RU2480153C1 - Method of predicting course of moderate to severe chronic obstructive lung disease - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to pulmonology and can be used for predicting course of moderate to severe chronic obstructive lung disease (COLD). Volume of forced exhalation for the first second (VFE₁) is measured. Bronchi-provoking pharmacological test with 0.33% methacholine solution is performed. Change of volume of forced exhalation for the first second (ΔVFE₁) from the initial value is registered. On the basis of said parameters determined are: post-bronchodilation residual volume of lungs and degree of hypersensitivity of respiratory ways, which are considered to be a risk factor. Other risk factors: patient's age, disease duration, number of exacerbations pre year, are also taken into account. Each risk factor is given a numerical value and gradation, which are used to determine prognostic coefficients F₁ and F₂ with further comparison of these values. If F₂ is larger than F₁, unfavourable course of COLD with progressing dyspnea is predicted. If F₁ value is larger than F₂, favourable clinical course of disease with low risk of severe dyspnea development is predicted.

EFFECT: method makes it possible to predict clinical course of said disease and activate pathogenetically justified therapy in due time.

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Description

The present invention relates to medicine, namely to pulmonology, functional diagnostics, and can be used to predict the course of moderate chronic obstructive pulmonary disease (COPD).

There are various methods for predicting the course and evaluating the clinical and functional state of patients with COPD.

So there is a method for accelerated prediction of COPD progression by determining the level of cytokine secretion, as a determining marker for reducing the volume of forced expiration in the first second (FEV ₁ ). To implement the method, an immunological study is carried out to determine the ability of immunocompetent cells (ICC) to produce transforming growth factor 1 (TGF-1) and fibroblast growth factor (bFGF). With a spontaneous level of TGF-β1 greater than or equal to 1122.71 ± 20.6 pg / ml and bFGF less than or equal to 7.2 ± 0.08 pg / ml, a favorable course of COPD is predicted with a decrease in FEV _{1 of} no more than 50 ml per year, and at a spontaneous level of TGF-β1 less than or equal to 1025.5 ± 11.7 pg / ml and bFGF 40.1 ± 0.9 pg / ml, an unfavorable course of COPD with a decrease in FEV _{1 of} more than 50 ml per year is predicted (Method for predicting progression chronic obstructive pulmonary disease. Pat. RF №2370773, IPC G01N 33/53; Kalinina EP, Lobanova EG, Ivanov EM, publ. 20.10.2009).

The main disadvantages of this method include the difficulty in determining cytokines in real clinical practice, as well as the pronounced variability of the rate of reduction of FEV ₁ in response to the treatment, since being a predictor of the severity of the disease, FEV ₁ does not reflect the activity of the disease and poorly correlates with clinical and functional status and quality of life of patients with COPD (Agusti A., Calverley PMA, Celli B. et al. Characterization of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010; 11 (1): 122. http: // respiratory-research. com / content / 11/1/122).

The closest in technical essence to the proposed one is a method for predicting the progression of COPD, including determining the severity of bronchial obstruction according to spirometric indicators (Method for predicting a stable course of chronic obstructive pulmonary disease. Pat. RF №2262889, IPC АВВ 5/091; Kolosov V.P., Kolosov A.V., published on 10.27.2005).

The known method is as follows. The forced expiratory volume in the first second (FEV ₁ ) is measured in liters, then a bronchial provocative pharmacological test is performed with a 0.1% solution of acetylcholine chloride and the change in forced expiratory volume in the first second (ΔОФВ ₁ ) in% of the initial value is determined. Then, using the discriminant equation: D = -2.94 · FEV ₁ + 1.34 · ΔOFV ₁ , the value of D. is determined. With a value of D greater than -19.34, a stable course of chronic obstructive pulmonary disease is predicted.

The disadvantages of this method include its unsatisfactory accuracy, since the assessment of the condition of a patient with COPD, based on only one spirometric indicator, does not reflect the variety and severity of the clinical and functional features of the disease. The FEV ₁ indicator used for prognostic value is a less accurate predictor of COPD progression than, for example, the severity of shortness of breath. Shortness of breath, being the main complaint of patients with COPD, has a low correlative relationship with the volume of forced expiration in the first second (FEV ₁ ). So, the 5-year survival of patients with COPD is significantly associated with dyspnea (p <0.001), but not with FEV ₁ (p = 0.20) (Nishimura K., Izumi T., Tsukino M. et al. Dyspnea is a better predictor of 5-year survival than airway obstruction in patients with COPD. Chest 2002; 121: p. 1434).

The task of the invention is to develop a method for predicting the course of COPD in patients with moderate disease.

The technical result of this proposal is to increase the accuracy of the prognosis in the early stages of the disease, due to the clinical analysis of the severity of dyspnea and the determination of factors that determine its level.

The technical result of the proposed method for predicting the course of COPD is achieved by measuring the forced expiratory volume in the first second (FEV ₁ ), conducting a bronchial provocative pharmacological test and determining the change in forced expiratory volume in the first second (ΔOFV ₁ ) from the initial value.

The difference between the method lies in the fact that as a bronchoconstrictor, a 0.33% solution of methacholine is inhaled.

The main distinguishing features of the proposed method is the additional definition of risk factors from the anamnesis of life and clinical and functional indicators: age, duration of the disease, the frequency of exacerbations per year, post-bronchodilation value of the residual lung volume from the proper value and the degree of hypersensitivity of the respiratory tract.

The identified risk factors set gradation and numerical values, and then determine the prognostic factors F ₁ and F ₂ according to the formulas

F ₁ = -1.32-0.39 A ₁ -0.93 A ₂ -0.54 A ₃ -0.62 A ₄ + 0.74 A ₅

F ₂ = -1.82 + 0.47 · A ₁ + 1.12 · A ₂ + 0.65 · A ₃ + 0.74 · A ₄ −0.89 · A ₅ ,

respectively, where A _1-5 gradations and numerical risk factors, and

A ₁ - age of the patient, years;

And ₂ - the duration of the disease, years;

And ₃ - postbronchodilation value of the residual lung volume (OOL),%;

And ₄ - the frequency of exacerbations per year;

And ₅ - the degree of hypersensitivity of the respiratory tract.

The difference of the proposed method also lies in the fact that with F ₂ greater than F _{1, an} unfavorable course of COPD with progression of dyspnea is predicted, and with a value of F ₁ greater than F _{2, a} favorable clinical course of the disease is predicted with a low risk of developing severe shortness of breath.

A comparative analysis with the prototype showed that the proposed method differs from the known above methods and, therefore, meets the criteria of the invention of "novelty."

To predict the severe clinical course of the disease and poor prognosis in patients with moderate COPD, the method of linear discriminant analysis was applied. 88 examined patients with COPD are divided into 2 groups depending on the severity of dyspnea according to the MRC scale: 48 patients with mild and 40 with severe degree of dyspnea. When dividing COPD patients into groups, depending on the severity of dyspnea, the following signs turned out to be most effective: degree of hypersensitivity of the respiratory tract, frequency of exacerbations / year, duration of the disease, post-bronchodilation value of residual lung volume (AOL) in% of the proper value, patient age.

The degree of hypersensitivity was evaluated on the basis of the indicator of the cumulative dose of methacholine (provocative dose - PD ₂₀ ), which caused a decrease in the value of FEV ₁ by 20% or more from the initial value. PD ₂₀ metacholine was calculated by linear interpolation according to generally accepted formulas

PD ₂₀ = antilog {logC ₁ + (logC ₂ -logC ₁ ) · (20-R ₁ ) / (R ₂ -R ₁ )},

where C ₁ - penultimate dose of methacholine (change in FEV ₁ less than 20%),

C ₂ - the last dose of methacholine (change in FEV ₁ ≥20%),

R ₁ -% reduction of FEV ₁ after C ₁ ,

R ₂ -% decrease in FEV ₁ after C ₂ .

A positive metacholine test, indicating the presence of hypersensitivity, corresponded to a value of PD ₂₀ less than or equal to 0.471 mg, while a severe degree of hypersensitivity (PD ₂₀ <0.04 mg) was assigned gradation 1, moderate (PD ₂₀ 0.04-0.22 mg ) - gradation 2 and mild hypersensitivity (PD ₂₀ 0.23-0.47 mg) gradation 3. Patients with a negative test (PD ₂₀ > 0.47 mg) were assigned gradation 4 (Ivanov A.F. Clinical and functional characteristics, peculiarities of the course and prognosis of bronchial asthma in young people who have been ill since childhood: Auth Ref ... dis candidate of medical sciences -.... Irkutsk, 2008, p 7).. The information content of the signs was evaluated by the Fisher F-test, with a significance level of p <0.05. The most informative coefficients of discriminant function in dividing patients with moderate COPD according to the degree of dyspnea are shown in Table 1.

Table 1 Signs K1i K2i Age (A ₁ ) -0.39 0.47 Duration of illness (A ₂ ) -0.93 1.12 OOL (A ₃ ) -0.54 0.65 The frequency of exacerbations / year (A ₄ ) -0.62 0.74 The degree of hypersensitivity (A ₅ ) 0.74 -0.89 Constant -1.32 -1.82

Based on the discriminant analysis, a system of two equations (F ₁ and F ₂ ) was constructed that characterizes the discriminant functions for two groups of patients with COPD: F ₁ - with shortness of breath, F ₂ - with severe shortness of breath.

F ₁ = Ko1 + ΣK1, i × Ai;

F ₂ = Ko2 + ΣK2, i × Ai;

Where

Ko1 is a constant for F ₁ ,

Co2 is a constant for F ₂ ,

K1, i are the values of the coefficients of the discriminant function for F ₁ ,

K2, i are the values of the coefficients of the discriminant function for F ₂ .

The determination of the values of prognostic factors F ₁ and F ₂ according to the formulas allows us to compare their quantitative characteristics, which are the estimated criteria for the risk of developing a clinically severe course of the disease and poor prognosis.

The authors of the proposed method found that with an absolute value of F ₁ greater than the absolute value of F ₂ , an adverse course of COPD with the progression of shortness of breath is predicted. If F _{1 is} greater than F _{2, a} low risk of severe dyspnea is predicted (favorable clinical course of the disease). The method allows to assess the severity of symptoms of COPD within one stage of the disease, as well as to determine the clinical and functional characteristics of the adverse course of the disease. This method contributes to the accuracy of the prognosis associated with the course of COPD in the early stages of the disease.

The forecast accuracy for discriminant analysis was 92.0%, namely, for a group of patients with mild shortness of breath - 93.8% and for patients with COPD with severe shortness of breath - 90.0%.

From the analysis of patent and specialized literature, the authors found that the proposed method has features that distinguish it not only from the prototype, but also other technical solutions in this and related fields of medicine. In the literature available to us, there is no method for predicting the course of COPD by the above risk factors for moderate disease for both men and women.

This allows us to conclude that the technical solution meets the criterion of "inventive step".

A method for predicting the course of COPD constituting the claimed invention is intended for use in healthcare. Clinical observations of the authors of the proposed method indicate that the use of the proposed technical solution allows the prognosis of a favorable and unfavorable clinical course of moderate COPD. From the above it follows that the claimed invention meets the condition of patentability "industrial applicability".

The proposed method is as follows.

A patient with COPD undergoes a general clinical examination and assesses the function of external respiration. Based on anamnestic, clinical and functional data, appropriate gradations and numerical values are assigned to established risk factors.

Then, according to the formulas, the values of the prognostic factors F ₁ and F _{2 are} determined, their numerical characteristics are compared, by which the prognosis of the COPD course is evaluated.

With a value of F ₁ greater than F _{2, a} pathogenic clinical course of the disease is predicted with a low risk of severe dyspnea.

If the absolute value of F _{2 is} greater than that of F ₁ , then the subject is predicted to have a high risk of developing severe shortness of breath in the next 5 years.

The proposed method for predicting the course of COPD in the early stages is illustrated by examples of specific performance.

Example 1. Patient M., 56 years old (A ₁ = -0.22 *). From the anamnesis: COPD of moderate severity, shortness of breath worries for 2 years (A ₂ = -0.91 *), after bronchodilator, the OOL value was 169.2% of the proper value (A ₃ = -0.73 *), 1 an exacerbation episode in the previous 12 months (A ₄ = -0.54 *), an inhalation provocation test with methacholine did not reveal airway hypersensitivity (PD ₂₀ > 0.47 mg) - gradation 1 (A ₅ = 1.37 *).

^* Standardized data obtained by the formula

,

,

- среднее значение; s - стандартное отклонение; Xj - результаты измерений распределения с исходной размерностью; Aj - стандартизованные значения исходного распределения со средним значением равным нулю и стандартным отклонением равным единице.Where

- average value; s is the standard deviation; Xj are the results of measurements of the distribution with the original dimension; Aj are the standardized values of the initial distribution with the average value equal to zero and the standard deviation equal to unity.

F ₁ = -1.32-0.39 · (-0.22) -0.93 · (-0.91) -0.54 · (-0.73) -0.62 · (-0.54 ) + 0.74 0.37 = 1.35

F ₂ = -1.82 + 0.47 · (-0.22) + 1.12 · (-0.91) + 0.65 · (-0.73) + 0.74 · (-0.54 ) -0.89 1.37 = -5.04

F _{1 is} greater than F ₂ , therefore, patient M. has a prognosis of a favorable clinical course of the disease and a low risk of severe dyspnea.

Assessment of the level of dyspnea in this patient on the MRC scale for 5 years of dynamic observation corresponds to a mild degree.

Example 2. Patient G., 61 years old (A ₁ = 0.49 *). From the anamnesis: COPD of moderate severity, shortness of breath disturbs for 5 years (A ₂ = -0.49 *), after the bronchodilator, the OOL value was 199.9% of the proper value (A ₃ = 2.16 *), 3 episodes were revealed exacerbations over the previous 12 months (A ₄ = 1.30 *), when conducting an inhalation provocation test with methacholine, a high degree of hypersensitivity (PD ₂₀ <0.04 mg) was determined - gradation 1 (A ₅ = -0.98 *). The data are standardized analogously to example 1.

F ₁ = -1.32-0.39 · 0.49-0.93 · (-0.49) -0.54 · 2.16-0.62 · 1.30 + 0.74 · (-0 , 98) = - 3.75

F ₂ = -1.82 + 0.47 · 0.49 + 1.12 · (-0.49) + 0.65 · 2.16 + 0.74 · 1.30-0.89 · (-0 , 98) = 1.09

F ₂ greater than F ₁ - high risk of adverse COPD with progression of dyspnea.

According to the MRC scale, a patient had mild shortness of breath in 2006. In 2011, a severe shortness of breath was confirmed for this patient on the MRC scale, leading to stops after several minutes of walking on flat terrain or when walking at a distance of 100 meters.

The patients shown in examples 1 and 2, although they have the same severity of COPD, are comparable indicators of bronchial obstruction, but the course of the disease is different for them, which is confirmed by the prognosis.

The forecast accuracy for discriminant analysis was 92.0%, namely, for a group of patients with mild shortness of breath - 93.8% and for patients with COPD with severe shortness of breath - 90.0%.

Thus, the proposed method makes it possible to predict a favorable and unfavorable clinical course of the disease in patients with moderate COPD and, in a timely manner, to activate pathogenetically substantiated therapy aimed at reducing pulmonary hyperinflation, hypersensitivity of the respiratory tract and preventing exacerbations in the early stages of COPD.

Claims (1)

A method for predicting the course of moderate chronic obstructive pulmonary disease, including measuring the volume of forced expiration in the first second (FEV ₁ ), conducting a bronchial provocative pharmacological test and determining the change in the volume of forced expiration in the first second (ΔOFV ₁ ) from the initial value, characterized in that as a bronchoconstrictor they inhalate a 0.33% solution of methacholine and additionally determine risk factors from the anamnesis of life and clinical and functional indicators: age, duration of the disease evasion, the frequency of exacerbations per year, the post-bronchodilation value of the residual lung volume from the proper value, the degree of hypersensitivity of the respiratory tract is estimated, their gradations and numerical values are established, and then the prognostic factors F ₁ and F _{2 are} determined by the formulas:
F ₁ = -1.32-0.39 · A ₁ -0.93 · A ₂ -0.54 · A ₃ -0.62 · A ₄ + 0.74 · A ₅ ;
F ₂ = -1.82 + 0.47 · A ₁ + 1.12 · A ₂ + 0.65 · A ₃ + 0.74 · A ₄ -0.89 · A ₅
respectively, where A _1-5 gradations and numerical risk factors, and
A ₁ - age of the patient, years;
And ₂ - the duration of the disease, years;
And ₃ - postbronchodilation value of the residual lung volume,%;
And ₄ - the frequency of exacerbations per year;
A ₅ - the degree of hypersensitivity of the respiratory tract
and with F ₂ greater than F _{1, an} unfavorable course of COPD with progression of dyspnea is predicted, and with a value of F ₁ greater than F _{2, a} favorable clinical course of the disease is predicted with a low risk of severe dyspnea.