Pulmonary Sarcoidosis - Diagnosis

Screening program for respiratory sarcoidosis

1. General blood and urine tests.
2. Biochemical blood test: determination of bilirubin, aminotransferases, alkaline phosphatase, total protein and protein fractions, seromucoid, sialic acids, haptoglobin, calcium, free and protein-bound oxyproline.
3. Immunological studies: determination of the content of B and T lymphocytes, subpopulations of T lymphocytes, immunoglobulins, circulating immune complexes.
4. Study of bronchial lavage fluid: cytological analysis, determination of the content of T-lymphocytes and their subpopulations, natural killers, immunoglobulins, activity of proteolytic enzymes and proteolysis inhibitors.
5. X-ray examination of the lungs.
6. Spirometry.
7. CT.
8. Bronchoscopy.
9. Biopsy and histological examination of biopsy specimens of lymph nodes and lung tissue obtained during transbronchial or open lung biopsy.

Laboratory data

Complete blood count. No specific changes. Hemoglobin content and red blood cell count are usually normal. Patients with the acute form of the disease have an increase in ESR and leukocytosis, while in the chronic form of the disease there may be no significant changes. Eosinophilia is observed in 20% of patients, and absolute lymphopenia in 50%.

General urine analysis - no significant changes.

Biochemical blood test - in the acute form of sarcoidosis, the levels of seromucoid, haptoglobin, sialic acids (biochemical markers of inflammation), and gamma globulins may increase. In the chronic form of the disease, these indicators change little. If the liver is involved in the pathological process, an increase in the level of bilirubin and aminotransferase activity may be observed.

Approximately 15-20% of patients have elevated calcium levels in the blood. Increased levels of proteolytic enzymes and antiproteolytic activity in the blood are also characteristic. In the active phase of the disease, an increase in the level of total or protein-bound oxyproline can be recorded, which is accompanied by increased excretion of oxyproline, glycosaminoglycans, and uroglycoproteins in the urine, reflecting fibrosis processes in the lungs. In chronic sarcoidosis, these indicators change insignificantly.

In patients with sarcoidosis, an increase in the content of angiotensin-converting enzyme is noted. This fact is important for the diagnosis of sarcoidosis, as well as determining its activity. Angiotensin-converting enzyme is produced by endothelial cells of the pulmonary vessels, as well as epithelioid cells of sarcoid granulomas. In other diseases of the bronchopulmonary system (tuberculosis, bronchial asthma, chronic obstructive bronchitis, lung cancer ), the level of angiotensin-converting enzyme in the blood serum is reduced. At the same time, the level of this enzyme is increased in diabetes mellitus, viral hepatitis, hyperthyroidism, silicosis, asbestosis, Gaucher disease.

In patients with sarcoidosis, an increase in the content of lysozyme in the blood was also noted.

Immunological studies. The acute form of sarcoidosis and pronounced exacerbation of the chronic course are characterized by a decrease in the number of T-lymphocytes and their functional capacity, as evidenced by the results of the reaction of the power transformation of lymphocytes with phytohemagglutinin. Also characteristic is a decrease in the content of T-lymphocytes-helpers and, accordingly, a decrease in the T-helper/T-suppressor index.

In patients with stage I pulmonary sarcoidosis, the activity of natural killers is reduced, in stages II and III in the exacerbation phase it is increased, in the remission phase it is not significantly changed. In the active phase of the disease, a decrease in the phagocytic function of leukocytes is also noted. Many patients have an increase in the absolute number of B-lymphocytes, as well as the level of IgA, IgG and circulating immune complexes, mainly in the active phase (acute sarcoidosis and exacerbation of the chronic form). In some cases, antipulmonary antibodies are also detected in the blood

Kveim test - used to diagnose sarcoidosis. Standard sarcoid antigen is injected intradermally into the forearm (0.15-0.2 ml) and after 3-4 weeks (the period of granuloma formation) the site of antigen injection is excised (skin together with subcutaneous fat) even in the absence of visible changes. The biopsy is examined histologically. A positive reaction is characterized by the development of a typical sarcoid granuloma. Erythema, which occurs 3-4 days after the antigen injection, is not taken into account. The diagnostic information content of the test is about 60-70%.

General clinical examination of sputum - significant changes, as a rule, are not detected.

Study of bronchial lavage fluid. Study of the fluid obtained during bronchial lavage (bronchial lavage fluid) is of great diagnostic importance. The following changes are characteristic:

• Cytological examination of bronchial lavage fluid - an increase in the total number of cells, an increase in the percentage of lymphocytes is noted, and these changes are especially pronounced in the active phase of the disease and are less noticeable in the remission phase. As sarcoidosis progresses and fibrosis processes increase, the content of neutrophils in the bronchial lavage fluid increases. The content of alveolar macrophages in the active phase of the disease is reduced, and as the active process subsides, it increases. Of course, the importance of cytological examination of bronchial lavage fluid or eudopulmonary cytogram should not be overestimated, since an increased content of lymphocytes in it is also noted in many patients with epidemiological fibrosing alveolitis, diffuse connective tissue diseases with damage to the pulmonary parenchyma, lung cancer and AIDS;
• immunological examination - increased IgA and IgM levels in the active phase of the disease; increased number of T-helpers, decreased level of T-suppressors, significantly increased T-helpers/T-suppressors ratio (in contrast to changes in peripheral blood); sharply increased activity of natural killers. The above immunological changes in bronchial lavage fluid are significantly less pronounced in the remission phase;
• biochemical study - increased activity of angiotensin-converting enzyme, proteolytic enzymes (including elastase) and decreased antiproteolytic activity.

Instrumental research

X-ray examination of the lungs. This method is of great importance in the diagnosis of sarcoidosis, especially when it comes to forms of the disease that do not manifest themselves with distinct clinical symptoms. As stated above, Wurm even identifies stages of sarcoidosis based on X-ray examination data.

The main radiological manifestations of pulmonary sarcoidosis are the following:

• Enlargement of the intrathoracic lymph nodes (mediastinal lymphadenopathy) is observed in 80-95% of patients and is essentially the first radiographic symptom of sarcoidosis (stage I of pulmonary sarcoidosis according to Wurm). Enlargement of the intrathoracic (bronchopulmonary) lymph nodes is usually bilateral (sometimes unilateral at the onset of the disease). Due to the enlargement of the intrathoracic lymph nodes, the roots of the lungs enlarge and expand. Enlarged lymph nodes have clear polycyclic outlines and a uniform structure. The stepped contour of the lymph node image is very characteristic due to the superposition of the shadows of the anterior and posterior groups of bronchopulmonary lymph nodes.

It is also possible that the median shadow in the mediastinum area may expand due to the simultaneous enlargement of the paratracheal and tracheobronchial lymph nodes. Approximately 1/3-1/4 of patients have calcifications in the enlarged lymph nodes - calcifications of various shapes. Calcifications are usually detected during the long-term course of the primary chronic form of sarcoidosis. In some cases, enlarged intrathoracic lymph nodes compress the nearby bronchi, which leads to the appearance of areas of hypoventilation and even atelectasis of the lungs (a rare symptom).

The indicated changes in the intrathoracic lymph nodes are better detected by computed tomography of the lungs or X-ray tomography.

As indicated, with sarcoidosis, spontaneous or treatment-induced regression of the disease is possible; in this case, the lymph nodes are significantly reduced in size, the polycyclicity of their contours disappears and they do not look like conglomerates;

• X-ray changes in the lungs depend on the duration of sarcoidosis. In the early stages of the disease, enrichment of the pulmonary pattern is noted due to peribronchial and perivascular reticular and strand shadows (stage II according to Wurm). Later, focal shadows of various sizes, rounded in shape, bilateral, scattered throughout all pulmonary fields appear (stages IIB-IIB-IIG according to Wurm, depending on the size of the foci).

The foci are located symmetrically, mainly in the lower and middle sections of the lungs. The lesions of the root zones are more pronounced than those of the peripheral sections.

As the foci resolve, the pulmonary pattern gradually normalizes. However, as the process progresses, intensive proliferation of connective tissue is observed - diffuse pneumosclerotic changes ("honeycomb lung") (stage III according to Wurm). In some patients, large confluent formations may be observed. Atypical radiographic changes in the lungs in the form of infiltrative changes are possible. Pleural damage with accumulation of fluid in the pleural cavities is also likely.

Radioisotope scanning of the lungs. This method is based on the ability of granulomatous lesions to accumulate the isotope citrate 67Ga. The isotope accumulates in the lymph nodes (intrathoracic, cervical, submandibular, if they are affected), pulmonary lesions, liver, spleen and other affected organs.

Bronchoscopy. Changes in the bronchi are observed in all patients with acute sarcoidosis and exacerbation of the chronic form of the disease. Characteristic are changes in the vessels of the bronchial mucosa (dilation, thickening, tortuosity), as well as tuberculous rashes (sarcoid granulomas) in the form of plaques of varying sizes (from millet grains to peas). At the stage of fibrosis of formed granulomas, ischemic spots are visible on the bronchial mucosa - pale areas devoid of vessels.

External respiration function examination. In patients with stage I sarcoidosis, there are no significant disorders of external respiration function. As the pathological process progresses, a moderately expressed restrictive syndrome develops, characterized by a decrease in vital capacity, a moderate decrease in the diffusion capacity of the lungs and a decrease in the partial oxygen tension in arterial blood. In case of severe lung damage in an advanced pathological process, bronchial patency disorders may be observed (in approximately 10-15% of patients).

Histological examination of biopsy specimens of affected organs. Histological examination of biopsy specimens allows to verify the diagnosis of sarcoidosis. First of all, biopsy is performed from the most accessible places - affected areas of skin, enlarged peripheral lymph nodes. Biopsy of the bronchial mucosa is also advisable if sarcoid nodules are detected during bronchoscopy. In some cases, transbronchial biopsy of lymph nodes and lung tissue may be effective. In case of isolated enlargement of intrathoracic lymph nodes, mediastinoscopy with corresponding biopsy of lymph nodes or parasternal mediastinotomy is performed.

If the results of transbronchial lung biopsy are negative and at the same time there are radiographic signs of bilateral focal changes in the lung tissue in the absence of intrathoracic lymphadenopathy (a rare situation), an open lung biopsy is performed. In case of severe liver damage, a biopsy is performed under laparoscopic control, less often - a biopsy of the salivary glands.

The diagnostic criterion for sarcoidosis is the detection of epithelial cell granulomas without necrosis in tissue biopsies (for a detailed description of granuloma, see “Pathogenesis and pathomorphology of sarcoidosis”).

Thoracoscopy - is performed if there are signs of pleural involvement in the pathological process. Whitish-yellowish sarcoid granulomas are visible on the pleural surface, which are also subject to biopsy.

ECG changes are observed when the heart is involved in the pathological process and are characterized by extrasystolic arrhythmia, rarely - atrial fibrillation, disturbances of atrioventricular and intraventricular conduction, decreased amplitude of the T wave, mainly in the left chest leads. In the case of primary chronic course and development of severe respiratory failure, deviation of the electrical axis of the heart to the right is possible, the appearance of signs of increased load on the myocardium of the right atrium (high pointed P waves).

Ultrasound examination of the heart - when the myocardium is involved in the pathological process, it reveals dilation of the heart cavities and a decrease in the contractility of the myocardium.

Determination of the activity of the pathological process

Determining the activity of sarcoidosis is of great clinical importance, as it allows one to decide on the need to prescribe glucocorticoid therapy.

According to the conference in Los Angeles (USA, 1993), the most informative tests that allow determining the activity of the pathological process in sarcoidosis are:

• clinical course of the disease (fever, polyarthralgia, polyarthritis, skin changes, erythema nodosum, uveitis, splenomegaly, increased shortness of breath and cough);
• negative dynamics of the radiological picture of the lungs;
• deterioration of the ventilation capacity of the lungs;
• increased activity of angiotensin-converting enzyme in the blood serum;
• changes in the ratio of cell populations and the ratio of T-helpers/T-suppressors.

Of course, one should take into account the increase in ESR, high levels of circulating immune complexes, and “biochemical inflammation syndrome,” but all of these indicators are given less importance.

Differential diagnosis of respiratory sarcoidosis

Lymphogranulomatosis

Lymphogranulomatosis (Hodgkin's disease) is a primary malignant neoplasm of the lymphatic system, characterized by its granulomatous structure with the presence of giant Berezovsky-Sternberg cells, occurring with damage to the lymph nodes and internal organs.

Differential diagnosis of sarcoidosis and lymphogranulomatosis is extremely important in terms of treatment and prognosis.

Lymphosarcoma

Lymphosarcoma is a malignant extramedullary tumor of lymphoblasts (or lymphoblasts and prolymphocytes). The disease is more common in men over 50 years of age. The primary focus (the organ from which the tumor clan originates) is the lymph nodes of the neck (usually unilateral lesions), less often - other groups of lymph nodes. In some cases, primary localization of the tumor in the mediastinal lymph nodes is possible. The specified localization of the affected lymph nodes (neck, mediastinum) makes it necessary to differentiate sarcoidosis from this disease.

The characteristic features of lymph node damage in lymphosarcoma are the following:

• preservation of normal properties of enlarged lymph nodes at the very beginning of the disease (lymph nodes are mobile, painless, densely elastic);
• rapid growth, compaction and subsequent formation of conglomerates;
• fusion of lymph nodes with surrounding tissues, loss of mobility as they continue to grow.

These features are not typical for sarcoidosis.

In mesenteric or gastrointestinal localization of lymphosarcoma, a tumor-like formation in the abdominal cavity can almost always be detected by palpation, accompanied by abdominal pain, nausea, vomiting, often bleeding, and symptoms of intestinal obstruction.

In the late stage of lymphosarcoma, generalized enlargement of the lymph nodes is possible, lung damage is observed, which is manifested by cough, shortness of breath, hemoptysis. In some cases, exudative pleurisy develops, kidney damage with hematuria, the liver enlarges

Lymphosarcoma is accompanied by fever, profuse sweating, weight loss. Spontaneous recovery or even a reduction in the symptoms of the disease is never observed.

This course of the disease is not typical for sarcoidosis, however, it should be remembered that in rare cases, sarcoidosis can affect the mesenteric or even retroperitoneal lymph nodes.

The final diagnosis of lymphosarcoma is established by a biopsy of the lymph nodes. The tumor cells are identical to the cells of acute lymphoblastic leukemia (lymphoblasts).

Briel-Simmers disease

Briel-Simmers disease is a non-Hodgkin's lymphoma of B-cell origin, most often occurring in middle-aged and elderly men. The disease is divided into two stages - benign (early) - lasts 4-6 years, and malignant - lasts about 1-2 years. In the early stage, there is an increase in the lymph nodes of any one group, most often the cervical, less often - axillary, inguinal. Enlarged lymph nodes are painless, not fused with each other, with the skin, mobile.

In the second (malignant) stage, the clinical picture is identical to the course of generalized lymphosarcoma. The development of compression syndrome (with damage to mediastinal lymph nodes) or ascites (with damage to mesenteric lymph nodes) is also characteristic.

The diagnosis of the disease is verified by a lymph node biopsy. In the early stage, a characteristic sign is a sharp increase in follicles (macrofollicular lymphoma). In the malignant stage, a lymph node biopsy reveals a picture characteristic of lymphosarcoma.

Metastasis of cancer to peripheral lymph nodes

In malignant tumors, metastasis and enlargement of the same groups of lymph nodes as in sarcoidosis are possible. Thyroid and laryngeal cancers most often metastasize to the cervical lymph nodes; breast, thyroid, and stomach cancers (Vikhrov's left-sided metastasis) to the supraclavicular lymph nodes; breast and lung cancer to the axillary lymph nodes; and tumors of the genitourinary organs to the inguinal lymph nodes.

The nature of the enlarged lymph nodes is determined quite easily - the clinical signs of the primary tumor are taken into account, as well as the results of a biopsy of the enlarged lymph nodes. Atypical cells and often cells characteristic of a certain tumor (for example, in hypernephroma, thyroid cancer) are determined in the biopsy.

Lung cancer

Differentiation of sarcoidosis from lung cancer usually occurs in stages I and II of sarcoidosis.

Acute leukemia

In acute leukemia, along with the enlargement of the peripheral lymph nodes, there may be an enlargement of the intrathoracic lymph nodes, which requires differential diagnostics between acute lymphoblastic leukemia and sarcoidosis. Differential diagnostics between these diseases is not difficult. Acute leukemia is characterized by a severe, progressive course without spontaneous remissions, fever, severe sweating, severe intoxication, anemia, thrombocytopenia, hemorrhagic syndrome. The appearance of blast cells in the peripheral blood, a leukemic "gap" (the leukocyte formula determines the youngest cells and mature ones, the number of intermediate forms is sharply reduced or they are absent altogether). Of course, sternal puncture is of decisive importance in the diagnosis of acute leukemia. A large number of blasts (more than 30%) are determined in the myelogram.

Tuberculosis

It is often necessary to conduct differential diagnostics of sarcoidosis and pulmonary forms of tuberculosis.

Lymph node involvement in sarcoidosis also needs to be differentiated from tuberculosis of the peripheral lymph nodes.

The damage to the lymph nodes in tuberculosis can be local (enlargement mainly of the cervical, less often of the axillary, very rarely of the inguinal lymph nodes) or generalized (involvement in the pathological process of at least three groups of lymph nodes).

Tuberculosis of the peripheral lymph nodes has the following characteristic signs:

• long, undulating course;
• soft or moderately dense consistency of the lymph nodes, their low mobility (due to the development of the inflammatory process);
• no pain on palpation;
• caseous melting of lymph nodes; in this case, the skin above the node becomes hyperemic, thins, fluctuation appears, then the contents break through, a fistula is formed. Subsequently, the fistula heals with the formation of a skin scar;
• reduction and significant compaction of the affected lymph nodes (they resemble pebbles) after the caseous process in them subsides;
• the possibility of relapse of tuberculous lesions and caseous decay;
• detection of Mycobacterium tuberculosis in fistula discharge.

The above-mentioned features of lymph node damage in tuberculosis are not at all characteristic of sarcoidosis. In cases difficult for diagnosis, it is necessary to perform a biopsy of the affected lymph node with subsequent histological examination. A positive tuberculin test is also characteristic of tuberculous lymphadenitis.

Chronic lymphocytic leukemia

In chronic lymphocytic leukemia, severe peripheral lymphadenopathy develops, and therefore it is necessary to differentiate chronic lymphocytic leukemia from sarcoidosis.

Chronic lymphocytic leukemia is characterized by the following features:

• enlarged lymph nodes (mainly cervical and axillary) reach significant sizes, are painless, are not fused with each other or with the skin, do not ulcerate or suppurate;
• the spleen and liver are enlarged;
• the number of leukocytes in the peripheral blood progressively increases, reaching large values (50-100 x 10 ⁹ /or more), and absolute lymphocytosis is observed (75-90% lymphocytes in the leukocyte formula) with a predominance of mature cells;
• Botkin-Gumprecht cells are detected in the blood smear - lymphocytes destroyed during the preparation of the smear.

Usually these signs allow to make a diagnosis of chronic lymphocytic leukemia. If the diagnosis is in doubt, a biopsy of peripheral lymph nodes can be performed. The pathomorphological substrate of chronic leukemia is predominantly mature lymphocytes, but lymphoblasts and prolymphocytes are also present.

Lymphocytoma

Lymphocytoma is a well-differentiated lymphocytic tumor. The primary localization of the tumor is extramedullary, in the peripheral lymph nodes, spleen, less often - in the stomach, lungs, skin. If the primary localization of the tumor clan is peripheral lymph nodes, then an increase in the cervical or axillary lymph nodes is most often noted. However, in the future, the pathological process inevitably gradually generalizes, which consists in an increase in other groups of peripheral lymph nodes and the spleen. This stage is characterized by a significant increase in lymphocytes in the peripheral blood. At this stage, it is easy to distinguish lymphocytoma from sarcoidosis. In difficult cases, a biopsy of the peripheral lymph node can be performed and thus differentiate these two diseases. It should be noted that with a significant spread of the process, it is difficult to distinguish lymphocytoma from chronic lymphocytic leukemia.

Infectious mononucleosis

Infectious mononucleosis is always accompanied by an increase in peripheral lymph nodes, so it is necessary to differentiate this disease from sarcoidosis.

Infectious mononucleosis can be differentiated based on the following characteristic symptoms:

• enlargement of the posterior cervical and occipital lymph nodes, they are of a dense elastic consistency, moderately painful, not fused with surrounding tissues, do not open, do not form fistulas;
• spontaneous decrease in the size of enlarged lymph nodes by the 10th-14th day of illness;
• presence of fever, hepatosplenomegaly;
• detection in the analysis of peripheral blood of leukocytosis, lymphocytosis, monocytosis and a characteristic sign - atypical mononuclear cells (lymphomanocytes);
• positive serological reaction of Paul-Bunnell, positive test of Lovrick-Wolner (agglutination of ram red blood cells treated with papain), Hoff-Bauer (agglutination of horse red blood cells).

Infectious lymphocytosis

Infectious lymphocytosis is a disease of viral etiology characterized by lymphocytosis. Enlargement of the cervical lymph nodes may be observed.

The characteristic features of infectious lymphocytosis are:

• moderate enlargement of the cervical lymph nodes and very rarely of others;
• subfebrile body temperature, weakness, rhinitis, conjunctivitis, dyspeptic symptoms, abdominal pain;
• pronounced leukocytosis (30-100 x 10 ⁹ /l), significant predominance of lymphocytes in the leukocyte formula - 60-90% of all cells;
• benign course - rapid onset of recovery, disappearance of clinical signs of the disease, complete normalization of the peripheral blood picture.

Examples of diagnosis formulation

1. Pulmonary sarcoidosis, stage I, remission phase, DNI.
2. Sarcoidosis of the lungs, stage II, acute phase, DNI. Sarcoidosis of the skin of the dorsum of both forearms. Nodular erythema in the area of both shins.

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