The article presents the basic concepts of non-atopic eosinophilic asthma separately and endotypes and phenotypes of asthma in children and adults; Approaches to the pharmacotherapy of these patients are considered. A clinical case of non-atopic asthma in a 14-year-old child is described.
Until recently, bronchial asthma (AD) in children and adults was defined as allergic (or atopic) and non-allergic (or non-atopic). The main difference between these two types of AD is based on the presence/absence of clinical symptoms of an allergic reaction and sensitization according to allergic diagnostics (skin tests and / or determination of specific IgE (sIgE) antibodies to various allergens).
However, thanks to the development and implementation of methods for sampling from the respiratory tract (induced sputum, cytology of nasal mucus), new analytical approaches for biological samples (evaluation of the microbiome of the respiratory tract and epigenetics) and new biostatistical methods, scientists managed to go beyond the old classification of atopic / non-atopic AD and eosinophilic asthma / non-eosinophilic AD [1, 2].
What is known today about eosinophilic asthma?
It would seem that a detailed history of the disease, including concomitant (comorbid) diseases, a study of the function of external respiration with a bronchodilator test, a general blood test, the detection of sIgE antibodies and counting peripheral blood eosinophils is information that is enough for the doctor to diagnose at the first stage patient allergic or non-allergic asthma.
The clinical symptoms for both types of the disease are the same
(wheezing, shortness of breath, the sensation of pressure in the chest, and cough), which vary in time and intensity of manifestations and reversibility of bronchial obstruction. However, even 10 years ago, scientists began to distinguish various subgroups of patients with AD based on the immunological features of the course of the disease, biomarker data, response to specific pharmacotherapy, and long-term prognosis. These are the so-called phenotypes – unique clinical characteristics or subtypes of AD.
The study of pathophysiological processes in various asthma variants (phenotypes) gave rise to the concept of “endotypes” – “an asthma subtype characterized by a specific functional or pathophysiological mechanism” of development. Indeed, the results of cluster analysis revealed several heterogeneous asthmatic subgroups with different pathophysiology and a different response to treatment.
Subgroups were classified into “endotypes” based on various traits, including sIgE levels, the number of eosinophils in induced sputum, and fractional expired nitrogen oxide (FeNO) characterized by a certain functional or pathophysiological mechanism of development ”.
Indeed, the results of cluster analysis revealed several heterogeneous asthmatic subgroups with different pathophysiology and different responses to treatment.
Subgroups were classified into “endotypes” based on various traits, including sIgE levels, the number of eosinophils in induced sputum, and fractional expired nitrogen oxide (FeNO). characterized by a certain functional or pathophysiological mechanism of “development”. Indeed, the results of cluster analysis revealed several heterogeneous asthmatic subgroups with different pathophysiology and a different response to treatment. Subgroups were classified into “endotypes” based on various traits, including sIgE levels, the number of eosinophils in induced sputum, and fractional expired nitrogen oxide (FeNO) [3–8].
As further studies have shown, “Th2-type inflammation in asthma is present in most, but absent in many” . In other words, it became clear that not one, but several endotypes can participate in the formation of a non-atopic BA.
Distinguish the Th2-endotype of AD, which includes allergic asthma – closely associated with atopy,
sIgE production and eosinophilic inflammation. AD with early onset in children and adolescents, and in adults the so-called eosinophilic asthma is widely known Th2-endotypes of AD. Several subgenotypes may exist within this endotype (with high levels of IL-5, high levels of IL-13 or high levels of total IgE) . At the same time, less than 50% of adult patients with eosinophilic AD lack sensitization to the most common aeroallergens, but the level of total IgE is increased, which may be due to the action of latent allergens in the form of the superantigen Staphylococcus aureus, similar to atopic dermatitis
The non-Th2 endotype is typical for AD patients who do not have atopy and allergy symptoms, that is, this endotype determines non-atopic asthma [1, 10, 11]. At the same time, this is also a heterogeneous group, which is associated more with neutrophilic inflammation in the airways and such cytokines as IL-17, IL-1b, TNF-α , and the chemokine receptor (CXCR2) [12, 13]. To date, two hypotheses have been proposed that explain the development of AD of a non-Th2 endotype: 1) activation of the IL-17-dependent pathway and 2) dysregulation of the innate immune response, causing neutrophilic airway inflammation.
The Th17 endotype is especially characteristic of severe steroid-resistant AD and also has little to do with atopy. Th17 cells produce IL-17A, IL-17F, and IL-22. Elevated levels of IL-17A + cells and IL-17A can be detected in lung biopsy and blood serum, respectively, in patients with severe AD compared with mild form . IL-17A is a cytokine produced by CCR6-expressing CD4 + T (Th17) cells that induce the secretion of IL-8 and IL-6, as well as several chemokines, resulting in the recruitment and activation of neutrophils and macrophages. Thus, IL-17A enhances Th2-cell-mediated eosinophilic airway inflammation and hypersensitivity in experimental animal models [14–16]. The level of IL-17A in the blood serum of patients with severe uncontrolled AD was significantly correlated with the levels of IL-4, IL-25,
Neutrophilic inflammation is associated with the development of bronchial hypersensitivity and airway remodeling, especially in patients with non-atopic AD. This type of inflammation with a predominance of Th1 / neutrophils are accompanied by a decrease in sensitivity to steroids, and neutralization of TNF-α restores it . It was shown that a change in the expression of Toll-like receptor genes and an increase in the expression of genes associated with IL-1b and TNF-α leads to an increase in the chemotaxis of neutrophils and their survival in the airways. Obviously, with this endotype, the atopic component of inflammation is also unlikely.
Mixed Endotype Th2 / Th17
Such an inflammation mechanism has been described relatively recently in AD and implies the differentiation of Th2 cells into double-positive Th2 / Th17 cells . IL-17, produced in response to the damaged epithelium, can enhance the production of IL-4 and IL-13 from Th2 cells, and, conversely, IL-4 and IL-13 can enhance the activation of Th17, increasing the expression of CD209a on dendritic cells [16 ]. These cells were identified in the bronchoalveolar fluid of patients with AD. This mixed endotype has been little studied. It is probably also associated with allergies.
Thus, as can be seen from the above, most AD endotypes correspond to non-atopic asthma.
As for AD phenotypes, previously accepted criteria (severe, mild, therapy-resistant asthma, etc.) also underwent strong changes . Italian scientists, emphasizing the heterogeneity of asthma due to individual genetic and epigenetic variability and the effects of individual environmental factors (which depend on regional characteristics, changing climatic conditions and population distribution) remind doctors that asthma is not associated with its etiopathogenesis only with allergies.
An attempt to unravel the asthma-allergic associations
A separate important aspect is an AD in children, which is mainly due to atopy. At the same time, data on risk factors responsible for the development of a particular phenotype of the disease in children are limited, because sampling methods from the respiratory tract are invasive.
It is known that almost 50% of children experience shortness of breath in the first year of life, although only 20% will have symptoms of shortness of breath in later childhood [18, 19]. In some children, the “wheezing” phenotype (wheezing, wheezing) continues until late childhood, while in others, in adolescence and adulthood.
In 2008, PRACTALL experts proposed the following AD phenotypes in children: virus-induced; allergen-induced; unresolved asthma; asthma of physical stress. Only in this document do scientists refer to persistent AD in children without appropriate allergic sensitization as “unresolved asthma”.
It is important to note at the same time that according to the analysis of bronchial biopsy samples obtained in children with wheezing (average age 5 years; range 2–10 years), pathomorphological changes (thickened basement membrane, increased number of eosinophils and cytokine expression) did not differ in children with non-atopic and atopic wheezing.
Recently, G. Longo et al. described a specific phenotype of non-allergic eosinophilic asthma in children (non-atopic persistent asthma), reminding scientists that a similar phenotype in children has not yet been recognized as a separate clinical phenotype in child asthma guidelines.
Perhaps eosinophilic non-allergic inflammation of the bronchi is controlled by congenital lymphoid Th2 cells as a result of direct stimulation by viruses and bacteria, the authors believe. Other authors in children have also described neutrophilic asthma.
Phenotypes can change over time due to differences in the severity of symptoms and risk factors. Undoubtedly, therapeutic intervention can also change the course of the disease over time. According to A. Boudier et al. after 10 years of monitoring adult patients with AD (n = 3,320), the phenotype persisted in 78% of the study participants.
The treatment of patients with non-atopic asthma does not differ from the treatment of allergic asthma and includes inhaled corticosteroids with the addition of long-acting β-agonists. To achieve disease control, additional therapy consists of increasing the dose of ICS, adding anti leukotriene drugs, or theophylline . The response to drugs can vary greatly because it is not clear whether AD includes a combination of different conditions or is it a single state with several mechanisms and phenotypes . The heterogeneity of phenotypes and the different response to anti-asthma drugs, especially in young children and patients with severe AD, confirm the importance of personalizing therapy in each case. So, Fitzpatrick et al. in a recent study showed that in preschool children with persistent AD such biomarkers of Th2 inflammation.
A weak short-term response to the treatment of inhaled corticosteroids in patients with non-atopic asthma is associated with the fact that these drugs are primarily intended to suppress eosinophilic inflammation.
In addition, the two phenotypes of asthma — atopic and non-atopic — were not correlated with respect to the expression of other potentially significant biological markers (for example, neuronal involvement markers or airway microbiomes).
Patients with severe asthma with a Th1 endotype and neutrophilia in induced sputum may benefit from macrolide therapy. In particular, a recent study once again showed that azithromycin reduces asthma exacerbations in both severe eosinophilic and non-eosinophilic asthma, which indicates the immunomodulating effect of macrolides.
Recently, omalizumab is also prescribed for non-atopic asthma, since in such patients the level of total IgE is often increased, including at the level of bronchial tissue . Recent advances in the treatment of patients with non-atopic asthma, but with clear signs of a high Th2 response, relate to drugs such as mepolizumab or reslizumab that block IL-5 [42, 43].
Approaches to the treatment of various asthma endotypes
Patient I., 14 years old, consulted an allergist with an unspecified diagnosis: “Chronic bronchitis of unknown etiology.”
Anamnesis of life. The heredity of allergic and other chronic diseases of the respiratory tract is not burdened. The mother had atopic dermatitis in her childhood, there were no further complaints. A girl from the first physiological pregnancy, the first independent birth. Apgar score at birth 8/9 points. The child grew and developed according to age, vaccinations were given by age. The girl was breast-fed up to 1.5 years. Of the diseases – rare acute respiratory infections, chickenpox.
For the first time, coughing without wheezing appeared at the age of 8 years. The cough was not associated with any provoking factors (contact with allergens, cold, physical activity). From the age of 13, nasal congestion appeared, with the preservation of smell and without other symptoms of allergic rhinitis (itchy nose, runny nose, sneezing). The girl was repeatedly examined:
according to x-ray and CT of the lungs – there is no data for chronic pathology; Ultrasound of the abdominal organs – without pathology; results of an allergological examination (skin tests, determination of sIgE for inhaled allergens – were negative); there are no data for gastroesophageal reflux. In a general blood test – without pathological changes.
On examination, changes from the internal organs were not detected.
When examining the function of external respiration in a child, all “curve-flow” indicators are normal, however, the test with bronchodilator salbutamol 200 mcg is sharply positive (FEV 1 + 22%).
Given the anamnestic and clinical laboratory data, the child is diagnosed with a non-atopic BA, controlled course. To confirm the diagnosis, a bronchial provocation test is indicated, which is currently not available in pediatric practice. The child is prescribed therapy with low doses of ciclesonide (160 mcg/day), nasal corticosteroids. An additional allergological examination (molecular allergy diagnosis) is recommended. After 2 months, according to the mother, the child has coughing attacks less frequently, although they have not completely stopped. Communication with triggers is also missing.