Metabolic diagnostic biomarkers for drug-induced interstitial pneumonia

Abstract

The development of biomarkers for diagnosis, condition diagnosis, and differential diagnosis of drug-induced interstitial pneumonia, in particular, diffuse alveolar damage (DAD) is performed. This method for diagnosing drug-induced interstitial pneumonia comprises measuring, in a sample derived from a subject, the level of at least one molecule selected from a group of lysophosphatidylcholine (LPC) molecules, and / or at least one molecule selected from a group of molecules included in a kynurenine pathway.

Description

[Technical field]

[0001] The present invention relates to a method for assisting in the diagnosis of the onset and progression of drug-induced interstitial pneumonia. [Background technology]

[0002] Drug-induced interstitial pneumonia is a general term for inflammatory adverse reactions of the interstitial space of the lungs caused by drugs. Interstitial pneumonia can be divided into those caused by clear causes such as pneumoconiosis and collagen disease, as well as drugs, and those caused by idiopathic causes that are unknown, and are further classified into various disease types. Each type has a different treatment and prognosis, so it is clinically important to differentiate between them.

[0003] Drug-induced interstitial pneumonia is diagnosed based on its similarity to known interstitial pneumonias such as idiopathic ones (Non-Patent Document 1). Among the types of drug-induced interstitial pneumonia, the most severe type is diffuse alveolar damage (DAD). DAD is a typical type seen in acute exacerbation cases of acute respiratory distress syndrome and idiopathic pulmonary fibrosis (Non-Patent Document 2), and even in drug-induced cases, DAD has poor response to treatment and a poor prognosis (Non-Patent Documents 1 and 2). Therefore, early detection and diagnosis of DAD are particularly important. In addition, disease types other than DAD include organizing pneumonia (OP) and nonspecific interstitial pneumonia (NSIP), but there are also cases that are difficult to classify by imaging tests or pathological tests, such as cases that do not fit any pattern or cases where multiple patterns are mixed, and image pattern classification has limitations (Non-Patent Document 3).

[0004] Diagnosing drug-induced interstitial pneumonia requires ruling out factors other than those caused by the drug, and it often takes time to confirm the diagnosis. Since imaging and pathological diagnosis alone impose a heavy financial and physical burden on patients, the use of biomarkers is considered useful.

[0005] Currently, sialylated glycan antigen KL-6 (KL-6), pulmonary surfactant protein A (SP-A), and pulmonary surfactant protein D (SP-D) are used as biomarkers for drug-induced interstitial pneumonia to aid in diagnosis, and it is known that KL-6 has a high positive rate for DAD (Non-Patent Documents 4, 5). These are indicators that reflect drug-induced interstitial pneumonia, but they can also increase in diseases other than smoking and interstitial pneumonia, and do not correlate with the severity of lung damage. In addition, although it is recommended to follow the progress of KL-6 based on the value before drug administration, it also increases in the exacerbation of existing interstitial pneumonia and opportunistic infections. In other words, these markers are not specific to drug-induced interstitial pneumonia, especially DAD-type drug-induced interstitial pneumonia, and are not very useful as markers for distinguishing disease types. In addition, KL-6, SP-D, and SP-A have the problem of remaining at high levels for a long period of time even after the condition has improved (Non-Patent Documents 4, 5), and therefore new biomarkers are needed. To date, proteins such as UBE2T, HK1, PMSE1, USO1, IFI16, and GLTP (Patent Document 1), as well as autoantibodies (Patent Document 2), have been proposed as marker candidates and patent applications have been filed. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Diagnosis and Treatment Guide for Drug-Induced Lung Injury Japan Respiratory Society [Non-Patent Document 2] Acute interstitial pneumonia (AIP) Journal of the Japanese Respiratory Society 42(1), -23-27, 2004 [Non-Patent Document 3] Masahiko Kusumoto CT diagnosis of drug-induced lung injury Lung Cancer 55,807-809.2015 [Non-Patent Document 4] Ishikawa N, et al., Utility of KL-6 / MUC1 in the clinical management of interstitial lung diseases, Respiratory Investig. 50, 3-13, 2012 [Non-Patent Document 5] Kawase S, et al., Change in serum KL-6 level from baseline is useful for predicting life-threatening EGFR-TKIs induced interstitial lung disease, Respiratory Research, 12:97, 2011 [Patent documents]

[0007] [Patent Document 1] JP2015-90323A [Patent Document 2] International Publication WO2014 / 148429 Brochure Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to develop biomarkers for diagnosing drug-induced interstitial pneumonia, diagnosing the disease progression, and diagnosing and predicting the disease type. [Means for solving the problem]

[0009] We used metabolomics, a method for comprehensively analyzing metabolite molecules, including more than 1,000 kinds of amino acids, amino acid derivatives, and lipids, to analyze blood samples from patients with drug-induced interstitial pneumonia. We focused on DAD and OP, and searched for metabolite molecules that significantly changed in the acute phase of drug-induced interstitial pneumonia compared to the convalescent phase group, using statistical significance and effect size (Hedge's g value) as indicators, based on the ion intensity of each metabolite molecule. Among the many samples in which KL-6 and SP-D values ​​did not change, we found lysophosphatidylcholine (LPC) molecules from plasma as a lipid molecule group that decreased particularly in the acute phase of DAD-type drug-induced interstitial pneumonia, and kynurenine molecules (kynurenine and quinolinic acid, which are involved in the kynurenine pathway) and their parent compound tryptophan as metabolite molecules that increased particularly in the acute phase of DAD-type drug-induced interstitial pneumonia.

[0010] Receiver operating characteristic curve (ROC) analysis showed that the LPC molecules distinguished the acute phase of DAD-type drug-induced interstitial pneumonia from the recovery phase of all drug-induced interstitial pneumonia patients with high accuracy (area under the curve: AUC 0.903-0.938), and from non-onset cases taking similar drugs with high accuracy (area under the curve: AUC 0.929-0.971). They also distinguished the acute phase of DAD-type drug-induced interstitial pneumonia from other lung diseases (lung cancer cases, pulmonary nontuberculous mycobacterial disease cases, idiopathic interstitial pneumonia cases, collagen disease cases, COPD (chronic obstructive pulmonary disease) cases, and bronchial asthma cases) with high accuracy (area under the curve: AUC 0.892-0.978). On the other hand, the kynurenine molecule group distinguished the acute phase of DAD-type drug-induced interstitial pneumonia from the recovery phase of all drug-induced interstitial pneumonia patients with high accuracy (area under the curve: AUC 0.915-0.947). In addition, the acute phase of DAD-type drug-induced interstitial pneumonia was also distinguished with high accuracy (area under the curve: AUC 0.882-0.957) from other lung diseases (lung cancer cases, pulmonary nontuberculous mycobacterial disease cases, idiopathic interstitial pneumonia cases, collagen disease lung cases, and COPD cases). It was shown that the LPC molecule group and the kynurenine molecule group can be useful biomarkers for drug-induced interstitial pneumonia, especially DAD-type drug-induced interstitial pneumonia.

[0011] The present invention has been completed based on these findings, and the gist of the present invention is as follows. (1) A method for testing for drug-induced interstitial pneumonia, comprising measuring the level of at least one molecule selected from a group of molecules involved in the kynurenine pathway and / or at least one molecule selected from a group of lysophosphatidylcholine (LPC) molecules in a sample derived from a subject. (2) The method described in (1), wherein the measured value assists in diagnosing the progression of drug-induced interstitial pneumonia. (3) The method described in (1), wherein the measured value assists in a specific diagnosis of drug-induced interstitial pneumonia. (4) The method according to any one of (1) to (3), wherein the drug-induced interstitial pneumonia is DAD-type drug-induced interstitial pneumonia. (5) The method according to any one of (1) to (4), wherein the group of molecules involved in the kynurenine pathway includes kynurenine, quinolinic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, 2-amino-3-carboxymuconic acid semialdehyde, picolinic acid, and tryptophan. (6) The method according to any one of (1) to (5), wherein the LPC molecule group comprises LPC(14:0), LPC(15:0), LPC(16:0), LPC(16:1), LPC(17:0), LPC(18:0), LPC(18:1), LPC(18:2), LPC(19:0), LPC(20:0), LPC(20:3), LPC(20:4), LPC(20:5) and LPC(22:6). (7) A method for diagnosing drug-induced interstitial pneumonia, comprising: a1. Obtaining a sample from a subject; b1. Measuring the level of at least one molecule selected from the group of molecules involved in the kynurenine pathway and / or at least one molecule selected from the group of lysophosphatidylcholine (LPC) molecules in a sample from a subject; and c1. Determine the presence or absence of drug-induced interstitial pneumonia based on the measured value of b1 and / or the ratio calculated from the measured values ​​of b1 of the two molecules. The method comprising: (8) A method for diagnosing drug-induced interstitial pneumonia, comprising: a1. Obtaining a sample from a subject; b1. Measuring the level of at least one molecule selected from the group of molecules involved in the kynurenine pathway and / or at least one molecule selected from the group of lysophosphatidylcholine (LPC) molecules in a sample from a subject; and c1. Determine the severity of drug-induced interstitial pneumonia based on the measured value of b1 and / or the ratio calculated from the measured values ​​of b1 of the two molecules. The method comprising: (9) A method for diagnosing and treating drug-induced interstitial pneumonia, comprising: a1. Obtaining a sample from a subject; b1. Measuring the level of at least one molecule selected from the group of molecules involved in the kynurenine pathway and / or at least one molecule selected from the group of lysophosphatidylcholine (LPC) molecules in a sample from a subject; c1. Determining the presence or absence of drug-induced interstitial pneumonia based on the measured value of b1 and / or the ratio calculated from the measured values ​​of b1 of the two molecules; and d1. To provide treatment for drug-induced interstitial pneumonia to subjects who are determined to be at high risk of developing drug-induced interstitial pneumonia. The method comprising: (10) A method for diagnosing and treating drug-induced interstitial pneumonia, comprising: a1. Obtaining a sample from a subject; b1. Measuring the level of at least one molecule selected from the group of molecules involved in the kynurenine pathway and / or at least one molecule selected from the group of lysophosphatidylcholine (LPC) molecules in a sample from a subject; c1. Determining the disease progression of drug-induced interstitial pneumonia based on the measured value of b1 and / or the ratio calculated from the measured values ​​of b1 of the two molecules; and d1. To provide treatment for drug-induced interstitial pneumonia to subjects who are determined to be at high risk of having acute drug-induced interstitial pneumonia. The method comprising: (11) A kit for testing for drug-induced interstitial pneumonia, comprising a reagent capable of measuring the level in a sample from a subject of at least one molecule selected from a group of molecules involved in the kynurenine pathway and / or at least one molecule selected from a group of lysophosphatidylcholine (LPC) molecules. Effect of the Invention

[0012] By measuring the blood or urinary concentrations of the metabolites discovered in this study, either alone or in combination, it is possible to diagnose with a high degree of accuracy whether a patient suspected of having drug-induced interstitial pneumonia has drug-induced interstitial pneumonia, particularly DAD, as well as the progression of the patient's disease and the activity of their drug-induced interstitial pneumonia. This specification includes the contents described in the specification and / or drawings of Japanese patent application No. 2020-21306, which is the priority basis of this application. [Brief description of the drawings]

[0013] [Figure 1]Plasma concentrations of LPC molecules in drug-induced interstitial pneumonia (acute and recovery phase), cases without interstitial pneumonia, and cases of other lung diseases. *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001 for A-DAD, †, p < 0.05; ††, p < 0.01; †††, p < 0.001; ††††, p < 0.0001 for A. One-way ANOVA and post-hoc. A, All acute-phase drug-induced interstitial pneumonia cases, A-DAD, DAD-type acute-phase drug-induced interstitial pneumonia cases, B, All convalescent-phase drug-induced interstitial pneumonia cases, C, Non-disease cases of drug-induced interstitial pneumonia caused by the same drug, D, Lung cancer cases, E, Fungal pneumonia cases, F, Bacterial infection cases, G, Nontuberculous mycobacterial pulmonary disease cases, H, Idiopathic interstitial pneumonia cases, I, Connective tissue disease lung cases, J, COPD case, K, bronchial asthma case. [Diagram 2] Serum concentrations of kyrunine, tryptophan, and quinolinic acid, and blood kyrunine / tryptophan ratio in patients with drug-induced interstitial pneumonia (acute and recovery phase), patients without interstitial pneumonia, and patients with other lung diseases. *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001 for A-DAD, †, p < 0.05; ††, p < 0.01; †††, p < 0.001; ††††, p < 0.0001 for A. One-way ANOVA and post-hoc. A, All acute-phase drug-induced interstitial pneumonia cases, A-DAD, DAD-type acute-phase drug-induced interstitial pneumonia cases, B, All convalescent-phase drug-induced interstitial pneumonia cases, C, Non-disease cases of drug-induced interstitial pneumonia due to use of the same drug, D, Lung cancer cases, F, Bacterial infection cases, G, Nontuberculous mycobacterial pulmonary disease cases, H, Idiopathic interstitial pneumonia cases, I, Connective tissue disease cases, J, COPD cases, K, Case of bronchial asthma. [Diagram 3]Urinary concentration of quinolinic acid in drug-induced interstitial pneumonia (acute and recovery phase). **, p < 0.01 for A-DAD, ††, p < 0.01 for A. One-way ANOVA and post-hoc. A, All cases of acute drug-induced interstitial pneumonia, A-DAD, DAD-type acute drug-induced interstitial pneumonia, B, All cases of recovery phase drug-induced interstitial pneumonia. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Hereinafter, an embodiment of the present invention will be described in detail. The present invention provides a method for testing for drug-induced interstitial pneumonia, comprising measuring the levels of at least one molecule selected from a lysophosphatidylcholine (LPC) molecule group and / or at least one molecule selected from a kynurenine pathway molecule group in a sample from a subject. The drug-induced interstitial pneumonia may be DAD-type drug-induced interstitial pneumonia.

[0015] Drug-induced interstitial pneumonia is defined as a drug-related respiratory disorder that occurs during drug administration and has inflammatory lesions in the interstitial area. The mechanism of onset is largely unknown except for a few drugs, but it is generally believed to be caused by direct toxicity or immune reaction. There is no specific clinical type of drug-induced interstitial pneumonia, and it is characterized by clinical findings, imaging findings, and histopathological patterns, and is basically classified based on the similarity to interstitial pneumonia caused by other causes. In general, acute onset mainly shows the clinical features of diffuse alveolar damage (DAD) type and hypersensitivity pneumonia (HP) type, while subacute to chronic onset often shows the clinical features of nonspecific interstitial pneumonia (NSIP) type and organizing pneumonia (OP) type. Of these, DAD type is poorly responsive to treatment and has a poor prognosis, and even if it recovers, fibrosis remains, so its diagnosis has great clinical significance.

[0016] Lysophosphatidylcholine (LPC) molecules are phospholipids with one fatty acid chain, and are the most abundant and widely distributed in the body. They are produced by hydrolysis of phosphatidylcholine (PC), a phospholipid with two fatty acid chains, by phospholipase A. LPC itself is a component of cell membranes and extracellular vesicles, and acts as a ligand for G protein-coupled receptors. In addition, active phospholipase A, which is responsible for the production of LPC, and phospholipases C and D, which are responsible for the decomposition of LPC, are activated by stimuli such as inflammation and immune responses, and their blood concentrations fluctuate in various diseases such as arteriosclerosis, diabetes, and cancer.

[0017] The LPC molecule group may include LPC(14:0), LPC(15:0), LPC(16:0), LPC(16:1), LPC(17:0), LPC(18:0), LPC(18:1), LPC(18:2), LPC(19:0), LPC(20:0), LPC(20:3), LPC(20:4), LPC(20:5) and LPC(22:6). The number in parentheses following LPC indicates the ratio of the number of carbons in the acyl group to the number of double bonds.

[0018] The kynurenine pathway is the main metabolic pathway of tryptophan, in which kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, 2-amino-3-carboxymuconic acid semialdehyde, quinolinic acid, and picolinic acid are biosynthesized in that order from the substrate tryptophan.

[0019] The enzymes involved in the kynurenine pathway are distributed in a wide range of tissues, and some are produced in response to stimulation of the immune and nervous systems. It has also been reported that molecules involved in the produced kynurenine pathway act on the immune and nervous systems, and are associated with imbalances in the activity of these enzymes and intermediate metabolites and products.

[0020] Thus, molecules involved in the kynurenine pathway may include tryptophan, kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, 2-amino-3-carboxymuconic acid semialdehyde, quinolinic acid, and picolinic acid.

[0021] In the present invention, the subject is a mammal suspected of developing drug-induced interstitial pneumonia, but may be any mammal that is considered to be at risk of developing drug-induced interstitial pneumonia. Typically, the subject is a human. Examples of samples derived from a subject include cells, tissues, body fluids, etc. obtained from the subject, specifically, blood (e.g., whole blood, serum, plasma, plasma exchange fluid, etc.), urine, and bronchoalveolar lavage fluid of the subject. Whole blood, serum, or plasma obtained by a normal blood test (clinical test) may be used as a blood sample. When measuring molecules of the LPC molecule group, the sample derived from the subject may be plasma, and when measuring molecules of the molecule group involved in the kynurenine pathway, the sample derived from the subject may be serum or urine.

[0022] In the method of the present invention, the levels of at least one molecule selected from the lysophosphatidylcholine (LPC) molecule group and / or at least one molecule selected from the kynurenine pathway molecule group are measured in a sample derived from a subject. Furthermore, the ratio of the measured values ​​of two molecules may be calculated. For example, for the kynurenine pathway molecule group excluding tryptophan, the ratio to its parent compound tryptophan is calculated from the measured level. The measurement means is not particularly limited and may be any known method, such as liquid chromatography, mass spectrometry, ligand binding, nuclear magnetic resonance spectroscopy, thin layer chromatography, colorimetry, or a combination thereof.

[0023] In the examples described later, an analytical method independently developed by the inventors was used using liquid chromatography and a mass spectrometer. Briefly, the method involves mixing an internal standard not present in a living body and an extract with a blood or urine sample to extract the target biomarker, separating the target biomarker using a two-liquid gradient and a reversed-phase column, or a potassium hydroxide gradient and an anion exchange column, and then performing Selected Reaction Monitoring (SRM) or Full Scan measurement by accurate mass using precursor ions and product ions for each biomarker ion in positive ion mode or negative ion mode.

[0024] The level of the molecule to be measured in the sample from the subject may be one type or multiple types. By referring to the measurement data of multiple molecules, more accurate evaluation may be possible. In addition, for the molecular group involved in the kynurenine pathway, accurate evaluation may be possible by referring to the ratio with the parent compound tryptophan obtained from the measurement data.

[0025] The level (e.g., concentration) of at least one LPC molecule selected from the group consisting of LPC(14:0), LPC(15:0), LPC(16:0), LPC(16:1), LPC(17:0), LPC(18:0), LPC(18:1), LPC(18:2), LPC(19:0), LPC(20:0), LPC(20:3), LPC(20:4), LPC(20:5) and LPC(22:6) in a sample from a subject is measured, and when the level is low, it is determined that there is a high possibility that the subject has developed drug-induced interstitial pneumonia, and when the level is high, it is determined that there is a low possibility that the subject has developed drug-induced interstitial pneumonia. The same applies to LPC(16:1), LPC(18:2), LPC(20:3), LPC(20:4), LPC(20:5) and LPC(22:6).

[0026] The levels (e.g., concentrations) of kynurenine and molecules located downstream in its metabolic pathway (e.g., 3-hydroxykynurenine, 3-hydroxyanthranilic acid, 2-amino-3-carboxymuconic acid semialdehyde, quinolinic acid, picolinic acid) in a sample from a subject are measured, and if the levels are high, it can be determined that there is a high possibility that drug-induced interstitial pneumonia has developed, and if the levels are low, it can be determined that there is a low possibility that drug-induced interstitial pneumonia has developed. The level (e.g., concentration) of tryptophan in a sample from a subject is measured, and if the level is low, it is determined that there is a high possibility that drug-induced interstitial pneumonia has developed, and if the level is high, it is determined that there is a low possibility that drug-induced interstitial pneumonia has developed. Furthermore, when the ratio of kynurenine and molecules downstream of its metabolic pathway to tryptophan is calculated, a high level can be determined to indicate a high possibility of drug-induced interstitial pneumonia, whereas a low level can be determined to indicate a low possibility of drug-induced interstitial pneumonia.

[0027] Therefore, the method of the present invention can assist in the diagnosis of drug-induced interstitial pneumonia (determination of the presence or absence of onset of drug-induced interstitial pneumonia). a1. Obtaining a sample from a subject; b1. Measuring the level of at least one molecule selected from the group of lysophosphatidylcholine (LPC) molecules and / or at least one molecule selected from the group of molecules involved in the kynurenine pathway in a sample from a subject; and c1. Determine the presence or absence of drug-induced interstitial pneumonia based on the measured value of b1 and / or the ratio calculated from the measured values ​​of b1 of the two molecules. The method further comprises:

[0028] As one example of the present invention, the diagnosis of drug-induced interstitial pneumonia can be performed according to the following criteria. The level (e.g., concentration) of at least one of the above molecules in a sample collected from a subject is measured, and the ratio is calculated. If a value higher (or lower) than a preset cutoff value or reference value is obtained, the subject is evaluated as having developed drug-induced interstitial pneumonia. This preset cutoff value or reference value can be appropriately set by a person skilled in the art. For example, the 95% confidence interval of the quantitative value of a healthy subject who has not developed drug-induced interstitial pneumonia or a case of non-development of drug-induced interstitial pneumonia who takes a similar drug can be used as the reference value, or the cutoff value can be set from an ROC curve. In one embodiment, for the diagnosis of drug-induced interstitial pneumonia using plasma or serum samples, the following cutoff value can be set based on the concentration at which Youden's Index [sensitivity - (100 - specificity)] is maximized (the value at which sensitivity and specificity are highest) as an index, based on the ROC curve analysis for discriminating between all acute cases of drug-induced interstitial pneumonia (A) in the Examples described below and cases that did not develop drug-induced interstitial pneumonia due to taking the same type of drug (C).LPC(14:0): 332.7 to 391.2 ng / ml ±15% (preferably, 370.9 ng / ml ±15%), LPC(15:0): 196.3 to 235.6 ng / ml ±15% (preferably, 209.8 ng / ml ±15%), LPC(16:0): 36.98 to 39.77 μg / ml ±15% (preferably, 38.88 μg / ml ±15%), LPC(17:0): 403.0 to 479.5 ±15% (preferably, 439.7 ng / ml ±15%), LPC(18:0): 9.21 to 11.37 μg / ml ±15% (preferably, 10.01 μg / ml ±15%), LPC(18:1): 6.04 to 7.20 μg / ml ±15% (preferably, 6.64 μg / ml ±15%), LPC(19:0): 39.13 to 45.89 ng / ml ±15% (preferably, 41.5 ng / ml ±15%), LPC(20:0): 36.85 to 42.79 ng / ml ±15% (preferably, 41.1 ng / ml ±15%), kynurenine: 445.9 to 500.5 ng / ml ±15% (preferably, 466.5 ng / ml ±15%), quinolinic acid: 74.7 to 97.2 ng / ml ±15% (preferably, 88.6 ng / ml ±15%), tryptophan: 9.54 to 10.35 μg / ml ±15% (preferably, 10.00 μg / ml ±15%), kynurenine / tryptophan ratio: 0.058 to 0.069 ±15% (preferably 0.064 ±15%). The ±15% mentioned above is a variation value taking into consideration the variation of the analysis system, etc., and there may be a ±15% variation for each of the upper and lower limits of the numerical range of the cutoff value, as well as for the preferred value. Alternatively, when at least one of the molecules shows an upward (or downward) trend compared with the past measured value, the possibility of the onset of drug-induced interstitial pneumonia is suspected. By changing the cutoff value or the reference value to a value for diagnosing DAD-type drug-induced interstitial pneumonia, it is possible to diagnose DAD-type drug-induced interstitial pneumonia in the same manner.In one embodiment, for the diagnosis of DAD-type drug-induced interstitial pneumonia, from an ROC curve analysis for discriminating between acute-phase cases of DAD-type drug-induced interstitial pneumonia (A-DAD) and cases (C) of drug-induced interstitial pneumonia not occurring due to taking the same type of drug in the Examples described below, the following cutoff value can be set using the concentration at which Youden's Index [sensitivity - (100 - specificity)] is maximized (the value at which sensitivity and specificity are highest) as an index for the cutoff value of the metabolite: LPC(14:0): 194.1 to 379.6 ng / ml ±15% (preferably, 267.0 ng / ml ±15%), LPC(15:0): 136.4 to 215.5 ng / ml ±15% (preferably, 177.6 ng / ml ±15%), LPC(16:0): 29.49 to 39.29 μg / ml ±15% (preferably, 33.78 μg / ml ±15%), LPC(17:0): 320.7 to 479.5 ng / ml ±15% (preferably, 383.3 ng / ml ±15%), LPC(18:0): 8.34 to 11.82 μg / ml ±15% (preferably, 9.86 μg / ml ±15%), LPC(18:1) : 7.43 to 9.93 μg / ml ± 15% (preferably, 8.23 ​​μg / ml ± 15%), LPC(19:0): 30.92 to 49.9 ng / ml ± 15% (preferably, 40.98 ng / ml ± 15%), LPC(20:0): 22.84 to 33.82 ng / ml ± 15% (preferably, 26.13 ng / ml ± 15%), kynurenine: 456.6 to 649.4 ng / ml ± 15% (preferably, 537.9 ng / ml ± 15%), quinolinic acid: 63.9 to 162.8 ng / ml ± 15% (preferably, 109.9 ng / ml ± 15%), tryptophan: 8.02 to 10.61 μg / ml ± 15% (preferably, 9.33 μg / ml ±15%), kynurenine / tryptophan ratio: 0.055 to 0.082 ±15% (preferably 0.064 ±15%). The above ±15% is a variation value taking into consideration the variability of the analytical system, etc., and the upper and lower limits of the numerical range of the above cutoff value, as well as the preferred value, may vary by ±15%. In the Examples described later, a significant decrease was observed in all plasma LPC molecules in acute DAD-type drug-induced interstitial pneumonia cases (A-DAD) compared with cases not developing drug-induced interstitial pneumonia taking the same drug (C) (Figure 1, A-DAD vs C). Also, a significant decrease was observed in all acute drug-induced interstitial pneumonia cases (A) compared with cases not developing drug-induced interstitial pneumonia taking the same drug (C) (Figure 1, A vs C). Serum kynurenine pathway molecules (kynurenine and quinolinic acid) and tryptophan molecules were significantly increased and decreased in acute DAD-type drug-induced interstitial pneumonia cases (A-DAD) compared with cases not developing drug-induced interstitial pneumonia taking the same drugs (C) (Figure 2, A-DAD vs C). In addition, in all acute drug-induced interstitial pneumonia cases (A), they were significantly increased and decreased, respectively, compared with cases not developing drug-induced interstitial pneumonia taking the same drugs (C) (Figure 2, A vs C).

[0029] The method of the present invention can also be used for the specific diagnosis of drug-induced interstitial pneumonia. In this specification, "specific diagnosis" refers to determining whether or not a subject has drug-induced interstitial pneumonia. The method of the present invention can also be used for the specific diagnosis of DAD-type drug-induced interstitial pneumonia, and in this case, "specific diagnosis" refers to determining whether or not a subject has DAD-pattern interstitial pneumonia. Since DAD is a particularly severe disease type among interstitial pneumonia disease types, the use of the method for the specific diagnosis of DAD is of great clinical significance. The level (e.g., concentration) of at least one LPC molecule selected from the group consisting of LPC(14:0), LPC(15:0), LPC(16:0), LPC(16:1), LPC(17:0), LPC(18:0), LPC(18:1), LPC(18:2), LPC(19:0), LPC(20:0), LPC(20:3), LPC(20:4), LPC(20:5) and LPC(22:6) in a sample derived from a subject is measured, and if the level is lower than a preset cutoff value or reference value, it is determined that the disease is highly likely to be drug-induced interstitial pneumonia, and if the level is higher than the cutoff value or reference value, it is determined that the disease is low likely to be drug-induced interstitial pneumonia. The preset cutoff value and reference value can be appropriately set by a person skilled in the art. For example, the 95% confidence interval of the quantitative value of cases of lung diseases other than drug-induced interstitial pneumonia can be used as the reference value, or the cutoff value can be set from the ROC curve. By changing the cutoff value or reference value to a value for a specific diagnosis of DAD-type drug-induced interstitial pneumonia, a specific diagnosis of DAD-type drug-induced interstitial pneumonia can be similarly performed. In the Examples described below, all plasma LPC molecules were significantly decreased in cases of acute DAD-type drug-induced interstitial pneumonia (A-DAD) compared with cases of lung cancer (D), pulmonary nontuberculous mycobacterial disease (G), idiopathic interstitial pneumonia (H), collagen vascular lung disease (I), COPD (J), and bronchial asthma (K) (Figure 1, A-DAD vs DK). In addition, in all acute-phase drug-induced interstitial pneumonia cases (A), significant decreases were observed in all LPC molecular groups in lung cancer cases (D), LPC(19:0) and LPC(20:0) in pulmonary nontuberculous mycobacterial disease cases (G), LPC(14:0), LPC(15:0), LPC(16:0), LPC(17:0), LPC(18:0), LPC(18:1), and LPC(20:0) in idiopathic interstitial pneumonia cases (H), all LPC molecular groups in collagen disease lung cases (I), LPC(14:0), LPC(16:0), LPC(18:0), LPC(18:1), and LPC(20:0) in COPD cases (J), and LPC(14:0) in asthma cases (K) (Figure 1, A vs DK).

[0030] The levels (e.g., concentrations) of kynurenine and molecules downstream of its metabolic pathway (e.g., 3-hydroxykynurenine, 3-hydroxyanthranilic acid, 2-amino-3-carboxymuconic acid semialdehyde, quinolinic acid, picolinic acid) in a sample from a subject are measured, and the ratio to tryptophan is calculated. If the level is higher than a preset cutoff value or reference value, it is determined that the disease is highly likely to be drug-induced interstitial pneumonia, and if the level is lower than the cutoff value or reference value, it is determined that the disease is low likely to be drug-induced interstitial pneumonia. The preset cutoff value or reference value can be appropriately set by a person skilled in the art. For example, the 95% confidence interval of the quantitative value of a case of developing a lung disease other than drug-induced interstitial pneumonia can be used as the reference value, or the cutoff value can be set from an ROC curve. By changing the cutoff value or reference value to a value for specific diagnosis of DAD-type drug-induced interstitial pneumonia, specific diagnosis of DAD-type drug-induced interstitial pneumonia can be performed in the same manner. In the examples described later, serum kynurenine molecules and quinolinic acid molecules were significantly increased in acute DAD-type drug-induced interstitial pneumonia cases (A-DAD) compared with lung cancer cases (D), bacterial infection cases (F), pulmonary nontuberculous mycobacterial disease cases (G), idiopathic interstitial pneumonia cases (H), collagen disease lung cases (I), COPD cases (J), and bronchial asthma cases (K) (Figure 2, A-DAD vs DK). Also, in all acute drug-induced interstitial pneumonia cases (A), a significant increase was observed in lung disease, similar to the DAD type (Figure 2, A vs DK).

[0031] The level (e.g., concentration) of tryptophan in a sample derived from a subject is measured, and if the level is lower than a preset cutoff value or reference value, it is determined that the disease is highly likely to be drug-induced interstitial pneumonia, and if the level is higher than the cutoff value or reference value, it is determined that the disease is low likely to be drug-induced interstitial pneumonia. The preset cutoff value or reference value can be appropriately set by a person skilled in the art. For example, the 95% confidence interval of the quantitative value of a case of developing a lung disease other than drug-induced interstitial pneumonia can be set as the reference value, or the cutoff value can be set from an ROC curve. By changing the cutoff value or reference value to a value for specific diagnosis of DAD-type drug-induced interstitial pneumonia, specific diagnosis of DAD-type drug-induced interstitial pneumonia can be performed in the same manner. In the Examples described later, a significant decrease in serum tryptophan molecules was observed in all cases except for bacterial infection cases (F) (Figure 2, A-DAD vs DK). In addition, a significant decrease was observed in all acute drug-induced interstitial pneumonia cases (A) in lung disease, similar to the DAD type (Figure 2, A vs DK). In one embodiment, for specific diagnosis of drug-induced interstitial pneumonia using plasma or serum samples, the following cutoff values ​​can be set based on the concentration at which Youden's Index [sensitivity-(100-specificity)] is maximized (the value at which sensitivity and specificity are highest) of the metabolite cutoff value from ROC curve analysis for discrimination of all acute drug-induced interstitial pneumonia cases (A) and lung cancer cases (D), fungal pneumonia cases (E), bacterial infection cases (F), pulmonary nontuberculous mycobacterial disease cases (G), idiopathic interstitial pneumonia cases (H), collagen disease lung cases (I), COPD cases (J), or bronchial asthma cases (K) in the examples described below. Upper row: appropriate value, lower row: preferred value. The ±15% in the table below is a variation value taking into consideration the variation of the analysis system, etc., and there may be a ±15% variation in each of the upper and lower limits of the numerical range of the appropriate value and the preferred value. JPEG0007633481000001.jpg192170 In another embodiment, for specific diagnosis of DAD-type drug-induced interstitial pneumonia using plasma or serum samples, the following cutoff values ​​can be set based on the concentration at which Youden's Index [sensitivity - (100 - specificity)] is maximized (the value at which sensitivity and specificity are highest) as the cutoff value of the metabolite from ROC curve analysis for discrimination between all acute-phase cases of DAD-type drug-induced interstitial pneumonia (A-DAD) and lung cancer cases (D), fungal pneumonia cases (E), bacterial infection cases (F), pulmonary nontuberculous mycobacterial disease cases (G), idiopathic interstitial pneumonia cases (H), collagen disease lung cases (I), COPD cases (J), or bronchial asthma cases (K) in the Examples described below. Upper row: appropriate value, lower row: preferred value. The ±15% in the table below is a variation value that takes into account variability in the analytical system, etc., and there may be a ±15% variation in the upper and lower limits of the numerical range of the appropriate value, as well as in the preferred value. JPEG0007633481000002.jpg195170

[0032] Therefore, the values ​​measured in the methods of the present invention can assist in the specific diagnosis of drug-induced interstitial pneumonia.

[0033] The subject to be specifically diagnosed with drug-induced interstitial pneumonia should be in the acute phase of the disease. In this specification, the term "acute phase of the disease" refers to the period near the worst stage of the disease. The acute phase is diagnosed by a respiratory specialist based on a combination of clinical symptoms, physical examination findings, blood test findings, chest image findings, respiratory function tests, pathological patterns, and other findings.

[0034] The method of the present invention can also be used to diagnose the progression of drug-induced interstitial pneumonia. In this specification, "disease progression diagnosis" refers to the assessment of the degree or change in the pathology (severity, treatment effect, etc.) of a subject diagnosed with drug-induced interstitial pneumonia. The method of the present invention can also be used to diagnose the progression of DAD-type drug-induced interstitial pneumonia. The level (e.g., concentration) of at least one LPC molecule selected from the group consisting of LPC(14:0), LPC(15:0), LPC(16:0), LPC(16:1), LPC(17:0), LPC(18:0), LPC(18:1), LPC(18:2), LPC(19:0), LPC(20:0), LPC(20:3), LPC(20:4), LPC(20:5) and LPC(22:6) in a sample derived from a subject is measured, and if the level is lower than a preset cutoff value or reference value, it is determined that there is a high possibility that the subject is in the acute phase of drug-induced interstitial pneumonia, and if the level is higher than the cutoff value or reference value, it is determined that there is a low possibility that the subject is in the acute phase of drug-induced interstitial pneumonia. These preset cutoff values ​​and reference values ​​can be appropriately set by those skilled in the art. For example, the 95% confidence interval of the quantitative value of the recovery-stage case of drug-induced interstitial pneumonia can be used as the reference value, and the cutoff value can be set from the ROC curve. By changing the cutoff value or the reference value to a value for diagnosing the disease progression of DAD-type drug-induced interstitial pneumonia, the disease progression of DAD-type drug-induced interstitial pneumonia can be similarly diagnosed. In one embodiment, for diagnosis of the progression of drug-induced interstitial pneumonia using plasma samples, the following cutoff value can be set based on the concentration at which Youden's Index [sensitivity - (100 - specificity)] is maximized (the value at which sensitivity and specificity are highest) as the cutoff value for the metabolite from the ROC curve analysis for discriminating between all acute phase cases of drug-induced interstitial pneumonia (A) and all convalescent phase cases of drug-induced interstitial pneumonia (B) in the Examples described below. LPC(14:0): 284.1 to 325.7 ng / ml ±15% (preferably, 291.0 ng / ml ±15%), LPC(15:0): 187.3 to 208.8 ng / ml ±15% (preferably, 200.5 ng / ml ±15%), LPC(16:0): 39.39 to 42.34 μg / ml ±15% (preferably, 40.89 μg / ml ±15%), LPC(17:0): 410.0 to 481.6 ng / ml ±15% (preferably, 439.8 ng / ml ±15%), LPC(18:0): 8.97 to 9.72 μg / ml ±15% (preferably, 9.26 μg / ml ±15%), LPC(18:1): 8.04 to 8.64 μg / ml ±15% (preferably, 8.28 μg / ml ±15%), LPC(19:0): 48.34 to 51.83 ng / ml ±15% (preferably, 49.46 ng / ml ±15%), LPC(20:0): 30.48 to 33.40 ng / ml ±15% (preferably, 32.47 ng / ml ±15%). The above ±15% is a variation value taking into consideration variability in the analysis system, etc., and there may be a variation of ±15% for each of the upper and lower limits of the numerical range of the above cutoff value, as well as for the preferred value. By changing the cutoff value or the reference value to a value for diagnosing DAD type drug-induced interstitial pneumonia, it is possible to diagnose DAD type drug-induced interstitial pneumonia in a similar manner. In one embodiment, for diagnosing the progression of DAD type drug-induced interstitial pneumonia using a plasma sample, the following cutoff value can be set using the concentration at which Youden's Index [sensitivity-(100-specificity)] is maximized (the value at which sensitivity and specificity are highest) as an index, based on the ROC curve analysis for discriminating between acute phase cases of DAD type drug-induced interstitial pneumonia (A-DAD) and all convalescent phase cases of drug-induced interstitial pneumonia (B) in the Examples described below. LPC(14:0): 226.9 to 299.1 ng / ml ±15% (preferably, 260.2 ng / ml ±15%), LPC(15:0): 157.9 to 217.5 ng / ml ±15% (preferably, 182.6 ng / ml ±15%), LPC(16:0): 29.62 to 38.29 μg / ml ±15% (preferably, 33.53 μg / ml ±15%), LPC(17:0): 315.3 to 444.5 ng / ml ±15% (preferably, 381.5 ng / ml ±15%), LPC(18:0): 9.02 to 11.12 μg / ml ±15% (preferably, 9.67 μg / ml ±15%), LPC(18:1) : 7.39 to 8.70 μg / ml ±15% (preferably 8.23 ​​μg / ml ±15%), LPC(19:0): 34.63 to 48.94 ng / ml ±15% (preferably 40.69 ng / ml ±15%), LPC(20:0): 23.20 to 32.97 ng / ml ±15% (preferably 28.05 ng / ml ±15%). The above ±15% is a variation value taking into consideration the variability of the analysis system, etc., and there may be a variation of ±15% for each of the upper and lower limits of the numerical range of the above cutoff value, as well as for the preferred value. In the Examples described later, a significant decrease was observed in all plasma LPC molecules in DAD-type acute-phase drug-induced interstitial pneumonia cases (Fig. 1, A-DAD) compared with all convalescent-phase drug-induced interstitial pneumonia cases (B) (Fig. 1, A-DAD vs. B). A significant decrease was also observed in all acute-phase drug-induced interstitial pneumonia cases (A) compared with all convalescent-phase drug-induced interstitial pneumonia cases (Fig. 1, A vs. B).

[0035] The levels (e.g., concentrations) of kynurenine and molecules downstream of its metabolic pathway (e.g., 3-hydroxykynurenine, 3-hydroxyanthranilic acid, 2-amino-3-carboxymuconic acid semialdehyde, quinolinic acid, picolinic acid) in a sample derived from a subject are measured, and in some cases, the ratio to tryptophan is further obtained. If the level or ratio is higher than a preset cutoff value or reference value, it is determined that there is a high possibility that the subject is in the acute phase of drug-induced interstitial pneumonia, and if the level is lower than the cutoff value or reference value, it is determined that there is a low possibility that the subject is in the acute phase of drug-induced interstitial pneumonia. The preset cutoff value or reference value can be appropriately set by a person skilled in the art. For example, the 95% confidence interval of the quantitative value of a case of drug-induced interstitial pneumonia in the recovery phase can be used as the reference value, or the cutoff value can be set from an ROC curve. By changing the cutoff value or reference value to a value for diagnosing the disease progression of DAD-type drug-induced interstitial pneumonia, the disease progression of DAD-type drug-induced interstitial pneumonia can be similarly diagnosed. In one embodiment, for diagnosis of the disease progression of drug-induced interstitial pneumonia using serum samples, the following cutoff values ​​can be set using the concentration at which Youden's Index [sensitivity-(100-specificity)] is maximized (the value at which sensitivity and specificity are highest) as an index based on the ROC curve analysis for discrimination between all acute-phase cases of drug-induced interstitial pneumonia (A) and all convalescent-phase cases of drug-induced interstitial pneumonia (B) in the Examples described below: Kynurenine: 508.5 to 555.8 ng / ml ±15% (preferably 522.3 ng / ml ±15%), quinolinic acid: 84.4 to 96.1 ng / ml ±15% (preferably 90.7 ng / ml ±15%), kynurenine / tryptophan ratio: 0.053 to 0.061 ±15% (preferably 0.056 ±15%). The above ±15% is a variation value taking into consideration variability in the analytical system, etc., and the upper and lower limits of the numerical range of the above cutoff value, as well as the preferred value, may vary by ±15%. By changing the cutoff value or the reference value to a value for diagnosing DAD type drug-induced interstitial pneumonia, it is possible to diagnose DAD type drug-induced interstitial pneumonia in a similar manner. In one embodiment, for diagnosing the progression of DAD type drug-induced interstitial pneumonia using a serum sample, the following cutoff value can be set using the concentration at which Youden's Index [sensitivity-(100-specificity)] is maximized (the value at which sensitivity and specificity are highest) as an index, based on the ROC curve analysis for discriminating between acute phase cases of DAD type drug-induced interstitial pneumonia (A-DAD) and all convalescent phase cases of drug-induced interstitial pneumonia (B) in the Examples described below. Kynurenine: 649.5 to 788.3 ng / ml ±15% (preferably, 707.1 ng / ml ±15%), quinolinic acid: 93.4 to 155.9 ng / ml ±15% (preferably, 125.1 ng / ml ±15%), kynurenine / tryptophan ratio: 0.055 to 0.075 ±15% (preferably, 0.064 ±15%). The above ±15% is a variation value taking into consideration variability in the analysis system, etc., and there may be a variation of ±15% for each of the upper and lower limits of the numerical range of the above cutoff values, as well as for the preferred values. In the Examples described later, serum kynurenine molecules and quinolinic acid molecules were significantly increased in acute-phase DAD-type drug-induced interstitial pneumonia cases (A-DAD) compared with all convalescent-phase drug-induced interstitial pneumonia cases (B) (Figure 2, A-DAD vs B and Figure 3, A-DAD vs B). Also, a significant increase was observed in all acute-phase drug-induced interstitial pneumonia cases (A) compared with all convalescent-phase drug-induced interstitial pneumonia cases (Figure 2, A vs B and Figure 3, A-DAD vs B).

[0036] The level (e.g., concentration) of tryptophan in a sample derived from a subject is measured, and if the level is lower than a preset cutoff value or reference value, it is determined that there is a high possibility that the subject is in the acute phase of drug-induced interstitial pneumonia, and if the level is higher than the cutoff value or reference value, it is determined that there is a low possibility that the subject is in the acute phase of drug-induced interstitial pneumonia. The preset cutoff value or reference value can be appropriately set by a person skilled in the art. For example, the 95% confidence interval of the quantitative value of a case of drug-induced interstitial pneumonia in the recovery phase can be set as the reference value, or the cutoff value can be set from an ROC curve. By changing the cutoff value or reference value to a value for diagnosing the disease progression of DAD-type drug-induced interstitial pneumonia, the disease progression of DAD-type drug-induced interstitial pneumonia can be similarly diagnosed. In one embodiment, for the diagnosis of the disease progression of drug-induced interstitial pneumonia using serum samples, the ROC curve analysis for the discrimination of all acute cases of drug-induced interstitial pneumonia (A) and all convalescent cases of drug-induced interstitial pneumonia (B) in the examples described later shows that the cutoff value of the metabolite can be set using the concentration at which Youden's Index [sensitivity-(100-specificity)] is maximized (the value at which sensitivity and specificity are highest) as an index. Tryptophan: 9.05 to 9.57 μg / ml ±15% (preferably, 9.32 μg / ml ±15%). The above ±15% is a variation value taking into consideration the variation of the analysis system, etc., and there may be a variation of ±15% for each of the upper and lower limits of the numerical range of the above cutoff value, as well as for the preferred value. By changing the cutoff value or the reference value to a value for diagnosing DAD type drug-induced interstitial pneumonia, it is possible to diagnose DAD type drug-induced interstitial pneumonia in the same manner. As an embodiment, for the diagnosis of the disease state of DAD type drug-induced interstitial pneumonia using a serum sample, the following cutoff values ​​can be set using the concentration at which Youden's Index [sensitivity-(100-specificity)] is maximized (the value at which sensitivity and specificity are highest) as an index, based on the ROC curve analysis regarding the discrimination between DAD type drug-induced interstitial pneumonia acute phase cases (A-DAD) and all drug-induced interstitial pneumonia recovery phase cases (B) in the examples described later. Tryptophan: 7.62 to 8.94 μg / ml ±15% (preferably, 8.44 μg / ml ±15%). The above ±15% is a variation value taking into consideration variability in the analytical system, etc., and the upper and lower limits of the numerical range of the above cutoff value, as well as the preferred value, may vary by ±15%. In the Examples described later, a significant decrease in serum tryptophan molecules was observed in DAD-type acute-phase drug-induced interstitial pneumonia cases (A-DAD) compared with all convalescent-phase drug-induced interstitial pneumonia cases (B) (Figure 2, A-DAD vs B). Also, a significant decrease was observed in all acute-phase drug-induced interstitial pneumonia cases (A) compared with all convalescent-phase drug-induced interstitial pneumonia cases (Figure 2, A vs B).

[0037] Therefore, the values ​​measured in the method of the present invention can assist in diagnosing the progression of drug-induced interstitial pneumonia. a1. Obtaining a sample from a subject; b1. Measuring the level of at least one molecule selected from the group of lysophosphatidylcholine (LPC) molecules and / or at least one molecule selected from the group of molecules involved in the kynurenine pathway in a sample from a subject; and c1. Determine the severity of drug-induced interstitial pneumonia based on the measured value of b1 and / or the ratio calculated from the measured values ​​of b1 of the two molecules. The method further comprises:

[0038] Furthermore, the levels of at least one molecule selected from the lysophosphatidylcholine (LPC) molecule group and / or at least one molecule selected from the kynurenine pathway molecule group in a sample derived from a subject determined to be likely to be in the acute phase of drug-induced interstitial pneumonia are measured once or multiple times at different times, and in some cases, the ratio of the measured values ​​of the two molecules (for example, the ratio of one molecule selected from the kynurenine pathway molecule group excluding tryptophan to tryptophan) is obtained, and when the level and / or ratio is close to a cutoff value or a reference value, or changes to above or below the cutoff value or reference value, it is determined that the subject has recovered from drug-induced interstitial pneumonia by treatment, and when the level remains higher or lower than the cutoff value or reference value, it is determined that the subject has not recovered from drug-induced interstitial pneumonia by treatment, or that the recovery is insufficient. The method of the present invention can be used not only for diagnosing the disease progression of drug-induced interstitial pneumonia, but also for examining the prognosis and confirming the effectiveness of treatment.

[0039] If it is determined that the subject is highly likely to have developed drug-induced interstitial pneumonia, the suspected drug is discontinued immediately. Next, a combination of tests, such as sputum and serum infectious disease tests, imaging tests, bronchoalveolar lavage tests, and pathological tests, are performed to confirm the diagnosis of drug-induced interstitial pneumonia. In severe cases of drug-induced interstitial pneumonia such as DAD, corticosteroids are started immediately. The treatment guidelines of the Japanese Respiratory Society recommend pulse therapy with methylprednisolone 500-1000 mg / day for three days, followed by a continuous dose of 0.5-1.0 mg / kg / day in prednisolone equivalent, followed by a gradual taper. There is no set standard for the rate of taper, and the dose is reduced while monitoring the response to treatment. For lung damage that is resistant or intractable to steroid treatment, multidisciplinary treatment is performed by combining immunosuppressants (cyclosporine, tacrolimus, etc.), neutrophil elastase inhibitors (sivelestat), polymyxin B immobilized fiber column (PMX) therapy, etc. These treatments have little evidence for drug-induced lung damage and are not covered by insurance, so they are actually used in accordance with acute exacerbation of IPF (idiopathic pulmonary fibrosis) and ARDS (acute respiratory distress syndrome). For respiratory failure, measures are taken according to the severity, such as high-flow oxygen administration, noninvasive positive pressure ventilation, or artificial respiration management under endotracheal intubation.

[0040] In the United States, the incidence of drug-induced interstitial pneumonia is not as high as in Japan (RESPIRATORY INVESTIGATION, Dec 2013, 51(4):260-77), and the first type of interstitial pneumonia to be mentioned is idiopathic interstitial pneumonia, not drug-induced. Although the American Thoracic Society has published a statement on diagnosis (disease type, etc.) (AM J RESPIR CRIT CARE MED. Sep 2013;188(6):733-48), it does not have treatment guidelines for general disease types, and treatment is basically left to the policy of each medical facility. For example, at the Mayo Clinic, drug therapy, oxygen therapy, pulmonary rehabilitation, and lung transplants are performed as treatments for general interstitial pneumonia (https: / / www.mayoclinic.org / diseases-conditions / interstitial-lung-disease / diagnosis-treatment / drc-20353113). Drug treatments include: 1) corticosteroids (prednisolone, etc.) and their combination with immunosuppressants: expected to slow or stabilize the progression of interstitial pneumonia; 2) drugs for the treatment of idiopathic pulmonary fibrosis (pirfenidone and nintedanib: expected to slow the progression of interstitial pneumonia); 3) gastric acid secretion inhibitors (lansoprazole, omeprazole, etc.: prevent reflux esophagitis, reduce aspiration of gastric juice, and suppress the worsening of lung damage). Oxygen therapy cannot prevent lung damage, but it is expected to make breathing easier, prevent and reduce complications due to low blood oxygen levels, and reduce blood pressure on the right side of the heart. Pulmonary rehabilitation improves quality of life, such as the ease of daily activities. Lung transplantation is the last resort for patients with severe interstitial pneumonia who have no other treatment options.

[0041] On the other hand, for IPF, a type of interstitial pneumonia, there are many patients and the prognosis is poor, so the American Thoracic Society has published treatment guidelines based on the results of clinical research (AMERICAN JOURNAL OF RESPIRATORY AND CRINICAL CARE MEDICINE, JULY 2015. 192(2):e3-19). Medications that are conditionally recommended as treatments for IPF include nintedanib (an inhibitor of tyrosine kinases such as vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR)), pirfenidone (anti-fibrotic effect), and gastric acid secretion inhibitors (prevention of gastroesophageal reflux disease and suppression of worsening lung damage). However, the efficacy of warfarin (an anticoagulant), imatinib (a selective tyrosine kinase inhibitor of platelet-derived growth factor (PDGF)), the combination of prednisone, azathioprine, and N-acetylcysteine, and ambrisentan (a selective endothelin receptor antagonist) have been questioned, and their use is not recommended, but this does not exclude their use. In the present invention, the above-mentioned treatment methods for interstitial pneumonia may be used.

[0042] The present invention relates to a method for diagnosing and treating drug-induced interstitial pneumonia, a1. Obtaining a sample from a subject; b1. Measuring the level of at least one molecule selected from the group of lysophosphatidylcholine (LPC) molecules and / or at least one molecule selected from the group of molecules involved in the kynurenine pathway in a sample from a subject; c1. Determining the presence or absence of drug-induced interstitial pneumonia based on the measured value of b1 and / or the ratio calculated from the measured values ​​of b1 of the two molecules; and d1. To provide treatment for drug-induced interstitial pneumonia to subjects who are determined to be at high risk of developing drug-induced interstitial pneumonia. The method further comprises:

[0043] The present invention also provides a method for diagnosing and treating drug-induced interstitial pneumonia, comprising: a1. Obtaining a sample from a subject; b1. Measuring the level of at least one molecule selected from the group of lysophosphatidylcholine (LPC) molecules and / or at least one molecule selected from the group of molecules involved in the kynurenine pathway in a sample from a subject; c1. Determining the disease progression of drug-induced interstitial pneumonia based on the measured value of b1 and / or the ratio calculated from the measured values ​​of b1 of the two molecules; and d1. To provide treatment for drug-induced interstitial pneumonia to subjects who are determined to be at high risk of having acute drug-induced interstitial pneumonia. The method further comprises:

[0044] The present invention also provides a kit for testing for drug-induced interstitial pneumonia, comprising a reagent capable of measuring the level, in a sample from a subject, of at least one molecule selected from the lysophosphatidylcholine (LPC) molecule group and / or at least one molecule selected from the molecule group involved in the kynurenine pathway.

[0045] As an example, the kit of the present invention may include reagents (e.g., methanol, acetonitrile, isopropanol, chloroform, and mixtures thereof) for extracting at least one molecule selected from the lysophosphatidylcholine (LPC) molecule group and / or at least one molecule selected from the kynurenine pathway molecule group from a sample derived from a subject, internal standards (e.g., LPC(12:0), LPC(13:0), LPC(18:1-d7), kynurenine-d6, quinolinic acid-d3, tryptophan-d5), derivatization reagents (e.g., 3-aminopyridyl-N-hydroxysuccinimidyl carbamate (APDS)), and instructions. The instructions may also include, in addition to the method for using the kit, criteria for evaluation and / or differentiation (discrimination) of acute exacerbation cases of drug-induced interstitial pneumonia and DAD-type drug-induced interstitial pneumonia. In addition, the kit should preferably include a column and a pretreatment filter in the case of LC / MS analysis, and standard substances and antibodies in the case of the ligand binding method.

[0046] The kit of the present invention can be used as a pharmaceutical for diagnosing a disease. EXAMPLES

[0047] The present invention will now be described in more detail with reference to examples. Example 1 (1) Sample Human interstitial pneumonia samples used in the analysis were collected and analyzed with the approval of the respective research ethics committees at four base hospitals (Shinshu University, Nippon Medical School, Chiba University, and Hiroshima University), the National Institute of Health Sciences, the Kihara Foundation, Astellas Pharma, and Daiichi Sankyo.

[0048] Blood samples were taken from patients suspected of developing interstitial pneumonia due to drugs at the above-mentioned base hospitals during the acute phase (near the worst stage) and recovery phase of drug-induced interstitial pneumonia. Blood and urine samples were taken early in the morning on an empty stomach during hospitalization, and at any time during outpatient care. Blood samples were taken at each base hospital with the patient's consent using a 7 mL EDTA-2K blood collection tube for plasma collection, and the blood was promptly mixed and centrifuged at 1,300 g x 10 minutes (15°C to 20°C). Blood samples were also taken using a silica microparticle blood collection tube for accelerating coagulation for serum collection, and the blood was promptly mixed, left at room temperature for 60 minutes, and then centrifuged at 1,300 g x 10 minutes (15°C to 20°C). The collected plasma and serum were frozen and stored at -80°C. Urine samples were taken by collecting midstream urine using a paper cup for urine collection, centrifuged at 1,300 g x 10 minutes (15°C to 20°C), and frozen and stored at -80°C.

[0049] Plasma samples from patients with drug-induced interstitial pneumonia were collected in the acute phase of 21 cases showing diffuse alveolar damage (DAD) pattern in diagnostic imaging, 83 cases showing other patterns, 65 cases collected in the convalescent phase of drug-induced interstitial pneumonia, 31 cases collected from patients who were administered the same drugs as the patients who developed drug-induced interstitial pneumonia but did not develop drug-induced interstitial pneumonia for more than 3 months, 74 cases collected from lung cancer patients, 2 cases collected from fungal / viral pneumonia patients, 17 cases collected from bacterial pneumonia patients, 20 cases collected from nontuberculous mycobacterial disease patients, 41 cases collected from idiopathic interstitial pneumonia patients, 27 cases collected from collagen disease lung patients, 15 cases collected from chronic obstructive pulmonary disease (COPD) patients, and 12 cases collected from bronchial asthma patients, and were used for analysis of LPC molecule groups. Serum samples from patients with drug-induced interstitial pneumonia were collected for analysis of kynurenine pathway molecules, including 21 samples collected in the acute phase of cases showing diffuse alveolar damage (DAD) pattern in diagnostic imaging, 81 samples collected in the acute phase of cases showing other patterns, 62 samples collected in the recovery phase of patients with drug-induced interstitial pneumonia, 30 samples collected from patients who were administered the same drugs as the patients who developed drug-induced interstitial pneumonia but did not develop drug-induced interstitial pneumonia for more than 3 months, 70 samples collected from lung cancer patients, 15 samples collected from patients with bacterial infections, 21 samples collected from patients with nontuberculous mycobacterial disease, 45 samples collected from patients with idiopathic interstitial pneumonia, 26 samples collected from patients with collagen disease, 15 samples collected from patients with chronic obstructive pulmonary disease (COPD), and 13 samples collected from patients with bronchial asthma. Urine samples from patients with drug-induced interstitial pneumonia were collected for quinolinic acid analysis, including 10 samples collected during the acute phase of cases that showed a diffuse alveolar damage (DAD) pattern in diagnostic imaging, 33 samples collected during the acute phase of cases that showed other patterns, and 32 samples collected during the recovery phase of drug-induced interstitial pneumonia.

[0050] (2) Selection of candidate metabolites for biomarkers of drug-induced interstitial pneumonia Candidate metabolites for biomarkers of drug-induced interstitial pneumonia were selected through exploration and validation using lipidomics analysis, which comprehensively analyzes hydrophobic metabolites, and metabolomics analysis, which comprehensively analyzes hydrophilic metabolites. In addition, 45 acute-phase cases of drug-induced interstitial pneumonia, including 9 cases with DAD patterns, and 33 convalescent-phase cases of drug-induced interstitial pneumonia, were used for exploration, and 60 acute-phase cases of drug-induced interstitial pneumonia, including 16 cases with DAD patterns, and 34 convalescent-phase cases of drug-induced interstitial pneumonia, which overlapped with some of the exploration samples, were used for validation. As a result of the search, 117 molecules were identified as promising biomarker candidates in cases with DAD pattern, with a significance probability of p < 0.05 or less and an absolute effect size of 0.8 or more. In particular, the LPC molecule group showed a low significance probability p and a high effect size. As a result of verification, six LPC molecules (LPC(14:0), LPC(16:1), LPC(17:0), LPC(18:0), LPC(18:2), LPC(20:5)) showed a significance probability of p < 0.05 or less and an absolute effect size of 0.8 or more. Furthermore, a similar tendency was observed in all other detectable LPC molecules (LPC(16:0), LPC(18:1), LPC(20:3), LPC(20:4), LPC(22:6)). Therefore, we quantified and evaluated eight LPC molecules for which standard samples are available and abundant as biomarkers for drug-induced interstitial pneumonia. As for hydrophilic metabolites, a search revealed that 14 molecules were promising biomarker candidates with a significance probability of p < 0.05 or less and an absolute effect size of 0.8 or more in cases showing DAD pattern, and verification revealed that six molecules (phenylalanyl-tryptophan, tryptophan, kynurenine, citrulline, glycerophosphocholine, and histidine) showed a significance probability of p < 0.05 or less and an absolute effect size of 0.8 or more. Furthermore, a similar tendency was observed for quinolinic acid, which is a molecule that belongs to the kynurenine pathway like tryptophan and kynurenine.Therefore, we quantified and evaluated the kynurenine pathway molecules as biomarkers for drug-induced interstitial pneumonia, including tryptophan, kynurenine, and quinolinic acid, which are abundant and have available standard samples.

[0051] (3) Quantitative methods for biomarkers Measurement and analysis of LPC molecular groups were performed using a ThermoFisher high performance liquid chromatography (LC; U3000) / mass spectrometer (MS; TSQ Quantiva) with a proprietary analytical method. Sample preparation consisted of mixing 5 μl of plasma with MeOH containing 2 ng / ml of an internal standard (LPC (12:0), which is not detectable in living organisms), and passing the mixture through a 0.22 um filter plate to remove protein components. 3 μl of the sample solution was introduced into the LC / MS. The LC conditions were as follows: mobile phase A was 10 mM aqueous ammonium formate, mobile phase B was 10 mM aqueous ammonium formate:isopropanol (1:100), and the separation column was an InertCore C18 (2.4 μm pore, 2.1 x 50 mm, GL Science) heated to 50°C. The initial condition was set to 35% B, which increased to 100% B in 2.5 minutes, was maintained at 100% B until 3.4 minutes, was decreased to 35% B at 3.41 minutes, and was maintained at 100% B until 5 minutes. The equilibration was performed while maintaining the pH at 35%. The MS was introduced from 0 to 0.1 min, 0.5 to 2.9 min, and 4.3 to 5 min during the analysis time, and the liquid was discharged by switching to the waste liquid line using a valve during the other time periods. The MS conditions were as follows. The ion source type was HESI (heated electrospray ionization), the ion mode was positive ion mode, the spray voltage was 3500 V, the sheath gas was 40 Arb, the Aux gas was 10 Arb, the sweep gas was 1 Arb, the ion transfer tube temp was 350 °C, and the vaporizer temp was 250 °C. SRM measurements were performed using the precursor ion and production ion for each ion in Table 1. The cycle time was 1 sec, the RF lens was 100 V, the Q1 resolution was 0.7 FWHM, the Q3 resolution was 0.7 FWHM, the CID gas was 1.5 mTorr, and the Chrom Filter was 3 sec. [Table 1] The calibration curve ranges of the measured molecules were set as follows: 1 μg / mL - 200 μg / mL for LPC(16:0), 0.4 μg / mL - 80 μg / mL for LPC(18:0) and LPC(18:1), 20 ng / mL - 4000 ng / mL for LPC(14:0), LPC(15:0) and LPC(17:0), and 2 ng / mL - 400 ng / mL for LPC(19:0) and LPC(20:0). Four types of Quality Control (QC) samples were used for each analytical unit to calculate the relative accuracy and precision, and the data for analytical units that were less than 15% were used.

[0052] Kynurenine and tryptophan molecules were measured and analyzed using a proprietary analytical method developed using a ThermoFisher high performance liquid chromatography (LC; U3000) / mass spectrometer (MS; TSQ Quantiva). Sample preparation consisted of mixing 50 μl of serum with 50 μl of water, and then mixing with MeOH containing internal standards (stable isotopes of kynurenine and tryptophan (kynurenine-d6 and tryptophan-d5) at 12.5 and 100 ng / ml, respectively), and passing the mixture through a 0.22 um filter plate to remove protein components. The mixture was then passed through a lipid-removing filter plate packed with C18 to remove lipid components. The collected sample liquid was diluted with three volumes of water, and 5 μl was introduced into the LC / MS. The LC conditions were as follows: mobile phase A was 0.3% formic acid water, mobile phase B was 0.3% formic acid methanol, and the separation column was a Triart Phenyl (1.9 μm pore, 2.1 x 100 mm, YMC) heated to 45°C. The initial conditions were set to 20% B, maintained for 0.5 min, and then B was diluted for 2.5 min. The concentration of B rose to 100%, maintained 100% for 4 minutes, dropped to 20% B at 4.1 minutes, and then maintained 20% B for 5 minutes to allow equilibration. The sample was introduced into the MS from 1.2 to 3.5 minutes during the analysis time, and the remaining time was drained by switching to the waste line using a valve. The MS conditions were as follows: the ion source type was HESI (heated electrospray ionization), the ion mode was positive ion mode, the spray voltage was 3500 V, the sheath gas was 40 Arb, the Aux gas was 10 Arb, the sweep gas was 1 Arb, the ion transfer tube temp was 350 °C, and the vaporizer temp was 250 °C. SRM measurements were performed using the precursor ion and production ion for each ion in Table 2.The cycle time was 0.5 sec, the RF Lens was a calibrated value, the Q1 Resolution was 0.7 FWHM, the Q3 Resolution was 0.7 FWHM, the CID Gas was 1.5 mTorr, and the Chroma Filter was 3 sec. The measurement and analysis of quinolinic acid was performed using a proprietary analytical method using ThermoFisher's ion chromatography (IC; Dionex ICS-5000+) / high-resolution mass spectrometer (HRMS; Q-Exactive). In this blood concentration measurement system, a significant matrix effect due to serum components was confirmed, so normal human pooled serum was used to prepare the calibration curve samples, rather than an alternative matrix such as bovine serum albumin solution. In addition, since a certain amount of quinolinic acid exists in human serum, in this measurement method, the calibration curve samples were prepared using quinolinic acid-d3, which has the same ionization efficiency as natural quinolinic acid, as an alternative molecule, and the blood concentration of quinolinic acid was calculated by substituting the measured values ​​of natural quinolinic acid into the calibration curve prepared with the measured values ​​of quinolinic acid-d3. Sample preparation consisted of mixing 20 μl of serum with 80 μl of water, then mixing with 400 μl of MeOH containing 18.4 ng / ml of internal standard (hippuric acid-d5), and passing the mixture through a 0.22 μm filter plate to remove protein components. The mixture was then passed through a lipid-removing filter plate packed with C18 to remove lipid components. 100 μl of the collected sample was completely dried in an evaporator, redissolved in 80 μl of distilled water, passed through a 0.22 μm PVDF filter column, and 5 μl was introduced into the IC / MS. The IC conditions were as follows: potassium hydroxide (KOH) aqueous solution was used as the mobile phase, and a Dionex IonPac AS11-HC-4 μm IC column (2 × 250 mm, Thermo Fisher Scientific) was used as the separation column, heated to 30°C. The initial condition was a KOH concentration of 10 mM, which was increased to 100 mM in 7 minutes, maintained at 100 mM until 8 minutes, decreased to 10 mM in 8.1 minutes, and then maintained at 10 mM until 10 minutes for equilibration. The MS conditions were as follows:The ion source type was HESI (heated electrospray ionization), the ion mode was negative ion mode, the spray voltage was -2000 V, the sheath gas was 40 Arb, the Aux gas was 10 Arb, the sweep gas was 0 Arb, the AUX gas heater temp was 300 °C, the capillary temp was 350 °C, and the RF lens was set to 35. SRM measurements were performed using the precursor ion and production ion for each ion in Table 2. The Automatic Gain Control (AGC) Target was 2 × 10. 5 The following parameters were used: Maximum injection time (IT) 100 msec, Isolation Window 1.0 m / z, Fixed First Mass 50.0 m / z, and Resolution 17,500. The instruments and main analytical conditions for measuring urinary concentrations were the same as those for blood concentrations, and full scan measurements using the exact mass of precursor ions were used. Correction for differences in urinary concentrations due to differences in water intake before sample collection was performed using the probabilistic quotient normalization (PQN) method for the area values ​​of each extracted component corrected with an internal standard substance. [Table 2] The calibration curve ranges for the measured molecules were set as follows: kynurenine 20 ng / mL - 4000 ng / mL, tryptophan 0.15 μg / mL - 30 μg / mL, and quinolinic acid 3.3 ng / mL - 836 ng / mL. Four types of Quality Control (QC) samples were used for each analytical unit to calculate the relative accuracy and precision, and the data for analytical units that were less than 15% were used.

[0053] (4) Performance of biomarkers for drug-induced interstitial pneumonia (comparison with recovered cases) Figure 1 shows the plasma concentrations of eight hydrophobic drug-induced interstitial pneumonia biomarkers (LPC molecule group; LPC(14:0), LPC(15:0), LPC(16:0), LPC(17:0), LPC(18:0), LPC(18:1), LPC(19:0), LPC(20:0)) in a dot plot. All LPC molecules were significantly decreased in acute-phase DAD-type drug-induced interstitial pneumonia cases (A-DAD) compared with all convalescent-phase drug-induced interstitial pneumonia cases (B) (A-DAD vs B). In addition, a significant decrease was observed in all acute-phase drug-induced interstitial pneumonia cases (A) compared with all convalescent-phase drug-induced interstitial pneumonia cases (A vs B). Figure 2 shows the serum concentrations of three hydrophilic biomarkers of drug-induced interstitial pneumonia (kynurenine pathway molecules; kynurenine, tryptophan, and quinolinic acid) in dot plots. Kynurenine, tryptophan, and quinolinic acid molecules were significantly increased (kynurenine and quinolinic acid) and (tryptophan) in DAD-type acute-phase drug-induced interstitial pneumonia cases (A-DAD) compared with all convalescent-phase drug-induced interstitial pneumonia cases (B) (A-DAD vs B). In addition, in all acute-phase drug-induced interstitial pneumonia cases (A), there was a significant increase and decrease, respectively, compared with all convalescent-phase drug-induced interstitial pneumonia cases (A vs B). Figure 3 shows the urinary concentration of quinolinic acid in a dot plot. Quinolinic acid molecules were significantly increased in acute-phase DAD-type drug-induced interstitial pneumonia cases (A-DAD) compared with all convalescent-phase drug-induced interstitial pneumonia cases (B) (A-DAD vs B). Additionally, a significant increase was observed in all acute-phase drug-induced interstitial pneumonia cases (A) compared with all convalescent-phase drug-induced interstitial pneumonia cases (A vs B). Table 3 summarizes the AUC values ​​obtained by ROC analysis to evaluate the performance of these drug-induced interstitial pneumonia biomarkers using plasma or serum concentrations to distinguish between acute DAD-type drug-induced interstitial pneumonia cases (A-DAD), which are particularly severe, and all cases of drug-induced interstitial pneumonia in the recovery phase (B). The LPC molecule group showed 0.903-0.938, the kynurenine molecule 0.912, the tryptophan molecule 0.800, the quinolinic acid molecule 0.884, and kynurenine / tryptophan 0.943, demonstrating good discrimination performance. Table 4 also summarizes the AUC values ​​obtained by ROC analysis to distinguish between all cases of acute drug-induced interstitial pneumonia cases (A) and all cases of drug-induced interstitial pneumonia in the recovery phase (B), using plasma or serum concentrations. The LPC molecule group showed 0.714-0.821, kynurenine molecules 0.827, tryptophan molecules 0.747, quinolinic acid molecules 0.808, and kynurenine / tryptophan 0.870, showing good discrimination performance for some of the LPC molecules, kynurenine, quinolinic acid, and kynurenine / tryptophan.

[0054] (5) Performance of biomarkers for drug-induced interstitial pneumonia (comparison with non-disease cases) A significant decrease in all plasma LPC molecules was observed in acute-phase DAD-type drug-induced interstitial pneumonia cases (A-DAD) compared with cases not developing drug-induced interstitial pneumonia taking the same drugs (C) (Figure 1, A-DAD vs C). A significant decrease was also observed in all acute-phase drug-induced interstitial pneumonia cases (A) compared with cases not developing drug-induced interstitial pneumonia taking the same drugs (C) (Figure 1, A vs C). Serum kynurenine, tryptophan, and quinolinic acid molecules were significantly increased (kynurenine and quinolinic acid) and decreased (tryptophan) in acute-phase DAD-type drug-induced interstitial pneumonia cases (A-DAD) compared with cases not developing drug-induced interstitial pneumonia taking the same drugs (C) (Figure 2, A-DAD vs C). In addition, in all acute-phase drug-induced interstitial pneumonia cases (A), significantly increased (kynurenine and quinolinic acid) and decreased (tryptophan) were observed compared with cases not developing drug-induced interstitial pneumonia taking the same drugs (C) (Figure 2, A vs C). The AUC values ​​of the receiver operating characteristic curve (ROC) analysis for distinguishing between acute-phase DAD-type drug-induced interstitial pneumonia cases (A-DAD) using plasma or serum concentrations were 0.929-0.971 for the LPC molecule group, 0.938 for kynurenine molecules, 0.802 for tryptophan molecules, 0.955 for quinolinic acid molecules, and 0.963 for kynurenine / tryptophan, demonstrating good discrimination performance (Table 3, C). The AUC values ​​of the ROC analysis for discriminating between acute-phase drug-induced interstitial pneumonia cases and all cases (A) using plasma or serum concentrations were 0.743-0.849 for the LPC molecule group, 0.851 for kynurenine molecules, 0.760 for tryptophan molecules, 0.901 for quinolinic acid molecules, and 0.895 for kynurenine / tryptophan, indicating good discrimination performance for some of the LPC molecules, kynurenine, quinolinic acid, and kynurenine / tryptophan (Table 4, C).

[0055] (6) Performance of biomarkers for drug-induced interstitial pneumonia (comparison with lung diseases) All plasma LPC molecules were significantly decreased in cases of acute DAD-type drug-induced interstitial pneumonia (A-DAD) compared with cases of lung cancer (D), pulmonary nontuberculous mycobacterial disease (G), idiopathic interstitial pneumonia (H), collagen disease lung (I), COPD (J), and bronchial asthma (K) (Figure 1, A-DAD vs DK). In addition, in all acute-phase drug-induced interstitial pneumonia cases (A), significant decreases were observed in all LPC molecular groups in lung cancer cases (D), LPC(19:0) and LPC(20:0) in pulmonary nontuberculous mycobacterial disease cases (G), LPC(14:0), LPC(15:0), LPC(16:0), LPC(17:0), LPC(18:0), LPC(18:1), and LPC(20:0) in idiopathic interstitial pneumonia cases (H), all LPC molecular groups in collagen disease lung cases (I), LPC(14:0), LPC(16:0), LPC(18:0), LPC(18:1), and LPC(20:0) in COPD cases (J), and LPC(14:0) in asthma cases (K) (Figure 1, A vs DK). Kynurenine and quinolinic acid molecules in serum were significantly increased in acute DAD-type drug-induced interstitial pneumonia cases (A-DAD) compared with lung cancer cases (D), bacterial infection cases (F), pulmonary nontuberculous mycobacterial disease cases (G), idiopathic interstitial pneumonia cases (H), collagen disease lung cases (I), COPD cases (J), and bronchial asthma cases (K). Tryptophan molecules were also significantly decreased in all cases except bacterial infection cases (F) (Figure 2, A-DAD vs DK). In addition, in all acute drug-induced interstitial pneumonia cases (A), significant increases and decreases were observed in lung disease, similar to DAD-type cases (Figure 2, A vs DK). Regarding the AUC values ​​of ROC analysis for the discrimination of acute-phase DAD-type drug-induced interstitial pneumonia cases (A-DAD) using plasma or serum concentrations, the LPC molecule group showed 0.880-0.923 (D), 0.900-0.978 (G), 0.916-0.96 (H), 0.892-0.944 (I), 0.937-0.981 (J), and 0.942-0.972 (K) for lung cancer cases (D), pulmonary nontuberculous mycobacterial disease cases (G), idiopathic interstitial pneumonia cases (H), collagen disease lung cases (I), COPD cases (J), and bronchial asthma cases (K). The kynurenine molecule group showed 0.880-0.923 (D), 0.900-0.978 (G), 0.916-0.96 (H), 0.892-0.944 (I), 0.937-0.981 (J), and 0.942-0.972 (K) for lung cancer cases (D), pulmonary nontuberculous mycobacterial disease cases (G), idiopathic interstitial pneumonia cases (H), collagen disease lung cases (I), COPD cases (J), and bronchial asthma cases (K). The β-glucosamine α ... The acid molecule showed 0.937 (D), 0.918 (F), 0.892 (G), 0.872 (H), 0.902 (I), 0.908 (J), and 0.980 (K) in the cases of lung cancer (D), bacterial infection (F), pulmonary nontuberculous mycobacterial disease (G), idiopathic interstitial pneumonia (H), collagen disease lung (I), COPD (J), and bronchial asthma (K). An showed good discrimination performance in the cases of lung cancer (D), bacterial infection (F), pulmonary nontuberculous mycobacterial disease (G), idiopathic interstitial pneumonia (H), collagen disease (I), COPD (J), and bronchial asthma (K) with 0.925 (D), 0.910 (F), 0.969 (G), 0.923 (H), 0.908 (I), 0.900 (J), and 0.977 (K) (Table 3, D-K). Regarding the AUC values ​​of the ROC analysis for discriminating between acute-phase drug-induced interstitial pneumonia cases and all cases (A) using plasma or serum concentrations, the LPC molecule group showed 0.671-0.811 (G), 0.689-0.802 (H), 0.699-0.823 (I), 0.709-0.812 (J), and 0.736-0.834 (K) for cases of pulmonary nontuberculous mycobacterial disease (G), idiopathic interstitial pneumonia (H), collagen vascular lung disease (I), COPD (J), and bronchial asthma (K), demonstrating good discrimination performance for some molecules (Table 4, D-K). On the other hand, the kynurenine molecule showed 0.820 (D), 0.866 (G), 0.816 (H), and 0.864 (K) in the lung cancer case (D), pulmonary nontuberculous mycobacterial disease case (G), idiopathic interstitial pneumonia case (H), and bronchial asthma case (K), respectively, while the tryptophan molecule showed 0.866 (K) in the bronchial asthma case (K), and the quinolinic The acid molecule showed 0.861 (D) and 0.925 (K) for the lung cancer case (D) and bronchial asthma case (K), while kynurenine / tryptophan showed 0.847 (D), 0.817 (F), 0.902 (G), 0.854 (H), 0.827 (I), 0.827 (J), and 0.919 (K) for the lung cancer case (D), bacterial infection case (F), pulmonary nontuberculous mycobacterial disease case (G), idiopathic interstitial pneumonia case (H), collagen disease lung case (I), COPD case (J), and bronchial asthma case (K), demonstrating good discrimination performance (Table 4, D-K). [Table 3] B, All cases of drug-induced interstitial pneumonia in the recovery stage, C, Non-disease cases of drug-induced interstitial pneumonia due to use of similar drugs, D, Lung cancer cases, E, Fungal pneumonia cases, F, Bacterial infection cases, G, Pulmonary nontuberculous mycobacterial disease cases, H, Idiopathic interstitial pneumonia cases, I, Connective tissue disease cases, J, COPD cases, K, Bronchial asthma cases The cutoff value for distinguishing and discriminating between A and BK obtained from ROC curve analysis is determined from the results of each ROC curve analysis, using the concentration at which Youden's Index [sensitivity - (100 - specificity)] is maximized (the value at which sensitivity and specificity are highest) as an index for the cutoff value of the metabolite. The values ​​in the table below are: upper: appropriate value, lower: preferred value. The ±15% in the table is a variation value that takes into account variability in the analysis system, etc., and there may be a ±15% variation in the upper and lower limits of the numerical range of the appropriate value, as well as in the preferred value. JPEG0007633481000006.jpg170128 [Table 4] The cutoff value for distinguishing and discriminating between A and BK obtained from ROC curve analysis is determined from the results of each ROC curve analysis, using the concentration at which Youden's Index [sensitivity - (100 - specificity)] is maximized (the value at which sensitivity and specificity are highest) as an index for the cutoff value of the metabolite. The values ​​in the table below are: upper: appropriate value, lower: preferred value. The ±15% in the table is a variation value that takes into account variability in the analysis system, etc., and there may be a ±15% variation in the upper and lower limits of the numerical range of the appropriate value, as well as in the preferred value. JPEG0007633481000008.jpg170118All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety. [Industrial Applicability]

[0056] The present invention can be used for in vitro diagnostics, clinical tests, and the like.

Claims

1. A method for testing for drug-induced interstitial pneumonia, comprising measuring the level of at least one molecule selected from the tryptophan and / or lysophosphatidylcholine (LPC) molecule group in a sample derived from a subject.

2. A method for testing drug-induced interstitial pneumonia, comprising measuring the levels in a sample derived from a subject of at least one molecule selected from a group of molecules included in the kynurenine pathway and / or at least one molecule selected from a group of lysophosphatidylcholine (LPC) molecules, wherein the measured values ​​assist in diagnosing the progression of the disease by determining whether the drug-induced interstitial pneumonia is in the acute phase or the recovery phase.

3. The method of claim 1, wherein the measured value aids in the specific diagnosis of drug-induced interstitial pneumonia.

4. The method according to any one of claims 1 to 3, wherein the drug-induced interstitial pneumonia is DAD-type drug-induced interstitial pneumonia.

5. The method according to claim 2, wherein the molecular group involved in the kynurenine pathway includes kynurenine, quinolinic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, 2-amino-3-carboxymuconic acid semialdehyde, picolinic acid and tryptophan.

6. 6. The method of any one of claims 1 to 5, wherein the LPC molecule group comprises LPC(14:0), LPC(15:0), LPC(16:0), LPC(16:1), LPC(17:0), LPC(18:0), LPC(18:1), LPC(18:2), LPC(19:0), LPC(20:0), LPC(20:3), LPC(20:4), LPC(20:5) and LPC(22:6).

7. A kit for testing for drug-induced interstitial pneumonia, comprising a reagent capable of measuring the level of at least one molecule selected from the tryptophan and / or lysophosphatidylcholine (LPC) molecule group in a sample derived from a subject.

8. A kit for diagnosing whether drug-induced interstitial pneumonia is in the acute or recovery phase, comprising a reagent capable of measuring the levels in a sample from a subject of at least one molecule selected from a group of molecules included in the kynurenine pathway and / or at least one molecule selected from a group of lysophosphatidylcholine (LPC) molecules.

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