Types, causes, diagnosis and treatment of granuloma in children

Figure 1. 3D reconstruction of skull bones with solitary eosinophilic granuloma https://radiopaedia.org/cases/eosinophilic-granuloma-skull

It was assumed that this was bone tuberculosis, but instead of the classic tuberculous tubercle, Taratynov saw accumulations of mononuclear cells (tissue macrophages or histiocytes) and eosinophils, as well as Charcot-Leiden crystals, which had previously been found in the sputum of patients with bronchial asthma. The morphological picture indicated “the existence of granulomas, clinically and macroscopically completely similar to tuberculous ones, recognizable only microscopically and consisting almost exclusively of eosinophils.”

Figure 2. Eosinophilic granuloma of bone: lesion of the hip in an 11-year-old girl (x-ray). Swelling and pain were noted for 3 months. https://radiopaedia.org/cases/langerhans-cell-histiocytosis-skeletal-manifestations

The previously unknown disease was named Taratynov's disease. Currently, this name is mainly used in Russian-language sources and has rather a historical meaning.

In the 1940s. similar cases were presented in articles by US doctors Sadao Othani, Joseph Ehrlich, Louis Lichtenstein and Henry Jaffe under the names “solitary granuloma of bone” and “eosinophilic granuloma of bone”.

Similar histiocytic infiltrates were described by other authors - Alfred Hand Jr, USA in 1893, Arthur Schüller (Austria) in 1915, Henry Cristian (USA) in 1920, Erich Letterer , Germany) in 1924, Sture Siwe (Sweden) in 1933, in connection with which the terms “Hand-Schüller-Christian disease” and “Abt-Letterer-Siwe disease” were introduced. However, later it was concluded that all of these are forms of the same disease, different in severity and localization of foci, called “histiocytosis X”

in 1953.

Figure 3 . Eosinophilic granuloma of the skull (X-ray) https://radiopaedia.org/cases/eosinophilic-granuloma-1

The answer to the question of what the histiocytes that form granulomas are was given in 1973 by pediatrician and morphologist Christian Nezelof (France), who identified them as Langerhans cells (a type of antigen-presenting cells localized in the epidermis). In this regard, since 1987, the name “histiocytosis X” was replaced by “Langerhans cell histiocytosis” ( LCH ).

The head of the Department of Pathology at St. Petersburg State University, Leonid Churilov, believes that Doctor Taratynov became the prototype of Doctor Zhivago. This bold assumption is supported by the coincidences in the life of Nikolai Taratynov and his family with the story of Yuri Zhivago: both victims of the revolution, military doctors, whose daughters were orphaned early and were raised by their father’s relatives. Nikolai Ivanovich Taratynov was shot and killed by a sailor, the brother of a patient who died in the hospital, in 1919 at the age of 32. You can learn more about Taratynov’s biography here.

Classification of granulomas and forms

In medicine, granulomas are classified according to several criteria: etiology, pathogenesis and morphology. Specific varieties are collected in a separate group. In the group according to the criterion of etiology there are types of established and unidentified etiology: infectious and non-infectious. The latter include dust granulomas, drug-type granulomas and neoplasms around foreign bodies. Pathogenesis group: immune and non-immune. The first type includes epithelioid cell granulomas. Non-immune ones occur due to toxic factors and acute infections. The morphological group is divided into two main groups: mature and epithelioid cell. According to the morphology of granulomas, there is the formation of a diffuse-type granulomatous infiltrate and the formation of tuberculoid-type granulomas.

Main types of granulomas

In medical practice, there are many types of neoplasms of this type. They can be single or multiple. It is not always possible to see the beginning of their formation, since pathogenic cells are located deep in the layers of the dermis. Granuloma in children and adults can appear and disappear without treatment. This should justify the need for gentle therapy in the future. Granulomas of the following type are most often diagnosed in children and adults:

• ring-shaped;
• pyogenic;
• tuberculosis.

Churg-Strauss syndrome (CSS) was described by Jacob Churg and Lotte Strauss in 1951 in 13 patients as a special form of periarteritis nodosa with severe bronchial asthma, fever, hypereosinophilia, diffuse granulomatous lesions of the walls of small vessels and extravascular connective tissue [1]. Currently, the classification criteria of the American Society of Rheumatology in the 2012 revision are used to designate SES - “eosinophilic granulomatosis with polyangiitis - EGPA” [2] or ICD-10 - section M30.1: polyarteritis with pulmonary involvement (allergic granulomatous angiitis) [ 3]. In 1990, the American College of Rheumatology proposed criteria for the diagnosis of this condition (Table 1) [4]. In addition to EGPA, the group of vasculitis with predominant damage to small vessels and the formation of antineutrophil cytoplasmic antibodies (ANCA) includes granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis (Table 2) [5].

Table 1. Diagnostic criteria for EGPA [4] Note. The diagnosis of EGPA in the presence of four or more signs is made with a sensitivity of 85% and a specificity of 99.7%.

Table 2. Clinical, morphological and laboratory characteristics of vasculitis with ANCA

In Northwestern Europe, the incidence of EGPA is 1.5–3.7 cases per 1 million adults per year [6], and the prevalence is 6.8–10.7 cases per 1 million adults [7, 8]. The incidence of EGPA in all age groups predominates in men and people of European origin (≈ 2 times higher) and increased with age, reaching maximum values ​​at 65–74 years [6, 8].

Etiology and mechanisms of development of the autoimmune process in EGPA

The etiology of EGPA, as well as the group of ANCA-associated vasculitides in general, is not completely known. Among the most likely causes, the impact of infectious factors [9] in combination with genetic predisposition is considered [10, 11]. In recent years, attention has been paid to the geographical factor (increasing incidence with distance from the equator) and the associated lack of vitamin D. The possibility of an autoimmune response to certain drugs [12] or toxic substances [13] cannot be ruled out.

It is assumed that sections of bacterial (viral) DNA containing unmethylated CpG (cytosine-phosphate-guanine) dinucleotides are recognized by Toll-like receptors of immunocompetent cells, which, through the synthesis of pro-inflammatory cytokines, initiates stimulation of neutrophils [14] and the release of azurophilic granule enzymes onto their surface - myeloperoxidase (MPO) and proteinase 3 (PR3) [15]. In unstimulated neutrophils, most of the MPO and PR3 are located in the cytoplasm, and a smaller part is on the cell surface. The ratio of MPO and PR3 on the membrane and in the cytoplasm at rest and during stimulation is determined by a number of factors, including genetic ones [16]. On the surface of neutrophils, MPO and PR3, due to the dysfunction of B- and T-regulatory cells, are recognized as antigens, which leads to the differentiation of B cells into plasma cells and the synthesis of class G antibodies (IgG) [14, 17]. These antibodies are directed against MPO or PR3 and are designated ANCA. Contact of antibodies with MPO and PR3 leads to activation of neutrophils with the development of granulomatous inflammation and vasculitis [15].

In clinical settings, the presence and type of ANCA are determined based on immunofluorescence (IF) and enzyme-linked immunosorbent assay (ELISA) [18]. Under I.F. There are two variants of ANCA fluorescence: cytoplasmic and perinuclear (perinuclear). Using the ELISA method, it was established that ANCAs with a cytoplasmic type of luminescence are in most cases directed against PR3 (PR3-ANCA), and those with a perinuclear type are directed against MPO (MPO-ANCA). PR3-ANCA are predominantly detected in Wegener's granulomatosis, while MPO-ANCA are mainly detected in EGPA and microscopic polyangiitis (see Table 2) [19].

Clinical manifestations

Clinical manifestations of EGPA, along with the involvement of the upper and lower respiratory tract, which are almost always affected, may include symptoms from other organs and systems [20].

During EGPA there are three stages that can overlap. At the first stage, an infectious agent or antigen initiates allergic inflammation with the development of rhinosinusitis, sinus polyposis and asthma. Asthma is the main manifestation of the disease during this period and occurs in 91–100% of cases [1, 21]. This stage can last from several months to several years, and, in addition to asthma and other pulmonary pathologies, includes nonspecific symptoms: general malaise, weight loss, fever, pain in the joints and muscles [22].

At the second stage, there is a significant (>10% or >1000 cells/mm3 of the total number of leukocytes) increase in eosinophils in the blood that persists with repeated tests. It is noted that disease activity often correlates with the number of eosinophils in the blood [23]. During the same period, infiltrates are formed in the internal organs, in which granulomatous inflammation with abundant inclusions of eosinophils is morphologically revealed [21]. Migratory pulmonary infiltrates are one of the key features of EGPA and are included in the criteria of the American Society of Rheumatology [4]. Along with infiltrates, more than 60% of patients with EGPA have other changes in the lungs. At the same time, changes in lung tissue can be observed not only with EGPA, but also with other hypereosinophilic syndromes [24].

At the third stage, signs of systemic vasculitis appear [1]. Histological changes in vasculitis are represented by the so-called low-immune inflammation, in which deposits of autoimmune complexes in the walls of blood vessels are usually not detected [25]. One of the distinctive features of vasculitis is skin manifestations in the form of purpura, confluent hemorrhagic spots mainly on the lower extremities (Fig. 1, a, b), as well as subcutaneous nodules, localized mainly on the head and arms [26]. Skin lesions, according to a number of studies [21, 27], are observed in more than 1/3 of patients and are more typical for ANCA-positive observations [21, 27]. Migrating pain syndrome in muscles and joints and arthritis are observed in 40-50% of cases and usually coincide with skin manifestations [28, 29].

Rice. 1. Patient 1. a - before starting therapy with methylprednisolone, prednisolone and cyclophosphamide; b - 3 days after the start of therapy.

Damage to internal organs during EGPA can be observed at the stages of eosinophilic infiltration and vasculitis, and there is a connection between the detection of ANCA in the blood and the clinical picture: damage to the lungs and myocardium is more typical at the stage of eosinophilic infiltrates, and involvement of the kidneys, skin, and peripheral nervous system (PNS) ) — for the stage of vasculitis [30, 31]. ANCA are detected at the stage of both eosinophilic infiltration (30-35% of patients) and vasculitis (~70%).

Cardiac disorders in EGPA include acute coronary syndrome, rhythm disturbances, pericarditis, and lesions of the valvular apparatus [24, 32]. In addition, subclinical changes in the myocardium and its membranes are possible, detected by MRI, PET and other additional examination methods [33]. The presence of cardiac disorders worsens the long-term prognosis (Table 3) [28], and may also be one of the reasons for an unfavorable outcome in the early period of the disease [34]. Damage to the gastrointestinal tract (GIT) due to eosinophilic infiltration of its mucous membrane and necrotizing vasculitis of mesenteric vessels with the development of hemorrhages, intestinal perforations and other complications is diagnosed in approximately 1/3 of patients [35]. Renal complications are usually observed at the stage of vasculitis; the main clinical syndrome is glomerulonephritis with a possible outcome in chronic renal failure [21, 36]. The addition of chronic renal failure and an increase in proteinuria are prognostically unfavorable signs (see Table 3) [28, 34].

Table 3. Scale for assessing the prognosis of EGPA [28] Note. Mortality within 5 years in the presence of the last three signs is 9, 18 and 42%, respectively [28].

Neurological manifestations of EGPA

Neurological symptoms in EGPA include damage to the PNS and CNS alone or in combination [21].

PNS damage

PNS involvement occurs in more than 50% of patients and is more often represented by multiple neuropathies [22, 27]. According to the results of one of the largest studies [21], in which 383 patients with EGPA were retrospectively analyzed, PNS involvement was noted in 197 (51.4%) patients, including multiple neuropathies in 175 (46.0%). The ulnar, radial and peroneal nerves are predominantly affected, less commonly the median, sural and tibial nerves [37]. Involvement of cranial nerves is also possible; the incidence of cranial neuropathies reaches 4.5–5.0% [21, 37]. Polyneuropathies are observed in 18-27% of cases and are more often the result of generalization of multiple neuropathies [22]. Morphological and electroneuromyographic studies show a decrease in the density of nerve trunks, pronounced axonal degeneration with relative preservation of myelin, which indicates predominantly primary axonopathy with secondary involvement of the myelin sheath [38].

We present an observation of EGPA with damage to the PNS.

Observation 1

Patient I.

, 53 years old, was admitted to the hospital on November 12, 2014 with complaints of weakness, numbness in the right leg and left arm, difficulty walking, pain in muscles and joints, weight loss, periodic fever, rashes on the elbows, legs and feet. Considers himself sick since August 2014, when periodic rises in temperature to subfebrile levels appeared in the evening, and general weakness. From the end of October 2014, these symptoms intensified, the increase in temperature (37.2-38.1 °C) became constant, shortness of breath and cough with difficult sputum and sometimes streaks of blood developed, and I lost 8 kg in 1 month. I took clarithromycin, acetylcysteine ​​and paracetamol. Due to the increase in these complaints and the lack of effect from therapy, he was hospitalized with a diagnosis of chronic purulent-obstructive bronchitis, exacerbation. Bronchial asthma of moderate severity, endogenous form.” From the age of 30, there was a history of polyposis of both maxillary sinuses, periodic rhinosinusitis, and from the age of 40, bronchial asthma with rare exacerbations; no sensitization was detected. Periodically uses inhaled forms of corticosteroids and adrenergic agonists. Notes an allergic reaction (urticaria) to acetylsalicylic acid.

On admission: moderate condition, conscious, alert, correctly oriented. The skin is clean, there is no swelling. According to the results of clinical and additional examinations, the lungs, heart and other internal organs are unremarkable. General and biochemical blood tests dated November 13, 2014 (Tables 4, 5) showed signs of an inflammatory process. While in the hospital, he noted the appearance of severe pain in the knee and ankle joints and numbness in the feet. Consulted by a neurologist: “Myalgia of unknown origin against the background of chronic purulent-obstructive bronchitis.” Discharged from the hospital on November 20, 2014 at his own request.

Table 4. Patient 1, complete blood count

Table 5. Patient 1, biochemical blood test Note. Here and in the table. 6-9: indicators that differ from the norm are highlighted in bold.

On 12/16/14 he was readmitted to the hospital due to the sudden development of weakness in his right leg. On admission the condition was of moderate severity. Conscious, in contact, fully oriented. On the skin of the elbows, legs and feet there are hemorrhagic rashes, confluent in some places and rising above the surface of the skin, which do not disappear with pressure (see Fig. 1, a). Symptoms of “pinch” and tourniquet are negative. Peripheral lymph nodes are not palpable. There is no swelling. During auscultation, breathing is not carried out into the lower parts of the left lung, the respiratory rate is 18 per minute. On the part of other internal organs - no deviations from the norm. In the neurological status, damage to the right tibial and peroneal nerves was noted in the form of weakness of the muscles of the lower leg and foot, decreased knee and loss of Achilles reflexes, as well as impaired superficial sensitivity in the area of ​​innervation of the roots L4-L5, L5-S1 on the right and the median nerve on the left. Over the next 2-3 days, neurological symptoms changed from multiple mononeuropathy to distal asymmetric polyneuropathy with motor and sensory impairment. During laboratory examination on December 17, 2014 (see Tables 4, 5), an increase in inflammatory changes and the appearance of eosinophilia were noted.

Due to the peculiarities of the medical history, the presence of infectious symptoms, myalgia, neuropathies and changes in general and biochemical blood tests, a differential diagnosis was made between EGPA and an infectious process, including borreliosis. Important for confirming the diagnosis of EGPA was the detection (12/18/14) of ANCA with a perinuclear type of luminescence: 74.2 U/ml (N=0-5).

After confirming the diagnosis of EGPA, combination therapy with corticosteroids (methylprednisolone 500 mg IV drip No. 3, then prednisolone 40 mg/day) and cyclophosphamide (single 600 mg IV drip) was started. 3 days after the start of treatment, the condition improved: the temperature returned to normal, arthralgia and myalgia almost completely regressed, hemorrhagic rashes decreased (see Fig. 1, b), as well as weakness in the arm and leg and sensory disturbances in the hands and lower extremities. During treatment, laboratory parameters approached normal (see Tables 4, 5). On January 15, 2015, he was discharged under the supervision of a rheumatologist and neurologist with recommendations to continue therapy with prednisolone at a dose of 75 mg daily, cyclophosphamide 1000 mg once a month with a repeat consultation with a rheumatologist after 1 month to decide on reducing the dose of prednisolone.

Thus, the patient had four out of six criteria (see Table 1) necessary to make a diagnosis of EGPA: bronchial asthma, polyposis of the maxillary sinuses, hypereosinophilia and multiple neuropathies. An additional feature confirming EGPA was the detection of ANCA. As in most previously described cases [21, 22], in this observation, PNS involvement was associated with the active stage of the disease, the development of vasculitis and the presence of ANCA.

CNS damage

Damage to the central nervous system during EGPA is observed in 10-15% of patients [21, 39] and is mainly represented by thrombosis of the venous sinuses and disorders of the cerebral and spinal circulation of an ischemic and hemorrhagic nature [40, 41]. Individuals with EGPA have a higher risk of venous and arterial complications than the average population [42], and vascular complications can develop during active and inactive stages of the disease. The development of cerebral strokes worsens the prognosis and may cause unfavorable outcomes [34].

We present an observation of EGPA with the development of cerebral vascular disorders.

Observation 2

Patient N.

, 34 years old, was admitted on August 19, 2014 to the intensive care unit with complaints of general weakness and headache in the right temporal region. From the anamnesis it is known that from the age of 18-20 years, polyposis of the nasal sinuses and periodic rhinosinusitis were noted. At the age of 25, I developed bronchial asthma. She was repeatedly hospitalized due to severe exacerbations, which were stopped only by intravenous administration of glucocorticosteroids. Sensitization to household, epidermal, and pollen allergens was not detected. At the age of 27, she noted the appearance of urticarial rashes on her legs, which disappeared after 3 days, leaving hyperpigmentation. A few months after this (in October 2008), based on clinical and laboratory data (asthma, polyposis of the paranasal sinuses, eosinophilia during repeated studies, changes in the lungs), ANCA, a negative variant of EGPA, was diagnosed. Observed in the clinic of therapy and occupational diseases of the First Moscow State Medical University named after. THEM. Sechenov: for a long time with good effect he takes methylprednisolone 8 mg/day, azathioprine 100 mg/day, seretide inhalations.

The deterioration occurred on August 16, 2014, when a severe headache appeared in the right temporal region. On August 19, 2014, due to sudden weakness in the left limbs, she was hospitalized. On examination: the condition is serious, complaints of headache in the occipital localization and awkwardness in the left limbs. The skin is clean. Peripheral lymph nodes are not palpable. Swelling of the eyelids and puffiness of the face are noted. On the part of internal organs during clinical and laboratory examination without pathology. In neurological status: conscious, fully oriented, making contact, but quickly depleted. Mild stiff neck, zygomatic ankylosing spondylitis sign on the right. Bilateral exophthalmos. The tongue deviates to the left. Other cranial nerves are normal. In the Barre test, it is more difficult to hold the left hand; in the test for the rhythm of active movements, the left hand lags behind. There are no movement disorders in the legs. Muscle tone is reduced without a clear difference between the sides. Tendon and periosteal reflexes of average vivacity, equal. Babinski's sign on the left. Missed hit when performing the finger-nose test on the left. No sensory disorders were identified. On August 20, 2014, for the first time in my life, a generalized tonic-clonic seizure occurred. Magnetic resonance angiography (MRA) and tomography (MRI) of the brain (08/20 and 08/21/14) revealed thrombosis of the sagittal, direct, right sigmoid and transverse sinuses and impaired blood outflow along the left sigmoid sinus (Fig. 2, a, arrows ) and ischemic stroke with hemorrhagic transformation in the right parieto-occipital region (Fig. 3, a, arrows). Due to extensive involvement of the cerebral venous system, clexane (0.5×2 times/day) and warfarin (5 mg/day) were added to the main therapy of EGPA (methylprednisolone 8 mg and azathioprine 100 mg).

Rice. 2. MR angiography of the cerebral vessels of patient 2 (T2). a - study dated 08/21/14; b - from 03.14.16.

Rice. 3. MRI of the brain of patient 2 (T2). a - study dated 08.20.14; b - from 03.14.16.

During laboratory examination, no changes were observed in the dynamics of general blood and urine tests. Repeated biochemical blood tests revealed an increase in cholesterol to 9.95 mmol/l (N<6.2), triglycerides - to 4.34 mmol/l (N<2.3), very low density lipoproteins - to 1.97 mmol /l (N<1.04), atherogenic coefficient - up to 5.2 (N<4.0) and fibrinogen - up to 6.22 g/l (N<3.95). The international normalized ratio (INR) and activated partial thromboplastin time (aPTT) were initially at the lower limits of normal and during therapy with Clexan and warfarin increased to the recommended values, and the level of fibrinogen decreased to the upper limits of normal (Table 6). On September 14, 2014, she was discharged under the supervision of a rheumatologist and neurologist with significant improvement and regression of neurological symptoms. Repeated MRA and MRI studies (03/14/16) showed restoration of blood flow through the venous sinuses and a decrease in the size of the lesion (see Fig. 2, b and 3, b).

Table 6. Patient 2, hemostasis indicators Note. PI—prothrombin index.

In this observation, thrombosis of the venous sinuses and ischemic stroke with hemorrhagic transformation developed in the inactive stage of EGPA. A feature of this observation was pronounced changes in the lipid spectrum, an increase in triglycerides and fibrinogen, which could potentiate hemostasis disorders and contribute to the development of vascular disorders.

Combined damage to the central nervous system and PNS

Much less frequently (2.5-4.2% of cases), exacerbation of EGPA can occur with combined damage to the central nervous system and PNS [21, 39].

We present an observation with the combined development of ischemic stroke and polyneuropathy.

Observation 3

Sick Ya.

, 77 years old, was admitted to the hospital on November 10, 2015 with complaints of general weakness, weakness in the lower and upper extremities, a feeling of “pins and needles” in the hands, swelling of the face and extremities. Considers himself sick for about 3-4 weeks, when these symptoms begin to increase. Due to weakness, she stopped leaving the house on her own. She had a low-grade fever, lost her appetite, and lost several kilograms during this period. After 1.5-2 weeks, swelling of the face and limbs began. During an outpatient examination, a general blood test revealed leukocytosis (14.6 × 109/l) and an increase in eosinophils to 37.4%; an MRI of the brain (10/29/15) revealed an ischemic stroke (0.8 × 0.5 cm) in acute stage in the subcortical structures of the right hemisphere and pansinusitis. MRA (10/29/15) showed no changes in cerebral vessels.

Since 2008, the patient has a history of bronchial asthma, non-atopic form, severe persistent course. She takes Symbicort regularly. Arterial hypertension (adapted to a blood pressure of 120/70 mm Hg), coronary heart disease, and angina pectoris have also been observed for a long time.

On admission the condition was of moderate severity. The skin is clean, there is pronounced swelling of the face, pastyness of the extremities. From the internal organs according to the results of a clinical examination without pathology. Neurological status: conscious, making contact, correctly oriented. There are no cerebral or meningeal symptoms. Slight smoothing of the right nasolabial fold. Other cranial nerves are without abnormalities. In the Barre test, the left limbs are held worse, and there is a slight limitation in the range of movements in the left limbs. The muscle tone is dystonic, with plastic elements on the right, and low on the left. Tendon and periosteal reflexes from the hands are alive, higher on the left. Knee, Achilles and plantar reflexes are absent. Due to general weakness, he walks with support and has a flexed posture and a shuffling gait. On the hands and feet - paresthesia and hyperesthesia, decreased pain sensitivity; deep sensitivity is preserved. General and biochemical blood tests revealed inflammatory changes, anemia, accelerated ESR and a high absolute and relative content of eosinophils (Tables 7, 8). Electroneuromyography (ENMG) dated November 18, 2015 (Table 9) showed predominant damage to axons and secondary damage to the myelin sheath.

Table 7. Patient 3, complete blood count

Table 8. Patient 3, biochemical blood test

Table 9. Patient 3, ENMG, motor SRV Note. SRV - speed of excitation propagation. Normal amplitude: * - ulnar nerve >6.0 mV, ** - median nerve >3.5 mV. Velocity is normal (for age ≥70 years): # - ulnar nerve ≥55.0 m/s, ## - median nerve ≥50.0 m/s.

Based on clinical, laboratory and ENMG changes, a preliminary diagnosis was made - EGPA. At the same time, the presence of somatic symptoms, polyneuropathy with predominant damage to axons, and changes in laboratory examination required the exclusion of an oncological process or blood disease. A CT scan of the lungs and abdominal organs, retroperitoneal space, and esophagogastroduodenoscopy revealed no evidence of an oncological process. Antineuronal antibodies ANNA 1 (Hu), PCA 1 (Yo-1), CV2, PNMa2, ANNA 2 (Ri) and AMPH were negative. Bone marrow specimen from the sternum: the number of undifferentiated blast cells is 1.2% (N=0.1-1.1%), no atypical cells were found, the sum of eosinophils is 30.0% (N=0.5-5.8 %); At the same time, irritation of the eosinophilic germ was noted: myelocytes 4.4% (N=0.2-0.3%), metamyelocytes 1.6% (N=0.2-0.3%), band cells 2.4 (N=0 .2—4.0%) and segmented 21.6% (N=0.2—3.2%). A study of ANCA (11/20/15) revealed their high titer of 1:320 (N<1:40) with a cytoplasmic type of luminescence. Antinuclear factor titer: 1:160 (N≤1:160). Thus, the diagnosis of EGPA was confirmed in the patient based on clinical and laboratory studies. To select combined immunosuppressive treatment, she was referred to the Research Institute of Rheumatology of the Russian Academy of Sciences.

A feature of this observation was a combined lesion of the central nervous system and PNS with the development of ischemic stroke and polyneuropathy in the active stage of newly diagnosed EGPA; as well as the detection of a cytoplasmic type of fluorescence of ANCA, which is more common in granulomatosis with polyangiitis (see Table 2) [5, 19]. However, persistent eosinophilia in the blood and bone marrow aspirate and signs of irritation of the eosinophilic germ during bone marrow examination confirmed the diagnosis of EGPA.

Mechanisms of neurological disorders in EGPA

According to the literature [37, 38], changes in the PNS during EGPA are associated with the development of necrotizing vasculitis with a predominant localization of the pathological process in the epineural space. Damage to the microvasculature in vasculitis is largely due to endothelial dysfunction with the development of local thrombosis and microhemorrhages due to the activation of eosinophils during their interaction with ANCA [43, 44]. Activated eosinophils release major basic protein, eosinophil cationic protein, eosinophil neurotoxin and tissue factor, which contribute to local prothrombotic changes [45, 46]. Along with vasculitis, in most patients, biopsy of peripheral nerves reveals eosinophilic infiltration of the vascular adventitia and local granulomatous inflammation [38, 47]. Thus, with EGPA, changes in the PNS develop as a result of the combined effects of vascular and toxic factors and granulomatous inflammation.

The increased risk of macrovascular complications in the form of cerebral strokes and sinus thrombosis in EGPA and other diseases with ANCA is primarily associated with systemic changes in hemostasis that are observed during the active and inactive periods of the disease [48]. In EGPA, hemostasis disorders predominantly affect the fibrinolysis and physiological anticoagulant systems. L. Mastalerz et al. [49] note significant changes in the structure of the fibrin clot: thus, in patients with EGPA, compared to healthy people, thicker fibrin threads and dense clots are detected, faster polymerization and an extended time of clot lysis, as well as a greater release of D-dimer from the clots. In addition, with EGPA and other vasculitis, the activity of factor XII, protein C and heparan sulfate decreases, and due to the release of tissue factor, the activity of the platelet component of hemostasis increases. The causes of systemic disorders of hemostasis are not completely clear. It is assumed that the chronic inflammatory process observed in these conditions may play a significant role in the shift to the prothrombotic side [50]. An additional potentiating effect on hemostasis disorders in these patients may be caused by associated risk factors: smoking, lipid disorders, early and accelerated atherosclerotic process, arterial hypertension, hormonal therapy, etc. [51].

Thus, literature data and the above observations indicate the frequent development of various neurological disorders during EGPA, which can dominate the clinical picture. Neurological disorders are based on necrotizing vasculitis, eosinophilic infiltration and systemic changes in hemostasis. The versatility of damage to the nervous system and the involvement of other organs and systems determine the importance of a comprehensive assessment of anamnestic, clinical and laboratory data, a study of the ANCA titer and the frequent need for a differential diagnosis of EGPA with infectious, oncological and systemic diseases. Detection of ANCA is an important laboratory sign confirming the diagnosis of EGPA, at the same time, the frequency of their detection depends on the phase of the disease: at the stage of eosinophilic infiltration, antibodies are detected in 30-45% of patients, and at the stage of advanced vasculitis - in more than 70% [20] . Timely initiation of combined immunosuppressive therapy promotes the reverse development of somatic, neurological and other disorders and normalization of laboratory parameters.

There is no conflict of interest.

Causes and development factors

Granuloma annulare in children can appear for various reasons, which have not yet been fully established. The provoking factor is a focus of chronic infection in the form of rheumatism, tonsillitis. The presence of diabetes mellitus, allergic diseases, and metabolic pathologies increases the risk of development. In children, a lot depends on the immune system. If there is a failure, the development of the neoplasm will be started. Pyogenic granuloma in a child occurs due to a pyococcal infection. The reason for the development lies in skin injuries, due to which infection gets into the wounds. It is localized mainly on the face, legs, fingers and arms. Eosinophilic granuloma is rarely found in young children. The peak incidence occurs between 5 and 10 years. The causes of such granuloma in a child are ambiguous. The question still remains open. Scientists suggest that immunopathological processes are the basis.

Stages of granuloma development

From the moment of inception, the neoplasm goes through 4 stages. At the initial stage, there is an accumulation of cells with a tendency to phagocytosis. At the second stage, the process of their rapid growth begins. The third stage is characterized by the transformation of phagocytes into epithelial cells. At the last fourth stage, granuloma formation occurs directly.

Main symptoms of eosinophilic granuloma

There are few symptoms of this disease, common to all its types is the appearance of a swelling or node in the affected area.
Eosinophilic bone granuloma has slightly more intense symptoms. Appears:

• Fatigue
• Temperature rises to 38-39°C
• Pallor
• Anemia
• Various skin changes
• Lethargy
• Weight loss

If the tumor is localized in the spine, the following occurs:

• Limited mobility
• Increased tendon contraction and foot clonus
• Back pain
• Mildly noticeable spinal deformities: scoliosis, lordosis, stoop, kyphosis. There is compression of the vertebra (flat vertebra), microscopic vertebral fractures with local hemorrhage appear.

Mild symptoms last 3-4 months, during this period diagnosing eosinophilic granuloma is very difficult, so in medical centers where the experience and qualifications of doctors are inferior to the level of training of Top Ikhilov medical staff, the patient may be given an erroneous diagnosis, for example:

• Bone form of tuberculosis
• Meningoradiculitis
• Rheumatism
• Osteomyelitis
• Osteosarcoma
• Neuroblastoma
• Fibrous osteodystrophy
• Lymphogranulomatosis
• Leukemia and many others.

Symptoms and signs

Granuloma annulare in children has different causes, but the symptoms do not change. Mainly affects the bones of the pelvis, skull, and spine. The course of the disease is slow. The symptom of eosinophilic granuloma is pain and swelling at the site of localization. There are cases where there is no discomfort. On the surface of the skin it appears as semicircular intradermal lesions. Granuloma annulare in children of a localized form is usually located on the hands and arms, feet and legs. It is diagnosed mainly before the age of 6 years. Ring-shaped lesions range in diameter from 2 to 5 cm. Giant sizes up to 10 cm are less common.

On the body, a pyogenic granuloma in a child does not exceed 2 cm in diameter. It has a thin surface and can bleed. The structure is fragile. Occurs quickly due to skin trauma. It does not turn pale when pressed. There is a rim of skin around the granuloma or it may be raised on a stalk. Rarely does a rash appear in the affected area. A characteristic symptom that children complain about is itching. Ring-shaped and pyogenic varieties occur in children more often than other neoplasms from the granulomatous group.

When to see a doctor

If papules of red-pink and bluish color appear on the skin, you should contact a dermatologist to confirm the diagnosis at JSC “Medicine” (clinic of Academician Roitberg) in the center of Moscow. Granuloma annulare in children causes and treatment depends on the degree of proliferation of foci and intensity. You will also need the help of a specialist in case of itching. Treating yourself or visiting a doctor is not a conflict of interest. Granuloma in a child may have characteristic causes, but the clinical manifestations can easily be confused with another serious disease. We are talking about lichen, which is sometimes mistakenly self-diagnosed based on external signs. There are a number of other diseases that stand apart, but can be mistaken for granuloma annulare: erythema raising, necrobiotic lesions, rheumatoid nodules.

Treatment of eosinophilic granuloma in Israel at the Top Ichilov Clinic

The effectiveness of treatment for this disease increases with the age of the patient.

As a rule, treatment is carried out in an inpatient setting. The patient is prescribed:

• A course of drug therapy using glucocorticoids in combination with cytostatics.
• If the spine is damaged, measures are taken to unload it: traction, a plaster bed, a corset.
• In rare cases, decompression of the spinal cord is performed.
• Radiation therapy relieves pain and mild neurological symptoms.
• In rare cases, surgical removal of the tumor is used, mainly if it is a bone tumor.

For Top Ichilov specialists, there are no rare and difficult to detect diseases; the only thing that can significantly reduce the effectiveness of treatment is the neglect of the disease, or late presentation of the patient. But this side of the treatment process is entirely up to you. Take the first step towards recovery, spend a few seconds of your time and fill out the form on our website to get a free consultation with a specialist. Top Ichilov medical consultants will quickly contact you and answer any of your questions.

Available diagnostic methods

At JSC “Medicine” (academician Roitberg’s clinic) near the Mayakovskaya metro station, you can comprehensively examine the health of adults and children. The latest equipment (ultrasound, MRI, CT) and advanced diagnostic methods, specially equipped rooms - everything is there to confirm or refute granuloma annulare in children. In the early stages of development, neoplasms cannot be detected. Symptoms appear when lesions appear on the surface of the epidermis. A diagnostic examination by a dermatologist is carried out when there are complaints of skin changes. Only after this do they turn to laboratory and histological analyzes of skin biopsies from lesions in case of suspicion of deep forms of lesions.

Clinical case

Based on Lam S. et al, Eosinophilic granuloma/Langerhans cell histiocytosis: Pediatric neurosurgery update. 2015

A 17-year-old young man was hospitalized due to an increasing scalp lesion over the past 6 weeks. The formation is painful on palpation and periodically bleeds due to ulceration, but no neurological deficit has been identified. CT and MRI revealed a large lesion in the frontal bone on the right, compressing the superior sagittal sinus. A total resection of the formation was performed, and the diagnosis of Langerhans cell histiocytosis of the skull bone was confirmed. At the outpatient stage, cytostatic therapy was carried out.

Figure 6. (a) CT examination without contrast - frontal scan (upper and middle part) and 3D reconstruction of the skull (lower part). (b) MRI scan. T1-weighted image in the coronal plane (top) and T2-weighted image in the sagittal plane

Sources

1. Coppes-Zantinga A., Egeler RM The Langerhans cell histiocytosis X files revealed. Br J Haematol, 2002. - V. 116 - N. 1 - P. 3–9.
2. Lam et al., Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis, 2013 - V. 8. - N 72.
3. Lam S., Reddy GD, Mayer R., Lin Y., Jea A. Eosinophilic granuloma/Langerhans cell histiocytosis: Pediatric neurosurgery update. Surg Neurol Int, 2015. - N. 6 (Suppl 17): S435 - S439.
4. Langerhans' Cell Histiocytosis (Histiocytosis X). What is it? Harvard Medical School. Harvard Health Publishing. October, 2014. www.health.harvard.edu
5. Sharma R., Singh R. et al. Langerhans cell histiocytosis (skeletal manifestations). Radiopaedia. https://radiopaedia.org/articles/langerhans-cell-histiocytosis-skeletal-manifestations-1
6. Shea C. R, James W. D. et al. Langerhans Cell Histiocytosis. Medscape, 2021. https://emedicine.medscape.com/article/1100579‑overview
7. Churilov L.P. Death on takeoff, or Who are you, Doctor Taratynov? Health is the basis of human potential: problems and ways to solve them, 2014. - T. 9 - No. 2 - P. 919–929.
8. Yusupova L. A., Yunusova E. I., Garayeva Z. Sh., Mavlyutova G. I. Histiocytosis X. Practical Medicine, 2014 - T. 08 - No. 14.

Methods of treating the disease

Granuloma annulare in children requires restrained treatment. The characteristics of the body allow us to expect spontaneous resolution. According to statistics, in 75% of cases, granulomas regress within 2 years. A granuloma may reappear on the skin of a child in 40% of patients. It is important that recurrent tumors behave benignly. For painful symptoms, corticosteroid ointment with a pronounced anti-inflammatory and antiallergic effect is used. Another treatment method is superficial scarification. How to treat granuloma annulare in a child without harm to health is an important topic. The methods are based on the use of physiotherapeutic procedures: PUVA therapy, ultraviolet irradiation and phototherapy, pulsed laser. The treatment of pyogenic neoplasm is characterized by excessive proliferation of blood capillaries. With this diagnosis, it is recommended to be treated by excision, curettage, liquid nitrogen and electrocoagulation. Granuloma annulare in children is treated within a month. The need for manipulation and use of ointments is determined individually.

Why does EEG occur?

The cause of EEG may be an allergy to flea bites or other ectoparasites, a reaction to food components, or environmental allergens, such as pollen or house dust.

Research has shown that in at least some (rather rare) cases, the tendency to develop eosinophilic skin diseases is genetically inherited. It has been suggested that genetic predisposition and environmental influences may play a joint role in the manifestation of eosinophilic skin diseases. The hypothesis that these pathologies are rarely caused by only one of the factors explains why EEG can occur during treatment or persist for several months or even years.

Prevention in children

Any granuloma in a child is treated only after consultation with a dermatologist. There are no special methods of prevention. Granuloma annulare in children has variable causes for the development of the disease. Taking into account the influence of immunity on the occurrence of formations, it is necessary to undergo timely treatment. It is necessary to take into account the infectious nature and metabolism in the body. Any disease should receive therapy to reduce risks. This is what prevention consists of – eliminating factors that can provoke the disease.

Eosinophilic granuloma: diagnosis in Israel

To detect eosinophilic granuloma, Top Ichilov doctors use the following modern diagnostic methods:

• Laboratory examination of blood and urine: with the disease, ESR and leukocyte content increase
• The main ones are various X-ray studies that allow us to determine the stage of the disease, as well as the location and structure of the tumor, mainly CT and bone scans
• Biopsy followed by histological examination revealing the cellular composition of the affected area

1. 5
2. 4
3. 3
4. 2
5. 1

(7 votes, average: 4.6 out of 5)

How to make an appointment with a dermatologist

You can make an appointment with a dermatologist using the special form “Make an appointment with a doctor” - just enter your data so that the administrator can call you back and coordinate the time of the visit. During the consultation, the doctor will examine the clinical picture, prescribe tests if necessary, and select treatment. You can make an appointment with a dermatologist using the number. JSC "Medicine" (clinic of academician Roitberg) has a convenient location at the address: 2nd Tverskoy-Yamskaya lane, building 10. Nearby there are metro stations: "Mayakovskaya", "Tverskaya", "Novoslobodskaya", "Belorusskaya", "Chekhovskaya" .