CN111721941B - Device for judging sepsis infection condition and application thereof - Google Patents

Device for judging sepsis infection condition and application thereof Download PDF

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CN111721941B
CN111721941B CN202010693297.XA CN202010693297A CN111721941B CN 111721941 B CN111721941 B CN 111721941B CN 202010693297 A CN202010693297 A CN 202010693297A CN 111721941 B CN111721941 B CN 111721941B
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cell count
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蒋兴宇
牟磊
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Southwest University of Science and Technology
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Abstract

The invention provides a device for judging sepsis infection and application thereof. The input variables of the device comprise the concentrations of C-reactive protein, procalcitonin and interleukin-6, and the concentrations of the three markers are used as input variables to construct a device for judging sepsis infection. The output variable of the device is mScare or mScaoreplus. The mScore or mScorplus is used as a new index of sepsis infection condition to judge the infection degree of a patient, the accuracy is high, bacterial infection and virus infection can be distinguished, the accurate diagnosis of a clinician is facilitated, and the mScorplus is an effective tool for detecting infection, distinguishing bacterial infection and virus infection and monitoring diseases.

Description

Device for judging sepsis infection condition and application thereof
Technical Field
The invention relates to the technical field of medical identification, in particular to a device for judging sepsis infection and application thereof.
Background
Sepsis (septicemia) refers to an acute systemic infection that occurs when various pathogenic bacteria invade the blood circulation and grow and reproduce in the blood, producing toxins. Bacteria that invade the blood stream are cleared by the body's defensive functions and are called bacteremia when they have no obvious toxemia symptoms. Sepsis, which is accompanied by multiple abscesses and has a longer course, is called sepsis (sepis).
Sepsis is a life-threatening disease caused by a deregulated inflammatory immune response, a systemic infection caused by bacteria, bacteria and viruses, leading to organ and immune system dysfunction. The incidence rate of sepsis is high, the illness state is dangerous, and the death rate is high. To treat sepsis, the first step is to learn pathogen information and host immune system information. Bacterial culture is the primary strategy to confirm the presence of bacteria.
The time required for traditional sepsis diagnosis is 1-5 days from bacterial culture to identification of the resulting small molecules. Because of the lack of a bacterial culturing step, obtaining detailed information of living bacteria and antibiotic susceptibility information directly from whole blood is difficult and time consuming. Once the pathogen is isolated and cultured, an antibiotic susceptibility test can be performed to understand the susceptibility (or tolerance) of the pathogenic microorganism to various antibiotics, thereby directing the use of the antibiotics. However, it can be seen from the novel coronavirus covd-19 that the isolation and cultivation of pathogens is dangerous and requires the operator to work with protective clothing between ultra-clean rooms.
POCT (Point-of-Care Testing, point-of-Care) sensors for pathogen recognition are mainly based on magnetic particle enrichment of DNA or RNA, followed by detection of the corresponding target using PCR amplification. However, this method is commonly used for common pathogenic microorganisms and is difficult to detect even by multiplex PCR once the unusual pathogens are encountered. POCT sensors for generating pathogen information are still in the development stage.
Due to the lack of a method for rapidly judging the sepsis condition of a patient, the condition of the patient can rapidly develop, and once the optimal treatment time is missed, the mortality rate can be greatly improved. Patients' conditions often develop rapidly in ward, especially ICU ward, and therefore, there is a great need for a rapid, simple to use, accurate POCT sensor.
In addition to starting from pathogen information, the development of the patient's immune system and organ function can be assessed to determine sepsis infections, such as analysis and use of whole blood count, cellular information (e.g., cell rigidity and cell motility), protein biomarkers, and some small molecules (e.g., lactic acid). These changes in cells and biological macromolecules often more reflect changes in information and disease progression in the patient. In particular, changes in some cytokines often represent abnormalities in the immune system. Cytokine Storm (Cytokine Storm) is a phenomenon in which cytokines are rapidly produced in large amounts when the immune system is against pathogens, and the cytokines signal immune cells (e.g., T cells and macrophages) to spread to the site of infection, and at the same time, the cytokines in turn activate secretory cells, stimulating them to produce more cytokines. Thus, by monitoring the content of these cells and biological macromolecules, it is possible to use for knowing patient information.
Host information is more readily available than bacterial information and can directly reflect the immune response of everyone. In order to make the determination of protein biomarkers portable, integrated, small, fast POCT platforms have been developed in combination with microelectromechanical systems (Micro-Electro-Mechanical System, MEMS), microfluidic chips and microsensors.
Therefore, how to quickly and accurately use the detection data of these biomarkers to obtain health data such as infection conditions, vital signs, etc. of individuals so as to prepare POCT sensors, so as to realize real-time monitoring of ICU patients is a problem in the art that needs to be solved.
Disclosure of Invention
In view of the problems of the prior art, the present invention provides a device for determining the condition of sepsis infection, which can guide a doctor in early diagnosis of sepsis in ICU patients, and the use thereof.
To achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a device for determining the condition of a sepsis infection, the input variables of the device being the concentration of C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6).
The device provided by the invention takes the concentration of three biomarkers of CRP, PCT and IL-6 as input variables. Since the cytokine IL-6 in the patient's body is expressed first and increases rapidly after infection with virus or bacteria, PCT and CRP are then expressed gradually and peak. Normally, the IL-6 concentration is less than 50pg/mLPCT concentration is less than 0.5ng/mL and the CRP concentration is less than 10. Mu.g/mL. Concentration variation intervals of CRP, PCT and IL-6 are close to 6 orders of magnitude, and erroneous judgment is easily caused by only one biomarker. Meanwhile, although PCT and CRP are widely used for sepsis monitoring, the downward trend in PCT and CRP may not indicate improvement in patients, especially when treated with antibiotics and other drugs. In this clinical setting PCT and CRP with antibiotics gradually decline, but sepsis is still severe.
Therefore, the combined detection of the three biomarkers can greatly improve the diagnosis accuracy and reduce the disease burden. In the device provided by the invention, the combined use of multiple biomarkers can avoid misdiagnosis aiming at single biomarkers, help clinicians to accurately diagnose and guide the accurate use of antibiotics, and play a vital role in the field of precision medicine. For ICU patients, systemic inflammatory response syndrome is very common, and the combined detection of three biomarkers can guide doctors to early diagnosis of sepsis in ICU patients.
Preferably, the concentrations of CRP, PCT and IL-6 are determined using microfluidic in vitro diagnostic immune chips. The concentration of each biomarker in the serum sample of the patient can be simultaneously and accurately obtained by utilizing the microfluidic in-vitro diagnosis immune chip.
Preferably, the input variables of the device further include white blood cell count and neutrophil percentage.
The white blood cell count and the neutrophil percentage are blood routine data. Among them, leukocytes are classified into circulating granulocytes (Circulating granulocytes, CGP) and marginal granulocytes (Marginal granulocytes, MGP). In the present invention, the white blood cells measured by white blood cell count are CGP. When infected with virus, MGP increases, resulting in a decrease in CGP. Although white blood cell counts and neutrophil percentages often lead to misdiagnosis, their abnormal elevation often represents the likelihood of bacterial infection.
In the present invention, new indicators mScare and mScarPlus for diagnosing infection are established based on diagnostic data of various biomarkers and blood routine.
The computation formula of mScore is shown in equation (1):
here, it should be noted that PCT is present in ng/mL, CRP in μg/mL and IL-6 in pg/mL. Wherein x is a calculation coefficient of PCT, and x is any number between 1 and 5; y is a calculation coefficient of CRP, and y is taken from any number between 1 and 5; z is the calculated coefficient of IL-6, and z is taken from any number between 1 and 5.
Preferably, the computation formula of the mScore is shown in equation (2):
as a preferred embodiment of the present invention, the output variable of the device for determining sepsis infection is mscore, and the calculation formula of the mscore is as follows:
when 4 is multiplied by 10 9 The white cell count of L is less than or equal to 10 multiplied by 10 9 And when the ratio of the ratio to the L is 50 percent or more and the percentage of the neutrophils is 70 percent or less, the calculation formula of the mScorplus is shown as an equation (3):
mScoreplus＝mScore (3)；
when the white blood cell count is less than 4 multiplied by 10 9 When the percentage of/L or neutrophil is less than 50%, the calculation formula of the mScorplus is shown in the equation (4):
mScore = mScore +5× (white blood cell count-4) +2× (neutrophil percentage-50) (4);
when the white blood cell count is more than 10 multiplied by 10 9 When the percentage of/L or neutrophil is more than 70%, the calculation formula of the mScorplus is shown in the equation (5):
mScore = mScore +5× (white blood cell count-10) +2× (neutrophil percentage-70) (5).
mScare and mScarePlus are effective tools for detecting infection, distinguishing between bacterial and viral infection, and monitoring disease.
As a preferred technical solution of the invention, the device comprises the following units:
and a detection unit: detecting the concentration of C-reactive protein, procalcitonin and interleukin-6 in the sample;
analysis unit: taking the detected concentrations of the C-reactive protein, procalcitonin and interleukin-6 as input variables, and inputting the input variables into a calculation formula for analysis;
an evaluation unit: outputting the mScore and/or mScorplus of the individual corresponding to the sample, and judging the sepsis infection condition of the individual.
Preferably, the detection unit comprises a microfluidic in-vitro diagnostic immune chip; preferably, the detection unit further detects the value of the white blood cell count and the percentage of neutrophils in the sample.
Preferably, mScore > 30 is judged as positive for infection, and mScore < 30 is judged as negative for infection;
preferably, mScorplus is greater than or equal to 80 and is judged to be positive for bacterial infection, mScorplus is less than or equal to 30 and is less than or equal to 80 and is judged to be positive for viral infection, and mScorplus is less than 30 and is judged to be negative for infection.
In a second aspect, the use of a device for determining the condition of a sepsis infection according to the first aspect for the manufacture of a point of care test (POCT) sensor.
The numerical ranges recited herein include not only the recited point values, but also any point values between the recited numerical ranges that are not recited, and are limited to, and for the sake of brevity, the invention is not intended to be exhaustive of the specific point values that the recited range includes.
Compared with the prior art, the invention has at least the following beneficial effects:
(1) The device provided by the invention takes three biomarkers of CRP, PCT and IL-6 as input variables, the three biomarkers have complementarity, and when the concentrations of CRP, PCT and IL-6 are used in combination, misdiagnosis aiming at a single biomarker can be avoided, and a clinician is helped to accurately diagnose and guide the accurate use of antibiotics; for ICU patients, CRP, PCT and IL-6 may guide doctors in early diagnosis of sepsis in ICU patients;
(2) The device for judging sepsis infection provided by the invention takes the concentrations of CRP, PCT and IL-6 as input variables to obtain newly defined mScore and mScore plus, wherein the sizes of the mScore and mScore plus reflect the severity of infection to a certain extent, and the detection of a plurality of samples has no misjudgment, so that misdiagnosis is reduced; and as can be seen from the receiver operation characteristic curve, the AUC value of the mScore is larger, and the prediction performance is better;
(3) The mScare and mScarePlus provided in the present invention are effective tools for detecting infection and distinguishing bacterial and viral infections, and at the same time, the trend of mScare can also show the severity of infection, which can help clinicians to accurately diagnose and guide accurate use of antibiotics and related drugs.
Drawings
FIG. 1 is a graph of the variation of CRP, PCT and IL-6 concentrations during infection in patients.
Fig. 2 is a coefficient optimization graph of mScore.
FIG. 3 is a graph showing the distribution of mScare values in the infected and uninfected state of example 2.
Fig. 4 is a waterfall plot of the mScore level for each sample of example 2.
FIG. 5 is a ROC graph of PCT, CRP, IL-6 and mScore for diagnosing bacterial infection in example 2.
FIG. 6 (a) is a graph showing the numerical distribution of the white blood cell count at the time of bacterial infection, viral infection and non-infection in example 2.
FIG. 6 (b) is a graph showing the numerical distribution of the percentages of neutrophils in example 2 when infected with bacteria, when infected with viruses, and when not infected with viruses.
FIG. 6 (c) is a graph showing the mScorplus number distribution of bacterial infection, viral infection and non-infection in example 2.
FIG. 7 (a) is a histogram of the fold increase in biomarker concentration in a representative serum sample of example 2.
FIG. 7 (b) is a bar graph of mScare and mScarePlus levels for representative serum samples in example 2.
FIG. 8 (a) is a graph showing the change in the concentrations of PCT, CRP and IL-6 in ICU patient 1 of example 3.
FIG. 8 (b) is a graph showing the variation of mScore values for ICU patient 1 in example 3.
Detailed Description
The following embodiments are further described with reference to the accompanying drawings, but the following examples are merely simple examples of the present invention and do not represent or limit the scope of the invention, which is defined by the claims.
Example 1
In this example, an inflammation index, mScare, was defined for more accurate detection of infection.
(1) The changes in CRP, PCT and IL-6 concentrations during infection in patients are shown in FIG. 1; in general, higher concentrations of PCT, CRP and IL-6, i.e. indicating more severe infections, the combination of these three biomarkers can complement each other and increase early diagnostic rates;
a new index mScore was defined based on the concentrations of these three biomarkers; the mScare was calculated as follows:
wherein x, y, z: calculation coefficients for different biomarkers.
First, assuming that all coefficients are 1 and only one of the coefficients is changed, then the AUC value of the resulting mScore is calculated. As shown in fig. 2, when x=1, y=1, and z=3, the AUC has a maximum value when compared to x=1, y=1, and z=1, or 2, and the AUC thereof=0.812.
By optimizing the coefficients in front of the different biomarkers we derive the following formula:
(2) Clinical variables such as blood test results, age and gender are also commonly used to determine patient disease status through communication with clinicians. The predictive performance of disease detection can be further enhanced by integrating this information into our established infection index, mScore. At this time, the index of further optimization was expressed by mScorPlus.
The specific calculation formula of mScorPlus is as follows:
when the white blood cell count and the neutrophil percentage have natural ranges (i.e., the white blood cell count is 4×10 or more 9 L is not more than 10×10 9 /L, or, when the percentage of neutrophils is 50% or more and 70% or less),
mScoreplus＝mScore；
when the white blood cell count is less than 4×10 9 When the/L or neutrophil percentage is less than 50%, we calculate mscore plus by the following formula:
mScore = mScore +5× (white blood cell count-4) +2× (neutrophil percentage-50);
when the white blood cell count is greater than 10×10 9 When the/L or neutrophil percentage is greater than 70%, we calculate mscore plus by the following formula:
mScore = mScore +5× (white blood cell count-10) +2× (neutrophil percentage-70).
Example 2
This example was used to study the clinical value of mScore and mScore plus.
In this example, 70 serum samples were used, including 36 bacterial infection samples, 24 viral infection samples, and 10 healthy human serum samples, all from the chinese people release army 306 hospital, to demonstrate the clinical value of the new indices mScore and mScore plus based on various biomarkers and CBC information.
(1) Clinical value of mScore
1. mScare is more effective in detecting infection than single biomarker
As shown in FIG. 3, the mScore has a P value of less than 0.0001, and the infected and uninfected mScores are 74.37.+ -. 48.69 and 3.04.+ -. 0.54, respectively. There was no false determination of whether an mScare is a single indicator, as opposed to an mScare, which distinguishes between infected and uninfected.
2. mScore has higher accuracy in distinguishing bacterial and viral infections
As shown in fig. 4, it can be seen from the waterfall plot (waterfall plot) that bacterial infection is higher than viral infection.
The area under the receiver operating characteristic curve (receiver operating characteristic curve, ROC curve) shows the area under the curve value (Area under the Curve, AUC) for each biomarker in diagnosing bacterial infection in a patient, when auc=1, with this predictive device at least one threshold is present to give a perfect prediction; when 0.5< AUC <1, a better random device, the larger the AUC value, the better the predictive performance of the biomarker.
As shown in FIG. 5, the ROC curve can be seen from the ROC curves of PCT, CRP, IL-6 and mScore. AUC of PCT, CRP, IL-6 and mScore are 0.77, 0.67, 0.70 and 0.81, respectively; thus, mScare has the highest accuracy in distinguishing bacterial infections.
(2) Clinical value of mScorPlus
In comparison with IL-6 and CRP, the concentration of PCT in viral infection is lower than that in bacterial infection. mScare showed a similar trend as PCT. To better differentiate bacterial and viral infections, we incorporate CBCs results into the mScore to yield a more accurate indicator: mScorPlus.
When infected with virus, the marginal granulocyte MGP increases, resulting in a decrease in circulating granulocyte CGP, which we commonly measure is CGP. Although white blood cell counts and neutrophil percentages often lead to misdiagnosis, their abnormal elevation, as shown in fig. 6 (a) and 6 (b), often represents the likelihood of bacterial infection. Thus, the device mScarePlus was also obtained using the white blood cell count and the neutrophil percentage as influencing factors, and the resulting mScarePlus profile is shown in FIG. 6 (c), which is capable of distinguishing between bacterial infection, viral infection and uninfected samples significantly.
Thus, by combining white blood cell count and neutrophil percentage information into an mScore, the mScore plus can accurately distinguish between bacterial and viral infections.
As shown in FIG. 7 (a), whose abscissa indicates serum sample number, PCT, CRP and IL-6 concentrations of all representative serum samples are abnormal, it is often difficult for a single biomarker to make a correct judgment because their concentrations vary greatly, even without any abnormality. Misleading occurs if we use only one of PCT, CRP and IL-6 as a disease state.
As shown in fig. 7 (b), all patients were found to be correctly diagnosed by examining the mScore and mScore plus of representative serum samples. Although PCT has been used as an important biomarker for infection in ICU patients at present, IL-6 is generally more sensitive than PCT at the early stage of infection, as demonstrated by the detection of serum samples 10, 24, 52, 28 and 40.
Meanwhile, when comparing the values of mScore and mScore plus, we found that for viral infection, mScore plus may be smaller than mScore, but not in bacterial infection, where the dashed boxes in fig. 7 (a) and 7 (b) are viral infected patients.
Example 3
This example is used to demonstrate that the trend of the biomarkers provided in the invention conforms to the theoretical trend.
Patient 1 had long failed to receive gastrointestinal feeding for the duodenal malignancy prior to entering the ICU, and therefore needed to be protected from fungal infection and secondary infection.
After entering the ICU, about 150mL of blood is drawn from the peritoneal drainage tube, which can lead to a drop in blood pressure and further to hemorrhagic shock. The immediate detection of inflammatory biomarkers using our dynamic multiplex POC immunoassay is very helpful for judging and controlling infections.
As shown in fig. 8 (a) and 8 (b), the patient was diagnosed with mild abdominal infection based on the detection results and clinical symptoms. Meropenem for injection is used to treat infections. However, a significant increase in IL-6 on the next day indicates uncontrolled infection. The patient was initially identified as being an infection caused by gram-positive cocci (alpha hemolytic streptococcus). Meropenem is used with teicoplanin to treat bacterial infections until the infection is fully controlled.
Meanwhile, this example also demonstrates that the trend of the mScore can also show the severity of the infection.
The size of the mScare reflects to some extent the severity of the infection, as defined by the mScare. As shown in fig. 8 (b), the trend of the mScore can also effectively monitor infection, and the exacerbation and decay of infection can be seen from the increase and decrease of the mScore.
In summary, how to accurately and rapidly obtain the concentrations of various biomarkers is important for accurately and timely determining the condition of a patient. The combination of CRP, PCT and IL-6 has been shown to be complementary and to improve diagnostic accuracy. mScare based on these biomarker combinations may further enhance the predictive performance of disease monitoring. The novel indexes mScare and mScarePlus provided by the invention can improve the clinical significance of single biomarkers, can jointly evaluate the physiological condition of a patient by combining CRP, PCT and IL-6, are effective tools for detecting infection and distinguishing bacterial and viral infection, can reduce the possibility of misdiagnosis, and improve the accuracy of early diagnosis.
The applicant declares that the above is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be apparent to those skilled in the art that any changes or substitutions that are easily conceivable within the technical scope of the present invention disclosed by the present invention fall within the scope of the present invention and the disclosure.

Claims (6)

1. A device for determining the condition of a sepsis infection, wherein the input variables of the device include concentrations of C-reactive protein, procalcitonin, and interleukin-6, and the input variables of the device further include white blood cell count and neutrophil percentage;
the output variable of the device is mScorplus;
when 4 is multiplied by 10 9 The white cell count of L is less than or equal to 10 multiplied by 10 9 And when the ratio of the ratio to the L is 50 percent or more and the percentage of the neutrophils is 70 percent or less, the calculation formula of the mScorplus is shown as an equation (3):
mScoreplus＝mScore (3)；
when the white blood cell count is less than 4 multiplied by 10 9 When the percentage of/L or neutrophil is less than 50%, the calculation formula of the mScorplus is shown in the equation (4):
mScore = mScore +5× (white blood cell count-4) +2× (neutrophil percentage-50) (4);
when the white blood cell count is more than 10 multiplied by 10 9 When the percentage of/L or neutrophil is more than 70%, the calculation formula of the mScorplus is shown in the equation (5):
mScore = mScore +5× (white blood cell count-10) +2× (neutrophil percentage-70) (5);
the mScorplus is more than or equal to 80 and is judged to be positive for bacterial infection, the mScorplus is more than or equal to 30 and is less than or equal to 80 and is judged to be positive for viral infection, and the mScorplus is less than 30 and is judged to be negative for infection;
wherein, the computation formula of the mScare is shown in the equation (1):
wherein x is the calculation coefficient of procalcitonin, and x is any number between 1 and 5; y is the calculation coefficient of the C reaction protein, and y is taken from any number between 1 and 5; z is the calculated coefficient of interleukin-6, and z is taken from any number between 1 and 5;
the device comprises the following units:
and a detection unit: detecting the concentration of C-reactive protein, procalcitonin and interleukin-6 in the sample;
analysis unit: taking the detected concentrations of the C-reactive protein, procalcitonin and interleukin-6 as input variables, and inputting the input variables into a calculation formula for analysis;
an evaluation unit: outputting the mScorplus of the individual corresponding to the sample, and judging the sepsis infection condition of the individual.
2. The device for determining sepsis infections according to claim 1, wherein the concentrations of C-reactive protein, procalcitonin and interleukin-6 are determined using a microfluidic in vitro diagnostic immuno-chip.
3. The apparatus for determining sepsis infections according to claim 2, wherein the mScore is calculated as shown in equation (2):
4. the device for determining the condition of a sepsis infection according to claim 1, wherein the detection unit comprises a microfluidic in vitro diagnostic immuno-chip.
5. The device for determining the condition of a sepsis infection according to claim 4, wherein the detection unit further detects the value of white blood cell count and percent neutrophils in the sample.
6. Use of a device according to any one of claims 1 to 5 for determining the condition of a sepsis infection in the manufacture of an on-line detection sensor.
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