Obliterative bronchiolitis: causes, symptoms, diagnosis, treatment

Obliterating bronchiolitis is a disease from the group of “diseases of the small respiratory tract” in which the bronchioles are affected - respiratory tracts with a diameter of less than 2-3 mm that do not have a cartilaginous base and mucous glands.

A distinction is made between terminal and respiratory bronchioles. Terminal (membranous) bronchioles are air-conducting respiratory tracts, their wall contains smooth muscle cells. Terminal bronchioles are divided into respiratory bronchioles of the 1st, 2nd, and 3rd order.

The third order respiratory bronchioles branch into alveolar passages, which branch 1 to 4 times and end in alveolar sacs. Three generations of respiratory bronchioles, alveolar passages, and alveolar sacs make up the respiratory section, where gas exchange between air and blood occurs.

The wall of the respiratory bronchioles contains ciliated epithelial cells and alveolocytes and does not have smooth muscle cells. The number of ciliated cells decreases as the respiratory bronchioles branch and the number of non-ciliated cuboidal cells increases.

Respiratory bronchioles are transitional airways, i.e. they participate in both air passage and gas exchange.

The cross-sectional area of the small airways is 53-186 cm3 ^, which is many times greater than the area of the trachea (3-4 cm3 ⁾ and large bronchi (4-10 cm3 ⁾. The small airways account for only 20% of the total respiratory resistance. That is why damage to the bronchioles in the early stages of the disease may not be accompanied by pronounced symptoms. A vivid clinical picture appears with advanced damage to the small airways.

Causes and pathogenesis of obliterating bronchiolitis

The main causes of the disease are:

• heart-lung complex and bone marrow transplant;
• viral infections (respiratory syncytial virus, HIV, adenovirus, cytomegalovirus, etc.);
• mycoplasma infection;
• inhalation of toxic substances (sulfur dioxide, nitrogen dioxide, chlorine, phosgene, ammonia, chloropicrin, etc.);
• diffuse connective tissue diseases (rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome);
• taking certain medications (D-penicillamine, gold preparations, sulfasalazine);
• inflammatory bowel disease;
• radiation therapy;
• IgA nephropathy;
• Stevens-Johnson syndrome (a type of acute erythema multiforme exudative, characterized by an extremely severe course).

The most well-studied forms are those that develop after lung transplantation. In most cases, the cause of obliterating bronchiolitis can be determined. If the cause is unknown, the disease is called idiopathic.

In obliterating bronchiolitis, inflammation and subsequently severe fibrosis develop in the bronchioles.

The main pathogenetic factors are:

• excessive production of cytokines, among which gamma interferon and interleukin 1-0 play an important role; in obliterating bronchiolitis, the gene expression of these cytokines is increased. Interleukin 1-beta regulates the growth of lymphocytes, their differentiation and cytotoxicity, and gamma interferon induces the expression of HLA class II antigens on the epithelial cells of the bronchioles and regulates the production of immunoglobulins;
• increased expression of HLA class II antigens on bronchiolar epithelial cells (this mechanism is important primarily in autoimmune, drug-induced post-transplant forms of the disease);
• activation of cytotoxic T-lymphocytes;
• high activity of platelet-derived growth factor, which stimulates fibroblast proliferation;
• increased secretion of fibronectin by bronchiolar epithelial cells, which is a chemotherapeutic agent for fibroblasts;
• significant increase in the activity of integrins, which perform the function of adhesion of fibroblasts, endothelial cells to fibronectin, fibrinogen. Adhesion of cells to fibronectin occurs with the help of alpha-5-beta-1-integrin, to fibrinogen - with the help of alpha-5-beta-3-integrin. These processes stimulate fibrosis formation in the bronchioles.

The main pathomorphological manifestations of the disease are:

• bronchiolar or peribronchiolar inflammatory infiltrate of varying density;
• development of bronchioloectasis with secretion stasis, accumulation of macrophages, and mucous plugs;
• partial or complete obliteration of the bronchioles by coarse scar connective tissue;

In obliterating bronchiolitis, terminal bronchioles are usually affected. Respiratory bronchioles, alveolar ducts, alveolar sacs and alveoli are not involved in the inflammatory process. In addition to small airways, large bronchi are also involved in the inflammatory process, in which cylindrical bronchioloectasis, mucous plugs, purulent exudate, and chronic inflammatory infiltrate are often found.

In post-transplant obliterating bronchiolitis, damage to the pulmonary vessels is characteristic.

Symptoms of obliterating bronchiolitis

The main clinical manifestations of obliterating bronchiolitis are the following:

1. Progressive dyspnea is a cardinal symptom of the disease. At first, dyspnea bothers mainly after physical exertion, but later it quickly increases and becomes constant.
2. An unproductive cough is a common symptom of the disease.
3. During auscultation of the lungs at different stages of the disease, dry wheezing rales are heard, sometimes a characteristic inspiratory "squeak", especially in the lower parts of the lungs, however, as the disease progresses, vesicular breathing becomes increasingly weakened and dry wheezing disappears.
4. The pathological process often involves large bronchi, in which colonization of bacterial (most often Pseudomonas aeruginosa) and fungal (Aspergillus fumigatus) flora may occur, causing high body temperature, productive cough, and possible formation of bronchiectasis.
5. In the later stages of the disease, diffuse warm cyanosis, “puffing” breathing, and pronounced tension of the accessory respiratory muscles develop.

The onset of obliterating bronchiolitis can be acute (after inhalation of hydrochloric acid or sulfur dioxide, after viral infections), delayed, i.e. after a clear interval (after inhalation of nitric oxide) and gradual, almost imperceptible - in diffuse connective tissue diseases and after lung transplantation.

Diagnosis of obliterating bronchiolitis

Instrumental research

X-ray of the lungs

X-ray examination may show increased transparency of the lungs (hyper-airiness), less often - weakly expressed dissemination of the focal-reticular type. However, these changes are observed in only 50% of patients.

High Resolution Computed Tomography

Normally, unchanged bronchioles are not visible on a CT scan, since their wall thickness is no more than 0.2 mm, which is less than the resolution of the method. In obliterating bronchiolitis, bronchioles become visible due to inflammatory and fibrous thickening of the walls.

Characteristic diagnostic signs on computed tomograms are:

• small branched opacities or centrilobular nodules (due to peribronchial thickenings);
• bronchiectasis, detected on exhalation in 70% of patients;
• mosaic oligemia of a "spotted" nature due to hypoventilation and "air trapping" (obliteration of the bronchioles prevents complete evacuation of air). Obliteration of the bronchioles is accompanied by secondary vasoconstriction against the background of local hypoxia. Mosaic oligemia is manifested by the fact that the area of the lung parenchyma corresponding to the unchanged bronchioles becomes denser on exhalation, and the affected areas become supertransparent.

Functional tests

A study of the external respiratory function reveals obstructive type disorders:

• decrease in maximum pulmonary ventilation;
• decrease in FVC and FEV1, as well as the Tiffeneau index (FEV/VC).

An increase in the concentration of nitric oxide in exhaled air is also considered characteristic.

Blood gas analysis

The most characteristic are hypoxemia and hypocapnia, hypercapnia is detected less often.

Bronchoscopy, lung biopsy

Bronchoscopy is uninformative, since the pathological process is localized distally to the bronchi, in the bronchioles, and is difficult to examine. Transbronchial or open lung biopsy reveals characteristic inflammatory and fibroplastic changes in the bronchioles.

Clinical classification

The International Society for Heart and Lung Transplantation (1993) suggests that the degree of obliterative bronchiolitis should be determined by determining the baseline FEV1 as the average of the two highest previous measurements, and then comparing the current FEV1 value with the baseline.

• Grade 0: FEV1 more than 80% of the baseline.
• Grade I: FEV1 - 66-79% of the initial level.
• Grade II: FEV1 - 51-65% of the initial level.
• Grade III: FEV1 less than 50% of baseline.

In addition, it is necessary to evaluate the histological picture to identify signs of obliterating bronchiolitis.

• Type A - no evidence of obliterating bronchiolitis (or biopsy was not performed).
• Type B - morphological signs of obliterating bronchiolitis.

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