Idiopathic fibrosing alveolitis: diagnosis

Laboratory data

1. A general blood test - the number of red blood cells and hemoglobin values are usually normal, however, with the development of severe respiratory failure, erythrocytosis appears and hemoglobin level rises. In 25% of patients, a slight degree of normochromic anemia is possible. The number of leukocytes is normal or moderately elevated, with an acute course of the disease, a shift of the leukocyte formula to the left is observed. Characteristic increase in ESR, the most pronounced with a high activity of the inflammatory process.
2. General urine analysis without significant changes. With the development of decompensated pulmonary heart, there is a moderate proteinuria, a microhematuria.
3. Biochemical analysis of blood - increased blood levels of seromucoid, haptoglobin, a2- and y-globulin (these indicators reflect the activity of the pathological process). Characteristic is also an increase in the level of LDH, the source of which are alveolar macrophages and type 2 alveolocytes. LDH levels correlate with the activity of the pathological process in the lungs.

An important marker of the activity of idiopathic fibrosing alveolitis is an increase in serum level of glycoproteins of surfaganga A and D, which is caused by a sharp increase in the permeability of the alveolar-capillary membrane.

With the development of decompensated pulmonary heart, a moderate increase in the content of bilirubin, alanine aminotransferase, gamma-glutamyl transpeptidase in the blood is possible.

4. Immunological analysis of blood is characterized by a decrease in the number of T-lymphocytes-suppressors and an increase in T-helpers, an increase in the overall level of immunoglobulins and cryoglobulins, increased titres of rheumatoid and antinuclear factors, and the appearance of anti-pulmonary antibodies, circulating immune complexes. These changes reflect the intensity of autoimmune processes and inflammation of the interstitium of the lungs.

In recent years, great importance is attached to the definition of mucin antigens in the blood, which reflect both the intensity of inflammation in pulmonary interstitium and the severity of autoimmune processes. Mucins are surface glycoproteins that provide "gluing", the union of epithelial cells (including alveolocytes) and the formation of a monolayer. The level of mucins in the blood reflects hyperplasia and hypertrophy of type 2 alveolocytes and their increased mucinogenesis function. In addition, mucins can be produced by goblet cells of the bronchial epithelium and the secretory cells of the glands of the submucosal layer. Mucins are markers of activity of pathological process and expression of autoimmune reactions. In the blood serum with idiopathic fibrosing alveolitis, mucin antigens SSEA-1, KL-6, 3EG5 are detected.

5. Investigation of the lavage fluid of the bronchi (obtained during bronchial flushing) - significantly increased the number of neutrophils, eosinophils, lymphocytes, alveolar macrophages, increased activity of the pro-clastic enzymes of elastase and collagenase (in the late stages of idiopathic fibrosing alveolitis, a decrease in proteolysis activity), significantly increased the content of immune complexes, IgG .

Characteristic for the active current alveolitis is the neutrophil-eosinophilic association and pronounced lymphocytosis. Severe eosinophilia of bronchial lavage fluid is observed in patients with an unfavorable prognosis and poor response to treatment with glucocorticoids. The cytological composition of bronchial lavage fluid is affected by smoking: smoking alveolar macrophages, neutrophils, eosinophils are significantly higher in comparison with non-smokers.

Of great importance is the definition in the lavage fluid of the bronchial lipids and certain proteins that reflect the synthesis and functioning of the surfactant. The following changes have been made:

• the overall level of phospholipids decreases (the lower their level, the worse the prognosis);
• the fractional composition of total phospholipids changes (the ratio of phosphatidylglycol to phosphatidylinositol decreases);
• the content of protein-contaminating agent-A decreases (this sign correlates with the activity of the alveolitis).

The activity of the inflammatory process in idiopathic fibrosing alveolitis is also indicated by the high concentration in the lavage bronchial fluid of its following components:

• mucin antigens KL-6 - products of secretion of alveolocytes of type 2;
• procollagen-3 peptidase (secreted by fibroblasts);
• elastase (produced by neutrophilic cells);
• histamine and tryptase (excreted during degranulation of mast cells);
• angiotensin-converting enzyme (produced by endothelial cells);
• fibronectin and vitronectin - components of the extracellular matrix.

6. Sputum analysis - no significant changes. With the addition of chronic bronchitis, the number of neutrophilic leukocytes is increased.

Instrumental research

Radiography of the lungs is the most important diagnostic method for idiopathic fibrosing alveolitis. There are bilateral changes mainly in the lower parts of the lungs.

Μ. Μ. Ilkovich (1998) gives three variants of radiological changes in idiopathic fibrosing alveolitis:

• primary lesion of interstitial lung tissue (mural variant);
• Primary alveolitis (desquamative variant);
• X-ray picture corresponding to the "honeycomb light".

The variant with the predominant lesion of the interstitial tissue is characterized in the early stages of the disease by a decrease in the transparency of the lungs by the type of "frosted glass," a certain decrease in the volume of the lower lobe of the lungs, a decrease in the structure of the roots, a mesh deformation of the pulmonary pattern, peribronchial-perivascular coupler changes. With the progression of IFA against a background of rough tyazhistosti and restructuring of the pulmonary pattern, rounded cystic enlightenments with a diameter of 0.5-2 cm ("honeycomb lung") appear. In later stages of idiopathic fibrosing alveolitis, tracheo-megalomy and deviation of the trachea to the right are possible.

The variant with primary lesion of alveoli (desquamative variant) is characterized by two-sided infiltrative darkening of various severity and extent.

In the formation of pulmonary hypertension, there is an expansion of the main branches of the pulmonary artery.

Johnson et al. (1997) consider the following radiographic signs as the most characteristic for idiopathic fibrosing alveolitis:

• outlined nodular-linear dimming (51%);
• changes in the type of "cellular lung" (15%);
• changes in the type of "frosted glass" (5%).

Computed tomography of the lungs is a highly informative method for diagnosing lung damage in idiopathic fibrosing alveolitis and allows to detect changes in pulmonary interstitium at the stage of the disease when conventional radiography of the lungs does not detect them.

The most characteristic signs of idiopathic fibrosing alveolitis with computed tomography of the lung are:

• uneven thickening of interalveolar and interlobular septa (pattern of lung mesh, most pronounced in subpleural and basal regions of the lungs);
• decrease in the transparency of pulmonary fields by the type of "frosted glass" (this sign is revealed with minimal thickening of the alveolar walls, interstitium or partial filling of the alveoli with cells, liquid, detritus);
• signs of "cellular lung" (revealed in 90% of cases) in the form of air cells ranging in size from 2 to 20 mm in diameter (determined much earlier than with lung radiography).

Angiopulmonography - allows to judge the state of pulmonary blood flow in patients with idiopathic fibrosing alveolitis. Expansions of the central branches of the pulmonary artery, narrowing and fuzzy contours on the periphery, slowing of the arterial phase of the blood flow, presence of sites of rapid arteriovenous shunting, accelerated contrast of the venous channel are revealed.

Scintigraphic examination of lungs with a radioactive Ga-method allows one to judge the activity of the alveolitis, since this isotope is concentrated in inflammation-altered tissues. Gali binds to transferrin receptors, which are expressed only on membranes of active alveolar macrophages and therefore a more intensive accumulation of gallium is observed in the active alveolitis. The coefficient of isotope accumulation depends on the severity of the alveolitis and does not depend on its prevalence.

Positron tomography scanning of lungs after inhalation of diethylene-triamine pentaacetate labeled with technetium-99 C-Tc-DTPA) - allows to estimate the permeability of the alveolar-capillary membrane and to reveal diffuse alveolar damage. With a pronounced active inflammatory process, the elimination half-life of the isotope (T1 / 2) is significantly reduced.

Bronchoscopy - does not play a significant role in the diagnosis of idiopathic fibrosing alveolitis. A bronchoscopy can reveal a picture of moderate catarrhal bronchitis.

Examination of the function of external respiration. For the idiopathic fibrosing alveolitis, the symptomatic complex of pulmonary ventilation is characteristic:

• increased respiratory rate;
• a decrease in the volume of inspiration;
• Reduction of the ZHEL, residual lung volume, total lung capacity;
• increased elastic resistance of the lungs;
• decrease in diffusivity of the lungs;
• absence of violations of bronchial patency or little expressed changes in it.

It should be noted that indices of spirography in the early stages of the disease may be normal, but at the same time, there may be a reduction in the total lung capacity, functional residual capacity and residual volume, which is revealed with the help of bodipletizmography or gas dilution method. The reduction in total lung capacity correlates with the severity of the inflammatory response in lung tissue and, unfortunately, with an unfavorable prognosis.

A highly sensitive method at an early stage of the ELISA is the analysis of the pressure-volume curve (by measuring the pressure in the middle third of the esophagus, which corresponds to the intrapleural pressure, followed by the recording of pressure and volume of the lungs in the range of the whole Jelly). With this technique, a decrease in lung elongation and a decrease in lung volume is revealed.

Of great importance is also the determination of the diffusivity of the lungs, which is studied using the single inhalation method of test gas (carbon monoxide) with respiratory arrest. In recent years, the technique of a single inhalation of carbon monoxide without delay of breathing with a gradual smooth exhalation is used. Idiopathic fibrosing alveolitis is characterized by a decrease in the diffusive capacity of the lungs, which is due to a decrease in pulmonary volumes, a thickening of the alveolar-capillary membrane, a decrease in the capillary network.

With a pronounced progression of the pathological process in idiopathic fibrosing alveolitis, obstructive disturbances at the level of the peripheral respiratory tract can form, which may be manifested by a decrease in the volume of forced expiration in the first second.

It should be noted that the study of the functional capacity of the lungs should be carried out not only at rest, but also during exercise, which is especially important for detecting disorders at an early stage of the disease.

Investigation of the gas composition of arterial blood. In the early stages of the disease, only with physical exertion, a decrease in the partial pressure of oxygen is observed, but as the disease progresses, hypoxemia appears in rest. Hypercapnia develops in the terminal stage of idiopathic fibrosing alveolitis (a pronounced increase in the saturation of the blood with carbon dioxide).

Open lung biopsy - this method is considered the "gold standard" for the diagnosis of idiopathic fibrosing alveolitis. The informativeness of the method exceeds 94%. The biopsy is performed from several sites of the lungs - with the greatest and least changes according to the radiography and computed tomography of the lungs. It is recommended to take 2-4 samples from the upper and lower lobes of the lung. Bioptates are subjected to morphological, bacteriological, virological, immunofluorescent, immunohastochemical and electron microscopic studies. With the help of these methods, typical for idiopathic fibrosing alveolitis are revealed changes.

In recent years, TV-escorted pulmonary biopsy has become increasingly widespread.

To diagnose idiopathic fibrosing alveolitis, a percutaneous puncture biopsy of the lungs is also suggested, which is about 90% informative, but the number of complications (primarily pneumothorax) is about 30%.

Transbronchial lung biopsy is rarely used due to its low informative value in the diagnosis of idiopathic fibrosing alveolitis, but it is important for differential diagnostics with sarcoidosis, obliterating bronchiolitis, bronchogenic carcinoma.

ECG - the changes characteristic of a chronic pulmonary heart (signs of myocardial hypertrophy of the right ventricle, deviation of the electric axis of the heart to the right) are determined.

Diagnostic criteria of idiopathic fibrosing alveolitis

The main criteria for diagnosing idiopathic fibrosing alveolitis are:

• progressive dyspnea (not due to any other disease);
• diffuse gray-ash cyanosis;
• shortening of the phases of inspiration and expiration;
• constant "gentle" crepitation, heard over both lungs;
• predominantly interstitial changes in both lungs,
• bilateral infiltrative darkening of varying severity and extent, a picture of the "cellular lung" with radiographic examination of the lungs);
• restrictive type of respiratory failure (according to spirography);
• hypoxia without hypercapnia at rest or only with physical exertion;
• a characteristic morphological pattern of lung biopsy specimens;
• the absence of a connection between the appearance of these criteria and any reliable etiologic factor.

Differential diagnosis

Most often idiopathic fibrosing alveolitis has to be differentiated with the following diseases.

1. Syndrome of fibrosing alveolitis in diffuse connective tissue diseases. The signs that distinguish this syndrome from idiopathic fibrosing alveolitis are:
   • the presence of severe systemic manifestations (lesions of the skin, kidneys, muscles, joints, nervous system); the clinical features of these manifestations are characteristic of certain nosological forms of diffuse connective tissue diseases;
   • frequent presence of a syndrome of a polyserositis (especially at a system lupus erythematosus);
   • articular syndrome;
   • determination in the blood of autoantibodies specific for certain nosological forms of diffuse connective tissue diseases (antinuclear antibodies in systemic lupus erythematosus, rheumatoid factor in rheumatoid arthritis, etc.);
   • absence of steadily progressing dyspnoea.
2. Sarcoidosis of the lungs from idiopathic fibrosing alveolitis is characterized by the following characteristic features:
   • systemic lesions (most often affected basal lymph nodes, lungs, skin, joints, less often - liver, spleen, heart, nervous and endocrine systems);
   • the presence of Löfgren's syndrome (combination of lyfridka, erythema nodosum, polyarthritis);
   • a positive Kveim reaction (see " Sarcoidosis ");
   • increased blood levels of the angiotensin-converting enzyme;
   • absence of severe progressive respiratory insufficiency of restrictive type (in some patients moderate manifestations thereof are possible);
   • relatively benign and malosymptomatic flow;
   • the presence of specific sarcoid tubercles on the bronchial mucosa (revealed by bronchoscopy);
   • the detection of characteristic epithelioid-cell granulomas in biopsy samples of lung tissue obtained with transbronchial biopsy.
3. Disseminated tuberculosis of the lungs. In contrast to idiopathic fibrosing alveolitis, disseminated pulmonary tuberculosis is characterized by:
   • anamnestic data (contact with a patient with tuberculosis, previous tuberculosis of the lungs or other organs);
   • recurrent fibrinous or exudative pleurisy;
   • frequent tuberculosis lesion of other organs and systems (kidneys, spine, etc.);
   • characteristic radiographic changes (a lot of symmetrical small focal shadows in all lung fields of 1-2 mm in size with a zone of perifocal inflammation, sometimes the formation of caverns);
   • positive tuberculin tests;
   • detection of tubercle bacillus in sputum, bronchial flushing waters.
4. Exogenous allergic alveolitis. A characteristic feature of exogenous allergic alveolitis is a clear connection between the development of the disease and a known etiologic factor.
5. Pneumocytosis. The most important signs that distinguish pneumoconiosis from idiopathic fibrosing alveolitis are:
   • link the development of the disease with work in dusty production;
   • the predominant localization of radiographic changes in the mid-lateral pulmonary fields and the tendency to merge small focal shadows into medium and large;
   • the detection of silicotic granulomas in biopsy specimens of lung tissue.
6. Idiopathic hemosiderosis. The main distinguishing feature of hemosiderosis of the lungs is a combination of hemoptysis, anemia, respiratory failure of a restrictive type.

Survey program

1. General blood analysis.
2. Immunological studies: determination of the content of B- and T-lymphocytes, subpopulations of T-lymphocytes, immunoglobulins, circulating immune complexes.
3. Biochemical blood test: determination of total protein, protein fractions, haptoglobin, seromucoid, bilirubin, alanine and asparagine aminotransferases, urea, creatinine.
4. ECG.
5. Radiography of the lungs (preferably a computed tomography of the lungs).
6. Determination of the gas composition of blood.
7. Spirography.
8. Investigation of bronchial lavage fluid: determination of the cellular composition, lipids and proteins of the surfactant, proteolytic enzymes, mucin antigens.
9. Open lung biopsy.

Examples of the formulation of the diagnosis

1. Idiopathic fibrosing alveolitis, acute course, respiratory failure of II st.
2. Idiopathic fibrosing alveolitis, chronic course, slow progression, respiratory failure of II st, chronic compensated pulmonary heart.

[1], [2], [3], [4], [5], [6], [7]