CN110988319A - Expiration detection method and device for pyloric screw infection and related inflammation - Google Patents
Expiration detection method and device for pyloric screw infection and related inflammation Download PDFInfo
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/02—Devices for withdrawing samples
- G01N1/22—Devices for withdrawing samples in the gaseous state
- G01N1/2247—Sampling from a flowing stream of gas
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/0004—Gaseous mixtures, e.g. polluted air
- G01N33/0009—General constructional details of gas analysers, e.g. portable test equipment
- G01N33/0027—General constructional details of gas analysers, e.g. portable test equipment concerning the detector
- G01N33/0036—General constructional details of gas analysers, e.g. portable test equipment concerning the detector specially adapted to detect a particular component
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Abstract
The invention provides a method and a device for breath detection of pyloric screw infection and related inflammation, which are characterized in that general beverages and foods are fasted for 3 hours and barbecue foods are fasted for 8-12 hours before testing; detecting the exhaled NO concentration before and after administration of the composition to promote NO production and stabilize the substrate; helicobacter pylori infection and related inflammation were detected based on the change in the difference in exhaled NO before and after substrate administration. The substrate for realizing the method consists of urea, acid and salt in a certain proportion; the breath NO detection device consists of a breath sampling and breath analyzing module and comprises breath flow, pressure, temperature and humidity and CO2And a NO sensor.
Description
Technical Field
The present invention relates to the field of breath detection of helicobacter pylori infection and inflammation and related diseases.
Background
Currently, the routine method for detecting H.pylori (Hp) infection is C13 or C14 labeled urea breath test, and its drawbacks include, but are not limited to: (1) urea labeled with C13 is difficult to obtain and expensive, whereas C14 has radiation problems; (2) only Hp could be detected, and the degree of Hp infection and inflammation caused by Hp infection could not be diagnosed.
Detection of NO of gastric origin may alternatively help to solve the above mentioned problems. Lipopolysaccharide, urease and ammonia related to Hp infection and inflammatory cytokines secreted by activated cells of the lipopolysaccharide can up-regulate inducible NO synthase (iNOS) to synthesize and generate more NO. Therefore, the level of NO concentration increases for Hp infection, and further increases for inflammation caused by Hp infection. The diagnosis of Hp infection and related inflammation can be facilitated by detecting the change of the concentration of endogenous NO. For example, serum NO levels are elevated in order of magnitude for a normal population that is Hp negative, a gastritis patient that is Hp negative, and a gastritis patient that is Hp positive (e.g., Fujian university bulletin, Vol. 6/month at 2003, pp. 169-170); for the same disease, such as gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, ulcer or even gastric cancer, the NO level in the Hp-positive patients is higher than that in the Hp-negative patients (for example, in 1781-1783 at 12 rd 3 rd month of 2003, Miss-Miss 2003). It was also found that the expiratory NO concentration levels detected without labeled substrate were also successively higher for Hp-negative normal populations, Hp-negative patients with gastritis or gastric ulcers, Hp-positive patients with functional and ulcerative dyspepsia (e.g., EUROPEAN JOURNAL OF INFLAMMATION Vol. 11, No. 1,279-282(2013), J. Breath Res. 09 Jan 2018, 12(2): 026005).
Although the results of academic research on the relevance of endogenous NO and Hp infection and related inflammatory diseases are consistent, the reported NO measurement data in the literature are large in difference and poor in repeatability, and although the possibility of detecting Hp infection and related inflammation by exhaled NO is shown, the possibility is converted into a standardized clinical practical technology, reliable, consistent and repeatable measurement results are obtained, and a plurality of problems need to be solved, including elimination or reduction of factors influencing the determination result of endogastric NO, and improvement of the accuracy, repeatability and stability of detection. For example, factors to consider include, but are not limited to: endogenous NO can be converted to nitrite ions, which reduces NO, while NO produced or ingested by the dietary environment increases NO; the respiratory system other than the stomach also produces NO, which increases NO. Furthermore, the concentration level of exhaled NO is also related to factors such as the manner of exhalation, flow rate, time and pressure. These technical problems, breath NO detection of Hp infection and inflammation and related diseases, have not been studied or even mentioned, nor have they been published.
The invention aims to overcome the defects of a urea breath test technology on the basis of academic research on the relevance of Hp infection and related inflammation and endogenous NO, and develop a breath detection method and a breath detection device without a C13 or C14 labeled substrate, so that the Hp infection and related inflammation can be detected noninvasively and instantly through the change of the concentration of NO in breath after the substrate is taken.
Disclosure of Invention
Under the action of Hp urease, hydrogenase and NO synthetase, the interaction and relative balance of various substances in gastric mucosa and gastric juice are shown as follows: CO 22/HCO3 -, NH3/NH4 -，H2/H-With NO/NO2 -. In principle, the detection of CO in exhaled breath2、NH3NO or/and H2The change in concentration of (a) may be informative of Hp infection, while the change in exhaled NO also contains information on Hp infectious inflammation. However, to obtain highly sensitive and specific diagnostic information, one needs to consider amplifying or increasing information associated with Hp infection while reducing or eliminating interfering information from other body sites or from the environmental diet.
First, we consider increasing the rate or concentration of NO production associated with Hp infection to improve the sensitivity and reproducibility or stability of exhaled NO detection for Hp infection diagnosis. Academic studies have shown that urea and acid as substrates promote more NH production in the stomach3And by Hp urease with NH3The up-regulation of iNOS synthesizes and generates more NO; the acid can promote urease activity, promote generation of more NO and prevent NO to NO2 -The conversion of (a) promotes and stabilizes the synthesis of NO, and improves the sensitivity, repeatability or stability of exhaled NO to Hp infection detection.
However, due to individualized differences in physiopathology, the pH or acidity of gastric juice varies from subject to subject and at different times, and the addition of acid alone is not sufficient to compensate or eliminate these differences, acting to stabilize NO. For example, we have found that the same subjects were dosed with urea and citric acid in the morning and afternoon, but that the difference in exhaled NO may be significant due to the differences in pH of the gastric juice itself over different periods of time, and may affect the diagnostic outcome of Hp infection. Experiments further find that the addition of a small amount of salt into urea and acid can buffer or reduce the influence of the change of the pH value of gastric juice, reduce the uncertainty of the change of exhaled NO and improve the repeatability or stability of detection.
Second, we consider eliminating or reducing the contribution of other body endogenous and environmental dietary exogenous sources to improve the specificity and consistency of exhaled NO detection for the diagnosis of Hp infection and inflammation. These contributions can be partially eliminated by taking the difference in the NO measurements of the breath before and after the urea + acid + salt preparation, but some of the contributions still have a time effect and are difficult to eliminate or reduce by the difference. For example, nitrate-containing foods, particularly roast foods, are degraded to NO in the stomach. We have found that exhaled NO rises to 30-60ppb within 1-2 hours and then falls to the pre-prandial basal level within 1-2 hours, these concentration changes exceeding the NO production level associated with Hp infection or stomach inflammation by 10-30 ppb. Thus, the difference in the exhalation test over this period of variation still contains the effect of the diet. To counteract these effects, we found that a fast of at least 3 hours was necessary. Similarly, NO in the environment can exceed 100ppb due to the position and time of vehicle emissions, and the subsequent exhaled NO detection result can be significantly affected after inhalation, and the effects can be eliminated by inhaling gas less than 5ppb and eliminating NO remaining in the dead space. In addition, excessive substrate entering the intestine from the stomach also produces NO by bacteria or cellular enzymes in the intestine, and the difference cannot completely eliminate these effects because NO is produced in the upper airway and the intestine itself and varies with time. Through research, we find that these effects can be reduced by regulating the measurement conditions of exhalation mode, flow rate, time, pressure, etc.
Exhaled NO measurements have been widely used for inflammation detection in respiratory diseases such as asthma, with standardized exhaled flow rates of 50ml/s and exhaled time of 10s, mainly NO produced by respiratory inflammatory cells, and less than 20% of NO from the gastrointestinal tract being detected. Thus, the existing methods and devices for exhaled NO testing are not suitable for detecting NO produced by Hp infection and associated inflammation. BreathWhen the flow rate is too high or the expiration time is too long and too short, the expiration NO contains the contribution of the NO in the air passage or the intestinal tract, and the result of the expiration NO detection on the diagnosis of the stomach Hp infection and related inflammation is influenced. By properly increasing the expiratory flow rate and selecting an appropriate expiration time to reach the end of expiration, the concentration of stomach NO gas in expiration can be increased, and the contribution of airway and intestinal tract NO can be reduced. We optimized the breath sampling conditions suitable for diagnosis of Hp infection and inflammation in the stomach by study: expiratory flow rate of 150-2The emptying time before reaching the plateau period and the sampling time when reaching the plateau period or the end of expiration does not exceed 1 second, and the expiratory pressure is required to be released>10cmH2O, close the soft palate which communicates the nasal cavity with the lower respiratory tract, and avoid the influence of the expiration of high-concentration NO gas in the nasal cavity from the inlet on the detection of stomach NO. By measuring the expiratory NO before and after the substrate is taken by Hp positive volunteers, the expiratory test condition is found that the expiratory NO measurement is carried out within 20-30 minutes after the substrate is taken, the expiratory NO concentration before the substrate is taken is subtracted, a repeatable significance difference can be obtained, the difference of the expiratory NO before and after the substrate is taken by different subjects can exceed 5ppb, and the lower detection limit and the accuracy of an expiratory NO detection device are required to be less than 5 ppb.
Thus, we propose a method for the detection of Hp infection and related inflammatory marker-free exhaled NO, characterized by fasting a general diet for 3 hours and a roast diet for 8-12 hours before testing; limited detection of exhaled NO concentration before substrate administration; then taking a substrate for promoting and stabilizing NO production in the stomach with proper warm water, and detecting the expiratory NO concentration after taking the substrate within 20-30 minutes after taking the substrate; calculating to obtain the difference concentration of NO in the breath before and after taking the substrate, and using the difference concentration for clinical diagnosis of Hp infection, inflammation and related diseases.
The substrate administered in the method of the present invention is a substrate for promoting and stabilizing the production of NO in the stomach. The substrate is mainly composed of urea, acid and salt, and the preferable components are food grade urea 50-100 mg, citric acid 2-4 g, malic acid or lactic acid, sodium citrate 20-40 mg, trisodium citrate or potassium citrate. To enhance the mouthfeel of the product, small amounts of sweeteners or other flavoring agents which do not metabolize to NO may be added.
The invention provides a device for detecting exhaled NO, which consists of an exhaled breath sampling module (100) and an exhaled breath analysis module (200), wherein the exhaled breath sampling module (100) consists of an exhalation tube (110), a pressure sensor (190) and CO2A sensor (163), a three-way electromagnetic valve (131) and an air chamber (120), an expiratory tube (110), CO2The sensor (163), the three-way electromagnetic valve I (131) and the air chamber (120) are connected in series, the other interface of the three-way electromagnetic valve I (131) is communicated with the atmosphere, and the pressure sensor (190) is connected to the expiratory tube (110) and the CO2On the pipeline between the sensors (163); the breath analysis module (200) is composed of a gas filtering device (180), a three-way electromagnetic valve II (132), an analysis pump (140), a humidity regulator (150) and an NO sensor (161), the three-way electromagnetic valve II (132) is connected to a pipeline between the three-way electromagnetic valve I (131) and the gas chamber (120), the analysis pump (140), the humidity regulator (150) and the NO sensor (161) are connected in series to the three-way electromagnetic valve II (132), and the other interface of the three-way electromagnetic valve II (132) is connected with the gas filtering device (180).
The parameters of the breath sampling module (100) controlling the breath sampling include the flow rate, time and pressure of the breath and the breath CO2Concentration, expiratory flow rate of 150-2O, expiration time is expiratory CO2Emptying before the plateau period is reached, and sampling within 1 second when the plateau period is reached; the NO sensor of the breath analysis module (200) performs analysis and determination on the sampled breath; the preferred NO sensor has a lower detection limit and accuracy of 3ppb and a response time of less than 15 seconds. The humidity regulator can regulate and balance the humidity of the gas entering the sensor every time, and eliminates the influence of the humidity of the gas sample on the signal. The gas filtering device (180) is internally provided with a filtering material, NO in the air can be adsorbed to obtain zero gas, and a contribution signal of the NO is obtained after accurate deduction.
The device scheme of the label-free breath detection of helicobacter pylori infection, inflammation and related diseases overcomes the defects of the existing instruments and technologies, can accurately sample and accurately analyze NO components generated by the stomach, and realizes that the breath NO detection technology is applied to clinical routine detection of helicobacter pylori infection, inflammation and related diseases.
Drawings
FIG. 1 is a device for label-free breath detection of H.pylori infection and related diseases.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the accompanying drawings and embodiments, it being understood that the specific embodiments described herein are only for the purpose of illustrating the present invention and are not to be construed as limiting the present invention.
Detailed description of the preferred embodiment
The embodiment adopts an expired air NO detection device modified based on a Shanghai medical nano coulomb expired air analyzer: as shown in figure 1, the device for the label-free breath detection of pyloric screw infection and related diseases comprises an exhalation sampling module and an exhalation analysis module, wherein the exhalation sampling module comprises an exhalation tube, a pressure sensor and CO2Sensor, three-way electromagnetic valve, air chamber, expiratory tube and CO2The sensor, the three-way electromagnetic valve I and the air chamber are connected in series, the other interface of the three-way electromagnetic valve I is communicated with the atmosphere, and the pressure sensor is connected to the expiratory tube and the CO2On the pipeline between the sensors; the breath analysis module is composed of a gas filtering device, a three-way electromagnetic valve II, an analysis pump, a humidity regulator and an NO sensor, the three-way electromagnetic valve II is connected to a pipeline between the three-way electromagnetic valve I and the air chamber, the analysis pump, the humidity regulator and the NO sensor are connected in series to the three-way electromagnetic valve II, and the other interface of the three-way electromagnetic valve II is connected with the gas filtering device. The NO sensor used in this example had a detection lower limit and accuracy of 3ppb and a response time of less than 15 seconds. The humidity regulator is a Nafion tube of Bo-pure company, can regulate and balance the humidity of gas entering the sensor every time, and eliminates the influence of the humidity of a gas sample on signals. The gas filtering device contains a filtering material, and can absorb NO in the air to obtain zero gas. The capacity of the air chamber is 50ml, and the flow rate of the analysis pump is 1.5 ml/s.
A substrate for promoting and stabilizing the production of NO in the stomach is formulated to have a composition of 60 mg of food grade urea, 3 g of citric acid, 20 mg of potassium citrate, and a small amount of a sweetener that does not readily produce detectable amounts of hydrogen.
The exhaled NO detection applied to the detection of helicobacter pylori infection was performed according to the following procedure:
1) general beverages and food were fasted for 3 hours and barbecued and sugar foods were fasted for 8-12 hours before testing;
2) enabling the patient to exhale by using the detection device, and detecting the fasting concentration of NO in the exhaled air before taking the substrate;
3) after the fasting concentration is detected, the substrate capsule is taken by proper warm water, after the capsule is taken for 25 minutes, the detection device is used again for expiration, and the substrate concentration of expiration NO after the substrate is taken is detected;
4) calculating to obtain the difference concentration of NO in the expired air before and after the substrate is taken, and judging whether the helicobacter pylori infection exists.
Each exhaled NO detection is performed according to the following steps:
1) the patient holds the expiratory tube to exhale, and the pressure sensor detects the pressure and starts to record the expiratory time;
2) the patient exhales according to the indicated flow requirement, the flow rate of the expired air is kept at 180mL/s, and the expired air passes through CO2Real-time detection of CO in expired air by sensor2Concentration, three-way electromagnetic valve firstly switches to exhaust after expiration, and CO is to be expired2Switching to exhale into the air chamber after the plateau period is reached, and continuing to exhale for 1 second, namely stopping exhaling and finishing sampling;
3) opening the analysis pump, switching the sample gas in the analysis gas chamber by the three-way electromagnetic valve II firstly, switching the three-way electromagnetic valve II after 30s to analyze the air filtered by the gas filtering device, and closing the analysis pump after 30s to finish analysis;
4) and calculating the concentration of the exhaled NO according to two sections of analysis signal data output by the NO sensor.
Detailed description of the invention
According to the detection method and the detection device of the embodiment I, the exhaled NO detection before and after the substrate taking is carried out on 42 volunteers. The results of 42 volunteers of the diagnosis of helicobacter pylori (Hp) infection by C14 Urea breath test and the presence or absence of chronic gastritis symptoms were divided into three groups, and the difference between the exhaled NO measurements before and after substrate administration was as follows
| Grouping | Number of people | Exhalation NO before taking substrate | Increase in exhaled NO after substrate administration |
| Hp negative asymptomatic | 16 | 7.4± 3.1 ppb | 2.6± 1.4 ppb |
| Hp-positive asymptomatic | 14 | 8.8 ± 4.2 ppb | 5.4 ± 2.9 ppb |
| Hp-positive symptomatic disease | 12 | 10.6 ± 5.4 ppb | 9.8 ± 4.5 ppb |
The data analysis of the above examples shows that, for three groups of subjects with negative Hp and positive Hp symptoms (with Hp infection but NO inflammation), and positive Hp symptoms (Hp infection + inflammation), the expiratory NO before substrate administration is sequentially increased but has NO significant difference (p > 0.05), and the difference of the expiratory NO before and after substrate administration is also sequentially and significantly increased (p < 0.05), so that the kit can be used for detecting H infection and related inflammation.
The invention is not limited to the embodiments shown and described, but any variations and modifications are within the scope of protection of the appended claims.
Claims (8)
1. A method for breath test of pyloric screw infection and related inflammation is characterized in that general beverages and foods are fasted for 3 hours and barbecue and sugar foods are fasted for 8-12 hours before test; detecting the fasting concentration of NO in the breath before taking the substrate; after the fasting concentration is detected, a substrate for promoting and stabilizing NO production in the stomach is taken by proper warm water, and the substrate concentration of exhaled NO after the substrate is taken is detected within 20-30 minutes after the substrate is taken; calculating to obtain the difference concentration of the exhaled NO before and after taking the substrate, and using the difference concentration to clinically diagnose the helicobacter pylori infection and related inflammation.
2. The method for breath test of pyloric screw infection and related inflammation according to claim 1, wherein said substrate for promoting and stabilizing the production of NO in the stomach is selected from the group consisting of urea, acid and salt.
3. The method of breath test for pyloric screw infection and related inflammation according to claim 2, wherein said urea is food grade urea in an amount of 50-100 mg, said acid is citric acid, malic acid or lactic acid in an amount of 2-4 g, and said salt is sodium citrate, trisodium citrate or potassium citrate in an amount of 20-40 mg.
4. The method for breath test of pyloric screw infection and related inflammatory conditions of claim 2, wherein said substrate is provided with a suitable amount of sweetener or other flavoring to enhance the taste of said breath test.
5. The breath test method of claim 1 for breath NO test of pyloric screw infection and related inflammatory conditionsThe device for measuring is characterized by consisting of an expiratory sampling module (100) and an expiratory analysis module (200), wherein the expiratory sampling module (100) consists of an expiratory tube (110), a pressure sensor (190) and CO2A sensor (163), a three-way electromagnetic valve (131) and an air chamber (120), an expiratory tube (110), CO2The sensor (163), the three-way electromagnetic valve I (131) and the air chamber (120) are connected in series, the other interface of the three-way electromagnetic valve I (131) is communicated with the atmosphere, and the pressure sensor (190) is connected to the expiratory tube (110) and the CO2On the pipeline between the sensors (163); the breath analysis module (200) is composed of a gas filtering device (180), a three-way electromagnetic valve II (132), an analysis pump (140), a humidity regulator (150) and an NO sensor (161), the three-way electromagnetic valve II (132) is connected to a pipeline between the three-way electromagnetic valve I (131) and the gas chamber (120), the analysis pump (140), the humidity regulator (150) and the NO sensor (161) are connected in series to the three-way electromagnetic valve II (132), and the other interface of the three-way electromagnetic valve II (132) is connected with the gas filtering device (180).
6. The apparatus for exhaled NO detection of claim 5, wherein the exhaled breath sampling module (100) monitors parameters of the exhaled breath sample, including the flow rate, time and pressure of the exhaled breath and the exhaled CO2The concentration of (c).
7. The apparatus for exhaled NO detection of claim 6, wherein the exhaled flow rate is 150->10cmH2O, the expiration time being expiratory CO2And when the concentration reaches the plateau period, the expired air before reaching the plateau period is emptied, and the expired air reaching the plateau period for 1 second is collected into the air chamber.
8. The apparatus for breath NO detection of claim 5, wherein said NO sensor of said breath analysis module has a detection lower limit and accuracy of less than 5ppb and a response time of less than 15 seconds.
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| RU2790397C1 (en) * | 2022-05-05 | 2023-02-17 | федеральное государственное бюджетное образовательное учреждение высшего образования "Северо-Западный государственный медицинский университет имени И.И. Мечникова" Министерства здравоохранения Российской Федерации | Method for non-invasive diagnosis of helicobacter pylori infection using 13c-urease breath test |
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| US20080077037A1 (en) * | 2003-04-21 | 2008-03-27 | Pelagia-Irene Gouma | Selective point of care nanoprobe breath analyzer |
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| RU2790397C1 (en) * | 2022-05-05 | 2023-02-17 | федеральное государственное бюджетное образовательное учреждение высшего образования "Северо-Западный государственный медицинский университет имени И.И. Мечникова" Министерства здравоохранения Российской Федерации | Method for non-invasive diagnosis of helicobacter pylori infection using 13c-urease breath test |
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