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Method for determining degree of severity of chronic obstructive pulmonary disease

IPC classes for russian patent Method for determining degree of severity of chronic obstructive pulmonary disease (RU 2516971):
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FIELD: medicine.

SUBSTANCE: blood is examined. The steroid hormones cortisol (nmole/l) and DHEA-S (mcmole/l), as well as the oxidative stress values - oxidative modified proteins (OMP, nM/mg, protein), malondialdehyde (MDA, nM/ml) and SH groups mg% are evaluated. The forced expiratory volume 1(%) FEV1 is calculated by formula on the basis of the derived values. If the derived FEV1 is within 50% to 80%, the presence of a moderate degree of chronic obstructive pulmonary disease; the FEV1 being within the range of 30 to 49% means a severe degree of chronic obstructive pulmonary disease (COPD), and the derived value being less than 30% shows an extremely severe degree of COPD.

EFFECT: reliable determination of a degree of severity of chronic obstructive pulmonary disease.

3 tbl, 2 ex

 

The invention relates to medicine, namely to pulmonology.

The assessment of severity of chronic obstructive pulmonary disease (COPD) is based on the intensity of symptoms, the severity of spirometric disorders and the presence of complications.

Was proposed a simple approach to determining the severity of COPD using a combination of indicators - body mass index, obstruction, dyspnea, exercise (school BODE). However, studies of the properties of this school, as a tool for quantitative assessment of patients with COPD is not fully understood and continuing to the present.

According to the recommendations of the GOLD spirometric classification of COPD provides documentation of the severity of the pathological process.

However, it is now becoming increasingly clear that the rate of FEV1 does not fully reflect the complex picture of the clinical manifestations of COPD (Agusti AGN, Noguera A, Sauleda J, et al. Systemic effects of chronic obstructive pulmonary disease. Eur. Respir. J. 2003). The presence of comorbidities is also important phenotypic characteristics of the disease.

There is a method of assessing the severity of COPD based on the definition of the level of secretion of transforming growth factor β 1 (TGF-β 1) and fibroblast growth factor (bFGF) (EN 2370773 C1).

Also there is a method of assessment based on the results of measurement of FEV1in l, changes the volume of the and forced expiratory volume in the first second of in % of initial value after bronchoprovocation pharmaceutical samples with 0.1% solution of acetylcholine chloride (RU 2262889 C1, 09.03.2004)and method of assessment of COPD based on metrics densitometry and planimetry in % in both lungs, determine the values of FEV1% proper (EN 2370773 C1, 20.10.2009 (prototype); RU 2359618 C1, 27.06.2009).

However, existing methods for the assessment of tedious, time-consuming and limited in the use of biological material.

Thus, the present invention was to find the technique that allows reliable assessment on the condition of eliminating the disadvantages of the known methods.

Achievable technical result is the assessment of severity of COPD.

It is known that chronic inflammation in chronic obstructive pulmonary disease (COPD) is a key factor in the progression of the disease. One of the main components of the pathogenesis of chronic inflammation is oxidative stress (OS). It is assumed that the imbalance between oxidants and antioxidants play an important role in the pathogenesis of chronic obstructive pulmonary disease. The formation of secondary products OS, toxic, possessing high biological activity "reactive molecules", such as free oxygen radicals, malonic dialdehyde (MDA), peroxynitrite, hypochlorite, leads to a direct cytotoxic effect. A number of compensatory reactions of the patient, aimed n is the maintenance of homeostasis in terms of OS, associated with activation of different systems. Great antiradical activity of antioxidant enzymes: superoxide dismutase (SOD), glutathione peroxidase (GP) and catalase. Among the low molecular weight antioxidants play an important role vitamins C and E, carotenes and steroid hormones - glucocorticoids, mineralocorticoids and sex hormones (Vladimirov, Y.A. Free radicals in biological systems. // Morozovsk. observat. Journe. 2000; Zelenkov NICHOLAS investigation of the mechanisms of oxidative stress in inflammation and opportunities for its antioxidant correction: author. dis. Novosibirsk, 2007; Willcox J.., Ash, S.L., G.L. Catignani Antioxidants and prevention of chronic disease // Critical rev. in food science and nutrition.2004; Stadtman E.R. Protein oxidation in aging and agerelated diseases // Heal, aging for funct. longevity.2001; Kazimierczuk VK, Maltsev V. Antioxidant system and its functioning in humans // Health of Ukraine. 2004; Hasnis E., A.Z. Reznick Antioxidants and healthy aging // Israel Med. Assoc. J. 2003).

It is known that COPD is often accompanied by imbalance of the adrenal system. In this leading value has lower concentrations of cortisol and DHEAS [Debigare R, Marquis K, Cote CH, et al. Catabolic/anabolic balance and muscle wasting in patients with COPD. Chest 2003. Karadag F, Ozcan H, Karul AB, et al. Sex hormone alterations and systemic inflammation in chronic obstructive pulmonary disease. Int J Clin Pract 2007; Scalvini S, Volterrani M, Vitacca M, et al. Plasma hormone levels and haemodynamics in patients with chronic obstructive lung disease. Monaldi Arch Chest Dis 1996; Gimenez M, Mohan-Kumar T, Humbert JC, et al. Haemtological and hormonal responses to dynamic exercise in patients with chronic airway obstruction. Eur J Clin Invest 1987).

Considering the complex influence of chronic OS and decrease in adrenal hormones on the process of chronic inflammation, an assumption was made that the increase in the content of peroxide oxidation and reduction of steroid hormones makes a significant contribution to the development of chronic inflammation and reduce bronchoobstructive.

On the basis of the above, we have developed a method of assessing the severity of COPD, based on indicators of OS (MDA, BIP and SH-groups) and steroid hormones (cortisol, DHEA-S).

To develop a new method of assessing the severity of COPD, we surveyed patients COPD stages II and III (table 1). Was conducted spirographis study (measurement of FEV1VC, FVC, FEV1/FVC), defined levels of cortisol, DHEA-S. in Addition, it was determined the MDA level, oxidative modified proteins (BIP), SH-groups, based on the assessed indicators of prooxidants and antioxidants in the blood.

Table 1.
Characteristics of patients COPD
Options Value
Men, n (%) 28 (80%)
W is ndini, n (%) 9(20%)
The average age, years 51,2±3,15
The experience of Smoking packs/years 46,0±17,2
Duration of COPD, years 12,1±1,7
FEV1% 64,3+11,1
MDA (nm/ml) the 14.90+2,58
BIP (nm/mg protein) 70,20±3,201
SH-mg group% 110,56±2,56
Cortisol (nmol/l) 7,63±0,46
DHEAS (µmol/l) 3,48±0,07

To assess the integrated effects of various hormone levels and indicators of oxidative stress on the degree of bronchoobstructive and hence the severity of COPD was conducted multiple regressions analysis. For modeling, was used to measure FEV1, reflecting the severity and level of bronchoobstructive (table 2).

Table 2
Index The coefficient estimates Standard error T-statistics The coefficient of reliability
FEV1 47,3467 1,34242 35,2695 0,0000
cortisol 0,00676571 0,00320378 2,11179 0,0426
DHEA- 0,19886 0,0556161 3,57559 0,0011
MDA -0,14714 0,0521696 -2,82042 0,0082
BIP -0,0398137 0,0168718 -2,35978 0,0246
SH-group 0,0196622 0,0101219 1,94254 0,0609

After statistical analysis, we identified the characteristics that are important in forming conclusions, and developed a mathematical model that allows for the use of these features to install extent the ü severity of COPD. These signs include: cortisol, DHEA-S, SH-groups, as well as MDA (malonic dialdehyde) and BIP. Based on the identified characteristics built a regression model, which allows a high degree of probability to refer the patient to a certain degree of severity of COPD. Built model (table. 3) is statistically significant with a coefficient of determination of 90.7 percent.

Table 3.
Assessing the adequacy of model
Sum of squares Degrees of freedom The mean square F-score The coefficient of reliability
model 193,179 5 38,6359 62,79 0,0000
result 19,6891 32 0,615285
only 212,868 37

R-squared (coefficient of reliability) = 90,7506%

R-squared (degrees of freedom) = 89,3054%

Standard error of the mean = 0,784401

The average absolute error = 0,54046

The coefficient Darby-Watson = 1,46327 (P=0,0250)

The resulting regression equation:

FEV1(%)-47,3467+0,00676571*cortisol+0,19886*DHEA-S-0,14714*MDA+0,0398137*SH-groups-0,0196622*BIP.

A continuous range of values regression model was divided into sub-bands. Determination of severity of COPD conducted depending on how the band got is:

from 50% to 80% for moderate COPD

from 30% to 49% - indicates the severe degree of severity of COPD,

less than 30%- very severe COPD.

According to the obtained multiple regression equation, we can calculate the severity of COPD, with reference to specific indicators of cortisol, DHEA-S, MDA, BIP and SH-groups.

The described model for practical application is presented in the form of the equation, the doctor is enough to make the values of cortisol, DHEA-S, SH-groups, MDA and BIP in this equation to obtain a conclusion about the severity of COPD.

The method is as follows.

Perform blood sampling. Determine the level of steroid hormones cortisol (nmol/l) DHEA-S (µmol/l), and define indicators of oxidative stress, the level of oxidative-modifica avannah proteins (BIP, nm/mg protein), the level of malondialdehyde (MDA (nm/ml) and SH-groups mg%.

The obtained values are substituted into the equation and calculate the value of the index FEV1(%), indicating the severity of COPD: FEV1(%)=47,3467+0,00676571*cortisol+0,19886*DHEA-S-0,14714*MDA+0,0398137*SH-groups-0,0196622*BIP.

When the value of the calculated index FEV1 50% to 80% - assess the presence of moderate severity of COPD, from 30 to 49% - severe severity of COPD, less than 30% - very severe COPD.

Example No. 1. Patient S., 58 years old, was admitted with a diagnosis of Chronic obstructive pulmonary disease, St, aggravation. Pulmocare. NAM 2.

Upon receipt complained of shortness of breath, congestion in the chest, cough with a small amount of sputum. From the anamnesis it is known that he considered himself ill for 8 years. Smokes about 30 years. Last admission 2 months ago. The patient noted a weak positive effect of therapy.

Objectively: the patient is in satisfactory Condition. Clear consciousness. The active position. NPV - 22 min. Chest emphysematous. Percutere is determined by the sound box. Auscultatory - weakened vesicular breathing, all fields of light audible dry mixed wheezing. BP - 120/80 mm Hg Ps=HR=92 per minute, satisfactory filling and voltage. Heart sounds rhythmic, muffled.

Laboratory data Common blood test on admission: Erythrocytes - a 3.5×1012the hemoglobin - 132 g/l, leucocytes - 13,8, lymphocytes - 18%, eosinophils - 8%, stab neutrophils - 5%, segmented neutrophils - 72%, monocytes - 6%, ESR - 18,0 mm/h

In the study of ATS: FVC - 57,2%; FEV1 - 54,2%; FEV1/FVC - 65,8%. Spirometrically the severity of COPD is regarded as moderate.

The content of cortisol blood - 0.1 nmol/l DHEA-µmol/l 1,4; MDA - of 15.2 nm/l, BIP - 65,8 nm/l; SH-groups - 94,2.

Based on our formula, the calculated severity of COPD=47,3467+0,00676571*0,1+0,19886*1,4-0,14714*15,2+0,0398137*94,2-0,0196622*65,8=47,8%.

Thus, the restriction of air flow amounted to 47.8% (from 30% to 49% of predicted values), which helped to clarify the severity - severe severity of COPD.

In connection with the obtained results, the patient was additionally appointed inhaled glucocorticosteroid (budesonide 200 mg per day) and a course of laser therapy for the correction Occidentale and hormonal status.

The patient was discharged on the 13th day of hospitalization, with significant improvement. Recommended further use of budesonide in combination with dlitelnodeystvuyuschie bronholitikam (formoterol 10 mg).

Example No. 2. Patient A., 63 years old, diagnosed with chronic obstructive pulmonary disease, exacerbation. NAM 2.

Upon receipt complained of shortness of breath, cough with sputum. From the anamnesis it is known that please take the em sick for about 20 years. Recent deterioration occurred a week ago, and with the above complaints, the patient was admitted in polvadera. From the anamnesis it is known that for the past 2 years uses dlitelnodeystvuyuschie bronholitin formoterol 10 mg, and short-acting anticholinergic drug ipratropium bromide up to 5 times per day. Notes 4 exacerbation in the past year.

Objectively. A state of moderate severity. Clear consciousness. The active position. Skin and visible mucous clean, damp, acrocyanosis. NPV - 24 per minute. Percutere is determined by clear pulmonary sound with boxed shade in all lung fields. Auscultatory - hard breathing, all fields lungs dry rales are heard. AD - 140/95 mm Hg Ps=HR=78 per minute, satisfactory filling and voltage. Heart sounds rhythmic, muffled.

Laboratory data: complete blood count on admission: Erythrocytes - 4,7·1012/l, hemoglobin - 142 g/l, leucocytes - 10,8·109/l, eosinophils - 8%, stab neutrophils - 5%, segmented - 67%, lymphocytes - 16%, monocytes - 4%, ESR=16 mm/hour.

In the study of respiratory function: FVC - 69,2%; FEV1 - 51,8%; FEV1/FVC - 62,7%. The content of cortisol blood - 12.5 nmol/l DHEA-From umol/l to 4.5; MDA - of 18.5 nm/l, BIP - 100,2 nm/l; SH-groups - 83,5. FEV1=47,3467+0,00676571*12,5+0,19886*4,5-0,14714*18,5+0,0198137*83,5-0,0196622*100,2=46,9%.

In this case, the intensity of bronchoobstructive svidetel is there about severe stage of COPD.

Patient assigned to combined drug formoterol/budesonide 160-320 mg and a course of laser therapy. Discharged on the 14th day of hospitalization.

Follow-up observation in the next 6 months showed no exacerbations during the entire period of observation.

Thus, our proposed method allows to determine the severity of COPD, which is important in clinical situations when the diagnosis is established based on the results of spirometric studies. In addition, the subsequent selection of treatment allows you to select pathogenetically-based therapy for the patient, leading to reduction of hospitalization and fewer exacerbations.

The method of assessment of the severity of chronic obstructive pulmonary disease (COPD), including the implementation of blood, determination of steroid hormones cortisol (nmol/l) DHEA-S (µmol/l), and indicators of oxidative stress oxidative modified proteins (BIP, nm/mg protein), the level of malondialdehyde (MDA (nm/ml) and SH-groups mg%, based on the obtained values calculate the value of the index FEV1(%), indicating the severity of COPD: FEV1(%)=47,3467+0,00676571*cortisol+0,19886*DHEA-S-0,14714*MDA+0,0398137*S-group-0,0196622*OMB, and when the value of the calculated index FEV1 50% to 80% - assess the presence of moderate extent and severity of COPD, from 30% to 49% - severe severity of COPD, less than 30% - very severe COPD.

 

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