WO2010094967A1

WO2010094967A1 - Apparatus and method for breath testing

Info

Publication number: WO2010094967A1
Application number: PCT/GB2010/050284
Authority: WO
Inventors: Trevor Smith; Ronald Logan-Sinclair
Original assignee: Bedfont Scientific Limited
Priority date: 2009-02-20
Filing date: 2010-02-18
Publication date: 2010-08-26
Also published as: GB0902880D0; EP2399125A1

Abstract

The present invention is concerned with an apparatus for measuring levels of gases in exhaled breath, especially but not exclusively orally exhaled breath. There is provided a breath testing apparatus comprising a sampling device, a sensor device and a selectively permeable means to balance the relative humidity of a sample to be tested with the ambient relative humidity of the ambient air present within the sensor device. Balancing the humidity level of the sample to be tested provides improved sensor device accuracy. In addition there is provided a method of using such an apparatus, to test a breath sample for a gas of interest. The apparatus and method are particularly suited to measuring levels or nitric oxide in a breath sample.

Description

APPARATUS AND METHOD FOR BREATH TESTING

The present invention relates to an apparatus capable of detecting exhaled gases in breath samples and methods of using such an apparatus. The present invention particularly, but not exclusively, relates to apparatus and methods for detecting nitric oxide in exhaled breath.

The detection of compounds present in human breath in order to diagnose disease is known in the art. For example, the presence of volatile compounds such as acetone, ammonia or sulphur are well known for use in detecting conditions such as diabetes, liver impairment and kidney dysfunction.

Nitric oxide (NO) has been identified as a biomarker for airway inflammation, particularly associated with asthma. Bench-top apparatus for detecting NO in parts per billion (ppb) levels have been available since the 1990s. These were developed for use by clinicians to help assess appropriate treatment for asthmatics. Such equipment generally utilises the gas sensing principle of chemiluminescence.

Gas sensors utilising the principle of electrochemistry can also be used, but problems exist with the NO detectors currently available; problems range from their sensitivity to humidity present in the breath sample to be tested to the relatively slow response time of the NO sensors in the apparatus.

The problem of humidity sensitivity is often due to the transient response time of a gas sensor to the sample moisture. Often, especially in the case of electrochemical gas sensors, the sensor's transient response to the sample humidity is many times greater than the gas sensor's response to the gas to be tested. This results in reduced accuracy of the gas sensor with regard to the gas to be tested. This reduced accuracy is a particular issue for measurement of gases which are present in relatively low levels in a breath sample, for example, as is the case in NO detection measurements. In addition this is a particular problem where the sample to be tested is a breath sample, as breath samples inherently have a high relative humidity level.

NO can be used as a biomarker in several ways to give information about a patient. There are in principle three types of "breath" which can be measured for the presence of NO. Firstly, orally exhaled air (exhaled from the lower respiratory tract but which has not passed through the nasal passages), secondly nasally exhaled air (i.e. that which has passed though the nasal passages, preferably that which comes exclusively from the nasal passages), and thirdly regurgitated air from the stomach. These different types of breath will all naturally contain different levels of NO and an increase or decrease of NO levels acts as an indicator of medical conditions.

Firstly, levels of NO in orally exhaled air, also described as lower respiratory tract breath in the art, can indicate the presence of airway inflammation, typical experienced by asthmatics. Higher than normal levels of NO in orally exhaled breath is, for example, used as an indicator of asthma. The measurement of NO levels in orally exhaled breath is also useful in monitoring chronic obstructive pulmonary disease and interstitial lung disease.

Secondly, nasally exhaled air levels of NO are higher than levels of NO in orally exhaled air in healthy individuals. Elevated levels of NO in nasally exhaled air above the normal level can indicate the presence of allergic rhinitis. Lower levels of NO in nasally exhaled air is indicative of primary ciliary dyskinesia, and extremely low levels of nasal NO have been reported in cystic fibrosis.

The third type of NO containing "breath" is that regurgitated from the stomach. NO levels in regurgitated air can be correlated with gastric disturbances, and a lower level of NO in the regurgitated air has been found to correlate with lower levels of stomach HCI, and so can be indicative of gastro-oesophageal reflux.

Where orally exhaled air is to be measured, it is important to ensure that the air has been inhaled via the mouth and not the though the nasal passages. Where this is not ensured, the level of NO in the exhaled breath will be appear higher as it will contain endogenous nasal NO in the sample.

The present invention is concerned with improved apparatus for measuring levels of gases in exhaled breath, especially but not exclusively orally exhaled breath. The invention is particularly suited to the detection of NO in humans, but may be used for the detection of other gases of diagnostic value as will become apparent. Furthermore, the invention may also be used for detecting nitric oxide and other gases of diagnostic value in the exhaled breath of animals in a veterinary application.

According to the present invention there is provided a breath testing apparatus comprising a sampling device, a sensor device and a selectively permeable means to balance the relative humidity of a sample to be tested with the ambient relative humidity of the ambient air present within the sensor device. Balancing the humidity level of the sample to be tested with the ambient relative humidity level of the ambient air present within the sensor device of the breath testing apparatus mitigates, or significantly reduces the humidity transient response of the a sensor within the sensor device. Therefore, the accuracy of the sensor device is improved.

It should be understood that the selectively permeable means is selectively permeable to water, such that water is allowed to pass through the selectively permeable means. However, it is highly preferred that substantially no permeation of the sample gases of interest occurs, such that the sample gases of interest are retained within the selectively permeable means and, in addition, there is no accumulation of these gases into the sample from the ambient air.

The ambient relatively humidity level is taken to mean the humidity level surrounding a sensor present within the sensor device. Typically the ambient relative humidity level within the sensor device will correspond to the relative humidity level of the air external to the sensor device.

In one particularly preferred embodiment of the present invention the air surrounding the selectively permeable means is in fluid communication with the air external to the device, preferably in a manner which allows relatively unhindered passive exchange of atmospheric air between the interior of the breath testing apparatus (especially the volume of air surrounding the selectively permeable means) and the air external to the apparatus. Preferably the breath testing apparatus is provided with vents or apertures to facilitate the passive exchange of air. Allowing such a free exchange of air reduces the risk of the relative humidity level of air surrounding the selectively permeable means increasing or decreasing over time as a result of permeation of water to or from the selectively permeable means during use of the apparatus.

In one embodiment of the present invention, a flow of atmospheric air from the environment external to the apparatus may be actively drawn or passed through the sensor device. Such a flow means that the ambient humidity surrounding the sensor is maintained at a humidity level substantially equal to the relative humidity of external air. The flow may be intermittent or substantially continuous. Preferably the flow is essentially constant except when a sample of exhaled air is being provided to the sensor, at which point the flow may be interrupted. Preferably the flow of external air to the sensor device is filtered and/or scrubbed, e.g. filtering might remove particulate matter and scrubbing may remove gases from the air. In one embodiment the air is scrubbed with a scrubber to remove NO. In this embodiment the air can conveniently be used to calibrate the sensor device to a zero value. Of course, this calibration could be applied to other gases of interest. It is, of course, desirable that the relative humidity of this flow of air is not altered by the filtering or scrubbing process.

Accordingly it is a preferred embodiment that the apparatus comprises a scrubber to remove the gas to be tested from a flow of ambient air being provided to the sensor device. Where the gas to be tested is NO, the air is scrubbed of NO, so that a zero level is detected by the sensor in the absence of the sample to be tested, this effectively "zeros" the sensor in preparation for sample introduction.

Additionally, or alternatively, a flow of external air preferably may be actively passed over the selectively permeable means. This can help expedite the balancing of the sample within the selectively permeable means and the ambient air. Where the external air is actively passed over the selectively permeable means it is preferable that the flow of external air is directed such that it provides a counter flow to the flow of the sample to be tested which is passing through the selectively permeable means. Such an arrangement of flow and counter flow is often referred to a "reverse flow" system.

In one embodiment of the present invention the sampling device may be provided with a sample drying means in the form of a drier device, a moisture filtration device, a moisture absorbent means or a moisture trap, or another means known to the person skilled in the art to remove moisture from the sample of exhaled air. Preferably the drying means is a moisture filtration device. Suitably the moisture filtration device may also filter particulate material from the sample to be tested, and any other unwanted components of the sample. The purpose of the sample drying means is to reduce the relative humidity level of the sample to be tested up stream of entry to the selectively permeable means - the relative humidity level is then increased during passage through the selectively permeable means until it is substantially equal to the ambient relative humidity level. An alternative, but generally less preferred embodiment is that the exhaled breath is not pre-dhed, and the passage through the selectively permeable means reduces the humidity of the exhaled air to ambient levels.

Reduction of the relative humidity level of the sample to be tested upstream of the selectively permeable means may reduce the time taken by the selectively permeable means to reach the ambient relative humidity air level. This arrangement may also allow for improved "fine tuning" of the balance of the humidity level of the sample to be tested and the humidity level of the ambient air present in the sensor device. Further benefits of this arrangement are described below.

Preferably the sample drying means reduces the relative humidity of the sample to be tested to less than 50% relative humidity, more preferably less than 10% relative humidity, and even more preferably less than 5% relative humidity. Most preferably the sample drying means may substantially remove all the water from the sample to be tested, such that the selectively permeable means allows the sample to be tested to take up moisture from the ambient air surrounding the selectively permeable device, until the humidity level within the sample to be tested is increased to balance with the ambient air humidity level present within the sensor device. Where the sample to be tested is an exhaled breath sample, the initial relative humidity of the sample to be tested may be over 90%, and the use of a sample drying means is particularly preferred where the sample is to be tested is a breath sample.

Preferably the selectively permeable means provides a surface which is selectively permeable to water, via which the relative humidity can be balanced via equilibration of the relative humidity level present on either side of the selectively permeable means' surface, across the water potential gradient present.

Desirably the selectively permeable means has a relatively large permeable surface area relative to the volume of the selectively permeable means.

Preferably the selectively permeable means is substantially chemically inert. Preferably the selectively permeable means is operational across a range of pressure and temperature parameters. However, it is desirable that the selectively permeable means functions at around atmospheric pressure and room temperature without the need for modification or utilisation of, for example, a cooling device.

More preferably the selectively permeable means comprises a micro- porous material, a hygroscopic copolymer material or an ionomer. More preferably the selectively permeable means comprises a ionomer, and desirably the ionomer comprises tetrafluoroethylene and a perfluorosulfonic acid, and suitably the ionomer consist of Nafion ^® (available from Purma-pure, Toms River, NJ, USA).

Preferably the selectively permeable means consist of one or more tubes, where the internal wall of the tube defines a lumen for the sample to be tested, and the external wall of the tube is in communication with ambient air. A tube profile inherently provides a relatively large relatively permeable surface area where balance of the relative humidity of the sample within the tube cavity can occur.

As will be evident to the person skilled in the art, it is necessary to provide a suitable residence time for the sample within the selectively permeable means to achieve the desired balancing of relative humidity. The desired residence time of a sample within the selectively permeable means will depend on a number of parameters including, the magnitude of the difference in relative humidity between the sample and the ambient air, the rate of diffusion of water across the selectively permeable means, the area for diffusion to occur across and the degree to which the relative humidities should be balanced. Where the selectively permeable means consists of tubes, the number of tubes and the overall length of tubing provided will, to a large extent, determine the residence time of the sample to be tested within the tube cavity. Suitable numbers of tubes and overall lengths required to provide sufficient relative humidity balance within the sample to be tested will be evident to the skilled person.

In general it is preferred that the overall length of tube is between 300 mm and 700 mm, and more preferably between 400 mm and 600 mm, most preferably the length is around 500 mm. This length of tube has been found to be particularly suited to the case where the sample to be tested has had substantially all of its moisture removed upstream of the selectively permeable means by a sample drying means and the tube consists of Nafion.

In a preferred embodiment of the present invention the apparatus comprises a pump to draw a flow of the sample into the selectively permeable means, and ultimately into the sensor device. Preferably the pump is positioned upstream of the selectively permeable means.

Suitably the apparatus comprises a pump adapted to draw a flow of external air to the sensor, which can provide calibration, as discussed above.

It is preferred that a single pump is adapted to selectively draw either the sample or a flow of external air to the sensor. The selection of the sample or flow of external air can be achieved through switching a valve, e.g. a solenoid valve, to one or other of the sample or the flow of external air. It is particularly preferred that the pump is adapted to run continuously when the apparatus is in use. Thus a flow of external air which is scrubbed off a gas to be measured (e.g. NO) is provided essentially continuously to the sensor, which allows for essentially constant calibration of the sensor and maintenance of the relative humidity of air within the sensor device at ambient levels. However, when a sample is to be measured the valve can be switched such that the sample is directed to the sensor device, preferably via the selectively permeable means.

In one embodiment of the present invention it is desirable that the breath testing apparatus be compact. Where this is the case, and the selectively permeable comprises a relatively long length of tube, e.g. 500 mm, it is desirable that the tube be provided in a coiled or folded configuration. Where the coiled or folding is employed it is important not to overly limit the permeable surface available for balancing the relative humidity of the sample within the tube cavity. As such, it may be preferably to provide the tube within a correspondingly coiled or folded protective outer sheath, such that the ambient relative humidity air can be provided between the sheath and the tube about the entire length of the tube. Clearly, the provision of such an outer sheath may be desirable in other embodiments of the apparatus and it is not intended to be limited to the case where the tube is provided in a folded/coiled configuration only, for example, such a sheath may be utilised to protect the tube, or aid retention of the selectively permeable means in a specific orientation within the sensor device.

Preferably the sampling device is removable from both the sensor device and the selectively permeable means. Preferably the sampling device and the selectively permeable means are provided with cooperating interface means which facilitates the connection and removal of the sampling device from the selectively permeable means. Suitably the connection between the sampling means and the selectively permeable means is substantially air tight. Desirably the cooperating interface means comprises a plug and socket arrangement. It is preferred that the interface means on the selectively permeable means comprises a recess into which the interface means on the sampling device is inserted. A retaining means to hold the component parts together, such as a clip, may be provided. However, the interface means are desirably formed such the friction between the two cooperating interface means is sufficient to hold the component parts together during use. It is preferred that the interface means are shaped such that they can fit together only in one orientation.

Additionally or alternatively, the selectively permeable means may be removable from the sampling device. This facilitates any cleaning or replacement of the selectively permeable means over prolonged use of the apparatus. Suitably an interface means is provided between the selectively permeable means and the sampling device as described above, and/or with a further interface provided between the selectively permeable means and the sensor device. Desirably the further interface is substantially the same as the interface as described above, in particular preferably it comprises a plug and socket arrangement, more preferably the further interface is formed such that the friction between the two cooperating further interface means is sufficient to hold the component parts together during use.

It is preferred that the cooperating interface means within the apparatus are shaped such that they can only fit together in a desired orientation and can only be connected to the correct partner. For example, the sampling device will be prevented from being connected directly to the sensor device in place of the selectively permeable means; this will prevent damage to the sensor from a high humidity sample entering the sensor device in error. The sampling device suitably comprises a patient contact means. The patient contact means suitably comprises a mouthpiece, a facemask, a nasal breath sampling means or a combination of one or more of these. A mouthpiece is preferred as it is simple to use. Preferably the patient contact means is removable to allow cleaning or disposal.

The sampling device preferably comprises a flow regulator or flow indicator. The flow regulator or flow indicator allows exhaled air to reach the gas sensor in a controlled manner.

The flow regulator may take the form of a mechanical device to restrict or otherwise actively control the flow of exhaled air. Such mechanical devices are known in the art.

The flow indicator may provide feedback to a user exhaling into the apparatus to facilitate modulation of the rate of exhalation to control the rate of exhalation to within desired levels.

Preferably the flow regulator or flow indicator is adapted to provide a flow rate of from 30 to 70 ml/s, especially from 45 to 55 ml/s (45 to 55 ml/s is recommended by the American Thoracic Society and The European Respiratory Society (ATS/ERS) recommendations for measuring exhaled NO levels).

The sampling device typically comprises a conduit running between the patient contact means and the selectively permeable means. The sampling device may optionally comprise an inlet to allow a person to inhale air through the sampling device. The inlet may comprise a scrubber to remove the gas of interest from the air being inhaled.

In one embodiment the conduit of the sampling device is provided with means of directing the sample to be tested into the selectively permeable means and, where the selectively permeable means is provided by one or more tubes, the sample to be tested is suitably directed in to the internal cavity of the one or more tubes. Means of directing the sample to be tested will be known to the person skilled in the art. The means of directing the sample may comprises one or more one-way valves to direct the paths of the inhaled and exhaled sample air. Preferably, the one or more one-way valves allow air to pass though an inlet to the patient during an inhalation phase, but close, preventing air passing out of the inlet, or otherwise by-passing the flow regulator or indicator, during an exhalation phase. Such one-way valves are well known in the art and, in one embodiment, may comprise a simple flap and aperture arrangement. In addition, such an outlet arrangement will direct exhaled air into the selectively permeable means.

Where an inlet for inhalation through the sampling device is provided, it is preferred that an inhalation filter or scrubber is provided to remove the gas of interest to be sampled from the inhaled air. Suitable inhalation filters or scrubbers for removing NO include a potassium permanganate KMnO₄ filter and/or carbon beads/carbon material filter. The inhalation filter may also be desirably configured to remove any particulates or other component parts of the ambient air which could adversely affect the operation and/or accuracy of the sensor device. It is desirable that the sampling device comprises infection control means to prevent infectious particles from passing through the sampling device into the selectively permeable means and the sensor device. Such infection control means may suitably comprise a filter which is able to remove particles as small as viruses, bacteria and other potentially infective microbes. Such filters are well known in the art. The infection control means is suitably positioned in the conduit between the patient contact means and the selectively permeable means. Where the sampling device comprises such an infection control means, it is a significant advantage that the selectively permeable means and the sensor device can be reused without the need for sterilisation between patients.

The present invention thus provides that the components of the breath sample test apparatus are separable from one another, such that the sampling device can be removed and/or replaced. This is advantageous as the sampling device, which is the point of contact for the patient can be disposed of after use and replaced with a new clean/sterile sampling device. In this way, the sampling device may be a single use, disposable unit.

Furthermore, where a sample drying means is provided, it is preferable that this is positioned in the sampling device conduit between the infection control means and the interface as this avoids contamination of the sample drying means.

The sensor of the sensor device is preferably adapted to detect levels of nitric oxide (NO) within the exhaled air, but may of course be suitable for any gas of diagnostic value, for example CO or H₂. Preferably the detector is able to detect NO down to ppb levels. In a preferred embodiment of the present invention the sensor device is adapted such that the sensor can be removed and replaced with a sensor for a different gas of interest. Other gases which may be of interest include carbon monoxide or hydrogen. This allows one sensor device to be used for a number of different sensing operations.

Typically the sensor is an electrochemical gas sensor. It is particularly advantageous to use a sensor that is temperature stable, this negates the need for heating or cooling of the sensor or exhaled air during use. This offers space saving opportunities in the apparatus design and simplicity of design and construction of the apparatus.

Preferably the sensor device contains an independent power source, such as a battery, such that it is portable and can be used away from the power grid. Preferably the sensor device contains a back-up battery to ensure power to a memory means within the sensor device which contains software and/or to the gas sensor.

Preferably the sensor device comprises a pressure regulator to control the pressure exerted upon the sensor. Desirably the pressure at the sensor, during use, does not exceed 150 mm H₂O. Preferably the pressure regulator comprises the pump which directs a portion of the sample to be tested to the sensor via the selectively permeable means. Controlling the pressure exerted upon the sensor may help to protect the sensor, and also further improve the accuracy of the sensor as changes in pressure do not need to be accounted for during sample testing. Additional or alternative pressure regulating means such as further pumps, flow restrictions and expansion volumes may be provided, for example after the selectively permeable means. It is envisaged that the breath testing apparatus of the present invention will be compact, and in particular will be shaped and sized such that it is suitable for hand-held operation; this advantageously allows the unit to be used in a domestic setting, without a trip to a trained clinician being necessary. This would allow suffers of, e.g. asthma, to assess their NO levels in the home and aid in their ongoing treatment and monitoring. Additionally, smaller apparatus for testing NO levels provide general space saving benefits.

Optionally, in one embodiment, the inlet for inhaling air draws a flow of scrubbed air through the sensor device. The air to be inhaled can thus conveniently pass though the sensor, which can then be calibrated to "zero" on the scrubbed free air being drawn in. This provides a convenient means of self calibration. The air can then pass via the selectively permeable means through the interface means into the sampling device and is inhaled by the patient.

The sampling device is suitably formed substantially from a plastics material. Conveniently the sampling device may be moulded. Suitably the plastics material is impregnated with an antimicrobial agent.

The sampling device may comprise a flow restriction means which provides sufficient resistance to exhalation such that the nasal vellum of the patient is closed during exhalation, and thus nasally exhaled air is substantially excluded from the tested breath.

The electronics and software required to control and operate a breath testing apparatus of the present invention are known in the art. In a further aspect, the present invention relates to a method of analysing the breath of a patient for the presence or amount of a gas of interest, wherein the patient exhales into a breath sample test apparatus as discussed above.

In a preferred embodiment the method is a method of analysing the NO content of the exhaled air of the patient.

Suitably the method comprises the steps of: - providing a breath testing apparatus as set out above; causing the patient to exhale a sample to be tested controlling the flow of the sample into the apparatus to a suitable rate; balancing the humidity of the sample to be tested with the ambient relative humidity within the breath testing apparatus sensor device; and analysing the exhaled breath for the presence or amount of a gas of interest.

Preferably the method comprises the optional step of:

- directing the sample to be tested through a selectively permeable means to allow balance of the humidity.

Suitably the selectively permeable means is as described above.

In one particularly preferred embodiment the method comprises the steps of: directing the sample to be tested through a selectively permeable means comprising a tube, to provide a sample flow within the tube cavity, and providing a counter flow of ambient relative humidity air within the selectively permeable means about the tube.

Such a counter flow method avoids an increase in the relative humidity of the ambient air within the apparatus. It will be understood that the selectively permeable means is in fluid communication with the sensor device as described above.

Preferably the method comprises the step of pumping ambient air from outside the device through the selectively permeable means and into the sensor device to calibrate the sensor. Preferably the ambient air has been scrubbed to remove the gas of interest to allow a zero reading, as described above.

Suitably when a sample of exhaled air is to be analysed the exhaled breath of the patient is pumped through the selectively permeable means to provide the sample to be analysed by the sensor device. Where the patient is in an inhalation phase the pump will direct ambient relative humidity air through the selectively permeable means. .

Preferably the method comprises the step of controlling the pressure exerted on the sensor of the sensor device. More preferably the pressure exerted upon the sensor is less than 150mm H₂O.

Suitably the rate of exhalation is between 45 and 55 ml/s for a time sufficient for sampling to occur. Most preferably, the rate of exhalation is 50ml/s.

Alternatively, though not preferably, the method further comprises the step of enabling the patient to inhale through the breath testing apparatus. Preferably this is facilitated by the provision of an inlet in the sampling device interface, or in the sensor device, as described above.

The method may comprise the step of comparing the result of the method with an expected value. From this a diagnostic or prognostic indication may be derived.

Suitably the method complies with ATS/ERS recommendations.

Embodiments of the present invention will now be described, by way of non-limiting example only, with reference to the accompanying drawings in which;

Fig 1 shows a schematic view of a breath test apparatus in accordance with one embodiment of the present invention; Fig 2 shows a schematic view of a breath test apparatus in accordance with an alternative embodiment of the present invention;

Fig 3 shows a more detailed schematic view of a breath test apparatus in accordance with an alternative embodiment of the present invention.

A breath test apparatus comprises a sampling device 30, a selectively permeable means 40, and a sensor device 50. The selectively permeable means 40 comprises a selectively permeable tube 9, made of Nafion. This tube 9 allows the selective permeation of water between the cavity defined by the tube, and the air surrounding the tube.

The sensor device 50, the selectively permeable means 40 and the sampling device 30 connect together via cooperating interface means 7. The interface means 7 are suitably tapered to ensure a neat fit (not shown). The connections formed are preferably substantially air tight. The sampling device 30 comprises a patient contact means 1 which is suitable for a patient to breathe into. The patient contact means 1 is removable and disposable so that it can be changed between uses. The patient contact means 1 comprises a mouthpiece, which is shaped and sized such that a patient can put the device into their mouth and form a seal with their lips. A pipe which is circular or elliptical in profile is suitable.

The patient contact means 1 is connected to a conduit 3 which leads to the selectively permeable means.

An infection control means 23, typically a filter capable of removing bacteria and viruses, is provided in the conduit to ensure that such unwanted infective agents do not pass into the device.

In one embodiment of the invention, as shown in Figure 2, the conduit 3 may be provided with a system to allow air to be inhaled through the sampling device through an inlet 17, and then during exhalation to be directed to the selectively permeable means. For example a first one way valve (not shown) which allows exhaled breath to pass through the conduit towards the selectively permeable means, but which does not allow return of air there through may be provided. An inlet 17 is provided which leads into the conduit 3, this may be positioned at a point between the patient contact means 1 and the first one way valve, if present. The inlet 17 is provided with a second one way valve which is adapted such that atmospheric air can pass through the valve into the conduit 3 when the patient inhales, but prevents air escaping from the inlet 17 during an exhalation phase. As a result of the arrangement of valves, when the patient inhales, air passes through the inlet 17 into the conduit 3, and through the patient contact means 1 and into the patient's airways. Upon exhalation the air passes into the conduit 3 and then though the first one way valve and through the remainder of the sampling device 30. The inlet 17 may comprise a scrubber 19 which is capable of removing NO (or other test gas) from the air passing into the conduit 3. A suitable NO scrubber material is KMnO₄ and/or carbon granules.

However such a system of inhaling air through the sampling device is not required, and it is possible that the patient does not inhale through the apparatus at all. Indeed, a preferred embodiment is shown in Figure 3 in which a different inlet arrangement is provided which allows for calibration of the sensor via a flow of e.g. NO free air from outside of the apparatus. This will be discussed in more detail below.

The selectively permeable means 40 comprises a tube 9 made of Nafion tubing. The selectively permeable means 40 is provided in selectable fluid communication with the conduit 3 of the sampling device. The tube 9 is a coiled tube of 500 mm in length, and is held within the apparatus. The coiling allows a relatively long tube to be accommodated within a relatively small volume within the apparatus. The volume of the apparatus where the selectively permeable means is housed is desirably in fluid communication with the air outside of the apparatus to allow the humidity of the air within the device to be equalised with air outside of the device, i.e. to remain at ambient levels. Thus the selectively permeable means is surrounded by air at ambient relative humidity.

Between the sampling device and the selectively permeable means there is provided a solenoid valve 45, which allows the optional selection of fluid communication between the selectively permeable means and the conduit of the sampling device in a first position, and in a second position the solenoid valve 45 disconnects the selectively permeable means from the sampling device and enters it into fluid communication with an inlet 17. The inlet 17 is in fluid communication with ambient air outside of the apparatus. The inlet 17 comprises a scrubber 19 which allows air from outside of the apparatus to have substantially all NO (or other test gas) removed there from as the air passes through.

A pump 35 is provided which draws a flow from either the sampling device or from the inlet 17, depending on the position of the valve 45. When in the second position, the valve allows a flow of air which has been scrubbed of the gas to be tested to be drawn by the pump 35 and direct it through the selectively permeable means and thereafter into the sensor device containing the sensor 13 where it serves to calibrate the gas sensor to a zero level. When the valve is in the first position the pump draws a flow from the sample of exhaled air in the conduit and directs it into the selectively permeable means and thereafter into the sensor device where the concentration of the gas of interest, e.g. NO, is measured.

The passage of the sample through the selectively permeable membrane allows for the relative humidity of the sample to be equilibrated with the relative humidity of the ambient air surrounding the selectively permeable means. Thus when the sample reaches the sensor, there is no transient response as a result of a change of humidity.

The sensor device 50 comprises an electrochemical gas sensor 13 which is mounted within the sensor device 50 such that the flow exiting the selectively permeable means 40 passes over the relevant portion of the gas sensor 13 before exiting the device through an exhaust port. Suitably the gas sensor 13 is arranged such that a gas entry surface faces into a diffusion cavity through which the flow from the selectively permeable means passes. The gas sensor 13 may be essentially any gas sensor, though sensors for NO, CO and H₂ are of particular interest.

The sensor device 50 may comprise a pressure regulator 25, which controls the pressure exerted upon the sensor by the flow of air existing the selectively permeable means 40.

The electrochemical gas sensor 13 is mounted in the sensor device 50 such that it is removable and may be replaced as required. This allows the sensor to be replaced if it is not performing as desired, or it may be replaced with a sensor for another type of gas. When the gas sensor 13 is changed to a sensor for a different type of gas it is clearly essential that the electronics and software within the sensor device are adapted to the change of sensor. However, this is not difficult to achieve, and may simply involve switching between a number of different software packages, which are conventional for each type of sensor. Desirably the sensor device 50 automatically detects the type of gas sensor 13 and adapts accordingly. This is conveniently achieved by providing each sensor with a suitable electronic indicator.

Suitable gas sensors are well known in the art. In particular, suitable electrochemical gas sensors are available that respond specifically to ppb levels of nitric oxide.

The gas sensor 13 is provided with a battery back-up to keep the sensor biased as necessary, even when the device is switched off.

With electrochemical gas sensors it is generally not necessary to heat the diffusion cavity, the breath sample or the sensor, as they are temperature stable. The apparatus comprises a user interface. Suitably the user interface comprises a display, and input means to allow a user to operate the device. A touch sensitive LCD display is a desirable system which combines both input and display functions. The display, amongst other functions, indicates the amount of gas of interest in a sample.

The breath test apparatus as set out above will generally provide enough resistance to exhalation to close the patient's nasal vellum during use. If additional resistance is required a constriction of the conduit 3 or other parts of the sampling device through which exhaled air passes may be provided.

In use a sampling device 30 is connected to the selectively permeable means 40, and the sensor device 50 to form the complete breath test apparatus. The sensor device 50 is then switched on and the gas sensor 13 allowed sufficient time to become fully functional - this may be around 1 minute with current gas sensors.

Before the sample is taken air is drawn through the scrubber 19, in the inlet 17, by the pump 35. This air is scrubbed of NO (or other gas of interest) by the scrubber so it can serve as a zero calibration value. The air passed through the selectively permeable means (no change in relative humidity is expected to occur as the flow of air will be at ambient humidity) and then into the sensor device. Here the sensor is calibrated to a zero value.

When a patient exhales the air passes through the infection control means 23 and through the conduit 3. In addition the exhaled breath passes through a sample drying means to reduce the relative humidity of the exhaled air to substantially zero. The sample drying means is provided by a moisture filter 29. When a desired point is reached in the exhalation and conditions are correct (e.g. flow rate) the solenoid valve moves to the first position, and a portion of the sample is drawn by the pump 35 into and through the selectively permeable means 40, which balances the humidity level with the ambient level, prior to passing the sample into the sensor device 50. The sample then comes into contact with the gas sensor 13 and diffuses into it. The gas sensor 13 detects the level of the gas of interest in the sample (e.g. NO) and an output is produced in the display.

Allowing the relative humidity of the sample to balance with the ambient relative humidity allows the accuracy of the sensor 13 to be improved by mitigating or reducing the transient response of the sensor 13 to a change in relative humidity when the sample arrives at the sensor.

The output from the gas sensor 13 will increase in direct proportion to the concentration of gas, e.g. NO in the sensor cavity. This output is amplified and fed to a microcontroller on a PCB, where it is first digitised before being processed by embedded software. Mathematical algorithms within the software create a 3-second running average of the rising sensor output, compensating for temperature effects by virtue of monitoring said parameter within the sensor device 50. When this averaged value reaches a peak and starts to subside, the software calculates the equivalent ppb concentration of this peak and displays it on the display. By this method, the value shown will represent the so-called "plateau concentration" of NO, as required by the ATS/ERS recommendations.

One particular advantage of the present invention is that the use of a selectively permeable device to balance the relative humidity of the sample to be tested with the ambient relative humidity in the sensor device facilitates an improvement in the accuracy of the sensor device. This is particularly advantageous where the sample to be tested is an exhaled breath sample with a high relative humidity level.

In addition the selectively permeable means is highly selective to water allowing the balancing of relative humidity of the sample to be tested, without loss or addition of the gas to be measured.

Furthermore, as the selectively permeable means is chemically inert, the apparatus can be re-used over a long period of time without a need to replace this component. This has cost saving advantages, as well as making the apparatus convenient for home use.

In an alternative embodiment of the invention an NO (or other gas of interest) scrubber 19 can be provided on the sensor device 50 such that, as a patient inhales, air is drawn through a vent 15 on the sensor device 50 and thereafter into the sampling device 30, via the selectively permeable means 40, through the interface means 7. This arrangement has the benefit that NO free air passing through the sensor device during inhalation can be used to "zero" the sensor.

Claims

1. A breath testing apparatus comprising a sampling device, a sensor device having a sensor and a selectively permeable means to balance the relative humidity of a sample to be tested with the ambient relative humidity of the ambient air present within the sensor device.

2. A breath testing apparatus according to claim 1 , where the selectively permeable means comprises a micro-porous material, a hygroscopic copolymer material or an ionomer.

3. A breath testing apparatus according to claim 2, where the selectively means comprises an ionomer comprising tetrafluoroethylene and a perfluorosulfonic acid.

4. A breath testing apparatus according to any preceding claim, where the selectively permeable means consists of one or more tubes.

5. A breath testing apparatus according to claim 4, where the overall length of tube is between 300 mm and 700 mm.

6. A breath testing apparatus according to claim 4 or 5, where the tube is provided in a coiled or folded configuration.

7. A breath testing apparatus according to any preceding claim where either

- the sensor device and the selectively permeable means, or - the selectively permeable means and the sampling device, or - the sampling device, the selectively permeable means and the sensor device, are provided with cooperating interface means.

8. A breath testing apparatus according to any preceding claim, where the sampling device comprises a sample drying means.

9. A breath testing apparatus according to claim 8, where the sample drying means is in the form of a drier device, a moisture filtration device, a moisture absorbent means or a moisture trap.

10. A breath testing apparatus according to any preceding claim comprising a patient contact means.

11.A breath testing apparatus according to any preceding claim, where the sampling device comprises an infection control means.

12.A breath testing apparatus according to any preceding claim comprising a scrubber.

13.A breath testing apparatus according to any preceding claim comprising at least one pump.

14.A breath testing apparatus according to any preceding claim, where the sampling device comprises a flow regulator or flow indicator.

15.A breath testing apparatus according to any preceding claim, where the sensor comprises an electrochemical sensor.

16.A breath testing apparatus according to any preceding claim, where the sensor device comprises a pressure regulator.

17.A breath testing apparatus according to any preceding claim comprising one or more valve.

18. A method of analysing the breath of a patient for the presence or amount of a gas of interest, wherein the patient exhales into a breath sample test apparatus as described in any one of claims 1 to 17.

19. A method according to claim 18 comprising the steps of:

- providing the breath testing apparatus;

- causing the patient to exhale a sample to be tested; - controlling the flow of the sample into the apparatus to a suitable rate;

- balancing the humidity of the sample to be tested with the ambient relative humidity within the breath testing apparatus sensor device; and - analysing the exhaled breath for the presence or amount of a gas of interest.

20. A method according to claim 19 comprising the step of:

21. A method according to claim 19 or 20 comprising the steps of:

- directing the sample to be tested through a selectively permeable means comprising a tube, to provide a sample flow within the tube cavity, and - providing a counter flow of ambient relative humidity air within the selectively permeable means about the tube.

22. A method according to any one of claims 19 to 21 comprising the step of pumping ambient air from outside the device through the selectively permeable means and into the sampling device to calibrate the sensor of the sensor device.

23. A method according to any one of claims 19 to 22 comprising the step of pumping the exhaled breath sample to be tested through the selectively permeable means to provide the sample to be analysed by the sensor device.

24. A method according to any one of claims 19 to 23 comprising the step of controlling the pressure exerted on the sensor of the sensor device.

25. A method according to any one of claims 19 to 24 comprising the step of comparing the results of the method with an expected value.