WO2022002971A1 - Sampling system and respiratory air examination system having a sampling system - Google Patents

Abstract

The present invention relates to a sampling system (4) for sampling expired air, comprising: a first sampling or metering device (14) to accommodate, or to be filled with, expired air from a first region of a respiratory tract; and a second sampling or metering device (16) to accommodate, or to be filled with, expired air from a second region of the respiratory tract. The present invention also relates to a test system or respiratory air examination system (2) for detecting a pathogen, in particular a virus, in particular a coronavirus, in particular the novel SARS-CoV-2 coronavirus (Covid-19) in expired air, comprising: a sampling system (4) of this type; and a respiratory air analysis device (6) comprising a multi-capillary column (18) and an ion mobility spectrometer (20); wherein a control unit (10) is designed to introduce expired air samples from the at least two sampling or metering devices (14, 16) one after the other into the respiratory air analysis device (6) for a separate analysis of the expired air from the first region of the respiratory tract and the expired air from the second region of the respiratory tract.

Description

description

Sampling system and breathing air analysis system with one

Sampling system

The present disclosure relates to a sampling system / sampling system for taking a sample of expiratory air, as well as a test system or

Breathing air examination system with such a sampling system for the detection of a pathogen, in particular a virus, directly in the expired air.

State of the art

Breathing air analysis devices comprising multicapillary columns (MCC) and ion mobility spectrometers (IMS) are known from the prior art, by means of which breathing air (exhaled air / exhaled air) of a living being / human can be examined / analyzed.

A multi-capillary column is a gas chromatographic column that consists of a large number of bundled individual capillaries that retain different analytes for different lengths of time. In other words, components of the expired air ideally require different lengths of time to pass through the multicapillary column, so that an expired air sample can be pre-separated by means of the multicapillary column (1st separation). The time it takes to pass through the multicapillary column is referred to as the retention time.

After the pre-separation in the multicapillary column, the constituents pass into the ion mobility spectrometer, namely initially in an ionization chamber section of the ion mobility spectrometer in which the gas constituents of the expired air are ionized. This is done with the help of an ionization source, usually by means of chemical ionization, for example by means of β radiation, for example radioactive nickel ( ⁶³ Ni). After the ionization, the ions pass through a barrier grid, if this is open, and are in a drift chamber section of the ion mobility spectrometer against the direction of flow of a drift gas accelerated towards a detection device. Ions of different mass or structure ideally achieve different drift speeds by absorbing energy from an electric field and collisions with the surrounding gas molecules, are thereby separated from one another (2nd separation) and hit the detection device one after the other. The time it takes to pass through the drift chamber section is referred to as the drift time. The ions in the ion mobility spectrometer are accelerated by means of an electric field. The analysis device on the detector outputs signal fluctuations which are generated by the ionized gas components of the expired air that hit the detection device. The detector is electrically decoupled from the incoming ion cloud by means of an aperture grid.

Furthermore, it is known from the prior art that a proof or test of whether a person is sick with the novel corona virus SARS-CoV-2 (Covid-19), usually via a swab from the mouth, nose or Pharynx takes place. The smear is checked / examined in a laboratory to determine whether it contains the genetic material of the virus. A method is used, the so-called polymerase chain reaction (PCR), by means of which a genetic material of the virus is replicated in vitro in several cycles. By using fluorescent substances, you can finally see whether the virus gene sequences you are looking for are present or not.

It has been found that the novel corona virus SARS-CoV-2 (Covid-19) can colonize a person's throat and / or lungs. In particular, in people / patients suffering from the novel corona virus SARS-CoV-2 (Covid-19), it turned out that the virus was in part undetectable in the throat / area, but that it infects the lungs of the patients on a large scale has. In other words, some patients received a negative test result from the throat swab and subsequent polymerase chain reaction (PCR), even though they were already in a critical condition due to their SARS-CoV-2 (Covid-19) disease because the virus was there has already settled in her lungs on a large scale. It is therefore true that a negative test result of the throat swab does not necessarily mean that the tested patient is not ill with the new type of corona virus SARS-CoV-2 (Covid-19). It also applies that with a positive The test result of the throat swab cannot directly indicate that / whether the patient's lungs are already infected with SARS-CoV-2 (Covid-19). In particular, further examinations, for example by means of computed tomography (CT) or x-rays, would be necessary in this case. The throat swab test also has the disadvantage that a test result is only available after a laboratory examination of the swab.

In addition, an overall analysis of exhaled / exhaled air using a multi-capillary column and ion mobility spectrometer has shown that a pathogen or virus such as the new corona virus SARS-CoV-2 (Covid-19) due to the large respiratory volumes and the low analyte - or virus concentration is difficult to detect. In addition, even with an overall analysis of the expired air, no statement can be made about which area of the respiratory tract / respiratory system the virus has reached or infected.

Brief description of the disclosure

The object of the present disclosure is to avoid or at least mitigate the disadvantages mentioned from the prior art. In particular, a test result should determine whether a person is infected with a pathogen / virus such as the novel corona virus SARS-CoV-2 (Covid-19) and / or which areas of the respiratory tract or respiratory system are infected by the virus, are available immediately and with minimal retardation / delay.

This object is achieved by a sampling system for taking a sample of expired air according to claim 1, as well as a test system or

Breathing air examination system with such a sampling system for the detection of a pathogen / virus in expired air according to claim 15. Advantageous embodiments and developments are claimed in the subclaims and / or are explained below.

The present disclosure relates first of all to a sampling system / sampling system for sampling / sampling (taking a sample or of samples) of expired air / exhaled air of a human / living being, with at least: a first sample receiving or dosing device, in particular sample loop or dosing loop, for receiving or filling with expired air from a first area of a respiratory tract / respiratory system, in particular throat expiratory air ; and a second sample receiving or dosing device (separate from the first sample receiving or dosing device), in particular a sample loop or dosing loop, for receiving or filling with expiratory air from a second area of the respiratory tract / respiratory system, in particular end-tidal expiratory air.

According to the present disclosure, a sampling system with at least two sample receiving or metering devices, which can be designed as sample or metering loops, for example, is thus provided. A first sample receiving or dosing device of the at least two sample receiving or dosing devices is preferably set up / prepared to use exhaled air / expired air from a first area of the respiratory tract, preferably with the pharynx - expiratory air (expired air on the pharynx or throat area of a person / Living being) to be filled. A second sample receiving or dosing device of the at least two sample receiving or dosing devices is preferably set up to be filled with exhaled air / expired air from a second area of the respiratory tract, preferably with end-tidal expiratory air (expired air from deeper areas of a human / living being's lungs) to become.

The sampling system according to the disclosure ensures that expired air from a first area of the respiratory tract is separated from expired air from a second area of the respiratory tract. The expired air from the first area of the respiratory tract is received / temporarily stored in the first sample receiving or dosing device, and the expired air from the second area of the respiratory tract is received / temporarily stored in the second sample receiving or dosing device. Thus, according to the disclosure, a sharp volume separation and a parallel sampling from the exhaled flow (in a single sampling step) from different areas of the respiratory tract (for example throat and lungs) are not essential Retardation / delay enables. This has the immediate consequence that in a next step - when the samples taken are given for analysis in a respiratory air analysis device - the at least two expired air samples from different areas of the respiratory tract can be analyzed independently of one another.

In principle, according to the present disclosure, it is also conceivable that more than two sample receiving or dosing devices, that is to say about three, four, five, etc., sample receiving or dosing devices are provided which are set up or prepared to take expiratory air from different Areas of the respiratory tract (for example throat, larynx, trachea, lungs, etc.) or different areas of the lungs (for example bronchi, bronchioles, alveoli) to be filled.

The sampling system preferably has a control unit which is used to control the sampling, in particular to control the filling of the first sample receiving or dosing device with expiratory air from the first area of the respiratory tract (e.g. throat expiratory air) and the second sample receiving or dosing device with expiratory air from the second area of the respiratory tract (e.g. end-tidal expiratory air) is set up. The control unit is particularly preferably set up to fill the first sample receiving or dosing device with pharynx expiratory air and to fill the second sample receiving or dosing device with end-tidal expiratory air.

The sampling system further preferably has a breathing cycle recording means, in particular a spirometer or a sensor, for example a CO 2 sensor, which is set up to record a breathing cycle (including inhalation / inspiration and exhalation / expiration), and recorded information about the current Forward breathing cycle to the control unit.

The control unit is preferably set up for sampling controlled by the breathing cycle. The breathing cycle is thus advantageously recorded by the breathing cycle recording means, and the control unit controls the sampling on the basis of the recorded breathing cycle.

A breathing cycle is basically to be understood as a continuously repetitive process of lung breathing, which consists of inspiration / inhalation and expiration / exhalation. A breathing cycle control of the present disclosure is carried out during expiration / exhalation on the basis that, during an expiration process, air is initially exhaled / blown out of the throat and later only air from deeper areas of the lungs (end-tidal exhalation air).

An advantageous embodiment is characterized in that the sampling is C02-controlled. For example, a C02 curve or a CÜ2 curve of the expiratory air can be recorded and transmitted to the control unit by means of a CO2 sensor. The basic rule here is that the C02 proportion tends to increase in the course of the expiratory process, since the C02 proportion in the pharyngeal expiratory air is lower than the C02 proportion in end-tidal expiratory air. Consequently, the control can basically be designed in such a way that a sample of expired air is taken from the first area of the respiratory tract (for example throat space expiratory air) when lower CO2 levels / values are determined in the expiratory air, and that a sample of expired air is taken from the second area of the Respiratory tract (e.g. end-tidal expiratory air) (later) when higher C02 proportions / values are determined in the expired air.

Another advantageous embodiment is characterized in that the sampling is volume-controlled. For example, a (breathing) volume curve or a (breathing) volume curve can be recorded and transmitted to the control unit by means of a spirometer in which a flow rate of expiratory air is measured and integrated to determine the volume. Here, too, the tidal volume expelled / released during exhalation / expiration increases in the course of the expiration process. Consequently, the control can in principle also be designed in such a way that a sample can be taken from Expiratory air from the first area of the respiratory tract (for example pharynx - expiratory air) takes place with a lower determined expelled volume of expiratory air, and that a sample of expired air from the second area of the respiratory tract (for example end-tidal expiratory air) takes place with a higher ascertained expelled volume of expiratory air.

However, the control is evidently not limited to being CO2-controlled or volume-controlled. For example, a time control (based on a start time of the expiration / the expiration process) or a pressure control is also conceivable. Basically, any control is obviously conceivable as long as it enables expired air from a first area of the respiratory tract (for example pharynx expiratory air) and expired air from a second area of the respiratory tract (for example end-tidal expiratory air) to separate / different ones in a suitable manner Sample receiving or dosing devices can be initiated.

According to a preferred embodiment, the breathing cycle control is calibrated patient-specifically. For example, a patient-specific, individual reference curve recorded in advance can be used to calibrate the breathing cycle control. Furthermore, it is also conceivable that a typical reference curve of a reference person (depending on gender, age, etc.) is used to calibrate the breathing cycle control.

Furthermore, the sampling system preferably has an actuator, in particular a shut-off device / organ, preferably a valve, particularly preferably a multi-way valve such as a two- / three- / four- / five- / six- / seven- / eight- / Nine / ten / etc. way valve, which is activated by the control unit to guide expiratory air during a single expiration process both in the first sample receiving or dosing device and in the second sample receiving or dosing device. In particular, the actuator is activated by the control unit in order to guide expired air one after the other (not simultaneously) into the first sample intake / dosing device and into the second sample intake / dosing device during a single expiration process. In other words, the both sample receiving or metering devices are preferably not filled with expiratory air at the same time. It is particularly preferred if the control unit controls the actuator, in the one (single) expiration process, pharynx - to direct expiratory air into the first sample receiving or dosing device and to direct end-tidal expiratory air into the second sample receiving or dosing device.

The control unit thus preferably controls an actuator which is designed, for example, as a multi-way valve. For example, expired air coming from a person / living being can be introduced into the first sample receiving device or metering device and into the second sample receiving device or metering device via a two- or three-way valve. The use of an eight-way valve for the actuator has also proven to be particularly preferred. However, according to the disclosure, various other actuators, shut-off devices / organs or valves are conceivable as long as they can lead expired air in a suitable manner into different / at least two sample receiving devices or metering devices.

The control unit is advantageously set up to feed expiratory air samples from the (fully) filled sample intake or metering devices one after the other into a respiratory air analysis device, in particular comprising a gas chromatographic column, in particular a multi-capillary column, and an ion mobility spectrometer, for a separate analysis of the expiratory air from the first Area of the respiratory tract and the expiratory air from the second area of the respiratory tract to give / introduce.

In other words, the control unit controls an introduction / introduction of the expired air samples into the breathing air analysis device in such a way that first the expired air sample from the first sample receiving or dosing device is put into the multi-capillary column and the ion mobility spectrometer, and thus first the expired air from the first Area of the respiratory tract is analyzed / examined, and that only then is the exhaled air sample from the second sample receiving or dosing device placed in the multi-capillary column and the ion mobility spectrometer, and thus only then / with a minimal time delay analyzes the exhaled air from the second area of the respiratory tract / is being investigated. However, it is just as conceivable that first the expired air from the second area of the respiratory tract and only then the expired air from the first area of the respiratory tract is analyzed / examined.

Thus, apparently, a separate / independent analysis of expired air from different areas of the respiratory tract can be carried out and the multicapillary column and the ion mobility spectrometer can be used to determine whether a pathogen / virus such as the novel corona virus SARS-CoV-2 (Covid- 19) is in the expired air, or conclusions can be drawn as to which areas / which area of the respiratory tract is infected by the pathogen / virus. In addition, the sampling system according to the disclosure also allows the detection if in a patient only the lower respiratory tract and not the throat are infected / colonized by the pathogen / virus, i.e. also in a case in which the currently usual detection by means of throat swab (PCR) would give a negative result. Apparently, a false test result is thus avoided.

According to the present disclosure, a sampling system for a breathing air analysis device (comprising at least one gas chromatographic column, in particular multi-capillary column (MCC) for gas chromatographic pre-separation and an ion mobility spectrometer (IMS)) is thus preferably provided.

The first sample receiving or dosing device and the second sample receiving or dosing device advantageously have different volumes. For example or preferably, the first sample receptacle / or

Dosing device (pharynx expiratory air sampling device) has a smaller / smaller volume and the second sample receiving / or dosing device (end-tidal expiratory air sampling device) has a larger / higher volume. In other words, the volumes of the at least two sample receiving devices or metering devices are not necessarily identical. According to a preferred embodiment, the first sample receiving or dosing device is provided for filling with pharynx expiratory air, the second sample receiving or dosing device is provided for filling with end-tidal expiratory air, and a volume of the first sample receiving or dosing device is less than a volume the second sample receiving or dosing device.

The volumes of the sample receiving or dosing devices are furthermore preferably determined / set in such a way that the sample receiving or dosing devices can be completely filled with a few breaths, in particular five to ten breaths.

This has the advantage that a person / patient / test person only has to blow / exhale a few times (five to ten times) in a single sampling step in order to completely fill the sample receiving or metering devices with sample air. It has been found that the sample air obtained in this way is sufficient to prove whether a pathogen / virus is present in the expired air and whether the pathogen / virus has infected the corresponding area of the respiratory tract.

For example, in an adult human, a first sample receiving or dosing device (preferably designed as a sample loop / dosing loop) can have a smaller volume (dead volume) of less than 100 milliliters (ml) to 600 milliliters (ml), and a second sample receiving or dosing device can be used. Dosing device (preferably designed as a sample loop / dosing loop) have a volume (dead volume) of 700 milliliters (ml) to 1200 milliliters (ml). Such sample receiving or dosing devices would be filled by an adult in about five to ten breaths. In principle, smaller volumes would be preferred for children. It is therefore true that the volumes of the sample receiving or dosing devices are preferably selected / determined as a function of the patient.

The sample receiving or metering devices of the present disclosure are moreover not restricted to the fact that they are sample loops or metering loops. Basically, any container that is used in a suitable manner a gas can take up and temporarily store, suitable to serve / function as a sample receiving or dosing device.

Samples are preferably taken during an expiration process only when a (first) predetermined (minimum) threshold value is reached, in particular a predetermined volume value or CO 2 value. In other words, the control unit is preferably set up to control the sampling accordingly.

In an advantageous manner, the predetermined threshold value is set in such a way that first of all expiratory air is removed from the throat.

For example, a predetermined minimum (exhalation) volume or a predetermined minimum CO 2 value is preferably established, from which sampling begins. In other words, the person / patient / test person first exhales a certain minimum tidal volume before starting the sampling for the first area of the respiratory tract. For example, the first predetermined threshold value is a volume value which is less than 800 milliliters, preferably less than 700 milliliters, particularly preferably less than 600 milliliters. In this context, minimum volumes of approximately 150 milliliters for children and minimum volumes of approximately 500 milliliters for adults have proven to be particularly suitable predetermined threshold values. In principle, however, the predetermined threshold value can also be very low and, for example, only 10 milliliters. Alternatively, the first predetermined threshold value can be a CO 2 value or proportion which is, for example, less than 1.6%, preferably less than 1.4%, particularly preferably less than 1.2%. In principle, however, very low CO 2 values or proportions from 0.04% are also conceivable for the first predetermined threshold value.

More preferably, the sampling is carried out in such a way that in the / each expiration process when a first predetermined threshold value (the predetermined minimum threshold value) is reached / is present, the first sample receiving or dosing device begins to be filled.

If a second predetermined threshold value is present, the filling of the first sample receiving or dosing device is terminated that when it is reached / present a third predetermined threshold value is started with a filling of the second sample receiving or dosing device, and that when a fourth predetermined threshold value is reached / present, the filling of the second sample receiving or dosing device is ended. In other words, the control unit is preferably set up to control the sampling accordingly.

In other words, during an exhalation process, time preferably first elapses before sampling for the first sample receiving or dosing device is started; the time preferably elapses between the end of the filling of the first sample receiving or dosing device and the start of the filling of the second sample receiving device. or dosing device, and even after the end of the filling of the second sample receiving or dosing device, the exhalation process is preferably not yet completed / ended.

This has the advantage that the respiratory volumes to be examined are not too large and, in particular, areas of the respiratory system can be examined which have been found to be affected by a corresponding pathogen / virus such as the novel corona virus SARS-CoV-2 (Covid-19) are particularly affected.

According to a preferred embodiment, the first predetermined threshold value, the second predetermined threshold value, the third predetermined threshold value and the fourth predetermined threshold value are each volume values which are set such that the first predetermined threshold value and the second predetermined threshold value are less than 800 milliliters and the third predetermined threshold value and the fourth predetermined threshold value are particularly preferably greater than 800 milliliters. The first predetermined threshold value and the second predetermined threshold value are advantageously in a range between 10 milliliters and 700 milliliters, preferably between 10 milliliters and 600 milliliters, particularly preferably between 10 milliliters and 500 milliliters. The third predetermined threshold value and the fourth predetermined threshold value are particularly preferably between 800 milliliters and a switchover point between expiration and inspiration, which is approximately 2 liters when taking a deep breath and exhaling to the maximum. This ensures that the first sample receiving or dosing device is filled with pharynx expiratory air and the second sample receiving or dosing device is filled with end-tidal expiratory air.

Alternatively, the first predetermined threshold value, the second predetermined threshold value, the third predetermined threshold value and the fourth predetermined threshold value can also each be CCh values or CCh components, which are defined in such a way that the first predetermined threshold value and the second predetermined threshold value are less than 1.6% and the third predetermined threshold and the fourth predetermined threshold are greater than 1.6%. The first predetermined threshold value and the second predetermined threshold value are particularly preferably in a range between 0.04% and 1.4%, preferably between 0.04% and 1.2%, particularly preferably between 0.04% and 1.0%. . The third predetermined threshold value and the fourth predetermined threshold value are particularly preferably between 1.6% and a switchover point between expiration and inspiration, which is approximately 4.0% when taking a deep breath and exhaling to the maximum.

Furthermore, the present disclosure relates to a test system, in particular a breathing air examination system, for the detection of a pathogen / virus in expired air, comprising: a sampling system as described above; and a breath air analysis device comprising a gas chromatographic column, in particular a multi-capillary column, and an ion mobility spectrometer; wherein a / the control unit is set up to give / introduce samples of the (completely filled) sample receiving or dosing devices one after the other into the breathing air analysis device for a separate analysis of the expired air from the first area of the respiratory tract and the expired air from the second area of the respiratory tract.

According to the present disclosure, a multi-capillary column (MCC) is preferably used as a gas chromatographic column. However, the present disclosure is not limited to this, and the gas chromatographic column can also be designed as a normal capillary column or as another gas chromatographic column. An expiratory air sample is preferably pre-separated by means of the multicapillary column, since components of the expired air require different lengths of time to pass through the multicapillary column (retention time). More preferably, after the pre-separation in the multicapillary column, the constituents of the expired air reach the ion mobility spectrometer, in which the ionized constituents of the expired air are accelerated to a detection device and require different lengths of time (drift time). The ionized components of the exhaled air that hit the detection device preferably generate signal fluctuations (peaks). Via the peak position in the ion mobility spectrometer chromatogram (IMS chromatogram), which is dependent on the drift time and the retention time, and via the intensity / the signal amplitude / the peak at the corresponding point in the chromatogram, it is preferable to demonstrate whether a pathogen / Virus is contained in the expired air or in the corresponding area of the respiratory tract and to what extent the corresponding area of the respiratory tract is infected by the pathogen / virus. It can be either a single peak or a combination of peaks.

In other words, the present disclosure relates to a sampling system with at least two sample receiving or dosing devices or dosing / sample loops, which optionally or preferably have different volumes, and which with each individual one of about five to ten breaths one after the other with expiratory air (first expiratory air from the pharynx into the first sample receiving or dosing device, then expired air from deeper areas of the lungs into the second sample receiving or dosing device), the filling of the at least two sample receiving or dosing devices being controlled by the breathing cycle, and the sampling system, in particular a control of the same, is set up, the filled sample receiving or dosing devices or dosing / sample loops one after the other in a breathing air analysis device (comprising multi-capillary column and ion mobility spectrometer) for a separate analysis of exhalation ionic air from the pharynx and expiratory air from deeper areas of the lungs, as well as for to initiate a separate detection of a pathogen / virus, in particular a corona virus, preferably the novel corona virus SARS-CoV-2 (Covid-19).

What is achieved by the present disclosure is that a person / patient / test person only needs to exhale a few times in a single sampling step so that expired air from different areas of the respiratory tract (for example pharynx and lungs) can be analyzed with minimal delay. In particular, no two separate sampling steps are required. It is thus avoided that a person / patient / test person comes into multiple contact with the sampling system. The present disclosure enables a quick test result / measurement result to be provided. In particular, test results / measurement results for different areas of the respiratory tract are available with a minimal delay and samples do not need to be taken to a laboratory. For example, test results / measurement results are available when a patient is admitted to a hospital. Furthermore, the sampling system according to the disclosure and the breathing air examination system according to the disclosure can be designed to be relatively compact and thus also suitable for general practitioners.

Brief description of the figures

The invention is explained further below with the aid of figures. Show it:

1 shows a schematic view of a test system / breathing air examination system according to the present disclosure;

2 shows a preferred embodiment of a test system /

Breathing air examination system according to the present disclosure;

3 shows an example of sampling in a metering loop / sample loop;

Figure 4 is a diagram of a human respiratory profile; 5 shows a diagram for explaining a respiratory cycle-controlled sampling according to the present disclosure;

6 shows a two-dimensional view of a first chromatogram in which a signal deflection is shown as a function of the drift time and the retention time;

7 shows a three-dimensional view of the first chromatogram, in which a signal deflection is shown as a function of the drift time and the retention time; and

8 shows a two-dimensional view of a second chromatogram in which a large number of signal fluctuations / peaks are shown as a function of the drift time and the retention time.

Figure description

The figures are merely of a schematic nature and serve exclusively for the understanding of the invention. The same elements are provided with the same reference symbols. The features of the individual exemplary embodiments can be interchanged with one another.

FIG. 1 shows a schematic view of a test system or respiratory air examination system 2 according to the present disclosure. The breathing air examination system 2 basically contains a sampling system / sampling system 4 and a breathing air analysis device 6.

The sampling system 4 contains a breathing cycle detection means 8, a control unit 10, an actuator 12, a first sample receiving / or dosing device 14 and a second sample receiving / or dosing device 16.

The respiratory air analysis device 6 contains a multi-capillary column 18 and an ion mobility spectrometer 20. According to the present disclosure, exhaled air / exhaled air of a person / patient / test person 22 first reaches the breathing cycle detection means 8, which is designed, for example, as a spirometer or as a sensor, in particular a CO2 sensor. The breathing cycle detection means 8 detects a breathing cycle comprising an inhalation / inspiration and an exhalation / expiration of the corresponding person / patient / test person 22. For example, the breathing cycle detection means 8 detects a volume profile / a volume curve, in particular if it is designed as a spirometer, or detects a C02 Curve or a C02 curve, especially if it is designed as a C02 sensor.

The breathing cycle recording means 8 forwards the recorded information about the breathing cycle to the control unit 10, which is preferably designed as a processor, in particular as a central arithmetic and processing unit (CPU). The control unit 10 is set up for the breathing cycle-controlled sampling / sampling, that is to say it controls sampling on the basis of the breathing cycle detected by the breathing cycle detection means 8. To this end, the control unit 10 controls the actuator 12.

According to the present disclosure, expired air comes from a person / patient / test person 22 via the respiratory cycle recording means 8 to the actuator 12 . Dosing device 14 as well as into the second sample receiving / or dosing device 16 (one after the other or not simultaneously). For example, the actuator 12 in the present case can be designed as a two-way or three-way valve. The sample receiving and / or metering devices 14, 16 can be designed as any container.

As will be explained in more detail below, the control unit 10 controls the actuator 12 on the basis of the respiratory cycle detected by the respiratory cycle detection means 8 in such a way that the first sample receiving / dosing device 14 receives expired air from a first region of a respiratory tract of the person / patient / Subjects 22, in particular with pharyngeal expiratory air, and that the second sample receiving / or metering device 16 is filled with expiratory air from a second area of a respiratory tract of the person / patient / test person 22, in particular with end-tidal expiratory air.

As indicated in Figure 1, the first sample receiving or

Dosing device 14 and the second sample receiving or dosing device 16 preferably have different volumes. The volume of the first sample receiving or dosing device 14 (for pharyngeal expiratory air) is preferably less than the volume of the second sample receiving or dosing device 16 (for end-tidal expiratory air). In principle, however, the volumes can also be identical. In any case, it applies to both sample receiving or dosing devices 14, 16 that they should be able to be completely filled with sample air with a few breaths, for example five to ten.

When the two sample intake or dosing devices 14, 16 are completely filled with sample air, the control unit 10 also controls the transfer / introduction of the exhaled air samples into the breathing air analysis device 6 , 16 successively given into the breath air analysis device 6. In other words, for example, the exhaled air sample is first introduced from the first sample receiving or dosing device 14 into the multicapillary column 18 and the ion mobility spectrometer 20 in order to be able to analyze the exhaled air from the first area of the respiratory tract first. In a second step, for example, the exhaled air sample from the second sample receiving or dosing device 16 is first introduced into the multicapillary column 18 and the ion mobility spectrometer 20 in order to then also be able to analyze the exhaled air from the second area of the respiratory tract.

A preferred embodiment of a test system /

Breathing air examination system 2 according to the present disclosure is described with reference to FIG. Similar to what is shown in the schematic view of FIG. 1, expired air comes from a person / patient / test person 22 via a respiratory cycle recording means (spirometer or CO 2 sensor) 8 to an actuator 12. The breathing cycle recording means 8 provides recorded information about a human respiratory cycle / Patients / test persons 22 to a control unit 10 and the control unit 10 controls the actuator 12 on the basis of the recorded information.

According to the preferred exemplary embodiment of FIG. 2, the actuator 12 is designed as an eight-way valve 24. The eight-way valve 24 enables expired air coming from the person / patient / test person 22 to be conducted into a first sample intake / or metering device 14, into a second sample intake / or metering device 16, or to a gas outlet 26 can be. According to the preferred embodiment of FIG. 2, the first sample receiving / or dosing device 14 is preferably designed as a first sample loop / dosing loop 28, and the second sample receiving / or dosing device 16 is preferably designed as a second sample loop / dosing loop 30.

It is also indicated in FIG. 2 that the first sample loop / metering loop 28 preferably has a smaller volume than the second sample loop / metering loop 30. In the present case, it applies (for an adult) that the first sample loop / dosing loop 28 preferably has a volume / dead volume of less than 600 milliliters, and that the second sample loop / dosing loop 30 preferably has a volume / dead volume of 700 milliliters to 1200 milliliters.

The control unit 10 also controls the actuator 12 or the eight-way valve 24 according to the preferred embodiment shown in FIG and that expired air from a second region of the respiratory tract of the person / patient / test person 22 is introduced into the second sample loop / metering loop 30.

If after a few breaths (five to ten) of the person / patient / test person 22 both the first sample loop / metering loop 28 and the second Sample loop / dosing loop 30 are completely filled with sample air, the expired air samples are given one after the other (via a corresponding control of the control unit 10) into a multicapillary column 18 and an ion mobility spectrometer 20. For example, the exhaled air sample from the first sample loop / dosing loop 28 together with a carrier gas coming from a carrier gas inlet 32 is first fed into the multicapillary column 18 and the ion mobility spectrometer 20 for analysis, and in a second step the expired air sample from the second sample loop / Dosing loop 30, together with a carrier gas coming from the carrier gas inlet 32, is fed into the multicapillary column 18 and the ion mobility spectrometer 20 for analysis. In principle, however, the exhaled air sample from the second sample loop / metering loop 30 can also be analyzed first, and only then the expiratory air sample from the first sample loop / metering loop 28 can be analyzed.

FIG. 3 shows a sample extraction in a sample loop / metering loop 28 or 30 using a six-way valve 33 -Way valve exist.

The illustration on the left in FIG. 3 shows that the sample loop / metering loop 28 or 30 is initially filled with expiratory air. In this state, ambient air can be pumped into the multicapillary column 18. As can be seen from the figure in the middle of FIG. 3, the six-way valve 33 can be switched in order to pump the exhaled air sample into the multicapillary column 18. The right-hand illustration of FIG. 3 shows a state in which the corresponding exhaled air sample has been completely pumped into the multicapillary column 18.

FIGS. 4 and 5 show diagrams of a breathing profile of a person / patient / test person 22 and serve to explain a breathing cycle-controlled sampling according to the present disclosure.

FIG. 4 shows a diagram of a breathing profile of a person 22, in which time (t) is on the horizontal axis and a tidal volume (V) is on the vertical axis. (eg in liters) or a volume flow rate (V / t) (eg in liters per second) is plotted. Exhalation / expiration is plotted in the negative vertical axis direction, and inhalation / inspiration is applied in the positive vertical axis direction. Furthermore, the diagram in FIG. 4 shows sampling areas 34 in which, according to the disclosure, sampling takes place. From FIG. 4 it can be seen in particular that a sample is only taken during an expiratory process when a predetermined threshold value is reached. In the case of volume-controlled sampling, for example by means of a spirometer, the predetermined threshold value is a predetermined volume value V1 or Vmin. As can be seen from FIG. 4, sampling takes place in the sampling areas 34 only when the predetermined threshold value / volume value V1 or Vmin has been reached during expiration. The predetermined threshold value of a minimum volume V1 or Vmin can evidently be set, for example, to -500 milliliters in adults and -150 milliliters in children.

How the sampling according to the disclosure takes place exactly in a single expiration process can be seen better from FIG. It is shown here that during an expiration process when a first predetermined threshold value V1 or Vmin is reached or present at a point in time t1, a filling of the first sample receiving / dosing device 14 or the first sample loop / dosing loop 28 begins When a second predetermined threshold value V2 is reached or is present at a point in time t2, the filling of the first sample receiving / or metering device 14 or the first sample loop / metering loop 28 is terminated that when a third predetermined threshold value V3 is reached or present at a time t3 a filling of the second sample receiving or dosing device 16 or the second sample loop / dosing loop 30 is started, and that when a fourth predetermined threshold value V4 is reached or present at a point in time t4, the filling of the second sample receiving / or dosing device 16 or the second sample loop / dosing loop 30 bee is found.

Expiratory air which reaches actuator 12 before time t1, between times t2 and t3, and after time t4, is preferably released and thus does not get into the sample receiving and / or metering devices 14, 16. For example, the expired air is let out via the gas outlet 26 shown in FIG.

FIGS. 4 and 5 show a preferred exemplary embodiment of a volume-controlled breathing cycle control, for example using a spirometer as the breathing cycle detection means 8. Other controls, such as a CO2-controlled breathing cycle control, can be implemented in a similar way. For example, in the case of the CO2-controlled breathing cycle control, only the mentioned volume values V1, V2, V3 and V4 would have to be exchanged for corresponding CO2 values.

Referring back to FIG. 1 and FIG. 2, the breathing air analysis carried out by means of the multicapillary column 18 and the ion mobility spectrometer 20 is explained in conclusion. It applies that expired air to be analyzed first (from an area of the respiratory tract) is pre-separated in the multi-capillary column 18, which is a gas chromatographic column (1st separation), since components of the expired air require different lengths of time to pass through the multi-capillary column 18 (retention time tR). After the pre-separation in the multicapillary column 18, the components of the expiratory air to be analyzed enter the ion mobility spectrometer 20, initially in an ionization chamber section 36 of the ion mobility spectrometer 20, in which the gas components of the expiratory air are ionized. This is done with the aid of an ionization source 38, for example radioactive nickel. After ionization, the ions pass through a barrier grid 40, also called Bradbury-Nielsen grid, and are in a drift chamber section 42 of the ion mobility spectrometer 20 against the flow direction of a drift gas coming from a drift gas inlet 44 to a detection device 46, also known as a Faraday plate called, accelerated. Immediately in front of the detection device 46, an aperture grid 48 is provided as a shielding grid for capacitive decoupling of the ions. Ions of different mass or structure reach different drift speeds, are thereby separated from one another (2nd separation) and hit the detection device one after the other (drift time io). The acceleration the ions in the ion mobility spectrometer 20 take place by means of an electric field. The breathing air analysis device 6 outputs signal deflections which are generated by the ionized gas components of the expiratory air that hit the detection device 46.

As can be seen from the chromatogram views in FIG. 6 and FIG. 7, a pathogen, in particular a virus, such as a corona virus (e.g. the novel corona virus SARS-CoV-2 (Covid-19)) appears at a certain point / Position, here referred to as virus position / site 50, in the chromatogram (see, for example, FIG. 6).

The virus position / site 50 is dependent on the retention time tp and the drift time to. The intensity / signal amplitude / peak at the corresponding virus position / site 50 in the chromatogram can then be used to detect whether the virus is contained in the expired air or in the corresponding area of the respiratory tract of the person / patient / test person 22 and the extent to which the corresponding area of the respiratory tract is infected by the virus (see FIG. 7).

For the sake of simplicity, only the location / position and the peak / signal amplitude of a virus are shown in FIGS. 6 and 7. It goes without saying, however, that in the chromatogram all other (gas) components occurring in the patient's exhaled air also have corresponding peaks / signal deflections at corresponding points / positions.

In this context, FIG. 8 shows, by way of example, a two-dimensional view of a (second) chromatogram in which a large number of signal fluctuations are shown as a function of the drift time to and the retention time tp.

For a more precise / better determination of whether a person / patient / test person 22 is sick with a certain pathogen / virus, a plurality of signal deflections / peaks 52 are preferably considered. For example, different signal swings / peaks 52 can be influenced by the particular pathogen / virus. It can be seen from FIG. 8 that, for example, three peaks / signal fluctuations 52 can be considered in order to be able to draw conclusions as to whether the particular pathogen / virus occurs / is contained in the respective exhaled air sample considered, or also which pathogen / virus is contained in each considered expiratory air sample is included.

To detect a pathogen / virus, the absolute heights and absolute positions of the individual signal deflections / peaks 52 are then considered. Furthermore, the relative positions and relative heights of the signal deflections / peaks 52 to one another are considered. However, only the heights can be viewed below one another. It has been found, for example, that with certain pathogens only individual signal fluctuations / peaks 52 increase and other signal fluctuations / peaks 52 decrease (compared to a healthy person). For example, if, compared to a healthy person, one of the signal swings / peaks 52 shown in FIG. 8 rises / becomes higher / is above a limit value and another of the signal swings / peaks 52 decreases / becomes smaller / below a limit value is to be inferred from a specific virus (e.g. influenza, human coronavirus, Sars-CoV-2, etc.). Another specific virus (eg influenza, human coronavirus, Sars-CoV-2, etc.) can be concluded, for example, if two of the signal fluctuations 52 shown in FIG. 8 rise / become higher / are above a limit value. Decision trees can thus be created which enable a specific pathogen / virus that is contained in the corresponding exhaled air sample to be determined / named. List of reference symbols

2 breathing air examination system

4 sampling system

6 Breath analysis device

8 breathing cycle detection means

10 control unit

12 actuator

14 first sample receiving / or dosing device 16 second sample receiving / or dosing device 18 multicapillary column

20 ion mobility spectrometers 22 human / patient / subject

24 eight-way valve

26 gas outlet

28 first sample loop / dosing loop 30 second sample loop / dosing loop

32 Carrier gas inlet

33 Six-way valve

34 Sampling area

36 ionization chamber section

38 ionization source

40 barriers

42 drift chamber section

44 Drift gas inlet

46 detection device

48 aperture grids

50 virus position / site

52 Signal deflection / peak

Claims

Expectations 1. Sampling system (4) for taking samples of expired air, comprising: a first sample receiving or metering device (14) for receiving or filling with expired air from a first region of a respiratory tract; and a second sample receiving or dosing device (16) for receiving or filling with expiratory air from a second region of the respiratory tract. 2. Sampling system (4) according to claim 1, further comprising a control unit (10) which is used to control the sampling, in particular to control the filling of the first sample receiving or dosing device (14) with expiratory air from the first area of the respiratory tract and the second Sample receiving or dosing device (16) is set up with expiratory air from the second region of the respiratory tract. 3. Sampling system (4) according to claim 2, wherein the control unit (10) is set up to fill the first sample receiving or dosing device (14) with pharynx expiratory air and to fill the second sample receiving or dosing device (16) with end-tidal expiratory air fill. 4. Sampling system (4) according to claim 2 or 3, further comprising a breath cycle detection means (8) which is set up to detect a breathing cycle and to pass on detected information about the breathing cycle to the control unit (10), the control unit (10) for breath cycle controlled sampling is set up. 5. Sampling system (4) according to any one of claims 2 to 4, further comprising an actuator (12) which is controlled by the control unit (10) to supply expired air in an expiration process both in the first sample receiving or dosing device (14) as also to pass into the second sample receiving or dosing device (16). 6. Sampling system (4) according to claim 5, wherein the control unit (10) controls the actuator (12), in which an expiratory process, pharynx expiratory air to the first sample receiving or dosing device (14) and end-tidal expiratory air in the second sample receptacle - or the dosing device (16). 7. Sampling system (4) according to one of claims 2 to 6, wherein the control unit (10) is set up, expired air samples of the at least two sample receiving or metering devices (14, 16) one after the other Breathing air analysis device (6), in particular comprising a gas chromatographic column, in particular a multi-capillary column (18), and an ion mobility spectrometer (20), for a separate analysis of the expired air from the first area of the respiratory tract and the expiratory air from the second area of the respiratory tract. 8. Sampling system (4) according to one of the preceding claims 1 to 7, wherein the first sample receiving or dosing device (14) and the second sample receiving or dosing device (16) have different volumes, the volumes are set such that the Sample receiving or metering devices (14, 16) can be completely filled with a few breaths, in particular five to ten breaths. 9. Sampling system (4) according to claim 8, wherein the first sample receiving or dosing device (14) is provided for filling with pharyngeal expiratory air, the second sample receiving or dosing device (16) is provided for filling with end-tidal expiratory air, and a Volume of the first sample receiving or dosing device (14) is less than a volume of the second sample receiving or dosing device (16). 10. Sampling system (4) according to claim 9, wherein the first sample receiving or dosing device (14) has a volume of less than 600 milliliters and the second sample receiving or dosing device (16) has a volume of 700 milliliters to 1200 milliliters. 11. Sampling system (4) according to one of the preceding claims 1 to 10, wherein the sampling takes place during an expiratory process only when a predetermined threshold value (V1), in particular volume value or C02 value, is reached, the predetermined threshold value (V1) being set in this way that first expiratory air is taken from the throat. 12. Sampling system (4) according to claim 11, wherein the first predetermined threshold value (V1) is a volume value which is less than 800 milliliters, preferably less than 700 milliliters, particularly preferably less than 600 milliliters. 13. Sampling system (4) according to one of the preceding claims 1 to 12, wherein the sampling takes place in such a way that during an expiration process when a first predetermined threshold value (V1) is reached or present, the first sample receiving or dosing device (14) is filled. it begins that when a second predetermined threshold value (V2) is reached or is present, the filling of the first sample receptacle or dosing device (14) is ended, and that when a third predetermined threshold value (V3) is reached or present, the second sample receptacle is filled - or metering device (16) is started, and that when a fourth predetermined threshold value (V4) is reached or present, the filling of the second sample receiving device or metering device (16) is ended. 14. Sampling system (4) according to one of the preceding claims 1 to 13, wherein the first predetermined threshold value (V1) and the second predetermined threshold value (V2) are volume values which are determined such that both the first predetermined threshold value (V1) and the second predetermined threshold value (V2) are less than 800 milliliters. 15.Test system or breathing air examination system (2), for the detection of a pathogen, in particular a virus, in particular a corona virus, in particular the novel corona virus SARS-CoV-2 (Covid-19), in expired air, with: a sampling system (4) according to one of the preceding claims 1 to 14; and a breathing air analysis device (6) comprising a gas chromatographic column, in particular a multi-capillary column (18), and an ion mobility spectrometer (20); wherein a / the control unit (10) is set up, expired air samples of the at least two sample receiving or dosing devices (14, 16) one after the other in the breathing air analysis device (6) for a separate analysis of the expired air from the first area of the respiratory tract and the expiratory air from the second area of the respiratory tract.