U.S. patent application number 11/698053 was filed with the patent office on 2007-06-21 for method for the rapid diagnosis of targets in human body fluids.
This patent application is currently assigned to RAPID PATHOGEN SCREENING INC.. Invention is credited to Franz Aberl, Jose S. Sambursky, Robert P. Sambursky, Marcus Scheibenzuber, Robert W. Vandine.
Application Number | 20070141564 11/698053 |
Document ID | / |
Family ID | 34837553 |
Filed Date | 2007-06-21 |
United States Patent
Application |
20070141564 |
Kind Code |
A1 |
Aberl; Franz ; et
al. |
June 21, 2007 |
Method for the rapid diagnosis of targets in human body fluids
Abstract
More particularly, the present invention relates to a method for
the detection of a target, e.g. pathogen in a human body fluid
wherein a body fluid sample is collected with a swab member.
Inventors: |
Aberl; Franz; (Princeton,
NJ) ; Scheibenzuber; Marcus; (Munich, DE) ;
Sambursky; Robert P.; (Philadelphia, PA) ; Vandine;
Robert W.; (Motoursville, PA) ; Sambursky; Jose
S.; (Johnson City, NY) |
Correspondence
Address: |
ROTHWELL, FIGG, ERNST & MANBECK, P.C.
1425 K STREET, N.W.
SUITE 800
WASHINGTON
DC
20005
US
|
Assignee: |
RAPID PATHOGEN SCREENING
INC.
Johnson City
NY
|
Family ID: |
34837553 |
Appl. No.: |
11/698053 |
Filed: |
January 26, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11052748 |
Feb 9, 2005 |
|
|
|
11698053 |
Jan 26, 2007 |
|
|
|
60542303 |
Feb 9, 2004 |
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Current U.S.
Class: |
435/5 |
Current CPC
Class: |
Y10T 436/255 20150115;
G01N 33/6893 20130101; G01N 33/487 20130101; Y10S 436/811 20130101;
G01N 33/56983 20130101; G01N 33/558 20130101; G01N 2333/07
20130101; Y10T 436/25375 20150115 |
Class at
Publication: |
435/005 |
International
Class: |
C12Q 1/70 20060101
C12Q001/70 |
Claims
1. A device for the detection of a target which is selected from
pathogens and/or allergy-associated components in a body fluid
comprising (i) a sample application zone, (ii) a detection zone,
(iii) a swab member for collecting a sample fluid, and (iv) means
for fixing the swab member in a position which directly contacts
the sample application zone in fluid communication therewith.
2. The device according to claim 1, further comprising a housing
with a first window for directly contacting the swab member with
the sample application zone and a second window over the detection
zone for reading the results.
3. The device according to claim 1, further comprising a waste zone
downstream from the sample application zone and the detection
zone.
4. The device according to claim 1, further comprising a carrier
backing.
5. The device according to claim 1, further comprising an absorbent
pad upstream from the sample application zone and the detection
zone.
6. The device according to claim 1, wherein said sample application
zone contains at least one labeled specific binding partner capable
of binding to an analyte and migrating to the detection zone.
7. The device according to claim 6, wherein the detection zone
contains an immobilized specific binding partner which binds to the
analyte.
8. The device according to claim 7, wherein the detection zone
further comprises a control line containing an immobilized specific
binding partner which binds said labeled binding partner and
indicates the functionality of the device.
9. The device according to claim 1, further comprising a conjugate
zone which contains at least one labeled specific binding partner
capable of binding to an analyte and migrating to the detection
zone.
10. The device according to claim 9, wherein said labeled specific
binding partner is labeled with an optically detectable label.
11. The device according to claim 6, wherein said labeled specific
binding partner is specific for a virus, microorganism or
parasite.
12. The device according to claim 6, wherein said labeled specific
binding partner is specific for an allergen or antiallergen.
13. The device according to claim 1, wherein said sample fluid is
fluid from a body surface selected from mucous membrane fluids,
secretions from glands and secretions from lesions or blisters.
14. The device according to claim 13, wherein said sample fluid is
selected from oral, nasal, ocular, genital, and rectal fluids, and
secretions from skin lesions or blisters.
15. The device according to claim 14, wherein said sample fluid is
an eye fluid.
16. The device according to claim 11, wherein said labeled specific
binding partner is specific for a virus, microorganism or parasite
which causes conjunctivitis.
17. The device according to claim 11, wherein said labeled specific
binding partner is specific for a pathogen selected from the group
consisting of adenoviruses, herpes viruses, Chlamydia,
cytomegaloviruses, pseudomonas, streptococci, haemophilus,
staphylococci, amoebae and combinations thereof.
18. The device according to claim 1, wherein said swab member
collects a sample volume of about 0.1 .mu.l to about 100 .mu.l.
19. The device according to claim 18, wherein said sample volume is
about 0.5 .mu.l to about 10 .mu.l.
20. The device according to claim 1, wherein said swab member is
sterile.
21. The device according to claim 1, wherein the swab member is
initially separate from the sample analysis device.
22. The device according to claim 1, wherein the swab member is an
integrated part of the device.
23. The device according to claim 1, where said device is a
chromatographic test strip.
24. The device according to claim 1, wherein said device has two
parts connected by a hinge, wherein the swab member is on one part,
and the sample application zone and detection zone are on another
part, such that when said hinge is closed, the swab member is held
in direct contact with the sample application zone.
Description
[0001] This application is divisional of U.S. Ser. No. 11/052,748
filed Feb. 9, 2005, which claims the benefit of U.S. Provisional
60/542,303, filed Feb. 9, 2004.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to a method for the detection
of targets, e.g. pathogens and/or allergy-associated components in
a human body fluid wherein a body fluid sample is collected with a
swab member. The samples are transferred from the swab member to a
sample analysis device, on which an analysis of the targets, e.g.
by immunochemical or enzymatic means can take place. The test
result may be displayed within a short period of time and can be
directly read out by the user. Further, a test kit for carrying out
the method of the invention is provided.
BACKGROUND OF THE INVENTION
[0003] Rapid, point-of-care analysis is becoming increasingly
important in the diagnosis and treatment of various viral and other
pathogenic microbiological agents (bacteria, others). Especially in
the acute status of a infectious disease medical doctors have a
need for immediate detection of the causal agent for the symptoms
observed.
[0004] Prior art discloses a rapid assay for HIV specific
antibodies in saliva samples. A saliva sample is gained by means of
a sampling stick. The saliva sample is diluted in a sample buffer
and a lateral flow immunoassay is dipped into the diluted saliva
sample [U.S. Pat. No. 5,714,341].
[0005] German Patent Nr. DE19622503 suggests to apply lateral flow
immunoassays for the detection of illegal narcotics in saliva or
sweat.
[0006] Conjunctivitis, commonly known as red eye or pink eye, may
be caused by several different agents including viruses, bacteria
and allergens. Different etiologies require different treatments.
Infectious conjunctivitis is typically contagious. Conjunctivitis
is generally diagnosed clinically, by gross examination, and
(during a routine eye exam) slit lamp biomicroscopy. This method
does not provide information on the specific infectious agent. If
specific (pathogen typing) diagnosis is necessary, swabs of the
inferior fornix are sent for laboratory analysis to determine the
type of pathogen. The preferred methods for laboratory analysis are
cell culture with confirmatory direct immunofluorescence, ELISA or
PCR. The disadvantage of this diagnostic strategy is that
laboratory analysis needs typically between two and ten days,
utilizes complex diagnostic equipment, and may require technical
skill in both performing and interpreting results. This time period
is problematic for a proper treatment of potentially infectious
forms of conjunctivitis that cannot be specifically
classified/connected with a certain pathogenic agent.
[0007] A publication by Uchio et al. (Opthalmology 104 (1997),
1294-1299) discloses a method for the detection of adenovirus in
eye fluid specimens. The method comprises collecting a sample of
eye fluid and detecting the analyte on a paper disc by enzyme
immunoadsorption. The detection, however, lacks specificity and
sensitivity.
[0008] Thus, it is the objective of the invention to provide a
sensitive and rapid non-invasive method for the detection of
pathogens, e.g. bacterial or viral infectious agents in body
fluids.
SUMMARY OF THE INVENTION
[0009] In a first aspect, the present invention relates to a method
for the detection of a target which is selected from pathogens
and/or allergy-associated components in a body fluid comprising the
steps: [0010] (a) non-invasively collecting a body fluid sample
with a swab member, [0011] (b) transferring the sample to a
application zone on a sample analysis device and [0012] (c)
analysing the sample.
[0013] In a further aspect, the invention relates to a method for
diagnosing conjunctivitis comprising the steps: [0014] (a)
non-invasively collecting an eye fluid sample with a swab member,
[0015] (b) transferring the sample to a application zone on a
sample analysis device and [0016] (c) analysing the sample.
[0017] In still a further aspect, the invention relates to a test
kit comprising [0018] (a) a swab member for non-invasively
collecting a body fluid sample, [0019] (b) a sample analysis device
comprising a detection zone, wherein the detection zone contains
reagents for determining the presence and/or amount of at least one
target which is selected from pathogens and/or allergy-associated
components.
[0020] In still a further aspect, the invention relates to a test
kit comprising [0021] (a) a swab member for non-invasively
collecting an eye fluid sample, [0022] (b) a sample analysis device
comprising a detection zone, wherein the detection zone contains
reagents for determining the presence and/or amount of at least one
target which is selected from pathogens and/or allergy-associated
components wherein the target is a causative agent or mediator of
conjunctivitis or a plurality of such causative agents and/or
mediators.
DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 shows a sample analysis device in the form of a
chromatographic test strip comprising a plurality of different
strip materials building an absorbent pad (1), an application zone
(2), a detection zone (3) and a waste zone (4). The strip materials
are arranged on an adhesive plastic backing (5). The absorbent pad
(1) is providing for adding an elution medium in order to
facilitate the transfer of the sample to the detection zone
(3).
[0024] FIG. 2 shows a plastic housing (6) containing the strip as
shown in FIG. 1. A sample application window (7) is provided for
bringing a swab member into contact with the strip. The test result
is displayed in the read out window (8).
[0025] FIG. 3 shows a swab member or collection device for
collecting a sample. The swab member comprises a plastic body (9)
with a sample collection material (11) fixed on it and an opening
(10) corresponding to a read out window when the swab member is
operatively in contact with a test strip.
[0026] FIG. 4 shows a test kit comprising a sample analysis device
according to FIGS. 1 and 2 and a swab member according to FIG.
3.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0027] The invention provides a sensitive and rapid method for the
detection of targets, e.g. pathogens and/or allergy-associated
components in samples collected by non-invasive means from a body
fluid. The pathogens are selected from viruses, microorganisms,
e.g. bacteria and parasites, e.g. amoebae or nematodes. The
allergy-associated components are selected from allergens and
anti-allergic components. The detection may comprise a direct
detection of the target, e.g. the pathogen and/or the detection of
antibodies against the target, e.g. the pathogen which are present
in the fluid sample to be tested. Preferably, the method comprises
a parallel determination of a plurality of targets.
[0028] The body fluid is preferably a fluid from a body surface
selected from mucose membrane fluids (of the oral, nasal, vaginal,
and ocular cavities) tears, secretions from glands and secretions
from lesions or blisters, e.g. lesions or blisters on the skin.
More preferably, the sample is selected from oral, nasal, ocular,
genital and rectal fluids and secretions from skin lesions or
blisters. Most preferably, the sample is an eye fluid. A
significant advantage of the method is that results are provided
within the medical consultation period, e.g. in few minutes.
Preferably, the results are provided in a time period up to 20
minutes, more preferably up to 15 minutes. Also, as the test is
noninvasive, it poses very little risk to the patient. Thus the
best available treatment can be applied on a timely basis for a
specific pathogen. A further advantage over prior art methods is
that only a few microliters of sample are required to perform an
analysis. The sample is preferably about 0.1 .mu.l to about 100
.mu.l, more preferably about 0.2 .mu.l to about 20 .mu.l and most
preferably about 0.5 .mu.l to about 10 .mu.l.
[0029] The invention may be performed by means of a simple test
kit. Handling of the test kit does not necessitate additional
laboratory equipment, further handling of reagents or
instrumentation. Another important advantage of the invention
described below is that the detection limit is typically 10 to 100
times lower than currently available diagnostic tests because
samples do not require dilution before they are transferred to the
analysis device. Therefore the disclosed method has proven to be
more sensitive and accurate than methods of the prior art.
[0030] The invention discloses a non-invasive method for the rapid
and point-of-care determination of pathogens from body fluids. The
method is suitable for diagnosis in human beings and animals, e.g.
pets or livestock animals. A preferred application is the detection
of pathogens in eye fluid, e.g. human eye fluid. In this embodiment
the pathogen to be detected is a causative agent of conjunctivitis
or a plurality of such causative agents. For example, the pathogen
is selected from the group of adenoviruses, herpesviruses,
chlamydiae, cytomegaloviruses and combinations thereof. More
preferably, a plurality of pathogens are detected on a single
sample analysis device. For example, the sample analysis device may
allow a simultaneous detection of a plurality of pathogens,
particularly of at least two, of at least three, of at least four
or of at least five pathogens selected from the group consisting of
adenoviruses, herpesviruses, chlamydiae, cytomegaloviruses,
pseudomonas, streptococci, haemophilus, staphylococci, amoebae,
particularly Acanthamoeba and nematodes, particularly Onchocera
volvulus. More preferably, the method comprises a simultaneous
detection of adenoviruses, herpesviruses, chlamydiae,
cytomegaloviruses and Acanthamoeba.
[0031] In addition the invention provides a non-invasive method for
the rapid and point-of-care determination of at least one
allergy-associated component, particularly an allergen (e.g.
pollen, dust, etc.) and/or an antiallergen, particularly a
component which is produced in the body in response to an
allergenic challenge (e.g. IgE, histamine, etc.), in a body fluid
as described above. More particularly, the invention relates to
methods and devices for the diagnosis of allergy-associated
components in eye fluid, e.g. human eye fluid. In a preferred
embodiment, the determination of at least one allergy-associated
component may be combined with the determination of at least one
pathogen as described above.
[0032] In the method of the invention, a body fluid sample is
non-invasively collected with a collection device or swab member,
respectively. The collection step preferably comprises wiping or
dabbing the swab member over a surface of the body containing body
fluid to be tested. Usually, the swab member is sterile. The swab
member may be dry or pretreated with a fluid before the collection
step. For example, using a gentle swirling motion, a sterile swab
member may be applied to the body surface or mucous membrane of
concern and allowed to capture any pathogens and/or
allergy-associated components contained in the body fluid.
[0033] The swab member may be a part which is separate from the
sample analysis device and the sample is transferred by contacting
the sample analysis device with the swab member under conditions
wherein at least a part of the sample on the swab member is
transferred to the sample analysis device. In this embodiment, the
swab member is preferably contacted with a sample application zone
on the analysis device from which the sample is then transferred to
the detection zone. The contact preferably comprises fixing the
swab member in a contact position with the sample analysis device
in which the sample collection zone of the swab member is in direct
contact with the sample application zone of the analysis device.
Thus, the swab member and/or the analysis device preferably
comprises fixing means for providing a fixed contact between both
parts in a predetermined position. Alternatively, the swab member
may be an integrated part of the sample analysis device and the
transfer comprises passing at least a part of the sample on the
swab member to the detection zone on the sample analysis
device.
[0034] The transfer of the sample from the swab member to the
detection zone on the sample analysis device is preferably a direct
transfer, i.e. the transfer takes place without pretreatment of the
sample on the swab member. Preferably, the transfer comprises an
elution of the sample from the swab member with an elution medium,
e.g. a buffer or water. The elution medium may be added from an
external source or may be provided e.g. as a reservoir within the
analysis device. Further, the transfer is preferably a
chromatographic and/or capillary transfer of fluid to the detection
zone on the sample analysis device.
[0035] In a preferred embodiment, the sample analysis device
comprises a chromatographic test strip, e.g. a lateral flow test
strip. The sample analysis device may comprise a sample application
zone, a detection zone, optionally a waste zone, optionally a
carrier backing, optionally a housing and optionally an opening for
result read out. The sample analysis in the detection zone may be
carried out by standard means, e.g. by an immunological or
enzymatic detection method. Preferably, the detection method
comprises the use of test reagents capable of specifically binding
the targets, e.g. pathogens to be tested or antibodies or other
receptors against these targets, e.g. pathogens and subsequent
visualisation of the bound entity, e.g. by enzymatic detection or
by means of direct labelling groups, such as colloidal gold.
[0036] In an especially preferred embodiment, the swab member is
placed on a lateral flow test strip. With this step the collected
specimen is transferred directly on an immunochromatographic or
enzymatic test strip. The test strip consists of one or several
capillary active fleeces or membranes. The detection process will
be either started directly with sample transfer or may require an
elution medium to be applied for sample analysis. Preferably this
elution medium is simple tap water. In the case of an
immunochemical test strip, the chosen elution medium moves towards
a detection zone and thereby passes the contact site within the
collection device. The analyte is diluted by the elution medium and
carried with it to the detection zone. In the detection zone the
analyte is determined by qualitative and/or quantitative methods,
e.g. in an immunological binding reaction.
[0037] The test strip can be made of one single chromatographic
material, or preferably several capillary active materials made of
the same or different materials and fixed on a carrier backing.
These materials are in close contact with each other so as to form
a transport path along which a liquid driven by capillary forces
flows from the start zone, passing the contact site of the swab and
the detection zone, towards a waste zone at the other end of the
strip.
[0038] Furthermore this invention is disclosing a device and test
kit for the performance of the described method.
[0039] In the method of invention, it is possible to make use of
different immunological testing procedures to detect bacterial or
viral constituents on one or several immunological binding
reactions. In a preferred embodiment, a chromatography test strip
contains: [0040] an application zone. [0041] a conjungate zone
containing at least one labeled binding partner that is able to
migrate with the elution medium. The binding partner is capable of
specifically binding to an analyte and to a further specific
reagent in the detection zone. [0042] a detection zone containing a
first section for the detection of a first analyte, e.g. a test
line, comprising an immobilized specific binding partner for the
analyte, and optionally further sections for the detections of
further analytes, and at least one control section, e.g. a control
line comprising an immobilized specific binding partner of an
indicator substance indicating the functionality of the test
kit.
[0043] In a preferred embodiment, the specific binding partners for
the analytes in the conjugate and the detection zone are
monoclonal, polyclonal or recombinant antibodies or fragments of
antibodies capable of binding to a pathogen. On the other hand, the
specific binding partners may also be antigens capable of binding
to antibodies against a pathogen or an allergen. Other types of
binding partners are bioorganic macromolecules like aptamers or
receptors. The conjugate zone may be located before, within or
after the sample application zone, seen in the running direction of
the eluent liquid. The test line(s) is(are) located after the
conjugate/application zone and the control line(s) is(are) located
after the test line. Together, the test line(s) and control line(s)
comprise the detection zone.
[0044] Depending on the type of detection method, different binding
partners are present in the different zones. In a sandwich
immunoassay, it is preferred to have a labeled, non-immobilized
analyte binding partner in the conjugate zone. The binding partner
forms a complex with the analyte which is bound to the immobilized
binding partner at the test line. In a preferred manner, the label
of the conjugate binding partner is an optically detectable label.
Forming a complex at the test line concentrates and immobilizes the
label and the test line gets visible for the bare eye, indicating a
positive test result. Particularly preferred are direct labels, and
more particularly gold labels which can be best recognized by the
bare eye. Additionally, an electronically photometrical read out
device can be used to obtain more precise results and a
semi-quantification of the analyte. Other labels may be latex,
fluorophores or phosphorophores.
[0045] In order to test ocular fluids, a sample may be collected
with a sample collection device from the patient's eye by a health
care professional. The sample collection device should be wiped or
dabbed slightly several times between in the inferior fornix of the
lower eye lid. If necessary the collection device may be wet with
sterile physiological saline to decrease patient's discomfort. This
procedure is well known in the ophthalmology practice as it is
necessary for collecting specimens for conventional laboratory
analysis. Generally the sample collection device comprises a
capillary active material suitable for receiving a body fluid
sample. In a preferred manner the sample collection material is
made out of fibers on the basis of cellulose, polyester, rayon or
calcium alginate. However, the sample collection device can also be
designed as a microengineered mechanical structure containing
microcapillaries and/or microchannels.
[0046] After the sample is collected, the collection device is
fixed to the plastic housing containing the test strip (FIG. 4) and
thereby the collection applicator is slightly pressed on the
application zone of the strip. The collection device remains in
this position.
[0047] In an alternative embodiment, the sample is taken by a
standard swab member as currently used in the physician's office or
emergency rooms. This swab member is subsequently pressed into the
application zone of the chromatographic test strip by means of an
additional device similar to the sample collection unit.
[0048] In another preferred embodiment, the sample is taken by a
swab member and the sample collection devices is pressed for only a
short time into the application zone of the chromatographic test
strip. A short period of time preferably means a time up to 20
seconds, particularly between 0.1 and 10 seconds. A transfer of the
sample is happening within the contact period.
[0049] In the next step, an elution medium is applied by dipping
the absorbent pad into the chromatographic liquid. The absorbent
pad is made of a particularly well-absorbing material which
delivers the liquid for the immunochemical or enzymatic reactions.
Preferred elution media are water or buffer solutions that are
conventionally used in immunoassays.
[0050] Alternatively the elution medium is contained in a reservoir
which may be integrated within the analysis device, e.g. as an
ampoule or a blister. The reservoir may be opened by fixing the
swab member or sample collection device on the detection part of
the device or by additional means.
[0051] After a time period of up to 15 minutes, preferably within
two to five minutes, the result can be read out in the detection
zone. The result is considered positive when at least a partial
area of the test line and the control line shows a color
change.
EXAMPLE
[0052] Test Kit for the Detection of Adenovirus from Patient's Eye
Swab
[0053] The structure of a test strip is depicted in FIG. 1.
[0054] The polyester fleece for the absorbent pad was manufactured
by Binzer, Hatzfeld, Federal Republic of Germany. The fleece is a
polyester fleece reinforced with 10% curalon. The thickness ranges
1 and 2 mm, the absorbance capacity is 1800 ml/m.sup.2.
[0055] The application/conjugate zone consists of 80 parts
polyester and 20 parts viscous staple fibers at a thickness of 0.32
mm and an absorbing capacity of 500 ml/m.sup.2. The fleece is
impregnated with the following solutions and then dried: 100 mmol/l
HEPES Buffer, pH 7.5, 100 mol/l NaCl, conjugate of gold particles
and anti-Hexon antibodies at a concentration that has an optical
density of 10 at 520 nm. Hexon is a protein that is common in the
capsid of human adenoviruses. The gold sol was manufactured
according to standard procedures (Fres. Nature Vol. 241, p. 20-22,
1973). Conjugation with the antibody was carried out according to
prior art procedure (J. Immunol. Meth. Vol. 34, p. 11-31, 1980).
The sample application takes place in the application/conjugate
zone.
[0056] The detection zone consists out of a nitrocellulose (NC)
membrane with a nominal pore size of 8 .mu.m and a thickness of 100
.mu.m produced by Schleicher & Schuell, Germany. The test line
contains a Hexon specific antibody (not labeled) which is specific
for a different epitope than the antibody immobilized on the gold.
The control contains the same antibody than the test line and binds
any excess of Hexon specific gold. The control line will appear in
any case even if Hexon is not present indicating that the test
worked correctly.
[0057] The chromatographic materials are in communication with each
other in order to create a fluid pathway.
[0058] A sample collection device is depicted in FIG. 3. The sample
collection material may consist of bibulous material such as highly
purified cotton fibers which are fixed to the plastic device by
ultrasonic welding. Alternative materials may be polyester, rayon,
polyamide or other fibrous polymeric materials.
[0059] A test kit for the detection of Adenovirus antigen (as
described in the example above) was used in the Emergency Room of
an Ophthalmologic Hospital to diagnose the clinical picture of a
"pink" eye. From every patient which has been tested with the test
kit a second sample was taken and analysed in the laboratory.
[0060] The laboratory reference method used in this study was a
combination of cell culture and immunfluorescence (IF) detection
(Rodrigues et al., Ophthalmology, March 1979; 86(3):452-64) which
is the current "laboratory gold standard" for determining the
presence of adenovirus in human ocular fluid.
[0061] Within the testing period the following results have been
achieved: TABLE-US-00001 Cell Culture/IF + - Adeno test kit + 5 2 -
0 21
[0062] These preliminary results are equivalent to a diagnostic
sensitivity of 100% and a diagnostic specificity of 91%. These.
values are superior to diagnostic characteristics of other state of
the art point-of-care devices.
* * * * *