Toxidermy

Toxidermy (toxicodermia) is a common toxic and allergic disease with predominant manifestations on the skin and mucous membranes, resulting from the hematogenous spread of chemical (medicinal, rarely - protein allergens that enter the body by ingestion or injection parenterally, with inhalation or with massive resorption through skin and mucous membrane.

For the first time the term "toxicoderma" was introduced by G Yadasson (18%). Who noted the predominantly medicinal origin of this disease. Many authors, both domestic and foreign, consider medicinal toxicodermia as the most frequent manifestation of a medicinal disease.

Causes of the toxemia

The main aetiology of toxicermosis are:

• medicinal preparations (antibiotics, sulfanilamides, analgesics, barbiturates, vitamins of group B, novocaine, furacilin, rivanol, etc.);
• chemical substances (chrome, nickel, cobalt, molybdenum, arsenic, mercury, etc.);
• food products (preservatives, exotic fruits, eggs, chocolate, coffee, mushrooms, fish, nuts, etc.).

[1], [2], [3], [4], [5], [6], [7], [8]

Risk factors

Risk factors are: genetic predisposition, neuroendocrine disorders, digestive system diseases, dysbacteriosis, rapid decay of microbes that cause a specific endotoxic reaction.

[9], [10], [11], [12], [13], [14]

Pathogenesis

Adverse events and complications of drug therapy on the basis of etiologic signs can be divided into toxic-metabolic, allergic, infectious, neurogenic and caused by discontinuation of medication.

Toxico-metabolic complications are usually associated with the chemical and pharmacological properties of the drug, its overdose, duration of application, cumulation, synergism. Toxic complications often have a specific character, typical for a certain drug or a group of similar chemical structures (mercury, arsenic, halogens).

Allergic reactions to chemical (medicamentous) or protein substances, as a rule, are related to the individual hypersensitivity of the patient. Penetration and the body of chemical or protein allergens stimulates its protection with the help of the immune system. Immunological reactions that occur with damage to skin tissues in case of toxicdermia, according to the nature of the course and the mechanism of development, are divided into immediate-type hypersensitivity (HST) and delayed type hypersensitivity (HRT) cytotoxic type of immune response.

To trigger allergic reactions of immediate type, the concentration of specific antibodies produced by immunocompetent cells (B-lymphocytes, plasma cells), the number of fixed antibodies on mast cell membranes, and a certain ratio between antigens and fixed antibodies are important. This is confirmed by the results of skin tests with penicillin and streptomycin.

An example of a drug reaction that develops exclusively or primarily in an immediate manner in the first hours after administration of sulfanilamide preparations, pyrazolone derivatives (amidopyrine, analgin) and barbituric acid (luminal, barbamyl) is toxicodermia such as urticaria, multiforme exudative erythema, and fixed erythema.

Allergic reactions of delayed type are caused by cells, mainly T-lymphocytes and macrophages, as well as lymphokines (transfer factor) and thymus hormones.

In the process of HRT development, repeated entry into the body of the antigen (chemical substance, protein) causes the migration of sensitized lymphocytes to the area where there is a protein fixed by the skin proteins antigen. As a result, when reacting with a fixed antigen, the sensitized lymphocytes secrete cellular mediators of lymphokines that have inflammatory and regulatory properties. Regulatory lymphokine (transfer factor) activates the functions of T- and B-cells. Inflammatory lymphokines include cytotoxins by which sensitized lymphocytes (specific T-effectors) are directly involved in immune cell lysis, as well as a humoral inflammatory factor that enhances the permeability of the capillary walls, which facilitates the migration of cells from the bloodstream to the allergic inflammation area. Most often, the toxic-allergic reaction according to the type of HRT is manifested by spotted-papular and spotted-vesicular elements with predominance of the hemorrhagic component

The immune response of the body to the receipt of a chemical substance can occur with damage to the skin tissue according to the type of T-cytotoxic reaction that is carried out by sensitized lymphocytes (T-effectors) together with macrophages lysing the cells. The destruction of cells occurs with direct contact with the cells-aggressors and secretion of cytotoxins by them - acid hydrolases. The cytotoxic effect is especially clearly traced in the pathogenesis of bullous toxidermia and Lyell's syndrome, in which epidermolysis is the leading pathomorphological feature.

Damage of cells and intercellular structures as a result of toxic effects of medications or allergic reactions informs them of an autoantigenic property that causes the formation of autoantibodies. Under appropriate conditions, "autoantigen-auto-immune-immune complexes" complexes enhance the process of damage to cells, organs, tissues, and vessels.

Autologous reactions play an important role in the pathogenesis of drug reactions such as vasculitis, systemic lupus erythematosus, eczematoid-like lesions.

In the development of some forms of toxemia, it is necessary to take into account the damaging and sensitizing skin of the microbial factor. Exposure to the skin of bromine and iodine preparations that change the sebum chemistry contributes to the activation of staphylococcal infection, which is involved in the pathogenesis of such toxicermiids as bromoderm and iododerm.

[15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]

Symptoms of the toxemia

Symptoms of toxicidermy are characterized more often by polymorphic, less often by monomorphic eruptions of inflammatory character, manifested against the background of a general state disorder.

Spotty-papular rashes are noted more often with the administration of antibiotics (penicillin, streptomycin, olegetin, griseofulvin, lamidil) analgesics, B vitamins, novocaine, rivanol, furacilin. Spots of an inflammatory nature, often hyperemic, ranging from point to drainage erythema, are usually located throughout the skin, often extending from the top down or affecting mainly the skin of folds or areas experiencing additional physical stress.

Stained nodular rash is usually disseminated, sometimes tends to focus and merge and is usually represented by lymphoid papules of round shape, bright pink in color. As the disease develops, usually on the 4th-5th day, peeling occurs on the surface of spots and papules, most often in the form of delicate translucent scales, covering the entire surface of the vysypnyh elements.

Under the influence of effective therapy, there is a resolution of the rashes, which in rare cases leave unstable hemosiderin pigmentation.

Eruptions on the skin are often accompanied by itching, fever to 38 ° C, general malaise, chills, headache. In the blood there is a moderate leukocytosis, eosinophilia.

Fixated (sulfanilamide) erythema

In 1894 the French dermatologist L. Brocq first proposed the term "fixed rashes". Currently, the synonym for "fixed erythema" is used to refer to medical spotted-plaque, spotty-urticarial or bladder rash, recurring at the same sites and leaving a persistent pigmentation.

In the vast majority of patients, the cause of this type of toxidermia is the intake of sulfonamides, less often other drugs (barbiturates, analgesics, antipyretic drugs).

Skin lesion with fixed erythema is characterized by the appearance first of single, and then - multiple foci. The primary focus is localized more often on the mucous membrane of the mouth, trunk, in the folds, on the back surface of the hands, on the feet, on the genital organs.

First, one or more spots of 2-5 cm in size are brownish-cyanotic or with a lilac shade, and the peripheral zone is brighter than the central one. Spot round, sharply delimited from healthy skin. In the future, the center of the spot slightly sinks, acquiring a grayish tint or from the center to the periphery, the regression of the rashes begins and their color becomes brown, the elements acquire the form of semirings, ruts and garlands. Sometimes a bubble can form in the center of the spotted elements.

Rashes are accompanied by a sensation of itching and burning. Elements on the skin exist up to 3 weeks. With the common form of fixed erythema, there is an increase in body temperature, muscle and joint pain. In the acute period of the disease, leukocytosis, eosinophilia and elevated ESR are observed in the blood.

[29], [30], [31], [32], [33], [34], [35]

Toxidermy by type of urticaria

Urticaria is a frequent reaction to various medications: penicillin, tetracycline, erythromycin, analgesics, trichopolum, novocaine, lidase, etc. Eruptions occur in the first days of the drug and are characterized by the appearance of blisters on the skin and severe itching. The size of urticaria eruptions varies from lentil to palm, the boundaries of the elements are clear, the consistency is tight-elastic (doughty), the shape is round or bizarre. Urticaria dermographism is often noted. The color of the elements is from bright red to pearl white.

Typically, the urticaria rash is abundant in nature, covering the entire skin of the face, trunk and extremities. In severe cases, the process is accompanied by swelling of the mucous membranes of the mouth and larynx, turning into Quincke's Edema.

When generalizing the skin process, general weakness, malaise, headache, elevation of body temperature to 38-38.5 ° C, arthralgia and myalgia are possible. In the blood there is a steady increase in the number of eosinophils.

Bromoderma and iododerma

Relatively rare and difficult to diagnose are the toxicdermia arising from the intake of bromide and iodide preparations, bromoderm and iododerm.

Bromoderms are characterized by a variety of eruptions: erythematous, urticaria, papule-pustular, vesicular, bullous, warty and acne-like.

Brominated eels, which are the most frequent and typical form of bromoderm, are manifested in the form of follicular pustules the size of a pinhead to lentils and abundant pinkish purple nodular elements that appear on the skin of the face, back and extremities. After healing, small superficial scars of brownish-violet color may remain.

Bromoderma tuberous (vegetative) occurs more often in young women. The rashes are the appearance of a few limited nodular and tumor-like plaques of violet-red color, rising 0.5 0.5 cm above the skin. The size of the nodes is from pea to pigeon egg, they are covered with blood-purulent, fairly dense crusts. After removing the crusts, an ulcerous tuberous surface is exposed, on which warty-papillary sprouting can develop. When squeezing the lesion on a growing surface, pus is abundant. The whole "swelling" resembles a soft sponge soaked in pus. Visible mucous membranes are rarely affected. The disease proceeds favorably leaving after itself atrophic scars and pigmentation.

Iododerma is most often manifested in bullous and tuberous form. Tuberous form can be complicated by vegetation. With bullous ioderm, rashes usually begin with intense blisters measuring 1 to 5 cm in diameter, filled with hemorrhagic contents. After opening the bubbles, a bottom is exposed, covered with significant vegetation.

Tuberoida iododerma begins with a nodule, which then turns into a pustule and a tumor-like formation up to 5 cm in diameter. The peripheral edge of the focus is slightly elevated and consists of small vesicles with liquid serous-purulent contents. Consistency of the focus is pastose, with pressure on the surface, pus with an admixture of blood is easily excreted. Most often the iododerm is localized on the face, less often - on the trunk and extremities.

Clinically, there is a great similarity of tuberous iododerm with bromoderm, associated with the same mechanism of emergence as a result of taking drugs belonging to one chemical group.

[36], [37], [38], [39], [40], [41], [42], [43]

Lyell's Syndrome

The first description of toxic epidermal necrolysis was made by the English physician A. Lyell in 1956 on the basis of clinical observation of 4 patients. In 1967, he published his observations of 128 cases of this disease, having analyzed his own results and the data of other English doctors. Up to the present time in the literature this syndrome is called differently: epidermolysis necrotic polymorphic: syndrome of "cooked skin"; burn-like necrotic epidermolysis; toxic-allergic epidermal necrolysis

A. Lyell characterizes the syndrome as a polyethological disease, in the development of which, depending on the leading cause, we can identify 4 etiological groups:

• The 1st group is an allergic reaction to an infectious, mainly staphylococcal, process, which is more often observed in childhood;
• The second group is the most common allergic reaction with drug treatment;
• 3rd group - idiopathic with unexplained cause of development;
• 4-th group - develops more often as a result of a combination of an infectious process with drug therapy against a background of altered immunological reactivity, with the direct participation of allergic mechanisms.

In the opinion of most authors, Lyell's syndrome develops as a nonspecific reaction to the effect of medications taken in various diseases. Most part of this disease is provoked by the reception of patients with sulfonamides, antibiotics and antipyretics, derivatives of barbituric acid.

It should be noted the high incidence of Lyell's syndrome from the simultaneous administration of sulfonamide drugs of prolonged action, antibiotics and antipyretic agents, among which are especially often used such as aspirin, analgin, amidopirin.

Drugs taken with various diseases (ARI, pneumonia, exacerbation of chronic tonsillitis, diseases of the cardiovascular system, kidneys, etc.) may have an allergic effect.

Investigating the pathogenesis of Lyell's syndrome, a number of authors prefer allergic theory. Proof of this assumption is the presence in the history of the overwhelming majority of the patients surveyed by them of various allergic diseases (allergic dermatitis, polynomas, hay fever bronchial asthma, urticaria, etc.). The patients showed an increase in fibrinolytic activity and an increase in clotting time, which confirms the leading role of vascular lesions in the development of Lyell's syndrome. Immunofluorescence did not reveal antinuclear and antimitochondrial antibodies in the epidermis, no changes in the content of immunoglobulins in the blood were detected. These data made it possible to confirm that Lyell's syndrome can not be interpreted as an immunodeficient phenomenon - it is based on acute cell damage caused by the liberation of lysosomal structures.

The development of Lyell's syndrome, regardless of the causes that caused this disease, begins suddenly, accompanied by a rise in body temperature of 38-40 ° C, a sharp deterioration in well-being, weakness, often headache and arthralgia. Skin manifestations occur on the 2nd-3rd day, most often in the form of erythematous spots with pronounced edema, resemble eruptions in polymorphic erythema. Then quickly, within a day, the hemorrhagic component joins, usually in the central part of the element, giving the erythema, along with the growing periphery, a contour of the iris type. Gradually, the central zone of the elements acquires a greyish-ash coloration - an exfoliation of the epidermis takes place.

According to some authors, the only reliable objective criterion for diagnosing the syndrome of Lyell's syndrome is epidermal necrolysis. Confirmation of the latter is typical symptomatology: on the lesions and outside them, on the areas of the "healthy" skin the epidermis exfoliates spontaneously and at the slightest touch (the symptom of "wet laundry") is rejected with the formation of extensive extremely painful erosive surfaces that produce abundant serous or serous-hemorrhagic exudates .

As the process progresses, bubbles filled with serous contents continue to appear, rapidly increasing in volume and size, with the slightest pressure on their surface, and even with the change in the patient's posture, the Symptom of Nikolsky is sharply positive (marginal and in apparently unchanged areas). The soreness of the entire skin is noted when touched. Simultaneously with cutaneous manifestations, the red rim of the lips can involve the mucous membranes of the cavities of the mouth and nose, of the genital organs. Often, the mucous membranes of the eyes are affected, which can lead to clouding of the cornea and reduced visual acuity, atony of lacrimal ducts and hypersecretion of the lacrimal glands.

Of the appendages of the skin, nails are especially often affected, and, more rarely, hair. In severe Lyell's syndrome, nail plate rejection can occur.

Extensive erosive surfaces on the skin and mucous membranes separate a profuse serous or serous-hemorrhagic exudate that dries up in some areas with the formation of crusts. In case of secondary infection, the nature of the discharge becomes purulent, a specific smell of "rotting protein" arises. The forced position of the patient due to the sharp soreness of the skin and erosive surfaces often leads to the appearance of ulcers mainly in places of pressure - in the region of the shoulder blades, elbows, sacrum and heels. The peculiarity of these ulcers is sluggish healing.

The defeat of the mucous membrane of the oral cavity is accompanied by salivation, because of severe soreness, swallowing and eating are difficult. Erosion of the mucous membrane of the urethra leads to a violation of urination.

In patients with Lyell's syndrome, internal organs can be damaged (hypostatic pneumonia, toxic-allergic myocarditis, dehydration, hemorrhagic glomerulonsphritis, anuria, activation of focally infected foci) against a background of a sharp decrease in the defenses of the body.

Stages

The severity of the flow distinguishes between light, medium severity and severe toxemia. Among the light lesions (I degree) can be classified as pruritus, mild urticaria, fixed erythema with single foci, patchy-papular form of exudative erythema, limited forms represented by papular rashes as a red flat lichen. The general condition of the patient does not change or changes insignificantly. Eosinophilia may be present in the blood.

To moderate to severe toxemia (grade II) include urticaria with a large number of blisters, Quinke stack, common eruptions of erythematous-spotted, erythematous, papular-vesicular and bullous character, hemorrhagic vasculitis as simple, rheumatoid or abdominal purpura. At this degree of the disease, there is an increase in body temperature, changes in blood, and sometimes damage to internal organs.

Severe lesions (grade III) include Lyell and Stevens-Johnson syndromes, erythroderms, nodular necrotic vasculitis, iododerma, bromoderma, as well as other medical and allergic rashes combined with anaphylactic shock, a symptomatic complex of serum sickness, systemic lupus erythematosus, and periarteritis nodosa.

Severe forms of toxemia, as a rule, accompany the defeat of internal organs and can lead a patient to death, especially with late diagnosis and inadequate therapy. The most common are patchy-papular, spotty-urticarious rashes rarely bullous, vesicular and pustular forms of toxemia.

[44], [45], [46], [47], [48], [49], [50], [51], [52], [53]

Diagnostics of the toxemia

In the blood of patients, a moderate, then significantly increasing leukocytosis (8.0-10.0-10 ⁹ / L), a neutrophilic shift to the left, an increase in the number of stab samples to 40-50% are noted in the blood of patients at first . In particularly severe forms of this disease, it is possible to develop agranulocytosis or pancytopenia. Biochemical changes in blood are expressed in a decrease in the content of potassium and calcium, hypoproteinemia. In the urine are determined moderate hematuria, pyuria, hyaline, waxy and granular cylinders appear - the result of the defeat of the tubular system of the kidneys.

[54], [55], [56], [57]

Treatment of the toxemia

The lightning course of the disease, leading to total defeat of the skin, a sharp deterioration in the general condition requires immediate urgent therapeutic measures. The basis of specialized and combined therapy are corticosteroid hormones (prednisolone, dexamethasone, triamcinolone), which are prescribed in the first days of the disease at a dose of 250 to 300 mg, depending on the severity of the process and the extent of the lesion. Attempts to manage patients without the use of corticosteroids or using small vines ended, as a rule, fatal

Recently, with Lyell's syndrome, along with usual hyposensitizing therapy (antihistamines, calcium preparations, ascorbic acid), haemodesis is used.

Massive therapy with corticosteroid hormones, extensive wound surfaces, which are the "entrance gates" for purulent infection, the development of hypostatic pneumonia, activation of focally infected foci cause the inclusion of antibiotics of the cephalosporin group in therapy at a daily dose of 4-6 g

An enormous role in the treatment of patients with Lyell's syndrome is played by external therapy and careful care of the skin and mucous membranes. The use of keratoplastic emulsions, ointments with the addition of antimicrobial agents in combination with sea buckthorn oil, dog rose, retinol acetate, daily dressings, treatment of erosive ulcer surfaces with solutions of aniline dyes are effective means of repairing damaged skin and mucous membranes.

In the prognostic relation, the timely hospitalization of the patient and the early diagnosis of the disease are of great importance in the Lyell syndrome.

Thus, in the treatment of any form of toxemia the main ones are:

• the withdrawal of the drug that caused Lyell's syndrome;
• application of cleansing enemas, diuretics;
• hyposensitizing therapy - calcium preparations, angi histamine drugs (suprastin, tavegil, diazolin, etc.):
• detoxification therapy (hemodez, sorbitol, etc.):
• the appointment of corticosteroid hormones in severe cases.