RU2796612C1 - Method for prediction of pulmonary fibrosis development in patients with interstitial lung diseases - Google Patents

Abstract

FIELD: medicine; pulmonology.

SUBSTANCE: sex of the patient, presence and severity of shortness of breath, weight loss, asymptomatic course of interstitial lung disease, history of smoking, time of diagnosis, presence of occupational and/or household hazards and/or systemic diseases of connective tissue, clubbing fingers and/or nailbed, end-inspiratory crepitus during auscultation, level of blood oxygen saturation after exercise is determined. The value of the prognostic coefficient F is determined by the original formula. F value equal to or greater than "0" predicts high risk, F value less than "0" predicts low risk of developing pulmonary fibrosis in a patient with interstitial lung disease.

EFFECT: method provides personal prognosis of development of pulmonary fibrosis at the onset of interstitial lung disease based on clinical and functional data widely available in routine medical use.

1 cl, 1 tbl, 8 dwg, 2 ex

Description

The present invention relates to the field of medicine, namely to pulmonology, and can be used to predict the development of pulmonary fibrosis in patients with various interstitial lung diseases (ILD).

ILD is a large heterogeneous group of predominantly chronic lesions of the lung parenchyma, characterized by varying degrees of inflammation and fibrosis, as well as their combination (An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias / W.D. Travis, U. Costabel, D. M. Hansell [et al.] // Am. J. Respir. Crit. Care Med. - 2013. - No. 6 (188) - pp. 733-748). The progressive nature of pulmonary fibrosis in ILD leads to respiratory failure, reduced quality of life and increases the risk of death (Chronic fibrosing interstitial lung diseases with a progressive fibrotic phenotype: resolution of the Interdisciplinary Expert Council / S.N. Avdeev, S.Yu. Chikina, I.E. Tyurin [et al.] // Pulmonology, 2021, No. 31 (4), pp. 505-510).

A known method for predicting the course of sarcoidosis - a disease from the group of ILD. To do this, conduct a morphological study of lung tissue and intrathoracic lymph nodes. By visual microscopy in the biopsy, the quantitative composition of the inflammatory infiltrate is examined. In 10 fields of view at ×100-fold magnification, the total number of cells is calculated as a percentage. If the value of macrophages is less than 70% in the field of view, lymphocytes is more than 28% in the field of view, and the lymphocytic-macrophage index is more than 0.38, a favorable course of respiratory sarcoidosis is predicted. If the value of macrophages is more than 81%, lymphocytes is less than 15% and the lymphocytic-macrophage index is less than 0.18, an unfavorable course of sarcoidosis is predicted (Pat. 2707510, Russian Federation, IPC: G01N 33/49. Palchikova I.A., Chernyavskaya G.M. et al.; Patent holder of the Federal State Budgetary Educational Institution of Higher Education "Siberian State Medical University" of the Ministry of Health of the Russian Federation - No. 2019120044, application 27.06.2019, publ. 27.11.2019, Bull. No. 33).

The disadvantages of this method include the impossibility of its use in patients with various interstitial lung diseases, since the known method is intended only for a limited part of patients - patients with sarcoidosis. Also, the disadvantages of this method include the need for mandatory surgical intervention to obtain material for subsequent morphological studies.

The closest in technical essence to the present invention is a method for predicting the risk of mortality in progressive fibrosing course of ILD (PF-ILD) by assessing risk factors such as forced vital capacity (FVC), age and nosological form of the disease. The following indicators of PF-ILD were found to increase the risk of death: FVC <70% at the time of inclusion in the study, a decrease in FVC by ≥10% from baseline for 1 year, the patient's age ≥50 years and a diagnosis of unclassified interstitial pneumonia or idiopathic interstitial pneumonia pneumonia, or hypersensitivity pneumonitis (Progressive fibrosing interstitial lung disease: a clinical cohort (the PROGRESS study) / M. Nasser, S. Larrieu, S. Si-Mohamed [et al.] // Eur. Respir. J. - 2021 - 57:2002718).

The disadvantages of this method include the impossibility of predicting the risk of developing pulmonary fibrosis in the onset of ILD, tk. predicting the risk of death is carried out with the already established PF-ILD.

The objective of the claimed invention is to develop a method for predicting the development of pulmonary fibrosis in patients with various interstitial lung diseases.

The technical result of this proposal is to provide the possibility of predicting the risk of developing pulmonary fibrosis at the onset of interstitial lung disease, by determining the most significant clinical and functional indicators of the patient's condition, established as a result of statistical processing of data obtained by constructing contingency tables.

The technical result of the proposed method for predicting the development of pulmonary fibrosis in patients with interstitial lung diseases is achieved by evaluating risk factors - forced lung capacity, age and nosological form of the disease.

Distinctive techniques of the proposed method lie in the fact that additionally establish: the patient's gender, the presence and severity of shortness of breath, weight loss, asymptomatic course of interstitial lung disease, history of smoking, time of diagnosis, the presence of occupational and/or household hazards and/or systemic diseases of the connective tissue , a symptom of "drumsticks" and / or "watch glasses", end-inspiratory crepitus on auscultation, the level of blood oxygen saturation after exercise.

The main difference of the proposed method is that the value of the prognostic coefficient F is determined by the formula:

F=-0.25-0.3706*X ₁ +0.0431*X ₂ +0.0324*X ₃ +0.1159*X ₄ -0.3189*X ₅ +

0.0424*X ₆ -0.2273*X ₇ +0.0264*X ₈ -0.0832*X ₉ +0.0948*X ₁₀ +0.0955*X ₁₁ +0.0743*X ₁₂ +

0.2943*X ₁₃ +0.0932*X ₁₄ +0.0878*X ₁₅ , where:

X ₁ - the patient's age is less than or equal to 44 years: yes - 1 point, no - 0 points;

X ₂ - the patient's age is equal to or greater than 65 years: yes - 1 point, no - 0 points;

X ₃ - the patient's gender is male: yes - 1 point, no - 0 points;

X ₄ - the presence of shortness of breath 3-4 points on the mMRC scale: yes - 1 point, no - 0 points;

X - no shortness of breath: yes - 1 point, no - 0 points;

X ₆ - weight loss: yes - 1 point, no - 0 points;

X ₇ - asymptomatic course of interstitial lung disease: yes - 1

point, no - 0 points;

X ₈ - history of smoking: yes - 1 point, no - 0 points;

X ₉ - time of diagnosis less than 3 months from the onset of the disease: yes - 1 point, no - 0 points;

X ₁₀ - time of diagnosis 1 year or more from the onset of the disease: yes - 1 point, no - 0 points;

X ₁₁ - the presence of occupational and / or household hazards and / or systemic diseases of the connective tissue: yes - 1 point, no - 0 points;

X ₁₂ - a symptom of "drum sticks" and / or "watch glasses": yes - 1 point, no - 0 points;

X ₁₃ - end-inspiratory crepitus during auscultation: yes - 1 point, no - 0 points;

X ₁₄ - the level of blood oxygen saturation after exercise is less than or equal to 89%: yes - 1 point, no - 0 points;

X ₁₅ - forced vital capacity of the lungs is less than 80%: yes - 1 point, no - 0 points

and F equal to or greater than "0" predicts a high risk, and F less than "0" predicts a low risk of developing pulmonary fibrosis in a patient with interstitial lung disease.

A comparative analysis of the proposed technical solution and the prototype allows us to conclude that the proposed technical solution meets the invention criterion of "novelty".

From the analysis of the patent and special literature, the authors found that the proposed method has features that distinguish it not only from the prototype, but also from other technical solutions in this and related fields of medicine. In the available literature, the authors have not identified a way to predict the risk of developing pulmonary fibrosis in various ILDs.

As a result of the research and the subsequent construction of contingency tables, the authors of the proposed method have established 15 most significant indicators that affect the development of pulmonary fibrosis. To predict the risk of developing pulmonary fibrosis, the method of linear multivariate regression was applied. The final parameters of the regression model are presented in the table below.

The prognostic coefficient was calculated as the sum of the products of the factors and their weight coefficients.

The established parameters make it possible to predict the risk of developing pulmonary fibrosis at the onset of interstitial lung disease, while the accuracy of the prediction in the regression analysis for the group of ILD patients with pulmonary fibrosis was 92.3%. The probability of an error of the first kind (false positive conclusion) is 0.05; probability of error of the second kind (false negative conclusion) -0.13.

The advantages of the proposed method include the fact that in the proposed method the risk of developing pulmonary fibrosis is predicted at the onset of the disease, while expensive research methods are not used.

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

The method constituting the claimed invention is intended for use in healthcare, namely in pulmonology. The possibility of its implementation is confirmed by the methods and means described in the application. Clinical observations of the authors of the proposed method indicate that the use of the proposed method allows you to establish the risk of developing fibrosing course of ILD in patients with interstitial lung diseases, which in turn determines the severity of the disease and its prognosis. The foregoing gives reason to believe that the proposed technical solution meets the criterion of the invention "industrial applicability".

The essence of the proposed method for predicting the development of pulmonary fibrosis in patients with interstitial lung diseases is illustrated by examples of a specific implementation. The following examples serve to illustrate, but do not limit the present invention.

Example #1.

Patient B., 65 years old, was consulted at the respiratory center in Irkutsk. Complaints of shortness of breath with little exertion (mMRC-3 points), unproductive cough, severe general weakness, fever up to 39.0°C, weight loss by 7 kg in 3 months. He considers himself ill for 2 months. From the anamnesis, it was established that the manifestations of rheumatoid arthritis (RA) in the patient were more than 20 years old, but the diagnosis was established 10 years ago; She received basic therapy irregularly, for 2 years she has been taking methotrexate 15 mg weekly. I do not smoke. Denies professional and domestic adverse effects. Suffering from coronary heart disease, arterial hypertension, for which he regularly takes perindopril, bisoprolol, rosuvostatin and acetylsalicylic acid. An objective examination revealed flexion contractures of the wrist joints. Deformity of the terminal phalanges of the fingers, crepitus during auscultation were not established. The level of blood saturation with oxygen (SpO ₂ )=92%. The study of the function of external respiration: FVC=82%.

Upon admission, the patient B. was examined, the results of high-resolution computed tomography (HRCT) of the chest are presented in figures 1-2, where: in Fig. 1 - computed tomography of the lungs in the axial projection; in fig. 2 - computed tomography of the lungs in the sagittal projection, where 1 - zones of the greatest intensity of "ground glass". There are no signs of pulmonary fibrosis. Based on clinical and radiological data, patient B. was diagnosed with "Methotrexate-induced interstitial lung disease. Respiratory failure (RD) 1. No respiratory dysfunction (RF)”.

When examining patient B., the following risk factors for the development of pulmonary fibrosis were established: age 65 years, severe shortness of breath, weight loss, the presence of RA. Also, one factor has been established that reduces the likelihood of developing pulmonary fibrosis - the period of diagnosis is less than 3 months. Other risk factors were '0'.

According to the established risk factors, the prognostic coefficient F was calculated using the formula:

F=-0.25-0.3706*0+0.0431*1+0.0324*0+0.1159*1-0.3189*0+0.0424*1-0.2273*0+0 .0264*0-0.0832*1+0.0948*0+0.0955*1+0.0743*0+0.2943*0+0.0932*0+0.0878*0=-0, 25-0.0431+0.1159+0.0424-0.0832+0.0955=-0.1225.

The resulting value of the prognostic coefficient F is less than "0", which made it possible to predict a low risk of developing pulmonary fibrosis.

HRCT of the chest, performed 12 months after the end of conventional therapy for drug-induced ILD and discontinuation of methotrexate, showed no evidence of pulmonary fibrosis (Fig. 3-4). In FIG. 3 - computed tomography of the lungs in the axial projection; fig. 4 - computed tomography of the lungs in the sagittal projection. There are no signs of pulmonary fibrosis.

Example #2.

Patient Z., 59 years old. Denies professional and domestic adverse effects. Smokes, intensity of smoking 30 pack/years. In 2011, she underwent treatment for breast cancer (sectoral resection, polychemotherapy (PCT), she cannot indicate the name of the drugs). In August 2018, the disease recurred, and PCT (paclitaxel, trastuzumab) was prescribed again. In October 2018, after the second course of PCT, dry cough, progressive dyspnea, fever up to 38°C, weakness appeared. Conducted HRCT of the chest (Fig. 5-6). In FIG. 5 - computed tomography of the lungs in axial projection, in Fig. 6 - computed tomography of the lungs in the coronal projection, where: 1 - zones of the greatest intensity of "ground glass", 2 - diffuse thickening of the interlobular septa. There are no signs of pulmonary fibrosis.

Patient Z. was hospitalized in the therapeutic department with a diagnosis of community-acquired bilateral polysegmental pneumonia of severe severity.

Against the background of intensive antibiotic therapy carried out for one month, the state with negative dynamics. Based on an integrative assessment of the patient's profile, in December 2018, the diagnosis was made: "Drug-induced acute interstitial pneumonia against the background of chemotherapy." At the time of diagnosis, the patient's condition was extremely severe, dyspnea on the mMRC scale was 4 points, SpO ₂ <70% (breathing was carried out using a ventilator), gross crepitus was determined in the lungs on both sides. There was no deformity of the terminal phalanges of the fingers. Due to the severity of the condition of patient Z., it was impossible to assess FVC.

As a result of the examination, 5 risk factors were found in patient Z. that increase the likelihood of developing pulmonary fibrosis: shortness of breath on the mMRC scale - 4 points, smoking, the presence of a drug effect that has a potential pneumotoxic effect (according to the pneumotox.com website; included in the concept of "household adverse exposure"), end-inspiratory crepitus on auscultation, SpO ₂ =70% and one reducing factor - the time of diagnosis of ILD was less than 3 months from the onset of the disease. Other risk factors were '0'.

To predict the risk of developing pulmonary fibrosis in patient Z., the coefficient F was calculated:

F=-0.25-0.3706*0+0.0431*0+0.0324*0+0.1159*1-0.3189*0+0.0424*0-0.2273*0+0 .0264*1-0.0832*1+0.0948*0+0.0955*1+0.0743*0+0.2943*1+0.0932*1+0.0878*0=-0, 25+0.1159+0.0264-0.0832+0.0955+0.2943+0.0932=0.2921.

The resulting prognostic coefficient F is greater than "0", which made it possible to predict a high risk of developing pulmonary fibrosis at the onset of the disease.

According to HRCT of the chest, carried out after 7 months of conventional therapy for LIIL (drug-induced interstitial lung disease), patient Z. was diagnosed with pulmonary fibrosis, predominant in the basal sections of both lungs (Fig. 7-8). In FIG. 7 shows computed tomography of the lungs in axial projection, FIG. 8 - computed tomography of the lungs in the sagittal projection: 3 - areas of pulmonary fibrosis.

The claimed method for predicting the risk of developing pulmonary fibrosis is based on statistical processing of a sample of data from 270 patients with various ILDs included in the ILD register of the city of Irkutsk. All patients underwent collection of complaints and anamnesis, objective examination, examination of respiratory function and HRCT. All cases of ILD were confirmed by the results of a multidisciplinary discussion. Out of 270 patients, 104 patients had signs of pulmonary fibrosis.

ILD was classified as fibrosing on the basis of chest computed tomography data for the previous 12 months if at least 10% of the lung volume of reticular changes was detected in combination with traction bronchiectasis and / or "honeycomb lung" (Nintedanib in progressive fibrosing interstitial lung diseases / K.R. Flaherty, A.U. Wells, V. Cottin [et al.] // N. Engl. J. Med. - 2019. - No. 381. - C. 1718-1727).

Fibrosing ILDs were dominated by ILD associated with RA and systemic scleroderma (SSD), chronic hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, and nonspecific interstitial pneumonia. Among 166 cases of ILD without fibrosis, the following prevailed: sarcoidosis; ILD associated with systemic connective tissue diseases other than RA and SJS; LIIZL and rare IZL.

For each patient included in the register, the coefficient F was calculated at the time of the first visit to the doctor about respiratory pathology, and the correspondence between the F value and the presence of pulmonary fibrosis during the period of advanced clinical manifestations was assessed.

The accuracy of the forecast during the regression analysis was 90.4%. Including, for the group of patients with ILD with pulmonary fibrosis - 92.3% and for patients with ILD without pulmonary fibrosis - 89.2%.

Thus, the claimed method, based on clinical and functional data widely available in routine practice, makes it possible to predict the development of pulmonary fibrosis at the onset of ILD.

Claims (20)

A method for predicting the development of pulmonary fibrosis in patients with interstitial lung diseases by assessing risk factors - forced vital capacity of the lungs, age and nosological form of the disease, characterized in that it determines the patient's gender, the presence and severity of dyspnea, weight loss, asymptomatic interstitial lung disease, smoking in history, time of diagnosis, presence of occupational and/or household hazards and/or systemic connective tissue diseases, "drumsticks" and/or "watch glasses" symptom, end-inspiratory crepitus on auscultation, blood oxygen saturation level after exercise, then determine the value of the prognostic coefficient F by the formula: F=-0.25-0.3706*X ₁ +0.0431*X ₂ +0.0324*X ₃ +0.1159*X ₄ -0.3189*X ₅ +0.0424*X ₆ - 0.2273*X ₇ +0.0264*X ₈ -0.0832*X ₉ +0.0948*X ₁₀ +0.0955*X ₁₁ + 0.0743*X ₁₂ +0.2943*X ₁₃ +0.0932*X ₁₄ +0.0878*X ₁₅ , where X ₁ - the patient's age is less than or equal to 44 years: yes - 1 point, no - 0 points; X ₂ - the patient's age is equal to or greater than 65 years: yes - 1 point, no - 0 points; X ₃ - the patient's gender is male: yes - 1 point, no - 0 points; X ₄ - the presence of shortness of breath 3-4 points on the mMRC scale: yes - 1 point, no - 0 points; X ₅ - no shortness of breath: yes - 1 point, no - 0 points; X ₆ - weight loss: yes - 1 point, no - 0 points; X ₇ - asymptomatic course of interstitial lung disease: yes - 1 point, no - 0 points; X ₈ - history of smoking: yes - 1 point, no - 0 points; X ₉ - time of diagnosis less than 3 months from the onset of the disease: yes - 1 point, no - 0 points; X ₁₀ - time of diagnosis 1 year or more from the onset of the disease: yes - 1 point, no - 0 points; X ₁₁ - the presence of occupational and / or household hazards and / or systemic diseases of the connective tissue: yes - 1 point, no - 0 points; X ₁₂ - symptom of "drum sticks" and/or "watch glasses": yes - 1 point, no - 0 points; X ₁₃ - end-inspiratory crepitus during auscultation: yes - 1 point, no - 0 points; X ₁₄ - the level of blood oxygen saturation after exercise is less than or equal to 89%: yes - 1 point, no - 0 points; X ₁₅ - forced vital capacity of the lungs is less than 80%: yes - 1 point, no - 0 points, and F equal to or greater than "0" predicts a high risk, and F less than "0" predicts a low risk of developing pulmonary fibrosis in a patient with interstitial lung disease.

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