RU2523888C1 - Method for prediction of progression of cystic fibrosis diagnosed by neonatal screening - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention describes a method for prediction of progression of cystic fibrosis diagnosed by neonatal screening taking into account sex, age; values of haemoglobin, leukocytes, alanine transaminase, aspartate transaminase, C-reactive protein; type of bacterial flora in nasal and pharyngeal smears, sweat chloride test to determine a prognostic coefficient of progression of cystic fibrosis (Kpcf) with using a regression equation: Kpcf=3.21946+0.526873*sex - 0.0488185*age - 0.0125638*haemoglobin+0.0302588*leukocytes - 0.0418016*alanine transaminase+0.00832224*aspartate transaminase+0,0736644*CRP+; 0.238719* nasal flora+0.442044* pharyngeal flora - 0.00669528*sweat chlorides, wherein: sex - 1 for boys, 0 for girls; age - completed months at the moment of examination; haemoglobin is peripheral blood haemoglobin, gram per litre, leukocytes is leukocyte count in cubic millimetre of peripheral blood; alanine transaminase is venous blood alanine transaminase, units per litre; aspartate transaminase is venous blood aspartate transaminase, units per litre; CRP is C-reactive protein, milligram per litre; nasal flora and pharyngeal flora is a type of bacterial flora in nasal smears and pharyngeal smears: 1 streptococcus, 2 Pseudomonas Aureginosa; 3 staphylococcus; 4 fungi; 5 no flora growth found (a smear is sterile); 6 enterococcus; 7 corynebacteria; 8 Neisseria; 9 acinetobacteria; 10 Escherichia coli; 11 Citrobacter; 12 Klebsiella; 13 Stenotrophomonas; 14 Haemophilus influenzae; 15 moraxella; 16 other types of flora; sweat chlorides is sweat chlorides, mmole/l; if the coefficient is less than 2.3, the course of the disease is predicted to be positive; if the coefficient is 2.3 and more, cystic fibrosis is predicted to aggravate.EFFECT: method enables reducing time consumption, requires no highly experienced doctors to be involved; it has the high accuracy and specificity.1 tbl, 2 ex

Description

The invention relates to medicine, in particular to pediatrics, can be used to predict the dynamics of the course of cystic fibrosis in children.

Today, it is widely accepted that cystic fibrosis disease is genetically determined by mutation of the CFTR gene (cystic fibrosis transmembrane conductivity regulator), is associated with damage to vital organs caused by impaired function of the exocrine glands of the body. The disease usually has a severe course and prognosis [V. Nikonova. Clinical efficacy and safety of inhaled antibacterial therapy in children with cystic fibrosis infected with Pseudomonas aeruginosa: abstract. diss. Ph.D., Moscow, 2012]. The interpretation of the postulate about the usual or severe prognosis and course in most known sources does not have a specific description, criteria for assessing the severity, or guidelines to assess the percentage of probability for a patient individually of a variant of the severe course of cystic fibrosis.

Among the sources containing detailed schemes for determining the prognosis and severity of cystic fibrosis, the following can be distinguished.

A known method for diagnosing a variant of the course of cystic fibrosis associated with a septic infection [application RU 2010150417 of 12/08/2010], according to which anamnestic data are clarified initially in children with cystic fibrosis with a pulmonary septic infection and a comprehensive immunological examination is carried out. Assess the level of lysozyme activity of blood serum, bactericidal activity of blood serum, C3 component of complement, concentration of interleukins: IL-1, IL-4, IL-6, IL-8, IFN and if the patient has a previous colonization of the respiratory tract with Pseudomonas aeruginosa, reducing bactericidal blood serum activity, C3 complement component relative to control parameters (25.1 ± 3.1%, 1.41 mg / ml, respectively), decrease or compliance with control indicators (7.9 ± 0.3 μg / ml) of serum lysozyme activity hyperproductions itokines: IL-4: 4-5-fold increase relative to the control indicators, IL-6: 5-10-fold increase relative to the control indicators, IL-8: more than 20-fold increase relative to the control indicators, against the background of a decrease or normal values relative to control indicators IFN- and IL-1 diagnose the fulminant course of the disease, and with an increase in the level of lysozyme activity of blood serum, the bactericidal activity of blood serum, the C3 component of the complement relative to the control indicators, 2-3 times increased eniya relative benchmarks production of cytokines IL-4, IL-6, IFN and IL-1 and 5-6 fold increase relative to benchmarks IL8 variant diagnose stable course of disease.

The disadvantages of the method: to carry out the forecast, it is necessary to simultaneously take into account the fluctuation ranges of many indicators, which makes the method difficult to apply in practice.

A known method for assessing the severity of cystic fibrosis in children (US Pat. RU 2441244, publ. 01.27.2012). The method consists in determining the content of matrix metalloproteinase-7 (MMP-7) in the patient's plasma. With MMP-7 values from 7.0 ng / ml and higher, the severity of cystic fibrosis is assessed as severe, with values from 5.0-7.0 ng / ml as average, with values of 2.0-5.0 ng / ml as easy. Using the method allows to increase the accuracy of diagnosis of the severity of pneumofibrosis in children with cystic fibrosis.

The disadvantages of the method: only one indicator is selected as a criterion, which is extremely insufficient and unreliable for such a multi-level and complex organization system as a human body.

A known method for assessing the course of a chronic inflammatory process in the bronchopulmonary system of a patient with cystic fibrosis (US Pat. RU No. 2216737, publ. 20.11.2003). The authors determine the level of alpha1-proteinase inhibitor and elastase activity in the patient’s sputum, characterized in that they additionally determine the levels of interleukin 8 and tumor necrosis factor-alpha and calculate the diagnostic coefficient K by the formula K = A + B + C / D, where A is the level interleukin-8; B - tumor necrosis factor-alpha level; C is the level of alpha1-proteinase inhibitor; D is the activity of elastase, and for values of 2.5 <K <5.5, the course of the chronic inflammatory process in the bronchopulmonary system is assessed as moderate to minimal activity, at 6.0 <K <9.0 - as moderate during exacerbation, and when K > 9.0 - how heavy.

The disadvantages of the method: as criteria for assessing the severity of the selected indicators, changes which are not specific for cystic fibrosis, their level depends on the pathological processes associated with immune disorders.

EFFECT: development of a method for predicting the dynamics of the course of cystic fibrosis in young children, based on the use of standard indicators determined by screening examination, which reduces the time spent, which does not require the participation of highly qualified doctors, which has high accuracy and specificity.

The technical result is achieved by determining the following indicators during neonatal screening of cystic fibrosis in children: gender, age in months, the level of hemoglobin and leukocytes in peripheral blood, the level of alanine aminotransferase (AlAT), aspartate aminotransferase (AsAT), C-reactive protein in venous blood , bacterial flora in nasal swabs and throat swabs, sweat chloride levels.

Using regression control, determine the coefficient of prognosis of the dynamics of the course of cystic fibrosis (Cdm).

Kdm = 3.21946 + 0.526873 * gender - 0.0488185 * age - 0.0125638 * hemoglobin + 0.0302588 * leukocytes - 0.0418016 * AlAT + 0.00832224 * AsAT + 0.0736644 * CRP +; 0.238719 * flora from the nose + 0.442044 * flora from the pharynx - 0.00669528 * chloride of sweat,

where: gender - for boys is indicated by the number 1, for girls by the number 0; age - the number of full months at the time of the survey; hemoglobin - the level of hemoglobin in peripheral blood in grams per liter, leukocytes - the number of leukocytes in a cubic millimeter of peripheral blood; AlAT is the level of alanine aminotransferase in venous blood in units per liter; AsAT - the level of aspartate aminotransferase in venous blood in units per liter; CRP is the level of c-reactive protein in milligrams per liter; flora from the nose and flora from the pharynx - the type of bacterial flora in smears from the nose or pharynx: 1 - streptococcus, 2 Pseudomonas aeruginosa; 3 staphylococcus; 4 mushrooms; 5 no flora growth (smear sterile); 6 enterococcus; 7 corinobacteria; 8 neiseria; 9 acinetobacter; 10 E. coli; 11-cytrobacter; 12 Klebsiella; 13 sternotofomonas; 14 hemophilia bacillus; 15 moraxella; 16 other species of flora; sweat chlorides - the level of sweat chlorides in mmol / L.

The equation was obtained by observing for at least five years thirty-one children with cystic fibrosis, with a mixed and predominantly pulmonary form, in whom cystic fibrosis was detected by neonatal screening.

The diagnosis of cystic fibrosis was made in accordance with the recommendations of the Republican program to improve the diagnosis, treatment and medical and social care for patients with cystic fibrosis (1998), which corresponds to the International Classification of Diseases (ICD), tenth revision (ICD-X), prepared by the WHO World Health Organization ( Geneva, 1992).

Clinical observations and special studies were carried out using general clinical, clinical, laboratory, biochemical, genetic, instrumental and bacteriological studies performed at the clinical bases of the Voronezh Medical Academy named after N.N. Burdenko at hospitals in Voronezh and the clinical base of the regional center of cystic fibrosis. Biochemical tests according to the neonatal screening program and genetic testing were carried out in the Interregional Medical and Genetic Center of Voronezh.

During the initial examination in children, the above indicators were determined, along with other generally accepted during clinical examination. During the constant dynamic observation in children for five years, the dynamics of the clinical course of cystic fibrosis against the background of the treatment was noted.

According to the results of a five-year observation, it was found that children can be divided into two groups according to the indicator we called “the type of dynamics of the clinical course”. The first group consisted of children who had a stable course of cystic fibrosis, that is, a course without negative dynamics, the second group consisted of children with deterioration in different periods of observation - from one to four years from the time of diagnosis. Using the indicator “type of clinical course dynamics” as a dependent, and the indicators measured at the initial examination as influencing, we constructed a regression equation that allows us to predict the indicator of interest to us. The determination coefficient R2 of the constructed model was 84.768%.

When calculating the forecast coefficient for the dynamics of the course of cystic fibrosis (Kdm) according to the management proposed by us, it was found that the average value for Kdm in the group without negative dynamics was 2.039062, in the group with a worsening state of 2.919052 (see table).

Table
The average values of the coefficients of the regression model of children with cystic fibrosis in the neonatal screening group using the data obtained during registration Type of clinical course dynamics average value average error maximum value minimum value without negative
dynamics 2.039062 0.205561 2,30505 1,676162 deterioration 2.919052 0.22928 3,179648 2,601513

Thus, in predicting the dynamics of the clinical course of cystic fibrosis in children, in order to timely and adequate choice of the course of treatment, the following rule should be used. When calculating the forecast coefficient for the dynamics of the course of cystic fibrosis (Cdm), if a value of less than 2.3 is obtained, then the disease will proceed without negative dynamics; if the coefficient is 2.3 or more, then a worsening of the condition should be expected, more careful approach to the appointment of a course of therapy.

Examples of clinical use.

Patient D., medical history No. 1033, 06/21/2007 year of birth, was in the III department of the Regional Children's Clinical Hospital No. 2 of the city of Voronezh in the center of cystic fibrosis from 07.23.2007 to 08.08.2007.

Clinical diagnosis: Cystic fibrosis, mixed form, severe course. Exocrine pancreatic insufficiency. Protein-energy deficiency, I degree. Heterozygote according to del F 508.

Hereditary history. On the mother's side, relatives have diseases of the gastrointestinal tract (colitis, gastritis). According to the father, there are indications of the presence of chronic bronchopulmonary diseases, peptic ulcer, intestinal diseases in relatives.

Medical history. The diagnosis of cystic fibrosis was established in the center of cystic fibrosis at the age of 1 month, confirmed by the result of a sweat test, sweat chloride - 121 mmol / L and DNA diagnostics - homozygous carriage of del F508 mutation.

According to the mother, the child from birth had unstable stools, frequent up to 6-8 times a day, plentiful, with an unpleasant odor, with droplets of fat, paroxysmal, unproductive, dry cough, poor weight gain with increased appetite attracted attention.

Screening results for screening for cystic fibrosis: age one month, hemoglobin 116 g / l, white blood cells 4.7 x 109, AlAT - 21 units / l; AsAT - + 18 units / l; CRP 1.0; inoculation of nasal swabs - streptococci; sowing throat swabs - streptococci; sweat chlorides 89.00 mmol / l.

The forecast coefficient for the dynamics of the course of cystic fibrosis 2.6969 is the course of cystic fibrosis with worsening condition.

Chest x-ray: the roots of the lungs are significantly widened, densified, structureless due to severe changes in the bronchi and fibrosis. A sharp increase and deformation of the bronchial pattern throughout the lungs.

Assigned basic and symptomatic therapy. Monitoring in the first year of life is recommended monthly, then every three months.

As of October 2010, there was a negative trend in the course of cystic fibrosis. In the first year of hospitalization for an exacerbation of the disease - six times, the average length of hospital stay at each hospitalization is 10 days. In the second year, five hospitalizations with an average hospital stay of 14 days. On the part of the respiratory system - the progression of chronic purulent bronchitis, the child has been operated on twice for intestinal obstruction.

In the third year of observation, the number of hospitalizations is 5, the average duration is 14 days. Clinical and laboratory indicators worsened, body weight deficiency, increased respiratory failure.

Progression of pulmonary fibrosis. The dynamics of the clinical course obtained with the use of our forecasting method with a worsening condition is confirmed by clinical and laboratory data.

Patient M., 4 years old, medical history No. 1652, September 1, 2008, was in the III department of the Regional Children's Clinical Hospital No. 2 of the city of Voronezh in the center of cystic fibrosis from 12/12/2008. November 11, 2008

Clinical diagnosis: cystic fibrosis, mixed form, severe course. Exocrine pancreatic insufficiency. Protein-energy deficiency, I degree. Heterozygote according to del F 508.

Hereditary history. Heredity is burdened: the mother has chronic bronchitis, the maternal grandmother has bronchial asthma, and the father’s relatives are healthy.

Medical history. The diagnosis of cystic fibrosis was made at the center of cystic fibrosis at the age of 2 months, confirmed by the result of a sweat test, sweat chloride - 95 mmol / l and DNA diagnostics - homozygous carriage of del F508 mutation.

Screening results for screening for cystic fibrosis: age five months, hemoglobin 152 g / l, white blood cells 7 x 109, AlAT - 38 units / l; AsAT - 40 units / l; CRP 1.0; inoculation of nasal swabs - streptococci; sowing smears from the throat - there is no growth of flora; sweat chlorides 120.00 mmol / l.

The forecast coefficient for the dynamics of the course of cystic fibrosis 2.2679 - the course of cystic fibrosis without negative dynamics, clinically stable.

Chest x-ray - a picture of bronchial obstruction.

As of October 2011, a clinically stable course of cystic fibrosis was noted. In the first year of hospitalization for an exacerbation of the disease, two, the average length of hospital stay at each hospitalization is 10 days. In the second year and the third year of observation, there were two hospitalizations, with an average hospital stay of 10 days. From the respiratory system, the picture of bronchial obstruction without significant changes. Lag in physical development.

The dynamics of a stable clinical course obtained using our forecasting method is confirmed by clinical and laboratory data.

Claims (1)

 A method for predicting the dynamics of the course of cystic fibrosis detected by neonatal screening, based on gender, age, hemoglobin, leukocytes, ALAT, ASAT, C-reactive protein, the type of bacterial flora in nasal swabs and in swabs from the throat, the level of sweat chloride, different the fact that they determine the forecast coefficient for the dynamics of the course of cystic fibrosis (Cdm) using regression control: Cdm = 3.21946 + 0.526873 * gender - 0.0488185 * age - 0.0125638 * hemoglobin + 0.0302588 * leukocytes - 0.0418016 * AlAT + 0.00832224 * AcAT + 0.0736644 * CRP +; 0.238719 * flora from the nose + 0.442044 * flora from the pharynx - 0.00669528 * sweat chlorides, where: gender - for boys, the number 1, for girls, the number 0; age - the number of full months at the time of the survey; hemoglobin - the level of hemoglobin in peripheral blood in grams per liter, leukocytes - the number of leukocytes in a cubic millimeter of peripheral blood; AlAT is the level of alanine aminotransferase in venous blood in units per liter; AsAT - the level of aspartate aminotransferase in venous blood in units per liter; CRP is the level of c-reactive protein in milligrams per liter; flora from the nose and flora from the pharynx - a type of bacterial flora in smears from the nose or pharynx: 1 streptococcus, 2 Pseudomonas aeruginosa; 3 staphylococcus; 4 mushrooms; 5 no flora growth (smear sterile); 6 enterococcus; 7 corinobacteria; 8 neiseria; 9 acinetobacter; 10 E. coli; 11 citrobacter; 12 Klebsiella; 13 sternotofomonas; 14 hemophilia bacillus; 15 moraxella; 16 other species of flora; sweat chlorides - the level of sweat chlorides in mmol / l; if the coefficient is less than 2.3, the course of the disease is predicted without negative dynamics; if the coefficient is 2.3 or more, the course of cystic fibrosis is predicted with a worsening condition.