CN114167062B - Marker and method for early diagnosis of intraperitoneal infectious complications - Google Patents

Marker and method for early diagnosis of intraperitoneal infectious complications Download PDF

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CN114167062B
CN114167062B CN202010950029.1A CN202010950029A CN114167062B CN 114167062 B CN114167062 B CN 114167062B CN 202010950029 A CN202010950029 A CN 202010950029A CN 114167062 B CN114167062 B CN 114167062B
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leakage
anastomotic
cavity
body cavity
patients
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CN114167062A (en
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吴舟桥
季加浮
李子禹
石晋瑶
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Beijing Cancer Hospital
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Beijing Cancer Hospital
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Abstract

The invention relates to a marker for early diagnosis of an infectious complication in a body cavity, and a related kit and a device, and simultaneously constructs a scoring method for the infectious complication in the cavity, a detection method for the risk level of the infectious complication in the cavity, and a method for screening the marker for the infectious complication in the body cavity. The invention realizes early diagnosis of infection in the body cavity, can effectively guide clinical intervention, reduces the death rate of patients in the perioperative period, and has extremely high clinical application value.

Description

Marker and method for early diagnosis of intraperitoneal infectious complications
Technical Field
The present application relates to the field of biomedical technology, and in particular, to a marker, method and device for early diagnosis of intraperitoneal infectious complications.
Background
The postoperative local infectious complications of the abdominal organ tissues are important factors for restricting the postoperative rehabilitation of patients. Such as anastomotic leakage, which is one of the most serious postoperative complications of intraperitoneal surgery, such as gastrointestinal surgery, occurs in association with the healing failure of the anastomotic orifice after reconstruction of the digestive tract. Once anastomotic leakage occurs, it can cause infection of abdomen and pelvic cavity, abscess, peritonitis, and even sepsis causes perioperative death of the patient. From literature reports, the incidence of anastomotic leakage after gastric surgery is between 1 and 6%, and the incidence of colorectal anastomotic leakage is between 4 and 33%. The anastomotic leakage seriously affects the postoperative safety of patients and places a serious burden on the medical and health system. From the foreign literature or domestic summarized data, about one third of perioperative deaths are directly related to anastomotic stoma leakage, and are the most main causes of perioperative deaths of patients with gastrointestinal tract operations at present. The anastomotic leakage extends the patient's stay in hospital and economic costs during stay in hospital. Although there is still a lack of domestic hygienic and economic analysis of stoma leakage, the stoma leakage greatly increases the hospitalization cost of the patient from the analysis of related data in the united states, the stomach stoma leakage is about $4.6, the colorectal is about $3.4, the height is about 3 times higher for other patients, and the hospitalization time is about 2 times longer for other patients. Even if the illness state is relieved after treatment, the postoperative life quality of patients with anastomotic stoma leakage is obviously inferior to that of other patients. The anastomotic leakage is also a high risk factor of local recurrence of tumors, and seriously affects the treatment effect and even the survival time limit of tumor patients.
For local infectious complications of body cavities, the diagnostic efficacy of clinical routine laboratory tests is limited. White blood cell count and CRP are widely used as routine laboratory test items for clinical diagnosis of postoperative infectious complications. In recent years, a great deal of research has been attempted to find out whether there is some indication between laboratory test items and the occurrence of anastomotic leakage, for early diagnosis of infectious complications of body cavities such as anastomotic leakage or abdominal abscess. However, most of the related research results do not show satisfactory results, and clinical commonly used laboratory indexes such as white blood cell count, C-reactive protein, troponin and the like have limited clinical value for predicting anastomotic leakage, so that it seems difficult to diagnose a disease which gradually changes from ' local ' lesions to systemic infections only through systemic ' infection manifestations.
In recent years, a great deal of research has been attempted to explore the risk factors for anastomotic stoma leakage after gastrointestinal surgery. Two multicentric retrospective studies from the netherlands analyzed clinical data of 36900 patients post colorectal surgery and 600 patients surgically treated for inflammatory bowel disease, respectively, and found that obesity and high american society of anesthesia (American Society of Anesthesiologists, ASA) scores were independent risk factors for anastomotic leakage. A study from multiple centers in China collected data from more than 300 resected patients with low levels in the rectum to obtain independent risk factors for male, diabetes, preoperative chemoradiotherapy and tumor site as anastomotic stoma leakage. One study from japan analyzed the independent risk factors for total gastrectomy post-operative stoma leakage with the aid of gastric cancer endoscopy, and it was thought that patients with lower prognosis nutritional index (Prognostic Nutritional Index, PNI) were more prone to stoma leakage. A domestic study reports that advanced age (age not less than 65 years), anemia (hemoglobin not more than 8.0 g/dL) and malnutrition are independent high-risk factors of anastomotic stoma leakage after gastric cancer operation. Other risk factors for post-surgical anastomotic stoma leakage include smoking alcoholism, low-level anastomosis, advanced cancer surgery, emergency surgery, massive blood loss, long surgery time, and pre-operative hormone use. However, a few analyses have found that in practice most patients will have one or more of the above risk factors, so merely listing risk factors does not necessarily provide practical utility to clinical work. For this type of study, there is a troublesome problem: these risk factors and related studies do not truly give a corresponding approach. In clinic, when patients with multiple risk factors are encountered, whether to continue surgery or whether to change the surgical scheme, there is still insufficient clinical evidence to directly support, and a solution is presented.
At present, the prevention of the anastomotic stoma leakage clinically has three aspects of preoperative, intraoperative and postoperative. Preoperative prevention, i.e., through preoperative evaluation, the patient with high risk factors is selected for targeted treatment, ensuring that the patient receives sufficient preoperative preparation, including preoperative smoking cessation, correction of aqueous electrolyte disorders and hypoalbuminemia, sufficient treatment of diabetic or anemic patients, 3 day preoperative oral antibiotics, and the like. The prevention in operation comprises fine operation in operation, ensures good blood circulation of an anastomotic stoma, no tension and the like, and is essentially the quality control and optimization of an operation level. In addition, the incidence of anastomotic leakage is reduced by using the albumin glue to strengthen the anastomotic stoma in clinic by a team, but after comprehensive analysis, the albumin glue has no definite effect on preventing the anastomotic leakage, and meanwhile, the application of the albumin glue in clinic is limited due to high price. Post-operative prophylaxis mainly includes the use of antibiotics for post-operative prophylaxis, routine imaging examinations such as digestive tract imaging, etc.
In this regard, early diagnosis of anastomotic stoma leakage is also one of the strategies for preventing postoperative anastomotic stoma leakage. The existing diagnostic methods are mostly routine laboratory tests, in which white blood cell count and CRP are widely used as routine laboratory test items for clinical diagnosis of postoperative infectious complications. In recent years there have been a number of studies trying to find out whether there is some indicative relationship between laboratory test items and the occurrence of anastomotic leakage for early diagnosis of anastomotic leakage or abdominal abscess. However, most of the related research results do not show satisfactory results, and clinical commonly used laboratory indexes such as white blood cell count, C-reactive protein, troponin and the like have limited clinical value for predicting anastomotic leakage, so that it seems difficult to diagnose a disease which gradually changes from ' local ' lesions to systemic infections only through systemic ' infection manifestations. Meanwhile, the clinical diagnosis and treatment effect on the anastomotic stoma leakage is not satisfactory, and a doctor can only wait until the anastomotic stoma leakage is serious to a certain extent, obvious laboratory index abnormality occurs, and can carry out definitive diagnosis by combining imaging or endoscopy. So most of the current diagnosis times for anastomotic leakage are 5-8 days post-operation and even later, and about half of patients diagnosed with leakage need to be treated again by surgery. It follows that the biggest obstacle to anastomotic leakage diagnosis is the lack of "early" and "local" monitoring means.
Disclosure of Invention
Aiming at the necessity and urgency of early diagnosis of infectious complications in a body cavity, the invention provides a set of reliable, convenient and timely novel method for early diagnosis of infectious complications in the body cavity in clinic, in particular to a novel method for early diagnosis of infectious complications in the abdominal cavity, postoperative complications of colorectal tumor and the like in clinic, and diagnostic markers, diagnostic kits, diagnostic devices, methods and the like related to the method.
The invention adopts the following technical scheme:
in a first aspect, a diagnostic marker is provided that includes a range of inflammatory factors selected from the group consisting of cytokines, matrix metalloproteinases, reactive oxygen species, vascular endothelial growth factors, tissue metalloproteinase inhibitors, C-reactive proteins, white blood cell count, and combinations of two or more factors, that are useful for diagnosing infectious complications within a body lumen when detected in a test sample or test site.
In a second aspect, a kit for early diagnosis of an infectious complication in a body cavity is provided for rapid, convenient and timely diagnosis of whether a patient is at risk of developing an infectious complication in a body cavity, the kit comprising a detection reagent and/or a detection device for detecting inflammatory factors.
In a third aspect, there is provided the use of a diagnostic marker for the preparation of a detection reagent or detection kit for early diagnosis of infectious complications in a body cavity; the kit comprises a detection reagent and/or a detection device for detecting inflammatory factors.
In a fourth aspect, there is provided a scoring method for detecting an infectious complication in a body cavity of a subject for scoring a risk of occurrence of the infectious complication in the body cavity of the detected subject, the method comprising the steps of:
1) Detecting the marker from the subject sample and its content, and
2) Calculating the content of the marker measured in the step 1) through the model 1 to obtain a value Y, namely the grade of the infectious complications in the body cavity;
wherein the statistical model 1 is: y=x1β1+x2β2+ … … … +xnβn+epsilon,
where Y is the intra-body cavity infectious complication score, X is the content (e.g., concentration) of a marker at a time point, beta is a coefficient, and ε is a constant, given the weight of the corresponding variable X in the intra-body cavity infectious complication score.
Wherein the values of beta and epsilon are determined by statistical methods, preferably LASSO regression.
Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to select the best index from inflammatory factors at different post-operative time points to construct a scoring system for infectious complications in body cavities. The correlation calculation is done through the R language "glrnet" package. LASSO regression is commonly applied to construct high latitude predictive models. The method uses L1 regularization penalty correction to shrink some regression coefficients exactly to zero. LASSO regression selects the best parameters from the high-dimensional data, and can avoid overfitting while considering the accuracy of the prediction model.
In a fifth aspect, there is provided a screening method for a marker for diagnosing an infectious complication in a body cavity of a subject, for screening for a diagnostic marker having more diagnostic value for the occurrence of an infectious complication in a body cavity of a subject, the method comprising the steps of:
1) Detecting the marker from the subject sample and its content, and
2) Carrying out statistical analysis on the content of the marker measured in the step 1) through the model 1;
wherein, the statistical model 1 is: y=x1β1+x2β2+ … … +xnβn+epsilon, Y is the in-body cavity infectious complications score, X is the content (e.g., concentration) of a certain marker at a certain point in time, beta is a coefficient, and epsilon is a constant, which is the weight of the corresponding variable X in the in-body cavity infectious complications score;
wherein, the statistical analysis method is preferably LASSO regression, and X1 … Xn remained in the model 1 obtained by the regression is the diagnostic marker obtained by screening.
In a sixth aspect, there is provided a method for detecting a risk level of developing an infectious complication in a body cavity of a subject for evaluating the risk level of developing an infectious complication in a body cavity of the subject, the method comprising the steps of:
1) Detecting the marker from the subject sample and its content, and
2) Calculating the content of the marker measured in the step 1) through the model 1 to obtain a value Y;
wherein the statistical model 1 is: y=x1β1+x2β2+ … … … +xnβn+epsilon,
wherein Y is the in-body cavity infectious complication score, X is the content (such as concentration) of a certain marker at a certain time point, beta is a coefficient, and epsilon is a constant, and is the weight of a corresponding variable X in the in-body cavity infectious complication score;
wherein the values of β and ε are determined by statistical methods, preferably LASSO regression;
3) Comparing the calculated value Y with a corresponding reference value, and when Y is larger than the reference value, the risk level of the infectious complications in the body cavity is relatively high; when Y is equal to or less than the reference value, the risk level of infectious complications in the body cavity is relatively low.
Wherein the corresponding reference value is calculated by a statistical method, preferably a Cut-Off value, that is, is obtained by ROC analysis. The subject's working characteristics (receiver operating characteristic curve, ROC curve) are used to measure the diagnostic efficacy of the diagnostic Index, and the maximum value of the about Index (Youden Index) is set as the optimum Cut-Off value of the ROC curve, and the about Index is calculated as: about dengue index = sensitivity + specificity-1.
In a seventh aspect, there is provided a device for early diagnosis of infectious complications in a body cavity, the device comprising an analysis unit 1, an analysis unit 2 and an analysis unit 3, wherein:
the analysis unit 1 is used for determining diagnostic markers and their corresponding contents (e.g. concentrations);
the analysis unit 2 is used for obtaining an analysis calculation result Y through the model 1 by one or more measured quantities obtained in the analysis unit 1;
the analysis unit 3 is used for comparing the calculation result Y in the analysis unit 2 with a corresponding reference value to obtain the risk level of the infectious complications in the body cavity;
preferably, further comprising an analysis unit 4, wherein:
the analysis unit 4 is used for recording and analyzing relevant clinical factors;
each analysis unit contains a corresponding computer-implemented algorithm.
Further, in the analysis unit 1, the content (e.g., concentration) of the diagnostic marker may be inputted; or one or more detection reagents or kits comprising detection of the amount (e.g., concentration) of the label for determining the amount of the corresponding label in the sample;
further, in the analysis unit 2, the statistical model 1 is: y=x1β1+x2β2+ … … … +xnβn+epsilon, where Y is the in-body cavity infectious complications score, X is the content (e.g., concentration) of a certain marker at a certain point in time, β is a coefficient, is the weight of the corresponding variable X in the in-body cavity infectious complications score, epsilon is a constant;
further, in the analysis unit 3, the corresponding reference value is calculated by a statistical method, preferably a Cut-Off value, that is, a maximum value of about log index obtained by ROC analysis; comparing the calculation result Y obtained by the analysis unit 2 with a corresponding reference value, and when Y is larger than the reference value, the risk level of the infectious complications in the body cavity is relatively high; when Y is less than or equal to the reference value, the risk level of the infectious complications in the body cavity is relatively low;
wherein, because the occurrence or non-occurrence of the anastomotic leakage is a classification variable, 0 represents "none" and 1 represents "have", and the probability of occurrence of the infectious complications in the body cavity obtained by the model is between 0 and 1. In the above formula, g (x) is a continuous variable, and the value range of 0 to 1 is not applicable, so that the Logistic transformation is used to convert g (x) into the risk probability between 0 and 1. Analysis calculations were performed using SPSS statistical software.
The invention has the beneficial effects that the product and the method can predict whether the infectious complications in the body cavity occur in advance, particularly the early diagnosis of the infectious complications after the intraperitoneal operation and colorectal tumor operation, and the risk level of the infectious complications can be judged on the 1 st day after the operation. Doctors can effectively distinguish low-risk and high-risk patients with the coelomic infectious complications according to the scores of the coelomic infectious complications, and determine whether the patients can recover from feeding and discharge or whether further imaging examination and antibiotic treatment are required to be timely given. The product and the method have extremely high clinical application value for early diagnosis of infectious complications in a body cavity.
Drawings
Fig. 1: inflammatory factor content in peritoneal drainage fluid
The concentration was converted to a 10-base logarithm. (a) IL-1 beta level in peritoneal drainage fluid after colorectal tumor surgery; (b) IL-6 levels in peritoneal drainage fluid after colorectal tumor surgery; (c) IL-10 levels in peritoneal drainage fluid after colorectal tumor surgery; (d) TNF-alpha levels in peritoneal drainage fluid following colorectal tumor surgery; (e) MMP-2 levels in the peritoneal drainage fluid after colorectal tumor surgery; (f) MMP-9 levels in peritoneal drainage fluid after colorectal tumor surgery.
Fig. 2: dynamic change of expression level of inflammatory factor in abdominal cavity drainage liquid after colorectal tumor operation
Fig. 3: ROC curve for diagnosing anastomotic leakage by scoring anastomotic leakage at each time node
Fig. 4: specific distribution of stoma leakage score in colorectal tumor surgical patients on postoperative day 1 and Cut-Off value of stoma leakage score
The specific embodiment is as follows:
the inflammatory factor is one or more than two factors selected from cytokines, matrix metalloproteinase, active oxygen cluster, vascular endothelial growth factor, tissue metalloproteinase inhibitor, C-reactive protein, white blood cell count, etc.
Further, the cytokine is selected from the group consisting of: one or two or more factors selected from Interleukin (IL), colony Stimulating Factor (CSF), interferon (IFN), tumor Necrosis Factor (TNF), chemokine (CK), and Growth Factor (GF).
Further, the interleukin is selected from the group consisting of: IL-1α, IL-1β, IL10, IL11, IL12A, IL12B, IL, IL15, IL16, IL17A, IL17B, IL17C, IL17D, IL17F, IL18Aa, IL18Ba, IL18Ca, IL19, IL1A, IL1B, IL F10, IL1RN, IL2, IL20, IL21, IL22F1a, IL22F2a, IL22F3a, IL22F4a, IL22F5a, IL23A, IL, IL25, IL26, IL27, IL31, IL33, IL36L1a, IL36L2a, IL36RN, IL4, IL5, IL6, IL7, IL8 or IL9, etc.; the colony stimulating factor is selected from the group consisting of: CNTF, CSF1, CSF2, CSF3, CTF1, or the like; the interferon is selected from the group consisting of: IFNA1, IFNA2, IFNA3, IFNA4, IFNB, IFNG, IFNL1, IFNL2, or the like; the tumor necrosis factor is selected from the group consisting of: TNF, tnfα, tnfβ, LTA, LTB, TNFSF, CD40LG, FASLG, CD70, TNFSF8, TNFSF9, TNFSF10L, TNFSF, TNFSF13La, TNFSF13B, TNFSF14, TNFSF15, TNFSF18, EDA, or the like; the chemokines are selected from the group consisting of: CC family, CCL26, CCLD1a, CCLD2a, CCLD3a, CCLD4a, CCLD5a, CCLD6a, CCLD7a, CCLD8a, CCLD9a, CCLD10a, CCLD11a, CCLD12a, CCLD13a, CCLD14a, CCLD15a, CCLD16a, CCL17, CCL19, CCL20, CCL21, CCL22, CCL25, CCL27, CCL28, CCL24, CXC family, CXCLD1a, CXCLD2a, CXCL8, CXCL9, CXCL10LAa, CXCL10LBa, CXCL11, CXCL12, CXCL13La, CXCL14, CXCL16, CXCL17, XC family, XCLAa, XCLBa, CX C family, or CXCL 3CL1, etc.; the growth factor is selected from TGFB1, TGFB2, TGFB3, VEGFA, etc.
Further, the matrix metalloproteinase is selected from: one or more of MMP-1, MMP-2, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-9 or MMP-10, etc.; preferably one or more of MMP-2, MMP-3, MMP-6 or MMP-9.
Further, the inflammatory factor is one or more selected from IL-1 beta, IL-6, IL-10, TNF-alpha, MMP-2 and MMP-9;
further, the inflammatory factor is one or more selected from IL-1 beta, IL-6, IL-10, TNF-alpha and MMP-9; or one or more than two of IL-1 beta, IL-6 and IL-10;
further preferred are one or more of the inflammatory factors IL-1 beta, IL-10, TNF-alpha, MMP-2 and MMP-9.
Further, the detection sample of the inflammatory factor is liquid in a body cavity, and the body cavity is selected from abdominal cavity, pelvic cavity, thoracic cavity environment, brain cavity and the like; the fluid in the body cavity is selected from the group consisting of fluid in the abdominal, pelvic, thoracic and/or cerebrospinal fluid; further, the liquid is cavity effusion or liquid obtained by drainage; further, the liquid is preferably an abdominal dropsy or an abdominal drainage liquid.
Further, the detection part of the inflammatory factor is an infection area in a body cavity or the periphery thereof; further, for a patient undergoing a surgery, for example, a patient undergoing a surgery of a body cavity, the inflammatory factor is selected from inflammatory factors of days 0-15 after the surgery; inflammatory factors of 0 to 7 days after operation are preferred, inflammatory factors of 0 to 5 days after operation are preferred, and inflammatory molecules of 0 to 3 days after operation are preferred; further preferred are inflammatory factors on day 0, day 1, day 2 or day 3 post-surgery; inflammatory factors on day 1 post-surgery are further preferred.
The subject of the present invention is a mammal, including a human, livestock, pet, laboratory animal, etc., wherein the human includes patients of various gender characteristics at various ages, further patients subjected to a first surgery or multiple surgeries. Further, the object is a patient with a disease related to organs or tissues of a body cavity, further is a patient with a disease related to abdominal cavity, pelvic cavity, thoracic cavity environment or cranial cavity, further is a postoperative patient with a disease related to abdominal cavity, pelvic cavity, thoracic cavity environment or cranial cavity, further is a patient with a postoperative patient with an abdominal cavity, thoracic cavity organ such as digestive system, urinary system, reproductive system, respiratory system or cardiovascular system; further is a postoperative patient of the viscera related diseases such as alimentary canal, liver, gall bladder, pancreas, spleen, kidney, ureter or bladder, or a postoperative patient of respiratory tract and heart; further, the patient is subjected to abdominal cavity operation, further is subjected to gastrointestinal operation, further is subjected to colorectal tumor operation, and further is subjected to clinical collection of abdominal cavity drainage liquid.
Among these, digestive system diseases include: digestive tract diseases such as digestive tract tumor, digestive tract inflammation, digestive tract ulcer, etc.; such as chronic active gastritis, chronic atrophic gastritis, gastric ulcer, duodenal ulcer, ulcerative colitis, inflammatory bowel disease, ulcerative colitis, crohn's disease (collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, besset's syndrome, infectious colitis, indeterminate colitis, ulcerative colitis, familial adenomatous polyposis, congenital megacolon, intestinal stenosis, proctitis, rectal mucositis, colon cancer, rectal cancer, fistula, intestinal obstruction, mechanical intestinal obstruction, paralytic intestinal obstruction, digestive tract fistula, pancreatic fistula, other unnatural fistulae (including rectovaginal fistula, rectovavesical fistula, intestinal internal fistula, etc.), ischemic bowel necrosis, blind intestinal cancer, rectal sigmoid colon cancer, gastric cancer, or the like.
Liver and gall diseases include: cholelithiasis, cholecystitis, cholangitis, chronic hepatitis or liver cancer, etc.;
pancreatic diseases include: pancreatitis, pancreatic cancer, pancreatic fistula; kidney: renal cancer, nephritis, kidney stones, pyelonephritis, or renal pelvis cancer, etc.;
spleen diseases include: spleen infarction, etc.;
bladder diseases include: bladder cancer, and the like;
genital disorders include: uterine, ovarian diseases such as endometrial cancer, ovarian cancer, uterine fibroids, endometriosis, adenomyosis, or chocolate cyst, etc.; vaginal diseases such as recto-vaginal fistulae, etc.;
celiac disease includes: infectious peritonitis, spontaneous peritonitis, tuberculous peritonitis or ascites without definite cause, etc.;
thoracic diseases include: bronchofistula, pneumonia, atelectasis or pleural effusion, etc.;
neurological diseases include: nervous system infections, such as intracranial infections, and the like.
The infectious complications in the body cavity are selected from infectious complications in the abdominal cavity, the pelvic cavity, the thoracic cavity or the brain cavity, and further relate to abdominal cavity infection, peritoneal effusion, peritonitis, abdominal abscess, sepsis, anastomotic leakage, pancreatic fistula, duodenal stump fistula, other alimentary canal fistulae, lymphatic fistulae, chylomicron and the like; further, an anastomotic stoma is preferred.
The clinical factors described in the present invention are: the patient's birthday, date of operation, age, sex, height, weight, BMI, ASA score, diabetes, smoking, alcoholism, medication (hypotensive, hypolipidemic, corticosteroid, anticoagulant, nonsteroidal antiinflammatory), history of heart disease, cardiovascular symptoms, peripheral vascular disease, history of respiratory disease, respiratory symptoms, preoperative ileus, neoadjuvant radiotherapy, neoadjuvant chemotherapy, prophylactic antibiotic use. Patient surgery (laparoscopic/laparoscopic resection), surgery mode modification, modification reasons, stage/emergency surgery, resection scope, stoma (type, primary, placement type, site, manual suture), surgical indication, surgery time, anesthesia, intraoperative complications, blood loss, hospital admission time, hospital discharge time, hospital stay period, drainage, stoma (location, type), air leakage test (including test results), surgeon (number of people and expertise), and the like.
In the present invention, the statistical method includes methods commonly used in the art, such as: the continuous variable data conforming to normal distribution can be recorded by adopting an average value +/-standard deviation, the classified variable data can be recorded in the form of quantity and percentage, the comparison between normal distribution continuous variable groups can be t-test, the comparison between non-normal distribution continuous variable groups can be non-parameter test, the comparison between two groups is Mann-Whitney test, the comparison between classified variable groups or single factor analysis is row X column X2 test and Fisher accurate test, and the factor with single factor having predictive value (P > 0.1) is included in multi-factor analysis. Inflammatory factors in the postoperative peritoneal drainage fluid can be screened and analyzed by adopting Least Absolute Shrinkage and Selection Operator (LASSO) regression. The multifactor analysis of the classification variables may employ Logistic regression analysis, and the results are represented by nomograms (nomograms). The reliability of the nomogram can be evaluated by using a calibration curve, and the clinical application value of the nomogram can be evaluated by using a decision curve and a clinical influence curve. The subject operating profile (receiver operating characteristic curve, ROC curve) can be used to measure the diagnostic efficacy of a diagnostic indicator. The maximum value of the Youden Index (Youden Index) can be set to the optimal Cut-Off value of the ROC curve, and all statistical results are considered statistically significant with a double-sided P < 0.05. The above analytical calculations can be accomplished using SPSS 20.0 statistical software, the R language "rms" and "rmda" packages, and the like.
In order to further illustrate the method for early diagnosing advanced infectious complications and the effects thereof, the following examples are given, which are only an example of the method of the present invention, and are not intended to limit the subject matter and scope of the present invention, and other equivalent techniques within the scope of the inventive concept are also within the scope of the present invention.
Example 1: quantitative analysis of inflammatory factors in peritoneal drainage fluid
1. Material
1.1 patient Condition and clinical data acquisition
Patient conditions: the rectum tumor operation is accepted, and the abdominal cavity drainage liquid is adopted.
Clinical data: the patient's birthday, date of operation, age, sex, height, weight, BMI, ASA score, diabetes, smoking, alcoholism, medication (hypotensive, hypolipidemic, corticosteroid, anticoagulant, nonsteroidal antiinflammatory), history of heart disease, cardiovascular symptoms, peripheral vascular disease, history of respiratory disease, respiratory symptoms, preoperative ileus, neoadjuvant radiotherapy, neoadjuvant chemotherapy, prophylactic antibiotic use. Patient surgery (laparoscopic/laparoscopic resection), surgery mode modification, modification reasons, stage/emergency surgery, resection scope, stoma (type, primary, placement type, site, manual suture), surgical indication, surgery time, anesthesia, intraoperative complications, blood loss, hospital admission time, hospital discharge time, hospital stay period, drainage, stoma (location, type), air leakage test (including test results), surgeon (number of people and expertise), and the like.
Information acquisition in operation: surgical mode (laparoscopic/laparoscopic resection), surgical mode modification, modification reasons, stage/emergency surgery, resection scope, stoma (type, primary, placement type, site, manual suture), surgical indication, surgical time, anesthesia, intraoperative complications, blood loss, time of admission, time of discharge, period of stay, drainage, stoma (location, type), air leakage test (including test results), surgeon (number of people and expertise).
Postoperative information acquisition: conventional laboratory test results (white blood cells, CRP, etc.), drainage shape, color, drainage volume, survival condition within 30 days after operation, readmission condition, secondary operation condition.
Post-operative complications registration of group-entered patients: prospective registration of postoperative complications of patients in the group is carried out, various databases are independently registered and entered by researchers and clinicians, and verification and summarization are carried out regularly.
Registering content and standard: the 21 complications were included in the registration category and the severity of the complications was ranked using the Clavien-Dindo ranking (CD ranking) as standard, as shown in Table 1.
TABLE 1 colorectal tumor postoperative complications diagnosis gist
1.2 Abdominal cavity drainage liquid sample collection and pretreatment
Three days after the operation of the patient, namely, the abdominal cavity drainage liquid (comprising the postoperative day to the postoperative day 3) is collected once at a fixed time point every day, and 20ml of the drainage liquid is collected each time. After sampling the peritoneal drainage liquid sample, centrifuging at 4 ℃ and 2800g for 10 minutes, and independently split-charging the supernatant and the precipitate and storing in a refrigerator at-80 ℃.
2. Method and procedure
Quantitative analysis of representative inflammatory factors IL-1 beta, IL-6, IL-10, TNF-alpha, MMP2 and MMP9 in the peritoneal drainage liquid is selected for quantitative analysis. And quantitatively analyzing the content of each factor by using a multi-factor ELISA method. Wherein the amounts of IL-1 beta, IL-6, IL-10 and TNF-alpha are detected using the HSTCMAG-28SK (EMD Millipore Co., USA) kit; the amounts of MMP2 and MMP9 were measured using the HMMP2MAG-55K (EMD Millipore Co., USA) kit.
3. Results
3.1 clinical results: 119 patients with gastric colorectal tumor postoperative, 72 men and 47 women; median age 60 (53-66); among them, 25 patients were diagnosed with postoperative complications within 30 days after surgery, and the complication occurrence rate was 21.0%. Wherein 12 patients have anastomotic leakage, and the occurrence rate of the anastomotic leakage is 10.08 percent.
3.2 levels of inflammatory factors in peritoneal drainage fluid after colorectal tumor surgery
The concentration of each inflammatory factor in the abdominal cavity drainage liquid after operation of a colorectal tumor patient is shown in table 2, the level of the inflammatory factor in the abdominal cavity drainage liquid is obviously higher than that of other patients within 3 days after operation of the patient with anastomotic leakage, and the difference has statistical significance. As shown in fig. 1.
TABLE 2 quantitative analysis results of inflammatory factors in abdominal drainage after colorectal tumor surgery
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Inflammatory factor concentration is expressed as median (quadruplex); differences are statistically indicated by bold (P < 0.05).
3.3 dynamic changes in inflammatory factor levels in peritoneal drainage fluid after colorectal tumor surgery
The level of inflammatory factors in the abdominal cavity drainage liquid after operation of the colorectal tumor patient shows dynamic change, wherein the dynamic change of the 6 inflammatory factors in the abdominal cavity drainage liquid of the anastomotic leakage patient is basically consistent with the change trend of the non-anastomotic leakage patient. The concentrations of IL-6, IL-10, MMP-2, MMP-9 are substantially the same in patients with and those without anastomotic leakage; the concentration of IL-1β in patients with anastomotic leakage was higher on the postoperative day to the third day than in patients without anastomotic leakage, and the concentration of TNF- α in patients with anastomotic leakage was slightly higher on the postoperative and the second day than in patients without anastomotic leakage. As shown in fig. 2.
Example 2: parameter selection and construction of anastomotic leakage scoring system
1. Parameter selection of colorectal tumor postoperative anastomotic stoma leakage scoring system
In order to further optimize the diagnosis efficacy of inflammatory factors in abdominal cavity drainage liquid after colorectal tumor operation on anastomotic stoma leakage, least Absolute Shrinkage and Selection Operator (LASSO) regression is adopted to screen the inflammatory factors in the abdominal cavity drainage liquid at different time points 3 days after colorectal tumor operation, and the optimal index is selected to construct an anastomotic stoma leakage prediction model. 3 indexes are screened from 6 inflammatory factor indexes on the same day of operation, 5 indexes are screened from 6 inflammatory factor indexes on the 1 st day after operation, 6 indexes are screened from 6 inflammatory factor indexes on the 2 nd day after operation, 5 indexes are screened from 6 inflammatory factor indexes on the 3 rd day after operation, and an anastomotic stoma leakage scoring system is established by taking the indexes as parameters. The calculation model of the anastomotic leakage score of different time nodes after colorectal tumor operation is shown in table 3.
TABLE 3 score model for node anastomotic leakage at time after colorectal tumor surgery
D0 day of surgery; d1 day after surgery; d2 day 2 post-operative; d3 day 3 post-surgery.
2. Diagnostic efficacy of anastomotic leakage scoring system on colorectal tumor postoperative anastomotic leakage
ROC curve analysis was used to analyze the effectiveness of the anastomotic leakage score for diagnosis of anastomotic leakage following colorectal tumor surgery, and the ROC analysis results for the anastomotic leakage score at different time nodes for the anastomotic leakage diagnosis are shown in fig. 3 and table 4. The diagnostic efficacy of the anastomotic leakage score for anastomotic leakage was highest on day 1 post-surgery, with AUC of 0.88 (p < 0.01).
Table 4 ROC analysis of anastomotic leakage score diagnosis of anastomotic leakage at various time nodes after colorectal tumor surgery
Area under AUC curve; differences are statistically indicated by bold (P < 0.05).
2. Setting of post-operation day 1 anastomotic stoma leakage score Cut-Off value and efficacy of anastomotic stoma leakage diagnosis
The anastomotic stoma leakage score diagnosis effect is optimal on the 1 st day after operation, the maximum value (sensitivity+specificity-1) -2.46 of the you index is selected as a screening critical value, and patients with the anastomotic stoma leakage score lower than-2.46 on the 1 st day after operation are classified as low risk groups, and patients with the anastomotic stoma leakage score higher than-2.46 are classified as high risk groups. Wherein, in 63 patients of the low-risk group, 1 person in the patients has anastomotic leakage, and in 36 patients of the high-risk group, 9 persons in the patients have anastomotic leakage, and in addition, 10 patients are not classified into the high-risk group or the low-risk group due to the lack of parameters required for calculating the score of the anastomotic leakage on the 1 st day after operation, wherein, 1 patient with anastomotic leakage is included. As shown in fig. 4.
As can be seen from comparison with clinical actual results, the scoring method of the present invention achieved a sensitivity of 90%, a specificity of 70%, a Positive Predictive Value (PPV) of 25% and a Negative Predictive Value (NPV) of 98%. Therefore, the scoring method has high sensitivity, and the negative predictive value has extremely high clinical guidance significance. As shown in table 5.
Table 5 diagnostic efficacy of the anastomotic leakage score on anastomotic leakage at day 1 post-operative
The foregoing shows and describes the basic principles and main features of the present invention, but is not intended to limit the same. It will be understood by those skilled in the art that various equivalent modifications and changes can be made without departing from the spirit and scope of the present invention, and it is intended to cover by the appended claims.

Claims (5)

1. Use of a marker composition that is a combination of IL-1 beta, IL-10, TNF-alpha, MMP2 and MMP9 for the preparation of a detection reagent for infectious complications in a body cavity after an early rectal tumor operation.
2. The use according to claim 1, wherein the marker composition is derived from a liquid in the abdominal cavity.
3. The use of claim 1, wherein the marker composition is a marker composition for a rectal tumor patient on the postoperative day, the first postoperative day, the second postoperative day, and the third postoperative day.
4. The use according to claim 1, wherein the intra-body-cavity infectious complications are selected from abdominal infectious complications.
5. Use according to claim 4, characterized in that: the infectious complications in the body cavity are anastomotic leakage.
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