Pulmonary Eosinophilias

Abstract

Eosinophilia is an increase in the number of eosinophils in the peripheral blood. Among eosinophilias, pulmonary eosinophilias are distinguished, which are manifested by radiological changes and an increased content of eosinophils in the lungs. The basis of pathological changes in pulmonary eosinophilia is the activation of eosinophils. They cause bronchospasm, bronchial hyperreactivity, increased vascular permeability and increased fibrosis processes. In the absence of bronchial hyperreactivity, eosinophils limit the development of allergic reactions, and block and eliminate inflammatory mediators (protective effect). With pathology, such protection is disrupted, and the pool of eosinophils increases and eosinophilia of an inflammatory-destructive nature appears with destruction of the interstitium (cytotoxic effect). The etiology of many pulmonary eosinophilias is unknown; there is a possibility that their occurrence may be influenced by certain medications, parasitic infestations and helminth infections. With many pulmonary eosinophilias, lesions also occur in the skin, bones, blood vessels, hepatobiliary and nervous systems. In the treatment of pulmonary eosinophilia, corticosteroids, interferons, monoclonal antibodies and extracorporeal hemocorrection are used. Symptomatic therapy is prescribed to eliminate the clinical symptoms of the disease and improve the quality of life.

1. Introduction

Pulmonary eosinophilia (PE) is a large heterogeneous group of pathological conditions, manifested radiographically by the presence of opacities in the lungs and an increase in the content of eosinophils in the lung tissue and often in the peripheral blood [1, 2, 3]. In some cases, PE can be asymptomatic and spontaneously undergo complete reversal, but some forms of PE pose a serious threat to the health and life of patients and require urgent treatment [4, 5].

2. Functions of eosinophils in the human organism

Eosinophils are blood cells with a large arsenal of protective functions. They originate from a common myelopoiesis precursor cell, and their maturation and differentiation are under the control of the thymus [5, 6].

Eosinophil maturation begins in the bone marrow within 34 hours. Then mature eosinophils enter the blood and circulate in it for about 2–4 hours. Then they accumulate in the integumentary tissues of various systems—the submucosal layer of the bronchi, gastrointestinal tract, and urinary system—where their content is 100 times higher in the blood. From these tissues, they are then returned to the bloodstream. In a healthy person, 50–250 eosinophils circulate in 1 microliter of blood. In pathological conditions, namely eosinophilia, the rate of appearance of eosinophils in the peripheral blood accelerates by two times [2, 5].

Migration and activation of eosinophils occurs under the influence of various chemotactic factors, including interleukin-5, immune complexes, and activated components of the complement system. Activation of eosinophils ends with their degranulation with the release into the blood of a significant amount of biologically active substances—mediators of allergic inflammation—with a wide spectrum of action. These substances are represented by the main macroprotein with significant toxic and destructive effects, free oxygen radicals—products of the inflammatory process, growth factors, platelet-activating factor, eicosanoids, pro-inflammatory cytokines, and others. Activated eosinophils have a wide range of biological effects (bronchospasm, bronchial hyperreactivity, increased vascular permeability, and increased fibrosis processes in tissues) [2, 4]. If there is no bronchial hyperreactivity, eosinophils limit the development of allergic processes by blocking and eliminating inflammatory mediators. This is reflected in their protective effect, which manifests itself in most allergic diseases. At the same time, during pathological processes, such a protective function is distorted, and the pool of eosinophils increases significantly, contributing to the appearance of eosinophilia.

Thus, in various situations, activation of eosinophils can be both physiological, protective (allergic reactions and helminth infestations) and pathological, and inflammatory and destructive in nature (pulmonary eosinophilia and granulomatous processes) [1, 7]. In these cases, eosinophils act as effector cells that cause the destruction of interstitial tissue. This is confirmed by numerous studies proving the cytotoxic effect of these cells. It is due to this effect that destructive changes occur in the lung parenchyma.

There are two known ways of lung damage in PE: the first way is the destruction of type I and III collagen due to collagenesis, the second way is damage to parenchyma cells due to granular proteins and free oxygen radicals.

3. Classification of PE

There is no generally accepted classification of PE. All PE are usually divided according to the etiological factor and clinical manifestations of the disease [6, 8, 9].

Based on clinical manifestations, the following six forms of the disease.

1. Simple eosinophilic pneumonia (SEP);

2. Acute eosinophilic pneumonia (AEP);

3. Chronic eosinophilic pneumonia (CEP);

4. Idiopathic hypereosinophilic syndrome (IHS);

5. Eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome);

6. Langerhans cell histiocytosis (LCH; Pulmonary granulomatosis, Histiocytosis X)

Based on origin (etiology), there are five forms of the disease:

1. Idiopathic PE

2. Allergic bronchopulmonary mycoses

3. PE for helminthiasis

4. Medicinal PEs

5. Food PE

4. Epidemiology of PE

PE is a rare disease. Parasitic eosinophilic pneumonias are common in regions where certain parasites are endemic.

Acute eosinophilic pneumonia develops at any age, even in previously healthy children, although the disease is most often observed in patients aged 20–40 years. Men are affected approximately twice as often as women. Acute eosinophilic pneumonia is associated with smoking. Chronic eosinophilic pneumonia develops more often in women than in men and is not associated with smoking. The relationship of the disease with radiation therapy for breast cancer is described [6, 8].

5. Eosinophilic pneumonia

Eosinophilic pneumonia (EP) is a disease accompanied by the accumulation of blood eosinophils in the pulmonary alveoli. There are several types of EP observed. The most common clinical manifestations of the disease are cough, fever, shortness of breath, and night sweats [7, 9]. The diagnosis of eosinophilic pneumonia is made on the basis of the clinical picture, objective examination data, blood counts, and radiological symptoms. Most types of eosinophilic pneumonia are recognizable and treatable with corticosteroids, and the prognosis is good [9, 10].

In this section, we will consider only six clinical forms of EP.

5.1 Simple eosinophilic pneumonia

The most common causes of simple eosinophilic pneumonia (SEP) or Loeffler’s syndrome are helminths, drugs, and fungal infections. There are Loeffler I (eosinophilic volatile pulmonary infiltrate) and Loeffler II (restrictive cardiomyopathy). In ICD-10, the disease is designated by code J82. 41.42: Eosinophilic asthma, Loeffler’s pneumonia. This syndrome is recorded in all countries, but most often in tropical climates. The frequency is the same among women and men, mainly occurring between the ages of 16 and 40 years [10, 11].

The disease may be asymptomatic and resolve spontaneously. Patients often experience a dry, unproductive cough, wheezing in the chest, mostly in upper parts, and a feeling of mild pain in the trachea, which is associated with irritation of mucosa during the passage of roundworm larvae or other parasites. The sputum is viscous and may have a slight bloody tint. X-ray examination of the lungs reveals bilateral round or oval infiltrates from several millimeters to several centimeters.

They are accompanied by an increase in the content of EP in peripheral blood by up to 10%. An increased content of EP and their degradation products—Charcot-Leyden crystals—is found in sputum. The level of IgE in the blood is usually elevated (more than 1000 IU/ml). Infiltrates in the lungs persist for several weeks, can migrate across the pulmonary fields, and resolve on their own without residual changes [12].

5.2 Acute eosinophilic pneumonia

Acute eosinophilic pneumonia (AEP) is one of the forms of pulmonary eosinophilia of unknown etiology (sometimes cases of the disease after taking aminopenicillins, tranquilizers, and other drugs) with acute manifestations of intoxication and respiratory symptoms. In severe cases, acute respiratory failure is possible [12, 13]. AEP is characterized by fever, attacks of shortness of breath, muscle, and pleural pain. Shortness of breath during the disease is associated with eosinophilic infiltration of the walls of the bronchi, the accumulation of eosinophils in the alveoli. When auscultating the lungs during the inhalation phase, moist fine rales are mainly heard. On a radiograph (more clearly on CT), merging areas of alveolar infiltration (ground glass symptom) with compaction of the interlobar septa and pleural effusion are detected (pleural effusion).

Laboratory test results reveal eosinophilia in the blood and lavage fluid in 25% of cases.

5.3 Chronic eosinophilic pneumonia

A disease with a chronic course, which is characterized by infiltration of the alveolar walls and pulmonary interstitium by eosinophils, as well as their accumulation in the lumen of the alveoli, the formation of microabscesses and bronchiolitis [13, 14]. The disease often appears after 50 years of age, develops gradually, the first symptoms, often appearing 3–5 months after the onset of the disease, are fever, general weakness, weight loss due to lack of appetite, shortness of breath and cough.

The etiology of chronic eosinophilic pneumonia (CEP) has not been studied.

A study of external respiration function reveals a mixed type of ventilation disorder. X-ray examination reveals bilateral infiltrates in the lateral and cortical areas of the lungs, more in the upper and middle sections [14, 15, 16]. Over time, the shadows become more pronounced, sometimes disappear and reappear, i.e. are of a volatile nature.

These changes are more clearly noted on computed tomography (CT).

When examining bronchoalveolar lavage fluid, eosinophilia is detected in more than 40% of cases, confirming the diagnosis of CEP [15, 16]. Histological examination of biopsy material against the background of slight fibrosis reveals eosinophils and histiocytes, as well as multinucleated giant cells.

5.4 Idiopathic hypereosinophilic syndrome

Idiopathic hypereosinophilic syndrome (IHES) is characterized by prolonged, more than 6 months, eosinophilia and eosinophilic infiltration of organs and tissues, which contributes to the characteristic multiple organ damage. The diagnosis of the disease is made on the basis of these symptoms, subject to the exclusion of eosinophilia of other etiologies (parasitic infestations, allergic diseases, and other causes of eosinophilia) [17]. The clinical picture of the disease is dominated by general malaise, muscle pain, dry cough, urticaria and/or angioedema (Quincke’s edema). In 80% or more cases, the nervous, cardiovascular, and digestive systems are involved in the process, vision deteriorates, and the hepatobiliary system is affected. Very high leukocytosis is noted. Heart damage often causes disability and indicates an unfavorable prognosis (death may occur) [17, 18]. The severity of the condition is also due to damage to the membranes of the heart in the form of eosinophilic endomyocarditis. In the final stage of the disease, aseptic microabscesses and necrosis form. As a result of the development of necrotic processes and thromboembolic complications, restrictive cardiomyopathy can form [19].

When thromboembolic complications occur in the vessels of the brain, symptoms of encephalitis and/or peripheral neuropathy appear. Manifestations of stroke or transient ischemic disorders are also possible. Embolic complications are often recurrent even during anticoagulant therapy. Encephalopathy in the clinic is manifested by a decrease in intelligence, memory, increased muscle tone, and gait disturbance (ataxia). The appearance of impaired sensation in the limbs and muscle atrophy in patients are symptoms of peripheral neuropathy [18, 19].

A serious problem with IHES is the skin manifestations of the disease in the form of angioedema, erythematous and urticarial rashes, and severe skin itching. The reason for such changes is associated with perivascular eosinophilic infiltration of the skin. From the respiratory system, shortness of breath and an unproductive cough are often noted. X-ray examination often reveals infiltrates resulting from migration of EF into the lung parenchyma. In the later stages of the disease, fibrosis of the lung tissue or infarction pneumonia may develop.

5.5 Eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) or Churg-Strauss syndrome (CSS) belongs to the group of eosinophilic granulomatosis with damage to the respiratory tract (eosinophilic bronchial asthma) and necrotizing vasculitis with damage to medium and small vessels [20]. The disease was first noted at the beginning of the last century. Later, in 1951, two pathologists Jacob Churg and Lotte Strauss described the clinicopathological signs of the disease on 13 patients, which was named in their honor—Churg-Strauss syndrome (CSS) [20]. The main manifestations in the examined patients were symptoms of severe bronchial asthma, fever, high eosinophilia, polyneuropathy, and heart and kidney failure. Many patients had pulmonary infiltrates, arterial hypertension, sinusitis, abdominal pain, and skin lesions in the form of purpura and subcutaneous nodes. The authors described the morphological triad of the syndrome as—necrotizing vasculitis, eosinophilic tissue infiltration and extravascular granulomas. Subsequently, it was found that EGPA also applies to necrotizing vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA).

According to an international consensus decision in 1992, Charge-Strauss syndrome was classified as a systemic vasculitis affecting small vessels. In 2012, the nomenclature of systemic vasculitides was revised and Charge-Strauss syndrome was replaced by the term “eosinophilic granulomatosis with polyangiitis” and began to refer to 21 groups of ANCA-associated vasculitis. EGPA is characterized by necrotizing granulomatous inflammation, predominantly affecting the respiratory tract, and necrotizing vasculitis, mainly of small and medium vessels, associated with asthma and eosinophilia. Only the upper or lower respiratory tract can be involved in the pathological process. ANCA is found in only 40% of patients with EGPA. Most often, ANCA is determined with glomerulonephritis, and most patients have a history of necrotizing glomerulonephritis [21, 22].

There are two hypotheses regarding the role of ANCA in the development of vasculitis.

According to the first hypothesis, antigens are released from granules of neutrophils or from lysosomes of monocytes, which are perceived by the body’s immune system as foreign. These antigens bind to the vascular wall and form antigen-antibody immune complexes. This complex triggers the complement system—protective proteins that participate in the body’s immune response. If the immune complex enters a cell, complement proteins destroy its membrane. When there are too many antibody-antigen complexes in the body, they accumulate in small vessels (for example, in the vessels of the skin) and cause local inflammation.

According to the second hypothesis, ANCA interact with neutrophils, which begin to damage vascular endothelial cells. ANCA-activated neutrophils additionally produce proinflammatory cytokines, which initiate an inflammatory response, which causes vascular damage [23]. In individuals with EGPA, pANCA titers have been shown to correlate with disease severity; a decrease in the titers of these antibodies reflected the effectiveness of the immunosuppressive therapy and, conversely, an increase in pANCA titers was considered as a sign of exacerbation of the disease [24, 25]. It has been shown that in individuals with EGPA, ANCA titers correlate with severity of the disease; the decrease in titers of these antibodies reflected the effectiveness ongoing immunosuppressive therapy and, conversely, an increase in pANCA titers was considered as a sign of exacerbation of the disease.

Depending on the presence of ANCA, two types of vasculitis are distinguished: ANCA-positive and ANCA-negative vasculitis.

ANCA-positive vasculitis is characterized by the development of glomerulonephritis, multiple mononeuritis (simultaneous or sequential damage to more than one group of nerves), and frequent exacerbations [26, 27, 28].

ANCA-negative vasculitis is characterized by a poorer prognosis associated with a high incidence of cardiomyopathy [29, 30].

EGPA is classified as a rare disease. According to epidemiological studies, the annual incidence per one million population is 0.5–6.8 cases [21, 31, 32, 33]. The disease is more common in northern latitudes at any age without gender differences [21, 34]. According to some authors, men get sick 1.3 times more often [35]. There are known cases of the disease in children and adolescents. SES also occurs in old age [36].

The etiology of development and pathogenesis of EGPA have not been fully studied, since the diagnosis of this disease, according to the criteria of the American College of Rheumatology, is carried out not in the early stages of its development, but much later, when the etiological and late trigger factors overlap each other, which makes correct diagnosis difficult, determining the reasons for its development [37]. The most likely etiological factors for this syndrome are genetic causes.

First of all, this is a polymorphism of genes encoding the synthesis of pro- and anti-inflammatory cytokines, antinuclear, and antineutrophil cytoplasmic antibodies (ANCA) and their physiological inhibitors [38, 39]. A connection between Churg-Strauss syndrome and certain antigens of the HLA-DR3 and HLA-DQ systems has been revealed [39].

EGPA is an idiopathic autoimmune process, but there are certain factors associated with the occurrence of this syndrome. Among them, we can note a drug based on monoclonal antibodies in the treatment of severe bronchial asthma (omalizumab), glucocorticosteroids, leukotriene receptor antagonists, and macrolides [40, 41]. Although a hereditary predisposition to SSS has not been noted, the results of genetic studies have shown the involvement of a number of predisposing hereditary factors, in particular, the interleukin IL10 haplotype-IL10.2, which is associated with increased expression of IL10 [42]; allelic variants of HLA-DRB1*04 and HLA-DRB1*07 and the HLA-DRB4 gene, which are more often detected in patients with SHS than in healthy individuals; and, possibly, the CD226 Gly307Ser polymorphism [43].

In the clinic, the disease is divided into three phases [44].

Phase 1—a combination of two respiratory allergies: bronchial asthma and allergic rhinitis, and recurrent sinusitis and polliposis [45]. Eosinophilic infiltrates in organs (in the lungs—eosinophilic pneumonia, reminiscent of chronic eosinophilic pneumonia).

Phase 2—the appearance of respiratory and extra-respiratory eosinophilic infiltrates.

Phase 3—the predominance of general symptoms in the clinical picture—intoxication, weight loss, myalgia, arthralgia, and general weakness.

The third phase of the disease usually occurs no earlier than 3 years later, and sometimes the manifestation of this phase can last more than one decade. This phase of the disease is characterized by systemic small vessel vasculitides combined with granulomatous infiltration.

The classic course of EGPA begins with damage to the upper respiratory tract (allergic rhinitis, often accompanied by polypous growths of the nasal mucosa). Simultaneously or later, bronchial asthma develops with frequent and severe attacks of broncho-obstructive syndrome [45]. This condition can last for years. Subsequently, eosinophilic infiltrates appear in the lungs and other organs. The final stage in the clinical picture of the syndrome is general symptoms—weakness, intoxication, weight loss, myalgia, and arthralgia.

From the peripheral nerves, multiple mononeuritis or asymmetric polyneuropathy are detected. The development of eosinophilic myocarditis, coronary arteritis, and pericarditis indicate an unfavorable prognosis of the disease. This prognosis is facilitated by the fact that these changes are detected already at the stage of heart failure (left ventricular failure and dilated cardiomyopathy) [24].

Common symptoms are fever, weight loss, arthralgia and myalgia, and weakness.

Thus, during the course of the disease, the following three stages can be roughly distinguished: the development of bronchial asthma and rhinitis, eosinophilic infiltrates in organs and, finally, vasculitis with extrapulmonary manifestations. In 3/4 of patients, allergic rhinitis occurs, combined with recurrent sinusitis and polyposis [45].

In 1/3 of patients, changes in the gastrointestinal tract are detected: gastric and duodenal ulcers, ulcerative colitis, cholecystitis, which are manifested by abdominal pain, diarrhea and may be complicated by bleeding or perforation [2, 46].

In 1/4, moderately severe kidney pathology is determined [46]. Patients with EGPA are characterized by anemia and an increase in ESR. Blood eosinophilia usually reaches 5–20 × 109/L, but can be higher [5]. High levels of eosinophilic neurotoxin in urine are also a marker of EGPA activity [30].

Diagnosis of EGPA is based on the results of clinical, laboratory, and instrumental studies. Due to the paucity of clinical data, the main attention is paid to changes obtained as a result of visualization of the upper respiratory tract (rhinoscopy, laryngoscopy, etc.), as well as methods of radiological diagnosis of the bronchopulmonary system—radiography and computed tomography of the lungs (CT). But it should be noted that X-ray examination is not always informative.

According to CT data, in 70% of cases at different stages of the disease, recurrent pulmonary eosinophilic infiltrates of various shapes and localization are detected. Typically, these infiltrates respond easily to steroid therapy (disappear quickly).

Sometimes an X-ray examination can reveal a combination of pulmonary parenchymal changes with pleural exudate and a change in the size of the heart.

To diagnose SSS, six criteria of the American Rheumatological Association are used:

1. attacks of asthma;

2. eosinophilia more than 10% of the total number of leukocytes;

3. mono- or polyneuropathy;

4. volatile infiltrates in the lungs;

5. sinusitis (clinical and radiological confirmed changes in the paranasal sinuses;

6. accumulation of eosinophils around the vessels determined in biopsy specimens.

The presence of four or more of the six criteria in a patient allows a diagnosis of SSS to be made with a sensitivity of 85% and a specificity of 99%.

5.6 Langerhans cell histiocytosis

LCH (Langerhans cell histiocytosis, eosinophilic granuloma of the lungs, differentiated histiocytosis, histiocytosis X) is a systemic disease characterized by the formation of specific cellular granulomas in various organs and tissues. Pulmonary changes are represented by inflammation of the pulmonary parenchyma with the formation of multiple cysts, manifested by the X-ray picture of a “honeycomb lung” [47]. Frequent localization of the process is the terminal bronchioles and alveoli of the upper and middle sections of the lungs. Sometimes extrapulmonary localization of granulomas is detected in the bones and pituitary gland with the development of diabetes insipidus. Young people aged 20–40 years are most often affected [48, 49]. The main pathogenetic links include the accumulation of Langerhans cells with the restructuring of the bronchial tree and impaired gas exchange [50]. Initially, an X-ray of the lungs reveals small- and medium-sized lesions, thin-walled single cysts located in the upper and middle sections, and the basal sections of the lungs are intact. As it progresses, pneumofibrosis and cystic restructuring increase, spreading to all segments of the lungs [51].

There is no information about the true prevalence of the disease; all that is known is that, thanks to the introduction of open lung biopsy, cases of diagnosing the disease have become more frequent.

The annual incidence of LCH is reported to be 4.6 cases per 1 million children under 15 years of age, with a male to female ratio of 1.2:1 [52].

The estimated incidence in adults is 1–2 cases per million, although LCH is likely underdiagnosed in this population [53]. According to other data, the incidence of LCH is 3–10 cases per 1 million children per year, with its peak occurring between birth and 4 years of age [54]. Boys get sick two times more often [55].

The etiology of LCH is unknown and much controversial. There are assumptions about both the immunological (impaired immune regulation) and the tumor and viral (herpes virus) nature of the disease. It is believed that the herpes virus causes autoaggression of the immune system, in response to which a somatic mutation of the V600E gene encoding the intracellular signaling protein BRAF occurs [56]. In the occurrence of the disease, a number of risk factors are noted, among which a special place is given to tobacco smoking. It has been proven that more than 90% of patients with histiocytosis are smokers [57, 58]. Other risk factors include living in environmentally unfavorable areas, poor nutrition, weak immunity, rheumatism, pulmonary diseases, and chronic inflammatory processes.

The main mechanism of LCH pathogenesis is the accumulation of histiocytes in tissues (dendritic cells-Langerhans cells). Dendritic cells are synthesized in the bone marrow and then migrate to different areas—pulmonary parenchyma, reticuloendothelial system, and dermis [59]. These cells absorb antigens entering the body from the environment and participate in the formation of the immune response. Lymphocytes, as a result of contact with histiocytes, release inflammatory cytokines and substances that activate histiocytes. With pathology (namely with histioitosis X), the process of apoptosis in dendritic cells is disrupted. This process, together with the growth factor secreted by lymphocytes, promotes their intensive proliferation and fusion with eosinophils. Pathological LCH cells actively interact with T-lymphocytes, which leads to the synthesis of a wide range of cytokines and chemokines that contribute to the formation of an inflammatory microenvironment (eosinophils, macrophages, and giant multinucleated osteoclast-like cells) in the lesion [60, 61].

The process ends with the formation of giant cell granulomas. As a result, normal organ tissue is gradually replaced by granulomas with a large number of T-lymphocytes (presumably the presence of a specific antigen).

5.7 Classification of LCH

Langerhans cell histiocytosis is classified according to the location of the lesion and the clinical form of the disease.

By localization of lesions:

• monosystemic form with single or multiple lesions of one anatomical area;

• multisystem form with or without signs of organ dysfunction.

According to clinical the form:

• disseminated form (primary acute, Abt-Letterer-Siwe disease), more often observed in children under 2 years of age, reminiscent of the course of a severe systemic infection, with rapid generalization of the process, progression of respiratory failure and high mortality;

• primary chronic form (Hand-Schüller-Christian disease), a more favorable course, gradual damage to various organs, clinically manifested by Christian’s triad: diabetes insipidus, unilateral exophthalmos, and destruction of the flat bones of the skull, more often observed in children and adolescents;

• eosinophilic granuloma (Taratynov’s disease). This is a relatively benign form of the disease with granulomas predominantly localized in the bones and lungs. In most cases, it develops in adults [62].

• The morphological structure of the process is represented by a granuloma, in the center of which there are Langerhans cells, surrounded by layers of eosinophils and lymphocytes. These cells are of monocyte-macrophage origin and are distinguished by a large nucleus and light gray cytoplasm containing granules. Langerhans cells are also found in healthy individuals in the skin, lungs, and pleura. The pathological growth of these cells is observed under the influence of tobacco smoke (in smokers), which increases the concentration of the neuropeptide bombesin, which is produced by neuroendocrine cells.

The clinical picture of LCH is characterized by a gradual onset with poorly expressed symptoms, so a clear identification of the onset of the disease is difficult. The disease in 1/4 of patients occurs completely without any symptoms or changes, primarily without radiological manifestations in the lungs. In 50% of cases in the LCH clinic, a nonproductive cough and decreased tolerance to physical activity appear; in 1/3 of cases, the cough is accompanied by general weakness, fever (low-grade and rarely febrile), and decreased appetite and weight. In some cases, the first manifestations of the disease may be spontaneous, often recurrent pneumothorax. Over time, as the disease progresses, granulomatous changes in the bones, skin, and pituitary gland join the existing symptoms. In the lungs, X-rays reveal reticular nodular infiltrates, localized mainly in the upper and middle zones of the pulmonary fields [63].

CT better visualizes cysts, honeycomb degeneration of lung tissue and their anatomical location, as well as thickening of interstitial tissue.

The result of pulmonary changes in the form of diffuse fibrosis (X-ray picture of the “honeycomb lung”) is respiratory failure, pulmonary hypertension, and the formation of chronic pulmonary heart syndrome. From the digestive and hepatobiliary systems, dyspepsia is possible in the form of nausea, vomiting, intestinal dysfunction (mainly diarrhea), dull pain, or heaviness in the right and left hypochondrium (hepato- and splenomegaly). Skin manifestations of the disease in the area of natural folds, as well as the head and ear canal, are observed in the form of hemorrhages and poorly healing ulcers. Some patients may experience bone pain due to osteolysis, manifested by symptoms of tooth loss, unilateral exophthalmos (lysis of the bones of the lower jaw, orbit), in severe cases—bone marrow failure, manifested by anemia with corresponding symptoms (dizziness, pallor of the skin and mucous membranes, and tachycardia). In the presence of granulomas in the posterior lobe of the pituitary gland, symptoms of diabetes insipidus (polydipsia, polyuria, and dry mouth) appear due to insufficiency of antidiuretic hormone [47, 59].

Among the complications of LCH, it is necessary to note a compression fracture of the spine, pulmonary hypertension, spontaneous pneumothorax (rupture of pulmonary bullae in the cortical zones), cirrhosis of the liver with liver failure. In rare cases, as consequences of diabetes insipidus (hyperosmolar hypohydration)—motor restlessness, muscle cramps, and coma [64].

Diagnosis of LCH is based on objective research data, as well as the results of laboratory, radiological and functional research methods. Pay attention to the presence of signs of respiratory failure (diffuse cyanosis of the skin, tension in the respiratory muscles); data from auscultation of the lungs (hard or weakened hard breathing with bilateral widespread dry rales of various sizes throughout all pulmonary fields); laboratory blood test data (increased erythrocyte sedimentation rate—ESR, eosinophilia, pancytopenia, increased liver enzymes, increased plasma osmolarity, prolongation of prothrombin time, and hypofibrinogenemia in liver failure) [63, 64].

X-ray examination reveals foci of osteolysis and destruction in the tubular bones and bones of the skull. On the X-ray of the lungs, against the background of an intensified pulmonary pattern, bilateral small-focal darkening is detected. A more informative method of radiodiagnosis is computed tomography (CT) and high-resolution CT (HRCT), which allows one to determine fibrosis of the pulmonary parenchyma.

A study of the function of external respiration (spirography and body plethysmography) reveals restrictive disorders of the ventilation function of the lungs with a decrease in their total capacity and elasticity indicators, as well as a decrease in the diffusion capacity of the lungs (DLco), which increases with physical activity.

Histological examination of a biopsy of the skin, lymph nodes, or lungs reveals an excessive number of giant Langerhans cells with eosinophilic cytoplasm, a bean-shaped nucleus, and the absence of nucleoli [65, 66].

In the generalized form of LCH, differential diagnosis is carried out mainly with acute leukemia, hemophagocytic syndrome, hyperparathyroidism, myeloma, osteomyelitis (with bone destruction), as well as skin allergies (eczema, atopic dermatitis, and psoriasis).

Pulmonary manifestations of the disease must be differentiated from tuberculosis and pulmonary sarcoidosis, lymphogranulomatosis, and fibrosing processes of another etiology.

6. Treatment of PE

6.1 Treatment of SEP

Treatment is mainly aimed at eliminating the causative factor: stopping the etiologically significant medication, deworming, and therapy for pulmonary mycosis. Conservative treatment also includes bronchodilators. Usually, due to the spontaneous resolution of pulmonary infiltrates, glucocorticosteroids (GCS) are not prescribed. But sometimes, a short treatment regimen with small doses of corticosteroids is used—20–25 mg/day prednisolone for 1 week, which leads to the rapid and complete disappearance of PEP symptoms. The prognosis of the disease is favorable.

6.2 Treatment of AEP

If a causative factor is detected, treatment is aimed at it and the administration of large doses of corticosteroids—prednisolone 2 mg/kg per day leads to a rapid and complete recovery without relapses. Initial therapy takes 1–2 weeks, then the daily dose is gradually reduced to 15–20 mg, which can be taken intermittently. The average duration of treatment with GCS is 3 months.

Since most patients with AEP are admitted to the hospital with respiratory failure (RF), initial treatment begins with respiratory support, which includes oxygen therapy and mechanical ventilation (ALV). Patients with AEP respond quickly to treatment with corticosteroids, and in most cases, resolution of the main symptoms is achieved within 1–3 days, and can be quickly disconnected from mechanical ventilation and oxygen therapy. In the vast majority of patients, X-ray changes in the lungs normalize within a week, but mild opacities of the lungs and pleurisy persist on high-resolution computed tomography (HRCT) of the chest for 2 weeks.

Patients on invasive respiratory support (IRS) are prescribed methylprednisolone 60–125 mg IV every 6 hours for 3 days until clinical improvement and extubation, followed by a reduction in the dose of oral prednisolone to 40–60 mg and tapering over 6–12 weeks. A 2-week course of treatment with an initial dose of prednisolone 30 mg per day (or methylprednisolone 60 mg intravenously every 6 hours in patients with DN) is sufficient.

However, the classic 6–12-week treatment regimen is mainly used.

The overall prognosis for AEP after treatment is good, with the disappearance of radiological infiltrates and the absence of long-term pulmonary complications. Unlike CEP, with OEP, after discontinuation of the course of steroid therapy, no relapses of the disease are observed.

6.3 Treatment of CEP

Begin treatment with low doses of corticosteroids (prednisolone 20 mg/day daily or every other day). After 6 months from the start of treatment, when steroid therapy is stopped, there is a high probability of relapse of the disease. This condition requires resumption of treatment, which lasts more than 1 year and is quite effective.

For this form of eosinophilic pneumonia, parenteral (intravenous and oral) administration of steroids is also effective. It must be borne in mind that the lack of effect of treatment makes the diagnosis of CEP questionable and requires further diagnostic search.

Another option for steroid therapy for CEP is the prescription of a high initial dose of prednisolone—from 40 to 60 mg, once a day. Often such treatment leads to surprisingly rapid clinical improvement (sometimes within 2 days). Complete resolution of clinical manifestations and radiological changes occurs within 14 days in most patients and within 1 month in all patients. Therefore, assessing the dynamics of these indicators is a reliable and effective way to monitor the effectiveness of therapy. Although CT is more sensitive in detecting radiological changes, its advantages in assessing the dynamics of the process have not been noted. The number of eosinophils in peripheral blood, ESR, and IgE concentrations can also be used to monitor the clinical course of the disease during treatment. However, not all patients experience pathological changes in laboratory test results.

6.4 Treatment of IHES

GCS for this form of pulmonary eosinophilia is prescribed only at the stage of multiorgan damage. At the initial stages of the disease, when high eosinofolia of the blood is detected and there are no signs of damage to the heart, lungs, nervous system, or skin, it is recommended to limit ourselves to monitoring the patient. GCS therapy, in cases of low effectiveness of prednisolone, is supplemented by the administration of cyclosporine and α-interferon.

It is always possible to completely get rid of the disease. But with the help of modern treatment methods, it is possible to reduce the risk of relapses, prevent irreversible damage to internal organs, and prolong the patient’s life.

Therapy uses drugs that affect the level of eosinophils—primarily corticosteroids, interferons, and monoclonal antibodies. To eliminate the clinical symptoms of the disease and improve the quality of life, symptomatic therapy is prescribed.

When treating patients with the myeloproliferative variant of IHES, the first-line drug is imatinib, especially when the recombinant protein FIP1L1-PDGFRA is detected. Discontinuation of the drug does not lead to relapse of the disease. In some patients, low dose imatinib is necessary to maintain long-term remission.

GCS are recommended for the lymphocytic variant of IGES (with a response in only half of the patients) and at the stage of multiorgan damage. If left untreated, restrictive heart failure quickly develops. Other treatments include chemotherapy drugs (hydroxyurea, vincristine, and etoposide), cyclosporine A, JAK kinase inhibitors, alemtuzumab, interferon-α, combination of interferon-α with hydroxyurea for the treatment of myeloproliferative variant, mepolizumab, benralizumab, and dexpramipexole.

The prognosis for idiopathic HES has improved markedly. Thus, the 3-year survival rate is 12%, the 5-year survival rate is 80%, and the 10-year survival rate is 70%. This suggests that advances in molecular biology may provide a better prognosis for patients with previously untreatable disease.

6.5 Treatment of EGPA (CSS)

High doses of systemic corticosteroids are used (prednisolone 1 mg/kg per day).

If there is no immediate effect from GCS, cyclophosphamide (2 mg/kg per day) is added for 6 months. When stabilization is achieved, you can switch to a maintenance dose of prednisolone (up to 20 mg/day).

It is advisable to continue immunosuppressive therapy with cyclophosphamide for up to 1 year, and maintenance monotherapy with prednisone for a long time, depending on the dynamics of the process. Combination therapy improves prognosis, provides 5-year survival in 90%, and 10-year survival in 75% of patients.

As initial treatment for patients with EGPA, pulse therapy with methylprednisolone is used, after which systemic corticosteroids—prednisolone, at a daily dose of 1 mg/kg—are continued for several months followed by dose reduction. In half of the patients, such treatment achieves stable remission [15]. An important indicator of achieving remission is maintaining a blood eosinophilia level of 1 × 109/l [6]. In cases of severe EGPA, ineffectiveness of systemic corticosteroids, development of relapses after discontinuation or reduction of the dose of systemic corticosteroids, therapy is supplemented with the prescription of cytostatics (azathioprine or cyclophosphamide). There is experience with the successful use of interferon and a combination of cyclosporine with intravenous immunoglobulin in patients with severe disease [10].

If the disease is resistant to traditional treatment, a significant improvement in the results of treatment of EGPA can be achieved through the use of modern technologies of extracorporeal hemocorrection [18]. The use of extracorporeal hemocorrection technologies in the treatment of EGPA, which makes it possible to selectively remove pathogenicity factors such as circulating immune complexes and autoaggressive antibodies from the body, makes it possible to significantly improve the results of treatment of this disease. In addition, the use of modern technologies of extracorporeal hemocorrection, as a rule, makes it possible to significantly reduce course doses of corticosteroids and cytostatics [7]. The 5-year survival rate for EGPA is 79% [7, 12].

6.6 Treatment of LCH

There are no generally accepted treatments for LCH. Patients often experience spontaneous remissions. It is necessary to quit smoking and avoid passive smoking. It is usually recommended to prescribe GCS, especially to those patients who have spontaneous pneumothorax or have identified reticular nodular infiltrates in the lungs. Lung transplantation is indicated for patients with honeycomb lung degeneration and severe signs of respiratory failure.

Patients must be hospitalized in a hospital. In severe DN, oxygen inhalation or transfer to mechanical ventilation is indicated. If there are signs of bone marrow failure, they resort to transfusion blood agents and the use of granulocyte colony-stimulating factor.

There is no etiotropic therapy for LCH. The most important stage in treatment is quitting smoking. Quitting smoking causes an improvement in the clinical, laboratory, and radiological picture. GCS (prednisolone and methylprednisolone) and chemotherapeutic agents (vinblastine, mercaptopurine, and etoposide) are used as pathogenetic therapy.

For the treatment of diabetes insipidus, hormone replacement therapy with vasopressin analogues (desmopressin) in the form of an intranasal spray or in tablet form is prescribed. For small osteolytic lesions, curettage is performed; for severe bone infiltration, resection or remote gamma therapy is performed. In case of a massive destructive process in the lung tissue, a lung transplant is performed.

Treatment of the single-system cutaneous form of LCH depends on the extent of the lesion. Local treatment is prescribed, consisting of the use of corticosteroids, mechlorethamine, or phototherapy. Since spontaneous remissions occur, individual lesions require only observation.

For patients with LCH with a single bone lesion, often after a biopsy of the lesion, it is sometimes necessary to curettage the lesion and administer a local steroid or use radiation therapy.

Indications for systemic treatment:

• single-system multifocal and multisystem diseases;

• changes in the bones of the skull and spine (increased risk of involvement of the central nervous system);

• involvement of high-risk organs, i.e. bone marrow, spleen, and liver.

Vinblastine (an anticancer drug) is often used for treatment in combination with prednisolone, in some cases with 6-mercaptopurine. The course of treatment usually lasts 12 months.

If the response to this treatment is unsatisfactory and the disease progresses, other cytostatics are used, for example, cytarabine, cladribine, vincristine, methotrexate, or mercaptopurine.

When a mutation is detected, based on the result of a molecular test, targeted treatments are used, significantly improving the prognosis in the most severe cases.

The prognosis for LCH in children and adults may be different. The disease may disappear spontaneously or develop into a disseminated form that is life-threatening.

In the single-system form, the prognosis is good; in the case of the multisystem form, it depends on the affected organs. Involvement of the central nervous system, bone marrow, liver, and spleen significantly worsen the prognosis.