enzyme, known devices such as spectrophotometers can be used to measure the signals such as light, color, etc. produced by reacting the substrate for the enzyme.

[0062] As a substrate for an enzyme, it can be appropriately selected from known substrates according to the type of the enzyme. For example, when alkaline phosphatase is used as an enzyme, as a substrate, chemiluminescent substrates such as CDP-Star (registered trademark) (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) (3-(4-methoxyspiro[1,2-dioxetane-3,2-(5'-chloro)tricyclo[3.3.1.13,7]decane]-4-yl)phenyl phosphate) can be listed; chromogenic substrates such as 5-bromo-4-chloro-3-indolyl phosphate (BCIP), 5-bromo-6-chloro-indolyl phosphate disodium, and p-nitrophenyl phosphate. When peroxidase is used as the enzyme, examples of the substrate include chemiluminescent substrates such as luminol and its derivatives, and chromogenic substrates such as 2,2'-azinobis(3-ethylbenzothiazoline-6-ammonium sulfonate) (ABTS), 1,2-phenylenediamine (OPD), and 3,3',5,5'-tetramethylbenzidine (TMB).

[0063] When the label is a radioisotope, known devices such as scintillation counters can be used to measure the radiation as a signal. In addition, when the label is a fluorescent substance, known devices such as fluorescence microplate readers can be used to measure the fluorescence as a signal. It should be noted that the excitation wavelength and the fluorescence wavelength can be appropriately determined according to the type of the fluorescent substance used.

[0064] The detection result of the signal can be used as the measurement result of the biomarker. For example, when the intensity of the signal is quantified, the measured value of the signal intensity itself or the value obtained from the measured value can be used as the measurement result of the biomarker. As the value obtained from the measured value of the signal intensity, for example, the value obtained by subtracting the measured value of the negative control sample or the background value from the measured value can be listed. In addition, the measured value of the signal intensity can be brought into the standard curve to determine the value of the amount or concentration of the biomarker. The negative control sample can be appropriately selected, and for example, a biological sample obtained from a healthy person can be listed.

[0065] In this embodiment, it is preferred to measure the free protein marker contained in the biological sample by a sandwich ELISA method using a capture antibody fixed to magnetic particles and a detection antibody labeled with a marker. In this case, a commercially available fully automatic immunoassay device such as the HISCL series (manufactured by Sysmex Co., Ltd.) can be used for measurement.

[0066] (Information about the condition of patients with interstitial pneumonia)

[0067] In the present embodiment, the measurement result of the biomarker becomes the identification index of IPAF and CTD-ILD. For example, as shown in the embodiment, the concentration of CXCL9 and CXCL10 in the biological sample of the patient group diagnosed as IPAF is significantly lower than that of the patient group diagnosed as CTD-ILD. Therefore, in the present embodiment, the measurement result of the biomarker can be obtained as the condition-related information of the interstitial pneumonia patient. As the condition-related information of the interstitial pneumonia patient, for example: the information indicating that the interstitial pneumonia patient is IPAF or the information indicating that the interstitial pneumonia patient is CTD-ILD can be enumerated. For example, when the measurement value of CXCL9 or the measurement value of CXCL10 is lower than the prescribed threshold corresponding to each biomarker, the measurement value can indicate that the patient is IPAF. Or, when the measurement value of CXCL9 or the measurement value of CXCL10 is the same as or higher than the prescribed threshold corresponding to each biomarker, the measurement value can indicate that the patient is CTD-ILD. More specific embodiments are described below.

[0068] In one embodiment, the measurement result of the biomarker is the measurement value of CXCL9. In this embodiment, when the measurement value of CXCL9 is lower than the prescribed threshold corresponding to CXCL9, the measurement value can indicate that the patient is IPAF. When the measurement value of CXCL9 is the same as or higher than the prescribed threshold corresponding to CXCL9, the measurement value can indicate that the patient is CTD-ILD. Here, the prescribed threshold corresponding to CXCL9 is a threshold for distinguishing IPAF and CTD-ILD.

[0069] In another embodiment, the measurement result of the biomarker is a measurement value of CXCL10. In this embodiment, when the measurement value of CXCL10 is lower than the prescribed threshold corresponding to CXCL10, the measurement value can indicate that the patient is IPAF. When the measurement value of CXCL10 is the same as or higher than the prescribed threshold corresponding to CXCL10, the measurement value can indicate that the patient is CTD-ILD. Here, the prescribed threshold corresponding to CXCL10 is a threshold for distinguishing IPAF from CTD-ILD.

[0070] In another embodiment, the measurement result of the biomarker is the measurement value of CXCL9 and the measurement value of CXCL10. In this embodiment, when the measurement value of CXCL9 is lower than the first threshold or the measurement value of CXCL10 is lower than the second threshold, these measurement values ​​can indicate that the patient is IPAF. When the measurement value of CXCL9 is the same as or higher than the first threshold and the measurement value of CXCL10 is the same as or higher than the second threshold, these measurement values ​​can indicate that the patient is CTD-ILD. Or, when the measurement value of CXCL9 is lower than the first threshold and the measurement value of CXCL10 is lower than the second threshold, these measurement values ​​can indicate that the patient is IPAF. In addition, when the measurement value of CXCL9 is the same as or higher than the first threshold or the measurement value of CXCL10 is the same as or higher than the second threshold, these measurement values ​​can indicate that the patient is CTD-ILD. Here, the first threshold is a prescribed threshold corresponding to CXCL9, and the second threshold is a prescribed threshold corresponding to CXCL10. The first threshold and the second threshold are thresholds for distinguishing IPAF and CTD-ILD.

[0071] In another embodiment, the measurement result of the biomarker also becomes an indicator for distinguishing IPAF from IPF. As shown in the examples, the concentration of CXCL10 in the biological sample of the patient group diagnosed with IPF is significantly lower than that of the patient group diagnosed with IPAF. Therefore, the condition-related information of the interstitial pneumonia patient can be information indicating that the interstitial pneumonia patient is IPF. In this embodiment, the measurement result of the biomarker is the measurement value of CXCL10. When the measurement value of CXCL10 is lower than the prescribed threshold value corresponding to CXCL10, the measurement value can indicate that the patient is IPF. When the measurement value of CXCL10 is the same as or higher than the prescribed threshold value corresponding to CXCL10, the measurement value can indicate that the patient is IPAF. Here, the prescribed threshold value corresponding to CXCL10 is a threshold value for distinguishing IPAF from IPF.

[0072] The prescribed threshold is not particularly limited and can be suitably set.For example, the measured value data of the biomarker of the patient with interstitial pneumonia can be accumulated, so as to set the prescribed threshold according to experience.For example, the threshold for distinguishing CTD-ILD and IPAF can be set as described below.First, biological samples are collected from multiple patients (CTD-ILD groups) diagnosed as CTD-ILD and multiple patients (IPAF groups) diagnosed as IPAF, and biomarkers are measured to obtain the measured value of biomarkers.Then, the value that can distinguish CTD-ILD groups and IPAF groups with the highest accuracy is obtained, and the value is set as the prescribed threshold.About the threshold for distinguishing IPAF and IPF, the measured value of the biomarker in the biological samples collected from multiple patients (IPF groups) diagnosed as IPAF groups and IPF can also be used to be set in the same manner.When setting the threshold, it is preferred to consider sensitivity, specificity, positive hit rate, negative hit rate, etc.

[0073] The biomarker measurement results obtained by the acquisition method of this embodiment can be used to determine the condition of patients with interstitial pneumonia. Doctors and other medical workers can use the measurement results to identify the condition, or they can combine the measurement results with other information to identify the condition. Here, "other information" includes physical findings, tissue findings or image findings, blood test results, and other medical findings.

[0074] (Embodiment using another biomarker)

[0075] The present inventors have found that by measuring KL-6 (Krebs von der Lungen Nr.6) and MMP9 (Matrix metalloproteinase 9) as another biomarker, IPAF and IPF can be distinguished by combining these measurement results with the measurement results of CXCL9 and CXCL10. Thus, in the present embodiment, the biomarker also includes at least one selected from KL-6 and MMP9. KL-6 is a type of sialylated sugar chain antigen and is well-known as a marker for interstitial pneumonia. MMP9 is an enzyme with activities such as decomposing type IV collagen and is well-known as a marker associated with pulmonary fibrosis. The amino acid sequences of KL-6 and MMP9 themselves are well-known, for example, they can be obtained from public databases such as NCBI. Regarding the determination of biomarkers, as described above.

[0076] As the measurement result of the biomarker, the measurement value of at least one selected from CXCL9 and CXCL10, and the measurement value of at least one selected from KL-6 and MMP9 can be cited. Preferably, the measurement result of the biomarker is a value obtained based on the measurement value of at least one selected from CXCL9 and CXCL10, and the measurement value of at least one selected from KL-6 and MMP9. As such a value, for example, a value obtained by multivariate analysis using the measurement value of each biomarker can be cited. As the value obtained by multivariate analysis, the predicted value obtained by multivariate logistic regression analysis is particularly preferred. Such a predicted value can be calculated by the following regression formula.

[0077] P=1 / [1+exp{-(a1x1+a2x2+···+a n x n +b)}]

[0078] In the above regression equation, x1~x n is the measured value of each biomarker, a1~a n is the regression coefficient of each biomarker, and b is a constant. The regression coefficient and the constant can be suitably set according to the type of the biomarker used. For example, a multivariate logistic model for distinguishing IPAF and IPF can be made by the measured value data of the biomarker in the biological sample collected from multiple patients diagnosed as IPAF and multiple patients diagnosed as IPF, and the regression coefficient and the constant can be set. The multivariate logistic model can be made using statistical analysis software such as SPSSStatistics (IBM company). In the present embodiment, the multivariate logistic model is preferably made in advance by the measured value data of the biomarker of IPAF patient and IPF patient.

[0079] In this embodiment, as the value obtained based on the measured value of at least one selected from CXCL9 and CXCL10 and the measured value of at least one selected from KL-6 and MMP9, it is preferred to use the predicted value obtained by multivariate logistic regression analysis of the measured value of CXCL9 and the measured value of KL-6, the measured value of CXCL9 and the measured value of MMP9, the measured value of CXCL10 and the measured value of KL-6, or the measured value of CXCL10 and the measured value of MMP9.

[0080] When at least one of CXCL9 and CXCL10 selected as a biomarker and at least one of KL-6 and MMP9 are measured, the measurement result of the biomarker becomes an identification index of IPAF and IPF. Specifically, as information related to the condition of an interstitial pneumonia patient, information indicating that the interstitial pneumonia patient is IPAF or information indicating that the interstitial pneumonia patient is IPF can be obtained. For example, when the measurement result of the biomarker is a predicted value obtained by multivariate logistic regression analysis using at least one measured value selected from CXCL9 and CXCL10 and at least one measured value selected from KL-6 and MMP9, the predicted value indicates the condition-related information of the interstitial pneumonia patient as follows by comparison with the threshold value. When the predicted value is the same as or higher than the specified threshold value, the predicted value can indicate that the patient is IPAF. Alternatively, when the predicted value is lower than the specified threshold value, the predicted value can indicate that the patient is IPF. Here, the specified threshold value is a threshold value for distinguishing IPAF and IPF. The setting of the specified threshold value is as described above.

[0081] [2. Method for determining the condition of patients with interstitial pneumonia]

[0082] In this embodiment, the measurement results of the biomarkers obtained by the above method can be used to determine the condition of the patient with interstitial pneumonia. In the method for determining the condition of the patient with interstitial pneumonia in this embodiment (hereinafter also referred to as "determination method"), first, at least one biomarker in the biological sample of the patient with interstitial pneumonia is measured. The details of the measurement are the same as those described in the acquisition method of this embodiment.

[0083] In the determination method of the present embodiment, the condition of the patient with interstitial pneumonia is determined based on the measurement result of the biomarker. Specifically, the patient with interstitial pneumonia is determined to be CTD-ILD or IPAF. The details of the measurement result of the biomarker are the same as the description in the acquisition method of the present embodiment. For example, when the measurement result of the biomarker is the measurement value of CXCL9 or the measurement value of CXCL10, when the measurement value of CXCL9 or the measurement value of CXCL10 is lower than the prescribed threshold corresponding to each biomarker, the patient is determined to be IPAF. Alternatively, when the measurement value of CXCL9 or the measurement value of CXCL10 is the same as or higher than the prescribed threshold corresponding to each biomarker, the patient is determined to be CTD-ILD. The details corresponding to the prescribed threshold of each biomarker are the same as the description in the acquisition method of the present embodiment. A more specific embodiment is described as follows.

[0084] In one embodiment, the measurement result of the biomarker is the measurement value of CXCL9. In this embodiment, when the measurement value of CXCL9 is lower than the prescribed threshold corresponding to CXCL9, the patient is determined to be IPAF. When the measurement value of CXCL9 is the same as or higher than the prescribed threshold corresponding to CXCL9, the patient is determined to be CTD-ILD. Here, the prescribed threshold corresponding to CXCL9 is a threshold for distinguishing IPAF and CTD-ILD.

[0085] In another embodiment, the measurement result of the biomarker is the measurement value of CXCL10. In this embodiment, when the measurement value of CXCL10 is lower than the prescribed threshold value corresponding to CXCL10, the patient is determined to be IPAF. When the measurement value of CXCL10 is the same as or higher than the prescribed threshold value corresponding to CXCL10, the patient is determined to be CTD-ILD. Here, the prescribed threshold value corresponding to CXCL10 is a threshold value for distinguishing IPAF from CTD-ILD.

[0086] In another embodiment, the measurement result of the biomarker is the measurement value of CXCL9 and the measurement value of CXCL10. In this embodiment, when the measurement value of CXCL9 is lower than the first threshold or the measurement value of CXCL10 is lower than the second threshold, the patient is determined to be IPAF. When the measurement value of CXCL9 is the same as or higher than the first threshold, and the measurement value of CXCL10 is the same as or higher than the second threshold, the patient is determined to be CTD-ILD. Or, when the measurement value of CXCL9 is lower than the first threshold and the measurement value of CXCL10 is lower than the second threshold, the patient is determined to be IPAF. In addition, when the measurement value of CXCL9 is the same as or higher than the first threshold or the measurement value of CXCL10 is the same as or higher than the second threshold, the patient is determined to be CTD-ILD. Here, the first threshold is a prescribed threshold corresponding to CXCL9, and the second threshold is a prescribed threshold corresponding to CXCL10. The first and second thresholds are thresholds for distinguishing IPAF and CTD-ILD.

[0087] In another embodiment, the interstitial pneumonia patient is determined to be IPAF or IPF based on the measurement result of the biomarker. In this embodiment, the measurement result of the biomarker is the measurement value of CXCL10. When the measurement value of CXCL10 is lower than the prescribed threshold corresponding to CXCL10, the patient is determined to be IPF. When the measurement value of CXCL10 is the same as or higher than the prescribed threshold corresponding to CXCL10, the patient is determined to be IPAF. Here, the prescribed threshold corresponding to CXCL10 is a threshold for distinguishing IPAF from IPF.

[0088] In this embodiment, the biomarker may further include at least one selected from KL-6 and MMP9. When at least one selected from CXCL9 and CXCL10 and at least one selected from KL-6 and MMP9 are measured, the details of the measurement results of the biomarkers are the same as those described in the acquisition method of this embodiment. Preferably, the measurement result of the biomarker is a value obtained based on the measurement value of at least one selected from CXCL9 and CXCL10 and the measurement value of at least one selected from KL-6 and MMP9. This value is a value obtained by multivariate analysis using the measurement values ​​of each biomarker, preferably a predicted value obtained by multivariate logistic regression analysis.

[0089] When the measurement result of the biomarker is, for example, a predicted value obtained by multivariate logistic regression analysis using at least one measured value selected from CXCL9 and CXCL10 and at least one measured value selected from KL-6 and MMP9, the condition of the patient with interstitial pneumonia is determined as follows by comparing the predicted value with the threshold. When the predicted value is the same as or higher than the specified threshold, the patient is determined to be IPAF. Alternatively, when the predicted value is lower than the specified threshold, the patient is determined to be IPF. Here, the specified threshold is a threshold for distinguishing IPAF from IPF. The setting of the specified threshold is as described above.

[0090] As described above, the determination method of the present embodiment can provide information to assist medical workers such as doctors in determining the condition of patients with interstitial pneumonia. Thus, for patients with interstitial pneumonia, appropriate treatment corresponding to the determined condition can be performed. For example, antifibrotic drugs are used in the treatment of IPF, but when a patient is determined to be IPAF by the determination method of the present embodiment, a regimen of administering immunosuppressive drugs such as steroids can be studied.

[0091] [3. Treatment of interstitial pneumonia]

[0092] The present invention also includes a method for treating patients with interstitial pneumonia according to the condition identified by the determination method of this embodiment. Therefore, one embodiment of the present invention relates to a method for treating interstitial pneumonia. The method for treating interstitial pneumonia of this embodiment includes a process for measuring CXCL10 in a biological sample of a patient with interstitial pneumonia, a process for determining that the patient is IPAF or IPF based on the measurement result of CXCL10, and a process for administering a therapeutic drug for interstitial pneumonia to the patient according to the determined condition, when the patient is diagnosed with IPAF, an immunosuppressant is administered to the patient, and when the patient is diagnosed with IPF, an anti-fibrotic drug is administered to the patient. In the determination process, when the measured value of CXCL10 is the same as or higher than the prescribed threshold corresponding to CXCL10, the patient is determined to be IPAF. Alternatively, when the measured value of CXCL10 is lower than the prescribed threshold corresponding to CXCL10, the patient is determined to be IPF. Here, the prescribed threshold is a threshold for distinguishing IPAF and IPF.

[0093] Another embodiment of the method for treating interstitial pneumonia includes a step of measuring at least one biomarker in a biological sample of an interstitial pneumonia patient, a step of determining that the patient is IPAF or IPF based on the measurement result of the biomarker, and a step of administering a therapeutic drug for interstitial pneumonia to the patient according to the determined condition, wherein the biomarker includes at least one selected from CXCL9 and CXCL10, and at least one selected from KL-6 and MMP9, when the patient is diagnosed with IPAF, the patient is administered an immunosuppressive drug, and when the patient is diagnosed with IPF, the patient is administered an anti-fibrotic drug. In this embodiment, the measurement result of the biomarker is preferably a value obtained by multivariate analysis using the measurement value of at least one selected from CXCL9 and CXCL10 and the measurement value of at least one selected from KL-6 and MMP9. More preferably, the measurement result of the biomarker is a predicted value obtained by multivariate logistic regression analysis. In the determination step, when the predicted value is the same as or higher than the specified threshold, the patient is determined to be IPAF. Alternatively, when the predicted value is lower than the specified threshold, the patient is determined to be IPF. Here, the prescribed threshold is a threshold for discriminating between IPAF and IPF.

[0094] The details of the determination of interstitial pneumonia patients, biological samples, biomarkers and predetermined threshold values ​​are the same as those described in the acquisition method of the present embodiment. In the administration process, it is preferred to administer a therapeutically effective amount of an immunosuppressant or an anti-fibrotic drug to the patient. As immunosuppressants, steroid drugs such as prednisolone and methylprednisolone can be listed; cyclophosphamide, azathioprine, cyclosporine, tacrolimus, etc. As anti-fibrotic drugs, pirfenidone, nintedanib, etc. can be listed. The therapeutically effective amount can be appropriately determined according to the interstitial pneumonia treatment guidelines, etc.

[0095] [4. Method for obtaining information related to treatment responsiveness of a patient diagnosed with IPAF]

[0096] There are not many reports on the evaluation of interstitial pneumonia by the IPAF diagnostic criteria proposed by ERS and ATS. Therefore, it is not clear how patients diagnosed with IPAF by this diagnostic criteria should be treated. However, we believe that basically, patients diagnosed with IPAF (hereinafter also referred to as "IPAF patients") should be treated with anti-inflammatory therapy using immunosuppressive drugs, etc. On the other hand, we also believe that for the case of IPAF showing a usual interstitial pneumonia (UIP) pattern in the morphological field (image or tissue), it is necessary to study the scheme of using anti-fibrotic drugs instead of anti-inflammatory therapy as in the treatment of IPF. Here, as shown in the example, for IPAF patients, a significant negative correlation was confirmed between the CXCL9 concentration in the serum before treatment with anti-inflammatory therapy and the amount of forced vital capacity recovered within 1 year. The results show that IPAF patients with high serum CXCL9 concentrations have a high response to anti-inflammatory therapy. The same tendency was also confirmed for CXCL10.

[0097] Thus, in this embodiment, the measurement result of at least one of the biomarkers selected from CXCL9 and CXCL10 can be an indicator for identifying the therapeutic responsiveness of IPAF patients to anti-inflammatory therapy. In the method for obtaining relevant information on the therapeutic responsiveness of IPAF patients in this embodiment, first, at least one of the biomarkers selected from CXCL9 and CXCL10 in the biological sample of the IPAF patient is measured. The IPAF patient can be a patient diagnosed by the IPAF diagnostic criteria proposed by ERS and ATS. Alternatively, the IPAF patient can be a patient diagnosed based on the determination results of the determination method of this embodiment. The details of the measurement of the biological sample and the biomarker are the same as those described in the acquisition method of this embodiment.

[0098] In this embodiment, when the measured value of CXCL9 or the measured value of CXCL10 is the same as or higher than the prescribed threshold value corresponding to each biomarker, the measured value can indicate that the IPAF patient is responsive to anti-inflammatory therapy. Alternatively, in this embodiment, when the measured value of CXCL9 or the measured value of CXCL10 is the same as or higher than the prescribed threshold value corresponding to each biomarker, it can be determined that the IPAF patient is responsive to anti-inflammatory therapy. When it is indicated or determined that the IPAF patient is responsive to anti-inflammatory therapy, it is expected that the anti-inflammatory therapy is effective for the patient. Here, the prescribed threshold is a threshold used to identify the therapeutic responsiveness of IPAF patients to anti-inflammatory therapy. This threshold can be, for example, the same as the threshold used to identify IPAF and IPF. The details of the setting of the threshold are the same as those described in the acquisition method of this embodiment. A more specific embodiment is described as follows.

[0099] In one embodiment, the measurement result of the biomarker is a measurement value of CXCL9. In this embodiment, when the measurement value of CXCL9 is the same as or higher than the prescribed threshold value corresponding to CXCL9, the measurement value can indicate that the IPAF patient is responsive to anti-inflammatory therapy. Alternatively, in this embodiment, when the measurement value of CXCL9 is the same as or higher than the prescribed threshold value corresponding to CXCL9, it can be determined that the IPAF patient is responsive to anti-inflammatory therapy. Here, the prescribed threshold value corresponding to CXCL9 is a threshold value for identifying the therapeutic responsiveness of IPAF patients to anti-inflammatory therapy.

[0100] In another embodiment, the measurement result of the biomarker is the measurement value of CXCL10. In this embodiment, when the measurement value of CXCL10 is the same as or higher than the prescribed threshold value corresponding to CXCL10, the measurement value can indicate that the IPAF patient is responsive to anti-inflammatory therapy. Alternatively, in this embodiment, when the measurement value of CXCL10 is the same as or higher than the prescribed threshold value corresponding to CXCL10, it can be determined that the IPAF patient is responsive to anti-inflammatory therapy. Here, the prescribed threshold value corresponding to CXCL10 is a threshold value for identifying the therapeutic responsiveness of IPAF patients to anti-inflammatory therapy.

[0101] In another embodiment, the measurement result of the biomarker is the measurement value of CXCL9 and the measurement value of CXCL10. In this embodiment, when the measurement value of CXCL9 is the same as or higher than the first threshold value, and the measurement value of CXCL10 is the same as or higher than the second threshold value, these measurement values ​​can indicate that the IPAF patient is responsive to anti-inflammatory therapy. Alternatively, in this embodiment, when the measurement value of CXCL9 is the same as or higher than the first threshold value, and the measurement value of CXCL10 is the same as or higher than the second threshold value, it can be determined that the IPAF patient is responsive to anti-inflammatory therapy. In addition, when the measurement value of CXCL9 is the same as or higher than the first threshold value, or the measurement value of CXCL10 is the same as or higher than the second threshold value, these measurement values ​​can indicate that the IPAF patient is responsive to anti-inflammatory therapy. Alternatively, in this embodiment, when the measurement value of CXCL9 is the same as or higher than the first threshold value, or the measurement value of CXCL10 is the same as or higher than the second threshold value, it can be determined that the IPAF patient is responsive to anti-inflammatory therapy. Here, the first threshold is a predetermined threshold corresponding to CXCL9, and the second threshold is a predetermined threshold corresponding to CXCL10. The first and second thresholds are thresholds for identifying the therapeutic responsiveness of IPAF patients to anti-inflammatory therapy.

[0102] [5. Test kit]

[0103] The scope of the present invention also includes a kit for use in the method and determination method of the present embodiment. That is, a kit (hereinafter also referred to as a "kit") is provided, which contains a reagent containing a substance that can specifically bind to CXCL9 and / or a reagent containing a substance that can specifically bind to CXCL10. The details of the substances that can specifically bind to CXCL9 and CXCL10 are the same as the description of the substance that can specifically bind to the biomarker used in the method of the present embodiment.

[0104] In the present embodiment, the reagent comprising a substance that can specifically bind to CXCL9 is preferably a combination of a reagent comprising a capture antibody for CXCL9 and a reagent comprising a detection antibody for CXCL9. In addition, the reagent comprising a substance that can specifically bind to CXCL10 is preferably a combination of a reagent comprising a capture antibody for CXCL10 and a reagent comprising a detection antibody for CXCL10. The detection antibody can be labeled with a marker. When the marker is an enzyme, the kit may include a substrate for the enzyme. The details of the capture antibody, the detection antibody, the marker and the substrate are the same as those described in the method of the present embodiment described above. The form of the capture antibody, the detection antibody, the marker and the substrate is not particularly limited, and can be a solid (e.g., a powder, a crystal, a lyophilized product, etc.) or a liquid (e.g., a solution, a suspension, an emulsion, etc.).

[0105] In this embodiment, the containers containing the reagents can be bundled into a box and provided to the user. The box can be accompanied by a document. The accompanying document can record the composition of the kit, the method of use, the relationship between the measurement results obtained by the kit and the condition of the patient with interstitial pneumonia, etc. An example of such a kit is shown in the accompanying drawings. Figure 1A In the kit shown, as the reagent containing a substance capable of specifically binding to CXCL9, there are a reagent containing a capture antibody against CXCL9 and a reagent containing a detection antibody against CXCL9, but the present invention is not limited to this example. Figure 1A , 11 represents a test kit, 12 represents a first container containing a reagent containing a capture antibody for CXCL9, 13 represents a second container containing a reagent containing a detection antibody for CXCL9, 14 represents a packaging box, and 15 represents an accompanying document. In this example, the first container can contain a reagent containing a capture antibody for CXCL10 instead of a reagent containing a capture antibody for CXCL9. The second container can contain a reagent containing a detection antibody for CXCL10 instead of a reagent containing a detection antibody for CXCL9. In this example, the test kit may further include a solid phase for fixing a capture antibody for CXCL9. The details of the solid phase are the same as those described in the acquisition method of this embodiment.

[0106] Figure 1B The kit further includes a reagent containing a substance capable of specifically binding to CXCL10, a reagent containing a capture antibody against CXCL10, and a reagent containing a detection antibody against CXCL10, but the present invention is not limited to this example. Figure 1B , 21 represents a reagent kit, 22 represents a first container containing a reagent containing a capture antibody against CXCL9, 23 represents a second container containing a reagent containing a detection antibody against CXCL9, 24 represents a third container containing a reagent containing a capture antibody against CXCL10, 25 represents a fourth container containing a reagent containing a detection antibody against CXCL10, 26 represents a packaging box, and 27 represents an accompanying document. In this example, the reagent kit may further include a solid phase for fixing the capture antibody against CXCL9 and the capture antibody against CXCL10, respectively. The details of the solid phase are the same as those described in the acquisition method of this embodiment.

[0107] The kit of this embodiment may further include at least one reagent selected from the following: a reagent containing a substance that can specifically bind to KL-6, and a reagent containing a substance that can specifically bind to MMP9. The reagent containing a substance that can specifically bind to KL-6 is preferably a combination of a reagent containing a capture antibody for KL-6 and a reagent containing a detection antibody for KL-6. In addition, the reagent containing a substance that can specifically bind to MMP9 is preferably a combination of a reagent containing a capture antibody for MMP9 and a reagent containing a detection antibody for MMP9.

[0108] The kit of the present embodiment may include calibrators for each biomarker. As an example of a calibrator, a calibrator for quantitative analysis of CXCL9 and a calibrator for quantitative analysis of CXCL10 may be cited. The calibrator for quantitative analysis of CXCL9 may, for example, include a buffer solution (negative control) without CXCL9 and a buffer solution containing a known concentration of CXCL9. The calibrator for quantitative analysis of CXCL10 may, for example, include a buffer solution (negative control) without CXCL10 and a buffer solution containing a known concentration of CXCL10. As another example of a calibrator, a buffer solution (negative control) without any one of CXCL9 and CXCL10, a buffer solution containing a known concentration of CXCL9, and a buffer solution containing a known concentration of CXCL10 may be included. As another example of a calibrator, a buffer solution (negative control) without any one of CXCL9 and CXCL10 may be included, and a buffer solution containing CXCL9 and CXCL10 of known concentrations may be included.

[0109] When the kit includes at least one reagent selected from a reagent containing a substance that can specifically bind to KL-6 and a reagent containing a substance that can specifically bind to MMP9, the kit may include calibrators for these biomarkers. As an example of a calibrator, a KL-6 quantitative calibrator and an MMP9 quantitative calibrator can be cited. The KL-6 quantitative calibrator, for example, may include a buffer solution (negative control) that does not contain KL-6 and a buffer solution containing a known concentration of KL-6. The MMP9 quantitative calibrator, for example, may include a buffer solution (negative control) that does not contain MMP9 and a buffer solution containing a known concentration of MMP9. As another example of a calibrator, a buffer solution (negative control) that does not contain any one of KL-6 and MMP9, a buffer solution containing a known concentration of KL-6, and a buffer solution containing a known concentration of MMP9 are provided. As another example of a calibrator, a buffer solution (negative control) that does not contain any one of KL-6 and MMP9 is provided, and a buffer solution containing KL-6 and MMP9 of respective known concentrations is provided.

[0110] [6. Device and computer program]

[0111] The scope of the present invention also includes a device and a computer program for implementing the method for determining the condition of an interstitial pneumonia patient of the present embodiment. An example of a device for determining the condition of an interstitial pneumonia patient of the present embodiment is described with reference to the accompanying drawings. However, the present embodiment is not limited to the method shown in this example. Figure 2 The determination device 10 shown includes a measurement device 20, a computer system 30, and a printer 40. The measurement device 20 and the printer 40 are connected to the computer system 30.

[0112] The type of measuring device is not particularly limited and can be appropriately selected according to the method of measuring the biomarker. Figure 2 In the example shown, the measuring device 20 is a commercially available automatic immunoassay device capable of detecting a chemiluminescent signal generated by a sandwich ELISA method using magnetic particles immobilized with a capture antibody and an enzyme-labeled detection antibody. However, the present invention is not limited to this example. When measuring a biomarker by an ELISA method, the measuring device is not particularly limited as long as it can detect a signal based on the marker used.

[0113] A reagent containing magnetic particles with fixed capture antibodies, a reagent containing detection antibodies labeled with an enzyme, and a biological sample collected from a patient with interstitial pneumonia are placed in a measuring device 20, which uses each reagent to perform an antigen-antibody reaction, obtains a chemiluminescent signal as optical information based on the enzyme-labeled antibody specifically bound to the biomarker, and sends the obtained optical information to a computer system 30.

[0114] The computer system 30 includes a computer body 300, an input unit 301, and a display unit 302. The display unit 302 displays the subject information, the determination result, etc. The computer system 30 receives the optical information from the measuring device 20. Then, the processor of the computer system 30 executes the computer program for determining the condition of the interstitial pneumonia patient installed in the hard disk 313 based on the optical information. It should be noted that Figure 2 As shown, the computer system 30 may be a device separate from the measuring device 20. Alternatively, the computer system 30 may be a device that can incorporate the measuring device 20. In the latter case, the computer system 30 itself may become the determination device 10. A computer program for determining the condition of an interstitial pneumonia patient may be installed in a commercially available automatic immunoassay device.

[0115] Reference Figure 3The computer main body 300 includes a CPU (Central Processing Unit) 310, a ROM (Read Only Memory) 311, a RAM (Random Access Memory) 312, a hard disk 313, an input / output interface 314, a reader 315, a communication interface 316, and an image output interface 317. The CPU 310, the ROM 311, the RAM 312, the hard disk 313, the input / output interface 314, the reader 315, the communication interface 316, and the image output interface 317 are connected via a bus 318 so that data communication is possible. In addition, the measuring device 20 and the printer 40 are connected via the communication interface 316 so that communication with the computer system 30 is possible.

[0116] CPU310 can execute programs stored in ROM311 or hard disk 313 and programs downloaded to RAM312. CPU310 obtains the measured value of the biomarker based on the optical information obtained by the measuring device 20. When measuring at least one selected from CXCL9 and CXCL10, and at least one selected from KL-6 and MMP9, CPU310 can obtain the value obtained from the measured value of these biomarkers, such as the predicted value obtained by multivariate logistic regression analysis. The details of these values ​​are the same as the description of the acquisition method of this embodiment. CPU310 determines the condition of interstitial pneumonia based on the obtained value and the specified threshold value stored in ROM311 or hard disk 313. CPU310 outputs and displays the determination result on the display unit 302. It should be noted that the threshold value corresponding to each biomarker can be stored in ROM311 or hard disk 313 in advance by the manufacturer when manufacturing the computer system. Alternatively, the threshold value corresponding to each biomarker can be input by the user using the input unit 301 and stored in ROM311 or hard disk 313.

[0117] ROM 311 is composed of a mask ROM, PROM, EPROM, EEPROM, etc. The computer program to be executed by CPU 310 and the data used when executing the computer program are recorded in ROM 311. ROM 411 records the data used for the determination process described later, such as the predetermined threshold value corresponding to each biomarker and the above-mentioned regression formula.

[0118] The RAM 312 is composed of an SRAM, a DRAM, etc. The RAM 312 is used when reading out programs recorded in the ROM 311 and the hard disk 313. When executing these programs, the RAM 312 is used as a work area of ​​the CPU 310.

[0119] The hard disk 313 is installed with computer programs such as an operating system and an application program (a program for determining the condition of an interstitial pneumonia patient) for CPU 310 to execute, and data used when executing the computer program. The hard disk 313 may also record data used in the determination process described later, such as a predetermined threshold value corresponding to each biomarker and the above-mentioned regression formula.

[0120] The reading device 315 is composed of a floppy disk drive, a CD-ROM drive, a DVD-ROM drive, a USB port, an SD card reader, a CF card reader, a memory stick reader, a solid state drive, etc. The reading device 315 can read a program or data recorded in the portable recording medium 50 .

[0121] The input / output interface 314 is composed of, for example, a serial interface such as USB, IEEE1394, RS-232C, a parallel interface such as SCSI, IDE, IEEE1284, and an analog interface including 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. The user can input various commands to the computer body 300 through the input unit 301.

[0122] The communication interface 316 is, for example, a wireless interface that complies with standards such as Ethernet (registered trademark) interface, IEEE802.11 series, Bluetooth (registered trademark), etc. The computer body 300 can send print data to the printer 40 or the like through the communication interface 316. The printer 40 is, for example, a laser printer, an inkjet printer, etc. When the communication interface 316 is a wireless interface, the computer body 300 can send data to mobile devices such as mobile phones and tablet terminals.

[0123] The image output interface 317 is connected to the display unit 302 composed of an LCD, a CRT, etc. Thus, the display unit 302 can output a video signal corresponding to the image data supplied from the CPU 310. The display unit 302 displays an image (screen) based on the input video signal.

[0124] Reference Figure 4A The determination process of the condition of an interstitial pneumonia patient performed by the determination device 10 is described. Here, the case where the measurement value of CXCL9 is obtained by the intensity of the chemiluminescent signal generated by the sandwich ELISA method, and the patient is determined to be IPAF or CTD-ILD using the obtained measurement value and a predetermined threshold value corresponding to CXCL9 is used as an example for description. However, the present embodiment is not limited to this example. The measurement value of CXCL10 may also be obtained instead of the measurement value of CXCL9.

[0125] In step S101, CPU310 obtains optical information (chemiluminescent signal) from the measuring device 20 and stores it in the hard disk 313. In step S102, CPU310 obtains the measured value of CXCL9 from the obtained optical information and stores it in the hard disk 313. In step S103, CPU310 compares the obtained measured value with the prescribed threshold stored in the hard disk 313. When the measured value is lower than the prescribed threshold, the process enters step S104. In step S104, CPU310 stores the determination result indicating that the patient is IPAF in the hard disk 313. When the measured value is the same as or higher than the prescribed threshold, the process enters step S105. In step S105, CPU310 stores the determination result indicating that the patient is CTD-ILD in the hard disk 313. In step S106, CPU310 outputs the determination result. For example, CPU310 displays the determination result in the display unit 302, prints it through the printer 40, or sends it to a mobile device such as a mobile phone or a tablet terminal. This makes it possible to provide doctors and the like with information that assists in determining the condition of patients with interstitial pneumonia.

[0126] Reference Figure 4B , the case where the measured value of CXCL9 and the measured value of CXCL10 are obtained and the determination is performed using these measured values ​​and the prescribed thresholds corresponding to each biomarker is described as an example. In this example, the first threshold is the prescribed threshold corresponding to CXCL9, and the second threshold is the prescribed threshold corresponding to CXCL10. Steps S201 and S207 are the same as the description of the above-mentioned steps S101 and S106, respectively. In step S202, the CPU 310 obtains the measured values ​​of CXCL9 and CXCL10 from the obtained optical information and stores them in the hard disk 313. In step S203, the CPU 310 compares the obtained measured value of CXCL9 with the first threshold stored in the hard disk 313. When the measured value of CXCL9 is lower than the first threshold, the processing enters step S204. In step S204, the CPU 310 compares the obtained measured value of CXCL10 with the second threshold stored in the hard disk 313. When the measured value of CXCL10 is lower than the second threshold, the processing enters step S205. In step S205 , the CPU 310 stores the determination result indicating that the patient has IPAF in the hard disk 313 .

[0127] In step S203, when the measured value of CXCL9 is equal to or higher than the first threshold value, the process proceeds to step S206. In step S204, when the measured value of CXCL10 is equal to or higher than the second threshold value, the process proceeds to step S206. In step S206, CPU 310 stores the determination result indicating that the patient is CTD-ILD in hard disk 313. In this example, the processes of step S203 and step S204 may be exchanged in order.

[0128] Reference Figure 4C , taking the case where the measurement value of CXCL10 is obtained and the patient is determined to be IPAF or IPF using the obtained measurement value and the prescribed threshold value corresponding to CXCL10 as an example for explanation. Steps S301 and S306 are the same as the description of the above-mentioned steps S101 and S106, respectively. In step S302, the CPU 310 obtains the measurement value of CXCL10 from the obtained optical information and stores it in the hard disk 313. In step S303, the CPU 310 compares the obtained measurement value with the prescribed threshold value stored in the hard disk 313. When the measurement value is the same as or higher than the prescribed threshold value, the processing enters step S304. In step S304, the CPU 310 stores the determination result indicating that the patient is IPAF in the hard disk 313. When the measurement value is lower than the prescribed threshold value, the processing enters step S305. In step S305, the CPU 310 stores the determination result indicating that the patient is IPF in the hard disk 313.

[0129] Reference Figure 4D , taking the case where the measured value of CXCL9 and the measured value of KL-6 are obtained, the predicted value P is calculated by the above-mentioned regression formula using these measured values, and the predicted value P and the specified threshold value are used for judgment as an example. However, the present embodiment is not limited to this example. The measured value of CXCL10 can be obtained instead of the measured value of CXCL9. In addition, the measured value of MMP9 can be obtained instead of the measured value of KL-6. Steps S401 and S407 are the same as the description of the above-mentioned steps S101 and S106, respectively. In step S402, CPU310 obtains the measured values ​​of CXCL9 and KL-6 from the obtained optical information and stores them in the hard disk 313. In step S403, CPU310 calculates the predicted value P based on the multivariate logistic model according to the regression formula stored in the hard disk 313, and stores it in the hard disk 313. In step S404, CPU310 compares the calculated predicted value P with the specified threshold value stored in the hard disk 313. When the predicted value P is the same as or higher than the prescribed threshold, the process proceeds to step S405. In step S405, the CPU 310 stores the determination result indicating that the patient is IPAF in the hard disk 313. When the predicted value P is lower than the prescribed threshold, the process proceeds to step S406. In step S406, the CPU 310 stores the determination result indicating that the patient is IPF in the hard disk 313.

[0130] The present invention will be described in more detail below in Examples, but the present invention is not limited to these Examples. Hereinafter, "HISCL" is a registered trademark of Sysmex Corporation.

[0131] [Example]

[0132] [Example 1]

[0133] (1) Biological samples

[0134] As biological samples, sera from 102 patients with interstitial pneumonia were used. Among the 102 patients, 16 were diagnosed with CTD-ILD (CTD-ILD group), 35 were diagnosed with IPAF (IPAF group), and 51 were diagnosed with IPF (IPF group).

[0135] (2) Determination of biomarkers

[0136] (2.1) Determination of CXCL9

[0137] The CXCL9 concentration in the serum of each patient was measured using the following R1 to R5 reagents using a fully automatic immunoassay device HISCL-5000 or HISCL-2000i (Sysmex Corporation).

[0138] ·R1 reagent

[0139] Anti-MIG monoclonal antibody (RANDOX) was digested with pepsin or IdeS protease by conventional methods to obtain Fab fragments. The Fab fragments were labeled with biotin by conventional methods and dissolved in a buffer containing 1% bovine serum albumin (BSA) and 0.5% casein to obtain R1 reagent.

[0140] ·R2 reagent

[0141] The magnetic particles with streptavidin fixed on the surface (hereinafter also referred to as "STA-bound magnetic particles". Average particle size 2 μm. The amount of streptavidin per 1 g of magnetic particles is 2.9-3.5 mg) are washed three times with 10 mM HEPES buffer (pH 7.5). The washed STA-bound magnetic particles are added to 10 mM HEPES (pH 7.5) in a manner such that the concentration of streptavidin reaches 18-22 μg / ml (the concentration of STA-bound magnetic particles reaches 0.48-0.52 mg / ml) to obtain R2 reagent.

[0142] ·R3 reagent

[0143] Anti-MIG monoclonal antibody (RANDOX) was digested with pepsin or IdeS protease by conventional methods to obtain Fab fragments. The Fab fragments were labeled with alkaline phosphatase (ALP) by conventional methods and dissolved in a buffer containing 1% BSA and 0.5% casein to obtain R3 reagent.

[0144] ·R4 reagent and R5 reagent

[0145] As the R4 reagent, HISCL R4 reagent (Sysmex Corporation) as a measurement buffer was used. As the R5 reagent, HISCL R5 reagent (Sysmex Corporation) containing CDP-Star (registered trademark) (Applied Biosystems) as a chemiluminescent substrate for ALP was used.

[0146] The measurement steps using HISCL-5000 or HISCL-2000i are as follows. After mixing serum (20 μL) and R1 reagent (50 μL), add R2 reagent (30 μL). Collect the magnetic particles in the resulting mixture by magnetism, remove the supernatant, and add HISCL washing solution (300 μL) to wash the magnetic particles. Remove the supernatant, add R3 reagent (100 μL) to the magnetic particles and mix. Collect the magnetic particles in the resulting mixture by magnetism, remove the supernatant, and add HISCL washing solution (300 μL) to wash the magnetic particles. Remove the supernatant, add R4 reagent (50 μL) and R5 reagent (100 μL) to the magnetic particles, and measure the chemiluminescence intensity. Substitute the obtained chemiluminescence intensity into the standard curve to determine the CXCL9 concentration.

[0147] (2.2) Determination of CXCL10

[0148] The CXCL10 concentration in the serum of each patient was measured by enzyme-linked immunosorbent assay (ELISA). The measurement steps of CXCL10 are as follows. In a 96-well plate, serum (100 μL) diluted 5 times by the specimen diluent was reacted with anti-CXCL10 mouse monoclonal antibody sensitized with 2 μg / mL for 2 hours. After washing 6 times with HISCL washing solution (300 μL), 100 μL of biotinylated goat anti-human CXCL10 antibody (0.0125 μg / mL, 1% BSA 0.5% casein PBS pH7.4) was added and reacted for 2 hours. After washing 6 times with HISCL washing solution (300 μL), 100 μL of streptavidin ALP was added and reacted for 20 minutes. After washing six times with HISCL washing solution (300 μL), 100 μL of R4 and R5 reagents mixed at a ratio of 1:2 were added, and the luminescent signal was counted using an ELISA reader. As the anti-CXCL10 antibody, Duoset DY266 manufactured by R&D Systems was used.

[0149] (3) Measurement results

[0150] The serum CXCL9 and CXCL10 concentrations of each patient group of CTD-ILD, IPAF, and IPF are shown in Figure 5 and 6. It can be seen that the concentrations of CXCL9 and CXCL10 in the IPAF group and the IPF group are significantly lower than those in the CTD-ILD group. Therefore, this indicates that CXCL9 and CXCL10 in serum can be used as biomarkers that can distinguish CTD-ILD from IPAF. In addition, it was found that the concentration of CXCL10 in the IPF group was significantly lower than that in the IPAF group. This indicates that CXCL10 in serum can be used as a biomarker that can distinguish IPAF from IPF.

[0151] [Example 2]

[0152] (1) Differentiation between CTD-ILD and IPAF

[0153] By ROC analysis, for the CXCL9 concentration and CXCL10 concentration in serum, the optimal cutoff value of the CTD-ILD group (16) and the IPAF group (35) of Example 1 was obtained. The sensitivity, specificity and area under the curve (AUC) of the determination using the set cutoff value were calculated. In this determination, when the CXCL9 or CXCL10 concentration is the same as or higher than the cutoff value, the patient is determined to be CTD-ILD. In addition, when the CXCL9 or CXCL10 concentration is lower than the cutoff value, the patient is determined not to be CTD-ILD. The ROC curve obtained is shown in Figure 7 and 8 Table 1 shows the cutoff value (pg / mL), sensitivity (%), specificity (%), and AUC of each biomarker.

[0154]

Table 1

[0155] Biomarkers Cutoff value Sensitivity (%) Specificity (%) AUC CXCL9 32.5 87 49 0.72 CXCL10 287.1 60 80 0.75

[0156] According to Table 1, in the determination of each value based on the CXCL9 concentration and the CXCL10 concentration in serum, the AUC value is more than 0.7, which supports that CXCL9 and CXCL10 in serum are useful biomarkers for distinguishing CTD-ILD and IPAF. In the past, the diagnosis of CTD-ILD was performed based on the diagnostic criteria of collagen disease, and the diagnosis of IPAF was performed based on the diagnostic criteria proposed by ERS and ATS. These diagnostic criteria include subjective factors such as doctor's observation results and image diagnosis. However, the above results show that the concentrations of CXCL9 and CXCL10 in the biological sample as objective indicators can be used as indicators for distinguishing CTD-ILD and IPAF.

[0157] (2) Differentiation between IPAF and IPF

[0158] By ROC analysis, the optimal cutoff value for distinguishing the IPAF group (35 subjects) and the IPF group (51 subjects) of Example 1 was obtained for the CXCL10 concentration in serum. The sensitivity, specificity and AUC of the determination using the set cutoff value were calculated. In this determination, when the CXCL10 concentration is the same as or higher than the cutoff value, the patient is determined to be IPAF. In addition, when the CXCL10 concentration is lower than the cutoff value, the patient is determined not to be IPAF. The obtained ROC curve is shown in Fig. 9 Table 2 shows the cutoff value (pg / mL) of CXCL10, the sensitivity (%), specificity (%) and AUC of the determination.

[0159]

Table 2

[0160] Biomarkers Cutoff value Sensitivity (%) Specificity (%) AUC CXCL10 226.6 40 96 0.67

[0161] According to Table 2, in the determination based on the CXCL10 concentration in serum, the AUC value is about 0.7, and it can be seen that IPAF and IPF can also be distinguished by the CXCL10 concentration value in serum. The specificity of this determination is particularly high, which shows that: in the distinction between IPAF and IPF, CXCL10 in serum is useful for excluding suspected IPF patients.

[0162] like Fig. 10A As shown in Figure 2, for IPAF patients, when the serum CXCL9 concentration before anti-inflammatory therapy was plotted as the horizontal axis and the forced vital capacity recovery (AFVC) within 1 year was plotted as the vertical axis, a significant negative correlation was confirmed between the serum CXCL9 concentration and ΔFVC. This suggests that patients with high serum CXCL9 concentrations have a high response to anti-inflammatory therapy. In addition, Fig. 10B As shown in the figures, although no statistical correlation was obtained with respect to the serum CXCL10 concentration, the same tendency was confirmed because patients with low serum CXCL10 concentrations did not show recovery of forced vital capacity.

[0163] [Example 3]

[0164] (1) Biological samples

[0165] As the biological sample, the serum of the interstitial pneumonia patient in Example 1 was used.

[0166] (2) Determination of biomarkers

[0167] (2.1) Determination of CXCL9 and CXCL10

[0168] As the CXCL9 and CXCL10 concentration values ​​in the serum of each patient, the measurement values ​​obtained in Example 1 were used.

[0169] (2.2) Determination of KL-6

[0170] The KL-6 concentration in the serum of each patient was measured using HISCL KL-6 reagent (Sekisui Medical Co., Ltd.) using ISCL-5000 or HISCL-2000i (Sysmex Co., Ltd.). The KL-6 measurement procedure was the same as the CXCL9 measurement in Example 1. The HISCL KL-6 reagent includes R1 reagent containing biotin-labeled mouse anti-KL-6 monoclonal antibody, R2 reagent containing STA-bound magnetic particles, R3 reagent containing ALP-labeled mouse anti-KL-6 monoclonal antibody, HISCL R4 reagent as a measurement buffer, HISCL R5 reagent containing CDP-Star (registered trademark), HISCL washing solution, and KL-6 calibrator.

[0171] (2.3) Determination of MMP9

[0172] The concentration of MMP9 in the serum of each patient in Example 1 was measured by enzyme-linked immunosorbent assay (ELISA). The measurement procedure of MMP9 is as follows. In a 96-well plate, serum (100 μL) diluted 5 times by the specimen diluent was reacted with anti-MMP9 mouse monoclonal antibody sensitized with 0.5 μg / mL for 2 hours. After washing 6 times with HISCL washing solution (300 μL), 100 μL of biotinylated goat anti-human MMP9 antibody (0.1 μg / mL, 1% BSA 0.5% casein TEA pH7.4) was added and reacted for 2 hours. After washing 6 times with HISCL washing solution (300 μL), 100 μL of streptavidin ALP was added and reacted for 20 minutes. After washing 6 times with HISCL washing solution (300 μL), 100 μL of R4 and R5 reagents mixed in a ratio of 1:2 were added, and the luminescent signal was counted with an enzyme reader. As the anti-MMP9 antibody, Duoset DY911 produced by R&D Systems was used.

[0173] (3) Differentiation between IPAF and IPF

[0174] A multivariate logistic regression analysis was performed using the concentrations of CXCL9, CXCL10, KL-6, and MMP9 in serum as explanatory variables. In this analysis, SPSS Statistics version 22.0 (IBM Corporation) was used. For the combination of CXCL9 and KL-6, the combination of CXCL9 and MMP9, the combination of CXCL10 and KL-6, and the combination of CXCL10 and MMP9, the optimal cutoff value for distinguishing the IPAF group (35 subjects) and the IPF group (51 subjects) of Example 1 was determined. The sensitivity, specificity, and AUC of the determination using the set cutoff value were calculated. In this determination, when the predicted value P obtained by the multivariate logistic regression analysis is the same as or higher than the cutoff value, the patient is determined to be IPAF. In addition, when the predicted value P is lower than the cutoff value, the patient is determined not to be IPAF. The resulting ROC curve is shown in Figures 11 to 14 Table 3 shows the cutoff value, sensitivity (%), specificity (%) and AUC of the determination.

[0175]

Table 3

[0176] Biomarkers Cutoff value Sensitivity (%) Specificity (%) AUC CXCL9 and KL-6 0.37 91 35 0.64 CXCL9 and MMP9 0.49 54 81 0.67 CXCL10 and KL-6 0.44 49 83 0.68 CXCL10 and MMP9 0.42 71 75 0.76

[0177] According to Table 3, in the determination based on any combination of biomarkers, the AUC value was about 0.7, indicating that this combination can be an indicator for distinguishing IPAF from IPF.

Claims

1. Use of a substance that can specifically bind to at least one biomarker in a biological sample of a patient with interstitial pneumonia in the manufacture of a kit for obtaining information related to the condition of a patient with interstitial pneumonia, wherein The biomarker comprises at least one selected from CXCL9 and CXCL10, and The measurement results of the biomarkers serve as the identification index for IPAF and CTD-ILD.

2. The use according to claim 1, wherein When the measured value of CXCL9 or the measured value of CXCL10 is below a specified threshold corresponding to each biomarker, the measured value indicates that the patient has IPAF.

3. The use according to claim 1, wherein When the measured value of CXCL9 or the measured value of CXCL10 is the same as or higher than the specified threshold value corresponding to each biomarker, the measured value indicates that the patient has CTD-ILD.

4. The use according to claim 1, wherein The biomarkers include CXCL10, The measurement result of CXCL10 serves as a distinguishing indicator between IPAF and IPF.

5. The use according to claim 4, wherein When the measured value of CXCL10 is the same as or higher than the prescribed threshold value corresponding to CXCL10, The measured value indicates that the patient has IPAF, The prescribed threshold is a threshold for distinguishing IPAF from IPF.

6. The use according to claim 4, wherein When the measured value of CXCL10 is lower than the prescribed threshold value corresponding to CXCL10, The measured value indicates that the patient has IPF, The prescribed threshold is a threshold for distinguishing IPAF from IPF.

7. The use according to claim 1, wherein The biomarkers further include at least one selected from KL-6 and MMP9, The measurement results of the biomarkers serve as a distinguishing indicator between IPAF and IPF.

8. The use according to claim 7, wherein The measurement result of the biomarker is a value obtained by the following measurement values: a measured value of at least one selected from CXCL9 and CXCL10, and A measured value of at least one selected from KL-6 and MMP9.

9. The use according to claim 8, wherein The obtained values ​​are predicted values ​​obtained through multivariate logistic regression analysis. When the predicted value is the same as or higher than the specified threshold, The predicted value indicates that the patient has IPAF, The prescribed threshold is a threshold for distinguishing IPAF from IPF.

10. The use according to claim 8, wherein The obtained values ​​are predicted values ​​obtained through multivariate logistic regression analysis. When the predicted value is lower than a specified threshold, The predicted value indicates that the patient has IPF, The prescribed threshold is a threshold for distinguishing IPAF from IPF.

11. Use of a substance capable of specifically binding to at least one biomarker in a biological sample of an interstitial pneumonia patient in the manufacture of a kit for determining the condition of an interstitial pneumonia patient, wherein The patient is determined to be IPAF or CTD-ILD based on the measurement results of the biomarkers, and The biomarker comprises at least one selected from CXCL9 and CXCL10.

12. The use according to claim 11, wherein In the determination, when the measured value of CXCL9 or the measured value of CXCL10 is lower than a predetermined threshold value corresponding to each biomarker, the patient is determined to have IPAF.

13. The use according to claim 11, wherein In the determination, when the measured value of CXCL9 or the measured value of CXCL10 is equal to or higher than a predetermined threshold value corresponding to each biomarker, the patient is determined to have CTD-ILD.

14. The use according to claim 11, wherein The biomarker includes CXCL10. In the determination, the patient is determined to be IPAF or IPF based on the measurement result of CXCL10.

15. The use according to claim 14, wherein In the above judgment, When the measured value of CXCL10 is the same as or higher than a predetermined threshold value corresponding to CXCL10, the patient is determined to have IPAF, The prescribed threshold is a threshold for distinguishing IPAF from IPF.

16. The use according to claim 14, wherein In the above judgment, When the measured value of CXCL10 is lower than a predetermined threshold value corresponding to CXCL10, the patient is determined to have IPF, The prescribed threshold is a threshold for distinguishing IPAF from IPF.

17. The use according to claim 11, wherein The biomarkers further include at least one selected from KL-6 and MMP9, In the determination, the patient is determined to be IPAF or IPF based on the measurement result of the biomarker.

18. The use according to claim 12, wherein: The measurement result of the biomarker is a value obtained from the measurement value of at least one selected from CXCL9 and CXCL10 and the measurement value of at least one selected from KL-6 and MMP9.

19. The use according to claim 18, wherein The obtained values ​​are predicted values ​​obtained through multivariate logistic regression analysis. When the predicted value is the same as or higher than a specified threshold, the patient is determined to be IPAF, The prescribed threshold is a threshold for distinguishing IPAF from IPF.

20. The use according to claim 18, wherein The obtained values ​​are predicted values ​​obtained through multivariate logistic regression analysis. When the predicted value is lower than a specified threshold, the patient is determined to have IPF, The prescribed threshold is a threshold for distinguishing IPAF from IPF.

21. Use of a substance capable of specifically binding to at least one biomarker in a biological sample of an IPAF patient in the manufacture of a kit for obtaining information related to treatment responsiveness of an IPAF patient, wherein The biomarker comprises at least one selected from CXCL9 and CXCL10, and The measurement results of the biomarkers serve as indicators for identifying treatment responsiveness to anti-inflammatory therapy.

22. The use according to claim 21, wherein When the measured value of CXCL9 or the measured value of CXCL10 is the same as or higher than the specified threshold value corresponding to each biomarker, the measured value indicates that the patient is responsive to anti-inflammatory therapy.

23. The use according to any one of claims 1 to 22, wherein The biological sample is a blood sample.

24. A computer readable medium having a computer program recorded thereon for determining the condition of a patient with interstitial pneumonia, wherein The computer program causes the computer to execute the following steps: The step of obtaining the measurement result of at least one biomarker in a biological sample of a patient with interstitial pneumonia; and The step of determining whether the patient is IPAF or CTD-ILD based on the measurement results of the biomarkers, and The biomarker comprises at least one selected from CXCL9 and CXCL10.

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