RU2442532C2 - Means of differential diagnostics of bronchial asthma clinico-pathogenetic variants and incipience of chronic obstructive lung disease - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine particularly to allergology and pulmonology and can be used in differential diagnostics of bronchial asthma (BA) - atopic asthma (AA), asthmatic triad (AT) and incipience of chronic obstructive lung disease (COLD). For this purpose respiratory function is checked of a patient and Tiffeneau index is defined. Then cytokines IL-4 and IL-8 concentration in periferic blood and antioxidant transferrin are defined. Further the mathematical model including the examined indexes is made and complex mathematic performance evaluation. On the first stage the regressive function is calculated according to the formula f _COLD/BA = 4.1609+ a*(-5.787)+b*(-0.062)+c*(0.01308)+d*(-0.1025) where Tiffeneau index (1 - value >70% of the due values, 0 - value <70% of the due values); b content IL-4 (equivalent units); c content IL-8 (equivalent units); d - transferrin content (equivalent units). Then the potential is calculated in respect to according to the formular P _COLD/BA =1/(1+y ^-fCOLD/BA ) where P _COLD/BA is potential COLD occurrence in respect to BA; e=2.718 is the base of the natural logarithm. With P _COLD/BA ≥0.5 the probability of COLD occurrence is higher in respect to BA - in this case COLD is diagnosed. If P _COLD/BA <0.5 the probability of BA occurrence is higher in respect to COLD. In this case pass to the second stage when the regressive function is calculated according to the formula F _AT/AA =-21.847+a*(26.607)+b*(-0.2227)+c*(0.1)+d*(-0.304). After this the probability of AT occurrence in respect to AA is calculated according to the formula P_AT/AA =1/(1+e ^-1AT/AA ) where P_AT/AA is the probability of At occurrence in respect to AA. With P_AT/AA ≥0.5 the probability of AT occurrence is higher in respect to AA then AT is diagnosed. If P P_AT/AA <0.5 the probability of AA occurrence is higher in respect to AT then AA is diagnosed.

EFFECT: means provides timely effective differential diagnostics of bronchial asthma clinico-pathogenetic variants and incipience of COLD for timely pathogenetic treatment of such diseases.

3 ex, 1 dwg

Description

The invention relates to medicine, namely to allergology and pulmonology, and can be used in clinical practice for the differential diagnosis of clinical and pathogenetic variants of bronchial asthma (BA) and the initial stage of chronic obstructive pulmonary disease (COPD).

Differential diagnosis of AD and COPD is an urgent problem of allergology, pulmonology and internal diseases. COPD and BA belong to diseases of the bronchopulmonary system, combined by the presence of bronchial obstruction, in the pathogenesis of which inflammation plays a leading role [4, 6]. Inflammation in AD and COPD is associated with a cascade of reactions involving a wide variety of cells, factors and mediators, the interaction of which forms a characteristic pathological process, and has its own characteristics, depending on the mechanism of formation of bronchial obstruction [5]. Currently, there are clear clinical signs, laboratory signs, and changes detected in the study of lung function, which can reliably verify AD and COPD. But, despite this, in some patients with chronic respiratory diseases accompanied by bronchial obstruction, especially at the initial stages of the development of COPD, when irreversible changes in the walls of the bronchi and systemic changes in other organs and tissues have not yet occurred, the differential diagnosis of AD and COPD is difficult. Particularly often, difficulties arise in the differential diagnosis of pseudo-allergic bronchial asthma and the initial stage of COPD. In this situation, general practitioners sometimes have to deal with similar clinical manifestations, as well as with the same type of changes in the immune and redox status.

Not all diagnostic methods are widely used. So, bronchoscopy with a biopsy of the bronchial mucosa or swabs from the bronchial mucosa was not widely used, since these methods are invasive and expensive.

A known method for the differential diagnosis of chronic obstructive pulmonary disease and bronchial asthma [2], including spirographic examination of bronchial patency with the determination of the function of the mucociliary system by direct non-invasive method in vivo in the phase of remission of the disease. When mucociliary system dysfunctions and bronchial obstruction are detected, chronic obstructive pulmonary disease with a negative provocative breakdown is diagnosed. With normal values of the function of the mucociliary system and impaired patency of the bronchi, including under the influence of a provocative test, bronchial asthma is diagnosed.

The known method is not sufficiently informative, it is applicable only in the phase of remission of the disease and is intended for the differential diagnosis of COPD and BA without taking into account its clinical and pathogenetic variant.

There is also a method for the differential diagnosis of chronic obstructive pulmonary disease, chronic bronchitis (chronic bronchitis) and bronchial asthma [3] using the constructed mathematical model using 5 informative indicators: age, forced expiratory volume in 1 second, induced sputum cytosis, neutrophil content in induced sputum and the fact of smoking. Depending on the values of the calculated probabilities, a diagnosis of the disease with the highest probability is established.

The known method is used only for the differential diagnosis of AD, CB and COPD, while not allowing differential diagnosis between the clinical and pathogenetic variants of AD.

There is a classification of AD according to pathogenesis, on the basis of which the following clinical and pathogenetic variants of bronchial asthma are distinguished: true allergic and pseudo-allergic [1]. Within these options are distinguished: atopic asthma (true allergic asthma) and asthmatic triad (pseudo-allergic asthma), which differ in the mechanism of formation of bronchial obstruction and are of interest to general practitioners and allergists.

The objective of the invention is to develop a method that provides effective differential diagnosis of the initial stage of COPD and two clinical and pathogenetic variants of bronchial asthma - atopic asthma (ABA) and asthmatic triad (AT).

The task is achieved due to the fact that according to the claimed method for differential diagnosis of clinical and pathogenetic variants of bronchial asthma (BA) - atopic bronchial asthma (ABA), asthmatic triad (AT) and the initial stage of chronic obstructive pulmonary disease (COPD) in a patient examine the function of external respiration and determine the Tiffno index, examine the peripheral blood and determine the content of cytokines - interleukin 4 (IL-4) and interleukin 8 (IL-8) and the content of transferrin antioxidant (TF), create a mathematical mode s, including the studied parameters. Then, a comprehensive mathematical assessment of the indicators is carried out with calculation according to the mathematical formulas of the regression functions and the probabilities of the presence of the disease - ABA, AT or COPD. Depending on the values of the calculated probabilities, a diagnosis of the disease is established.

It was established that for this category of patients, the selected parameters are important criteria for differential diagnosis. Investigation of the function of external respiration with the determination of the Tiffno index, the level of cytokines with the determination of the content of IL-4 and IL-8 and the oxidant-antioxidant system with the determination of the TF content are safe, fast-performing methods. Each of these methods individually is not always highly informative and sufficient for differential diagnosis of data from clinically similar diseases, especially at the initial stage of the development of COPD. The constructed mathematical model allows for the effective differential diagnosis of ABA, AT and COPD.

The method is as follows.

A patient with suspected COPD or BA is examined. Assessment of the function of external respiration is carried out by spirography and analysis of the curve "flow - volume". The data obtained is subjected to computer processing, proper indicators are calculated. The result is expressed as a percentage of due values. Analyze the ratio of forced expiratory volume in 1 second to the vital capacity of the lungs (Tiffno index). The concentration of cytokines (IL-4, IL-8) in the serum of peripheral blood is determined by enzyme-linked immunosorbent assay, for example, using test systems CJSC Vector-Best (Novosibirsk, Russia). To assess the oxidant-antioxidant status of patients using a direct research method - the method of electron paramagnetic resonance (EPR). To do this, peripheral blood is placed in plastic containers (3 cm long, 0.4 cm in diameter) and frozen at the temperature of liquid nitrogen. Samples for studying electronic magnetic characteristics are stored in liquid nitrogen until the moment of measurement. Registration of electronic paramagnetic characteristics of the blood is carried out at a temperature of 77 K on a radio spectrometer.

Digital values of 4 informative indicators included in the mathematical model are determined: Tiffno index, content of IL-4, IL-8, TF. Make the necessary calculations.

First step:

The calculation of the regression function according to the formula:

f _{COPD / BA} = 4.1609 + a * (- 5.787) + b * (- 0.062) + c * (0.01308) + d * (- 0.1025),

where a is the Tiffno index (1 - value ≥70% of the required values, 0 - value <70% of the due values);

b - the content of IL-4 (conventional units);

c is the content of IL-8 (conventional units);

d is the content of transferrin (conventional units).

Then calculate the probability of having COPD in relation to BA by the formula:

p _{COPD / BA} = 1 / (1 + e ^{-f COPD / BA} ),

where p _{COPD / BA} is the probability of having COPD in patients with BA;

e = 2.718 ... is the base of the natural logarithm.

With a p _{COPD / AD} value ≥0.5, there is a greater likelihood of COPD in relation to AD. In this case, the diagnosis of COPD is established.

If p _{COPD / BA is} <0.5, the probability of BA relative to COPD is greater. Diagnose AD. To determine the clinical and pathogenetic variants of bronchial asthma - atopic asthma (ABA) and asthmatic triad (AT) proceed to the second stage.

Second phase:

The calculation of the regression function according to the formula:

f _{AT / ABA} = -21.847 + a * (26.607) + b * (- 0.2227) + c * (0.1) + d * (- 0.304)

Then calculate the probability of the presence of antibodies in relation to ABA by the formula:

p _{AT / ABA} = 1 / (1 + e ^{-fAT / ABA} ),

where p _{AT / ABA} is the probability of the presence of antibodies in patients with respect to ABA.

With a p value of _{AT / ABA} ≥0.5, the probability of having AT with respect to ABA is greater. In this case, AT is diagnosed. With a p value of _{AT / ABA} <0.5, the likelihood of having ABA with respect to AT is more likely. In this case, ABA is diagnosed.

The inventive method can be demonstrated in the following examples.

Example 1

Patient P., 45 years old. Received complaints of a productive cough with sputum, mainly in the morning, shortness of breath when walking fast. Anamnesis - smokes. Preliminary diagnosis: COPD I degree, stage of exacerbation. The patient was examined according to the proposed method, as a result of which the following indicators were obtained: Tiffno index - 69.8%, IL-4 content - 18.52 (conventional units), IL-8 - 17.62 (conventional units) , TF - 4.23 (conventional units).

1. Calculation of regression functions:

f _{COPD / BA} = 4.1609 + 0 * (- 5.787) +18.52 * (- 0.062) + 17.62 * (0.01308) +4.23 * (- 0.1025) = 2.809.

Probability calculation:

p _{COPD / BA} = 1 / (1 + e ^{-f COPD / BA} ) = 1 / (1 + 2.72 ^-2.809 ) = 0.94.

The diagnosis of COPD in relation to AD is likely by 94%, therefore, the diagnosis of COPD is established.

Example 2

Patient G., 46 years old. Received complaints of paroxysmal cough, asthma attacks, accompanied by distance wheezing. Anamnesis - suffers from a disease from early childhood, does not smoke. Preliminary diagnosis: atopic asthma, acute stage, moderate severity. The patient was examined according to the proposed method, as a result of which the following indicators were obtained: Tiffno index - 89%, IL-4 content - 38 (conventional units), IL-8 - 18.8 (conventional units), TF - 3 , 8 (conventional units).

1. The calculation of the regression function:

f _{COPD / BA} = 4.1609 + 1 * (- 5.787) +38 * (- 0.062) + 18.8 * (0.01308) +3.8 * (- 0.1025) = - 4.1256.

Probability calculation:

p _{COPD / BA} = 1 / (1 + e ^{-f COPD / BA} ) = 1 / (1 + 2.72 ^4.1256 ) = 0.015.

The diagnosis of COPD is 1.5% probable in relation to AD, that is, the probability of AD is 98.5%. We calculate the probability of AT with respect to ABA.

2. The calculation of the regression function:

f _{AT / ABA} = -21.847 + 1 * (26.607) +38 * (- 0.2227) + 18.8 * (0.1) -3.8 * (0.304) =

= -2.9778.

Probability calculation:

p _{AT / ABA} = 1 / (1 + e ^{-fAT / ABA} ) = 1 / (1 + 2.72 ^2.9778 ) = 0.048.

A diagnosis of AB in relation to ABA is likely to be 4.8%, that is, the probability of ABA is 95.2%. Thus, the obtained data allow us to establish a diagnosis of ABA.

Example 3

Patient B., 43 years old. Received complaints of paroxysmal cough during the day, asthma attacks provoked by aspirin, accompanied by distance wheezing. Anamnesis - smokes. Preliminary diagnosis: AD, pseudo-atopic (asthmatic triad). The patient was examined according to the proposed method, as a result of which the following indicators were obtained: Tiffno index - 78.4%, IL-4 content - 20.88 (conventional units), IL-8 - 28.57 (conventional units) , TF - 6.607 (conventional units).

1. The calculation of the regression function:

f _{COPD / BA} = 4.1609 + 1 * (- 5.787) +20.88 * (- 0.062) + 28.57 * (0.01308) + 6.607 * (- 0.1025) = - 3.224.

Probability calculation:

p _{COPD / BA} = 1 / (1 + e ^{-fX COPD / BA} ) = 1 / (1 + 2.72 ^3.224 ) = 0.038.

The diagnosis of COPD is probable in relation to AD by 3.8%, that is, the probability of diagnosis of AD is 96.2%. We calculate the probability of AT with respect to ABA.

2. The calculation of the regression function:

f _{AT / ABA} = -21.847 + 1 * (26.607) +20.88 * (- 0.2227) + 28.57 * (0.1) -6.607 * (0.304) = 0.958.

p _{AT / ABA} = 1 / (1 + e ^{-fAT / ABA} ) = 1 / (1 + 2.72 ^-0.958 ) = 0.724.

The diagnosis of AT in relation to ABA is 72.4% likely, that is, the probability of AT is 72.4%. Thus, the data obtained make it possible to establish a diagnosis of AT.

The mathematical model was developed using the statistical package STATISTICA 6.0. The model was tested on a group of 42 patients (15 ABA patients, 16 AT patients, 11 COPD patients).

The operational characteristics for each pathology were calculated: sensitivity (Se) (COPD - 93%; ABA - 86%; AT - 81%); specificity (Sp) (COPD - 96%; ABA - 88%; AT - 93%); diagnostic efficiency (DE) (COPD - 94.5%; ABA - 87%; AT - 87%).

The developed method provides timely and effective differential diagnosis of clinical and pathogenetic variants of asthma (atopic bronchial asthma and asthmatic triad) and the initial stage of COPD.

Information sources

1. Smirnova, S.V. The pathogenesis of true allergies and pseudo-allergies / S.V. Smirnova, V.I. Pytsky: educational method. allowance. - Krasnoyarsk-Moscow, 2002 .-- 21 p.

2. A method for the differential diagnosis of chronic obstructive pulmonary disease. RU 2262095 C1, date publ. 10/10/2005.

3. A method for the differential diagnosis of bronchial asthma, chronic bronchitis and chronic obstructive pulmonary disease. RU 2310381 C2, date publ. 11/20/2007.

4. Shmelev, E.I. Bronchial asthma in combination with chronic obstructive pulmonary disease: strategic problems of therapy / E.I.Shmelev // Consilium medicum. - 2006. - No. 8. - S. 846-851.

5. Barnes, P.J. Mechanisms in COPD: differences from asthma / P.J. Barnes // Chest. - 2000. - V.117, Suppl. 2. - P.10S-14S.

6. Dworski, R. Oxidant stress in asthma / R. Dworski // Thorax. - 2000 .-- V.55 (Suppl. 2). - P.S51-S53.

Claims (1)

A method for differential diagnosis of clinical and pathogenetic variants of bronchial asthma (BA) - atonic bronchial asthma (ABA), asthmatic triad (AT) and the initial stage of chronic obstructive pulmonary disease (COPD), comprising examining a patient, characterized in that the patient is examined for respiratory function and determine the Tiffno index, examine the peripheral blood and determine the content of the cytokine IL-4, the content of the cytokine IL-8, the content of transferrin antioxidant, create a mathematical model that includes research emye indicators, carried out a comprehensive assessment of a mathematical calculation with the first stage of regression mathematical formula function
f _{COPD / BA} = 4.1609 + a · (-5.787) + b · (-0.062) + c · (0.01308) + d · (-0.1025),
where a is the Tiffno index (1 - value ≥70% of the required values, 0 - value <70% of the due values);
b - the content of IL-4 (conventional units);
c is the content of IL-8 (conventional units);
d is the content of transferrin (conventional units), then the probability of having COPD in relation to AD is calculated according to the formula:
p _{COPD / BA} = ^1/1 + e ^-f _{COPD / BA} ),
where p _{COPD / BA} is the probability of having COPD in patients with BA;
e = 2.718 ... - the basis of the natural logarithm,
with a p _{COPD / BA} value ≥0.5, there is a greater likelihood of COPD in relation to BA - in this case, COPD is diagnosed;
if p _{COPD / BA} <0.5 is more likely to have BA relative to COPD, then proceed to the second stage, calculating the regression function according to the formula
f _{AT / ABA} = -21.847 + a · (26,607) + b · (-0,2227) + c · (0,1) + d · (-0,304),
then calculate the probability of the presence of antibodies in relation to ABA by the formula
p _{AT / ABA} = 1 / (1 + e ^-f _{AT / ABA} ),
where p _{AT / ABA} is the probability of the presence of antibodies in patients with respect to ABA,
and with a p _{AT / ABA} value ≥0.5, there is a greater likelihood of having AT with respect to ABA - diagnose AB, and with a p _{AT / ABA} value <0.5 more with a chance of having ABA with respect to AB - diagnose ABA.