FR3164890A1 - Method and system for monitoring the immune activities of a subject - Google Patents

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 measurements taken by the device (30), - a memory (60) capable of storing the measurements taken by the device (30) and/or the data calculated by the means (40) and the subject's personal data, - a computing means (70) capable of determining the subject's level of immune activity from at least one exhaled air data point generated in real time by the means (40) and/or stored in the memory (60), - a communication and management interface (80) adapted to display said level of the subject's immune activity and/or subscores of immunological activity, inflammatory activity, and digestive inflammation. and/or pulmonary inflammation. Figure to be published with the abbreviation: Figure 4

Description

Method and system for monitoring the immune activities of a subject

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

Inflammation is the body's biological response to an attack, 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 attack, characterized by vasodilation, extravasation, and leukocyte involvement, while chronic inflammation corresponds to the establishment of a different, persistent response 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 considered contributing factors to diseases with inflammatory components, such as insulin resistance, obesity, cardiovascular disease, immune diseases, 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.

Furthermore, a weakened immune system, such as leukopenia, can contraindicate the implementation of treatments (such as immunotherapy or chemotherapy). It should also be noted that a decrease in immunosurveillance, linked to immunosenescence, can lead to the emergence of malignant diseases. Moreover, it has also been shown that during episodes of sleep deprivation or intense stress, the immune response can be impacted; thus, with weakened defenses, this creates a favorable environment for viral infections.

• de prédire la survenue d’épisodes de perturbation du système immunitaire, comme par exemple la survenue de flambée inflammatoire, ou un affaiblissement du système immunitaire,
• de vérifier l’efficacité de mesures de prévention (de la survenue de symptômes),
• de planifier la mise en œuvre de mesures de prévention, par exemple en amont de la survenue de symptômes, et/ou
• de détecter une adaptation physiopathologique particulière en rapport avec une activité ou des événements rencontrés par le sujet (tels qu’un niveau d’activité sportive, une alimentation spécifique ou autre).

There is a need for the assessment and monitoring of the body's overall immune activity, non-invasively and as frequently as possible, to allow for precise tracking 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).

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 own inflammatory status. Furthermore, the causality of CRP levels is highly variable. Elevated CRP levels make it difficult to interpret even marginal elevations. This further complicates the personalization of inflammatory monitoring and the establishment of a link between individual events (such as food intake, exposure to environmental factors, or physical activity) and the onset of inflammation, or even recurrent or persistent chronic microinflammation with potentially significant consequences. Moreover, inflammation can be systemic or localized, for example, in the intestines or lungs; CRP measurement alone cannot pinpoint the site of inflammation.

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 could allow for non-invasive diagnosis of certain pathologies or physiological states. The detection of volatile organic compounds and their use in managing metabolic health, 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).

Application WO2020/065241 concerns 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, notably the hydrogen breath test, which measure sugar digestion problems and provide information regarding the risk of small intestinal bacterial overgrowth (SIBO).

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 areas of wellness and sports, including the measurement of transcutaneous _VO2 and _VCO2 of the subject and the measurement of exhaled air data at rest.

One aim of the invention is to enable the measurement of a subject's individual overall immune activity level by measuring the volatile organic compounds in their exhaled breath. Another aim is to enable the monitoring of changes in the subject's overall immune activity. A further aim is to predict changes in overall immune activity levels based on the occurrence of events throughout the subject's life.

Brief summary of the invention

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

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

The said system includes:

- a sensor for the air exhaled by said subject,

- a device for measuring exhaled air comprising:

• un capteur apte à détecter, dans l’air exhalé, un niveau de méthane,
• un capteur apte à détecter, dans l’air exhalé, un niveau d’hydrogène (H2),
• un capteur apte à détecter, dans l’air exhalé, un niveau de CO2,
• un capteur apte à détecter, dans l’air exhalé, un niveau de corps cétoniques,
• un capteur apte à détecter, dans l’air exhalé, un niveau de monoxyde d’azote,
• un moyen de mesure de la température de l’air exhalé, et/ou
• un moyen de mesure du niveau d’humidité de l’air exhalé ;

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 nitrogen monoxide levels in exhaled air,
• a means of measuring the temperature of exhaled air, and/or
• a means of measuring the humidity level of exhaled air;

• une concentration de méthane (CH4),
• une concentration d’hydrogène (H2),
• une concentration de CO2,
• une concentration en corps cétoniques,
• une concentration en monoxyde d’azote (NO),
• une température, et/ou
• un niveau d’humidité ;

- suitable computing means for communicating with the exhaled air measurement device and capable of determining exhaled air data from the measurements taken by the measurement 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 nitric oxide (NO),
• a temperature, and/or
• a level of humidity;

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

- a computing means capable of determining the level of immune activity of the subject from at least one exhaled air data point generated in real time by the computing means and/or stored in memory,

- a suitable communication and management interface to present 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 said sub-score of pulmonary inflammation.

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

• un moyen de mesure de la température cutanée de surface,
• un capteur apte à détecter un niveau de protéine C réactive (CRP),
• un capteur apte à détecter un niveau de lactate,
• un capteur apte à détecter un niveau de glucose,
• un capteur apte à détecter au moins un niveau d’une cytokine telle que l’IL1, l’IL2, l’IL6, l’IL10, le TNF alpha, l’interféron alpha, ou le TGFß,
• un moyen de mesure de la saturation sanguine en oxygène (O₂),
• un moyen de mesure du niveau d’humidité de la peau,
• un moyen de mesure du pH de la peau

- it also includes 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 IL1, IL2, IL6, IL10, TNF alpha, interferon alpha, or TGFβ,
• a means of measuring blood oxygen saturation ( _O2 ),
• a means of measuring the skin's moisture level,
• a method for measuring skin pH

the means of calculation of 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 chosen from at least one concentration of circulating lactates, a blood glucose, a concentration of circulating CRP, a concentration of circulating cytokine, 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 means of calculation to determine a level of the subject's immune activity from at least one sub-score selected from: an immunological activity sub-score, an inflammatory activity sub-score, a digestive inflammation sub-score and/or a pulmonary inflammation sub-score;

- the calculation means 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 norm of the subject and/or a collective norm of a group of subjects;

• une concentration de méthane,
• une concentration d’hydrogène (H₂),
• une concentration de CO₂,
• une concentration en corps cétoniques,
• une concentration en monoxyde d’azote,
• une température,
• un niveau d’humidité de l’air exhalé,
• une concentration en lactate circulant,
• une glycémie,
• une concentration en CRP circulant,
• une concentration d’au moins une cytokine telle que l’IL1, l’IL2, l’IL6, l’IL10, le TNF alpha, l’interféron alpha, ou le TGFß,
• une hydratation de la peau, et/ou
• une saturation sanguine en O₂,

- the calculation method is configured to determine an individual standard for the subject for said level of the subject's 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 concentration of methane,
• a concentration of hydrogen ( _H2 ),
• a concentration of _CO2 ,
• a concentration of ketone bodies,
• a concentration of nitric oxide,
• a temperature,
• a level of humidity in the exhaled air,
• a circulating lactate concentration,
• blood glucose level
• a concentration of circulating CRP,
• a concentration of at least one cytokine such as IL1, IL2, IL6, IL10, TNF alpha, interferon alpha, or TGFβ,
• skin hydration, and/or
• blood _oxygen saturation,

memory being capable of storing said individual norm of the subject;

- the communication interface is configured to periodically record events experienced by the subject in the subject's personal data;

- the calculation means is configured to correlate the events experienced 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.

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:

i) Calculate, from a database including 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 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, and/or

- the level of humidity in the exhaled air,

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:

- a circulating lactate concentration,

- a blood glucose level,

- a concentration of circulating CRP,

- a concentration of at least one cytokine such as IL1, IL2, IL6, IL10, TNF alpha, interferon alpha, or TGFβ,

- skin hydration, and/or

- blood _oxygen saturation;

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

Depending on other optional characteristics of the process, the latter may optionally include one or more of the following characteristics, alone or in combination:

- a step of determining a standard for the subject comprising, over a determined period, 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;

- the determination of the subject's standard 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;

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

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

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 for 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 subject's immune activity.

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 the implementation of 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.

Other features, details and advantages will become apparent upon reading the detailed description below and the attached figures, which illustrate:

FIG. 1 is a schematic representation of the immune activity measurement system 10 of a subject according to the invention, according to one embodiment.

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.

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.

FIG. 4 is a flowchart concerning the method 100 for calculating the score of the subject's immune activities according to an embodiment.

Detailed description

System for measuring the immune activity of a subject.

There FIG. 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.

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.

The exhaled air sensor 20 according to the invention allows a portion of the air exhaled by a subject to be directed and/or concentrated 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 exhalation, by the subject, into the exhaled air measurement device.

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 the 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, this standalone device, comprising the exhaled air sensor 20 and the exhaled air measurement device 30, is sufficiently compact to be portable and easily handled by the subject, for example, to fit in a human hand. For example, this standalone device measures no more than 20 cm in length, 10 cm in width, and 5 cm in depth.

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, for example, a speed, a flow rate) measured by said sensor 20 in a sample of exhaled air from the subject.

• un spiromètre 31 apte à mesurer le volume d’air expiré exhalé par le sujet et le débit correspondant,
• un capteur 32 apte à détecter un niveau de méthane (CH₄),
• un capteur 33 apte à détecter un niveau d’hydrogène (H₂),
• un capteur 34 apte à détecter un niveau de CO₂,
• un capteur 35 apte à détecter un niveau de corps cétoniques, tels que l’acétylacétate, le β-D-hydroxybutyrate et/ou l’acétone,
• un capteur 36 apte à détecter un niveau de monoxyde d’azote (NO),
• un moyen de mesure de la température 37 de l’air exhalé, et/ou
• un moyen de mesure du niveau d’humidité 38 de l’air exhalé.

In one 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, β-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.

• un spiromètre 31 apte à mesurer le volume d’air expiré exhalé par le sujet et le débit correspondant,

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,

• un capteur 32 apte à détecter un niveau de méthane (CH₄),
• un capteur 33 apte à détecter un niveau d’hydrogène (H₂),
• un capteur 34 apte à détecter un niveau de CO₂,
• un capteur 35 apte à détecter un niveau de corps cétoniques,
• un capteur 36 apte à détecter un niveau de monoxyde d’azote (NO),
• un moyen de mesure de la température 37 de l’air exhalé,
• un moyen de mesure du niveau d’humidité 38 de l’air exhalé.

and at least 2, 3, 4, 5, or 6 sensors chosen 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.

• un spiromètre 31 apte à mesurer le volume d’air expiré exhalé par le sujet et le débit correspondant,
• un capteur 32 apte à détecter un niveau de méthane,
• un capteur 33 apte à détecter un niveau d’hydrogène (H₂),
• un capteur 34 apte à détecter un niveau de CO₂,
• un capteur 35 apte à détecter un niveau de corps cétoniques,
• un capteur 36 apte à détecter un niveau de monoxyde d’azote (NO),
• un moyen de mesure de la température 37 de l’air exhalé, et
• un moyen de mesure du niveau d’humidité 38 de l’air exhalé.

In a more specific 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,
• 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.

• un spiromètre 31 apte à mesurer le volume d’air expiré exhalé par le sujet et le débit correspondant,

In a more specific 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,

• un capteur 32 apte à détecter un niveau de méthane,
• un capteur 33 apte à détecter un niveau d’hydrogène (H₂),
• un capteur 34 apte à détecter un niveau de CO₂,
• un capteur 35 apte à détecter un niveau de corps cétoniques,
• un capteur 36 apte à détecter un niveau de monoxyde d’azote (NO).

and at least 2, 3, 4, or 5 sensors chosen 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).

The spirometer 31, usable in 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.

Gas sensors capable of detecting levels of gases such as hydrogen ( _H₂ ), methane ( _CH₄ ), _CO₂ , NO, and even ketones, are examples of non-dispersive infrared (NDIR) sensors. These sensors detect gases in a gaseous environment based on 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 at the characteristic wavelength of the light.

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

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.

Other gas sensors capable of detecting levels of gases such as hydrogen ( _H₂ ), methane ( _CH₄ ), _CO₂ , NO, and even ketone bodies, include metal oxide-based gas sensors (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.

Regarding the detection of hydrogen ( _H2 ), palladium-doped sensors are particularly suitable.

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 resulting current. 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 us to determine the concentration of the gas (Paul Le Maout. Analysis of exhaled air by nanocomposite sensor matrices: the electronic nose for diagnostic assistance. Application to renal failures. Electronics. Ecole nationale supérieure Mines-Télécom Atlantique, 2019.).

Methods for measuring exhaled air temperature 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) thermistors. These sensors are particularly useful for correcting the levels or data measured by other sensors, as these can be distorted by the exhaled air temperature.

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.

A capacitive humidity sensor measures humidity by detecting changes in electrical capacitance due to moisture in the environment. This type of sensor typically 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.

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

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 (ADC). The digital value can then be used by a computing means 70 or a communication and management interface 80.

• une concentration de méthane (CH₄),
• une concentration d’hydrogène (H₂),
• une concentration de CO₂,
• une concentration en corps cétoniques,
• une concentration en monoxyde d’azote (NO),
• une température corporelle interne ou une température de l’air exhalé, et/ou
• un niveau d’humidité.

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 sample of exhaled air, at least one exhaled air 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),
• an internal body temperature or an exhaled air temperature, and/or
• a level of humidity.

• une concentration de méthane (CH₄),
• une concentration d’hydrogène (H₂),
• une concentration de CO₂,
• une concentration en corps cétoniques,
• une concentration en monoxyde d’azote (NO),
• une température corporelle interne ou une température de l’air exhalé,
• un niveau d’humidité,

In one 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 measurement 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,

thus characterizing the sample of air exhaled from the subject.

• une concentration de méthane (CH₄),
• une concentration d’hydrogène (H₂),
• une concentration de CO₂,
• une concentration en corps cétoniques,
• une concentration en monoxyde d’azote (NO),

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),

thus characterizing the sample of air exhaled from the subject.

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

The system for measuring the immune activity of a subject according to the invention also includes:

- at least one memory 60 capable of storing the measurements taken by the measuring device 30 and/or the data calculated by the computing means 40 and the subject's personal data,

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

- at least one communication and management interface 80 adapted to present said subject's immune activity score, said immunological activity subscore, said inflammatory activity subscore, said digestive inflammation subscore, and/or said pulmonary inflammation subscore.

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.

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 being therefore capable of receiving the electrical signals transmitted by the sensors of the exhaled air measurement device 30.

• au moins une interface radio courte portée notamment de type « Bluetooth », « Wifi » ou autre, et/ou
• ou encore au moins une interface de communication en champ proche notamment de type NFC ou RFID.

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.

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 a self-contained device within the immune activity level measurement system 10, as illustrated in the FIG. 2 and mentioned above.

• une concentration de méthane (CH₄),
• une concentration d’hydrogène (H₂),
• une concentration de CO₂,
• une concentration en corps cétoniques,
• une concentration en monoxyde d’azote (NO),
• une température corporelle interne ou une température de l’air exhalé, et/ou
• un niveau d’humidité.

At least one calculation means 40 is capable, from the signals sent by 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 level of humidity.

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 measurement device 30 are also stored in at least one memory 60 capable of storing the measurements taken by the sensors of the measurement device 30. The at least one exhaled air data and/or the signals sent by at least one sensor of the exhaled air measurement device 30 are recorded in the memory 60 with each expiration of the subject in the exhaled air sensor 20.

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

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

• des données une concentration de méthane (CH₄),
• une concentration d’hydrogène (H₂),
• une concentration de CO₂,
• une concentration en corps cétoniques,
• une concentration en monoxyde d’azote (NO),
• une température corporelle interne ou une température de l’air exhalé, et/ou
• un niveau d’humidité.

In one 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 level of humidity.

In one 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.

In the art, a subject's immune status is assessed, notably through a complete blood count with differential, blood smear analysis, and even the identification of lymphocyte subpopulations using specific markers by flow cytometry. Analysis of certain immune mediators, such as cytokines, reveals the activity level of the immune system. Such examinations require blood samples and a significant amount of analysis time to obtain results. A subject's immune status encompasses the activity of their cellular or humoral immunity, as well as the gut microbiota. Measuring the subject's level of immune activity, as determined by the system 10 according to the invention, reflects the subject's immune status and allows for its evaluation and monitoring, without requiring the numerous lengthy and costly examinations mentioned above.

Immunological activity, as defined by this invention, is the homeostasis of the immune system, that is, its level of regulation in identifying and destroying elements perceived as foreign to the subject's organism. An excessively high level of immunological activity can, for example, indicate immunological activity tending towards undesirable autoimmune reactions. Measuring such a level is of particular interest, for example, when determining the timing of administration for treatments that activate the immune system.

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 this overall inflammatory state.

Pulmonary inflammation refers to the inflammatory state of the oropharyngeal and pulmonary system. Detecting data from exhaled air in 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, among other things, the inflammatory state of the oropharyngeal and pulmonary system.

Digestive inflammation refers to the inflammatory state of the intestinal system. This can be analyzed by detecting data from exhaled air, which notably reflects the state and quality of the gut microbiota and the intestinal system. This state can be linked to an intestinal or even digestive pathology, but also to the presence of a more systemic or distant pathology.

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.

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.

A subscore for lung inflammation is calculated, for example, from exhaled air data such as temperature, humidity level, and CO2 concentration.₂, the volume and/or flow rate of exhaled air and/or the concentration of NO.

A subscore of digestive inflammation 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.

In another particular embodiment, the subject's level of 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.

In one embodiment, at least one computing means 70 includes 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 one or more years, in the absence of any particular event or after 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, monthly, seasonal, or annual rhythm, respectively over several days, months, corresponding seasons, or years.

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.

A collective standard, as defined in the invention, relates to an exhaled air measurement, an immune activity level, and/or at least one subscore as described above, and refers to a mean reference value for said measurement, 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 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 the collective norm, for an exhaled air data of immune activity level or at least one subscore.

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.

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 particularly, the artificial intelligence of at least one computing means 70 is trained to predict the occurrence of a significant alteration of exhaled air data; The system uses one of the sub-scores to predict the subject's level of immune activity, specifically to predict a significant alteration in the subject's immune activity, linked, for example, to an event experienced by the subject. For instance, 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 particular food, the intake of a particular medication, and/or specific 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 calculation method 70 is configured to identify personal events experienced by the subject that result in a significant alteration of their immune activity, such as identifying the consumption of a particular food as a source of altered immune activity and/or inflammatory activity.

• un moyen de mesure de la température cutanée de surface 51,
• un capteur 52 apte à détecter un niveau de protéine C réactive (CRP),
• un capteur 53 apte à détecter un niveau de lactates,
• un capteur 54 apte à détecter un niveau de glucose,
• un capteur 55 apte à détecter au moins un niveau d’une cytokine telle que IL1, l’IL2, l’IL6, l’IL10, le TNF alpha, l’interféron alpha, ou le TGFß
• un moyen de mesure de la saturation sanguine en oxygène (O₂) 56,
• un moyen de mesure du niveau d’humidité 57 de la peau.
• un moyen de mesure du pH 58 de la peau.

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 of 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, IL10, TNF alpha, interferon alpha, or TGFβ
• a means of measuring blood oxygen ( _O2 ) saturation 56,
• a means of measuring the moisture level of the skin.
• a means of measuring the pH 58 of the skin.

• un moyen de mesure de la température cutanée de surface 51,
• un capteur 52 apte à détecter, un niveau de protéine C réactive (CRP),
• un capteur 53 apte à détecter, un niveau de lactates,
• un capteur 54 apte à détecter, un niveau de glucose,
• un capteur 55 apte à détecter au moins un niveau d’une cytokine telle que IL1, l’IL2, l’IL6, l’IL10, le TNF alpha, l’interféron alpha, ou le TGFß,
• un moyen de mesure de la saturation sanguine en oxygène (O₂) 56,
• un moyen de mesure du niveau d’humidité 57 de la peau,
• un moyen de mesure du pH 58 de la peau.

In a particular embodiment, said cutaneous measuring device 50 comprises at least two sensors or means selected from:

• a means of 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, IL10, TNF alpha, interferon alpha, or TGFβ,
• 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.

• un moyen de mesure de la température cutanée de surface 51,
• un capteur 52 apte à détecter, un niveau de protéine C réactive (CRP),
• un capteur 53 apte à détecter, un niveau de lactate,
• un capteur 54 apte à détecter, un niveau de glucose,
• un capteur 55 apte à détecter au moins un niveau d’une cytokine telle que IL1, l’IL2, l’IL6, l’IL10, le TNF alpha, l’interféron alpha, ou le TGFß,
• un moyen de mesure de la saturation sanguine en oxygène (O₂) 56, et
• un moyen de mesure du niveau d’humidité 57 de la peau,
• un moyen de mesure du pH 58 de la peau.

In a further particular embodiment, said cutaneous measuring device 50 comprises 3, 4, 5, 6, 7, or 8 of the sensors or means mentioned above. More specifically, said cutaneous measuring device 50 comprises:

• a means of 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, IL10, TNF alpha, interferon alpha, or TGFβ,
• 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.

Means for measuring skin surface temperature 51 that can be used 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.

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 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.

A wide variety of sensors exist in the field capable of detecting lactate, glucose, and/or CRP levels. These sensors can be selected from:

- electrochemical biosensors,

- optical sensors (fluorescence or plasmonic),

- Surface plasmon resonance (SPR) sensors

- microfluidic sensors, and/or

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

In a particular embodiment, a sensor capable of 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)

Impedance sensors are suitable for detecting proteins such as those mentioned in Song et al. (2019) and can be used in the system of the invention to detect interstitial cytokine levels. Relevant cytokines within the scope of the invention may include IL-1, IL-2, IL-6, IL-10, TNF-alpha, interferon-alpha, or TGF-β. IL-6 and TNF-alpha are of particular interest within the scope of the invention because their monitoring makes it possible to anticipate cytokine storms, which are particularly deadly during viral pandemics, and to determine the optimal time to administer immunomodulatory treatment.

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

The cutaneous measuring device 50 is a device located on the subject's skin, which allows the transcutaneous measurement (e.g., 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 cutaneous data from the data and levels measured by the sensors, such as circulating lactate concentration, blood glucose, circulating CRP concentration, the concentration of at least one circulating cytokine such as IL-1, IL-2, IL-6, IL-10, TNF-alpha, interferon-alpha, or TGF-β, 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 are 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.

• un sous score d’activité immunologique du sujet calculé, par exemple, à partir des données d’air exhalé telles que mentionnées ci-dessus et/ou des données cutanées du sujet telles que la température cutanée et/ou le niveau d’hydratation.
• Un sous score d’activité inflammatoire du sujet calculé, par exemple, à partir des données d’air exhalé telles que mentionnées ci-dessus et/ou des données cutanées du sujet telles que la température cutanée, de pH, le niveau d’hydratation, la concentration en CRP circulante, la concentration en lactate circulant, la concentration en au moins une cytokine circulante telle que IL1, l’IL2, l’IL6, l’IL10, le TNF alpha, l’interféron alpha, ou le TGFß et/ou la glycémie.
• Un sous score d’inflammation pulmonaire du sujet calculé, par exemple, à partir des données d’air exhalé telles que mentionnées ci-dessus et/ou des données cutanées du sujet telles que la température cutanée, le niveau d’hydratation, la concentration en au moins une cytokine circulante telle que l’IL1, l’IL2, l’IL6, l’IL10, le TNF alpha, l’interféron alpha, ou le TGFß, la concentration en CRP circulante et/ou la saturation sanguine en oxygène (O₂).
• Un sous score d’inflammation digestive du sujet calculé, par exemple, à partir des données d’air exhalé telles que mentionnées ci-dessus et/ou des données cutanées du sujet telles que la température cutanée, la concentration en au moins une cytokine circulante telle que l’IL1, l’IL2, l’IL6, l’IL10, le TNF alpha, l’interféron alpha, ou le TGFß, le niveau d’hydratation, et/ou la concentration en CRP circulante.

Thus, at least one calculation method 70 is then suitable for calculating 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 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, hydration level, circulating CRP concentration, circulating lactate concentration, concentration of at least one circulating cytokine such as IL1, IL2, IL6, IL10, TNF alpha, interferon alpha, or TGFβ and/or blood glucose.
• A subscore of lung inflammation of the subject calculated, for example, from exhaled air data as mentioned above and/or skin data of the subject such as skin temperature, hydration level, concentration of at least one circulating cytokine such as IL1, IL2, IL6, IL10, TNF alpha, interferon alpha, or TGFβ, circulating CRP concentration and/or blood oxygen saturation ( _O2 ).
• 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, IL2, IL6, IL10, TNF alpha, interferon alpha, or TGFβ, hydration level, and/or circulating CRP concentration.

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, 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 sub-scores; 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 and the occurrence(s) of personal events experienced by the subject, the calculation 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 intake of a particular food as a source of an alteration of the subject's immune activity and/or a source of inflammatory activity.

The communication and management interface 80 can be configured to allow the subject to feed 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...). The communication and management interface 80 can be configured to allow the subject to control or adjust the computing means 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 relating to 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 computing means 70. Furthermore, the communication and management interface 80 can 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.

Advantageously, as illustrated in the FIG. 3 The immune activity level measurement system 10 comprises a mobile communication device 90 including the communication and management interface 80, computing means 40, 70 and memory 60 communicating with the exhaled air measurement device 30 and optionally 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 may be an application through which the subject enters personal data and personal experiences and consults exhaled air 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.

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

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 the cutaneous 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.

Method for monitoring the immune activity of a subject

There FIG. 4 illustrates an embodiment of a method for monitoring the level of immune activity of a subject 100 implementing a system for measuring a level of immune activity 10, the method is described below.

In step 110, at least one exhaled air value for the subject is calculated. This value is calculated, for example, by the calculation means 40 of the immune activity level calculation system 10, from a physiological level or value 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, medication, enema, or beverage intake, 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, medication, enema, or beverage intake are not taken into account.

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 measurement 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.

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

These exhaled air and skin data (when 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 levels. For example, this makes it possible to evaluate the presence or absence of inflammation, or even a state of micro-inflammation, in the tested subject. Micro-inflammation is defined as a low-level, background inflammatory state compared to acute inflammatory episodes.

An additional step 140 of the method 100 according to the invention may include detecting at least one significant deviation between at least one exhaled air data point, skin data (when the system measures skin data), the subject's 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 (change) in the subject's immune activity, for example, an increase in immune activity, the presence or increase of inflammatory activity in the subject, or a decrease in the subject's inflammatory state.

• une norme collective correspondant à une valeur moyenne de référence pour ladite donnée d’air exhalé, donnée cutanée, le niveau d’activité immunitaire et/ou le sous score telle qu’observée pour un ensemble de sujets partageant des caractéristiques communes, ou
• une norme individuelle du sujet, correspondant à la valeur moyenne observée pour ladite donnée d’air exhalé, donnée cutanée, ledit niveau d’activité immunitaire ou ledit sous score pour une série de leurs valeurs mesurées sur 1 jour, 2, 3, 4, 5, 6, 7 jours, voire deux semaines, trois semaines, voire un mois, voire une année, en l’absence d’évènement particulier ou en retirant les valeurs manifestement anormales de la série de valeur.

The reference values can correspond, as mentioned above, to:

• a collective standard corresponding to a mean 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 of 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.

For the determination of the individual norm of subject 150, at least one exhaled air data point, at least one skin data point, the aforementioned level of immune activity, or at least one of the subscores mentioned, are determined repeatedly 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 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.

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 activity, 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.

Step 170 of the process 100 includes analyzing and detecting a correlation between the significant deviation detected in step 140 and the individual subject. This step may involve creating and using a neural network trained with an individual subject norm or a collective subject norm as defined above. The neural network can be stored in memory 60 of system 10 of the invention. Typically, the neural network is trained with data from the individual or collective norm until it converges. The continuous acquisition of exhaled air or skin data, immune activity levels and/or subscores, as well as personal experiences, allows artificial intelligence to predict significant alterations in the subject's immune activities, such as, for example, an increase in inflammatory activity in 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 disorders. Such pathologies include, for example, pathologies with diffuse effects at the level of the body such as connective tissue diseases such as: rheumatoid arthritis, ankylosing spondylitis, systemic lupus, systemic scleroderma, Gougerot-Sjögren syndrome (or Sjögren's syndrome), inflammatory myopathies; such as primary vasculitis such as: giant cell arteritis, Takashu disease, Kawasaki disease, polyarteritis nodosa, Wegner's disease, Churg-Strauss syndrome, microscopic palyangitis, anti-GBM antibody vasculitis (or disease), Behçet's disease; or even more specific pathologies of certain organs or tissues such as, for example: multiple sclerosis, psoriasis, Crohn's disease, Guillain-Barré syndrome, myasthenia gravis, Lambert-Eaton disease, or pemphigoid, etc…

Thus, 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 symptoms, and therefore to implement therapeutic or symptomatic solutions aimed at preventing or reducing the symptoms of this crisis, before it occurs, or its consequences on the individual's life. In particular, this can allow for the early initiation of therapy, resulting in better prevention, 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.

A crisis or flare-up, as defined in the invention, refers in particular to an exacerbation of the symptoms of these chronic conditions. 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 condition as described above.

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).

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

Some 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 patient's body. These treatments necessitate the assessment of the patient's immune activity before administration. For example, immunotherapy can exacerbate certain undesirable immune disorders, and some chemotherapies are known, conversely, to negatively impact the immune system. The invention makes it possible to monitor the patient's immune activity to determine the optimal administration window for such treatments. The invention also makes it possible to detect significant 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. This treatment may be contraindicated in cases of excessively low immune activity or, conversely, in cases of excessively high immune activity. For example, in the case of a treatment to trigger strong immune responses, such as immunotherapy, it would be advisable to wait or implement solutions to reduce immune activity that is too high relative to the subject's norm, as determined using the method of the invention, for example, by using the immune activity scoring system of the invention.

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 that require validation of the subject's suitability for receiving them. The device, processes, and/or methods according to the invention enable remote monitoring of patient data, particularly the subject's immune activity. This can, in particular, reduce travel to healthcare facilities, eliminate unnecessary biological sampling, and even improve therapy administration 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.

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 the organism of a subject, apart from any pathology, by allowing the subject to maintain and control the immune homeostasis of the subject.

Claims (14)

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 the subject's personal data,
- 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 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. 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 cytokine such as IL1, IL2, IL6, IL10, TNF alpha, interferon alpha, or TGFβ,
• 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 calculation means (40) of the system for measuring a level of immune activity (10) being adapted to communicate with the skin measuring device (50) and capable of determining skin data of the subject selected from at least one circulating lactate concentration, a blood glucose level, a circulating CRP concentration, a circulating cytokine concentration, said skin data being able to be stored by the storage memory (60) capable of storing the measurements made by the skin measuring device (50) and used by the calculation means (70) to determine the level of immune activity of the subject from at least one subscore selected from: said immunological activity subscore, said inflammatory activity subscore, said digestive inflammation subscore and/or said pulmonary inflammation subscore. A system for measuring the 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. 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 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 concentration of methane,
• a concentration of hydrogen ( _H2 ),
• a concentration of _CO2 ,
• a concentration of ketone bodies,
• a concentration of nitric oxide,
• a temperature,
• a level of humidity in the exhaled air,
• a circulating lactate concentration,
• blood glucose level
• a concentration of circulating CRP,
• a concentration of at least one cytokine such as IL1, IL2, IL6, IL10, TNF alpha, interferon alpha, or TGFβ,
• skin hydration, and/or
• blood _oxygen saturation,

memory (60) being capable of storing said individual norm of the subject. System for measuring a level of immune activity (10) of a subject according to one of the preceding claims characterized in that the communication interface (80) is configured to periodically record in the memory (60) of events experienced by the subject in the subject's personal data. 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. 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) Calculate (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 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, and/or
- the level of humidity in the exhaled air,
ii) Optionally, calculate (120), 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:
- a circulating lactate concentration,
- a blood glucose level,
- a concentration of circulating CRP,
- a concentration of at least one cytokine such as IL1, IL2, IL6, IL10, TNF alpha, interferon alpha, or TGFβ,
- skin hydration, and/or
- blood _oxygen saturation;
iii) determine a level of immune activity (130) of the subject from the data obtained in i) and optionally ii). 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. 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. Method for monitoring the immune activity (100) of a subject according to any one of claims 7 to 9, further comprising a step comprising: 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. 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. 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. 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. 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 (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 exhaled air data, and optionally at least one skin data of the subject.