RU2770290C9 - Method for assessing the threshold of olfaction in children - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine and concerns a kit for assessing the threshold of smell in pediatric patients, including a combination of olfactants and a non-olfactant, which is distilled water, instructions for use, test tubes or vials with tightly fitting non-rubberized lids, where olfactants are aqueous compositions of alcoholic tincture of valerian, aqueous solution of acetic acid, aqueous solution of ammonia, and where dilution for tincture of valerian and acetic acid starts from 0.64 vol. %, for ammonia solution from 0.512 vol. %, where each olfactant is presented in the form of fourteen consecutive two-act dilutions; where the instructions for use, including sensitivity scores to the dilution of olfactants and the threshold of smell in pediatric patients in the range from 0 to 14 points. The group of inventions also concerns a method for assessing the threshold of smell in pediatric patients using the specified set; the use of the specified set for assessing the threshold of smell in pediatric patients.

EFFECT: group of inventions provides an assessment of the threshold of olfaction in pediatric patients.

4 cl, 8 tbl, 3 ex

Description

This technical solution relates to the field of medicine, physiology, and can be used in neurology, otolaryngology, functional diagnostics to detect olfactory disorders in patients, as well as for scientific purposes.

State of the art

The role of assessing the sense of smell in humans has become relevant in connection with a new global threat - a pandemic of a new coronavirus infection COVID-19. As is known, olfactory disorder is considered as a specific symptom of this infection [1, 2]. There is still no clear clarity both regarding the frequency, which in the general population of patients can range from 32% to 69%, and regarding the pathogenesis, as well as regarding the outcomes of olfactory impairment in COVID-19 [3, 4].

It is known that in the phylogenetic aspect, the sense of smell is the most ancient sensory channel of brain activation. All sensory systems are very plastic, the processes of functioning of the auditory and visual systems have been studied and described in some detail, however, the understanding of the neural changes that occur with the loss of the olfactory sense has not yet been largely achieved [5].

In foreign clinical practice, the odor identification test is widely used. In the past, most studies of odor identification in children used tests intended for testing adults: as recently as 2008, there was no "suitable clinical test" to measure olfactory function in children [6]. Over the past decade, olfactory tests designed for use in children have appeared [7, 8].

It should be noted that odor identification includes a level of cognitive and linguistic complexity, which in children is still in the formative stage, therefore, in children, the results of odor identification testing do not always fully reflect the perceptual olfactory function itself. A separate problem is population cultural and linguistic differences, which do not allow us to count on the adequate application of the methods developed in North America and Europe for testing olfactory identification abilities in Russia, where neither our own developments nor the adaptation of foreign methods have been carried out for the children's population.

The most accurate quantitative method available in the clinic seems to be the assessment of the smell threshold of odors. The measurement of the odor detection threshold does not require knowledge of the identity of odors, since it does not test the ability to determine the ownership of an odor, but is aimed at quantifying the ability to smell odors of olfactory sensitivity directly. But results from trials of this methodology in children, especially preschoolers, have been patchy, partly reflecting problems of attention and reliability, as well as the impact of retesting [9].

A method is known from the prior art (Snap & Sniff® “smell sticks”), which uses simple and convenient olfactory tests for clinical use (in our country they are not available for use) [10]. However, in their part of the olfactory threshold assessment, they consist of one odorant (in Snap & Sniff®, “smell sticks” are phenylethanol, which does not reflect the completeness and reliability of the entire picture of olfactory impairment, since it does not take into account the contribution of trigeminal afferentation to olfaction [11] ).

The disadvantage of the above method is an incomplete study of the sense of smell. Also, a significant limitation is that this method has not been studied and has not been adapted to the Russian population, the test systems that use them are not certified for use in domestic healthcare and, accordingly, are not generally available for Russian clinical practice.

The closest analogue is the method known from the prior art for determining the threshold of smell in adult patients, which is characterized by the use of dilutions of three olfactory substances prepared under normal conditions: 1) valerian tincture (perception through the olfactory nerve), 2) acetic acid solution (olfactory and trigeminal nerve) , 3) ammonia solution (mainly trigeminal nerve) [12]. The disadvantages of this method include the fact that it is not possible to apply it in pediatric clinical practice. In addition, this method has not been tested in people with olfactory pathology, so its effectiveness and reliability in clinical practice is unknown.

The person skilled in the art knows that the physiological thresholds of smell in children differ from the physiological thresholds of smell in adults, not only in the normal state, but in the pathological state. In addition, for various odorants, the physiological thresholds of smell in children vary differentially: in the direction of increased or decreased sensitivity.

There is a need to develop an effective, reliable, accurate and easily accessible technical solution for pediatric clinical practice to assess the threshold of smell in patients (children).

Disclosure of the essence of the invention

The importance of studying sensory disorders using the example of hypoosmia and anosmia in various somatic diseases is due to the initially chosen strategy: the application of a promising standardized diagnostic technology to current nosology in the age period susceptible to the treatment of the main somatic pathology will improve clinical approaches to the management of pediatric patients

In the context of the COVID-19 pandemic, the challenge is to develop an effective, reliable, accurate and clinically applicable technical solution for assessing the threshold of smell in pediatric patients.

The technical result lies in the fact that the proposed technical solution is effective, safe for pediatric patients from 6 years old, with complaints of impaired sense of smell, reliable and easily accessible in clinical practice.

The technical result is achieved by the fact that the proposed technical solution uses the appropriate combination, including aqueous compositions of olfactory substances (olfactant), where the olfactant is an aqueous solution of valerian tincture, acetic acid, ammonia in effective and suitable dilutions for pediatric patients; neolfactant selected from distilled water.

Also, the technical result is achieved by implementing a technical solution in a certain sequence using a dilution sensitivity score system in the range from 0 points to 14 points, where the dilution sensitivity score advises the selected concentration of olfactant compositions, which are valerian tincture, acetic acid solution, ammonia, respectively . Where, the higher the score value - the higher the olfactory sensitivity and the lower the threshold of smell. The lower the score, the lower the olfactory sensitivity and the higher the threshold of smell.

Terms and designations used in the present description have the following meanings

Olfactory sensitivity is understood as the olfactory sensitivity due to two cranial nerves: the olfactory nerve, the trigeminal nerve.

Olfactive substances (olfactants) are odorous substances that irritate the branches of the olfactory and trigeminal nerves.

To determine the olfactory sensitivity, the following odorous substances can be selected: cloves, lavender, anise, benzene, xylene, valerian, which affect the olfactory sensitivity due to the olfactory nerve; camphor, ether, chloroform, acetic acid, ammonia - affecting the olfactory sensitivity due to the trigeminal nerve.

Under hyposmia understand a marked decrease in olfactory function in a patient (human, mammal).

Under anosmia understand the complete lack of smell in a patient (human, mammal).

In one aspect, the present technical solution is a method for assessing the thresholds of smell in pediatric patients, which can be adopted in clinical practice.

In another aspect, the present technical solution is a combination for use in a method for assessing olfactory thresholds in pediatric patients, including aqueous compositions of olfactory substances, where the olfactory substances are an alcoholic solution of valerian tincture, aqueous solutions of acetic acid and ammonia, in effective and suitable dilutions for pediatric patients. patients, as well as a neolfactant selected from distilled water.

In addition, an aspect of the technical solution may be directed to the use of the appropriate combination and the appropriate method in pediatric clinical practice.

In another aspect, the present technical solution is a kit for assessing the thresholds of smell in pediatric patients, including the appropriate combination of compositions of olfactory substances, such as valerian tincture, acetic acid solution, ammonia; test tubes or vials with ground non-rubberized lids; instructions for use containing a dilution sensitivity score system in the range from 0 points to 14 points, where the dilution sensitivity score corresponds to the selected concentration of olfactory substances, which are aqueous solutions of valerian tincture, acetic acid solution, ammonia in appropriate effective concentrations. The implementation of the claimed method. The method for assessing the threshold of smell is carried out sequentially; use test tubes/vials with tight-fitting, non-rubberized lids (rubber has an odor and may affect the reliability of the results), to prevent volatilization, containing appropriate dilutions of specific olfactants: from smaller to larger, substances of the corresponding modality of the olfactory analyzer in order from the reception of the olfactory nerve to trigeminal nerve.

Odor identification is carried out at a distance of 1 to 2 cm from the nose, sequentially by bringing a test tube/vial to each nostril for a time interval of 2 seconds. The subject, at the request of the researcher, takes 2 short breaths, while it is proposed to draw in air through the nose somewhat more actively than with simple breathing. Next, the subject must answer the question if he smells any smell.

When the subject reported that he had smelled, he was asked to confirm his choice of olfactant by three times the correct choice from a pair of test tubes "olfactant with a given concentration - neolfactant". Distilled water was chosen as the neolfactant.

The minimum percentage concentration of an olfactory substance recognized by the subject is the “identification threshold” of the substance of the corresponding modality of the olfactory analyzer.

The lowest concentration of olfactant (that is, the weakest odor) is presented first for identification, in the sequence of the corresponding modality of the olfactory analyzer. If the subject does not smell, he is presented with the next largest concentration (twice as high) of the olfactant in the sequence of the corresponding modality of the olfactory analyzer, then the next largest concentration of this olfactant in the sequence of the corresponding modality of the olfactory analyzer, until the subject will not report that it smells.

At the beginning, the ability (sensitivity and efficiency) of the claimed method for assessing the threshold of smell was tested to demonstrate differences between the state of smell in normal and pathological conditions. As a pathology, a model of the transferred COVID-19 disease was used.

Initially, dilution ranges of certain olfactory substances suitable for use in pediatric clinical practice were empirically selected based on an expanded sample of children with an intact sense of smell, taking into account possible population variation.

From the group of olfactants, a 20% alcohol tincture of valerian, 70% aqueous solution of acetic acid, 10% aqueous solution of ammonia (ammonia) were selected, from which combinations of aqueous solutions were prepared with acceptable dilution ranges and suitable for pediatric clinical practice (fifteen combinations for each selected olfactory substance):

20% alcohol tincture of valerian and from 70% aqueous acetic acid solution in effective ranges from 0.00015625% vol./about. up to 2.56% v/v c: 0.00015625% v/v, 0.0003125% v/v, 0.000625% v/v, 0.00125% v/v, 0.0025% v/v ., 0.005% v/v, 0.01% v/v, 0.02% v/v, 0.04% v/v, 0.08% v/v, 0.16% v/v, 0.32% v/v, 0.64% v/v, 1.28% v/v, 2.56% v/v respectively;

from 10% aqueous ammonia solution in effective ranges from 0.000125% vol./about. up to 2.048% v/v: 0.000125% v/v, 0.00025% v/v, 0.0005% v/v, 0.001% v/v, 0.002% v/v ./v, 0.004% v/v, 0.008% v/v, 0.016% v/v, 0.032% v/v, 0.064% v/v, 0.128% v/v v/v, 0.256% v/v, 0.512% v/v, 1.024% v/v, 2.048% v/v

The olfactory threshold was assessed in points, each dilution level is assigned a point: a minimum of 1 point is the highest concentration, a maximum of 15 points is the lowest concentration. The higher the score, the higher the ability to recognize the olfactant (the lower the perception threshold).

The main group included children over 6 years old, living in one district of the northern administrative district of Moscow, who fell ill with COVID-19 from 03/20/2020 to 05/10/2020. Recovery was confirmed by two negative responses to PCR diagnostics of the SARS-CoV-2 virus in cell scraping from the nasopharynx or oropharynx with an interval of one day; enrollment in the study was carried out at least 1 week after the first negative response to PCR diagnostics of the SARS-CoV virus -2 in cell scraping from the nasopharynx or oropharynx, confirming the fact of recovery (recovery was confirmed by two negative PCR diagnostics of the SARS-CoV-2 virus in cell scraping from the nasopharynx or oropharynx with an interval of one day). The control group included children older than 6 years who did not tolerate COVID-19: who had no contact with patients with COVID-19, who did not have hyperthermic, catarrhal, olfactory, asthenic or any other symptoms of an acute illness within the next 45 days from the date of inclusion. The research methods included a neurological examination, verification of cognitive status, an examination by an ENT doctor, and a study of smell. In order to avoid overworking children, which could affect its results, the study of each participant was carried out for 2 days.

Criteria for non-inclusion in both groups: decreased intelligence, severe neuropsychiatric diseases; acute inflammation of the nasopharyngeal mucosa on the day of the study; acute respiratory infection; exacerbation of allergic rhinitis with lesions of the nasopharyngeal mucosa.

Statistical processing of the results was carried out using a special electronic computer program, any known to a specialist in this field of technology. Using descriptive statistics, mean values and standard deviations (±σ) were calculated. For a comparative assessment of the significance of differences in the average values of the smell threshold in the main analysis and in additional subgroups, the nonparametric U-parametric Mann-Whitney test for independent samples of the T-Student for independent samples was used. The significance level (asymptotic two-tailed significance) was taken as p<0.05 with a 95% confidence interval.

We examined 61 children in the age range from 6 to 18 years who had COVID-19 (main group). The main group included children at least 1 week after the first negative response to PCR diagnostics of the SARS-CoV-2 virus in cell scraping from the nasopharynx or oropharynx, confirming the fact of recovery. COVID-19 infection has been used as a model for a disease known to be highly likely to cause impaired olfactory function. The control group consisted of 20 healthy children.

In sub-step IA, the distribution of matched dilutions in a sample of healthy children was examined.

The results of a set of measures for examining 20 healthy children are presented below (Table 2).

Based on the resulting distribution of odor recognition of the presented fifteen dilutions, the optimal ranges of twelve dilutions for each odorant were determined. To do this, the next lower concentration before it was added to the dilutions with the lowest concentration, which were determined by the children, since it is recommended to start the study with a concentration that is not determined by any of the subjects.

After that, even higher concentrations were added to the highest concentration, which was determined by conditionally healthy children, until the total number of dilutions was 12.

The combination with the optimal (effective) range of concentrations of prepared compositions from olfactory substances turned out to be the most preferable. to 0.64%) vol./vol., and from the olfactory substance 10% aqueous ammonia solution, a dilution was prepared in an effective concentration of 0.000125% vol./vol. up to 0.256% vol./about., where each selected olfactory substance is presented in the form of twelve consecutive two-act dilutions, starting from 0.64% vol./about. and starting from 0.256% vol./about. respectively.

At sub-step 1B, a comparison was made of the discrimination of olfactants in the selected range of dilutions (smell threshold). The results of comparing the olfactory thresholds obtained by the developed method in two groups are presented below.

The olfactory thresholds of all three olfactants were significantly higher in children with COVID-19 infection. That is, they sensed olfactants at higher concentrations and were therefore less sensitive to odors. Children who recovered from COVID-19 showed poorer smelling abilities compared to children who did not have the infection.

At the same time, the sense of smell decreased somewhat more than others in relation to valerian tincture. No gender differences were identified. None of the participants developed allergic, respiratory, psychological, or other health problems related to the examination. Thus, the claimed method has shown high clinical sensitivity and safety in pediatric patients with impaired sense of smell.

Sense of smell after recovery was equally affected in those who had complaints of impaired sense of smell at the time of infection with COVID-19, compared with those who did not have these complaints (Table 4).

Thus, the data obtained indicate that the complaints of children and the observations of parents do not fully reflect the dysfunction of the sense of smell. Apparently, the level of olfactory impairment that is subclinical for a subjective assessment, especially characteristic of children with COVID-19, is quite common, which proves the prospect of using the claimed method to determine olfactory impairment, especially in pediatric clinical practice (in children).

At the second stage, in order to maximally adapt the method to wide application, taking into account possible population differences in the state of smell in Russian children, we expanded the specified range of dilutions. To this end, based on the results of the distribution of smell thresholds in healthy children at the first stage, according to which the distribution was shifted to lower dilutions, we added three more low dilutions to achieve a more uniform range of sensitivity, bringing their total number to 15. We checked the distribution indicated dilutions in an expanded sample of healthy children over 6 years of age who have not had COVID-19, who have not been in contact with patients with COVID-19, who did not have hyperthermic, catarrhal, olfactory, asthenic or any other symptoms of an acute illness within the next 45 days from the date of inclusion and on the day of the study. In total, 60 children were included in this group at the second stage.

The results of the distribution of sensitivity to various dilutions of olfactants are presented below.

Based on the results of the analysis, we finally determined the optimal range of dilutions for assessing the thresholds of smell in children, excluding one dilution and leaving their number equal to fourteen.

The conditions for determining the optimal range were: 1) the lowest dilution should not be determined by any healthy participant; 2) the highest dilution should also not be recognized by any healthy participant; 3) the range should be selected in such a way that the recognition of healthy participants is somewhat shifted to low dilutions - this is necessary for greater sensitivity to the method for determining high olfactory thresholds in pathology.

Based on the method of counting data that we tested at the first stage, we recommend using a scoring of the result of determining the smell threshold in the claimed method.

Based on the results of the study, an effective and safe combination of compositions of olfactory substances prepared from 20% alcohol tincture of valerian and from 70% aqueous solution of acetic acid in dilution with an effective concentration from 0.000078% v/v to 0.64% was finally determined for pediatric patients. v / v, and from the olfactive substance 10% aqueous ammonia solution dilution in an effective concentration from 0.0000625% v / v to 0.512% v / v, where each selected olfactory substance is presented in the form of fourteen consecutive two-act dilutions, starting from 0.64 % v/v and starting from 0.512%) v/v, respectively, the combination also includes a non-olfactory substance in the form of distilled water.

According to the results of the studies, the highest efficiency of the developed method for assessing the threshold of smell in pediatric clinical practice was confirmed, where the effectiveness of the claimed method is achieved when using a combination of aqueous compositions of olfactory substances prepared from 20% alcohol tincture of valerian and from 70% aqueous solution of acetic acid diluted with an effective concentration from 0.000078% v / v to 0.64% v / v, and from the olfactory substance 10% aqueous ammonia solution, dilution in an effective concentration from 0.0000625% v / v to 0.512% v / v, where each selected olfactory substance presented as fourteen consecutive two-act dilutions, starting at 0.64% v / v and starting at 0.512% v / v, respectively, paired with a non-olfactory substance in the form of distilled water.

As a result of the study, it was determined that the greatest efficiency of the claimed method is achieved when using the developed dilution sensitivity score system in the range from 0 points to 14 points, where the dilution sensitivity score advises the selected concentration of compositions of olfactory substances, which are valerian tincture, acetic acid solution , ammonia (table 7). The higher the score, the higher the olfactory sensitivity and the lower the threshold of smell. The lower the score, the lower the olfactory sensitivity and the higher the threshold of smell.

According to the results of the study, it was determined that the greatest efficiency of the claimed method is achieved when using a kit for evaluating the threshold of smell in pediatric clinical practice, including a combination of aqueous compositions of olfactory substances prepared from 20% alcohol tincture of valerian and from 70% aqueous solution of acetic acid diluted with effective concentration from 0.000078%) v / v to 0.64% v / v, and from the olfactory substance 10% aqueous ammonia solution (ammonia) dilution in effective concentration from 0.0000625% v / v to 0.512% v / v , where each selected olfactory substance is presented as fourteen consecutive two-act dilutions, starting from 0.64% v/v and starting from 0.512% v/v, respectively; non-olfactory substance in the form of distilled water; bottles or test tubes with tight lids, instructions for use, containing a point system of sensitivity to dilution in the range from 0 points to 14 points, corresponding to the selected concentration of aqueous compositions of olfactory substances, which are valerian tincture, acetic acid solution, ammonia.

The possibility of implementing the claimed technical solution is disclosed in the proposed examples.

1. Example

Patient M., 12 years old, had a COVID-19 infection with clinical symptoms of febrile fever for 3 days, chills, cough, loss of smell for 7 days. When examined after 4 weeks, there were no signs of COVID-19 infection and neurological disorders, moderate signs of asthenia and decreased sense of smell remained. The result of PCR analysis for SARS-CoV-2 is negative twice.

When conducting olfactometry, a combination was used to assess the threshold of smell in pediatric clinical practice, including aqueous compositions of olfactory substances prepared from 20% alcohol tincture of valerian and from 70% aqueous solution of acetic acid in dilution with an effective concentration of 0.000078% v/v to 0 ,64% v / v, and from the olfactory 10% aqueous solution of ammonia dilution in an effective concentration from 0.0000625% v / v to 0.512% v / v, where each selected olfactory substance is presented in the form of fourteen consecutive two-act dilutions, starting from 0.64% v/v and starting from 0.512% v/v, respectively; non-olfactory substance in the form of distilled water. Test tubes with tight, non-rubberized lids were used (rubber has an odor and can affect the reliability of the result), which contained the corresponding aqueous compositions of valerian tincture, acetic acid, and ammonia.

Instructions for use containing a point system of dilution sensitivity in the range from 0 points to 14 points, advising the selected concentration of aqueous compositions of olfactory substances, which are valerian tincture, acetic acid solution, ammonia.

Olfactometry was carried out according to the claimed method from smallest to largest, substances of the corresponding modality of the olfactory analyzer in order from the reception of the olfactory nerve to the trigeminal nerve.

Odor identification is carried out at a distance of 1 cm from the nose, sequentially, bringing test tubes to each nostril for a time interval of 2 seconds. The subject, at the request of the researcher, takes 2 short breaths, while it is proposed to draw in air through the nose somewhat more actively than with simple breathing. Next, the subject must answer the question if he smells any smell.

When the subject reported that he smelled the smell, he is asked to confirm his choice of olfactant by three correct choices from a pair of test tubes "olfactant with a given concentration - neolfactant". Distilled water was chosen as the neolfactant.

The olfactory thresholds of all three olfactants showed a significant decrease in olfaction. Sensitivity to valerian n-ke was 6 points (average norm - 9.05 out of 14 points), to acetic acid - 5 points (average norm 8.7 points), to ammonia solution - 3 points (average norm - 9, 5 points). Diagnosis: hyposmia.

2. Example

Patient C, 8 years old, had an asymptomatic COVID-19 infection, was in contact with parents who had a mild infection. According to the child and parents, there was no loss and / or decrease in taste and smell. When examined by a pediatrician, a neurologist 4 weeks after the COVID-19 infection, no neurological and somatic disorders were detected, the child did not complain.

When conducting olfactometry (see example 1). Odor identification was carried out at a distance of 2 cm, where vials with ground non-rubber caps were used.

The thresholds of smell for all three olfactants were reduced: sensitivity to valerian n-ke was 3 points (average norm - 9.05 out of 14 points), to acetic acid -2 points (average norm 8.7 points), to ammonia solution - 2 points (average norm - 9.5 points).

Diagnosis: hyposmia.

3. Sample comparison

Conducted a comparative analysis of the sensitivity of the method developed by us and the known method. For this purpose, olfactants were recognized by 60 healthy children from the prototype model and compared with the previous study of our model, presented in Table 5.

Most of the children smelled the highest dilution of valerian tincture (38 out of 60) and acetic acid (36 out of 60), and a significant part of the children (15 out of 60) smelled the ammonia solution also in the highest dilution. Obviously, in such a situation, the maximum dilutions presented in the prototype cannot be considered the extreme limits of sensitivity, rather they reflect the average sensitivity, and high sensitivity is reflected by much higher dilutions that are not represented in the prototype.

Comparison with the distribution of sensitivity to olfactants in our dilutions (Table 5) shows the real distribution of the sensitivity range.

Thus, the dilutions of olfactants presented in the prototype do not reflect the range of sensitivity to them in children and cannot be used in pediatric clinical and scientific practice.

In addition, the listing of dilutions shows the uneven change in dilutions in the prototype, in which the step of increasing the dilution is not stable, but ranges from 2 to 2.5, which is imperfect from a methodological point of view, especially for use in scientific research. In our method, the dilution change step is stable and divisible by 2.

The presented examples do not limit the scope of the claims of the present technical solution and serve only for the purpose of illustrating and disclosing all aspects of the claimed technical solution.

Industrial Applicability

All the above examples confirm the implementation and application of all aspects of the claimed technical solution in the field of medicine, physiology, and can be used in neurology, otolaryngology, functional diagnostics to detect impaired sense of smell in patients, as well as for scientific purposes.

All aspects of the claimed technical solution in clinical pediatric practice are suitable for highly sensitive

quantitative assessment of the threshold of smell, reflecting the response at the level of differentiated primary sensory afferentation along several cranial nerves.

All aspects of the claimed technical solution can be used both for additional monitoring of the level of disease control achieved, and for clarifying the severity of changes in the cognitive sphere that followed against the background of prolonged olfactory deficiency.

Thus, the set technical task is realized.

List of used literature

1. Vaira LA, Salzano G, Deiana G, De Riu G. Anosmia and ageusia: common findings in COVID-19 patients. Laryngoscope. 2020. doi:10.1002/lary.28692.

2. Lechien JR, Chiesa-Estomba CM, De Siati DR, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol. 2020; 1-11.

3. Qiu C, Cui C, Hautefort C, et al. Olfactory and Gustatory Dysfunction as an Early Identifier of COVID-19 in Adults and Children: An International Multicenter Study [published online ahead of print, 2020 Jun 16]. Otolaryngol Head Neck Surg. 2020.

4. Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE, Spudich S. Neuro-pathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coro-navirus Disease 2019: A Review [published online ahead of print, 2020 May 29]. JAMA Neurol. 2020; ten.

5. Kollndorfer K Jakab A Mueller C A Trattnig S Schopf V. 2015. Effects of chronic peripheral olfactory loss on functional brain networks. neuroscience. 310:589-599.

6. Close D.G. Laing, C. Segovia, T. Fark, et al. Tests for screening olfactory and gustatory function in school-age children. Otolaryngol Head Neck Surg, 139 (2008), pp. 74-82.

7. Close V.A. Schriever, E. Mori, W. Petters, C. Boerner, M. Smitka, T. Hummel. The "Sniffm' Kids" test - a 14-item odor identification test for children. PLoS One, 9 (2014), p.e101086.

8 Close E.L. Cameron, R.L. Doty. Odor identification testing in children and young adults using the smell wheel. Int J Pediatr Otorhinolaryngol, 77 (2013), pp. 346-350.

9. E. Leslie Cameron. Olfactory perception in children, World Journal of Otorhinolaryngology - Head and Neck Surgery, Volume 4, Issue 1, 2018, Pages 57-66.

10. Doty RL. Measurement of chemosensory function. World J Otorhinolaryngol Head Neck Surg. 2018 Jun 28;4(1):11-28.

11. Doty RL, Brugger WE, Jurs PC, Orndorff MA, Snyder PJ, Lowry LD. Intranasal trigeminal stimulation from odorous volatiles: psychometric responses from anosmic and normal humans. Physiol Behav. Feb 1978; 20(2): 175-85.

12. Method for performing threshold olfactometry. Patent of the Russian Federation RU 2169364 C1, authors: Domrachev A.A., Afonkin V.Yu., Savchenkov Yu.I., Amelchugov S.P., Erlikh I.A. 06/20/2001.

Claims (4)

1. Kit for assessing the threshold of smell in pediatric patients, including a combination of olfactants and neolfactant, which is distilled water, instructions for use, test tubes or vials with tight-fitting non-rubberized caps; characterized in that olfactants are aqueous compositions of an alcoholic tincture of valerian, an aqueous solution of acetic acid, an aqueous solution of ammonia, and characterized in that the dilution for tincture of valerian and acetic acid starts from 0.64% v/v, for an ammonia solution from 0.512% v/v, where each olfactant is presented as fourteen consecutive two-act dilutions; where instructions for use, including points of sensitivity to dilution of olfactants and the threshold of smell in pediatric patients in the range from 0 to 14 points; and where the higher the score, the higher the olfactory sensitivity and the lower the smell threshold, and the lower the score, the lower the olfactory sensitivity and the higher the smell threshold. 2. A method for assessing the threshold of smell in pediatric patients, including a set according to claim 1, characterized in that it is brought to 2 s of the combination from the set according to claim 1 at a distance of 1 to 2 cm to each nostril of the patient's nose in the sequence of modality of the olfactory analyzer from the lowest concentration of olfactant; patients take two short breaths, while actively inhaling the presented olfactant with their nose; after that, they report that they smelled an olfactant or did not smell an olfactant, where the olfactant chosen by the patients is in an effective concentration; if patients choose an olfactant with an effective concentration, then patients confirm their choice three times by choosing the same olfactant in combination with a neolfactant; if patients do not smell the presented olfactant, present the olfactant with the next concentration twice as high in the sequence of the olfactory analyzer modality until the patients report that they smell the olfactant with an effective concentration; next assessing the threshold of smell in pediatric patients using sensitivity scores for dilution of olfactants, where sensitivity scores for dilution of olfactants in the range from 0 to 14 points correspond to the selected concentration of olfactants; and where the higher the score, the higher the olfactory sensitivity and the lower the smell threshold, and the lower the score, the lower the olfactory sensitivity and the higher the smell threshold. 3. The method according to claim 2, additionally characterized in that the modality sequence of the olfactory analyzer is the order of presentation of olfactants from those affecting the olfactory sensitivity due to the olfactory nerve - aqueous compositions of alcoholic tincture of valerian, to those affecting the olfactory sensitivity due to the trigeminal nerve - an aqueous solution acetic acid and an aqueous solution of ammonia. 4. Use of the kit according to claim 1 to assess the threshold of smell in pediatric patients.