Methods of breath analysis

Abstract

Systems and methods have been developed for implementing a breath testing system that conveniently samples exhaled intestinal gases from a patient's breath. This may include a system having a manifold containing temperature-regulating components (e.g., thermistors and resistive heating elements) that maintain the temperature of the gas above the patient's body temperature. In some instances, the system determines an indication of whether a patient has SIBO by adjusting for changes in breath hydrogen concentration due to the patient's exhaled methane level.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 949,057, entitled "BREATH GAS ANALYSIS," filed December 17, 2019, the contents of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present invention relates to a system and method for analyzing gas exhaled in a patient's breath. [Background technology]

[0003] 2. Background of the Invention The following description contains information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the claimed invention, or that any publication specifically or implicitly mentioned is prior art.

[0004] The human gastrointestinal system is typically home to billions of bacterial cells that aid in digestion, but can become harmful if they overgrow. These bacteria feed on the food a person ingests, producing both useful and harmful by-products. Typically, thousands of times fewer bacteria are found in the small intestine compared to the large intestine. However, in some patients with small intestinal bacterial overgrowth ("SIBO"), the number of bacteria in the small intestine increases to a point where it approaches the volume of the large intestine. SIBO can cause excess gas production, resulting in unpleasant and uncomfortable symptoms for patients. For example, patients with excess gas production may experience abdominal pain, bloating, excessive burping, flatus, general discomfort, and nausea. SIBO is thought to affect a significant number of adults (approximately 10%).

[0005] Although research (e.g., that disclosed in U.S. Pat. No. 8,388,935) is extensive, the relationship between SIBO and many conditions, such as irritable bowel syndrome (IBS), fibromyalgia, chronic pelvic pain syndrome, depression, psychiatric disorders, halitosis, tinnitus, sugar cravings, autism, attention deficit / hyperactivity disorder, drug sensitivity, autoimmune diseases, and Crohn's disease, is incompletely defined. With currently available tools, caregivers can correlate some of these conditions with SIBO in some patients. Unfortunately, however, because each patient's bacterial landscape is so unique, it is difficult, if not impossible, to achieve a universal correlation. Therefore, a single laboratory test is unlikely to be determinative for diagnostic purposes.

[0006] CH exhaled during breath 4 and H 2 Concentrations of CH have been shown to be associated with SIBO in many studies, but appear to be affected somewhat differently in different patients. 4 (-1 to 50 ppm) and H 2 Concentrations of (-1 to 50 ppm) have been shown to be clinically significant.

[0007] Additionally, excess methane production has been shown to be associated with obesity, and excess gas production has been shown to be associated with irritable bowel syndrome. Recently, there has been a higher level of interest in SIBO due to its possible link to irritable bowel syndrome. Additionally, higher levels of methane are an indication of SIBO, which causes constipation.

[0008] Currently, SIBO is diagnosed using a prescribed diet prior to laboratory testing of the patient's breath. For example, the patient may ingest carbohydrates such as lactulose (typically 10 g) or glucose (typically 50 g). After ingestion, the patient's breath samples are analyzed for hydrogen, typically every 15-20 minutes for up to three hours. When the patient is administered glucose, an increase in hydrogen concentration, typically above 10 parts per million (ppm) above baseline levels, indicates a positive test.

[0009] Lactulose is a sugar that is digested by colonic bacteria but not by the human host. Ingested lactulose will pass undigested through the small intestine and reach the colon where bacteria produce gas. In healthy individuals, after ingestion of lactulose, a single peak in breath gas occurs as lactulose enters the colon. Individuals with SIBO may produce two significant peaks in breath gas. The first abnormal peak occurs as lactulose passes through gas-producing bacteria in the small intestine and the second normal peak occurs as lactulose enters the colon. If the baseline level of hydrogen rises above 20 ppm after ingestion of lactulose, this may indicate a positive test. Recently, many studies have shown limitations in the use of lactulose in diagnosing SIBO, mainly because of the high false positive rate. Hydrogen breath tests may only be able to diagnose 60% of patients with SIBO. Much less research has been done on combined methane / hydrogen detection to improve SIBO diagnosis. This is especially true for studies measuring hydrogen sulfide and combining hydrogen sulfide with methane and hydrogen detection.

[0010] Therefore, there remains a need in the art for devices or systems that measure hydrogen, methane, and hydrogen sulfide, either individually or in combination. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] U.S. Patent No. 8,388,935 Summary of the Invention

[0012] overview Thus, consumption of certain foods has been shown to lead to increased gas production, which leads to various diseases, including SIBO.However, it is cumbersome to determine the exact foods and amounts responsible for excess gas production in each individual.For example, to test for SIBO, individuals must come to a lab for gas testing or breathe into a bag and send it for analysis.Therefore, it is not practical to test a patient's breath over many different meals and over a long period of time.

[0013] Thus, most individuals are unable to determine or correlate SIBO or its symptoms to specific foods, since intestinal gas must be tested in isolated cases, usually after a sugary meal. Therefore, it is difficult to obtain sufficient information of the gas produced in a particular individual to bring about a conclusion about food consumption patterns that may lead to excessive gas production. There is a need for a portable SIBO testing device that patients can use to frequently test breath levels, and at the same time, input and save information about the time and contents of meals consumed before testing. With this information and appropriate data analysis, patients can then discover the correlation between the foods they eat and SIBO symptoms and gas levels.

[0014] Thus, systems and methods have been developed for the implementation of portable SIBO testing systems that conveniently sample intestinal gas exhaled from a patient's breath. These devices may be in the form of handheld meters that integrate a smartphone or other device with an application that allows the user to record data regarding the foods consumed.

[0015] Additionally, systems and methods have been developed for accurately testing gases using clinical grade testing devices. In some examples, this includes systems using manifolds to maintain the temperature of exhaled breath as it flows through the channels of the manifold. In some examples, the systems use gas sensors with probes that test the contents of exhaled breath as it flows through the channels of the manifold. In some examples, the systems can utilize thermistors and resistive heating elements connected to printed circuit boards to heat the channels and / or manifolds to maintain the exhaled breath at a temperature above body temperature and prevent condensation or moisture that could damage the sensors or bias the gas concentration readings.

[0016] In some examples, the disclosed technology provides an ex vivo method for detecting gas concentrations in exhaled breath, the method including receiving a batch of exhaled breath from a patient; heating the batch of exhaled breath to a temperature above 37° C. while drawing in and drawing out air at a constant flow rate through a flow path; detecting the gas concentrations in the flow path using an array of electrochemical sensors; and displaying the gas concentrations.

[0017] It will be understood that this example method and all other methods disclosed herein are suitable for implementation as ex vivo methods. In such embodiments, the various steps of the method are not all performed in the patient's body. A person skilled in the art wishing to implement the present invention will recognize the many ways in which the method of the present invention may be implemented ex vivo.

[0018] It will be appreciated that the reference to "receiving a batch of exhaled breath from a patient" does not require that the batch of exhaled breath that will be subjected to further steps of the method be received directly from the patient into the described flow path. Rather, the batch of exhaled breath may be received "indirectly", for example, via collection in a suitable container or passageway, and the collected batch may then be subjected to further steps of the method ex vivo. A suitable container may, for example, be selected from the group consisting of an exhaled breath bag, a balloon, a conduit, a passageway, a breathing tube or other suitable device, container or passageway.

[0019] For the avoidance of doubt, ex vivo embodiments of the method of the present invention specifically encompass those in which a batch of exhaled breath from a patient is no longer in fluid communication with the patient when it undergoes further steps of the method. For example, a batch of exhaled breath may no longer be in fluid communication with the patient when it is in the recited flow path. Optionally, the batch of exhaled breath may be collected by a mask, container, bag, tube, or other such device attached to the patient, but when it is in the flow path and subjected to further steps of the method, it may no longer be in fluid communication with the mask or the patient. Such separation of the batch may be achieved by any suitable device, feature, and process. It will be understood that in such embodiments, the recited steps of the method are not performed on a human body, since the batch of exhaled breath undergoing analysis is no longer in direct communication with the patient. [Brief description of the drawings]

[0020] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and, together with the description herein, explain and illustrate the principles of the invention. The drawings are intended to illustrate major features of exemplary embodiments in a diagrammatic manner. The drawings are not intended to depict every feature of an actual embodiment, nor the relative dimensions of the depicted elements, and are not drawn to scale.

[0021] [Figure 1] 1 shows a bar graph illustrating the importance of methane in SIBO diagnosis (prior art), in accordance with various embodiments of the present invention. [Figure 1A] 1 shows a perspective view of a gas detection device interfacing with a mobile device according to various embodiments of the present invention. [Figure 1B] 1 shows a perspective view of a gas detection device interfacing with a mobile device according to various embodiments of the present invention. [Diagram 2] 1 shows a perspective view of a gas detection device according to various embodiments of the present invention. [Figure 3A] 1 shows a perspective view of a gas detection device according to various embodiments of the present invention. [Figure 3B] 1 shows a perspective view of a gas detection device according to various embodiments of the present invention. [Figure 4] 1 shows a perspective view of a gas detection device and an associated breath tube kit according to various embodiments of the present invention. [Diagram 5] 1 shows a flow chart illustrating a breath testing method according to various embodiments of the present invention. [Figure 6] 1 shows a bar graph illustrating hydrogen production rates of methane and non-methanogens according to various embodiments of the present invention. [Figure 7] 1 shows a bar graph illustrating age-specific patient populations with elevated methane levels according to various embodiments of the present invention. [Figure 8] 1 shows a side view of a gas detection device according to various embodiments of the present invention. [Figure 9] 1 shows a top view of a gas detection device according to various embodiments of the present invention. [Figure 10] 1 shows a top view of a gas detection device according to various embodiments of the present invention. [Figure 11] 1 shows a flow chart illustrating a breath testing method according to various embodiments of the present invention. [Figure 12] 1 shows a table illustrating the subject demographics of one exemplary study using the present technology, according to various embodiments of the present invention. [Figure 13] 1 shows a table illustrating a comparison of symptoms based on the presence or absence of H2S, according to various embodiments of the present invention. [Figure 14] 1 shows a table illustrating breath test results using an example of a four-gas device disclosed herein, according to various embodiments of the present invention. [Figure 15A] 1 shows comparative data for an example of a four-gas device compared to conventional breath testing equipment, in accordance with various embodiments of the present invention, in particular a graph showing the correlation between the devices based on H2 levels. [Figure 15B]1 shows comparative data for an example of a four-gas device compared to conventional breath testing equipment, in accordance with various embodiments of the present invention, in particular a graph showing the correlation between the devices based on CH4 levels of ≧10 ppm. [Figure 16] 1 shows a bar graph illustrating the severity of diarrhea in H2S positive subjects in one exemplary study using the techniques of the present disclosure, according to various embodiments of the present invention. [Figure 17] 1 shows a Venn diagram illustrating the overlapping patterns of positive breath tests revealed by an example of a four-gas device according to the present disclosure used in one exemplary study, according to various embodiments of the present invention. [Figure 18A] 1 shows a scatter plot of breath tests from one exemplary study using the techniques of the present disclosure, in particular H2 detection by local regression line, according to various embodiments of the present invention. [Figure 18B] 1 shows a scatter plot of breath tests from one exemplary study using the technology of the present disclosure, specifically CH4 detection by local regression line. [Figure 18C] 1 shows a scatter plot of breath tests from one exemplary study using the technology of the present disclosure, specifically, H2S detection by local regression line. [Figure 19A] 1 shows a bar graph of H2 consumption as indicated by breath test based on the presence of CH4 and H2S from one exemplary study using the techniques of the present disclosure, according to various embodiments of the present invention. All subjects are shown. [Figure 19B] 1 shows a bar graph of H2 consumption suggested by breath testing based on the presence of CH4 and H2S from one exemplary study using the techniques of the present disclosure, with outliers removed, according to various embodiments of the present invention. [Figure 20A] 1 shows a Venn diagram of CH4 and H2S positive subjects from one exemplary study using the techniques of the present disclosure, according to various embodiments of the present invention. [Figure 20B] 1 shows a bar graph illustrating the effect of CH4 on diarrhea severity in the presence of H2S, according to various embodiments of the present invention.

[0022] In the drawings, for ease of understanding and convenience, the same reference numbers and any initial letters identify elements or acts that are the same or similar in structure or function. To easily identify the description of any particular element or act, the most significant digits in the reference number indicate the figure number in which that element is first introduced. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Detailed Description Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Szycher's Dictionary of Medical Devices CRC Press, 1995 may provide useful guidance for many of the terms and phrases used herein. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that may be used in the realization of the present invention. Indeed, the present invention is not limited in any manner to the methods and materials specifically described.

[0024] In some embodiments, characteristics such as dimensions, shapes, and relative positions used to describe and claim certain embodiments of the invention should be understood as being modified by the term "about."

[0025] Various embodiments of the present invention are described below. The following description provides specific details for a thorough understanding and enabling description of these embodiments. However, those skilled in the relevant art will understand that the present invention can be practiced without many of these details. Similarly, those skilled in the relevant art will also understand that the present invention may include many other obvious features that are not detailed herein. In addition, some well-known structures or functions may not be presented or detailed below in order to avoid unnecessarily obscuring the relevant description.

[0026] The terminology used below should be interpreted in its broadest reasonable manner, even when used in conjunction with a detailed description of certain specific embodiments of the present invention. In fact, certain terms may even be emphasized below; however, any terminology that is intended to be interpreted in any limited manner is expressly and specifically so defined in this detailed description section.

[0027] As mentioned above, consumption of certain foods has been shown to lead to increased gas production, which leads to various diseases, including SIBO.However, it is difficult to determine the exact foods and amounts responsible for excess gas production in each individual.For example, to test for SIBO, individuals must come to a lab for gas testing or breathe into a bag and send it for analysis.Therefore, it is not practical to test a patient's breath over many different meals and over a long period of time.

[0028] Therefore, because intestinal gas must be tested in isolated cases, usually after a certain sugary meal, most individuals cannot determine or correlate SIBO or its symptoms to specific foods, amounts, and times.Therefore, it is difficult to obtain sufficient information on the gas produced in a particular individual to draw conclusions about food consumption patterns that may lead to excessive gas production.Therefore, there is a need for a portable SIBO test meter that patients can use to test after various meals and time points, and at the same time log information about the time and content of the meals consumed before testing.

[0029] The device, which can be used frequently, provides the user with a system for frequent and consistent monitoring of exhaled breath and associated bacteria levels. With this information and appropriate data analysis, the user can then discover correlations between the foods they eat and SIBO symptoms and gas levels.

[0030] Thus, systems and methods have been developed for gas testing devices (e.g., portable SIBO testing meters) that conveniently test for intestinal gas exhaled from a patient's breath. These devices may be in the form of handheld meters that integrate a smartphone or other device with an application or other software that allows the user to record data regarding the foods consumed.

[0031] Additionally, systems and methods have been developed for accurately testing gases using clinical grade testing devices. In some examples, this includes systems that use manifolds to maintain the temperature of exhaled breath as it flows through the channels of the manifold. In some examples, the systems use gas sensors with probes that test the content of exhaled breath as it flows through the channels of the manifold. In some examples, the systems can utilize thermistors and resistive heating elements connected to printed circuit boards to heat the channels and / or manifolds to maintain the exhaled breath at a temperature above body temperature and prevent condensation or moisture that could damage the sensors or bias the gas concentration readings.

[0032] This is particularly advantageous because the system does not require desiccants, adsorbents or other absorption techniques to remove moisture. In addition, humidity levels are more consistent, allowing for more accurate readings throughout the manifold and allowing for a larger number of sensors, e.g. CO 2 , H 2 , C.H. 4 , and H 2 All four breath sensors, including the S sensor, are available so that all four gases can be tested at once. In some instances, the integration of the manifold and sensors can advantageously allow the same device to measure all four gases simultaneously while providing accurate and consistent readings.

[0033] Breath capture device In some embodiments, the breath sampling systems disclosed herein may include a breath capture device that measures the flow and directs the gas to components that measure the level of the gas. In some embodiments, these may include tubes or other structures. In another example, the device may include a quartz crystal. In another example, the gas volume may be measured via colorimetry and / or by tin oxide. In another example, the device may include individual cartridges to detect specific gases. For example, the device may include a CO 2 , C.H. 4 and / or H 2 Each device may include an individual cartridge for S. The cartridges may be disposable such that the device can last for multiple uses (e.g., 300 reads) and / or for a predetermined time (e.g., 1-2 years). In another example, each disposable cartridge can last for multiple uses (e.g., 10-50 reads) and / or for a predetermined time (e.g., 1-3 months).

[0034] In some embodiments, the devices and methods disclosed herein may include a flow control and moisture control module that prevents moisture and flow variations and partial pressure of gas from distorting the results. This may include a heating element that heats the channels of the device to a temperature above body temperature in some examples. In addition, the device may include a backflow prevention mechanism so that exhaled air does not escape and remains isolated for testing. Moisture control may be included before or after the flow regulator to regulate air humidity to a consistent level, or to remove all moisture if there is sensor cross-sensitivity, or to prevent general moisture contamination.

[0035] A carbon dioxide sensor (which may work in conjunction with the flow sensor) then quantifies the lung air volume that is exposed to air and passing through the device (the exhaled air is nominally 4% CO 2 and is not significantly affected by SIBO levels).

[0036] Portable Hydrogen Device In some embodiments, a small portable device is disclosed. In some embodiments, the portable device is a H 2 An electrochemical sensor may be used to measure CO 2 It may also have normalization methods such as detection. In some embodiments, the device communicates with a smartphone via Bluetooth to send data to it, and a USB, cellular, or other connection sends the data for processing and display. In some embodiments, the device can also be built as an iPhone attachment that physically attaches to the device.

[0037] Portable Clinical Devices In some embodiments, a durable and reusable sensor is used to measure CO 2 , H 2 , C.H. 4 , and H 2 A clinical grade portable analytical device capable of detecting CO may be utilized. In some embodiments, the device may operate from a rechargeable battery. In some embodiments, the device may operate from a rechargeable battery. 2 can be detected using NDIR cells, 2 S could be detected by the fuel cell sensor. 2 can be detected by an Alphasense electrochemical cell or equivalent, as in some embodiments.

[0038] In some embodiments, the device can connect via Bluetooth to a smartphone application to upload data. This data is processed both on the smartphone and on a cloud server that also has the ability to share results with medical professionals. The device also accepts user input, such as time-stamped activity and clinically relevant symptoms.

[0039] Complete Clinical Device In some embodiments, CO 2 , H 2 , C.H. 4 , and H 2A clinical medical device capable of detecting S with high accuracy is disclosed. The device may use an electrochemical sensor, a gas chromatograph, an ion mobility spectrometer, a TDLS, or a flame ionization detector, or a combination of these technologies or others. As with other devices, a reading is available shortly after the sample passes through the detector. Some of these generic sensor technologies can be expensive and are more amenable to being a centralized tool to which samples are sent.

[0040] In this embodiment, the patient breathes into the breath collector, or in an alternative embodiment, a bag that the patient has pre-filled by breathing into can be attached to the connector or gas inlet by the clinician. After analysis, the data is printed or sent to a PC, and the clinician may be required to pass a purge gas (e.g., for recalibration and / or purging of breath) through the device (e.g., inert nitrogen or an accurate H 2 S, H 2 , CO 2 and C.H. 4 another gas having a concentration).

[0041] Computer Applications The devices disclosed herein can input and store data regarding food consumption and / or interface with various computing devices that are configured with instructions to operate the various components, heating systems, flow motors and meters and other components. An essential tool for both home and clinical devices is the associated software application in the form of a smartphone application or other software program. The device can connect to either a smartphone via Bluetooth, or the hardware and transmit data. The application connects to the internet for updates, cloud data storage, or some combination of information processing. The clinical version is set up with a dedicated tablet, wired to the device to display and process the results.

[0042] In the case of a home device, software can be implemented to help the patient make their own choices and conclusions from the data regarding how their diet affects their SIBO readings and how they should change their diet. It is also important to link activities (e.g., eating) with the measurements in a way that the patient can understand. These requirements are not significant technical risks. Many devices according to the present embodiment are designed today and many engineers are capable of such projects.

[0043] In some examples, the software may include various control logic that maintains closed loop control for temperature regulation of gas flow paths within the device, which may include various manifolds or pipes of a clinical or portable device having various heating elements that can heat air.

[0044] How to get data from patients Various protocols may be utilized to determine when a patient tests for gas and what symptom and dietary information the patient enters after testing. For example, in some embodiments, the patient may only use the device when experiencing symptoms of SIBO. In these embodiments, the application's user interface may ask the patient which of predefined symptom categories the user is experiencing, such as bloating, constipation, diarrhea, etc.

[0045] The application may then request what types of foods the patient has consumed within the last 12 hours, 6 hours, 4 hours, 20 minutes, or other relevant time frame in terms of SIBO gas production. In some embodiments, the system has certain predefined categories of foods and amounts. For example, the program may have sugar-based, lipid-based, or protein-based food categories. In other embodiments, the program may have an indication of food categories in the database that are linked to certain nutritional values ​​or ingredients related to SIBO. For example, the type of sugar per food may be indicated, e.g., glucose, sucrose, lactose, etc.

[0046] The system may request and store the data in memory, which may be shared with a server or stored locally. In some embodiments, the application asks the user for information including gender, height, weight, age, and SIBO-related characteristics. This information may be utilized in the cloud to correlate similar patient intakes with associated gas. Additionally, certain patients may produce certain combinations or types of gas or have certain profiles of bacteria.

[0047] In some embodiments, the patient may be given a lactulose or glucose breath test to test for gases produced in response to certain substances. The caregiver may also instruct the patient to fast for one, two or other specified period of time to determine the concentration of methane in the patient's breath.

[0048] Data Analysis of SIBO and Other Correlates In some embodiments, once the data is acquired, it may be logged for analysis on a per patient basis. In other embodiments, a processor or associated control system may analyze the data. For example, the device may look at patterns of symptoms that correlate to certain foods, times, and / or breath. For example, in some embodiments, the system may correlate certain gas levels (e.g., above a threshold level known to be abnormal or having a characteristic double spike rather than a single) with eating a certain amount of a certain type of sugar within a certain period of time. In some embodiments, machine learning algorithms are utilized to match the type of condition that best suits SIBO for a given patient.

[0049] In other embodiments, the correlation may be more direct and may be a correlation between the frequency of SIBO symptoms and the consumption of certain types of food within a predefined time frame. 2 , H 2 S, or CH 4 The system can then determine whether a particular class of food (e.g., foods containing sucrose) results in a spike in a particular gas or combination of gases above a predefined threshold. In other embodiments, the system can output a graph of the average and standard deviation of post-prandial gas levels for a particular type or class of food.

[0050] In some embodiments, the system may correlate the level of hydrogen change over time or after receiving a lactulose or glucose regimen. In addition, the system may further test both hydrogen and methane before and after ingestion of sugar and lactulose as disclosed herein to detect changes in concentration in cases. The system may then process the data to determine a methane-calibrated hydrogen change. The system may then calibrate the hydrogen change to the patient's current methane production to determine a more accurate indication of whether the patient has SIBO.

[0051] In some embodiments, the system outputs the data in the form of a chart, allowing the user to analyze foods associated with gas levels in an easy and convenient manner, hi some embodiments, foods can be ranked in terms of the amount of increased gas production they cause.

[0052] Thus, consumption of certain foods has been shown to lead to increased gas production, which leads to various diseases, including SIBO.However, it is difficult to determine the exact foods and amounts responsible for excess gas production in each individual.For example, to test for SIBO, individuals must come to a lab for gas testing or breathe into a bag and send it for analysis.Therefore, it is not practical to test a patient's breath over many different meals and over a long period of time. EXAMPLES

[0053] Below are examples of various devices that may be utilized in accordance with the present disclosure. These examples are not intended to be limiting, but merely to provide examples of various features and methods that may be employed to effectively test a patient's breath.

[0054] 1A-1B show an example of an embodiment of a gas detection device 100 that may be attached to a mobile device 110. The device includes a mobile interface 130, which may be any standard mobile connection for an iPhone, Blackberry, or other mobile phone, such as a standard jack (as shown). In some embodiments, the connection is Bluetooth, Wi-Fi, or other wireless connection.

[0055] The device also includes a retractable mouthpiece 120, depicted in FIG. 1B, or other suitable breath collection device. In some embodiments, a connection to the mouthpiece 120 allows the mouthpiece 120 to be removed and rotated into a position inside the gas detection device 100. The mouthpiece may be utilized in a clinical or other system for capturing and testing breath, as disclosed herein. In some embodiments, the mouthpiece 120 may be stored or replaced separately. This allows the mouthpiece to be kept hygienic and easily connected for each breath test.

[0056] 2 shows an embodiment of a gas detection device 100 including a mouthpiece 120 and a flow meter 210. In some embodiments, the gas detection device utilizes a test strip 220 with colorimetric-based gas sensing technology. In some embodiments, a test strip 250 is inserted into an opening or slot 230 in the gas detection device 100. The device may include a display or indicator 240 that shows the gas level. In some embodiments, the test strip 220 is viewable behind a glass or plastic transparent window, which is the display 240.

[0057] As the patient breathes into the mouthpiece 120, the flow meter provides the patient with feedback regarding the appropriate breath strength. The test strip may then change color based on the amount of gas contained in the patient's exhaled breath. Thus, an optical reader can convert the color change into a gas concentration, or the patient can obtain a qualitative or quantitative assessment by visually inspecting the color change. In some embodiments, the test strip provides a threshold indication (e.g., a rather binary or elementary measurement) of whether the patient has a gas that is indicative of SIBO or another condition. In other embodiments, the exact gas level is detected and stored.

[0058] 3A-3B show an embodiment of the gas testing device 100 including a rotatable breath collector 310 for directing exhaled breath into the test chamber and mouthpiece 120. This embodiment includes a display 240 for displaying the results of the test. FIG. 3B shows the breath collector 310 rotated outwardly and positioned so that the patient can breathe into the mouthpiece 120 and the breath collector 310 can then collect the exhaled breath. As shown, after the breath collector 310 has rotated outward, the mouthpiece 120 can be attached. This rotation allows the passage of the breath collector 310 to remain protected from access while not in use, keeping the device compact. These aspects may be added to clinical or tabletop breath testing systems as disclosed herein.

[0059] FIG. 4 shows an embodiment of a clinical gas testing device 100 including a breath collector 310 and a display 240. In some embodiments, the clinical gas testing device 100 may include a larger test chamber and employ more accurate and precise sensing technology. In some embodiments, the clinical gas testing device 100 may include a purge canister 410 to purge the test chamber of breath from the patient. This allows the chamber to be recalibrated from baseline gas levels after each use. In some embodiments, the canister 410 and breath collector 310 are disposable components and are individually packaged for each use, as shown in FIG. 4. In some embodiments, the clinical gas testing device 100 may include a pipe or manifold that is heated or has directly heated gas in the passageway to prevent humidity or gas temperature from affecting the results.

[0060] FIG. 5 illustrates an embodiment of a method for testing a patient's breath utilizing various gas detection devices 100 as disclosed herein. For example, breath is first collected (510) and directed to a testing chamber. In some embodiments, a flow meter and pump can control the flow rate of breath routed through the testing chamber (520). This can keep the partial pressure of the relevant gas constant or otherwise increase the accuracy of the results. Moisture can then also be controlled (530) to avoid inaccurate sensor readings that can be caused for various reasons based on, for example, gas detection techniques utilizing heating elements as disclosed herein.

[0061] Some embodiments then use the exhaled breath level as a proxy for the amount of breath exhaled, CO 2 In some embodiments, the sensor includes a carbon dioxide sensor (540) for correlating the amount of CO 2 The amount or concentration of a gas can be correlated to determine how long air should be retained in the lungs. The detected levels of the relevant gas can then be adjusted according to the appropriate ratio.

[0062] After (or simultaneously or prior to) testing for carbon dioxide, other gas levels of clinical relevance may be detected (550). For example, the system may then detect H 2 , C.H. 4 and / or H 2 S may be tested. Additionally, backflow is prevented (560) to prevent changes in concentration once testing has begun with any such device. Finally, after testing, the exhaled breath may be purged and the device recalibrated (570). In some embodiments, recalibration is accomplished by purging the device with a canister of gas(es) at known concentration(s) and / or known flow rate(s). In other embodiments, the fan and door may be opened to allow ambient air into the device.

[0063] Example: Methane calibrated hydrogen levels The lactulose breath test is increasingly being used to diagnose small intestinal bacterial overgrowth (SIBO). Over the last decade, data have been accumulating about the importance of methane in the tested breath, especially in the context of constipation. During methane production, methanogenic archaea in the intestine convert four hydrogens (H 2 ) gas molecule to produce one methane (CH 4 ), based on stoichiometry, the hydrogen levels in a breath test (and therefore the interpretation of the breath test) can be affected if detectable methane (and therefore methanogens) are present. The inventors performed a study of a large breath test database to determine the effect of methane on the interpretation of hydrogen results.

[0064] Consecutive patients presenting to a tertiary care center for lactulose breath testing between November 2005 and October 2013 were eligible for the study. For breath testing, subjects presented after a 12-hour fast. After baseline breath sampling, 10 g of lactulose was administered, followed by breath sampling every 15 minutes for a minimum of 90 minutes. Breath samples were then analyzed on a Quintron SC or Breathtracker™ gas chromatograph (Quintron Instrument Co., Milwaukee, WI) to measure CO 2 Hydrogen and methane were measured after correction for . Breath methane was defined as ≥ 3 ppm at any time during the test. The remaining subjects were considered non-methane subjects. Subjects were excluded if they were non-gas producers (neither hydrogen nor methane ≥ 3 ppm at any time during the test). Hydrogen and methane interactions were examined by comparing methane and non-methane breath tests.

[0065] A total of 14,847 breath tests were performed during this period, of which 804 (5.4%) were non-methane, non-hydrogen producers. Of the remaining 14,043 tests (71% female, mean age = 47.4 ± 18.3 years), 2412 (17.2%) were positive for methane. H consistent with SIBO 2 Regardless of whether 60 or 90 minutes is used to interpret the changes, the methane breath test 2 When examining the change in hydrogen production from baseline for the 60 or 90 minute breath test interpretations, the methane breath test also resulted in a lower increase in hydrogen from baseline compared to the non-methane breath test (Table 1 and Figure 6). Additionally, the incidence of H2O considered as SIBO in methane producers (23.1%) compared to non-methane subjects (55.7%) was significantly higher in methane producers (23.1%) compared to non-methane subjects (55.7%). 2 The incidence of breath tests with elevated levels of ≥ 20 ppm was significantly lower (OR = 0.20, 95% CI = 0.18-0.22) (Figure 6).

[0066] (Table 1) TIFF0007644120000001.tif34165

[0067] Based on the results, the presence of methane is associated with a significant decrease in hydrogen levels, dramatically changing the interpretation of hydrogen in breath tests for the identification of bacterial overgrowth. Based on these findings, it is imperative to report methane production in clinical reports and research studies.

[0068] Methane fasting breath test Excessive methane production may be associated with constipation and bloating. Eradication of methanogens and reduction of methane production has been shown to improve such symptoms. In a recent consensus conference at the 2015 American Digestive Disease Week, a methane level of ≥ 10 parts per million (ppm) during a standard 2-hour breath test was considered the cutoff for excess methane production. Unlike hydrogen gas, patients with excess methane continue to excrete high levels of methane in the fasting state.

[0069] Therefore, we compared the accuracy of single fasting measurements of methane with the lactulose breath test as the gold standard. To conduct the study, a database of 14,847 consecutive lactulose breath tests (71% women) from November 2005 to October 2013 was developed at a tertiary center. Definitive record linkage was performed and repeat studies of 12,183 subjects were excluded. All subjects had measurements of exhaled methane, hydrogen, and carbon dioxide after a 12-h fast. Patients were administered lactulose (10 g) and measurements were repeated every 15 min for at least 2 h.

[0070] Patients were classified as excessive methane producers if methane levels ≥ 10 ppm were detected at any time point in the study (gold standard). Various fasting methane level test characteristics were compared with the gold standard. Sensitivity > 95% and specificity > 98% were selected a priori for test performance. Comparisons were made using Fisher's exact test. Results: Of 12183 subjects, 1891 (15.5%) were excessive methane producers (68.5% female; mean age 51.9 ± 17.7; age range 3-97 years). The accuracy of various fasting methane levels to identify these patients is shown in Table 1. Although all single fasting methane measurements performed well, a cutoff of ≥ 5 ppm was selected with sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of 96.1%, 99.7%, 98.5%, and 99.3%, respectively (Tables 2 and 3). Test performance was not statistically confounded by age or sex (Table 4).

[0071] In the largest database of lactulose breath tests analyzed to date, a single fasting measurement of exhaled methane is highly sensitive and specific for identifying excessive methane producers compared to a full lactulose breath test. This approach significantly reduces costs, shortens study time, and eliminates the troublesome symptoms associated with lactulose ingestion. Age and gender do not affect the accuracy of fasting methane levels.

[0072] Table 2. Test characteristics of various single fasting methane levels compared with the gold standard test. TIFF0007644120000002.tif119165*A single methane level of 10 ppm or greater meets the gold standard test for a positive methane test. CI: confidence interval; NPV: negative predictive value; PPV: positive predictive value.

[0073] Table 3. 2 x 2 contingency table of fasting methane levels ≥ 5 ppm compared with the gold standard test TIFF0007644120000003.tif34165

[0074] Table 4. Robust performance of fasting methane levels ≥ 5 ppm based on sex and age with overlapping confidence intervals. TIFF0007644120000004.tif40165

[0075] Methane production and age There is growing clinical evidence that excess methane production may be associated with constipation and bloating. Eradication of methanogens and reduction of methane production have been shown to ameliorate such symptoms. In human studies, intestinal methanogen colonization increases throughout childhood but peaks during adolescence. However, large-scale studies exploring the demographic determinants of methane production are lacking.

[0076] A database was developed consisting of 14,847 consecutive lactulose breath tests performed at a single center from November 2005 to October 2013. Definitive record linkage was performed using date of birth, medical record number, surname, and first name to exclude repeat studies. Thus, a total of 12,183 breath tests were classified into six categories: 1-Normal: methane level < 3 parts per million (ppm) and hydrogen level < 20 ppm within the first 90 minutes. 2-Hydrogen positive: methane level < 3 ppm and hydrogen level ≥ 20 ppm within 90 minutes. 3-Methane positive: methane level ≥ 3 ppm and hydrogen < 20 ppm. 4-Hydrogen and methane positive: methane level ≥ 3 ppm and hydrogen level > 20 ppm within 90 minutes. 5-Plate: methane < 3 ppm and hydrogen ≤ 3 ppm, with variation ≤ 1 ppm within 120 minutes. 6-Equivocal: Hydrogen levels >20 ppm and methane <3 ppm at baseline before lactulose ingestion.

[0077] Of the 14,847 breath test subjects, most were female (71%). The mean age at the time of breath test was 46.9 ± 18.3 years (range 2-101). The percentage of each category of breath test results is presented in Table 1. Male subjects were significantly more likely to produce excessive amounts of methane (18.21% vs. 16.07%, p<0.01); however, there were no other significant differences between the two genders. Regardless of gender and hydrogen production, those producing abnormally high amounts of methane were significantly older than non-methane gas producers, with a mean age of 52.3 years, an age difference of 5.8 years (p<0.01). The equivocal group was the youngest group, with a mean age of 34.8 years (p<0.01). The prevalence of methane production appeared to increase with age, as shown in Figure 7.

[0078] In the largest database of lactulose breath tests analyzed to date, the prevalence of methane gas in breath tests increases more than five-fold with age, with the oldest age group having the highest prevalence of methanogens. This finding may explain why age is a known risk factor for constipation. Finally, men are slightly but significantly more likely to be methanogens than women, by a difference of approximately 2%, the clinical significance of which has yet to be determined.

[0079] (Table 5) Percentage of breath test categories TIFF0007644120000005.tif46165

[0080] Example: Exhalation system with manifold In some instances, systems and methods have been developed for determining the concentration of multiple breath samples using multiple sensors with a single device, and one breath sample from a patient. For example, a reliable determination of whether a patient has SIBO can be made using CO2 for reasons disclosed herein. 2 , H 2 , H 2 S, and CH 4Each of the gases may need to be tested for, therefore measuring each of these gases in a single exhaled breath from the patient would be the most efficient and accurate way to determine their concentrations and apply diagnostic algorithms.

[0081] However, developing a system that can test for multiple gases using multiple sensors is difficult for a variety of reasons. For example, exhaled patient breath is typically fully saturated with water and contains 100% relative humidity. Thus, when this breath passes through a room temperature testing device, at least some of the water will condense on the surfaces of the device that it comes into contact with. This is problematic for a number of reasons, for example, some sensors used to test gas concentrations are sensitive to humidity, which biases the readings. In addition, condensation can damage certain types of sensors.

[0082] Thus, to remove humidity before the exhaled air passes through the sensor to ensure an accurate reading, some previous devices utilized a desiccant or other absorbent (e.g., an activated aluminum bed to initially remove moisture). However, using absorbent materials is not advantageous for a number of reasons: (1) the absorbent material must be replaced periodically, (2) the amount of moisture absorbed with each breath changes as the absorbent becomes saturated, creating calibration problems, especially for low concentrations of gases such as hydrogen sulfide, and (3) extra volume is required in the manifold (and in the breath) so that there is space for the breath to first pass through the absorbent material.

[0083] Additionally, the absorbing material may actually absorb certain gases. For example, H 2 S is known to be absorbed by certain absorbent materials, including desiccants. Therefore, the use of desiccants is particularly useful for preventing the absorption of H 2 This is not advantageous for systems testing multiple gases including S.

[0084] Thus, systems and methods have been developed to test for multiple gases in exhaled breath without the use of absorption techniques. In some examples, this includes systems that use a manifold to maintain the temperature of the exhaled breath as it flows through the channels of the manifold. In this example, the gas is heated to at least body temperature or above to avoid condensation of moisture in the exhaled breath. This prevents the need to use desiccants or other absorption techniques. Additionally, some electrochemical sensors are more sensitive at higher temperatures, so that less time is required to obtain an accurate reading when heated to certain temperature ranges (e.g., 40° C. and above), which is advantageous for reasons described herein.

[0085] Additionally, the device must maintain the breath at a consistent temperature and flow rate while testing it to ensure accurate measurements are obtained once the sensor is calibrated. This is due to the fact that H, which has a relatively low concentration (e.g., 9-10 ppb) compared to other gases present in breath, is a volatile gas. 2 This is particularly important for gases such as S. Furthermore, because the total volume of gas for a patient exhaled sample is relatively small, maintaining consistent temperatures and flow rates can be difficult when multiple gas sensors are required (e.g., three or four gas sensors as disclosed herein) as longer gas flow paths are required for the gas to contact the sensor probe of each sensor.

[0086] In some examples, a metal manifold with high thermal conductivity can be utilized to maintain the temperature of the gas passing through the channels within a narrow range, which is controlled using temperature control elements (e.g., PCBs with thermistors and heating elements) as disclosed herein. Furthermore, when utilizing a single channel introducing sensors in series rather than splitting the gas flow path into parallel channels for each sensor, less total volume is required to allow enough gas to pass through the sensors to record accurate readings in the disclosed temperature ranges.

[0087] In some instances, the channel can be split into two channels with sensors attached at the top and bottom, allowing multiple sensors (e.g., 2, 3, 4, etc.) to be introduced into the channel within a short distance. However, the inventors have found that in some cases, splitting the gas flow path into parallel channels requires too much gas in some configurations.

[0088] Additionally, in some embodiments, a methane sensor may not require a constant flow rate and temperature, so a relatively large and accurate methane sensor may be utilized that is separate from the manifold and connected to the manifold channel by a pipe or other gas flow path.

[0089] Since a constant flow rate is required, the sooner the sensor obtains an accurate reading, the smaller the volume of gas required. Thus, in some embodiments, a baffle, bump, or other partial obstruction is utilized to introduce turbulence into the flow adjacent to each or a portion of the sensor measuring probe. This provides increased gas exchange time, and therefore a smaller total volume of exhaled air is required.

[0090] So, these features together allow single-breath or small volumes of air to be introduced into the system without the use of desiccants and with at least CO 2 , H 2 , H 2 S, and CH 4 The system can measure SIBO status and obtain stable and accurate readings, allowing the system to accurately assess a patient's SIBO status and other potential indications.

[0091] Detection of all four gases can be important to determine the full picture of whether a patient has SIBO and to diagnose related conditions. For example, as described in International Patent Publication No. WO2018 / 154937, entitled "MEASUREMENT OF HYDROGEN SULFIDE DURING BREATH TESTING," published August 30, 2018, the contents of which are incorporated herein by reference in their entirety, normal H 2 and C.H. 4 Some subjects are characterized as having levels of H 2 The studies referenced in this application are discussed in more detail in the Examples below. Thus, testing for all three gases can be important to determine the overall diagnostic picture of a patient, and this is particularly true for H. 2 This includes inspection of S. As described herein, prior art systems do not have these same features and advantages.

[0092] 8 is an example of a system used to test exhaled breath from a patient. The system may include a gas inlet 820 that receives gas exhaled from the patient. The gas inlet may be any suitable valve or other port. In some examples, the inlet 820 may be connected to various breath collection devices as disclosed herein, or may be connected to a balloon or bag with pre-collected gas.

[0093] The inlet 820 may be in gas communication with the gas flow passages 810 through a manifold 860. The manifold 860 may be any suitable thermally conductive material, and the gas flow passages 810 are constructed through the manifold 860. For example, the manifold 860 may be made of metal and may have channels, pipes, or pathways constructed for the gas to flow through. In some examples, the manifold 860 may be constructed from stainless steel. In some examples, the manifold 860 may be copper clad. In other examples, the manifold 860 may be a pipe or other suitable mechanical part that includes the gas flow passages 810. In some examples, the manifold 860 may be made from a heat resistant material or insulator, and the thermal regulating element may directly maintain the gas temperature without heating the manifold material.

[0094] The system may include a thermal regulating element 870 that includes a temperature sensor and a heating element. In some examples, the thermal regulating element 870 may be a printed circuit board that includes thermistors that measure the temperature of the manifold 860 and / or the gas flow paths 810, and various heating elements (e.g., resistive films) that heat the manifold and / or the air flow paths.

[0095] In some examples, the heating element may include traces printed on a printed circuit board instead of a separate coil, allowing for a more compact construction and lower manufacturing costs. Traces on a printed circuit board can be used advantageously because the required temperature range is below the melting point of the printed circuit board, and therefore generally below levels that would cause damage.

[0096] In some examples, the thermal regulating element 870 may include multiple temperature sensors and heating elements that individually regulate different portions or zones of the manifold 860. For example, there may be individual regulation combinations (temperature sensors and heating elements) for the zones, which may include the following zones: (1) the top and bottom of the manifold, (2) the zones adjacent to each of the sensors, (3) the front and back halves of the manifold, (4) the pipes, flow paths, or channels between the sensors, or other suitable distribution based on the temperature tolerance and sensitivity of the regulation system. For example, thermistors and heating elements may be located in the center or portions of each of the zones to optimally heat the zones.

[0097] These different thermal regulating elements 870 may be included on separate printed circuit boards, on the same printed circuit board, or may utilize other suitable control systems and connections. In some examples, thermal regulating elements 870 may be configured to sense the gas temperature in gas flow path 810 and heat manifold 860 or directly heat the gas in gas flow path 810.

[0098] The element may be configured to regulate the temperature using a closed loop feedback system. This may include regulating the temperature to be above body temperature (37° C.) to prevent condensation from exhaled air forming on components and wearing out the system or causing inaccurate gas concentration readings. In some examples, the system may use a threshold of 40° C. (minimum temperature), or other suitable threshold, e.g., 38° C., 39° C., or 37° C. as the minimum temperature. In some examples, the thermal regulating element 870 may keep the temperature of the gas in the manifold and / or passageways within 1° C., 2° C., or other suitable range (e.g., 38-40° C., or 40-42° C.).

[0099] The gas flow path 810 is for example, methane (CH 4 ), hydrogen (H 2 ), hydrogen sulfide (H 2 S), and / or carbon dioxide (CO 2) may include various sensors 800 for sensing various gases, including argon, argon, and argon gases. The sensors may be electrochemical sensors, laser-based sensors, or other suitable sensors. In some examples, the hydrogen, hydrogen sulfide, and carbon dioxide sensors may be electrochemical-based sensors, and the methane sensor may be a laser-based sensor located at the end or outside of the manifold 860.

[0100] The sensors 800 may be incorporated into the manifold 860, or alternatively may be arranged and constructed within a system such that the sensor probes 800 of the sensors can detect gas flowing through the gas flow path 810. In some examples, a linear or nearly linear gas flow path 810 may include a series of sensors 800 that sequentially test the gas as it passes through the gas flow path 810. In other examples, the gas flow path 810 may be split into separate channels and the sensors 800 may test the gas in parallel or other combinations of serial and parallel.

[0101] In some examples, the gas flow path 810 may have sensors 800 entering the flow path only from the top or bottom. In other examples, sensors 800 may be mounted on both the top and bottom of the gas flow path 810, so that the straight or parallel flow path 810 required for all four or three sensor probes (or any other number of sensor probes) may be shorter.

[0102] In some examples, the system may include a pump 840, e.g., a diaphragm pump, for pumping the exhaled air at a constant rate through the gas flow path 810, and a flow meter 850. This may be important because some sensors 800 require a constant calibrated flow rate to record an accurate gas concentration reading.

[0103] Additionally, the system may include a gas outlet 830 through which gas in the gas flow path exits the system. In some examples, after taking a reading, the system activates a pump 840 to purge the gas flow path 810 of excess exhaled air from the patient, such that ambient air is drawn through the gas inlet 820 and exhausted through the gas outlet 830. In some examples, this may occur automatically after each reading for a predetermined period of time, for example, a few seconds, 20 seconds, 30 seconds, 1 minute, or other suitable time frame.

[0104] 9 shows a top view of one example of a system. In this example, thermal regulating element 870 includes a printed circuit board adjacent to manifold 860. In this example, the printed circuit board may include various thermistors or other temperature sensors and heating elements located at various locations to regulate various zones of manifold 860. As shown, portions of gas flow path 810 may include pipes and other portions may be channels in manifold 860, or manifold 860 may itself be constructed from pipes.

[0105] 10 shows a top or bottom view of one example of a breath sensing system according to the present disclosure. In this example, the gas flow path is shown as a channel in a manifold 860, which is shown as a block of metal or other thermally conductive or resistive material. In this example, the sensors 800 are positioned at successive positions along the gas flow path 810, with baffles or partial blockages 1010 adjacent to each sensor 800 along the flow path 810. In other examples, the gas flow path 810 is divided into separate channels or gas flow paths 810, with each of the different sensors 800 having a probe that accesses the gas flow path 810.

[0106] The baffle or partial obstruction 1010 may be a bump, indentation, or other shape or configuration that directs gas toward the sensor 800 or sensor probe, and in some embodiments, introduces turbulence into the gas flow. In other embodiments, a constant flow rate is still maintained without creating turbulence, but the main flow of gas is directed toward the sensor 800 using the baffle 1010.

[0107] 11 shows a flow chart of an example of a method for testing a patient's breath for various concentrations of gases. As disclosed herein, this may be done for a variety of reasons or results / outputs, such as to diagnose a patient with a certain disease, such as SIBO, based in part on the detected gas concentrations.

[0108] First, the system may receive exhaled breath from the patient (1100). This may be from a breath collector, such as a nozzle, bag, or other suitable device. The exhaled breath is then heated in the flow path through the manifold (1110). This may be done with a variety of thermal regulation systems and at various locations along the flow path. For example, the system may heat the exhaled breath before entering a particular sensor or all of the sensors. In one example, the exhaled breath may be first heated before being passed through the sensor.

[0109] In other examples, the system may heat the exhaled gas at various points along its travel through the gas flow path. As disclosed herein, various systems may be utilized to heat components that make up the gas flow path (e.g., directly heat the manifold) or to directly heat the gas itself. For example, the regulation system may sense the temperature of the manifold (1112), for example, using a thermistor in contact with the manifold 860 or an infrared temperature sensor or other suitable temperature sensor.

[0110] This data may then be used to implement a closed feedback loop with various heating elements (1114), which may include resistive heaters to heat components of the system to the appropriate temperature based on feedback from temperature sensors (usually heated above body temperature to avoid condensation, unless the system initially includes a dehumidifier, in which case the temperature may be lower).

[0111] The system may then sense gas concentrations along the flow path with various sensors (1120). This may include methane 1132, hydrogen 1134, hydrogen sulfide 1136, carbon dioxide 1138, or other relevant gases, depending on the application for monitoring or diagnosing the patient. These gas concentrations may then be displayed (1124), stored, transmitted, or further utilized to determine and display the patient's disease status, for example, whether the patient has SIBO (1122) or the likelihood that the patient has SIBO. In some examples, the methane (1132) sensor 800 may be connected separately from the manifold, or instead may be connected to the manifold channel with a pipe. This may be the case when the methane sensor is a larger and more accurate sensor that does not easily fit into the manifold and does not require consistent flow rates and temperatures to accurately measure methane concentration.

[0112] In some examples, the system can determine the hydrogen and methane concentrations of the patient's exhaled gases, determine the methane calibrated change in hydrogen level, and then output an indication of whether the patient has SIBO based on the detected hydrogen level. Additionally, the system may determine or diagnose other diseases based on the exhaled breath detected by the system.

[0113] Example: The importance of hydrogen sulfide in clinical breath testing: Validation of a new four-gas breath testing device As previously discussed, detection of all four gases is critical to providing an accurate determination of whether a patient has SIBO and to diagnosing associated conditions. For example, as disclosed herein, a manifold heating system can be used to measure the CO2 , H 2 , H 2 S, and CH 4 A study evaluating one example of a device that tested breath levels tested all four gases, particularly H 2 S) was determined to be crucial for assessing the results.

[0114] For example, normal H 2 and C.H. 4 Some subjects are characterized as having levels of H 2 The test was positive for S. In addition, H 2 is CH 4 and H 2 S, so all four gases can be tested (e.g. CO 2 Calibrating the SIBO test (with a calibration curve) is crucial to accurately correlate SIBO and its systems to these gas levels, as testing any subset may not accurately assess the diagnosis and severity of symptoms in a given patient, given the interactions between gases.

[0115] Finally, H 2 S was found to be associated with certain diarrhea phenotypes. Thus, testing for all four gases may be important to determine the overall diagnostic picture of a patient, especially H. 2 This includes testing for S. As described herein, prior art systems do not have these same features and advantages. Below is a summary of the study and its findings.

[0116] General Hydrogen (H 2 ) breath tests were used to evaluate for small intestinal bacterial overgrowth (SIBO) during the workup of diarrhea. 2 While the levels of methane (CH 4 ) is associated with constipation. CH 4 Organisms that produce hydrogen sulfide (H 2 Both organisms that produce H 2 It consumes H 2S cannot be studied using conventional breath testing systems and methods. Therefore, a novel four-gas device (H 2 , C.H. 4 , H 2 S and CO 2 ) to determine whether it offers a more comprehensive breath test.

[0117] Subsequent subjects referred for breath testing were eligible. Subjects provided a baseline breath sample and, after ingesting 10 g of lactulose, provided further samples every 15 minutes for 120 minutes. Subjects completed a symptom questionnaire. H 2 and C.H. 4 Samples were analyzed for 100% CI 0.01 to 0.01. Results from both devices were compared, and gas patterns from the 4-gas device were correlated with symptoms. Gas interactions were also evaluated.

[0118] 298 subjects completed the study. Measurements from both instruments were strongly correlated (H2: R = 0.90; CH4: R = 0.97). Using the 4-gas device, a positive threshold for H2S was determined to be ≥ 1.2 ppm and was associated with diarrhea. 56.9% of subjects with H2S ≥ 1.2 ppm reported severe compared to moderate or mild diarrhea (P = 0.01). The additional presence of CH4, H2S, or both had a significant effect on H2 levels and diarrhea severity. CH4 was favored by reduced diarrhea (P = 0.02).

[0119] Research Background Breath testing has been used clinically for over 30 years in the evaluation of small intestinal bacterial overgrowth (SIBO), most notably in the workup of diarrhea of ​​unknown etiology [1]. The technique was originally based on the principle that gases produced by enteric bacteria during fermentation processes are unique and not produced by the human host. However, the physiological consequences of these gases in terms of human disease have only recently begun to be understood.

[0120] In current breath testing technology, patients ingest a fermentable substrate after a period of fasting. Breath samples are obtained at baseline and at regular intervals over the following hours to measure hydrogen (H 2 ) and carbon dioxide (CO 2 ) level. H 2 is produced exclusively by gut bacteria, whereas CO 2 H was produced by human cells and measured in breath samples to correct for alveolar concentrations. Based on the recent North American consensus on breath testing [2], H >20 parts per million (ppm) within 90 minutes of administration of a fermentable substrate was 2 This pattern of elevated H 2 Production of erythrocyte sedimentation appears to predict response to antibiotics [3], but studies have shown that H 2 It was not possible to correlate the levels with the severity of diarrhea or other symptoms for which testing was indicated. 4 has attracted considerable attention because it predicts constipation and appears to be proportional to its severity.

[0121] In the intestinal tract, gas production and utilization is a complex process involving interactions between various bacteria. 2 is known to be produced in large quantities by fermentative bacteria, but is also a substrate for the production of other gases.[6] For example, four H 2 is used by methanogenic archaea to produce one molecule of CH 4 [6] In addition, H 2 At least two other processing pathways for acetic acid: acetic acid production by homoacetogenic bacteria and hydrogen sulfide (H 2 Given the complex interactions between these gases, it is not possible to fully understand clinical breath testing without measuring all of these microbially produced gases.

[0122] In this study, all four gases (H 2 , C.H. 4 , H 2 S and CO 2We have tested a new device that can measure the H 2 Whether measurement of S levels can predict clinical symptoms and whether H 2 , C.H. 4 , and H 2 This study was undertaken to determine whether a better understanding of the competitive interactions between S could provide, among other aspects, a more comprehensive breath test.

[0123] method In this study, subjects were required to undergo a 24-hour preparation period immediately prior to the study, during which they avoided consumption of fruits, vegetables, dairy products, and legumes for the first 12 hours, and then fasted for the second 12 hours. Subjects were not permitted to smoke or exercise immediately prior to or during the test. A baseline breath sample was collected. Subjects then consumed 10 g of lactulose dissolved in 200 mL of water. Breath samples were subsequently collected every 15 minutes for the remaining 120 minutes. Samples were analyzed immediately, with a 20 cc sample analyzed using a QuinTron BreathTracker™ (QuinTron Instruments Co., Milwaukee, WI) and the remaining samples analyzed using a novel 4-gas detection device. Both devices analyzed breath components via gas chromatography and adjusted the output to 5.50% CO based on intra-alveolar levels. 2 Corrected for concentration.

[0124] The new four-gas detection device required calibration before use. After a short warm-up period, the machine was first calibrated with ambient air and then with a mixture of ambient air and calibration gas (QuinTron Instruments Co., Milwaukee, WI). A total of three runs were made for each calibration set. The machine remained calibrated for 16 hours. To analyze a sample, the bag was attached to the machine via the inlet, the stopcock was opened, and the machine was run for 120 seconds with real-time output via the computer interface. Each run was followed by a 30 second purge cycle. The four-gas device simultaneously measured all gases (H2, CH4, H2S, and CO2) in ppm with an accuracy of ±0.2 ppm.

[0125] During the breath test, subjects were asked to complete a detailed questionnaire regarding medical history, demographics, and bowel symptoms. Symptom severity was measured using a 0-100 mm visual analog scale (VAS).

[0126] For both devices (conventional and new 4-gas devices), a positive breath test was determined based on the recent North American consensus [2]. 2 A test was considered positive if there was an increase of ≥ 20 ppm from baseline at or before 90 minutes. 4 A level of ≥ 10 ppm at any time during the breath test was considered positive. 2 Because the positivity threshold for S was not predefined, its positivity threshold was determined based on the results of the present study.

[0127] Data Processing To verify the accuracy of the new four-gas detection device, 2 and C.H. 4 All measurements of H were compared to those from the previous QuinTron device to ensure that the new device accurately measured these gases. In addition, there was no significant difference in the positive H between the devices. 2 and C.H. 4 The breath test agreement level was determined. 2S levels were assessed throughout the study to determine the range and meaningfulness of values ​​for this additional gas. Gas profiles were then compared with symptom severity among study subjects. Finally, H 2 But, CH 4 and H 2 Assuming that H is a substrate for the production of both S and H 2 To further understand the scientific and clinical value of adding S to clinical breath testing, the interactions between these three gases were evaluated.

[0128] Spearman correlation was performed to compare the two breath testing techniques. Positive H between the QuinTron device and the new device 2 and C.H. 4 Cohen's kappa coefficient was used to assess the level of agreement of the breath tests. However, because the new device has an error level of ±0.2 ppm for these gases and QuinTron reports an error level of ±2 ppm (10 times less sensitive), this error level was included in the analysis of positive breath tests for the QuinTron device. Descriptive analyses were performed to examine the distribution of population characteristics, diagnostic records, and symptom severity via the VAS. Spearman correlations between symptom VAS scores were assessed.

[0129] All 20 symptoms were grouped into three categories: foregut symptoms, irritable bowel syndrome (IBS) symptoms, and diarrhea-predominant irritable bowel syndrome (IBS-D) symptoms. It should be noted that IBS-D symptoms also fall within the IBS category. Foregut symptoms include burping, hoarseness, loud cough, difficulty swallowing, coughing after meals, difficulty breathing, uncomfortable cough, feeling of something stuck in the throat, and heartburn or chest pain. IBS symptoms include bloating, excess gas, feeling of incomplete evacuation, abdominal pain, constipation, diarrhea, urgency to defecate, mucus discharge from the rectum, and tenesmus during defecation. Bloating, excess gas, abdominal pain, diarrhea, urgency to defecate, and mucus discharge from the rectum were classified as IBS-D symptoms.

[0130] H 2To determine whether S production was an indicator of IBS-D / diarrhea-related symptoms, an initial generalized linear regression model was fitted to test for association, followed by H1 regression using Wilcoxon regression with derived variables. 2 The threshold for S positivity was evaluated. The optimal discrimination level was determined to be ≥ 1.2 ppm and used to 2 A positive test was defined as S. Combination analyses were used to further evaluate combinations of IBS-D symptoms, where n is the number of IBS-D symptoms. Probability = nC1 + nC2 + … + nCn

[0131] Second, to visualize gas patterns over time, localized regression (LOESS) was performed on the H 2 , C.H. 4 , and H 2 Fitted at S level and stratified by number of gases consumed. 4 Positive but H 2 Subjects who were not S positive were classified as "no positive gas consumption" and CH 4 or H 2 Subjects who were positive for either S but not both were classified as “Consumed gas positive 1” and CH 4 and H 2 Subjects who were positive for both S were classified as “consumption gas positive 2.” To further evaluate the consumption gas interaction, the cumulative H between consumption gas groups was 2 Generation was compared using an ANOVA model followed by Tukey post-hoc tests.

[0132] Statistical analyses were performed using SAS (Statistical Analysis System) version 9.4 (SAS Institute Inc., Cary, NC) and R version 3.4.3 software (R Foundation for Statistical Computing, Vienna, Austria).

[0133] result A total of 300 subjects were recruited for the study. Of these, 2 did not fully complete the questionnaire and were excluded, resulting in 298 subjects being included in the final analysis. Of these 298 subjects, 196 were female (66%). The mean age was 49 years (range 19-88 years) and the mean BMI was 24.7 kg / m2 (range 15.7-54.1 kg / m2). Of the 298 subjects, 40% were diagnosed with IBS, 44% with constipation, 4% with ulcerative colitis, 7% with Crohn's disease, and 6% with a history of intestinal infection. In addition, 18% had undergone a hospital breath test within the last year, 30% had experienced weight loss, and 7% reported bloody stools. The population characteristics and questionnaire results are presented in Figure 12.

[0134] The severity of 20 symptoms was measured by VAS. Of these, 14 were normally distributed. The remaining 6 were largely left skewed because of their infrequency and included: mucus discharge from the rectum; difficulty swallowing food, liquids, or tablets; coughing after eating or lying down; dyspnea or choking fits; persistent or uncomfortable cough; and feeling of something stuck in the throat or a lump in the throat. Of these 6 symptoms, 5 were in the foregut category.

[0135] Comparing breath testing technologies H from QuinTron instruments and a new 4-gas device 2 and C.H. 4 The results of the two instruments were strongly correlated, as shown in Figures 15A and 15B. In addition, after adjusting for the higher error level of the QuinTron, there was a positive H correlation between the two instruments. 2 and C.H. 4 There was moderate to substantial agreement for the breath tests (kappa=0.72 and 0.52, respectively). Following this validation, the remaining analyses presented below were performed using results from the new 4-gas device only.

[0136] positive H 2 S-level definition H 2 The association between S symptoms and IBS-D symptoms was assessed using generalized linear regression and was evaluated using a 1 ppm H 2It was found that an increase in H levels correlated with an increase in the diarrhea VAS score of 15.8 (p=0.04) and an increase in bowel urgency of 16.2 (p=0.04). 2 After evaluating the S threshold, H 2 The data showed that S levels of ≥ 1.2 ppm were the optimal threshold in relation to diarrhea severity.

[0137] H 2 The relationship between S and diarrhea positive H 2 After establishing the definition of the S breath test, symptoms were assessed based on this threshold. In univariate analysis, the severity of diarrhea and defecation urgency was significantly associated with H 2 H than S-negative group 2 The differences were significantly greater in the S-positive group (52±32 vs. 41±31, p=0.01 and 51±32 vs. 42±32, p=0.04, respectively) (FIG. 13). Combinations of symptoms were further evaluated using the same thresholds.

[0138] Diarrhea and urgency to defecate are H 2 The H score was significantly different between the S positive vs. negative groups (52±29 vs. 42±28, p=0.01). In addition, abdominal pain + diarrhea and abdominal pain + diarrhea + bowel urgency were also significantly different, as shown in FIG 13. As shown in FIG 16, the H score was significantly different between subjects reporting mild diarrhea (diarrhea score <10 on the VAS), moderate diarrhea (diarrhea score ≥10 and <50), and severe diarrhea (diarrhea score ≥50). 2 There was also a statistically significant difference between the proportion of S positives. 2 The percentage of S positives (56.94%) reported moderate diarrhea. 2 The percentage of H reporting mild or no diarrhea was higher than that of S positives (30.56%). 2 was higher than the percentage of S positive (12.50%) (p=0.01).

[0139] Breath test gas patterns Based on the results from the novel 4-gas device, many subjects had positive H 2and C.H. 4 As shown in Figures 17A-17C, there was an overlapping pattern between the breath test results, i.e., subjects who tested positive for two or more gases. During traditional breath tests (i.e., tests performed using the QuinTron device), patients often 4 None and H 2 [7] When analyzed with the novel four-gas device, 29.4% of these subjects had no detectable H 2 Not only was it found to have S, but it was also found to have positive H 2 The newly defined threshold for the S breath test (≥ 1.2 ppm) was also met.

[0140] The North American Consensus on Breath Testing states that H 2 and C.H. 4 A clear pattern of carbohydrate intake was observed over a 90-120 minute period. 2 While it leads to an increase in the levels of CH 4 recognized that methanogenesis (especially hydrogenotrophic methanogenesis) requires the presence or absence of H, not carbohydrates. 2 These patterns were also observed in the present study (Figures 18A and 18B). 2 The production of S also requires H as a substrate, not carbohydrates. 2 Because it required H 2 S levels also remained stable following carbohydrate ingestion, as shown in FIG. 18C.

[0141] CH 4 and H 2 Both the production of S and H as substrates 2 Since it requires H 2 The effect of these gases on the levels of CH 4 and H 2 S is the product of H 2 Because consumption was involved, we called it “consumption gas.” Of the study subjects, 180 were classified as “non-consumption gas positive,” and 103 subjects were classified as “consumption gas positive 1” (CH4 Positive for or H 2 S), and 15 were “consumption gas positive 2” (CH 4 In this comparison, the H2S group was positive for both H2S and H2S. 2 The H levels in gas 1 and gas 2 are higher than those in the other two groups. 2 The regression lines of H overlapped with each other as shown in FIG. 19A. However, as shown in FIG. 19B, 2 The pattern declined continuously with increasing number of gases consumed, except for one outlier subject. Specifically, the cumulative H 2 Levels were 56 ppm higher than those in the gas consumed 1 group (p=0.04), 106 ppm higher than those in the gas consumed 2 group (p=0.09), and 62 ppm higher than when any gas consumed was positive (p=0.005).

[0142] CH 4 , H 2 Direct interactions between S and diarrhea CH 4 It is known to slow intestinal transit and is associated with constipation rather than diarrhea. 2 Regarding consumption of H 2 Since it is known that CH competes with S, the interaction between these gases on diarrhea was investigated. To do this, CH 4 , H 2 Subjects who were positive for H, S, or both were evaluated. 2 S is associated with more severe diarrhea, whereas CH 4 But it seemed like a crucial gas. 4 Subjects who were positive only for H 2 They had less severe diarrhea than subjects who were positive for S only. 4 and H 2 Subjects who were positive for both H and S were 2 They presented with less severe diarrhea than subjects who were positive for S alone.

[0143] analysis H2 , C.H. 4 and CO 2 Plus H 2 This study is the first to demonstrate that a four-gas breath test device based on the disclosed technology that can detect S can significantly add to the utility of clinical breath testing. First, humans can exhale detectable and variable H 2 It was found that the H 2 S is diarrhea, and 2 In association with other related symptoms that were not previously linked to H 2 We found that the inclusion of S explained at least a subset of the "flat" breath tests. 2 Adding S is H 2 Level and CH 4 This will improve understanding of interactions with the body and allow for more complete breath testing.

[0144] CH 4 While these findings are interesting, clinical breath testing was originally developed to 2 However, the H 2 No studies have clearly defined the association between production levels and clinical symptoms, leading to skepticism regarding the clinical significance of breath tests. Some commentators have even suggested that breath tests simply determine transit time and cannot be used to diagnose SIBO

[14] ,

[15] . Part of the reason for the skepticism surrounding breath tests may stem from the fact that existing tests are imperfect and therefore may produce inconclusive results (e.g., flat test). 2 and C.H. 4 Measurement of α-amyloides alone provides an incomplete understanding of the complex microbial interactions that occur in the intestinal tract.

[0145] H 2 H is produced during fermentation and is also consumed by other organisms. 2 There are three pathways for the disposal of H2O. Methanogens (e.g., M. smithii) can dispose of 4 molecules of H2O. 2 Using one molecule of CH 4[6] The second pathway is by sulfur-reducing bacteria, which convert five molecules of H 2 Using one molecule of H 2 The third alternative pathway involves the production of H by acetogenic bacteria. 2 This is a process of H2O in the intestine, not a pathway that produces gas. 2 Moreover, such complex interactions between different gut bacteria may limit the absolute H production in breath tests. 2 This highlights the difficulty of finding a direct linear association between the levels of H 2 and C.H. 4 H added to 2 Measurement of S is important for a more complete understanding of microbe-host interactions.

[0146] Another common problem during breath testing is the "flat" pattern, where the clinical breath test produces a constant level of H throughout the test. 2 indicates, CH 4 One interpretation is that CH 4 and H 2 A possible explanation for this would be a complete lack of H-producing organisms in the gut. However, this is highly unlikely. Current research shows that in these "flat" breath tests, 2 S has been shown to be frequently present, and H by sulfur-reducing bacteria 2 The consumption of H 2 It was suggested that this could lead to an inaccurate assessment of production.

[0147] In addition, H 2 Measurement of levels alone provides an incomplete understanding of the clinical picture. For example, studies of SIBO have suggested a link between positive breath tests and IBS,10,11 but no association has been found between the severity of any symptoms and the H in the breath test. 2 There is no clear relationship between H 2 S proved to be more common than expected, with 24% of subjects reporting H 2 In addition, diarrhea was associated with a positive test for H in the breath test. 2This was particularly related to the presence and levels of S.

[0148] These results suggest that CH 4 and H 2 This further suggests that there is a balance-counterbalance effect between H and S. First, the production of these gases is 2 This requires the consumption of H 2 Level is CH 4 , H 2 S, or both. This finding is consistent with the 2 The measured value is CH 4 and H 2 Because S influences the clinician's H 2 This is important because it suggests that we cannot rely solely on measurements. 4 However, the effect of H on diarrhea severity was 2 It appears to counteract the effect of S. 4 is known to be associated with and a cause of constipation [9]. 2 S is known to have toxic effects on epithelium

[16] . 2 Even when S is present, CH 4 appears to have a profound effect on diarrhea severity.

[0149] In conclusion, this study is the first to demonstrate the efficacy and utility of a novel 4-gas device for clinical breath testing in subjects evaluated for SIBO. Based on these results, we recommend the use of H 2 There are clear advantages to adding S measurements, providing the most comprehensive in vivo analysis of human gut microbe-gas interactions to date. 2 Measurement of S answers important questions about breath tests such as the flat test. 2 S appears to be associated with diarrheal phenotype, whereas H 2 Conclusions: This study demonstrates the importance of measuring all four gases during breath testing.

[0150] SELECTED EMBODIMENTS While the above description and appended claims disclose numerous embodiments of the present invention, other alternative aspects of the present invention are disclosed in the additional embodiments below.

[0151] 1. A system for testing a patient's breath for concentrations of various gases, comprising: Breath collector; a gas inlet connectable to said breath collector; Gas outlet; a manifold including a gas flow passage in gas communication with the gas inlet and the gas outlet; at least one gas sensor configured to output sensor data related to a concentration of gas passing through the gas flow path; a heating element in thermal communication with said manifold; a temperature sensor configured to output temperature data related to a temperature of the manifold; a control system including one or more processors and memory for determining a concentration of a gas based on the output sensor data; and A display that outputs the determined gas concentration. The system comprising:

[0152] The at least one gas sensor is 4 Sensor, CO 2 Sensor, H 2 Sensor, or H 2 The system includes at least one of S sensors.

[0153] The at least one gas sensor is disposed in series along the gas flow path. 2 Sensor, H 2 Sensors and H 2 S sensor, and the gas flow path comprises a single channel in the manifold.

[0154] The first baffle is 2A second baffle is disposed adjacent to the sensor. 2 The first and second baffles are disposed adjacent to the H S sensor. 2 S sensor and the H 2 The system is sized and shaped to facilitate gas exchange with the sensor.

[0155] The system further includes a pump configured to pump gas through the gas flow path based on feedback from a flow meter configured to detect a flow rate through the gas flow path.

[0156] The system wherein the temperature sensor is a thermistor connected to a printed circuit board.

[0157] The system wherein the heating element is connected to the printed circuit board.

[0158] The system wherein the heating element comprises a trace printed on the printed circuit board.

[0159] The system, wherein the heating element includes a plurality of heating elements, each of the plurality of heating elements configured to heat one of a series of zones of the manifold.

[0160] The system, wherein the temperature sensor includes a plurality of temperature sensors, each of the plurality of temperature sensors configured to output temperature data relating to one of the series of zones of the manifold.

[0161] The system, wherein the control system is configured to maintain a minimum temperature of the manifold by applying energy to the heating element based on data output from the temperature sensor.

[0162] The system, wherein the manifold comprises a metal block and the gas flow path is constructed through the metal block.

[0163] The system wherein the manifold comprises a thermally conductive material.

[0164] The system, wherein the thermally conductive material comprises stainless steel or copper.

[0165] The system, wherein the gas flow path includes a baffle disposed adjacent to the at least one gas sensor.

[0166] The system, wherein the minimum temperature is 38 to 41°C.

[0167] The system, wherein the minimum temperature is 40°C.

[0168] The system, wherein the control system is configured to determine an indication of whether the patient has SIBO based on the output sensor data.

[0169] The output sensor data is 4 Sensor, CO 2 Sensor, H 2 Sensors and H 2 The system includes data output from an S sensor.

[0170] The output sensor data is H 2 If the control system indicates an increase in S levels, the control system is further configured to output an indication of diarrhea for the patient.

[0171] The output sensor data is, during the lactulose breath test, 2 S levels increased, and CH 4 and H 2 If the control system indicates that the exhaled breath level has not increased, the system is further configured to output a positive indication of SIBO.

[0172] A method for detecting a gas concentration in exhaled breath, comprising: receiving a batch of exhaled breath from a patient; heating said batch of exhaled breath to a temperature above 37°C while drawing in and drawing out air at a constant flow rate through a flow path; sensing gas concentrations in the flow path using an array of electrochemical sensors; and Displaying the gas concentration. The method comprising:

[0173] The gas concentration is CH 4 , CO 2 , H 2 , and H 2 The method further comprising the step of:

[0174] The method, wherein the flow path is routed through a manifold.

[0175] The method, wherein the step of heating the batch of exhaled breath comprises maintaining the manifold at a temperature above 37°C.

[0176] The gas concentration is at least CH 4 and H 2 wherein the control system is further configured to determine an indication of whether the patient has SIBO based on the gas concentration.

[0177] A method for detecting a gas concentration in exhaled breath, comprising: receiving a batch of exhaled breath from a patient; heating said batch of exhaled breath to a temperature above 37°C while drawing in and drawing out air at a constant flow rate through a flow path; sensing gas concentrations in the flow path using an array of electrochemical sensors; and Displaying the gas concentration. A method comprising:

[0178] The gas concentration is CH 4 , CO 2 , H 2 , and H 2 The method of claim 22, comprising a S concentration.

[0179] The method of claim 22 , wherein the flow path is routed through a manifold.

[0180] 25. The method of claim 24, wherein the step of heating the batch of exhaled breath comprises maintaining the manifold at a temperature above 37°C.

[0181] The gas concentration is at least CH 4 and H 2 23. The method of claim 22, wherein the control system is further configured to determine an indication of whether the patient has SIBO based on the gas concentration.

[0182] References TIFF0007644120000006.tif176160TIFF0007644120000007.tif236160TIFF0007644120000008.tif12160

[0183] Computer and Hardware Implementations of the Disclosure It should be understood at the outset that the disclosure herein may be implemented in any type of hardware and / or software, including pre-programmed general-purpose computing devices and / or control systems including one or more processors and memories. For example, the system may be implemented using a server, a personal computer, a portable computer, a thin client, or any suitable device or devices. The disclosure and / or its components may be a single device at a single location, or multiple devices at single or multiple locations, interconnected using any suitable communication protocol, over any communication medium, such as electrical cable, fiber optic cable, or wirelessly.

[0184] It should also be noted that the present disclosure is illustrated and described herein as having a number of modules performing specific functions. It should be understood that these modules are merely illustrated diagrammatically based on their functionality for clarity and do not necessarily represent specific hardware or software. In this regard, these modules may be hardware and / or software implemented to substantially perform the specific functions discussed. Furthermore, each module may be combined together within the present disclosure or may be divided into further modules based on the specific functions desired. Thus, the present disclosure should not be construed as limiting the present invention, but should be understood as merely illustrating one exemplary implementation of the present invention.

[0185] A computing system may include clients and servers. Clients and servers are generally remote from each other and typically interact through a communication network. The relationship of client and server arises by virtue of computer programs running on the respective computers and having a client-server relationship to each other. In some implementations, a server sends data (e.g., HTML pages) to a client device (e.g., for the purpose of displaying the data to and receiving user input from a user interacting with the client device). Data generated at the client device (e.g., a result of user interaction) may be received from the client device at the server.

[0186] Implementations of the subject matter described herein may be implemented in a computing system that includes back-end components, e.g., a data server, or includes middleware components, e.g., an application server, or includes front-end components, e.g., a client computer having a graphical user interface or web browser through which a user can interact with an implementation of the subject matter described herein, or any combination of one or more such back-end, middleware, or front-end components. The components of the system may be interconnected by any form or medium of digital data communication, e.g., a communications network. Examples of communications networks include local area networks ("LANs") and wide area networks ("WANs"), internetworks (e.g., the Internet), and peer-to-peer networks (e.g., ad-hoc peer-to-peer networks).

[0187] Implementations of the subject matter and operations described herein may be implemented in digital electronic circuitry, or in computer software, firmware, or hardware, including the structures disclosed herein and their structural equivalents, or in one or more combinations thereof. Implementations of the subject matter described herein may be implemented as one or more computer programs, i.e., one or more modules of computer program instructions, encoded on a computer storage medium for execution by or to control the operation of a data processing device. Alternatively, or in addition, the program instructions may be encoded in an artificially generated propagated signal, e.g., a machine-generated electrical, optical, or electromagnetic signal, that is generated to encode information for transmission to an appropriate receiving device for execution by the data processing device. The computer storage medium may be, or may be included in, a computer readable storage device, a computer readable storage substrate, a random or serial access memory array or device, or one or more combinations thereof. Furthermore, although a computer storage medium is not a propagating signal, a computer storage medium may be a source or destination of computer program instructions encoded in an artificially generated propagated signal. The computer storage medium may also be, or be contained in, one or more separate physical components or media (e.g., multiple CDs, disks, or other storage devices).

[0188] The operations described herein may be implemented as operations performed by a data processing apparatus on data stored in one or more computer-readable storage devices or received from other sources.

[0189] The term "data processing apparatus" encompasses all kinds of apparatus, devices, and machines for processing data, including, by way of example, programmable processors, computers, systems on chips, or a combination or combinations of the foregoing. The apparatus may include special purpose logic circuitry, such as a field programmable gate array (FPGA) or an application specific integrated circuit (ASIC). In addition to hardware, the apparatus may also include code that creates an execution environment for the subject computer program, such as code that constitutes a processor firmware, a protocol stack, a database management system, an operating system, a cross-platform runtime environment, a virtual machine, or one or more combinations thereof. The apparatus and execution environment may implement a variety of different computing model infrastructures, such as web services, distributed computing, and grid computing infrastructures.

[0190] A computer program (also known as a program, software, software application, script, or code) may be written in any form of programming language, including compiled or interpreted, declarative or procedural, and may be developed in any form, including as a stand-alone program or as a module, component, subroutine, object, or other unit suitable for use in a computing environment. A computer program may correspond to a file in a file system, but need not. A program may be stored in a portion of a file that holds other programs or data (e.g., one or more scripts stored in a markup language document), in a single file dedicated to the program in question, or in multiple coordinated files (e.g., a file that stores one or more modules, subprograms, or portions of code). A computer program may be developed to run on one computer or on multiple computers, located at one site or distributed across multiple sites and interconnected by a communication network.

[0191] The processes and logic flows described herein may be performed by one or more programmable processors executing one or more computer programs to perform operations by operating on input data to generate output. The processes and logic flows may also be performed by, or apparatus implemented as, special purpose logic circuitry, such as an FPGA (field programmable gate array) or an ASIC (application specific integrated circuit).

[0192] Processors suitable for executing computer programs include, by way of example, both general-purpose and special-purpose microprocessors, and any one or more processors of any kind of digital computer. Generally, a processor receives instructions and data from a read-only memory or a random-access memory, or both. The essential elements of a computer are a processor for performing operations according to instructions, and one or more memory devices for storing instructions and data. Generally, a computer also includes one or more mass storage devices, such as magnetic disks, magneto-optical disks, or optical disks, for storing data, or is operatively coupled to receive data from them, transfer data to them, or both. However, a computer need not have such devices. Moreover, a computer can be embedded in another device, such as a mobile phone, a personal digital assistant (PDA), a mobile audio or video player, a game console, a global positioning system (GPS) receiver, or a portable storage device (e.g., a universal serial bus (USB) flash drive), to name a few. Devices suitable for storing computer program instructions and data include all types of non-volatile memory, media, and memory devices, including, by way of example, semiconductor memory devices, such as EPROM, EEPROM, and flash memory devices, magnetic disks, such as internal hard disks or removable disks, magneto-optical disks, and CD-ROM and DVD-ROM disks. The processor and memory may be supplemented by, or incorporated in, special purpose logic circuitry.

[0193] conclusion The various methods and techniques described above provide many ways to implement the present invention. Of course, it should be understood that not all of the described objectives or advantages can be achieved according to any particular embodiment described herein. Thus, for example, one skilled in the art will recognize that the method can be implemented in a manner that achieves or optimizes one advantage or a group of advantages as taught herein, without necessarily achieving other objectives or advantages taught or shown herein. Various alternatives are mentioned herein. It should be understood that some embodiments specifically include one, another, or several features, while other embodiments specifically exclude one, another, or several features, while still other embodiments reduce a particular feature by including one, another, or several advantageous features.

[0194] Moreover, those skilled in the art will recognize the applicability of various features from various embodiments. Similarly, those skilled in the art may use various combinations of the various elements, features, and steps described above, as well as other known equivalents of each such elements, features, or steps, to implement methods in accordance with the principles described herein. Among the various elements, features, and steps, some are specifically included and others are specifically excluded in different embodiments.

[0195] Although the present application has been disclosed in the context of certain specific embodiments and examples, it will be understood by those skilled in the art that the embodiments of the present application extend to other alternative embodiments and / or uses thereof, and modifications and equivalents beyond the specifically disclosed embodiments.

[0196] In some embodiments, the terms "a," "an," "the," and similar references used in the context of describing certain embodiments of the present application can be construed to cover both the singular and the plural (especially in the specific context of the claims below). The use of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referring to each of the individual values ​​falling within the range. Unless otherwise indicated herein, each of the individual values ​​is incorporated into the specification as if it were individually set forth herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of exemplary language (e.g., "etc.") provided in any and all examples, or with respect to certain embodiments of the present specification is intended merely to better illuminate the application and does not limit the scope of the application unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the application.

[0197] Certain embodiments of the present application are described herein. Modifications of these embodiments will be apparent to those of ordinary skill in the art upon reading the description. It is contemplated that those of ordinary skill in the art may employ such modifications as appropriate and may practice the present application otherwise than as specifically described herein. Accordingly, many embodiments of the present application include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, unless otherwise indicated herein or clearly contradicted by context, the present application includes any combination of the above-described elements in all possible variations thereof.

[0198] Particular implementations of the subject matter have been described. Other implementations are within the scope of the following claims. In some cases, the actions recited in the claims can be performed in a different order and still achieve desirable results. In addition, the processes depicted in the accompanying figures do not necessarily require the particular order or sequence shown to achieve desirable results.

[0199] All patents, patent applications, published patent applications, and other materials, such as articles, books, specifications, publications, documents, articles, and / or the like, referenced herein are hereby incorporated by reference in their entirety for all purposes, except for any prosecution history related to any of the foregoing, any of the foregoing that is inconsistent with or inconsistent with this document, or any of the foregoing that may now or later have a limiting effect on the broadest scope of any claims related hereto. By way of example, in the event of an inconsistency or contradiction between any explanation, definition, and / or term use accompanying the incorporated materials and any explanation, definition, and / or term use accompanying this document, the explanation, definition, and / or term use in this document shall control.

[0200] Finally, it should be understood that the embodiments of the present application disclosed herein are illustrative of the principles of the embodiments of the present application. Other modifications that may be employed are within the scope of the present application. Thus, by way of example, but not of limitation, alternative configurations of the embodiments of the present application may be utilized in accordance with the teachings herein. Thus, the embodiments of the present application are not limited to those precisely as shown and described.

Claims

1. 1. A system for testing a patient's breath for concentrations of various gases, comprising: Breath collector; a gas inlet connectable to said breath collector; Gas outlet; a manifold including a gas flow passage in gas communication with the gas inlet and the gas outlet; at least one gas sensor configured to output sensor data related to a concentration of gas passing through the gas flow path; a heating element in thermal communication with the manifold; a temperature sensor configured to output temperature data related to a temperature of the manifold; a control system including one or more processors and memory for determining a concentration of a gas based on the output sensor data; and A display that outputs the determined gas concentration. Including, the at least one gas sensor includes a CO2 sensor, an H2 sensor, and an H2S sensor arranged in series along the gas flow path; the gas flow path comprises a single channel in the manifold; The system.

2. The at least one gas sensor is ４ The system of claim 1 further comprising a sensor.

3. The first baffle is ２ A second baffle is disposed adjacent to the sensor. ２ The first and second baffles are disposed adjacent to the H S sensor. ２ S sensor and the H ２ The system of claim 1 , sized and shaped to facilitate gas exchange with the sensor.

4. 10. The system of claim 1, further comprising a pump configured to pump gas through the gas flow path based on feedback from a flow meter configured to detect flow rate through the gas flow path.

5. The system of claim 1 , wherein the temperature sensor is a thermistor connected to a printed circuit board.

6. The system of claim 5 , wherein the heating element is connected to the printed circuit board.

7. The system of claim 5 , wherein the heating element comprises a trace printed on the printed circuit board.

8. The system of claim 3 , wherein the heating element comprises a plurality of heating elements, each of the plurality of heating elements configured to heat one of a series of zones of the manifold.

9. The system of claim 8 , wherein the temperature sensor comprises a plurality of temperature sensors, each of the plurality of temperature sensors configured to output temperature data relating to one of the series of zones of the manifold.

10. The system of claim 1 , wherein the control system is configured to maintain a minimum temperature of the manifold by energizing the heating element based on data output from the temperature sensor.

11. The system of claim 1 , wherein the manifold comprises a metal block, the gas flow passage being constructed through the metal block.

12. The system of claim 1 , wherein the manifold comprises a thermally conductive material.

13. The system of claim 12 , wherein the thermally conductive material comprises stainless steel or copper.

14. The system of claim 1 , wherein the gas flow path includes a baffle disposed adjacent to the at least one gas sensor.

15. The system of claim 10, wherein the minimum temperature is between 38 and 41°C.

16. The system of claim 10, wherein the minimum temperature is 40°C.

17. 3. The system of claim 2, wherein the control system is configured to determine an indication of whether the patient has small intestinal bacterial overgrowth (SIBO) based on the output sensor data.

18. The output sensor data is ４ Sensor, the CO ２ Sensor, said H ２ The sensor, and the H ２ 20. The system of claim 17, including data output from an S sensor.

19. The output sensor data is H ２ 20. The system of claim 18, wherein the control system is further configured to output an indication of diarrhea for the patient if indicating an increased S level.

20. The output sensor data is, during the lactulose breath test, ２ S levels increased and CH ４ and H ２ 20. The system of claim 18, wherein the control system is further configured to output a positive indication of SIBO if the breath level indicates no increase.

21. A method for detecting a gas concentration in exhaled breath, the method being performed by the system according to any one of claims 1 to 20, comprising: receiving a batch of exhaled breath from a patient by said breath collector; heating the batch of exhaled breath with the heating element to a temperature above 37° C. while drawing in and drawing out the batch of exhaled breath at a constant flow rate through the gas flow path; sensing a gas concentration in the gas flow path with the at least one gas sensor; determining, by the control system, a concentration of the gas by processing data from the sensor; and displaying the gas concentration with the display. The method comprising:

22. The gas concentration is CH ４ , CO ２ , H ２ , and H ２ The method of claim 21 , comprising the S concentration.

23. The method of claim 21 , wherein the gas flow path is routed through the manifold.

24. 24. The method of claim 23, wherein the step of heating the batch of exhaled breath comprises maintaining the manifold at a temperature above 37°C.

25. The gas concentration is at least CH ４ and H ２ 22. The method of claim 21, further comprising determining, by the control system, an indication of whether the patient has SIBO based on the gas concentration.

Images