Histiocytosis X lung: causes, symptoms, diagnosis, treatment

Histiocytosis X of the lungs (histiocytic granulomatosis of the lungs, eosinophilic granuloma, pulmonary granulomatosis X, histiocytosis X) is a disease of the reticulohistiocytic system of unknown etiology, characterized by the proliferation of histiocytes (X cells) and the formation of histiocytic granulomas in the lungs and other organs and tissues.

Pulmonary Langerhans cell granulomatosis is a monoclonal proliferation of these cells in the interstitium and airspaces of the lung. The cause of X-lung histiocytosis is unknown, but smoking is of primary importance. Manifestations are dyspnea, cough, fatigue, and/or pleuritic chest pain. Diagnosis is based on history, imaging studies, bronchoalveolar lavage fluid, and biopsy. Treatment of X-lung histiocytosis involves smoking cessation. Glucocorticoids are used in many cases, but the efficacy is unknown. Lung transplantation is effective when combined with smoking cessation. Prognosis is generally good, although patients have an increased risk of malignancy.

Histiocytosis X of the lungs occurs with a frequency of 5 per 1 million inhabitants. Men and women are equally affected. In women, the disease develops later, but any differences in the timing of the onset of the disease in representatives of different sexes may reflect differences in attitudes towards smoking.

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What causes histiocytosis X of the lungs?

The causes of the disease are unknown. The pathogenesis has been studied insufficiently. The role of autoimmune mechanisms in the development of histiocytosis X is not excluded. Pulmonary Langerhans cell granulomatosis is a disease in which monoclonal CD1a-positive Langerhans cells (a subtype of histiocytes) infiltrate the bronchioles and alveolar interstitium, where they are found in combination with lymphocytes, plasma cells, neutrophils and eosinophils. Pulmonary granulomatosis X is one of the manifestations of Langerhans cell histiocytosis, which can affect organs in isolation (most often the lungs, skin, bones, pituitary gland and lymph nodes) or simultaneously. Pulmonary granulomatosis X occurs in isolation in more than 85% of cases.

A characteristic pathomorphological feature of the disease is the formation of peculiar granulomas and the systemic nature of organ and tissue damage. Granulomas are most often found in the lungs and bones, but they can also be localized in the skin, soft tissues, liver, kidneys, gastrointestinal tract, spleen, and lymph nodes. The main cells of the granuloma are histiocytes originating from the bone marrow.

A distinction is made between the acute form of histiocytosis X (Abt-Leggerer-Siwe disease) and the primary chronic form (Höfda-Schüller-Christian disease).

The acute form is characterized by an increase in the volume of the lungs, the formation of multiple cysts up to 1 cm in diameter; microscopic examination reveals granulomas of histiocytes, eosinophils, and plasma cells.

In chronic histiocytosis X, numerous small nodules can be seen on the surface of the lungs, pleural deposits, emphysematous swellings resembling cysts are determined, and the lungs have a honeycomb structure when cut. Microscopic examination of the lungs at early stages reveals granulomas consisting of histiocytes, plasma cells, eosinophils, and lymphocytes. Subsequently, cystic formations and emphysematous thin-walled bullae are formed quite early. The development of fibrous tissue is also characteristic.

Pathophysiological mechanisms may include enlargement and proliferation of Langerhans cells in response to cytokines and growth factors released by alveolar macrophages in response to cigarette smoke.

Symptoms of Histiocytosis X of the Lungs

Typical symptoms of X lung histiocytosis are dyspnea, nonproductive cough, fatigue, and/or pleuritic chest pain, with sudden spontaneous pneumothorax developing in 10–25% of patients. About 15% of patients remain asymptomatic and are discovered incidentally on chest radiography performed for another reason. Bone pain due to cysts (18%), skin rashes (13%), and polyuria due to diabetes insipidus (5%) are the most common extrapulmonary manifestations, occurring in 15% of patients, but are rarely the presenting symptoms of X lung histiocytosis. Symptoms of X lung histiocytosis are scant; physical examination findings are usually normal.

Abt-Letterer-Siwe disease (acute histiocytosis X) occurs predominantly in children under 3 years of age and has the following main manifestations:

• acute onset of the disease with high body temperature, chills, severe cough (usually dry and painful), shortness of breath;
• rapid generalization of the pathological process with the appearance of clinical signs of damage to bones, kidneys, skin, and the central nervous system (meningeal syndrome, severe encephalopathy);
• development of purulent otitis is possible.

Death may occur within a few months.

The primary chronic form of histiocytosis X (Heth-Schüller-Christchen disease) occurs predominantly in young people, usually aged 15-35 years.

Patients complain of such symptoms of histiocytosis of the X lungs as: shortness of breath, dry cough, general weakness. In some patients, the disease begins with sudden acute pain in the chest, which is caused by the development of spontaneous pneumothorax. An absolutely asymptomatic onset of the disease is possible, and only an accidental fluorographic or X-ray examination reveals changes in the lungs. Due to the damage to the skeletal system by the granulomatous process, pain in the bones may appear, most often the bones of the skull, pelvis, and ribs are affected. Destruction of the sella turcica is also possible. In this case, the hypothalamic-pituitary zone is damaged, the secretion of antidiuretic hormone is disrupted, and the clinical picture of diabetes insipidus appears - severe dry mouth, thirst, frequent profuse urination, while light urine with a low relative density (1.001-1.002 kg / l) is excreted.

On examination of patients, acrocyanosis, thickening of the terminal phalanges in the form of "drumsticks" and nails in the form of "watch glasses" are determined. These symptoms of histiocytosis of the tenth lung are especially pronounced in the case of a long-term existence of the disease and severe respiratory failure. Many patients have xanthelasmas (lipid yellow spots in the eyelid area, usually the upper ones). If the spine is affected, its curvature can be detected. Percussion of the bones of the skull, ribs, pelvis, and spine reveals painful points. Histiocytic infiltration of the orbit causes exophthalmos in some patients. It should be taken into account that unilateral exophthalmos is possible.

Percussion of the lungs reveals a normal clear pulmonary sound, with the development of emphysema - a box sound, with the appearance of pneumothorax - a tympanic sound. Auscultation of the lungs reveals a weakening of vesicular breathing, less often - dry wheezing, very rarely - crepitation in the lower sections. With the development of pneumothorax, breathing in its projection is absent.

When the liver is involved in the pathological process, its enlargement and slight soreness are observed. Enlargement of the spleen and lymph nodes is possible.

Kidney damage is manifested by a decrease in the amount of urine, and the development of acute renal failure is possible.

Diagnosis of histiocytosis X of the lungs

Histiocytosis X of the lungs is suspected based on the history, physical examination, and chest radiography; confirmation is achieved by high-resolution CT (HRCT), bronchoscopy with biopsy, and bronchoalveolar lavage.

Chest radiography shows classic bilateral symmetric focal infiltrates in the middle and upper lung fields with cystic changes in the presence of normal or increased lung volumes. The lower lungs are often spared. The onset of the disease may be similar to that of COPD or lymphangioleiomyomatosis. HRCT confirmation of cysts in the middle and upper lobes (often bizarre) and/or focal lesions with interstitial thickening is considered pathognomonic for type X histiocytosis. Function studies may be normal or restrictive, obstructive, or mixed, depending on the stage of the disease when the study is performed. Diffusing capacity for carbon monoxide (DLC0) is often decreased, which reduces exercise tolerance.

Bronchoscopy and biopsy are performed when radiological methods and lung function tests are uninformative. Detection of CDIa cells in bronchoalveolar lavage fluid, constituting more than 5% of the total number of cells, has a high specificity for this disease. Histological examination of biopsy material reveals proliferation of Langerhans cells with the formation of a small number of eosinophil clusters (structures previously defined as eosinophilic granuloma) in the center of cellular fibrous nodes, which may have a stellate configuration. Immunohistochemical staining is positive for CDIa cells, S-100 protein, and HLA-DR antigens.

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Laboratory diagnostics of histiocytosis X of the lungs

1. Complete blood count: in the acute form of the disease, anemia, leukocytosis, thrombocytopenia, and increased ESR are characteristic. In the chronic form of the disease, there are no significant changes, but many patients experience an increase in ESR.
2. General urine analysis - in the acute form of the disease, as well as in case of kidney damage during the chronic course, proteinuria, cylindruria, and microhematuria are detected.
3. Biochemical blood test: in the acute form of the disease, a biochemical inflammation syndrome appears (increased levels of seromucoid, sialic acids, a1-, a2- and y-globulins); cholesterol, copper may increase, and in the malignant course of the disease, the activity of the angiotensin-converting enzyme increases. Liver damage is accompanied by an increase in the level of bilirubin, alanine aminotransferase, and with the development of acute renal failure, the content of creatinine and urea increases.
4. Immunological studies. There are usually no specific changes. Increased levels of immunoglobulins, circulating immune complexes, decreased T-suppressors and natural killers may be observed.
5. Examination of bronchial lavage fluid reveals lymphocytosis and an increase in the number of T-suppressors.

Instrumental diagnostics of histiocytosis X of the lungs

• X-ray examination of the lungs. Usually, 3 X-ray stages of the disease are distinguished.

The first stage is typical for the early phase of histiocytosis X. Its main manifestations are the presence of bilateral small focal darkening against the background of increased pulmonary pattern. Small focal darkening corresponds to the proliferation of histiocytes and the formation of granulomas. No enlargement of the intrathoracic lymph nodes is observed.

The second stage is characterized by the development of interstitial fibrosis, which is manifested by a finely reticular (small-cell) pulmonary pattern.

The third stage (final) is manifested by cystic-bullous formations with a “honeycomb lung” pattern, pronounced fibrous-sclerotic manifestations.

• Transbronchial or open lung biopsy - is performed for the purpose of final verification of the diagnosis. Biopsy specimens reveal a characteristic sign of the disease - a granuloma consisting of proliferating histiocytes. In stages 2 and 3 of the disease, biopsy is not performed, since it is usually no longer possible to detect granulomas.
• External respiratory function examination. Disturbances in the ventilation function are detected in 80-90% of patients. Restrictive type of respiratory failure is typical (decreased VC, increased residual volume of the lungs). Disturbances in bronchial patency are also detected, as indicated by a decrease in FEV and the Tiffno index (FEV1/VC ratio), a decrease in the volume of maximum volume flow rate of 25, 50 and 75% VC (MVF 25, 50, 75).
• Blood gas analysis. A decrease in partial oxygen tension is characteristic.
• Fiberoptic bronchoscopy. There are no specific or significant changes in the bronchi.
• Perfusion scintigraphy of the lungs. Characteristic is a sharp disturbance of microcirculation, areas of sharply reduced blood flow are determined.
• Computer tomography of the lungs. Thin-walled cystic-bullous formations of various sizes are determined. They are located in all parts of the lungs.
• ECG. With the development of pulmonary emphysema, a deviation of the electrical axis of the heart to the right, a clockwise rotation of the heart around the longitudinal axis (deep S waves in almost all chest leads) can be observed.

Diagnostic criteria for histiocytosis X of the lungs

The main diagnostic criteria for the primary chronic form of histiocytosis X can be considered:

• recurrent pneumothorax;
• restrictive and obstructive ventilation disorders;
• the possibility of systemic damage to organs and tissues;
• formation of a "honeycomb lung" (detected radiologically);
• detection of histiocytic granuloma in lung tissue biopsies.

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Treatment of histiocytosis X of the lungs

The mainstay of treatment is smoking cessation, which results in resolution of symptoms in about a third of patients. As in other IBLARs, empirical use of glucocorticoids and cytotoxic agents is common practice, even though their efficacy is unproven. Lung transplantation is the treatment of choice in healthy patients with progressive respiratory failure, but disease may recur in the graft if the patient continues to smoke.

Spontaneous resolution of symptoms occurs in some patients with minimal manifestations of the disease; 5-year survival is approximately 75%, median survival of patients is 12 years. However, some patients develop slowly progressive disease, for which clinically significant prognostic factors are duration of smoking, age, presence of multiorgan involvement, persistent symptoms of lung X histiocytosis indicating generalization of the process, multiple cysts on chest radiograph, decreased DL, low FEV/FVC ratio (< 66%), high residual volume (RV) to total lung capacity (TLC) ratio (> 33%) and the need for long-term glucocorticoid therapy. The cause of death is respiratory failure or development of malignant tumors. An increased risk of lung cancer is due to smoking.