Although the most typical forms of respiratory mycoplasmosis and chlamydia are pneumonia (often occurring with obstructive syndrome), their clinical forms are described in the form of acute and recurrent obstructive bronchitis, a high infection rate of patients with bronchial asthma and obstructive bronchitis with these microorganisms has been established, reaching 32 – 90% for different pathogens .
Available evidence of the participation of mycoplasmas and chlamydia in the development of bronchial obstructive syndrome can conditionally be divided into three groups: epidemiological, pathophysiological and clinical.
I. Epidemiological data.
Bronchial asthma.
According to JS Seggev et al. (1986), in 21% of patients with bronchial asthma during exacerbation, specific IgM antibodies to M. pneumoniae were determined in high titers. Mycoplasma infection of the lungs, like a viral one, is often detected during the development of severe exacerbations of bronchial asthma (in 41 of 142 examined patients, i.e., in 29%), which may be evidence of its role in the induction of these exacerbations. The role of M. pneumoniae in the induction of exacerbations of bronchial asthma may also be evidenced by data on a very high percentage of colonization of the respiratory tract of patients with asthma compared with healthy individuals – 24.7% and 5.7%, respectively. In earlier works of domestic researchers, there are indications that among patients with chronic nonspecific lung diseases, mixed virus, mycoplasma or monomicoplasma infection was diagnosed in 14 – 57% of patients. It is interesting to identify these patients, along with M. pneumoniae, M. hominis.
In young children with asthma, a more massive infection with respiratory viruses and M. pneumoniae was revealed, which is manifested by hyperproduction of antibodies to these pathogens. L. G. Kuzmenko et al. (1999), using the serological method and polymerase chain reaction (PCR), found that the infection rate of M. pneumoniae in children with bronchial asthma is 88%. Other authors found antimycoplasmic antibodies in a smaller percentage of cases (66%) in children with asthma, noting the relationship of the active infection process with the development of seizures.
Both acute asthma attacks and the chronic course of bronchial asthma are associated with serologically confirmed chlamydial respiratory infection, which confirms the role of this intracellular pathogen in the development of airway hyperresponsiveness. According to domestic researchers, the infection of children with asthma with chlamydia ranges from 19.7% to 61%. When studying the species structure of chlamydia associated with bronchial asthma, it was revealed that in the vast majority of cases it is C. pneumoniae – 32.3%. C. trachomatis and C. psittaci are infected only 4.4% of patients with bronchial asthma. However, according to S. M. Gavalov et al. (1999) serological markers of C. psittaci infection were detected in 43% of children with bronchial asthma.
Obstructive bronchitis.
Some authors consider Mycoplasma pneumoniae one of the main etiological factors of acute obstructive bronchitis and bronchiolitis. According to N. M. Nazarenko et al. (2001), infection with this pathogen is detected in 85% of children with recurrent obstructive bronchitis.
According to V.N. Kholopkin et al. (1999) anti-chlamydial antibodies are found in 69% of young children suffering from recurrent obstructive bronchitis. The causative agent of ornithosis, C. psittaci, is considered one of the causes of chronic lung diseases that occur in violation of bronchial obstruction. According to S. M. Gavalov et al. (1999) serological markers of C. psittaci infection were detected in 67% of the examined children with recurrent obstructive bronchitis.
The results of a survey of adult patients with a diagnosis of chronic obstructive bronchitis showed that antibodies to C. pneumoniae classes of IgG and IgA are detected in comparison with the control group (practically healthy people) much more often and in higher titers. A high level of C. pneumoniae infection in patients with chronic obstructive pulmonary disease (COPD) was found in a study in Turkey: 11 (22%) out of 49 patients. According to M. Lionen (1998), in more than half of severe cases of COPD, there is a relationship between the symptoms of the disease and infection with C. pneumoniae; according to other researchers, about 1/3 of COPD relapses are associated with mycoplasmas and chlamydia.
In a large percentage of cases in patients with asthma and obstructive bronchitis, a mixed infection due to mycoplasmas and chlamydia is detected. According to our data, serologically confirmed infection caused by M. pneumoniae is registered in 53% of children with bronchial asthma and in 28% of patients with obstructive bronchitis, M. hominis – infection – in 55% and 67%, chlamydial infection – in 47% and 55 %, respectively, while in 28% and 37%, respectively, a mixed mycoplasma-chlamydial infection is recorded.
II. Pathophysiological data.
The pathogenesis of the development of bronchial obstruction in the considered obstructive pulmonary diseases under conditions of infection with mycoplasmas and chlamydia is different and is determined both by the nature of the interaction of the infectious agent with the macroorganism, and the state of the respiratory tract, bronchial hyperreactivity. The mechanisms of infectious-caused bronchial hyperreactivity can conditionally be divided into immunological and non-immunological.
Immunological mechanisms include the development of allergic reactions of immediate and delayed hypersensitivity.
The immunological basis of allergic inflammation is the polarization of CD4 + T-lymphocytes towards a subpopulation of Th2 cells. These cells under the influence of allergenic stimuli produce interleukins (IL) – IL3, IL4, IL5, IL6, IL10, the total effect of which is manifested in increased production of IgE antibodies. Subsequently, IgE antibodies are fixed on mast cells, basophils and eosinophils recruited under the influence of the same cytokines into the respiratory tract.
The causative role of mycoplasma infection in the development of bronchial asthma is demonstrated by the detection of specific IgE antibodies to M. pneumoniae, a positive immediate scarification test for M. pneumoniae. Specific IgE antibodies are synthesized by C. pneumoniae.
According to our data, in children with bronchial asthma not infected with mycoplasmas, significantly more often (p <0.05), compared with infected, normal values of total IgE in serum were recorded. In patients with “mycoplasma” asthma, on the contrary, indicators of total IgE were more often higher than normal by more than 10 times; while with “chlamydial” asthma, an increase in the concentration of total IgE by 2-10 times was most often detected. In general, in children infected with intracellular pathogens, the level of total IgE in the blood serum was exceeded significantly more often (p <0.01), by more than 10 times and significantly less frequently (p <0.05) – normal indicators of total IgE were compared to uninfected.
Other researchers have also found an increase in total IgE in asthma patients infected with mycoplasmas / chlamydia. An increase in the level of total IgE, apparently, distinguishes “mycoplasma” and “chlamydial” asthma from other variants of infectious-dependent bronchial asthma, which, according to some researchers, are characterized by normal values of total IgE.
Detection of eosinophilic infiltrates in the lungs and peripheral blood eosinophilia with chlamydial, ornithous pneumonia, and pneumonia caused by C. trachomatis (up to 15%) can be additional evidence of the development of the effector phase of allergic reactions in chlamydial infections. Blood eosinophilia was statistically significantly more often observed in patients with bronchial asthma infected with chlamydia, compared with uninfected. Some authors have observed a correlation between the number of eosinophils in the peripheral blood in patients with bronchial asthma and the degree of impaired respiratory function, as well as the concentration of the large main protein of eosinophils and bronchial hyperreactivity.
At the same time, non-atopic immunological mechanisms also take part in the pathogenesis of bronchial asthma, especially an infection-dependent form, in particular, the possible role of delayed-type hypersensitivity in the pathogenesis of this form of the disease is discussed.
Although population-based studies suggest a relationship between the prevalence of atopy and bronchial asthma, or between levels of IgE and bronchial asthma, most researchers do not find a complete correlation between the increase in atopy and the number of patients with bronchial asthma. This suggests that the significance of atopy as a cause of bronchial asthma can be exaggerated and that atopy should be considered only as one of the factors, even if very important, necessary for the development of the disease. According to some reports, in 30% of patients with atopic diseases, normal serum IgE values are recorded. It is assumed that the type of cell inflammation and bronchial hyperreactivity syndrome depend on a set of locally acting cytokines, the synthesis and secretion of which in tissues is not necessarily the result of IgE-mediated reactions.
The specific stimulation of lymphocytes in M. pneumoniae infection causes the development of HRT. Morphological signs of HRT were reproduced both during experimental infection of animals and in an organ culture of lung tissue, and were determined by autopsy. Skin-allergic HRT reactions were detected in intranasally infected guinea pigs. After intravenous administration of the M. pneumoniae antigen, anaphylactic shock developed with typical anaphylactic bowel contracture. According to the authors, bronchospasm phenomena observed in patients with mycoplasma pneumonia may be pathogenetically associated with a similar increase in smooth muscle reactivity.
According to autopsy data, deaths from mycoplasma pneumonia show characteristic changes in the interalveolar septa: histiocyte proliferation, leukocyte infiltration, the formation of peribronchial, peribronchiolar and perivascular lymphoid infiltrates. The lymphocytic reaction is caused by mycoplasma mitogens and is not protective. Apparently, it can be the result of not only hypersensitivity to the pathogen, but also the polyclonal activation of lymphocytes by mycoplasmas.
There are suggestions of a similar development of the immune response along the Th1-dependent pathway in chronic chlamydia caused by C. pneumoniae and proceeding as typical bronchial asthma in allergy-prone individuals. In this case, the cellular composition of the inflammatory infiltrate in the respiratory tract will differ from the atopic variant of bronchial asthma with an increase in the proportion of neutrophils and the predominance of Th1 lymphocytes. The development of Th1 polarization, HRT, has been described in genital chlamydia and Reiter’s disease caused by C. trachomatis. In general, the development of HRT, T-cell immune response, activation of Th1 cells is determined by the intracellular localization of pathogens.
High rates of infection of patients with obstructive pulmonary diseases with mycoplasmas and chlamydia can be explained from immunological positions. Common to these infections with obligate or optional intracellular localization of the pathogen is the control and provision of protective immunity with T-lymphocytes, CD4 + -, Th1-cells. On the other hand, what is common for bronchial asthma and obstructive bronchitis is precisely T – cell immunological deficiency, a decrease in the number and functional state of CD3 + cells (T – lymphocytes), CD4 + cells or CD8 + cells, Th1 cells, including under conditions infection with mycoplasmas / chlamydia. It is indicated that low levels of interferon-g and hyperproduction of IL-5 in patients with atopic bronchial asthma facilitate infection and contribute to the persistence of C. pneumoniae. According to a number of researchers in children with asthma, recurrent obstructive bronchitis, suffering from chlamydial infection, there is a decrease in the functional activity of T-lymphocytes. Some authors attribute mycoplasmas and chlamydia to the causative agents of opportunistic infections due to the fact that the diseases they cause often occur against the background of a violation of the immune status.
Infectious agents, acting through non-specific mechanisms, and in individuals without a predisposition to allergies who are previously healthy, create all the necessary conditions in the respiratory tract for the formation of bronchial hypereactivity, its fixation and the development of chronic obstructive pulmonary diseases. The participation of nonspecific inflammatory mechanisms involved in impaired bronchial patency in the development of mycoplasmosis and chlamydia was confirmed by immunological, functional and morphological studies of these infections.
So, it has been shown that with respiratory mycoplasmosis there is a significant slowdown in airway clearance from mucus and extraneous microflora for a period of up to 1 year – 3 years after mycoplasma pneumonia. A decrease in the functions of the respiratory system and ciliary activity of the ciliated epithelium contributes to an increase in the invasiveness of the pathogen, the occurrence of exogenous reinfection and penetration of pathogenic microflora into the lung tissue, mixed infection, and the protracted and chronic course of infectious processes. Typical morphological findings in this infection are diffuse dystrophic and inflammatory lesions of the bronchi, desquamative tracheobronchitis and alveolitis due to mycoplasma lesions of alveolocytes, peribronchial and perivascular interstitial plasma cell infiltration, distelectases due to inactivation of surfactant.
Chlamydia tropic to the cylindrical epithelium. Under the influence of C. pneumoniae, IL-1b, IL-6, TNFa are released, ciliary epithelium ciliostasis occurs, and a correlation of bronchial asthma symptoms with the synthesis of specific IgE antibodies and with these chlamydia-stimulated processes is shown. Propagating in macrophages, chlamydia can disrupt their protective functions, the existence of chronic chlamydial infection before the onset of clinically developed bronchial asthma is also shown. Morphologically, respiratory chlamydia is characterized by interstitial lymphocytic infiltration, proliferation and degenerative changes in the bronchial epithelium, swelling of the bronchial glands, detection of necrotic bronchioles with their and alveoli consolidation.
Violation of the clearance of the contents of the bronchi and increased permeability of the damaged epithelium creates the possibility of additional infection of the bronchi with bacteria and fungi and penetration through the mucous membrane of the bronchi of inhaled allerenes and toxic substances.
Studies of large groups of adults who had an infection of the upper or lower respiratory tract showed that patients with serologically confirmed mycoplasma, chlamydia had significantly lower FEV1 in the acute period and greater reversibility of this indicator than patients with a different etiology.
III. Clinical data.
Bronchial asthma
It was established that M. pneumoniae and C. pneumoniae can cause both the onset of the disease and cause its exacerbation and severe course options. According to P. Endres (1982), pneumotropic viruses and mycoplasma cause 70% of severe asthmatic conditions.
There are some general clinical features of the course of bronchial asthma against the background of mycoplasma and chlamydial infections in children. These include a prolonged nosad, sometimes pertussis-like cough, more frequent asthma attacks, a prolonged course of an acute attack of bronchial asthma, a slow clinical and laboratory dynamics of the process, a more persistent decrease in bronchial obstruction, the development of an attack of the disease at normal body temperature, the absence of toxicosis, laboratory signs activity of inflammation, as well as the lack of effectiveness of basic therapy and improvement of the condition against the background of etiotropic antibacterial therapy with macrolides.
The anamnestic features of the course of bronchial asthma against the background of chlamydophilus infection in children caused by Clamydophila pneumoniae and Clamydophila psittaci are described. Compared with uninfected chlamydia, infected patients revealed a higher incidence of chronic bronchitis, tonsillitis and sinusitis in parents and relatives; complicated by the development of conjunctivitis and pneumopathy during the neonatal period; more frequent keeping of domestic animals (cats, dogs, birds), which are known to be a source of infection; the manifestation of asthma mainly at an early age with the development of a characteristic symptom complex: obsessive cough, shortness of breath, low-grade fever. The mild course of asthma in patients with chlamydophyllosis was two times less common than uninfected and was characterized by a lack of seasonality in 45.9% of patients; among triggers of attacks, acute respiratory viral infections and physical activity were more often noted, while in children with asthma without chlamydophilic infection, exposure to an allergen in combination with acute respiratory viral infections or without it.
However, according to R.F. Hamitov et al. (2000), the majority of the anamnestic, clinical, and laboratory differences in bronchial asthma in adults, occurring in combination with mycoplasma (in 38% of cases) and chlamydial (in 35%) infections and in their absence, are not statistically significant.
The efficacy of etiotropic therapy of mycoplasmosis and chlamydia with macrolides in combination with immunocorrectors (polyoxidonium, thymomimetics) in children with bronchial asthma has been shown. The role of C. pneumoniae in the pathogenesis of exacerbation of the disease can be confirmed by clinical and laboratory data on a decrease in airway reactivity in children with bronchial asthma after stopping this infection, achieved with antibiotic therapy with erythromycin or clarithromycin.
Studies in the UK and the USA have revealed a statistically significant increase in steroid dependence of forms of bronchial asthma in patients infected with C. pneumoniae, compared with uninfected. After specific antibiotic therapy, an improvement in the course of the disease and a decrease in steroid dependence were noted.
Our comprehensive assessment of clinical and medical history data and indicators of laboratory and instrumental examination methods in children with bronchial asthma, depending on the infection by pathogens of mycoplasmosis and chlamydia, allowed us to determine the characteristic features of these diseases in conditions of mycoplasma and chlamydial infections.
“Mycoplasma” bronchial asthma more often, compared with a disease not associated with this pathogen, started at the age of 3-7 years (p <0.001) and less often in infancy (p <0.05), and the duration of the disease was more often 5 years (p <0.001) and less than 1 year (p <0.001). Real pregnancy in mothers of infected children was more often complicated by early gestosis (p <0.05). Children infected with mycoplasmas, compared with uninfected, more often suffered asphyxia during childbirth (p <0.05) and acute pneumonia (p <0.05), less often suffered from atopic dermatitis (p <0.05). The clinical picture of exacerbation of the disease in patients infected with mycoplasmas was characterized by a more frequent detection of box percussion sound (p <0.01), weakened breathing (p <0.01), locality / asymmetry of physical data over the lungs (p <0.001).
Patients with “chlamydial” asthma less often, compared with uninfected chlamydia, the trigger of the attack was pungent odors (p <0.05), the disease more often began at the age of 1-3 years (p <0.05); these patients more often suffered from atopic dermatitis (p <0.01) and hypertrophy of the tonsils (p <0.05). The clinical picture of the attack in patients infected with chlamydia was characterized by a more frequent detection of subfebrile condition (p <0.05), tachycardia that did not correspond to the degree of fever (p <0.05), less often (p <0.01) a percussion sound was detected over the lungs. An X-ray examination in children with chlamydial asthma more often (p <0.05) revealed atelectasis.
In general, in patients with bronchial asthma infected with mycoplasmas and chlamydia, compared with uninfected, the disease less often began in infancy (p <0.05) and more often in the age of 3-7 years (p <0.001), which coincided with a period of expanding socialization of the child and is consistent with data on the spread of mycoplasma and chlamydial infections in organized groups (Bartlett J.J., 2000, Tartakovsky I.S., 2000). Patients infected with these pathogens often suffered from prolonged (more than 3 weeks) cough (p <0.001), malnutrition (p <0.05), atopic dermatitis (p <0.05), palatine hypertrophy (p <0.05) and pharyngeal (p <0.01) tonsils, suffered acute pneumonia in the post-neonatal period (p <0.01), in half of the children with bronchial obstructive syndrome (p <0.05), while some of the children had its mycoplasma / chlamydial etiology . Exacerbation of bronchial asthma under conditions of infection with mycoplasmas / chlamydia was characterized by greater severity, as evidenced by the high frequency of registration of cyanosis (p <0.05) and tachypnea with respiration rates exceeding normative indices by 50-100% (p <0.05) . Compared to uninfected patients, dry cough (p <0.05), respiratory depression during auscultation of the lungs (p <0.001), locality / asymmetry of physical data over the lungs (p <0.001), probably reflecting the presence of atelectasis, which were more often recorded in infected patients (p <0.05). In a clinical blood test in patients infected with mycoplasmas and chlamydia, more often, compared with uninfected, an increase in ESR of more than 20 mm / h was recorded (p <0.05); in a biochemical blood test – an increase in the level of seromucoid (p <0.05) and lactate dehydrogenase (LDH) (p <0.01).
Based on the foregoing, it can be seen that bronchial asthma in children infected with mycoplasmas and chlamydia has both atopic features (high history of allergic diseases, early asthma, an increase in total serum IgE), and non-atopic, infectious dependent form of the disease (“experience” of more than 5 years, the preceding disease pneumonia, cough lasting more than 3 weeks and concomitant pathology of ENT organs, the severity of seizures, accompanied by a pronounced inflammatory reaction, sensitization to bacterial allergens), including some characteristic features of mycoplasmosis and / or chlamydia. These, in particular, include acute pneumonia in the post-neonatal period in patients with mycoplasmosis; the presence of tachycardia that does not correspond to body temperature in patients with chlamydial infection; cough lasting more than 3 weeks, palatine tonsil hypertrophy, locality or asymmetry of physical data, probably due to the development of atelectasis, an improvement in the condition and a decrease in the severity of bronchial obstructive syndrome during etiotropic antibacterial therapy – in general, in the group of patients infected with mycoplasmas and chlamydia. Similar features are known from descriptions of these infections.
In the outcome of SARS, the formation of bronchial hyperreactivity is described [125, 276]. In patients with chlamydial infection, the development of tachycardia that does not correspond to body temperature and other heart rhythm disturbances, in particular, with Reiter’s disease, is described. The ability of mycoplasmas and chlamydia to cause a prolonged, lasting more than 3 weeks, paroxysmal, whooping cough, including in patients with bronchial asthma, is known. Of particular interest is the study of the role of chlamydia and mycoplasmas in the development of bronchial asthma in connection with the allocation of the “cough” variant of asthma. With chlamydial pneumonia, whooping cough is observed – obsessive, acyclic, but not accompanied by reprise, unlike whooping cough, is a cough (in young children, a cough is stockato). A prolonged, debilitating, unproductive cough is the leading clinical symptom of mycoplasmosis. One of the reasons for this cough with these infections is the loss of tonus of the membranous part of the trachea and the main bronchi, which leads to their dyskinesia. The asymmetry of wheezing and infiltrative changes is considered as a characteristic sign of mycoplasma bronchitis and pneumonia.
Obstructive bronchitis
When assessing the clinical features of mycoplasma obstructive bronchitis, it should be noted that the role of M. pneumoniae is especially great in recurrent obstructive bronchitis and in older children. According to our data, the characteristics of mycoplasma obstructive bronchitis in children are allergic dermatoses with a family history (p <0.05), cough lasting more than 3 weeks before the present disease (p <0.05), hypertrophy of the tonsils (p <0.05).
Acute, recurrent, and chronic obstructive bronchitis, bronchiolitis of chlamydial etiology are described. It is indicated that more often bronchitis caused by C. pneumoniae occurs in older children and adolescents, being in some cases the debut of bronchial asthma of late onset. At the same time, in young children, a characteristic feature of chlamydial bronchitis caused by C. trachomatis is the absence of bronchial obstruction, although severe chlamydial bronchiolitis has been described. According to V.F. Uchaykin (1998), the state of bronchial obstruction for respiratory chlamydia is not characteristic and, if it is present, it is necessary to think of a mixed chlamydial-viral, mainly chlamydial-syncytial infection.
Clinical features of obstructive bronchitis of chlamydial etiology are the frequent recurrence and long duration of each episode of bronchial obstruction, the absence of intoxication, resistance to traditional therapy, as well as, according to our data, cough lasting more than 3 weeks (p <0.05), respiratory depression during auscultation of the lungs ( p <0.05), locality and / or asymmetry of physical data (p <0.05), tachycardia not corresponding to the degree of fever (p <0.05), splenomegaly (p <0.01), increased serum alanine aminotransferase blood (p <0.05), deformation and / or severity of the pulmonary vascular pattern during chest x-ray (p <0.01).
Recurrence of obstructive syndrome in mycoplasma and chlamydial infections and the formation of chronic obstructive, asthmatic bronchitis are associated with the persistence of these pathogens in the respiratory tract, especially in conditions of immunodeficiency, chronic inflammation and the bronchial hyperreactivity supported by it.
The literature provides numerous examples of the positive effects of macrolide therapy in combination with immunocorrectors on the course of recurrent obstructive bronchitis of chlamydial etiology, confirmed by a decrease in titers or the disappearance of specific antibodies.