US20220322963A1 - Diagnosis of tuberculosis and other diseases using exhaled breath - Google Patents

Diagnosis of tuberculosis and other diseases using exhaled breath Download PDF

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US20220322963A1
US20220322963A1 US17/638,800 US202017638800A US2022322963A1 US 20220322963 A1 US20220322963 A1 US 20220322963A1 US 202017638800 A US202017638800 A US 202017638800A US 2022322963 A1 US2022322963 A1 US 2022322963A1
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sample
eba
particles
component
exhaled breath
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Wayne A. Bryden
Charles J. Call
Robin Wood
Dapeng Chen
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Zeteo Tech Inc
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Zeteo Tech Inc
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • G01N30/7206—Mass spectrometers interfaced to gas chromatograph
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A61B10/0045—Devices for taking samples of body liquids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
    • A61B5/082—Evaluation by breath analysis, e.g. determination of the chemical composition of exhaled breath
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
    • A61B5/083—Measuring rate of metabolism by using breath test, e.g. measuring rate of oxygen consumption
    • A61B5/0836—Measuring rate of CO2 production
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
    • A61B5/097—Devices for facilitating collection of breath or for directing breath into or through measuring devices
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/02—Devices for withdrawing samples
    • G01N1/22—Devices for withdrawing samples in the gaseous state
    • G01N1/2202—Devices for withdrawing samples in the gaseous state involving separation of sample components during sampling
    • G01N1/2205—Devices for withdrawing samples in the gaseous state involving separation of sample components during sampling with filters
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/40—Concentrating samples
    • G01N1/4077—Concentrating samples by other techniques involving separation of suspended solids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/497—Physical analysis of biological material of gaseous biological material, e.g. breath
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A61B2010/0083—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements for taking gas samples
    • A61B2010/0087—Breath samples
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/02—Details of sensors specially adapted for in-vivo measurements
    • A61B2562/029—Humidity sensors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
    • A61B5/083—Measuring rate of metabolism by using breath test, e.g. measuring rate of oxygen consumption
    • A61B5/0833—Measuring rate of oxygen consumption
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
    • A61B5/087—Measuring breath flow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
    • A61B5/091—Measuring volume of inspired or expired gases, e.g. to determine lung capacity
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/40—Concentrating samples
    • G01N1/4077—Concentrating samples by other techniques involving separation of suspended solids
    • G01N2001/4088—Concentrating samples by other techniques involving separation of suspended solids filtration
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N2030/022—Column chromatography characterised by the kind of separation mechanism
    • G01N2030/025—Gas chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/12—Pulmonary diseases

Definitions

  • Tuberculosis has surpassed HIV/AIDS as a global killer with more than 4000 daily deaths. (Patterson, B., et al., 2018). The rate of decline in incidence remains inadequate at a reported 1.5% per annum and it is unlikely that treatment alone will significantly reduce the burden of disease.
  • Mycobacterium tuberculosis (Mtb) genotyping studies have found that recent transmission, rather than reactivation, accounts for the majority (54%) of incident TB cases.
  • the physical process of TB transmission remains poorly understood and the application of new technologies to elucidate key events in infectious aerosol production, release, and inhalation, has been slow. Empirical studies to characterize airborne infectious particles have been sparse.
  • sputum As a diagnostic sample is a limiting factor due to the challenges of collecting it from patients and to its complex composition. The viscosity of the material restricts test sensitivity, increases sample-to-sample heterogeneity, and increases costs and labor associated with testing. Moreover, sputum production (which requires coughing) is an occupational hazard for healthcare workers. Sputum has several drawbacks as a sample medium. First, only about 50% of patients can provide a good sputum sample.
  • ACF Active case finding
  • WHO Active case finding
  • ACF is “systematic identification of people with suspected active TB, using tests, examinations, or other procedures that can applied rapidly.”
  • the goal of ACF is to get those infected to treatment earlier, reducing the average period of infection, and thereby reducing the spread of the disease.
  • ACF can help to reduce or prevent significant TB transmission.
  • the two size bins of collected particles were analyzed for influenza virus using a genomics-based method, reverse transcriptase polymerase chain reaction (rt-PCR).
  • PCR technology uses biomolecular probes, combined with other biomolecules including enzymes, to amplify a specific sequence of DNA if that particular sequence is present in the sample.
  • the targeted sequences are believed to be specific to the disease being identified.
  • McDevitt et al. showed that EBA samples can be used to diagnose influenza.
  • the disclosed devices and methods have several shortcomings from a practical standpoint. First, the breath aerosol sample is collected into discrete samples that are several milliliters in volume, and thus, considerable effort is needed to concentrate the sample.
  • the diagnostic device is not coupled to or integrated with the sample collector and is not amenable for use as an ACF tool.
  • the ability to automate the RNA assays to create an autonomous diagnostic tool for TB analysis is not clear.
  • a method to determine whether sufficient volume of cough or breath aerosol was generated by a particular patient is not described. As a result, if a sample is found to be negative for influenza it may be due to a false negative resulting from inadequate sample collection. It is well known that there are large variabilities among humans with respect to the volume of aerosolized lung fluid produced during various breathing maneuvers.
  • the devices and methods are also characterized by low-cost on a per patient basis and are autonomous.
  • an exemplary autonomous system for diagnosis of respiratory diseases in an individual using exhaled breath comprising a sample collection subsystem comprising a sample extraction component configured to receive an individual's face for extracting breath aerosol (EBA) particles expelled from the individual during a predetermined number of breath maneuvers into a flow of air fed into the extraction component and a sample capture component fluidly connected to the sample extraction component by an interface tubing and configured to separate and collect the EBA particles from exhaled breath and air as a collected sample, and a sample analysis subsystem fluidly connected to the sample capture component, the sample analysis subsystem comprising a sample processing component to spot a small amount of the collected sample on a sample plate and concentrate the collected sample on the sample plate and a diagnostic device for analyzing the sample.
  • a sample collection subsystem comprising a sample extraction component configured to receive an individual's face for extracting breath aerosol (EBA) particles expelled from the individual during a predetermined number of breath maneuvers into a flow of air fed into the extraction component and a sample capture component fluidly connected to the
  • the EBA particles may comprise at least one of microbes, virus, metabolite biomarkers, lipid biomarkers, and proteomic biomarkers characteristic of the respiratory disease.
  • the flow rate of air entering the sample capture component may be between about 100 L/min and about 1000 L/min.
  • the flow rate of air entering the sample capture component may be between about 50 L/min and about 500 L/min.
  • the volume of the collected sample may be between about 100 microliter and about 1 ml.
  • the sample capture component may further comprise an air pump, and an impactor wherein the air pump provides the flow of air to carry the exhaled breath from the extraction component into the impactor and wherein the impactor separates the EBA particles from exhaled breath to produce the collected sample.
  • the impactor may comprise at least one of a cyclone, a wetted wall cyclone, one or more wetted film impactors, and an impinger.
  • the system may further comprise at least one virtual impaction stage disposed upstream of the impactor.
  • the sample extraction component may comprise at least one of a cone shaped device, a shroud, CPR rescue mask, a CPAP mask, a ventilator mask, and a medical universal mouthpiece.
  • the sample collection subsystem may further comprise a containment booth for receiving the individual and isolating the individual's exhaled breath from the ambient air wherein the extraction component is fluidly connected to the capture component through a wall of the containment booth.
  • the diagnostic device comprises may comprise at least one of PCR, rt-PCR, immuno-based assay, mass spectrometer (MS), MALDI-MS, ESI-MS, GC-MS, GC-IMS and MALDI-TOFMS.
  • the system may further comprise one or more chilling devices configured to be in thermal communication with the walls of at least one of the interface tubing and the sample capture component to chill the sample capture component.
  • the sample capture component may be chilled to a temperature greater than about 0° C. and less than about 10° C. using the one or more chilling devices.
  • the sample capture component may be chilled to a temperature greater than about 0° C. and less than about 4° C. using the one or more chilling devices.
  • the exemplary system may further comprise a sterilization component to disinfect the sample collection subsystem.
  • the sterilization component may comprise at least one of a nebulizer for spraying a disinfectant, one or more UV lights to produce UV radiation, a steam generator, an ozone generator, a peroxide vapor generator, and a combination thereof.
  • the disinfectant may comprise at least one of 60% ethanol in water, at least 60% isopropanol in water, and a peroxide solution.
  • the collected sample may be transferred to the sample processing component using at least one of a dispensing pump, gravity-induced flow, and a robotic sample transfer system.
  • the dispensing pump may be a peristaltic pump.
  • the interface tubing may be made of at least one of copper, and nickel-copper alloy 400.
  • the sample capture component may be made of at least one of copper, and nickel-copper Alloy 400.
  • the diagnostic device may comprise a MALDI-TOFMS.
  • the sample processing component may further comprise at least one of a fluid reservoir, and a fluid dispensing pump to dispense about 1 microliter of fluid on the collected sample disposed on the sample substrate.
  • the fluid may comprise at least one of a solvent, a MALDI matrix chemical, water, and an acid.
  • the individual may be at least one of a person infected with at least one of tuberculosis and a corona virus disease, and a person who is not infected.
  • the lipid biomarkers may comprise biomarkers characteristic of Mtb.
  • the sample capture element may further comprise a packed bed column disposed in fluid communication with the sample extraction component to selectively capture EBA particles.
  • the packed bed column may comprise solid particles comprising at least one of resins, cellulose, silica, agarose, and hydrated Fe 3 O 4 nanoparticles.
  • the packed bed column may comprise resin beads having C18 functional groups on the surface.
  • the EBA particles may comprise at least one of microbes, virus, metabolite biomarkers, lipid biomarkers, and proteomic biomarkers characteristic of the respiratory disease.
  • the processing step may further comprise concentrating the sample by drying the sample using suitable drying means.
  • the diagnostic device may comprise MALDI-TOFMS.
  • the collecting step using the sample capture component may comprise flowing the output from the extracting step into a packed bed column to selectively capture the EBA particles and extracting the EBA particles from the packed bed column using at least one of about 12.5% acetic acid, about 70% isopropanol, about 5% TFA, about 5% formic acid, and about 10% HCl in a sample extraction system to produce a collected sample.
  • the exemplary method may further comprise the step of digesting the collected sample to generate a peptide sample characteristic of the EBA particles.
  • the packed bed column may comprise solid particles comprising at least one of resins, cellulose, silica, agarose, and hydrated Fe 3 O 4 nanoparticles.
  • the packed bed column may comprise resin beads having C18 functional groups on the surface.
  • Disclosed is an autonomous method for diagnosing of respiratory diseases in an individual using exhaled breath comprising instructing the individual to position a sample extraction component for extracting EBA particles from exhaled breath, initiating a predetermined set of breathing maneuvers to expel EBA particles from exhaled breath into a flow of air fed into the sample extraction component, flowing the EBA particles in air into a sample capture component while chilling the walls of the sample capture component and an interface tubing that fluidly connects the sample extraction component and the sample capture component, producing a collected sample, processing the collected sample comprising the steps of treating the sample using at least one of a solvent, a MALDI matrix chemical, water, and an acid, and mixtures thereof, and analyzing the plated sample using MALDI-TOFMS.
  • the flow rate of air entering the sample capture component may be between about 100 L/min and about 1000 L/min.
  • the flow rate of air entering the sample capture component may be between about 50 L/min and about 500 L/min.
  • the volume of the collected sample may be between about 100 microliter and about 1 ml.
  • the predetermined set of breath maneuvers may comprise the following steps, performing a deep exhale to clear the individual's lungs, pausing for up to 10 s; performing an FVC inhale, performing a deep exhale, and, repeating the above sequence for up to 10 times.
  • the exemplary method may further comprise at least one of the steps of tidal breathing, coughing, normal FVC breaths, speaking, and sneezing.
  • the respiratory diseases may comprise at least one of tuberculosis, influenza, pneumonia, cancer, and a disease caused by a corona virus.
  • the number of pre-determined breath maneuvers may be determined by one or more sensors that indicate at least one of the volume of particles exhaled and the volume of breath exhaled.
  • the one or more sensors may comprise at least one of a CO 2 sensor, an oxygen sensor, a humidity sensor, an optical particle size counter, an aerodynamic particle sizer, and a nephelometer.
  • an exemplary system for diagnosis of a respiratory disease caused by aerosolized virus and bacteria particles comprising a sample capture component to collect EBA particles in a predetermined volume of air into a flow of air fed into the sample capture component as a collected sample wherein the air flow is between about 30 L/min and about 1000 L/min and a sample analysis subsystem fluidly connected to the sample capture component, the sample analysis subsystem comprising a sample processing component to spot a small amount of the collected sample on a sample plate and treat the collected sample on the sample plate, and a diagnostic device for analyzing the sample.
  • the sample processing component may comprise fluidic components to treat the sample using at least one of a solvent, a MALDI matrix chemical, water, and an acid, and mixtures thereof.
  • the system may further comprise one or more sensors configured be in fluid communication with the sample extraction component wherein the output of the one or more sensors is used to calculate the total cumulative volume of exhaled breath aerosol particles entering the sample capture component.
  • the one or more sensors may further comprise at least one of a CO 2 sensor, an oxygen sensor, a humidity sensor, an optical particle size counter, an aerodynamic particle sizer, and a nephelometer.
  • the predetermined volume of air may be determined using the output of the one or more sensors.
  • FIG. 3 Perspective view of a containment booth that may be optionally used in the EBA sample collection subsystem.
  • FIGS. 6A-C Particle size distribution variability in exhaled breath from three healthy individuals using the modified FVC breathing maneuvers.
  • FIG. 7 Carbon dioxide measurements in exhaled breath during various breathing maneuvers.
  • FIG. 8 Volume of lung fluid collected from exhaled breath during different breathing maneuvers.
  • FIG. 9 Weighted principal component analysis (PCA) of MS signals acquired from positive and negative ion modes of TB and non-TB samples.
  • PCA principal component analysis
  • aerosol generally means a suspension of particles dispersed in air or gas.
  • “Autonomous” diagnostic systems and methods mean generating a diagnostic test result “with no or minimal intervention by a medical professional.”
  • the U.S. FDA classifies medical devices based on the risks associated with the device and by evaluating the amount of regulation that provides a reasonable assurance of the device's safety and effectiveness.
  • Devices are classified into one of three regulatory classes: class I, class II, or class III. Class I includes devices with the lowest risk and Class III includes those with the greatest risk. All classes of devices as subject to General Controls. General Controls are the baseline requirements of the Food, Drug and Cosmetic (FD&C) Act that apply to all medical devices.
  • FD&C Food, Drug and Cosmetic
  • In vitro diagnostic products are those reagents, instruments, and systems intended for use in diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body.
  • the exemplary devices disclosed herein can operate and produce a high-confidence result autonomously, and consequently, has the potential to be regulated as a Class I device. In some regions of the world with high burdens of TB infection, access to medically trained personnel is very limited.
  • An autonomous diagnostic system is preferred to one that is not autonomous.
  • Booth 106 may also be a modified version of the Respiratory Aerosol Sampling Chamber (RASC) chamber described by Wood et al. (2016) and may incorporate the features and capabilities described therein.
  • RASC Respiratory Aerosol Sampling Chamber
  • RASC Respiratory Aerosol Sampling Chamber
  • Component 104 serves to extract the aerosol particles emitted though the mouth and nose of patient 105 into a stream of air that acts as a sheath fluid (normally air) supplied from air source 107 , which assists in transporting the aerosol toward the exit of component 104 , and into sample capture component 108 without depositing on the walls of component 104 .
  • Air source 107 may be an air pump or compressor.
  • Sample capture component 108 may include condensation growth tubes to grow submicron particles into micron sized particles.
  • Biomarkers may include lipids from Mtb cell walls, and these lipids may be used in disease diagnosis in addition to Mtb cells. Close to 100% of the exhaled sample is collected. There is no need to dilute the sample 115 collected with saline solution.
  • Sample 115 may be transferred to the analysis subsystem 102 using a pump 116 , which is preferably a peristaltic pump. Valve 116 may be used to either route the condensed sample 115 to the analysis subsystem 102 or to a waste receptacle, for example, during decontamination of sample collection system 101 .
  • the volume of EBA sample fluid of less than about 1 ml is preferred and targeted.
  • the exemplary disclosed system may be capable of and producing between about 100 microliter and about 200 microliter of fluid. Therefore, not all of the exemplary EBA sample capture components as identified herein are preferred for use in the disclosed exemplary sample collection subsystem 101 for an autonomous system.
  • the BioSampler and Coriolis aerosol sampler collect EBA aerosol particles into aqueous samples that are greater than 10 ml in volume. This large volume results in a very dilute sample, and a particle concentration method is needed.
  • a preferable aerosol capture component 108 would have high inlet air flow rate to entrain a large fraction of the particles in exhaled breath, even during a cough a sneeze flow rate of exhaled breath is very uneven in time.
  • McDevitt's wetted film impactor uses an injection of steam upstream of the impactor which is then condensed to provides samples that are collected into 50 ml centrifuge tubes, and then concentrated using a centrifuge.
  • Sample 115 may be placed in a cup and exposed to a source of vacuum to cause the fluid to evaporate to concentrate the sample.
  • Sample 115 may be mixed with a high volatility solvent (for example, methanol, ethanol, and acetonitrile) to accelerate the evaporative process.
  • a high volatility solvent for example, methanol, ethanol, and acetonitrile
  • Sample 115 may be subjected to a bead-based extraction.
  • Bead based extraction may be used to extract biomarkers from a dilute solution.
  • a micron sized magnetic bead may be coated with a glycan material that binds well with protein biomarkers such as EBA particles.
  • the beads may be intimately mixed with the EBA sample by an oscillating magnetic field. After a period of mixing, the beads may be pulled to one side with a constant magnetic field, and then released into a small volume of solvent to extract the EBA particles as a concentrated sample.
  • diagnostic devices may be adapted for use in analysis subsystem 102 , that include, but are not limited to devices that perform genomics-based assays (such as PCR, rt-PCR and whole genome sequencing), biomarker recognition assays (such as ELISA), and spectral analysis such a mass spectrometry (MS).
  • genomics-based assays such as PCR, rt-PCR and whole genome sequencing
  • biomarker recognition assays such as ELISA
  • MS mass spectrometry
  • MS mass spectrometry
  • MS mass spectrometry
  • MS mass spectrometry
  • MS is preferable on account of its speed of analysis.
  • the MS techniques that are preferable for biomarker identification are electrospray ionization (ESI) and matrix assisted laser desorption ionization (MALDI) MS.
  • ESI electrospray ionization
  • MALDI matrix assisted laser desorption ionization
  • ESI may be coupled to high resolution mass spectrometers such as the Oribtrap (ThermoFisher) ESI-MS devices are typically very large and heavy, and require a high level of expertise to operate, and are not suitable for autonomous operation or applications such as point of care diagnostics.
  • MALDI-MS devices may be compact, lightweight, consume less than 100 watts of power and provide sample analysis in less than 15 minutes.
  • MALDI-MS is a preferred diagnostic device for point-of-care diagnostics suitable for ACF. Including time for sample preparation, the analysis time using MS may be less than about 15 minutes.
  • matrix assisted laser desorption ionization large molecules may be analyzed intact using mass spectrometry.
  • the target particle analyte
  • a matrix chemical which preferentially absorbs light (often ultraviolet wavelengths) from a laser.
  • the biological molecules would decompose by pyrolysis when exposed to a laser beam in a mass spectrometer.
  • the matrix chemical also transfers charge to the vaporized molecules, creating ions that are then accelerated down a flight tube by the electric field.
  • Microbiology and proteomics have become major application areas for mass spectrometry; examples include the identification of bacteria, discovering chemical structures, and deriving protein functions.
  • the MALDI matrix solution is spotted on to the sample on a MALDI plate to yield a uniform homogenous layer of MALDI matrix material on the sample.
  • the solvents vaporize, leaving only the recrystallized matrix with the sample spread through the matrix crystals.
  • the acid partially degrades the cell membrane of the sample making the proteins available for ionization and analysis in an MS.
  • Other MALDI matrix materials include 3,5-dimethoxy-4-hydroxycinnamic acid (sinapinic acid), ⁇ -cyano-4-hydroxycinnamic acid ( ⁇ -cyano or ⁇ -matrix) and 2,5-dihydroxybenzoic acid (DHB) as described in U.S. Pat. No. 8,409,870.
  • sample 115 comprises condensed volatile organic compounds in exhaled breath and cooled liquid sample comprising EBA. Therefore, sample 115 may be routed to diagnostic devices 122 to analyze condensed volatile organics and to device 121 to analyze non-volatile EBA particles.
  • the liquid sample 115 may be warmed using a heater, driving of the volatile compounds into a diagnostic device 122 such as GC-MS, GC-IMS, volatile ion chromatography, or any other type of analysis method suitable for analyzing volatile organic compounds.
  • a diagnostic device 122 such as GC-MS, GC-IMS, volatile ion chromatography, or any other type of analysis method suitable for analyzing volatile organic compounds.
  • Hashoul discloses use of sensors for detecting pulmonary diseases including TB from exhaled breath.
  • Hashoul describes breath analysis of 226 symptomatic high-risk patients using GC (gas chromatography)-MS, pointing out several biomarkers of active pulmonary TB. They suggested biomarkers in oxidative stress products, such as alkanes and alkane derivatives, and volatile metabolites of Mycobacterium tuberculosis, such as cyclohexane and benzene derivatives.
  • FIG. 5 is a schematic diagram of an exemplary diagnostic method 200 using an exemplary system 100 as previously disclosed herein.
  • Exemplary method 200 may be used to perform autonomous point-of-care diagnosis based on exhaled breath.
  • the individual 105 may directed to be seated; the chair may optionally be located in containment booth 106 .
  • extraction component 104 may be removably fitted to the individual's head or a cone that is larger than the head is positioned to fit loosely around the individual's head.
  • Sample capture component 108 is activated which causes air to be drawn around the patient's head and into the sample capture device.
  • a cyclone When a cyclone is used as sample capture component 108 air flow to component 108 and chilling of the cyclone body and inlet tubing 109 are initiated.
  • Preferably filtered sheath air is supplied to component 104 .
  • Sheath air may be humidified, preferably to greater than 90% relative humidity.
  • Individual 105 is then instructed to perform one or more predetermined maneuvers 203 which may include a pre-set number of repetitions.
  • the maneuvers may include performing one or more FVC or modified FVC maneuvers for generating EBA samples from the lower respiratory tract, producing one or more cough samples for generating EBA predominately from the upper respiratory tract, and producing one or more sneeze samples that generates EBA predominately from the nasal passages/upper respiratory tract.
  • a modified FVC is an FVC preceded by a deep exhale followed by a 5 to 10 second pause. This exhale and pause cause bronchiole closure, followed by its reopening during the FVC inhalation. The closing and reopening of the small lung passages including the alveoli is believed to result in increased particle production.
  • a maneuver may include a coughing, FVC breathing, modified FVC breathing and sneezing. For diagnosis of some other diseases all maneuvers may be needed. Sneezing may be induced by injecting a small dose of pepper or other spices in aerosol form into the nasal passages.
  • sample processing step 204 sample 115 is automatically transferred from collection subsystem 101 for sample processing in analysis subsystem 102 .
  • the type of sample processing depends on the type of diagnostic device.
  • sample processing may comprise the steps of plating the sample 115 on to a MALDI-MS sample disk using a peristaltic pump, heating the disk to concentrate the sample, adding the MALDI matrix/acid/solvent (described below) and drying the disk.
  • the sample disk is then analyzed using a MALDI-MS in step 205 .
  • the spectrum obtained is compared to spectra from samples that were known positives to specific respiratory infections, and also to spectra of samples form patients know to be healthy, and a diagnosis of the patient is generated. The result may then be communicated to a clinician or to the patient.
  • the extraction component 204 is attached to the patient, and sample extraction is initiated, the exemplary method is autonomous (with the exception of asking the patient to the leave the chair) after performing the required maneuvers and generates a test result of the diagnosis.
  • FIGS. 6A-C shows the normal variability of breath aerosol from healthy individuals for 10 repetitions of the FVC breath maneuver. Even for health individuals, the variability in the amount and particle size distribution of exhaled breath aerosol is very large. The data were captured using a LASEX II (PMS, City, Colo.). A similar variability was also notice during EBA collection from cough maneuvers. Particle size distributions help to determine the total exhaled particle mass by integrating the particle size distribution over time. This aspect helps to determine if the sample collected is sufficient for analysis.
  • FIG. 7 shows the carbon dioxide measurements in exhaled breath during bronchiole film burst (BB), FCV and cough maneuvers. A strong correlation was observed by Patterson et al. between CO 2 production rate and aerosol particle production. Measured CO 2 may be also used to calculate exhaled air volume as described in Wood et al.
  • the solid particles may comprise functional groups immobilized on the surface of the particles wherein the functional groups comprise at least one of C18 (octadecyl), octyl, ethyl, cyclohexyl, phenyl, cyanopropyl, aminopropyl, 2,3-dihydroxypropoxypropyl, trimethyl-aminopropyl, carboxypropyl, benzenesulfonic acid, propylsulfonic acid, an ion exchange phase, a polymer phase, antibodies, glycans, lipids, DNA and RNA.
  • the functional groups comprise at least one of C18 (octadecyl), octyl, ethyl, cyclohexyl, phenyl, cyanopropyl, aminopropyl, 2,3-dihydroxypropoxypropyl, trimethyl-aminopropyl, carboxypropyl, benzenesulfonic acid, propyl
  • the ion exchange phase may comprise at least one of diethylaminoethyl cellulose, QAE Sephadex, Q sepharose, and carboxymethyl cellulose.
  • the polymer phase comprises at least one of polystyrene-co-1,4-divinylbenzene, methacrylates, polyvinyl alcohol, starch, and agarose.
  • the antibodies may comprise at least one of anti-human albumin, anti-Influenza A virus NP and Anti-SARS-CoV-2 virus.
  • the antibodies may be immobilized on protein A/G agarose beads.
  • the capture element may be cooled to a temperature at or below ambient temperature.
  • the exemplary systems and methods disclosed herein may comprise robotic systems and components.
  • the systems and methods may comprise a robotic sample transfer system to spot a collected sample on a sample plate and conduct further processing or sample treatment, and analysis of the treated sample.
  • EBA particles in a collected liquid sample may be aerosolized using a nebulizer and coated “on-the-fly” using a MALDI matrix to form coated aerosol EBA particles.
  • the coated particles may be analyzed using aerosol time of flight mass spectrometry (ATOFMS). “On-the-fly” means that the particles comprising the aerosol are not collected onto a surface (for example, onto the surface of a MALDI plate) or into a liquid as a step in the coating process.
  • ATOFMS aerosol time of flight mass spectrometry

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