Use of IFP35 family protein in diagnosis of sepsis or related diseases thereof

Abstract

Provided is a use of an IFP35 family protein in diagnosis of sepsis or related diseases thereof. Provided is an IFP35 family protein as a marker for diagnosis, screening, severity assessment, monitoring, efficacy assessment, or prognosis assessment of sepsis or related diseases thereof, and non-sepsis infectious diseases. By measuring the content, the expression level and / or activity of the IFP35 family protein, diagnosis, screening, severity assessment, monitoring, efficacy assessment, or prognosis assessment of sepsis or related diseases thereof, and non-sepsis infectious diseases can be realized.

Description

Application of IFP35 family proteins in the diagnosis of sepsis or related diseases

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application No. 2024101850721 filed on February 19, 2024 and Chinese patent application No. 2024109078113 filed on July 8, 2024, the contents of which are incorporated herein by reference. Technical Field

[0003] The present invention belongs to the field of biomedicine technology, and specifically relates to the application of IFP35 family proteins in diagnosing sepsis or related diseases. Background Art

[0004] Sepsis is one of the most challenging critical illnesses in the medical field. With the emergence of drug-resistant bacteria, rising cancer incidence, increased invasive medical procedures, and an aging population, the incidence of sepsis is increasing year by year, posing a serious threat to human life and health while also placing a significant economic burden on society.

[0005] In 2017, there were an estimated 49 million cases of sepsis worldwide, and approximately 11 million deaths from sepsis, accounting for approximately 20% of all deaths worldwide. A 2020 study of ICUs in 44 hospitals in my country showed that the incidence of ICU sepsis was 20.6%. Regarding treatment costs, a 2022 study estimated global sepsis treatment costs between 2010 and 2022, showing that the median total cost of hospitalization for sepsis was €36,191 (€17,158-€53,349). Furthermore, the prognosis for sepsis treatment is not optimistic. According to a WHO report, only half of patients discharged from the hospital with sepsis fully recover, 40% of sepsis patients are rehospitalized within 90 days of discharge, and one-third die within a year. In addition, some survivors will also experience disease-related post-symptoms, including fatigue, neuromuscular weakness, chronic pain, post-traumatic stress disorder, cognitive impairment, functional impairment and depression, which not only increases the burden of sepsis treatment for individuals, but also increases the burden on the healthcare system and society.

[0006] The Sequential Organ Failure Assessment (SOFA) score, the quick SOFA score (qSOFA), and procalcitonin (PCT) currently used in clinical diagnosis of sepsis all have significant limitations. The SOFA score requires assessment of the function of multiple organ systems (respiratory, hematologic, hepatic, cardiovascular, neurologic, and renal) to determine the extent of organ damage. This cumbersome process, involving multisystem laboratory testing, hinders rapid diagnosis and can lead to delayed diagnosis. By the time sepsis is diagnosed based on the SOFA score, the patient's condition is already critical, potentially missing the optimal treatment window. Furthermore, organ dysfunction caused by non-sepsis factors can also result in a SOFA score ≥2, potentially leading to misdiagnosis. The qSOFA score is used for the early and rapid diagnosis of sepsis, but its screening criteria (systolic blood pressure ≤100 mmHg, respiratory rate ≥22 breaths / min, and altered consciousness for a sepsis diagnosis of two of the three criteria) are overly sensitive, easily leading to overdiagnosis of sepsis. Procalcitonin (PCT) is a well-established indicator for detecting inflammatory responses caused by bacterial infections. While its sensitivity and specificity for diagnosing bacterial sepsis can reach approximately 80%, this indicator is limited to sepsis caused by Gram-negative bacteria and is less effective for sepsis caused by other factors. Furthermore, PCT levels can be affected by a variety of non-infectious factors, including early-stage severe trauma / burns, major surgery, acute pancreatitis, advanced cancer, acute and chronic viral hepatitis, and post-sustained cardiopulmonary resuscitation. These factors can lead to nonspecific elevations in PCT levels.

[0007] Due to the lack of accurate early diagnosis and effective treatment options, the mortality rate of sepsis has not significantly decreased in the past 20 years. To effectively reduce the life-threatening and economic burden of sepsis, researchers and medical professionals are urgently needed to conduct in-depth research on the pathogenic mechanisms of sepsis and identify highly specific and sensitive indicators for early identification and diagnosis of sepsis and monitoring of the disease, providing accurate guidance for timely and effective intervention in the development of sepsis. Summary of the Invention

[0008] The purpose of the first aspect of the present invention is to provide a method for detecting IFP35 family proteins for use in the preparation of products for the diagnosis, screening, severity assessment, monitoring, efficacy assessment, or prognosis assessment of sepsis or its related diseases, or non-septic infectious diseases.

[0009] The second aspect of the present invention aims to provide a system for diagnosing, screening, severity assessment, monitoring, efficacy assessment, or prognosis assessment of sepsis or its related diseases, or non-septic infectious diseases.

[0010] The third aspect of the present invention aims to provide a method for constructing a model of sepsis or its related diseases, or non-sepsis infectious diseases.

[0011] The fourth aspect of the present invention aims to provide a method for diagnosing, screening, severity assessment, monitoring, efficacy assessment, or prognosis assessment of sepsis or its related diseases, or non-septic infectious diseases.

[0012] In order to achieve the above object, the technical solution adopted by the present invention is:

[0013] The first aspect of the present invention provides the use of a substance for detecting IFP35 family proteins in the preparation of a product:

[0014] The product is used for any one of a1) to a3):

[0015] a1) Diagnosis, screening, severity assessment (risk stratification), monitoring, efficacy evaluation, or prognosis assessment of sepsis (including severe sepsis);

[0016] a2) Diagnosis, screening, severity assessment (risk stratification), monitoring, efficacy evaluation, or prognosis assessment of sepsis-related diseases;

[0017] a3) Diagnosis, screening, severity assessment (risk stratification), monitoring, efficacy evaluation, or prognosis assessment of non-sepsis infectious diseases.

[0018] Preferably, the sepsis-related disease comprises septic shock (infectious shock, septic shock).

[0019] Preferably, sepsis refers to life-threatening organ dysfunction caused by dysregulated host response to infection.

[0020] Preferably, the septic shock (also known as infectious shock, septic shock) refers to sepsis that requires the use of vasoactive drugs to maintain a mean arterial pressure > 65 mmHg and a blood lactate concentration > 2 mmol / L after adequate fluid resuscitation.

[0021] Preferably, the IFP35 family protein comprises interferon-induced protein 35kD (IFP35) and / or N-Myc interacting protein (NMI); further NMI.

[0022] Preferably, the non-septic infectious disease includes at least one of severe pneumonia, non-severe community-acquired pneumonia, interstitial lung disease, bacterial pneumonia, Aspergillus pneumonia, Mycoplasma pneumonia, pulmonary viral infection (cytomegalovirus), pneumonia in immunosuppressed hosts, lung abscess with pneumonia, acute lower respiratory tract infection, bronchiectasis with infection, bronchitis, deep neck abscess, infective endocarditis, viral myocarditis, acute cholecystitis, hepatobiliary stones with cholangitis, acute pyelonephritis, urinary tract infection, peritonitis, pleurisy, liver cyst, empyema, and stent infection.

[0023] Preferably, the test sample of the product is selected from at least one of body fluids, tissues, cells, and excretions of the subject to be tested; further, it is body fluid.

[0024] Preferably, the body fluid comprises at least one of blood, lymph, pleural effusion, cerebrospinal fluid, joint fluid, ascites, saliva, lymph, and body fluid; further comprises blood.

[0025] Preferably, the blood comprises at least one of serum, plasma, dried blood spots, and whole blood; further comprises serum.

[0026] Preferably, the excrement comprises at least one of urine, feces, and tears.

[0027] Preferably, the test sample is selected from the serum of the subject to be tested.

[0028] Preferably, the subject to be tested includes mammals, such as humans, non-human primates (such as gorillas and apes), rodents (such as rats, mice, and guinea pigs), pets (such as cats and dogs), and livestock (such as horses, cows, sheep, pigs, and rabbits).

[0029] Preferably, the subject to be tested includes humans.

[0030] Preferably, when the product is used for the diagnosis of sepsis, the subjects of the test sample of the product are severe subjects.

[0031] Preferably, the use of a substance for detecting IFP35 family proteins in the preparation of a product:

[0032] The product is used for any one of b1) to b6):

[0033] b1) Distinguishing between subjects with severe sepsis and subjects without severe sepsis;

[0034] b2) distinguishing between non-sepsis test subjects and sepsis test subjects, wherein the non-sepsis test subjects include healthy test subjects and / or non-sepsis infection test subjects;

[0035] b3) distinguishing between subjects with non-septic infection and healthy subjects;

[0036] b4) Prognostic assessment and / or efficacy evaluation of sepsis;

[0037] b5) Differentiate between septic shock and non-septic shock;

[0038] b6) Differentiate between sepsis and organ dysfunction caused by non-infectious factors.

[0039] Preferably, the non-sepsis infection test subject is a test subject suffering from a non-sepsis infectious disease.

[0040] Preferably, the non-septic infectious disease includes at least one of severe pneumonia, non-severe community-acquired pneumonia, interstitial lung disease, bacterial pneumonia, Aspergillus pneumonia, Mycoplasma pneumonia, pulmonary viral infection (cytomegalovirus), pneumonia in immunosuppressed hosts, lung abscess with pneumonia, acute lower respiratory tract infection, bronchiectasis with infection, bronchitis, deep neck abscess, infective endocarditis, viral myocarditis, acute cholecystitis, hepatobiliary stones with cholangitis, acute pyelonephritis, urinary tract infection, peritonitis, pleurisy, liver cyst, empyema, and stent infection.

[0041] Preferably, the non-septic shock includes at least one of cardiogenic shock, hypovolemic shock, obstructive shock, neurogenic shock, and anaphylactic shock; and further includes cardiogenic shock, hypovolemic shock, and neurogenic shock.

[0042] Preferably, the non-infectious factors include at least one of severe trauma, extensive burns, major surgery, and chemical poisoning.

[0043] Preferably, the severe trauma includes at least one of multiple traumas (such as multiple traumas caused by serious traffic accidents), open chest and abdominal injuries, and extremely severe craniocerebral injuries.

[0044] Preferably, the distinguishing between sepsis and organ dysfunction caused by non-infectious factors is distinguishing between sepsis occurring after major surgery and no sepsis occurring after major surgery.

[0045] Preferably, the distinguishing between sepsis and organ dysfunction caused by non-infectious factors is distinguishing between sepsis and severe trauma without sepsis.

[0046] Preferably, the substance for detecting IFP35 family proteins comprises a substance for quantitatively detecting IFP35 family proteins.

[0047] Preferably, the substance for detecting IFP35 family proteins comprises a substance for detecting IFP35 family proteins at the gene level and / or protein level.

[0048] Preferably, the substance comprises a substance for one or more detection techniques or methods selected from the group consisting of immunohistochemistry, Western blotting, Northern blotting, PCR, biochip, nucleic acid sequencing, amino acid sequencing, high performance liquid chromatography, capillary gel electrophoresis, near infrared spectroscopy, mass spectrometry, surface plasmon resonance technology, immuno-PCR technology, and biotin-avidin technology.

[0049] Preferably, the immunohistochemistry method comprises at least one of enzyme-linked immunosorbent assay, immunofluorescence assay, radioimmunoassay, immunoprecipitation, immunochemiluminescence, colloidal gold immunoassay, fluorescence immunochromatography, complement fixation analysis, and flow cytometry fluorescence separation technology; further enzyme-linked immunosorbent assay; and further double antibody sandwich method.

[0050] Preferably, the substance for detecting IFP35 family proteins is selected from one or more of: a substance specific to IFP35 family proteins, a probe specific to IFP35 family proteins, a gene chip, a protein chip, and a PCR primer.

[0051] Preferably, the substance specific to IFP35 family proteins comprises any one of c1) to c3):

[0052] c1) antibodies that specifically bind to IFP35 family proteins;

[0053] c2) a ligand protein or polypeptide that specifically binds to an IFP35 family protein;

[0054] c3) Non-protein compounds that specifically recognize IFP35 family proteins.

[0055] Preferably, the antibody comprises at least one of a polyclonal antibody, a monoclonal antibody, a single-chain antibody, a functional antibody fragment, an antibody Fab region, a nanobody, a chimeric antibody, and a multispecific antibody.

[0056] Preferably, the substance for detecting IFP35 family proteins is an interferon-induced protein 35kD (IFP35) antibody and / or an N-Myc interacting protein (NMI) antibody; further, an N-Myc interacting protein (NMI) antibody.

[0057] Preferably, the product comprises at least one of a reagent, a kit, a test paper, a chip, and a system.

[0058] Preferably, the product further comprises substances for detecting other markers for the diagnosis, screening, severity assessment, monitoring, efficacy assessment, or prognosis assessment of sepsis or its related diseases, such as Ang1-7 disclosed in CN117147877A, pro-adrenomedullin (proADM) disclosed in CN111094986B, bone morphogenic protein-9 disclosed in CN116990523A, 4-hydroxyphenylacetic acid disclosed in CN114184693A, insulin-like growth factor binding protein 6 disclosed in CN116773820A, IER3 disclosed in CN112011603A, PSP / reg disclosed in CN101796418A, etc.

[0059] Preferably, the product further comprises auxiliary detection reagents for gene expression levels, and the auxiliary detection reagents for gene expression levels include: reaction reagents for visualizing the amplicons corresponding to the primers, RNA extraction reagents, reverse transcription reagents, cDNA amplification reagents, standard substances for preparing standard curves, and at least one of positive controls.

[0060] Preferably, the product further comprises auxiliary detection reagents for protein expression, and the auxiliary detection reagents for protein expression include at least one of a color developer, a blocking solution, an antibody diluent, a washing buffer, a color stop solution, a standard substance for preparing a standard curve, and a positive control substance.

[0061] A second aspect of the present invention provides a system for disease diagnosis, screening, severity assessment (risk stratification), monitoring, efficacy assessment, or prognosis assessment, comprising:

[0062] Detection module: used to detect the content, activity and / or expression of IFP35 family proteins in the test sample; and

[0063] Diagnosis, monitoring, or evaluation module: diagnose, screen for disease, monitor the course of disease, evaluate disease severity, treatment efficacy, or prognosis based on the content, activity, and / or expression of IFP35 family proteins in a test sample; and

[0064] Result output module: outputs the results of disease diagnosis, screening, severity assessment, monitoring, efficacy evaluation, or prognosis assessment;

[0065] The disease is any one of d1) to d3):

[0066] d1) Sepsis; d2) Sepsis-related diseases; d3) Non-septic infectious diseases.

[0067] Preferably, the IFP35 family protein comprises interferon-induced protein 35kD (IFP35) and / or N-Myc interacting protein (NMI); further NMI.

[0068] Preferably, the sepsis-related disease comprises septic shock (infectious shock, septic shock).

[0069] Preferably, the non-septic infectious disease includes at least one of severe pneumonia, non-severe community-acquired pneumonia, interstitial lung disease, bacterial pneumonia, Aspergillus pneumonia, Mycoplasma pneumonia, pulmonary viral infection (cytomegalovirus), pneumonia in immunosuppressed hosts, lung abscess with pneumonia, acute lower respiratory tract infection, bronchiectasis with infection, bronchitis, deep neck abscess, infective endocarditis, viral myocarditis, acute cholecystitis, hepatobiliary stones with cholangitis, acute pyelonephritis, urinary tract infection, peritonitis, pleurisy, liver cyst, empyema, and stent infection.

[0070] Preferably, the test sample is selected from at least one of body fluids, tissues, cells, and excretions of the subject to be tested; further, it is body fluid.

[0071] Preferably, the body fluid comprises at least one of blood, lymph, pleural effusion, cerebrospinal fluid, joint fluid, ascites, saliva, lymph, and body fluid; further comprises blood.

[0072] Preferably, the blood comprises at least one of serum, plasma, dried blood spots, and whole blood; further comprises serum.

[0073] Preferably, the excrement comprises at least one of urine, feces, and tears.

[0074] Preferably, the test sample is selected from the serum of the subject to be tested.

[0075] Preferably, the subject to be tested includes mammals, such as humans, non-human primates (such as gorillas and apes), rodents (such as rats, mice, and guinea pigs), pets (such as cats and dogs), and livestock (such as horses, cows, sheep, pigs, and rabbits).

[0076] Preferably, the subject to be tested comprises a human.

[0077] Preferably, when the system is used for the diagnosis of sepsis, the subject to be tested is a critically ill subject to be tested.

[0078] Preferably, the system is used for any one of b1) to b6):

[0079] b1) Distinguishing between subjects with severe sepsis and subjects without severe sepsis;

[0080] b2) distinguishing between non-sepsis test subjects and sepsis test subjects, wherein the non-sepsis test subjects include healthy test subjects and / or non-sepsis infection test subjects;

[0081] b3) distinguishing between subjects with non-septic infection and healthy subjects;

[0082] b4) Prognostic assessment and / or efficacy evaluation of sepsis;

[0083] b5) Differentiate between septic shock and non-septic shock;

[0084] b6) Differentiate between sepsis and organ dysfunction caused by non-infectious factors.

[0085] Preferably, the non-sepsis infection test subject is a test subject suffering from a non-sepsis infectious disease.

[0086] Preferably, the non-septic infectious disease includes at least one of severe pneumonia, non-severe community-acquired pneumonia, interstitial lung disease, bacterial pneumonia, Aspergillus pneumonia, Mycoplasma pneumonia, pulmonary viral infection (cytomegalovirus), pneumonia in immunosuppressed hosts, lung abscess with pneumonia, acute lower respiratory tract infection, bronchiectasis with infection, bronchitis, deep neck abscess, infective endocarditis, viral myocarditis, acute cholecystitis, hepatobiliary stones with cholangitis, acute pyelonephritis, urinary tract infection, peritonitis, pleurisy, liver cyst, empyema, and stent infection.

[0087] Preferably, the non-septic shock includes at least one of cardiogenic shock, hypovolemic shock, obstructive shock, neurogenic shock, and anaphylactic shock; and further includes cardiogenic shock, hypovolemic shock, and neurogenic shock.

[0088] Preferably, the non-infectious factors include at least one of severe trauma, extensive burns, major surgery, and chemical poisoning.

[0089] Preferably, the severe trauma includes at least one of multiple traumas (such as multiple traumas caused by serious traffic accidents), open chest and abdominal injuries, and extremely severe craniocerebral injuries.

[0090] Preferably, the distinguishing between sepsis and organ dysfunction caused by non-infectious factors is distinguishing between sepsis occurring after major surgery and no sepsis occurring after major surgery.

[0091] Preferably, the distinguishing between sepsis and organ dysfunction caused by non-infectious factors is distinguishing between sepsis and severe trauma without sepsis.

[0092] Preferably, the detection module comprises the product (reagent, kit, test paper, or chip) in the first aspect of the present invention.

[0093] The third aspect of the present invention provides a method for constructing a disease model, wherein the content, expression and / or activity of IFP35 family proteins in the model are increased; the disease is any one of d1) to d3):

[0094] d1) Sepsis; d2) Sepsis-related diseases; d3) Non-septic infectious diseases.

[0095] Preferably, the disease is any one of d1) to d2).

[0096] Preferably, the IFP35 family protein comprises interferon-induced protein 35kD (IFP35) and / or N-Myc interacting protein (NMI); further NMI.

[0097] Preferably, the sepsis-related disease comprises septic shock (infectious shock, septic shock).

[0098] Preferably, the non-septic infectious disease includes at least one of severe pneumonia, non-severe community-acquired pneumonia, interstitial lung disease, bacterial pneumonia, Aspergillus pneumonia, Mycoplasma pneumonia, pulmonary viral infection (cytomegalovirus), pneumonia in immunosuppressed hosts, lung abscess with pneumonia, acute lower respiratory tract infection, bronchiectasis with infection, bronchitis, deep neck abscess, infective endocarditis, viral myocarditis, acute cholecystitis, hepatobiliary stones with cholangitis, acute pyelonephritis, urinary tract infection, peritonitis, pleurisy, liver cyst, empyema, and stent infection.

[0099] Preferably, the model is an animal model.

[0100] Preferably, the animal is a rat, a mouse, or a guinea pig.

[0101] A fourth aspect of the present invention provides a method comprising the steps of detecting the content, expression level and / or activity of an IFP35 family protein in a test sample;

[0102] The method is used for any one of a1) to a3):

[0103] a1) Diagnosis, screening, severity assessment (risk stratification), monitoring, efficacy evaluation, or prognosis assessment of sepsis (including severe sepsis);

[0104] a2) Diagnosis, screening, severity assessment (risk stratification), monitoring, efficacy evaluation, or prognosis assessment of sepsis-related diseases;

[0105] a3) Diagnosis, screening, severity assessment (risk stratification), monitoring, efficacy evaluation, or prognosis assessment of non-sepsis infectious diseases.

[0106] Preferably, the sepsis-related disease comprises septic shock (infectious shock).

[0107] Preferably, the IFP35 family protein comprises interferon-induced protein 35kD (IFP35) and / or N-Myc interacting protein (NMI); further NMI.

[0108] Preferably, the non-septic infectious disease includes at least one of severe pneumonia, non-severe community-acquired pneumonia, interstitial lung disease, bacterial pneumonia, Aspergillus pneumonia, Mycoplasma pneumonia, pulmonary viral infection (cytomegalovirus), pneumonia in immunosuppressed hosts, lung abscess with pneumonia, acute lower respiratory tract infection, bronchiectasis with infection, bronchitis, deep neck abscess, infective endocarditis, viral myocarditis, acute cholecystitis, hepatobiliary stones with cholangitis, acute pyelonephritis, urinary tract infection, peritonitis, pleurisy, liver cyst, empyema, and stent infection.

[0109] Preferably, the test sample is selected from at least one of body fluids, tissues, cells, and excretions of the subject to be tested; further, it is body fluid.

[0110] Preferably, the body fluid comprises at least one of blood, lymph, pleural effusion, cerebrospinal fluid, joint fluid, ascites, saliva, lymph, and body fluid; further comprises blood.

[0111] Preferably, the blood comprises at least one of serum, plasma, dried blood spots, and whole blood; further comprises serum.

[0112] Preferably, the excrement comprises at least one of urine, feces, and tears.

[0113] Preferably, the test sample is selected from the serum of the subject to be tested.

[0114] Preferably, the subject to be tested includes mammals, such as humans, non-human primates (such as gorillas and apes), rodents (such as rats, mice, and guinea pigs), pets (such as cats and dogs), and livestock (such as horses, cows, sheep, pigs, and rabbits).

[0115] Preferably, the subject to be tested comprises a human.

[0116] Preferably, the method is used for the diagnosis of sepsis, and the subject of the test sample is a critically ill subject.

[0117] Preferably, the method is used for any one of b1) to b6):

[0118] b1) Distinguishing between subjects with severe sepsis and subjects without severe sepsis;

[0119] b2) distinguishing between non-sepsis test subjects and sepsis test subjects, wherein the non-sepsis test subjects include healthy test subjects and / or non-sepsis infection test subjects;

[0120] b3) distinguishing between subjects with non-septic infection and healthy subjects;

[0121] b4) Prognostic assessment and / or efficacy evaluation of sepsis;

[0122] b5) Differentiate between septic shock and non-septic shock;

[0123] b6) Differentiate between sepsis and organ dysfunction caused by non-infectious factors.

[0124] Preferably, the non-sepsis infection test subject is a test subject suffering from a non-sepsis infectious disease.

[0125] Preferably, the non-septic infectious disease includes at least one of severe pneumonia, non-severe community-acquired pneumonia, interstitial lung disease, bacterial pneumonia, Aspergillus pneumonia, Mycoplasma pneumonia, pulmonary viral infection (cytomegalovirus), pneumonia in immunosuppressed hosts, lung abscess with pneumonia, acute lower respiratory tract infection, bronchiectasis with infection, bronchitis, deep neck abscess, infective endocarditis, viral myocarditis, acute cholecystitis, hepatobiliary stones with cholangitis, acute pyelonephritis, urinary tract infection, peritonitis, pleurisy, liver cyst, empyema, and stent infection.

[0126] Preferably, the non-septic shock includes at least one of cardiogenic shock, hypovolemic shock, obstructive shock, neurogenic shock, and anaphylactic shock; and further includes cardiogenic shock, hypovolemic shock, and neurogenic shock.

[0127] Preferably, the non-infectious factors include at least one of severe trauma, extensive burns, major surgery, and chemical poisoning.

[0128] Preferably, the severe trauma includes at least one of multiple traumas (such as multiple traumas caused by serious traffic accidents), open chest and abdominal injuries, and extremely severe craniocerebral injuries.

[0129] Preferably, the product of the first aspect of the present invention is used to detect the content, expression level and / or activity of IFP35 family proteins in a test sample.

[0130] The beneficial effects of the present invention are:

[0131] The present invention discloses for the first time that IFP35 family proteins can be used as markers for the diagnosis, screening, severity assessment, monitoring, efficacy evaluation, or prognosis assessment of sepsis or its related diseases, or non-septic infectious diseases. By detecting the content, expression level and / or activity of IFP35 family proteins, the diagnosis, screening, severity assessment, monitoring, efficacy evaluation, or prognosis assessment of sepsis or its related diseases, or non-septic infectious diseases can be achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0132] Figure 1 is a comparison of serum NMI, PCT, WBC and PaO2 / FiO2 levels among healthy volunteers, non-septic infection patients and septic patients (2022 data): A is a comparison of serum NMI levels among healthy volunteers, non-septic infection patients and septic patients; B is a comparison of serum PCT levels among non-septic infection patients and septic patients; C is a comparison of serum WBC levels among non-septic infection patients and septic patients; D is a comparison of serum PaO2 / FiO2 levels among non-septic infection patients and septic patients.

[0133] Figure 2 is the ROC curve diagram of NMI for diagnosing sepsis and non-sepsis infection patients and PCT for diagnosing sepsis (2022 data): Among them, A is the ROC curve diagram of NMI for distinguishing between sepsis and non-sepsis infection patients; B is the ROC curve diagram of NMI for distinguishing between sepsis and healthy people; C is the ROC curve diagram of NMI for distinguishing between sepsis and non-sepsis (healthy people and non-sepsis infection patients); D is the ROC curve diagram of NMI for distinguishing between non-sepsis infection patients and healthy people; E is the ROC curve diagram of NMI for distinguishing between sepsis and non-sepsis infection patients.

[0134] Figure 3 is a comparison of serum NMI levels in healthy volunteers, non-septic infection patients and sepsis patients (data from 2023).

[0135] Figure 4 is the ROC curve of NMI for diagnosing sepsis and non-sepsis infection patients (2023 data): Among them, A is the ROC curve of NMI for distinguishing between sepsis and non-sepsis infection patients; B is the ROC curve of NMI for distinguishing between sepsis and healthy people; C is the ROC curve of NMI for distinguishing between sepsis and non-sepsis (healthy people and non-sepsis infection patients); D is the ROC curve of NMI for distinguishing between non-sepsis infection patients and healthy people.

[0136] Figure 5 is a graph comparing the serum NMI levels of all healthy volunteers, non-septic infection patients, and sepsis patients.

[0137] Figure 6 is the ROC curve diagram of NMI for diagnosing all patients with sepsis and non-sepsis infection: A is the ROC curve diagram of NMI for distinguishing patients with sepsis from patients with non-sepsis infection; B is the ROC curve diagram of NMI for distinguishing patients with sepsis from healthy people; C is the ROC curve diagram of NMI for distinguishing patients with sepsis from non-sepsis (healthy people and patients with non-sepsis infection); D is the ROC curve diagram of NMI for distinguishing patients with non-sepsis infection from healthy people.

[0138] Figure 7 shows the comparison of serum NMI levels between 15 critically ill patients with sepsis and 69 critically ill patients without sepsis, as well as the ROC curve analysis results: A is the comparison of serum NMI levels between 15 critically ill patients with sepsis and 69 critically ill patients without sepsis; B is the ROC curve of NMI distinguishing 15 critically ill patients with sepsis from 69 critically ill patients without sepsis.

[0139] Figure 8 is a comparison of serum NMI levels in 34 critically ill patients with sepsis and 174 critically ill patients without sepsis, as well as the ROC curve analysis results: A is a comparison of serum NMI levels in 34 critically ill patients with sepsis and 174 critically ill patients without sepsis; B is a ROC curve diagram of NMI distinguishing 34 critically ill patients with sepsis from 174 critically ill patients without sepsis.

[0140] Figure 9 is a comparison of serum NMI levels between all critically ill patients with sepsis and non-septic critically ill patients and an ROC curve analysis: A is a comparison of serum NMI levels between all critically ill patients with sepsis and non-septic critically ill patients; B is an ROC curve diagram of NMI distinguishing all critically ill patients with sepsis from non-septic critically ill patients.

[0141] Figure 10 is a graph comparing the serum NMI, PCT, CRP, IL-6, SOFA score and APACHE II score levels between critically ill patients with sepsis and critically ill patients without sepsis: A is a graph comparing the serum NMI levels between critically ill patients with sepsis and critically ill patients without sepsis; B is a graph comparing the SOFA scores between critically ill patients with sepsis and critically ill patients without sepsis; C is a graph comparing the APACHE II scores between critically ill patients with sepsis and critically ill patients without sepsis; D is a graph comparing the serum PCT levels between critically ill patients with sepsis and critically ill patients without sepsis; E is a graph comparing the serum CRP levels between critically ill patients with sepsis and critically ill patients without sepsis; and F is a graph comparing the serum IL-6 levels between critically ill patients with sepsis and critically ill patients without sepsis.

[0142] Figure 11 is the ROC curve diagram of NMI, PCT, CRP and IL-6 for diagnosing sepsis in critically ill patients: A is the ROC curve diagram of NMI for diagnosing sepsis in critically ill patients; B is the ROC curve diagram of PCT for diagnosing sepsis in critically ill patients; C is the ROC curve diagram of CRP for diagnosing sepsis in critically ill patients; D is the ROC curve diagram of IL-6 for diagnosing sepsis in critically ill patients.

[0143] Figure 12 shows the differences in serum NMI levels between 11 patients with septic shock and 8 patients without septic shock, as well as ROC curves for differential diagnosis: Figure A shows the comparison of serum NMI levels between 11 patients with septic shock and 8 patients without septic shock; Figure B shows the ROC curve for NMI in differentiating 11 patients with septic shock from 8 patients without septic shock.

[0144] Figure 13 shows the difference in serum NMI levels between 22 patients with septic shock and 17 patients without septic shock, as well as the ROC curve for differential diagnosis: Figure A shows the comparison of the difference in serum NMI levels between 22 patients with septic shock and 17 patients without septic shock; Figure B shows the ROC curve for NMI in differentiating 22 patients with septic shock from 17 patients without septic shock.

[0145] Figure 14 shows the difference in serum NMI levels between all patients with septic shock and non-septic shock, as well as the ROC curve for differential diagnosis: A is a comparison of the difference in serum NMI levels between all patients with septic shock and non-septic shock; B is a ROC curve for NMI in distinguishing all patients with septic shock from those without septic shock.

[0146] Figure 15 is a graph showing the difference in serum NMI levels and the ROC curve for differential diagnosis between 7 critically ill patients with trauma (multiple organ dysfunction caused by multiple trauma) and 15 patients with sepsis (multiple organ dysfunction caused by sepsis): A is a graph showing the comparison of the difference in serum NMI levels between 7 critically ill patients with trauma (multiple organ dysfunction caused by multiple trauma) and 15 patients with sepsis (multiple organ dysfunction caused by sepsis); B is a graph showing the ROC curve for NMI in distinguishing 7 critically ill patients with trauma (multiple organ dysfunction caused by multiple trauma) from 15 patients with sepsis (multiple organ dysfunction caused by sepsis).

[0147] Figure 16 is a graph showing the difference in serum NMI levels and the ROC curve for differential diagnosis between 15 critically ill patients with trauma (multiple organ dysfunction caused by multiple trauma) and 34 patients with sepsis (multiple organ dysfunction caused by sepsis): A is a graph showing the comparison of the difference in serum NMI levels between 15 critically ill patients with trauma (multiple organ dysfunction caused by multiple trauma) and 34 patients with sepsis (multiple organ dysfunction caused by sepsis); B is a ROC curve for NMI in distinguishing 15 critically ill patients with trauma (multiple organ dysfunction caused by multiple trauma) from 34 patients with sepsis (multiple organ dysfunction caused by sepsis).

[0148] Figure 17 is a diagram showing the difference in serum NMI levels between all critically ill trauma patients and patients with sepsis, as well as the ROC curve for differential diagnosis: A is a diagram showing the comparison of the difference in serum NMI levels between all critically ill trauma patients and patients with sepsis; B is a diagram showing the ROC curve for NMI in distinguishing all critically ill trauma patients from patients with sepsis.

[0149] Figure 18 shows the changes and differences in serum NMI and PCT levels in patients with sepsis and non-sepsis among major surgery patients: A is a graph comparing changes in serum PCT levels in patients with sepsis and non-sepsis among major surgery patients; B is a graph comparing differences in serum PCT levels in patients with sepsis and non-sepsis among major surgery patients; C is a graph comparing changes in serum NMI levels in patients with sepsis and non-sepsis among major surgery patients; and D is a graph comparing differences in serum NMI levels in patients with sepsis and non-sepsis among major surgery patients.

[0150] Figure 19 is a graph showing the relationship between the changes / differences in NMI levels before and after treatment of sepsis patients collected in 2022 and patient outcomes: A is a graph showing the comparison of changes / differences in NMI levels before and after treatment in the recovery group of sepsis patients; B is a graph showing the comparison of changes / differences in NMI levels before and after treatment in the no-recovery group of sepsis patients; C is a graph showing the comparison of changes / differences in NMI levels before and after treatment in the Dead group of sepsis patients; D is a graph showing the comparison of differences in NMI levels among sepsis patients in the recovery group, no-recovery group, and Dead group before treatment; E is a graph showing the comparison of differences in NMI levels among sepsis patients in the recovery group, no-recovery group, and Dead group after treatment.

[0151] Figure 20 is a graph showing the relationship between the changes / differences in PCT levels before and after treatment and patient outcomes in patients with sepsis collected in 2022: A is a graph showing the comparison of changes / differences in PCT levels before and after treatment in patients with sepsis in the recovery group; B is a graph showing the comparison of changes / differences in PCT levels before and after treatment in patients with sepsis in the no-recovery group; C is a graph showing the comparison of changes / differences in PCT levels before and after treatment in patients with sepsis in the Dead group; D is a graph showing the comparison of differences in PCT levels among patients with sepsis in the recovery group, no-recovery group, and Dead group before treatment; E is a graph showing the comparison of differences in PCT levels among patients with sepsis in the recovery group, no-recovery group, and Dead group after treatment.

[0152] Figure 21 is a graph showing the relationship between the changes / differences in NMI levels before and after treatment and patient outcomes in patients with sepsis collected in 2023: A is a graph showing the comparison of changes / differences in NMI levels in patients with sepsis in the recovery group before and after treatment; B is a graph showing the comparison of changes / differences in NMI levels in patients with sepsis in the no-recovery group before and after treatment; C is a graph showing the comparison of changes / differences in NMI levels in patients with sepsis in the Dead group before and after treatment; D is a graph showing the comparison of differences in NMI levels among patients with sepsis in the recovery group, no-recovery group, and Dead group before treatment; E is a graph showing the comparison of differences in NMI levels among patients with sepsis in the recovery group, no-recovery group, and Dead group after treatment.

[0153] Figure 22 is a graph showing the relationship between the changes / differences in PCT levels before and after treatment and patient outcomes in patients with sepsis collected in 2023: A is a graph showing the comparison of changes / differences in PCT levels in patients with sepsis in the recovery group before and after treatment; B is a graph showing the comparison of changes / differences in PCT levels in patients with sepsis in the no-recovery group before and after treatment; C is a graph showing the comparison of changes / differences in PCT levels in patients with sepsis in the Dead group before and after treatment; D is a graph showing the comparison of differences in PCT levels among patients with sepsis in the recovery group, no-recovery group, and Dead group before treatment; E is a graph showing the comparison of differences in PCT levels among patients with sepsis in the recovery group, no-recovery group, and Dead group after treatment.

[0154] Figure 23 is a graph showing the differences in serum IFP35 levels between 9 patients with sepsis and 9 patients with non-septic infection, as well as ROC curves for differential diagnosis: Figure A is a graph showing the comparison of serum IFP35 levels between 9 patients with sepsis and 9 patients with non-septic infection; Figure B is a graph showing the ROC curve for IFP35 in differentiating 9 patients with sepsis and 9 patients with non-septic infection.

[0155] Figure 24 shows the differences in serum IFP35 levels between 26 patients with sepsis and 26 patients with non-septic infection, as well as ROC curves for differential diagnosis: Figure A shows the comparison of serum IFP35 levels between 26 patients with sepsis and 26 patients with non-septic infection; Figure B shows the ROC curve for IFP35 in differentiating 26 patients with sepsis and 26 patients with non-septic infection.

[0156] Figure 25 shows a comparison of serum IFP35 levels between 9 critically ill patients with sepsis and 11 critically ill patients without sepsis, as well as the ROC curve analysis results: Figure A shows a comparison of serum IFP35 levels between 9 critically ill patients with sepsis and 11 critically ill patients without sepsis; Figure B shows the ROC curve of IFP35 for distinguishing 9 critically ill patients with sepsis from 11 critically ill patients without sepsis.

[0157] Figure 26 shows a comparison of serum IFP35 levels between 21 critically ill patients with sepsis and 28 critically ill patients without sepsis, as well as the ROC curve analysis results: Figure A shows a comparison of serum IFP35 levels between 21 critically ill patients with sepsis and 28 critically ill patients without sepsis; Figure B shows the ROC curve of IFP35 for distinguishing 21 critically ill patients with sepsis from 28 critically ill patients without sepsis.

[0158] Figure 27 shows the differences in serum IFP35 levels between 11 patients with septic shock and 8 patients without septic shock, as well as ROC curves for differential diagnosis. Figure A shows the comparison of serum IFP35 levels between 11 patients with septic shock and 8 patients without septic shock; Figure B shows the ROC curve for IFP35 in differentiating 11 patients with septic shock from 8 patients without septic shock.

[0159] Figure 28 shows the differences in serum IFP35 levels between 19 patients with septic shock and 12 patients without septic shock, as well as ROC curves for differential diagnosis. Figure A shows the comparison of serum IFP35 levels between 19 patients with septic shock and 12 patients without septic shock; Figure B shows the ROC curve for IFP35 in differentiating 19 patients with septic shock from 12 patients without septic shock.

[0160] Figure 29 shows the difference in serum IFP35 levels and ROC curves for differential diagnosis between 8 critically ill patients with trauma (multiple organ dysfunction caused by multiple trauma) and 11 patients with sepsis (multiple organ dysfunction caused by sepsis): Figure A shows the comparison of the difference in serum IFP35 levels between 8 critically ill patients with trauma (multiple organ dysfunction caused by multiple trauma) and 11 patients with sepsis (multiple organ dysfunction caused by sepsis); Figure B shows the ROC curve of IFP35 in differentiating 8 critically ill patients with trauma (multiple organ dysfunction caused by multiple trauma) from 11 patients with sepsis (multiple organ dysfunction caused by sepsis).

[0161] Figure 30 is a graph showing the differences in serum IFP35 levels and ROC curves for differential diagnosis between 10 critically ill patients with trauma (multiple organ dysfunction caused by multiple trauma) and 19 patients with sepsis (multiple organ dysfunction caused by sepsis): Figure A is a graph comparing the differences in serum IFP35 levels between 10 critically ill patients with trauma (multiple organ dysfunction caused by multiple trauma) and 19 patients with sepsis (multiple organ dysfunction caused by sepsis); Figure B is a ROC curve of IFP35 for distinguishing between 10 critically ill patients with trauma (multiple organ dysfunction caused by multiple trauma) and 19 patients with sepsis (multiple organ dysfunction caused by sepsis).

[0162] In the above figures, ns indicates p>0.05; * indicates p<0.05; ** indicates p<0.01; **** indicates p<0.0001. DETAILED DESCRIPTION

[0163] The present invention is further described in detail below through specific examples.

[0164] It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0165] The experimental methods in the following examples, where specific conditions are not specified, were generally performed under conventional conditions or the conditions recommended by the manufacturers. The materials and reagents used in these examples were commercially available unless otherwise specified.

[0166] Example 1 Application of IFP35 Family Proteins in Diagnosis of Sepsis and / or Septic Shock

[0167] 1. Test methods

[0168] 1.1 Study population

[0169] The study population in this embodiment covers healthy volunteers undergoing physical examinations, patients with non-septic infections, critically ill patients with non-septic infections, and patients with sepsis.

[0170] Diagnosis of sepsis: refer to the International Consensus on the Definition of Sepsis and Septic Shock (3rd Edition)<Sepsis 3.0> )》standards, etc. for diagnosis.

[0171] Non-sepsis infection diagnosis: The patient has signs of infection (such as elevated white blood cell count, CRP, or PCT), and the attending physician diagnoses the patient with an infectious disease based on clinical diagnosis and treatment, including severe pneumonia, non-severe community-acquired pneumonia, interstitial lung disease, bacterial pneumonia, Aspergillus pneumonia, Mycoplasma pneumoniae pneumonia, pulmonary viral infection (cytomegalovirus), pneumonia in immunosuppressed hosts, lung abscess with pneumonia, acute lower respiratory tract infection, bronchiectasis with infection, bronchitis, deep neck abscess, infective endocarditis, viral myocarditis, acute cholecystitis, hepatobiliary stones with cholangitis, acute pyelonephritis, urinary tract infection, peritonitis, pleuritis, liver cyst, empyema, and stent infection, but does not meet the above-mentioned sepsis diagnosis.

[0172] Non-septic critically ill patients: patients admitted to the ICU for monitoring and treatment due to non-septic reasons.

[0173] Severely ill patients with sepsis: Severely ill patients with sepsis admitted to the ICU for monitoring and treatment.

[0174] Healthy control diagnosis: healthy people with no medical problems found during routine physical examination.

[0175] 1.2 Study Type

[0176] The study design is observational and does not require additional visits, laboratory analyses, or assessments beyond those required in routine clinical practice. No randomized or protocol-driven treatment will be administered or provided to the subjects during the study.

[0177] 1.3 Admission criteria

[0178] 1) Sepsis patient group

[0179] a) Inclusion criteria:

[0180] According to the Sepsis 3.0 diagnostic criteria for sepsis, the following conditions must be met:

[0181] (1) Clear pathogen infection (with pathogen detection and infection evidence);

[0182] (2) SOFA score increased by >2 compared with baseline.

[0183] Septic shock: After adequate fluid resuscitation, vasoactive drugs are still required to maintain mean arterial pressure > 65 mmHg and blood lactate concentration > 2 mmol / L.

[0184] b) Exclusion criteria:

[0185] (1) Age <18 years old;

[0186] (2) pregnancy and lactation;

[0187] (3) Malignant tumors;

[0188] (4) After continuous cardiopulmonary resuscitation.

[0189] 2) Infection group (non-sepsis)

[0190] a) Inclusion criteria:

[0191] (1) Clear pathogen infection (with pathogen detection and infection evidence);

[0192] b) Exclusion criteria:

[0193] (1) Age <18 years old;

[0194] (2) pregnancy and lactation;

[0195] (3) Malignant tumors;

[0196] (4) After continuous cardiopulmonary resuscitation.

[0197] 3) Critically ill patients

[0198] a) Inclusion criteria:

[0199] (1) Patients transferred to the ICU and requiring intensive care due to various factors such as trauma causing the following conditions:

[0200] Brain failure, various shocks, respiratory failure, heart failure, liver failure, kidney failure, etc.

[0201] b) Exclusion criteria:

[0202] (1) Age <18 years old;

[0203] (2) pregnancy and lactation;

[0204] (3) after continuous cardiopulmonary resuscitation;

[0205] (4) Immune deficiency / severe impairment.

[0206] 4) Healthy control group

[0207] Healthy people with no medical problems during routine physical examinations

[0208] 1.4 Collection of clinical data

[0209] Patients were screened according to the inclusion and exclusion criteria, and the following information of each enrolled patient was recorded, including basic demographic data, patient information: admission time, discharge time, diagnosis, survival status, outcome, body temperature, oxygenation index, infection factors, infection site, underlying diseases / comorbidities: diabetes, hypertension, cardiovascular disease, chronic obstructive pulmonary disease, chronic kidney disease, chronic liver disease, malignant tumors, immunosuppressive status (including the use of immunosuppressants), etc., and clinical test results: white blood cell count, bilirubin, procalcitonin PCT, IL-6, CRP, SOFA score, APACHE II score, etc.

[0210] 1.5 Clinical serum sample collection and processing

[0211] 1) Collect the remaining serum from the enrolled patients after routine hospital testing; or

[0212] 2) Blood collection (red or yellow capped blood collection tubes). After blood collection, let the tube rest at room temperature for 2 hours. Centrifuge at 3000 rpm (1000-1200g) for 10 minutes. Separate the upper serum layer into cryovials (1 mL per tube) and store at -80°C. Record any abnormalities in the serum sample, such as hemolysis and chyle.

[0213] 1.6 Detection of NMI in serum samples

[0214] The detection of NMI (UniProtKB: Q13287) levels in serum samples was commissioned by Guangzhou Darui Biotechnology Co., Ltd. The detection method was magnetic microparticle chemiluminescence immunoassay (CLIA).

[0215] 1.7 Data Processing and Analysis

[0216] The median and interquartile range were used to describe the basic characteristics of skewed or unknown distributions of continuous data. Nonparametric tests were used for data that did not conform to a normal distribution. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the diagnostic efficacy of the marker, and the cutoff value, sensitivity, and specificity were determined based on the Youden index. The Spearman test was used to assess the correlation between the marker and indicators such as PCT. Logistic regression was used to analyze the statistical significance of the marker's effect on 28-day survival. The significance criteria were as follows: *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.

[0217] 2. Experimental Results

[0218] 2.1 Application of NMI in screening and differentiating non-septic individuals (healthy individuals and / or patients with non-septic infections) from septic patients, and between healthy individuals and patients with non-septic infections

[0219] In 2022, serum samples were collected from the Department of Laboratory Medicine of the First Affiliated Hospital of Guangzhou Medical University from 150 healthy individuals undergoing physical examinations, 100 patients with non-septic infections, and 53 patients with sepsis. NMI levels were measured. Table 1 shows the patient demographics, health status, medical history, and selected laboratory characteristics. As can be seen in the table, there were no statistically significant differences in age and gender between the sepsis and non-septic infection groups. There were also no statistically significant differences in underlying medical conditions such as hypertension, diabetes, cardiovascular disease, renal insufficiency, and chronic kidney disease.

[0220] Table 1. Demographic information and overall distribution of various markers in patients with sepsis and non-septic infection

[0221] The results of NMI levels in serum samples from each group are shown in Table 2 and Figure 1A. Statistical results showed that the median NMI level in the serum of healthy controls was 0.3250 pg / mL (0.095, 2.211), with 99% of healthy controls having NMI levels below 32.42 pg / mL. The median NMI level in the serum of 100 patients with non-septic infections (Other diseases) was 140.6 pg / mL (72.69, 212.7), significantly different from the NMI levels in healthy controls. Furthermore, 99% of non-septic patients had serum NMI levels below 531.1 pg / mL. The median NMI level in the serum of 53 patients with sepsis (Sepsis) was 932.1 pg / mL (511.6, 1787), which was statistically significantly different from the serum NMI levels in the healthy control and non-septic infection groups. This indicates that NMI is specifically highly expressed in patients with sepsis, while in patients with other non-septic infections, the serum level of NMI is slightly elevated.

[0222] In addition, the analysis results of the above 100 patients with non-septic infection and 53 patients with sepsis showed that the levels of the clinical indicator PCT were significantly different between the sepsis and non-septic infection groups (Figure 1B), which is consistent with the facts, but its discrimination is lower than that of NMI; the white blood cell content, an infection indicator, was not significantly different between the sepsis and non-septic infection groups (Figure 1C); and the oxygenation index PaO2 / FiO2 was significantly different between the sepsis and non-septic infection groups (Figure 1D), which is consistent with the facts.

[0223] The above NMI content test results show that the serum NMI level in patients with sepsis is significantly higher than that in patients with non-sepsis infection, and can fairly accurately distinguish patients with sepsis from patients with non-sepsis infection; the serum NMI level in patients with sepsis is significantly higher than that in healthy people, and can fairly accurately distinguish patients with sepsis from healthy people; therefore, NMI has the potential to screen and distinguish patients with sepsis from non-sepsis (healthy people and / or patients with non-sepsis infection). In addition, the serum NMI level in patients with non-sepsis infection is also significantly higher than that in healthy people, and can fairly accurately distinguish patients with non-sepsis infection from healthy people. Therefore, NMI has the potential to screen and distinguish patients with non-sepsis infection from healthy people.

[0224] Table 2. Expression levels and differences of four markers / detection indicators between patients with sepsis and non-septic infection

[0225] The receiver operating characteristic (ROC) curve analysis was performed on the NMI content of the above-mentioned groups of samples, and the results are shown in FIG2 .

[0226] The receiver operating characteristic (ROC) curve for NMI screening and differentiation between patients with sepsis and those without sepsis is shown in Figure 2A. The area under the curve (AUC) reached 0.9458, with a 95% confidence interval of 0.894-0.998. The cutoff value for differentiating patients with sepsis from those without sepsis using serum NMI was 345.5 pg / mL, with a sensitivity of 92.45% and a specificity of 94%.

[0227] The receiver operating characteristic (ROC) curve for NMI screening and differentiation between sepsis patients and healthy controls is shown in Figure 2B. The area under the curve (AUC) reached 0.9997, with a 95% confidence interval of 0.999-1.000. The cutoff value for screening and differentiation between sepsis patients and healthy controls using serum NMI was 23.91 pg / mL, with a sensitivity of 100% and a specificity of 98.67%.

[0228] The receiver operating characteristic (ROC) curve for NMI screening and differentiation between sepsis patients and non-sepsis patients (non-sepsis patients and healthy controls) is shown in Figure 2, Panel C. The area under the curve (AUC) reached 0.9782, with a 95% confidence interval (CI) of 0.957-0.999. The cutoff value for differentiating between sepsis patients and non-sepsis patients using serum NMI was 307.5 pg / mL, with a sensitivity of 94.34% and a specificity of 96.4%.

[0229] The receiver operating characteristic (ROC) curve for NMI screening and differentiation between non-septic patients and healthy controls is shown in Figure 2D. The area under the curve (AUC) reached 0.9587, with a 95% confidence interval (CI) of 0.923-0.994. The cutoff value for differentiating between non-septic patients and healthy controls based on serum NMI levels was 17.79 pg / mL, with a sensitivity of 92% and a specificity of 98%.

[0230] Furthermore, the receiver operating characteristic (ROC) curve for PCT in differentiating patients with sepsis from those without sepsis is shown in Figure 2, Panel E. The area under the curve (AUC) was 0.7559, with a 95% confidence interval (CI) of 0.672-0.840. The cutoff value of 0.4 ng / mL for distinguishing patients with sepsis from those without sepsis showed a sensitivity of 83.33% and a specificity of 64.52%. This indicates that serum NMI outperforms the currently used PCT in diagnosing sepsis.

[0231] In order to clarify whether the NMI content in serum can be used to screen and distinguish sepsis patients from non-sepsis populations (healthy people and / or patients with non-sepsis infection), as well as to distinguish patients with non-sepsis infection from healthy people, serum samples from 241 healthy people, 148 sepsis patients and 42 patients with non-sepsis infection were collected from the Department of Laboratory of the First Affiliated Hospital of Guangzhou Medical University in 2023, and the NMI content was measured (Figure 3) and ROC curve analysis was performed (Figure 4).

[0232] As shown in Figure 3, the median serum NMI level in 241 healthy individuals was 0.305 pg / mL (0.053 pg / mL, 2.498 pg / mL), with 99% of healthy individuals having NMI levels below 34.04 pg / mL. The median serum NMI level in 42 patients with non-septic infections was 72.81 pg / mL (30.32 pg / mL, 131.6 pg / mL), significantly different from the serum NMI levels in healthy individuals. Furthermore, 99% of non-septic patients had serum NMI levels below 499.4 pg / mL. The median serum NMI level in 148 patients with sepsis was 780.2 pg / mL (370.8 pg / mL, 1688 pg / mL), which was statistically significantly different from the serum NMI levels in the healthy control group and the non-septic infection group. This indicates that NMI is specifically highly expressed in patients with sepsis, while in patients with other non-septic infections, the serum level of NMI is slightly elevated.

[0233] The receiver operating characteristic (ROC) curve for NMI screening and differentiation between patients with sepsis and those without sepsis is shown in Figure 4A. The area under the curve (AUC) reached 0.9533, with a 95% confidence interval (CI) of 0.925–0.982. The cutoff value for differentiating patients with sepsis from those without sepsis using serum NMI was 194.1 pg / mL, with a sensitivity of 91.22% and a specificity of 92.86%.

[0234] The receiver operating characteristic (ROC) curve for NMI screening and differentiation between sepsis patients and healthy controls is shown in Figure 4B. The area under the curve (AUC) reached 1.000, with a 95% confidence interval of 0.999-1.000. The cutoff value for differentiating between sepsis patients and healthy controls based on serum NMI levels was 40.08 pg / mL, with a sensitivity of 100% and a specificity of 99.64%.

[0235] The receiver operating characteristic (ROC) curve for NMI screening and differentiation between sepsis patients and non-sepsis patients (non-sepsis infection patients plus healthy controls) is shown in Figure 4, Panel C. The area under the curve (AUC) reached 0.9930, with a 95% confidence interval (CI) of 0.988-0.998. The cutoff value for differentiating between sepsis patients and non-sepsis patients using serum NMI was 126.4 pg / mL, with a sensitivity of 94.59% and a specificity of 96.11%.

[0236] The receiver operating characteristic (ROC) curve for NMI screening and differentiation between non-septic patients and healthy controls is shown in Figure 4D. The area under the curve (AUC) reached 0.9293, with a 95% confidence interval (CI) of 0.868-0.991. The cutoff value for differentiating between non-septic patients and healthy controls based on serum NMI levels was 10.97 pg / mL, with a sensitivity of 85.71% and a specificity of 95.32%.

[0237] Combining all the above cases, we obtained the overall expression of NMI in different populations (Figure 5) and the performance parameters for distinguishing between septic and non-septic populations (Figure 6).

[0238] The median serum NMI level in 391 healthy individuals undergoing physical examinations was 0.310 pg / mL (0.065 pg / mL, 2.35 pg / mL), and 99% of healthy individuals had NMI levels below 31.51 pg / mL. The median serum NMI level in 142 patients with non-septic infections was 124.7 pg / mL (55.38 pg / mL, 192.8 pg / mL), which was significantly different from the serum NMI levels in healthy individuals. Furthermore, 99% of non-septic patients had serum NMI levels below 517.9 pg / mL. The median serum NMI level in 201 patients with sepsis was 799.8 pg / mL (424.4 pg / mL, 1660 pg / mL), which was statistically significantly different from the serum NMI levels in the healthy control group and the non-septic infection group. This indicates that NMI is specifically highly expressed in patients with sepsis, while in patients with other non-septic infections, the serum level of NMI is slightly elevated.

[0239] The receiver operating characteristic (ROC) curve for NMI screening and differentiation between patients with sepsis and those without sepsis is shown in Figure 6A. The area under the curve (AUC) reached 0.9334, with a 95% confidence interval of 0.907-0.960. The cutoff value for differentiating patients with sepsis from those without sepsis using serum NMI was 337.9 pg / mL, with a sensitivity of 82.59% and a specificity of 95.07%.

[0240] The receiver operating characteristic (ROC) curve for NMI screening and differentiation between sepsis patients and healthy controls is shown in Figure 6B. The area under the curve (AUC) reached 0.9999, with a 95% confidence interval (CI) of 0.997-1.000. The cutoff value for differentiating between sepsis patients and healthy controls based on serum NMI levels was 40.06 pg / mL, with a sensitivity of 99.5% and a specificity of 99.74%.

[0241] The receiver operating characteristic (ROC) curve for NMI screening and differentiation between sepsis patients and non-sepsis patients (non-sepsis patients and healthy controls) is shown in Figure 6, Panel C. The area under the curve (AUC) reached 0.9822, with a 95% confidence interval (CI) of 0.975-0.990. The cutoff value for differentiating between sepsis patients and non-sepsis patients using serum NMI was 194.1 pg / mL, with a sensitivity of 92.04% and a specificity of 93.62%.

[0242] The receiver operating characteristic (ROC) curve for NMI screening and differentiation between non-septic patients and healthy controls is shown in Figure 6D. The area under the curve (AUC) reached 0.9498, with a 95% confidence interval (CI) of 0.919-0.981. The cutoff value for differentiating between non-septic patients and healthy controls based on serum NMI levels was 20.44 pg / mL, with a sensitivity of 88.03% and a specificity of 98.47%.

[0243] 2.2 Application of NMI in differentiating critically ill patients with non-sepsis from critically ill patients with sepsis

[0244] Epidemiological studies have shown that the mortality rate of sepsis has surpassed that of myocardial infarction, becoming the leading cause of death in intensive care unit (ICU) patients without cardiac conditions. Furthermore, sepsis often occurs in patients with serious illnesses, such as severe burns, multiple trauma, and those following surgery. Therefore, rapid diagnosis and differential diagnosis of sepsis in ICU patients are crucial for timely and accurate treatment.

[0245] The inventors first collected serum samples from 84 critically ill patients in the Department of Critical Care Medicine of the Seventh Affiliated Hospital of Sun Yat-sen University, and measured and statistically analyzed the NMI content in the serum samples. According to whether the patients developed sepsis during their stay in the ICU, the ICU patients were divided into two groups: a sepsis group (critically ill patients with sepsis / septic shock) and other critical illness groups (critically ill patients not caused by sepsis). Among the 84 critically ill patients, 15 patients developed sepsis / septic shock, accounting for 17.6%, which is consistent with the current data and literature reports that the incidence of ICU sepsis is approximately 20%. The results of serum NMI content detection in 84 critically ill patients are shown in Figure 7. Among the 69 critically ill patients without sepsis, the median serum NMI level was 5.15 pg / mL (0.00, 22.38), nearly comparable to that of the healthy population. The median serum NMI level in the 15 critically ill patients with sepsis was 690.8 pg / mL (469.0, 1522), significantly higher than that of the 69 critically ill patients without sepsis. Receiver-operating characteristic (ROC) curve analysis showed an area under the curve (AUC) of 0.996, a 95% confidence interval of 0.987-1.000, and a cutoff of 109.6 pg / mL, resulting in a sensitivity of 100% and a specificity of 94.2%.

[0246] These results indicate that when critically ill patients develop sepsis, NMI levels in their blood are significantly elevated; whereas when critically ill patients do not develop sepsis, NMI levels in their blood are extremely low, close to normal levels. Therefore, measuring NMI levels in the blood of critically ill patients can be used to quickly determine / monitor whether sepsis has occurred in these patients, enabling prompt detection and symptomatic treatment.

[0247] To determine whether the serum NMI level can be used to distinguish between non-septic critically ill patients and septic critically ill patients, the inventors collected serum samples from 174 non-septic critically ill patients and 34 septic critically ill patients from the Department of Critical Care Medicine of the Seventh Affiliated Hospital of Sun Yat-sen University, and measured the NMI level and analyzed the receiver operating characteristic (ROC) curve. The results are shown in Figure 8. The median serum NMI level in the 174 non-septic critically ill patients was 6.155 pg / mL (0.365, 36.3); the median serum NMI level in the 34 septic critically ill patients was 808.1 pg / mL (503.5, 1646), which was significantly higher than the serum NMI level in the 174 non-septic critically ill patients (Figure 8A). This test result is consistent with the test results of the above 84 critically ill patients, indicating that when critically ill patients develop sepsis, the NMI content in the blood will indeed increase significantly; while when critically ill patients do not develop sepsis, the NMI content in the blood is at an extremely low level, close to the level of normal people.

[0248] The inventors performed a receiver operating characteristic (ROC) curve analysis to evaluate the effectiveness of serum NMI levels in distinguishing non-septic critically ill patients from septic critically ill patients. The results are shown in Figure 8B. The area under the curve (AUC) reached 0.923, with a 95% confidence interval of 0.849-0.997 and a cutoff value of 294.8 pg / mL. This yielded a sensitivity of 85.29% and a specificity of 98.85%.

[0249] The inventors combined and analyzed two batches of samples collected from the Department of Critical Care Medicine of the Seventh Affiliated Hospital of Sun Yat-sen University. The results are shown in Figure 9. The median serum NMI level of 243 non-septic critically ill patients was 5.500 pg / mL (0.310, 29.06); the median serum NMI level of 49 critically ill patients with sepsis was 806 pg / mL (498, 1524), which was significantly higher than the serum NMI level of 243 non-septic critically ill patients. The results of ROC curve analysis showed that the area under the curve (AUC) of NMI for distinguishing critically ill patients with sepsis from non-septic critically ill patients reached 0.9456, with a 95% confidence interval of 0.895-0.997 and a cutoff value of 284.5 pg / mL. Its sensitivity was 87.76% and specificity was 99.18%.

[0250] In addition, data on other inflammatory indicators, including PCT, CRP, IL-6, and organ function score indicators SOFA and APACHE II, were collected from the above-mentioned 174 non-sepsis critically ill patients and 21 severe sepsis patients among the 34 severe sepsis patients, as well as 51 severe non-sepsis patients. The inventors also conducted a statistical analysis of these indicators, and the results are shown in Figure 10. The results showed that the median NMI content, SOFA score, and APACHE II score of serum samples in the severe sepsis group were significantly higher than those in the non-sepsis critically ill patient group, indicating that the degree of organ damage and severity of the disease in sepsis patients were significantly higher than those in the non-sepsis group, and the difference in NMI content was associated with organ function damage in sepsis patients. However, there was no difference in the expression of other inflammatory indicators, including CRP and IL-6, between severe sepsis patients and non-sepsis patients. In addition, the expression level of PCT in non-sepsis critically ill patients was higher than that in sepsis critically ill patients.

[0251] Furthermore, the inventors performed ROC curve analysis on various inflammatory indicators, and the results are shown in Figure 11. As can be seen from the figure, the AUC value of NMI reached 0.9881, with excellent diagnostic performance, consistent with the above results. In contrast, the AUC value of PCT was 0.6505, the AUC of CRP was 0.5751, and the AUC of IL-6 was 0.5552, showing no ability to distinguish between severe sepsis and non-sepsis. This shows that NMI can very effectively distinguish between sepsis and non-sepsis in critically ill patients with complex conditions, while the commonly used clinical inflammatory indicators PCT, CRP, and IL-6 do not have this characteristic.

[0252] 2.3 Application of NMI in differentiating septic shock from non-septic shock

[0253] The "Sepsis Diagnosis and Treatment Guidelines (2023)" emphasizes that sepsis must be differentiated from organ dysfunction caused by non-infectious factors, and septic shock must be differentiated from shock caused by other causes. Septic shock is a severe syndrome of circulatory and cellular metabolic disorders caused by sepsis, also known as infectious shock or septic shock. Other causes of shock include cardiogenic shock due to abnormal cardiac function, hypovolemic shock due to massive blood and fluid loss, obstructive shock, neurogenic shock, and anaphylactic shock.

[0254] The inventors found 8 patients with non-sepsis shock and 11 patients with septic shock from a first batch of 84 critically ill patients collected from the Department of Critical Care Medicine of the Seventh Affiliated Hospital of Sun Yat-sen University. The non-sepsis shock patients included hypovolemic shock, cardiogenic shock, neurogenic shock, obstructive shock, and anaphylactic shock.

[0255] Statistical analysis results (Figure 12A) showed that the median NMI level in serum samples from 11 patients with septic shock at multiple time points was 968.2 pg / mL (469, 1325), while the median NMI level in serum from 8 patients without septic shock was 4.34 pg / mL (0.28, 21.72), significantly lower than that in patients with septic shock. Therefore, it is speculated that the serum level of NMI has the ability to distinguish between septic shock and non-septic shock. The receiver operating characteristic (ROC) curve analysis results (Figure 12B) showed that the AUC for distinguishing between septic shock and non-septic shock using serum NMI in shock patients reached 0.998, with a 95% confidence interval of 0.993-1.000 and a cutoff of 215.8 pg / mL, resulting in a sensitivity of 100% and a specificity of 98.81%.

[0256] To verify that the serum NMI level in shock patients can be used to distinguish septic shock from non-septic shock, the inventors separated the data of 17 non-septic shock patients and 22 septic shock patients from the second batch of 208 critically ill patients collected from the Department of Critical Care Medicine of the Seventh Affiliated Hospital of Sun Yat-sen University and performed statistical analysis.

[0257] Statistical analysis of serum NMI levels (Figure 13A) showed that the median NMI level in serum samples from 22 patients with septic shock at multiple time points was 576.9 pg / mL (range, 404.1, 940.5), while the median NMI level in 17 patients without septic shock was 12.67 pg / mL (range, 1.57, 50.12), significantly lower than that in patients with septic shock. Receiver operating characteristic (ROC) curve analysis (Figure 13B) demonstrated that serum NMI levels in shock patients had an AUC of 0.9814 for distinguishing septic shock from non-septic shock, with a cutoff of 263.1 pg / mL, a sensitivity of 95.33%, and a specificity of 98.7%. These results confirm that serum NMI levels are effective in distinguishing septic shock from non-septic shock.

[0258] The inventors combined the test results of the samples of the above two batches of shock patients for statistics and analysis, and the results are shown in Figure 14. The statistical analysis of the NMI content results showed that the median NMI content of all serum samples of 25 non-septic shock patients was 7.94pg / mL (0.475, 37.27), which is close to the level of healthy people. The median NMI content of all serum samples of 33 patients with septic shock was 666.3pg / mL (421.1, 1198). The difference in NMI content between the two groups of serum samples was extremely significant. ROC curve analysis of the two groups of data showed that the area under the curve AUC of NMI for distinguishing between septic shock and non-septic shock patients reached 0.9893, the 95% confidence interval was 0.978-1.000, the cutoff value was 253.4pg / mL, the sensitivity reached 96.84%, and the specificity reached 98.76% (B in Figure 14). These data indicate that serum NMI levels have excellent efficacy in distinguishing patients with septic shock from those without septic shock.

[0259] 2.4 Application of NMI in differentiating sepsis from organ dysfunction caused by non-infectious factors

[0260] Severe trauma, extensive burns, and post-major surgery can lead to insufficient effective circulating blood volume, suppressed cardiac function, and severe hypoxia, leading to multiple organ dysfunction. Diffuse bleeding, hypothermia (especially temperature ≤34°C), and acidosis can lead to life-threatening coagulopathy. Soft tissue injury leads to acute inflammation, further exacerbating this process. Therefore, multiple organ dysfunction in patients with sepsis needs to be differentiated from organ dysfunction caused by some of the non-infectious factors mentioned above.

[0261] The inventors isolated sample test data from 7 critically ill patients with multiple trauma who did not develop sepsis during ICU treatment from the first batch of 84 critically ill patients collected from the Department of Critical Care Medicine of the Seventh Affiliated Hospital of Sun Yat-sen University and performed statistical analysis. The results are shown in Figure 15. The median NMI level of serum samples of these 7 critically ill patients with multiple trauma at multiple time points was 5.09 pg / mL (0.00, 24.73), which was significantly lower than that of patients with sepsis. Therefore, it is speculated that the serum level of NMI has the ability to distinguish multiple organ dysfunction caused by multiple trauma and sepsis. Using the NMI data of serum samples of 15 sepsis patients in the first batch of 84 critically ill patients as a control, ROC curve analysis was performed on the data of the 7 patients with multiple trauma. The results showed that the AUC of serum NMI content for distinguishing multiple organ dysfunction caused by trauma from sepsis reached 1.000, with a 95% confidence interval of 1.000-1.000 and a cutoff value of 120.9 pg / mL, a sensitivity of 100%, and a specificity of 100%.

[0262] To validate the ability of serum NMI levels to distinguish between critical illness caused by severe trauma and sepsis, the inventors analyzed the data from 15 critically ill patients with multiple trauma from a second cohort of 208 critically ill patients collected from the Department of Critical Care Medicine at the Seventh Affiliated Hospital of Sun Yat-sen University. The results are shown in Figure 16. The median NMI level in serum samples from these 15 critically ill patients with multiple trauma at multiple time points was 1.23 pg / mL (range, 0.13, 9.84), significantly lower than that in patients with septic shock. Using the NMI data from serum samples from 34 patients with sepsis among the 208 critically ill patients as a control, receiver operating characteristic (ROC) curve analysis of the data from the 15 patients with multiple trauma demonstrated that serum NMI levels had an AUC of 0.9389 for distinguishing between trauma and sepsis, with a 95% confidence interval of 0.870-1.000 and a cutoff of 73.84 pg / mL. This yielded a sensitivity of 91.18% and a specificity of 99.15%.

[0263] The inventors combined and analyzed the sample test results of the above two batches of trauma patients, and the results are shown in Figure 17. The median NMI content of 172 serum samples from 22 trauma patients who did not develop sepsis was 2.59 pg / mL (0.08, 13.48), which is comparable to the level of healthy people and significantly lower than that of sepsis. The results of ROC curve analysis showed that the AUC of serum NMI content in distinguishing multiple organ dysfunction caused by trauma and sepsis reached 0.957, with a 95% confidence interval of 0.909-1.000, a cutoff value of 73.84 pg / mL, a sensitivity of 93.88%, and a specificity of 98.26%. This data shows that the serum NMI content has excellent efficacy in distinguishing between severe trauma patients (without sepsis) and sepsis patients (multiple organ dysfunction caused by trauma and sepsis).

[0264] Furthermore, after major surgery, PCT, a common clinical indicator of bacterial infection / sepsis, will nonspecifically increase and may not return to normal until three days later. If sepsis develops after surgery, the diagnosis of sepsis based on PCT testing will be compromised.

[0265] The inventors isolated and analyzed serum sample data from eight patients who underwent major surgery during hospitalization from a collection of critically ill patients. Patients 1-4 did not develop sepsis after surgery, while patients 5-8 developed sepsis after surgery.

[0266] Figure 18, A, shows the trend of changes in serum PCT levels in 8 surgical patients. As can be seen from the figure, PCT levels increased significantly after major surgery, regardless of whether sepsis developed postoperatively, and were significantly higher than the normal PCT level (<0.05 ng / mL). Statistical analysis of PCT levels in serum samples from postoperative patients showed no statistically significant difference in serum PCT levels between patients who did not develop sepsis and those who did (Figure 18, B), indicating that the increase in PCT was unrelated to the occurrence of sepsis and was a nonspecific increase caused by major surgery.

[0267] Figure 18, C, shows the trend of changes in serum NMI levels in 8 surgical patients. As can be seen from the figure, after major surgery, when sepsis develops, the serum NMI level will increase significantly; while when sepsis does not develop, the serum NMI level will not increase or increase slightly. Statistics of the NMI content data of serum samples from postoperative patients show that the NMI level in patients who develop sepsis after surgery is significantly higher than that in patients who do not develop sepsis after surgery (Figure 18, D), which means that the increase in NMI is not related to the implementation of major surgery and is not affected by major surgery, but is specifically related to the occurrence of sepsis.

[0268] 2.5 Application of NMI in sepsis treatment efficacy / prognosis assessment

[0269] The inventors conducted a statistical analysis of the NMI levels in serum samples collected from 32 sepsis patients at the time of admission / diagnosis (within 3 days) and discharge (within 3 days) from the Department of Laboratory of the First Affiliated Hospital of Guangzhou Medical University in 2022. According to the treatment outcomes of sepsis patients, the patients were divided into a treatment improvement / recovery group (recovery, 11 cases), a no improvement / automatic discharge group (no-recovery, 14 cases), and a death group (dead, 7 cases). The test results are shown in Figure 19. The inventors found that:

[0270] ① NMI levels varied among sepsis patients in the recovery group at admission, with a median of 1113 pg / mL (397.4, 2000). After treatment, NMI levels in improved patients decreased to lower levels (Figure 19A), with a median of 177.7 pg / mL (72.0, 515.0). Given the diagnostic efficacy of NMI for sepsis, NMI levels in improved patients at discharge can be diagnosed as non-septic.

[0271] ② The median NMI level for sepsis patients in the no-recovery group at admission was 546.6 pg / mL (314.1, 776.6). After treatment, the NMI level in patients who were discharged voluntarily did not decrease significantly (Figure 19B), with a median of 473.9 pg / mL (399.7, 785.0). Based on the NMI criteria for diagnosing sepsis, these patients were still at elevated NMI levels at discharge, indicating they were still in a sepsis-prone state, and their physicians recommended continued hospitalization.

[0272] ③ The median NMI level in the dead group of sepsis patients at admission was 698.3 pg / mL (642.2, 1634). After treatment, the NMI level in the deceased patients actually increased (Figure 19, C), reaching a median of 1271 pg / mL (625.1, 2196). According to the NMI criteria for diagnosing sepsis, these patients remained in a sepsis-prone state, and their condition worsened, leading to death.

[0273] The above results show that there was no statistical difference in NMI levels among the three groups of patients at admission (Figure 19, D). However, upon discharge, NMI levels showed differences depending on the outcome (Figure 19, E). That is, the NMI levels of patients who improved after treatment decreased, while the NMI levels of patients who did not improve or died did not decrease, but increased. This result shows that the NMI level can indicate the treatment effect / prognosis of sepsis patients. That is, a decrease in NMI level after treatment means that the treatment of sepsis patients is effective; a persistently high level or even an increase after treatment indicates that the patient's condition is not under control or is even continuing to deteriorate, and there is a risk of death.

[0274] The inventors also analyzed the PCT content in the serum samples of the above-mentioned sepsis patients, and the results are shown in Figure 20. The inventors found that:

[0275] ① The PCT levels of sepsis patients in the recovery group at the time of admission / diagnosis varied, with a median of 4.38 ng / mL (1.29, 10.34). After treatment, the PCT levels of improved patients decreased to a lower level (Figure 20A), with a median of 0.21 pg / mL (0.06, 1.00).

[0276] ②The median PCT level of sepsis patients in the no-recovery group at the time of admission / diagnosis was 3.125 ng / mL (0.46, 6.27). After treatment, the PCT level of patients who were discharged voluntarily decreased (Figure 20B), with a median of 0.5 ng / mL (0.305, 5.7).

[0277] ③The median PCT level of patients in the Dead group at the time of admission / diagnosis of sepsis was 1.78 ng / mL (0.61, 36.48). After treatment, the PCT level of deceased patients did not drop to normal levels (Figure 20C), and the median PCT level was 6.94 pg / mL (1.47, 28.48).

[0278] The above results show that there was no statistical difference in the PCT levels of the three groups of patients at the time of admission / diagnosis (D in Figure 20), but the PCT levels showed differences according to the different outcomes at the time of discharge (E in Figure 20), that is, the PCT levels of patients who improved after treatment decreased, the PCT levels of patients who did not improve also did not decrease, and the PCT levels of patients who died remained at a high level overall.

[0279] In order to verify that NMI can be used as a marker for the treatment effect / prognosis evaluation of patients with sepsis, the NMI content of serum samples collected from 83 sepsis patients admitted / diagnosed (within 3 days) and discharged (within 3 days) from the Department of Laboratory of the First Affiliated Hospital of Guangzhou Medical University in 2023 was statistically analyzed. According to the treatment outcomes of sepsis patients, the patients were divided into a treatment improvement / recovery group (recovery, 22 cases), a no improvement / automatic discharge group (no-recovery, 38 cases) and a death group (dead, 23 cases). The test results are shown in Figure 21. The inventors found that:

[0280] ① In the recovery group, NMI levels varied between high and low levels at admission for sepsis patients, with a median of 595.6 pg / mL (359.9, 1060). After treatment, NMI levels in improved patients decreased to lower levels (Figure 21A), with a median of 107.3 pg / mL (59.49, 265.4). Based on the NMI criteria for diagnosing sepsis, NMI levels in improved patients at discharge could be diagnosed as non-sepsis.

[0281] ② In the no-recovery group, the median NMI level was 426.8 pg / mL (278.3, 1464) at admission. After treatment, the NMI level in patients who were discharged voluntarily increased (Figure 21B), reaching a median of 769.7 pg / mL (341.9, 1443). Based on the NMI criteria for diagnosing sepsis, these patients were still at high NMI levels at discharge, indicating they were still in a sepsis-prone state, and their physicians recommended continued hospitalization.

[0282] The median NMI level in the dead group of sepsis patients at admission was 370.7 pg / mL (137, 1160). After treatment, the NMI level in the deceased patients increased (Figure 21, C), reaching a median of 940.1 pg / mL (262.8, 2099). According to the NMI criteria for diagnosing sepsis, these patients remained in a sepsis-prone state, and their condition worsened, leading to death.

[0283] The above results show that there was no statistical difference in NMI levels among the three groups of patients at admission (Figure 21D). However, upon discharge, NMI levels showed differences depending on the outcome (Figure 21E). That is, the NMI levels of patients who improved after treatment decreased, while the NMI levels of patients who did not improve or died did not decrease, but increased. This result shows that the NMI level can indicate the treatment effect / prognosis of sepsis patients. That is, a decrease in NMI level after treatment means that the treatment of sepsis patients is effective; a persistently high level or even an increase after treatment indicates that the patient's condition is not under control or is even continuing to deteriorate, and there is a risk of death.

[0284] A statistical analysis of PCT levels in serum samples from the 83 sepsis patients at admission (within 3 days) and discharge (within 3 days) was performed. PCT data for some patients were missing. Based on the treatment outcomes of sepsis patients, the patients were divided into a recovery group (20 patients), a no-recovery group (14 patients), and a death group (9 patients). The test results are shown in Figure 22. The inventors found that:

[0285] ① The PCT levels of sepsis patients in the recovery group at admission varied, with a median of 2.16 ng / mL (0.143, 28.53). After treatment, the PCT levels of improved patients decreased to a lower level (Figure 22A), with a median of 0.26 pg / mL (0.05, 0.497).

[0286] ②The median PCT level of sepsis patients in the no-recovery group was 6.510 ng / mL (1.98, 24.6) at admission. After treatment, the PCT level of patients who were discharged voluntarily decreased (Figure 22B), with a median of 0.94 ng / mL (0.447, 1.798).

[0287] ③The median PCT level of patients with sepsis in the Dead group at admission was 8.95 ng / mL (2.145, 34.75). After treatment, the PCT level of deceased patients did not drop to normal levels (Figure 22C), and the median was 9.66 pg / mL (2.875, 27.18).

[0288] The above results show that there was no statistical difference in the PCT levels of the three groups of patients at the time of admission (D in Figure 22), while the PCT levels showed differences according to the different outcomes at the time of discharge (E in Figure 22), that is, the PCT levels of patients who improved after treatment decreased, the PCT levels of patients who did not improve also did not decrease, and the PCT levels of patients who died remained at a high level overall. Since PCT is a specific indicator of bacterial infection, a decrease in PCT indicates the effectiveness of antibiotic use. The level of PCT is related to the severity of bacterial infection, but it is not highly correlated with multiple organ failure caused by sepsis. Most of the patients in the non-improved group gave up treatment because of their serious condition. The bacterial infection of these patients was controlled and the PCT levels decreased. However, due to multiple organ failure, the patient's condition was not effectively controlled.

[0289] Combining the above results of NMI and PCT, it can be seen that the serum level of NMI can indicate the severity of sepsis, treatment effect and prognosis of patients.

[0290] 2.6 Application of IFP35 in differentiating sepsis from non-septic infections in infected populations

[0291] The inventors first collected the first batch of small samples from the First Affiliated Hospital of Guangzhou Medical University, including 9 patients with sepsis and 9 patients with non-septic infection. The ELISA kit (human IFP35 (hIFP35) (Cat. No.: E5498Hu) quantitative detection kit obtained from BT LAB, the detection method was carried out according to the kit instructions) was used to measure and analyze the IFP35 content in the serum samples of all patients. The results are shown in Figure 23. The median serum IFP35 content of 9 patients with sepsis was 704pg / mL (416.5,986), and the median serum IFP35 content of 9 patients with non-septic infection was 168pg / mL (93.5,298.5). The statistical results showed that the serum IFP35 content of patients with sepsis was significantly higher than that of patients with non-septic infection.

[0292] The results of ROC curve analysis showed that the area under the curve (AUC) of IFP35 for distinguishing patients with sepsis from those without sepsis infection reached 0.938, with a 95% confidence interval of 0.827-1.000 and a cutoff value of 380.5 pg / mL, a sensitivity of 88.9%, and a specificity of 88.9% ( Figure 23 ).

[0293] The above results show that the serum level of IFP35 in patients with sepsis is significantly increased and the content is significantly higher than that in patients with non-septic infection, and can be used for the diagnosis of sepsis in infected populations.

[0294] To confirm whether the IFP35 content in serum can really be used to distinguish between sepsis and non-sepsis patients, the inventors measured the IFP35 content in serum samples of a second batch of infected patients (26 sepsis patients and 26 non-sepsis infection patients) collected from the First Affiliated Hospital of Guangzhou Medical University and performed ROC curve analysis. The results are shown in FIG24 .

[0295] The median serum IFP35 level in 26 patients with sepsis was 683 pg / mL (436.8, 937.5), while the median serum IFP35 level in 26 patients with non-septic infections was 169 pg / mL (83.75, 243). Statistical results showed that serum IFP35 levels in patients with sepsis were significantly higher than those in patients with non-septic infections.

[0296] The results of ROC curve analysis showed that the area under the curve (AUC) of IFP35 for distinguishing patients with sepsis from those without sepsis infection reached 0.945, with a 95% confidence interval of 0.885-1.000 and a cutoff value of 371.5 pg / mL, a sensitivity of 92.3%, and a specificity of 88.5% ( Figure 24 ).

[0297] The above test data show that the serum IFP35 content can be used to diagnose sepsis in infected people.

[0298] 2.7 Application of IFP35 in differentiating sepsis from non-sepsis in critically ill patients

[0299] The inventors collected a small number of samples from the Department of Critical Care Medicine of the Seventh Affiliated Hospital of Sun Yat-sen University, including 9 patients with sepsis and 11 critically ill patients without sepsis. The IFP35 content in serum samples of all patients was measured and analyzed using an ELISA kit (human IFP35 (hIFP35) (Cat. No.: E5498Hu) quantitative detection kit obtained from BT LAB, and the detection method was carried out according to the kit instructions). The results are shown in Figure 25. The median serum IFP35 content of 9 patients with sepsis was 486 pg / mL (276.5, 684.3), and the median serum IFP35 content of 11 critically ill patients without sepsis was 222 pg / mL (162.5, 307). The statistical results showed that the serum IFP35 content of patients with sepsis was higher than that of critically ill patients without sepsis.

[0300] The results of ROC curve analysis showed that the area under the curve (AUC) of IFP35 for distinguishing between septic and non-septic critically ill patients reached 0.808, with a 95% confidence interval of 0.593-1.000 and a cutoff value of 321 pg / mL, a sensitivity of 81.8%, and a specificity of 77.8% ( Figure 25 ).

[0301] These results indicate that serum levels of IFP35 can be used for the diagnosis of sepsis in critically ill patients.

[0302] To confirm whether the serum IFP35 content can be used to distinguish between sepsis and non-sepsis patients in critically ill patients, the inventors measured the IFP35 content in serum samples of a second batch of critically ill patients (21 sepsis patients and 28 non-sepsis critically ill patients) collected from the Department of Critical Care Medicine of the Seventh Affiliated Hospital of Sun Yat-sen University and performed ROC curve analysis. The results are shown in FIG26 .

[0303] The median serum IFP35 level in 21 patients with sepsis was 504 pg / mL (314, 714.3), while the median serum IFP35 level in 28 critically ill patients without sepsis was 183.8 pg / mL (120, 270.5). Statistical results showed that serum IFP35 levels in patients with sepsis were significantly higher than those in critically ill patients without sepsis.

[0304] The results of ROC curve analysis showed that the area under the curve (AUC) of IFP35 for distinguishing between septic and non-septic critically ill patients reached 0.8776, with a 95% confidence interval of 0.774-0.982 and a cutoff value of 362.8 pg / mL, a sensitivity of 92.9%, and a specificity of 76.2% ( Figure 26 ).

[0305] The above test data show that the serum IFP35 content can be used to diagnose sepsis in critically ill patients.

[0306] 2.8 Application of IFP35 in differentiating septic shock from non-septic shock

[0307] The "Sepsis Diagnosis and Treatment Guidelines (2023)" emphasizes that sepsis must be differentiated from organ dysfunction caused by non-infectious factors, and septic shock must be differentiated from shock caused by other causes. Septic shock is a severe syndrome of circulatory and cellular metabolic disorders caused by sepsis, also known as infectious shock or septic shock. Other causes of shock include cardiogenic shock due to abnormal cardiac function, hypovolemic shock due to massive blood and fluid loss, obstructive shock, neurogenic shock, and anaphylactic shock.

[0308] The inventors conducted a comparative analysis of serum IFP35 levels in a first cohort of eight patients with non-sepsis shock and 11 patients with septic shock, collected from the Department of Critical Care Medicine at the Seventh Affiliated Hospital of Sun Yat-sen University. Non-septic shock includes cardiogenic shock, hypovolemic shock, obstructive shock, neurogenic shock, and anaphylactic shock. Clinically, especially in the ICU, it is crucial to determine the cause of patient shock.

[0309] Statistical analysis results (Figure 27A) showed that the median serum IFP35 level in 8 patients with non-septic shock was 192.3 pg / mL (range, 40.63, 315.4), while the median IFP35 level in 11 patients with septic shock was 504.0 pg / mL (range, 394.5, 736.0). Serum IFP35 levels in patients with non-septic shock were significantly lower than those in patients with septic shock. Therefore, it is speculated that serum IFP35 levels have the ability to distinguish between septic shock and non-septic shock. Receiver operating characteristic (ROC) curve analysis (Figure 27B) showed that serum IFP35 levels in shock patients had an AUC of 0.886 for distinguishing between septic shock and non-septic shock, with a 95% confidence interval of 0.7374-1.000 and a cutoff of 361.8 pg / mL, resulting in a sensitivity of 87.5% and a specificity of 81.82%.

[0310] To verify that serum IFP35 levels in shock patients can be used to distinguish septic shock from non-septic shock, the inventors performed a statistical analysis of serum IFP35 levels in a second batch of 12 non-septic shock patients and 19 septic shock patients collected from the Department of Critical Care Medicine of the Seventh Affiliated Hospital of Sun Yat-sen University.

[0311] The results of the second batch of sample data (Figure 28A) showed that the median serum IFP35 level in 12 patients with non-septic shock was 218.0 pg / mL (range, 121.5, 323.9), while the median IFP35 level in 19 patients with septic shock was 486.0 pg / mL (range, 262.5, 714.0). Serum IFP35 levels in patients with non-septic shock were significantly lower than those in patients with septic shock. Receiver operating characteristic (ROC) curve analysis (Figure 28B) showed that serum IFP35 levels in shock patients distinguished between septic shock and non-septic shock with an AUC of 0.816, a 95% confidence interval of 0.667-0.964, and a cutoff of 362.8 pg / mL, resulting in a sensitivity of 91.67% and a specificity of 68.42%. These data indicate that serum IFP35 levels have excellent efficacy in distinguishing patients with septic shock from those without septic shock.

[0312] 2.9 Application of IFP35 in differentiating sepsis from organ dysfunction caused by non-infectious factors

[0313] Severe trauma, extensive burns, and post-major surgery can lead to insufficient effective circulating blood volume, suppressed cardiac function, and severe hypoxia, leading to multiple organ dysfunction. Diffuse bleeding, hypothermia (especially temperature ≤34°C), and acidosis can lead to life-threatening coagulopathy. Soft tissue injury leads to acute inflammation, further exacerbating this process. Therefore, multiple organ dysfunction in patients with sepsis needs to be differentiated from organ dysfunction caused by some of the non-infectious factors mentioned above.

[0314] The inventors measured serum IFP35 levels in a first cohort of eight patients with multiple trauma (critically ill patients with multiple trauma who did not develop sepsis) collected from the Department of Critical Care Medicine of the Seventh Affiliated Hospital of Sun Yat-sen University. These patients were admitted to the ICU for severe trauma. Severe trauma patients suffer from multiple organ dysfunctions, and secondary infection after trauma is a high-risk factor for sepsis. Therefore, clinically, especially in the ICU, it is necessary to differentially diagnose organ dysfunction in patients with severe trauma from organ dysfunction caused by sepsis, as well as monitor the occurrence of sepsis.

[0315] Statistical analysis results (Figure 29A) showed that the median serum IFP35 level in 8 patients with multiple trauma was 167.3 pg / mL (range, 143.8, 221.0). Compared with data from septic patients (with organ dysfunction, multiple organ dysfunction caused by sepsis) as a control, serum IFP35 levels in patients with multiple trauma were significantly lower than those in 11 patients with septic shock (504.0 pg / mL). Therefore, it is speculated that serum IFP35 levels have the ability to distinguish multiple organ dysfunction caused by multiple trauma from multiple trauma and sepsis. Receiver operating characteristic (ROC) curve analysis (Figure 29B) showed that serum IFP35 had an AUC of 0.9205 for distinguishing multiple organ dysfunction caused by multiple trauma and sepsis, with a 95% confidence interval of 0.800-1.00 and a cutoff value of 311.8 pg / mL, resulting in a sensitivity of 87.5% and a specificity of 81.82%.

[0316] To verify that serum IFP35 levels can be used to distinguish multiple organ dysfunction caused by multiple trauma and sepsis, the inventors measured and statistically analyzed the serum IFP35 levels of a second batch of 10 multiple trauma patients collected from the Department of Critical Care Medicine of the Seventh Affiliated Hospital of Sun Yat-sen University.

[0317] The results of the second batch of sample data (Figure 30A) showed that the median serum IFP35 level in 10 patients with multiple trauma was 216.3 pg / mL (113.6, 270.6), significantly lower than the serum IFP35 level in 19 patients with sepsis (486.0 pg / mL). The receiver operating characteristic (ROC) curve analysis (Figure 30B) showed that serum IFP35 had an AUC of 0.853 for distinguishing between multiple organ dysfunction caused by trauma and sepsis, with a 95% confidence interval of 0.715-0.990 and a cutoff of 321.0 pg / mL, a sensitivity of 90.0%, and a specificity of 73.68%. These data demonstrate that serum IFP35 levels are highly effective in distinguishing between critically ill trauma patients (without sepsis) and patients with sepsis (with multiple organ dysfunction caused by trauma and sepsis).

[0318] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. Application of substances for detecting IFP35 family proteins in product preparation: The product is used for any one of a1) to a3): a1) Diagnosis, screening, severity assessment, monitoring, efficacy evaluation, or prognosis assessment of sepsis; a2) Diagnosis, screening, severity assessment, monitoring, efficacy evaluation, or prognosis assessment of sepsis-related diseases; a3) Diagnosis, screening, severity assessment, monitoring, efficacy evaluation, or prognosis assessment of non-septic infectious diseases.

2. The use according to claim 1, characterized in that: The IFP35 family protein includes IFP35 and / or NMI; Preferably, the sepsis-related disease comprises septic shock; Preferably, the non-septic infectious disease comprises at least one of severe pneumonia, non-severe community-acquired pneumonia, interstitial lung disease, bacterial pneumonia, Aspergillus pneumonia, Mycoplasma pneumonia, pulmonary viral infection, pneumonia in immunosuppressed hosts, lung abscess associated with pneumonia, acute lower respiratory tract infection, bronchiectasis with infection, bronchitis, deep neck abscess, infective endocarditis, viral myocarditis, acute cholecystitis, hepatobiliary stones with cholangitis, acute pyelonephritis, urinary tract infection, peritonitis, pleurisy, liver cyst, empyema, and stent infection; Preferably, the test sample of the product is selected from at least one of body fluids, tissues, cells, and excretions of the subject to be tested; Preferably, the body fluid comprises at least one of blood, lymph, pleural effusion, cerebrospinal fluid, joint fluid, ascites, saliva, lymph, and body fluid; Preferably, the blood comprises at least one of serum, plasma, dried blood spots, and whole blood; Preferably, the excreta comprises at least one of urine, feces, and tears; Preferably, the subject to be tested comprises a mammal; Preferably, the subject to be tested includes humans.

3. The use according to claim 2, characterized in that: When the product is used for the diagnosis of sepsis, the subjects of the test samples of the product are severe subjects; Preferably, the product is used for any one of b1) to b6): b1) Distinguishing between subjects with severe sepsis and subjects without severe sepsis; b2) distinguishing between non-sepsis test subjects and sepsis test subjects, wherein the non-sepsis test subjects include healthy test subjects and / or non-sepsis infection test subjects; b3) distinguishing between subjects with non-septic infection and healthy subjects; b4) Prognostic assessment and / or efficacy evaluation of sepsis; b5) Differentiate between septic shock and non-septic shock; b6) Differentiate between sepsis and organ dysfunction caused by non-infectious factors; Preferably, the non-sepsis infection test subject is a test subject suffering from a non-sepsis infectious disease; Preferably, the non-septic infectious disease comprises at least one of severe pneumonia, non-severe community-acquired pneumonia, interstitial lung disease, bacterial pneumonia, Aspergillus pneumonia, Mycoplasma pneumonia, pulmonary viral infection, pneumonia in immunosuppressed hosts, lung abscess associated with pneumonia, acute lower respiratory tract infection, bronchiectasis with infection, bronchitis, deep neck abscess, infective endocarditis, viral myocarditis, acute cholecystitis, hepatobiliary stones with cholangitis, acute pyelonephritis, urinary tract infection, peritonitis, pleurisy, liver cyst, empyema, and stent infection; Preferably, the non-septic shock includes at least one of cardiogenic shock, hypovolemic shock, obstructive shock, neurogenic shock, and anaphylactic shock; Preferably, the non-infectious factors include at least one of severe trauma, extensive burns, major surgery, and chemical poisoning.

4. The use according to any one of claims 1 to 3, characterized in that: The substance for detecting IFP35 family proteins includes substances for detecting IFP35 family proteins at the gene level and / or protein level; Preferably, the substance comprises a substance for one or more detection techniques or methods selected from the group consisting of immunohistochemistry, Western blotting, Northern blotting, PCR, biochip, nucleic acid sequencing, amino acid sequencing, high performance liquid chromatography, capillary gel electrophoresis, near infrared spectroscopy, mass spectrometry, surface plasmon resonance, immuno-PCR, and biotin-avidin technology; Preferably, the immunohistochemistry method comprises at least one of enzyme-linked immunosorbent assay, immunofluorescence assay, radioimmunoassay, immunoprecipitation, immunochemiluminescence, colloidal gold immunoassay, fluorescence immunochromatography, complement fixation assay, and flow cytometry fluorescence separation technique; Preferably, the substance for detecting IFP35 family proteins is selected from: one or more of a substance specific to IFP35 family proteins, a probe specific to IFP35 family proteins, a gene chip, a protein chip, and a PCR primer; Preferably, the substance specific to IFP35 family proteins comprises any one of c1) to c3): c1) antibodies that specifically bind to IFP35 family proteins; c2) a ligand protein or polypeptide that specifically binds to an IFP35 family protein; c3) non-protein compounds that specifically recognize IFP35 family proteins; Preferably, the antibody comprises at least one of a polyclonal antibody, a monoclonal antibody, a single-chain antibody, a functional antibody fragment, an antibody Fab region, a nanobody, a chimeric antibody, and a multispecific antibody; Preferably, the substance for detecting IFP35 family proteins is IFP35 antibody and / or NMI antibody.

5. The use according to claim 4, characterized in that: The product comprises at least one of a reagent, a kit, a test paper, a chip, and a system; Preferably, the product further comprises substances for detecting other markers used for diagnosis, severity assessment, monitoring, efficacy assessment, or prognosis assessment of sepsis or its related diseases; Preferably, the product further comprises auxiliary detection reagents for gene expression, and the auxiliary detection reagents for gene expression include: a reaction reagent for visualizing the amplicon corresponding to the primer, an RNA extraction reagent, a reverse transcription reagent, a cDNA amplification reagent, a standard substance for preparing a standard curve, and at least one of a positive control substance; Preferably, the product further comprises an auxiliary detection reagent for protein expression, and the auxiliary detection reagent for protein expression comprises at least one of a color developer, a blocking solution, an antibody diluent, a washing buffer, a color stop solution, a standard substance for preparing a standard curve, and a positive control substance.

6. A system for disease diagnosis, screening, severity assessment, monitoring, efficacy assessment, or prognosis assessment, comprising: Detection module: used to detect the content, activity and / or expression of IFP35 family proteins in the test sample; and Diagnosis, monitoring, or evaluation module: diagnose, screen for disease, monitor the course of disease, evaluate disease severity, treatment efficacy, or prognosis based on the content, activity, and / or expression of IFP35 family proteins in a test sample; and Result output module: outputs the results of disease diagnosis, screening, severity assessment, monitoring, efficacy evaluation, or prognosis assessment; The disease is any one of d1) to d3): d1) Sepsis; d2) Sepsis-related diseases; d3) Non-septic infectious diseases.

7. The system according to claim 6, characterized in that: The IFP35 family protein includes IFP35 and / or NMI; Preferably, the sepsis-related disease comprises septic shock; Preferably, the non-septic infectious disease comprises at least one of severe pneumonia, non-severe community-acquired pneumonia, interstitial lung disease, bacterial pneumonia, Aspergillus pneumonia, Mycoplasma pneumonia, pulmonary viral infection, pneumonia in immunosuppressed hosts, lung abscess associated with pneumonia, acute lower respiratory tract infection, bronchiectasis with infection, bronchitis, deep neck abscess, infective endocarditis, viral myocarditis, acute cholecystitis, hepatobiliary stones with cholangitis, acute pyelonephritis, urinary tract infection, peritonitis, pleurisy, liver cyst, empyema, and stent infection; Preferably, the test sample is selected from at least one of body fluids, tissues, cells, and excretions of the subject to be tested; Preferably, the body fluid comprises at least one of blood, lymph, pleural effusion, cerebrospinal fluid, joint fluid, ascites, saliva, lymph, and body fluid; Preferably, the blood comprises at least one of serum, plasma, dried blood spots, and whole blood; Preferably, the excreta comprises at least one of urine, feces, and tears; Preferably, the subject to be tested comprises a mammal; Preferably, the subject to be tested comprises a human; Preferably, when the system is used for the diagnosis of sepsis, the subject to be tested is a critically ill subject to be tested.

8. The system according to claim 6 or 7, characterized in that: The system is used for any one of b1) to b6): b1) Distinguishing between subjects with severe sepsis and subjects without severe sepsis; b2) distinguishing between non-sepsis test subjects and sepsis test subjects, wherein the non-sepsis test subjects include healthy test subjects and / or non-sepsis infection test subjects; b3) distinguishing between subjects with non-septic infection and healthy subjects; b4) Prognostic assessment and / or efficacy evaluation of sepsis; b5) Differentiate between septic shock and non-septic shock; b6) Differentiate between sepsis and organ dysfunction caused by non-infectious factors; Preferably, the non-sepsis infection test subject is a test subject suffering from a non-sepsis infectious disease; Preferably, the non-septic infectious disease comprises at least one of severe pneumonia, non-severe community-acquired pneumonia, interstitial lung disease, bacterial pneumonia, Aspergillus pneumonia, Mycoplasma pneumonia, pulmonary viral infection, pneumonia in immunosuppressed hosts, lung abscess associated with pneumonia, acute lower respiratory tract infection, bronchiectasis with infection, bronchitis, deep neck abscess, infective endocarditis, viral myocarditis, acute cholecystitis, hepatobiliary stones with cholangitis, acute pyelonephritis, urinary tract infection, peritonitis, pleurisy, liver cyst, empyema, and stent infection; Preferably, the non-septic shock includes at least one of cardiogenic shock, hypovolemic shock, obstructive shock, neurogenic shock, and anaphylactic shock; Preferably, the non-infectious factors include at least one of severe trauma, extensive burns, major surgery, and chemical poisoning; Preferably, the detection module comprises the product according to any one of claims 1 to 5.

9. A method for constructing a disease model, comprising increasing the content, expression, and / or activity of an IFP35 family protein in the model; the disease being any one of d1) to d3): d1) Sepsis; d2) Sepsis-related diseases; d3) Non-septic infectious diseases.

10. The method according to claim 9, characterized in that: The IFP35 family protein includes IFP35 and / or NMI; Preferably, the sepsis-related disease comprises septic shock; Preferably, the non-septic infectious disease comprises at least one of severe pneumonia, non-severe community-acquired pneumonia, interstitial lung disease, bacterial pneumonia, Aspergillus pneumonia, Mycoplasma pneumonia, pulmonary viral infection, pneumonia in immunosuppressed hosts, lung abscess associated with pneumonia, acute lower respiratory tract infection, bronchiectasis with infection, bronchitis, deep neck abscess, infective endocarditis, viral myocarditis, acute cholecystitis, hepatobiliary stones with cholangitis, acute pyelonephritis, urinary tract infection, peritonitis, pleurisy, liver cyst, empyema, and stent infection; Preferably, the model is an animal model; Preferably, the animal is a rat, a mouse, or a guinea pig.

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