In the year of the 30th anniversary of Asthma-Service, we recall the most significant articles from its employees. One of them is devoted to the cause of bronchial asthma and was published in the Medical Bulletin.
Bronchial asthma: a new look at the cause of the disease
The concepts of “asthma” and “allergy” have been inextricably linked for more than 100 years. When talking about asthma, they always think of allergies, and vice versa. The question remained unresolved for a long time: does allergies cause asthma or do they exist and develop independently of each other? Numerous studies aimed at establishing a link between asthma and allergies eventually found their reflection in the summary of the International Committee of Experts of the WHO GINA program – the Global Initiative to Control Bronchial Asthma. The experts came to the following conclusion: “… the main unresolved issue remains to establish whether exposure to allergens … is a real underlying factor in the occurrence of bronchial asthma or allergen exposure should be attributed to trigger exposures that exacerbate its course …”
From the data published in the literature, the following conclusions can be drawn:
1. Positive allergy tests are detected in 30-50% of the population in developed countries, but often the disease does not develop.2. Most studies do not find a complete correlation between the increase in the frequency of positive tests for allergies and the number of patients with bronchial asthma.3. At the population level, the participation of allergic mechanisms has been proven in 40% of patients with bronchial asthma, both children and adults. In other cases, asthma is classified as endogenous, i.e. disease not combined with allergies. More trivial considerations can also be given. For thousands of years, people have been familiar with pollen, grass, oranges and cockroaches … Cockroaches are contemporaries of dinosaurs, but primitive people did not complain about allergies from cockroaches, although there were more of them (cockroaches) at other times. And now there seem to be fewer cockroaches, but there are more and more patients with asthma and allergies. This is first. Secondly, maybe there is some specific asthmatic allergen? But all allergens have been known for hundreds of years, and no new ones have been discovered. Nevertheless, allergies have common immunological mechanisms with asthma. They are associated with two different types of helper lymphocyte subpopulations : Th1 and Th2. Cells of the first type implement a normal response that protects the body from everything foreign, primarily from infection. With the predominance of the activity of the second subpopulation – Th2-helpers – in the immune system, the synthesis of antibodies-reagins to various substances begins. And the immune system perceives as alien not only microorganisms, but also much of what surrounds it: the hair of dogs and cats, the pollen of trees and flowers, food products, medicines, and so on. Th2 helpers actively involved in the pathogenesis of bronchial asthma produce cytokines IL-4, IL-5, IL-9, IL-13 and IL-16. Th2 cytokines are responsible for the classic delayed-type hypersensitivity reaction (or cell-mediated hypersensitivity reaction). And the cytokine IL-5, produced under the action of Th2 helpers, determines the eosinophilic nature of inflammation associated with allergies or not.
This means that the factor leading to the development of the inflammatory process and the switch from Th1- to Th2-helper response will be the true and unique cause of bronchial asthma. And if such a factor exists, then the inflammation caused by it in the bronchial tree, on the one hand, leads to asthma, and on the other hand, to atopy (allergy), which aggravates its course or exists without clinical symptoms, as a marker of changes in the immune system.
What is this factor? It is clear that it must be closely related in some specific way to the immune system. But, as you know, evolutionarily the human immune system arose and developed primarily as a system of protecting the body from infection. Therefore, it is logical to assume that infection is the factor leading to the activation of inflammation in the bronchial tree and the switch of immunity from Th1 to Th2-helper response and the development of asthma. In addition, we can recall the not so long ago infectious-allergic bronchial asthma that existed in the classification. Naturally, questions arise: what is it: an infection, how is it associated with atopy and asthma?
Bacteriological analysis of the contents of the respiratory tract and intestines of patients revealed the predominant microbes. They turned out to be fungal microorganisms (69.8% of all tests). Moreover, yeast-like fungi of the genus Candida were present in sputum in 63.3% of cases, fungi of the genus Aspergillus and Penicillium – in 2.3 and 4.1% of cases, respectively. So, fungal microflora was the most common in the sputum of patients with bronchial asthma. Almost all of these microorganisms were found in association with bacteria. The data obtained coincided with studies of recent years, which indicate an increasing occurrence (over 80% of cases) of fungal flora in sputum cultures in patients with bronchial asthma. A study on dysbacteriosis revealed the presence of yeast-like fungi of the genus Candida in 99.6% of patients from all examined.
As you know, Candida can cause the usual carriage in clinically healthy people. It is a saprophyte that lives on the skin, in the oral cavity and intestinal mucosa of healthy people, while possessing pathogenic properties. On the skin of a healthy person, it is detected in 19-70%, in the oral cavity in adults – in 20-30% and in newborns – in 90% (!) Of cases, and in the intestines of adults and children – in 36 and 50%, respectively. And according to our data, Candida spp . it is sown in most cases with bronchial asthma from sputum and intestines.
An analysis of epidemiological data revealed that there is a direct relationship between an increase in the prevalence of Candida in the population and an increase in the incidence of bronchial asthma.
In the 50s of the last century, the incidence of asthma was 0.1-0.5%, and the frequency of candidiasis – from 5 to 15%.
In the 60-80s, asthma was detected in 1-3% of the population, and the frequency of candidiasis reached 20-53%.
And in our time – in 1990-2001. – the average incidence rate was 4-15%, and candidiasis – 60-70%. Thus, both indicators over the years have simultaneously increased by at least 5-10 times. When
Candida fungi enter the mucous membranes in favorable situations (massive antibiotic therapy) due to frequent recurrences of respiratory infections, weakness of local immune defense, etc.), they begin to multiply actively and, releasing locally acting toxins , cause damage to the epithelium. And candidotoxins secreted by fungi are able to release histamine from mast cells, leading to inflammation. It is in this way that when fungi of the genus Candida enter the bronchial tree, they are quite capable of activating the initial inflammatory process. And then the reactions of the immune system are launched with all the ensuing consequences.
Thus, the beginning of reproduction of Candida and the release of toxins by it causes an initial inflammatory process, which can proceed as a neutrophil. This also happens because in the presence of fungal flora, the pathogenicity of other microbes increases dramatically, and they also take an active part in the development and progression of the inflammatory process on the mucous membranes of the respiratory tract. In the future, after switching from Th1- to Th2-helper response, the nature of inflammation changes to eosinophilic and asthma itself is formed. Scientific literature data confirm that fungi of the genus Candida are able to switch the normal Th1-helper immune response to the Th2-pathological one.
All these processes can be considered as a failure of the innate immune cellular mechanisms (causing massive tissue damage due to phagocytosis) to free themselves from the massive invasion and colonization of fungi of the genus Candida . And as a result of this, the immune system is forced to switch to a less damaging – antibody -forming pathway with the participation of Th2 helpers, which leads to atopy . The formed atopy causes allergic ( antibody-mediated ) reactions of an immediate type to allergens “guilty” for the body, manifesting itself as sudden paroxysms of spasm against the background of an inflammatory process persisting in the bronchial tree.
At the same time, inflammatory reactions of a cell-mediated (delayed) type occur in the bronchi with the participation of killer T-lymphocytes. As already mentioned, they develop when the immune system encounters antigens on the surface of foreign cells. Thus, it can be assumed that the main cause of the development of bronchial asthma is yeast-like fungi of the genus Candida . They are considered saprophytes that live in the human oral cavity and intestines. With uncontrolled reproduction and colonization on the intestinal mucosa, they induce a rearrangement of the immune response from the Th1- to the Th2-helper pathway, which leads to allergies. When inhaled in association with bacteria, they induce initial neutrophilic inflammation. And the transition from Th1- to Th2-helper pathway translates the inflammatory process into eosinophilic, which ends with the formation of bronchial asthma itself.
And so there can be both allergies without asthma and asthma without allergies. In the case of their combination, allergy is one of the factors that further aggravate the inflammatory process in the bronchial tree and contribute to its chronicity .
Aggravating the spread of asthma and allergies is the frequent prescription of antibiotics, which leads to massive colonization of Candida in the human body. And if we once again recall the data on the frequency of candida and asthma in different years, we can see that their growth is observed precisely with the beginning of the “era” of active use of broad-spectrum antibiotics (late 50s – early 60s). This issue is discussed in detail in the well-known monograph by A. Arievich and Z. Stepanishcheva “Candidamycosis as a complication of antibiotic therapy”, which was published precisely in these years.
The current level of candidacy (from 20 to 70%) cannot be considered normal. It is no coincidence that in recent years the frequency of local and systemic candidiasis has increased to such an extent that broad-spectrum antifungal drugs are advertised in the media. And when all the above considerations are taken into account, it becomes clear why the GINA International Committee of Experts came to the following conclusion: this area.” Thus, all three factors: the broad start of antibiotic therapy, the growth of candida and the incidence of bronchial asthma fall on the same period.
The fungal onset of asthma also explains another fact: a more frequent incidence among relatives, since the household route of transmission of this infection is well known. There are cases of sequentially developing asthma in non-blood relatives in contact with each other, for example, a husband and wife. This is inexplicable from the standpoint of heredity, but from the standpoint of the transmission of the contagious beginning, it has a certain logic. And lastly, the incidence among siblings is higher in twins. This is due to the fact that the likelihood of simultaneous infection with fungi from the mother in twins is much higher. Therefore, there have been unsuccessful attempts to link asthma to heredity, which is explained by the infectious nature of bronchial asthma. And among identical twins, there are concordant cases, when both are sick, and discordant , when one of the twins is sick and the other is healthy.
Careful clinical and epidemiological studies have shown that fungi of the genus Candida should be found only in 5% of healthy people on the oral and pharyngeal mucosa. The uncontrolled growth of this number has led to adverse consequences in public health. Apparently, microorganisms as the cause of inflammatory diseases, and not just asthma, play a more important role, especially in cases where they affect human organs and systems by switching the immune system to an unusual path. And reconsidering the relationship between a person and a microbe from this point of view will lead to a significant change in ideas about causality in medicine in general.