Method and system for monitoring the immune activities of a subject

Abstract

A system for measuring the level of immune activity (10) of a subject comprising: - an exhaled air sensor (20), - an exhaled air measurement device (30), - computing means (40) capable of determining exhaled air data from the subject based on measurements taken by the device (30), - a memory (60) capable of storing measurements taken by the device (30) and / or data calculated by the means (40) and personal data of the subject, - a computing means (70) capable of determining a level of immune activity of the subject based on at least one exhaled air data generated in real time by the means (40) and / or stored in the memory (60), - a communication and management interface (80) adapted to present said level of immune activity of the subject and / or sub-scores of immunological activity, inflammatory activity, digestive inflammation, and / or pulmonary inflammation. Figure to be published with the abbreviation: Figure 4

Description

Title of the invention: Method and system for monitoring the immune activities of a subject. Technical field

[0001] The invention belongs to the medical field, particularly to the field of embedded devices for measuring physiological data. More specifically, the invention relates to a system for monitoring the immune activities of a subject. The invention specifically concerns a system and a method for evaluating the immune activities of said subject. The system and method are adapted to predict the overall immune activity of the subject. Previous technique

[0002] Inflammation is the body's biological response to an insult such as infection, pathogens, irritants (chemicals, radiation, heat, etc.), or abnormal cells. It can be acute or chronic. Acute inflammation corresponds to the initial and often significant response of an organism to an insult, characterized by vasodilation, extravasation, and leukocyte involvement, while chronic inflammation corresponds to the establishment of a different response that persists over time. It can be of pathological origin, for example, associated with an autoimmune disease that can cause premature aging.Chronic inflammation is also associated with the Western lifestyle: sedentary behavior, highly processed foods, lack of sleep, pollution, and alterations in the gut microbiota are all considered contributing factors to pathologies with inflammatory components, such as insulin resistance, obesity, cardiovascular disease, immune disorders, Alzheimer's disease, and mood and behavioral disorders. Thus, inflammatory states of varying intensity can occur for varying durations and depend, in particular, on the body's exposure to certain environmental or dietary factors. An individual's inflammatory state has consequences for their overall well-being and the development of chronic diseases, and must also be taken into account in the context of cancer treatments such as immunotherapy, which can trigger autoimmune or inflammatory diseases.

[0003] Also, a weakening of the immune system, such as leukopenia, may contraindicate the implementation of treatments (such as immunotherapy or chemotherapy, for example). It should also be noted that a decrease in immunosurveillance, linked to immunosenescence, may leading to the emergence of malignant pathologies. Furthermore, it has also been shown that during episodes of sleep deprivation or intense stress the immune response can be impacted, thus with weakened defenses, it is a favorable environment for viral infections.

[0004] There is a need for the assessment and monitoring of the body's overall immune activity, non-invasively and as frequently as possible, in order to allow for precise monitoring and even the prediction of its evolution. Such assessment and monitoring notably allow for: - to predict the occurrence of episodes of immune system disruption, such as the onset of an inflammatory flare-up, or a weakening of the immune system, - to verify the effectiveness of preventive measures (against the occurrence of symptoms), - to plan the implementation of preventive measures, for example before the onset of symptoms, and / or - to detect a particular pathophysiological adaptation related to an activity or events encountered by the subject (such as a level of sporting activity, a specific diet or other).

[0005] The inflammatory state is usually measured by the level of C-reactive protein (CRP) in plasma or serum. CRP is a liver enzyme synthesized primarily by the liver but also by adipose tissue. CRP is an early, sensitive, and specific marker of the inflammatory response, and its levels are proportional to the intensity of the response. It appears within 6 hours of acute inflammation and reaches a peak within 48 hours. However, measuring blood CRP levels requires a blood test, which prevents individuals from independently monitoring their inflammatory state. Furthermore, the highly variable causality of elevated CRP levels makes it difficult to interpret a marginal increase.This makes it even more difficult to personalize the monitoring of inflammatory status and also to establish a link between individual personal events (such as the consumption of certain foods, exposure to certain environmental factors, physical activity) and the occurrence of inflammation, or even recurrent or persistent chronic micro-inflammation with its more or less significant consequences. Furthermore, inflammation can be systemic or localized, for example, in the intestines or lungs; CRP measurement does not allow for the detection of the site of inflammation.

[0006] The search for biomarkers in exhaled air (or breathomics, in Anglo-Saxon terminology) is an important area of ​​research (Roquencourt C, et al. 2022). These biomarkers would allow for non-invasive diagnosis of certain pathologies. or physiological states. The detection of volatile organic compounds and their use in metabolic health management, in relation to the gut microbiota, are discussed, for example, by Lee JH & Zhu J. (2021). Markers of airway inflammation are known to be detectable in the exhaled air of smokers (Garey et al. 2004).

[0007] Application WO2020 / 065241 relates to an apparatus for measuring the concentration of at least one of ethanol, CO, CO2 and / or H2O in a gas exhaled by a breath fluid. This apparatus is particularly suitable for use as a breathalyzer. Furthermore, there are now devices for testing exhaled gases, and in particular the hydrogen breath test, which measure sugar digestion problems and provide information regarding the risk of small intestinal bacterial overgrowth (SIBO).

[0008] Application WO2008079323 relates in particular to the diagnosis of pulmonary embolism via the monitoring of parameters derived from exhaled CO2. International application WO2013009589 relates to the field of embedded devices for measuring physiological data, particularly in the field of wellness and sports, including the measurement of transcutaneous VO2 and VCO2 of the subject and the measurement of exhaled air data at rest.

[0009] One object of the invention is to enable, by measuring the volatile organic compounds in the exhaled air of a subject, the measurement of a subject's overall immune activity level. Another object of the invention is to enable monitoring the evolution of the subject's overall immune activity. A further object of the invention is to predict the evolution of the overall immune activity level based on the occurrence of events during the subject's lifetime. Brief summary of the invention

[0010] A system for measuring the level of immune activity of a subject is therefore proposed, based on data determined from the air exhaled by said subject.

[0011] This system constitutes a non-invasive, rapid alternative that does not require the intervention of medical, biological or nursing personnel, and allows the subject to independently monitor their level of immune activity, or even anticipate its evolution.

[0012] Said system comprising:

[0013] - a sensor for the air exhaled by said subject,

[0014] - a device for measuring exhaled air comprising:

[0015] a spirometer capable of measuring the volume of air exhaled by the subject and the corresponding flow rate, and at least two sensors chosen from the following list: - a sensor capable of detecting methane levels in exhaled air, a sensor capable of detecting hydrogen (H2) levels in exhaled air, a sensor capable of detecting CO2 levels in exhaled air, a sensor capable of detecting, in exhaled air, the level of ketone bodies, a sensor capable of detecting a level of carbon monoxide in exhaled air nitrogen, a means of measuring the temperature of the exhaled air, and / or a means of measuring the humidity level of the exhaled air;

[0016] - computing means adapted for communicating with the measuring device of exhaled air and capable of determining exhaled air data from the measurements taken by the measuring device, this exhaled air data including at least one data point chosen from: a concentration of methane (CH4), a concentration of hydrogen (H2), a concentration of CO2, a concentration of ketone bodies, a concentration of nitrogen monoxide (NO), a temperature, and / or a humidity level;

[0017] - a memory capable of storing the measurements taken by the measuring device exhaled air and / or data calculated by the computing means and personal data of the subject,

[0018] - a calculation means suitable for determining a level of immune activity of the subject based on at least one exhaled air data point generated in real time by the computing means and / or stored in memory,

[0019] - a communication and management interface adapted to present said level of the subject's immune activity, said immunological activity subscore, said inflammatory activity subscore, said digestive inflammation subscore, and / or said pulmonary inflammation subscore.

[0020] Depending on other optional features of the system, the latter may optionally include one or more of the following features, alone or in combination:

[0021] - it further comprises a cutaneous measuring device comprising: a means of measuring surface skin temperature, a sensor capable of detecting a level of C-reactive protein (CRP), a sensor capable of detecting a lactate level, a sensor capable of detecting glucose levels, a sensor capable of detecting at least one level of a cytokine such as IL-1, IL-2, IL-6, IL-1O, TNF-alpha, interferon-alpha, or TGFB, - a means of measuring blood oxygen (O2) saturation, - a means of measuring the skin's moisture level, - a means of measuring skin pH

[0022] the means for calculating the system for measuring a level of immune activity being adapted to communicate with the cutaneous measuring device and capable of determining cutaneous data of the subject selected from at least one circulating lactate concentration, blood glucose, circulating CRP concentration, circulating cytokine concentration, said cutaneous data being able to be stored by the storage memory capable of storing the measurements made by the cutaneous measuring device and used by the calculation means to determine a level of the subject's immune activity from at least one subscore selected from: an immunological activity subscore, an inflammatory activity subscore, a digestive inflammation subscore and / or a pulmonary inflammation subscore;

[0023] - the calculation means is configured to identify a significant deviation for said the subject's level of immune activity, said immunological activity subscore, said inflammatory activity subscore, said digestive inflammation subscore, and / or for said pulmonary inflammation subscore with an individual standard for the subject and / or a collective standard for a group of subjects;

[0024] - the calculation means is configured to determine an individual standard of the subject for said level of immune activity of the subject, said sub-score of immunological activity, said sub-score of inflammatory activity, said sub-score of digestive inflammation, and / or for said sub-score of pulmonary inflammation, from a longitudinal series of data of the subject including at least one data point chosen from: - a concentration of methane, - a concentration of hydrogen (H2), - a concentration of CO2, - a concentration of ketone bodies, - a concentration of nitric oxide, - a temperature, - the level of humidity in the exhaled air, - a circulating lactate concentration, - a blood glucose level, - a concentration of circulating CRP, - a concentration of at least one cytokine such as IL-1, IL-2, IL-6, IL-10, TNF-alpha, interferon-alpha, or TGF-1, - skin hydration, and / or - blood oxygen saturation,

[0025] memory being capable of storing said individual norm of the subject;

[0026] - the communication interface is configured to periodically record in the memory of events experienced by the subject in the subject's personal data;

[0027] - the computing means is configured to correlate the experienced events by the subject and the subject's level of immune activity, said immunological activity subscore, said inflammatory activity subscore, said digestive inflammation subscore, and / or said pulmonary inflammation subscore to identify, among the events experienced by the subject, the events associated, for said at least one score or subscore, with a significant deviation from the individual norm of the subject or a collective norm of a group of subjects.

[0028] According to a second object, the invention relates to a method for monitoring the immune activity of a subject, implementing the immune activity measurement system according to the invention, comprising the following steps:

[0029] i) Calculate, from a database comprising at least one level of methane, hydrogen (H2), ketone bodies, nitric oxide, temperature, humidity, and volume and flow rates of the subject's exhaled air, at least one exhaled air data point selected from:

[0030] - a concentration of methane,

[0031] - a concentration of hydrogen (H2),

[0032] - a concentration of CO2,

[0033] - a concentration of ketone bodies,

[0034] - a concentration of nitric oxide,

[0035] - a temperature, and / or

[0036] - a level of humidity in the exhaled air,

[0037] ii) Optionally, calculate, from at least one level of circulating lactate, glucose, CRP and the skin moisture level and / or blood O2 level of the subject recorded in said database, at least one skin data point chosen from:

[0038] - a circulating lactate concentration,

[0039] - a blood glucose level,

[0040] - a circulating CRP concentration,

[0041] - a concentration of at least one cytokine such as IL1, IL2, IL6, IL1O, the TNF alpha, alpha interferon, or TGFB,

[0042] - skin hydration, and / or

[0043] - blood oxygen saturation;

[0044] iii) determine a level of immune activity of the subject from the data obtained in i) and optionally ii).

[0045] According to other optional features of the process, the latter may optionally include one or more of the following features, alone or in combination:

[0046] - a step of determining a standard of the subject comprising, over a period determined, the recurrent determination of at least one exhaled air data, and optionally of a cutaneous data and the determination of normal values ​​for said at least one exhaled air and cutaneous data specific to said subject;

[0047] - the determination of the subject's standard includes the recurrent determination of minus one exhaled air data point, and optionally one skin data point, takes place over a period selected from, one day, one week, 30 days or one or more years;

[0048] - a step comprising: Detecting at least one significant deviation for at least one exhaled air data, and optionally at least one skin data point, said at least one deviation indicating a change in the subject's immune activity;

[0049] - a step of recording at least one event experienced by the subject.

[0050] According to a third object, the invention relates to a method for predicting the occurrence of an alteration in immune activity in a subject comprising the implementation of the method according to the invention and a step of predicting the occurrence of abnormal immune activity in the subject when the subject experiences an event previously detected as correlated with at least one significant deviation for at least one exhaled air data, and optionally at least one skin data, with reference values, said at least one deviation indicating a change in the immune activity of the subject.

[0051] According to a fourth object, the invention relates to a method for determining the appropriate therapeutic window for administering a treatment to a subject based on the immune activity of said subject, comprising implementing the method according to the invention, characterized in that the appropriate therapeutic window is determined based on at least one level of immune activity of the subject, and / or at least one data point of exhaled air, and optionally at least one data point of the subject's skin. Brief description of the drawings

[0052] Other features, details and advantages will become apparent from the detailed description below and the accompanying figures, which illustrate:

[0053] [Fig-1] is a schematic representation of the activity measurement system immune 10 of a subject according to the invention, according to an embodiment.

[0054] [Fig.2] is a schematic representation of an element of the immune activity measurement system 10 of a subject, in which the exhaled air sensor 20 and the exhaled air measurement device 30 are associated.

[0055] [Fig.3] is a schematic representation of the immune activity measurement system 10 of a subject, comprising a smartphone, the exhaled air sensor 20 including the exhaled air measurement device 30, and optionally in which the exhaled air sensor 20 and the exhaled air measurement device 30 are associated.

[0056] [Fig.4] is a flowchart concerning the method 100 of calculating the score of the subject's immune activities according to an embodiment. Detailed description

[0057] System for measuring the immune activity of a subject.

[0058] Figure 1 illustrates an embodiment of a system for measuring the immune activity 10 of a subject. For the purposes of the invention, subject means any mammal, the immune activity measurement system 10 being particularly suited to a human.

[0059] This system 10 includes an exhaled air sensor 20 capable of receiving a quantity of air exhaled by the subject. Such devices are known from the prior art, for example, from application WO2020065241.

[0060] The exhaled air sensor 20 according to the invention makes it possible to direct and / or concentrate a portion of the air exhaled by a subject towards an exhaled air measurement device 30. Exhaled air means, in the sense of the invention, the air contained in a breath fluid of the subject during expiration, by the subject, into the exhaled air measurement device.

[0061] The exhaled air measurement device 30 itself may include various sensors enabling the measurement of at least one level of a molecule and / or physiological data related to the subject's immune activities. In a particular embodiment, as illustrated in [Fig. 2], the exhaled air sensor 20 integrates the exhaled air measurement device 30 and functions as a standalone device within the immune activity scoring system 10. Ideally, the standalone device comprising the exhaled air sensor 20 and the exhaled air measurement device 30 is sufficiently compact to be portable and manageable by the subject, for example, to fit in a human subject's hand. For example, the standalone device does not exceed 20 cm in length, 10 cm in width, and 5 cm in depth.

[0062] Sensors suitable for integration into the exhaled air measurement device 30 are commercially available and are capable of detecting and quantifying the levels of at least one chemical species or at least one physical quantity (such as that for example a speed, a flow rate) measured by said sensor 20 in a sample of air exhaled from the subject.

[0063] In a particular embodiment, these sensors are chosen from - a spirometer 31 capable of measuring the volume of air exhaled by the subject and the corresponding flow rate, - a sensor 32 capable of detecting a level of methane (CH4), - a sensor 33 capable of detecting a level of hydrogen (H2), - a sensor 34 capable of detecting a CO2 level, - a sensor 35 capable of detecting a level of ketone bodies, such as acetoacetate, 3-D-hydroxybutyrate and / or acetone, - a sensor 36 capable of detecting a level of nitrogen monoxide (NO), - a means of measuring the temperature 37 of exhaled air, and / or - a means of measuring the humidity level 38 of exhaled air.

[0064] In a particular embodiment, an exhaled air measurement device 30 comprises: - a spirometer 31 capable of measuring the volume of air exhaled by the subject and the corresponding flow rate,

[0065] and at least 2, 3, 4, 5, 6 sensors selected from: - a sensor 32 capable of detecting a level of methane (CH4), - a sensor 33 capable of detecting a level of hydrogen (H2), - a sensor 34 capable of detecting a CO2 level, - a sensor 35 capable of detecting a level of ketone bodies, - a sensor 36 capable of detecting a level of nitrogen monoxide (NO), - a means of measuring the temperature of exhaled air, - a means of measuring the humidity level 38 of exhaled air.

[0066] In a more particular embodiment, the air measurement device Exhaled 30 includes: - a spirometer 31 capable of measuring the volume of air exhaled by the subject and the corresponding flow rate, - a sensor 32 capable of detecting a level of methane, - a sensor 33 capable of detecting a level of hydrogen (H2), - a sensor 34 capable of detecting a CO2 level, - a sensor 35 capable of detecting a level of ketone bodies, - a sensor 36 capable of detecting a level of nitrogen monoxide (NO), - a means of measuring the temperature 37 of exhaled air, and - a means of measuring the humidity level 38 of exhaled air.

[0067] In a further particular embodiment, the exhaled air measurement device 30 comprises: - a spirometer 31 capable of measuring the volume of air exhaled by the subject and the corresponding flow rate,

[0068] and at least 2, 3, 4, 5 sensors selected from: - a sensor 32 capable of detecting a level of methane, - a sensor 33 capable of detecting a level of hydrogen (H2), - a sensor 34 capable of detecting a CO2 level, - a sensor 35 capable of detecting a level of ketone bodies, - a sensor 36 capable of detecting a level of nitrogen monoxide (NO).

[0069] The spirometer 31 usable in the system 10 of the invention refers to means capable of measuring the volumes and associated flow rates exhaled by the subject, and integrated into or associated with the exhaled air device according to the invention. The technologies enabling spirometry are well known to those skilled in the art; for example, in one embodiment, spirometry can be implemented using ultrasonic sensors or turbines such as those used in ultrasonic sensor or turbine spirometers.

[0070] Gas sensors capable of detecting levels of gases such as hydrogen (H2), methane (CH4), CO2, NO, or even ketone bodies, are examples of non-dispersive infrared (NDIR) sensors. These sensors detect gases in a gaseous environment by their absorption characteristics. The key components of such sensors are an infrared source, a light tube, an interference filter (wavelength), and an infrared detector. The gas is pumped or diffused into the light tube, and the electronics measure the absorption of the characteristic wavelength of the light.

[0071] The HITRAN database (for, according to Anglo-Saxon terminology, High Resolution Transmission,<https: / / hitran.org / > ) is a spectroscopic database that compiles spectroscopic parameters to predict and simulate the absorption and emission of light in gaseous media for, in particular, but not exclusively, the aforementioned species.

[0072] In a particular embodiment, volatile organic compounds contained in the air can be detected by means of a sensor using infrared technology such as, for example, described in patent FR308676.

[0073] Other gas sensors capable of detecting levels of gases such as hydrogen (H2), methane (CH4), CO2, NO, or even ketone bodies, are, for example, metal oxide-based gas sensors (or MOS sensors). Such MOS sensors are presented, for example, by Vajhadin et al. (2021). Depending on the semiconductor used, it is possible to detect different compounds.

[0074] Regarding the detection of hydrogen (H2), palladium-doped sensors are particularly suitable.

[0075] Electrochemical sensors are also capable of detecting methane (CH4), H2, CO2, NO, and even ketone bodies. The principle of the electrochemical sensor, also called an amperometric sensor, is to use an electrolyte that reacts with the gas in exhaled air and to measure the current produced. For this, a semi-permeable membrane allows the gas to diffuse into the electrolyte, which can be liquid or solid. A redox reaction occurs at the working electrode. The current is measured between this electrode and the auxiliary electrode. A third reference electrode is used to maintain a measurement point at a constant potential, since this electrode does not participate in the redox reaction, and therefore no current flows through it. Measuring the current allows the gas concentration to be determined (Paul Le Maout).Analysis of exhaled air using nanocomposite sensor arrays: the electronic nose for diagnostic assistance. Application to renal failure. Electronics. Ecole nationale supérieure Mines-Télécom Atlantique, 2019.

[0076] Means of measuring the temperature of exhaled air 37 are known to those skilled in the art; for example, they can be selected from semiconductor sensors or thermistor probes, such as negative temperature coefficient (NTC) thermistor probes. These sensors are particularly useful for correcting the levels or data measured by the sensors, which can be distorted by the temperature of the exhaled air.

[0077] Means of measuring the level of humidity of exhaled air 38 are known to those skilled in the art, for example, in one embodiment, they can be selected from capacitive or resistive sensors.

[0078] A capacitive humidity sensor measures humidity by detecting variations in electrical capacitance due to the humidity present in the environment. This type of sensor generally uses a dielectric material (such as a polymer) whose electrical properties change, specifically its dielectric constant, depending on the humidity, thus affecting the capacitor's capacitance.

[0079] A resistive humidity sensor measures humidity by detecting variations in electrical resistance caused by moisture present in the environment. These sensors generally use a material whose resistance changes with humidity, such as a polymer or a hygroscopic salt.

[0080] The electrical signal can be amplified, conditioned and converted into a digital value by a computing means 40 such as an analog-to-digital converter (CAN). The numerical value which can then be used by a computing means 70 or a communication and management interface 80.

[0081] In the system 10 according to the invention, said levels and / or quantities measured by said sensors are transmitted to computing means 40 capable of determining, for said exhaled air sample, at least one exhaled air data point selected from: - a concentration of methane (CH4), - a concentration of hydrogen (H2), - a concentration of CO2, - a concentration of ketone bodies, - a concentration of nitric oxide (NO), - an internal body temperature or an exhaled air temperature, and / or - a humidity level.

[0082] In a particular embodiment, at least 2, 3, 4, 5, or even 6 of the exhaled air data mentioned above are determined from the levels and / or quantities determined by the sensors of the exhaled air measuring device 30. In a further particular embodiment, the computing means 40 are capable of determining exhaled air data comprising: - a concentration of methane (CH4), - a concentration of hydrogen (H2), - a concentration of CO2, - a concentration of ketone bodies, - a concentration of nitric oxide (NO), - an internal body temperature or an exhaled air temperature, - a level of humidity,

[0083] thus characterizing the sample of air exhaled from the subject.

[0084] In another particular embodiment, the calculation means 40 are capable of determining exhaled air data comprising: - a concentration of methane (CH4), - a concentration of hydrogen (H2), - a concentration of CO2, - a concentration of ketone bodies, - a concentration of nitric oxide (NO),

[0085] thus characterizing the sample of air exhaled from the subject.

[0086] In a particular embodiment, the ketone bodies measured by the sensors of the invention are selected from acetoacetate (IUPAC name: 3-oxobutanoic acid), [3-D-hydroxybutyrate (IUPAC name: 3-hydroxybutanoic acid) and / or acetone (IUPAC name: propan-2-one).

[0087] The system for measuring the immune activity 10 of a subject according to the invention also comprises:

[0088] - at least one memory 60 capable of storing the measurements taken by the device measurement 30 and / or data calculated by the means of calculation 40 and personal data of the subject,

[0089] - at least one calculation means 70 capable of calculating an immune activity score of the subject based on at least one exhaled air data point generated in real time by the computing means and / or stored in memory 60,

[0090] - at least one communication and management interface 80 adapted for present said subject immune activity score, said immunological activity subscore, said inflammatory activity subscore, said digestive inflammation subscore, and / or said pulmonary inflammation subscore.

[0091] In one embodiment, in the immune activity measurement system 10, the exhaled air sensor 20, the exhaled air measurement device 30, at least one memory 60, at least one computing means 70 and at least one communication and management interface 80 are integrated together in the same device.

[0092] In this particular embodiment, the sensors of the exhaled air measurement device are physically connected to at least one memory 60 and / or at least one computing means 70, the at least one memory 60 and at least one computing means 70 thus being capable of receiving the electrical signals transmitted by the sensors of the exhaled air measurement device 30.

[0093] In another embodiment, the signals from the sensors of the exhaled air measurement device 30 are transmitted to at least one memory 60 and / or to at least one computing means 40 and / or to at least one computing means 70 via a communication interface comprising: - at least one short-range radio interface, such as "Bluetooth", "WiFi" or other, and / or - or at least a near field communication interface, such as NFC or RFID.

[0094] This embodiment is particularly suited to the immune activity measurement systems 10 according to the invention in which the exhaled air sensor 20 integrates the exhaled air measurement device 30 and is presented as an autonomous device in the immune activity level measurement system 10, as illustrated in [Fig.2] and mentioned above.

[0095] The at least one calculation means 40 is capable, from the signals sent by the at least one sensor of the exhaled air measurement device 30, of calculating at least one exhaled air data such as, for example, as a function of the sensor(s) integrated into the device 30: - a concentration of methane (CH4), - a concentration of hydrogen (H2), - a concentration of CO2, - a concentration of ketone bodies, - a concentration of nitric oxide (NO), - an internal body temperature or an exhaled air temperature, and / or - a humidity level.

[0096] At least one memory 60 stores at least one exhaled air data calculated by at least one calculation means 40. In one embodiment, the signals sent by at least one sensor of the exhaled air measuring device 30 are also stored in at least one memory 60 capable of storing the measurements taken by the sensors of the measuring device 30. The at least one exhaled air data and / or the signals sent by at least one sensor of the exhaled air measuring device 30 are recorded in the memory 60 with each expiration of the subject in the exhaled air sensor 20.

[0097] In one embodiment, memory 60 also stores personal data or personal events of the subject, such as, for example, the subject's feelings about their health, their physical activities (such as sports, travel, rest periods), their psychological state (such as stress, anxiety, depression), food ingested, the time of ingestion, or medication taken, and temporal data such as durations or times of occurrence of these events. The subject's personal data or personal events can be recorded in memory 60 throughout the day or periodically, for example, once a day, once a week, or once a month.

[0098] From at least one exhaled air data, at least one calculation means 70 is capable of calculating a level of immune activity of the subject.

[0099] In a particular embodiment, the subject's immune activity level is calculated from at least two exhaled air data selected from: - data on methane (CH4) concentration, - a concentration of hydrogen (H2), - a concentration of CO2, - a concentration of ketone bodies, - a concentration of nitric oxide (NO), - an internal body temperature or an exhaled air temperature, and / or - a humidity level.

[0100] In a particular embodiment, the subject's immune activity level is a composite score, and includes the calculation of at least one subscore chosen from among an immunological activity subscore, an inflammatory activity subscore, a digestive inflammation subscore and / or a pulmonary inflammation subscore of the subject.

[0101] In the art, a subject's immune status is assessed, in particular, from a complete blood count with differential, blood smear analysis, or even the determination of lymphocyte subpopulations with specific markers by flow cytometry. Analysis of certain immune mediators, such as cytokines, allows for determining the activity level of the immune system. Such examinations require blood sampling and a significant amount of analysis time to obtain results. A subject's immune status includes the activity of their cellular or humoral immunity, but also includes the gut microbiota. Measuring the subject's level of immune activity, determined using the system 10 according to the invention, reflects the subject's immune status, allows for its evaluation and its evolution, without requiring the multiplication of the aforementioned lengthy and costly examinations.

[0102] Immunological activity, as defined in the invention, is defined as the homeostasis of the immune system, that is, its level of regulation of the identification of elements perceived as foreign to the subject's organism and their destruction. An excessively high level of immunological activity can, for example, be a sign of immunological activity tending towards undesirable autoimmune reactions. Measuring such a level is of particular interest, for example, in determining the timing of administration of treatments that activate the immune system.

[0103] Inflammatory activity, as defined in the invention, refers to the overall inflammatory state of the body, including inflammation of the oropharyngeal, pulmonary, or intestinal systems. The inflammatory activity score therefore reflects the overall inflammatory state.

[0104] Pulmonary inflammation refers to the inflammatory state of the oropharyngeal and pulmonary system. The detection of exhaled air data from the oropharyngeal and pulmonary system can indicate pulmonary inflammation, which may be related to a pathology of the oropharyngeal or pulmonary system, but also to the presence of a more systemic or distant pathology. Thus, the pulmonary inflammation subscore reflects, in particular, the inflammatory state of the oropharyngeal and pulmonary system, but not exclusively.

[0105] Digestive inflammation, understood as the inflammatory state of the intestinal system, can be analyzed by detecting exhaled air data, which notably reflect the state and quality of the intestinal microbiota and the system intestinal. This condition may be linked to an intestinal or even digestive pathology, but also to the presence of a more systemic or distant pathology.

[0106] A subscore of the subject's immunological activity is calculated, for example, from exhaled air data such as ketone body concentration, temperature and / or humidity level of the exhaled air.

[0107] An inflammatory activity subscore is calculated, for example, from exhaled air data such as temperature, humidity level, NO concentration, ketone body concentration, temperature and / or CO2 concentration.

[0108] A subscore of pulmonary inflammation is calculated, for example, from exhaled air data such as temperature, humidity level, CO2 concentration, volume and / or flow rate of exhaled air and / or NO concentration.

[0109] A digestive inflammation subscore is calculated, for example, from exhaled air data such as temperature, humidity level and / or CH4 concentration, H2 concentration, ketone body concentration and / or CO2 concentration.

[0110] In another particular embodiment, the level of the subject's immune activity is calculated from the values ​​of at least one subscore chosen from an immunological activity subscore, an inflammatory activity subscore, a digestive inflammation subscore and / or a pulmonary inflammation subscore.

[0111] In one embodiment, at least one computing means 70 comprises an artificial intelligence capable of determining, from a longitudinal series of exhaled air data and / or data relating to the level of immune activity, and / or to one of the subscores of immunological activity, inflammatory activity, digestive inflammation activity and / or pulmonary inflammation, an individual standard for the subject for said exhaled air data, and / or said data relating to the level of immune activity, and / or the subscore of immunological activity, the subscore of inflammatory activity, the subscore of digestive inflammation and / or the subscore of pulmonary inflammation.The individual norm for a subject, for a given exhaled air value, immune activity level, and / or a subscore such as those mentioned below, may be understood as the average value observed for said value, immune activity level, or subscore over a series of their values ​​measured over 1, 2, 3, 4, 5, 6, or 7 days, or even two weeks, three weeks, one month, or even one or more years, in the absence of any particular event or by removing manifestly abnormal values ​​from the series. In another embodiment, said individual norm for the subject may be understood as the average value of the values ​​observed for a given exhaled air value, immune activity score, and / or a subscore such as those mentioned below according to a circadian rhythm. monthly, seasonal, or annual, respectively over several days, months, corresponding seasons, years.

[0112] According to a particular embodiment, at least one calculation means 70 is capable of identifying, within a series of values ​​of an exhaled air data, of an immune activity level and / or of at least one of the subscores as described above, the value or values ​​showing a significant deviation from an individual norm of the subject or a collective norm concerning the said data, level and / or subscores.

[0113] A collective standard, within the meaning of the invention, relates to an exhaled air value, an immune activity level, and / or at least one subscore as described above, and refers to a mean reference value for said value, said immune activity level, and / or at least one subscore as observed for a group of subjects sharing common characteristics. These characteristics are means of stratifying the subjects and may relate, for example, to age, sex, ethnicity, diet, and the presence or absence of a chronic or acute pathology in the subjects.

[0114] In a particular embodiment, a deviation will be considered significant if the subject presents an alteration (i.e. an increase or a decrease) greater than 1%, 2%, 5%, 10%, 15%, 20% or even 25% with the reference value of the individual norm of the subject or of the collective norm, for an exhaled air data of immune activity level or at least one subscore.

[0115] Alteration, as defined in the invention, means an increase or decrease in the measurement of a value, level, score, or physical value (such as concentration, volume, temperature, or relative proportion), relative to a reference value, individual or collective standard as defined above.

[0116] According to a particular embodiment, the artificial intelligence of at least one computing means 70 is trained to identify, from exhaled air data, the level of immune activity, and / or at least one of the subscores recorded in memory 60, personal events significantly associated with a significant alteration of said exhaled air data, said level of immune activity, and / or the subscores, relative to an individual or collective norm for the subject. In a further particular embodiment, the artificial intelligence of at least one computing means 70 is trained to predict the evolution of the subject's immune activity in the hours or days following the subject's consultation of the immune activity level measurement system 10 of the invention.Even more specifically, the artificial intelligence of at least one computing means 70 is trained to predict the occurrence of a significant alteration of an exhaled air data; of the subject's immune activity level of one of the subscores, . That is to say, to predict a significant alteration in the subject's immune activity, linked, for example, to an event experienced by the subject. For example, artificial intelligence is trained to predict the risk of an increase in the subject's inflammatory activity, linked, for example, to the ingestion of a food, the intake of a medication, and / or a particular physical activity. Advantageously, by combining data on the evolution of the subject's immune activity with the occurrence(s) of personal events experienced by the subject, the computational means 70 is configured to identify personal events experienced by the subject that result in a significant alteration of the subject's immune activity, such as identifying the consumption of a particular food as a source of altered immune activity and / or a source of inflammatory activity.

[0117] In one embodiment, the immune activity level measurement system 10 of the invention may also include a cutaneous measurement device 50 comprising at least one sensor or means selected from: - a means for measuring surface skin temperature 51, - a 52-sensor capable of detecting a level of C-reactive protein (CRP), - a sensor 53 capable of detecting a lactate level, - a sensor 54 capable of detecting a glucose level, - a sensor 55 capable of detecting at least one level of a cytokine such as IL1, IL2, IL6, IL1O, TNF alpha, interferon alpha, or TGFB - a means of measuring blood oxygen (O2) saturation 56, - a means of measuring the moisture level 57 of the skin. - a means of measuring the pH 58 of the skin.

[0118] In a particular embodiment, said cutaneous measuring device 50 includes at least two sensors or means selected from: - a means for measuring surface skin temperature 51, - a 52-sensor capable of detecting a level of C-reactive protein (CRP), - a sensor 53 capable of detecting a lactate level, - a sensor 54 capable of detecting a glucose level, - a sensor 55 capable of detecting at least one level of a cytokine such as IL1, IL2,1TL6, IL1O, TNF alpha, interferon alpha, or TGFB, - a means of measuring blood oxygen (O2) saturation 56, - a means of measuring the skin's moisture level 57, - a means of measuring the pH 58 of the skin.

[0119] In a further particular embodiment, said cutaneous measuring device 50 comprising 3, 4, 5, 6, 7 or 8 of the sensors or means mentioned above. More particularly, said cutaneous measuring device 50 comprises: - a means for measuring surface skin temperature 51, - a sensor 52 capable of detecting a level of C-reactive protein (CRP), - a sensor 53 capable of detecting a lactate level, - a sensor 54 capable of detecting a glucose level, - a sensor 55 capable of detecting at least one level of a cytokine such as IL1, IL2, IL6, IL1O, TNF alpha, interferon alpha, or TGFB, - a means of measuring blood oxygen (O2) saturation 56, and - a means of measuring the skin's moisture level 57, - a means of measuring the pH 58 of the skin.

[0120] Means for measuring skin surface temperature 51 usable in the system of the invention are known to those skilled in the art; they can be selected, for example, from semiconductor sensors or thermistor probes, such as negative temperature coefficient (NTC) thermistor probes. These sensors 51 are particularly useful for correcting the levels or data measured by the sensors, which can be distorted by skin temperature.

[0121] Means of measuring skin pH 58 usable in the system of the invention are known to those skilled in the art; they can be selected, for example, from among electrochemical sensors (glass-based sensors or ion-selective electrodes), polymer-based sensors, polyaniline-based sensors, optical sensors, field-effect transistor-based sensors, nanomaterial-based sensors, and sensors integrated into wearable devices. These sensors are particularly useful for correcting the levels or data measured by the sensors, which can be distorted by skin temperature.

[0122] A wide variety of sensors exist in the art that are capable of detecting lactate, glucose, and / or CRP levels. These sensors can be selected from:

[0123] - electrochemical biosensors,

[0124] - optical sensors (fluorescence or plasmonic),

[0125] - Surface plasmon resonance (SPR) sensors

[0126] - microfluidic sensors, and / or

[0127] - field-effect transistor sensors (in Anglo-Saxon terminology, "Field- effect transistor or FET).

[0128] In a particular embodiment, a sensor suitable for detecting the level of usable CRP in the system of the invention is known to those skilled in the art; for example, such a sensor may be such as that described by Yazhou Lei et al. (2019)

[0129] Impedance sensors 55 are suitable for detecting proteins such as those mentioned in Song et al. (2019) and are usable in the system of the invention for detecting interstitial cytokine levels. Relevant cytokines within the scope of the invention may be IL-1, IL-1, IL-2, IL-6, IL-1, TNF-alpha, interferon. alpha, or TGFB. IL6 and TNF alpha are of particular interest in the context of the invention because their monitoring makes it possible to anticipate cytokine storms, which are particularly deadly during episodes of viral pandemics, as well as to know the ideal time to administer immunomodulatory treatment.

[0130] Microneedle devices are particularly well-suited to support these sensors of the skin device Wang et al. (2023). Means 57 suitable for measuring a skin moisture level usable in the system 10 of the invention can be selected from capacitive sensors, resistive sensors or conductive polymer sensors as described above.

[0131] The cutaneous measuring device 50 is a device located on the subject's skin, which allows the transcutaneous measurement (for example, in the cutaneous interstitial tissue) of the aforementioned levels and data. At least one computing means 40 is adapted to communicate with said cutaneous measuring device 50 and capable of determining the subject's skin data from the data and levels measured by the sensors, such as circulating lactate concentration, blood glucose, circulating CRP concentration, concentration of at least one circulating cytokine such as 1TL1, 1TL2, IL6, 1TL10, TNF alpha, interferon alpha, or TGFB, body temperature, hydration level, pH, and / or oxygen saturation.In embodiments where the immune activity level measurement system 10 incorporates a skin measurement device 50, at least one memory 60 is also capable of storing the subject's skin data and the transcutaneous measurements taken by the sensors of the skin measurement device 50. The subject's skin data is advantageously combined with the subject's exhaled air data in calculating the subject's immune activity level and / or at least one subscore selected from: an immunological activity subscore, an inflammatory activity subscore, a digestive inflammation subscore, and / or a pulmonary inflammation subscore. Although exhaled air data are reliable and allow for quite satisfactory monitoring of the subject's immune activity, taking skin data into account allows for a more precise and comprehensive assessment thereof.

[0132] Thus, at least one calculation method 70 is then adapted to calculate at least one of the following sub-scores: - a subscore of the subject's immunological activity calculated, for example, from exhaled air data as mentioned above and / or from the subject's skin data such as skin temperature and / or hydration level. - A subscore of the subject's inflammatory activity calculated, for example, from exhaled air data as mentioned above and / or the subject's skin data such as skin temperature, pH, and level hydration, circulating CRP concentration, circulating lactate concentration, concentration of at least one circulating cytokine such as IL1, 1TL2, IL6, IL1O, TNF alpha, interferon alpha, or TGFB and / or blood glucose. - A subscore of pulmonary inflammation of the subject calculated, for example, from exhaled air data as mentioned above and / or cutaneous data of the subject such as skin temperature, hydration level, concentration of at least one circulating cytokine such as 1TL1,1TL2,1TL6, ITLIO, TNF alpha, interferon alpha, or TGFB, circulating CRP concentration and / or blood oxygen (O2) saturation. - A subscore of digestive inflammation of the subject calculated, for example, from exhaled air data as mentioned above and / or cutaneous data of the subject such as skin temperature, concentration of at least one circulating cytokine such as IL1, 1TL2, IL6, ITLIO, TNF alpha, interferon alpha, or TGFB, hydration level, and / or circulating CRP concentration.

[0133] As mentioned previously, the artificial intelligence of at least one computing means 70 is trained to identify, from skin data combined or not with exhaled area data, the level of immune activity and / or at least one of the subscores obtained with exhaled air data combined or not with skin data and recorded in memory 60, the personal events significantly associated with a significant alteration of said data, said level of immune activity and / or said subscores, compared to an individual or collective norm for the subject. In a further specific embodiment, the artificial intelligence of at least one computing means 70 is trained to predict the evolution of the subject's immune activity in the hours or days following the subject's consultation of the immune activity level measurement system 10 of the invention.More specifically, the artificial intelligence of at least one computing method 70 is trained to predict the occurrence of a significant alteration in exhaled air data, skin data, the subject's immune activity level, or one of the subscores; that is, to predict a significant alteration in the subject's immune activities, linked, for example, to an event experienced by the subject. For example, the artificial intelligence is trained to predict the risk of an increase in the subject's inflammatory activity, linked, for example, to the ingestion of a food, the intake of a medication, and / or a particular physical activity. Advantageously, by combining data on the evolution of the subject's immune activity with the occurrence(s) of the personal event(s) experienced by the subject, the computing method... 70 is configured to identify personal events experienced by the subject that result in a significant alteration of the subject's immune activity, such as identifying the consumption of a particular food as a source of altered immune activity and / or inflammatory activity.

[0134] The communication and management interface 80 can be configured to allow the subject to populate the memory 60 with their personal data, such as physiological data relevant to the assessment and monitoring of the subject's immune status (e.g., age, sex, ethnicity, pathology, treatment, etc.). The communication and management interface 80 can be configured to allow the subject to control or adapt the computing resources 40 and / or the memory 60.The communication and management interface 80 can also be configured to present the subject with exhaled air or skin data of an immune activity level, an immunological activity subscore, an inflammatory activity subscore, a digestive inflammation activity subscore, and / or a pulmonary inflammation subscore, as determined by the calculation means 70. The communication and management interface 80 can also be configured to present the user with a prognosis of the evolution of their immune activity, as previously described, in the hours or days following the subject's consultation of the communication and management interface 80. In a particular embodiment, the prognosis of the evolution of a subject's immune activity may include the prediction of the onset or worsening of symptoms related to a chronic condition.

[0135] Advantageously, as illustrated in [Fig.3], the level measurement system. The immune activity monitoring system 10 includes a mobile communication device 90 comprising the communication and management interface 80, the computing means 40, 70 and the memory 60, communicating with the exhaled air measurement device 30 and optionally with the skin measurement device 50, via a short-range communication interface using the Bluetooth protocol, or for example, but not limited to, the ISM, Wi-Fi, ANT or Zigbee protocols. The mobile communication device 90 may be, for example, a smartphone or a smartwatch.The communication and management interface 80 can be an application through which the subject enters personal data and personal events experienced and consults exhaled air data or skin data; the level of immune activity, the immunological activity subscore, the inflammatory activity subscore, the digestive inflammation subscore and / or the pulmonary inflammation subscore.

[0136] Of course, the mobile communication device 90 can automatically exchange personal events experienced, or data Personal data recorded or measured with the communication and management interface. Any other connected device, such as a smart ring, bracelet, motion sensor, etc., can also transmit personal data and personal events experienced by the user to the system. Thus, in a particular embodiment, the system may include at least one other connected device, such as a smart ring, bracelet, or motion sensor, capable of transmitting personal data and personal events experienced by the user to the system of the invention.

[0137] In another embodiment, the computing means 40, 70, and the memory 60 are stored on a remote device which receives the signals sent by the exhaled area measurement device 30 and optionally by the skin measurement device 50. The mobile communication device 90 can then, for example, transmit said signals via a 3G, 4G or 5G type communication interface.The mobile communication device 90 can then also receive information from at least one computing means 70 such as exhaled air or skin data, an immune activity level, and / or an immunological activity subscore, an inflammatory activity subscore, a digestive inflammation subscore and / or a pulmonary inflammation subscore, the detection of an alteration in one of the said exhaled air or skin level data and / or subscores, and / or the prediction of the occurrence of an inflammatory episode in the subject's body.

[0138] Method for monitoring the immune activity of a subject

[0139] Figure 4 illustrates one embodiment of a method for monitoring the activity level. immune system of a subject 100 implementing a system for measuring a level of immune activity 10, the process is described below.

[0140] In step 110, at least one exhaled air data point for the subject is calculated. This at least one data point is calculated, for example by the calculation means 40 of the immune activity level calculation system 10, from a physiological level or data point detected by a sensor of the exhaled air measurement device 30, which is stored in a database, for example in memory 60 or used in real time. In one embodiment, the database includes at least one level of methane, hydrogen (H2), ketone bodies, nitric oxide, carbon dioxide, temperature, humidity, and / or volume and flow rates of the subject's exhaled air.In one particular embodiment, exhaled air data calculated within 15, 10, or even 5 minutes following an event such as food intake, medication administration, enema administration, or beverage consumption, or any other exogenous event that alters the composition of exhaled air, are not considered by the system. Thus, in one embodiment, exhaled air data 5, 10, or even 15 minutes after food intake, medication administration, enema administration, or beverage consumption are not considered. Not taken into account. In a method of carrying out exhaled air data following 5, 10 or even 15 minutes, the intake of food, medicine, enema, or drink is not taken into account.

[0141] In an optional step 120, at least one skin data point of the subject is calculated. This at least one skin data point is calculated, for example, by the calculation means 40 from a physiological level or data point detected by a sensor of the skin measuring device 50, which is stored in a database, for example in memory 60. In one embodiment, the database includes at least one level of circulating lactate, glucose, cytokines, CRP, and a level of skin moisture and / or the level of O2 in the subject's blood.

[0142] During a step 130, at least one data point of exhaled air, of the subject's immune activity level, of an immunological activity subscore, of an inflammatory activity subscore, of a digestive inflammation subscore, and / or of a pulmonary inflammation subscore of the subject, is calculated, for example by the calculation means 70, said data of exhaled air, of the immune activity level and / or of said subscores reflecting the immune activity of the subject.In a particular embodiment, at least one exhaled air data, one skin data (when skin data are measured by the system), of the subject's immune activity level, of an immunological activity subscore, of an inflammatory activity subscore, of a digestive inflammation subscore, and / or of a pulmonary inflammation subscore of the subject, is calculated, for example by calculation means 70, said exhaled air, skin, immune activity level and / or said subscores reflecting the subject's immune activity.

[0143] Said exhaled air and skin data, when the latter are measured, along with immune activity levels and / or subscores, allow for the assessment and long-term monitoring of the subject's immune activity, both systemically and at the intestinal or pulmonary level. For example, this makes it possible to evaluate the presence or absence of inflammation, or even a state of micro-inflammation, in the subject being tested. Micro-inflammation is defined as a background inflammatory state, at a low level compared to acute inflammatory episodes.

[0144] An additional step 140 of the method 100 according to the invention may include the detection of at least one significant deviation between at least one exhaled air, skin (when the system measures skin data), subject immune activity level, at least one immunological activity subscore, at least one inflammatory activity subscore, at least one digestive inflammation subscore, and / or at least one pulmonary inflammation subscore of the subject determined in step 130 and reference values. This step 130 may be performed by the calculation means 70 of the system 10 of the invention. A significant deviation indicates an alteration (modification) of the subject's immune activity, for example an increase in immune activity, for example the presence or increase of inflammatory activity in the subject or a decrease in the subject's inflammatory state.

[0145] Reference values ​​may correspond, as mentioned above, to: - a collective standard corresponding to an average reference value for said exhaled air data, skin data, level of immune activity and / or subscore as observed for a group of subjects sharing common characteristics, or - an individual standard for the subject, corresponding to the average value observed for said exhaled air data, skin data, said level of immune activity or said subscore for a series of their values ​​measured over 1 day, 2, 3, 4, 5, 6, 7 days, or even two weeks, three weeks, or even one month, or even one year, in the absence of any particular event or by removing the manifestly abnormal values ​​from the series of values.

[0146] For the determination of the individual norm of subject 150, at least one exhaled air data point, at least one skin data point, said level of immune activity, or at least one of the subscores as mentioned, are determined recurrently over a period such as one day, 2, 3, 4, 5, or 6 days (with, for example, several data points such as exhaled air data, and optionally several skin data points collected on each day), or even one week, two weeks, or even three weeks, or even several months or a year. This determination of the individual norm of the subject can be implemented with the system 10 of the invention.

[0147] An additional step 160 of the process 100 may include recording at least one personal event experienced by the subject, such as an event related to their health, physical activities, psychological state, food intake, or medication intake, as well as associated temporal data such as the duration or timing of these personal events. Step 160 is not linked to the other steps of the process and can therefore be carried out independently or concurrently with them. This step can be performed using the communication and management interface 80, and the data relating to the at least one personal event experienced by the subject can be stored in memory 60.

[0148] A step 170 of the process 100 comprises the analysis and detection of a correlation between the significant deviation detected in step 140. This step may include the creation and use of a neural network trained with an individual subject norm or a collective subject norm as defined above. The neural network may be stored in the memory 60 of the system 10 of the invention. Classically, the network The neural network is trained with individual or group norm data until it converges. The continuous acquisition of exhaled air or skin data, immune activity levels and / or subscores, as well as personal life events, allows artificial intelligence to predict significant alterations in a subject's immune activity, such as, for example, an increase in inflammatory activity within the subject's body. This is of particular interest to subjects suffering from chronic immune disorders, for predicting the onset of a crisis or flare-up of these conditions.Examples of such pathologies include, for instance, pathologies with diffuse effects throughout the body, such as connective tissue diseases like rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, systemic scleroderma, Sjögren's syndrome, and inflammatory myopathies; primary vasculitides such as giant cell arteritis, Takashu's disease, Kawasaki disease, polyarteritis nodosa, Wegner's disease, Churg-Strauss syndrome, microscopic palyangitis, anti-GBM antibody vasculitis, and Behçet's disease; or pathologies more specific to certain organs or tissues such as multiple sclerosis, psoriasis, Crohn's disease, Guillain-Barré syndrome, myasthenia gravis, Lambert-Eaton disease, and pemphigoid, etc.

[0149] Thus, the method 100 of the invention makes it possible to detect the onset of a crisis or flare-up of these diseases before the appearance of its symptoms, and therefore to implement therapeutic or symptomatic solutions aimed at preventing or reducing the symptoms of this crisis, before the crisis occurs, or its consequences in the subject's life. In particular, this can allow for the early initiation of therapy, resulting in better prevention, or a reduction in the intensity of the crisis and its symptoms, or even a reduction in the doses administered in this therapy, due to this early intervention.

[0150] A crisis or flare-up, as defined in the invention, refers in particular to an exacerbation of the symptoms of these chronic pathologies. In one particular embodiment, the method 100 of the invention is used to predict a significant alteration in the subject's immune activity. In a further particular embodiment, the method 100 of the invention is used to predict the onset of a crisis or flare-up of a pathology as described above.

[0151] In a particular embodiment, artificial intelligence can be trained to associate the aforementioned data and levels with plasma levels of biomarkers associated, for example, with inflammation (such as a plasma TNF level), sports activity or a level of metabolic activity (such as an irisin level), a level of autophagy (such as a spermidine level).

[0152] Method for determining the appropriate administration window for administering a treatment to a subject based on immune activity

[0153] Certain treatments have undesirable effects on the immune system and therefore their administration may be contraindicated in cases of excessive or, conversely, insufficient immune activity in the subject's body. These treatments necessitate the assessment of the subject's immune activity before administration. For example, immunotherapy can exacerbate certain undesirable immune pathologies, and some chemotherapies are known, conversely, to negatively impact the immune system. The invention makes it possible to monitor the subject's immune activity to determine the optimal administration window for such treatments. The invention also makes it possible to detect excessive alterations during these treatments.Thus, in one aspect, the invention also relates to a method for determining the therapeutic window for administering a treatment to a subject based on exhaled air and skin data, the subject's level of immune activity, at least one subscore of immunological activity, at least one subscore of inflammatory activity, at least one subscore of digestive inflammation, and / or at least one subscore of pulmonary inflammation. The treatment may be contraindicated in cases of insufficient immune activity or, conversely, in cases of excessive immune activity.Thus, for example, in the case of a treatment to trigger strong immune responses, such as immunotherapy, it will be desirable to wait for or implement solutions for reducing immune activity that is too high compared to the subject's norm as determined using the method of the invention, for example by using the system for calculating an immune activity score of the invention.

[0154] It will be understood that the devices, processes, and / or methods of the present invention are of particular interest in the context of conducting clinical trials or administering therapies requiring validation that the subject is suitable to receive them. The device, processes, and / or methods according to the invention allow for the remote monitoring of patient data, and in particular, the immune activity of the subject's body. This can, in particular, reduce travel to healthcare facilities, eliminate unnecessary biological sampling, and even improve the administration of therapies by allowing remote determination of whether the subject is in a suitable condition for administration, thereby improving the subject's quality of life and contributing to greater treatment efficacy.

[0155] More broadly, it will also be understood that the devices and processes and / or methods of the present invention are of particular interest in the context of improving the general condition of a subject's organism, apart from any pathology, by allowing the subject to maintain and control the subject's immune homeostasis. References

[0156] Garey KW, Neuhauser MM, Robbins RA, Danziger LH, Rubinstein I. Markers of inflammation in exhaled breath condensate of young healthy smokers. Chest. 2004

[0157] Lee JH & Zhu J. (2021). Analyzes of short-chain fatty acids and exhaled breath volatiles in dietary intervention trials for metabolic diseases. Exp Biol Med (Maywood). 2021 Apr;246(7):778-789

[0158] Roquencourt C, Grassin-Delyle S, Thévenot EA. ptairMS: real-time processing and analysis of PTR-TOF-MS data for biomarker discovery in exhaled breath. Bioinformatics. 2022 Jan

[0159] Song N, Xie P, Shen W, Oh H, Zhang Y, Vitale F, Javanmard M, Allen MG. A microwell-based impédance sensor on an insertable microneedle for real-time in vivo cytokine détection. Microsyst Nanoeng. 2021 Nov 26;7:96.

[0160] Vajhadin F, Mazloum-Ardakani M, Amini A. Métal oxide-based gas sensors for the détection of exhaled breath markers. Med Devices Sens. 2021 Feb;4(l):el0161.

[0161] Wang J, Lu Z, Cai R, Zheng H, Yu J, Zhang Y, Gu Z. Microneedle-based transdermal détection and sensing devices. Lab Chip. 2023 Mar 1 ;23(5):869-887. doi: 10.1039 / d21c00790h. PMID: 36629050.

[0162] Yazhou Lei et al. A self-powered electronic-skin for detecting CRP level in body fluid based on the piezoelectric-biosensing coupling effect of GaN. nanowireSmart Mater. Struct. (2019). 28 105001.

Claims

1. Demands System for measuring the level of immune activity (10) of a subject comprising: - a sensor for the air exhaled (20) by said subject, - a device for measuring exhaled air (30) comprising: a spirometer (31) capable of measuring the volume of air exhaled by the subject and the corresponding flow rate, and at least two sensors chosen from the following list: - a sensor (32) capable of detecting, in exhaled air, a level of methane, - a sensor (33) capable of detecting, in exhaled air, a level of hydrogen (H2), - a sensor (34) capable of detecting, in exhaled air, a level of CO2, - a sensor (35) capable of detecting, in exhaled air, a level of ketone bodies, - a sensor (36) capable of detecting, in exhaled air, a level of nitrogen monoxide, - a means of measuring the temperature (37) of exhaled air, and / or - a means of measuring the humidity level (38) of exhaled air; - computing means (40) adapted to communicate with the exhaled air measurement device (30) and capable of determining exhaled air data from the measurements taken by the measurement device (30), this exhaled air data comprising at least one data point chosen from: - a concentration of methane (CH4), - a concentration of hydrogen (H2), - a concentration of CO2, - a concentration of ketone bodies, - a concentration of nitric oxide (NO), - a temperature, and / or - a level of humidity; - a memory (60) capable of storing the measurements taken by the exhaled air measurement device (30) and / or the data calculated by the computing means (40) and personal data of the subject, - a computing means (70) capable of determining a level of the subject's immune activity from at least one exhaled air data generated in real time by the computing means (40) and / or stored in the memory (60), - a communication and management interface (80) adapted to present said level of immune activity of the subject, an immunological activity subscore, an inflammatory activity subscore, a digestive inflammation subscore, and / or a pulmonary inflammation subscore.

2. A system for measuring the level of immune activity (10) of a subject according to any one of the preceding claims, further comprising a cutaneous measuring device (50) comprising: - a means for measuring skin surface temperature (51), - a sensor (52) capable of detecting a level of C-reactive protein (CRP), - a sensor (53) capable of detecting a lactate level, - a sensor (54) capable of detecting a glucose level, - a sensor (55) capable of detecting at least one level of a cytokines such as IL-1, IL-2, IL-6, IL-1O, TNF-alpha, interferon-alpha, or TGFB, - a means of measuring blood oxygen (O2) saturation (56), - a means of measuring the moisture level (57) of the skin, - a means of measuring the pH (58) of the skin, The computing means (40) of the system for measuring a level of immune activity (10) are adapted to communicate with the skin measuring device (50) and are capable of determining skin data of the subject selected from at least one circulating lactate concentration, blood glucose level, circulating CRP concentration, and circulating cytokine concentration. This skin data can be stored by the storage memory (60) capable of storing the measurements performed by the skin measuring device (50) and used by the computing means (70) to determine the level of the subject's immune activity based on at least one subscore selected from: said immunological activity subscore, said inflammatory activity subscore, said digestive inflammation subscore and / or said pulmonary inflammation subscore.

3. A system for measuring a level of immune activity (10) of a subject according to claim 1 or 2, characterized in that the calculation means (70) is configured to identify a significant deviation for said level of immune activity of the subject, said subscore of immunological activity, said subscore of inflammatory activity, said subscore of digestive inflammation, and / or for said subscore of pulmonary inflammation with an individual standard of the subject and / or a collective standard of a group of subjects.

4. A system for measuring a subject's level of immune activity (10) according to any one of the preceding claims, characterized in that the calculation means (70) is configured to determine an individual standard for the subject's level of immune activity, said immunological activity subscore, said inflammatory activity subscore, said digestive inflammation subscore, and / or for said pulmonary inflammation subscore, from a longitudinal series of subject data comprising at least one data point selected from: - a methane concentration, - a hydrogen (H2) concentration, - a CO2 concentration, - a ketone body concentration, - a nitric oxide concentration, - a temperature, - an exhaled air humidity level, - a circulating lactate concentration, - a blood glucose level, - a circulating CRP concentration,- a concentration of at least one cytokine such as IL-1, IL-2, IL-6, IL-1O, TNF-alpha, interferon-alpha, or TGFB, - skin hydration, and / or - blood oxygen saturation, memory (60) being capable of storing said individual norm of the subject.

5. A system for measuring the level of immune activity (10) of a subject according to any one of the preceding claims, characterized in that the communication interface (80) is configured to periodically record in memory (60) events experienced by the subject in the subject's personal data.

6. A system for measuring the level of immune activity (10) of a subject according to claim 3 characterized in that the calculation means (60) is configured to correlate the events experienced by the subject and the level of immune activity of the subject, said immunological activity subscore, said inflammatory activity subscore, said digestive inflammation subscore, and / or said pulmonary inflammation subscore to identify, among the events experienced by the subject, the events associated, for said at least one score or subscore, with a significant deviation from the individual norm of the subject or a collective norm of a group of subjects.

7. A method for monitoring the immune activity (100) of a subject, implementing the immune activity measurement system (10) according to any one of the preceding claims, comprising the following steps: i) Calculating (110) from a database comprising at least one level of methane, hydrogen (H2), ketone bodies, nitric oxide, temperature, humidity, and volume and flow rates of the subject's exhaled air, at least one exhaled air data point selected from: - a methane concentration, - a hydrogen (H2) concentration, - a CO2 concentration, - a ketone body concentration, - a nitric oxide concentration, - a temperature, and / or - a humidity level of the exhaled air, ii) Optionally, calculating (120) from at least one level of circulating lactate, glucose, CRP, and humidity level of the skin and / or the level of O2 in the blood of the subject recorded in said database, at least one skin data chosen from: - a circulating lactate concentration, - a blood glucose level, - a circulating CRP concentration, - a concentration of at least one cytokine such as IL1, IL2, IL6, IL1O, TNF alpha, interferon alpha, or TGFB, - a skin hydration, and / or - a blood O2 saturation; iii) determine a level of immune activity (130) of the subject from the data obtained in i) and optionally ii).

8. Method for monitoring the immune activity (100) of a subject according to claim 7, comprising a step of determining a standard (140) of the subject comprising, over a specified period, the recurrent determination of at least one exhaled air data, and optionally of a skin data and the determination of normal values ​​for said at least one exhaled air and skin data specific to said subject.

9. A method for monitoring the immune activity (100) of a subject according to claim 8, wherein the determination of the subject's standard (140) includes the recurrent determination of at least one exhaled air data, and optionally of a skin data, takes place over a period selected from, one day, one week, 30 days or one or more years.

10. A method for monitoring the immune activity (100) of a subject according to any one of claims 7 to 9, further comprising a step of: Detecting at least one significant deviation (150) for at least one exhaled air data, and optionally at least one skin data, said at least one deviation indicating a change in the immune activity of the subject.

11. Method for monitoring the immune activity (100) of a subject according to any one of claims 7 to 10, further comprising a step of recording at least one event (160) experienced by the subject.

12. A method for monitoring the immune activity of a subject according to claim 11 comprising the analysis (170) of at least one significant deviation and at least one event experienced by the subject and the detection of a correlation between said at least one significant deviation and at least one event experienced by the subject.

13. Method for predicting the occurrence of an alteration in immune activity in a subject comprising implementing the method according to claim 12 and a step of predicting the occurrence of abnormal immune activity in the subject when the subject experiences an event previously detected as correlated with at least one significant deviation for at least one exhaled air data, and optionally at least one skin data, with reference values, said at least one deviation indicating an alteration in the subject's immune activity.

14. Method for determining the appropriate therapeutic window for administering a treatment to a subject based on the immune activity of said subject comprising implementation of the method (100) according to any one of claims 7 to 12, characterized in that the appropriate therapeutic window is determined based on at least one level of immune activity of the subject, and / or at least one data point of exhaled air, and optionally at least one data point of the subject's skin.

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