Lyell´s syndrome provoked by external drug use

Alexandr B. Krivosheev; Кривошеев Александр Борисович; Tamara V. Ermachenko; Ермаченко Тамара Викторовна; Pavel P. Khavin; Хавин Павел Петрович; Inga A. Krivosheeva; Кривошеева Инга Анатольевна; Dmitry V. Morozov; Морозов Дмитрий Вильевич

doi:10.17816/dv62377

Lyell´s syndrome provoked by external drug use

Authors: Krivosheev A.B.¹, Ermachenko T.V.², Khavin P.P.³, Krivosheeva I.A.², Morozov D.V.²
Affiliations:
1. Novosibirsk State Medical University
2. City Clinical Hospital No 1
3. City Clnical Hospital No 1
Issue: Vol 24, No 1 (2021)
Pages: 25-34
Section: CLINICAL PICTURE, DIAGNOSIS, AND THERAPY OF DERMATOSES
Submitted: 01.03.2021
Accepted: 17.03.2021
Published: 15.02.2021
URL: https://rjsvd.com/1560-9588/article/view/62377
DOI: https://doi.org/10.17816/dv62377
ID: 62377

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Abstract

Lyell´s syndrome is rare. Up to 10 cases are registered per million population per year. The mortality rate for Lyell’s syndrome is 5–12%.

Two patients were observed aged, respectively, 38 years and 72 years with Lyell’s syndrome. The disease manifested itself against the background of local application of drugs. In one case ― Doloben’s gel as an analgesic at the site of a bruise of the right hand. In another case, a 20% solution of chlorohxidin biogluconate as a mouth rinse for stomatitis. The first symptoms of the disease occurred locally at the site of application of these medicines. In the first case, the skin of the right hand, in the second ― the mucous membrane of the mouth. The outcome of the disease depended on early diagnosis, urgent hospitalization in a specialized department, from the area of skin lesions, the appointment of adequate therapy.

Lyell’s syndrome can occur at any age, and the risk of developing the disease increases in those over the age of 40. In the elderly, SL in terms of the first symptoms and rate of disease progression, the nature of skin and mucous membrane lesions does not have any fundamental differences with those in younger patients. The distinctive features and risk factors of Lyell’s syndrome in the elderly include, firstly, its occurrence against the background of the already formed comorbid age-related pathology of internal organs, secondly, the concomitant age-related pathology during the development of an acute toxic-allergic reaction is decompensated, a multiorgan failure is formed, which is the cause of more severe Lyell’s syndrome and higher mortality. In young people, a comorbid viral infection can be considered a risk factor, especially the combination of HIV-infection and chronic hepatitis C.

Keywords

Lyell’s syndrome, comorbid pathology of internal organs, HIV-infection, chronic hepatitis C

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In 1956, A. Lyell [1] first described a peculiar pathological condition characterized by an acute onset, necrotic changes in the epidermis, rash of large blisters and the formation of extensive erosions, high temperature and general grave condition, describing it as "toxic epidermal necrolysis" ( Heating element). Subsequently, this symptom complex was called Lyell's Syndrome (SL) [2]. Currently, SL is considered as a severe, immunoallergic drug-induced disease that threatens the patient's life, representing an acute visceral skin pathology and characterized by intense epidermal detachment and epidermal necrosis with the formation of extensive blisters and erosions on the skin and mucous membranes [3, 4].

SL is rare. Up to 10 cases per 1 million population are registered per year [5]. In 1967 A. Lyell [6] presented information about 128 patients with TEN. In the domestic literature, the issue of SL is covered in sufficient detail [2, 7-9]. Recently, the problem of SL in the elderly has become very relevant [8, 10]. SL is induced by various factors, but more often with the infusion, intramuscular or oral administration of drugs, as well as the intake of biologically active food supplements [7, 11, 12]. There are isolated reports of the occurrence of severe allergic dermatosis to the local use of medications, in particular furacilin solutions [13] and baking soda [14]. We observed two patients who developed Lyell's syndrome with topical drug use. Patient L., 38 years old, was admitted to the admission department of the clinic on April 17, 2018 with complaints of the appearance of a rash on the skin of the back, trunk, extremities, which had a tendency to the rapid spread of blisters with serous contents, and an increase in temperature to 37.8 ° С ... History of chronic hepatitis C (about 20 years), opiate addiction (2010-2014 intravenous heroin use). Since 2010, HIV infection (HIV-RNA positive, titer 4.08E + 0.5 copies / ml), specific antiretroviral therapy has not been carried out. Smokes since 20 years. Allergic reactions have not been previously note.

Is sick 04/09/2018, when he was injured - a bruise of the right hand. On the recommendation of a traumatologist, I applied Ketorol gel locally (in the area of injury) for 4 days, and then Dolobena gel. 2 days after the start of its use, rashes appeared on the right hand in the form of light brown spots, round in shape with even borders, ranging in size from 2 to 4 cm, which within 2-3 days spread to the skin of the face, trunk, chest, back , upper and lower extremities, At the site of rashes in the distal parts of the upper and lower extremities, blisters of a round and / or oval shape began to appear, which gradually increased in size, the temperature rose to 38.7 ° C, which was the reason for emergency hospitalization in the intensive care unit. Upon admission, the patient's condition is serious. In the lungs, breathing is hard, it is carried out in all departments, there is no wheezing. Respiration rate 20 per minute. Heart sounds are muffled, rhythmic, heart rate is 100 per minute, there is no pulse deficit. The abdomen is soft, painless. The liver along the edge of the costal arch, dimensions according to Kurlov 10 × 9 × 6 cm, the spleen is not enlarged. Rashes in the form of spots of light brown color, rounded, ranging in size from 2 to 4-5 cm, not rising above the surface of the skin, tend to merge, acquiring an irregular configuration (Fig. 1). On the dorsum of the right hand, in the place of the opened bladder, there is a large erosion of irregular outlines, 8 × 3 cm in size, the bottom of the erosion covered with fibrin, along the edges of the epidermis, which on contact easily exfoliate with adjacent skin areas (Nikolsky's symptom is positive) (Fig. 1). On the left foot on the outer surface there are two rounded blisters up to 3 cm in diameter, with a dense cover, serous contents, painless. Surface of palms and soles has a solid red-brick color. The color intensity has become brighter. Nikolsky's symptom is negative (Fig. 2). According to the results of general clinical, biochemical, instrumental studies, significant deviations from the standard values were not found. Diagnosed with Lyell's Syndrome. Stage 4A HIV infection without antiretroviral therapy, chronic hepatitis C of minimal activity, contusion of the right hand. Upon admission to the department (04/17/2018), the patient was injected intravenously with prednisolone 90 mg; from 18.04. Until 04/20/2018, pulse therapy was carried out: ivipred (methylprednisolone) 1000 mg / day intravenously; From 21.04.2018 the patient was transferred to oral administration of metipred (methylprednisolone) in a daily dose of 24 mg; The complex therapy included: Suprastin 2 tablets per day; omeprazole 20 mg 2 tablets per day; hepritis 5000 IU 2 times a day subcutaneously; sterofundil 500 ml tablets per day; erosion was topically treated with betatin solution.

Against the background of the therapy, the temperature returned to normal on the 2nd day. New eruptions did not appear. By the 20th day of treatment, the skin rash resolved, the erosion was epithelialized. Receives metipred 4 mg (table 1). Discharged on 07.05.2018 in satisfactory condition. Monitoring and treatment at the regional AIDS center is recommended. Patient L., 72 years old, in February 2016 she underwent a planned replacement of dentures. After 2-3 weeks of using them, stomatitis developed. On the recommendation of the dentist, a 20% solution of chlorhixedine biogluconate began to be used locally in the form of rinsing the oral cavity. On 19.03.2016, for the first time, there were difficulties in swallowing, and then blistering eruptions appeared on the mucous membrane of the right cheek. She continued to use the recommended drug, since she regarded changes in the oral mucosa as a manifestation of stomatitis. A day later, the rash spread to the entire surface of the oral mucosa. At the same time, itching arose in the eye area. Over the next day, rashes appeared in the form of light brown spots up to 4 cm in size on the skin of the upper extremities and trunk, which tended to merge. Rinsing with a solution of chlorhixedine biogluconate was stopped. On 03/22/2016, the ambulance team urgently delivered the patient to the emergency department of the clinic and was hospitalized in the intensive care unit with a diagnosis of Lyell's syndrome.

A history of more than 10 years of arterial hypertension of the 3rd degree, stage III, risk 4 (receives basic antihypertensive therapy: Betaloc-Zok 50 mg / day and cardiomagnyl 75 mg / day); type 2 diabetes mellitus for about 10 years (takes metformin 500 mg / day and diabeton 60 mg / day); ischemic heart disease arrhythmic variant, paroxysmal form of atrial fibrillation. Allergic reactions have not been previously observed. He denies tuberculosis, HIV infection, viral hepatitis. In the emergency room, the patient was examined by an otolaryngologist and an ophthalmologist. The otolaryngologist's conclusion: the nasal mucosa is dry, slightly hyperemic, the pharynx is hyperemic, on the surface of the soft palate there is erosion up to 1 cm in diameter and a separate mass of desquamated epithelium, the mucous membrane of the larynx is hyperemic, the laryngeal lumen is sufficient, there are no signs of stenosis. Recommended: vaseline oil, 2 drops 3 times a day, rinsing the mouth with drinking water, voice mode. The optometrist diagnosed sluggish conjunctivitis. Recommended treatment: solution of ciprolet and sodium sulfacyl, 1 drop 4 times a day in both eyes, treatment of the conjunctiva of the eyes with distilled water. Physical examination. The condition is serious, conscious, contact, adequate. The skin is pale, dry, cyanotic in the area of the hands. On the skin of the chest, abdomen, back, buttocks, upper and lower extremities, rashes in the form of spots up to 3-4 cm in size, reddish color of irregular outlines with a tendency to merge, on the hands and the torso contains multiple bubbles, dense, painless, up to 3 cm in size with serous-hemorrhagic contents. In the lungs, hard breathing, wheezing is not heard, the respiratory rate is 18 per minute. Heart sounds are muffled, rhythmic, heart rate is 68 per minute, blood pressure is 125/80 mm Hg. Art. The abdomen is soft, moderately painful in the epigastrium, the symptoms of irritation of the peritoneum are negative, the liver protrudes from under the costal arch by 1 cm, the size of the liver according to Kurlov is 12 × 9 × 6 cm. Diuresis is adequate, the stool is independent. Survey data. Complete blood count: Hb 125 g / l, er. 4.1 × 1012 / l, watering can. 7.3 × 109 / L, Ht 37.1%, thrombus. 269 × 109 / l, p. 11%, seg. 76%, limf. 12%, mon. 2%, eos. 0%; ESR 37 mm / h. General urine analysis: protein 0.28 g / l, watering can. 6, erit. 2, epit. 1-2 in f / s, pH 5.0, relative density 1025, sugar 5.6 mmol / l. Blood biochemistry (indicators are presented in the dynamics of which significant changes were recorded during the observation period): Creatinine-phosphokinase 88.7-564.7 nmol / L (normal up to 172 nmol / L), albumin 40.5-30.8 g / L , (norm 35 g / l), total protein 73-50.1 g / l (norm up to 80 g / l), urea 8.4-12.9 g / l (norm up to 7.6 g / l), C-reactive protein 162.5-276.6 g / l (norm up to 5 g / l), fibrinogen 5.2-9.6 g / l (norm up to 4 g / l), fasting glucose 15.8-20 , 2 mmol / l (the norm is up to 5.5 mmol / l). Instrumental examination. ECG. Normosystolic variant of atrial fibrillation. Chest X-ray. Moderate congestion in the pulmonary circulation, pronounced signs of pulmonary emphysema. Infiltrative changes not. Ultrasonography of the abdominal organs. Hepatomegaly, signs of fatty hepatosis and chronic pyelonephritis. The basic therapy was started: a solution of prednisolone 180 mg / day intravenously, Solu-medrol 500 mg / day intravenously, kvamatel 40 mg 2 times a day intravenously, infusion therapy in a volume of up to 2 liters per day. After consulting an endocrinologist, the patient was transferred to insulin therapy (Bisulin N 14 IU and Bisulin R 2-3 IU with glycemia more than 12-15 mmol / L). The patient was examined by a dermatologist. Conclusion: drug toxicoderma of the type of Lyell's syndrome. Since March 24, 2016, the progression of skin changes has been noted. The appearance of new blisters on the feet, back and buttocks is noted, a generalized reddish rash, swelling of the hands with skin detachment (Nikolsky's symptom is positive). The prednisolone dose was increased to 320 mg / day. 03/27/2016: the condition is serious, unstable; the patient is conscious, speech contact is difficult due to erosive damage to the oral mucosa. Lips dry, cracked, crusted with blood. On the skin of the face, in place of the opened erosion blisters with uneven edges, ranging in size from 2-3 to 6 cm.Nikolsky's symptom is negative. The brushes are edematous, reddish-brick in color with areas of epidermal detachment (Fig. 3). The appearance of new blisters and skin detachment on the feet were noted. The dose of prednisolone is increased to 360 mg / day. 03/31/2016: negative dynamics: the rashes have acquired a generalized character, there is a clear tendency to their fusion, Nikolsky's symptom is positive with minimal physical contacts, there is a massive detachment of the skin on the back and buttocks (Fig. 4). 04/01/2016 with an increase in the symptoms of cardiovascular and respiratory failure, biological death was stated on the 14th day after the onset of the disease. Sectional histological examination data: Skin micropreparation: necrolysis of most of the epidermis; in the area of the skin defect, the superficial layers of the dermis are necrotic; moderate focal neutrophilic and lymphocytic infiltration; plethora of vessels of the dermis (Fig. 5). Microdrug of the heart: plethora and edema of the interstitium; fragmentation of myocytes; uneven hypertrophy and uneven thinning of fibers; focal stromal and parenchymal fatty degeneration (Fig. 6). Liver microdrug: vascular congestion; hepatocytes in a state of hydroscopic infiltration; moderate sclerosis of the portal tracts (Fig. 7). Kidney microscope: the lumens of the vessels of the interstitium are dilated, full-blooded; sclerosis of part of the glomeruli and blood vessels of the stroma, edema of the interstitium; focal necronephrosis; focal lymphoid infiltration (Fig. 8). Pancreas microdrug: sclerosis and stromal lipomatosis; parenchyma autolysis; the islets of Largengans are edematous, sclerosed (Fig. 9). Microdrug of lung tissue: plethora of capillaries of interalveolar septa and interstitial vessels; areas of atelectasis alternate with areas of emphysema; the epithelium of the bronchi is desquamated; perivascular and peribronchial sclerosis (Fig. 10).

The conclusion of the pathologist: Lyell's toxic epidermal bullosa necrolysis. Dystrophic changes in internal organs. Discussion From modern positions, SL is considered as an acute and severe allergic reaction, which is a potentially life-threatening disease, characterized by extensive damage to the skin and mucous membranes with the appearance of epidermal necrolysis (Nikolsky's symptom is positive), accompanied by severe intoxication and dysfunction of internal organs, provoked by taking medications [4, 15, 16]. The exact pathogenetic mechanisms leading to the development of SL can only be partially explained. Currently, a large role in the development of SL is assigned to the genetically determined predisposition of the organism to various allergic reactions [17]. The presented observations allow us to discuss a number of issues related to the diagnosis, tactics of management and prognosis of SL. Firstly, in the two patients observed, the first clinical symptoms in the initial stages of the formation of the disease turned out to be identical and were characterized by the following signs: 1. The focus of the manifestation of SL and its further progression was the local application of the drug. In the first case - the area of the skin of the right hand (the place of injury), in the second - the oral mucosa (stomatitis).

2. The lesion of the skin and mucous membranes was accompanied by a rapid spread of rashes in the first 2-3 days after the onset of the disease, and up to 60% of the skin in the first patient and at least 80% in the second patient was involved in the pathological process. In elderly patients, SL in terms of the first symptoms and progression of the disease, the nature of lesions of the skin and mucous membranes does not fundamentally differ from those in younger patients. Secondly. From our point of view, the risk factors for the manifestation of SL should include the patient's advanced age and comorbid pathology of internal organs, for which the patient received corrective therapy. With the development of a toxic-allergic reaction, diseases of the internal organs are prone to decompensation, as a result of which multiple organ failure is formed, which is the cause of a more severe course of SL and higher mortality. We also believe that comorbid viral infection (in our case, HIV infection in combination with chronic HCV infection) in a young patient can also be classified as risk factors for SL [18]. Thirdly. The main pathogenetic mechanism of SL formation is the Saparreli-Schwartzman phenomenon - an immunological reaction that initiates intensive processes in the skin and mucous membranes, accompanied by necrosis of epithelial cells and general intoxication of the body. This disrupts the detoxification of toxins, increases the severity of metabolic disorders, which leads to a rapid deterioration of the condition and can lead to death [19, 20]. In our opinion, SL is not only a toxic lesion of the skin and mucous membranes, but a systemic disease with damage to many organs, which is confirmed by morphological examination. Systemic damage in SL was also reported by E. Huseyin et al. [21]. Summing up the discussion, it should be noted that, on the one hand, our clinical observations broaden the understanding of the probable etiological risk factors provoking the development of SL, which may include local use of drugs, and on the other hand, it can be stated that the manifestation of SL is unpredictable, and the systemic nature of the lesion with the development of multiple organ failure makes the prognosis of the disease extremely unfavorable [22].

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