RU2614723C1 - Method for early differential diagnostics of acute appendicitis and acute intestinal infection - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to surgery and can be used for early differential diagnostics of acute appendicitis and acute intestinal infection. For this purpose biomarkers are identified in patient's blood samples and integral index, obtained as a result of regression analysis, is calculated. Quantity of monocytes, levels of general bilirubin and glucose are used as biomarkers. Integral index is represented as differential-diagnostic criterion (DDC), which is calculated by formula: DDC=0.165*[general bilirubin]+0.475*[glucose]-0.18*[monocytes], where [general bilirubin] is level of bilirubin in blood in mcmol/l, [glucose] is level of glucose in blood in mol/l, [monocytes] is per cent of monocytes among blood leukocytes. If DDC value<4.0, acute intestinal infection is diagnosed, and if values are ≥4.0, acute appendicitis is diagnosed.

EFFECT: provision of early differential diagnostics of acute appendicitis and acute intestinal infection.

2 tbl, 2 ex

Description

The invention relates to medicine, in particular surgery and infectious diseases, and can be used for early differential diagnosis of acute appendicitis with diarrheal syndrome and acute intestinal infection on the first day a patient enters a hospital. To implement the method in patients with a combination of diarrhea syndrome and acute abdominal pain, the percentage of monocytes in the blood leukocytes, the glucose level and the level of bilirubin are determined in the blood and the differential diagnostic criterion (DDK) is calculated according to the developed formula. With values of DDK <4.0, a conclusion is drawn about the presence of acute intestinal infection in the patient, and at values of 4.0 and higher, the presence of acute appendicitis.

Therapeutic tactics in acute appendicitis consists in the possible early removal of a pathologically altered vermiform appendix [1], while the social significance of the problem of acute appendicitis is due to its high prevalence [2, 3]. At the same time, diagnostic errors in a hospital that are already detected during surgery, according to various authors, range from 3% to 15%, and at the prehospital stage and on the first day a patient enters a hospital, up to 50% [3, 4]. Especially a lot of questions and disagreements on the indications for surgery arise in cases where acute appendicitis occurs against the background of acute intestinal infections [5, 6]. The problem is that the clinical picture of acute intestinal infections and acute appendicitis includes abdominal pain, intoxication, signs of inflammation, and it is quite similar in its symptoms, especially in the presence of diarrheal syndrome [5, 6]. This feature can lead to overdiagnosis and unnecessary operations, or, conversely, to underdiagnosis and late surgical interventions with the development of life-threatening complications [5, 7], and the later the diagnosis of acute appendicitis is made, the higher the mortality rate [8]. For this reason, the issues of early differential diagnosis of acute appendicitis and acute intestinal infections are relevant.

In the modern differential diagnosis of acute appendicitis, the leading place is played by imaging methods - ultrasound, computed tomography, magnetic resonance imaging of the abdominal organs, as well as diagnostic laparoscopy, which significantly increase the accuracy of diagnosis compared to clinical research, including in combination with laboratory tests [9]. The main disadvantage of these methods is their inaccessibility for most domestic medical institutions, especially on the first day of admission to the hospital, as well as lower efficiency in the conditions of early differential diagnosis [7]. In acute intestinal infections, the basis of diagnosis is the detection of microbial pathogens of these diseases in the biological material from the patient by the method of polymerase chain reaction (NDP) or by inoculation on artificial nutrient media, which requires a certain amount of time [10]. From this point of view, special attention is paid to simpler and more reliable methods of early diagnosis based on clinical and laboratory signs.

Currently, the domestic and international patent database contains a certain amount of information about laboratory methods for diagnosing acute appendicitis and methods for differential diagnosis of acute appendicitis and acute intestinal infections using laboratory data.

Since the goal of differential diagnosis in this aspect is to exclude acute appendicitis, attempts to laboratory diagnose it based on determining the quantitative fraction of microorganisms taxonomically significant for a given disease [11], neutrophilic shift index [12], and sorption ability of red blood cells [13] ], orthohydroxygippuric acid levels [14] or uroerythrin in the urine of sick people [15]. The disadvantage of these methods is their orientation to the determination of only one of the many non-specific biomarkers of acute appendicitis, which, due to their surrogate nature, should be used, at least in the form of a diagnostic complex.

At present, the most popular method for the early diagnosis of acute appendicitis is the Alvarado scale proposed abroad [16, 17], which is recommended to be used even before instrumental research methods [18, 19]. The Alvarado scale includes 6 clinical symptoms and 2 routine laboratory tests [16, 17].

From this point of view, methods based on the calculation of scales, criteria, indices based on several indicators deserve more attention. Among these methods for diagnosing acute appendicitis are: (1) calculation of the diagnostic index for the number of leukocytes, stab and segmented neutrophils in the blood, taking into account the number of heartbeats [20], (2) determination of the risk index for the development of acute appendicitis of allergic genesis using a complex including leukocyte intoxication index; C-reactive protein level; levels of immunoglobulins of classes G and E in peripheral blood; the level of circulating immune complexes [21]; (3) characterization of post-translational changes in protein complexes by mass spectrometry [22]. Most of these methods do not belong to the category of routine and widely available for the purposes of differential diagnosis at the prehospital level and / or are not sufficiently supported by the mathematical apparatus, which affects their sensitivity, specificity, reproducibility.

A known method for evaluating appendicitis [23] is that in the blood samples of children with suspected appendicitis, the presence of biomarkers associated with a high risk of developing this disease is determined - the number of leukocytes in the blood (WBC), the level of C-reactive protein (CRP) and complex 2 proteins that make up the factor that inhibits the migration of leukocytes - MRP 8/14 (calprotectin). In accordance with a specially developed mathematical formula, based on the values of these three biomarkers, a quantitative index is calculated, which is compared with a certain reference value of the index. In the process of developing a formula for calculating the index, the patent authors preliminarily selected a whole series of laboratory parameters of patients with acute appendicitis who underwent regression analysis and received the logistic regression equation, which included only 3 indicators out of 10. The obtained equation was used as a formula for calculating the diagnostic index (AppyScore) : AppyScore = 0.1177 * WBC SI Unit + 0.0202 * [CRP] μg / ml + 1.6 * [MRP] μg / ml + (C) Cutoff. For values ≤4.0, the test for acute appendicitis is considered negative. The test is recommended for early diagnosis of the disease (up to 72 hours from the onset of symptoms), and its diagnostic value is: AUROC = 0.81 [23]. This method is selected for the prototype. However, the biomarkers included in the kit are not routine, their determination requires special training of laboratory workers, the availability of special equipment and expensive reagents in the laboratory, time costs that do not make it easy to perform research at the pre-hospital stage or in the hospital ward.

The objective of the invention is to conduct an early differential diagnosis of acute appendicitis and acute intestinal infection.

The technical result is to ensure the availability of differential diagnosis of acute appendicitis and acute intestinal infection at the prehospital stage or in the hospital ward.

This is achieved due to the fact that the percentage of monocytes among blood leukocytes, the levels of total bilirubin and glucose in the blood are used as biomarkers of acute appendicitis, on the basis of which the integral indicator is calculated - the differential diagnostic criterion (DLC), calculated by the formula: DDC = 0.165 * [total bilirubin] + 0.475 * [glucose] - 0.18 * [monocytes] - and with a DCC value <4.0 they diagnose acute intestinal infection, and with values ≥4.0 they diagnose acute appendicitis.

In the process of developing the method, 277 260 patients were under observation, of which 144 patients with a bacteriologically confirmed diagnosis of acute intestinal infection and 116 patients with a diagnosis of acute appendicitis, confirmed instrumentally and during surgery, as well as 17 people with a combination of acute appendicitis and acute intestinal infection . All patients signed informed consent to study their blood samples. The gender and age characteristics of patients in the comparison groups did not significantly differ.

All patients underwent a clinical study of peripheral blood with the calculation of the formed elements per unit volume on a hematological analyzer (BECMAN-COULTER, USA) in accordance with the instructions for the use of equipment and reagents. Biochemical examinations, including the quantitative determination of bilirubin, urea, creatinine, total cholesterol, total protein, albumin, glucose, alanine aminotransferase activity, aspartate aminotransferase (ACT), alkaline phosphatase, L-amylase, gamma-glutamyl transpeptidase, and prothrombin chemical analysis, were carried out on a Bi - 902 Automatic analyzer (Japan), Erba XL-600 (Germany), A-25 Bio Systems (Spain) in accordance with the instructions for use of devices and reagents. The study of the acid-base state of the blood was determined on a GASTAT-604ox analyzer of blood gases and electrolytes (Japan) in accordance with the instructions for use of the device and reagents. The spectrum of the analyzed parameters of the acid-base state of the blood included: a hydrogen index (pH), partial pressure of oxygen and carbon dioxide, the content of sodium, potassium, calcium ions, deviation of the concentration of buffer bases from the normal level (BE).

It was found that the number of routine laboratory indicators, potentially possessing at a statistically significant level signs of differential criteria for acute appendicitis compared with acute intestinal infection, include:

- more pronounced leukocytosis,

- lack of stab neutrophil shift,

- more pronounced lymphopenia,

- more pronounced monocytopenia,

- higher blood protein total protein,

- a higher blood content of total bilirubin,

- higher blood cholesterol

- higher activity in the blood of alkaline phosphatase,

- higher activity in the blood of total amylase,

- higher blood glucose,

- a more pronounced alkaline shift in the pH of the blood,

- less pronounced tension of carbon dioxide in arterial blood,

- a more pronounced oxygen tension in arterial blood,

- lower blood levels of sodium ions,

- lower blood potassium ions,

- lower blood calcium levels

- a more pronounced deviation of BE from control.

The 95% confidence intervals of these and other blood parameters in the compared groups of patients and the probability of their differences (p), as well as the diagnostic accuracy expressed by the AUROC value for each indicator when comparing data on the comparison groups are presented in table 1.

Determination of the diagnostic accuracy of the test by the ratio of its sensitivity and specificity (construction of the ROC curve), expressed in AUROC values, made it possible to select the following diagnostically significant indicators from among informative signs:

- the number of white blood cells in the blood,

- the percentage of stab neutrophils among white blood cells,

- the percentage of segmented neutrophils among blood leukocytes,

- percentage of lymphocytes among white blood cells,

- the percentage of monocytes among white blood cells,

- the level of total bilirubin in the blood,

- blood cholesterol level,

- blood glucose level,

- blood pH

- partial pressure of carbon dioxide in arterial blood,

- partial pressure of oxygen in arterial blood.

All these signs were used as independent variables in the regression analysis, in which the boundary value of the clinical signs of acute intestinal infection and acute appendicitis, equal to 8 points, was used as a dependent variable (Table 2).

During the regression analysis using the SPSS statistical software package (version 21), a linear regression equation was obtained, in which out of 9 tested indicators, only 3 parameters were selected that have a reliable effect on the result and are able to perform the functions of differentially significant biomarkers. The resulting regression equation was as follows: DDC = 0.165 * [total bilirubin] + 0.475 * [glucose] - 0.18 * [percentage of monocytes], where [total bilirubin] is the level of blood bilirubin in µmol / l, [glucose] is the level blood glucose in mol / l, [monocytes] - percentage of monocytes among blood leukocytes. As a result of the substitution of specific values of the patient’s indicators in the formula, an integral indicator was obtained, designated as a differential diagnostic criterion (DDC) for acute intestinal infection and acute appendicitis.

To determine the values of the differential diagnostic criterion, which make it possible to differentiate between acute appeticitis and acute intestinal infections, 95% confidence intervals of DDC in different groups of patients were calculated and determined

diagnostic accuracy of the value (correlation of sensitivity and specificity) of this criterion by constructing ROC-curves and

determination of the AUROC value (area under the ROC curve) (Fig. 1).

As follows from the figure, the group of patients with acute intestinal infections with values of the differential diagnostic criterion <4 quite clearly differed from the group of patients with acute appendicitis with values of DCC ≥ 4.0. As can be seen from the AUROC value, the diagnostic accuracy of this distinction was quite high and amounted to 0.822.

Thus, as a result of the studies, among the entire array of information indicators for the differential diagnosis of acute intestinal infections and acute appendicitis, only three laboratory parameters (biomarkers) were selected - the number of monocytes, the levels of total bilirubin and glucose; to determine the ranges of values of the integral indicator - the differential diagnostic criterion (DDC), characteristic only for acute appendicitis or only for acute intestinal infections: DDC with values <4.0 with diagnostic accuracy (AUROC) 0.82 indicates the presence of acute intestinal infection in the patient , and with values ≥4 it indicates the presence of acute appendicitis.

The method is illustrated in FIG. one:

- 95% confidence intervals DDC and ROC-curves to assess the diagnostic significance of differences in DDC between comparison groups.

The method is as follows:

in a patient with suspected acute appendicitis or acute intestinal infection, venous blood is drawn.

To count the number of monocytes, venous blood is placed in a tube with an anticoagulant, such as BDVacutainerK2E. The content of the monocytic fraction of leukocytes is determined automatically (for example, by a cytochemical method using a Beckman Coulter AcT 5diff hematology analyzer (USA)).

To determine the total bilirubin and glucose in blood serum, venous blood obtained without anticoagulants was sedimented in a centrifuge tube at room temperature (15-20 ° C) for 30 minutes until a clot formed completely. After clot retraction, the sample is centrifuged at 1000-1200 g for 10 minutes. After centrifugation, the serum is poured into secondary tubes. The determination of serum total bilirubin and glucose levels is carried out automatically (for example, using a biochemical analyzer; for example, a Roche Hitachi 902 analyzer-automaton (France), using a diazoreagent for total bilirubin (for example, Roche Bilirubin DPD Bil-T and a set of reagents for the determination of glucose SIS1 glucose oxidase method).

The results obtained are substituted into the formula:

DDC = 0.165 * [total bilirubin] + 0.475 * [glucose] - 0.18 * [monocytes], where [total bilirubin] - blood bilirubin level in µmol / l, [glucose] - blood glucose level in mol / l, [ monocytes] - percentage of monocytes among blood leukocytes. The value of DDC is calculated, and with a value of DDC <4.0, a diagnosis of acute intestinal infection is diagnosed, and for values ≥4.0, acute appendicitis is diagnosed.

Clinical example 1.

Patient M., 19 years old, on the morning of April 28, 2014 noted the appearance of abdominal pain mainly in the right iliac region, aching in nature, after a while the following symptoms joined: nausea, weakness, fever up to 37.1 ° C, then the existing symptoms were joined by repeated vomiting (10 times, during the day) and loose stool without pathological impurities (15 times during the day). Without a diagnosis, on April 29, the patient was taken by an ambulance to the emergency department of the hospital No. 2, where, after examining the patient and consulting the surgeon, he was diagnosed with acute appendicitis. Acute intestinal infection. " The patient was transferred to the surgical department of the hospital No. 2 for further examination and treatment.

Upon repeated examination in the surgical department, the patient's condition was assessed as moderate, the skin was pale in color, skin turgor was reduced, body temperature was 37.1 ° C. In the lungs, vesicular breathing, no wheezing, NPV 20 per minute. Heart sounds are rhythmic, no noise. Pulse 80 beats per minute, blood pressure 100/80 mm Hg The tongue is dry, covered with a white coating, on palpation the abdomen is soft, not swollen, participates in the act of breathing, painful in the right iliac region. With auscultation: intestinal motility is not enhanced, uniform, pathological noises are not heard. The liver and spleen are not enlarged. Symptoms of Rowzing, Sitkovsky, Voskresensky are doubtful. Urination is not impaired, there was no stool in the department.

Clinical blood test on the day of admission to the hospital: white blood cells - 17.2 * 10 ⁹ / l, red blood cells - 5.17 * 10 ¹² / l, hemotocrit - 45.5%, hemoglobin - 150 g / l, platelets - 249 * 10 ⁹ / l, ESR - 4 * mm / h, eosinophils - 2%, stab - 3%, segmented - 78%, monocytes - 5%, lymphocytes - 12%.

Biochemical blood test on the day of admission to the hospital: total protein - 86 g / l, urea - 5.4 mol / l, creatinine - 110 μmol / l, total bilirubin - 14 μmol / l, cholesterol - 4.5 mol / l, ALT - 17 units / L, ACT - 24 units / L, alkaline phosphatase - 71 mol / L, total amylase - 78 IU / L, glucose - 4.9 mmol / L.

Coagulogram on the day of admission to the hospital: APTT - 27 s, IPT - 80%, fibrinogen - 4.38 g / l, MHO - 1.25.

Analysis of the acid-base composition of blood on the day of admission to the hospital: pH - 7.396, pCO ₂ - 47 mmHg, pO ₂ - 49 mmHg, Na - 141 mmol / L, K - 4.51 mmol / L, Ca - 1.29 mmol / L, BE - 3.6 mmol / L.

Since the patient revealed dubious appendicular symptoms, leukocytosis, the patient underwent diagnostic laparoscopy, as a result of which the diagnosis of acute appendicitis was removed. A patient with a diagnosis of “Bacterial intestinal infection, gastroenteric variant” was transferred to the intestinal infection department of ICD No. 2 for further treatment.

A retrospectively performed calculation of the differential diagnostic criterion (DDC) in patient M. according to the results of clinical and biochemical blood tests showed the following:

DDC = 0.165 * 14 + 0.475 * 4.9 - 0.18 * 5 = 3.74

Values of DDK <4 in this case indicate in favor of acute intestinal infection.

As follows from the example as a whole, that the timely determination of DDC would avoid diagnostic laparoscopy in the patient and promptly make a preliminary diagnosis of "Acute intestinal infection", which was confirmed after a few days by the data of bacteriological examination of feces.

Clinical example 2.

Patient L., 34 years old, fell ill on August 14, 2013, when he felt cutting pain in the abdomen, mainly in the right departments, later there was nausea, repeated vomiting (8 times a day), multiple loose stools, without pathological impurities (per day 10 times), further noted an increase in body temperature to 38 ° C. After worsening on August 15, the patient was hospitalized in the hospital No. 2 with an emergency medical treatment with a diagnosis of acute intestinal infection. Acute appendicitis? Acute peritonitis? ” Upon examination at the admission department and consultation with the surgeon, the patient was diagnosed with an acute intestinal infection. Acute appendicitis, ”and he was transferred to the surgical department for further observation and treatment.

Upon re-examination in the surgical department, the patient's condition is moderate, the skin is pale in color, skin turgor is reduced. Body temperature 38 ° C. In the lungs, vesicular breathing, no wheezing, NPV 20 per minute. Heart sounds are rhythmic, no noise. Pulse 80 beats per minute, blood pressure 110/70 mm Hg The tongue is dry, covered with a white coating, on palpation the abdomen is soft, does not swell, participates in the act of breathing, painful in the right iliac region. With auscultation: intestinal motility is not enhanced, uniform, pathological noises are not heard. The liver and spleen are not enlarged. Symptoms of Kocher, Rowzing, Sitkovsky, Voskresensky, Shchetkin-Blumberg are positive. Urination is not impaired, there was no stool in the department.

Clinical blood test on the day of admission to the hospital: white blood cells - 18.3 * 10 ⁹ / L, red blood cells - 4.82 * 10 ¹² / L, hemotocrit - 43.6%, hemoglobin - 156 g / L, platelets - 326 * 10 ⁹ / l, ESR - 11 * mm / h, eosinophils - 0%, stab - 2%, segmented - 94%, monocytes - 3%, lymphocytes - 1%.

Biochemical blood test on the day of admission to the hospital: total protein - 64 g / l, urea - 6.3 mol / l, creatinine - 82 μmol / l, total bilirubin - 23 μmol / l, cholesterol - 5.6 mol / l, ALT - 31 units / L, ACT - 24 units / L, alkaline phosphatase - 99 mol / L, total amylase - 47 IU / L, glucose -6.5 mmol / L.

Coagulogram on the day of admission to the hospital: PTI - 83%, fibrinogen - 4.8 g / l, MHO - 1.2.

Analysis of the acid-base composition of blood on the day of admission to the hospital: pH - 7.419, pCO2 - 48 mmHg, pO2 - 25.4 mmHg, Na - 136 mmol / L, K - 3.83 mmol / L, Ca - 1.06 mmol / L, BE - 4.8 mmol / L.

General analysis of urine on the day of admission to the hospital: Relative density of urine - 1.083 g / l, protein - 0.47 g / l, pH - 6.5, white blood cells - 2, red blood cells - 2.

After an appendectomy and histological examination of the appendix, the patient was diagnosed with phlegmonous appendicitis.

A retrospectively performed calculation of the differential diagnostic criterion (DDC) in patient M. according to the results of clinical and biochemical blood tests showed the following:

DDC = 0.165 * 23 + 0.475 * 6.5 - 0.18 * 3 = 6.35

Values of DDC> 4 testified in favor of the diagnosis of acute appendicitis, which confirmed the results of surgical intervention, as well as the negative result of bacteriological examination for the presence of pathogens of acute intestinal infection in the feces of the patient.

Clinical example 3.

Patient G., 35 years old, on the night of September 12, 2014 felt weakness, abdominal pain and fever up to 37.5 ° C, a single vomiting was noted. The next day, multiple loose stools without pathological impurities and cramping abdominal pain were added to the existing symptoms. An ambulance was called, with a diagnosis of intestinal infection of unknown etiology, the patient was hospitalized in the hospital № 2. In the admission department, the patient was confirmed with a preliminary diagnosis of "Intestinal infection of unknown etiology? Acute appendicitis? ”, It was decided to transfer the patient to the surgical department for further examination and treatment.

In the surgical department, the patient was diagnosed with moderate severity. Body temperature 37.5 ° C. Vesicular breathing in the lungs, no wheezing, NPV 19 per minute. Heart sounds are rhythmic, no noise. Pulse 88 beats per minute, blood pressure 110/70 mm Hg The tongue is dry, covered with a white coating, upon palpation the abdomen is soft, swollen, participates in the act of breathing, painful in all departments. On auscultation: intestinal motility is sluggish, pathological noises are not observed. The liver and spleen are not enlarged. Symptoms of Kocher, Shchetkin-Blumberg positive. Urination is not impaired, there was no stool in the department.

Clinical blood test on the day of admission to the hospital: white blood cells - 22 * 10 ⁹ / l, red blood cells - 5.24 * 10 ¹² / l, hematocrit - 41.8%, hemoglobin - 139 g / l, platelets - 301 * 10 ⁹ / l, ESR - 27 * mm / h, eosinophils - 1%, stab - 29%, segmented - 59%, monocytes - 1%, lymphocytes - 11%.

A biochemical blood test on the day of admission to the hospital: total protein - 72 g / l, urea - 5.6 mol / l, creatinine - 119 μmol / l, total bilirubin - 10 μmol / l, cholesterol - 3.5 mol / l, ALT - 26 units / L, ACT - 40 units / L, alkaline phosphatase - 59 mol / L, total amylase - 39 IU / L, glucose - 4.6 mmol / L.

Coagulogram on the day of admission to the hospital: APTT - 22 sec, IPT - 76%, fibrinogen - 448 g / l, MHO - 1.25.

Analysis of the acid-base composition of blood on the day of admission to the hospital: pH 7.4, pCO2 46 mmHg, pO2 57 mmHg, Na 135 mmol / L, K 3 mmol / L, Ca 0.98 mmol / L , BE - 6.6 mmol / L.

Based on the results of laboratory studies, the calculation of DDK was performed, which showed the following result:

DDC = 0.165 * 10 + 0.475 * 4.6 - 0.18 * 1 = 4.0.

Despite the dubious diagnosis, the patient, focusing on the value of DDK = 4.0, was performed emergency appendectomy. Histological examination of the removed appendix has confirmed the presence of phlegmonous appendicitis.

Literature

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Claims (1)

A method for early differential diagnosis of acute appendicitis and acute intestinal infection, including the identification of biomarkers from patient’s blood samples and the calculation of the integral indicator obtained as a result of regression analysis, characterized in that the number of monocytes, total bilirubin and glucose levels are used as biomarkers, and the integral indicator is presented as a differential diagnostic criterion (DDC), which is calculated by the formula: DDC = 0.165 * [total bilirubin] + 0.475 * [glucose] -0.18 * [monocytes], where [total beat ubin] - the level of blood bilirubin in micromol / l, [glucose] - the level of blood glucose in mol / l, [monocytes] - the percentage of monocytes among blood leukocytes, and with a DCC value <4.0 they diagnose acute intestinal infection, and with values ≥ 4.0 diagnose acute appendicitis.

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