Treatment of acute respiratory distress syndrome with alternating electric field

Abstract

A method of treating acute respiratory distress syndrome (ARDS) in a subject by applying an alternating electric field (AEF) to a torso region of the subject. ARDS may be caused by sepsis, viral infection, bacterial infection, near drowning, chemical inhalation, acute pancreatitis, and chest injury. The viral infection may be a novel coronavirus infection or a long-term symptom of a novel coronavirus infection. The ARDS may be identified using Berlin definitions.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 356,590, filed on June 29, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0003] Acute respiratory distress syndrome (ARDS) is a life-threatening respiratory disease characterized in particular by hypoxia, lung stiffness, and activation and proliferation of alveolar T cells. The influx of immune cells activates epithelial and endothelial cells, releasing a large number of proinflammatory mediators that propagate a profound inflammatory response and a range of cytotoxic substances, leading to lung parenchymal damage. Risk factors for ARDS include advanced age, female sex, smoking, alcohol consumption, aortic vascular surgery, cardiovascular surgery, and traumatic brain injury.

[0004] Current treatment options for ARDS are complex and have variable efficacy. Anti-inflammatory drugs are administered systemically and can result in a reduced immune response that prevents specific damage to T cells in the lungs. Unfortunately, no drug has been shown to be effective in preventing or controlling ARDS. The mainstay of treatment strategy is supportive care, focused on: 1) reducing the shunt fraction; 2) increasing oxygen delivery; 3) reducing oxygen consumption; and 4) avoiding further injury. Patients receive mechanical ventilation, diuretics are used to prevent fluid overload, and nutritional support is given until improvement is observed. The patient's ventilation pattern affects lung recovery.

[0005] ARDS can be caused by a variety of common diseases and can have a long-term impact on quality of life. To date, there is no effective treatment to improve the lives of patients. Therefore, alternative methods of treating ARDS in patients are needed. Summary of the invention

[0006] The present invention provides a method of treating acute respiratory distress syndrome (ARDS) in a subject by applying an alternating electric field (AEF) to the torso region of the subject. Some examples of the method provide applying the AEF to the upper body of the subject, particularly the lungs of the subject.

[0007] In some instances of the method, ARDS is caused by sepsis, viral infection, bacterial infection, near drowning, chemical inhalation, acute pancreatitis, chest injury, or a combination thereof. In some instances, ARDS is identified and / or characterized using the Berlin definition.

[0008] In some instances of the method, the subject suffers from COVID-19 or long-term COVID-19. In some instances of the method, the subject has pulmonary fibrosis or cytokine storm. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 Shown is the effect of AEF on T cell proliferation in samples stimulated with phytohemagglutinin (PHA) compared to unstimulated samples.

[0010] Figure 2 Shown is the typical progression of ARDS symptoms.

[0011] Figure 3 The Berlin definition criteria for mild, moderate, and severe ARDS are shown. DETAILED DESCRIPTION

[0012] In the in vivo setting, AEF therapy can be delivered using wearable and portable devices such as A delivery system (which is traditionally used to apply AEF to a subject with a tumor) or similar device. In the context of treating tumors, AEF therapy is often referred to as "tumor treating fields" or "TTFields" therapy. The device consists of an electric field generator, four adhesive patches (non-invasive insulated sensor arrays), a rechargeable battery, and a carrying case. The transducer arrays are attached to the skin and connected to the device and battery. In preclinical settings, Inovitro TM AEF is applied in vitro using the TTFields laboratory bench system or similar devices. TM The device comprises an AEF generator and a base plate containing eight ceramic disks. Cells are plated on a coverslip placed inside each culture dish. AEF is applied using two pairs of perpendicular transducer arrays insulated by high dielectric constant ceramics in each disk. In both in vivo and in vitro environments, the orientation of the AEF field can be switched at different intervals (e.g., 90° every 1 second) to cover different orientation axes of cell division. In the context of treating tumors, AEF therapy has been used to disrupt cell division by applying an alternating electric field to cancer cells in a target area of ​​the body.

[0013] The increase of neutrophil to lymphocyte ratio (NLR) is due to the increase of neutrophil count and the decrease of lymphocyte count. NLR represents the balance between neutrophil and lymphocyte levels in the body and is an indicator of systemic inflammation. In this case, high NLR may indicate that the patient suffers from severe inflammatory progression, such as ARDS suitable for treatment according to the method taught herein. For example, an NLR higher than about 3.53 can be considered as an abnormally high NLR, indicating ARDS suitable for treatment.

[0014] Although not wishing to be bound by theory, local treatment of ARDS in the lung or lung draining lymph nodes using AEF can produce an anti-proliferative effect on alveolar T cells and reduce the local inflammation that leads to late ARDS, the consequences of which are such as pulmonary fibrosis and cytokine storm. Therefore, by triggering a local anti-inflammatory response specifically in the lung, the methods of the present invention allow for an immune response in other areas of the body to avoid the spread of infection.

[0015] Figure 1 The effect of AEF on T cell proliferation in samples stimulated with phytohemagglutinin (PHA) compared to unstimulated samples is shown. Figure 1 As shown, PHA stimulation is potent, leading to activation and proliferation as well as activation-induced cell death. This affects cell number and viability. No proliferation was detected in PHA-unstimulated samples, and the number of cells in AEF samples was approximately 85% of the standard incubation control group (left, P = .01). The viability (% live / dead) of unstimulated cultures in AEF did not change compared to the control group, indicating that AEF has little to no effect on the viability of unstimulated T cells. In PHA-stimulated samples, PHA drives some T cell proliferation and affects cell number and viability. In stimulated AEF cultured samples, the number of non-proliferating (CFSEhigh) T cells was approximately 65% ​​of that in controls (p=0.015 and p=0.03 for CD4+ and CD8+ cells, respectively). Survival remained unchanged (right). In the same samples, the number of proliferating T cells in AEF cultured samples was significantly reduced to approximately 25% of that in controls (p=0.009 and p=0.01 for CD4+ and CD8+, respectively), accompanied by a decrease in survival, especially of CD8+ T cells (52% in controls and 40% in AEF). Note that in Figure 1 In the figure, the bars labeled "TTFields" represent in vitro samples treated with AEF with an electric field strength of 2-2.5 V / cm (peak-to-peak) and a frequency of 200 kHz.

[0016] Symptoms of ARDS may begin 4-7 days after onset and develop over the next 21 days, such as Figure 2 shown.

[0017] The diagnosis of ARDS is based on the following criteria: acute onset, bilateral pulmonary infiltrates on chest radiograph of noncardiac etiology, and impaired oxygenation (PaO2 / FiO2 ratio less than 300 mmHg; see below for the Berlin definition). ARDS is further subdivided into mild (PaO2 / FiO2 200 to 300 mmHg), moderate (PaO2 / FiO2 100 to 200 mmHg), and severe (PaO2 / FiO2 less than 100 mmHg) subtypes. Mortality and ventilator-free days increase with severity.

[0018] Lung protective ventilation strategies to reduce lung injury follow the goals set by the NIH-NHLBI ARDS Clinical Network Mechanical Ventilation Protocol (ARDSnet): tidal volume (V) of 4-8 mL / kg ideal body weight (IBW), respiratory rate (RR) up to 35 bpm, SpO2 88%-95%, plateau pressure (P) less than 30 cm H2O, pH target 7.30-7.45, and inspiratory-expiratory time ratio less than 1. ARDSnet believes that positive end-expiratory pressure (PEEP) can be used to maintain the patient's oxygenation. www.ncbi.nlm.nih.gov / books / NBK436002 / .

[0019] ARDS can be classified using the Berlin definition of ARDS, which relies on the calculated ratio of oxygen in the patient's arterial blood (PaO2) to oxygen in the inspired air (FiO2). Ranieri et al., JAMA, 2012 Jun 20; 307(23):2526-33. Figure 3 As shown, according to the Berlin definition, patients with a PaO2 / FiO2 ratio of less than 300 are considered to have ARDS. The Berlin definition is the currently used definition of ARDS, which was updated in 2012 from an earlier definition of ARDS defined in 1994, known as the American-European Consensus Conference (AECC) definition.

[0020] 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 definition of ARDS defines ARDS as mild, moderate, or severe based on the PaO2 / FiO2 ratio. The Berlin definition of ARDS requires a positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) greater than or equal to 5 cm H2O.

[0021] The PaO2 / FiO2 ratio can be determined by arterial blood gas (ABG) analysis. To calculate the PaO2 / FiO2 ratio, PaO2 is measured in mmHg and FiO2 is expressed as a decimal between 0.21 and 1. For example, if a patient has a PaO2 of 100 mmHg while receiving 80% oxygen, the PaO2 / FiO2 ratio is 125 mmHg (i.e., 100 mmHg / 0.8). The PaO2 / FiO2 ratio is also known as the Horowitz index, the Carrico index, or simply the P / F ratio.

[0022] The PaO2 / FiO2 ratio may be expressed with or without the unit mmHg. For example, a PaO2 / FiO2 ratio of 125 mmHg may be expressed simply as "125". PaO2 / FiO2 ratios expressed herein without units should be understood to reflect units of mmHg.

[0023] The PaO2 / FiO2 ratio is a valuable clinical indicator of a patient’s respiratory status while receiving supplemental oxygen. Bedside clinicians can use the PaO2 / FiO2 ratio to monitor the degree of hypoxemia, rapidly detect early progression of respiratory failure, and intensify treatment. For example, positioning a patient prone may improve oxygenation as ARDS progresses from mild to moderate ARDS. www.nursingcenter.com / ncblog / march-2020 / calculating-severity-of-ards

[0024] 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 also include neuromuscular blockers, beta-adrenergic agonists, neutrophil elastase inhibitors, antibiotics (if the cause is bacterial infection), diuretics (for clearing lung fluid), bronchodilators and respiratory support agents, autoinflammatory drugs (such as glucocorticoids (e.g., methylprednisolone)), inhaled pulmonary vasodilators, and other new anti-inflammatory therapeutic drugs (such as IL-6 inhibitors), which are not specifically used to treat ARDS. In particular, the treatment of ARDS may include neuromuscular blockade to reduce oxygen consumption, extracorporeal membrane oxygenation (ECMO), or inhaled nitric oxide (Ramanathan et al., Volume 8, Issue 5, P433-434, 2020). Unfortunately, to date, no drug treatment has been proven to be particularly effective for ARDS patients.

[0025] Some survivors of ARDS experience symptoms such as obstructive and restrictive hypoventilation, weakness, and exhaustion even months after treatment termination.

[0026] The presently disclosed method of treating ARDS comprises applying an AEF field to the torso region of a subject, particularly the upper body, and more particularly the lungs of the subject.

[0027] In some cases of the method, ARDS is caused by any of a variety of pathological conditions, such as coronavirus disease 2019 (new coronavirus infection (COVID-19)), sepsis, inhalation of hazardous substances, pneumonia or severe influenza, near drowning, acute pancreatitis, and chest or other major injuries. See https: / / www.nature.com / articles / s41572-019-0069-0 and https: / / journal-inflammation.biomedcentral.com / articles / 10.1186 / s12950-018-0202-y. Symptoms of ARDS may appear 4-7 days after onset. In some embodiments, ARDS may be caused by a pathological condition, but the pathological condition may have resolved while ARDS persists. Therefore, in some embodiments, the patient in need of treatment for ARDS does not have an infection, such as a lung infection.

[0028] In some instances, the method includes diagnosing the subject with ARDS by chest X-ray, blood test, CAT imaging, symptoms, oxygen saturation measurement, or echocardiogram. In some instances, the subject exhibits symptoms of ARDS, which may include one or more of severe shortness of breath, difficulty breathing, low blood pressure, or extreme fatigue.

[0029] In some instances, the method includes an initial step of diagnosing a patient or identifying a patient for treatment by determining that the patient's PaO2 / FiO2 ratio is less than 300, 200-300 (indicating mild ARDS), 100-199 (indicating moderate ARDS), or less than 100 (indicating severe ARDS). In some instances, 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 instances, the subject's lungs are tumor-free, or the subject is tumor-free. In some instances, the subject has not been diagnosed with cancer, such as lung cancer.

[0030] In some examples, the subject's lungs are free of infection, such as a viral infection (eg, coronavirus) and / or a bacterial infection.

[0031] In some examples, the 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, the 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.

[0032] In some instances, the method comprises treating the patient with AEF until the NLR is reduced by a clinically significant amount, such as 25%, 30%, 50%, or 75%. Alternatively, the method may comprise treating the patient with AEF until the NLR is reduced to less than 3.5, 3.25, 3, 2.75, 2.5, 2.25, 2, or 1.75, or by at least a specific amount, such as at least 0.2, 0.25, 0.5, 0.75, 1, 1.25, or 1.5.

[0033] The therapeutic drug for treating ARDS or a cause of ARDS can be administered to the subject before, after, or during the application of the AEF. In some instances, at least a portion of the AEF is applied simultaneously with the administration of the therapeutic drug. In some instances, the therapeutic drug is administered before or after the application of the AEF, 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 of the application of the AEF.

[0034] In some cases of this method, the therapeutic agent used in combination with AEF therapy includes a neuromuscular blocker, a beta-adrenergic agonist, a neutrophil elastase inhibitor, an antibiotic, a diuretic, a bronchodilator, an anti-inflammatory agent (such as a glucocorticoid, e.g., methylprednisolone, dexamethasone), an inhaled pulmonary vasodilator, an IL-6 inhibitor (e.g., siltuximab, tocilizumab, and sarilumab), a surfactant, inhaled nitric oxide, an antioxidant, or a protease inhibitor (e.g., famotidine). The therapeutically effective amount of the drug can be determined by, for example, a person of ordinary skill in the art based on the drug or product label or based on the results of an experiment or clinical trial, which is designed to determine the therapeutically effective dose, pharmacokinetics, or other properties of the drug.

[0035] In some instances, the method further comprises administering respiratory support to the subject before, after, or during the application of the AEF. The respiratory support may be oxygen therapy, in particular, the respiratory support may be high flow oxygen therapy (HFNO) or hyperbaric oxygen therapy. In some instances, respiratory support is administered before or after the application of the AEF, and respiratory support 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 of the application of the AEF.

[0036] In some examples, the AEF is applied for at least 24 hours, at least 72 hours, or at least 30 days. The application of the AEF can be continuous or intermittent (e.g., at intervals of 1, 2, 3, 6, 12, or 24 hours).

[0037] In some examples, the AEF is applied discontinuously or intermittently in a given day. For example, the AEF field can be applied from about 4 to about 24 hours per day, optionally with a break of about 5 minutes to about 1 hour between applications. Alternatively, in a given day, the AEF can be applied from about 50% to about 100% of the time, from about 60% to about 90% of the time, or about 80% of the time.

[0038] In some examples, the alternating electric field has an electric field strength of 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 may be measured in at least a portion of the area where the AEF is applied.

[0039] In some instances, the frequency of the AEF is between 50 kHz and 10 MHz, between 50 kHz and 10 MHz, between 100 kHz and 500 kHz, between 75 kHz and 500 kHz, between 100 kHz and 300 kHz, between 80 kHz and 300 kHz, between 100 kHz and 200 kHz, between 125 kHz and 175 kHz, or about 150 kHz.

[0040] AEF may be applied in a single direction (unidirectional AEF), or may be applied alternately between different directions (multidirectional AEF). In multidirectional AEF, AEF may be applied in directions that are, for example, approximately 30, 45, 60, 90, 120, 135, or 150 degrees apart.

[0041] Illustrative embodiments of the invention include a method of treating ARDS in a subject by applying an AEF to the torso region of the subject. Illustrative embodiments also include an AEF device or oxygen or oxygen delivery device for treating ARDS by the methods described herein.

[0042] In one aspect of these illustrative embodiments, the subject is not diagnosed as having cancer or the subject is not suffering from infection. On the other hand, the subject has pulmonary fibrosis or cytokine storm. In any of these embodiments, the method may include administering to the subject a therapeutic drug for treating ARDS or the cause of ARDS, wherein the therapeutic drug may include, for example, neuromuscular blockers, beta-adrenergic agonists, neutrophil elastase inhibitors, antibiotics, diuretics, bronchodilators, anti-inflammatory agents (such as glucocorticoids, such as methylprednisolone), inhaled pulmonary vasodilators, IL-6 inhibitors (such as tocilizumab, salilumab and siltuximab), surfactants, inhaled nitric oxide, antioxidants or protease inhibitors.

[0043] In any of these embodiments, the method may include administering respiratory support, such as oxygen therapy, high flow oxygen therapy (HFNO), or hyperbaric oxygen therapy, to the subject. In any of these embodiments, the AEF may be applied to an upper body region of the subject, for example, to 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 between 50kHz and 10MHz, between 125kHz and 175kHz, or the frequency of the AEF may be about 150kHz. In any of these embodiments, the intensity of the AEF may be between 0.1V / cm and 20V / cm, or between 1.0V / cm and 4V / cm.

[0044] In any of these embodiments, the method may include diagnosing a subject with ARDS, for example, by chest X-ray, blood test, CAT imaging, symptoms, oxygen saturation measurement, or echocardiogram. In any of these embodiments, the subject may exhibit one or more ARDS symptoms, such as severe shortness of breath, dyspnea, hypotension, or extreme fatigue.

[0045] In any of these embodiments, the subject or the subject's lung can be tumor-free.

[0046] In any of these embodiments, the method may include an initial step of determining the subject's PaO2 / FiO2 ratio, wherein 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 the AEF may be 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.

[0047] In any of these embodiments, the method may include an initial step of determining the subject's neutrophil to lymphocyte ratio (NLR).AEF may be applied until the NLR is below 3.5 or decreases by at least 0.2.

[0048] Illustrative embodiments of the invention include therapeutic agents for treating acute respiratory distress syndrome (ARDS) in a subject, wherein the treatment comprises applying an alternating electric field (AEF) to a torso region of the subject, and wherein the therapeutic agent is selected from neuromuscular blockers, beta-adrenergic agonists, neutrophil elastase inhibitors, antibiotics, diuretics, bronchodilators, anti-inflammatory agents (such as glucocorticoids, e.g., methylprednisolone), inhaled pulmonary vasodilators, IL-6 inhibitors (such as tocilizumab, salizumab, and siltuximab), surfactants, inhaled nitric oxide, antioxidants, and protease inhibitors.

[0049] Illustrative embodiments of the invention include oxygen for treating acute respiratory distress syndrome (ARDS) in a subject, wherein the treatment includes applying an alternating electric field (AEF) to a torso region of the subject and delivering oxygen to the lungs of the subject.

[0050] In some illustrative embodiments of oxygen for treating acute respiratory distress syndrome in a subject, the treatment further comprises administering a therapeutic agent selected from a neuromuscular blocker, a beta-adrenergic agonist, a neutrophil elastase inhibitor, an antibiotic, a diuretic, a bronchodilator, an anti-inflammatory agent (such as a glucocorticoid, e.g., methylprednisolone), an inhaled pulmonary vasodilator, an IL-6 inhibitor (such as tocilizumab, salilumab, and siltuximab), a surfactant, inhaled nitric oxide, an antioxidant, and a protease inhibitor.

[0051] Illustrative embodiments of the invention include nitric oxide gas for treating acute respiratory distress syndrome (ARDS) in a subject, wherein the treatment includes applying an alternating electric field (AEF) to a torso region of the subject and delivering the nitric oxide gas to the lungs of the subject.

[0052] In some illustrative embodiments described herein, the subject has not been diagnosed with cancer, or wherein the subject does not have an infection.

[0053] Some illustrative embodiments described herein further include administering respiratory support to the subject, preferably oxygen therapy, high flow oxygen therapy (HFNO), or hyperbaric oxygen therapy.

[0054] In some illustrative embodiments described herein, the AEF is applied to an upper body region of a subject, preferably the lungs of the subject.

[0055] In some illustrative embodiments described herein, the AEF is applied for at least 24 hours, at least 72 hours, or at least 30 days, wherein the frequency of the AEF is between 50 kHz and 10 MHz, between 125 kHz and 175 kHz, or a frequency of about 150 kHz, and / or wherein the intensity of the AEF is between 0.1 V / cm and 20 V / cm, or an intensity of 1.0 V / cm to 4 V / cm.

[0056] Some illustrative embodiments described herein also include diagnosing a subject with ARDS by chest X-ray, blood tests, CAT imaging, symptoms, oxygen saturation measurements, or echocardiography.

[0057] In some illustrative embodiments described herein, the subject presents symptoms of ARDS, such as one or more of severe shortness of breath, dyspnea, hypotension, or extreme fatigue, or wherein the subject presents pulmonary fibrosis or cytokine storm.

[0058] In some illustrative embodiments described herein, the subject is tumor-free, preferably the subject's lungs are tumor-free.

[0059] Some illustrative embodiments described herein also include an initial step of determining a PaO2 / FiO2 ratio of a subject, wherein the PaO2 / FiO2 ratio of the subject is 300 mmHg or less, 200-300 mmHg, 100-199 mmHg, or less than 100 mmHg. For example, the AEF is applied until the PaO2 / FiO2 ratio of the subject increases by 50%, 100%, 150%, or 200%. For example, the AEF is applied until the PaO2 / FiO2 ratio of the subject exceeds 300 mmHg, or increases by 50 mmHg, 75 mmHg, 100 mmHg, 150 mmHg, 200 mmHg, or 250 mmHg.

[0060] Some illustrative embodiments described herein also include an initial step of determining the subject's neutrophil to lymphocyte ratio (NLR). For example, AEF is applied until the NLR is below 3.5 or decreases by at least 0.2.

[0061] In another aspect, a kit for treating ARDS by any of the methods described herein is provided. For example, the kit may include an AEF device as described herein, a device for delivering oxygen to a subject as described herein, and / or one or more therapeutic drugs for treating ARDS as described herein as components. The kit may be provided in a container, which may be, for example, a housing of a suitable size and shape to accommodate the kit components for treating ARDS, such as a box, a cabinet, or a room.

[0062] All technical documents or patents cited herein are incorporated by reference in their entirety to the specific context in which they are specified.

[0063] Although the present invention has been disclosed with reference to certain embodiments, various modifications, changes and variations of the described embodiments are possible without departing from the field and scope of the invention as defined in the appended claims. Therefore, it is intended that the present invention not be limited to the described embodiments, but rather has the full scope defined by the language of the following appended claims and their equivalents.

Claims

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

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

3. Oxygen according to any one of claims 1 to 2, wherein the subject has not been diagnosed with cancer, or wherein the subject does not have an infection.

4. Oxygen according to any one of claims 1 to 3, further comprising administering respiratory support to the subject, preferably oxygen therapy, high flow oxygen therapy (HFNO) or hyperbaric oxygen therapy.

5. Oxygen according to any one of claims 1 to 4, wherein the AEF is applied to the upper body area of ​​the subject, preferably the lungs of the subject.

6. Oxygen according to any one of claims 1 to 5, wherein the AEF is applied for at least 24 hours, at least 72 hours or at least 30 days, wherein the frequency of the AEF is between 50 kHz and 10 MHz, between 125 kHz and 175 kHz, or the frequency is about 150 kHz, and / or wherein the intensity of the AEF is between 0.1 V / cm and 20 V / cm, or the intensity is between 1.0 V / cm and 4 V / cm.

7. The oxygen of any one of claims 1 to 6, further comprising diagnosing the subject with ARDS by chest X-ray, blood test, CAT imaging, symptoms, oxygen saturation measurement, or echocardiogram.

8. Oxygen according to any one of claims 1 to 7, wherein the subject presents symptoms of ARDS, such as one or more of severe shortness of breath, dyspnea, hypotension or extreme fatigue, or wherein the subject presents pulmonary fibrosis or cytokine storm.

9. Oxygen according to any one of claims 1 to 8, wherein the subject is tumor-free, preferably the subject's lungs are tumor-free.

10. Oxygen according to any one of claims 1 to 9, further comprising an initial step of determining the subject's PaO2 / FiO2 ratio, wherein the subject's PaO2 / FiO2 ratio is 300 mmHg or less, 200-300 mmHg, 100-199 mmHg, or less than 100 mmHg.

11. Oxygen according to claim 10, wherein the AEF is applied until the subject's PaO2 / FiO2 ratio increases by 50%, 100%, 150% or 200%.

12. The oxygen of claim 10, wherein 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.

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

14. Oxygen according to claim 13, wherein the AEF is applied until the NLR is below 3.5 or decreases by at least 0.

2.

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

16. The therapeutic agent of claim 2, wherein the treatment further comprises administration of oxygen.

17. The therapeutic agent according to any one of claims 15 to 16, wherein the subject has not been diagnosed as having cancer, or wherein the subject does not have an infection.

18. The therapeutic agent according to any one of claims 15 to 17, further comprising administering respiratory support to the subject, preferably oxygen therapy, high flow oxygen therapy (HFNO) or hyperbaric oxygen therapy.

19. The therapeutic agent according to any one of claims 15 to 18, wherein the AEF is applied to the upper body area of ​​the subject, preferably the lungs of the subject.

20. The therapeutic agent of any one of claims 15 to 19, wherein the AEF is applied for at least 24 hours, at least 72 hours, or at least 30 days, wherein the frequency of the AEF is between 50 kHz and 10 MHz, between 125 kHz and 175 kHz, or the frequency is about 150 kHz, and / or wherein the intensity of the AEF is between 0.1 V / cm and 20 V / cm, or the intensity is between 1.0 V / cm and 4 V / cm.

21. The therapeutic agent of any one of claims 15 to 20, 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 of any one of claims 15 to 21, wherein the subject presents ARDS symptoms, such as one or more of severe shortness of breath, dyspnea, hypotension, or extreme fatigue, or wherein the subject presents pulmonary fibrosis or cytokine storm.

23. The therapeutic agent according to any one of claims 15 to 22, wherein the subject is tumor-free, preferably the subject is lung tumor-free.

24. The therapeutic agent of any one of claims 15 to 23, further comprising an initial step of determining the subject's PaO2 / FiO2 ratio, wherein the subject's PaO2 / FiO2 ratio is 300 mmHg or less, 200-300 mmHg, 100-199 mmHg, or less than 100 mmHg.

25. The therapeutic agent of any one of claims 15 to 24, wherein the AEF is applied until the subject's PaO2 / FiO2 ratio increases by 50%, 100%, 150%, or 200%.

26. The therapeutic agent of any one of claims 15 to 25, wherein 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.

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

28. The therapeutic agent of claim 27, wherein the AEF is applied until the NLR is below 3.5 or decreases by at least 0.2.

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