阅读说明：本技术 用于获取被测试者的呼吸试样的方法和装置 (Method and device for acquiring breath sample of tested person ) 是由 F·拉尔默 于 2019-07-23 设计创作，主要内容包括：本发明涉及用于获取被测试者的呼吸试样的一种方法和一种装置,其中被测试者吸入优选比环境温度冷的微滴雾(100)。将随后由被测试者呼出的和/或咳出的材料作为呼吸试样捕集在一个或者多个捕集容器(109)中。(The invention relates to a method and a device for acquiring a breath sample of a test subject, wherein the test subject inhales a droplet mist (100) which is preferably colder than the ambient temperature. The material subsequently exhaled and/or expectorated by the test subject is captured as a breath sample in one or more capture containers (109).)

1. Method for obtaining a breath sample of a test subject, characterized in that the test subject inhales a droplet mist (100) and traps as a breath sample material which is subsequently exhaled and/or expectorated by the test subject.

2. The method according to claim 1, wherein the droplet mist (100) is cooler than ambient temperature.

3. The method according to claim 1 or claim 2, wherein the droplet mist (100) is generated with an ultrasonic nebulizer (101).

4. Method according to any of the preceding claims, characterized in that the cooling of the droplet mist (100) is performed by means of ice or by means of at least one peltier element (106).

5. The method according to any of the preceding claims, characterized in that the exhaled and/or expectorated material is conducted to at least one trapping vessel (109; 209).

6. Method according to any of the preceding claims, characterized in that the exhaled and/or expectorated material is guided through a filter (111; 211) for binding the material.

7. A device (10) for acquiring a breath sample of a subject comprises means (114) for generating a droplet mist (100) and means (126) for inhaling the droplet mist by the subject and for trapping exhaled and/or expectorated material.

8. The device according to claim 7, characterized in that the means (114) for generating the droplet mist (100) have a storage container (103) for storing the liquid (102) to be atomized and an ultrasonic generator (101).

9. The device according to claim 7 or claim 8, wherein the storage container (103) is a disposable article.

10. Device according to any one of claims 7 to 10, characterized in that a cooling means (106) is provided in the means (114) for generating the droplet mist (100).

11. The device according to any of claims 7 to 10, characterized in that the means (126; 206) for suction and for trapping comprise at least one non-return valve (108) and at least one trapping vessel (109; 209).

12. The device according to claim 11, characterized in that the trapping container (109; 209) comprises at least one filter (111; 211) for binding exhaled and/or expectorated material.

13. The apparatus of claim 12, wherein the apparatus is a portable electronic deviceThe filter (111; 211) is SiO₂And (4) firing the materials.

14. Device according to claim 12, characterized in that the filter (111; 211) comprises a porous Teflon material, in particular a porous Teflon membrane.

15. Device according to any one of claims 7 to 14, characterized in that the means (126; 206) for suction and for trapping are constituted by one or more disposable articles.

Technical Field

The present invention relates to a method for acquiring a breath sample of a test subject and to a device provided for acquiring a breath sample of a test subject.

Background

It is known to derive information about the state of health of a subject or patient from a breath sample. For example, different proteins or other substances (biomarkers) can be isolated from the obtained respiratory sample, which allow conclusions to be drawn about the presence of cancer in the lungs, metabolic disturbances in the lungs, infections of the lungs, or also about the presence of systemic diseases, such as cancer or general infections. For example, tubercle bacillus can be isolated from the obtained breath sample within the scope of tuberculosis screening. For the diagnosis of lung infections or lung inflammations, which are so-called respiratory infections, specific bacteria or viruses can be isolated from the respiratory sample, further analyzed and possibly identified. Genetic material, in particular DNA, can also be isolated from the breath sample, in order to be able to deduce therefrom the possible presence of viruses, bacteria, fungi or also tumour cells. The necessary analytical methods, in particular molecular biological methods, were created for this. Such an analysis method can also be used for automated process control, so that it can be used, for example, in a larger population in the area of screening. In addition to this, the evaluation of breath samples can be used within the scope of optimization of medical treatments, for example in the monitoring of antibiotic therapy for bacterial infections or in the monitoring and optimization of cancer treatments. Furthermore, the evaluation of the breath sample can be used within the scope of stratification of the patient, i.e. for the risk assessment of the disease. A general advantage of the examination of breath samples is that they can be acquired (non-invasively) in a very simple and non-burdensome manner for the patient.

To obtain samples from breath, breath condensate extraction has been used to date. For this purpose, the moisture contained in the exhaled breath is in the cold trapCondensation on the surface. However, small molecules are mainly dissolved in the breath condensate, which are only convincing in special cases. For example, breath condensates are suitable for determining H₂O₂Said H is monitored for Chronic Obstructive Pulmonary Disease (COPD)₂O₂And (6) checking. Furthermore, there are solutions for trapping aerosols (very small water droplets released during exhalation in the lungs) and separating them out, for example, together with moisture condensates.

Disclosure of Invention

The invention provides a method for acquiring a breath sample of a test subject, wherein the test subject inhales a droplet mist. Preferably the droplet mist is cooler than ambient temperature. The material subsequently exhaled and/or expectorated by the test subject is captured as a breath sample. In this way, particularly diagnostically meaningful and convincing material from the lungs can be obtained and used for analysis. The droplets of the inhaled mist interact with the internal surfaces of the bronchial system, wherein a magnitude-independent exchange with the material on said surfaces occurs. That is, the water droplets absorb material located there, such as salts, bacteria, fungal spores, viruses, variable cancer cells, DNA, RNA, proteins, and the like, from the surface of the bronchial system. At the same time, contact with cold or at least subjectively cold water droplets causes a light cough stimulus, which in turn rapidly coughs out and can trap the water droplets laden with sample material. The temperature of the droplet mist is preferably lower than ambient temperature. As ambient temperature is generally meant the temperature in the enclosed space where the method is used, i.e. room temperature (about 18-22 ℃). Preferably the temperature of the droplet mist is between 0 ℃ and 15 ℃. In order to create a subjective feeling for a cold droplet mist, it is sometimes sufficient to atomize only or to shape the droplets by the evaporation cold associated with the atomization. Therefore, the droplet mist is also referred to as cold droplet mist hereinafter. The described method has significant advantages over conventional methods, namely: much more material can be obtained from the lung surface, especially also larger particles that are very valuable diagnostically. By the triggered cough stimulus, macroscopic particles as well as solid constituents can even be taken from the surface of the lung. Thus, significantly more meaningful sample material can be collected using the methods described herein than using conventional breath condensate capture methods, for example.

In addition to triggering a mild cough stimulus, the described method has the additional advantage that: due to the low temperature of the water droplets, a significant proportion of the cold water droplets themselves also leave the lungs with the expectorated gas stream and do not evaporate during their residence in the respiratory tract. Water vapor is not well suited as a carrier for biological sample materials because it can only absorb very small molecules. In contrast, by means of the droplet mist of the method described here, it is possible to obtain a much more valuable sample material for analysis.

The methods described herein are suitable, for example, for use in the context of tuberculosis screening. In tuberculosis screening, saliva samples of patients are conventionally taken, in which saliva bacteria to be confirmed may be present. The liquefaction of the often very thick and viscous saliva and the separation of the bacteria possibly contained therein is difficult and cumbersome, and thus screening based on saliva samples is often difficult for a large patient population. The method described is suitable in a special manner for tuberculosis screening, since in the method according to the invention a cough response is brought about in a controlled manner and furthermore a transport mechanism for the tubercle bacillus is provided by the droplet mist, which receives it and transports it out of the lungs.

In a preferred embodiment of the method, the droplet mist is generated using an ultrasonic atomizer known per se. The generation of mist by means of ultrasound has the following advantages: droplet generation is not premised on heating of the liquid to be atomized. In the sonication itself, only a small degree of heating of the liquid to be nebulized occurs. However, sometimes the nebulized and liquid droplet form with the evaporation coldness associated therewith is sufficient for generating a cough stimulus for the subjective feeling of coldness and the resulting triggering. The cold sensation is enhanced in a particularly preferred manner by: the mist produced and/or the liquid to be atomized is cooled. In a very simple and practical embodiment, for example, ice can be introduced into the liquid to be atomized. In a further embodiment, for example, a peltier element or another cooling element can be provided which cools the liquid and/or mist to be atomized itself.

Devices for ultrasonic atomization are known per se and can be obtained cost-effectively. Suitable devices are, for example, installed in so-called home inhalers which can in principle be used for the method described here.

For the method described here, provision is made for the droplet mist to be inhaled first and the exhaled and/or expectorated material to be captured afterwards. For this purpose, a suitable device can be provided, by means of which the droplet mist is first inhaled. The exhaled gas flow is then blown back into the device and guided inside the device to a suitable collecting container, for example by means of a non-return valve. The exhaled gas flow or the exhaled and/or expectorated material is preferably guided during the trapping process through a filter (such as a filter frit) on which the material to be analyzed is bound. Thus, bacteria, viruses, fungi, fungal spores, DNA, RNA and/or proteins contained in the exhaled air stream can for example be bound and collected on a filter before the material is further processed and analysed, for example immunologically or molecularly biologically. For the analysis, it is advantageously possible to use automated methods, such as lab-on-a-chip, which are particularly suitable in the first place for screening methods or other methods with a high throughput.

The invention also relates to a device for acquiring a breath sample of a test subject. Here, the device comprises means for generating a mist of droplets, preferably at a temperature below ambient temperature. Furthermore, a mechanism is provided for inhaling a droplet mist by the test subject and for trapping exhaled and/or expectorated material. The generation of the droplet mist is preferably carried out by means of ultrasound technology. For this purpose, in addition to the actual ultrasonic generator, a storage container for storing the liquid to be atomized is provided. In particular, this relates to an aqueous solution, such as water. If appropriate, further additives, such as dissolved salt (NaCl), in particular in a physiological or isotonic concentration of approximately 0.9g/l water (154 mmol/l), can be contained in the aqueous solution. Such physiological saline solution has the same osmotic pressure as blood, so that droplets of mist based on saline solution are not absorbed or reabsorbed by the lungs and leave the lungs again particularly well upon expectoration.

The storage container for storing the liquid to be atomized suitably has an air flow inlet and a droplet mist outlet. The actual mist generation or atomization is carried out with an ultrasonic generator known per se. The water in the storage container can be slowly atomized, for example, by means of an ultrasonic generator. Furthermore, a cooling mechanism is preferably provided in the mechanism for generating a mist of droplets. For this purpose, a peltier cooling element can be provided, which cools the water stored in the storage container. In a particularly simple, but nevertheless practical embodiment of the device, the liquid to be atomized can be cooled, for example, by means of one or more ice cubes. In a preferred manner, the stored water to be atomized is kept at a temperature in the range between 0 ℃ and 15 ℃, in particular between 0 ℃ and 5 ℃, since the triggered cough stimuli are enhanced by these temperature ranges. The requirements for cooling of the stored liquid or for cooling of the droplet mist can also depend on the environmental conditions. In regions with high ambient temperatures (e.g. africa), a sufficiently high cooling power is of interest for ensuring the cold state of the droplet mist.

The ultrasound generator and the cooling device can be operated, for example, electrically, for example by means of a mobile battery or also by means of an electrical network.

The storage container itself can be a disposable article, such as a corresponding plastic container. The storage container and other components of the device are configured as disposable articles, which has the particular advantage that: the container and other components can be removed after use and the risk of infection is eliminated for the personnel who subsequently use the device. Thus, special sterilization precautions can then be dispensed with.

The mechanism for inhaling the droplet mist and for trapping exhaled/expectorated material can be equipped with a check valve, so that the flow of exhaled air and exhaled and/or expectorated material can be directed into one or more trapping containers. Furthermore, at least one filter is preferably arranged in one or more of the trapping vessels, wherein the filter is arranged to bind or trap exhaled and/or expectorated material. The filter can be, for example, SiO₂A frit or other suitable filter material with which bacteria, fungi, fungal spores, viruses, cells, DNA, RNA and/or proteins, among others, can be retained. Particularly suitable are filters composed of porous teflon, for example porous teflon membranes. The pore size of such filters is suitably so small that pathogens or other substances that are to be examined in the breath sample are trapped. Suitable pore sizes are in particular in the range from 0.01 to 10 μm, in particular from 0.2 to 5 μm, preferably from 0.5 to 2 μm. For example, filter materials which are used in the context of sterile filtration and which are available as commercially available bacterial or pathogen filters are suitable. The choice of a suitable filter can also depend on the material to be analyzed, with other filters (e.g., 5-10 μm pore size) being more suitable than for the validation of a particular protein or DNA or RNA (e.g., pore size 0.1-1 μm), such as for the validation of bacteria (e.g., tubercle bacillus) or cells. For many applications, filters having pore sizes of 0.5-2 μm are suitable. The use of a membrane-like filter material has the following particular advantages, namely: the membrane can be used over a large area, for example by flange connection of a funnel equipped with the membrane. This reduces the resistance to breathing during expectoration, making the application more comfortable and easy for the subject. For making breath samplesFor further analysis, the material to be examined can be flushed, for example, from a flat filter, for example in a lab-on-a-chip.

It is particularly preferred that the means for inhaling a mist of droplets and for trapping exhaled and/or expectorated material is constituted by one or more disposable articles. The trapping containers can be, for example, the customary Eppendorf ® filter containers or filter frits. The remaining means for inhaling the droplet mist and for trapping or for filtering the exhaled and/or expectorated air flow are preferably provided for a single use, in order to avoid contamination by potentially infectious materials. With the use of corresponding disposable articles, it is also not necessary, for example, to design the check valve in a construction that is impermeable to pathogens, since contamination is precluded by the material being removed after use. Corresponding articles can be produced, for example, as plastic parts, which can be provided cost-effectively and can be easily adapted to the respective requirements. For example, it can also be provided that the storage container for storing the liquid to be atomized and the mechanism for inhaling the droplet mist and for trapping the exhaled and/or expectorated material are provided as a one-piece article.

Drawings

Further features and advantages of the invention emerge from the following description of an embodiment with reference to the accompanying drawings. The individual features can be realized in each case by themselves or in combination with one another.

In the drawings:

fig. 1 shows a schematic cross-sectional view of a device for acquiring a breath sample of a test subject; and is

Fig. 2 shows a view of a mechanism for inhaling a droplet mist and for trapping exhaled and/or expectorated material as part of the device according to the invention.

Detailed Description

Fig. 1 shows in schematic form the components of a device 10 for taking breath samples. The device 10 here comprises means 114 for generating a droplet mist 100, wherein in this embodiment the droplet mist is generated by means of an ultrasonic generator 101. A liquid 102 to be atomized, in particular an aqueous liquid or pure water (tap water), is located in a storage container 103. The droplet mist 100 is generated in the storage container 103 by applying ultrasonic waves to the storage container 103 by means of an ultrasonic generator 101 which in the present embodiment is operated with a high-frequency Alternating Current (AC). The storage container 103 here comprises an air flow inlet 104 and a droplet mist outlet 105. Air flows in through the air flow inlet 104, which is here depicted by means of arrows, and the droplet mist 100 leaves the storage container 103 through the droplet mist outlet 105, which is in turn depicted by means of arrows. For the method according to the invention, a droplet mist is used, which is preferably at a temperature below ambient temperature and which triggers a gentle cough stimulus when the droplet mist is inhaled by the test person. The cold droplet mist can be generated in different ways. In this embodiment, a peltier cooling element 106 is provided, which can be operated, for example, with Direct Current (DC). The aqueous solution or water 102 in the storage container 103 is cooled by the cooling element 106, so that the droplet mist 100 formed is also cold. In another embodiment, for example, ice or ice cubes are placed in the liquid 102. In this way, a cold droplet mist 100 can also be generated. On the other hand, the evaporative cooling of the generated droplets by atomization can sometimes be sufficient to trigger subjective cold sensations and cough stimuli of the test subject.

For the purposes of the present invention, it is possible to use conventional, commercially available devices having an ultrasound function and, if appropriate, a cooling function, into which, for example, the reservoir 103 with the liquid 102 to be atomized is inserted. The storage container 103 can be coupled to a real ultrasound generator/cooler by means of another coupling medium, in particular a liquid. The storage container 103 can be designed as a disposable article, for example, from a correspondingly shaped plastic in a cost-effective manner. Thus, for example, the storage container 103 can be removed after use. The ultrasound generator 101 and the possibly present peltier cooling element 106 can be provided for mains operation or also for mobile battery operation.

Furthermore, the device 10 comprises a mechanism 126 by means of which the droplet mist 100 can be inhaled by the test person and which the test person can exhale or expectorate the droplet mist, so that the mechanism 126 is furthermore provided for trapping exhaled and/or expectorated material. The mechanism 126 is preferably designed as a disposable article so that it can be removed after use in order to exclude possible infections on another test subject due to infectious material. The mechanism 126 includes a suction inlet and a suction tube 107 through which the droplet mist 100 is sucked by the subject (arrow 115). The suction pipe 107 can be configured as a suction nozzle. In other embodiments, the suction nozzle can be plugged or screwed onto the suction tube 107, for example. The inhalation tube 107 is furthermore used for blowing in an exhaled and/or expectorated gas flow after inhalation of the droplet mist. In order to divert the gas flow, here depicted by the arrow 116, a non-return valve 108 is arranged between the suction pipe 107 and the end of the mechanism 126, through which the generated droplet mist 100 flows into the mechanism 126. The exhaled gas flow is guided by means of this check valve 108 into a trap container 109. This collecting container 109 can be constructed, for example, in the form of commercially available Eppendorf filter containers which can be plugged into corresponding lateral openings or lateral pipe connections 110 of the suction pipe 107. In this preferred embodiment, the collecting vessel 109 comprises a filter 111, in particular a filter frit, for example made of silicon oxide, on which the exhaled and/or expectorated material is collected. In order not to generate a significant counter pressure when exhaled air is blown into the mechanism 126, the collecting container is provided with an outflow opening 112, through which the blown exhaled air can flow out in the direction of the arrow. After the test subject has inhaled the droplet mist and the exhaled and/or expectorated material is blown back into the device 126, the collecting container 109 with the filter 111 contained therein can be removed in a simple manner and the filter 111 can be removed and further processed, in particular for further analysis of the material.

The means 126 is connected to the means (mist generator) 114 in such a way that the generated droplet mist 100 can flow through the means 126. For this purpose, the mechanism 126 can be inserted or screwed into the droplet mist outlet 105, for example, via the connection 113. For this purpose, suitable seals or threads can be provided in the region of the connection. The connection 113 on the rear side of the non-return valve 108 can, for example, be inserted directly into the droplet mist outlet 105, wherein additional sealing means can be provided here for ensuring a sealed closure.

The non-return valve 108 is expediently realized as a simple mechanical non-return valve, so that the droplet mist 100 or the water droplet/air mixture is sucked in only by the mist generator 114, which is formed in particular by the storage container 103, the ultrasound generator 101 and, if appropriate, the peltier cooling element 106, but can no longer be returned. Such a check valve 108 can be made of plastic, for example, and can be obtained cost-effectively.

In order to prepare the sample, the means 126 can first be connected to the means 114 or the storage container 103, before the ultrasound and, if necessary, the peltier cooling means are coupled, for example, by means of additional sample water as a coupling medium. Here, commercially available atomizing devices can be used. The process of these steps of inhaling the mist of droplets 100 and blowing the exhaled air stream into the mechanism 126 can be repeated one or more times. After the sampling is finished, the entire mechanism 126 can be separated from the mist generator 114. The one or more trapping vessels 109 can, for example, be broken off or screwed off and the biological material contained therein, which can possibly be bound to the filter 111, can, for example, be analyzed in molecular biology, for example by means of lab-on-a-chip analysis.

If the device 126 and, if appropriate, the storage container 103 are designed as disposable articles, the entire device 126 and, if appropriate, the storage container 103 can be removed after removal of the capture container 109, since these components can be contaminated by pathogens. These components can also be intermediately stored with a disinfecting solution, for example, and subsequently removed, for example burnt off.

If the storage container 103 is also designed as a disposable product, it is not necessary to design the check valve 108 in a construction that is impervious to pathogens, since contamination by disposable products is inherently precluded. In general, therefore, the means 126 and the storage container 103 can also be produced as one or more inexpensive plastic parts, which do not represent a significant cost factor. For example, the intake tube 107, together with the pipe connection 110 and the check valve 108 and the connection 113 can be produced as a one-piece product. It is also possible to combine these elements as a one-piece article together with the storage container 103. This makes the use particularly simple, since, for the preparation of a sample, only one or more collection containers 109 have to be plugged onto one or more pipe connections 110 and the storage container 103 has to be inserted into the respective ultrasound/cooling device.

Fig. 2 shows a mechanism 206 for inhaling a mist of droplets and for trapping exhaled/expectorated material, wherein the mechanism 206 is provided for two trapping containers 209. These collection containers 209 each having a filter 211 are plugged by a pipe joint 210 on the opposite side of the suction pipe 207. In other embodiments, instead of a pipe connection, a predetermined breaking point 210 can be provided, so that the collection container 209 can be broken off or closed after use in order to be sent for further analysis. Furthermore, the mechanism 206 is configured similarly to the mechanism 126 of FIG. 1, with a check valve 208 disposed within the mechanism 206. With this region 213, the means 206 can be inserted or screwed into a droplet mist outlet of a storage container for a mist generator with liquid to be atomized, wherein corresponding threads can be provided.

The device described here is used for acquiring a breath sample of a test subject, wherein a droplet mist generated in the device, preferably having a temperature lower than the ambient temperature, is inhaled and interacts with the surface of the respiratory tract of the test subject, wherein the biological material located there is absorbed and at the same time a cough stimulus is generated, which causes the expectoration of water droplets laden with sample material. By means of the provided non-return valve of the essentially disposable device, the expired aerosol is necessarily deflected by the preferably provided filter of the collecting container, so that the biological sample material is retained on the filter. The capture container with the filter loaded in this way can be separated and, for example, be submitted to the analysis and diagnostic processes of molecular biology in preferably lab-on-a-chip systems. These devices and methods are particularly suitable for screening the lungs for bacterial infections such as tuberculosis screening. However, other diseases of the lung, such as systemic diseases caused by bacteria, fungi or viruses, or tumor diseases, can also be diagnosed and/or monitored using this method and the described device.