RU2711453C1 - Method for evaluating the unfavorable course of chronic obstructive pulmonary disease and arterial hypertension when combined - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention refers to medicine, namely to pulmonology and cardiology, and can be used for assessing the development of unfavorable course of chronic obstructive pulmonary disease (COPD) and arterial hypertension (AH) when combined. Patient with COPD with AH is examined for cell immunity values: blood serum CD3- and CD4-T-lymphocyte count and heart rate variability (HRV) values: SDNN is mean-square deviation, RMSSD is mean-square value between duration of adjacent R-R intervals. Risk of unfavorable clinical course of COPD with AH is evaluated by using the mathematical formula: p=1/(1+e), where p – probability of unfavorable clinical course of COPD with AH; z=3.4*x H1+0.8*xH2-2.3*xH3-1.7*xH4+(-7.74), H1 – T-lymphocytes CD3+(x10 cells/l), H2 – CD4+T-lymphocytes (x10 cells/l), H3 – SDNN (s), H4 – RMSSD (s). If p is from 0.1 to 0.5, the risk of unfavorable course of COPD with AH is considered to be a low risk. At p from 0.5 to 0.8 as high. At p from 0.9 to 1.1 as very high.EFFECT: method provides calculating an individual risk of unfavorable course in COPD and AH in a simple and accessible way by determining the CD3-, CD4- (T-lymphocyte) content× 10*9 cells/l) in blood serum and HRV: SDNN, which is one of the main HRV values, and RMSSD by cardiointervalogramm data.1 cl, 4 tbl, 3 ex

Description

The invention relates to medicine, namely to pulmonology, cardiology and preventive medicine and can be used to assess the development of an unfavorable course of chronic obstructive pulmonary disease (COPD) and arterial hypertension (AH) when combined.

Currently, it is known that COPD and hypertension can be considered as systemic, polyetiological and polypathogenetic diseases, which naturally are combined due to their greater prevalence, as well as the commonality of a number of etiological and pathogenetic factors. The combination of COPD with hypertension is considered as a striking example of comorbid pathology, which occurs in 34.4% of the population and aggravates the course of diseases, which leads to an increase in mortality by a factor of 2–3 (Zadionchenko V.S., 2014), and also significantly increases the risk of cardio -vascular complications. In this case, immunological and autonomic changes have a great influence on the course of the disease and prognosis in patients with COPD in combination with hypertension. In this regard, we have proposed a method for assessing the development of an unfavorable course of COPD in combination with hypertension.

Currently, methods are known in pulmonology and cardiology to predict the risk of developing an unfavorable course of COPD and hypertension when combined.

A known method for predicting the course of moderate COPD (patent No. 2480153), including measuring the volume of forced expiration in the first second (FEV), conducting a bronchopulmonary pharmacological test to determine the change in the volume of forced expiration in the first second (ΔOFV1) compared with the initial value. As a bronchoconstrictor, a 0.33% methacholine solution is inhaled. Risk factors are determined from the history of life and clinical and functional indicators: age, duration of the disease, frequency of exacerbations per year, post-bronchodilation value of the residual lung volume and its comparison with the proper value; assess the degree of hypersensitivity of the respiratory tract, establish their gradations and numerical values, and then determine the prognostic factors F1 and F2 according to the formulas: F1 = -) 1.32-0.39⋅A-0.93A-0.54⋅A-0, 62⋅A + 0.74⋅A;

F2 = -1.82 + 0.47⋅A + 1.12⋅A + 0.65⋅A + 0.74⋅A-0.89⋅A, respectively, where A1 is the gradation and numerical risk factors, and A2 is the age patient, years; A3 - the duration of the disease, years; A4 - postbronchodilation value of the residual lung volume,%; A5 - the frequency of exacerbations per year; A6 is the degree of hypersensitivity of the respiratory tract and, with F greater than F, an unfavorable course of COPD with progression of dyspnea is predicted, and with a value of F1 greater than F2, a favorable clinical course of the disease with a low risk of severe dyspnea is predicted.

The main disadvantages of this method include the fact that the used index of FEV ₁ according to spirometric studies on prognostic value is a less accurate predictor of the progression of COPD; this method determines the prognosis only for the moderate course of the disease, does not include the severe stage of the disease, and is not used for the comorbid course of COPD and arterial hypertension.

Also known is a method for assessing the severity of chronic obstructive pulmonary disease (patent No. 2516971 dated 05.20.2014 Titova L.A. et al.), Including performing blood sampling, determining the level of steroid hormones cortisol (nmol / L) and DHEA-C (μmol / l), as well as the level of indicators of oxidative stress - oxidatively modified proteins (OMB, nM / mg, protein), the level of malondialdehyde (MDA, nM / ml) and SH-groups mg%, based on the obtained values, the FEV1 value is calculated ( %), indicating the severity of COPD: FEV1 (%) = 47.3467 + 0.00676571 * cortis l + 0.19886 * DHEA-S 0.14714 * MDA + 0.0398137 * SH-groups -0.0196622 * OMB, and if the value of the calculated FEV1 is from 50% to 80%, the presence of moderate severity of COPD is assessed, from 30 to 49% - severe COPD severity, less than 30% - extremely severe COPD.

The disadvantages of this method is that the determined FEV1 indicator does not fully reflect the complex picture of the clinical manifestations of COPD. The used assessment methods are laborious, limited in the use of biological material. This method does not predict the course of COPD in combination with hypertension.

As a prototype, the authors propose a method for predicting the development of a comorbid form of arterial hypertension and chronic obstructive pulmonary disease (patent No. 2620566). A method for predicting the development of a comorbid form of arterial hypertension (AH) and chronic obstructive pulmonary disease (COPD) is characterized in that in a patient with arterial hypertension or chronic obstructive pulmonary disease, the genotypes of the M235T polymorphic locus of the angiotensinogen gene (AGT) and the type I angiotensinogen receptor polymorphic locus A1166C of the type I angiotensinogen receptor A1166C are determined. II (AGTR1) and if the patient has the T / T genotype of the M235T polymorphic locus of the AGT gene and the A / C genotype of the A1166C polymorphic locus A1166C of the AGTR1 gene, a high probability of development is predicted omorbidnoy AH and COPD for 10 years after the opening of the first diseases. The indicated likelihood of developing comorbid hypertension and COPD is 61.5%.

The disadvantage of this method is that it is time-consuming, difficult to use; genotyping is carried out only in large specialized clinics. It allows predicting the development of hypertension or COPD after the debut of one of the diseases, but does not predict the severity of COPD.

The task to which the invention is directed is to calculate the individual risk of developing an adverse course in patients with COPD and hypertension in a simpler and more affordable way. This problem is solved by determining the content of T-lymphocytes CD3-, CD4- (× 10 * 9 cells / l) in blood serum and HRV indices: SDNN (sec) (standard deviation (RMS), which is one of the main indicators of cardiac variability rhythm, and RMSSD (sec) (rms between the duration of adjacent RR intervals) according to the cardiointervalogram (CIG).

Determination of the adverse combined course of arterial hypertension of chronic obstructive pulmonary disease allows:

1. adjust the program of diagnostic measures in patients with COPD and hypertension;

2. formulate recommendations for the secondary prevention of the disease

in a combination of hypertension and COPD;

3. increase the effectiveness of rehabilitation measures in this category of patients.

The novelty of the study is the determination in patients with a comorbid course of COPD and AH of individual indicators of cellular immunity: the content of T-lymphocytes CD3-, CD4- (× 10 * 9 cells / l) in the blood serum and HRV: SDNN (sec) (mean square deviation (RMS), which is one of the main indicators of heart rate variability, and RMSSD (sec) (rms between the duration of adjacent RR intervals) according to the cardiointervalogram (CIG).

A formula has been developed for calculating the individual risk of developing an unfavorable course of COPD in combination with hypertension. The proposed method is time-consuming, affordable, without contraindications and reflecting the possibility of early diagnosis of an adverse course of COPD and hypertension.

The object of the study was COPD patients with hypertension and without hypertension. Criteria for inclusion in the study: 2 (moderate) and 3 (severe) severity of COPD (according to the values of the post-bronchodilation volume of forced expiration in the first second - FEV1 and according to GOLD, 2011) in a stable stage with or without AH. Criteria for exclusion from the study: 1 (mild) and 4 (extremely severe) degrees of COPD, respiratory failure III degree, severe pulmonary hypertension (mean pressure in the pulmonary artery ≥55 mm Hg), decompensation of chronic pulmonary heart disease, symptomatic arterial hypertension, blood diseases, chronic heart failure of the II B-III stage (III-IV FC NYHA), acute diseases and chronic diseases in the acute stage, oncological diseases. The subject of the study was clinical, functional, immunological parameters and indicators of vegetative-vascular regulation of patients, including those with different degrees of hypertension (tab. 1, 2, 3).

The severity of clinical symptoms was determined by assessing the dyspnea scale and the CAT assessment test. The modified dyspnea scale mMRC provides for determining the degree of dyspnea from 0 to 4, which corresponds to its severity: 0 - no, 1 - mild, 2 - medium, 3 - severe, 4 - extremely severe. According to the description, the degree of dyspnea can be assessed in each patient with COPD. To perform an assessment test for COPD - CAT, the patient must answer 8 questions, independently evaluate the severity of some symptoms from 0 to 5 points. The CAT test most accurately reflects the patient’s well-being at the moment.

To distinguish groups of patients (A, B, C and D) according to GOLD 2011, it is necessary to assess the severity of clinical symptoms according to the mMRC scale (0-1 or ≥2) and the CAT questionnaire (<10 or> 10), to determine the degree of air speed limitation flow by the value of post-bronchodilation FEV ₁ (<50% or> 50%) and the frequency of exacerbations of COPD during the year (≤1, ≥2). If the patient in the previous year has even 1 exacerbation leading to hospitalization (i.e. severe exacerbation), the patient must be considered a high-risk group (GOLD 2013).

The method was as follows.

At stage 1, blood sampling was performed in patients with COPD and hypertension. To characterize the immune status, the leukocyte blood count, relative and absolute number of lymphocytes were calculated; immunophenotyping of lymphocytes with the determination of lymphocytes expressing CD19-, CD3-, CD4-, CD8 antigens, determination of the levels of immunoglobulins of classes A, M, G (Ig A, Ig M, Ig G); When analyzing the immunogram, the levels of their critical values according to A.M. Zemskov and Pinegin dispersion value (tab. 2).

In venous blood stabilized with the anticoagulant K3EDTA (ethylene diamine tetraacetate potassium salt), the relative and absolute numbers of lymphocytes expressing CD19, CD3, CD4, and CD8 antigens were determined. The relative number of each cell population was expressed as a percentage of all lymphocytes, the absolute - in × 10 * 9 cells / L. The immunophenotyping procedure was performed using a two-platform non-washing technology. Lymphocyte staining was performed with monoclonal antibodies (IOTest, Beckman Coulter, Inc.) specific for CD19 and CD3 antigens, for CD4 and CD8 antigens and labeled with FITC (Fluorescein Isothyocyanate) and PE (Phycoerythrin), respectively. Fixation and lysis steps were performed using the Partec CyLyse® Erythrocyte Lysing kit (Partec GmbH, Germany). The relative number of lymphocyte populations carrying CD antigens was determined on a Partec CyFlow SL® flow cytometer (Partec GmbH, Germany). The lymphocytic gate was isolated according to the physical parameters of light scattering direct (FSC, Forward Scatter) and lateral (SSC, Side Scatter). The absolute number of cells in each population was calculated based on the results of determining the total number of lymphocytes using the Micros ES60 automatic hematology analyzer (Horiba ABX, France).

At the second stage, an analysis of heart rate variability (HRV) was performed using a cardiointervalogram recorded over a short (5-minute) period of time using the KAD-03 hardware-software complex. HRV assessment was carried out in accordance with the recommendations of the European Society of Cardiology. The study of HRV was started 1.5-2 hours after eating, in a quiet room. Before the study, physiotherapeutic procedures and drug treatment were canceled. Before the start of the study, a period of adaptation to environmental conditions was carried out for 5-10 minutes. The recording was carried out in a supine position, with calm breathing. In women, the study was conducted in the intermenstrual period.

By step-by-step method of testing significant predictors, a group of four features was formed: the content of T-lymphocytes CD3-, CD4- (× 10 * 9 cells / l) in blood serum and HRV indices: SDNN (sec) (standard deviation (SD)) which is one of the main indicators of heart rate variability, and RMSSD (sec) (rms value between the duration of adjacent RR intervals) according to the cardiointervalogram (CIG).

Variable logistic regression equations for calculating the individual risk of an adverse course of COPD with hypertension.

The coefficients of the variables of the binary logistic regression equation of the model for calculating the individual risk of developing an unfavorable course of COPD with hypertension are shown in the table (table 4).

The final equation for calculating the individual risk of adverse COPD with hypertension is as follows:

P = 1 / (1 + e ^z ),

where p is the probability of developing an unfavorable course of COPD with hypertension;

z = 3.4 * x H1 + 0.8 * x H2 -2.3 * x H3 -1.7 * x H4 + (- 7.74),

H1-T lymphocytes CD3 + (x10 ⁹ cells / l),

H2 - T-lymphocytes CD4 + (x10 ⁹ cells / l),

H3 - SDNN (s),

H4 - RMSSD (sec).

And with a p value from 0.1 to 0.5, the risk of developing an unfavorable course of COPD with hypertension is assessed as a low risk; p from 0.5 to 0.8 as high; p from 0.9 to 1.1 as very high.

The quality of the prognostic COPD model in combination with hypertension was evaluated. The sensitivity of the model is 76%, specificity 91%.

Example No. 1

Patient K., 73 years old. Diagnosis: COPD 3 (severe) degree.

Immunophenotyping of lymphocytes:

CD3 + T-lymphocytes (2.35 × 10 * 9 cells / L), CD4 + T-lymphocytes (1.33 × 10 * 9 cells / L).

Cardiointervalogram data:

Time analysis: SDNN = 74 ms; RMSSD = 78 ms;

Substitute these values in the desired equation, we obtain:

z = 3.4 * 2.35 + 0.8 * 1.33 + (- 2.3) * 0.074 + (- 1.7) * 0.078 + (- 7.74) = 1.0

thus p = 1 / (1 + e ^z ) = 0.3, therefore, a low risk of developing an unfavorable course of COPD in combination with hypertension. The patient is assigned to group B (low risk of exacerbations) (tab. 1).

Example No. 2

Patient K., 51 years old, Diagnosis: COPD 3 (severe) degree. AH stage II, 3 degrees, risk 4.

Immunophenotyping of lymphocytes:

CD3 + T-lymphocytes (1.20 × 10 * 9 cells / L), CD4 + T-lymphocytes (0.48 × 10 * 9 cells / L),

Cardiointervalogram data:

Time analysis: SDNN = 58 ms; RMSSD = 61 ms;

Substitute these values in the desired equation, we obtain:

z = 3.4 * 1.20 + 0.8 * 0.48 + (- 2.3) * 0.058 + (- 1.7) * 0.061 + (- 7.74) = - 2.05

thus p = 1 / (1 + e ^z ) = 0.9, therefore a very high risk of developing an unfavorable course of COPD in combination with hypertension. The patient is assigned to group D (very high risk of exacerbations) (tab. 1).

Example No. 3

Patient O., 59 years old. Diagnosis: COPD 3 (severe) degree. AT stage II, 2 degrees, risk 3.

Immunophenotyping of lymphocytes:

CD3 + T-lymphocytes (1.82 × 10 * 9 cells / L), CD4 + T-lymphocytes (1.01 × 10 * 9 cells / L).

Cardiointervalogram data:

Time analysis: SDNN = 65 ms; RMSSD = 70 ms.

Substitute these values in the desired equation, we obtain:

z = 3.4 * 1.82 + 0.8 * 1.01 + (- 2.3) * 0.065 + (- 1.7) * 0.070 + (- 7.74) = - 1,

thus p = 1 / (1 + e ^z ) = 0.7 therefore a high risk of developing an unfavorable course of COPD in combination with hypertension. The patient is assigned to group C (high risk of exacerbations) (tab. 1).

List of references:

1. Akramova, E.G. Analysis of variance of the QT interval in chronic respiratory pathology [Text] / E.G. Akramova // XXI National Congress on respiratory diseases. - 2013 .-- S. 263-264.

2. Avdeev, S.N. Chronic Obstructive Pulmonary Disease: A Pocket Guide for Practitioners, 2nd Edition [Text] / S.N. Avdeev. -Moscow: Atmosphere, 2010 .-- 160 p.

3. Arterial hypertension and bronchial obstructive pathology - features of the clinical picture [Text] / L.G. Ratova [et al.] // Systemic hypertension. 2012. -№1.-C. 5-10.

4. Arterial hypertension in patients with chronic obstructive pulmonary disease - in search of phenotypes. Part 2. [Text] / V.V. Lee [et al.] // Archive of Internal Medicine. - 2013. - No. 2. - S. 29-34.

5. Arterial hypertension in patients with chronic obstructive pulmonary disease - in search of phenotypes. Part 1. [Text] / V.V. Lee [et al.] // Archive of Internal Medicine. - 2013. - No. 1 (9). - S. 19-24.

6. Afanasyeva, E.A. A study of the prevalence of risk factors for chronic noncommunicable diseases in people who applied to adult health centers in the Moscow Region [Text] / E.A. Afanasyev, E.S. Ivanova, Yu.D. Shlyagin // Cardiovascular therapy and prevention. - 2015. - No. 14 (June). - S. 4-5.

7. Berezikova, E.N. Clinical observation of patients with a very high cardiovascular risk at the outpatient stage [Text] / E.N. Berezikova, A.A. Popova, I.A. Grebenkina // Cardiovascular therapy and prevention. - 2015. - No. 14 (June). - S. 23.

12. Cardiopulmonary factors associated with atrial fibrillation in patients with chronic obstructive pulmonary disease [Text] / E.I. Leonova [et al.] // Rational pharmacotherapy in cardiology. - 2016. - No. 12 (1). - S. 26-30.

13. Quality of life of patients with arterial hypertension [Text] / N.V. Orlova [et al.] // Cardiovascular therapy and prevention. - 2015. - No. 14. - S. 7.

14. Kovalchuk, L.V. The participation of the immune system in the formation and progression of cardiovascular disease [Text] / L.V. Kovalchuk [et al.] // Vestnik RSMU. - 2010. - No. 1. - S. 11-18.

15. High-normal blood pressure is associated with increased resting sympathetic activity but normal responses to stress-test / D. Hering [et al.] // Blood pressure. - 2013 .-- Vol. 22 (3). - P. 183-187.

16. Hill, K. Anxiety and depression in end-stage COPD / K. Hill // Eur. Respir. J. 2008. - Vol. 31. - P. 667-677.

17. Holguin, F. Comorbidity and mortality in COPD-related hospitalizations in the United States 1979 to 2001 / Holguin F, Folch E, Redd S.C. // Chest. - 2005. - Vol. 128 (4) .- P. 2005-2011.

Note. * - significance of differences between subgroups with I and III degree of hypertension according to the Mann-Whitney criterion (p <0.05).

* mMRC - Medical Research Council Dyspnea Scale (modified dyspnea scale); CAT - COPD Assesment Test (COPD assessment test); FEV ₁ - forced expiratory volume in 1 second; FZHEL - forced vital capacity of the lungs; Group B (low risk of exacerbations, symptoms are not very pronounced); group C (high risk of exacerbations, symptoms are pronounced); group D (high risk of exacerbations, symptoms are pronounced);

Note. * - significance of differences between groups according to the Mann-Whitney criterion (p <0.01).

* SDNN - standard deviation of the values of the intervals RR;

RMSSD - standard deviation of the differences of consecutive RR intervals; pNN50 is the fraction of adjacent RR intervals that differ by more than 50 ms;

HRVtr-triangular index.

Claims (8)

A method for assessing the development of an unfavorable course of chronic obstructive pulmonary disease (COPD) and arterial hypertension (AH) when combined, which consists in the fact that a patient with COPD with AH determines the parameters of cellular immunity: the content of T-lymphocytes CD3- and CD4- in blood serum and heart rate variability indicators: SDNN - standard deviation, RMSSD - mean square value between the duration of adjacent RR intervals; assess the risk of developing an unfavorable course of COPD with hypertension using the mathematical formula: p = 1 / (1 + e ^z ), where p is the probability of developing an unfavorable course of COPD with hypertension; z = 3.4 * x H1 + 0.8 * x H2 -2.3 * x H3 -1.7 * x H4 + (- 7.74), H1 - T-lymphocytes CD3 + (x10 ⁹ cells / l), H2 - T-lymphocytes CD4 + (x10 ⁹ cells / l), H3 - SDNN (s), H4 - RMSSD (sec); and with a p value from 0.1 to 0.5, the risk of developing an unfavorable course of COPD with hypertension is assessed as low risk, with p from 0.5 to 0.8 as high, with p from 0.9 to 1.1 as very high .