Treatment of Acute Respiratory Distress Syndrome by Alternating Electric Fields

Abstract

A method for treating acute respiratory distress syndrome (ARDS) in a subject is provided by applying an alternating electric field (AEF) to a region of the subject's torso. ARDS can be caused by sepsis, viral infection, bacterial infection, drowning, chemical inhalation, acute pancreatitis, chest injury, etc. The viral infection can be COVID-19 or long COVID. ARDS can be identified using the Berlin definition.

Description

Background Art

[0001] [Cross - reference to Related Applications] This application claims the benefit of U.S. Provisional Application No. 63 / 356,590, filed on Jun. 29, 2022, the entire content of which is incorporated herein by reference.

[0002] Acute respiratory distress syndrome (ARDS) is a life - threatening respiratory disease characterized by hypoxia, lung stiffness, activation and proliferation of alveolar T cells, etc. The influx of immune cells activates epithelial and endothelial cells, releasing a large number of pro - inflammatory mediators, propagating a profound inflammatory response and a series of cytotoxic species, causing damage to the lung parenchyma. Risk factors for ARDS include advanced age, female gender, smoking, alcohol consumption, aortic vascular surgery, cardiovascular surgery, traumatic brain injury, etc.

[0003] Current treatments for ARDS are complex and vary in effectiveness. Anti - inflammatory drugs are administered systemically and may reduce immune responses that are not related to damaging lung T cells. Unfortunately, no drug has been proven effective in preventing or managing ARDS. The main treatment strategy is supportive care, focusing on 1) reducing the shunt rate, 2) increasing oxygen supply, 3) decreasing oxygen consumption, and 4) avoiding further damage. Patients wear mechanical ventilators, receive diuretics to prevent fluid overload, and are given nutritional support until improvement is seen. The mode of the patient's ventilator affects lung recovery.

[0004] ARDS can occur from various common medical conditions and can potentially affect the quality of life over a long period. To date, there has been no effective treatment to improve the lives of patients. Therefore, alternative methods are needed for the treatment of ARDS patients.

Summary of the Invention

[0005] The present disclosure provides a method for treating acute respiratory distress syndrome (ARDS) in a subject by applying an alternating electric field (AEF) to a region of the subject's torso. In some examples of this method, applying an AEF to the upper body of the subject, particularly to the lungs of the subject, is provided.

[0006] In some examples of this method, ARDS is caused by sepsis, viral infection, bacterial infection, drowning, chemical inhalation, acute pancreatitis, chest injury, or combinations thereof. Optionally, ARDS is identified and / or characterized using the Berlin definition.

[0007] In some cases of this method, the subject is suffering from COVID-19 or long COVID. In some examples of this method, the subject exhibits pulmonary fibrosis or a cytokine storm.

Brief Description of the Drawings

[0008]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0009] In vivo, AEF therapy can be implemented using wearable and portable devices such as the Optune® Delivery System (which has been conventionally used to apply AEF to subjects with tumors) or similar devices. In tumor treatment, AEF therapy is often referred to as "tumor treatment field" or "TT field" therapy. Optune® includes an electric field generator, four adhesive patches (a non-invasive insulated transducer array), a rechargeable battery, and a carrying case. The transducer array is attached to the skin and connected to the device and the battery. In a preclinical setting, AEF can be applied in vivo using an Inovitro™ TT field laboratory bench system or similar devices. Inovitro™ includes an AEF generator and a base plate that includes eight ceramic dishes per plate. Cells are seeded on a cover glass placed in each dish. AEF is applied using two sets of orthogonal transducer arrays insulated by a high dielectric constant ceramic within each dish. In both in vivo and in vitro settings, the direction of the AEF field can be switched at various intervals (e.g., 90° every second), so that various direction axes of cell division can be covered. In tumor treatment, AEF therapy has been used to apply an alternating electric field to cancer cells in the target area of the body to inhibit cell division.

[0010] An increase in the neutrophil-to-lymphocyte ratio (NLR) is due to an increase in the number of neutrophils and a decrease in the number of lymphocytes. NLR represents the balance of the levels of neutrophils and lymphocytes in the body and serves as an indicator of systemic inflammation. In this case, a high NLR may indicate that the patient is suffering from severe inflammatory progression, such as ARDS, which is considered suitable for treatment according to the methods taught herein. For example, if the NLR exceeds about 3.53, it can be considered that the NLR is abnormally high and indicates ARDS that requires treatment.

[0011] Although not bound by theory, treating ARDS in the lung or lymph nodes in the pulmonary inflow region locally using AEF may produce an anti-proliferative effect on alveolar T cells, reducing local inflammation that leads to late-stage ARDS such as pulmonary fibrosis and cytokine storm. Thus, this method enables immune responses in other regions of the body and avoids the spread of infection by causing a locally specific anti-inflammatory response in the lung.

[0012] Figure 1 shows the effect of AEF on T cell proliferation in samples stimulated with phytohemagglutinin (PHA) and unstimulated samples. As shown in Figure 1, PHA stimulation is strong, resulting in both activation and proliferation, as well as activation-induced cell death. This affects both cell number and viability. In samples not stimulated with PHA, no proliferation was detected, and the cell number in the AEF samples was approximately 85% of that of the standardly incubated control (left, P =.01). Since no change was detected in the viability (% live / dead) of unstimulated cultures in the AEF and control groups, it was suggested that AEF has little or no effect on the viability of unstimulated T cells. In PHA-stimulated samples, PHA proliferated some of the T cells, affecting both cell number and viability. The number of non-proliferative (CFSEhigh) T cells in the stimulated AEF culture samples was approximately 65% of that of the control group (p = 0.015 and p = 0.03 for CD4+ and CD8+ cells, respectively). There was no change in viability (right). In the same samples, the number of proliferating T cells in the AEF culture samples was significantly reduced to approximately 25% of that of the control group (p = 0.009 and p = 0.01 for CD4+ and CD8+ respectively), and in particular, the viability of CD8+ T cells also decreased (52% in the control group and 40% in AEF). In Figure 1, the bar labeled "TT field" represents in vivo samples treated with AEF at an electric field strength of 2 - 2.5 V / cm (peak-to-peak) and a frequency of 200 kHz.

[0013] As shown in Figure 2, the symptoms of ARDS begin 4 - 7 days after onset and can progress over the next 21 days.

[0014] The diagnosis of ARDS is based on criteria such as acute onset, bilateral lung infiltrates of non - cardiac origin on chest radiograph, and the degree of oxygenation impairment (PaO2 / FiO2 ratio less than 300 mmHg; see below for the Berlin definition). ARDS is further classified into mild (PaO2 / FiO2 200 - 300 mmHg), moderate (PaO2 / FiO2 100 - 200 mmHg), and severe (PaO2 / FiO2 less than 100 mmHg) subtypes. Mortality and the number of days without using a ventilator increase according to the severity.

[0015] Lung - protective ventilation strategies to reduce lung injury follow the goals set by the NIH - NHLBI ARDS Clinical Network mechanical ventilation protocol (ARDSnet). The tidal volume (V) is 4 - 8 mL / kg of ideal body weight (IBW), the respiratory rate (RR) is a maximum of 35 bpm, SpO2 is 88% - 95%, the plateau pressure (P) is less than 30 cmH2O, the pH target is 7.30 - 7.45, and the ratio of inspiratory time to expiratory time is less than 1. As recognized in ARDSnet (www.ncbi.nlm.nih.gov / books / NBK436002 / ), positive end - expiratory pressure (PEEP) can be used to maintain the patient's oxygenation.

[0016] ARDS can be classified based on the Berlin definition of ARDS, which depends on the calculated ratio of the patient's arterial blood oxygen concentration (PaO2) to the oxygen concentration in the inhaled air (FiO2) (Ranieri et al., JAMA, 2012 Jun 20; 307(23):2526 - 33). As shown in Figure 3, according to the Berlin definition, patients with a PaO2 / FiO2 ratio less than 300 are considered to have ARDS. The Berlin definition is currently used as the updated definition of ARDS in 2012 from the previous ARDS definition called the American - European Consensus Conference (AECC) definition defined in 1994.

[0017] According to the Berlin Definition, the severity of ARDS is defined by the degree of hypoxemia calculated as the PaO2 / FiO2 ratio. Figure 3 shows how the Berlin ARDS Definition defines ARDS as mild, moderate, or severe based on the PaO2 / FiO2 ratio. In the Berlin Definition of ARDS, positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) of 5 cmH2O or more is required.

[0018] The PaO2 / FiO2 ratio can be measured by arterial blood gas (ABG) analysis. To calculate the PaO2 / FiO2 ratio, measure PaO2 in mmHg and represent FiO2 as a decimal between 0.21 and 1. For example, if the PaO2 is 100 mmHg when the patient is receiving 80% oxygen, the PaO2 / FiO2 ratio is 125 mmHg (i.e., 100 mmHg / 0.8). The PaO2 / FiO2 ratio is also called the Horowitz Index, the Calhoun Index, or simply the P / F ratio.

[0019] The PaO2 / FiO2 ratio can be expressed with or without the mmHg unit. For example, the PaO2 / FiO2 ratio can be simply written as "125" when it is 125 mmHg. Here, the PaO2 / FiO2 ratio expressed without units is understood to reflect the mmHg unit.

[0020] The PaO2 / FiO2 ratio is an important indicator for clinically measuring the respiratory status of patients receiving oxygen supplementation. Bedside clinicians can use the PaO2 / FiO2 ratio to monitor the degree of hypoxemia, quickly detect the early progression of respiratory failure, and intensify treatment. For example, if an ARDS patient progresses from mild to moderate ARDS, placing the patient in the prone position may improve oxygen supply (www.nursingcenter.com / ncblog / march-2020 / calculating-severity-of-ards).

[0021] Treatments for ARDS and acute lung injury (ALI) include glucocorticoids, surfactants, inhaled nitric oxide, antioxidants, protease inhibitors, and various other anti-inflammatory treatments. Existing treatments for ARDS include neuromuscular blocking agents, β-adrenergic agonists, neutrophil elastase inhibitors, antibiotics if the cause is a bacterial infection, diuretics to remove water from the lungs, bronchodilators and respiratory assist drugs, autoinflammatory drugs such as glucocorticoids (e.g., methylprednisolone), inhaled pulmonary vasodilators, and other new anti-inflammatory therapeutic agents such as IL-6 inhibitors that are not specifically established for the treatment of ARDS. In particular, the treatment of severe ARDS may include neuromuscular blockade to reduce oxygen consumption, extracorporeal membrane oxygenation (ECMO), or inhalation of nitric oxide ((Ramanathan et al., Volume 8, Issue 5, P433-434, 2020). Unfortunately, to date, there has been no drug treatment proven to be particularly effective for ARDS patients.

[0022] Among the survivors of ARDS, some experience symptoms such as obstructive ventilation insufficiency, restrictive ventilation insufficiency, debilitation, and fatigue for several months after the end of treatment.

[0023] The currently disclosed method for treating ARDS includes applying an AEF field to the body of the subject, particularly the upper body, and more specifically the lung region of the subject.

[0024] In some examples of this method, ARDS is caused by any of a variety of medical conditions, such as coronavirus disease 2019 (COVID-19), sepsis, inhalation of harmful substances, pneumonia or severe influenza, near drowning, acute pancreatitis, chest or other serious trauma. See https: / / www.nature.com / articles / s41572-019-0069-0 and https: / / journal-inflammation.biomedcentral.com / articles / 10.1186 / s12950-018-0202-y. The symptoms of ARDS can begin 4 to 7 days after onset. In some embodiments, ARDS can be caused by a pathological condition, but the pathological condition can resolve while ARDS persists. Thus, in some embodiments, patients in need of treatment for ARDS do not, for example, have an infection in the lungs.

[0025] In some cases, this method includes diagnosing a subject with ARDS by chest X-ray, blood test, CAT scan, symptoms, oxygen saturation measurement, or echocardiogram. In some cases, the subject exhibits symptoms of ARDS, which can include one or more of severe shortness of breath, difficulty breathing, low blood pressure, or extreme fatigue.

[0026] In some cases, this method includes an initial step of diagnosing a patient or identifying a patient for treatment by determining whether the patient's PaO2 / FiO2 ratio is less than 300, between 200 and 300 (indicating mild ARDS), between 100 and 199 (indicating moderate ARDS), or less than 100 (indicating severe ARDS). In some cases, the initial step of diagnosing a patient includes determining that the patient's NLR is greater than about 3.5, such as greater than about 3.75 or 4. In some cases, it may be determined that the subject does not have a tumor in the lungs or that the subject does not have a tumor himself. In some cases, the subject may not be diagnosed with cancer such as lung cancer.

[0027] In some cases, the lungs of the subject may be free of infections such as viral infections (e.g., coronavirus) or bacterial infections.

[0028] In some cases, this method includes treating the patient with AEF until the PaO2 / FiO2 ratio increases by a clinically significant amount, such as 50%, 100%, 150%, or 200%. Alternatively, this method may include treating the patient with AEF until the PaO2 / FiO2 ratio exceeds 300 mmHg or increases by at least a specific amount, such as at least 50 mmHg, 75 mmHg, 100 mmHg, 150 mmHg, 200 mmHg, or 250 mmHg.

[0029] In some cases, this method includes treating the patient with AEF until the NLR decreases by a clinically significant amount, such as 25%, 30%, 50%, or 75%. Alternatively, this method may include treating the patient with AEF until the NLR decreases below 3.5, 3.25, 3, 2.75, 2.5, 2.25, 2, or 1.75 or decreases by at least a specific amount, such as at least 0.2, 0.25, 0.5, 0.75, 1, 1.25, or 1.5.

[0030] Therapeutic agents for treating ARDS or the cause of ARDS can be administered to the subject before, after, or during the application of AEF. In some cases, at least a portion of the application of AEF is performed simultaneously with the administration of the therapeutic agent. In some examples where the therapeutic agent is administered before or after the application of AEF, the therapeutic agent is administered within about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 72 hours, or about 1 week after the application of AEF.

[0031] In some examples of this method, the therapeutic agents used in combination with AEF therapy include neuromuscular blocking agents, β - adrenergic agonists, neutrophil elastase inhibitors, antibiotics, diuretics, bronchodilators, anti - inflammatory drugs (glucocorticoids such as methylprednisolone, dexamethasone, etc.), inhaled pulmonary vasodilators, IL - 6 inhibitors (e.g., siltuximab, tocilizumab, sarilumab, etc.), surfactants, inhaled nitric oxide, antioxidants, or protease inhibitors (e.g., famotidine). The therapeutically effective amount of the agent can be determined by a person skilled in the art, for example, from the label of the agent or product, or from the results of experiments or clinical trials designed to determine the therapeutically effective dosage, pharmacokinetics, or other characteristics of the agent.

[0032] In some cases, this method further includes providing respiratory assistance to the subject before, after, or during the application of AEF. The respiratory assistance can be oxygen therapy, and in particular, the respiratory assistance can be high - flow nasal oxygen therapy (HFNO) or hyperbaric oxygen therapy. In some examples where the respiratory assistance is provided before or after the application of AEF, the respiratory assistance is provided within about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 72 hours, or about 1 week after the application of AEF.

[0033] In some cases, AEF is applied for at least 24 hours, at least 72 hours, or at least 30 days. The application of AEF can be continuous or discontinuous with breaks (e.g., breaks every 1, 2, 3, 6, 12, or 24 hours).

[0034] In some cases, AEF is applied discontinuously or intermittently on specific days. For example, the AEF field is applied for about 4 hours to about 24 hours per day, and a break of about 5 minutes to about 1 hour can be optionally provided during the application. Alternatively, AEF can be applied for about 50% to about 100% of the time, about 60% to about 90% of the time, or about 80% of the time during a specific day.

[0035] In some cases, the electric field strength of the alternating electric field is 0.1 to 20 V / cm (RMS), 0.5 to 10 V / cm, 1 to 10 V / cm, 1 to 4 V / cm, or 1 to 2.5 V / cm. The electric field strength can be measured in at least a part of the region where the AEF is applied.

[0036] In some cases, the frequency of the AEF is 50 kHz to 10 MHz, 50 kHz to 10 MHz, 100 kHz to 500 kHz, 75 kHz to 500 kHz, 100 kHz to 300 kHz, 80 kHz to 300 kHz, 100 kHz to 200 kHz, 125 kHz to 175 kHz, or about 150 kHz.

[0037] The AEF can be applied along a single direction (unidirectional AEF) or can be applied alternately between different directions (multidirectional AEF). In the multidirectional AEF, the AEF can be applied, for example, in directions separated by about 30, 45, 60, 90, 120, 135, or 150 degrees.

[0038] Exemplary embodiments of the present invention include a method of treating ARDS in a subject by applying an AEF to a region of the subject's torso. Exemplary embodiments also include an AEF device or oxygen gas or oxygen supply device for use in treating ARDS by the methods described herein.

[0039] In one aspect of these exemplary embodiments, the subject has not been diagnosed with cancer or the subject does not suffer from an infectious disease. In another aspect, the subject exhibits pulmonary fibrosis or a cytokine storm. In any of these embodiments, the method can include administering to the subject a therapeutic agent for treating ARDS or the cause of ARDS, and the therapeutic agent can include, for example, a neuromuscular blocking agent, a β-adrenergic agonist, a neutrophil elastase inhibitor, an antibiotic, a diuretic, a bronchodilator, an anti-inflammatory agent (such as a glucocorticoid like methylprednisolone), an inhaled pulmonary vasodilator, an IL-6 inhibitor (such as tocilizumab, sarilumab, siltuximab), a surfactant, inhaled nitric oxide, an antioxidant, or a protease inhibitor.

[0040] In any of these embodiments, the method may include administering respiratory assistance, such as oxygen therapy, high-flow nasal oxygen (HFNO), or hyperbaric oxygen therapy, to the subject. In any of these embodiments, the AEF may be applied to a region of the upper body of the subject, such as the lungs. In any of these embodiments, the AEF may be applied for at least 24 hours, at least 72 hours, or at least 30 days. In any of these embodiments, the frequency of the AEF may be 50 kHz to 10 MHz, 125 kHz to 175 kHz, or about 150 kHz. In any of these embodiments, the intensity of the AEF is 0.1 V / cm to 20 V / cm or 1.0 V / cm to 4 V / cm.

[0041] In any of these embodiments, the method may include diagnosing whether the subject has ARDS, for example, by chest X-ray, blood test, CAT scan, symptoms, oxygen saturation measurement, or echocardiogram. In any of these embodiments, the subject may exhibit one or more symptoms of ARDS, such as severe shortness of breath, dyspnea, low blood pressure, or extreme fatigue.

[0042] In any of these embodiments, there may be no tumor present in the subject or in the subject's lungs.

[0043] In any of these embodiments, the method may include an initial step of determining the subject's PaO2 / FiO2 ratio, and the subject's PaO2 / FiO2 ratio is 300 mmHg or less, 200 - 300 mmHg, 100 - 199 mmHg, or less than 100 mmHg. In any of these embodiments, the AEF may be applied until the subject's PaO2 / FiO2 ratio increases by 50%, 100%, 150%, or 200%, or until the subject's PaO2 / FiO2 ratio exceeds 300 mmHg or increases by 50 mmHg, 75 mmHg, 100 mmHg, 150 mmHg, 200 mmHg, or 250 mmHg.

[0044] In any of these embodiments, the method may include an initial step of determining the neutrophil-to-lymphocyte ratio (NLR) of the subject. The AEF may be applied until the NLR is less than 3.5 or has decreased by at least 0.2.

[0045] Exemplary embodiments of the present invention include a therapeutic agent for use in the treatment of acute respiratory distress syndrome (ARDS) in a subject, the treatment including applying an alternating electric field (AEF) to a region of the subject's body, and the therapeutic agent being selected from the group consisting of a neuromuscular blocking agent, a β-adrenergic agonist, a neutrophil elastase inhibitor, an antibiotic, a diuretic, a bronchodilator, an anti-inflammatory agent (a glucocorticoid such as methylprednisolone), an inhaled pulmonary vasodilator, an IL-6 inhibitor (such as tocilizumab, sarilumab, siltuximab), a surfactant, inhaled nitric oxide, an antioxidant, and a protease inhibitor.

[0046] Exemplary embodiments of the present invention include oxygen gas for use in the treatment of acute respiratory distress syndrome (ARDS) in a subject, the treatment including applying an alternating electric field (AEF) to a region of the subject's body and delivering oxygen gas to the subject's lungs.

[0047] In some exemplary embodiments of oxygen gas for use in the treatment of acute respiratory distress syndrome in a subject, the treatment further includes administering a therapeutic agent selected from the group consisting of a neuromuscular blocking agent, a β-adrenergic agonist, a neutrophil elastase inhibitor, an antibiotic, a diuretic, a bronchodilator, an anti-inflammatory agent (such as a glucocorticoid such as methylprednisolone), an inhaled pulmonary vasodilator, an IL-6 inhibitor (such as tocilizumab, sarilumab, siltuximab), a surfactant, inhaled nitric oxide, an antioxidant, and a protease inhibitor.

[0048] Exemplary embodiments of the present invention include nitric oxide gas for use in the treatment of acute respiratory distress syndrome (ARDS) in a subject, the treatment including applying an alternating electric field (AEF) to a region of the subject's body and delivering nitric oxide gas to the subject's lungs.

[0049] In some exemplary embodiments described herein, the subject has not been diagnosed with cancer or does not have an infectious disease.

[0050] Some exemplary embodiments described herein further comprise subjecting the subject to respiratory assistance, preferably oxygen therapy, high-flow nasal oxygen (HFNO), or hyperbaric oxygen therapy.

[0051] In some exemplary embodiments described herein, the AEF is applied to the upper body region of the subject, preferably to the lungs of the subject.

[0052] In some exemplary embodiments described herein, the AEF is applied for at least 24 hours, at least 72 hours, or at least 30 days, the frequency of the AEF is 50 kHz to 10 MHz, 125 kHz to 175 kHz, or about 150 kHz, and / or the intensity of the AEF is 0.1 V / cm to 20 V / cm, or 1.0 V / cm to 4 V / cm.

[0053] Some exemplary embodiments described herein further comprise diagnosing the subject with ARDS by chest X-ray, blood test, CAT scan, symptoms, oxygen saturation measurement, or echocardiogram.

[0054] In some exemplary embodiments described herein, the subject exhibits symptoms of ARDS such as one or more of severe shortness of breath, dyspnea, low blood pressure, or extreme fatigue, or exhibits pulmonary fibrosis or a cytokine storm.

[0055] In some exemplary embodiments described herein, the subject has no tumor, preferably no tumor in the lungs of the subject.

[0056] Some exemplary embodiments described herein further include an initial step of determining a subject's PaO2 / FiO2 ratio, where the subject's PaO2 / FiO2 ratio is 300 mmHg or less, 200 - 300 mmHg, 100 - 199 mmHg, or less than 100 mmHg. For example, the AEF is applied until the subject's PaO2 / FiO2 ratio increases by 50%, 100%, 150%, or 200%. For example, the AEF is applied until the subject's PaO2 / FiO2 ratio exceeds 300 mmHg or increases by 50 mmHg, 75 mmHg, 100 mmHg, 150 mmHg, 200 mmHg, or 250 mmHg.

[0057] Some exemplary embodiments described herein further include an initial step of determining a subject's neutrophil-to-lymphocyte ratio (NLR). For example, the AEF is applied until the NLR is less than 3.5 or decreases by at least 0.2.

[0058] In another aspect, a kit for use in treating ARDS by any of the methods described herein is provided. For example, the kit may include, as components, an AEF device as described herein, a device for delivering oxygen gas to a subject as described herein, and / or one or more therapeutic agents described herein for treating ARDS. The kit may be provided in a container, such as a housing, e.g., a box, closet, or room, sized and shaped to accommodate the components of the kit for use in treating ARDS.

[0059] All technical documents or patents cited herein are hereby incorporated by reference in their entirety in the particular context shown.

[0060] Although the present invention has been disclosed with reference to specific embodiments, numerous modifications, changes, and variations can be made to the described embodiments without departing from the scope and scope of the present invention as defined in the appended claims. Therefore, the present invention is not intended to be limited to the above embodiments, but is intended to have all of the scope defined by the language of the following claims and equivalents thereto.

Claims

1. A composition comprising oxygen gas for use in the treatment of acute respiratory distress syndrome (ARDS) in a subject, wherein the treatment comprises applying an alternating electric field (AEF) to a region of the subject's torso and delivering oxygen gas to the subject's lungs.

2. The composition according to claim 1, further comprising administering a therapeutic agent selected from the group consisting of neuromuscular blockers, β-adrenergic agonists, neutrophil elastase inhibitors, antibiotics, diuretics, bronchodilators, anti-inflammatory agents (e.g., glucocorticoids such as methylprednisolone), inhaled pulmonary vasodilators, IL-6 inhibitors (e.g., tocilizumab, sarilumab, and siltuximab), surfactants, inhaled nitric oxide, antioxidants, and protease inhibitors.

3. The composition according to claim 1, wherein the subject has not been diagnosed with cancer, or the subject is not suffering from an infectious disease.

4. The composition according to claim 1, further comprising providing the subject with respiratory support, preferably oxygen therapy, high-flow oxygen therapy (HFNO), or hyperbaric oxygen therapy.

5. The composition according to claim 1, wherein the AEF is applied to the upper body region of the subject, preferably to the lungs of the subject.

6. The composition according to claim 1, wherein the AEF is applied for at least 24 hours, at least 72 hours, or at least 30 days, the frequency of the AEF is 50 kHz to 10 MHz, 125 kHz to 175 kHz, or about 150 kHz, and / or the intensity of the AEF is 0.1 V / cm to 20 V / cm, or 1.0 V / cm to 4 V / cm.

7. The composition according to claim 1, further comprising diagnosing the subject with ARDS by chest X-ray, blood test, CAT imaging, symptoms, oxygen saturation measurement, or echocardiography.

8. The composition according to claim 1, wherein the subject is exhibiting symptoms of ARDS such as severe shortness of breath, dyspnea, hypotension, or extreme fatigue, or is exhibiting pulmonary fibrosis or cytokine storm.

9. The composition according to claim 1, wherein the subject is free of tumors, preferably the subject's lungs are free of tumors.

10. The PaO of the aforementioned subject ２ / FiO ２ The process further includes an initial step of determining the ratio of the subject's PaO ２ / FiO ２ The composition according to claim 1, wherein the ratio is 300 mmHg or less, 200 to 300 mmHg, 100 to 199 mmHg, or less than 100 mmHg.

11. The PaO of the aforementioned subject ２ / FiO ２ The composition according to claim 10, wherein the AEF is applied until the ratio increases by 50%, 100%, 150%, or 200%.

12. The PaO of the aforementioned subject ２ / FiO ２ The composition according to claim 10, wherein the AEF is applied until the ratio exceeds 300 mmHg or increases by 50 mmHg, 75 mmHg, 100 mmHg, 150 mmHg, 200 mmHg, or 250 mmHg.

13. The composition according to any one of claims 1 to 12, further comprising an initial step of determining the neutrophil-to-lymphocyte ratio (NLR) of the subject.

14. The composition according to claim 13, wherein the AEF is applied until the NLR is less than 3.5 or decreases by at least 0.

2.

15. A therapeutic agent for use in treating acute respiratory distress syndrome (ARDS) in a subject, wherein the treatment comprises applying an alternating electric field (AEF) to a region of the subject's torso, and the therapeutic agent is selected from the group consisting of neuromuscular blockers, β-adrenergic agonists, neutrophil elastase inhibitors, antibiotics, diuretics, bronchodilators, anti-inflammatory agents (e.g., glucocorticoids such as methylprednisolone), inhaled pulmonary vasodilators, IL-6 inhibitors (e.g., tocilizumab, sarilumab, and siltuximab), surfactants, inhaled nitric oxide, antioxidants, and protease inhibitors.

16. The therapeutic agent according to claim 2, further comprising administering oxygen gas as part of the treatment.

17. The therapeutic agent according to claim 15, wherein the subject has not been diagnosed with cancer or is not suffering from an infectious disease.

18. The therapeutic agent according to claim 15, further comprising providing the subject with respiratory support, preferably oxygen therapy, high-flow oxygen therapy (HFNO), or hyperbaric oxygen therapy.

19. The therapeutic agent according to claim 15, wherein the AEF is applied to the upper body region of the subject, preferably to the lungs of the subject.

20. The therapeutic agent according to claim 15, wherein the AEF is applied for at least 24 hours, at least 72 hours, or at least 30 days, the frequency of the AEF is 50 kHz to 10 MHz, 125 kHz to 175 kHz, or about 150 kHz, and / or the intensity of the AEF is 0.1 V / cm to 20 V / cm, or 1.0 V / cm to 4 V / cm.

21. The therapeutic agent according to claim 15, further comprising diagnosing the subject with ARDS by chest X-ray, blood test, CAT imaging, symptoms, oxygen saturation measurement, or echocardiography.

22. The therapeutic agent according to claim 15, wherein the subject is exhibiting symptoms of ARDS such as severe shortness of breath, dyspnea, hypotension, or extreme fatigue, or is exhibiting pulmonary fibrosis or cytokine storm.

23. The therapeutic agent according to claim 15, wherein the subject is free of tumors, preferably the subject's lungs are free of tumors.

24. The PaO of the subject ２ / FiO ２ The method further includes an initial step of determining the ratio, and the PaO of the subject ２ / FiO ２ ratio is 300 mmHg or less, 200 to 300 mmHg, 100 to 199 mmHg, or less than 100 mmHg. The therapeutic agent according to claim 15

25. The PaO of the aforementioned subject ２ / FiO ２ The therapeutic agent according to claim 15, wherein the AEF is applied until the ratio increases by 50%, 100%, 150%, or 200%.

26. The PaO of the aforementioned subject ２ / FiO ２ The therapeutic agent according to claim 15, wherein the AEF is applied until the ratio exceeds 300 mmHg or increases by 50 mmHg, 75 mmHg, 100 mmHg, 150 mmHg, 200 mmHg, or 250 mmHg.

27. A therapeutic agent according to any one of claims 15 to 26, further comprising an initial step of determining the neutrophil-to-lymphocyte ratio (NLR) of a subject.

28. The therapeutic agent according to claim 27, wherein the AEF is applied until the NLR is less than 3.5 or decreases by at least 0.2.

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