Abstract:
A tool for telemedicine including an improved breath collection system of human breath to facilitate the analysis of volatile organic components (VOCs) contained in human breath in which breath tests can be performed at remote sites for rapid detection of different diseases. The system can include a standoff breath collection device including an arcuate structure for concentration and analysis of volatile organic components (VOCs) at the point-of-use that avoids the use of mouthpieces found in conventional breath collection apparatuses.

Description:
CROSS REFERENCE TO RELATED APPLICATION 
       [0001]    This application claims the benefit of U.S. Provisional Patent Application No. 61/607,775 filed Mar. 7, 2012, the entirety of which is hereby incorporated by reference into this application. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates a new tool for telemedicine including an improved breath collection system of human breath to facilitate the analysis of volatile organic components (VOCs) contained in human breath in which breath tests can be performed at remote sites for rapid detection of different diseases. The invention can employ a standoff technique for the collection of a breath sample that eliminates the need for a donor to breathe into a mouthpiece. 
       BACKGROUND OF THE INVENTION 
       [0003]    The early history of breath testing: In the 18 th  century, Lavoisier developed a breath test for carbon dioxide in the breath. This was the first chemical probe of metabolism, and it provided the first evidence that foodstuffs are oxidized in the body. During the 19 th  century, colorimetric breath tests detected ethanol in alcohol drinkers, and acetone in diabetics with ketoacidosis. The introduction of radio-labeled drugs in the 20 th  century led to new breath tests for digestive disorders including Helicobacter pylori infection and pancreatic insufficiency. 
         [0004]    The first microanalysis of breath volatile organic components (VOCs) was reported by Linus Pauling in 1971. He froze breath volatile organic components (VOCs) in a tube chilled in acetone and dry ice, and analyzed the concentrated sample using the then-new technology of GC. This resulted in the remarkable discovery that normal human breath contains a large number of volatile organic components (VOCs) in very low concentrations. Subsequent studies have shown that a sample of human breath contains several hundred different volatile organic components (VOCs), most of them in picomolar (10 −12  M) concentrations. 
         [0005]    Limitations of early breath testing technology: Initially, breath microanalysis could only be performed in specialized laboratories. Pauling&#39;s pioneering research employed bulky and expensive bench-top instruments for breath volatile organic components (VOCs) microanalysis. The first clinical studies of breath biomarkers of lung cancer during the 1980s required patients to donate breath samples in a laboratory. The main technical challenge is sample collection: while it is simple to inflate a plastic bag with breath, the samples are usually too contaminated to detect breath volatile organic components (VOCs) in picomolar concentrations. The main sources of error in breath sample collection: chemical contamination, resistance to expiration, water condensation, dead-space air dilution, and container adsorption artifact  3   
         [0006]    Advances in laboratory-based breath volatile organic components (VOCs) analysis: Progress in clinical applications of breath testing was slow until the development of the breath collection apparatus (BCA) that enabled breath volatile organic components (VOCs) sample collections in the field via a subject breathing into a mouth piece. Breath volatile organic components (VOCs) samples are captured onto sorbent traps that are sealed hermetically and sent to the laboratory for analysis by benchtop instruments e.g., automated thermal desorption with gas chromatography and mass spectroscopy (ATD/GC/MS). This technique is useful for biomarker discovery, but its value in clinical practice is limited by the high cost of the instrumentation, and the comparatively slow turnaround time of a laboratory-based procedure. 
         [0007]    Clinical applications of breath testing: BCA technology made it possible, for the first time, to perform large multicenter studies of breath testing. These studies have demonstrated that breath volatile organic components (VOCs) contain sensitive and specific biomarkers of different diseases. 
         [0008]    Based on the above, the breath of humans and animals contains a large number of volatile organic components (VOCs). Many of these volatile organic components (VOCs) are now recognized as biomarkers of disease, so that a breath test for volatile organic components (VOCs) offers a safe and non-invasive approach to disease detection. However, this presents several technical difficulties. The most abundant breath volatile organic components (VOCs) (e.g., acetone, isoprene, and pentane) are present in nanomolar concentrations (10 −9  mol/L) but the majority of breath volatile organic components (VOCs) are present in much lower concentrations, e.g., picomolar (10 −12  moll), or even as low as parts per trillion. These concentrations are often below the lower limits of detection of most laboratory instruments in current use. As a result, the breath sample of interest must be collected and concentrated prior to assay. In addition, there are concomitant risks of artifactual contamination of the breath sample during the collection process. Consequently, there is a need for a breath collection system that overcomes these difficulties and delivers test results rapidly, and can be employed at the point-of-care to collect, concentrate and analyze breath volatile organic components (VOCs), transmit the data expeditiously to a central site for analytical interpretation of the data and to send the results of the breath test to the point-of-care. 
       SUMMARY OF THE INVENTION 
       [0009]    The present invention relates to a telemedicine system and method for remote collection and analysis of volatile organic components (VOCs) in breath in which breath tests can be performed at a point-of-care system and analysis of collected data can be performed at a central site for rapid detection of different diseases. The central site can include processing for interpretation of analytic data from the point-of-care system to identify if a pattern of volatile organic components (VOCs) in the sample is consistent with a particular disease. Example diseases include active pulmonary tuberculosis, lung cancer, or breast cancer. A plurality of point-of-care systems can interface with the central site. Algorithm learning can be used at the central site to refine diagnostic algorithms used in interpretation of the analytic data to improve their accuracy based on accumulated data from collected breath samples at the point-of-care system in an ongoing fashion. 
         [0010]    Reports can be generated at the central site and can include an interpretation of high or low risk of a disease, such as active pulmonary tuberculosis. The reports can be transmitted to the point-of-care instrument. 
         [0011]    The central site can provide remote instrument monitoring quality assurance to ensure that the point-of-care system is performing according to design parameters. The central site can provide modification of analytical parameters used in the analysis of volatile organic components (VOCs) at the point-of-care system in order to optimize detection of specific diseases. The central site can provide customer management for the point-of-care system, such as instrument monitoring and billing services. 
         [0012]    As an application of telemedicine, data from collection of breath, concentration, desorption and analysis steps performed at the remote point-of-care system can be transmitted to the central site via the Internet or telephone. The central site can resolve breath specific features including for example instrument management issues (calibration) and information about the evolving epidemiology of diseases of interest (e.g. new strains of influenza and tuberculosis). 
         [0013]    The present invention also provides a standoff breath collection system at the point-of-care system and a method that avoids the use of mouthpieces and the disadvantages associated with breath collection apparatuses requiring mouthpieces. The standoff breath collection system of the present invention provides a donor system having the advantage to collect and analyze a sample of breath without incurring disadvantages, such as the donor need not be conscious; samples can be collected from unconscious or drowsy subjects, the donor need not be cooperative since there is no need to maintain a seal between the lips and the mouthpiece, the donor does not need to wear a nose-clip, there is no resistance to overcome during expiration, and the donor breathes normally while the sample is collected, the risk of contamination of the device with microorganisms is greatly reduced, and collection of a breath volatile organic components (VOCs) sample entails no use of disposable items. 
         [0014]    The invention will be more fully described by reference to the following drawings. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0015]      FIG. 1  is a schematic diagram of a system for remote collection and analysis of volatile organic components (VOCs) in breath. 
           [0016]      FIG. 2  is a schematic diagram of a system for remote collection and analysis of volatile organic components (VOCs) in breath including a plurality of point-of-care systems. 
           [0017]      FIG. 3  is a schematic view of a donor system used in the breath collection system of the present invention. 
           [0018]      FIG. 4  is a chromatogram of normal human breath analyzed for n-alkanes having different chain lengths using the breath collection system of present invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0019]    Reference will now be made in greater detail to a preferred embodiment of the invention, an example of which is illustrated in the accompanying drawings. Wherever possible, the same reference numerals will be used throughout the drawings and the description to refer to the same or like parts. 
         [0020]      FIG. 1  is a schematic diagram of remote collection and analysis of volatile organic components in breath system  10 . Breath collection system  10  includes point-of-care system  12  and central site system  22 . 
         [0021]    Point-of-care system  12  includes breath collector  13  to collect human breath  11  for analysis. Concentrator  14  receives collected alveolar breath  11 . Concentrator  14  can be used to concentrate volatile organic components (VOCs) of breath  11 . For example, concentrator  14  can pump a sample of breath through a sorbent trap that contains a resin, for example Tenax or activated carbon, such as Carbotrap or Carbopack. The sorbent trap can be a stainless steel tube containing the resin. Concentrator  14  can include functions for controlling thermodynamic factors such as managing the interaction of water, volatile organic components (VOCs) and condensation. Concentrator  14  can include designs that manage water, volatile organic components (VOCs) and temperature changes post expiration. In one embodiment, concentrator  14  includes heated inlet ports followed by cooled traps and controls to cool surroundings from which warm breath is extracted. 
         [0022]    A concentrated volatile organic components (VOCs) sample is thermally desorbed from concentrator  14  in desorption unit  16 . Analysis of volatile organic components unit  17  receives volatile organic components (VOCs) which have been desorbed from concentrator  14 . Analysis of volatile organic components unit  17  can employ a gas chromatograph (GC) to separate the volatile organic components (VOCs), combined with a detector, such as a surface acoustic wave detector (GC SAW) (Z-nose 4200, commercially available from Electronic Sensor Technology, Newbury Park, Calif.), a flame ionization detector (FID), or a mass spectrometer (GC MS). Volatile organic components (VOCs) can also be analyzed with other detection techniques such as infra-red spectrometry or array detection. 
         [0023]    Analysis of volatile organic components unit  17  can also employ several different kinds of array detectors, including for example chemoresistor arrays. The detectors employ the same basic mechanism: different components of the array respond differently to volatile organic components (VOCs) in the sample, so that the combination of signals from the array components generates a unique pattern according to the abundance of different volatile organic components (VOCs) in the sample. Analytical instruments used in analysis of volatile organic components unit  17  can be periodically calibrated e.g. with a calibration standard comprising mixture of analytes with known composition in known quantities, for example n-alkanes. 
         [0024]    Processor  18  receives data from analysis of volatile organic components unit  17 . Processor  18  can forward data  19  over communications network  20  to central site  22 . For example, communications network  20  can include the internet and telephone. 
         [0025]    Processor  23  at central site  22  receives data  19 . Processor  23  can include interpretation of analytic data module  24  to identify if a pattern of volatile organic components (VOCs) in the sample is consistent with a particular disease. Example diseases include active pulmonary tuberculosis, lung cancer, or breast cancer. 
         [0026]    Interpretation of analytic data module  24  can include algorithm learning to refine diagnostic algorithms used in interpretation of analytic data module  24  at central site  22  and improve their accuracy based on accumulated data from collected breath samples  11  at point-of-care system  12  in an ongoing fashion. Data  21  generated by interpretation of analytic data module  24  can be used in generate report module  25 , remote control of point-of-care module  27  and consumer management module  28 . 
         [0027]    Generate report module  25  at central site  22  can generate report  26  including data  21  from interpretation of analytic data module  24 . For example, report  26  can include an interpretation of high or low risk of active pulmonary tuberculosis. Report  26  can be transmitted to point-of-care system  12  from central site  22  over communications network  20 . 
         [0028]    Remote control of point-of-care module  27  can provide instrument monitoring quality assurance to ensure that point-of-care system  12  is performing according to design parameters based on data  21  determined at interpretation of data module  24 . Remote control of point-of-care module  27  can provide instrument calibration of instruments or apparatus used in point-of-care system  12  to quantify the abundance of volatile organic components (VOCs) in breath samples  11  analyzed at point-of-care system  12 . 
         [0029]    Remote control of point-of-care module  27  can provide modification of analytical parameters used in analysis of volatile organic components unit  17  in order to optimize detection of specific diseases. For example, central site  22  can instruct point-of-care system  12  to modify the analytical parameters, such as, for example, to alter the GC temperature ramp for improved detection of a specific disease. 
         [0030]    Customer management module  28  can employ data  21  from point-of-care system  12  to generate billing services for services performed at point-of-care system  12  and central site  22 . For example, customer management module  28  can generate invoices which are forwarded to point-of-care system  12  from central site  22  over communications network  20 . Data  21  from interpretation of analytic data module  24 , generate report module  25  and consumer management module  28  can be displayed at display  29  at central site  22  or can be forwarded to point-of-care system  12  to be displayed at display  30 . 
         [0031]    Embodiments of processor  18  and processor  23  may be implemented in connection with a special purpose or general purpose computer that include both hardware and/or software components. 
         [0032]    Embodiments may also include physical computer-readable media and/or intangible computer-readable media for carrying or having computer-executable instructions, data structures, and/or data signals stored thereon. Such physical computer-readable media and/or intangible computer-readable media can be any available media that can be accessed by a general purpose or special purpose computer. By way of example, and not limitation, such physical computer-readable media can include RAM, ROM, EEPROM, CD-ROM or other optical disk storage, magnetic disk storage or other magnetic storage devices, other semiconductor storage media, or any other physical medium which can be used to store desired data in the form of computer-executable instructions, data structures and/or data signals, and which can be accessed by a general purpose or special purpose computer. Within a general purpose or special purpose computer, intangible computer-readable media can include electromagnetic means for conveying a data signal from one part of the computer to another, such as through circuitry residing in the computer. 
         [0033]    When information is transferred or provided over a network or another communications connection (either hardwired, wireless, or a combination of hardwired or wireless) to a computer, hardwired devices for sending and receiving computer-executable instructions, data structures, and/or data signals (e.g., wires, cables, optical fibers, electronic circuitry, chemical, and the like) should properly be viewed as physical computer-readable mediums while wireless carriers or wireless mediums for sending and/or receiving computer-executable instructions, data structures, and/or data signals (e.g., radio communications, satellite communications, infrared communications, and the like) should properly be viewed as intangible computer-readable mediums. Combinations of the above should also be included within the scope of computer-readable media. 
         [0034]    Computer-executable instructions include, for example, instructions, data, and/or data signals which cause a general purpose computer, special purpose computer, or special purpose processing device to perform a certain function or group of functions. Although not required, aspects of the invention have been described herein in the general context of computer-executable instructions, such as program modules, being executed by computers, in network environments and/or non-network environments. Generally, program modules include routines, programs, objects, components, and content structures that perform particular tasks or implement particular abstract content types. Computer-executable instructions, associated content structures, and program modules represent examples of program code for executing aspects of the methods disclosed herein. 
         [0035]    Embodiments may also include computer program products for use in the systems of the present invention, the computer program product having a physical computer-readable medium having computer readable program code stored thereon, the computer readable program code comprising computer executable instructions that, when executed by a processor, cause the system to perform the methods of the present invention. 
         [0036]    Breath collector  13  and concentrator  14  can be a valved collection unit including a mouth piece. A suitable breath collector is described in U.S. Pat. No. 6,726,637. In one embodiment, features of the breath collection apparatus described in U.S. Pat. Nos. 5,465,728 and 6,725,637 hereby both incorporated by reference into this application can be used for collection, concentration, desorption and analytics of volatile organic components (VOCs). 
         [0037]    A plurality of point-of-care systems  12  can interface to central site  12 , as shown in  FIG. 2 . Each of point-of-care systems  12  can provide telemedicine for patients at the respective point-of-care systems  12 . 
         [0038]    Alternatively, point-of-care system  12  includes dome system  100  including the following main components: collection dome  120 , tube linking apex of dome interior to analytical system  140 , hydraulic lifter (hand operated)  110 , analytical system  130 , room air fan  160  and laptop computer element  150 . 
         [0039]    Collection dome  120  can comprise a clear acrylic hemisphere. A suitable collection dome is about 24 inches to about 48 inches in diameter, for example about 38 inches (91 cm) in diameter. 
         [0040]    Suspension frame  101  supports collection dome  120  and ancillary apparatus comprising a hydraulic patient lifter  110  (commercially available from Invacare Corporation, Elyria, Ohio). Suspension frame  101  can include wheels  102 . 
         [0041]    Fan  160  supported by fan support  161  is attached to suspension frame  101  with support  163 . Fan  160  can comprise a 10 inch (24 cm) diameter fixed room air fan (commercially available from Vornado Air Circulation Systems Inc., Andover, Kans.). 
         [0042]    Analytical system  130  can include concentrator  14 , desorber  16 , and analysis of volatile organic components unit  17  surface acoustic wave detector (GC SAW). Laptop computer element  150  can include processor  18 . Laptop computer  150  can be used for controlling the fan  160 . Laptop computer  150  can be attached to computer support  164 . Fan support  161  and computer support  164  can be attached or integral with support  163 . 
         [0043]    Tubing  140  can link a sampling point at apex  122  of dome  120  to the intake of concentrator  14  on analysis of volatile organic components unit  17 , such as GC/SAW housed in analytical system  130 . Tubing  140  can be comprised of a non-reactive and chemically clean tubing Tygon®. 
         [0044]    Computer  150  is employed to control sample collection by activation of fan  160 , and to control collection, concentration and analysis of the breath volatile organic components (VOCs) sample in analytical system  130 . Computer  150  can also be employed as a remote collection and analysis of volatile organic components (VOCs) in breath to upload chromatographic data and instrument data to a central site  22  via the internet, and to download interpretations of the data to the user and the patient. 
         [0045]    An ultraviolet disinfection lamp  125  can be incorporated into dome  120  to sterilize interior surface  126  of dome  120  after use. This precaution need only be employed in a high-burden country where pulmonary tuberculosis and other infectious diseases are endemic. 
         [0046]    Remote collection and analysis of volatile organic components (VOCs) in breath system  10  including dome system  100  can be operated as follows: 
         [0047]    1. Positioning of the dome: Dome system  100  is wheeled to the point-of-use so that collection dome  120  is positioned centrally over the breath donor&#39;s head. The breath donor may be seated comfortably, though collection dome  120  may also be employed when the breath donor is standing, or lying recumbent. When the breath donor is standing or sitting, collection dome  120  is lowered to a point where its lower edge is parallel with the shoulders. When the breath donor is lying recumbent, the collection dome  120  is lowered to a point where its lower edge is approximately one inch (2 to 3 cm) above the chest. 
         [0048]    2. Positioning of the fan: Fan  160  is positioned to blow near vertically into collection dome  120  in order to replace its contents with room air. 
         [0049]    3. Air sample collection and analysis: 
         [0050]    (a) Time zero to 2.0 minutes: Fan  160  and analytical system  130  including concentrator  12  are both switched on. During this period, collection dome  120  is constantly flushed with room air so that all breath volatile organic components (VOCs) are expelled. The concentrator  12  collects room air from apex  122  of collection dome  120  at 35 ml/min for about 2.0 min. Fan  160  and analytical system  130  including pre-concentrator pump are both switched off at the end of the 2.0 minute period. 
         [0051]    (b) Time: 2.0 to 7.0 minutes: Desorber  16  is switched on, and a stream of pure helium is introduced into the sorbent trap of desorber  16  in order to rapidly flush the concentrated volatile organic components (VOCs) from the room air sample on to a column of the GC at analysis of volatile organic components unit  17 . The volatile organic components (VOCs) are analyzed by fast GC/SAW, as the column temperature is ramped from ambient temperature to 220° C. over a period of about 2.0 min in analysis of volatile organic components unit  17 . The GC column is then cooled to ambient temperature. 
         [0052]    During this period, breath volatile organic components (VOCs) accumulate at apex  122  of collection dome  120 . The breath donor should not engage in activities that might modify the composition of breath volatile organic components (VOCs), such as tobacco smoking, eating or drinking. However, other activities such as speaking, reading or watching television will not affect the accumulation of the breath sample at apex  122  of collection dome  120 . 
         [0053]    4. Breath sample collection and analysis: 
         [0054]    Time: 7.0 to 9.0 minutes. Concentrator  12  in analysis of volatile organic components unit  17 , such as GC/SAW, is switched on again, and the process of collection, concentration and analysis is repeated as described above. However, the sample now comprises breath from apex  122  of collection dome  120  instead of room air. At about 9.0 minutes, collection dome  120  is raised and the breath donor may leave, 
         [0055]    5. Data transmission: Chromatographic data analysis of volatile organic components unit  17  can be transmitted from the point-of-care system  12  to a central site  22  over communications network  20  via the internet or a telephone link, as shown in  FIG. 1 . 
         [0056]    6. Calibration of the chromatogram: Concentrator  12  in analysis of volatile organic components unit  17 , such as GC/SAW.GC/SAW is calibrated at the beginning of each day of usage by injecting a known quantity of a standard solution containing a mixture of volatile organic components (VOCs) in known concentrations, for example, a mixture of standard n-alkanes. The abundance of a volatile organic components (VOCs) peak observed in a chromatogram of breath or air is normalized to the standard i.e. V b /I b  where V b  denotes the area under the curve (AUC) detected by GC/SAW in breath, and I b  denotes the AUC of the chromatographic peak associated with the internal standard. 
         [0057]    7. Analysis of data: The alveolar gradient of each volatile organic components (VOCs) peak (i.e. abundance in breath minus abundance in ambient room air) can be determined as alveolar gradient=V b /I b −V a /I a  V a  and where V a  and I a  denote corresponding values derived from the associated sample of room air. The polarity of the alveolar gradient varies with the kinetics of volatile organic components (VOCs) metabolism: its value is positive when synthesis is greater than clearance, and negative when clearance is greater than synthesis. 
       Physiological Basis of the Invention 
       [0058]    Human breath is excreted at body temperature, about 36.7° C. In an air-conditioned environment, ambient room air is cooler (usually about 20-25° C.). Hence, expired breath rises upwards in an air-conditioned environment because it is displaced by the cooler denser room air. The physiological basis of dome system  100  is to capture expired breath into a container as it is displaced upwards. The container employed in this invention is collection dome  120  including an inverted hemispherical bowl constructed of clear acrylic plastic. However, containers of different sizes and shapes may fulfill the same function equally well. The captured breath is then pumped from apex  122  of dome  120  to collector  12  including a volatile organic components (VOCs) trap. 
       Analysis of the Collected Sample 
       [0059]    The volatile organic components (VOCs) trap may contain a sorbent resin (e.g. Tenax OD) or activated carbon (e.g. Carbotrap 0). The volatile organic components (VOCs) trap may be removed, in order to analyze the sample at another site, or else the sample may be thermally desorbed by desorber  14  for analysis at the point-of-care system  12 . 
         [0060]    Results in humans: The device was evaluated in normal human subjects. The analytical system comprised a pre-concentrator (a sorbent trap containing Tenax 0), a thermal desorber, and a gas chromatograph with a surface acoustic wave detector (GC/SAW). A laptop computer controlled the collection and analysis procedure. The human trial was conducted following the detailed procedure described above under “Usage of the device”. 
         [0061]    Pursuant to the human trial, a representative chromatogram of human breath volatile organic components (VOCs) was obtained and is shown in  FIG. 4 . As shown in  FIG. 4 , each peak represents a different volatile organic component (VOC) in the breath sample of the subject, and the area under curve of the peak varies with the abundance of the volatile organic components (VOCs) in the breath sample. The x-axis is the scan number. Typically, the chromatogram is generated in approximately one minute. Peaks are labeled by automated recognition software, In this case, peaks identified by letters of the alphabet represent volatile organic components (VOCs) whose retention times are similar to those previously programmed for identification (n-alkanes with different chain lengths), while the numbered peaks are all other volatile organic components (VOCs). A volatile organic components (VOCs) peak may be identified qualitatively by its retention time, and then quantified by its area under curve. 
         [0062]    It is to be understood that the above-described embodiments are illustrative of only a few of the many possible specific embodiments, which can represent applications of the principles of the invention. Numerous and varied other arrangements can be readily devised in accordance with these principles by those skilled in the art without departing from the spirit and scope of the invention.