CN117849341A - Application of neopterin in asymptomatic neurosyphilis detection - Google Patents
Application of neopterin in asymptomatic neurosyphilis detection Download PDFInfo
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Abstract
The invention relates to application of neopterin in asymptomatic neurosyphilis detection. In particular, the invention provides a kit for detecting asymptomatic neural syphilis, comprising a first detection reagent for detecting the concentration of neopterin in cerebrospinal fluid and a second detection reagent for detecting the white blood cell count of the cerebrospinal fluid. The invention also provides the application of the neopterin in preparing products for detecting asymptomatic neurosyphilis. The invention further provides an evaluation system for evaluating a patient's risk of having asymptomatic neurosyphilis, the evaluation system comprising a detection module and an evaluation module and being evaluated based on the cerebrospinal fluid concentration of neopterin. The invention can be used for detecting asymptomatic neurosyphilis, and is particularly suitable for distinguishing asymptomatic neurosyphilis from latent syphilis.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to application of neopterin in asymptomatic neurosyphilis detection.
Background
Syphilis is a systemic, chronic transmission disease caused by infection of a human body by treponema pallidum subspecies pallidum (also known as treponema pallidum), which can cause damage to multiple systems and organs of the human body, produce multiple clinical manifestations, cause tissue destruction, malfunction and even endanger life. Syphilis is one of the most common sexually transmitted infections worldwide, and the estimated world health organization estimates that the number of new cases of syphilis in the population of 15-49 years worldwide is 630 ten thousand. At present, the incidence rate of syphilis is increased year by year, and the nerve syphilis is also increased year by year, and the reported incidence rate of recessive syphilis is increased to 10.75%, so that the high incidence rate and high disability rate of syphilis seriously threaten the health of people.
Nerve syphilis is a chronic infectious disease of brain, spinal cord and peripheral nerve damage caused by invasion of treponema pallidum into the nervous system, and can occur in various stages of syphilis disease course. It is generally believed that about 20% of untreated patients with syphilis may develop asymptomatic neurotoxic, with 10% of the latter being able to progress to symptomatic neurotoxic.
At present, no gold standard exists for diagnosing the nerve syphilis, and comprehensive analysis needs to be carried out according to the medical history, symptoms, physical signs, laboratories, electrophysiologies, neuropsychology, neuroimaging and the like of patients.
Patients with latent syphilis (recessive syphilis) have no clinical manifestations of any syphilis, no symptoms and signs of any impaired nervous system, and only positive serological tests for syphilis and positive serological tests for non-syphilis spirochetes. Syphilis serum fixation (syphilis serofast), i.e. the serum test of non-syphilis spirochete is maintained at a certain titer (generally at 1:8 or below, but not fresh beyond 1:8) after the standardized anti-syphilis treatment and the follow-up for a certain time (1 year of first-stage syphilis follow-up, 2 years of second-stage syphilis follow-up, 3 years of later-stage syphilis follow-up), and the re-infection, the nerve syphilis, the cardiovascular syphilis, the biological false positive and the like are eliminated, and the syphilis serum fixation is obtained. Asymptomatic neurosyphilis patients, although also free of obvious symptoms and signs, have abnormal changes in cerebrospinal fluid. Because no specific detection index exists in the existing nerve syphilis and the existing detection means are imperfect, the asymptomatic nerve syphilis is often misdiagnosed as the hidden syphilis or the hidden syphilis serum is fixed.
Because the asymptomatic nerve syphilis and the latent syphilis have common characteristics, no obvious symptoms and signs exist, the asymptomatic nerve syphilis and the latent syphilis are easily mixed in diagnosis, so that the asymptomatic nerve syphilis is not diagnosed in time, the optimal treatment time is missed, the illness progress and aggravation are caused, the symptomatic nerve syphilis is developed, serious consequences are formed, disability or life threatening are caused, serious economic and mental burden is caused for the country, the family and the patient, and the social instability factor is increased. Thus, there is a particular need in the art of syphilis diagnosis for techniques that allow for the timely and convenient detection of asymptomatic neurosyphilis.
Neopterin is a breakdown product of adenosine triphosphate and has been reported to be a marker of activation of the cellular immune system, but its role in diagnosis and treatment of patients with syphilis has never been reported, in particular, it has not been reported to be useful for asymptomatic neurotensin detection, and it has not been reported to be useful for distinguishing asymptomatic neurotensin from latent syphilis. The present inventors have found through studies that neopterin can be used to detect asymptomatic neural syphilis, and is particularly suitable for distinguishing latent syphilis from asymptomatic neural syphilis, thereby completing the present invention.
Disclosure of Invention
The first aspect of the invention provides a kit for detecting asymptomatic neurosyphilis, the kit comprising a first detection reagent and optionally a second detection reagent, the first detection reagent being a detection reagent for detecting the concentration of neopterin in cerebrospinal fluid, the second detection reagent being a detection reagent for detecting the white blood cell count of the cerebrospinal fluid.
In a second aspect, the invention provides the use of neopterin in the manufacture of a product for the detection of asymptomatic neurosyphilis.
In a third aspect the present invention provides an assessment system for assessing the risk of a patient suffering from asymptomatic neurosyphilis, the assessment system comprising a detection module and an assessment module; wherein:
the detection module comprises a first detection module for detecting the concentration of the cerebrospinal fluid of neopterin and a second detection module for detecting the white blood cell count of the cerebrospinal fluid; the evaluation module comprises a readable carrier storing evaluation rules;
the evaluation rule is: when the neopterin concentration of cerebrospinal fluid and/or the white blood cell count of cerebrospinal fluid is detected to be above the corresponding cut-off value, then the syphilis patient is assessed as being at high risk of having asymptomatic neurosyphilis; conversely, the syphilis patient is assessed as being at low risk of having asymptomatic neurosyphilis.
Compared with the prior art, the invention can separate the asymptomatic neural syphilis from other types of syphilis, especially latency Mei Duou, thereby realizing early identification, early treatment and prevention of the asymptomatic neural syphilis from developing into symptomatic neural syphilis with serious consequences.
Drawings
Fig. 1 shows the difference in the expression levels of neopterin in both the latent syphilis (LS, n=29) and asymptomatic neurosyphilis (ANS, n=30). Each box plot includes a lower quartile (lower horizontal line), a median (middle horizontal line), and an upper quartile (upper horizontal line). The Student's T-Test was used to compare normal distribution data between the two groups and the Mann-Whitney U Test was used to compare non-normal distribution data. The p value of 0.05 or less is considered to be statistically significant.
Fig. 2 shows the difference in expression levels of neurofilament light chain (NF-L) in both LS (n=29) and ANS (n=30) groups. Each box plot includes a lower quartile (lower horizontal line), a median (middle horizontal line), and an upper quartile (upper horizontal line). The Student's T-Test was used to compare normal distribution data between the two groups and the Mann-Whitney U Test was used to compare non-normal distribution data. The p value of 0.05 or less is considered to be statistically significant.
Fig. 3 shows the differences in expression levels of the clinical parameter cerebrospinal fluid white blood cell count (CSF wbc) in both LS (n=29) and ANS (n=30) groups. Each box plot includes a lower quartile (lower horizontal line), a median (middle horizontal line), and an upper quartile (upper horizontal line). The Student's T-Test was used to compare normal distribution data between the two groups and the Mann-Whitney U Test was used to compare non-normal distribution data. The p value of 0.05 or less is considered to be statistically significant.
Fig. 4 shows the difference in expression levels of clinical parameters cerebrospinal fluid protein (CSF protein) in both LS (n=29) and ANS (n=30) groups. Each box plot includes a lower quartile (lower horizontal line), a median (middle horizontal line), and an upper quartile (upper horizontal line). The Student's T-Test was used to compare normal distribution data between the two groups and the Mann-Whitney U Test was used to compare non-normal distribution data. The p value of 0.05 or less is considered to be statistically significant.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. However, the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by one of ordinary skill in the art without undue burden from the present disclosure, are within the scope of the present invention based on the embodiments described herein.
As described above, the present invention provides in a first aspect a kit for detecting asymptomatic neurosyphilis, the kit comprising a first detection reagent for detecting the concentration of neopterin in cerebrospinal fluid and optionally a second detection reagent for detecting the white blood cell count of the cerebrospinal fluid.
The inventors have studied and found that the area under the curve (AUC) of the subject's working characteristic curve (ROC, receiver operating characteristic curve) plotted against the cerebrospinal fluid concentration of neopterin is significantly greater than 0.7 and the corresponding p-value is significantly less than 0.05. Thus, the cerebrospinal fluid concentration of neopterin is particularly suitable for detecting whether a patient with syphilis without symptoms of impaired nervous system has asymptomatic neurotoxicity.
The inventors have also found that the area under the curve (AUC) of the subject's working characteristic curve (ROC, receiver operating characteristic curve) plotted against CSF wbc is also significantly greater than 0.7 and the corresponding p-value is significantly less than 0.05. Thus, CSF wbc is also suitable for detecting whether a patient with syphilis without symptoms of a damaged nervous system has asymptomatic neurotoxicity.
In some embodiments, the first detection reagent is an antibody or antibody pair against neopterin.
In some preferred embodiments, the antibody is a monoclonal antibody against neopterin.
In other preferred embodiments, the antibody pair consists of a combination of a coated antibody and a detection antibody for detection of neopterin.
In a second aspect, the invention provides the use of neopterin in the manufacture of a product for the detection of asymptomatic neurotoxicity.
In some preferred embodiments, the product is any one of a kit, a detection chip, and a detection array.
In some more preferred embodiments, the kit is a kit according to the first aspect of the invention.
In other preferred embodiments, the detection chip is a detection chip loaded with a first detection reagent and optionally a second detection reagent.
In other preferred embodiments, the detection array is a detection array loaded with a first detection reagent and optionally a second detection reagent. Wherein the first detection reagent is a detection reagent for detecting the concentration of neopterin in cerebrospinal fluid; the second detection reagent is a detection reagent for detecting the white blood cell count of the cerebrospinal fluid. That is, the detection chip and the detection array may be loaded with at least the first detection reagent, and may be further loaded with the second detection reagent.
In a third aspect, the invention provides an assessment system for assessing a patient's risk of suffering from asymptomatic neurosyphilis, the assessment system comprising a detection module and an assessment module; wherein:
the detection module comprises a first detection module for detecting the concentration of the cerebrospinal fluid of neopterin and a second detection module for detecting the white blood cell count of the cerebrospinal fluid; the evaluation module comprises a readable carrier storing evaluation rules;
the evaluation rule is: when the neopterin concentration of cerebrospinal fluid and/or the white blood cell count of cerebrospinal fluid is detected to be above the corresponding cut-off value, then the syphilis patient is assessed as being at high risk of having asymptomatic neurosyphilis; conversely, the syphilis patient is assessed as being at low risk of having asymptomatic neurosyphilis.
The cut-off value, also called cutoff value, is a judgment standard, which is a boundary value for judging the positive and negative of the test, and determines the normal value of a certain index to distinguish between normal and abnormal. The most common method of determining cut-off values is to plot the subject's working characteristics (receiver operating characteristic curve, ROC curves). The point on the ROC curve, which is the shortest distance from the upper left corner, is defined as the critical point, and the point is the point where the tangent line of the ROC curve intersects the curve, and the sensitivity and specificity are high. Determination of the cut-off value is well within the ability of those skilled in the art, e.g., obtainable by conventional SPSS software.
In some embodiments, the detection module comprises the first detection module. In this case, the evaluation rule is: when the concentration of neopterin in cerebrospinal fluid is detected to be higher than the corresponding cut-off value, then the syphilis patient is assessed as being at high risk of having asymptomatic neurotensin; conversely, the syphilis patient is assessed as being at low risk of having asymptomatic neurosyphilis.
In some embodiments, the detection module further comprises the second detection module. In this case, the detection module includes not only the first detection module but also the second detection module.
During detection, the first detection module can be started to detect the concentration of the neopterin cerebrospinal fluid, and then the second detection module is started to detect the CSF wbc; of course, the second detection module may be started to detect CSF wbc first, and then the first detection module may be started to detect neopterin; in addition, the first detection module and the second detection module can be started simultaneously, so that the simultaneous detection of the neopterin of cerebrospinal fluid and the white blood cell count can be realized.
In the evaluation, if the result of the evaluation according to neopterin and the result of the evaluation according to the white blood cell count are identical, the identical evaluation result is taken as the final evaluation result. If the results of the evaluation according to neopterin and the results of the evaluation according to white blood cell count are inconsistent, then either the results of the evaluation according to neopterin are used, or the detection and evaluation are performed again. In the case of performing the detection and evaluation again, if the result of the re-evaluation based on neopterin and the result of the re-evaluation based on the white blood cell count agree, the result of the re-evaluation based on neopterin is taken as the final evaluation result, and if the result of the re-evaluation based on neopterin and the result of the re-evaluation based on the white blood cell count agree again, the result of the evaluation based on neopterin and the white blood cell count agree with each other two times before and after. If the results of the evaluation according to neopterin and the two times before and after the white blood cell count are identical, the result of the re-evaluation according to neopterin is in control.
Examples
The present invention will be illustrated by examples below, but the scope of the present invention is not limited to these examples.
1. Conditions of the subject
In an embodiment of the present invention, the present inventors recruited 59 patients affiliated with Beijing forum Hospital, university of capital medical science, including 29 Latent Syphilis (LS) patients and 30 Asymptomatic Neurosyphilis (ANS) patients, according to the national health industry standard (WS 273-2018) of China in 2018. None of these patients was diagnosed with aids. The specific judgment criteria for patients with latent syphilis and asymptomatic neurosyphilis are as follows:
1.1 criteria for Latent Syphilis (LS)
(1) There is a history of syphilis infection;
(2) Serum non-treponema pallidum test positive;
(3) Positive serum treponema pallidum test;
(4) Absence of symptoms and signs of neurological damage; (5) no abnormality in CSF was found.
1.2 judgment criteria for Asymptomatic Neural Syphilis (ANS)
(1) There is a history of syphilis infection;
(2) Positive serum treponema pallidum test;
(3) Absence of symptoms and signs of neurological damage;
(4) CSF VDRL (TRUST) test positive; or negative in CSF VDRL (TRUST) assay, while positive in CSF treponema pallidum assay or > 5/μl of CSF white blood cells or >45mg/dl of CSF protein.
The embodiments of the present invention were approved by the ethics committee of the Beijing forum hospital affiliated with the university of capital medical science and all participants provided signed informed consent.
2. Sample collection
Patient CSF samples are collected as part of a routine diagnostic test. After lumbar puncture, a 2mL CSF sample was left. The supernatant of CSF was extracted by centrifugation at 1500rpm for 10 minutes and stored at-80℃until analysis.
3. CSF concentration determination of neopterin and filamin light chain (NF-L)
The concentration of CSF neopterin and NF-L was measured using a commercial enzyme-linked immunosorbent assay kit (IBL, hamburg, germany) according to the manufacturer's instructions. The optical density was measured at 450nm using a microplate reader (Spectra Max M2, england). CSF neopterin levels are expressed in nmol/L and NF-L levels are expressed in pg/mL.
4. Statistical analysis of data
Statistical analysis of all data was performed using the R program (https:// cran. R-project. Org /), SPSS (IBM Corporation, new York, NY, USA) or GraphPad Prism7 (GraphPad Software, la Jolla, calif., USA). For normally distributed data, data is represented as mean ± standard deviation, while for non-normally distributed data, data is represented as median (quarter bit spacing). The Student's T-Test was used to compare normal distribution data between two groups and the Mann-Whitney U Test was used to compare non-normal distribution data. The p value of 0.05 or less is considered to be statistically significant.
5. Data processing
(1) Detection of group differences
Statistical analysis was performed on the differences between the two groups of different parameters using GraphPad Prism7 software. For normally distributed data, data is represented as mean ± standard deviation, while for non-normally distributed data, data is represented as median (quarter bit spacing). The Student's T-Test was used to compare normal distribution data between two groups and the Mann-Whitney U Test was used to compare non-normal distribution data. The p value of 0.05 or less is considered to be statistically significant.
(2) ROC analysis
ROC analysis was performed using SPSS software to evaluate the diagnostic accuracy of each parameter. AUC was used for the discrimination evaluation of each parameter.
6. Analysis of results
Figures 1 to 4 show the differences in expression levels of neopterin, NF-L and clinical parameters white blood cell count and protein level of CSF in both the latent syphilis (LS, n=29) and asymptomatic neurosyphilis (ANS, n=30) groups. Each box plot includes a lower quartile (lower horizontal line), a median (middle horizontal line), and an upper quartile (upper horizontal line). The Student's T-Test was used to compare normal distribution data between two groups and the Mann-Whitney U Test was used to compare non-normal distribution data. The p value of 0.05 or less is considered to be statistically significant.
As can be seen from fig. 1 to 4, the expression levels of neopterin and clinical parameters of CSF, white blood cell count and protein level, were significantly different in both the latent and asymptomatic neurosyphilis groups, but the expression levels of NF-L were not statistically significantly different in both the latent and asymptomatic neurosyphilis groups.
Table 1 shows the subject work profile analysis data for neopterin, NF-L, and clinical parameters white blood cell count and protein level.
As can be seen from table 1, the concentration of neopterin and the white blood cell count of the cerebrospinal fluid are significantly different between latent syphilis and asymptomatic neurosyphilis (p-value is less than 0.05) and the AUC of neopterin is significantly greater than 0.7, so that both the concentration of neopterin and the white blood cell count of the cerebrospinal fluid can be used to detect whether a syphilis patient without symptoms of a neurological impairment suffers from asymptomatic neurosyphilis, in particular to separate latent syphilis from asymptomatic nerve Mei Duou, but the AUC of neopterin is higher than the white blood cell count in the cerebrospinal fluid, and therefore the concentration of neopterin in the cerebrospinal fluid is more advantageous in distinguishing latent syphilis from asymptomatic neurosyphilis areas than white blood cell counts. However, the concentration of NF-L in cerebrospinal fluid and protein levels do not separate latent syphilis from asymptomatic nerves Mei Duou, which are consistent with clinical cerebrospinal fluid parameter testing.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. A kit for detecting asymptomatic neurosyphilis, characterized in that the kit comprises a first detection reagent and optionally a second detection reagent, the first detection reagent being a detection reagent for detecting the concentration of neopterin in cerebrospinal fluid, the second detection reagent being a detection reagent for detecting the white blood cell count of the cerebrospinal fluid.
2. The kit of claim 1, wherein:
the first detection reagent is an antibody or antibody pair against neopterin.
3. The kit of claim 2, wherein:
the antibody is a monoclonal antibody against neopterin; and/or
The antibody pairs consist of a combination of coated antibodies and detection antibodies for detection of neopterin.
4. Use of neopterin in the manufacture of a product for detecting asymptomatic neurosyphilis.
5. The use according to claim 4, characterized in that the use is of neopterin as a molecular marker for asymptomatic neurotensin.
6. The use according to claim 4, characterized in that:
the product is any one of a kit, a detection chip and a detection array.
7. The use according to claim 6, characterized in that:
the kit is the kit of any one of claims 1 to 3; the detection chip is a detection chip loaded with a first detection reagent and an optional second detection reagent; the detection array is a detection array carrying the first detection reagent and optionally the second detection reagent;
the first detection reagent is used for detecting the concentration of neopterin in cerebrospinal fluid; the second detection reagent is a detection reagent for detecting the white blood cell count of the cerebrospinal fluid.
8. An assessment system for assessing the risk of a patient suffering from asymptomatic neurosyphilis, characterized in that the assessment system comprises a detection module and an assessment module; wherein:
the detection module comprises a first detection module for detecting the concentration of the cerebrospinal fluid of neopterin and a second detection module for detecting the white blood cell count of the cerebrospinal fluid; the evaluation module comprises a readable carrier storing evaluation rules;
the evaluation rule is: when the neopterin concentration of cerebrospinal fluid and/or the white blood cell count of cerebrospinal fluid is detected to be above the corresponding cut-off value, then the syphilis patient is assessed as being at high risk of having asymptomatic neurosyphilis; conversely, the syphilis patient is assessed as being at low risk of having asymptomatic neurosyphilis.
9. The evaluation system according to claim 8, wherein:
the evaluation rule is: when the concentration of neopterin in cerebrospinal fluid is detected to be higher than the corresponding cut-off value, then the syphilis patient is assessed as being at high risk of having asymptomatic neurotensin; conversely, the syphilis patient is assessed as being at low risk of having asymptomatic neurosyphilis.
10. The evaluation system according to claim 8, wherein:
the evaluation rule is: when the neopterin concentration of cerebrospinal fluid and the white blood cell count of cerebrospinal fluid are detected to be higher than the respective cut-off values, then the syphilis patient is assessed as having a high risk of having asymptomatic neurosyphilis; conversely, the syphilis patient is assessed as being at low risk of having asymptomatic neurosyphilis.
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