US20040063197A1 - Automatic point source biological agent detection system - Google Patents
Automatic point source biological agent detection system Download PDFInfo
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- US20040063197A1 US20040063197A1 US10/441,100 US44110003A US2004063197A1 US 20040063197 A1 US20040063197 A1 US 20040063197A1 US 44110003 A US44110003 A US 44110003A US 2004063197 A1 US2004063197 A1 US 2004063197A1
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- biological agent
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Definitions
- This invention is directed to biohazard detection systems and more particularly to a biohazard detection system for detecting biological agents, such as bacillus anthracis, in pieces of mail.
- the current state of the art in biological agent detection systems includes: (1) automated systems used, for example, by the military that utilize a form of immunoassay technology; and (2) manual systems including bio-identifier apparatus used in laboratories by skilled laboratory technicians.
- the automated immunoassay systems used by the military have not demonstrated sufficient sensitivity or specificity to be acceptable for use in civilian applications such as mail screening within the United States Postal Service (USPS).
- USPS United States Postal Service
- manual systems that require skilled technicians to perform sample preparation and to interpret test results are impractical in an industrial environment.
- a typical automated bio-detection system in accordance with the known prior art is comprised of the following subsystems: (a) a trigger to detect the presence of a bio-agent and start the sample collection process; (b) an aerosol collector for collecting samples from the air; and, (c) an identifier to identify the specific bio-agent.
- a collected liquid sample is manually taken from an aerosol collector, prepared, and introduced manually into a bio-agent identifier. This process is time consuming, hazardous, and can lead to erroneous results from improper sample preparation.
- the subject invention utilizes the polymerase chain reaction (PCR) technology that is particularly adapted for USPS application.
- PCR polymerase chain reaction
- the limit of detection for immunoassay based technology is in the range of 10,000 to 100,000 spores per ml of sample.
- PCR has demonstrated the ability to detect less than 200 spores per ml of sample. This difference in sensitivity is critical, and may make the difference between detecting and missing a lethal threat in the USPS application. Since PCR detects the actual DNA sequence of an agent, it is also, much less likely to cause false positives than the systems based on immunoassay techniques.
- an automatic biohazard detection system which combines automated fluidic transport apparatus with aerosol collector apparatus and biological agent identifier apparatus.
- the invention includes means for implementing the following features: particle collection and pre-separation using a collection hood and dry cyclone passive filtration system; continuous particle collection into a liquid sample; automated fluid transfer to a sample analysis cartridge at pre-scheduled times; automated cartridge handling and transfer to polymerase chain reaction (PCR) type bio-agent identifier apparatus for detecting an actual DNA sequence so as to identify a bio-agent; automatic retesting upon various error conditions; automatic confirmation testing upon preliminary positive results; automated fluid transfer to archive containers at the completion of analysis; and automated notification/reporting system to alert designated personnel/organizations upon the occurance of selected events.
- the entire biohazard system is under control of a centralized command and control computer.
- the biological agent detection system in accordance with the subject invention is not limited to, but is of particular importance to the US Postal Service (USPS) due to the fact that it would enhance the safety of its work force by quickly detecting the presence of toxic biological agents in a mail processing facility.
- USPS US Postal Service
- the system would notify facility personnel so that appropriate actions may be taken quickly to contain a threat from biological agents, such as bacillus anthracis, in mail being processed at the facility, thereby preventing dispersion of biological agents between USPS facilities and to the general public.
- optical trigger device may still be used, for example, to create a record of particle concentration spikes that occur during the mail processing window. This record will permit one to identify the contaminated machine and the approximate time the contaminated letter passed the machine after the identifier indicates that a biological agent is present.
- the subject system is compatible with the integration of a trigger that operates in parallel with the continuous collection process. In such an implementation, the trigger would be used to initiate the transfer of the sample for analysis, resulting in a more timely response to an incident.
- FIGS. 1A and 1B are block diagrams illustrative of two versions of a fully automatic bio-detection system control architecture of a United States Postal Service (USPS) site in accordance with the subject invention
- FIG. 2 is a block diagram illustrative of the apparatus located at a USPS site in accordance with the subject invention
- FIG. 3 is a system block diagram further illustrative of the apparatus shown in FIG. 2;
- FIGS. 4 A- 4 D are illustrative of the location and mechanical details of two types of aerosol sampling systems located at a mail processing facility;
- FIG. 5 is a front planar view of an illustrative embodiment of the subject invention including an aerosol particle concentrator, automatic fluidic sample preparation system, a cartridge storage and handling system, and PCR identifier apparatus in accordance with a preferred embodiment of the invention;
- FIGS. 6A, 6B and 6 C are perspective views respectively illustrative of top and exploded views of a sample cartridge utilized in connection with PCR identifier apparatus shown in FIG. 5;
- FIG. 7 is a diagram illustrative of the operation performed in the sample cartridge shown in FIGS. 6 A- 6 C.
- FIG. 8 is a diagram illustrative of a flow chart of the operation of the bio-detection system in accordance with the subject invention.
- a biohazard detection system (BDS) 10 for a mail processing facility such as, but not limited to a United States Postal Service (USPS) site, can monitor a single unit of mail processing equipment (MPE), or two or more MPEs depending upon the configuration of the mail processing system to be monitored. In the case of two or more bio-detection systems, different system configurations are possible.
- MPE mail processing equipment
- the BDS 10 includes a plurality of monitoring units 12 1 . . . 12 n , (FIG. 1A) and 12 1 . . . 12 4 (FIG. 1B) whereas FIG. 2 is illustrative of a single monitor unit 12 .
- one or a plurality of the monitoring units 12 is under the control of a central site command and control unit 14 which connects to an external visibility and incident response network 16 .
- a single site controller 15 is disclosed
- FIG. 1B discloses a primary controller 151 as well as a backup controller 152 .
- each monitor unit 12 1 . . . 12 n is coupled to the site command and control unit 14 via a hardwired network connection 18 .
- a hardwired link 18 and an RF link 19 are utilized.
- LAN (primary) and modem (backup) communications implementation are provided.
- Each of the monitor units 12 1 . . . 12 n includes three major sub-systems under the control of a respective machine control processor 20 , namely: an aerosol collector/concentrator and fluidics transfer sub-system 22 , a cartridge handling sub-system 24 , and a bio-identifier sub-system 26 , to be described in greater detail hereinafter.
- a particle counter 28 can also be added when desired.
- the various sub-systems 22 , 24 and 26 are located on a common chassis including a cabinet shown by reference numeral 30 .
- each monitor unit 12 of the subject BDS 10 includes a sampling hood 32 for sampling the air around one or more specific points, in this instance a pinch point location 34 located in the mail transport path 36 of high speed automated mail processing equipment (MPE).
- FIG. 4A shows the transport path 36 of a facer/canceller system used for canceling letters.
- Typical mail processing equipment such as the facer/canceller transports mail items vertically by pinching the letter between two belts 11 and 13 as shown in FIG. 4C.
- the mail processing equipment switches from a loosely held, non-singulated flow of mail pieces to a singulated flow when a singulator 15 pinches an individual mail piece and pulls it away from the non-singulated items.
- the location of the sampling hood 32 at the pinch point location 34 is based upon testing that demonstrates that particles contained in mail pieces are expelled when the mail piece is pinched by the singulator 15 .
- the sampling hood 32 is configured to capture virtually all of the particles expelled from the envelope at this critical location.
- the sampling hood 32 includes a pair of side channels 17 1 and 17 2 fixed on either side of the mail path 31 .
- the side channels 17 1 and 17 2 have cut-outs 19 1 and 19 2 to allow the mail transport belts 11 and 13 to pass through while still capturing the majority of the particles expelled from the mail piece.
- a pair of gaskets 21 1 and 21 2 are located at the top of the side channels 17 1 and 17 2 to interface with a hinged hood 32 .
- the hinged hood 32 when in the lowered position, is the final element of a tunnel consisting of the baseplate 23 of the mail processing equipment, the two side channels 17 1 and 17 2 and the hinged hood 32 .
- the hinged hood has been shaped to guide the particles to the entry point of the sampling hose 37 located at the downstream end of the tunnel.
- the tunnel has been sized so that the sampling volume of the aerosol concentrator (nominally 450 liters per minute) creates sufficient face velocity of the air in the tunnel so that particles in the inhalable threat region (up to 10 microns) will not settle out inside the tunnel, but remain aerosolized.
- the motion of the letters through the tunnel creates airflow through the tunnel and mixes the air so that the particles do not settle out within the tunnel and are available for sampling at the entry point to the sampling hose 37 leading to the aerosol concentrator 22 .
- the hood 32 is hinged to allow it to be lifted out of the way to clear mail jams that sometimes occur at the singulator.
- Alternate sampling systems have also been designed for other pieces of mail processing equipment.
- a manifold system 35 has been designed for a flat canceller as shown in FIG. 4D.
- This manifold system creates a downward airflow in the stacker area 37 of the flats canceller. After the flats are cancelled, they are stacked or placed back into an organized group so that they can be placed into a container and transported to downstream processing.
- a rotating arm 39 pushes against the flats to keep space available for the next flat coming from the canceller.
- the rotating arm 39 repeatedly impacts the flats sitting in the stacker, which has been shown to cause particles in the flat mail piece to be expelled.
- the particles are sent via a hose 37 through a dry cyclone 38 , which is preferably located in the BDS cabinet 30 , as shown in FIG. 4B, that utilizes the particle aerodynamic size to separate out larger particles, from those that are in the inhalable size range, and therefore pose the highest threat to human health.
- This cleans up the aerosol sample, and prevents large dust and fibrous particles from clogging the downstream equipment and interfering with the bio-detection process.
- the large particles are captured in a container 40 and disposed of. No filter media that can become clogged with dust is utilized.
- the container 40 is also preferably located in the cabinet 30 .
- the air from the pinch point 34 can, when desired, be continuously monitored by an optional particle counter 28 , as shown in FIG. 3, which determines the number of particles per second in a number of size ranges passing by the air sample point.
- the particle counter 28 provides a historical record of particle count that may assist one in identifying the contaminated mail sorting machine and the approximate time a contaminated letter passed through the machine in the event the monitor unit described below detects a biological agent. If the particle counter 28 detects a spike in particles with characteristics that match the target of interest, such as bacillus anthracis, the system can use this event to automatically trigger a sample analysis process to be described hereinafter.
- Particle characteristics evaluated can include count, size, shape, and fluorescence signature, among others. It is also possible to use a mass spectrometer, not shown, as a trigger.
- a BDS system in accordance with the subject invention normally operates without a particle counter 28 ; however, when utilized it can perform bio-agent analyses periodically based upon the operational schedule formulated in the USPS facility.
- Each of the monitor units 12 1 . . . 12 n includes an aerosol collector/concentrator 22 , an automated sample cartridge handling system 24 , and a bio-identifier 26 as shown in FIG. 5.
- an aerosol particle collector/concentrator assembly 22 preferably a SpinCon® system, constantly draws an air sample from the sampling hood 32 and impinges the sample into approximately 10 ml of liquid located in a glass collector, not shown.
- the solution is pumped out of the collector to a reservoir where it is optionally mixed with a buffer liquid by one or more buffer pumps 44 .
- a fraction, nominally 2 ml, of the mixed sample is pumped into one of the cartridges 46 at a fill station 48 after being transported thereto by a two-axis end effector (gripper/manipulator) 50 which forms part of the cartridge handling system 24 . Additional buffer and treatment solutions may also be added, when desired, to the cartridge at the fill station 48 .
- the end effector 50 then automatically inserts the cartridge 46 into the biological identifier apparatus 26 , preferably a GeneXpertTM system instrument 47 that implements a polymerase chain reaction (PCR) analysis capable of determining with a high degree of reliability if any particles in the liquid sample comprise a biological agent.
- the instrument 47 automatically processes the sample and performs a PCR analysis to determine if one or more biological agents are present. If the test result is either positive for the agent(s) under test, or non-determinate, indicating that certain internal controls included in the PCR analysis did not perform correctly, an additional test is performed using an additional fraction of the original sample and a new cartridge.
- the remaining sample is transferred from the reservoir into a waste bottle 52 , or to archive bottles 54 for later laboratory confirmatory analysis and retention as evidence.
- the system can optionally individually archive all samples or only those that generate a positive test result.
- the bio-identifier apparatus 24 is preferably controlled by the remote central site command and control system 14 (FIG. 1) that provides interface with the USPS network 16 but can be configured for local control if desired.
- the BDS continuously collects aerosol particles from selected pinch point locations along the mail transport path 36 of the MPE as shown in FIGS. 4A and 4B. Periodically, scheduled based on the operating plan of the site, the liquid sample containing the particles will be analyzed using an automated PCR test. This initial analysis is termed a Preliminary, or Screening Test. If the test is negative for agents of interest, no action is necessary, and the facility operations will continue as usual.
- the system will automatically perform a confirmation (Reflex)-test, optionally utilizing a criteria that is independent from the Screening Test, such as a secondary gene sequence from the target organism.
- Preliminary positive and confirmation test results are reported to a Visibility/Incident Response network. The results can be used to make the most appropriate decisions regarding personnel evacuation and emergency response scenarios, and further analysis of the archived sample using an outside laboratory.
- FIG. 8 is illustrative of this sequence of events.
- the site command and control system 14 provides coordination and communication of all components in the overall biohazard detection system (BDS).
- the site command and control system 14 is designed to: (a) provide a single user interface to the entire bio-detection system; (b) allow the user to quickly determine the status of all components associated with the system; and (c) accept input to change parameters which allow for the configuration changes including options like frequency of testing the collected sample, number of reports to print, passwords and access levels, thresholds levels which display warnings for faults and other system status.
- the site command and control system 14 provides an alarm when a positive reading has been obtained from the bio-identifier instrument 47 .
- the system 14 includes a control computer, not shown, that provides an interface to the operators and supervisors about the status of the overall system. This computer is furthermore networked to all sensor devices (like particle counters) and to each monitor unit. 12 .
- the system 14 provides the higher level data collection of statistics of each component that is necessary for reports and on screen visibility.
- the system 14 also provides data about the test results from the bio-identifier and relates particle counter data with each PCR test occurrence and trends particle counter results over specified periods of time.
- Each monitor unit 12 contains a machine control processor 20 that sends and receives commands to and from the control computer of site command and control system 14 .
- the control processor 20 performs machine control functions which: (a) controls the fluid interface between the collector/concentrator sub-system 22 and the bio-identifier sub-system 26 ; and (b) responds to any faults or alarms from the collector/concentrator 22 and the bio-identifier subsystem 26 .
- Machine control functionality provided by the processor 20 has been separated from the site command and control computer 14 because the machine control processor 20 handles time critical commands that affect the operation of the system components in the monitor unit 12 and which includes the aerosol collector/concentrator sub-system 22 , the cartridge handling sub-system 24 , and the bio-identifier sub-system 26 .
- the preferred embodiment of this equipment comprises a proprietary SpinCon® system developed by Midwest Research Instititute (MRI).
- MRI Midwest Research Instititute
- the SpinCon® apparatus 22 is an efficient device proven to be well suited for a broad range of advanced air sampling requirements, including the collection of bio-aerosols, particulate matter, and soluble vapors.
- the primary sample collection component of the SpinCon® system 22 consists of a vertical glass tube, not shown, open on the top end, with a nearly tangential, vertical slit cut into the side and is called the contactor. Fluid is placed in the contactor and air is drawn through the slit and out through the open top end of the contactor.
- the slit acts like a venturi/air blast atomizer; as the air passes through the slit, it speeds up and then impacts the spinning fluid in the contactor forming a wet cyclone.
- the collection fluid then atomizes into many small droplets, greatly increasing the surface area in contact with the air. These droplets then begin to follow the air path.
- the slit is only nearly tangential so the air path is across a chord of the contactor's circular cross-section. At this time, particles in the air are picked up by the fluid. As the air and droplets reach the other side of the contactor, the droplets impinge on the wall and the fluid flow is reformed.
- the same fluid is re-atomized over and over, thus causing the concentration of particles in the fluid to increase linearly with time.
- the spinning fluid in the contactor only covers 30 to 40 percent of the slit, which is why only 30 to 40 percent of the air is sampled that is pulled into the unit.
- the SpinCon® system 22 is very effective in collecting biologicals (sizes 1-10 microns) as well as many types of smaller particles and even chemicals (agglomerated sizes ⁇ 1 micron.) This is due to the atomized state of the fluid at the point of collection; the massive surface area collects the larger particles, while Brownian motion, which governs the motion of small particles, enables the smaller particles to be picked up in the fluid.
- the cartridge handling sub-system 24 as shown in FIG. 5 mechanically links the apparatus of the collector/concentrator subsystem 22 with the PCR test instrument 47 of the bio-identifier subsystem 26 .
- the cartridge handling sub-system 24 also includes a track 54 which is located over a cartridge storage rack 56 which holds a predetermined number of liquid sample cartridges 46 so as to provide up to 10 hours or unattended operation.
- the processor 20 (FIG. 3) includes a controller that executes the cartridge handling process and interfaces with the rest of the subject BDS to coordinate the sample transfer and identification processes.
- the two-axis end effector/manipulator 50 shown in FIG. 5 comprises a mechanical assembly which is a simple, inexpensive design that has a form-factor that favors the footprint of the bio-detection apparatus 26 (long X short Y). It shares the same cabinet 30 as the collector/concentrator 22 and bio-identifier 26 , resulting in a compact, integrated detection system.
- Cartridge Handling System 24 Additional features include: (a) stepping motor operates with position feedback; (b) it simultaneously presents liquid sample cartridges 46 , one at a time, to three hypodermic needles, two of which, 60 and 62 , are shown in FIG. 5, for sample and wash buffer fill, with no additional axes of motion; (c) no direct operator interface; and (d) controller interface to higher level control; and (e) insert/extract mechanism 64 , to the bio-identifier instrument 47 .
- PCR polymerase chain reaction
- PCR technology has been selected for the subject invention because of its superior sensitivity and specificity.
- the limit of detection for immunoassay based technology is in the range of 10,000 to 100,000 spores per ml of sample.
- PCR has demonstrated the ability to detect less than 200 spores per ml of sample.
- This difference in sensitivity is critical, and can make the difference between detecting and missing a lethal threat, for example, in a USPS application. Since PCR detects the actual DNA sequence of an agent, it is also much less likely to cause a false positive than the systems based on immunoassay techniques. Also, sequences associated with the actual virulence properties of the organism can be targeted. This will also be critical for a USPS application, since a false positive may result in a major financial loss if it causes an unnecessary shutdown of a mail processing facility.
- PCR techniques have become recognized as one of the most reliable laboratory techniques, along with culture methods, to validate immunoassay and other field screening techniques. In recent years the development of real time PCR techniques have allowed the reaction to be performed in 30 minutes or less. This enables the use of PCR in field applications where rapid results are required.
- all current PCR methods require sample preparation to remove inhibitors (such as the humic acids from soil) from the sample that may result in a false negative and add reagents necessary to run PCR. This sample processing requires significant laboratory operations that USPS personnel could not reliably perform in the current mail processing facilities. For this reason, most PCR systems, cannot be used in the USPS application or similar industrial environments.
- the subject invention uses a PCR bio-identifier system that completely automates both sample processing and detection processing and comprises a GeneXpertTM system developed by Cepheid of Sunnyvale, Calif.
- This system consists of two components, a disposable multi-chamber cartridge such as shown in FIGS. 6 A- 6 C by reference numeral 46 and a PCR analysis instrument 47 .
- the aerosol collector 22 described previously automatically loads a liquid sample into a GeneXpertTM cartridge 46 which is then transported to the GeneXpertTM instrument 47 by the manipulator assembly 50 .
- the GeneXpertTM instrument 47 then automatically performs the entire sample preparation, PCR amplification, and results analysis with no additional intervention by the user.
- the fluid sample and liquid reagents are automatically transported from one chamber 60 (FIG. 6B) to another within the disposable cartridge as shown in FIG. 7. Fluids are mixed, molecules and organisms are separated, purification is accomplished, filtering is performed, lysing is completed, all automatically with no operator intervention.
- the GeneXpertTM system automates all fluidic processing steps.
- (c) inhibitor removal Many types of common biological samples, including common dirt, contain extraneous chemicals that impede the PCR detection reaction. The presence of these inhibiting chemicals can cause PCR reaction to fail, thereby resulting in a false negative.
- the GeneXpertTM instrument 47 captures the spores, then actually washes them with a PCR-compatible buffer solution to remove any potential inhibiting chemicals prior to performing the PCR reaction itself. Systems which do not remove inhibitory chemicals can easily report a false negative;
- pathogens can be present in raw samples or can be released into the air at extremely low concentrations, yet still remain infectious.
- the GeneXpertTM instrument 47 actually extracts and concentrates the spores from a relatively large original sample volume (up to several mL) into a small PCR reaction tube of the cartridge 46 .
- Other PCR instruments simply take a small portion of the available liquid sample and perform PCR on this small portion.
- the system routinely achieves a sensitivity at least 10 times better than competitive products which do not concentrate the sample;
- the GeneXpertTM instrument 47 has a versatile multiplexing capability in that multiple DNA targets can be detected simultaneously in the same PCR reaction tube 60 of a cartridge. Multiplexing capability is a critical feature for DNA analysis and pathogen detection. For example, with the GeneXpertTM system, a single test or analysis for up to four agents can be performed within a single disposable cartridge 46 . Alternatively, a completely confirmatory test for an agent such as bacillus anthracis can be performed within a single cartridge 46 . This assay would include three probes for the three different DNA segments and one probe for an internal control.
- probe check An internal control scheme that eliminates the need for these external controls is achieved by a unique combination of an internal control and probe integrity check called probe check.
- the internal control consists of a piece of DNA whose sequence is different than the target DNA and a corresponding probe that is included in the PCR bead.
- the internal control is co-amplified along with the test reaction and is used to assure that the reagent is functional and that PCR inhibitors have been successfully removed during sample preparation.
- the biological agent detection system (BDS) in accordance with the subject invention is deployed on mail processing equipment (MPE).
- MPE mail processing equipment
- the operation of the subject bio-detection system is controlled by the machine control processor 20 , and its operation is synchronized with the operation of the monitored MPE so that it is only allowed to operate when the BDS collector/concentrator is operational.
- the flow chart shown in FIG. 8 illustrates the operational sequence.
- the BDS Prior to collecting samples, the BDS must be initialized and prepared for data collection.
- the collection parameters include the setup for each run in sequential order for the tour.
- the run setup will indicate the machine ID sample number, start time, stop time, and the assay description.
- the assay description is associated with a command sequence used by the GeneXpertTM to perform the PCR analysis.
- the command sequences are stored locally in the machine control processor 20 (FIG. 3).
- the supervisory console 14 (FIGS. 1A and 1B) will have the capability to download a new assay description and associated command sequence to the machine control processor; and, (3) powers up the BDS cabinets.
- the system will automatically perform a communications and systems status check; rinse and prime the fluid lines; and indicate whether fluid levels are low.
- the BDS initiates the air collection process. This enables the collector/concentrator sub-system 22 to start operation.
- An indicator not shown, on the cabinet 30 (FIG. 5) provides an indication that the system is active.
- Air is then sampled from one or more areas 34 of the MPE as shown in FIGS. 4A and 4B.
- the sampling area(s) have been empirically determined based on tests that located areas where high volumes of particles come out of the mail pieces as they are processed.
- the output of the air collection hood 32 is routed via tube 37 which is a grounded anti-static tube to the dry cyclone pre-separator 38 that is designed to eliminate particles that are larger than the inhalation threat range of 1-10 microns.
- the sampled aerosol is routed via 40 to the SpinCon® collector/concentrator apparatus 22 (as shown in FIG. 5). As noted above, the apparatus 22 impinges the air into a small volume of liquid.
- the aerosol collector operates at a flow about 450 lpm. As air passes through the unit, cyclonic mixing transfers a high portion of the target particles into the liquid. The liquid medium remains in the collector/concentrator 22 to continuously concentrate the target particles into the liquid.
- 10 ml of sterile water is injected into the system. During the collection, the water level is monitored, and evaporated water is replaced by injecting makeup water to maintain to 10 ml sample volume.
- the machine control processor 20 sends a signal to the collector/concentrator 22 to transfer a sample out for analysis.
- the aerosol collection process and facer/canceller operation are paused while the sample is transferred into the collection reservoir 43 (FIG. 5), and the collector/concentrator 22 is then refilled to start the next collection window.
- liquid sample As the liquid sample is transferred into the reservoir 43 , it is mixed with a solution containing additives that minimize PCR inhibition. The liquid sample is then allowed to sit in the reservoir for a time, e.g., approximately two minutes, to allow thorough mixing of the additive solution, and allow any large particles to settle to the bottom of the reservoir bottle(s) 42 .
- the gripper mechanism 52 of the end effector 50 of the cartridge handling system 24 as shown in FIG. 5 retrieves a PCR cartridge 46 from the storage rack 56 , and places it in position at the “liquid fill” station 48 in the BDS cabinet as shown in FIG. 5.
- the three needles at the liquid fill station 48 two of which are shown by reference numerals 60 and 62 , pierce a seal on the top of the cartridge 46 , and allows the sample and wash buffer solutions to be added to the appropriate cartridge chambers.
- the liquid transfers are performed utilizing peristaltic pumps 44 . Once the sample transfer is complete, the cartridge 46 is placed into the GeneXpertTM instrument 47 , and the sample analysis process is started.
- PCR thermal cycling analysis begins.
- the primary PCR test is called a Screening Test. This test targets one or more gene sequences for each of the organisms of interest.
- the Screening Test also includes an internal control signal that provides a built-in positive control that the PCR reaction has proceeded properly.
- the fluorescence signals in the cartridge reaction chamber are monitored and analyzed on each thermal cycle using an algorithm that analyzes the shape of the PCR growth curve, including features such as its cycle threshold and endpoint to deteermine whether the PCR result indicates the presence of the target organism.
- test results of the Screening Test are negative (N).
- the test results are sent to the site command and control system 14 (FIG. 1) where the results are logged.
- the test cartridge 46 is removed from the GeneXpertTM instrument 47 and placed back into its position on the cartridge storage rack 56 .
- the remaining liquid sample in the reservoir bottle(s) 42 is transferred to an archive bottle 54 (or optionally to a waste bottle 52 if the “archive all” parameter is turned OFF).
- the SpinCon® reservoir 43 is then available for the next sample.
- test results are also sent to the site command and control system 14 , where notifications are sent out again, according to a prescribed notification and response scenario.
- the system has the capability of utilizing an alternate assay for the repeat test based on the nature of the error on the original screening test. If, based on the background fluorescence, it appears as if there was a bead rehydration or other processing problem, a portion of the archived sample will be utilized to repeat the same assay in a new cartridge 46 . If the error appears to be an inhibited sample, a portion of the archived sample will be utilized to perform a slightly modified assay. This assay will: (1) perform additional washes; (2) utilize a higher level of dilution; and (3) adjust the positive detection thresholds based on the modified dilution.
- N negative
- the GeneXpertTM test results are sent to the site command and control system 14 , where the results are logged and test result notifications are sent out.
- the original screening cartridge, the reflex cartridge, and the archive tube can optionally be manually retrieved from the system and saved in refrigerated storage for further analysis to determine the cause of the preliminary positive.
- Reflex Process Error/Inhibition For a Reflex Process Error/Inhibition result, no local alarms or emergency response actions are initiated, the test results are sent to the site command and control system 14 , where the results are logged and notifications are sent out according to a prescribed notification and response scenario. Another reflex test can be performed, as long as sufficient sample is available.
Abstract
This invention is directed to a method and apparatus using polymerase chain reaction (PCR) technology for automatically collecting air samples and identifying biological agents in the air sample. A fully automated system is provided that is capable of detecting transient events such as bacillus anthracis in a piece of mail being processed on high-speed mail processing equipment. The system includes apparatus for implementing the following features: particle collection and pre-separation using a collection hood and dry cyclone passive filtration system; continuous particle collection into a liquid sample; automated fluid transfer to a PCR analysis cartridge at pre-scheduled times; automated cartridge handling and transfer to PCR bio-agent identification apparatus for detecting a bio-agent in a piece of mail; automatic retesting of the liquid sample upon various error conditions; automatic confirmation testing upon preliminary positive results; automated fluid transfer to archive containers at the completion of analysis; and, automated notification/reporting system to alert designated personnel/organizations upon the occurance of selected events such as the presence of bacillus antracis.
Description
- This is a Non-Provisional application which claims priority of the filing date of related Provisional Application Serial No. 60/381,351, filed on May 20, 2002, and which is incorporated herein in its entirety by reference for any and all purposes.
- This invention is directed to biohazard detection systems and more particularly to a biohazard detection system for detecting biological agents, such as bacillus anthracis, in pieces of mail.
- The current state of the art in biological agent detection systems includes: (1) automated systems used, for example, by the military that utilize a form of immunoassay technology; and (2) manual systems including bio-identifier apparatus used in laboratories by skilled laboratory technicians. The automated immunoassay systems used by the military have not demonstrated sufficient sensitivity or specificity to be acceptable for use in civilian applications such as mail screening within the United States Postal Service (USPS). Likewise, manual systems that require skilled technicians to perform sample preparation and to interpret test results are impractical in an industrial environment.
- A typical automated bio-detection system in accordance with the known prior art is comprised of the following subsystems: (a) a trigger to detect the presence of a bio-agent and start the sample collection process; (b) an aerosol collector for collecting samples from the air; and, (c) an identifier to identify the specific bio-agent.
- In a manual detection system, a collected liquid sample is manually taken from an aerosol collector, prepared, and introduced manually into a bio-agent identifier. This process is time consuming, hazardous, and can lead to erroneous results from improper sample preparation.
- In the USPS environment, various bio-detection systems have been tested in connection with Mail Processing Equipment (MPE) but have been found to be unreliable in distinguishing between letters spiked with bacterial spores from uncontaminated letters or letters containing hoax powders.
- Accordingly, it is the primary object of the subject invention to detect an aerosolized biological agent in an aerosol sample.
- It is a further object of the subject invention to detect an aerosolized biological agent originating from a piece of mail.
- It is another object of the subject invention to provide a biological agent detection system which achieves higher sensitivity and lower false positives (false alarm) rates than current technology.
- The subject invention utilizes the polymerase chain reaction (PCR) technology that is particularly adapted for USPS application. The limit of detection for immunoassay based technology is in the range of 10,000 to 100,000 spores per ml of sample. PCR has demonstrated the ability to detect less than 200 spores per ml of sample. This difference in sensitivity is critical, and may make the difference between detecting and missing a lethal threat in the USPS application. Since PCR detects the actual DNA sequence of an agent, it is also, much less likely to cause false positives than the systems based on immunoassay techniques.
- This is achieved by an automatic biohazard detection system (BDS) which combines automated fluidic transport apparatus with aerosol collector apparatus and biological agent identifier apparatus. The invention includes means for implementing the following features: particle collection and pre-separation using a collection hood and dry cyclone passive filtration system; continuous particle collection into a liquid sample; automated fluid transfer to a sample analysis cartridge at pre-scheduled times; automated cartridge handling and transfer to polymerase chain reaction (PCR) type bio-agent identifier apparatus for detecting an actual DNA sequence so as to identify a bio-agent; automatic retesting upon various error conditions; automatic confirmation testing upon preliminary positive results; automated fluid transfer to archive containers at the completion of analysis; and automated notification/reporting system to alert designated personnel/organizations upon the occurance of selected events. The entire biohazard system is under control of a centralized command and control computer.
- The biological agent detection system in accordance with the subject invention is not limited to, but is of particular importance to the US Postal Service (USPS) due to the fact that it would enhance the safety of its work force by quickly detecting the presence of toxic biological agents in a mail processing facility. The system would notify facility personnel so that appropriate actions may be taken quickly to contain a threat from biological agents, such as bacillus anthracis, in mail being processed at the facility, thereby preventing dispersion of biological agents between USPS facilities and to the general public.
- The subject approach makes the system operation independent of an optical trigger input. When desirable, however, an optical trigger device may still be used, for example, to create a record of particle concentration spikes that occur during the mail processing window. This record will permit one to identify the contaminated machine and the approximate time the contaminated letter passed the machine after the identifier indicates that a biological agent is present. In the future, if optical trigger reliability improves, the subject system is compatible with the integration of a trigger that operates in parallel with the continuous collection process. In such an implementation, the trigger would be used to initiate the transfer of the sample for analysis, resulting in a more timely response to an incident.
- Further scope of applicability of the present invention will become apparent from the detailed description provided hereinafter. It should be understood, however, that the detailed description and specific example, while disclosing the preferred embodiment of the invention, is provided by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art
- The present invention will become more fully understood from the detailed description provided hereinbelow and the accompanying drawings which are given by way of illustration only, and wherein:
- FIGS. 1A and 1B are block diagrams illustrative of two versions of a fully automatic bio-detection system control architecture of a United States Postal Service (USPS) site in accordance with the subject invention;
- FIG. 2 is a block diagram illustrative of the apparatus located at a USPS site in accordance with the subject invention;
- FIG. 3 is a system block diagram further illustrative of the apparatus shown in FIG. 2;
- FIGS.4A-4D are illustrative of the location and mechanical details of two types of aerosol sampling systems located at a mail processing facility;
- FIG. 5 is a front planar view of an illustrative embodiment of the subject invention including an aerosol particle concentrator, automatic fluidic sample preparation system, a cartridge storage and handling system, and PCR identifier apparatus in accordance with a preferred embodiment of the invention;
- FIGS. 6A, 6B and6C are perspective views respectively illustrative of top and exploded views of a sample cartridge utilized in connection with PCR identifier apparatus shown in FIG. 5;
- FIG. 7 is a diagram illustrative of the operation performed in the sample cartridge shown in FIGS.6A-6C; and
- FIG. 8 is a diagram illustrative of a flow chart of the operation of the bio-detection system in accordance with the subject invention.
- Referring now to the various drawing figures, where like reference numerals refer to like components throughout, a biohazard detection system (BDS)10 for a mail processing facility, such as, but not limited to a United States Postal Service (USPS) site, can monitor a single unit of mail processing equipment (MPE), or two or more MPEs depending upon the configuration of the mail processing system to be monitored. In the case of two or more bio-detection systems, different system configurations are possible.
- With respect to the block diagrams shown in FIGS. 1A and 1B, the
BDS 10 includes a plurality ofmonitoring units 12 1 . . . 12 n, (FIG. 1A) and 12 1 . . . 12 4 (FIG. 1B) whereas FIG. 2 is illustrative of asingle monitor unit 12. In either case, one or a plurality of themonitoring units 12 is under the control of a central site command andcontrol unit 14 which connects to an external visibility andincident response network 16. In FIG. 1A, asingle site controller 15 is disclosed, while FIG. 1B discloses aprimary controller 151 as well as abackup controller 152. - As shown in FIG. 1A, each
monitor unit 12 1 . . . 12 n is coupled to the site command andcontrol unit 14 via ahardwired network connection 18. In FIG. 1B, both ahardwired link 18 and anRF link 19 are utilized. Also, LAN (primary) and modem (backup) communications implementation are provided. Each of themonitor units 12 1 . . . 12 n includes three major sub-systems under the control of a respectivemachine control processor 20, namely: an aerosol collector/concentrator andfluidics transfer sub-system 22, acartridge handling sub-system 24, and abio-identifier sub-system 26, to be described in greater detail hereinafter. - A
particle counter 28, as shown in FIG. 2, can also be added when desired. Thevarious sub-systems reference numeral 30. - Referring now collectively to FIGS.3, and 4A-4D, each
monitor unit 12 of thesubject BDS 10 includes asampling hood 32 for sampling the air around one or more specific points, in this instance apinch point location 34 located in themail transport path 36 of high speed automated mail processing equipment (MPE). FIG. 4A shows thetransport path 36 of a facer/canceller system used for canceling letters. Typical mail processing equipment such as the facer/canceller transports mail items vertically by pinching the letter between twobelts pinch point location 34, the mail processing equipment switches from a loosely held, non-singulated flow of mail pieces to a singulated flow when asingulator 15 pinches an individual mail piece and pulls it away from the non-singulated items. The location of thesampling hood 32 at thepinch point location 34 is based upon testing that demonstrates that particles contained in mail pieces are expelled when the mail piece is pinched by thesingulator 15. Thesampling hood 32 is configured to capture virtually all of the particles expelled from the envelope at this critical location. Thesampling hood 32 includes a pair of side channels 17 1 and 17 2 fixed on either side of themail path 31. The side channels 17 1 and 17 2 have cut-outs mail transport belts hood 32. The hingedhood 32, when in the lowered position, is the final element of a tunnel consisting of thebaseplate 23 of the mail processing equipment, the two side channels 17 1 and 17 2 and the hingedhood 32. The hinged hood has been shaped to guide the particles to the entry point of thesampling hose 37 located at the downstream end of the tunnel. The tunnel has been sized so that the sampling volume of the aerosol concentrator (nominally 450 liters per minute) creates sufficient face velocity of the air in the tunnel so that particles in the inhalable threat region (up to 10 microns) will not settle out inside the tunnel, but remain aerosolized. In addition, the motion of the letters through the tunnel creates airflow through the tunnel and mixes the air so that the particles do not settle out within the tunnel and are available for sampling at the entry point to thesampling hose 37 leading to theaerosol concentrator 22. Thehood 32 is hinged to allow it to be lifted out of the way to clear mail jams that sometimes occur at the singulator. - Alternate sampling systems have also been designed for other pieces of mail processing equipment. In particular, a
manifold system 35 has been designed for a flat canceller as shown in FIG. 4D. This manifold system creates a downward airflow in thestacker area 37 of the flats canceller. After the flats are cancelled, they are stacked or placed back into an organized group so that they can be placed into a container and transported to downstream processing. As the flats sit in the stacker, arotating arm 39 pushes against the flats to keep space available for the next flat coming from the canceller. Therotating arm 39 repeatedly impacts the flats sitting in the stacker, which has been shown to cause particles in the flat mail piece to be expelled. These expelled particles are then drawn down through the perforations in the baseplate(s) 41, into the suction manifolds 43, and on through the remaining components of the system. Similar sampling hood or sampling manifold designs have been developed for other types of mail processing equipment. - The first time that a letter, for example, is pinched at
pinch point location 34, air is pushed out of the envelope. If there are particles inside the envelope, some will come out of the envelope at that point. Sampling is performed within thehood 32 situated atlocation 34 by capturing the particles that are emitted at the pinch point. The design of the hood and the sampling rate of the air collector are matched so that the air inside thehood 32 is sampled at a rate that will evacuate virtually all of the particles present along this portion of the transport. This has two benefits, namely: it reduces the dust that is created by the mail processing operation, thereby reducing the cleaning maintenance required, and it ensures that as many target particles as possible are captured for analysis. - After the particles are captured, they are sent via a
hose 37 through adry cyclone 38, which is preferably located in theBDS cabinet 30, as shown in FIG. 4B, that utilizes the particle aerodynamic size to separate out larger particles, from those that are in the inhalable size range, and therefore pose the highest threat to human health. This cleans up the aerosol sample, and prevents large dust and fibrous particles from clogging the downstream equipment and interfering with the bio-detection process. The large particles are captured in acontainer 40 and disposed of. No filter media that can become clogged with dust is utilized. Thecontainer 40 is also preferably located in thecabinet 30. - The air from the
pinch point 34 can, when desired, be continuously monitored by anoptional particle counter 28, as shown in FIG. 3, which determines the number of particles per second in a number of size ranges passing by the air sample point. Theparticle counter 28 provides a historical record of particle count that may assist one in identifying the contaminated mail sorting machine and the approximate time a contaminated letter passed through the machine in the event the monitor unit described below detects a biological agent. If theparticle counter 28 detects a spike in particles with characteristics that match the target of interest, such as bacillus anthracis, the system can use this event to automatically trigger a sample analysis process to be described hereinafter. Particle characteristics evaluated can include count, size, shape, and fluorescence signature, among others. It is also possible to use a mass spectrometer, not shown, as a trigger. - As noted, a BDS system in accordance with the subject invention normally operates without a
particle counter 28; however, when utilized it can perform bio-agent analyses periodically based upon the operational schedule formulated in the USPS facility. - Each of the
monitor units 12 1 . . . 12 n, as noted above, includes an aerosol collector/concentrator 22, an automated samplecartridge handling system 24, and a bio-identifier 26 as shown in FIG. 5. - Referring now to FIG. 5, an aerosol particle collector/
concentrator assembly 22, preferably a SpinCon® system, constantly draws an air sample from thesampling hood 32 and impinges the sample into approximately 10 ml of liquid located in a glass collector, not shown. At selected times derived from the operational schedule formulated for the particular installation, the solution is pumped out of the collector to a reservoir where it is optionally mixed with a buffer liquid by one or more buffer pumps 44. A fraction, nominally 2 ml, of the mixed sample is pumped into one of thecartridges 46 at afill station 48 after being transported thereto by a two-axis end effector (gripper/manipulator) 50 which forms part of thecartridge handling system 24. Additional buffer and treatment solutions may also be added, when desired, to the cartridge at thefill station 48. - The
end effector 50 then automatically inserts thecartridge 46 into thebiological identifier apparatus 26, preferably a GeneXpert™ system instrument 47 that implements a polymerase chain reaction (PCR) analysis capable of determining with a high degree of reliability if any particles in the liquid sample comprise a biological agent. Theinstrument 47 automatically processes the sample and performs a PCR analysis to determine if one or more biological agents are present. If the test result is either positive for the agent(s) under test, or non-determinate, indicating that certain internal controls included in the PCR analysis did not perform correctly, an additional test is performed using an additional fraction of the original sample and a new cartridge. At the completion of the analysis, the remaining sample is transferred from the reservoir into awaste bottle 52, or to archivebottles 54 for later laboratory confirmatory analysis and retention as evidence. The system can optionally individually archive all samples or only those that generate a positive test result. - The
bio-identifier apparatus 24 is preferably controlled by the remote central site command and control system 14 (FIG. 1) that provides interface with theUSPS network 16 but can be configured for local control if desired. - The BDS continuously collects aerosol particles from selected pinch point locations along the
mail transport path 36 of the MPE as shown in FIGS. 4A and 4B. Periodically, scheduled based on the operating plan of the site, the liquid sample containing the particles will be analyzed using an automated PCR test. This initial analysis is termed a Preliminary, or Screening Test. If the test is negative for agents of interest, no action is necessary, and the facility operations will continue as usual. - If the result of the test is a “preliminary positive”, the system will automatically perform a confirmation (Reflex)-test, optionally utilizing a criteria that is independent from the Screening Test, such as a secondary gene sequence from the target organism. Preliminary positive and confirmation test results are reported to a Visibility/Incident Response network. The results can be used to make the most appropriate decisions regarding personnel evacuation and emergency response scenarios, and further analysis of the archived sample using an outside laboratory. FIG. 8 is illustrative of this sequence of events.
- Site Control
- Considering the subject invention in greater detail, the site command and control system14 (FIGS. 1A and 1B) provides coordination and communication of all components in the overall biohazard detection system (BDS). The site command and
control system 14 is designed to: (a) provide a single user interface to the entire bio-detection system; (b) allow the user to quickly determine the status of all components associated with the system; and (c) accept input to change parameters which allow for the configuration changes including options like frequency of testing the collected sample, number of reports to print, passwords and access levels, thresholds levels which display warnings for faults and other system status. At its most basic level, the site command andcontrol system 14 provides an alarm when a positive reading has been obtained from thebio-identifier instrument 47. Thesystem 14 includes a control computer, not shown, that provides an interface to the operators and supervisors about the status of the overall system. This computer is furthermore networked to all sensor devices (like particle counters) and to each monitor unit. 12. Thesystem 14 provides the higher level data collection of statistics of each component that is necessary for reports and on screen visibility. Thesystem 14 also provides data about the test results from the bio-identifier and relates particle counter data with each PCR test occurrence and trends particle counter results over specified periods of time. - Machine Control
- Each
monitor unit 12 contains amachine control processor 20 that sends and receives commands to and from the control computer of site command andcontrol system 14. Thecontrol processor 20 performs machine control functions which: (a) controls the fluid interface between the collector/concentrator sub-system 22 and thebio-identifier sub-system 26; and (b) responds to any faults or alarms from the collector/concentrator 22 and thebio-identifier subsystem 26. - Machine control functionality provided by the
processor 20 has been separated from the site command andcontrol computer 14 because themachine control processor 20 handles time critical commands that affect the operation of the system components in themonitor unit 12 and which includes the aerosol collector/concentrator sub-system 22, thecartridge handling sub-system 24, and thebio-identifier sub-system 26. - Aerosol Collector/Concentrator
- Several different types of aerosol collector/
concentrators 22 can be used with the subject system, however, the preferred embodiment of this equipment comprises a proprietary SpinCon® system developed by Midwest Research Instititute (MRI). TheSpinCon® apparatus 22 is an efficient device proven to be well suited for a broad range of advanced air sampling requirements, including the collection of bio-aerosols, particulate matter, and soluble vapors. The primary sample collection component of theSpinCon® system 22 consists of a vertical glass tube, not shown, open on the top end, with a nearly tangential, vertical slit cut into the side and is called the contactor. Fluid is placed in the contactor and air is drawn through the slit and out through the open top end of the contactor. The slit acts like a venturi/air blast atomizer; as the air passes through the slit, it speeds up and then impacts the spinning fluid in the contactor forming a wet cyclone. The collection fluid then atomizes into many small droplets, greatly increasing the surface area in contact with the air. These droplets then begin to follow the air path. The slit is only nearly tangential so the air path is across a chord of the contactor's circular cross-section. At this time, particles in the air are picked up by the fluid. As the air and droplets reach the other side of the contactor, the droplets impinge on the wall and the fluid flow is reformed. The same fluid is re-atomized over and over, thus causing the concentration of particles in the fluid to increase linearly with time. The spinning fluid in the contactor only covers 30 to 40 percent of the slit, which is why only 30 to 40 percent of the air is sampled that is pulled into the unit. - The
SpinCon® system 22 is very effective in collecting biologicals (sizes 1-10 microns) as well as many types of smaller particles and even chemicals (agglomerated sizes <1 micron.) This is due to the atomized state of the fluid at the point of collection; the massive surface area collects the larger particles, while Brownian motion, which governs the motion of small particles, enables the smaller particles to be picked up in the fluid. - Cartridge Handling Automation:
- The
cartridge handling sub-system 24 as shown in FIG. 5 mechanically links the apparatus of the collector/concentrator subsystem 22 with thePCR test instrument 47 of thebio-identifier subsystem 26. In addition to the two-axis end effector ormanipulator assembly 50 which includes agripper 52 for securely holding acartridge 46, thecartridge handling sub-system 24 also includes atrack 54 which is located over acartridge storage rack 56 which holds a predetermined number ofliquid sample cartridges 46 so as to provide up to 10 hours or unattended operation. The processor 20 (FIG. 3) includes a controller that executes the cartridge handling process and interfaces with the rest of the subject BDS to coordinate the sample transfer and identification processes. - The two-axis end effector/
manipulator 50 shown in FIG. 5 comprises a mechanical assembly which is a simple, inexpensive design that has a form-factor that favors the footprint of the bio-detection apparatus 26 (long X short Y). It shares thesame cabinet 30 as the collector/concentrator 22 andbio-identifier 26, resulting in a compact, integrated detection system. - Additional features of the
Cartridge Handling System 24 include: (a) stepping motor operates with position feedback; (b) it simultaneously presentsliquid sample cartridges 46, one at a time, to three hypodermic needles, two of which, 60 and 62, are shown in FIG. 5, for sample and wash buffer fill, with no additional axes of motion; (c) no direct operator interface; and (d) controller interface to higher level control; and (e) insert/extract mechanism 64, to thebio-identifier instrument 47. - Bio Identifier:
- As noted above, two technologies are commonly used in the detection of biological warfare agents: namely, (1) immunoassay and (2) polymerase chain reaction (PCR). Immunoassay technology is based on the specific interaction of antibodies with pathogen. This interaction is usually detected optically or electrochemically. PCR, on the other hand, directly detects the DNA sequence of an agent.
- PCR technology has been selected for the subject invention because of its superior sensitivity and specificity. The limit of detection for immunoassay based technology is in the range of 10,000 to 100,000 spores per ml of sample. PCR has demonstrated the ability to detect less than 200 spores per ml of sample. This difference in sensitivity is critical, and can make the difference between detecting and missing a lethal threat, for example, in a USPS application. Since PCR detects the actual DNA sequence of an agent, it is also much less likely to cause a false positive than the systems based on immunoassay techniques. Also, sequences associated with the actual virulence properties of the organism can be targeted. This will also be critical for a USPS application, since a false positive may result in a major financial loss if it causes an unnecessary shutdown of a mail processing facility.
- PCR techniques have become recognized as one of the most reliable laboratory techniques, along with culture methods, to validate immunoassay and other field screening techniques. In recent years the development of real time PCR techniques have allowed the reaction to be performed in 30 minutes or less. This enables the use of PCR in field applications where rapid results are required. However, all current PCR methods require sample preparation to remove inhibitors (such as the humic acids from soil) from the sample that may result in a false negative and add reagents necessary to run PCR. This sample processing requires significant laboratory operations that USPS personnel could not reliably perform in the current mail processing facilities. For this reason, most PCR systems, cannot be used in the USPS application or similar industrial environments.
- The subject invention uses a PCR bio-identifier system that completely automates both sample processing and detection processing and comprises a GeneXpert™ system developed by Cepheid of Sunnyvale, Calif. This system consists of two components, a disposable multi-chamber cartridge such as shown in FIGS.6A-6C by
reference numeral 46 and aPCR analysis instrument 47. Theaerosol collector 22 described previously automatically loads a liquid sample into aGeneXpert™ cartridge 46 which is then transported to theGeneXpert™ instrument 47 by themanipulator assembly 50. TheGeneXpert™ instrument 47 then automatically performs the entire sample preparation, PCR amplification, and results analysis with no additional intervention by the user. The fluid sample and liquid reagents are automatically transported from one chamber 60 (FIG. 6B) to another within the disposable cartridge as shown in FIG. 7. Fluids are mixed, molecules and organisms are separated, purification is accomplished, filtering is performed, lysing is completed, all automatically with no operator intervention. The GeneXpert™ system automates all fluidic processing steps. - The key advantages of the GeneXpert
™ bio-identifier system 26 utilized in the subject invention are: - (a) on-board PCR reagents—The critical PCR chemicals (or reagents) are “on-board” the
GeneXpert™ cartridge 46, and are installed at the factory. Thus, the operator does not need to handle the sensitive reagents. Since they are pre-mixed and lyophilized at the factory, there is no chance for mistakes in mixing by an operator and thus there is no need to refrigerate the cartridges; - (b) spore lysing—The
GeneXpert™ instrument 47 incorporates an ultrasonic lysing region which actually cracks open the spore, releasing the DNA from inside the organism, in about 15 seconds. This capability does not exist with any other known DNA analysis system. Systems that do not lyse the organism cannot guarantee that the DNA from the organism is actually available for PCR detection. Such systems that do not lyse can readily report a false negative, especially for spores such as bacillus anthracis; - (c) inhibitor removal—Many types of common biological samples, including common dirt, contain extraneous chemicals that impede the PCR detection reaction. The presence of these inhibiting chemicals can cause PCR reaction to fail, thereby resulting in a false negative. The
GeneXpert™ instrument 47 captures the spores, then actually washes them with a PCR-compatible buffer solution to remove any potential inhibiting chemicals prior to performing the PCR reaction itself. Systems which do not remove inhibitory chemicals can easily report a false negative; - (d) pathogen concentration—Pathogens can be present in raw samples or can be released into the air at extremely low concentrations, yet still remain infectious. In order to ensure that such pathogens can be detected with the highest possible sensitivity, the
GeneXpert™ instrument 47 actually extracts and concentrates the spores from a relatively large original sample volume (up to several mL) into a small PCR reaction tube of thecartridge 46. Other PCR instruments simply take a small portion of the available liquid sample and perform PCR on this small portion. As a result of the concentrating ability of theGeneXpert™ apparatus 47, the system routinely achieves a sensitivity at least 10 times better than competitive products which do not concentrate the sample; - (e) no environmental contamination or cross contamination—Since all the fluidic activity for PCR detection occurs automatically and is completely contained inside the
GeneXpert™ cartridge 46, it is impossible for theGeneXpert™ instrument 47 to inadvertently contaminate the environment or the instrument with PCR product. For example, if a specific sample tests positive for bacillus anthracis, the resulting liquid is now very concentrated with bacillus anthracis DNA. In a manual-based system, small portions of this liquid could escape into the environment as liquids are pipetted or moved from tube to tube. If bacillus anthracis DNA from the PCR reaction escapes into the environment, this could become a source of contaminating DNA which could cause a false positive during subsequent tests. Since fluids are always retained inside theGeneXpert™ cartridge 46, such potential false positives are eliminated; - (f) robust reaction tubes—
GeneXpert™ cartridges 46 andintegrated reaction tubes 60 as shown in FIG. 6B are all plastic. In contrast, other products have glass reaction tubes. These glass tubes easily break. When they do break, they not only present a maintenance, service, and reliability issue, but they can also contaminate the environment with bacillus anthracis DNA, again providing a source for potential false positives during subsequent tests; and, - (g) multi-target detection—When using PCR, the definitive identification of bacillus anthracis, for example, requires the detection of two different DNA segments. The
GeneXpert™ instrument 47 has a versatile multiplexing capability in that multiple DNA targets can be detected simultaneously in the samePCR reaction tube 60 of a cartridge. Multiplexing capability is a critical feature for DNA analysis and pathogen detection. For example, with the GeneXpert™ system, a single test or analysis for up to four agents can be performed within a singledisposable cartridge 46. Alternatively, a completely confirmatory test for an agent such as bacillus anthracis can be performed within asingle cartridge 46. This assay would include three probes for the three different DNA segments and one probe for an internal control. With theGeneXpert™ instrument 47, this can be done in asingle test cartridge 46. Finally, most robust PCR chemistries require an internal “control” DNA sequence. This control sequence is amplified and detected along with the “target” DNA (such as bacillus anthracis) to assure that the PCR chemistry is performing properly—basically a validation or quality check. TheGeneXpert™ instrument 47 has four independent optical detection channels. Accordingly, these advanced, but necessary, multiplexing chemistries can be utilized for: (1) multiple pathogen detection; (2) confirmatory testing; and/or (3) test quality/validation control. - In current PCR methods, separate positive and negative controls must be run to assure reagent integrity or successful removal of inhibitors during sample preparation. A new internal control scheme that eliminates the need for these external controls is achieved by a unique combination of an internal control and probe integrity check called probe check. The internal control consists of a piece of DNA whose sequence is different than the target DNA and a corresponding probe that is included in the PCR bead. The internal control is co-amplified along with the test reaction and is used to assure that the reagent is functional and that PCR inhibitors have been successfully removed during sample preparation.
- System Operation
- In a USPS installation, the biological agent detection system (BDS) in accordance with the subject invention is deployed on mail processing equipment (MPE). The operation of the subject bio-detection system is controlled by the
machine control processor 20, and its operation is synchronized with the operation of the monitored MPE so that it is only allowed to operate when the BDS collector/concentrator is operational. The flow chart shown in FIG. 8 illustrates the operational sequence. - Prior to collecting samples, the BDS must be initialized and prepared for data collection. The following describes the daily setup tasks: (1) start-up of site command and control system; (2) set collection parameters for the day. The collection parameters include the setup for each run in sequential order for the tour. The run setup will indicate the machine ID sample number, start time, stop time, and the assay description. The assay description is associated with a command sequence used by the GeneXpert™ to perform the PCR analysis. The command sequences are stored locally in the machine control processor20 (FIG. 3). The supervisory console 14 (FIGS. 1A and 1B) will have the capability to download a new assay description and associated command sequence to the machine control processor; and, (3) powers up the BDS cabinets. The system will automatically perform a communications and systems status check; rinse and prime the fluid lines; and indicate whether fluid levels are low.
- At the specified start time, the BDS initiates the air collection process. This enables the collector/
concentrator sub-system 22 to start operation. An indicator, not shown, on the cabinet 30 (FIG. 5) provides an indication that the system is active. - Air is then sampled from one or
more areas 34 of the MPE as shown in FIGS. 4A and 4B. The sampling area(s) have been empirically determined based on tests that located areas where high volumes of particles come out of the mail pieces as they are processed. The output of theair collection hood 32 is routed viatube 37 which is a grounded anti-static tube to thedry cyclone pre-separator 38 that is designed to eliminate particles that are larger than the inhalation threat range of 1-10 microns. - From the dry-
cyclone 38, the sampled aerosol is routed via 40 to the SpinCon® collector/concentrator apparatus 22 (as shown in FIG. 5). As noted above, theapparatus 22 impinges the air into a small volume of liquid. The aerosol collector operates at a flow about 450 lpm. As air passes through the unit, cyclonic mixing transfers a high portion of the target particles into the liquid. The liquid medium remains in the collector/concentrator 22 to continuously concentrate the target particles into the liquid. At the start of the collection process, 10 ml of sterile water is injected into the system. During the collection, the water level is monitored, and evaporated water is replaced by injecting makeup water to maintain to 10 ml sample volume. - At a planned “stop time” or in response to a trigger input, the
machine control processor 20 sends a signal to the collector/concentrator 22 to transfer a sample out for analysis. The aerosol collection process and facer/canceller operation are paused while the sample is transferred into the collection reservoir 43 (FIG. 5), and the collector/concentrator 22 is then refilled to start the next collection window. - As the liquid sample is transferred into the
reservoir 43, it is mixed with a solution containing additives that minimize PCR inhibition. The liquid sample is then allowed to sit in the reservoir for a time, e.g., approximately two minutes, to allow thorough mixing of the additive solution, and allow any large particles to settle to the bottom of the reservoir bottle(s) 42. - While the liquid is setting, the
gripper mechanism 52 of theend effector 50 of thecartridge handling system 24 as shown in FIG. 5 retrieves aPCR cartridge 46 from thestorage rack 56, and places it in position at the “liquid fill”station 48 in the BDS cabinet as shown in FIG. 5. The three needles at theliquid fill station 48, two of which are shown byreference numerals cartridge 46, and allows the sample and wash buffer solutions to be added to the appropriate cartridge chambers. - The liquid transfers are performed utilizing
peristaltic pumps 44. Once the sample transfer is complete, thecartridge 46 is placed into theGeneXpert™ instrument 47, and the sample analysis process is started. - After the
cartridge 46 is inserted into theGeneXpert™ instrument 47, an automated sample preparation process begins. The sample is concentrated, washed, sonicated, mixed with the PCR reagents, and moved into a reaction tube 60 (FIG. 6B) for PCR thermal-cycling as shown in FIG. 7. Each of these steps, along with the parameters that control the PCR analysis itself, is elaborated in an assay file that is specific to the test being performed. - Tests
- After the sample preparation steps are complete, PCR thermal cycling analysis begins. The primary PCR test is called a Screening Test. This test targets one or more gene sequences for each of the organisms of interest. In addition to the target organisms, the Screening Test also includes an internal control signal that provides a built-in positive control that the PCR reaction has proceeded properly. As the PCR thermal cycles are performed, the fluorescence signals in the cartridge reaction chamber are monitored and analyzed on each thermal cycle using an algorithm that analyzes the shape of the PCR growth curve, including features such as its cycle threshold and endpoint to deteermine whether the PCR result indicates the presence of the target organism.
- (Screening Negative)—In normal conditions, the test results of the Screening Test are negative (N). The test results are sent to the site command and control system14 (FIG. 1) where the results are logged. The
test cartridge 46 is removed from theGeneXpert™ instrument 47 and placed back into its position on thecartridge storage rack 56. The remaining liquid sample in the reservoir bottle(s) 42 is transferred to an archive bottle 54 (or optionally to awaste bottle 52 if the “archive all” parameter is turned OFF). TheSpinCon® reservoir 43 is then available for the next sample. - (Screening Positive/Preliminary Positive)—If the
PCR bio-identifier instrument 47 detects a positive (Y) Screening Test result, the results are sent to the site command andcontrol system 14, where notifications are sent out according to a prescribed notification and response scenario and a Reflex Test is next performed as will be described hereinafter. - (Screening Process Error/Inhibition)—If the
PCR bio-identifier instrument 47 detects an invalid screening result, the test results are also sent to the site command andcontrol system 14, where notifications are sent out again, according to a prescribed notification and response scenario. The system has the capability of utilizing an alternate assay for the repeat test based on the nature of the error on the original screening test. If, based on the background fluorescence, it appears as if there was a bead rehydration or other processing problem, a portion of the archived sample will be utilized to repeat the same assay in anew cartridge 46. If the error appears to be an inhibited sample, a portion of the archived sample will be utilized to perform a slightly modified assay. This assay will: (1) perform additional washes; (2) utilize a higher level of dilution; and (3) adjust the positive detection thresholds based on the modified dilution. - (Reflex Test)—In response to a positive (Y) Screening Test result, (a) the site command and
control system 14 will send out Preliminary Positive notifications to the designated contact list, (b) the cartridge handling system 24 (FIG. 5) will retrieve the cartridge to be used for the Reflex Test, and transport it to the fill station where a fraction of the sample remaining in the reservoir and buffer solutions are transferred into it, and depending on the agents to be tested for, the Reflex Test may simply consist of a repeat of the Screening Test, or it may be performed on a special “reflex”cartridge 46′ containing primers for alternate genetic sequences, (c) the appropriate assay for the reflex cartridge is selected, and (d) thereflex cartridge 46′ will then be automatically loaded into theGeneXpert™ instrument 47 and a Reflex analysis will be performed. - (Reflex Negative)—The system will transfer the remaining liquid sample into an
archive tube 54. For a negative (N) Reflex Test result, no site alarms or emergency response action are initiated, the GeneXpert™ test results are sent to the site command andcontrol system 14, where the results are logged and test result notifications are sent out. The original screening cartridge, the reflex cartridge, and the archive tube can optionally be manually retrieved from the system and saved in refrigerated storage for further analysis to determine the cause of the preliminary positive. - (Reflex Process Error/Inhibition)—For a Reflex Process Error/Inhibition result, no local alarms or emergency response actions are initiated, the test results are sent to the site command and
control system 14, where the results are logged and notifications are sent out according to a prescribed notification and response scenario. Another reflex test can be performed, as long as sufficient sample is available. - (Reflex Positive)—The system will transfer the remaining liquid sample into an
archive bottle 54. For a positive (Y) Reflex Test result, the GeneXpert™ test results are sent to the site command andcontrol system 14, where the results are logged and test result notifications are sent out. The site emergency response plan is put into effect. - Thus what has been shown and described is a unique biohazard detection system for detecting toxic biological agents, particularly bacillus anthracis, in a facility which, for example, handles and processes items, such as mail.
- The detailed description provided above, however, merely illustrates the principles of the invention. It will thus be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are thus within its spirit and scope.
Claims (37)
1. A fully automatic biological agent detection system, comprising:
biological agent identifier apparatus;
collection apparatus for collecting an aerosol sample of particles of an aerosolized biological agent at at least one monitored location;
aerosol concentrator apparatus for producing a liquid sample of the aerosol sample;
an automated fluidics apparatus for storing and delivering a portion of the liquid sample to a cartridge type receptacle;
an automated mechanical handling system for transporting the receptacle from a staging area to a liquid fill point of the fluidics apparatus and then to the biological agent identifier apparatus; and
control apparatus for providing overall automated control of the system, for controlling the apparatus at said at least one monitored location, and for reporting the test results provided by the identifier apparatus to a predetermined location.
2. The system according to claim 1 wherein the collection apparatus operates continuously to collect samples of particles and wherein the system for transporting operates periodically to transport a receptacle from a staging area to a liquid fill point of the fluidics apparatus and then to the biological agent identifier apparatus.
3. The system according to claim 2 wherein the fluidics apparatus periodically delivers a portion of the liquid sample to said receptacle prior to the receptacle being transported to the biological agent identifier apparatus.
4. The system according to claim 1 wherein the collection apparatus includes a shroud/hood positioned at a collection point of the monitored location.
5. The system according to claim 4 wherein the shroud/hood is located along a mail transport path of mail processing equipment.
6. The system according to claim 5 wherein the shroud/hood is located at a mail pinch point along the mail transport path and including mail pinching apparatus located adjacent the shroud/hood.
7. The system according to claim 1 wherein the concentrator apparatus includes a dry cyclone pre-separator and a wet-cyclone aerosol concentrator assembly.
8. The system according to claim 1 wherein the fluidics apparatus is capable of temporarily holding a sample in a reservoir where it can be accessed for one or more analyses, while the aerosol concentrator apparatus is collecting a next sample.
9. The system according to claim 1 wherein the fluidics apparatus additionally archives a remaining portion of the liquid sample.
10. The system according to claim 1 wherein the mechanical handling system includes a gripper type end effector for picking up and transporting the cartridge type receptacle.
11. The system according to claim 10 wherein the staging area includes a storage rack for holding a plurality of cartridge type receptacles and wherein the end effector is located above the storage rack.
12. The system according to claim 11 wherein the storage rack is an elongatd rack holding the cartridge type receptacles in a linear arrangement and wherein the end effector is located on and automatically moves in two orthogonal directions on an elongated track above the storage rack for grabbing, transporting and returning one receptacle at a time, to and from the fluidics apparatus and the biological agent identifier apparatus.
13. The sytem according to claim 12 wherein the fluidics apparatus and the identifier apparatus are aligned with the storage rack so that only two axes of motion are required of the end effector.
14. The system according to claim 13 wherein the end effector is controlled by a machine controller forming part of said control apparatus.
15. The system according to claim 14 wherein the machine controller also controls the automatic operation of the fluidics apparatus and an insert/extract cartridge mechanism forming part of the biological agent identifier apparatus.
16. The system according to claim 1 wherein the biological agent identifier apparatus comprises a polymerase chain reaction (PCR) bioagent identifier.
17. The system according to claim 16 wherein the identifier apparatus includes at least one screening cartridge containing an assay for a single gene sequence of a target biological agent and an internal control.
18. The system according to claim 16 wherein the identifier apparatus comprises a single bay unit including automatic cartridge exchange.
19. The system according to claim 1 wherein the control apparatus includes a local machine control computer connected to and controlling the operation of the biological agent identifier apparatus, the aerosol concentrator apparatus, the fluidics apparatus, and the mechanical handling system.
20. The system according to claim 19 wherein the control apparatus additionally includes a remote site command and control computer connected to and controlling the machine control computer as well as communicating the test results to said predetermined location.
21. The system according to claim 20 wherein the site command and control computer is connected to the machine control computer via a hardwire link.
22. The system according to claim 20 wherein the site command and control computer is connected to the machine control computer via an RF link.
23. The system according to claim 18 wherein the site command and control computer include a primary and a backup control computer.
24. The system according to claim 1 and additionally including a cabinet for housing the aerosol concentrator apparatus, the fluidics apparatus, the mechanical handling system, and the biological agent identifier apparatus.
25. A method of detecting a biological agent in items to be delivered and being transported along a transport path, comprising the steps of:
collecting an aerosol sample from said items at at least one location of the transport path;
producing a liquid sample of the aerosol sample;
delivering a portion of the liquid sample to a cartridge type receptacle;
mechanically transporting the receptacle to biological agent identifier apparatus wherein said identifier apparatus analyses the liquid sample for particles of a predetermined biological agent;
reporting the results of the analyses provided by the identifier apparatus to a predetermined location; and,
providing overall automated control of the method.
26. The method according to claim 25 wherein said items comprise mail items.
27. The method according to claim 25 wherein the step of collecting an aerosol sample includes the step of pinching said items at a pinch point along the transport path.
28. The method according to claim 27 wherein the step of collecting an aerosol sample includes locating an apparatus for pinching said items and a shroud/hood for collecting aerosol samples pinched from said items.
29. The method according to claim 28 wherein the step of transporting comprises transporting a receptable containing the liquid sample periodically to biological agent identifier apparatus.
30. The method according to claim 29 wherein the step of transporting includes using a mechanical handling system having a gripper type end effector for picking up and transporting the cartridge type receptacle under the control of a local machine controller.
31. The method according to claim 30 wherein the step of transporting includes periodically picking up and transporting a cartridge type receptacle from a plurality of receptacles located in a rack located beneath the end effector.
32. The method according to claim 28 whererin the step of delivering a portion of the liquid sample includes the step of temporarily storing the sample in a reservoir where it can be accessed for one or more analyses.
33. The method according to claim 32 wherein the step of delivering includes archiving a remaining portion of the liquid sample.
34. The method according to claim 25 wherein the biological agent identifier apparatus comprisese a polymerase chain reactor (PCT) bio-agent identifier.
35. The method according to claim 25 wherein the step of producing a liquid sample includes using a dry cyclone pre-separator and a web cyclone aerosol concentrator assembly.
36. The method of claim 25 wherein said step of providing control of the method includes using local machine control computer apparatus.
37. The method of claim 30 wherein said step of providing control of the method also includes a remote site control computer apparatus.
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Cited By (39)
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IL164224A0 (en) | 2005-12-18 |
EP1508025A2 (en) | 2005-02-23 |
IL164321A0 (en) | 2005-12-18 |
WO2004018704A3 (en) | 2004-06-10 |
AU2003285852B2 (en) | 2006-12-14 |
KR20050084787A (en) | 2005-08-29 |
EP1508024A1 (en) | 2005-02-23 |
RU2004128464A (en) | 2005-08-10 |
US7405073B2 (en) | 2008-07-29 |
JP2005526522A (en) | 2005-09-08 |
RU2004128463A (en) | 2005-07-10 |
CA2481665A1 (en) | 2003-12-04 |
RU2316748C2 (en) | 2008-02-10 |
WO2004018704A9 (en) | 2004-04-22 |
AU2003239506A1 (en) | 2003-12-12 |
JP2005526977A (en) | 2005-09-08 |
CA2482031A1 (en) | 2004-03-04 |
AU2003285852A1 (en) | 2004-03-11 |
US20040063198A1 (en) | 2004-04-01 |
RU2318197C2 (en) | 2008-02-27 |
KR20050037991A (en) | 2005-04-25 |
WO2003100382A1 (en) | 2003-12-04 |
AU2003239506B2 (en) | 2007-08-02 |
WO2004018704A2 (en) | 2004-03-04 |
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