Biomarker for predicting progression risk of pulmonary fibrosis in patient suffering from interstitial pneumonia with acute aggravation

Abstract

To provide means for determining a progression risk of pulmonary fibrosis in a patient suffering from interstitial pneumonia with acute aggravation.SOLUTION: A method of collecting data to determine a progression risk of pulmonary fibrosis in a patient suffering from interstitial pneumonia with acute aggravation, includes a step for obtaining a measured value of heme oxygenase-1 in a specimen of the patient.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present disclosure relates to biomarkers. More specifically, the present disclosure relates to biomarkers that may be useful in the field of diagnosis and treatment of interstitial pneumonia. [Background technology]

[0002] Interstitial pneumonia is a disease in which inflammation occurs in the interstitium of the lungs, leading to thickening and fibrosis of the interstitium and impaired gas exchange. Interstitial pneumonias include idiopathic interstitial pneumonias (IIPs), which have no identified cause, and further include idiopathic pulmonary fibrosis (IPF). IIPs is one of the designated intractable diseases under Japan's "Act on Medical Care for Patients with Intractable Diseases."

[0003] Interstitial pneumonia generally progresses slowly, but the phenomenon in which respiratory failure progresses rapidly in a short period of time is called "acute exacerbation (AE)" and is medically recognized as a pathological condition with a poor prognosis that may require intervention centered on intensive care in addition to chronic treatment. The "Diagnosis and Treatment Guidelines for Idiopathic Interstitial Pneumonia" (2004) by the Committee for the Preparation of Diffuse Lung Disease Diagnosis and Treatment Guidelines of the Japanese Respiratory Society and the Diffuse Lung Disease Research Group of the Ministry of Health, Labor and Welfare Science Research Specific Disease Countermeasures Program states that, within the course of IPF, the following symptoms should be present within one month: (1) increased dyspnea, (2) honeycomb findings + newly developed ground-glass opacities / infiltrates on HRCT (high-resolution computed tomography), (3) a decrease in arterial blood oxygen tension (PaO 2 A case in which all of the above conditions are present (a decrease of 10 mmHg or more) is considered an "acute exacerbation." This definition excludes obvious pulmonary infection, pneumothorax, malignant tumor, pulmonary embolism, and heart failure. A similar definition can also be applied to acute exacerbations of interstitial pneumonia other than IPF (Non-Patent Document 1).

[0004] Non-Patent Document 2 reports that a group of interstitial pneumonia patients with AE had higher serum heme oxygenase-1 (hereinafter referred to as HO-1) levels than a group of interstitial pneumonia patients without AE. Non-Patent Document 2 also describes the possibility that serum HO-1 may be useful as a biomarker for predicting whether or not interstitial pneumonia patients will die in hospital. However, Non-Patent Document 2 started from the premise that a small number of specific interstitial pneumonia patients (28 patients) could be distinguished into "with AE" and "without AE", and observed that the former group had higher serum HO-1 levels.

[0005] Patent Document 1 focuses on patients with interstitial pneumonia, particularly those with acute respiratory worsening (ARW), a condition presenting symptoms such as obvious increased dyspnea, and describes the use of HO-1 in blood samples as a biomarker that indicates the possibility that the dyspnea symptoms are due to acute exacerbation rather than a condition other than acute exacerbation (e.g., respiratory infection, etc.).

[0006] One of the symptoms that characterizes AE of interstitial pneumonia is pulmonary fibrosis. Fibrosis is formed by improper repair of widespread ground-glass opacity (GGO) areas seen on HRCT (high-resolution computed tomography). GGO occurs when air in the alveoli is partially replaced by other substances (such as liquid) and becomes denser, and is thought to mainly reflect inflammatory events. As pulmonary fibrosis progresses, numerous holes (small air spaces) that can be seen with the naked eye are formed as a result of fibrosis, and this state is called honeycomb lung because it has a honeycomb-like shape.

[0007] For patients diagnosed with AE, whether they will experience minimal pulmonary fibrosis or further progression is important for patient prognosis and selection of appropriate treatment, but there were no known means to predict which trajectory a patient was likely to experience. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] CHEST 2007;132:214-220 [Non-Patent Document 2] Canadian Respiratory Journal, Volume 2018, Article ID 7260178 [Patent documents]

[0009] [Patent Document 1] International Publication No. 2022 / 059687 Summary of the Invention [Problem to be solved by the invention]

[0010] An objective of various embodiments of the present disclosure is to provide a means for determining the risk of developing pulmonary fibrosis in interstitial pneumonia patients with acute exacerbations. [Means for solving the problem]

[0011] The present inventors found that the level of HO-1 in samples from patients with interstitial pneumonia diagnosed with acute exacerbation significantly correlated with the presence or absence of subsequent progression to honeycomb lung.

[0012] Thus, in one aspect, the present disclosure provides: [1] A method for collecting data to determine the risk of progression of pulmonary fibrosis in a patient with interstitial pneumonia having an acute exacerbation, the method comprising a step of obtaining a measurement of heme oxygenase-1 (hereinafter referred to as HO-1) in a sample from the patient. [2] Obtaining a measurement of heme oxygenase-1 (hereinafter referred to as HO-1) concentration in a sample from an interstitial pneumonia patient with acute exacerbation; and A step of making a judgment according to the following criteria: if the measured value of the HO-1 concentration is equal to or greater than a reference value, the patient is judged to have a high risk of developing pulmonary fibrosis, and if the measured value is less than the reference value, the patient is judged to have a low risk of developing pulmonary fibrosis. A method comprising: [3] The method according to [1] or [2], wherein the sample is whole blood, serum, or plasma. [4] (a) an antibody or antibody fragment that specifically recognizes HO-1; (b) an explanation that the determination is made according to the following criteria: if the measured value of the HO-1 concentration in a sample from a patient with interstitial pneumonia having acute exacerbation is equal to or greater than a reference value, the patient is determined to have a high risk of developing pulmonary fibrosis; if the measured value is less than the reference value, the patient is determined to have a low risk of developing pulmonary fibrosis. A kit for carrying out the method according to any one of [1] to [3], comprising: [Brief description of the drawings]

[0013] [Figure 1] Figure 1 is a plot showing the distribution of HO-1 concentrations in serum collected from each patient at the time of diagnosis of acute exacerbation of interstitial pneumonia, in the group with (+) and the group without (-) increased honeycomb lung (a) or GGO (b) between the time of diagnosis of acute exacerbation and the time of subsequent follow-up. [Diagram 2] Figure 2 is a plot showing the distribution of serum SP-D (a) or KL-6 (b) concentrations collected from each patient at the time of diagnosis of acute exacerbation of interstitial pneumonia in the group with (+) and the group without (-) increased honeycomb lung development between the time of diagnosis of acute exacerbation and the subsequent follow-up. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] In one aspect, a method is provided for collecting data to determine the risk of developing pulmonary fibrosis in an interstitial pneumonia patient having an acute exacerbation, the method comprising obtaining a measurement of HO-1 in a sample from the patient.

[0015] In this disclosure, the term acute exacerbation in the context of interstitial pneumonia is defined as "the onset of (1) increased dyspnea, (2) honeycombing findings + new ground-glass opacities / infiltrates on HRCT findings, (3) a decrease in arterial blood oxygen tension (PaO 2 10mmHg or more), but excluding obvious respiratory infection, pneumothorax, malignant tumor, pulmonary embolism, and heart failure." Therefore, the patient in the present disclosure may not only have dyspnea, but may be a patient who is exhibiting increased dyspnea or a progressive dyspnea symptom. Furthermore, in addition to the above-mentioned dyspnea symptoms, the patient in the present disclosure may have honeycomb lungs and newly developed ground-glass opacities and / or infiltrative shadows by HRCT (high-resolution computed tomography) within one month, and a significant decrease in arterial blood oxygen tension (PaO 2 The PaO 2 is the PaO measured under the same oxygen dose. 2 means...

[0016] Pulmonary fibrosis, as is well known to those skilled in the art, is a condition in which excessive fibrous connective tissue is formed in the pulmonary interstitium. As fibrosis progresses, numerous holes (small air spaces) called honeycomb lungs can be identified by CT scans, etc.

[0017] A sample means a material for medical testing that is separated from a patient's body. In the past, there was a lack of basic knowledge about whether it was possible to predict the risk of progression of pulmonary fibrosis in an interstitial pneumonia patient with acute exacerbation by performing some measurement on the sample, not on the patient himself. The embodiment of the present disclosure is based on the discovery of a method for collecting data for making a judgment about the risk. Specifically, a measurement value of the HO-1 concentration in a patient's sample can provide such data. The HO-1 concentration here refers to the HO-1 concentration of a sample taken from a patient at a certain time point in a case where it is intended to determine whether the degree of pulmonary fibrosis (more specifically, the degree of honeycomb lung) will progress in the future (for example, within one month, two months, three months, or six months) in a patient with acute exacerbation of interstitial pneumonia at that time point.

[0018] HO-1 itself is a protein known to those skilled in the art and is a type of enzyme responsible for heme metabolism. HO-1 catalyzes the reaction of decomposing heme into biliverdin, iron, and carbon monoxide, and is known to exhibit anti-inflammatory and antioxidant effects in mammals, including humans. HO-1 is also known as Heat shock protein 32.

[0019] The specimen in the embodiment of the present disclosure may be a blood-derived specimen, and may be whole blood, serum, or plasma. Although the HO-1 concentrations in whole blood, serum, and plasma are correlated with each other, it may be particularly preferable to use serum in terms of quantification accuracy. Obtaining a measurement of the HO-1 concentration in the specimen may include measuring the HO-1 concentration in the specimen by a method known to those skilled in the art, such as, for example, ELISA (Enzyme-Linked Immunosorbent Assay). An example of an optimal ELISA measurement method is described in Hara et al., Canadian Respiratory Journal, Volume 2018, Article ID 9627420. This is called a modified ELISA method, in which PBS (phosphate-buffered saline) containing 1% BSA (bovine serum albumin), 0.05% Tween 20, 0.1 M NaCl, 5 mM EDTA (ethylenediaminetetraacetic acid), and 50 μg / mL mouse IgG is used as the assay buffer for reacting with the detection antibody, and the serum is diluted 1:20 to measure the HO-1 concentration using an anti-HO-1 polyclonal antibody.

[0020] The step of obtaining a measured value of the HO-1 concentration may include measuring the concentration of HO-1 using an antibody or antibody fragment that specifically recognizes HO-1. Measuring the concentration of HO-1 using an antibody or antibody fragment that specifically recognizes HO-1 may more specifically include contacting the antibody or antibody fragment with a sample and measuring the amount of binding by detecting the antibody or antibody fragment bound to HO-1 in the sample. Thus, various methods for measuring the amount of protein based on the specific recognition of an antibody or antibody fragment are known to those skilled in the art. ELISA is one example.

[0021] In the present disclosure, "concentration" refers to the amount of HO-1 present per unit amount of sample, typically expressed as mass or moles of HO-1 per unit volume of sample. However, "concentration" is not necessarily quantified in units of mass or moles, and may also be quantified and displayed as signal intensity (e.g., absorbance) based on the amount of HO-1 present per unit volume, depending on the specific measurement method. Also, concentration is not necessarily quantified as the amount of HO-1 per unit volume of sample, and may be, for example, the amount of HO-1 per unit weight of sample. Mass and weight may be used interchangeably.

[0022] The sample used in the embodiment of the present disclosure is taken from an interstitial pneumonia patient to be subjected to the above-mentioned determination, i.e., is derived from the interstitial pneumonia patient. Thus, the method of the present embodiment can be performed in vitro. A sample can be taken from a human patient by a suitable method known to those skilled in the art. Methods for taking whole blood, serum, or plasma from a human patient are well known to those skilled in the art. Before the step of obtaining a measurement value of the HO-1 concentration, a blood sample can be taken from the interstitial pneumonia patient, and / or a sample taken from the interstitial pneumonia patient can be provided or prepared.

[0023] In the present disclosure, "determining" whether it is A or B includes not only an embodiment in which a dichotomous judgment is made by concluding either A or B, but also an embodiment in which the magnitude of the possibility is analyzed and relatively evaluated, for example, that A is more likely. That is, in the judgment, the measured value of the HO-1 concentration can be used as an index positively correlated with the possibility of pulmonary fibrosis progressing. That is, the measured value of the HO-1 concentration in the sample provides an index that the higher the measured value, the higher the risk of pulmonary fibrosis progressing, and the lower the measured value, the lower the risk of pulmonary fibrosis progressing. In other words, this embodiment provides the use of HO-1 as a biomarker that indicates the possibility of pulmonary fibrosis progressing (possibility can be rephrased as "risk") or evaluates that possibility.

[0024] Furthermore, among multiple acute exacerbation patients, patients with higher HO-1 concentrations can be evaluated as being more likely to develop pulmonary fibrosis than patients with lower HO-1 concentrations. Alternatively, when HO-1 concentrations are measured at multiple time points from the same patient, it can be evaluated that the patient is more likely to develop pulmonary fibrosis at the time point when the HO-1 concentration is higher than at the time point when the HO-1 concentration is lower.

[0025] In one aspect, a method is provided, comprising the steps of: obtaining a measurement of HO-1 concentration in a sample from an interstitial pneumonia patient having acute exacerbation; and determining that the patient is at high risk of developing pulmonary fibrosis if the measurement of HO-1 concentration is equal to or greater than a reference value, and determining that the patient is at low risk of developing pulmonary fibrosis if the measurement of HO-1 concentration is less than the reference value. In the former step, data is collected for determining the risk of developing pulmonary fibrosis in the patient. The explanation of the elements in the above-mentioned embodiment can be applied to this step. The measurement of HO-1 concentration is then compared with a reference value, where an HO-1 concentration measurement equal to or greater than the reference value indicates a high risk of developing pulmonary fibrosis in the patient, and an HO-1 concentration measurement less than the reference value indicates a low risk of developing pulmonary fibrosis in the patient. The method according to these embodiments can also be considered as a method for medical analysis of acute exacerbation of interstitial pneumonia.

[0026] In another aspect, there is provided a method further comprising, after the method of the above embodiment, performing a chest imaging test to reassess pulmonary fibrosis in a patient determined to be at high risk for progression of pulmonary fibrosis, and / or administering a new or increased dose of an antifibrotic drug. The chest imaging test may be a CT scan.

[0027] The reference value can be appropriately set by the practitioner with reference to the present disclosure, and according to the specific type of assay for measuring HO-1 concentration and the specific purpose of carrying out the method of the present embodiment.For example, if a higher reference value is used, the specificity of determining the risk of fibrosis progression of the patient is increased, and as a result, the possibility of misidentifying a non-progressive fibrosis patient as a progressive fibrosis patient is reduced, but at the expense of the ability to correctly determine a true progressive fibrosis patient without overlooking it.If a lower reference value is used, the sensitivity of determining the risk of fibrosis progression of the patient is increased, and therefore the ability to correctly determine a true progressive fibrosis patient without overlooking it is improved, and the possibility of misidentifying a true progressive fibrosis patient as a non-progressive fibrosis patient is reduced, but at the expense of the ability to correctly determine a true non-progressive fibrosis patient as a non-progressive fibrosis patient.

[0028] The reference value may be a value determined in advance. For example, the reference value may be a value determined in advance based on the corresponding measured values ​​of HO-1 concentration of multiple patients (also referred to as reference patients in the present disclosure) confirmed to have the presence or absence of fibrosis progression. It is preferable to use a reference value determined based on the measured values ​​of HO-1 concentration of at least 10 or more, 20 or more, 50 or more, or 100 or more reference patients confirmed to have the presence or absence of fibrosis progression. The multiple reference patients referred to here are all patients with interstitial pneumonia with acute exacerbation, like the patient to be assessed, and the corresponding measured values ​​of HO-1 concentration are the HO-1 concentrations in samples collected from the reference patients. "Corresponding" means that the type of sample and the type of assay for measuring the HO-1 concentration are common. These multiple reference patients may be patients belonging to a common category, such as a specific medical institution, country, region, age range, sex, or any combination thereof. It is preferable that the reference value is determined based on the measured values ​​of HO-1 concentration of multiple reference patients belonging to the same category as the patient to be assessed.

[0029] In one embodiment, the reference value is a value selected from a range lower than the median (or average) of HO-1 concentration measurements of multiple reference patients confirmed to have the presence of fibrosis progression and higher than the median (or average) of HO-1 concentration measurements of multiple reference patients confirmed to have the absence of fibrosis progression. In a specific embodiment, the reference value for HO-1 concentration of a serum sample, measured by, for example, ELISA, may be a value between 15 ng / mL and 50 ng / mL, but this is merely one specific example.

[0030] In the present disclosure, the HO-1 concentration as the reference value may be preferably a concentration determined by the modified ELISA method described in Hara et al., or a concentration determined by another measurement method that is correlated with the modified ELISA method. Even for the same sample, the measured values ​​may differ due to differences in the measurement method (or its sensitivity), but it is within the ordinary skill of a person skilled in the art to determine or compare the reference value by correcting such differences, for example, by obtaining measurements for a standard sample of known amount.

[0031] In the present disclosure, the "step of making a determination" may include printing the determination result (e.g., a determination result indicating that the patient is at high risk of pulmonary fibrosis progression or at low risk of pulmonary fibrosis progression) on a solid medium and / or displaying it on an electronic display device. The solid medium may be, for example, paper, a resin film, etc. The electronic display device may be, for example, a liquid crystal display, a light emitting diode display, an electroluminescence display, etc.

[0032] The method may include determining that the patient is at high risk of developing pulmonary fibrosis, and the patient needs to be treated with an antifibrotic agent or an antifibrotic agent at an increased dose.Then, the antifibrotic agent can be administered to the patient according to the determination.Examples of antifibrotic agents include, but are not limited to, pirfenidone, nintedanib, and combinations thereof.

[0033] In another aspect, the present disclosure provides a kit for carrying out the method according to the above-mentioned embodiment. The kit according to one embodiment may include an antibody or antibody fragment that specifically recognizes HO-1. In addition, the kit may include instructions for making a determination according to the method according to the above-mentioned embodiment. The instructions may be instructions and may be package inserts that explain that the determination is made according to the following criteria: if the measured value of the HO-1 concentration in a sample from an interstitial pneumonia patient with acute exacerbation is equal to or greater than a reference value, the patient is determined to have a high risk of developing pulmonary fibrosis, and if the measured value is less than the reference value, the patient is determined to have a low risk of developing pulmonary fibrosis. The instructions explain that the measured value of the HO-1 concentration obtained from a sample from an interstitial pneumonia patient with acute exacerbation can be interpreted as data for determining the risk of developing pulmonary fibrosis in the patient. The instructions may further include one or more of the specific items described above for the embodiment of the method, such as the reference value.

[0034] The kit may be, for example, an ELISA kit, in which case the kit may include, in addition to the above-mentioned antibody or antibody fragment(s), any one or more of an assay buffer, an assay plate, a label capable of binding to any of the above-mentioned antibodies or antibody fragments (e.g. a label conjugated to a secondary antibody), or a substance that generates a signal from the label.

[0035] Examples of the label include enzymes such as alkaline phosphatase and peroxidase. Examples of substances that generate signals from the label include substrates for the above enzymes. Substrates for alkaline phosphatase include, for example, 9-[(phenyloxy)(phosphoryloxy)methylidene]-10-methylacridan·disodium salt, 9-[(4-chlorophenylthio)(phosphoryloxy)methylidene]-10-methylacridan·disodium salt (Lumigen TMAPS-5) and the like, and examples of substrates for peroxidase include tetramethylbenzidine, o-phenylenediamine, etc. These substrates can generate detectable signals such as color development, luminescence, or fluorescence of a specific wavelength in the presence of the corresponding enzyme.

[0036] The label may be directly bound to the antibody (e.g., anti-HO-1 antibody or secondary antibody) or may not be directly bound to the antibody. When the label is not directly bound to the antibody, the label can be indirectly bound to the antibody, for example, in the reaction solution, via a pair of affinity substances. An example of such a pair of affinity substances is a combination of biotin and streptavidin. Specifically, for example, an antibody bound to biotin can be combined with an enzyme bound to streptavidin.

[0037] The instructions are typically provided in the form of printed paper or other sheet-like material, but may also be provided in the form of a non-transitory computer-readable recording medium having the instruction data recorded thereon. The sheet-like material may form the container of the kit. EXAMPLES

[0038] Specific embodiments will be described below with reference to examples, but these are provided for illustrative purposes and the present invention is not limited to these examples.

[0039] [Research methods and materials] Untreated patients hospitalized with newly diagnosed acute exacerbation (AE) of interstitial pneumonia were included in the study. The diagnosis of AE was based on criteria established in the art and described herein.

[0040] High-resolution computed tomography (HRCT) data were independently reviewed by three experienced pulmonologists and evaluated using the semiquantitative scoring method described by Ooi et al., Acta Radiol. 2003; 44: 258-264. Specifically, lung lobes were divided into six regions (three regions in each lung), and lung abnormalities on HRCT images were classified as ground-glass opacity (GGO), consolidation (a shadow in which air in the alveoli is lost and no blood vessels can be recognized inside), reticular fibrosis, and honeycombing, and scored based on the area percentage (%) of lesions in each of the six lung regions (0%: 0 points, 1-25%: 1 point, 26-50%: 2 points, 51-75%: 3 points, 76% or more: 4 points). A global score was calculated by adding up the scores for each abnormality in all lung regions. HRCT scans were performed at the time of diagnosis of the AE, i.e., baseline, and at follow-up. Forty-one patients had a follow-up HRCT scan. The median time between baseline and follow-up was 36 days. Patients were grouped based on whether they had an increase in the global score (i.e., increasing abnormalities) for each of the above abnormalities between the two time points.

[0041] Serum HO-1 levels were measured in patients at the time of AE diagnosis using the IMMUNOSET HO-1 (human) ELISA development set (Enzo, Farmingdale, NY, USA). Details of HO-1 measurement by ELISA are described in Hara et al., supra. Other blood markers were also measured at the same time as HO-1 measurement, including surfactant protein-D (SP-D) (normal <110 ng / mL) and Krebs von den Lungen-6 (KL-6) (normal <500 U / mL).

[0042] Data were statistically analyzed using JMP12 (SAS Institute, Cary, NC) and R software, version 4.2.1 (The R Foundation for Statistical Computing, Vienna, Austria) and expressed as medians (25th–75th percentiles). Between-group comparisons were performed using chi-square and Wilcoxon rank-sum tests. Nonparametric Spearman's rank correlation coefficients were calculated to assess correlations between serum HO-1 levels and other clinical parameters. A P value of less than 0.05 was considered significant.

[0043] [Results and Discussion] Figure 1 shows the distribution of serum HO-1 concentrations at the time of diagnosis of acute exacerbation in patients divided into those who had (+) or did not have (-) an increase or worsening of honeycomb lung (a) or GGO (b) between the time of diagnosis of acute exacerbation of interstitial pneumonia and the time of follow-up. It can be seen that patients who had a progression of fibrosis manifested as an increase in honeycomb lung had significantly higher HO-1 levels at the time of diagnosis of acute exacerbation (Figure 1a). In other words, the presence or absence of subsequent progression of fibrosis can be predicted based on the HO-1 concentration measurements in samples taken at the time of diagnosis or onset of acute exacerbation. On the other hand, there was no significant difference in HO-1 levels at the time of diagnosis of acute exacerbation between the group with and without an increase in GGO (Figure 1b). There was poor correlation between HO-1 levels and baseline honeycomb lung score, KL-6 levels, etc. at the time of diagnosis of acute exacerbation (not shown). Therefore, HO-1 appears to be a marker reflecting the potential for future fibrosis progression rather than the degree of fibrosis at that time.

[0044] Figure 2 shows the same plots of serum levels of SP-D (a) or KL-6 (b) as in Figure 1a, but with the difference that the serum levels of SP-D (a) or KL-6 (b) at the time of diagnosis of acute exacerbation are not significantly correlated with the presence or absence of honeycombing (P values ​​0.946 and 0.118, respectively) at the time of diagnosis of acute exacerbation. SP-D and KL-6 are biomarkers widely used in clinical settings to evaluate disease activity in interstitial pneumonia. Among them, KL-6 is known to correlate with pulmonary fibrosis. However, the data in Figure 2b suggest that KL-6 is not useful as a marker for predicting whether future fibrosis progression will occur at the time of diagnosis of acute exacerbation.

Claims

1. A method for collecting data for determining the risk of progression of pulmonary fibrosis in a patient with interstitial pneumonia having an acute exacerbation, the method comprising a step of obtaining a measurement of heme oxygenase-1 (hereinafter referred to as HO-1) in a sample from the patient.

2. Obtaining a measurement of heme oxygenase-1 (hereinafter referred to as HO-1) concentration in a sample from an interstitial pneumonia patient having an acute exacerbation; and A step of making a judgment according to the following criteria: if the measured value of the HO-1 concentration is equal to or greater than a reference value, the patient is judged to have a high risk of developing pulmonary fibrosis; if the measured value is less than the reference value, the patient is judged to have a low risk of developing pulmonary fibrosis. A method comprising:

3. The method of claim 1 or 2, wherein the sample is whole blood, serum, or plasma.

4. (a) an antibody or antibody fragment that specifically recognizes HO-1; (b) An instruction manual explaining that the judgment is made according to the following criteria: if the measured value of the HO-1 concentration in a sample of a patient with interstitial pneumonia having acute exacerbation is equal to or greater than a reference value, the patient is judged to have a high risk of developing pulmonary fibrosis; if the measured value is less than the reference value, the patient is judged to have a low risk of developing pulmonary fibrosis. A kit for carrying out the method according to claim 1 or 2, comprising:

Images