Chemistry: analytical and immunological testing – Automated chemical analysis
Reexamination Certificate
2000-04-19
2002-07-30
Snay, Jeffrey (Department: 1743)
Chemistry: analytical and immunological testing
Automated chemical analysis
C436S063000, C436S163000, C436S169000, C600S573000, C600S584000, C604S318000, C604S358000
Reexamination Certificate
active
06426227
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to a device and method for analyzing bodily fluids of bodily secretions to diagnose a pathological state. More specifically, the present invention relates to a device and method for sampling bodily fluids collected by and contained in an absorbent pad and subsequently relaying the samples to an analyzer which performs a series of analytical tests either simultaneously or in sequence.
An early study of bacterial vaginosis (BV) involved comparisons of the pH of vaginal fluids of women known to be suffering from BV with those known to be free of the disease. Gardner, H. L., et al., Am. J. Obstet. Gynecol. 69:962 (1955). All of the BV positive women in the study were determined to have a vaginal fluid pH greater than 4.5, and 91% of these women had a vaginal fluid pH greater than 5.0. Of the normal (disease-free) women in the test, 92% were found to have vaginal pH between 4.0 and 4.7. The conclusion drawn from the study was that a vaginal pH equal to or greater than 5.0 in conjunction with other clinical criteria was indicative of the presence of BV.
Subsequent studies culminating by Amsel, R., et al., Am. J. Med. 74:14-22 (1983), resulted in a reduction of the pH threshold for BV to 4.5, and established the remaining criteria as vaginal fluid homogeneity, the whiff test (treatment with alkali followed by an olfactory test to detect for an amine odor), and the presence of clue cells. These are commonly referred to as the Amsel clinical criteria for BV. The conclusion was based on a study group of 397 women in which 81% of BV positive women were found to have a pH greater than 4.5 while only 23% of the normal women were found to have a vaginal fluid pH greater than 4.5.
Studies subsequent to the report by Amsel et al. have now adjusted the pH threshold to 4.7. One of these is the study of Holst, E., J. Clin. Microbiol. 28:2035-2039 (1990), in which 100% of the women diagnosed as BV positive by the Amsel criteria were reported to have vaginal fluid pH greater than 4.7. Another is the study by Eschenbach, D. A., Am. J. Obstet. Gynecol. 158(4):819-828 (1988), in which all 257 women in the study group who had at least 20% clue cells were shown to have a vaginal fluid pH greater than or equal to 4.7, leading to the conclusion that a threshold value of 4.7 correlated best with the other clinical evidence of BV. Krohn, M. A., et al., J. Clin. Microbiol. 27(6):1266-1271 (1989), also verified the correlation between the vaginal fluid pH threshold of 4.7 and the presence of clue cells, and Holmes, K. K., and coworkers further confirmed the pH 4.7 threshold as an indicator of BV—Holmes, K. K., et al., eds., Sexually Transmitted Diseases, McGraw-Hill, New York (1990), Chapter 46:527-545 (Holmes, K. K., et al.), and Chapter 47:547-559 (Hillier, S. L., et al.).
The whiff test, which is one of the Amsel criteria, originated in a study by Pheifer, et al., N. Engl. J. Med. 298:1429-1434 (1978), that reported the presence of a characteristic fishy amine odor upon the addition of 10% KOH to a vaginal fluid specimen from a woman with BV. The odor is caused by the alkaline volatilization of amine salts found in the vaginal fluid of women with BV. Unfortunately, the test is highly subjective, it exposes the health care worker to potential biological hazards, and it is disagreeable and vulnerable to error, since it is performed on a microscope slide which, due to the transient nature of the amine odor, must be placed directly under the nose and sniffed immediately after the addition of the KOH.
Alternatives to the whiff test are analytical procedures such as high voltage electrophoresis (Chen, K. C. S., et al., J. Clin. Invest. 63:828-835 (1979)), thin-layer chromatography (Chen, K. C. S., et al., J. Infect. Dis. 145:337-345 (1982), and Sanderson, B. E., et al., Br. J. Vener. Dis. 59:302-305 (1983)), gas chromatography (Gravett, M. G., et al. Obstet. Gynecol. 67:229-237 (1986), and Dravenieks, A., et al., J. Pharma. Sc. 59:495-501 (1970)), and high-performance liquid chromatography (Cook, R. L., et al., J. Clin. Microbiol. 30:870-877 (1992)). These procedures, although more accurate and reliable than the whiff test, are expensive, time-consuming, and not suitable for on-site testing in a physician's office or clinic.
Clue cells, which constitute a further Amsel criterion, are independently correlated with BV, and in the hands of a skilled microscopist are a very sensitive and specific indication of this infection. Clue cells are squamous vaginal epithelial cells found in vaginal fluid when BV is present. The cells are covered with numerous bacteria, giving them a stippled or granular appearance, and their borders are obscured or fuzzy because of the adherence of numerous rods or cocci. According to standard clinical practice, a diagnosis of BV is established when at least 20% of the detectable epithelial cells are clue cells. Holmes, et al., Sexually Transmitted Diseases, 2d ed., McGraw-Hill, Inc., New York, 1990.
Distinguishing between true clue cells in which the adherent bacteria completely obscure the edges of the cells and cells with simply a few adherent bacteria requires training and experience. One source of error is similarity in appearance between clue cells and trichomonads, white blood cells and other vaginal fluid components, frequently resulting in an incorrect identification of these cells as clue cells, and therefore false positive test results. Another is that clue cells when present are frequently obscured by numerous vaginal fluid components causing the clinician to miss the clue cells completely or to quantify them at levels below their actual level. This can result in a false negative test result. Therefore, it would be highly desirable to have a distinct analyte that is accurately and conveniently monitored and whose presence is correlated with clue cells.
U.S. Pat. No. 5,217,444 to Schoenfeld teaches an absorbent pad, for use in absorbing secretions from a person's body, which includes a pH indicator material indicating by a color change the acidity or alkalinity of a liquid coming into contact with it. The pH indicator material is wetted by the secretions absorbed by the pad, and thereby provides an indication of the health condition of the person's body.
U.S. Pat. No. 5,853,669 to Wolfbeis teaches a hydrophilic accommodating layer disposed on a hydrophobic mechanically stable support element, which layer contains an indicator dye in an immobilized form for the purpose of visual or optical indication of the pH of a sample which can be used as the pH indicator in the pad of Schoenfeld and in other applications as well.
The prior art teaches devices which, upon contact with liquid bodily secretions, has the capacity to change color by virtue of a pH indicator contained in the device. To this end, see U.S. Pat. Nos. 5,217,444 which is further described above and 5,769,813. In many cases an aberrant pH is an indication of a pathological state, for example an infection by a pathogen. Although the aforesaid prior art device indicates that there is a need for a specific medical diagnosis, it does not provide such a diagnosis. It does, however, suggest that there is sufficient biological material contained in the absorbent material of a tampon or hygienic pad to be used for medical diagnostics. This is especially true if analytical methods such as PCR or ELISA, which have signal amplification as inherent properties, are employed to make a final diagnosis.
Use of vaginal secretions contained in an absorbent pad (tampon or hygienic pad) offers a number of advantages when compared to other methods of obtaining samples of the same secretion. For example, most patients are capable of inserting and removing such a pad without aide. This means that a sample can be obtained without a gynecological examination. In addition, a patient suspecting an infection could bring or send a pad containing a sample to her doctor, making a subsequent appointment to receive the results and a prescription for treatment, if so req
Kritzman Amnon
Lilach Bonstein
Schoenfeld Alex
Common Sense Ltd.
Snay Jeffrey
Winston & Strawn
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