Interstitial pneumonia treatment device, interstitial pneumonia treatment system, interstitial pneumonia treatment method, method for assisting in detection of symptoms of interstitial pneumonia, and use of device for treatment of interstitial pneumonia

Abstract

Provided are: a non-invasive, simple, and compact interstitial pneumonia treatment device having a therapeutic effect on interstitial pneumonia; an interstitial pneumonia treatment system using the same; an interstitial pneumonia treatment method; a method for assisting in the detection of symptoms of interstitial pneumonia; and use of the device for treating interstitial pneumonia. The present invention pertains to: an interstitial pneumonia treatment device for reducing the symptoms of interstitial pneumonia of a subject suffering from interstitial pneumonia, the device comprising an auricular nerve stimulation means that is installed so as to be disposed at two or more different sites of the auricle of the subject and includes at least two electrodes configured so as to be capable of electrical stimulation at the two or more sites. Also provided are an interstitial pneumonia treatment system, an interstitial pneumonia treatment method, a method for assisting in the detection of symptoms of interstitial pneumonia, and use of the device for the treatment of interstitial pneumonia.

Description

Interstitial pneumonia treatment device, interstitial pneumonia treatment system, interstitial pneumonia treatment method, method for assisting in the detection of symptoms of interstitial pneumonia, and use of the device for the treatment of interstitial pneumonia

[0001] The present invention relates to an interstitial pneumonia treatment device for reducing interstitial pneumonia symptoms in a subject suffering from interstitial pneumonia, an interstitial pneumonia treatment system including the same, a method for treating interstitial pneumonia using the same, a method for assisting in the detection of interstitial pneumonia symptoms, and the use of the device for treating interstitial pneumonia. This application claims priority to U.S. Patent Application No. 63 / 550,043, provisionally filed in the U.S. on February 6, 2024, the contents of which are incorporated herein by reference.

[0002] Interstitial pneumonia is a general term for diseases that manifest as bilateral diffuse shadows on chest X-rays or CT scans, with inflammation and fibrotic lesions occurring in the interstitial space of the lungs. Interstitial pneumonia has a wide range of causes, but those with unknown causes are collectively referred to as idiopathic interstitial pneumonia. Among idiopathic interstitial pneumonias, idiopathic pulmonary fibrosis (IPF) accounts for 80-90% of cases. Its prevalence in Japan is 0.01%, but including undiagnosed patients, it is said to account for approximately 0.1% of the population. Because lung fibrosis progresses gradually in IPF, the prognosis is relatively poor, with the average survival time from initial diagnosis estimated at approximately 61-69 months.

[0003] In recent years, it has been pointed out that there are also interstitial pneumonias other than IPF that have a poor prognosis, such as progressive fibrosing interstitial lung diseases (PF-ILD). These pathologies cause restrictive ventilatory disorders, and as the condition progresses, an imbalance between ventilation and blood flow occurs, leading to respiratory failure even at rest. Furthermore, even in patients who have no symptoms at rest, significant hypoxemia manifests during exercise, significantly affecting ADL and prognosis.

[0004] On the other hand, low-frequency stimulation therapy, which can perform nerve stimulation non-invasively, is currently covered by insurance for painful conditions and is mainly used in the field of orthopedics to treat rheumatoid arthritis, osteoarthritis, etc., and is attracting attention for its ability to reduce pain and improve patients' quality of life. For example, low-frequency stimulation therapy in the field of respiratory diseases is expected to be a means of preventing disuse in patients with significantly reduced exercise tolerance due to respiratory failure.

[0005] In addition to IPF, there have been studies using neuromuscular electrical stimulation using low-frequency stimulators as an alternative to rehabilitation in patients with chronic obstructive pulmonary disease and COVID-19, with some reports of improved exercise tolerance. Regarding the relationship between breathing and nerve stimulation, it has been reported that in healthy individuals, hypoxia stimulates arterial chemoreceptors, resulting in increased sympathetic nervous activity. Furthermore, significant sympathetic nervous activation has also been reported in patients with hypoxemia due to chronic respiratory disease, suggesting that suppressing sympathetic nerves and stimulating parasympathetic nerves may improve complications and prognosis. Numerous randomized controlled trials have demonstrated the efficacy, respiratory function improvement, and safety of low-frequency therapy in chronic obstructive pulmonary disease, a chronic respiratory disease. However, most of these studies are limited to examining physical effects and are limited to research.

[0006] Low-frequency stimulation therapy originated in the acupuncture and moxibustion treatment of traditional Chinese medicine. Traditional Chinese medicine has a long history of use as a treatment for a variety of illnesses and conditions. In particular, acupuncture treatments include not only the actual insertion of needles into the body, but also non-invasive pressure methods using blunt needles, electroacupuncture therapy, which applies a weak electric current to the needles, and the aforementioned low-frequency therapy device, which applies a pulsed electric current through an adhesive pad. These treatments are covered by insurance and used in medical practice.

[0007] However, much remains unclear about the molecular mechanisms underlying these treatments' therapeutic effects on specific diseases and pathologies. Auricular acupuncture, a type of acupuncture, has been used as a form of acupuncture therapy, but it was systematized in Europe and the United States rather than China. The pioneer of auricular acupuncture was Dr. Paul Nogier of France, who completed a model of the ear as a body part replica around 1953. In particular, the auricular branches of the vagus nerve are abundant in the tragus and concha regions. In Japan, there are papers documenting the use of auricular acupuncture to treat epilepsy rather than implantable vagus nerve stimulation, which is approved for epilepsy treatment. It is believed that some of the therapeutic effects of auricular acupuncture are due to vagus nerve stimulation. Furthermore, artificial stimulation of the vagus nerve was rediscovered by Dr. Kevin Tracy as an inflammatory reflex, and it was reported that vagal-sympathetic nerve crosstalk suppresses the immune response systemically. Clinical studies have shown favorable results in its application to rheumatoid arthritis and inflammatory bowel disease.

[0008] Furthermore, the co-researchers of this study have also reported that the activation of specific neural circuits via pain, in the presence of autoreactive T cells in the blood, can be converted into an inflammatory response mediated by IL-6 amplifiers at specific vascular sites, which can cause inflammatory diseases.

[0009] As an example of a system for stimulating nerves in the ear, Patent Document 1 discloses an auricular nerve stimulation device that is wearable by a user and configured to stimulate the auricular branch of the vagus nerve (ABVN) in the user's ear, the device comprising at least two electrodes designed to be placed in the auricle and the cavity of the concha, respectively, and the electrodes electrically stimulate the nerve branches of the auricle and the cavity of the concha, the device being configured as a wireless earphone having an ear mold and a miniaturized faceplate, the electrodes being placed in the ear mold, the ear mold being customized to fit the anatomical structure of the user's ear so that the auricle electrode is a large-area electrode that covers almost the entire surface of the concha of the user's ear, a photoplethysmography or biosensor having a miniaturized configuration being placed in the ear mold, and the miniaturized faceplate being configured to be in-the-ear (ITE) configuration and behind-the-ear (B) configuration. The present invention discloses an auricular nerve stimulation device and system incorporating all elements of an electronic circuit constructed on a printed circuit board (PCB) that combines rigid and flexible elements, in both a TE (flexible, flexible, and flexible) configuration. The present invention also discloses a method of operating an auricular nerve stimulation system, in which the therapeutic stimulation conditions are used to treat at least one of epilepsy, chronic stress, pre-diabetes, obesity, depression, chronic tinnitus, migraine, rehabilitation after ischemic stroke, alleviation of chronic inflammation, muscle regeneration and growth, ventricular arrhythmia, respiratory symptoms associated with COVID-19, and enhancement of associative memory to assist patients with Alzheimer's disease and other dementia types. This technology seeks to provide a wearable, connected auricular nerve stimulation device that stimulates the nerve branches of the navicular and cavum conchae with higher efficiency, is comfortable to wear, and can be personalized to accommodate each user and their needs.

[0010] Special Publication No. 2023-503291

[0011] Patent Document 1 envisions the treatment of diseases that may be related to nerves, such as epilepsy or stress, but does not mention interstitial pneumonia, nor does it disclose any effects on specific diseases or configurations suitable for those diseases.

[0012] Based on the above background, the inventors hypothesized that pain suppression and vagus nerve stimulation by low-frequency stimulation therapy may contribute to inflammation control, and in the field of respiratory medicine, this could lead to the suppression of inflammation in interstitial pneumonia, and focused on the use of low-frequency stimulation to treat interstitial pneumonia. Therefore, they conducted further research on patients with interstitial pneumonia who were symptomatic despite adequate treatment due to the progression of respiratory failure, and administered low-frequency therapy to alleviate symptoms. They also verified its effectiveness in improving symptoms, safety, and the occurrence of adverse events, and attempted to evaluate its effect on inflammation control, including its impact on the immune system.

[0013] The present invention has been made in view of the above background, and its purpose is to provide a non-invasive, simple, and compact interstitial pneumonia treatment device that has a therapeutic effect on interstitial pneumonia, an interstitial pneumonia treatment system that uses the same, an interstitial pneumonia treatment method, and a method for assisting in the detection of interstitial pneumonia symptoms, and use of the device for the treatment of interstitial pneumonia.

[0014] The present invention includes the following aspects: [1] An interstitial pneumonia treatment device for reducing the symptoms of interstitial pneumonia in a subject suffering from interstitial pneumonia, comprising: an auricular nerve stimulation means that is installed to be placed at two or more different sites on the auricle of the subject and that includes at least two electrodes configured to be able to electrically stimulate the two or more sites. [2] The interstitial pneumonia treatment device according to [1], wherein the auricular nerve stimulation means is designed to be placed in the auricular navicular cavity and the cavity of the concha, respectively, and includes at least two electrodes configured to be able to electrically stimulate the nerve branches of the auricular navicular cavity and the cavity of the concha. [3] The interstitial pneumonia treatment device according to [1] or [2], comprising control means that is capable of controlling electrical stimulation conditions, including the number of times, duration, current, or frequency of application of the electrical stimulation, and the control means is configured to store and select the electrical stimulation conditions for each subject. [4] The interstitial pneumonia treatment device according to [3], wherein the electrical stimulation conditions are a current of 1 to 20 mA and a frequency of 2 to 100 Hz. [5] An interstitial pneumonia treatment system comprising: the interstitial pneumonia treatment device according to any one of [1] to [4]; and pneumonia symptom detection means for detecting the degree of interstitial pneumonia symptoms. [6] The interstitial pneumonia treatment system according to [5], wherein the pneumonia symptom detection means comprises detection means for at least one of a fibrosis marker, an inflammatory marker, K-BILD, Borg, or CV-RR. [7] An interstitial pneumonia treatment method for reducing interstitial pneumonia symptoms in a subject suffering from interstitial pneumonia, comprising an auricular nerve stimulation step of applying electrical stimulation to two or more different sites on the subject's auricle. [8] The method for treating interstitial pneumonia according to [7], wherein the method uses an interstitial pneumonia treatment device equipped with an auricular nerve stimulation means including at least two electrodes designed to apply electrical stimulation to the interior of the concha navicularis and the cavity of the concha of the subject, and configured to enable electrical stimulation of the nerve branches of the concha navicularis and the cavity of the concha. [9] The method for treating interstitial pneumonia according to [7] or [8], wherein the auricular nerve stimulation step selects electrical stimulation conditions, including the number of times, duration, current, or frequency of electrical stimulation, for each subject.

[10] The method for treating interstitial pneumonia according to any one of [7] to [9], wherein the electrical stimulation conditions are a current of 1 to 20 mA and a frequency of 2 to 100 Hz.

[11] The method for treating interstitial pneumonia according to any one of [7] to

[10] , further comprising a pneumonia symptom detection step of detecting the severity of interstitial pneumonia symptoms.

[12] The method for treating interstitial pneumonia according to

[11] , wherein the pneumonia symptom detection step comprises a step of detecting at least one of a fibrosis marker, an inflammatory marker, K-BILD, Borg, or CV-RR.

[13] A method for assisting in the detection of interstitial pneumonia symptoms in a subject, wherein the subject has undergone electrical stimulation at two or more different sites on the subject's auricle, and wherein a marker of the interstitial pneumonia symptom in the subject is detected.

[14] The method for assisting in the detection of symptoms of interstitial pneumonia according to

[13] , wherein the marker for the symptom of interstitial pneumonia is a fibrosis marker, an inflammatory marker, K-BILD, Borg, or CV-RR of the subject.

[15] Use of a device for treating interstitial pneumonia, the device comprising auricular nerve stimulation means designed to be placed at two or more different sites on the auricle of a subject suffering from interstitial pneumonia and including at least two electrodes configured to enable electrical stimulation to the two or more sites.

[16] Use of the device for treating interstitial pneumonia according to

[15] , the device comprising auricular nerve stimulation means designed to be placed within the auricle and the cavity of the concha, respectively, and including at least two electrodes configured to enable electrical stimulation to the nerve branches of the auricle and the cavity of the concha.

[17] The device for use in treating interstitial pneumonia according to

[15] or

[16] , comprising a control means capable of controlling electrical stimulation conditions including the number of times, duration, current, or frequency of application of the electrical stimulation, and the control means is configured to store and select the electrical stimulation conditions for each subject.

[18] The device for use in treating interstitial pneumonia according to

[17] , wherein the electrical stimulation conditions are a current of 1 to 20 mA and a frequency of 2 to 100 Hz.

[0015] The present invention provides a non-invasive, simple, and compact interstitial pneumonia treatment device that has a therapeutic effect on interstitial pneumonia, an interstitial pneumonia treatment system using the same, a method for treating interstitial pneumonia, and a method for assisting in the detection of symptoms of interstitial pneumonia and use of the device for treating interstitial pneumonia.

[0016] FIG. 1 is a schematic diagram showing one aspect of the interstitial pneumonia treatment device of this embodiment. FIG. 2 is a schematic diagram showing another aspect of the interstitial pneumonia treatment device of this embodiment. FIG. 3 is a schematic diagram showing yet another aspect of the interstitial pneumonia treatment device of this embodiment. FIG. 4 is a schematic diagram showing the evaluation flow of this embodiment. FIG. 5 is a photograph showing an example of the interstitial pneumonia treatment device used in this embodiment. FIG. 6 is a photograph showing a current-carrying member included in the interstitial pneumonia treatment device used in this embodiment. FIG. 7 is a photograph showing a screen of the control means of the interstitial pneumonia treatment device used in this embodiment. FIG. 8 is a photograph showing the interstitial pneumonia treatment device used in this embodiment being held on a subject.

[0017] Hereinafter, the interstitial pneumonia treatment device, interstitial pneumonia treatment system, interstitial pneumonia treatment method, and use of the method and device for assisting in the detection of interstitial pneumonia symptoms according to the present invention for the treatment of interstitial pneumonia will be described with reference to exemplary embodiments, although the present invention is not limited to the following exemplary embodiments.

[0018] [Interstitial pneumonia treatment device] The interstitial pneumonia treatment device of this embodiment is an interstitial pneumonia treatment device for reducing the symptoms of interstitial pneumonia in a subject suffering from interstitial pneumonia, and is equipped with auricular nerve stimulation means that is installed so as to be placed in two or more different parts of the auricle of the subject and includes at least two electrodes configured to be able to electrically stimulate the two or more parts.

[0019] Interstitial pneumonia broadly refers to diseases in which inflammation and fibrosis occur in the interstitial space of the lungs. Patients with various types of interstitial pneumonia can be included, but idiopathic interstitial pneumonia, which is difficult to diagnose and treat, is more preferred, and idiopathic pulmonary fibrosis is even more preferred. Subjects with interstitial pneumonia broadly include not only patients diagnosed with interstitial pneumonia, but also subjects suspected of having interstitial pneumonia.

[0020] Reducing the symptoms of interstitial pneumonia refers to preventing symptoms in subjects who do not have clear or only mild symptoms, and also refers to preventing recurrence of interstitial pneumonia after it has been cured.

[0021] The two or more different regions of the subject's auricle may be any two or more regions of the auricle. For example, they may be the front and back of a region with the same name (e.g., the front and back of the earlobe or the helix), or they may be different regions (e.g., the interior of the concha navicularis and the cavity of the concha). It is also preferable that the two or more different regions of the auricle are configured to allow electrical stimulation of nerve branches in the auricle.

[0022] The interstitial pneumonia treatment device of this embodiment preferably includes a holding member that allows the electrodes to be placed on the auricle. A plurality of holding members may be provided for each electrode, or a single holding member may be used to place a plurality of electrodes.

[0023] 1 is a schematic diagram showing one embodiment of the interstitial pneumonia treatment device according to the present embodiment. The interstitial pneumonia treatment device 1A includes a holding member 2A, an electrode, and an electric current-carrying member 3A including a mechanism for applying electric current to the electrode.

[0024] The holding member 2A is a clip or the like that can clamp any part of the auricle. In the example shown in the figure, it clamps the front and back of the earlobe of the subject P, but the clip shown in the figure can clamp the front and back of any part of the auricle (such as the ear shaft, auricle tubercle, or earlobe). Opposing holding portions of the clip of the holding member 2A each include an electrode and are connected to the current-carrying member 3A. In this embodiment, the two or more different parts of the auricle of the subject P are the front and back of the part of the auricle that is clamped by the opposing holding portions of the clip of the holding member 2A (the earlobe in the example shown in the figure), and the holding portions press and position electrodes against the respective parts of the auricle. These electrode parts serve as auricular nerve stimulation means that can apply electrical stimulation to each of the parts.

[0025] The current-carrying member 3A is connected to a control means (not shown) that supplies and controls an external power source. The control means is configured to control the electrical stimulation conditions, including the number of times, duration, current, or frequency, to which the electrical stimulation is applied. The control means is configured to store and select the electrical stimulation conditions for each subject. Specifically, the control means includes a storage device that stores the electrical stimulation conditions and allows selection when applying electrical stimulation.

[0026] The electrical stimulation conditions are preferably a current of 1 to 20 mA and a frequency of 2 to 100 Hz, which are suitable for reducing the symptoms of interstitial pneumonia in a subject.

[0027] (Auricle Holding Mode) Furthermore, it is also preferable that the interstitial pneumonia treatment device of this embodiment is equipped with an auricle nerve stimulation means that is designed to be placed inside the concha navicularis and the cavity of the concha of the subject, and includes at least two electrodes configured to enable electrical stimulation of the nerve branches of the concha navicularis and the cavity of the concha.

[0028] An example of such an interstitial pneumonia treatment device is the auricular nerve stimulation device described in Patent Document 1.

[0029] FIG. 2 is a schematic diagram illustrating another embodiment of the interstitial pneumonia treatment device according to the present embodiment. The interstitial pneumonia treatment device 1B includes a holding member 2B. In this embodiment, the holding member 2B is configured to be held in the ear by being shaped to fit a portion of the auricle of the subject P. For example, the holding member 2B may have a portion curved along the base of the helix or a portion that fits into the cavity of the auricle, allowing it to be held in the ear at these portions. In the example shown in the figure, the holding member 2B is in the shape of a curved rod, and has a portion curved along the base of the helix and a portion that fits into the cavity of the concha navicularis and the cavity of the concha of the subject P, respectively. The portion curved along the base of the helix may be made of a deformable material and may be deformed along the base of the helix when held in the auricle.

[0030] In the illustrated example, electrodes are provided on the holding member 2B at the locations within the concha cavity and the cavity of the concha that contact the auricle. The electrode positions are selected to enable electrical stimulation of the nerve branches between the concha and the cavity of the concha, thereby forming an auricular nerve stimulation means. The shape of the holding member 2B may be designed to be suitable for use by an unspecified subject P, or may be designed to fit the body of a specific individual subject P (the shape and size of the auricle). The interstitial pneumonia treatment device 1B is connected to an external power supply and control component via an electrically conductive component, but this is not shown here. Other configurations may be similar to those of the clip holding mode.

[0031] As a variation of this embodiment, the holding member 2B may simply have a structure that can fit into any part of the auricle cavity. For example, it may have the same shape as the part of a conventional earphone or the like that is held in the ear.

[0032] (Adhesive Retention Mode) Figure 3 is a schematic diagram showing another mode of the interstitial pneumonia treatment device of this embodiment. In this mode, two holding members 2C of the interstitial pneumonia treatment device 1C are each provided so as to cover a portion of the electrode connected to the current-carrying member 3C. The holding members 2C are configured to be able to be held on the auricles of the subject P by applying an adhesive agent to their surfaces that can adhere to both the constituent material of the holding members 2C and the skin of the subject P. By holding the holding members 2C on the auricles of the subject P, the electrodes are configured to be positioned at two or more different sites on the auricles of the subject P.

[0033] The adhesive may be any component capable of adhering, and may have adhesive properties. For example, it may be any of various adhesives or pressure-sensitive adhesives. Alternatively, a portion of the holding member 2C may be in the form of double-sided tape, and the portion where the double-sided tape does not adhere may be the adhesive. In the example shown in the figure, a hydrogel pressure-sensitive adhesive is used as the adhesive.

[0034] The holding members 2C are placed at two or more different locations on the subject's auricle. In the example shown in the figure, the holding members 2C and electrodes are placed in the auricle of the subject's concha and the cavity of the concha, respectively, so that electrical stimulation can be applied to the nerve branches of the auricle and the cavity of the concha.

[0035] The interstitial pneumonia treatment device 1C may be partially disposable. For example, the adhesive or a part of the holding member 2C having the adhesive may be configured to be replaced each time the device is removed from the subject P. The other configurations may be the same as those of the clip holding mode.

[0036] As a variation of this embodiment, the holding member may be a patch or the like that can be attached to any part of the auricle. In this case, the patch may have an electrode on the attachment surface side, and may be attached to the auricle while holding the electrode on the auricle. There may be one patch for each electrode, or one patch may have multiple electrodes.

[0037] [Interstitial pneumonia treatment system] The interstitial pneumonia treatment system of this embodiment includes an interstitial pneumonia treatment device and pneumonia symptom detection means for detecting the severity of interstitial pneumonia symptoms.

[0038] The pneumonia symptom detection means can be any means capable of detecting pneumonia symptoms. For example, a device, a composition, etc. can be used. In one embodiment, the pneumonia symptom detection means may include a composition, etc., containing a component related to pneumonia symptoms. These means are preferably means for detecting at least one of a fibrosis marker, an inflammatory marker, K-BILD, Borg, or CV-RR, and more preferably two or more of the above.

[0039] [Method for treating interstitial pneumonia] The method for treating interstitial pneumonia of this embodiment is a method for reducing the symptoms of interstitial pneumonia in a subject suffering from interstitial pneumonia, and includes an auricular nerve stimulation step of applying electrical stimulation to two or more different parts of the subject's auricle.

[0040] The interstitial pneumonia treatment method of this embodiment may use any of the interstitial pneumonia treatment devices. For example, an interstitial pneumonia treatment device may be used that includes an auricular nerve stimulation means that is installed so as to be placed at two or more different sites on the subject's auricle and that includes at least two electrodes configured to be able to electrically stimulate the two or more sites. Alternatively, an interstitial pneumonia treatment device may be used that includes an auricular nerve stimulation means that is designed to apply electrical stimulation to the interior of the subject's concha and cavity of the concha and that includes at least two electrodes configured to be able to electrically stimulate the nerve branches of the concha and cavity of the concha.

[0041] The auricular nerve stimulation step may involve selecting electrical stimulation conditions, including the number of times, duration, current, or frequency, of electrical stimulation for each subject. This step may involve using an interstitial pneumonia treatment device equipped with a control means capable of controlling the electrical stimulation conditions, including the number of times, duration, current, or frequency of electrical stimulation. The electrical stimulation conditions may include a current of 1 to 20 mA and a frequency of 2 to 100 Hz.

[0042] The interstitial pneumonia treatment method of this embodiment may further include a pneumonia symptom detection step of detecting the severity of interstitial pneumonia symptoms. The pneumonia symptom detection step may include a step of detecting at least one of a fibrosis marker, an inflammatory marker, K-BILD, Borg, or CV-RR. These configurations can also be appropriately selected from the configurations of the interstitial pneumonia treatment device described above.

[0043] [Use of device for treating interstitial pneumonia] The use of the device for treating interstitial pneumonia in this embodiment is the use of a device for treating interstitial pneumonia, which is equipped with an auricular nerve stimulation means including at least two electrodes designed to be placed at two or more different sites on the auricle of a subject suffering from interstitial pneumonia and configured to enable electrical stimulation to the two or more sites.

[0044] The device may be equipped with an auricular nerve stimulation means including at least two electrodes designed to be placed in the concha navicularis and the cavity of the concha, respectively, and configured to provide electrical stimulation to the nerve branches of the concha navicularis and the cavity of the concha. The device may also be equipped with a control means capable of controlling the electrical stimulation conditions, including the number of times, duration, current, or frequency of the electrical stimulation, and the control means may be configured to store and select the electrical stimulation conditions for each subject. The electrical stimulation conditions for the device may be a current of 1 to 20 mA and a frequency of 2 to 100 Hz. The device configuration may also be appropriately selected from the configurations for treating interstitial pneumonia described above.

[0045] [Effects of this embodiment] This embodiment provides a non-invasive, simple, and compact interstitial pneumonia treatment device that has a therapeutic effect on interstitial pneumonia, an interstitial pneumonia treatment system using the same, an interstitial pneumonia treatment method, and a method for assisting in the detection of interstitial pneumonia symptoms, and use of the device for the treatment of interstitial pneumonia.

[0046] The present inventors have performed treatment using a non-invasive low-frequency therapy device, which is covered by insurance for painful diseases, for the purpose of symptom relief in patients with clinically diagnosed interstitial pneumonia who are experiencing dyspnea despite adequate treatment due to the progression of respiratory failure, and have evaluated the effectiveness in improving respiratory symptoms, safety, and occurrence of adverse events. As a result, as shown in the Examples, the applicability of low-frequency therapy to interstitial pneumonia was evaluated, and the possibility of clinical application was demonstrated.

[0047] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0048] [Test Example 1] Subjects who showed signs of interstitial pneumonia according to the test condition selection criteria described below and who provided a certain level of consent were treated using the interstitial pneumonia treatment device of this embodiment, and the effects were evaluated. Figure 4 is a schematic diagram showing the evaluation flow of this example.

[0049] Fig. 5 is a photograph showing an example of an interstitial pneumonia treatment device used in this example. The interstitial pneumonia treatment device used was one with a configuration similar to the clip-shaped interstitial pneumonia treatment device 1A described above. (a) is a front view of the clip's holding member, viewed from the holding portion facing the clip. (b) is a side view of the clip's holding member. (c) is a perspective view of the clip in an open state. Fig. 6 is a photograph showing a current-carrying member included in the interstitial pneumonia treatment device used in this example. The figure shows the auricle stimulation means equipped with electrodes of the interstitial pneumonia treatment device, the current-carrying member, and the control means connected to them and equipped with a power source for supplying power.

[0050] 7A and 7B are photographs showing the screen of the control means of the interstitial pneumonia treatment device used in this example, both of which display information on the electrical stimulation being applied.

[0051] 8 is a photograph showing the interstitial pneumonia treatment device used in this example being held on a subject. In this example, the device is held by pinching the front and back of the earlobe of the subject's auricle with the clip-shaped holding parts of the holding member.

[0052] The subjects received electrical stimulation once a day for one hour. Stimulation was performed at 1.5 mA, 25 Hz, and 250 μsec as standard. The treatment using this interstitial pneumonia treatment device is shown in Table 1.

[0053]

[0054] The effects of treatment with the interstitial pneumonia treatment device on two subjects are shown in Tables 2 and 3. In the tables, KL-6: fibrosis marker CRP: inflammation marker K-BILD: interstitial pneumonia stress questionnaire. The higher the better Borg: perceived difficulty of exercise. The lower the better CV-RR: how much vagal reflex (decrease in heart rate) can be induced with deep inspiration. A value of 2% or less indicates autonomic dysfunction.

[0055]

[0056]

[0057] As shown in the table, in all subjects, the therapeutic effect of interstitial pneumonia was observed at the first visit compared to the pre-treatment values ​​(baseline). That is, improvements were also observed in interstitial pneumonia markers related to fibrosis and inflammation, deep breathing ability, and evaluations related to patient QOL such as stress and kinesthetic sensation. These results demonstrate that the interstitial pneumonia treatment device of this embodiment and the interstitial pneumonia treatment method using the same are effective in treating interstitial pneumonia.

[0058] [Reference: Study Conditions] The conditions for the study conducted are listed below. (Research Subjects and Eligibility Criteria) (1) Study subjects were deemed eligible if they (2) met all of the inclusion criteria and (3) did not fall under any of the exclusion criteria. (1) Study Subjects: Patients with interstitial pneumonia who were outpatients or hospitalized at Hokkaido University Hospital (Respiratory Medicine Department) between the date of permission and January 31, 2028. (2) Inclusion Criteria: Patients who met all of the following criteria were eligible: Those aged 18 years or older at the time of consent acquisition, those who have been clinically diagnosed with interstitial pneumonia through chest imaging or respiratory function testing, those with a resting arterial oxygen partial pressure of less than 70 Torr or less than 80 Torr and an SpO2 of less than 90% during a 6-minute walking test, those with subjective symptoms such as shortness of breath or difficulty breathing, and those who were able to actively understand the informed consent document after receiving a sufficient explanation regarding participation in this study and who voluntarily provided written consent. (3) Exclusion criteria: Patients who meet any of the following criteria will be excluded from the study: those who have developed acute heart failure, myocardial infarction, pulmonary edema, or acute exacerbation of interstitial pneumonia within the past three months, those with a history of progressive brain lesions, those using concomitant vagus nerve stimulation therapy, those with a history of epilepsy, those with a history of severe cardiovascular disease, those with pneumothorax, those with uncontrolled infections, those who are pregnant or breastfeeding, those with skin hypersensitivity or a history of skin symptoms caused by metals, those who have difficulty with oral intake, those with severe renal dysfunction (estimated glomerular filtration rate (eGFR) less than 30 ml / min), those using a cardiac pacemaker or implantable cardioverter defibrillator, and others who the principal investigator or co-investigator deems unsuitable as study participants.

[0059] (Research Methods) (1) Research Type and Design: Multi-institutional collaborative, non-controlled, open-label, exploratory clinical trial. If residual samples are present during normal treatment, these will be used. In other cases, samples will be collected for the purpose of this study. Written consent will be obtained. Eligibility will then be confirmed, and assessments such as physical activity and respiratory function tests will be conducted within an eight-week observation period. Low-frequency treatment will begin, and various clinical indicators will be assessed initially at four weeks, then every 12 weeks thereafter, for a total of 52 weeks. Regarding the observation period, because this is a chronic disease, it will take years to observe changes in exercise tolerance and physical function, and other large-scale intervention studies have also set observation periods of 52 weeks, so this was considered appropriate. (2) Medical equipment and stimulation conditions used in the clinical study: Treatment will be performed using a low-frequency therapy device (JMDN code: 35372000, https: / / www.std.pmda.go.jp / scripts / stdDB / JMDN / stdDB_jmdn_resr.cgi?Sig=1&Select=1&jmdn_no=2867&kjn_no=10123) or equivalent. Bathing will be avoided during stimulation, and walking and movement will be permitted, but only to the extent that the electrodes do not slip. Toileting, eating, and sleeping are permitted during stimulation. A sticker will be attached to the auricle, and stimulation will be performed once a day for one hour. Stimulation will be performed at 1.5 mA, 25 Hz, and 250 μsec as standard. However, because patients may become accustomed to stimulation, the researcher will check and adjust the frequency to within 1-20 mA and 2-100 Hz, aiming for a stimulation that produces a crackling sound but does not cause pain. To check whether the device is functioning properly, check the machine's log or check the voltage etc. at the outpatient clinic. Participants will be considered eligible if they wear the device for 70% of the observation period. The research co-investigator will explain how to use the device to the research subject when obtaining consent.

[0060] The stimulation settings were determined based on the safety confirmed in previous reports, the effectiveness confirmed in ongoing research by collaborators based on those reports, and the stimulation dose prescribed for commonly available home low-frequency therapy devices. The equipment used in this study is a low-frequency stimulation device owned by the Department of Molecular Neuroimmunology, Institute of Gene Regulation, Hokkaido University, which will be loaned to the research subjects on a day convenient for them before stimulation begins. While the same low-frequency therapy device will generally be used, a different low-frequency therapy device with the same capabilities may be used due to availability and price.

[0061] (3) Samples to be used and their measurement parameters Samples to be used: blood (10-20 mL: using newly collected blood samples and residual samples from regular medical care), urine (10-20 mL: using residual samples from regular medical care), bronchoalveolar lavage fluid (10-20 mL: using residual samples from regular medical care), oral mucosa (collected using a DNA sample collection kit from oral mucosa using a cotton swab, etc. (iSWAB DNA Collection Kit (Funakoshi) etc.): using residual samples from regular medical care), surplus tissue samples obtained in regular medical care (frozen samples, FFPE samples, FFPE tissue microarray samples, PAXgene fixed samples). The "regular medical care" period refers to the period before and during the study participation period. Measurement parameters: blood cell tests, blood biochemistry tests, urine tests. Gene and molecular expression analysis was performed using blood cells, serum, plasma, blood and urinary exosomes, bronchoalveolar lavage fluid, oral mucosal cells, and surplus tissue samples (frozen samples, FFPE samples, FFPE tissue microarray samples, and PAXgene-fixed samples) generated during treatment and diagnosis. These gene expression analyses can be performed using a Leica laser microdissection (Leica LMD7000). The target genes and molecules are as follows: molecules expressed by immune cells, molecules involved in inflammatory responses and their induced expression, IL-6 amplifier-regulated genes and target genes5, and disease-related genes. Measurements are performed at the Institute for Genetic Medicine, Hokkaido University. For samples from Hokkaido University Hospital, 10-20 mL of peripheral blood is collected and sent refrigerated. Urine samples are collected using standard urine collection methods, and 10-20 mL is sent refrigerated or frozen. Other samples are sent refrigerated or frozen by mail. Information and data storage and disposal are handled appropriately by the Department of Molecular Neuroimmunology, Institute for Genetic Medicine, Hokkaido University. Thin sections will be prepared from frozen samples, FFPE samples, FFPE tissue microarray samples, and PAXgene-fixed samples, and then analyzed using standard immunohistochemistry methods to determine protein expression, phosphorylation, and the presence or absence of mutant proteins, to identify cell groups in which IL-6 amplifiers are activated.These analyses are performed using antibodies such as Phospho-Stat3 (Tyr705) (D3A7) XP® Rabbit mAb (#9145) and Phospho-NF-κB p65 (Ser536) Antibody (#3031), purchased from manufacturers such as Cell Signaling. Samples collected from Hokkaido University Hospital undergo isolation of peripheral blood mononuclear cells (PBMCs), plasma, and serum at the Institute for Genetic Medicine, Hokkaido University, and extraction of DNA, RNA, protein, and exosomes from the samples. The samples are then transported to analytical facilities under refrigeration or freezing conditions via courier. Analysis of peripheral blood mononuclear cells and isolated plasma and serum is performed at Hokkaido University and other analytical facilities listed in the table below. Analysis of DNA and RNA from samples is performed at Hokkaido University and other analytical facilities listed in the table below. Analysis of protein from samples is performed at Hokkaido University and other analytical facilities listed in the table below. Analysis of exosomes from samples is performed at Hokkaido University and other analytical facilities listed in the table below. The lymphoblast cell line will be established at the Tokyo Medical and Dental University Institute for Intractable Diseases.

[0062] (Observation and investigation items and implementation methods) The investigation, observation and evaluation items, as well as the hospital visit schedule for this study, are as follows: 1) Basic information on subjects: diagnosis, age, sex, height, weight, medical history, lifestyle history (smoking history, dental caries, etc.), medications currently being taken (including immunosuppressants), and whether or not biological agents have been used in the past. 2) Research equipment usage status: Check the low-frequency stimulation usage notes. 3) Physical findings: blood pressure, pulse rate, oxygen saturation. 4) Clinical tests: the following items will be tested, including blood tests, physiological tests, and imaging tests, and the data will be used in this study. Test items 1-4 and 6-8 for this study will be routinely performed, but their frequency may increase. Items 2, 5, and 9 are items that will be added to the study objectives. 1: Hematology and biochemistry tests (measured in-hospital): white blood cell count, white blood cell differential, red blood cell count, platelet count, hemoglobin, AST, ALT, ALP, γ-GTP, total bilirubin, albumin, LDH, BUN, Cre, CK, Na, K, Cl, Ca, KL-6, SP-A, SP-D, BNP (approximately 10 mL) 2: Blood collection for analysis 10-20 mL (analysis details are described in 4(3)) 3: Arterial blood gas analysis 4: Electrocardiogram 5: Coefficient of variation of RR interval (CV R-R ) (obtained simultaneously with the electrocardiogram) 6: Respiratory function test 7: Chest imaging (chest X-ray or CT scan) 8: 6-minute walking test 9: Physical activity assessment (modified Borg scale, MRC shortness of breath scale, King's Brief Interstitial Lung Disease (K-BILD) 5) Adverse events The above will be recorded in a case report form and submitted to the research office.

[0063] (Evaluation items (endpoints)) (1) Primary endpoint: Presence or absence of progression of respiratory failure as assessed by respiratory function tests following low-frequency treatment. Progression of respiratory failure is defined as a 5% or greater decrease in forced vital capacity, taking into account the criteria for PF-ILD. (2) Secondary endpoints: Rate of improvement in exercise tolerance during the observation period, assessed by the MRC Shortness of Breath Scale, modified Borg scale, 6-minute walk test, and arterial blood gas analysis. Safety of low-frequency treatment, and the occurrence of adverse events, etc. Changes in QOL before and after low-frequency treatment (by K-BILD). Presence or absence of acute exacerbation during low-frequency treatment. Presence or absence of a relationship between the localization of immune cells before and after low-frequency treatment, positive expression of molecules whose expression is induced by inflammation, expression intensity, and the presence or absence of disease-related gene variants and the pathological condition. Correlation between the state of inflammation and clinicopathological factors and the expression state of other analyzed molecules.

[0064] (Target number of cases, rationale for setting it, and statistical analysis method) (1) Target number of cases and rationale for setting it: 30. The rationale for setting it was set as the number that could be implemented within the above-mentioned study period. This is because the number of patients currently receiving treatment at our hospital who meet the conditions is limited. Also, previous reports on low-frequency therapy for chronic respiratory diseases have shown significant results with a similar number of patients. (2) Statistical analysis method: Success will be defined as the primary endpoint of improvement in subjective symptoms before and after treatment, and improvement or maintenance of respiratory function. Secondary endpoints of safety and QOL will be examined before and after treatment. Data from the INPULSIS and INBUILD trials will be used as historical controls, and comparisons will be made with this study regarding the amount of decline and rate of change in forced vital capacity, the incidence of acute exacerbations, survival rate, occurrence of adverse events, and QOL assessed by the K-BILD questionnaire. A detailed statistical analysis plan will be prepared and published before the first patient is enrolled in the study.

[0065] While preferred embodiments of the present invention have been described and illustrated, it should be understood that these are exemplary of the present invention and should not be considered limiting. Additions, omissions, substitutions, and other modifications can be made without departing from the spirit or scope of the present invention. Accordingly, the present invention is not to be deemed limited by the foregoing description, but is limited only by the scope of the appended claims.

[0066] The present invention provides a non-invasive, simple, and compact interstitial pneumonia treatment device that has a therapeutic effect on interstitial pneumonia, an interstitial pneumonia treatment system using the same, a method for treating interstitial pneumonia, and a method for assisting in the detection of symptoms of interstitial pneumonia, and use of the device for treating interstitial pneumonia.

[0067] 1A, 1B, 1C Interstitial pneumonia treatment device 2A, 2B, 2C Holding member 3A, 3C Current-carrying member P Target person

Claims

1. An interstitial pneumonia treatment device for reducing the symptoms of interstitial pneumonia in a subject suffering from interstitial pneumonia, the interstitial pneumonia treatment device comprising an auricular nerve stimulation means that is installed so as to be placed at two or more different sites on the auricle of the subject and that includes at least two electrodes configured to be able to electrically stimulate the two or more sites.

2. The interstitial pneumonia treatment device of claim 1, wherein the auricular nerve stimulation means is designed to be placed in the concha navicularis and the cavity of the concha of the subject, respectively, and includes at least two electrodes configured to enable electrical stimulation of the nerve branches of the concha navicularis and the cavity of the concha.

3. An interstitial pneumonia treatment device according to claim 1 or 2, comprising control means capable of controlling electrical stimulation conditions including the number of times, duration, current, or frequency of application of the electrical stimulation, said control means being configured to store and select the electrical stimulation conditions for each subject.

4. The interstitial pneumonia treatment device according to claim 3, wherein the electrical stimulation conditions are a current of 1 to 20 mA and a frequency of 2 to 100 Hz.

5. An interstitial pneumonia treatment system comprising: an interstitial pneumonia treatment device according to claim 1 or 2; and pneumonia symptom detection means for detecting the severity of interstitial pneumonia symptoms.

6. The interstitial pneumonia treatment system according to claim 5, wherein the pneumonia symptom detection means includes means for detecting at least one of a fibrosis marker, an inflammation marker, K-BILD, Borg, or CV-RR.

7. A method for treating interstitial pneumonia to reduce symptoms of interstitial pneumonia in a subject suffering from interstitial pneumonia, the method comprising an auricular nerve stimulation step of applying electrical stimulation to two or more different sites on the subject's auricle.

8. A method for treating interstitial pneumonia as described in claim 7, using an interstitial pneumonia treatment device equipped with an auricular nerve stimulation means including at least two electrodes designed to apply electrical stimulation to the interior of the subject's concha navicularis and the cavity of the concha, and configured to enable electrical stimulation of the nerve branches of the concha navicularis and the cavity of the concha.

9. The method for treating interstitial pneumonia according to claim 7 or 8, wherein the auricular nerve stimulation step selects electrical stimulation conditions, including the number of times, duration, current, or frequency of electrical stimulation, for each subject.

10. The method for treating interstitial pneumonia according to claim 9, wherein the electrical stimulation conditions are a current of 1 to 20 mA and a frequency of 2 to 100 Hz.

11. The method for treating interstitial pneumonia according to claim 7 or 8, further comprising a pneumonia symptom detection step of detecting the severity of interstitial pneumonia symptoms.

12. The method for treating interstitial pneumonia according to claim 11, wherein the step of detecting pneumonia symptoms includes a step of detecting at least one of a fibrosis marker, an inflammation marker, K-BILD, Borg, or CV-RR.

13. A method for assisting in the detection of symptoms of interstitial pneumonia in a subject, the subject being a subject after electrical stimulation is applied to two or more different sites on the subject's auricle, the method detecting a marker of the symptom of interstitial pneumonia in the subject.

14. A method for assisting in the detection of symptoms of interstitial pneumonia according to claim 13, wherein the marker for the symptoms of interstitial pneumonia is a fibrosis marker, an inflammatory marker, K-BILD, Borg or CV-RR in the subject.

15. Use of a device for treating interstitial pneumonia, the device comprising an auricular nerve stimulation means including at least two electrodes designed to be placed at two or more different sites on the auricle of a subject suffering from interstitial pneumonia and configured to enable electrical stimulation to the two or more sites.

16. The use for treating interstitial pneumonia according to claim 15, wherein the device comprises an auricular nerve stimulation means including at least two electrodes designed to be placed in the concha navicularis and the cavity of the concha, respectively, and configured to enable electrical stimulation of the nerve branches of the concha navicularis and the cavity of the concha.

17. The use for treating interstitial pneumonia according to claim 15 or 16, wherein the device comprises a control means capable of controlling electrical stimulation conditions including the number of times, duration, current or frequency of application of the electrical stimulation, and the control means is configured to store and select the electrical stimulation conditions for each subject.

18. The use of the device for treating interstitial pneumonia according to claim 17, wherein the electrical stimulation conditions are a current of 1 to 20 mA and a frequency of 2 to 100 Hz.

Images