RU2389025C1 - Method of forecasting of recurrent course of laryngotracheitis in children - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: initially anamnestic data and clinical features of laryngotracheitis are specified, microbiological and virological studies are conducted in a smear from posterior pharyngeal wall, level of cytokines is determined (interleukine-4, interleukine-6, interferon-α, interferon-γ) and general IgE in peripheral blood, and at presence in a child the following symptoms: allergic pathology in case history, effuse of Streptococcus agalacticae, viral-viral and bacterial-bacterial associations, development of croup syndrome up to 2 stage, reducing of red blood cell level <2.9*10 billion/l and hemoglobin <89 g/l in clinical blood analysis, as well as determining the level of cytokines in peripheral blood: interleukine-4 is higher than 14.8 ng/ml, interleukine-6 is higher than 16.1 ng/ml, interferon-α is higher than 147.8 ng/ml, interferon-γ is lower than 16.9 ng/ml; the level of total IgE in the serum is higher than 47.0, relapsing course is predicted. Using the method enables to determine characteristics of the course of laryngotracheitis in children at an early stage, to take adequate programs of anti-recidivating treatment and conduct targeted immunotherapy.

EFFECT: reduction in frequency of laryngotracheitis recuring in children.

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Description

The invention relates to medicine, namely to pediatrics, and can be used to predict the recurrent course of laryngotracheitis in children.

In recent years, there has been a clear tendency to increase the frequency of repeated episodes of laryngotracheitis in children, which not only complicates the course of a respiratory disease, but can also lead to a life-threatening condition (“false” croup) [Grishkina L.Yu., 1995, Karpov V .V., Safronenko L.A., 1999, Uchaykin V.F., et al., 1999, Namazova L.S., et al., 2004, Orlova S.N., Ryvkin A.I., 2008, Lekomtseva OI, Grishkin I.G., 2008, Litmanovitch M., 1990, Nikolai T., 1996, Kovacevic S., 2000].

Recurrence of laryngitis / laryngotracheitis in childhood contributes to the formation of chronic inflammatory processes and hyperresponsiveness of the upper respiratory tract, adversely affects the maturation of the child’s immune system, which leads to the development of secondary immunosuppression [Korovina N.A., 2001, Zaitseva O.V., 2004, Uchaykin V.F., 2005, Malakhov A.B., et al., 2007, Makarova Z.S., et al., 2007, Bellanti JA, 1997]. Each new respiratory infection provokes more and more serious disorders of the immune system, contributing to the formation of both chronic inflammatory diseases of the pharynx and respiratory allergies [Torshkhoeva P.M. et al., 2006, Egorov VB, et al., 2008].

Currently, in available sources of domestic and foreign literature, we have not found statistically reliable methods for predicting the course of laryngotracheitis in children. This may be due to the fact that the pathogenetic basis of relapse has not yet been fully disclosed. The lack of methods for predicting the course of laryngotracheitis makes it impossible to develop adequate methods of anti-relapse treatment.

At the same time, certain anamnestic features and trends of immunological disorders (including the level of cytokines in peripheral blood) were revealed in children with acute and relapsing course of laryngotracheitis (Pathogenetic rationale and advantages of treatment of acute respiratory infections with croup syndrome in children Claratadin. / F.S. Kharlamova , V.Yu. Krylatykh, TP Legkova et al. // Children's infections. - 2003. - No. 1 (2). - P.36-40. Effective treatment of croup syndrome with the help of the Gepon immunomodulator. / O.V. Kladova, F.S. Kharlamova, A.A. Shcherbakova and others // Russian Medical Journal. - 20 02. - Volume 10. - No. 3 (147). - S.138-141). In addition, there are known methods for determining the prognosis of the course of the disease (acute and recurrent), based on the assessment of the level of cytokines in peripheral blood, in particular, a method for predicting the course of reactive arthritis in children (Cherkasov N.S., Antonova A.A. Patent for invention No. 2322677 from 04/20/2008, "A method for predicting the nature of the course of reactive arthritis in preschool children").

However, this approach was not used to predict the course of laryngotracheitis, and the noted features were not statistically significant, which did not allow the authors to consider them as prognostic factors significant for predicting the course of the disease.

The disadvantages of the known analogues are:

- the lack of an adequate integrated approach that takes into account the importance of anamnestic, microbiological, clinical and immunological factors for the implementation of the relapsing course of laryngotracheitis in children;

- lack of objective prognostic factors of the recurring course of the disease, calculated using statistical research methods.

The inventive method for predicting the recurrent course of laryngotracheitis is new and is not described in the literature.

The aim of the invention is the early identification of pediatric patients threatened by the development of the relapsing course of laryngotracheitis, the justification of the methods of anti-relapse, including immunocorrecting, treatment and reducing the frequency of recurrence of laryngotracheitis in children.

The goal is achieved by initially clarifying the anamnestic data and clinical features of laryngotracheitis; conduct microbiological and virological studies in a smear from the posterior pharyngeal wall by PCR, serological or luminescent microscopy; determine the level of cytokines IL-4, IL-6, IFNα, IFNγ; determine the level of total IgE in peripheral blood; a general blood test is performed and if there is a history of allergic pathology, the detection of Streptococcus agalacticae, virus-viral or bacterial-bacterial associations, the development of croup syndrome to 2 degrees, a decrease in the level of red blood cells <2.9 × 10 billion / l and hemoglobin <89 g / l, IL-4 content above 14.8 ng / ml, IL-6 above 16.1 ng / ml, IFNα above 147.8 ng / ml, IFNγ below 16.9 ng / ml, total IgE level above 47.0 IU / ml predict a relapse.

Recently, there has been a pronounced tendency to increase the frequency of recurrence of laryngotracheitis in children. So, according to the Regional Children's Clinical Hospital of the city of Astrakhan, 44 children were hospitalized for recurrent laryngotracheitis in 2005, in 2007 - 87 children, in 2007 - 104 children. Diseases are often difficult, complicated by the development of croup syndrome of varying severity. Severe stages of laryngotracheitis can be fatal.

The relapsing course of laryngotracheitis in children helps maintain a chronic inflammatory process in the upper respiratory tract, the formation of chronic foci of infection, the development of allergic inflammation, and provokes impaired immune homeostasis. Further weakening of the body's defenses leads to frequent repeated infectious diseases, a delay in the physical and psychomotor development of children.

The issues of predicting the course of laryngotracheitis in children have been and remain very relevant at present. Solving these issues would contribute to a differentiated approach to the choice of rehabilitation methods and anti-relapse treatment for children with recurrent laryngotracheitis. In addition, this would highlight the risk group among children with the first episode of the disease, who are threatened by the occurrence of relapses of laryngotracheitis in the future.

The key link in resolving the issue can be the use of prognostic criteria to determine the level of cytokines and total immunoglobulin E in peripheral blood, since the modern concept of the pathogenesis of recurrent croup involves the combined action of multiple trigger factors (including infectious, allergic, etc.) against a background of an immunological response with a predominance of Th2 immune response.

The technical result of the claimed invention is a reasonable allocation among children with the first episode of laryngotracheitis of the risk group for the recurrence of the disease in the future, the development of anti-relapse treatment methods, the implementation of timely and adequate immunocorrective therapy.

In addition to generally accepted clinical and laboratory diagnostic methods, we used an additional examination scheme, including the determination of RNA and DNA viruses in a smear from the surface of the tonsils, palatine arches and posterior wall of the oropharynx by polymerase chain reaction (PCR), and antigenic substances of a viral nature in a nasal smear by luminescence microscopy, the formation of specific antiviral antibodies of the IgM class and the increase of their titer using the formulation of serological reactions, bacteriological studies, determination of the level I have pro- and anti-inflammatory cytokines (IL-4, IL-6, IFNα, IFNγ) and total immunoglobulin E in serum.

The choice of immunological diagnostic methods was determined by their sufficient information content described by other authors, their availability for a large number of laboratories of medical institutions, and the relatively low cost of examination, which together should contribute to the wide practical use of the results of our work.

To make an individual forecast for the development of the disease in children, the method of mathematical modeling was used, based on the principles of calculating prognostic factors (PC). The PC value was calculated using the informational version of the Bayes formula. Computer processing was carried out according to the method proposed by A.A. Dzhumagaziev et al. (2001). Prediction coefficients were combined into a forecast table.

We evaluated the prognostic significance of anamnestic, clinical and laboratory factors, as well as the significance of changes in the level of individual cytokines and total immunoglobulin E in peripheral blood for the development of repeated episodes of the disease.

The studied factors, taking into account the obtained prognostic coefficients (PC), were classified according to the degree of significance into: negative, weakly associative and significantly affecting the development of the recurrent course of laryngotracheitis (LT). For weakly associating signs with a PC less than 5.0 were taken. Factors with a PC over 5.0 were defined as significant or significant for the implementation of the relapsing course of RT.

As a result of statistical processing of the obtained results (Table 1), it turned out that a number of factors play a significant role for the development of the relapsing course of RT. These include: a history of allergic pathology (PK = 7.71), development of croup syndrome up to grade 2 (PK = 8.96), seeding with a microbiological study of Streptococcus agalacticae (PK = 7.71) and bacterial-bacterial associations (PK = 5.95), isolation of viral-virus associations (PC = 7.71) using virological methods, as well as the level of red blood cells in the general blood test below 2.9 × 10 billion / l (PC = 7.78) and the level hemoglobin <89 g / l (PK = 8.46).

A significant effect on the recurrent course of laryngotracheitis is also exerted by a change in the level of cytokines, in particular: the level of IL-4 in peripheral blood above 14.8 ng / ml (PK = 12.64), the level of IL-6 in peripheral blood above 16.1 ng / ml (PC = 6.99), IFNα level above 147.8 ng / ml (PC = 7.11), IFNγ level below 16.9 ng / ml (PC = 8.83), total serum IgE level above 47.0 IU / ml (PC = 7.35).

The proposed method for predicting the course of laryngotracheitis has been successfully tested by us in 95 children with acute and recurrent laryngotracheitis who are being treated at the State Children's Clinical Hospital "OIKB" and the Department of Allergology and Immunorehabilitation of the CSTO in Astrakhan, aged 2 to 13 years.

Below are the results of testing.

Example 1. Fedor K., 3 years old (born September 7, 2004).

Date of receipt: 10/20/2007.

Date of discharge: 01.11.2007.

Diagnosis: Acute respiratory viral infection (clinically) of moderate severity. Laryngotracheitis. Croup 2 tbsp. DN 1 degree.

Received complaints of difficulty breathing, coughing, hoarseness, fever, runny nose, nasal congestion.

A child from the group of frequently ill children. Initially, upon admission, it was noted that a similar episode of laryngotracheitis with ARVI occurred 6 times this year. The boy suffers from seasonal allergic rhinitis.

From the anamnesis: he fell ill acutely, from a rise in temperature to febrile numbers, a runny nose. Treated at home independently by symptomatic means. On the third day of the disease, a barking cough, hoarseness of the voice appeared. At night, the child's condition began to worsen: there was rapid noisy breathing, difficulty breathing. A child in an ambulance delivered to the DEC.

At admission: a serious condition, restless. Moody, lethargic. The appetite is sharply reduced. No vomiting. Meningeal symptoms are negative. The voice is hoarse. Temperature 38.9 °. A child of hypersthenic physique, with the phenomena of paratrophy. Marked pallor of the skin and visible mucous membranes, cyanosis of the nasolabial triangle was noted. Breathing is noisy, with participation in the act of breathing intercostal muscles. Retraction on inspiration of the jugular fossa is noted, inhalation is difficult. During auscultation, hard breathing is heard in the lungs, no wheezing, BH - 56 per minute. Percussion over the lungs is a pulmonary sound with a boxy tint. Heart sounds are muffled, heart rate - 144 beats per minute. The abdomen is soft, painless on palpation. Liver, spleen not enlarged. Urination is free. The chair is designed, without pathological impurities.

On examination:

General blood test: Er - 2.53 × 10 / l, HB 86 g / l, Le 5.2 × 10 / l, e - 5, p - 3, s - 32, l - 54, m - 6, ESR - 3 mm / hour.

In a smear from the surface of the tonsils, palatine arches and posterior wall of the oropharynx, PCR detected RNA of influenza virus and RNA of influenza A.

The pathogen was not detected in a nasal swab using luminescence microscopy, which is probably due to the child arriving on day 4 of the disease, while this diagnostic method is informative only in the first three days of the disease.

When staging serological reactions in the blood, a 4-fold increase in the titer of antibodies to parainfluenza and influenza A viruses was detected.

In a smear from the posterior wall of the oropharynx during bacteriological examination, abundant growth of Streptococcus anginosus was found.

Allergological research: enzyme-linked immunosorbent assay (ELISA) revealed an increase in the level of total IgE in peripheral blood to 62.0 IU / ml.

The study of serum cytokines: IL-4 - 15.2 ng / ml, IL-6 - 18.0 ng / ml, IFNα - 225.3 ng / ml, IFNγ - 11.2 ng / ml.

Taking into account the criteria identified prognostically significant for the recurring course: a history of allergic pathology, isolation of Streptococcus anginosus, virus-viral associations, the development of croup syndrome to 2 degrees, a decrease in the level of red blood cells to 2.53 × 10 / l and hemoglobin to 86 g / l, the level of IL-4 - 15.2 ng / ml, IL-6 - 18.0 ng / ml, IFNα - 225.3 ng / ml, IFNγ - 11.2 ng / ml, as well as an increase in total IgE to 62, 0 IU / ml for laryngotracheitis is regarded as recurrent.

He received complex treatment, including antiviral (immunofan), antibacterial therapy (vice), inhalation with budesonide, detoxification therapy based on Gross, desensitizing drugs, physiotherapy.

Given the recurrent course of laryngotracheitis, it is recommended to include in the complex of anti-relapse measures during outpatient monitoring: a hypoallergenic diet, desensitizing drugs, repeat the course of immunofan, iron preparations for the correction of detected anemia.

In the examination, it is recommended that routine allergy tests be performed to identify causally significant allergens, repeated bacteriological examination of the oropharynx, a hematologist’s consultation, and monitoring of the performance of a general blood test.

Example 2. Polina M., 2 years old (born May 23, 2006).

Date of receipt: 1.02.2008

Date of discharge: 02/12/2008

Diagnosis: Acute respiratory viral infection (clinically) of moderate severity. Laryngotracheitis.

Received complaints of fever to febrile numbers, hoarseness, cough.

Initially, upon admission, it was revealed that a similar episode with ARVI is the first.

From the anamnesis: acutely ill. The disease began with a severe headache, a rise in body temperature to febrile numbers. On the second day of the disease, the girl developed a barking cough, a hoarse voice, continued to fever up to 39 °. Examined by the district doctor, sent to hospitalization at the DEC.

At admission: a state of moderate severity. Active. Body temperature - 37.2 °. Barking cough, hoarse voice. The skin and mucous membranes of the gas and cheeks are pale. Hyperemia of the pharynx, granularity of the posterior pharyngeal wall are noted. In the lungs against the background of hard breathing, wheezing is heard. During auscultation of the heart, tones are muffled, rhythmic, a rough systolic murmur at the apex and at the V point, inconstant. The abdomen is soft, painless. The liver and spleen are not enlarged. Stool and diuresis are not changed.

On examination:

Complete blood count: Er - 3.5 × 10 / l, HB - 122 g / l, Le - 8.7 × 10 / l, e - 7, p - 2, s - 29, l - 54, m - 8 , ESR - 5 mm / hour.

Parainfluenza virus RNA was detected in a smear from the surface of the tonsils, palatine arches and posterior wall of the oropharynx by PCR.

With luminescent microscopy, a glow to parainfluenza viruses was detected in a nasal swab.

The method of paired sera (serological reactions) in the girl revealed a diagnostic increase in the titer of antibodies to the parainfluenza virus.

When plating material on selective media from the posterior wall of the oropharynx during bacteriological examination, Staphylococcus aureus was found.

X-ray of the chest organs: a slight increase in the pulmonary pattern due to perivascular and peribronchial changes, non-structure of the roots of the lungs, lung tissue without focal and infiltrative changes.

Allergological research: the level of total IgE in peripheral blood is 42.0 IU / ml.

The study of cytokines: IL-4 - 11.2 ng / ml, IL - 6 - 15.2 ng / ml, IFNα - 125.9 ng / ml, IFNγ - 24.2 ng / ml.

Given the absence of criteria prognostically significant for the recurrent course in the child, the course of the disease in this child is regarded as acute, with a low risk of repeated episodes of laryngotracheitis.

Example 3. Pavel K., 3 years old (November 2, 2003).

Date of receipt: December 6, 2007.

Date of discharge: 12/14/2007.

Diagnosis: Acute respiratory viral infection (clinically) of moderate severity. Laryngotracheitis. Croup 2 degrees.

Initially, upon admission, it was noted that a similar episode of laryngotracheitis with ARVI occurred 4 times this year. The boy suffers from atopic dermatitis.

He was admitted with complaints of hoarseness, barking cough, weakness, lethargy, temperature up to 39 °, noisy breathing, with difficulty breathing.

From the anamnesis it is known that this disease began acutely with a headache, a rise in body temperature to 38.6 °. On the night of 6.12 a barking cough appeared, his voice hoarse, the child began to choke. They called SMEs, hospitalized at the OIKB.

At admission: serious condition. The child is agitated, moody. Body temperature - 39.2 °. No appetite. Barking cough, hoarse voice. The skin is pale, pronounced cyanosis of the nasolabial triangle. When examining the oral cavity, hyperemia of the pharynx is noted. Breathing is noisy, with participation in the act of breathing intercostal muscles. Retraction on inspiration of the jugular fossa is noted, inhalation is difficult. During auscultation in the lungs, hard breathing is heard, wire rales, BH - 60 per minute. Percussion over the lungs is a pulmonary sound with a boxy tint. Heart sounds are muffled, heart rate - 148 beats per minute. The abdomen is soft, painless on palpation. The liver and spleen are not enlarged. Stool without pathological impurities. Urination is free, painless.

On examination:

Complete blood count: Er 2.1 × 10 / L, HB 79 g / L, Le 9.1 × 10 / L, 6-1, e - 8, n - 2, s - 41, l - 39, m - 9, ESR - 15 mm / hour.

In a smear from the surface of the tonsils, palatine arches and posterior wall of the oropharynx, the DNA of adenovirus and RNA of the respiratory syncytial virus were detected by PCR.

A luminescence to adenovirus and respiratory syncytial virus was detected in a nasal swab using luminescent microscopy.

When staging serological reactions, an increase in antibody titer of 4 times to adenovirus and respiratory syncytial virus was detected.

Bacteriological examination of a smear from the posterior wall of the oropharynx revealed seeding of Streptococcus anginosus and Staphylococcus aureus.

Allergological research: the level of total IgE in peripheral blood is 56.7 IU / ml.

The study of cytokines: IL-4 - 15.2 ng / ml, IL-6 - 21.1 ng / ml, IFNα - 154.6 ng / ml, IFNγ - 8.1 ng / ml.

The following prognostically significant signs were revealed in this child: the isolation of bacterial-bacterial and viral-viral associations with bacteriological and virological research methods, a decrease in the level of red blood cells to 2.1 × 10 / l and hemoglobin to 79 g / l in the general blood test, and the level of IL-4 - 15.2 ng / ml, IL-6 - 21.1 ng / ml, IFNα - 154.6 ng / ml, IFNγ - 8.1 ng / ml, the level of total IgE - 56.7 IU / ml Thus, this child is predicted to be at high risk of subsequent relapses of the disease.

The child underwent complex treatment with the inclusion of etiotropic, pathogenetic, symptomatic treatment.

Given the recurrent course of laryngotracheitis, it was decided to include in the complex of anti-relapse measures: anti-inflammatory drugs (fenspiride), correction of anemia with iron preparations.

In the examination, a routine recommended repeated bacteriological examination of the oropharynx, consultation with a hematologist, monitoring the dynamics of the performance of a general blood test.

The main advantages of the proposed method for predicting the recurrent course of laryngotracheitis in children is a high degree of informativeness and reliability of the identified criteria, objectification of an individual prognosis of the course of the disease, based on an in-depth analysis of clinical and medical history and immunological parameters, as well as the possibility of identifying children who are at risk of relapse at the first episode of the disease further laryngotracheitis and the development of differentiated methods of approach to prot ivorecid treatment.

A high degree of informativeness and reliability of prognostic criteria is achieved:

1. An integrated approach that takes into account the importance of anamnestic, microbiological, clinical and immunological factors for the implementation of the relapsing course of laryngotracheitis in children.

2. Conducting a statistically reliable analysis based on the calculation of prognostic factors.

3. Determining the level of pro- and anti-inflammatory cytokines, which allows you to specify the severity and nature of the inflammatory process (infectious or allergic).

4. Identification of the imbalance of pro- and anti-inflammatory cytokines, which may be the basis for choosing an adequate immunocorrective therapy.

Thus, we have developed criteria for predicting the recurrent course of laryngotracheitis in children, which allows us to determine the features of the course of laryngotracheitis in the early stages, apply adequate anti-relapse treatment programs and conduct targeted immunocorrective therapy, which will help reduce the frequency of recurrence of laryngotracheitis in children.

Claims (1)

A method for predicting the recurrent course of laryngotracheitis in children, characterized in that the anamnestic data and clinical features of laryngotracheitis are initially clarified, conduct microbiological and virological examination in a smear from the posterior pharyngeal wall by PCR, serological or luminescent microscopy; determine the level of cytokines IL-4, IL-6, IFNα, IFNγ; determine the level of total IgE in peripheral blood; a general blood test is performed and if there is a history of allergic pathology, the detection of Streptococcus agalacticae, virus-viral or bacterial-bacterial associations, the development of croup syndrome to 2 degrees, a decrease in the level of red blood cells <2.9 ∙ 10 billion / l and hemoglobin <89 g / l in the general blood test, the content of IL-4 is higher than 14.8 ng / ml, IL-6 is higher than 16.1 ng / ml, IFNα is higher than 147.8 ng / ml, IFNγ is lower than 16.9 ng / ml; a total IgE level above 47.0 IU / ml relapse is predicted.